clinical presentation of covid 19

Coronavirus Disease 2019 (COVID-19) Clinical Presentation

• Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
• Sections Coronavirus Disease 2019 (COVID-19)
• Practice Essentials
• Route of Transmission
• Pathophysiology
• Epidemiology
• Physical Examination
• Complications
• Approach Considerations
• Laboratory Studies
• CT Scanning
• Chest Radiography
• Medical Care
• Antiviral Agents
• Immunomodulators and Other Investigational Therapies
• Investigational Antibody-Directed Therapies
• Antithrombotics
• Renin Angiotensin System Blockade and COVID-19
• Diabetes and COVID-19
• Therapies Determined Ineffective
• QT Prolongation with Potential COVID-19 Pharmacotherapies
• Investigational Devices
• Guidelines Summary
• Guidelines on the Diagnosis of COVID-19: Molecular Diagnostic Testing by the Infectious Diseases Society of America
• Guidelines on the Diagnosis of COVID-19: Antigen Testing (January 2023) by the Infectious Diseases Society of America (IDSA)
• Infectious Diseases Society of America (IDSA) Management Guidelines
• CDC Sample Collection and Testing Guidelines for COVID-19
• Thromboembolism Prevention and Treatment
• Interim Guidance for Managing Healthcare Personnel with SARS-CoV-2 Infection or Exposure to SARS-CoV-2 by the CDC
• Guidance for Hospitals on Containing Spread of COVID-19
• CDC Evaluating and Testing Persons Under Investigation (PUI) for COVID-19 Clinical Guidelines
• Medication Summary
• Corticosteroids
• Immunomodulators
• Complement Inhibitors
• COVID-19, Monoclonal Antibodies
• Questions & Answers
• Media Gallery

COVID-19 can manifest with a range of symptoms from mild to severe, such as fever, cough, shortness of breath, malaise, and respiratory distress, [ 46 , 102 ]    typically appearing 2 days to 2 weeks after exposure. Xu et al's analysis of Omicron subvariants revealed no significant differences in key time-to-event periods, with Omicron BA.1 showing the shortest incubation period at 3.49 days. Variability in estimates across virus lineages suggests differences in study populations and interventions. [ 103 ]

Another study found a mean incubation period of 5.1 days, with the majority developing symptoms within 11.5 days. [ 104 ]    Both treated and untreated patients experienced symptom and viral rebound effects, indicating potential challenges in managing the disease [ 105 ]  These studies provide valuable insights into time-to-event periods and transmission dynamics across different COVID-19 variants, contributing to our understanding of the evolving pandemic.

The following symptoms may indicate COVID-19 [ 102 ] :

• Fever or chills
• Shortness of breath or difficulty breathing
• Muscle or body aches
• New loss of taste or smell
• Sore throat
• Congestion or runny nose
• Nausea or vomiting

Other reported symptoms include the following:

• Sputum production
• Respiratory distress
• Neurologic (eg, headache, altered mentality) 

An extensive analysis by Wu and McGoogan revealed that 81% of COVID-19 cases were mild, 14% severe, 5% critical, and 2.3% fatal, with consistent findings observed across multiple studies [ 106 , 107 , 108 ] ; Williamson et al further emphasized that severe disease and mortality were more common in males, older individuals, those in poverty, Black individuals, and patients with specific medical conditions. [ 109 ]

Additional research highlighted the predictive value of frailty over age or comorbidities, [ 110 ] the potential risk associated with blood type A, the protective effect of blood type O, [ 111 , 112 ] and common symptoms like anosmia and ageusia, underscoring the need for prompt reporting and appropriate precautions for suspected cases. [ 6 , 113 , 114 , 115 , 9 ]

Patients who are under investigation for COVID-19 should be evaluated in a private room with the door closed (an airborne infection isolation room is ideal) and asked to wear a surgical mask. All other standard contact and airborne precautions should be observed, and treating healthcare personnel should wear eye protection. [ 9 ]

The most common serious manifestation of COVID-19 upon initial presentation is pneumonia. Fever, cough, dyspnea, and abnormalities on chest imaging are common in these cases. [ 116 , 117 , 118 , 119 ]

Huang and colleagues found that, among patients with pneumonia, 99% had fever, 70% reported fatigue, 59% had dry cough, 40% had anorexia, 35% experienced myalgias, 31% had dyspnea, and 27% had sputum production. [ 116 ]

Complications of COVID-19 include  pneumonia ,  acute respiratory distress syndrome , cardiac injury, arrhythmia,  septic shock , liver dysfunction,  acute kidney injury , and multi-organ failure, among others.

Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. The common complications among hospitalized patients include pneumonia (75%), ARDS (15%), AKI (9%), and acute liver injury (19%). Cardiac injury has been increasingly noted, including troponin elevation, acute heart failure, dysrhythmias, and myocarditis. Ten percent to 25 percent of hospitalized patients with COVID-19 experience prothrombotic coagulopathy resulting in venous and arterial thromboembolic events. Neurologic manifestations include impaired consciousness and stroke. ICU case fatality is reported up to 40%. [ 107 ]  

Patients with long-term post-COVID-19 symptoms may experience fatigue, dyspnea, cough, anxiety, depression, "brain fog," gastrointestinal issues, sleep difficulties, joint pain, and chest pain for weeks to months after acute illness, a condition referred to as Post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Guidelines from the NIH and UK NICE define long COVID as persistent symptoms lasting over 12 weeks after COVID-19 infection, with ongoing research aimed at understanding these lingering symptoms. [ 120 ] [ 121 ]

Luo et al conducted a systematic review and meta-analysis or 211 studies involving more than 13 million individuals to assess persistent symptoms after COVID-19. [ 122 ] Common symptoms included fatigue, dyspnea, post-traumatic stress disorder, anxiety, and depression. Factors associated with a higher prevalence of persistent symptoms included female gender, older age, severe illness during acute COVID-19, multiple comorbidities, prolonged hospital stay, and high body mass index. Patients with severe illness in the acute phase or from Europe tended to exhibit a higher prevalence of certain symptoms, whereas children had lower rates. Individuals with COVID-19 had a significantly higher prevalence of persistent symptoms compared to non-COVID-19 individuals. The researchers report that their findings emphasize the need for long-term monitoring and support for COVID-19 survivors.

Please see  Long COVID-19 .

Reinfection

COVID-19 reinfection is defined as an infected person who has undergone full vaccination, whether they have had a booster or boosters. According to the CDC, reinfection is COVID-19 infection of an individual with 2 different viral strains that occurs at least 45 days apart. It also may occur when an individual has 2 positive CoV-2 RT-PCR tests with negative tests between the 2 positive tests. [ 123 , 124 ]

Anecdotal reports have suggested the return of COVID-19 symptoms shortly after completing a 5-day antiviral course in both high and lower risk patients. A retrospective cohort study during the Omicron variant phase from January through June 2022 found COVID-19 rebound rates after nirmatrelvir/ritonavir and molnupiravir treatment. These rates included percentages for COVID-19 infection, symptoms, and hospitalizations at 7-day and 30-day intervals. [ 125 ] The CDC has also issued a health advisory regarding rebound cases in May 2022.

Pfizer, the manufacturer of nirmatrelvir/ritonavir, announced that the drug did not show a statistically significant effect in preventing active disease in those exposed to active cases, with no genomic evidence of resistance. [ 126 ] Concerns have been raised about treatment failures, risk factors, immune response interference, and the contagiousness of relapsed patients. [ 127 , 128 ]

There is a belief that all individuals with confirmed COVID-19 should be started on nirmatrelvir/ritonavir, regardless of their clinical state. The optimal duration of therapy and patient factors contributing to rebound infections require further exploration. Current therapeutic approaches are based on limited data, and individualized regimens guided by symptoms, physical findings, and laboratory results are recommended.

Nirmatrelvir/ritonavir is considered a bridging antiviral and may need to be reevaluated as variants of concern can develop resistance quickly. Other antivirals may be more effective as the virus evolves.

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• The heart is normal in size. There are diffuse, patchy opacities throughout both lungs, which may represent multifocal viral/bacterial pneumonia versus pulmonary edema. These opacities are particularly confluent along the periphery of the right lung. There is left midlung platelike atelectasis. Obscuration of the left costophrenic angle may represent consolidation versus a pleural effusion with atelectasis. There is no pneumothorax.
• The heart is normal in size. There are bilateral hazy opacities, with lower lobe predominance. These findings are consistent with multifocal/viral pneumonia. No pleural effusion or pneumothorax are seen.
• The heart is normal in size. Patchy opacities are seen throughout the lung fields. Patchy areas of consolidation at the right lung base partially silhouettes the right diaphragm. There is no effusion or pneumothorax. Degenerative changes of the thoracic spine are noted.
• The same patient as above 10 days later.
• The trachea is in midline. The cardiomediastinal silhouette is normal in size. There are diffuse hazy reticulonodular opacities in both lungs. Differential diagnoses include viral pneumonia, multifocal bacterial pneumonia or ARDS. There is no pleural effusion or pneumothorax.
• Axial chest CT demonstrates patchy ground-glass opacities with peripheral distribution.
• Coronal reconstruction chest CT of the same patient above, showing patchy ground-glass opacities.
• Axial chest CT shows bilateral patchy consolidations (arrows), some with peripheral ground-glass opacity. Findings are in peripheral and subpleural distribution.
• Table 1. SARS-CoV-2 Monoclonal Antibodies – inactive EUAs

Contributor Information and Disclosures

David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS Associate Professor of Medicine and Pediatrics, Adult and Pediatric Infectious Diseases, Rutgers New Jersey Medical School David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS is a member of the following medical societies: American Academy of HIV Medicine , American Academy of Pediatrics , American College of Physicians , American Medical Association , HIV Medicine Association , Infectious Diseases Society of America , Medical Society of New Jersey , Pediatric Infectious Diseases Society Disclosure: Nothing to disclose.

Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP Antimicrobial Stewardship Program Coordinator, Infectious Diseases Pharmacy Residency Program Director, Department of Pharmaceutical and Nutrition Care, Division of Infectious Diseases, Nebraska Medicine; Clinical Associate Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center Scott J Bergman, PharmD, FCCP, FIDSA, BCPS, BCIDP is a member of the following medical societies: American Association of Colleges of Pharmacy , American College of Clinical Pharmacy , American Pharmacists Association , American Society for Microbiology , American Society of Health-System Pharmacists , Infectious Diseases Society of America , Society of Infectious Diseases Pharmacists Disclosure: Received research grant from: Merck & Co., Inc.

Keith M Olsen, PharmD, FCCP, FCCM Dean and Professor, College of Pharmacy, University of Nebraska Medical Center Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Nothing to disclose.

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Medical Association , Association of Professors of Medicine , Infectious Diseases Society of America , Oklahoma State Medical Association , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Molly Marie Miller, PharmD Clinical Infectious Diseases Pharmacist Practitioner, Nebraska Medicine Molly Marie Miller, PharmD is a member of the following medical societies: Society of Infectious Diseases Pharmacists Disclosure: Nothing to disclose.

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Article Contents

Introduction, viral life cycle and host cell invasion, disease pathophysiology, asymptomatic phase, invasion and infection of the upper respiratory tract, involvement of the lower respiratory tract and progression to acute respiratory distress syndrome (ards), viral transmission and clinical features, diagnosis and imaging, management strategies, management of sepsis/septic shock, other therapies for covid-19, search for a vaccine.

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COVID-19: Current understanding of its Pathophysiology, Clinical presentation and Treatment

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Anant Parasher, COVID-19: Current understanding of its Pathophysiology, Clinical presentation and Treatment, Postgraduate Medical Journal , Volume 97, Issue 1147, May 2021, Pages 312–320, https://doi.org/10.1136/postgradmedj-2020-138577

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The severe acute respiratory syndrome (SARS) coronavirus-2 is a novel coronavirus belonging to the family Coronaviridae and is now known to be responsible for the outbreak of a series of recent acute atypical respiratory infections originating in Wuhan, China. The disease caused by this virus, termed coronavirus disease 19 or simply COVID-19, has rapidly spread throughout the world at an alarming pace and has been declared a pandemic by the WHO on March 11, 2020. In this review, an update on the pathophysiology, clinical presentation and the most recent management strategies for COVID-19 has been described.

A search was conducted for literature and various articles/case reports from 1997 to 2020 in PUBMED/MEDLINE for the keywords coronavirus, SARS, Middle East respiratory syndrome and mRNA virus.

COVID-19 has now spread globally with increasing morbidity and mortality among all populations. In the absence of a proper and effective antibody test, the diagnosis is presently based on a reverse-transcription PCR of nasopharyngeal and oropharyngeal swab samples. The clinical spectrum of the disease presents in the form of a mild, moderate or severe illness. Most patients are either asymptomatic carriers who despite being without symptoms have the potential to be infectious to others coming in close contact, or have a mild influenza-like illness which cannot be differentiated from a simple upper respiratory tract infection. Moderate and severe cases require hospitalisation as well as intensive therapy which includes non-invasive as well as invasive ventilation, along with antipyretics, antivirals, antibiotics and steroids. Complicated cases may require treatment by immunomodulatory drugs and plasma exchange therapy. The search for an effective vaccine for COVID-19 is presently in full swing, with pharmaceutical corporations having started human trials in many countries.

A series of acute atypical respiratory infections ravaged the Wuhan city of Hubei province of China in December 2019. The pathogen responsible for these atypical infections was soon discovered to be a novel coronavirus belonging to the family Coronaviridae and was named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It was seen to be highly homologous to the SARS coronavirus (SARS-CoV), which was responsible for the respiratory pandemic during the 2002–2003 period. 1   2 The respiratory illness caused by this virus was termed as coronavirus disease 2019 or simply COVID-19 by the WHO, and the outbreak was considered to have started via a zoonotic spread from the seafood markets in Wuhan, China. Subsequently, human-to-human transmission was recognised to be responsible for the community spread of the disease, being reported in approximately 200 countries worldwide. 3 , 4 , 5 , 6

After being broadcast as a public health emergency on January 30, 2020, COVID-19 was subsequently declared a pandemic on March 11, 2020 by the WHO. The SARS-CoV-2, which initially led to a severe pneumonia outbreak in China, has now rapidly spread all throughout the globe. As of July 6, 2020, there were almost 11.5 million cases worldwide, with approximately 536 893 reported deaths. 7   8

The virus is transmitted via respiratory droplets and aerosols from person to person. Once inside the body, the virus binds to host receptors and enters host cells through endocytosis or membrane fusion. The coronaviruses are made up of four structural proteins, namely, the spike (S), membrane (M), envelop (E) and nucleocapsid (N) proteins. 6   9 The S protein is seen to be protruding from the viral surface and is the most important one for host attachment and penetration. This protein is composed of two functional subunits (S 1 and S 2 ), among which S 1 is responsible for binding to the host cell receptor and S 2 subunit plays a role in the fusion of viral and host cellular membranes. 6

ACE-2 has been identified as a functional receptor for SARS-CoV and is highly expressed on the pulmonary epithelial cells. 10 It is through this host receptor that the S protein binds initially to start the host cell invasion by the virus. 11 , 12 , 13 After binding of SARS-CoV-2 to the ACE-2, the S protein undergoes activation via a two-step protease cleavage: the first one for priming at the S1/S2 cleavage site and the second cleavage for activation at a position adjacent to a fusion peptide within the S 2 subunit. 14 , 15 , 16 , 17 The initial cleavage stabilises the S2 subunit at the attachment site and the subsequent cleavage presumably activates the S protein causing conformational changes leading to viral and host cell membrane fusion. 18

Postmembrane fusion, the virus enters the pulmonary alveolar epithelial cells and the viral contents are released inside. Now inside the host cell, the virus undergoes replication and formation of a negative strand RNA by the pre-existing single-strand positive RNA through RNA polymerase activity (transcription). This newly formed negative strand RNA serves to produce new strands of positive RNAs which then go on to synthesise new proteins in the cell cytoplasm (translation). 19 , 20 , 21 The viral N protein binds the new genomic RNA and the M protein facilitates integration to the cellular endoplasmic reticulum. These newly formed Nucleocapsids are then enclosed in the ER membrane and transported to the lumen, from where they are transported via golgi vesicles to the cell membrane and then via exocytosis to the extracellular space. The new viral particles are now ready to invade the adjacent epithelial cells as well as for providing fresh infective material for community transmission via respiratory droplets. 6 An overview of the viral life cycle is shown in figure 1 .

The severe acute respiratory syndrome coronavirus-2 life cycle.

Although much has been discovered regarding the transmission and presentation, less is known about the pathophysiology of COVID-19. An overview of the disease pathophysiology has been shown in figure 2 . 6   22   23

Pathophysiology of COVID-19. CXCL-10, C-X-C motif chemokine ligand 10; IFN, interferon; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TNF-α, tumour necrosis factor-α; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.

The SARS-CoV-2 which is received via respiratory aerosols binds to the nasal epithelial cells in the upper respiratory tract. The main host receptor for viral entry into cells is the ACE-2, which is seen to be highly expressed in adult nasal epithelial cells. 24   25 The virus undergoes local replication and propagation, along with the infection of ciliated cells in the conducting airways. 26 This stage lasts a couple of days and the immune response generated during this phase is a limited one. In spite of having a low viral load at this time, the individuals are highly infectious, and the virus can be detected via nasal swab testing.

In this stage, there is migration of the virus from the nasal epithelium to the upper respiratory tract via the conducting airways. Due to the involvement of the upper airways, the disease manifests with symptoms of fever, malaise and dry cough. There is a greater immune response during this phase involving the release of C-X-C motif chemokine ligand 10 (CXCL-10) and interferons (IFN-β and IFN-λ) from the virus-infected cells. 27 The majority of patients do not progress beyond this phase as the mounted immune response is sufficient to contain the spread of infection.

About one-fifth of all infected patients progress to this stage of disease and develop severe symptoms. The virus invades and enters the type 2 alveolar epithelial cells via the host receptor ACE-2 and starts to undergo replication to produce more viral Nucleocapsids. The virus-laden pneumocytes now release many different cytokines and inflammatory markers such as interleukins (IL-1, IL-6, IL-8, IL-120 and IL-12), tumour necrosis factor-α (TNF-α), IFN-λ and IFN-β, CXCL-10, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). This ‘cytokine storm’ acts as a chemoattractant for neutrophils, CD4 helper T cells and CD8 cytotoxic T cells, which then begin to get sequestered in the lung tissue. These cells are responsible for fighting off the virus, but in doing so are responsible for the subsequent inflammation and lung injury. The host cell undergoes apoptosis with the release of new viral particles, which then infect the adjacent type 2 alveolar epithelial cells in the same manner. Due to the persistent injury caused by the sequestered inflammatory cells and viral replication leading to loss of both type 1 and type 2 pneumocytes, there is diffuse alveolar damage eventually culminating in an acute respiratory distress syndrome. 6   28

COVID-19 virus is mainly spread from person to person via respiratory droplet transmission, which occurs when a person is in close contact with someone who is actively coughing or sneezing. This occurs through exposure of the mucosal surfaces of the host, that is, eyes, nose and mouth, to the incoming infective respiratory droplets. 3 29–33 Transmission of the virus may also occur through fomites used by or used on the infected individual such as bedsheets, blankets, kitchen utensils, thermometers and stethoscopes. Airborne transmission has not been reported for COVID-19, except in specific circumstances in which procedures that generate aerosols are performed, that is, endotracheal intubation, bronchoscopy, open suctioning, nebulisation with oxygen, bronchodilators or steroids, bag and mask ventilation before intubation, tracheostomy and cardiopulmonary resuscitation. 29   33   34

The incubation period of COVID-19, which is the time period from exposure to the virus to symptom onset, is 5–6 days, but can be up to 14 days. During this period, also known as the ‘pre-symptomatic’ period, the infected individuals can be contagious and transmit the virus to healthy individuals in the population. 35 The patients of COVID-19 belong mostly to the 40–70 years age group, and most commonly present with fever, body aches, breathlessness, malaise and dry cough, although patients may present with asymptomatic, mild, moderate or severe disease ( table 1 ). 1 36–39 Some patients may also present with gastrointestinal symptoms such as abdominal pain, vomiting and loose stools. 40   41 The complications seen in patients with COVID-19 infection are caused mostly due to the ‘cytokine storm’ and are summarised in table 2 . 42

Clinical spectrum of COVID-19 disease 1 36–41

Complications seen in patients with COVID-19 42

Molecular tests (RT-PCR)

Samples are collected from the upper respiratory tract via nasopharyngeal and oropharyngeal swabs and from the lower respiratory tract via expectorated sputum and bronchoalveolar lavage (only for mechanically ventilated patients). After being stored at 4°C, the samples are sent to the laboratory where amplification of the viral genetic material is done through a reverse-transcription process. 6 This involves the synthesis of a double-stranded DNA molecule from the existing viral RNA by either reverse-transcription PCR (RT-PCR) or a real-time RT-PCR. 43   44 Finally, the conserved portions of the SARS-CoV-2 genetic code are identified on the amplified genetic material. 6

The test is recommended to be repeated for verification in cases of a positive test and again to confirm viral clearance in COVID-19 positive cases. The sensitivity of these tests is not very high, that is, approximately 53.3% of COVID-19-confirmed patients had positive oropharyngeal swabs, and about 71% of patients came out to be RT-PCR positive with sputum samples. 45   46 The RT-PCR results usually show positivity after 2–8 days. 47

Till date, no effective antibody test has been developed. A centers for disease control and prevention (CDC) research on a test developed by the US Vaccine Research Centre at the National Institutes of Health is ongoing, which seems to have a specificity higher than 99% with a sensitivity of 96%. 6

Blood tests

A normal or decreased white blood cell count (and lymphopenia) can be observed in many cases, which is also considered to be indicative of a worse prognosis.

Increased levels of lactate dehydrogenase, C reactive protein, creatine kinase (CK MB and CK MM), aspartate amino-transferase and alanine amino-transferase can be seen. 6

Increased D-dimer levels and an elevated neutrophil-to-lymphocyte ratio are seen in some patients. 48

Coagulation abnormalities can be observed in severe cases, as indicated by increase in prothrombin time and international normalised ratio.

Chest X-ray

Chest X-ray is usually inconclusive in the early stages of the disease and might not show any significant changes. As the infection progresses, bilateral multifocal alveolar opacities are observed, which may also be associated with pleural effusion. 6

High-resolution CT (HRCT) is extremely sensitive and the method of choice for diagnosing COVID-19 pneumonia, even in initial stages of the illness. The most commonly seen features are multifocal bilateral ‘ground-glass’ areas associated with consolidation and a patchy peripheral distribution, with greater involvement of the lower lobes. A ‘reversed halo sign’ is also seen in some patients, which is identified as a focal area of patchy opacities surrounded by a peripheral ring with consolidation. Other findings include pleural effusion, cavitation, calcification, and lymphadenopathy. 6

A brief summary of all investigations designed for COVID-19 is given in table 3 .

Investigations for COVID-19

ALT, alanine amino-transferase; AST, aspartate amino-transferase; CRP, C reactive protein; HRCT, high-resolution CT; INR, international randomised ratio; LDH, lactate dehydrogenase; PT, prothrombin time; RT-PCR, reverse-transcription PCR; rRT-PCR, real-time reverse-transcriptionPCR; WBC, white blood count.

As no vaccine is presently available for COVID-19, the treatment is mainly symptomatic and supportive in most cases. Initially, the patient presenting to the emergency is categorised into mild, moderate or severe according to the symptoms on presentation. Most patients present with mild-to-moderate symptoms such as fever, persistent dry cough, body aches and occasional breathlessness. A small fraction of patients may also present with acute respiratory failure and acute respiratory distress syndrome with associated sepsis or multiorgan failure. The complete management protocol for patients with COVID-19 is depicted in figure 3 .

Treatment protocol for patients with COVID-19. RR, respiratory rate; SpO2, oxygen saturation; HCQS, hydroxychloroquine; ECG, electrocardiogram; HFNO, high flow nasal oxygen; NIV, non-invasive ventilation; I/V, intravenous; LMWH, low molecular weight heparin; CBC, complete blood count; LDH, lactate dehydrogenase; CRP, c- reactive protein; ICU, intensive care unit; ARDS, acute respiratory distress syndrome.

Mild cases (SpO 2 levels of 94%–97% in room air)

Oxygen therapy via nasal cannula/simple face mask/venturi mask/non-rebreather mask.

For management of patients presenting with respiratory distress due to COVID-19, the emergency room should be well-stocked with functioning oxygen systems, pulse oximeters and single-use disposable oxygen-delivering interfaces such as nasal cannulas, simple face masks, venturi masks, non-rebreather (NRB) masks and masks with reservoir bag. 49

Oxygen therapy is started with the arrival of the patient in the emergency and is administered according to the severity of presentation. For patients presenting with mild breathlessness and a SpO 2 level between 94% and 97%, a simple face mask or a nasal cannula can be used for oxygen delivery. In patients maintaining a SpO 2 <94%, patients with chronic obstructive pulmonary disease (COPD), a respiratory rate >30/min or persistent dyspnoea, oxygen is to be administered via a 40% venturi mask to ensure a higher level of fixed oxygen delivery. Reassessment is to be done after 10 min and if stable again at 6 hours. 6 If there is little or no improvement after 6 hours on a venturi mask, non-invasive ventilation (NIV) is to be considered. 6 NRB masks limit the dispersion of aerosol, thereby offering a safer alternative for supplemental oxygen delivery. 50

In addition to oxygen therapy, mild cases may be managed on a symptomatic basis with antipyretics (acetaminophen) for fever and pain, oral fluid supplementation and adequate nutrition. Hydroxychloroquine (HCQS) may be considered for cases having high-risk features such as age greater than 60 years and comorbidities such as morbid obesity, hypertension, COPD, diabetes, chronic kidney/liver disease and cerebrovascular disease. 49

Moderate cases (SpO 2 levels of 90%–94% in room air)

Patients with moderate disease (SpO 2 of 90%–94% in room air) are to be isolated to contain the virus transmission. A detailed clinical history is to be taken including history of pre-existing comorbid conditions. There should be monitoring of vital signs and oxygen saturation (SpO 2 levels), along with investigations such as a complete blood count, ECG and chest X-ray examination. 49   51

High-flow nasal oxygen (HFNO) therapy and NIV

HFNO therapy is used in these cases where it is not possible to maintain SpO 2 >92% and/or there is no improvement in dyspnoea through standard oxygen therapy via face mask. The oxygen flow rate in HFNO therapy is roughly 30–40 L/min, and it is to be continuously adjusted according to the clinical response of the patient. It is also found to be beneficial for continuous positive airway pressure (CPAP) breaks between cycles as well as in critically ill patients for whom assisted fibre-optic tracheal intubation is required. 52 This therapy should not be used in a hypercapnic patient, and owing to a higher risk of aerosolisation, it must only be used in negative pressure rooms. Patients who do not improve after an hour with flow >50 L/min and FiO2>70% are recommended to be switched over to NIV.

NIV by CPAP has an important role in managing the respiratory failure caused due to COVID-19. NIV is usually administered through a full face mask or an oro-nasal mask, but can also be given via a helmet in order to reduce aerosolisation. CPAP is started with 8–10 cm H 2 O and FiO 2 60% and adjusted according to patient compliance. 6

Other therapies in moderate COVID-19 disease include HCQS 400 mg two times per day stat followed by 200 mg two times per day for next 4 days (in cases without evidence of cardiac disease), intravenous methylprednisolone 0.5–1 mg/kg for 3 days (preferably within 48 hours of admission), and anticoagulation via prophylactic dose of low molecular weight heparin (LMWH) (enoxaparin 40 mg per day sub-cutaneous (SC)). 6   49   53 Antibiotics are recommended for management of secondary bacterial infections. The patient is to be monitored for signs of haemodynamic instability and increased oxygen demand as indicated by the use of accessory muscles of respiration.

Although there have been concerns regarding aerosol generation with the use of HFNO therapy and NIV, negative pressure rooms and administration of oxygen through a well-fitting helmet, respectively, have largely addressed this issue. Patients receiving HFNO therapy should be monitored by personnel who have experience with endotracheal intubation in case the patient does not improve after a short duration or decompensates abruptly.

