oral presentation about covid 19

• Case report
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• Published: 20 May 2021

Tongue ulcer in a patient with COVID-19: a case presentation

• Mohammad Bashir Nejabi 1 ,
• Noor Ahmad Shah Noor 1 ,
• Nahid Raufi 2 , 3 ,
• Mohammad Yasir Essar 1 , 4 ,
• Ehsanullah Ehsan 5 ,
• Jaffer Shah 4 , 6 ,
• Asghar Shah 7 &
• Arash Nemat   ORCID: orcid.org/0000-0001-6051-2698 8 , 9  

BMC Oral Health volume  21 , Article number:  273 ( 2021 ) Cite this article

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The emergence of COVID-19 has devastated many parts of the world. From asymptomatic to symptomatic, the virus causes a wide spectrum of presentations. COVID-19 patients may present with oral manifestations. In Afghanistan, where COVID-19 has severely strained the health care system, much of the population lacks proper oral hygiene. This makes the oral cavity a perfect site for SARS-CoV-2 to manifest clinical signs.

Case presentation

A 62-year-old male was evaluated in the Dentistry Teaching Clinic of Kabul University of Medical Sciences for a painful erosive lesion on dorsal surface of his tongue. He also complained of fever, cough, and taste alteration. He was referred to Afghan Japan Hospital for COVID-19 testing and tested positive. He was followed on for the treatment of SARS-CoV2. After 2 weeks, the patient tested negative and returned to the dentistry clinic for follow-up. Although there were no other signs of COVID-19, the painful erosive lesion on his tongue persisted. Oral evaluation were performed and the patient was advised to practice good hygiene. After 10 days, we observed an asymptomatic geographic tongue without fever and myalgias and the lesion of dorsal surface of tongue improved from severe condition to moderate.

In conclusion, patients with suspected or confirmed SARS-CoV-2 should be screened for symptoms and physical findings in the oral mucosa To prevent such an outcome, awareness programs need to be implemented for the diagnosis and management of clinical symptoms among patients.

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The novel coronavirus disease 2019 (COVID-19), a viral disease declared a pandemic by the World Health Organization (WHO) in March 2020, has caused a global health crisis affecting tens of millions of people with devastating health and economic consequences [ 1 ]. The disease is caused by the novel severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2), which causes viral pneumonia [ 2 ]. This virus creates widely varied clinical symptoms, from asymptomatic to mild, severe, and critical [ 3 ]. Most cases present with mild symptoms, including dry cough, fever, sore throat, nasal congestion, and myalgias. Severe COVID-19 is characterized by severe pneumonia, and critical cases include respiratory failure, septic shock, and multiple organ failure. It has been reported that atypical manifestations could be in some cases the first or only manifestations of this disease [ 4 ]. Oral manifestations have been reported in multiple publications [ 5 , 6 , 7 ]. The palate and tongue were the most frequent locations, followed by gingiva and lips. Pain was reported by 75% of patients and 25% reported taste alterations [ 8 , 9 , 10 , 11 , 12 , 13 ]. Furthermore, the most frequently reported oral manifestations include ulcerative lesions, vesiculobullous/macular lesions, and acute sialadenitis of the parotid gland (parotitis)[ 14 ]. The etiology of oral lesions in patients with COVID‐19 is still uncertain and seems to be multi‐factorial. The appearance of such lesions may be related to the direct or indirect action of SARS‐CoV‐2 on the oral mucosa cells, hypersensitivity of drugs used in the treatment of COVID‐19,downgrading of the general state of health of the patient due to the disease and long period of hospitalization [ 15 ]. There may be a link between COVID-19 and oral manifestations, but these signs may often go undetected due to a lack of intraoral examination during hospital admission [ 16 ]. Therefore, in this article, we aimed to report a case of oral manifestation in a COVID-19 diagnosed patient. This case builds on the findings of previous studies while highlighting the importance of full mouth examination to better understand the pathobiology of these oral alterations.

On 16th August 2020, a 62-year-old male presented to the Dentistry Teaching Clinic of Kabul University of Medical Sciences, due to a painful erosive ulcer on the dorsal surface of the tongue for one week. The patient reported that two weeks prior he had developed fever, cough, taste alterations, olfactory dysfunction, and chest tightness. He was referred to the local COVID-19 Hospital (Afghan-Japan Hospital) for the treatment of SARS-CoV-2. His rRT-PCR test was positive. He was treated with azithromycin 500 mg daily for one week and ceftriaxone 1 g twice a day for 3 days. After 2 weeks, a repeat COVID-19 test returned negative. When he came to the dentistry clinic, all of his symptoms had resolved except fora painful erosive lesion on the dorsal surface of his tongue. The patient had a history of controlled diabetes mellitus-type-2 and moderate hypertension. He did not have a history of any oral diseases such as candidiasis, lichen planus, or HSV.