Severe cases (SpO 2 levels ≤90% in room air or patients with ARDS)

For patients presenting with severe disease/ARDS, immediate oxygen therapy is to be started at 5 L/min and titrate flow rate for a target of SpO 2 ≥90% in non-pregnant adults and SpO 2 ≥92–96% in pregnant patients. 49 As compared to standard oxygen therapy delivered via face mask, HFNO therapy is much more effective in reducing the need for intubation in these cases. In cases of hypercapnia (exacerbation of obstructive lung disease and cardiogenic pulmonary oedema), haemodynamic instability, multiorgan failure, abnormal mental status or worsening of oxygen saturation below 90%, invasive ventilation via endotracheal intubation has to be considered promptly. 49   51

Endotracheal intubation and mechanical ventilation

Endotracheal intubation is usually performed by specialised personnel, after donning all personal protective equipment such as full-body gown, a N95 mask and protective goggles. Preoxygenation with 100% oxygen for 5 min is done via the CPAP method, and if possible, rapid sequence intubation should be preferred. Mechanical ventilation is initiated with lower tidal volumes (4–8 mL/kg body weight) and lower inspiratory pressures (plateau pressure <30 cm H 2 O). In patients with severe ARDS, prone ventilation for 16–18 hours per day is recommended but requires sufficient human resources and expertise to be performed safely. In patients with moderate or severe ARDS, higher positive end-expiratory pressure (PEEP) is suggested which has the benefits of decreasing trauma due to atelectasis and increased recruitment of alveoli, but can cause complications due to lung over-distension and increase in the pulmonary vascular resistance. 49   51

Extracorporeal membrane oxygenation (ECMO) for patients with refractory hypoxemia despite endotracheal intubation and mechanical ventilation should be considered if feasible. In COVID-19 patients, ECMO may represent an efficient support in case of refractory hypoxemia and/or cardiogenic/septic shock unresponsive to maximal therapy. 54

Septic shock in adults can be confirmed when, along with the background of a definite infection, there is presence of tachycardia, tachypnoea, hyperthermia, increased lactate levels and the requirement of vasopressor support to maintain mean arterial pressure ≥65 mm Hg, all in the absence of hypovolemia. 49 Management includes broad-spectrum antibiotics, fluid resuscitation and vasopressors for prevention/management of shock and peripheral hypo-perfusion. The preferred fluids in cases of septic shock are usually isotonic crystalloids (normal saline and ringer’s lactate), given at the rate of at least 30 mL/kg in the first 3 hours. Excess fluid resuscitation may lead to signs of volume overload (raised jugular venous pressure, chest crepitations and hepatomegaly) and requires discontinuation or reduction of intravenous fluids. Dobutamine is to be started if the patient shows signs of poor perfusion and cardiogenic shock despite the ongoing antibiotic and vasopressor support. 49   51

Antibiotics

Although not always recommended in viral pneumonia, an optimum and effective antibiotic regimen helps prevent or manage secondary bacterial infections and sepsis. Macrolides such as azithromycin are quite effective in preventing pulmonary infections in patients with viral pneumonias, in addition to having a significant anti-inflammatory effect on the airways. 55

Corticosteroids

Steroids can be used for a short period of time, that is, 3–5 days in patients who show progressive deterioration of oxygen saturation, increased activation of the pro-inflammatory response and rapid worsening of features on chest imaging. Methylprednisolone was the first and only steroid indicated initially, at a dose not exceeding 0.5–1 mg/kg/day for moderate cases and 1–2 mg/kg/day for severe cases. Higher doses were not recommended in view of the delay in viral clearance due to steroid mediated immunosuppression. 32   49   56   57

Recently, dexamethasone has also been found to be effective for decreasing mortality in severe and critically ill cases. 58

Antiviral drugs

The following antiviral drugs have been put to use for COVID-19 patients so far.

Remdesivir (CIPREMI/COVIFOR)

It was initially suggested by some preclinical studies that remdesivir has in vitro activity against multiple RNA viruses (including Ebola) and could be beneficial for both prophylaxis and treatment of coronavirus infections. 6   49   59 Remdesivir is a broad-spectrum antiviral agent, and acts by blocking the action of viral RNA-dependent RNA polymerase. This causes evasion of proofreading by viral exoribonuclease, causing a significantly decreased production of viral RNA. 60 In a mouse model of SARS-CoV, remdesivir was observed to reduce the lung viral load and improve pulmonary function. 61 It was used to treat the first case of COVID-19 infection in the USA, who showed rapid improvement after 1 day of remdesivir treatment. 62

In two separate studies, although remdesivir was seen to be superior to placebo in decreasing rates of lower respiratory tract infections and shortening hospital stay, there was no significant difference seen between a 5-day course and a 10-day course of remdesivir. 63   64 In comparison, therapeutic doses of lopinavir (LPV)/ritonavir (RTV) although did improve pulmonary function, but were not able to reduce virus replication or prevent severe lung damage. Thus, it is indicated that remdesivir has shown more potential than LPV/RTV in the treatment of COVID-19. 65   66 It may be considered in patients with moderate disease at a loading dose of 200 mg intravenous over 1–2 hours on day 1, followed by 100 mg intravenous daily for 5–10 days. Contraindications to the use of remdesivir include use in children, pregnant or lactating females, and patients with severe hepatic or renal impairment. 49

Thus, it is implied that remdesivir is best suited for hospitalised patients with COVID-19 having moderate-to-severe disease, and requiring supplemental oxygen therapy. On May 1, 2020, the US Food and Drug Administration (USFDA) gave emergency use approval for remdesivir in patients hospitalised with severe COVID-19; the final approval being given in light of tentative evidence of remdesivir efficacy in such patients. However, it is to be noted that treatment with remdesivir alone is not likely to be sufficient given the high mortality despite its use.

Lopinavir/ritonavir (KALETRA)

LPV has been shown to inhibit the coronavirus protease activity in vitro and in animal studies and to lower mortality rates as seen in a cohort study. 67 Effective dose of LPV is 400 mg orally every 12 hours, and based on the effectiveness of this drug during the previous SARS and Middle East respiratory syndrome virus outbreaks, it was initially seen as a potential treatment option for COVID-19. 68 However, a recent randomised controlled trial demonstrated no definitive benefit of LPV/RTV therapy as compared to routine management protocol. 69

Oseltamivir (TAMIFLU)

Although designed and used against influenza virus outbreaks, oseltamivir (75 mg two times per day for 5 days) was tested for patients with COVID-19 along with standard supportive care in two case series from Wuhan, China. As such, no clear additional benefit of oseltamivir therapy was observed in these patients. 70   71

Favipiravir (FABIFLU)

Favipiravir shows activity against RNA viruses by conversion into the ribofuranosyl triphosphate derivative by host enzymes and subsequent selective inhibition of the viral RNA-dependent RNA polymerase. It was initially discovered by the Toyama Chemical Company in Japan for therapeutic use in resistant cases of influenza. The drug has also shown effectiveness in the treatment of avian influenza and may be an alternative option for the treatment of illness caused by pathogens such as the Ebola virus and COVID-19. 72

Favipiravir has been recently launched under the trade name ‘FabiFlu’ by Glenmark Pharmaceuticals in June 2020 for patients with mild-to-moderate COVID-19, thereby becoming the first approved oral favipiravir medication for the treatment of COVID-19 in India. The recommended dose is 1800 mg two times per day on day 1, followed by 800 mg two times per day up until day 14. Favipiravir has proven in vitro activity against SARS CoV-2 virus and shows a significant improvement in mild-to-moderate cases with COVID-19. It is associated with rapid reduction of the viral load and an early symptomatic improvement. 72   73

Although individual antiviral drugs have proven to be somewhat effective in mild-to-moderate cases, future strategies should evaluate combination of antiviral agents, or antivirals with other therapeutic approaches, to improve patient outcomes in the critically ill COVID-19 cases.

Immunomodulatory drugs (tocilizumab, chloroquine and hydroxychloroquine)

Tocilizumab.

Tocilizumab is a humanised IgG1 monoclonal antibody, directed against the IL-6 receptor and commonly used in the treatment of rheumatoid arthritis, juvenile arthritis and giant cell arteritis. It may be considered in patients with moderate disease having raised inflammatory markers (IL-6) with progressively increasing oxygen demand and in mechanically ventilated patients unresponsive to therapy. The dosage is 8 mg/kg (maximum 800 mg at one time) given slowly in 100 mL normal saline (NS) over 1 hour, which can be repeated once after 12–24 hours if needed. Active tuberculosis and neutropenia are contraindications to the use of tocilizumab. 49   74 Treatment with tocilizumab, whether administered intravenously or subcutaneously, might reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia. 75

Chloroquine and hydroxychloroquine

Chloroquine is a widely used antimalarial drug that has been shown to have broad-spectrum antiviral activity. 76 Chloroquine (500 mg every 12 hours) blocks the virus infection by an increase in the endosomal pH required for virus/cell fusion, as well as by preventing SARS-CoV receptor glycosylation. 77 It has shown efficacy in reduction of exacerbation of COVID-19 pneumonia as well as accelerated viral and symptomatic clearance. 78

HCQS (200 mg every 12 hours) is a chloroquine analogue with a better safety profile and an anti-SARS-CoV activity in vitro. 79 HCQS was found to be more potent than chloroquine in SARS-CoV-2-infected Vero cells and also shown to be significantly associated with viral load reduction. 80   81 Although this antiviral effect is seen to be enhanced by the macrolide azithromycin, the combined use of both drugs can lead to an increased incidence of QT interval prolongation and cardiac arrhythmias. 82

Both chloroquine and HCQS have been observed to have immunomodulatory effects and have the capacity to suppress the massive immune response in COVID-19 (cytokine storm) induced by mediators such as IL-1, IL-6 and IL-10. 83   84

Plasma exchange via convalescent plasma

It was observed that the COVID-19 virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralised by plasma from several convalescent patients. 85 This therapy may be considered in patients with severe disease who do not show improvement (oxygen requirement is progressively increasing) despite use of steroids. Some important requirements for this procedure include an adequate antibody titre in the convalescent plasma, ABO compatibility and cross-matching of the donor plasma. The recipient should be closely monitored for several hours post-transfusion for any transfusion-related adverse events and its use should be avoided in patients with IgA deficiency or Ig allergies. Dose ranges from 4 to 13 mL/kg, and usually, a single dose of 200 mL is given slowly over 2 hours. 49 To ensure high efficacy via a high antibody titre, the convalescent plasma has to be collected within 2 weeks of patient recovery from COVID-19. 86

Supplementary therapies

Prophylactic anticoagulation via low molecular weight heparin (LMWH) (eg, enoxaparin 40 mg SC) should be given for anticoagulation in moderate (once time per day) to severe patients (two times per day) in view of the high risk of thromboembolism. Comorbidities such as associated hypertension, hypothyroidism or diabetes should be managed accordingly. In case of pregnant females presenting with severe disease, needful consultations should be taken from obstetric, neonatal and intensive care specialists. Psychological counselling should be ensured for patients suffering from fear and anxiety in view of being diagnosed with COVID-19. 49

The various treatment strategies for COVID-19 are summarised in table 4 .

Management strategies for COVID-19

HCQS, hydroxychloroquine; HFNO, high-flow nasal oxygen; IL, interleukin; NIV, non-invasive ventilation; I.V, intravenous; ARDS, acute respiratory distress syndrome.

The S glycoprotein of the SARS-CoV-2 is the target for most vaccines under development presently. 87 Some of the pharmaceutical companies with vaccine development under process have been described below. 88

Moderna Therapeutics announced its first experimental mRNA COVID-19 vaccine (mRNA-1273) in February 2020, ready for human testing. In May, the company announced the vaccine had produced antibodies in all 45 healthy volunteers, ages from 18 to 55, in this initial clinical phase. In early May, the company received permission from the USFDA to start a phase II study of its vaccine and expects to begin a phase III clinical trial in July.

At the end of April 2020, the company had enrolled 40 healthy volunteers in its phase I clinical trial and is preparing to start a phase II/III clinical trial soon.

University of Oxford (England)

A clinical trial with more than 500 participants showed that the potential vaccine has an 80% chance for success by using a modified virus to trigger the immune system. The university has partnered with pharmaceutical company AstraZeneca, and a late-stage clinical trial is planned to be initiated by the middle of this year.

University of Queensland (Australia)

Preclinical testing has been started in April by growing viral proteins in cell cultures.

CanSino Biologics and Sinovac Biotech (China)

CanSino Biologics aimed to assess the safety and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the S glycoprotein of the SARS-CoV-2 strain. The vaccine is seen to be tolerable, with humoral responses against SARS-CoV-2 peaking at day 28 postvaccination in healthy adults, and rapid specific T cell responses noted from day 14 postvaccination. The findings definitely warrant further investigation. 89

Sinovac Biotech’s COVID-19 vaccine candidate, dubbed Corona Vac, induced neutralising antibodies 14 days after vaccination. More than 90% of the 600 healthy volunteers in the phase 2 part of the phase 1/2 study showed the immune response. 90

Other pharmaceutical companies

Johnson & Johnson have announced the initiation of early-stage human clinical trials in late July. Pfizer has also teamed up with a German company to develop a vaccine; their initial clinical trial with 200 participants is already underway in April. Human testing has already been started in the USA in early May.

ICMR, NIV AND Zydus Cadila (India)

Recently, two COVID-19 vaccine candidates— Covaxin , developed by Bharat Biotech in collaboration with the Indian Council of Medical Research (ICMR) and the National Institute of Virology (NIV), and ZyCov-D vaccine by Zydus Cadila—have been approved for phase II and phase III human clinical trials, by the Drug Controller General of India. 91

The COVID-19 pandemic is now an international health emergency. Transmission via close contact from person to person has rapidly amplified the spread of disease, making it even more difficult to contain its spread in the community. The patient may be completely asymptomatic with a positive swab test, may present with a mild influenza-like illness or may present with serious symptoms that require hospitalisation. There is presently no effective antibody test available for rapid diagnosis, but HRCT scans of the chest have been seen to be quite sensitive and specific. In the absence of an effective vaccine, treatment is mainly supportive with oxygen therapy, antivirals, steroids, HCQS and antibiotics. Complicated cases and cases refractory to standard therapy may require immunomodulatory drugs and plasma exchange therapy via convalescent sera from recovered patients. Advances in viral genetic sequencing and technology have certainly paved the way for the development of a vaccine for COVID-19, with many pharmaceutical corporations already having started human trials.

The COVID-19 pandemic has now spread all across the globe, causing significant morbidity and mortality.

To date, there is still a dire need of an effective, rapid and sensitive serology test for COVID-19.

Several new and effective treatment options are now available, including antivirals, immunomodulators, corticosteroids and plasma exchange therapy.

The search for a potent vaccine has been initiated by many pharmaceutical institutions around the world, with many countries having started human clinical trials.

Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: a review [published online ahead of print, 20 April 2020]. Clin Immunol 2020;215:108427. doi:10.1016/j.clim.2020.108427.

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What are the obstacles in developing a rapid, effectivce and sensitive serology test for COVID-19?

Can the early implementation of HFNO and NIV improve patient prognosis in moderate to severe cases?

Are re-infections possible in individuals already once affected by the disease?

Can herd immunity boost the fight against COVID-19?

AP did the research and compilation of the literature as well as the editing and final submission of the manuscript.

The author has not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

None declared.

Not required.

Not commissioned; externally peer reviewed.

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• Introduction
• Observations
• Clinical Presentation
• Assessment and Diagnosis
• Disparities
• Prevention and Vaccine Development
• Conclusions
• Article Information

Based on data from World Health Organization (WHO) COVID-19 situation reports. The COVID-19 outbreak was first recognized in Wuhan, China, in early December 2019. The number of confirmed COVID-19 cases is displayed by date of report and WHO region. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2.

Current understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced host immune response. SARS-CoV-2 targets cells through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor. The serine protease type 2 transmembrane serine proteas (TMPRSS2) in the host cell further promotes viral uptake by cleaving ACE2 and activating the SARS-CoV-2 S protein. In the early stage, viral copy numbers can be high in the lower respiratory tract. Inflammatory signaling molecules are released by infected cells and alveolar macrophages in addition to recruited T lymphocytes, monocytes, and neutrophils. In the late stage, pulmonary edema can fill the alveolar spaces with hyaline membrane formation, compatible with early-phase acute respiratory distress syndrome.

A, Transverse thin-section computed tomographic scan of a 76-year-old man, 5 days after symptom onset, showing subpleural ground-glass opacity and consolidation with subpleural sparing. B, Transverse thin-section computed tomographic scan of a 76-year-old man, 21 days after symptom onset, showing bilateral and peripheral predominant consolidation, ground-glass with reticulation, and bronchodilatation. C, Pathological manifestations of lung tissue in a patient with severe pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showing interstitial mononuclear inflammatory infiltrates dominated by lymphocytes (magnification, ×10). D, Pathological manifestations of lung tissue in a patient with severe pneumonia caused by SARS-CoV-2 showing diffuse alveolar damage with edema and fibrine deposition, indicating acute respiratory distress syndrome with early fibrosis (magnification, ×10). Images courtesy of Inge A. H. van den Berk, MD (Department of Radiology, Amsterdam UMC), and Bernadette Schurink, MD (Department of Pathology, Amsterdam UMC).

Eric Topol, MD, Scripps Research EVP and omnivorous science health care and tech commentator, discusses the evolving COVID-19 pandemic. Recorded July 23, 2020.

• Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) JAMA Review May 12, 2020 This narrative review summarizes what is currently known about how SARS-CoV-2 infects cells and causes disease as a basis for considering whether chloroquine, remdisivir and other antivirals, or other existing drugs might be effective treatment for coronavirus disease 2019 (COVID-19). James M. Sanders, PhD, PharmD; Marguerite L. Monogue, PharmD; Tomasz Z. Jodlowski, PharmD; James B. Cutrell, MD
• Ensuring Scientific Integrity and Public Confidence in the Search for Effective COVID-19 Treatment JAMA Viewpoint May 19, 2020 This Viewpoint discusses the risks to patients and public health posed by the FDA’s politically pressured Emergency Use Authorization (EUA) of chloroquine and hydroxychloroquine for COVID-19 treatment, and proposes principles to follow to ensure new therapies are studied properly and quickly to maximize benefits and minimize risks to patients. Jesse L. Goodman, MD, MPH; Luciana Borio, MD
• Monoclonal Antibodies for Prevention and Treatment of COVID-19 JAMA Viewpoint July 14, 2020 This Viewpoint discusses the potential role of neutralizing monoclonal antibodies (MAbs) as a treatment for coronavirus disease 2019 (COVID-19) and as a means of prevention in high-risk populations, and it also raises possible limitations of the approach that need to be disproven or addressed for the strategy to be effective. Mary Marovich, MD; John R. Mascola, MD; Myron S. Cohen, MD
• Presence of Genetic Variants Among Young Men With Severe COVID-19 JAMA Preliminary Communication August 18, 2020 This case series describes rare putative X-chromosomal loss-of-function variants associated with impaired peripheral mononuclear blood cell interferon signaling in 4 young male patients hospitalized with severe coronavirus disease 2019 (COVID-19) in the Netherlands. Caspar I. van der Made, MD; Annet Simons, PhD; Janneke Schuurs-Hoeijmakers, MD, PhD; Guus van den Heuvel, MD; Tuomo Mantere, PhD; Simone Kersten, MSc; Rosanne C. van Deuren, MSc; Marloes Steehouwer, BSc; Simon V. van Reijmersdal, BSc; Martin Jaeger, PhD; Tom Hofste, BSc; Galuh Astuti, PhD; Jordi Corominas Galbany, PhD; Vyne van der Schoot, MD, PhD; Hans van der Hoeven, MD, PhD; Wanda Hagmolen of ten Have, MD, PhD; Eva Klijn, MD, PhD; Catrien van den Meer, MD; Jeroen Fiddelaers, MD; Quirijn de Mast, MD, PhD; Chantal P. Bleeker-Rovers, MD, PhD; Leo A. B. Joosten, PhD; Helger G. Yntema, PhD; Christian Gilissen, PhD; Marcel Nelen, PhD; Jos W. M. van der Meer, MD, PhD; Han G. Brunner, MD, PhD; Mihai G. Netea, MD, PhD; Frank L. van de Veerdonk, MD, PhD; Alexander Hoischen, PhD
• Strongyloides Hyperinfection Risk in COVID-19 Patients Treated With Dexamethasone JAMA Viewpoint August 18, 2020 Anticipating widespread global use of dexamethasone for COVID-19 in the wake of RECOVERY trial findings, this Viewpoint summarizes the theoretical risk of triggering Strongyloides hyperinfection/dissemination syndrome in people with asymptomatic strongyloidiasis, and proposes an algorithm to for assessing and managing the risk in outpatient and hospital settings. William M. Stauffer, MD, MSPH; Jonathan D. Alpern, MD; Patricia F. Walker, MD, DTM&H
• Patient Information: COVID-19 JAMA JAMA Patient Page August 25, 2020 This JAMA Patient Page provides an overview of COVID-19 transmission, symptoms, diagnosis, disease course, and treatment. W. Joost Wiersinga, MD, PhD, MBA; Hallie C. Prescott, MD, MSc
• Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions JAMA Research Letter October 20, 2020 This study compares levels of tumor necrosis factor α, IL-6, and IL-8 in critically ill patients with coronavirus disease 2019 (COVID-19) vs those with other critical illness to better characterize the contribution of cytokine storm to COVID-19 pathophysiology. Matthijs Kox, PhD; Nicole J. B. Waalders, BSc; Emma J. Kooistra, BSc; Jelle Gerretsen, BSc; Peter Pickkers, MD, PhD
• Racial/Ethnic Variation in Nasal Transmembrane Serine Protease 2 ( TMPRSS2 ) Gene Expression Facilitating Coronavirus Entry JAMA Research Letter October 20, 2020 This cross-sectional study used nasal epithelium collected in 2015-2018 to compare expression of TMPRSS2, a facilitator of SARS-CoV-2 viral entry and spread, among Asian, Black, Latino, and White patients as well as patients of mixed race/ethnicity within a New York City health system. Supinda Bunyavanich, MD, MPH, MPhil; Chantal Grant, MD; Alfin Vicencio, MD
• Therapy for Early COVID-19—A Critical Need JAMA Viewpoint December 1, 2020 In this Viewpoint, Fauci and NIAID colleagues review leading candidates for treatment of mild to moderate coronavirus disease 2019 (COVID-19) to prevent disease progression and longer-term complications, including emerging antiviral drugs, immune-modulating agents, and antibody-based therapies, and the challenges of developing randomized trials to rapidly evaluate the safety and efficacy of each. Peter S. Kim, MD; Sarah W. Read, MD, MHS; Anthony S. Fauci, MD

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Wiersinga WJ , Rhodes A , Cheng AC , Peacock SJ , Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19) : A Review . JAMA. 2020;324(8):782–793. doi:10.1001/jama.2020.12839

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Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19) : A Review

• 1 Division of Infectious Diseases, Department of Medicine, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands
• 2 Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands
• 3 Department of Intensive Care Medicine, St George's University Hospitals Foundation Trust, London, United Kingdom
• 4 Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Australia
• 5 School of Public Health and Preventive Medicine, Monash University, Monash University, Melbourne, Australia
• 6 National Infection Service, Public Health England, London, United Kingdom
• 7 Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
• 8 Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor
• 9 VA Center for Clinical Management Research, Ann Arbor, Michigan
• Review Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) James M. Sanders, PhD, PharmD; Marguerite L. Monogue, PharmD; Tomasz Z. Jodlowski, PharmD; James B. Cutrell, MD JAMA
• Viewpoint Ensuring Scientific Integrity and Public Confidence in the Search for Effective COVID-19 Treatment Jesse L. Goodman, MD, MPH; Luciana Borio, MD JAMA
• Viewpoint Monoclonal Antibodies for Prevention and Treatment of COVID-19 Mary Marovich, MD; John R. Mascola, MD; Myron S. Cohen, MD JAMA
• Preliminary Communication Presence of Genetic Variants Among Young Men With Severe COVID-19 Caspar I. van der Made, MD; Annet Simons, PhD; Janneke Schuurs-Hoeijmakers, MD, PhD; Guus van den Heuvel, MD; Tuomo Mantere, PhD; Simone Kersten, MSc; Rosanne C. van Deuren, MSc; Marloes Steehouwer, BSc; Simon V. van Reijmersdal, BSc; Martin Jaeger, PhD; Tom Hofste, BSc; Galuh Astuti, PhD; Jordi Corominas Galbany, PhD; Vyne van der Schoot, MD, PhD; Hans van der Hoeven, MD, PhD; Wanda Hagmolen of ten Have, MD, PhD; Eva Klijn, MD, PhD; Catrien van den Meer, MD; Jeroen Fiddelaers, MD; Quirijn de Mast, MD, PhD; Chantal P. Bleeker-Rovers, MD, PhD; Leo A. B. Joosten, PhD; Helger G. Yntema, PhD; Christian Gilissen, PhD; Marcel Nelen, PhD; Jos W. M. van der Meer, MD, PhD; Han G. Brunner, MD, PhD; Mihai G. Netea, MD, PhD; Frank L. van de Veerdonk, MD, PhD; Alexander Hoischen, PhD JAMA
• Viewpoint Strongyloides Hyperinfection Risk in COVID-19 Patients Treated With Dexamethasone William M. Stauffer, MD, MSPH; Jonathan D. Alpern, MD; Patricia F. Walker, MD, DTM&H JAMA
• JAMA Patient Page Patient Information: COVID-19 W. Joost Wiersinga, MD, PhD, MBA; Hallie C. Prescott, MD, MSc JAMA
• Research Letter Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions Matthijs Kox, PhD; Nicole J. B. Waalders, BSc; Emma J. Kooistra, BSc; Jelle Gerretsen, BSc; Peter Pickkers, MD, PhD JAMA
• Research Letter Racial/Ethnic Variation in Nasal Transmembrane Serine Protease 2 ( TMPRSS2 ) Gene Expression Facilitating Coronavirus Entry Supinda Bunyavanich, MD, MPH, MPhil; Chantal Grant, MD; Alfin Vicencio, MD JAMA
• Viewpoint Therapy for Early COVID-19—A Critical Need Peter S. Kim, MD; Sarah W. Read, MD, MHS; Anthony S. Fauci, MD JAMA

Importance   The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19.

Observations   SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies.

Conclusions and Relevance   As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

The coronavirus disease 2019 (COVID-19) pandemic has caused a sudden significant increase in hospitalizations for pneumonia with multiorgan disease. COVID-19 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection may be asymptomatic or it may cause a wide spectrum of symptoms, such as mild symptoms of upper respiratory tract infection and life-threatening sepsis. COVID-19 first emerged in December 2019, when a cluster of patients with pneumonia of unknown cause was recognized in Wuhan, China. As of July 1, 2020, SARS-CoV-2 has affected more than 200 countries, resulting in more than 10 million identified cases with 508 000 confirmed deaths ( Figure 1 ). This review summarizes current evidence regarding pathophysiology, transmission, diagnosis, and management of COVID-19.

We searched PubMed, LitCovid, and MedRxiv using the search terms coronavirus , severe acute respiratory syndrome coronavirus 2 , 2019-nCoV , SARS-CoV-2 , SARS-CoV , MERS-CoV , and COVID-19 for studies published from January 1, 2002, to June 15, 2020, and manually searched the references of select articles for additional relevant articles. Ongoing or completed clinical trials were identified using the disease search term coronavirus infection on ClinicalTrials.gov, the Chinese Clinical Trial Registry, and the International Clinical Trials Registry Platform. We selected articles relevant to a general medicine readership, prioritizing randomized clinical trials, systematic reviews, and clinical practice guidelines.

Coronaviruses are large, enveloped, single-stranded RNA viruses found in humans and other mammals, such as dogs, cats, chicken, cattle, pigs, and birds. Coronaviruses cause respiratory, gastrointestinal, and neurological disease. The most common coronaviruses in clinical practice are 229E, OC43, NL63, and HKU1, which typically cause common cold symptoms in immunocompetent individuals. SARS-CoV-2 is the third coronavirus that has caused severe disease in humans to spread globally in the past 2 decades. 1 The first coronavirus that caused severe disease was severe acute respiratory syndrome (SARS), which was thought to originate in Foshan, China, and resulted in the 2002-2003 SARS-CoV pandemic. 2 The second was the coronavirus-caused Middle East respiratory syndrome (MERS), which originated from the Arabian peninsula in 2012. 3

SARS-CoV-2 has a diameter of 60 nm to 140 nm and distinctive spikes, ranging from 9 nm to 12 nm, giving the virions the appearance of a solar corona ( Figure 2 ). 4 Through genetic recombination and variation, coronaviruses can adapt to and infect new hosts. Bats are thought to be a natural reservoir for SARS-CoV-2, but it has been suggested that humans became infected with SARS-CoV-2 via an intermediate host, such as the pangolin. 5 , 6

Early in infection, SARS-CoV-2 targets cells, such as nasal and bronchial epithelial cells and pneumocytes, through the viral structural spike (S) protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor 7 ( Figure 2 ). The type 2 transmembrane serine protease (TMPRSS2), present in the host cell, promotes viral uptake by cleaving ACE2 and activating the SARS-CoV-2 S protein, which mediates coronavirus entry into host cells. 7 ACE2 and TMPRSS2 are expressed in host target cells, particularly alveolar epithelial type II cells. 8 , 9 Similar to other respiratory viral diseases, such as influenza, profound lymphopenia may occur in individuals with COVID-19 when SARS-CoV-2 infects and kills T lymphocyte cells. In addition, the viral inflammatory response, consisting of both the innate and the adaptive immune response (comprising humoral and cell-mediated immunity), impairs lymphopoiesis and increases lymphocyte apoptosis. Although upregulation of ACE2 receptors from ACE inhibitor and angiotensin receptor blocker medications has been hypothesized to increase susceptibility to SARS-CoV-2 infection, large observational cohorts have not found an association between these medications and risk of infection or hospital mortality due to COVID-19. 10 , 11 For example, in a study 4480 patients with COVID-19 from Denmark, previous treatment with ACE inhibitors or angiotensin receptor blockers was not associated with mortality. 11

In later stages of infection, when viral replication accelerates, epithelial-endothelial barrier integrity is compromised. In addition to epithelial cells, SARS-CoV-2 infects pulmonary capillary endothelial cells, accentuating the inflammatory response and triggering an influx of monocytes and neutrophils. Autopsy studies have shown diffuse thickening of the alveolar wall with mononuclear cells and macrophages infiltrating airspaces in addition to endothelialitis. 12 Interstitial mononuclear inflammatory infiltrates and edema develop and appear as ground-glass opacities on computed tomographic imaging. Pulmonary edema filling the alveolar spaces with hyaline membrane formation follows, compatible with early-phase acute respiratory distress syndrome (ARDS). 12 Bradykinin-dependent lung angioedema may contribute to disease. 13 Collectively, endothelial barrier disruption, dysfunctional alveolar-capillary oxygen transmission, and impaired oxygen diffusion capacity are characteristic features of COVID-19.

In severe COVID-19, fulminant activation of coagulation and consumption of clotting factors occur. 14 , 15 A report from Wuhan, China, indicated that 71% of 183 individuals who died of COVID-19 met criteria for diffuse intravascular coagulation. 14 Inflamed lung tissues and pulmonary endothelial cells may result in microthrombi formation and contribute to the high incidence of thrombotic complications, such as deep venous thrombosis, pulmonary embolism, and thrombotic arterial complications (eg, limb ischemia, ischemic stroke, myocardial infarction) in critically ill patients. 16 The development of viral sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, may further contribute to multiorgan failure.

Epidemiologic data suggest that droplets expelled during face-to-face exposure during talking, coughing, or sneezing is the most common mode of transmission ( Box 1 ). Prolonged exposure to an infected person (being within 6 feet for at least 15 minutes) and briefer exposures to individuals who are symptomatic (eg, coughing) are associated with higher risk for transmission, while brief exposures to asymptomatic contacts are less likely to result in transmission. 25 Contact surface spread (touching a surface with virus on it) is another possible mode of transmission. Transmission may also occur via aerosols (smaller droplets that remain suspended in air), but it is unclear if this is a significant source of infection in humans outside of a laboratory setting. 26 , 27 The existence of aerosols in physiological states (eg, coughing) or the detection of nucleic acid in the air does not mean that small airborne particles are infectious. 28 Maternal COVID-19 is currently believed to be associated with low risk for vertical transmission. In most reported series, the mothers' infection with SARS-CoV-2 occurred in the third trimester of pregnancy, with no maternal deaths and a favorable clinical course in the neonates. 29 - 31

Transmission, Symptoms, and Complications of Coronavirus Disease 2019 (COVID-19)

Transmission 17 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs primarily via respiratory droplets from face-to-face contact and, to a lesser degree, via contaminated surfaces. Aerosol spread may occur, but the role of aerosol spread in humans remains unclear. An estimated 48% to 62% of transmission may occur via presymptomatic carriers.

Common symptoms 18 in hospitalized patients include fever (70%-90%), dry cough (60%-86%), shortness of breath (53%-80%), fatigue (38%), myalgias (15%-44%), nausea/vomiting or diarrhea (15%-39%), headache, weakness (25%), and rhinorrhea (7%). Anosmia or ageusia may be the sole presenting symptom in approximately 3% of individuals with COVID-19.

Common laboratory abnormalities 19 among hospitalized patients include lymphopenia (83%), elevated inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-α, IL-1, IL-6), and abnormal coagulation parameters (eg, prolonged prothrombin time, thrombocytopenia, elevated D-dimer [46% of patients], low fibrinogen).

Common radiographic findings of individuals with COVID-19 include bilateral, lower-lobe predominate infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe ground-glass opacities and/or consolidation on chest computed tomographic imaging.

Common complications 18 , 20 - 24 among hospitalized patients with COVID-19 include pneumonia (75%); acute respiratory distress syndrome (15%); acute liver injury, characterized by elevations in aspartate transaminase, alanine transaminase, and bilirubin (19%); cardiac injury, including troponin elevation (7%-17%), acute heart failure, dysrhythmias, and myocarditis; prothrombotic coagulopathy resulting in venous and arterial thromboembolic events (10%-25%); acute kidney injury (9%); neurologic manifestations, including impaired consciousness (8%) and acute cerebrovascular disease (3%); and shock (6%).

Rare complications among critically ill patients with COVID-19 include cytokine storm and macrophage activation syndrome (ie, secondary hemophagocytic lymphohistiocytosis).

The clinical significance of SARS-CoV-2 transmission from inanimate surfaces is difficult to interpret without knowing the minimum dose of virus particles that can initiate infection. Viral load appears to persist at higher levels on impermeable surfaces, such as stainless steel and plastic, than permeable surfaces, such as cardboard. 32 Virus has been identified on impermeable surfaces for up to 3 to 4 days after inoculation. 32 Widespread viral contamination of hospital rooms has been documented. 28 However, it is thought that the amount of virus detected on surfaces decays rapidly within 48 to 72 hours. 32 Although the detection of virus on surfaces reinforces the potential for transmission via fomites (objects such as a doorknob, cutlery, or clothing that may be contaminated with SARS-CoV-2) and the need for adequate environmental hygiene, droplet spread via face-to-face contact remains the primary mode of transmission.

Viral load in the upper respiratory tract appears to peak around the time of symptom onset and viral shedding begins approximately 2 to 3 days prior to the onset of symptoms. 33 Asymptomatic and presymptomatic carriers can transmit SARS-CoV-2. 34 , 35 In Singapore, presymptomatic transmission has been described in clusters of patients with close contact (eg, through churchgoing or singing class) approximately 1 to 3 days before the source patient developed symptoms. 34 Presymptomatic transmission is thought to be a major contributor to the spread of SARS-CoV-2. Modeling studies from China and Singapore estimated the percentage of infections transmitted from a presymptomatic individual as 48% to 62%. 17 Pharyngeal shedding is high during the first week of infection at a time in which symptoms are still mild, which might explain the efficient transmission of SARS-CoV-2, because infected individuals can be infectious before they realize they are ill. 36 Although studies have described rates of asymptomatic infection, ranging from 4% to 32%, it is unclear whether these reports represent truly asymptomatic infection by individuals who never develop symptoms, transmission by individuals with very mild symptoms, or transmission by individuals who are asymptomatic at the time of transmission but subsequently develop symptoms. 37 - 39 A systematic review on this topic suggested that true asymptomatic infection is probably uncommon. 38

Although viral nucleic acid can be detectable in throat swabs for up to 6 weeks after the onset of illness, several studies suggest that viral cultures are generally negative for SARS-CoV-2 8 days after symptom onset. 33 , 36 , 40 This is supported by epidemiological studies that have shown that transmission did not occur to contacts whose exposure to the index case started more than 5 days after the onset of symptoms in the index case. 41 This suggests that individuals can be released from isolation based on clinical improvement. The Centers for Disease Control and Prevention recommend isolating for at least 10 days after symptom onset and 3 days after improvement of symptoms. 42 However, there remains uncertainty about whether serial testing is required for specific subgroups, such as immunosuppressed patients or critically ill patients for whom symptom resolution may be delayed or older adults residing in short- or long-term care facilities.

The mean (interquartile range) incubation period (the time from exposure to symptom onset) for COVID-19 is approximately 5 (2-7) days. 43 , 44 Approximately 97.5% of individuals who develop symptoms will do so within 11.5 days of infection. 43 The median (interquartile range) interval from symptom onset to hospital admission is 7 (3-9) days. 45 The median age of hospitalized patients varies between 47 and 73 years, with most cohorts having a male preponderance of approximately 60%. 44 , 46 , 47 Among patients hospitalized with COVID-19, 74% to 86% are aged at least 50 years. 45 , 47

COVID-19 has various clinical manifestations ( Box 1 and Box 2 ). In a study of 44 672 patients with COVID-19 in China, 81% of patients had mild manifestations, 14% had severe manifestations, and 5% had critical manifestations (defined by respiratory failure, septic shock, and/or multiple organ dysfunction). 48 A study of 20 133 individuals hospitalized with COVID-19 in the UK reported that 17.1% were admitted to high-dependency or intensive care units (ICUs). 47

Commonly Asked Questions About Coronavirus Disease 2019 (COVID-19)

How is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) most commonly transmitted?

SARS-CoV-2 is most commonly spread via respiratory droplets (eg, from coughing, sneezing, shouting) during face-to-face exposure or by surface contamination.

What are the most common symptoms of COVID-19?

The 3 most common symptoms are fever, cough, and shortness of breath. Additional symptoms include weakness, fatigue, nausea, vomiting, diarrhea, changes to taste and smell.

How is the diagnosis made?

Diagnosis of COVID-19 is typically made by polymerase chain reaction testing of a nasopharyngeal swab. However, given the possibility of false-negative test results, clinical, laboratory, and imaging findings may also be used to make a presumptive diagnosis for individuals for whom there is a high index of clinical suspicion of infection.

What are current evidence-based treatments for individuals with COVID-19?

Supportive care, including supplemental oxygen, is the main treatment for most patients. Recent trials indicate that dexamethasone decreases mortality (subgroup analysis suggests benefit is limited to patients who require supplemental oxygen and who have symptoms for >7 d) and remdesivir improves time to recovery (subgroup analysis suggests benefit is limited to patients not receiving mechanical ventilation).

What percentage of people are asymptomatic carriers, and how important are they in transmitting the disease?

True asymptomatic infection is believed to be uncommon. The average time from exposure to symptoms onset is 5 days, and up to 62% of transmission may occur prior to the onset of symptoms.

Are masks effective at preventing spread?

Yes. Face masks reduce the spread of viral respiratory infection. N95 respirators and surgical masks both provide substantial protection (compared with no mask), and surgical masks provide greater protection than cloth masks. However, physical distancing is also associated with substantial reduction of viral transmission, with greater distances providing greater protection. Additional measures such as hand and environmental disinfection are also important.

Although only approximately 25% of infected patients have comorbidities, 60% to 90% of hospitalized infected patients have comorbidities. 45 - 49 The most common comorbidities in hospitalized patients include hypertension (present in 48%-57% of patients), diabetes (17%-34%), cardiovascular disease (21%-28%), chronic pulmonary disease (4%-10%), chronic kidney disease (3%-13%), malignancy (6%-8%), and chronic liver disease (<5%). 45 , 46 , 49

The most common symptoms in hospitalized patients are fever (up to 90% of patients), dry cough (60%-86%), shortness of breath (53%-80%), fatigue (38%), nausea/vomiting or diarrhea (15%-39%), and myalgia (15%-44%). 18 , 44 - 47 , 49 , 50 Patients can also present with nonclassical symptoms, such as isolated gastrointestinal symptoms. 18 Olfactory and/or gustatory dysfunctions have been reported in 64% to 80% of patients. 51 - 53 Anosmia or ageusia may be the sole presenting symptom in approximately 3% of patients. 53

Complications of COVID-19 include impaired function of the heart, brain, lung, liver, kidney, and coagulation system. COVID-19 can lead to myocarditis, cardiomyopathy, ventricular arrhythmias, and hemodynamic instability. 20 , 54 Acute cerebrovascular disease and encephalitis are observed with severe illness (in up to 8% of patients). 21 , 52 Venous and arterial thromboembolic events occur in 10% to 25% in hospitalized patients with COVID-19. 19 , 22 In the ICU, venous and arterial thromboembolic events may occur in up to 31% to 59% of patients with COVID-19. 16 , 22

Approximately 17% to 35% of hospitalized patients with COVID-19 are treated in an ICU, most commonly due to hypoxemic respiratory failure. Among patients in the ICU with COVID-19, 29% to 91% require invasive mechanical ventilation. 47 , 49 , 55 , 56 In addition to respiratory failure, hospitalized patients may develop acute kidney injury (9%), liver dysfunction (19%), bleeding and coagulation dysfunction (10%-25%), and septic shock (6%). 18 , 19 , 23 , 49 , 56

Approximately 2% to 5% of individuals with laboratory-confirmed COVID-19 are younger than 18 years, with a median age of 11 years. Children with COVID-19 have milder symptoms that are predominantly limited to the upper respiratory tract, and rarely require hospitalization. It is unclear why children are less susceptible to COVID-19. Potential explanations include that children have less robust immune responses (ie, no cytokine storm), partial immunity from other viral exposures, and lower rates of exposure to SARS-CoV-2. Although most pediatric cases are mild, a small percentage (<7%) of children admitted to the hospital for COVID-19 develop severe disease requiring mechanical ventilation. 57 A rare multisystem inflammatory syndrome similar to Kawasaki disease has recently been described in children in Europe and North America with SARS-CoV-2 infection. 58 , 59 This multisystem inflammatory syndrome in children is uncommon (2 in 100 000 persons aged <21 years). 60

Diagnosis of COVID-19 is typically made using polymerase chain reaction testing via nasal swab ( Box 2 ). However, because of false-negative test result rates of SARS-CoV-2 PCR testing of nasal swabs, clinical, laboratory, and imaging findings may also be used to make a presumptive diagnosis.

Reverse transcription polymerase chain reaction–based SARS-CoV-2 RNA detection from respiratory samples (eg, nasopharynx) is the standard for diagnosis. However, the sensitivity of testing varies with timing of testing relative to exposure. One modeling study estimated sensitivity at 33% 4 days after exposure, 62% on the day of symptom onset, and 80% 3 days after symptom onset. 61 - 63 Factors contributing to false-negative test results include the adequacy of the specimen collection technique, time from exposure, and specimen source. Lower respiratory samples, such as bronchoalveolar lavage fluid, are more sensitive than upper respiratory samples. Among 1070 specimens collected from 205 patients with COVID-19 in China, bronchoalveolar lavage fluid specimens had the highest positive rates of SARS-CoV-2 PCR testing results (93%), followed by sputum (72%), nasal swabs (63%), and pharyngeal swabs (32%). 61 SARS-CoV-2 can also be detected in feces, but not in urine. 61 Saliva may be an alternative specimen source that requires less personal protective equipment and fewer swabs, but requires further validation. 64

Several serological tests can also aid in the diagnosis and measurement of responses to novel vaccines. 62 , 65 , 66 However, the presence of antibodies may not confer immunity because not all antibodies produced in response to infection are neutralizing. Whether and how frequently second infections with SARS-CoV-2 occur remain unknown. Whether presence of antibody changes susceptibility to subsequent infection or how long antibody protection lasts are unknown. IgM antibodies are detectable within 5 days of infection, with higher IgM levels during weeks 2 to 3 of illness, while an IgG response is first seen approximately 14 days after symptom onset. 62 , 65 Higher antibody titers occur with more severe disease. 66 Available serological assays include point-of-care assays and high throughput enzyme immunoassays. However, test performance, accuracy, and validity are variable. 67

A systematic review of 19 studies of 2874 patients who were mostly from China (mean age, 52 years), of whom 88% were hospitalized, reported the typical range of laboratory abnormalities seen in COVID-19, including elevated serum C-reactive protein (increased in >60% of patients), lactate dehydrogenase (increased in approximately 50%-60%), alanine aminotransferase (elevated in approximately 25%), and aspartate aminotransferase (approximately 33%). 24 Approximately 75% of patients had low albumin. 24 The most common hematological abnormality is lymphopenia (absolute lymphocyte count <1.0 × 10 9 /L), which is present in up to 83% of hospitalized patients with COVID-19. 44 , 50 In conjunction with coagulopathy, modest prolongation of prothrombin times (prolonged in >5% of patients), mild thrombocytopenia (present in approximately 30% of patients) and elevated D-dimer values (present in 43%-60% of patients) are common. 14 , 15 , 19 , 44 , 68 However, most of these laboratory characteristics are nonspecific and are common in pneumonia. More severe laboratory abnormalities have been associated with more severe infection. 44 , 50 , 69 D-dimer and, to a lesser extent, lymphopenia seem to have the largest prognostic associations. 69

The characteristic chest computed tomographic imaging abnormalities for COVID-19 are diffuse, peripheral ground-glass opacities ( Figure 3 ). 70 Ground-glass opacities have ill-defined margins, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura. 70 Early in the disease, chest computed tomographic imaging findings in approximately 15% of individuals and chest radiograph findings in approximately 40% of individuals can be normal. 44 Rapid evolution of abnormalities can occur in the first 2 weeks after symptom onset, after which they subside gradually. 70 , 71

Chest computed tomographic imaging findings are nonspecific and overlap with other infections, so the diagnostic value of chest computed tomographic imaging for COVID-19 is limited. Some patients admitted to the hospital with polymerase chain reaction testing–confirmed SARS-CoV-2 infection have normal computed tomographic imaging findings, while abnormal chest computed tomographic imaging findings compatible with COVID-19 occur days before detection of SARS-CoV-2 RNA in other patients. 70 , 71

Currently, best practices for supportive management of acute hypoxic respiratory failure and ARDS should be followed. 72 - 74 Evidence-based guideline initiatives have been established by many countries and professional societies, 72 - 74 including guidelines that are updated regularly by the National Institutes of Health. 74

More than 75% of patients hospitalized with COVID-19 require supplemental oxygen therapy. For patients who are unresponsive to conventional oxygen therapy, heated high-flow nasal canula oxygen may be administered. 72 For patients requiring invasive mechanical ventilation, lung-protective ventilation with low tidal volumes (4-8 mL/kg, predicted body weight) and plateau pressure less than 30 mg Hg is recommended. 72 Additionally, prone positioning, a higher positive end-expiratory pressure strategy, and short-term neuromuscular blockade with cisatracurium or other muscle relaxants may facilitate oxygenation. Although some patients with COVID-19–related respiratory failure have high lung compliance, 75 they are still likely to benefit from lung-protective ventilation. 76 Cohorts of patients with ARDS have displayed similar heterogeneity in lung compliance, and even patients with greater compliance have shown benefit from lower tidal volume strategies. 76

The threshold for intubation in COVID-19–related respiratory failure is controversial, because many patients have normal work of breathing but severe hypoxemia. 77 “Earlier” intubation allows time for a more controlled intubation process, which is important given the logistical challenges of moving patients to an airborne isolation room and donning personal protective equipment prior to intubation. However, hypoxemia in the absence of respiratory distress is well tolerated, and patients may do well without mechanical ventilation. Earlier intubation thresholds may result in treating some patients with mechanical ventilation unnecessarily and exposing them to additional complications. Currently, insufficient evidence exists to make recommendations regarding earlier vs later intubation.

In observational studies, approximately 8% of hospitalized patients with COVID-19 experience a bacterial or fungal co-infection, but up to 72% are treated with broad-spectrum antibiotics. 78 Awaiting further data, it may be prudent to withhold antibacterial drugs in patients with COVID-19 and reserve them for those who present with radiological findings and/or inflammatory markers compatible with co-infection or who are immunocompromised and/or critically ill. 72

The following classes of drugs are being evaluated or developed for the management of COVID-19: antivirals (eg, remdesivir, favipiravir), antibodies (eg, convalescent plasma, hyperimmune immunoglobulins), anti-inflammatory agents (dexamethasone, statins), targeted immunomodulatory therapies (eg, tocilizumab, sarilumab, anakinra, ruxolitinib), anticoagulants (eg, heparin), and antifibrotics (eg, tyrosine kinase inhibitors). It is likely that different treatment modalities might have different efficacies at different stages of illness and in different manifestations of disease. Viral inhibition would be expected to be most effective early in infection, while, in hospitalized patients, immunomodulatory agents may be useful to prevent disease progression and anticoagulants may be useful to prevent thromboembolic complications.

More than 200 trials of chloroquine/hydroxychloroquine, compounds that inhibit viral entry and endocytosis of SARS-CoV-2 in vitro and may have beneficial immunomodulatory effects in vivo, 79 , 80 have been initiated, but early data from clinical trials in hospitalized patients with COVID-19 have not demonstrated clear benefit. 81 - 83 A clinical trial of 150 patients in China admitted to the hospital for mild to moderate COVID-19 did not find an effect on negative conversion of SARS-CoV-2 by 28 days (the main outcome measure) when compared with standard of care alone. 83 Two retrospective studies found no effect of hydroxychloroquine on risk of intubation or mortality among patients hospitalized for COVID-19. 84 , 85 One of these retrospective multicenter cohort studies compared in-hospital mortality between those treated with hydroxychloroquine plus azithromycin (735 patients), hydroxychloroquine alone (271 patients), azithromycin alone (211 patients), and neither drug (221 patients), but reported no differences across the groups. 84 Adverse effects are common, most notably QT prolongation with an increased risk of cardiac complications in an already vulnerable population. 82 , 84 These findings do not support off-label use of (hydroxy)chloroquine either with or without the coadministration of azithromycin. Randomized clinical trials are ongoing and should provide more guidance.

Most antiviral drugs undergoing clinical testing in patients with COVID-19 are repurposed antiviral agents originally developed against influenza, HIV, Ebola, or SARS/MERS. 79 , 86 Use of the protease inhibitor lopinavir-ritonavir, which disrupts viral replication in vitro, did not show benefit when compared with standard care in a randomized, controlled, open-label trial of 199 hospitalized adult patients with severe COVID-19. 87 Among the RNA-dependent RNA polymerase inhibitors, which halt SARS-CoV-2 replication, being evaluated, including ribavirin, favipiravir, and remdesivir, the latter seems to be the most promising. 79 , 88 The first preliminary results of a double-blind, randomized, placebo-controlled trial of 1063 adults hospitalized with COVID-19 and evidence of lower respiratory tract involvement who were randomly assigned to receive intravenous remdesivir or placebo for up to 10 days demonstrated that patients randomized to receive remdesivir had a shorter time to recovery than patients in the placebo group (11 vs 15 days). 88 A separate randomized, open-label trial among 397 hospitalized patients with COVID-19 who did not require mechanical ventilation reported that 5 days of treatment with remdesivir was not different than 10 days in terms of clinical status on day 14. 89 The effect of remdesivir on survival remains unknown.

Treatment with plasma obtained from patients who have recovered from viral infections was first reported during the 1918 flu pandemic. A first report of 5 critically ill patients with COVID-19 treated with convalescent plasma containing neutralizing antibody showed improvement in clinical status among all participants, defined as a combination of changes of body temperature, Sequential Organ Failure Assessment score, partial pressure of oxygen/fraction of inspired oxygen, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation supports before and after convalescent plasma transfusion status. 90 However, a subsequent multicenter, open-label, randomized clinical trial of 103 patients in China with severe COVID-19 found no statistical difference in time to clinical improvement within 28 days among patients randomized to receive convalescent plasma vs standard treatment alone (51.9% vs 43.1%). 91 However, the trial was stopped early because of slowing enrollment, which limited the power to detect a clinically important difference. Alternative approaches being studied include the use of convalescent plasma-derived hyperimmune globulin and monoclonal antibodies targeting SARS-CoV-2. 92 , 93

Alternative therapeutic strategies consist of modulating the inflammatory response in patients with COVID-19. Monoclonal antibodies directed against key inflammatory mediators, such as interferon gamma, interleukin 1, interleukin 6, and complement factor 5a, all target the overwhelming inflammatory response following SARS-CoV-2 infection with the goal of preventing organ damage. 79 , 86 , 94 Of these, the interleukin 6 inhibitors tocilizumab and sarilumab are best studied, with more than a dozen randomized clinical trials underway. 94 Tyrosine kinase inhibitors, such as imatinib, are studied for their potential to prevent pulmonary vascular leakage in individuals with COVID-19.

Studies of corticosteroids for viral pneumonia and ARDS have yielded mixed results. 72 , 73 However, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, which randomized 2104 patients with COVID-19 to receive 6 mg daily of dexamethasone for up to 10 days and 4321 to receive usual care, found that dexamethasone reduced 28-day all-cause mortality (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]; P  < .001). 95 The benefit was greatest in patients with symptoms for more than 7 days and patients who required mechanical ventilation. By contrast, there was no benefit (and possibility for harm) among patients with shorter symptom duration and no supplemental oxygen requirement. A retrospective cohort study of 201 patients in Wuhan, China, with confirmed COVID-19 pneumonia and ARDS reported that treatment with methylprednisolone was associated with reduced risk of death (hazard ratio, 0.38 [95% CI, 0.20-0.72]). 69

Thromboembolic prophylaxis with subcutaneous low molecular weight heparin is recommended for all hospitalized patients with COVID-19. 15 , 19 Studies are ongoing to assess whether certain patients (ie, those with elevated D-dimer) benefit from therapeutic anticoagulation.

A disproportionate percentage of COVID-19 hospitalizations and deaths occurs in lower-income and minority populations. 45 , 96 , 97 In a report by the Centers for Disease Control and Prevention of 580 hospitalized patients for whom race data were available, 33% were Black and 45% were White, while 18% of residents in the surrounding community were Black and 59% were White. 45 The disproportionate prevalence of COVID-19 among Black patients was separately reported in a retrospective cohort study of 3626 patients with COVID-19 from Louisiana, in which 77% of patients hospitalized with COVID-19 and 71% of patients who died of COVID-19 were Black, but Black individuals comprised only 31% of the area population. 97 , 98 This disproportionate burden may be a reflection of disparities in housing, transportation, employment, and health. Minority populations are more likely to live in densely populated communities or housing, depend on public transportation, or work in jobs for which telework was not possible (eg, bus driver, food service worker). Black individuals also have a higher prevalence of chronic health conditions than White individuals. 98 , 99

Overall hospital mortality from COVID-19 is approximately 15% to 20%, but up to 40% among patients requiring ICU admission. However, mortality rates vary across cohorts, reflecting differences in the completeness of testing and case identification, variable thresholds for hospitalization, and differences in outcomes. Hospital mortality ranges from less than 5% among patients younger than 40 years to 35% for patients aged 70 to 79 years and greater than 60% for patients aged 80 to 89 years. 46 Estimated overall death rates by age group per 1000 confirmed cases are provided in the Table . Because not all people who die during the pandemic are tested for COVID-19, actual numbers of deaths from COVID-19 are higher than reported numbers.

Although long-term outcomes from COVID-19 are currently unknown, patients with severe illness are likely to suffer substantial sequelae. Survival from sepsis is associated with increased risk for mortality for at least 2 years, new physical disability, new cognitive impairment, and increased vulnerability to recurrent infection and further health deterioration. Similar sequalae are likely to be seen in survivors of severe COVID-19. 100

COVID-19 is a potentially preventable disease. The relationship between the intensity of public health action and the control of transmission is clear from the epidemiology of infection around the world. 25 , 101 , 102 However, because most countries have implemented multiple infection control measures, it is difficult to determine the relative benefit of each. 103 , 104 This question is increasingly important because continued interventions will be required until effective vaccines or treatments become available. In general, these interventions can be divided into those consisting of personal actions (eg, physical distancing, personal hygiene, and use of protective equipment), case and contact identification (eg, test-trace-track-isolate, reactive school or workplace closure), regulatory actions (eg, governmental limits on sizes of gatherings or business capacity; stay-at-home orders; proactive school, workplace, and public transport closure or restriction; cordon sanitaire or internal border closures), and international border measures (eg, border closure or enforced quarantine). A key priority is to identify the combination of measures that minimizes societal and economic disruption while adequately controlling infection. Optimal measures may vary between countries based on resource limitations, geography (eg, island nations and international border measures), population, and political factors (eg, health literacy, trust in government, cultural and linguistic diversity).

The evidence underlying these public health interventions has not changed since the 1918 flu pandemic. 105 Mathematical modeling studies and empirical evidence support that public health interventions, including home quarantine after infection, restricting mass gatherings, travel restrictions, and social distancing, are associated with reduced rates of transmission. 101 , 102 , 106 Risk of resurgence follows when these interventions are lifted.

A human vaccine is currently not available for SARS-CoV-2, but approximately 120 candidates are under development. Approaches include the use of nucleic acids (DNA or RNA), inactivated or live attenuated virus, viral vectors, and recombinant proteins or virus particles. 107 , 108 Challenges to developing an effective vaccine consist of technical barriers (eg, whether S or receptor-binding domain proteins provoke more protective antibodies, prior exposure to adenovirus serotype 5 [which impairs immunogenicity in the viral vector vaccine], need for adjuvant), feasibility of large-scale production and regulation (eg, ensuring safety and effectiveness), and legal barriers (eg, technology transfer and licensure agreements). The SARS-CoV-2 S protein appears to be a promising immunogen for protection, but whether targeting the full-length protein or only the receptor-binding domain is sufficient to prevent transmission remains unclear. 108 Other considerations include the potential duration of immunity and thus the number of vaccine doses needed to confer immunity. 62 , 108 More than a dozen candidate SARS-CoV-2 vaccines are currently being tested in phase 1-3 trials.

Other approaches to prevention are likely to emerge in the coming months, including monoclonal antibodies, hyperimmune globulin, and convalscent titer. If proved effective, these approaches could be used in high-risk individuals, including health care workers, other essential workers, and older adults (particularly those in nursing homes or long-term care facilities).

This review has several limitations. First, information regarding SARS CoV-2 is limited. Second, information provided here is based on current evidence, but may be modified as more information becomes available. Third, few randomized trials have been published to guide management of COVID-19.

As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

Accepted for Publication: June 30, 2020.

Corresponding Author: W. Joost Wiersinga, MD, PhD, Division of Infectious Diseases, Department of Medicine, Amsterdam UMC, location AMC, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands ( [email protected] ).

Published Online: July 10, 2020. doi:10.1001/jama.2020.12839

Conflict of Interest Disclosures: Dr Wiersinga is supported by the Netherlands Organisation of Scientific Research outside the submitted work. Dr Prescott reported receiving grants from the US Agency for Healthcare Research and Quality (HCP by R01 HS026725), the National Institutes of Health/National Institute of General Medical Sciences, and the US Department of Veterans Affairs outside the submitted work, being the sepsis physician lead for the Hospital Medicine Safety Continuous Quality Initiative funded by BlueCross/BlueShield of Michigan, and serving on the steering committee for MI-COVID-19, a Michigan statewide registry to improve care for patients with COVID-19 in Michigan. Dr Rhodes reported being the co-chair of the Surviving Sepsis Campaign. Dr Cheng reported being a member of Australian government advisory committees, including those involved in COVID-19. No other disclosures were reported.

Disclaimer: This article does not represent the views of the US Department of Veterans Affairs or the US government. This material is the result of work supported with resources and use of facilities at the Ann Arbor VA Medical Center. The opinions in this article do not necessarily represent those of the Australian government or advisory committees.

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REVIEW article

Coronavirus disease (covid-19): comprehensive review of clinical presentation.

• 1 Department of Medicine, King Edward Medical University/ Mayo Hospital, Lahore, Pakistan
• 2 Department of Anesthesia and Intensive Care, Post-Graduate Medical Institute/LGH, Lahore, Pakistan
• 3 Rajarshee Chhatrapati Shahu Maharaj Government Medical College, Kolhapur, India
• 4 Department of Medicine, Faculty of Medicine, University of Tlemcen, Tlemcen, Algeria
• 5 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
• 6 Institute of Research and Development, Duy Tan University, Da Nang, Vietnam

COVID-19 is a rapidly growing pandemic with its first case identified during December 2019 in Wuhan, Hubei Province, China. Due to the rampant rise in the number of cases in China and globally, WHO declared COVID-19 as a pandemic on 11th March 2020. The disease is transmitted via respiratory droplets of infected patients during coughing or sneezing and affects primarily the lung parenchyma. The spectrum of clinical manifestations can be seen in COVID-19 patients ranging from asymptomatic infections to severe disease resulting in mortality. Although respiratory involvement is most common in COVID-19 patients, the virus can affect other organ systems as well. The systemic inflammation induced by the disease along with multisystem expression of Angiotensin Converting Enzyme 2 (ACE2), a receptor which allows viral entry into cells, explains the manifestation of extra-pulmonary symptoms affecting the gastrointestinal, cardiovascular, hematological, renal, musculoskeletal, and endocrine system. Here, we have reviewed the extensive literature available on COVID-19 about various clinical presentations based on the organ system involved as well as clinical presentation in specific population including children, pregnant women, and immunocompromised patients. We have also briefly discussed about the Multisystemic Inflammatory Syndrome occurring in children and adults with COVID-19. Understanding the various clinical presentations can help clinicians diagnose COVID-19 in an early stage and ensure appropriate measures to be undertaken in order to prevent further spread of the disease.

Introduction

COVID-19 is a growing pandemic with initial cases identified in Wuhan, Hubei province, China toward the end of December 2019. Labeled as Novel Coronavirus 2019 (2019-nCoV) initially by the Chinese Center for Disease Control and Prevention (CDC) which was subsequently renamed as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) due to its homology with SARS-CoV by the International Committee on Taxonomy of Viruses (ICTV) ( 1 , 2 ). The World Health Organization (WHO) later renamed the disease caused by SARS-CoV-2 as Coronavirus Disease-2019 (COVID-19) ( 3 ). COVID-19 is primarily a disease of the respiratory system affecting lung parenchyma with fever, cough, and shortness of breath as the predominant symptoms. Recent studies have shown that it can affect multiple organ systems and cause development of extra-pulmonary symptoms. Presence of extra-pulmonary symptoms can often lead to late diagnosis and sometimes even mis-diagnosis of COVID-19 which can be detrimental to patients. As researchers globally continue to understand COVID-19 and its implications on the human body, knowledge about the various clinical presentations of COVID-19 is paramount in early diagnosing and treatment in order to decrease the morbidity and mortality caused by the disease.

Epidemiology and Pathophysiology

While studying the early transmission dynamics of COVID-19 outbreak in Wuhan, many cases were found to be linked to the Huanan wholesale seafood market. Further investigation revealed <10% of the total cases could be linked to the market which led to the conclusion of human-to-human transmission of the virus occurring through respiratory droplets and contact transmission contributing to the rise in the number of affected individuals ( 4 ). The exponential rise in the number of cases in China and reporting of cases outside China in multiple countries led WHO to declare COVID-19 as a pandemic on 11th March 2020 ( 5 ).

SARS-CoV-2 tends to infect all age groups and is transmitted via direct contact or respiratory droplets generated during coughing or sneezing by the infected patient during both symptomatic or pre-symptomatic phase of infection. Other routes of transmission include fecal-oral route and fomites along with small risk of vertical transmission from mother to child if infection occurs during third trimester of pregnancy ( 6 , 7 ). There has also been evidence of asymptomatic transmission of COVID-19 ( 8 ). The concept of super spreaders in relation to COVID-19 is emerging where a single individual either symptomatic or asymptomatic can infect a disproportionately large number of individuals in an appropriate super spreading conditions such as mass gathering due to production of large number of infectious agent for prolonged duration of time ( 9 ). As per the literature, the incubation period of COVID-19 ranges from 2 to 14 days with a mean incubation period of 3 days ( 10 ). The basic Reproduction number (Ro) of SARS-CoV-2 is 2–2.5. Each individual infected with COVID-19 can infect 2–2.5 other individuals in a naïve population which also explains the exponential growth in the number of cases ( 10 ). The disease tends to be of mild to moderate severity in roughly 80% of patients, and severe disease is associated with infants, elderly patients above 65 years, and patients with other comorbidities such as diabetes mellitus, hypertension, coronary artery disease, and other chronic conditions ( 1 , 2 ). COVID-19 has also been found to be more severe in males than in females with a case fatality rate of 2.8% in males and 1.7% in females ( 11 ). The major organ system affected by the virus is the respiratory system, but it can affect other organ systems either directly or by the effect of host immune response. SARS-CoV-2, the causative agent of COVID-19, after entering the human host initially replicates in the epithelial mucosa of the upper respiratory tract (nose and pharynx) followed by migration to the lungs where further replication of virus occurs causing transient viraemia. The virus uses Angiotensin Converting Enzyme 2 (ACE2) receptor as a primary entry to cells. ACE2 is found abundantly in the mucosal lining of the respiratory tract, vascular endothelial cells, heart, intestine, and kidney. Thus, the virus has potential for replication in all these organs. After entry into cells, the virus undergoes further rapid replication within the target cells and induces extensive epithelial and endothelial dysfunction leading to exponential inflammatory response with the production of a large amount of proinflammatory cytokines and chemokines. Activation of proinflammatory cytokines and chemokines leads to neutrophil activation and migrations and results in the characteristic cytokine storm. The immunological downregulation of ACE2 by the virus contributes to acute lung injury in COVID-19. ACE2 also regulates the renin angiotensin system (RAS); thus, downregulation of ACE2 also causes dysfunction of RAS which contributes to enhanced inflammation ( 2 , 11 – 15 ). These entire factors contribute to symptoms of COVID-19 with sepsis, multi-organ dysfunction, acute respiratory distress syndrome (ARDS), and prothrombotic state leading to an exacerbation of organ dysfunction.

Clinical Manifestation

We review here the system based clinical features of COVID-19.

Respiratory

According to report from WHO-China-Joint Mission on COVID-19, 55,924 laboratories confirmed cases of COVID-19 had fever (87.9%), dry cough (67.7%), fatigue (38.1%), sputum production (33.4%), difficulty breathing (18.6%), sore throat (13.9%), chills (11.4%), nasal congestion (4.8%), and hemoptysis (0.9%) ( 1 ).

Some patients may rapidly progress to acute lung injury and ARDS with septic shock. The median interval between the onset of initial symptoms to development of dyspnea, hospital admission, and ARDS was 5, 7, and 8 days respectively ( 10 ). Some patients with COVID-19 may have reduced oxygen saturation in blood (≤ 93%) with oxygen saturation down to 50 or 60% but remained stable without significant distress, and as such, were termed as salient hypoxia or happy hypoxia ( 16 , 17 ). Trial of oxygen therapy, prone positioning, high flow continuous positive airway pressure, non-re-breathable mask alongside trial of anticoagulation are often used to manage these patients ( 16 , 17 ). However, further study is required to define the role of these strategies in management.

The most frequent radiological abnormality among 975 patients with COVID-19 in computed tomography (CT) scan of chest was ground glass opacity (56.4%) and bilateral patchy shadowing (51.8%) ( 18 ). A scientific review of 2,814 patients have shown that the most common chest CT finding in COVID-19 patients was ground glass opacity followed by consolidation. However, the findings can vary in different patients and at various stages of diseases. Other CT findings include interlobular septal thickening, reticular pattern, crazy paving, etc. Atypical findings like air bronchogram, bronchial wall thickening, nodule, pleural effusion, and lymphadenopathy have also been noted in some studies ( 19 ). A study showed that among 877 patients with non-severe diseases and 173 patients with severe diseases, 17.9 and 2.9% of the patients did not have any detectable radiological abnormalities, respectively ( 18 ).

ENT (Ear, Nose, and Throat)

ENT manifestations are one of the most frequent symptoms encountered by physicians in COVID-19. A peculiar clinical presentation in some COVID-19 patients includes the deterioration of sense, taste (dysgeusia), and loss of smell (anosmia). A systematic review and meta-analysis of 10 studies with 1,627 participants surveyed for olfactory deterioration and 9 studies with 1,390 participants examined for gustatory symptoms demonstrated prevalence of 52.73 and 43.93% of these symptoms among COVID-19 patients, respectively. These clinical features may often present at earlier stages of the disease ( 20 ). Additionally, sore throat, rhinorrhea, nasal congestion, tonsil edema, and enlarged cervical lymph nodes are commonly seen among otolaryngological dysfunctions in patients ( 21 ). A large observational study of 1,099 COVID-19 patients reported tonsils swelling in 23 patients (2.1%), throat congestion in 19 patients (1.7%) and enlarged lymph nodes in 2 patients (0.2%) ( 18 ). This can be explained by the fact that there is a high expression of ACE2 receptors on the epithelial cells of the oral and nasal mucosa including the tongue. It has been known that the novel coronavirus has a strong binding affinity to ACE2 receptors through which it invades host cells ( 22 ). This theory may explain the exhibition of extra-respiratory symptoms including ENT manifestations as part of COVID-19 symptoms.

Cardiovascular

Cardiac manifestation in patient with COVID-19 can occur due to cardiac strain secondary to hypoxia and respiratory failure, direct effect of SARS-CoV-2 on heart or secondary to inflammation and cytokine storm, metabolic derangements, rupture of plaque and coronary occlusion by thrombus, and consequences of drugs used for treatment ( 23 – 25 ). The need for intensive care admission, non-invasive ventilation (46.3 vs. 3.9%), and invasive mechanical ventilation (22 vs. 4.2%) were higher among patients with cardiac ailments as compared to those without cardiac involvement as well as higher hospital mortality than those without myocardial involvement (51.2 vs. 4.5%) ( 26 ). These patients tend to have electrocardiographic (ECG) changes as well as elevations in high sensitivity cardiac troponin (hsCTn) and N- terminal pro-B-type natriuretic peptide (NT proBNP) which corresponded to raised inflammatory markers. Hypertension, acute and fulminant myocarditis, ventricular arrhythmias, atrial fibrillation, stress cardiomyopathy, hypotension and heart failure, acute coronary syndrome (ACS) with ST elevation or depression MI with normal coronaries have been reported ( 23 , 27 ). In a Chinese cohort of 138 patients, 16.7% had arrhythmias with risk higher among those needing ICU care with no mention of the type of arrhythmia that was present ( 28 ). Less frequently, cardiac symptoms like chest pain or tightness and palpitation can be the initial presenting features without fever producing a diagnostic dilemma. Some of these patients eventually go on to develop respiratory symptoms as diseases progress ( 29 ). Patients who have recovered from acute illness may develop arrhythmias as a result of myocardial scar and need future monitoring ( 27 ). One important point to note is use of Renin Angiotensin Aldosterone System (RAAS) modulators in patients with COVID-19. Guidelines from ACC/AHA/HFSA recommends continuing them in high risk patient based on goal directed therapy approach supported by a recent systematic review and meta-analysis conducted by Hasan et. Al. which demonstrated use of ACEI/ARB in COVID-19 patients is associated with lower odds/ hazards of mortality and development of severe/critical diseases as compared to no use of ACEI/ARB ( 30 , 31 ).

Gastrointestinal

In the initial cohort of patients from China, nausea or vomiting and diarrhea were present in 5 and 3.7% of patients ( 1 ). Review of data from 2,023 patients showed anorexia to be the most frequently occurring gastrointestinal symptom in adults. Diarrhea was the most common presenting gastrointestinal symptom in both adults and children while vomiting was found to be more common in children ( 32 ). Other rare symptoms included nausea, abdominal pain, and gastrointestinal bleeding. There have been few instances where COVID-19 patients presented with only gastrointestinal symptoms without the development of fever or respiratory symptoms at the onset and during disease progression ( 33 ). In a smaller cohort of 204 patients, 50.5% had some form of intestinal symptoms and of those, 5.8% had only intestinal symptoms while the remaining patients developed respiratory symptoms subsequently. The most common symptoms reported among them was anorexia (78.64%), non-dehydrating diarrhea (34%), vomiting (3.9%), and abdominal pain (1.94%) ( 34 ). In addition, those with GI symptoms tend to have a longer interval between symptom onset and hospital admission (9 vs. 7.3 days) possibly due to lack of clinical suspicion and delay in diagnosis. Patients with gastrointestinal symptoms tend to have higher elevation in AST and ALT indicating coexistent liver injury ( 34 ). The mechanism behind GI illness is not clearly known but could be due to direct invasion of virus via ACE2 receptor in the intestinal mucosa. This can be supported by the fact that viral RNA can be detected in stool samples of COVID-19 patients which may also hint toward possible fecal-oral transmission ( 35 ). Liver dysfunction is likely secondary to the use of hepatotoxic drugs, hypoxia induced liver injury, systemic inflammation, and multi organ failure ( 36 ).

Renal manifestation in patients with COVID-19 can occur due to direct invasion of podocytes and proximal tubular cells by SARS-CoV-2 virus, secondary endothelial dysfunction causing effacement of foot process with vacuolation and detachment of podocytes, and acute proximal tubular dysfunction ( 37 ). Furthermore, hypoxia, cytokine storm, rhabdomyolysis, nephrotoxic drugs, and overlying infections can all exacerbate renal injury ( 38 ). Based on initial reports, prevalence of Acute Kidney Injury (AKI) among COVID-19 hospitalized patients range from 0.5 to 29%. In a cohort of 701 patients, proteinuria (43.9%), hematuria (26.7%), elevated creatinine (14.4%), elevated blood urea nitrogen (13.1%), and low glomerular filtration rate (≤ 60 ml/min/1.73 m 2 ) (13.1%) were present at the time of hospital admission with 5.1% developing AKI during the illness. AKI was more prevalent among those with baseline renal impairment ( 39 ). In another large cohort of 5,449 patients, 36.6% had AKI with prevalence higher among mechanically ventilated patients compared to non-ventilated patients (89.7 vs. 21.7%) ( 40 ). Patients developing renal impairment are prone to have higher mortality within the hospital. Another point to highlight is the presentation of COVID-19 in renal transplant recipients. Due to immunosuppression, these patients are likely to have low fever at presentation with swift clinical decline and requirement for mechanical ventilation with high mortality as compared to the general population ( 41 ).

Neurological

Most patients with COVID-19 develop neurological symptoms along with respiratory symptoms during the course of illness; however, several case reports in review of literature document patient presentation of neurological dysfunction without typical symptoms of fever, cough, and difficulty breathing ( 42 ). There is a 2.5-fold enhanced risk of severe illness and increased death in patients with a history of previous stroke with similar findings among those with Parkinson's diseases. The prevalence of neurological features ranges from 6 to 36% along with hypoxic ischemic encephalopathy up to 20% in some series of patients ( 43 ). Neurological symptoms tend to occur early in the course of illness (median 1–2 days) with most common neurological features being headache, confusion, delirium, anosmia or hyposmia, dysgeusia or ageusia, altered mental status, ataxia, and seizures ( 44 ). Among patients admitted with COVID-19, the prevalence of ischemic stroke ranges from 2.5 to 5% despite receiving prophylaxis for venous thromboembolism. Patients prone to have established cardiovascular risk factors are likely to have a more severe diseases ( 43 ). Other presentations include viral encephalitis, acute necrotizing encephalopathy (ANE), infectious toxic encephalopathy, meningitis, Guillain Barre Syndrome (GBS), Miller Fisher syndrome, and polyneuritis cranialis with GBS being the first feature of COVID-19 in few cases ( 42 , 43 , 45 ). In COVID-19 patients, CNS features are possibly due to direct invasion of neurons and glial cells by SARS-CoV-2 as well as by endothelial dysfunction of blood brain barrier (BBB). Virus can gain access to CNS via hematogenous spread or retrograde movement across the olfactory bulb. The virus can be detected in CSF by RT-PCR and on brain parenchyma during autopsy. The fact that most patients develop anosmia or hyposmia during illness support this theory ( 45 ). After entry, the virus can cause reactive gliosis with activation of the inflammatory cascade. The combination of systemic inflammation, cytokine storm, and coagulation dysfunction can impair BBB function and alter brain equilibrium causing neuronal death ( 42 ).

Ocular manifestations can vary from conjunctival injection to frank conjunctivitis. In a Chinese cohort of 38 patients, 31.6% had ocular symptoms consisting primarily of conjunctivitis while conjunctival hyperemia, foreign body sensation in eye, chemosis, tearing or epiphora were more common among severe COVID-19 patients. Among them SARS-CoV-2 can be demonstrated in conjunctival as well as nasopharyngeal swab in 5.2% of patients, indicating a potential route for viral transmission ( 46 ). Conjunctivitis or tearing can be the initial presenting symptoms of COVID-19. Despite this fact, there is no documented case of severe ocular features relating to COVID-19.

Similar to other viral infections, SARS-CoV-2 can also produce varied dermatological features. A study of 88 patients from Italy showed that about 20.4% had some form of skin manifestations with 44.4% developing features at onset and duration of the disease progression ( 47 ). Maculopapular exanthem (36.1%) was identified as most common dermatological features followed by papulovesicular rash (34.7%), painful acral red purple papules (15.3%), urticaria (9.7%), livedo reticularis (2.8%), and petechiae (1.4%) ( 48 ). A study of 375 COVID-19 cases in Spain identified five different patterns of cutaneous manifestations in patients: acral areas of erythema with vesicles or pustules (pseudo-chilblain) (19%), other vesicular eruptions (9%), urticarial lesions (19%), maculopapular eruptions (47%), and livedo or necrosis (6%) ( 49 ). Majority of patients had lesions on the trunk with some experiencing lesions on hands and feet. There are case reports of COVID-19 associated with erythema multiforme and Kawasaki Disease in children ( 50 , 51 ). Pathogenesis behind skin involvement remains unclear with some features explained by small vessel vasculitis, thrombotic events like DIC, hyaline thrombus formation, acral ischemia, or the direct effect of the virus like other viral illnesses ( 52 ).

Musculoskeletal

The initial report from China revealed 14.8% of patients had myalgia or arthralgia among 55,924 COVID-19 patients. A review article reports that of 12,046 patients, fatigue was identified in 25.6% and myalgia and/or arthralgia in 15.5% with most patients reporting symptoms from the start of illness ( 53 ). There are reports suggesting myositis and rhabdomyolysis with markedly elevated creatinine kinase can occur during COVID-19 illness especially in patients with severe diseases and multi organ failure. Additionally, in some patients, rhabdomyolysis has been documented as the initial presentation of COVID-19 illness without typical respiratory symptoms ( 54 , 55 ). A case series of four patients developing acute arthritis during hospital admission for COVID-19 has been reported with exacerbation of crystal arthropathy (gout and calcium pyrophosphate diseases) but negative for SARS-CoV-2 RT-PCR in synovial fluid ( 56 ). Treatment with steroids and colchicine was used in all four cases. An important consideration to note was that all four patients developed arthritis despite previous treatment with immunomodulatory therapy (hydroxychloroquine, tocilizumab, and pulse methylprednisolone).

Hematological

As stated, COVID-19 is a systemic disease inducing systemic inflammation and occasionally cytokine storm. This can significantly impact the process of hematopoiesis and hemostasis. During early disease, normal or decreased leukocyte and lymphocyte counts were documented with marked lymphopenia as the diseases progressed, especially in those with cytokine storms and severe disease. In a study of 1,099 patients, lymphopenia, thrombocytopenia, and leukopenia were present in 83.2, 36.2, and 33.7%, respectively, with findings more marked in those with severe diseases ( 18 ). Leukocytosis in COVID-19 patients might suggest a bacterial infection or a superinfection with leukocytosis found more commonly in severe cases (11.4%) as compared to mild and moderate cases (4.8%) ( 18 ). Similarly, thrombocytopenia has been found to be more common (57.7%) in severe cases in contrast to mild and moderate cases (31.6%) ( 18 ). Lymphopenia was also linked with an increased necessity for ICU admission and the risk of ARDS. Thrombocytosis with elevated platelet to lymphocyte ratio may indicate a more marked cytokine storm ( 57 ).

Also, coagulation abnormality can manifest in the form of thrombocytopenia, prolonged prothrombin time (PT), low serum fibrinogen level, and raised D-dimer suggesting Disseminated Intravascular Coagulation (DIC) with these changes more marked in those with severe diseases ( 58 ). Raised lactate dehydrogenase (LDH) and serum ferritin were also present and correlated with the degree of systemic inflammation. In a study of 426 COVID-19 patients, C-Reactive Protein (CRP) was noted to be increased in 75–93% of patients, more commonly in patients with severe disease. Serum procalcitonin levels might not be altered at admission, but progressive increase in its value can suggest a worsening prognosis. Severe disease is linked to increased ALT, bilirubin, serum urea, creatinine, and lowered serum albumin ( 59 ). A study of 1,426 patients showed that Interleukin-6 (IL-6) were raised more in patients with severe COVID-19 than non-severe COVID-19 with progressive rise indicating an increased risk of mortality. Thus, its levels could be regarded as an important prognostic indicator for the extensive inflammation and cytokine storm in COVID-19 patients ( 60 ). Other plasma cytokines and chemokines like IL1B, IFNγ, IP10, MCP, etc. have also been found to be elevated in patients with COVID-19 both in severe and non-severe diseases. Additionally, GCSF, IP10, IL2, IL7, IL10, MCP1, MIP1A, and TNFα were increased in patients who require ICU admission which indicates that cytokine storm is associated with a severe disease ( 61 ).

Endocrine and Reproductive

From the available literature there is no doubt that diabetes mellitus is an important risk factor for COVID-19 illness and is associated with increased risk of development of severe disease. Additionally, there are case reports of subacute thyroiditis linked to SARS-CoV-2 infection ( 62 , 63 ). Based on the statement released from European Society of Endocrinology, patients with primary adrenal failure and congenital adrenal hyperplasia may have theoretically increased susceptibility to infection with higher risk of complications and ultimately mortality but there is no current evidence to support this ( 64 ). The dose of steroids may need to be doubled if there is a clinical suspicion of infection in these patients.

Several claims have been made regarding the impact of COVID-19 on male reproductive function, hypothesizing that COVID-19 can cause potential testicular damage either by binding directly to testicular ACE2 receptors, which are highly expressed in the testicles or by damaging the testis indirectly by exciting local immune system ( 65 ). A study comparing 81 male COVID-19 patients with 100 age matched healthy adults highlighted the presence of low testosterone levels, high levels of luteinizing hormone (LH), low testosterone/LH ratios, low Follicle stimulating hormone (FSH) to LH ratio, and raised serum prolactin. This may suggest a potential COVID-19 testicular damage affecting the Leydig cells in the testis ( 66 ). COVID-19 infected male patients may have reduced sperm count and decreased motility leading to diminished male fertility for 3 months post-infection ( 67 ).

Clinical Presentation in Specific Population

In children.

A case series of 72,314 cases published by the Chinese Center for Disease Control and Prevention reported that 0.9% of the total patients were between 0 and 9 years of age, and 1.2% of the total patients were between 10 and 19 years of age ( 68 ). The most common symptoms found in children are fever, (59%), cough (46%), few cases (12%) of gastrointestinal symptoms, and some cases (26%) showed no specific symptoms initially with patchy consolidation and ground glass opacities in CT chest findings ( 69 ). Chilblain-like acral eruptions, purpuric, and erythema multiforme-like lesions have been found to be more common in children and young adult patients mainly with asymptomatic or mild disease ( 70 ). Lymphopenia in children is relatively less common which is in direct contrast in cases of SARS in children where lymphopenia was more commonly noted ( 69 ).

Multisystem inflammatory syndrome (MIS) is another feared complication of Covid-19 seen in children. Abrams et al. systematically summarized the clinical evidence of 8 studies reporting MIS in 440 children. The median age of patients ranged from 7.3 to 10 years with 59% of all patients being male. The greatest proportion of patients had gastrointestinal symptoms (87%) followed by mucocutaneous symptoms (73%) and cardiovascular symptoms (71%) while fewer patients reported respiratory (47%), neurologic (22%), and musculoskeletal (21%) symptoms. Ferritin and d-dimer were elevated in 50% of patients, and C-reactive protein, interleukin-6, and fibrinogen were elevated in at least 75% of patients. Additionally, 100% of children with cardiovascular involvement reported elevated cardiac-damage markers such as Troponin. Although respiratory manifestation is most frequently expressed in adults, children with MIS exhibited less pulmonary symptoms and more of the other manifestations ( 71 ).

In Pregnant Women

The most common symptoms reported in pregnant women are fever (61.96%), cough (38.04%), malaise (30.49%), myalgia (21.43%), sore throat (12%), and dyspnea (12.05%). Other symptoms found in pregnant women are diarrhea and nasal congestion ( 72 ). In a systematic review including 92 patients, 67.4% manifested diseases at presentation with 31.7% having negative RT-PCR though they had features of viral pneumonia. Only one patient required admission to intensive care and 0% mortality. Fetal outcomes were reported as: 63.8% preterm delivery, 61.1% fetal distress, 80% Cesarean section delivery, 76.92% neonatal intensive care admission, 42.8% low birth weight, and 66.67% had lymphopenia ( 72 ). There was no evidence of vertical transmission. A study of 41 pregnant women with COVID-19 showed that consolidation was more commonly found in CT of pregnant women in contrast to ground-glass opacities in CT of non-pregnant adults ( 73 ). WHO also recommends encouraging lactating mothers with confirmed or suspected COVID-19 to begin or continue breastfeeding including 24-h rooming in, skin to skin contact, and kangaroo mother care especially in immediate postnatal period ( 74 ). On July 14th, 2020, Vivanti et al. published the first case of transplacental transmission of COVID-19 from a 23-years-old pregnant woman to her baby ( 75 ). Thereafter, more studies reported the possibility of the vertical transmission of COVID-19. In this context, Kotlayer et al. published a systematic review of 38 studies. Out of 936 neonates from COVID-19 mothers, 27 tested positive for the virus indicating a pooled proportion of 3.2% (2.2–4.3) for vertical transmission ( 7 ).

In Immuno-Compromised Population

Due to their impaired immune response, it is not surprising that immunocompromised patients with COVID-19 infection might be at greater risk of developing severe forms of the disease and co-infections in comparison to normal populations. Nevertheless, recent studies showed the association between cytokine storm syndrome and the overreaction of the immune system with COVID-19 raising the possibility that immunodeficient states might alleviate the overexpression of the host immune system and thereby prevent deadly forms of the disease ( 76 ). After the RECOVERY trial ( 77 ) that showed the efficacy of dexamethasone in lowering the mortality in severe forms of the disease, many questions were raised regarding whether immunocompromised patients have a greater or lower risk of developing severe forms of the disease. In order to address these questions, Minotti et al. recently published a systematic review that included 16 studies with 110 patients presenting mostly with cancer along with transplantation and immunodeficiency. Out of the 110 patients, 72 (65.5%) recovered without being admitted to the intensive care unit while 23 (20.9%) died ( 76 ). The authors concluded that immunosuppression in both children and adults seem to have a better disease course in comparison to normal population. One of the limitations of this study is that the conclusion was made only based on qualitative synthesis and no meta-analysis was performed. On the other hand, Gao et al. performed a meta-analysis on 8 relevant studies with 4,007 patients. The study showed that immunosuppression and immunodeficiency were associated with non-statistically significant increased risk of severe COVID-19 disease ( 78 ). Additionally, Mirzaei et al. summarized the clinical evidence of 252 HIV positive patients co-infected with COVID-19. The clinical manifestation did not differ from that of the general population. However, out of the 252 patients, 204 (80.9%) were male. Low CD4 count (<200 cells/mm 3 ) were reported for 23 of 176 patients (13.1%). COVID-19 symptoms were present in 223 patients with the most common symptoms of fever in 165 (74.0%) patients, cough in 130 (58.3%), headache in 44 (19.7%), arthralgia and myalgia in 33 (14.8%), gastrointestinal symptoms in 29 (13.0%) followed by sore throat in 18 (8.1%) patients ( 79 ). The number of deaths accounted for 36 (14.3%). Similar to the general population, immunocompromised, and HIV patients were no different in terms of clinical manifestation or severity. However, the results from these studies should be interpreted with caution and more studies are recommended to establish the link between this particular group of patients with severity of the disease.

Multisystem Involvement in COVID-19

As evident from the discussion above, SARS-CoV-2 can affect multiple organ systems and produce a wide array of clinical presentation of COVID-19. Certain studies conducted in Europe and United States have shown that COVID-19 can also have a multi-systemic presentation in individuals in form of a multi-system inflammatory syndrome (MIS) which has been found in both children and adults and is known as MIS-C and MIS-A, respectively ( 80 – 83 ).

According to a recent CDC report about MIS-A, it was found that only half of the patients with MIS-A had preceding respiratory symptoms of COVID-19 ~2–5 weeks before ( 80 ). The most common clinical signs and symptoms included fever, chest pain, palpitations, diarrhea, abdominal pain, vomiting, skin rash, etc. Nearly all patients had electro-cardiological abnormalities like arrythmias, elevated troponin levels, and electrocardiography evidence of left or right ventricular dysfunction. Even though most patients had minimal respiratory symptoms, chest imaging had features of ground glass opacity and pleural effusion. All patients had signs of elevated laboratory markers of inflammation, coagulation markers, and lymphopenia ( 80 ).

MIS-C can clinically mimic Kawasaki Disease ( 81 ). By the end of July, about 570 cases of MIS-C with COVID-19 were found in the United States ( 81 ). In MIS-C, there is involvement of at least four organ systems, most commonly the gastrointestinal system followed by cardiovascular and dermatological systems ( 81 ). Prominent signs and symptoms found in children with MIS-C were abdominal pain, vomiting, skin rash, diarrhea, hypotension, and conjunctival injection. The majority of the children needed ICU admission due to the development of severe complications including cardiac dysfunction, shock, myocarditis, coronary artery aneurysm, and acute kidney injury ( 81 ).

Association Between Clinical Presentations, COVID-19 Severity and Prognosis

Evaluation of 55,924 laboratory confirmed COVID-19 cases in China, the presence of dyspnea, respiratory rate ≥ 30/min, blood saturation levels ≤ 93%, PaO2/FiO2 ratio ≤ 300, lung infiltrates ≥ 50% of the lung fields between 12 and 48 h were associated with severe COVID-19 infection ( 1 ). Clinical signs suggestive of respiratory failure, septic shock, or multiple organ dysfunction/failure were associated with critical disease and poor prognosis ( 1 ). Individuals at highest risk of severe disease and deaths were patients with age > 80 years and associated co-morbidities such as underlying cardiovascular disease, diabetes, hypertension, chronic respiratory disease, and cancer ( 1 ). Another study done with 418 patients in Catalonia (Spain) showed that dyspnea was an important predictor of severe disease while confusion was an important predictor of death, and the presence of cough was strongly associated with good prognosis ( 84 ). Advanced age, male sex, and obesity were independent markers of poor prognosis while eosinophilia was a marker of less severe disease ( 84 ). The mortality was lower in patients with symptoms of diarrhea, arthromyalgia, headache, and loss of smell and taste sensations while low oxygen saturation, high CRP levels, and higher number of lung quadrants affected on Xray were found to be associated with severe disease and death ( 84 ).

COVID-19 is a viral illness which can cause multi-systemic manifestations. Review of existing literature concludes that SARS-CoV-2 can affect any organ system either directly or indirectly leading to a myriad of clinical presentation. The most commonly affected system is the respiratory system with presenting symptoms of fever, cough, and shortness of breath, etc. Other systems which can be affected in COVID-19 include ENT (sore throat, loss of taste, smell, and sensations, and rhinorrhea), cardiovascular system (chest pain, chest tightness, palpitations, and arrhythmias), gastrointestinal system (anorexia, diarrhea, vomiting, nausea, and abdominal pain), renal (proteinuria, hematuria, and acute kidney injury), neurological (headache, confusion, delirium, and altered mental status), ocular (conjunctival hyperemia, foreign body sensation in the eye, chemosis, and tearing), cutaneous (rash, papules, and urticaria), musculoskeletal system (myalgia and arthralgia), hematological (lymphopenia, thrombocytopenia, leukopenia, elevated inflammatory markers, and elevated coagulation markers), endocrine (low testosterone, low FSH, and high LH) and reproductive system (decreased sperm count and decreased sperm motility). Clinical presentation in specific populations like children, pregnant women, and immunocompromised people may vary which emphasizes the importance of further investigation in order to avoid late diagnosis of COVID-19. Severe multi-systemic involvement in COVID-19 in the form of MIS-C and MIS-A can cause significant morbidity and mortality if undiagnosed. The clinical presentations of respiratory failure, acute kidney injury, septic shock, cardiovascular arrest is associated with severe COVID-19 disease and can result in poor prognosis. In the light of exponentially growing pandemic, every patient presenting to hospital must be tested for SARS-CoV-2 by RT-PCR if resources are available to detect early presentations of diseases even if the features are atypical. Understanding of the various clinical presentations of COVID-19 will help the clinicians in early detection, treatment, and isolation of patients in order to contain the virus and slow down the pandemic.

Author Contributions

All authors have contributed equally to the work, and all agreed to be accountable for the content of the work.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We would like to thank Ms. Sairah Zia (American University of Caribbean, School of Medicine, Sint Maarten), a native speaker of English, for proofreading the manuscript.

Abbreviations

ACC/AHA/HFSA, American College of Cardiology/American Heart Association/Heart Failure Society of America; IL1B, Interleukin 1B; IFNγ, Interferon Gamma; IP10, Interferon-inducible Protein 10; MCP1, Monocyte Chemoattractant Protein 1; GCSF, Granulocyte Colony Stimulating Factor; IL2, Interleukin 2; IL7, Interleukin 7; IL10, Interleukin 10; MIP1A, Macrophage Inflammatory Protein-1 alpha; TNFα, Tumor Necrosis Factor alpha.

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Keywords: SARS-CoV-2, Covid-19, symptomatology, clinical presentation, signs and symptoms, clinical features, coronavirus

Citation: Mehta OP, Bhandari P, Raut A, Kacimi SEO and Huy NT (2021) Coronavirus Disease (COVID-19): Comprehensive Review of Clinical Presentation. Front. Public Health 8:582932. doi: 10.3389/fpubh.2020.582932

Received: 13 July 2020; Accepted: 15 December 2020; Published: 15 January 2021.

Reviewed by:

Copyright © 2021 Mehta, Bhandari, Raut, Kacimi and Huy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Nguyen Tien Huy, tienhuy@nagasaki-u.ac.jp

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• Published: 28 September 2024

Clinical presentations, systemic inflammation response and ANDC scores in hospitalized patients with COVID-19

• Jung Lung Hsu 1 , 2 , 3 , 4 ,
• Mei-Chuen Liu 5 ,
• Po-Wei Tsau 1 ,
• Fu-Tsai Chung 6 , 7 , 8 ,
• Shu-Min Lin 8 ,
• Mei-Lan Chen 9 &
• Long-Sun Ro 2  

Scientific Reports volume  14 , Article number:  22480 ( 2024 ) Cite this article

Metrics details

• Inflammation
• Neurological disorders
• Signs and symptoms
• Viral infection

The association of anosmia/ageusia with a positive severe respiratory syndrome coronavirus 2 (SARS-CoV-2) test is well-established, suggesting these symptoms are reliable indicators of coronavirus disease 2019 (COVID-19) infection. This study investigates the clinical characteristics and systemic inflammatory markers in hospitalized COVID-19 patients in Taiwan, focusing on those with anosmia/ageusia. We conducted a retrospective observational study on 231 hospitalized COVID-19 patients (alpha variant) from April to July 2021. Clinical symptoms, dyspnea grading, and laboratory investigations, including neutrophil-lymphocyte ratios (NLRs), platelet-lymphocyte ratios (PLRs), and ANDC scores (an early warning score), were analyzed. Cough (64.1%), fever (58.9%), and dyspnea (56.3%) were the most common symptoms, while anosmia/ageusia affected 9% of patients. Those with anosmia/ageusia were younger, had lower BMI, lower systemic inflammatory markers, and better ANDC scores than those without these symptoms. Female patients exhibited lower NLR values and ANDC scores compared to male patients (all p  < 0.05). Multivariable regression analysis demonstrated significant associations between NLR and CRP and ferritin levels (all p  < 0.01), and between PLR and ESR and ferritin levels ( p  < 0.01). Categorized ANDC scores significantly correlated with the total hospital length of stay (all p  < 0.05). Despite ethnic differences in the prevalence of anosmia/ageusia, our study highlights similar clinical presentations and inflammatory profiles to those observed in Western countries. The ANDC score effectively predicted hospital stay duration. These findings suggest that anosmia/ageusia may be associated with less severe disease and a lower inflammatory response, particularly in younger and female patients. The ANDC score can serve as a valuable prognostic tool in assessing the severity and expected hospital stay of COVID-19 patients.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and became a pandemic when the first cases were reported in late 2019. During the period of April 2023, more than 760 million confirmed cases of COVID-19 have been reported worldwide. Clinical symptoms of COVID-19 can range from no symptoms to critical illness characterized by acute respiratory failure requiring mechanical ventilation, septic shock and multiple organ failure 1 . The most common initial symptoms are fever, cough, sore throat, nasal congestion, dyspnea, nausea/vomiting, myalgia and diarrhea 2 . Several neurological signs/symptoms have been reported, including anosmia, ageusia, stroke, cranial nerve deficits, encephalopathy and seizures 3 . Recently, a study using digital surveillance platforms in six countries revealed that anosmia and ageusia had strong associations with self-reported positive SARS-CoV-2 tests 4 .

Although COVID-19 may present primarily as a lower respiratory tract infection transmitted via air droplets, accumulating data suggest multiorgan involvement in patients who are infected 5 . This systemic involvement is thought to be mainly due to SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2) receptors on several different human cells 6 . Several clinical features and systemic inflammatory markers could be used as predictors for poor prognosis of COVID-19 infection, such as older age, underlying comorbidities, obesity, higher neutrophil-lymphocyte ratios (NLRs), platelet-lymphocyte ratios (PLRs), D-dimer levels and ANDC scores (which stand for age (A), NLR (N), d-dimer (D) and C-reactive protein (C), an early warning score to predict mortality risk for patients with COVID-19) 7 , 8 , 9 . Some studies have been performed on the importance of anosmia/ageusia as clinical features 10 , 11 . Previous studies revealed that anosmia/ageusia may be a predictor of a milder course of COVID rather than a more severe form 12 , 13 . Moreover, olfactory disturbances appeared to have less prognostic value in predicting the severity of COVID-19 disease than systemic inflammation markers had been reported 14 . Recently, new variants of SARS-CoV-2 have different properties than the alpha variant, and omicron which has been dominant for over two years causes much less chemosensory dysfunction 15 . Because geographic variations in host predisposition to COVID-19 related anosmia/ageusia with high rates in Western countries and lower rates in East Asia had been reported 16 . In addition, clinical symptoms, comorbidities and inflammatory profile such as levels of C-reactive protein (CRP) showed a significant difference between the China and North America with COVID-19 infection 17 . It would be of interest to explore the association between the anosmia/ageusia and systemic inflammation in Taiwan and compare with previous literatures.

There are only a few studies in Taiwan that focus on clinical manifestations, including a retrospective study of the clinical features of COVID-19 among Taiwanese pediatric patients 18 . In this retrospective observational study, we aimed to elucidate the clinical features, anosmia/ageusia and systemic inflammatory markers and prognosis of patients admitted with COVID-19. We hypothesize that hospitalized COVID-19 patients with anosmia/ageusia may have different clinical presentations and prognosis.

Clinical and laboratory characteristics of hospitalized COVID-19 patients

A total of 231 patients with a confirmed diagnosis of COVID-19 based on nasopharyngeal screening and/or detection of SARS-CoV-2 by RT‒PCR were recruited. The median age was 62 years (IQR: 49–71 years), and 51.9% of patients were male. The median total score for initial symptoms was 3 (IQR: 2–4), and the first three symptoms were cough (64.1%), fever (58.9%), and dyspnea (56.3%). Anosmia/ageusia affected 9.1% of patients. The median severity of dyspnea was grade 1 (IQR: 0–2), and the median severity of CXR was 2 (IQR: 2–4). Laboratory tests revealed increased systemic inflammation, such as elevated median values of NLR, CRP, D-dimer and ferritin tests. The median value of the lowest RT‒PCR Ct value was 22.3 (IQR: 18.5–28.9). The median total length of stay was 14 days (IQR: 10–21), and approximately 10% of patients experienced in-hospital mortality. For 63.6% of patients, an antiviral agent was used, and for 33.8% of patients, a monoclonal antibody drug was used as an emergency treatment for COVID-19 infection. Table  1 depicts the detailed characteristics of all hospitalized COVID-19 patients.

To compare the clinical characteristics of the patients from the tertiary medical center and those from the district hospital, we used Wilcoxon rank-sum tests. As shown in Table  1 , there was no significant difference in median age, but there was a higher proportion of male patients in the tertiary medical center ( p  = 0.53 and 0.02, respectively). There was a significantly higher median total score of initial symptoms and a higher severity of dyspnea among the patients admitted to the tertiary medical center than among those admitted to the district hospital ( p  < 0.01 and p  = 0.02, respectively). Laboratory tests showed significantly higher WBC counts, higher median NLR, ANDC and inflammatory markers such as CRP, D-dimer and ferritin in the patients admitted to the tertiary medical center than in those admitted to the district hospital (all p  < 0.05). No significant difference was found in the lowest RT‒PCR Ct values between the different hospital settings. Regarding admission outcomes, the total length of stay was significantly longer in the patients admitted to the tertiary medical center than in those admitted to the district hospital ( p  < 0.01), but there was no significant difference in in-hospital mortality ( p  = 0.60). A significantly higher proportion of patients used antiviral agents ( p  = 0.02) and monoclonal antibodies ( p  < 0.01) in the tertiary medical centers than in the district hospitals. All these results showed that COVID-19 patients have a higher clinical severity in tertiary medical centers than in district hospitals.

Significant features in COVID-19 patients with anosmia /ageusia and gender differences

To investigate the clinical significance of anosmia/ageusia symptoms in patients with COVID-19, we compared the clinical and laboratory findings in both groups (Table  2 ). Among patients with anosmia/ageusia symptoms, there was a significant difference in median age, BMI and higher median total score of initial symptoms ( p  < 0.01, p  < 0.01 and p  = 0.01, respectively). However, COVID-19 patients with anosmia/ageusia had no significant differences of initial endotracheal intubation, severity of dyspnea, total length of stay and in-hospital mortality than those without anosmia/ageusia (all p  > 0.05). Laboratory tests showed a significantly lower values of ESR, CRP, LDH and ferritin levels in patient with anosmia/ageusia group (all p  < 0.05) but there were no significant differences in the NLR or PLR values between the two groups. A significant lower ANDC total scores were found in patients with anosmia/ageusia ( p  < 0.01). There was no significant difference in the lowest RT‒PCR Ct values between the two groups ( p  = 0.74). In terms of admission outcomes, there were no significant differences in in-hospital mortality or total length of stay. When compared the clinical features and laboratory tests between the gender difference in patients with COVID-19, no significant differences were found in age, BMI, anosmia/ageusia, total scores of initial symptoms and other clinical features (all p  > 0.05)(Table  3 ). However, significant lower values of NLR, ANDC, CRP and ferritin were found in female group (all p  < 0.01).

In addition, we examined the associations between the severity of dyspnea and clinical characteristics and the interaction between the laboratory tests. We graded the severity of dyspnea from 0 to 2 as low grade and 3 to 4 as high grade. Approximately 23.8% of patients were classified as having a high grade of dyspnea during the initial admission. The median age was 62 years in the low dyspnea severity group and 59 years in the high dyspnea severity group, with borderline significance ( p  = 0.05). The median total score of initial symptoms was significantly higher in the high severity dyspnea group than in the low severity dyspnea group, but there was no significant difference in the presence or absence of anosmia/ageusia symptoms. In the high dyspnea group, a significantly higher proportion of patients underwent endotracheal intubation during the hospital course ( p  = 0.03), but there were no associations with in-hospital mortality or total length of stay. Regarding laboratory tests, there were no significant differences in terms of the NLR or PLR, CRP, ferritin or the lowest RT‒PCR Ct values between the two groups.

Associations between systemic inflammatory markers, ANDC scores and clinical features

Finally, the NLR and PLR values for patients with COVID-19 were investigated in the current study. The NLR, PLR, ESR, CRP, D-dimer and ferritin variables were logarithmically transformed because these variables did not fit normal distributions. Regression analysis showed that the NLR and PLR were significantly associated with age, ESR, CRP, D-dimer and ferritin levels (all p  < 0.05) (Fig.  1 ). Using multivariable regression analysis, the NLR showed significant associations with CRP and ferritin levels (all p  < 0.01). The PLR had significant associations with ESR and ferritin levels ( p  < 0.01 and 0.01, respectively). The lowest RT‒PCR Ct value was not associated with the NLR or PLR ( p  = 0.08 and 0.10, respectively). The NLR and PLR did not show significant differences in relation to the Taylor scores from CXR, in-hospital mortality or in-hospital endotracheal intubation (all p  > 0.05).

The log-transformed neutrophil-lymphocyte ratio (NLR) showed significant associations with the levels of ferritin ( a ) and the levels of CRP ( b ). The platelet-lymphocyte ratio (PLR) showed significant associations with the levels of ferritin ( c ) and ESR ( d ) in patients with COVID-19.

To explore the associations between the ANDC score and clinical outcomes, Wilcoxon rank-sum tests were performed among lower, median and higher ANDC scores group and the total length of stay. Significant between group differences were found in low score group (median:11, IQR:10–14 days), moderate score group (median:14.5, IQR:11–21 days) and high score group (median:24.5, IQR:13.3–44.3) (all p  < 0.01 by post-hoc analysis). However, no significant group difference was found in in-hospital mortality ( p  = 0.73).

In this study, we presented the clinical and laboratory characteristics of hospitalized patients with COVID-19 in Taiwan from April 2021 to July 2021. Our results showed that admitted patients presented with an average of 3 initial clinical symptoms, of which 23.8% had high-grade dyspnea. 9% of COVID-19 patients presented with anosmia/ageusia. Patients admitted to the tertiary medical center had a more severe degree of COVID-19 signs and symptoms, as evidenced by a higher severity of dyspnea, higher inflammatory markers, a higher proportion of use of monoclonal antibodies as rescue therapy for COVID-19, and a longer length of hospital stay. The presence of anosmia/ageusia symptoms was associated with younger age, lower BMI and lower systemic inflammatory markers. Lower ANDC scores indicate less disease severity in patients with the presence of anosmia/ageusia symptoms. In addition, female patients with COVID-19 had less systemic inflammation as evidenced by lower levels of CRP, ferritin, NLR, and better prognostic markers as evidenced by lower ANDC scores. Finally, laboratory tests revealed that NLR and PLR had significant associations with inflammatory markers and different severity of ANDC scores revealed the difference in total length of stay.

Anosmia/ageusia is now generally recognized as a relatively early symptom and/or complication in patients with COVID-19, with highly variable outcomes between studies and wide ranges of prevalence for olfactory dysfunction (0-98%) and gustatory dysfunction (0–89%) 19,20 . After 4 months, 52.9% of patients reported partial recovery, and 2.0% reported no recovery in one study 21 . However, the geographic variations were highly significant: Caucasians had a three times higher probability of chemosensory dysfunctions (54.8%) than Asians (17.7%) 22 . The psychological impact of anosmia/ageusia on activities of daily living can be very distressing, and it is important for physicians to be aware of it, as many patients reported that their symptoms were trivialized by health care providers 23 . Psychological distress, depression and anxiety might be related to anosmia/ageusia after COVID-19 infection 24 . Currently, there is no effective treatment, but recovery is generally possible over time 25 .

In our study, we demonstrated that patients with anosmia/ageusia had a younger age, lower BMI and higher number of initial clinical symptoms, which is compatible with previous findings 10 , 22 . Besides, lower inflammatory response was found in patient with anosmia/ageusia than those without had been documented, which is compatible with our study 26 . Furthermore, a mild disease course in patients with anosmia/ageusia was also demonstrated, as revealed in those patients with lower ANDC scores. From our study, no significant differences were found in the lowest RT‒PCR Ct value between patients with anosmia/ageusia and those without, suggesting that the viral load in the blood may not represent the viral load in the nasopharyngeal mucosa. The lower inflammatory response may reveal local rather than systemic inflammation in these patients as the previous report 27 . Gender difference in COVID-19 infection had also been found as male had high risk of critical illness and mortality rate 28 , 29 . Several factors may contribute to these differences such as lifestyle, genetic factor, the role of sex hormone, comorbidities and inflammation 28 . In our study, although no significant differences were found in clinical outcomes such as total length of stay or in-hospital mortality, however, a significantly better prognosis revealed by low ANDC score was found in female. Because the ANDC score was calculated by NLR, CRP and D-dimer, lower systemic inflammatory response in female may contribute to the good outcome.

The NLR and PLR are indicators of a systematic inflammatory response and have been used in several COVID-19 studies 30 , 31 . In one study, the NLR was used as an excellent predictor of disease severity of COVID-19 infection, in-hospital mortality, risk of death or clinical course deterioration 32 . The PLR is another parameter calculated from the complete blood count and is referred to as a nonspecific marker of inflammation that is associated with increased morbidity and mortality in COVID-19 33 . In our study, both the NLR and PLR showed significant associations with other inflammatory markers, even after adjustment for multiple covariates. Moreover, an association between CRP and the NLR has been found in previous studies 34 . The combined use of CRP with NLR may lower the CRP cutoff point in distinguishing between infectious and noninfectious inflammation in hemodialysis patients 34 . However, NLR and PLR markers were not associated with in-hospital mortality, in-hospital endotracheal intubation, or total length of stay in our study. These findings may be due to the relatively small sample size in our study. In addition, the NLR and PLR were significantly associated with the severity scores of chest computed tomography in a previous study 35 . In contrast, in this study, neither the NLR nor the PLR showed significant associations with the CXR Taylor score (all p  > 0.05), which may relate to our sample size. The ANDC score had been used as prognostic marker for COVID-19 mortality. In our study, we also found that categorized the ANDC as low, moderate and high score could differentiate total length of stay in hospital.

Limitations.

The current study has several limitations. First, this study only recruited a relatively small sample of patients with COVID-19 in one tertiary medical center and one district hospital, which cannot represent all hospitalized patients in Taiwan. Nevertheless, our findings revealed the detailed clinical characteristics of admitted patients in the first surge wave of COVID-19 in 2021. Due to the early and appropriate measures conducted by the Taiwanese medical authority, the incidence of newly confirmed COVID-19 cases was lower during that time 36 . Second, we recorded initial clinical symptoms, including anosmia/ageusia symptoms, based on patients’ self-reports during history taking, which may have the potential for recall bias in this study. In addition, mild to moderate patients who might not have been admitted to the hospital, and very severe patients who initially had impaired consciousness, could not be recruited in the current study. The anomia/ageusia symptoms in these non-admitted patients could not be adequately assessed. Third, we did not perform chest computed tomography for all admitted patients. Furthermore, no vaccinations were performed on our medical staff, and therefore routine ear-nose-throat examinations or chest computed tomography imaging might have been difficult to perform for all patients at that time. In addition, no objective tests for anosmia were performed due to the lack of vaccination for medical personnel at that time, which may affect the accuracy of the reported prevalence of anosmia based solely on self-reports. Although we performed severity grading scores based on CXR and in the high dyspnea group, a significantly higher proportion of patients underwent endotracheal intubation during the hospital course. We acknowledge that this score could not totally represent the severity score from chest computed tomography. We were limited by the availability of the facility during the COVID-19 pandemic periods. However, the severity grading scores based on CXR were carefully evaluated by radiologists who were blinded to the patients’ clinical status. Nevertheless, our clinical grading system for dyspnea provided a feasible tool to assess the severity of dyspnea and showed an association with future in-hospital endotracheal intubation. These findings need to be verified by a prospective cohort study in the future.

Conclusions

We presented the clinical manifestations of hospitalized patients with COVID-19 in Taiwan during the first wave of the COVID-19 pandemic period in 2021. Patients with anosmia/ageusia had younger age, lower BMI, and lower inflammatory markers than those without anosmia/ageusia. Female patients had less severe inflammation and a better prognostic score. The prevalence of COVID-19 patients with olfactory and gustatory dysfunction showed geographic differences, but our study elucidated the clinical features and inflammatory profiles were similar. The ANDC score could be used as a prognostic marker in patients with COVID-19.

Subjects: From April 2021 to July 2021, patients admitted to two hospital wards (one tertiary medical center and one district hospital) with a diagnosis of COVID-19 based on nasopharyngeal screening and/or detection of SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (RT‒PCR) were recruited 37 . At that time, more than 95% of COVID-19 infections were caused by B.1.1.1.7 (Alpha variant), which was identified by next-generation sequencing by the laboratory of the Taiwan Centre of Disease Control ( https://www.cdc.gov.tw/EpidemicTheme/Detail/zKNFqsVWxUoUqE6fyhmBNA?archiveId=gkvCMsVNSYDHOByZjP2jkA ). Using the chart review method, we recorded demographic data, the date of onset of symptoms and clinical features. Fourteen initial clinical symptoms, such as fever (defined as a body temperature > = 37.5 °C), dry cough, sore throat, sputum production, dyspnea, myalgia, diarrhea, nausea/vomiting, nasal congestion, conjunctivitis, anosmia, ageusia, headache and impaired consciousness, were documented as present or absent and summed as the total score of initial symptoms for further analysis. Major comorbidities such as hypertension, diabetes mellitus, dyslipidemia, obesity (defined as body mass index (BMI) > = 25 kg/m 2 ), chronic obstructive pulmonary disease, chronic kidney disease, smoking, heart disease and active cancer treatment were also documented as present or absent and summed as total scores of comorbidities.

Dyspnea was classified as present or absent by the treating physician based on the patient’s subjective feeling of shortness of breath. Although the severity of dyspnea could be measured using the Borg scale 38 , it was difficult to perform this measurement for all patients with COVID-19. Rather, we graded the severity of dyspnea according to the nursing care record into 5 grades: grade 0: no dyspnea symptoms; grade 1: only one record of dyspnea during one-third of the day; grade 2: at least two records of dyspnea during two-thirds of the day; grade 3: dyspnea while performing basic daily activities all day; and grade 4: dyspnea while lying down and during preparation for intubation. We recorded the first available measurement of oxygen saturation by pulse oximetry together with the conditions under which it was measured, either room air or supplemental inspired oxygen.

Laboratory data, including total white blood cell (WBC) and differential counts, erythrocyte sedimentation rate (ESR), inflammatory markers (such as the NLR and PLR, CRP, D-dimer, ferritin), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine, lactate dehydrogenase (LDH), chest X-ray (CXR) and other imaging data, were documented at the most severe stage of the hospital course. The NLR, PLR and ANDC [Total points of ANDC = 1.14×age − 20 (years) + 1.63 ×NLR + 5.00×D − dimer(mg/L) + 0.14×CRP(mg/L)] were calculated by previous literatures 9 , 39 . The severity of ANDC was classified as lows score group (ANDC < 59), moderate score group (59 ≤ ANDC ≤ 101) and high score group (ANDC > 101) as previous literature 9 . The lowest RT‒PCR cycle threshold (RT‒PCR Ct) values were also collected and analyzed. The severity of the CXR was measured using the Taylor score; in brief, CXR findings were categorized as follows: 1 = normal; 2 = patchy atelectasis and/or hyperinflation and/or bronchial wall thickening; 3 = focal consolidation; 4 = multifocal consolidation; and 5 = diffuse alveolar changes 40 . Finally, the admission outcome was measured by length of stay, in-hospital mortality, in-hospital endotracheal intubation and emergency use of antiviral drugs such as remdesivir and/or monoclonal antibodies (such as tocilizumab, bamlanivimab, etesevimab, casirivimab and imdevimab) and a novel traditional Chinese medicine formula, Taiwan Chingguan Yihau (NRICM101) for treating COVID-19, and the medications were documented as used or not used for each patient 41 .

Institutional review board

This study was approved by the ethics review board of Chang Gung Memorial Hospital (approval number 202101086B0). The Chang Gung Memorial Hospital IRB has approved the waiver of informed consent. All methods were performed in accordance with the relevant guidelines and regulations.

Statistical analysis

Normally distributed continuous variables were assessed with the Shapiro‒Wilk test. Continuous variables were log-transformed in the statistical analysis whenever appropriate. A linear regression model was used to model the effect of the studied variables on continuous data. Data are presented as the medians and interquartile ranges (IQRs), and nonparametric tests such as the Wilcoxon rank-sum test were performed where appropriate. Pearson’s χ2 test was used for cross-tabulations. The significance level was set at 0.05. All data analyses were performed using SPSS (version 21.0, Chicago, IL).

Data availability

Data Availability: All data used in this study are included in the manuscript and will be available upon request by contacting: Prof. Long-Sun Ro.

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Hsu, J.L., Liu, MC., Tsau, PW. et al. Clinical presentations, systemic inflammation response and ANDC scores in hospitalized patients with COVID-19. Sci Rep 14 , 22480 (2024). https://doi.org/10.1038/s41598-024-73001-x

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Research Article

A SONAR report on Nirmatrelvir/ritonavir-associated rebound COVID-19: Using new databases for evaluating new diseases

Roles Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations Department of Southern Network on Adverse Reactions (SONAR), University of South Carolina, Columbia, South Carolina, United States of America, Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America

Roles Writing – review & editing

¶ ‡ JM is co-first author on this work.

Affiliation Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America

Affiliation Division of Hematology/Oncology, Department of Internal Medicine, Omaha School of Medicine University of Nebraska, Omaha, Nebraska, United States of America

Roles Project administration, Writing – review & editing

Affiliation Department of Southern Network on Adverse Reactions (SONAR), University of South Carolina, Columbia, South Carolina, United States of America

Roles Conceptualization, Writing – review & editing

Affiliations Department of Southern Network on Adverse Reactions (SONAR), University of South Carolina, Columbia, South Carolina, United States of America, Hematology/Oncology, Highland Hospital, Alameda Health System, Oakland, California, United States of America

Affiliations Department of Southern Network on Adverse Reactions (SONAR), University of South Carolina, Columbia, South Carolina, United States of America, Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine Northwestern University, Chicago, Illinois, United States of America

Affiliation Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

Affiliation City of Hope Comprehensive Cancer Center and the Beckman Research Institute, Duarte, California, United States of America

• Charles L. Bennett, 
• Joseph Magagnoli, 
• Krishna Gundabolu, 
• Peter Georgantopoulos, 
• Akida Lebby, 
• Gretchen Watson, 
• Kevin Knopf, 
• Linda Martin, 
• Kenneth R. Carson, 

• Published: September 25, 2024
• https://doi.org/10.1371/journal.pone.0308205
• Reader Comments

Introduction

In May 2022, the Centers for Disease Control and Prevention disseminated an alert advising that “a few” persons with Nirmatrelvir/ritonavir (NM/R)-associated rebound of COVID-19 infection had been identified. Three case reports appearing as pre-print postings described the first cases. Analyses in March 2023 by NM/R’s manufacturer and the Food and Drug Administration (FDA) reported no association between NM/R and COVID-19 rebound in a large phase 3 randomized clinical trial. Our study evaluated if social media databases or electronically disseminated new articles might provide insights related to the putative new toxicity, NM/R-associated COVID-19 rebound.

Information on NM/R-associated COVID-19 rebound cases was abstracted from preprint postings of non-peer-reviewed manuscripts, social media websites, electronically disseminated print and television media reports, a new FDA adverse event database for drugs that received Emergency Use Approval, and news articles in scientific journals.

Thirty-five persons experienced presumed or documented NM/R-associated COVID-19 rebound, based on information described in preprint services (n = 27), Twitter postings and related news articles (n = 7), and news articles without related Twitter reports (n = 1). These reports included information on dates of initial COVID-19 illness and rebound onset, COVID-19 testing, vaccine status, presentation, and outcome. A new FDA safety database identified 12,500 possible cases of this toxicity, but the quality of these data was poor. Preprint postings preceded peer-reviewed publications describing the same cases by four months. Social media websites including Instagram, Reddit, YouTube, the Center for Disease Control and Prevention’s (CDC) Health Alert Network, CDC Twitter, and Facebook did not provide clinically meaningful information on individual cases.

Preprint services and Twitter facilitated identification of the largest case series of NM/R-associated COVID-19 rebound. The cases were reported in non-peer-reviewed media several weeks prior to the first peer-reviewed electronically disseminated publication of one person with this diagnosis.

Citation: Bennett CL, Magagnoli J, Gundabolu K, Georgantopoulos P, Lebby A, Watson G, et al. (2024) A SONAR report on Nirmatrelvir/ritonavir-associated rebound COVID-19: Using new databases for evaluating new diseases. PLoS ONE 19(9): e0308205. https://doi.org/10.1371/journal.pone.0308205

Editor: Satish Rojekar, Icahn School of Medicine at Mount Sinai Department of Pharmacological Sciences, UNITED STATES OF AMERICA

Received: November 9, 2023; Accepted: July 18, 2024; Published: September 25, 2024

Copyright: © 2024 Bennett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: "All relevant data are within the paper and its Supporting information files."

Funding: Supported in part by the National Cancer Institute (1R01 CA102713; CLB), the Beckman Research Institute and the City of Hope Comprehensive Cancer Center, Duarte, California (CLB and STR). Part of this work was performed by CLB while he was funded as a Visiting Scholar at the City of Hope National Medical Center, Duarte, Ca.

Competing interests: The authors have declared that no competing interests exist.

In the ongoing development of COVID-19 treatments and vaccines, it is crucial to promptly recognize potential adverse effects. Our Southern Network on Adverse Reactions (SONAR) pharmacovigilance program plays a key role in this process. SONAR, funded by the state of South Carolina and the National Cancer Institute, focuses on identifying and reporting clinical information related to serious adverse drug reactions in hematology, oncology, and, since 2020, COVID-19 [ 1 ]. In a recent investigation, we utilized Twitter reports and examined the US Centers for Disease Control and Prevention’s (CDC) Vaccine Adverse Event Report System (VAERS) to identify the first fatality related to Vaccine-Induced Thrombocytopenic Thrombosis (VITT) among young women who had received the Ad26.COV2.S COVID-19 vaccine [ 2 ].

In this update, we expand the scope of SONAR to include newer data sources developed since 2000 including pre-print services, social media, a database for side effects of drugs with Emergency Use Authorization from the US Food and Drug Administration (FDA), and the CDC’s Health Alert Network which augment older databases of electronically disseminated news articles (primarily identified through Google). This expansion aims to identify potential new toxicities associated with Nirmatrelvir/Ritonavir (NM/R)-associated COVID-19 rebound [ 3 – 20 ].

NM/R, an oral antiviral granted Emergency Use Authorization (EUA) in December 2021, demonstrated efficacy in reducing risks of severe illness, hospitalization, and death for individuals 12 years of age or older with mild-to-moderate COVID-19 who had not been vaccinated or boosted. The CDC first reported Covid Rebound in May 2022, describing vaccinated and boosted individuals who developed symptomatic COVID-19 despite prior antigen negativity after NM/R treatment.

While CDC publications from late 2022 highlighted a "few NM/R COVID-19 rebound" cases, a combined analyses by the FDA and Pfizer of a randomized double-blind clinical trial did not establish a clear association between NM/R treatment and COVID-19 rebound. Our analysis allows for early identification of NM/R-associated COVID-19 rebound before peer-reviewed manuscripts were published. This initiative investigates the value of analyzing newer data sources in conjunction with older data sources to facilitate early detection of adverse events associated with a syndrome, NM/R-associated COVID-19 rebound, that was first identified in 2022.

Background and methods

We analyzed datasets containing non-peer-reviewed material describing NM/R-associated presumed or documented COVID-19 rebound cases. The search period was from the time the FDA issued an EUA in December 2021 to the time of the first peer-reviewed publication of one case of NM/R-associated COVID-19 rebound on June 20, 2022 (as an e-publication). The first data set included cases described in postings on three major pre-print websites- Research Square, medRxiv, or a PMC COVID-19 pilot project that is hosted by Elsevier Incorporated (Tables 1 and 2 ). The second data set included social media postings on Twitter (for cases and their spouses described on social media on Twitter (now X), and electronic news sites postings (for CNN News, NBC News, New York Times, Associated Press, NPR, Washington Post, Wall Street Journal, JAMA News, San Francisco Chronicle, the Daily Mail, LA Times, CDC’s Health Alert Network, and CDC’s Health Advisory Communications) using search terms “Paxlovid,” “NM/R” and “Covid Rebound” (Tables 3 and 4 ). Abstracted data included information on COVID-19 vaccine, booster status, symptoms, COVID-19 antigen status, time from COVID-19 positive test to negative tests, time from negative to second positive COVID-19 test (for documented “Covid Rebound” cases only), NM/R treatment days, days from NM/R discontinuation to COVID-19 diagnosis and/or COVID-19 positive polymerase chain reaction (PCR) test, date of NM/R re-initiation (if given), and outcome. NM/R-associated rebound was either presumed (Covid-19 antigen positive test at time of rebound) or documented (COVID-19 viral identification at time of rebound). Each of these cases had a positive antigen or PCR test at the time of the initial COVID-19 infection, a negative antigen or PCR test subsequently, and then either a positive antigen or PCR test at the time of rebound (presumed case) or virally genotyped COVID-19 at time of rebound (documented case). The case report form was validated in our prior analysis of VITT [ 2 ].

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We reviewed adverse event report information contained in FDA Adverse Event Reporting System’s (FAERS) Dashboard Database for Drugs that received EUA. We also reviewed case information on adverse reaction(s), seriousness, outcomes, gender, adverse event date, age, and medication manufacturer.

We used the key words “COVID-19,” “Paxlovid,” and “rebound” to identify and then analyze reports of NM/R-associated COVID-19 rebound which had been described on Google. Searches identified information in electronically posted news media reports. Abstracted information included media name, name of the person with COVID-19 and NM/R rebound, and the same elements evaluated in earlier disseminations on Twitter.

Two research assistants independently abstracted relevant data. Concordance was > 95%. Discrepancies were adjudicated by the Principal Investigator. Because the manuscript included no identifiable human information, it was designated as Expedited Human Subjects review (University of South Carolina IRB ID: Pro00132017).

Overall, 35 persons with presumed or documented NM/R-associated COVID-19 rebound illnesses were identified. Their median age was 53 years (range, 31 to 81 years), 45.5% were male with and in two instances gender was not provided. All 35 individuals had received at least two COVID-19 vaccinations and almost all had received an additional COVID-19 booster. NM/R treatment was for 5 days, beginning generally with the onset of symptoms and a positive PCR COVID-19 antigen test on either day 0 or 1. Rebound symptoms began a median of day 9 days after COVID-19 outset (range, 4 to 19 days) and resolved at a median of day 17 (range 6 to 28 days).

Pre-print cases (n = 27)

Among 27 NM/R-associated presumed or documented NM/R-associated COVID-19 rebound cases identified in preprint postings, investigators confirmed with whole gene sequencing techniques 19 cases of Covid-19 rebound. Among these cases the median age was 47.5 years (range, 31 to 71 years), and 38.9% were male ( Table 1 ). Pre-print sources for these 19 cases included Research Square (4 cases published in April and May 2022) and MedRxIV (15 cases published in May and June 2022). Detailed case information on all of these 19 cases was subsequently published as an e-Correspondence in the New England Journal of Medicine in September 2022 (for three cases reported initially in Research Square), two electronic publications in Clinical Infectious Diseases (in June 2022); for 14 cases reported initially in MedRxIV), and Journal of Infection (in October 2022 for three cases reported initially in MedRxIV). Three pre-print publications were posted between April 1 and June 7, 2022 [ 3 – 5 ]. The related three peer-reviewed publications appeared about 50 days later as two electronically disseminated peer-reviewed pre-prints in the journal Clinical Infectious Diseases or as one peer-reviewed e-correspondence in the New England Journal of Medicine [ 6 – 10 ]. Of note, publication of the New England Journal of Medicine (NEJM) e-Correspondence on September 7, 2022 occurred after the authors responded to two rounds of comments from peer-reviewers and the editor [ 8 ]. The e-Correspondence was initially submitted on May 12, 2022- one day before version 2 of the pre-print was posted and 11 days before the version 3 pre-print was posted [ 8 ]. Initial revisions were requested on June 2 and submitted on June 6. The second round of revisions was requested on June 20 and submitted on June 23. The final version of the e-Correspondence was accepted on July 13, 2022 and appeared in the print journal on September 7, 2022 [ 8 ]. The three pre-print versions of data from Charness, Carlin, and others that preceded the NEJM e-Correspondence were viewed 21,817 times and were downloaded 1400 times.

For these 19 individuals with confirmed NM/R- associated COVID-19 rebound, the rebound occurred about 10 days after the initial COVID-19 infection and 5 days after each individual had completed five days of NM/R treatment, involved persons of all ages, few persons had pre-existing comorbid illnesses or immunodeficiencies, and all 19 cases of confirmed NM/R-associated COVID-19 rebound survived and were not hospitalized. All 19 cases had been vaccinated twice and boosted twice against COVID-19. Most patients with documented NMN/R-associated COVID-19 rebound had no symptoms at the time of relapse. Longer- term information on the 19 cases was not reported.

An additional eight cases of presumed NM/R-associated COVID-19 rebound with viral PCR testing or rapid antigen testing were published in pre-print publications. The median age of these individuals was 55 years (range, 31 to 68 years), and 57.1% were male ( Table 2 ). Specific pre-print websites were medRxIV (1 case) and Research Square (7 cases). Three cases included in the version 1 Research Square pre-print publication NM/R-associated COVID-19 cases were also referred to in a May 2002 CDC Health Alert about NM/R-associated COVID-19 rebound. All 8 cases of presumed NM/R-associated COVID-19 rebound described in Table 2 had presented with mild symptoms, usually an upper respiratory infection, at around day 10 after the initial infection and 5 days after completing a 5-day NM/R regimen. All 8 cases survived and were not hospitalized. Longer-term information on the cases was not reported.

Social media and electronic media (n = 8 cases)

Review of posts on Twitter identified seven individuals with presumed NM/R-associated COVID-19 rebound and electronically disseminated news articles described these same persons as well as one additional person with presumed NM/R-associated COVID-19 rebound [ 21 – 36 ]. The median age of the eight individuals was 64.5 years (range 50 to 81 years), and 50% were female ( Table 3 ). In each instance individuals took NM/R for the prescribed time of five days. In two instances reports included information on the number of days before presumed “Rebound COVID-19” was diagnosed.

The first description in the United States of persons with possible COVID-19 NM/R -rebound was disseminated in social media in February 2022. Clinical information was not included in this report and therefore a diagnosis of presumed or documented NM/R-associated COVID-19 rebound could not be made. Overall, social media COVID-19 NM/R rebound case information differed amongst the four major social media sites. Many individuals reported to Facebook that NM/R provided relief from COVID-19 symptoms, that they would take NM/R again, and sought to inform others about potential NM/R downsides. YouTube and Instagram social media provided very little information about clinical symptoms among persons with COVID-19 rebound. Reddit had pretty complete information on patient symptoms. Overall, data completeness was poor for all cases reported in social media, except for Twitter reports from three physicians (Robert Wachter MD (describing his wife’s case), Peter Hotez MD PhD (describing himself), and Tatiana Powell MD (describing herself) and additional Twitter (now known as X) reports describing clinical conditions of famous individuals including President Joseph Biden, First Lady Jill Biden PhD, former Centers for Disease Control and Prevention Director Rochelle Walensky MD MPH, former Chief Medical Advisor to the President of the United States Anthony Fauci MD, and late-night television talk show host Stephen Colbert.

Detailed case information on Twitter for famous persons as well as in related electronic news releases was reviewed. Clinical information for three persons whose case information was initially disseminated on Twitter (now known as X) by three physicians who frequently report on COVID-19 issues was also reviewed. Two of these three physicians (Peter Hotez MD PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine and Tatiana Powell MD, an associate professor of oncology at the Johns Hopkins University School of Medicine) described their own clinical and laboratory findings when each of these physicians developed of presumed NM/R-associated COVID-19 rebound and the third case, Katie Wachter, was the wife of Robert Wachter MD, chair of the University of California, San Francisco’s Department of Medicine ( Table 3 ). Each of the cases had initially recovered from COVID-19 and developed presumed COVID-19 NM/R rebound. Information for each of the famous persons identified above was disseminated both on Twitter (now known as X) and on electronic news postings.

Details of the eight cases are described below

News article cases involving famous individuals (5 individuals). Four of these cases are also described in Twitter reports.

The then 79-year-old President of the United States, was vaccinated twice and boosted twice with the BNT1682 vaccine and developed a positive COVID-19 test and cold symptoms. He completed a 5-day course of NM/R, had negative COVID-19 tests, but experienced COVID-19 antigen-test positive NM/R rebound event three days later. He tested COVID-19 positive for 7 days with COVID-19 NM/R rebound before testing negative on day 12.

The then 71-year-old First Lady of the United States was vaccinated twice and boosted twice with the BNT1682 vaccine and subsequently developed COVID-19. She was treated with 5 days of NM/R, rendering her COVID-19 negative. She experienced symptomless COVID-19 NM/R rebound diagnosed by a COVID-19 positive antigen test and subsequently, after testing COVID-19 antigen negative for two consecutive days, she quarantined for five additional days and was not retreated with NM/R throughout the rebound episode.

The then 81-year-old former Head of the National Institutes of Allergy Immunology and Infectious Diseases, became COVID-19 positive despite two doses of COVID-19 vaccine and two booster doses of COVID-19 vaccine. He received 5-days of NM/R. He tested COVID-19 antigen negative for three days. On day four, he was COVID-19 antigen positive, COVID-19 NM/R rebound was diagnosed, and his symptoms were more intense than those that he experienced with initial infection. His physician prescribed a second five-day NM/R course. On day four of this course, he was still COVID-19 antigen positive. A few days later, he tested COVID-19 antigen negative.

The then 53-year-old former Director of the CDC tested COVID-19 antigen positive after previously receiving two doses of a COVID-19 vaccine and two COVID-19 vaccine boosters. The leader received a 5-day course of NM/R and tested COVID-19 antigen negative afterwards, but subsequently developed PCR-detected COVID-19 antigen positive rebound.

The then 57-year-old late night television talk show host, reported by Twitter that he had COVID-19 illness despite two vaccine doses and one booster. He was treated with 5-days of NM/R but developed a PCR-positive COVID-19 rebound.

Reports in news media on these five cases included complete information on vaccination status, COVID-19 testing information, and dates of starting and stopping NM/R. The information disseminated on Twitter was also disseminated on the same day in electronic news communications for four of the five famous individuals Rocehelle Walensky MD being the lone exception with her information not being disseminated in the print news media on the same day that it appeared on Twitter.

Twitter and news media information of persons who were not nationally famous (n = 3 cases)

Twitter described case-specific information on three persons with presumed cases of NM/R-associated COVID-19 rebound. Related clinical information for each case was reported on electronic news communications disseminated by the Journal of the American Medical Association or the San Francisco Chronicle. This follow-up information appeared between five and eight days after the initial tweeted medical information.

Robert Wachter MD, a Chairman of Medicine at the University of California at San Francisco School of Medicine reported on Twitter that his wife, Katie, who had been fully COVID-19 vaccinated and boosted, had experienced COVID-19 NM/R rebound. She tested COVID-19 antigen positive on day 0. NM/R began the following day. On day 2 of NM/R, she felt better. On day 5, she completed NM/R. On day 8, she tested COVID-19 antigen negative. A few days later presumed NM/R rebound was diagnosed. At 5-weeks follow-up, her husband reported that she had lingering “brain fog” and that she was experiencing severe fatigue.

A 45-year-old oncologist at the Johns Hopkins University School of Oncology reported on Twitter that after she had been fully vaccinated and boosted, she developed symptomatic Rapid Antigen test-positive COVID-19 infection. Eight days after completing 5 days of NM/R, she was COVID-19 positive. She tweeted that she was taking a second 5-day course of NM/R. On Day 27, negative COVID-19 Rapid Antigen Test was negative.

A 60-year old Dean of a graduate school as part of medical school, described on Twitter his own case. He received five-days of NM/R for antigen-positive COVID-19 infection. Five days later, he reported developing rhinorrhea and sore throat and a had a positive COVID-19 antigen test. He took a second 5-day NM/R treatment, and his symptoms improved. His COVID-19 antigen test returned to negative.

FAERS dashboard analysis

As of July 29, 2022, there were 4,850 de-identified FAERS reports about NM/R and disease recurrence in the new FAERS Dashboard [ 9 , 11 , 37 ]. In one instance COVID-19 recurrence was fatal, in four instances it was described as life-threatening, and in nine instances recurrence contributed to disability. In 45 instances individuals were hospitalized, in 88 cases outcomes of CIVID-19 recurrence were described as having outcomes other than death, life-threatening, disabled, hospitalized, or non-serious events, and 4703 instances of COVID-19 recurrence events were described as “non-serious” [ 37 ]. Information on number of days until NM/R-associated COVID-19 rebound symptoms occurred was generally missing. Disproportionality analysis showed that NM/R use was significantly associated with disease occurrence (relative odds risk (ROR): 212.01; 95% confidence interval (CI): 162.85–276.01). When restricting the FAERS analysis to 3129 reports from healthcare professionals, NM/R use was associated with even higher correlation with disease recurrence (ROR: 421.38; 95% CI: 273.60–648.99). Overall, NM/R-associated COVID-19 recurrence (“rebound” was not recorded in the FAERS reports) accounted for 40.4% of all NM/R adverse events reported to FAERS. Disproportionality analysis found that NM/R was significantly associated with disease recurrence, while no signal was detected for any of the other COVID-19 drugs including casirivimab/imdevimab, remdesivir, bamlanivimab, bamlanivimab/etesvimab, sotrovimab, baricitnib, bebltelovimab, cilgavimab/tixagevimab, and tocilizumab. Moreover, the FAERS analysis indicated that for most patients with NM/R-associated “disease recurrence” was “non-serious”. The authors concluded that the association between NM/R and COVID-19 disease recurrence should not be overlooked.

Summary of findings for 35 well-described presumed or documented NM/R-associated COVID-19 rebound patients

A synthesis of the findings from this case series is that NM/R-associated COVID-19 rebound is likely to be more common that initially reported by the CDC, the FDA, and Pfizer; affects males and females of all ages (most of whom do not have comorbid or immunologic illnesses), presents about five days after completing a 5-day course of NM/R; and occurs among persons who had been fully vaccinated and boosted at the time of onset. Presentation was either asymptomatic among persons who were being serially evaluated with COVID-19 viral testing or included mild or moderate symptoms, usually upper respiratory infection-like symptoms. Only three individuals were retreated with NM/R. In each instance symptoms resolved within days and in no instance were individuals hospitalized. One of these three individuals with COVID-19 rebound has developed a documented long COVID syndrome. Viral genotyping analyses for 17 persons indicated that cases of rebound NMR-associated COVID-19 did not represent mutated virus, but rather they were infected with a COVID-19 virus with the same genotype as that which was identified at time of initial infection.

Preprint services and Twitter facilitated identification of 35 cases of NM/R-associated COVID-19 rebound which were reported prior to the first peer-reviewed publication of one case of a person with this diagnosis ( S1 Table ). In these 35 cases people experienced mild upper respiratory infection like symptoms, or were asymptomatic at the time of NM/R-associated COVID-19 rebound.

Twenty seven of the 35 cases were comprehensively described in pre-prints about two months before the related information was published in peer-reviewed medical journals. Of 125,000 articles published on the pandemic within 10 months of the first confirmed case, more than 30,000 were on pre-print servers [ 38 ]. COVID-19 preprints were accessed more, cited more, and shared more on on-line platforms than non-COVID-19 preprints. COVID-19 preprints have fewer words per manuscript and reviewed faster than non-COVID-19 preprints. Most pre-prints for NM/R-associated COVID-19 rebound appeared at least five months prior to peer-reviewed publications describing similar findings.

Social media, specifically Twitter (now known as X), provided information on eight cases of NM/R-associated COVID-19 rebound. Twitter cases for four famous individuals appeared in social media on the same day that electronic news media described these cases. For three additional Twitter disseminated cases describing a Chairman of Medicine’s wife, a Dean of Tropical Medicine, and an academic oncologist, about one week elapsed before electronic print media described the cases initially described on Twitter. The three authors of tweets describing these three cases did not publish case histories in peer-reviewed medical journals. Rather, each physician frequently tweeted information on COVID-19 under their name, indicating that they felt that the best way to communicate accurate health information that they had read, analyzed, or personally collected was via tweeting this information.

One recent study found that over 2,000 physicians use Twitter, with all of these individuals “tweeting” more than once per day and having more than 300 followers each [ 39 ]. Among health care providers, Twitter has increased in popularity by allowing health care professionals to reach a brand audience that includes other physicians, medical trainees, other health care professionals and patients and is an open access source of information [ 40 – 42 ]. Twitter allows researchers and clinicians to connect and share information about interesting case studies, such as those included in this case series. Exchange of case information on Twitter can facilitate research, such as follow-on peer-reviewed case series of persons with NM/R-associated COVID-19 rebound that were electronically published in June 2022 [ 43 ].

We acknowledge that a major concern relates to the accuracy of information disseminated on Twitter. There is no systematic way to evaluate Twitter misinformation. However, independent corroborative information on six tweeted cases involving an associate professor of oncology a large medical school, a dean of a school of tropical medicine, the wife of a chairman of medicine at another large medical school, a senior person in the Biden administration and his wife, a former director an institute of the National Institute of Health, a former Director of the CDC, and a national late night talk show host. Their circumstances were also widely reported in news articles that appeared in the Washington Post, the New York Times, and in JAMA news reports.

This pharmacovigilance initiative performed well with respect to synthesizing information on 35 persons with NM/R-associated COVID-19 rebound about reporting this information about two to three months before peer-reviewed publications describing many of these same caseswere electronically or hard-copy published in peer-reviewed medical journals.

Before the first report on NM/R-associated COVID-19 rebound appeared as an e-publication in Clinical Infectious Diseases in June 2022, news media and a preprint posting from researchers at Scripps Research Institute reported that NM/R-associated COVID-19 rebound was likely to be common. A medRXIV pre-print reporting on viral kinetics of SARS-CoV-@ Omicron infection in 36 mRNA-vaccinated individuals (11 of whom were treated with NM/R). The researchers showed that NM/R treatment was associated with greater incidence of COVID-19 viral rebound compared to no treatment.

In our study, COVID-19 rebound onset occurred on aggregate within days of completing a 5-day regimen of NM/R and rarely resulted in hospitalization or long-term sequelae. Similarly, the CDC reported that review of patient information from two randomized double-blind phase II and phase III clinical trials of adult outpatients with mild to moderate COVID-19, only 1 of 77 patients treated with NM/R experienced viral rebound [ 10 ]. This person did not require in-hospital medical attention. Only three individuals reported herein with NM/R-associated COVID-19 rebound described worse clinical symptoms with the onset of COVID-19 rebound. These three individuals received second NM/R courses. All three rapidly recovered. It was reassuring that cases identified that a single omicron COVID-19 strain was present with initial infection and with subsequent rebound which is consistent with incompletely treated rather than NM/R-resistant COVID-19 infection.

Experiences described in the case series raise concern that five days may have been too short for treating COVID-19. Pfizer has initiated a trial comparing 5-days versus 10-days of NM/R among immunocompromised persons. Also, our findings do not provide insight about the duration of time for isolation that is required after a case of NM/R-associated COVID-19 rebound occurs. The authors of one large case series reported that increases in antibody and cellular immune responses occurred during rebound compared with the acute COVID-19 presentation [ 20 ]. Also, they report that there is no evidence to support the hypotheses that humoral or cellular immune responses led to symptomatic rebounds or that resistant mutations had occurred during COVID-19 rebound [ 20 ].

Our novel approach for evaluating toxicities from COVID-19 treatments or vaccines using newer data sources augmented by older data sources facilitated early identification of NM/R-associated COVID-19 rebound in this study as well as vaccine-induced thrombocytopenic purpura and other hematologic toxicities caused by novel COVID-19 vaccine associated hematologic toxicity [ 2 , 43 ]. Case information reported on Research Square preprints server were publicly disseminated two to three months earlier than the first peer-reviewed report describing these three whole genome sequenced cases of NM/R-associated COVID-19 rebound and 10 cases of assumed NM/R associated COVID-19 rebound [ 30 ]. COVID- 19 has created an increased demand for early adverse event identification that has been aided by pre-prints and social media, many of which focus on COVID-19 rebound [ 44 – 53 ]. SONAR is helping to meet that demand [ 31 ].

Since the beginning of the COVID-19 epidemic, daily social media usage per individual in the United States has averaged 65 minutes.

1998. Facebook has 190 million users in the US annually [ 45 ]. It allows its users to form groups. Once members receive access, they can interact through discussion with other members. When searching for COVID-19 adverse event discussion groups, a group entitled “Covid Vaccine–Long Haul Autoimmune Support” populated a private group with 3,600 members. The group description includes: “If you have taken the vaccine and one or more days later experienced dizziness, mental fog, heart palpitations, panic attacks, headaches, chills, weakness, tingling of skull and/or spinal cord, ER visits with perfect vitals this is the place for you”. A mean of 985 Facebook posts have occurred monthly.

2005. Reddit website has 53 million users annually in the US [ 48 ]. Reddit users submit content to the site that is voted up or down by other members. Posts are organized into “communities” or “subreddits”. Submissions with larger number of upvotes appear at the top of the posts.

2006. Twitter has 63 million users annually [ 46 ]. It allows 200 characters per “tweet.” This information can be “re-tweeted” but not modified.

2008. The CDC Twitter account has 4.7 million followers (versus 4.2 million Facebook followers and 2.6 million Instagram followers). The CDC broadcast on Twitter includes messages that are viewed as intentional, engaging, and informative about COVID-19. A unique aspect to this platform is that Twitter posts can appear at the top of a page. CDC has currently one post pinned with a tool that allows one to search the COVID-19 community level in their geographic area. There are guidelines detailing action that community members should take at each level including vaccination timing and mask wearing.

2010. Instagram has 143 million users in the US annually [ 47 ]. Its platform differs has pages but no groups. Content creators have the option to post on their feed or to add to their initial story. Feed posts remain on the profile whereas story posts disappear after 24 hours. Multiple photos can be posted in a thread, along with a caption. Discussion occurs as comments and members of the Instagram community can respond to comments from one another.

2015. CDC’s Health Alert Network (HAN) is CDC’s primary method of sharing cleared information about urgent public health incidents with public information officers; federal, state, territorial, tribal, and local public health practitioners; clinicians; and public health laboratories. CDC’s HAN collaborates with federal, state, territorial, tribal, and city/county partners to develop protocols and stakeholder relationships that will ensure a robust interoperable platform for the rapid distribution of public health information. The HAN messaging system directly and indirectly transmits Health Alerts, Advisories, Updates, and Info Services to more than one million recipients.

Pre-print of non-peer-reviewed manuscripts

2018. Research Square allows authors to share work early, gain feedback from the community, and make manuscript changes on subsequent versions of the submission prior to peer review acceptance in a journal. Over 150,000 pre-prints have been submitted to Research Square. In 2021, Research Square was purchased by Elsevier.

2018. medRxiv allows researchers to submit pre-prints to this site. This has been the primary site for pre-prints for COVID-19, peaking at 40% of all COVID-19 manuscripts in 2020 and now decreasing to 28% of all COVID-19 manuscripts in 2022.

2020. In a Pilot Project by PubMedCentral (PMC) and PubMed , authors are allowed to post pre-prints in the PubMedCentral repository if the work was produced by NIH funded research and the paper has also been submitted to a peer-reviewed journal. No revisions are allowed to be made to the submission.

FDA pilot website projects

2021. The COVID-19 EUA FAERS Public Dashboard shows Adverse Events Related to COVID-19 Products. It is a public data dashboard showing human adverse event reports for drugs and therapeutic products used under emergency use authorization (EUA) during COVID-19. It provides weekly updates of adverse event reports submitted to FAERS.

Supporting information

S1 table. 21 st century datasets utilized in evaluating nm/r-associated covid-19 rebound..

https://doi.org/10.1371/journal.pone.0308205.s001

Acknowledgments

We would like to thank Michael Charness MD for providing the authors with detailed information about the process that he and his colleagues went through as they published a Correspondence on NM/R-associated COVID-19 rebound in the New England Journal of Medicine, representing the first peer-reviewed correspondence in the medical literature.

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Acute Cerebellitis Following COVID-19: Alarming Clinical Presentation Challenged by Normal Paraclinical Findings

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• Samantha Poloni 1 ,
• Abdoulaye Hamani 1 ,
• Valentine Kassis 1 ,
• Pauline Escoffier 1 ,
• Beate Hagenkotter 2 ,
• Vincent Gendrin 1 ,
• Souheil Zayet 1 &
• Timothée Klopfenstein   ORCID: orcid.org/0000-0003-4334-9889 1  

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We report the case of an acute cerebellitis following COVID-19 in 32-year-old man who presented with a life-threatening critical cerebellar syndrome contrasting with normal paraclinical findings. Despite this fulminant critical presentation, the patient fully recovered in 37 days after early treatment with high-dose steroids and intravenous immunoglobulins. This case highlights the need for clinicians to be aware of acute cerebellitis following COVID-19, despite normal laboratory, imaging and electroencephalography findings and the importance to start appropriate treatment as soon as possible.

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Introduction

Neurological damage in the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is well described, with a wide range of symptoms such as olfactory and gustatory disorders, headache or dizziness [ 1 , 2 ]. Approximately 35% of the patients are neurologically impaired [ 3 , 4 ], and this percentage further increases in case of severe infection under intensive care [ 5 , 6 ]. Onset of neurological disorders may also appear several weeks after the acute phase and could be immune-mediated [ 7 ]. We report herein the case of an acute cerebellitis (AC), probably immune-mediated, following SARS-CoV-2 infection in an immunocompetent adult patient.

The patient’s written consent was obtained. We made sure to keep participant data confidential and in compliance with the Declaration of Helsinki of 1964 and its later amendments.

Case Presentation

A 32-years-old Caucasian man, with no past medical history, was admitted to the emergency department on 31 October 2023 because of acute dysarthria and gait disorder associated with fever (38.7 °C), without seizures or impaired consciousness or coma (Glasgow Coma Scale score 15), following headache and severe asthenia. Physical examination revealed a cerebellar syndrome, with ataxia, dysarthria and dysmetria. These appeared 2 weeks after a mild respiratory viral infection with similar cases in his family members with suspected coronavirus disease 2019 (COVID-19). The patient had no history of drug use or recent vaccination.

At admission, all routine laboratory findings were in normal ranges, including C-reactive protein (CRP) at 0.14 mg/dL. Two nasopharyngeal COVID-19 real-time polymerase chain reaction (RT-PCR) tests performed 2 days apart were weakly positive (E gene cycle threshold at 38.7 and 35.0) which confirmed a previous SARS-CoV-2 infection. Brain computed tomography angiography and subsequent brain magnetic resonance imaging (MRI) were normal (in T1, T2, fluid-attenuated inversion recovery [FLAIR] sequences, diffusion weighted imaging [DWI] and apparent diffusion coefficient [ADC] measurements).

Lumbar puncture (LP) showed clear cerebrospinal fluid (CSF) with normal pressure, minimal pleocytosis (6 white blood cells/mm 3 , 430 red blood cells/mm 3 ), normal protein level (0.31 g/L), normal glucose and negative direct examination (Table  1 ). The FilmArray ® meningitis/encephalitis panel was negative. An empiric treatment with intravenous (IV) infusions of amoxicillin 12 g daily and aciclovir 15 mg/kg/8 h was started.

On day 3, the cerebellar syndrome worsened, with severe dysarthria and ataxia. A second LP was performed showing correction of pleiocytosis with 2 white blood cells/mm 3 , increased protein level (0.52 g/L), normal glucose level, and no malignant cells. Electroencephalogram (EEG) on day 3 and MRI with angiography on day 4 were normal. Thus, a post-infectious autoimmune cerebellitis was suspected, regarding the clinical presentation in the context of a recent COVID-19. IV methylprednisolone (1 g/day) was started on day 4. Amoxicillin was stopped after confirmation of negative CSF cultures at 72 h.

On day 7, the patient was transferred to the intensive care unit (ICU) because of swallowing disorders with a Scale for Assessment and Rating of Ataxia (SARA) score of 36/40. IV immunoglobulins (IgIV) were started at a dose of 0.4 g/kg daily (28 g/day) for 5 days.

On day 8, symptoms were improving. A whole-body [18F]-fluorodeoxyglucose positron emission tomography ( 18 FDG-PET) was normal. Aciclovir was stopped following negative herpes simplex virus and varicella-zoster virus-specific PCR on follow-up LP, and steroids were also discontinued after 5 days.

On day 9, the patient was discharged from ICU to the neurology department. The only remaining symptom was ataxia, which had already started improving. Brain MRI and EEG follow-up were also normal, with no changes. He was transferred to a rehabilitation centre on day 23 with SARA score of 3/40. When he was fully discharged from hospital on day 30, he only had slight dysphonia with a SARA score of 1/40. On day 37 the patient had fully recovered, including from his dysphonia with a SARA score of 0/40. We did not observe any relapse afterwards, during a 5-month follow-up period.

COVID-19-related AC must be suspected in case of acute cerebellar syndrome which appears several days or weeks (9 weeks at most) after SARS-CoV-2 infection [ 8 , 9 ]. Our patient had initially a critical cerebellar syndrome with life-threatening risk that required critical care. Despite this fulminant critical presentation, the patient fully recovered in 37 days; our main assumption is that the patient have been quickly treated with high doses of steroids (day 4) and IgIV (day 7). This hypothesis is supported by other case reports where late initiation of treatment with steroids or IgIV (i.e. after day 7 of symptoms) affected the kinetics of symptom improvement and may lead to incomplete or delayed recovery [ 8 , 9 , 10 ].

Our case had an alarming clinical presentation challenged by normal paraclinical findings. Among the 20 patients reported with COVID-19-related cerebellitis in the Plumacker et al. cohort, 32% (6/19) had a normal brain MRI, and 61% (11/18) had no abnormality on CSF analyses [ 8 ]. Thus, AC following COVID-19 must be suspected even if laboratory and imaging findings are normal. In case of AC following COVID-19 with CSF pleiocytosis, differential diagnoses as viral or bacterial encephalitis are challenging [ 8 , 9 ]. These diagnoses must be ruled out by CSF microbiological analysis, but without delaying treatment regarding the risk of neurological sequelae [ 8 ]. Since the first case of AC following SARS-CoV-2 infection reported by Fadakar et al. in 2020, several dozen cases have been described [ 8 , 11 , 12 , 13 , 14 ], and various pathophysiological mechanisms have been described for cerebellum region damage, such as direct virus infection, immune-mediated mechanisms, or damage secondary to hypoxemia [ 8 , 11 , 12 , 13 ]. A systematic review of post-COVID cerebellitis cases reveals a male predilection, indicating a possible gender-related susceptibility [ 14 ]. In our case, cerebellar symptoms occurred 2 weeks after COVID-19, and all blood and CSF parameters were normal (including COVID-19 RT-PCR in the CSF and immunological investigations). This can lead one to diagnose a post-viral AC but cannot confirm a viral invasion of the central nervous system. On the other hand, the chronology of events (delayed onset) and the almost immediate response to steroids and immunoglobulins are in favour of an immune-mediated mechanism, but this could not be strictly confirmed because of the lack of antibodies detected in blood and CSF. In other studies, in most cases, high doses of steroids and/or IV immunoglobulins are administered with favourable results [ 8 ].

This case highlights the need for clinicians to be aware of AC following COVID-19, despite normal laboratory, imaging and EEG findings and the importance to start appropriate treatment as soon as possible.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Conceptualization, Timothée Klopfenstein; Investigation, Timothée Klopfenstein; Methodology, Timothée Klopfenstein; Resources, Samantha Poloni, Abdoulaye Hamani, Pauline Escoffier, and Valentine Kassis; Supervision, Timothée Klopfenstein. and Souheil Zayet; Validation, Timothée Klopfenstein, Souheil Zayet, Beate Hagenkotter, and Vincent Gendrin; Writing—original draft, Samantha Poloni; Writing—review and editing, Timothée Klopfenstein, Souheil Zayet, Beate Hagenkotter, and Vincent Gendrin.

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Poloni, S., Hamani, A., Kassis, V. et al. Acute Cerebellitis Following COVID-19: Alarming Clinical Presentation Challenged by Normal Paraclinical Findings. Infect Dis Ther (2024). https://doi.org/10.1007/s40121-024-01048-4

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Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis

Carlos k. h. wong.

1 Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

2 Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Janet Y. H. Wong

3 School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Eric H. M. Tang

Abraham k. c. wai.

4 Emergency Medicine Unit, Li Ka Shing, Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Associated Data

This systematic review and meta-analysis investigated the comorbidities, symptoms, clinical characteristics and treatment of COVID-19 patients. Epidemiological studies published in 2020 (from January–March) on the clinical presentation, laboratory findings and treatments of COVID-19 patients were identified from PubMed/MEDLINE and Embase databases. Studies published in English by 27th March, 2020 with original data were included. Primary outcomes included comorbidities of COVID-19 patients, their symptoms presented on hospital admission, laboratory results, radiological outcomes, and pharmacological and in-patient treatments. 76 studies were included in this meta-analysis, accounting for a total of 11,028 COVID-19 patients in multiple countries. A random-effects model was used to aggregate estimates across eligible studies and produce meta-analytic estimates. The most common comorbidities were hypertension (18.1%, 95% CI 15.4–20.8%). The most frequently identified symptoms were fever (72.4%, 95% CI 67.2–77.7%) and cough (55.5%, 95% CI 50.7–60.3%). For pharmacological treatment, 63.9% (95% CI 52.5–75.3%), 62.4% (95% CI 47.9–76.8%) and 29.7% (95% CI 21.8–37.6%) of patients were given antibiotics, antiviral, and corticosteroid, respectively. Notably, 62.6% (95% CI 39.9–85.4%) and 20.2% (95% CI 14.6–25.9%) of in-patients received oxygen therapy and non-invasive mechanical ventilation, respectively. This meta-analysis informed healthcare providers about the timely status of characteristics and treatments of COVID-19 patients across different countries.

PROSPERO Registration Number: CRD42020176589

Introduction

Following the possible patient zero of coronavirus infection identified in early December 2019 1 , the Coronavirus Disease 2019 (COVID-19) has been recognized as a pandemic in mid-March 2020 2 , after the increasing global attention to the exponential growth of confirmed cases 3 . As on 29th March, 2020, around 690 thousand persons were confirmed infected, affecting 199 countries and territories around the world, in addition to 2 international conveyances: the Diamond Princess cruise ship harbored in Yokohama, Japan, and the Holland America's MS Zaandam cruise ship. Overall, more than 32 thousand died and about 146 thousand have recovered 4 .

A novel bat-origin virus, 2019 novel coronavirus, was identified by means of deep sequencing analysis. SARS-CoV-2 was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%) 5 , both of which were respectively responsible for two zoonotic human coronavirus epidemics in the early twenty-first century. Following a few initial human infections 6 , the disease could easily be transmitted to a substantial number of individuals with increased social gathering 7 and population mobility during holidays in December and January 8 . An early report has described its high infectivity 9 even before the infected becomes symptomatic 10 . These natural and social factors have potentially influenced the general progression and trajectory of the COVID-19 epidemiology.

By the end of March 2020, there have been approximately 3000 reports about COVID-19 11 . The number of COVID-19-related reports keeps growing everyday, yet it is still far from a clear picture on the spectrum of clinical conditions, transmissibility and mortality, alongside the limitation of medical reports associated with reporting in real time the evolution of an emerging pathogen in its early phase. Previous reports covered mostly the COVID-19 patients in China. With the spread of the virus to other continents, there is an imminent need to review the current knowledge on the clinical features and outcomes of the early patients, so that further research and measures on epidemic control could be developed in this epoch of the pandemic.

Search strategy and selection criteria

The systematic review was conducted according to the protocol registered in the PROSPERO database (CRD42020176589). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline throughout this review, data were identified by searches of MEDLINE, Embase and references from relevant articles using the search terms "COVID", “SARS-CoV-2”, and “novel coronavirus” (Supplementary material 1 ). Articles published in English up to 27th March, 2020 were included. National containment measures have been implemented at many countries, irrespective of lockdown, curfew, or stay-at-home orders, since the mid of March 2020 12 , except for China where imposed Hubei province lockdown at 23th January 2020, Studies with original data including original articles, short and brief communication, letters, correspondences were included. Editorials, viewpoints, infographics, commentaries, reviews, or studies without original data were excluded. Studies were also excluded if they were animal studies, modelling studies, or did not measure symptoms presentation, laboratory findings, treatment and therapeutics during hospitalization.

After the removal of duplicate records, two reviewers (CW and CHA) independently screened the eligibility criteria of study titles, abstracts and full-texts, and reference lists of the studies retrieved by the literature search. Disagreements regarding the procedures of database search, study selection and eligibility were resolved by discussion. The second and the last authors (JW and AW) verified the eligibility of included studies.

Outcomes definitions

Signs and symptoms were defined as the presentation of fever, cough, sore throat, headache, dyspnea, muscle pain, diarrhea, rhinorrhea, anosmia, and ageusia at the hospital admission 13 .

Laboratory findings included a complete blood count (white blood count, neutrophil, lymphocyte, platelet count), procalcitonin, prothrombin time, urea, and serum biochemical measurements (including electrolytes, renal-function and liver-function values, creatine kinase, lactate dehydrogenase, C-reactive protein, Erythrocyte sedimentation rate), and treatment measures (i.e. antiviral therapy, antibiotics, corticosteroid therapy, mechanical ventilation, intubation, respiratory support, and renal replacement therapy). Radiological outcomes included bilateral involvement identified and pneumonia identified by chest radiograph.

Comorbidities of patients evaluated in this study were hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular disease, chronic kidney disease, liver disease and cancer.

In-patient treatment included intensive care unit admission, oxygen therapy, non-invasive ventilation, mechanical ventilation, Extracorporeal membrane oxygenation (ECMO), renal replacement therapy, and pharmacological treatment. Use of antiviral and interferon drugs (Lopinavir/ritonavir, Ribavirin, Umifenovir, Interferon-alpha, or Interferon-beta), antibiotic drugs, corticosteroid, and inotropes (Nor-adrenaline, Adrenaline, Vasopressin, Phenylephrine, Dopamine, or Dobutamine) were considered.

Data analysis

Three authors (CW, EHMT and CHA) extracted data using a standardized spreadsheet to record the article type, country of origin, surname of first author, year of publications, sample size, demographics, comorbidities, symptoms, laboratory and radiology results, pharmacological and non-pharmacological treatments.

We aggregated estimates across 90 eligible studies to produce meta-analytic estimates using a random-effects model. For dichotomous outcomes, we estimated the proportion and its respective 95% confidence interval. For laboratory parameters as continuous outcomes, we estimated the mean and standard deviation from the median and interquartile range if the mean and standard deviation were not available from the study 14 , and calculated the mean and its respective 95% confidence intervals. Random-effect models on DerSimonian and Laird method were adopted due to the significant heterogeneity, checked by the I 2 statistics and the p values. I 2 statistic of < 25%, 25–75% and ≥ 75% is considered as low, moderate, high likelihood of heterogeneity. Pooled estimates were calculated and presented by using forest plots. Publication bias was estimated by Egger’s regression test. Funnel plots of outcomes were also presented to assess publication bias.

All statistical analyses were conducted using the STATA Version 13.0 (Statacorp, College Station, TX). The random effects model was generated by the Stata packages ‘Metaprop’ for proportions 15 and ‘Metan’ for continuous variables 16 .

The selection and screen process are presented in Fig.  1 . A total of 241 studies were found by our searching strategy (71 in PubMed and 170 in Embase). 46 records were excluded due to duplication. After screening the abstracts and titles, 100 English studies were with original data and included in full-text screening. By further excluding 10 studies with not reporting symptoms presentation, laboratory findings, treatment and therapeutics, 90 studies 17 – 106 and 76 studies with more than one COVID-19 case 17 – 31 , 34 – 39 , 42 – 45 , 49 – 51 , 53 , 57 – 64 , 67 , 69 , 70 , 72 – 79 , 81 – 96 , 98 , 100 – 105 were included in the current systematic review and meta-analysis respectively. 73.3% 66 studies were conducted in China. Newcastle–Ottawa Quality Assessment Scale has been used to assess study quality of each included cohort study 107 . 30% (27/90) of included studies had satisfactory or good quality. The summary of the included study is shown in Table ​ Table1 1 .

PRISMA flowchart reporting identification, searching and selection processes.

Summary of 90 reviewed studies.

COVID-19 Coronavirus Disease 2019, US The United States, UK The United Kingdom, SD standard deviation, NA not available.

Of those 90 eligible studies, 11,028 COVID-19 patients were identified and included in the systematic review. More than half of patients (6336, 57.5%) were from mainland China. The pooled mean age was 45.8 (95% CI 38.6–52.5) years and 49.3% (pooled 95% CI 45.6–53.0%) of them were male.

For specific comorbidity status, the most prevalent comorbidity was hypertension (18.1%, 95% CI 15.4–20.8%), followed by cardiovascular disease (11.8%, 95% CI 9.4–14.2%) and diabetes (10.4%, 95% CI 8.7–12.1%). The pooled prevalence (95% CI) of COPD, chronic kidney disease, liver disease and cancer were 2.0% (1.3–2.7%), 5.2% (1.7–8.8%), 2.5% (1.7–3.4%) and 2.1% (1.3–2.8%) respectively. Moderate to substantial heterogeneity between reviewed studies were found, with I 2 statistics ranging from 39.4 to 95.9% ( p values between < 0.001–0.041), except for liver disease (I 2 statistics: 1.7%, p  = 0.433). Detailed results for comorbidity status are displayed in Fig.  2 .

Random-effects meta-analytic estimates for comorbidities. ( A ) Diabetes mellitus, ( B ) Hypertension, ( C ) Cardiovascular disease, ( D ) Chronic obstructive pulmonary disease, ( E ) Chronic kidney disease, ( F ) Cancer.

Regarding the symptoms presented at hospital admission, the most frequent symptoms were fever (pooled prevalence: 72.4%, 95% CI 67.2–77.7%) and cough (pooled prevalence: 55.5%, 95% CI 50.7–60.3%). Sore throat (pooled prevalence: 16.2%, 95% CI 12.7–19.7%), dyspnoea (pooled prevalence: 18.8%, 95% CI 14.7–22.8%) and muscle pain (pooled prevalence: 22.1%, 95% CI 18.6–25.5%) were also common symptoms found in COVID-19 patients, but headache (pooled prevalence: 10.5%, 95% CI 8.7–12.4%), diarrhoea (pooled prevalence: 7.9%, 95% CI 6.3–9.6%), rhinorrhoea (pooled prevalence: 9.2%, 95% CI 5.6–12.8%) were less common. However, none of the included papers reported prevalence of anosmia and ageusia. The I 2 statistics varied from 68.5 to 97.1% (all p values < 0.001), indicating a high heterogeneity exists across studies. Figure  3 shows the pooled proportion of symptoms of patients presented at hospital.

Random-effects meta-analytic estimates for presenting symptoms. ( A ) Fever, ( B ) Cough, ( C ) Dyspnoea, ( D ) Sore throat, ( E ) Muscle pain, ( F ) Headache.

For laboratory parameters, white blood cell (pooled mean: 5.31 × 10 9 /L, 95% CI 5.03–5.58 × 10 9 /L), neutrophil (pooled mean: 3.60 × 10 9 /L, 95% CI 3.31–3.89 × 10 9 /L), lymphocyte (pooled mean: 1.11 × 10 9 /L, 95% CI 1.04–1.17 × 10 9 /L), platelet count (pooled mean: 179.5 U/L, 95% CI 172.6–186.3 U/L), aspartate aminotransferase (pooled mean: 30.3 U/L, 95% CI 27.9–32.7 U/L), alanine aminotransferase (pooled mean: 27.0 U/L, 95% CI 24.4–29.6 U/L) and C-reactive protein (CRP) (pooled mean: 22.0 mg/L, 95% CI 18.3–25.8 mg/L) and D-dimer (0.93 mg/L, 95% CI 0.68–1.18 mg/L) were the common laboratory test taken for COVID-19 patients. Above results and other clinical factors are depicted in Fig.  4 . Same with the comorbidity status and symptoms, high likelihood of heterogeneity was detected by I 2 statistics for a majority of clinical parameters.

Random-effects meta-analytic estimates for laboratory parameters. ( A ) White blood cell, ( B ) Lymphocyte, ( C ) Neutrophil, ( D ) C-creative protein, ( E ) D-dimer, ( F ) Lactate dehydrogenase.

Figure  5 presents the distribution of the pharmacological treatments received for COVID-19 patients. 10.6% of patients admitted to intensive care units (pooled 95% CI 8.1–13.2%). For drug treatment, 63.9% (pooled 95% CI 52.5–75.3%), 62.4% (pooled 95% CI 47.9–76.8%) and 29.7% (pooled 95% CI 21.8–37.6%) patients used antibiotics, antiviral, and corticosteroid, respectively. 41.3% (pooled 95% CI 14.3–68.3%) and 50.7% (pooled 95% CI 9.2–92.3%) reported using Lopinavir/Ritonavir and interferon-alpha as antiviral drug treatment, respectively. Among 14 studies reporting proportion of corticosteroid used, 7 studies (50%) specified the formulation of corticosteroid as systemic corticosteroid. The remaining one specified the use of methylprednisolone. No reviewed studies reported the proportion of patients receiving Ribavirin, Interferon-beta, or inotropes.

Random-effects meta-analytic estimates for pharmacological treatments and intensive unit care at hospital. ( A ) Antiviral or interferon drugs, ( B ) Lopinavir/Ritonavir, ( C ) Interferon alpha (IFN-α), ( D ) Antibiotic drugs, ( E ) Corticosteroid, ( F ) Admission to Intensive care unit.

The prevalence of radiological outcomes and non-pharmacological treatments were presented in Fig.  6 . Radiology findings detected chest X-ray abnormalities, with 74.4% (95% CI 67.6–81.1%) of patients with bilateral involvement and 74.9% (95% CI 68.0–81.8%) of patients with viral pneumonia. 62.6% (pooled 95% CI 39.9–85.4%), 20.2% (pooled 95% CI 14.6–25.9%), 15.3% (pooled 95% CI 11.0–19.7%), 1.1% (pooled 95% CI 0.4–1.8%) and 4.7% (pooled 95% CI 2.1–7.4%) took oxygen therapy, non-invasive ventilation, mechanical ventilation, ECMO and dialysis respectively.

Random-effects meta-analytic estimates for radiological findings and non-pharmacological treatments at hospital. ( A ) Bilateral involvement, ( B ) Pneumonia, ( C ) Oxygen therapy, ( D ) Non-invasive ventilation, ( E ) Extracorporeal membrane oxygenation (ECMO), ( F ) Dialysis.

The funnel plots and results Egger’s test of comorbidity status, symptoms presented, laboratory test and treatment were presented in eFigure 1 – S5 in the Supplement. 63% (19/30) of the funnel plots (eFigure 1 – S5 ) showed significance in the Egger’s test for asymmetry, suggesting the possibility of publication bias or small-study effects caused by clinical heterogeneity.

This meta-analysis reveals the condition of global medical community responding to COVID-19 in the early phase. During the past 4 months, a new major epidemic focus of COVID-19, some without traceable origin, has been identified. Following its first identification in Wuhan, China, the virus has been rapidly spreading to Europe, North America, Asia, and the Middle East, in addition to African and Latin American countries. Three months since Wuhan CDC admitted that there was a cluster of unknown pneumonia cases related to Huanan Seafood Market and a new coronavirus was identified as the cause of the pneumonia 108 , as on 1 April, 2020, there have been 858,371 persons confirmed infected with COVID-19, affecting 202 countries and territories around the world. Although this rapid review is limited by the domination of reports from patients in China, and the patient population is of relative male dominance reflecting the gender imbalance of the Chinese population 109 , it provides essential information.

In this review, the pooled mean age was 45.8 years. Similar to the MERS-CoV pandemic 110 , middle-aged adults were the at-risk group for COVID-19 infections in the initial phase, which was different from the H1N1 influenza pandemic where children and adolescents were more frequently affected 111 . Biological differences may affect the clinical presentations of infections; however, in this review, studies examining the asymptomatic COVID-19 infections or reporting any previous infections were not included. It is suggested that another systematic review should be conducted to compare the age-specific incidence rates between the pre-pandemic and post-pandemic periods, so as to understand the pattern and spread of the disease, and tailor specific strategies in infection control.

Both sexes exhibited clinical presentations similar in symptomatology and frequency to those noted in other severe acute respiratory infections, namely influenza A H1N1 112 and SARS 113 , 114 . These generally included fever, new onset or exacerbation of cough, breathing difficulty, sore throat and muscle pain. Among critically ill patients usually presented with dyspnoea and chest tightness 22 , 29 , 39 , 72 , 141 (4.6%) of them with persistent or progressive hypoxia resulted in the requirement of intubation and mechanical ventilation 115 , while 194 (6.4%) of them required non-invasive ventilation, yielding a total of 11% of patients requiring ventilatory support, which was similar to SARS 116 .

The major comorbidities identified in this review included hypertension, cardiovascular diseases and diabetes mellitus. Meanwhile, the percentages of patients with chronic renal diseases and cancer were relatively low. These chronic conditions influencing the severity of COVID-19 had also been noted to have similar effects in other respiratory illnesses such as SARS, MERS-CoV and influenza 117 , 118 . Higher mortality had been observed among older patients and those with comorbidities.

Early diagnosis of COVID-19 was based on recognition of epidemiological linkages; the presence of typical clinical, laboratory, and radiographic features; and the exclusion of other respiratory pathogens. The case definition had initially been narrow, but was gradually broadened to allow for the detection of more cases, as milder cases and those without epidemiological links to Wuhan or other known cases had been identified 119 , 120 . Laboratory investigations among COVID-19 patients did not reveal specific characteristics—lymphopenia and elevated inflammatory markers such as CRP are some of the most common haematological and biochemical abnormalities, which had also been noticed in SARS 121 . None of these features were specific to COVID-19. Therefore, diagnosis should be confirmed by SARS-CoV–2 specific microbiological and serological studies, although initial management will continue to be based on a clinical and epidemiological assessment of the likelihood of a COVID-19 infection.

Radiology imaging often plays an important role in evaluating patients with acute respiratory distress; however, in this review, radiological findings of SARS-CoV-2 pneumonia were non-specific. Despite chest radiograph usually revealed bilateral involvement and Computed Tomography usually showed bilateral multiple ground-glass opacities or consolidation, there were also patients with normal chest radiograph, implying that chest radiograph might not have high specificity to rule out pneumonia in COVID-19.

Limited clinical data were available for asymptomatic COVID-19 infected persons. Nevertheless, asymptomatic infection could be unknowingly contagious 122 . From some of the official figures, 6.4% of 150 non-travel-related COVID-19 infections in Singapore 123 , 39.9% of cases from the Diamond Princess cruise ship in Japan 124 , and up to 78% of cases in China as extracted on April 1st, 2020, were found to be asymptomatic 122 . 76% (68/90) studies based on hospital setting which provided care and disease management to symptomatic patients had limited number of asymptomatic cases of COVID-19 infection. This review calls for further studies about clinical data of asymptomatic cases. Asymptomatic infection intensifies the challenges of isolation measures. More global reports are crucially needed to give a better picture of the spectrum of presentations among all COVID-19 infected persons. Also, public health policies including social and physical distancing, monitoring and surveillance, as well as contact tracing, are necessary to reduce the spread of COVID-19.

Concerning potential treatment regime, 62.4% of patients received antivirals or interferons (including oseltamivir, lopinavir-ritonavir, interferon alfa), while 63.9% received antibiotics (such as moxifloxacin, and ceftriaxone). In this review, around one-third of patients were given steroid, suggestive as an adjunct to IFN, or sepsis management. Interferon and antiviral agents such as ribavirin, and lopinavir-ritonavir were used during SARS, and the initial uncontrolled reports then noted resolution of fever and improvement in oxygenation and radiographic appearance 113 , 125 , 126 , without further evidence on its effectiveness. At the time of manuscript preparation, there has been no clear evidence guiding the use of antivirals 127 . Further research is needed to inform clinicians of the appropriate use of antivirals for specific groups of infected patients.

Limitations of this meta-analysis should be considered. First, a high statistical heterogeneity was found, which could be related to the highly varied sample sizes (9 to 4226 patients) and study designs. Second, variations of follow-up period may miss the event leading to heterogeneity. In fact, some patients were still hospitalized in the included studies. Third, since only a few studies had compared the comorbidities of severe and non-severe patients, sensitivity analysis and subgroup analysis were not conducted. Fourthly, the frequency and severity of signs and symptoms reported in included studies, primarily based on hospitalized COVID-19 patients were over-estimated. Moreover, different cutoffs for abnormal laboratory findings were applied across countries, and counties within the same countries. Lastly, this meta-analysis reviewed only a limited number of reports written in English, with a predominant patient population from China. This review is expected to inform clinicians of the epidemiology of COVID-19 at this early stage. A recent report estimated the number of confirmed cases in China could reach as high as 232,000 (95% CI 161,000, 359,000) with the case definition adopted in 5th Edition. In this connection, further evidence on the epidemiology is in imminent need.

Supplementary information

Acknowledgements, author contributions.

C.W., J.W. and A.W. contributed equally to all aspects of study design, conduct, data interpretation, and the writing of the manuscript. C.W., E.T. and C.H.A. contributed to eligibility screening, data extraction from eligible studies, and data analysis and interpretation.

There was no funding source for this study.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Carlos K. H. Wong and Janet Y. H. Wong.

is available for this paper at 10.1038/s41598-020-74988-9.

• Open access
• Published: 27 September 2024

Changes in incidence and clinical features of tuberculosis with regard to the COVID-19 outbreak in Southern Iran

• Mohammad Javad Fallahi 1 , 2 ,
• Mohammad Nazemi 3 ,
• Ali Zeighami 3 &
• Reza Shahriarirad 1 , 3  

BMC Infectious Diseases volume  24 , Article number:  1043 ( 2024 ) Cite this article

Metrics details

Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a significant global health threat. It results in substantial mortality and may be underrecognized due to insufficient screening and diagnostic challenges. Furthermore, TB’s impact is closely linked to complex socioeconomic and healthcare factors. The COVID-19 pandemic has exacerbated these challenges due to similarities in clinical presentation and transmission dynamics with TB. Socioeconomic factors such as limited access to healthcare services, resource constraints, and social stigma further complicate TB management. Historically, TB faced increased burdens during natural disasters, wars, and pandemics. This study analyzes TB incidence changes, emphasizing the crucial need for timely diagnosis within the context of COVID-19 measures.

This cross-sectional study, conducted at Shiraz’s TB referral center in Southern Iran, covered the period from January 1, 2018, to December 31, 2022. We analyzed patient data, including epidemiological and demographic factors, clinical and radiological features, and treatment outcomes. Data were compared between the pre-COVID-19 pandemic era and the COVID-19 pandemic era (from March 2020), using standard and regression analyses. A P-value of less than 0.05 was considered statistically significant.

We analyzed 388 TB patients with a mean age of 48.38 ± 20.53 years, including 264 pulmonary cases (68.0%). The highest incidence of TB was recorded in 2019, representing 27.6% of the cases. During the COVID-19 era, logistic regression analysis identified significant associations with higher education levels ( P  = 0.032; OR = 1.380; 95% CI: 1.028–1.851), a decrease in symptoms such as sputum production ( P  = 0.004; OR = 0.342; 95% CI: 0.166–0.705) and chills ( P  = 0.036; OR = 0.282; 95% CI: 0.087–0.919), and an increase in symptoms of fatigue ( P  = 0.006; OR = 2.856; 95% CI: 1.358–6.005).

The COVID-19 pandemic has had a prolonged impact on TB cases in our country, resulting in a reduction in reported cases due to challenges in quarantine and screening. However, it has also led to a shift in TB patterns and a potential increase in latent TB cases and future mortality rates. Addressing the repercussions requires enhanced control strategies, prioritized service delivery, and secured funding for intensified case finding, expanded contact-tracing, community engagement, digital health tools, and uninterrupted access to medications.

Peer Review reports

In the ever-evolving landscape of global health challenges, Tuberculosis (TB) remains one of the most contagious and hazardous diseases, influenced by a complex array of interconnected factors [ 1 ]. This holds especially true in developing countries such as Iran, where the nature of the disease adds layers of complexity to its prevalence and patterns. TB’s reach extends beyond microbial dynamics, intertwining with socioeconomic, geopolitical, and healthcare realities unique to the region. Healthcare workers in low- and middle-income countries are particularly at risk of contracting tuberculosis, with several reports documenting a substantial burden and predominantly poor outcomes among these workers [ 2 , 3 , 4 , 5 ].

In 2015, the TB incidence rate in Iran was 16 per 100,000 people, decreasing to 14 per 100,000 in 2016 and 2017 [ 6 , 7 , 8 ]. The cost of treating a new smear-positive TB patient is approximately USD 1,409 [ 9 ]. A 2019 systematic review and meta-analysis found that healthcare workers in northern and western Iran had the highest prevalence of latent TB, which is asymptomatic and controlled by the immune system [ 10 , 11 ]. Iran’s extensive borders with high TB-burden countries—such as Azerbaijan, Turkmenistan, Armenia, Pakistan, Afghanistan, and Iraq—combined with increased immigration and travel, complicate efforts to control TB [ 12 , 13 , 14 , 15 , 16 , 17 ].

For policymakers, clinicians, and the public health community, understanding the nature of TB is not merely an academic pursuit but a crucial imperative. As we delve into the intricate dance of variables shaping TB’s course in this endemic setting, it becomes clear that effective policies, informed clinical practices, and targeted public health interventions must continually adapt to keep pace with the shifting dynamics of this resilient infectious disease. In this context, the COVID-19 pandemic has undoubtedly been one of the most influential factors affecting TB management, incidence, and patterns. This influence extends from similarities in clinical and paraclinical features and transmission methods to social stigma and changes in healthcare adaptations such as social distancing, quarantines, and hospital policies [ 18 ].

Throughout history, TB has faced increased burdens due to disruptions from natural disasters, wars, and infectious pandemics. The Russian flu of 1889 and the Spanish influenza of 1918 increased TB-related mortality [ 19 ]. During both World Wars, TB was attributed to a quarter of the deaths [ 20 ]. The HIV pandemic in 1980 saw TB as an opportunistic infection leading to widespread mortality [ 21 ]. Additionally, outbreaks such as the 2001 Severe Acute Respiratory Syndrome (SARS) in Hong Kong, the 2013–2016 Ebola outbreak in West Africa, and the 2014 Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Saudi Arabia impacted TB programs, escalating disease burden and mortality in the affected regions in the following years [ 22 , 23 , 24 ].

he responses to TB and COVID-19 involve complex interactions across various levels of prevention, diagnosis, and treatment [ 25 , 26 , 27 , 28 , 29 ]. A modeling analysis from the STOP TB Partnership indicates that the COVID-19 pandemic is severely disrupting TB services, impacting prevention, detection, and treatment efforts [ 30 ]. This disruption is most noticeable in resource-limited settings but also affects wealthier regions [ 30 ]. As a result, future increases in TB incidence and mortality are expected, potentially jeopardizing progress and delaying the goals of the End TB Strategy [ 30 ]. The potential use of platforms like Xpert for TB diagnosis offers benefits, but during the COVID-19 emergency, there is a risk that existing diagnostic equipment may be redirected away from TB. Protective gear is essential for laboratory personnel handling viral samples [ 25 , 26 ]. Cough is a key symptom for diagnosing TB, but its presence alongside other symptoms like fever complicates distinguishing TB from COVID-19 and other respiratory infections, especially in the absence of effective diagnostic tools [ 25 ]. Physical distancing measures may hinder active case finding and community-based TB and HIV management in high-burden areas, though they could help reduce TB transmission, as seen with influenza [ 27 , 31 , 32 ]. Additionally, both clinical and programmatic TB treatment approaches, including drug procurement, particularly for second-line drugs, may be adversely affected. The anticipated economic crisis post-COVID-19 may exacerbate poverty, social unrest, and malnutrition, further increasing TB incidence and mortality [ 33 , 34 , 35 ].

Tadolini et al. [ 25 ] reported the first cohort among 49 active TB and COVID-19 co-infection cases, in which 38.8% of patients, COVID-19 appeared during anti-TB treatment, potentially due to inadequate protection against SARS-CoV-2, which also impacted two healthcare workers. Diagnoses of TB and COVID-19 were made either simultaneously or within seven days in nine patients, complicating differential diagnosis; clinical assessments for COVID-19 might have facilitated the identification of pre-existing TB, although the role of COVID-19 in TB pathogenesis remains unclear. In 14 patients, COVID-19 was diagnosed before TB, highlighting the need for larger studies to explore if SARS-CoV-2 affects the progression of latent TB to active disease. Symptoms overlap may have led to earlier COVID-19 diagnosis, potentially revealing TB at an earlier stage. Additionally, seven patients with TB sequelae developed COVID-19, presenting higher mortality rates and multiple comorbidities, underscoring the need for further research into the impact of TB sequelae. The pandemic has also significantly impacted the healthcare system, particularly affecting hospital admissions and ICU capacity. Data on BCG vaccination are limited, with information available for only 30 patients, of whom 19 had been previously vaccinated; therefore, no definitive conclusions about its protective role can be drawn. Furthermore, there is currently no data available on drug–drug interactions.

Given the similarities in clinical presentations and transmission methods between COVID-19 and TB, it is crucial not to neglect timely TB diagnosis, especially in the context of the COVID-19 pandemic, which involves quarantine and self-isolation. The decline in routine care center visits and also misdiagnose of Coronavirus instead of TB may lead to under diagnose of actual TB prevalence rates and isolating rules and quarantine could aid in breaking the transmission chain of mycobacterium tuberculosis. Our previous research explored the potential impact of the COVID-19 pandemic on TB [ 18 ]. Based on our primary hypothesis and concerns, we analyzed changes in TB patterns and presentations before and after the COVID-19 era. We also aim to highlight how the COVID-19 pandemic and associated policies have affected TB patterns in our province. By examining these aspects, our research provides valuable insights into managing and preventing both TB and COVID-19, offering a nuanced understanding that will help address future public health challenges in infectious disease management.

Material and method

This cross-sectional study was conducted at the TB referral center in Shiraz, Southern Iran, from January 1, 2018, to December 31, 2022. Our center is the primary treatment facility for TB cases in the province. All patients diagnosed with TB, including those with concurrent HIV infection, are documented and followed up. Inclusion criteria included all patients with a confirmed diagnosis of TB, according to the WHO and national TB standard diagnostic guidelines [ 36 ], including pulmonary smear results or radiological/clinical features suggestive of TB, during the specified period. There were no age restrictions or specific exclusion criteria for this study.

Patient data were extracted from their records and included epidemiological and demographic factors, clinical and radiological features, and treatment outcomes Patient information was anonymized by removing identifying details, and each patient was assigned a unique number to ensure confidentiality.

Data were entered into SPSS version 26.0 for analysis. Normally distributed variables were reported as means with standard deviations (SD), non-normally distributed variables as medians with interquartile ranges (IQR), and categorical variables as percentages (%). The Chi-square test was used for evaluating categorical variables, while the independent t-test and analysis of variance (ANOVA) were used for continuous variables with normal distribution. The Mann-Whitney U test and Kruskal-Wallis test were used for continuous variables with non-normal distribution. Bonferroni correction was applied for pairwise comparisons in the ANOVA test for continuous variables. Data were compared between the pre-COVID-19 pandemic era and the COVID-19 pandemic era (from March 2020 to the end of the study). Logistic regression analysis was performed to assess associations between dependent variables and the factors evaluated in our study. 95% confidence intervals (95% CI) were calculated for all applicable estimates. Missing data were addressed using appropriate imputation techniques, and valid percentages/values were reported to ensure the robustness of the analysis. A P-value of less than 0.05 was considered statistically significant.

Our study covered the period from January 1, 2018, to December 31, 2022, encompassing five years. During this period, a total of 388 patients with a confirmed diagnosis of TB were included, with a mean age of 48.38 ± 20.53 years. Of these patients, 233 (60.2%) were male and 154 (39.8%) were female. As shown in Fig.  1 , the highest number of TB cases occurred in 2019, with 107 cases (27.6%). This was followed by 2018 with 93 cases (24.0%), 2022 with 67 cases (17.3%), 2020 with 61 cases (15.7%), and 2021 with 60 cases (15.5%).

Frequency of tuberculosis cases throughout the years. Yellow indicator marks the start of the Corona-virus pandemic in Shiraz, Southern west Iran

Among the 388 patients in our study, 264 (68.0%) had pulmonary TB, while 124 (32.0%) had extrapulmonary TB, with no cases of concurrent pulmonary and extrapulmonary involvement. For the purpose of our analysis, we focused on pulmonary TB cases and compared their characteristics over the years. Supplementary Table 1 presents a comparison of the epidemiological and clinical features of pulmonary tuberculosis in our study. The lowest number of pulmonary TB cases was observed in 2020, which coincides with the onset of the COVID-19 pandemic in Iran.

Based on the ANOVA test, there was no significant association between the years and the average age of TB patients. However, post-hoc tests revealed that patients in 2021 were significantly older than those in 2018 ( P  = 0.044) and 2019 ( P  = 0.030), with no significant difference compared to 2020 ( P  = 0.057) or 2022 ( P  = 0.302). There was a significant increase in the proportion of non-Iranian TB patients over the years ( P  = 0.03).

Significant changes were noted in symptom patterns over time. Notably, there was a relative decrease in hemoptysis and a relative increase in fatigue from 2018 to 2022. Variations were also observed in symptoms such as sputum production, weight loss, dyspnea, and chills. Additionally, significant changes were observed in the X-ray pattern of upper right lung involvement throughout the study period.

We further analyzed data by dividing the study period into pre-COVID-19 (before March 2020) and COVID-19 eras. Among the pulmonary and extrapulmonary TB cases, 216 (55.7%) were identified in the pre-COVID-19 era, while 172 (44.3%) occurred during the COVID-19 era. We compared pulmonary TB cases between these two periods, with results presented in Table  1 .

As demonstrated in Table  1 , following the COVID-19 pandemic, there was a significant increase in the number of non-Iranian TB cases. Additionally, there was a notable decrease in symptoms such as sputum production, chills, and hemoptysis, while symptoms including weight loss, dyspnea, and fatigue increased. The proportion of abnormal X-rays also rose from 77.9 to 88.2%, and the average treatment duration decreased.

We assessed the trends between the two time points based on the variables included in our study. Logistic regression analysis revealed significant associations with several factors: higher education levels ( P  = 0.032; OR = 1.380; 95% CI: 1.028–1.851), a decrease in symptoms such as sputum production ( P  = 0.004; OR = 0.342; 95% CI: 0.166–0.705) and chills ( P  = 0.036; OR = 0.282; 95% CI: 0.087–0.919), and an increase in symptoms of fatigue ( P  = 0.006; OR = 2.856; 95% CI: 1.358–6.005).

TB is a complex health challenge influenced by diverse factors, exhibiting varied patterns. We previously discussed the potential effects of the COVID-19 pandemic and TB [ 18 ], and following our primary hypothesis and concern, we opted to compare the changes in TB pattern and presentations before and after the COVID-19 era, which as demonstrated, aligned with our primary concern that the COVID-19 pandemic caused slight changes in TB patterns.

The first notable change was the decrease in the number of cases during late 2019 and early 2020. Based on the WHO 2023 global tuberculosis report [ 1 ], a significant drop of 18% in the incidence of TB cases was observed in 2019 and 2020, following an increase in cases from 2017 to 2019, from 7.1 million to 5.8 million, with a partial recovery to 6.4 million in 2021, and 7.5 million in 2022. The rebound in TB cases in 2022, exceeded the pre-COVID level of 7.1 million cases in 2019, and was characterized as the highest number of newly diagnosed TB cases recorded in a single year. This represented the most significant annual total since the WHO initiated global TB monitoring in the mid-1990s [ 1 ]. This pattern corresponds with the pattern of TB cases in our report, with a peak in number of cases in 2019, followed by visible drop in 2020 (by 15.5%) and an increase towards 2022. We believe that this trend may be the result of delayed diagnosis following the COVID-19 pandemic, which covers a considerable backlog of people who developed TB in previous years. However, WHO reported a narrowing of the global gap between TB incidence and newly detected cases from 4 million in 2020 and 2021, to 3.1 million in 2022, which is relatively similar to the pre-pandemic period [ 1 ]. Anticipating a rise in TB cases in our province, healthcare workers and policymakers must prioritize effective treatment, early diagnosis, and comprehensive measures to address this emerging public health challenge.

Studies revealed an average 5% decrease in TB mortality rates between 2000 and 2018, in which TB maintained the highest death rate among single infectious pathogenic factors, even surpassing HIV. However, in 2022, this dynamic shifted as TB was surpassed by COVID-19 [ 1 , 37 ]. As per WHO global reports, an observed decrement of 19% in TB mortality rates spanning the years 2015 to 2022 denotes a noteworthy trend. However, it is crucial to note that this decline, albeit commendable, remains insufficient in meeting the predetermined WHO End TB Strategy milestone of a 75% reduction by the year 2025 [ 1 ]. The mortality rate in our study was 7.6%, however the mortality rate did not significantly defer during our study period. However, an intriguing trend emerged when comparing specific years, revealing a decrease from 9.2% in 2019 to 5.1% in 2020 and 5.7% in 2021. This decline may be attributed to the misclassification of TB cases, where individuals, especially those who died before receiving medical care and investigations, who succumbed to TB or other pulmonary symptoms, were inaccurately labeled as COVID-19 cases. This misattribution potentially contributed to the observed reduction in recorded mortality rates. Early detection of TB, especially in multidrug-resistant tuberculosis, is vital [ 38 ]. Significance lies in the timely diagnosis, impacting both the individual’s disease prognosis and the potential transmission within the community, thereby influencing the reproductive rate of the TB epidemic [ 39 , 40 ].

In high-burden areas, tuberculosis deaths could increase by up to 20% over 5 years due to the COVID-19 pandemic. Delays in timely diagnosis and treatment, resulting from prolonged COVID-19 interventions, may lead to a loss of life-years comparable to the direct impact of COVID-19 in regions with significant malaria and HIV/tuberculosis epidemics. Prioritizing critical prevention activities and healthcare services for HIV, tuberculosis, and malaria is vital to mitigate the overall impact of the COVID-19 pandemic [ 41 ]. It is evident that age and co-morbidities, such as HIV co-infection, poverty, diabetes, and malnutrition, are key factors influencing mortality in COVID-19, which these determinants also play a role in the mortality associated with TB [ 42 ]. Studies also indicate that TB and COVID-19 form a concerning combination, requiring urgent attention. TB should be recognized as a potential contributor to severe cases of COVID-19, and individuals with TB should be given priority in COVID-19 preventive measures, such as vaccination [ 43 ].

The emergence of the highly transmissible COVID-19 variants and severe vaccine access disparities—where less than 15% of people in low-income countries had received a dose by March 2022—led to additional COVID-19 waves in 2022 and beyond. Without a global vaccination effort, LMICs struggled to control the pandemic effectively [ 44 ]. As a result, the impact of COVID-19 on tuberculosis exceeded previous predictions, underscoring ongoing global neglect and making it unlikely that the End TB Strategy targets will be met by 2030 [ 45 ]. A study by Migliori et al. in 2020 reported that TB services across 43 centers in 19 countries experienced significant disruptions due to the COVID-19 pandemic [ 29 ]. The total number of TB cases dropped from 32,898 in 2019 to 16,396 in 2020, with a sharp decline beginning in March 2020, coinciding with lockdowns in many countries. This decline was observed globally, except in Australia, Singapore, and Virginia. Similarly, drug-resistant TB cases decreased from 4,717 in 2019 to 1,527 in 2020, starting in March, and TB-related hospital discharges also fell dramatically after an initial increase in early 2020. TB deaths decreased overall but rose in May 2020, possibly due to misattribution to COVID-19 or under-reporting. Newly diagnosed TB cases in outpatient clinics fell from 7,364 in 2019 to 5,703 in 2020, with a notable drop in March 2020. Despite fewer outpatient visits, telehealth usage surged in 2020, reflecting adaptations to pandemic-related challenges. Diagnoses of TB infection and the number of tests performed also declined. The study also evaluated the impact of COVID-19 on TB services across 19 countries in 2020, compared to 2019, found a significant decrease in both TB cases and drug-resistant TB diagnoses [ 29 ]. This decline is attributed to reduced access to care, lockdowns, and delayed reporting. While most countries, especially those with high TB burden, experienced these reductions, Australia and Virginia (USA) reported a modest increase in TB notifications due to enhanced surveillance [ 46 , 47 , 48 ]. Even in countries with low TB incidence, such as Italy, France, and Spain, TB cases declined. The drop in TB deaths in 2020 was accompanied by an increase in May and July, likely due to misattribution to COVID-19 and other issues like under-reporting. Telehealth services increased significantly in response to distancing measures [ 49 ]. The study highlights the severe disruptions in TB care caused by the pandemic and emphasizes the need to reallocate resources to prepare for a potential TB resurgence.

The reduction of TB in Iran has been significantly influenced by free treatment, heightened public awareness, improved hygiene practices, the establishment of new TB research centers, and enhanced access to faster and more accurate TB diagnostics [ 50 ]. TB healthcare services and centers in our province were still active during the COVID-19 pandemic, while this was not the case in many other countries where healthcare personnel engaged in TB management have been redeployed to address the COVID-19 emergency. Findings from 33 centers across 16 countries on five continents revealed a decline in attendance at tuberculosis centers during the initial four months of the 2020 pandemic compared to the same timeframe in 2019. Resource allocation was one of the most vital aspects of the pandemic to guarantee the uninterrupted provision of tuberculosis care throughout the ongoing pandemic [ 51 ]. Even brief interruptions can result in sustained rises in TB incidence and mortality. The WHO and specialized scientific publications anticipate a detrimental impact of the COVID-19 pandemic on the global TB epidemic [ 7 , 52 , 53 ]. This is attributed to increased strain on healthcare systems due to COVID-19, potentially weakening National TB programs [ 28 ]. Cilloni et al.‘s modeling analysis suggests that a 50% reduction in TB transmission during lockdowns, followed by a 3-month service suspension and 10-month recovery, may lead to an extra 1.19 million TB cases and 361,000 deaths in India over 5 years. Kenya could see 24,700 cases and 12,500 deaths, and Ukraine, 4,350 cases and 1,340 deaths. The buildup of undetected TB during lockdowns is a major concern. Rapid restoration of TB services and implementing targeted “catch-up” interventions post-lockdown are vital for preventing long-term increases in TB burden and mitigating negative consequences of disruptions [ 54 ].

Political commitment, strategic planning, community mobilization, and research and development are essential in combating both TB and COVID-19. Effective TB control relies on sustainable treatment programs, while addressing pandemics like COVID-19 requires robust emergency response capabilities. Prompt action to manage COVID-19 at early stages can enhance preparedness and resource allocation [ 55 ]. Efficient triage and isolation of cases help optimize healthcare resources, prevent system overload, and control epidemic spread [ 28 ]. Shortages of staff, protective equipment, tests, and drugs are longstanding issues in TB management, and these challenges have now extended to other programs and systems due to COVID-19. The pandemic is expected to impact lung health significantly, potentially leading to a rise in TB cases in the coming years. It has already caused delays in achieving the End-TB Strategy goals, necessitating increased focus and investment in TB control [ 56 ]. On the other hand, COVID-19 is transforming TB management by accelerating the adoption of digital innovations that ease the workload of healthcare workers [ 56 ]. The pandemic has also highlighted existing vulnerabilities in TB management, underscoring the need for innovation and digital solutions to address these issues and regain momentum in TB control efforts [ 56 ].

The surge in TB cases in Iran has been a subject of concern, and our research has revealed a noteworthy increase in non-Iranian TB patients throughout the years. Particularly, a substantial proportion of immigrants in Iran originate from Afghanistan, a country with a high incidence of TB, including neighboring Pakistan, which ranks among the nations with the highest TB cases globally. A spatio-temporal study in Pakistan identified northern and western regions as high-risk TB clusters, areas that share borders with eastern and southeastern Iran [ 57 ]. Previous research in Iran’s have shown that Afghan and Pakistani immigrants significantly contribute to TB incidence [ 58 , 59 , 60 ]. A study by Doosti et al. in Iran also reported that 12% of their TB cases were from Afghanistan [ 61 ]. Furthermore, previous studies have indicated that 97.1% of non-Iranian TB cases were among Afghan immigrants, with significant TB rates observed in Fars, Yazd, and Khorasan provinces due to Afghan immigration for treatment [ 62 , 63 ]. This trend intensified during the COVID-19 pandemic, as more immigrants sought medical care at our provincial referral centers, driven by the availability of affordable medications and the lack of adequate healthcare in their home regions. The influx of individuals from these regions may contribute significantly to the rise in TB cases in Iran. Understanding and addressing the implications of immigration on TB transmission is crucial for developing targeted public health interventions to mitigate the impact of this infectious disease in the context of population movement. This insight underscores the importance of cross-border collaboration and comprehensive strategies to manage and prevent tuberculosis transmission, particularly among vulnerable immigrant populations.

Many factors may influence the trend and prevalence of TB cases, such as pulmonary TB has shown to be influenced by seasonality changes in previous studies, showing the highest incidence in late spring to early summer in Iran [ 64 , 65 ]. A study from our province, Fars, also demonstrated a peak in incidence during warm seasons, specifically in May and June [ 66 ]. This was also in line with our findings, which as demonstrated in Fig.  1 , a relatively increase in number of cases is observed during the warm seasons, especially May and June. One reason of this occurrence may be due to the compromised immune function resulting from insufficient vitamin D during colder seasons [ 67 , 68 ]. Although in normal circumstances, the relatively elevated sun exposure during cold seasons in Fars province arises a question regarding whether vitamin D deficiency plays a role in the seasonal patterns observed in pulmonary tuberculosis, however, the enforced quarantine due to the COVID-19 pandemic may contribute to this theory.

Due to stringent physical-distancing measures, many avoided seeking medical care, fearing SARS-CoV-2 exposure in healthcare settings. Facilities noted fewer patients adhering to treatment schedules during lockdowns, posing risks for TB control and drug-resistant TB development [ 69 ]. Reallocating resources to control COVID-19 may have inadvertently affected TB diagnosis and treatment [ 52 ]. Overlapping respiratory symptoms between the two diseases, such as cough and difficulty breathing, could hinder TB diagnosis, as patients with respiratory symptoms are prioritized for COVID-19 screening. Yet, these overlapping symptoms might expedite access to imaging services, potentially revealing pre-existing TB during COVID-19 evaluation. In the context of clinical diagnosis, symptoms of TB and COVID-19 often overlap [ 70 ]. Additionally, COVID-19 can occur during TB treatment or reveal subclinical TB, a common scenario in TB-endemic regions [ 45 ]. In our assessment of clinical features, we observed a notable shift in symptoms reported by patients during the COVID-19 pandemic compared to the pre-COVID era. Specifically, there has been a significant decrease in patients presenting with symptoms such as sputum production and chills. Conversely, there has been an increase in cases characterized by fatigue, a symptom that is less specific and may have been underreported or overlooked. This change can be attributed to the heightened public awareness and extensive dissemination of information regarding COVID-19 symptoms, in which during the pandemic, patients with symptoms were more likely to seek medical attention due to the widespread concern about viral infections. As a result, cases of TB that presented with less characteristic symptoms, such as fatigue, or even asymptomatic have become more noticeable. This shift underscores the impact of the pandemic on the detection and diagnosis of TB, highlighting a tendency for atypical TB presentations to be identified more frequently as patients and healthcare providers adapted to the evolving clinical landscape.

Currently, in the post-pandemic period, Iran has eased stringent COVID-19 quarantine measures, moving towards more targeted interventions and preventive strategies. Our study serves multiple purposes: it underscores the immediate impact of COVID-19 on TB incidence and stresses the critical need for timely TB diagnosis amid pandemic-induced disruptions. Furthermore, we acknowledge the importance of addressing post-pandemic TB trends, particularly latent TB cases.

Our study demonstrates that the COVID-19 pandemic has had a prolonged impact on TB cases in our country. We observed a significant reduction in TB case numbers, attributed to decreased transmission during quarantine, challenges in screening, potential misdiagnosis, and fewer healthcare center visits. Given these trends, we anticipate an increase in TB mortality rates and latent TB cases in the coming years. To mitigate the effects of the pandemic on TB and protect the progress made over the past decade, it is essential to enhance TB control strategies. This includes prioritizing service delivery, securing funding for intensified case finding, expanding contact tracing, engaging communities to maintain awareness of TB symptoms and vaccination, leveraging digital health tools for remote TB management, and ensuring uninterrupted access to medications and diagnostics. Securing dedicated funding and mobilizing resources are crucial for addressing the challenges posed by the COVID-19 pandemic. Further research and cost-effectiveness assessments are needed to determine the most effective strategies for managing TB and other infectious diseases during emergency situations.

Data availability

All data regarding this study has been reported in the manuscript. Please contact the corresponding author if you are interested in any further information.

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Acknowledgements

This study was the subject of the medical degree dissertation of Dr. Mohammad Nazemi.

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M.J.F and R.S. designed the study. M.N. and A.Z. collected the data and drafted the manuscript. R.S. analyzed the data and drafted the manuscript. M.J.F revised the manuscript. All authors read and approving the final manuscript.

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Correspondence to Reza Shahriarirad .

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Fallahi, M.J., Nazemi, M., Zeighami, A. et al. Changes in incidence and clinical features of tuberculosis with regard to the COVID-19 outbreak in Southern Iran. BMC Infect Dis 24 , 1043 (2024). https://doi.org/10.1186/s12879-024-09947-0

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DOI : https://doi.org/10.1186/s12879-024-09947-0

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Clinical Presentation of COVID-19: Case Series and Review of the Literature

Affiliation.

• 1 Department of Mental health and Public Medicine, University of Campania, 80131 Naples, Italy.
• PMID: 32674450
• PMCID: PMC7399865
• DOI: 10.3390/ijerph17145062

COVID-19 infection has a broad spectrum of severity ranging from an asymptomatic form to a severe acute respiratory syndrome that requires mechanical ventilation. Starting with the description of our case series, we evaluated the clinical presentation and evolution of COVID-19. This article is addressed particularly to physicians caring for patients with COVID-19 in their clinical practice. The intent is to identify the subjects in whom the infection is most likely to evolve and the best methods of management in the early phase of infection to determine which patients should be hospitalized and which could be monitored at home. Asymptomatic patients should be followed to evaluate the appearance of symptoms. Patients with mild symptoms lasting more than a week, and without evidence of pneumonia, can be managed at home. Patients with evidence of pulmonary involvement, especially in patients over 60 years of age, and/or with a comorbidity, and/or with the presence of severe extrapulmonary manifestations, should be admitted to a hospital for careful clinical-laboratory monitoring.

Keywords: COVID-19; SARS-CoV-2; clinical presentation; natural history.

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Conflict of interest statement

The authors declare no conflicts of interest.

Management of COVID-19 patients according…

Management of COVID-19 patients according to the clinical presentation.

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