Physical examination revealed normal temperature (37C); blood pressure 135/88 mmHg, heart rate 80; respiratory rate 19, and oxygen saturation 98%. We observed a white geographic ulcer with irregular borders on the dorsum of the tongue.

Laboratory examinations showed normal differential leukocyte count (DLC) and total leukocyte count (TLC), C-reactive protein 22.4/L, and glucose 120 mg/L. Computed tomography of lungs showed mild glass ground opacification bilaterally. Polymerase chain reaction (PCR) of a pharyngeal sample detected HSV-1 and he was treated with intravenous Acyclovir 5 mg/kg three times a day for 7 days with no effect on the oral lesions during the treatment.

For pain control of the ulcer, our dentist administered photobiomodulation therapy (PBMT) for 10 days. After 2 days of PBMT, the patient reported relief of symptoms and on the 11th day after PBMT treatment, the lesion partially resolved [ 17 ]. Besides the mentioned therapy, we recommended antibiotics (Azithromycin 500 mg for 1 week), antiseptic agents (Chlorhexidine 0.12%, alcohol-free mouth rinses, and H2O2 1%), and antifungal agents (fluconazole 200 mg tablets for 1 week) for the prevention of secondary infections. The patient was advised to avoid hot and spicy foods, but to drink plenty of fluids and eat a bland diet. We also advised the patient to practice good oral hygiene.

On August 30, 2020, he returned for a follow-up. During the examination, the patient had fewer clinical symptoms, and the size and mass of the lesion were changed to moderate compare to the severe form on the first examination. (Fig.  1 ).

a Fissured tongue with white scars after the COVID 19 recovery; b After 4 weeks the patient felt better and only he was complaining of burning on his tongue during the eating hot foods; c 4 weeks after the first examination

Discussion and conclusion

Current research shows that the damage of coronavirus to respiratory and other organs could be related to the distribution of angiotensin-converting enzyme 2 (ACE2) receptors in the human system [ 18 ]. Therefore, cells with ACE2 receptor distribution may become host cells for the virus and further cause inflammatory reactions in related organs and tissues, such as the tongue, mucosa and salivary glands. In an analysis of 49 confirmed COVID patients, Zhong and colleagues found high expression of ACE2, and a high detection rate of SARS-CoV-2 RNA in saliva [ 19 ]. Moreover, existing evidence has not established an efficient and safe pharmacological agent against COVID-19 yet, and the potential ones are related to several adverse reactions, including oral lesions. Also, COVID-19 acute infection, along with associated therapeutic measures, could potentially contribute to adverse outcomes concerning oral health, likely leading to various opportunistic fungal infections, recurrent oral herpes simplex virus (HSV-1) infection, fixed drug eruptions, dysgeusia, xerostomia linked to decreased salivary flow, ulcerations and gingivitis as a result of the weak immune system and/or susceptible oral mucosa [ 20 , 21 ]. Moreover, lack of oral hygiene, stress, immunosuppression, vasculitis and hyper-inflammatory response secondary to COVID-19 are some of the major predisposing factors for oral lesions in COVID-19 positive patients [ 22 ]. Similar oral conditions were presented by our patient and others have been previously reported [ 9 , 23 ].

The existing literature on oral manifestations of COVID-19 provides support for our findings, treatment administered, and the ulcer outcome. A review of more than 170 COVID-19 positive cases found changes in tongue sensation and onset of tongue ulceration to be the most common symptoms [ 24 ]. The use of photobiomodulation therapy (PBMT) in managing oral lesions has been well documented [ 25 ]. Also, the specific use of PBMT as an effective treatment in COVID-19 patients was reported by Soheilifar and colleagues [ 26 ]. Prior reporting has indicated improvements in lesion outcomes after treatment. Carreras‐Presas reported three cases of intraoral lesions that were all treated between 3 and 10 days [ 27 ].

The occurrence of oral signs and symptoms should be considered in COVID-19 patients, including dysgeusia, petechiae, candidiasis, traumatic ulcers, HSV-1 infection, geographical tongue, thrush-like ulcers, among others. S antos and colleagues reported a case of oral mucosal lesions in a COVID-19 patient [ 28 ]. Other oral manifestations of the case included recurrent herpes simplex, candidiasis, and benign migratory glossitis. The researchers posit that some oral conditions may be a result of COVID-19 treatment and for this reason, oral health professionals should be included in the clinical care team. A review of 210 COVID-19 cases which reported prone positioning and mechanical ventilation devices in the ICU as resulting in oral mucocutaneous complications reached similar conclusions [ 29 ]. Hence, the importance of the clinical examination of the oral mucosa in patients with infectious diseases in the ICU should be emphasized, considering the need for support, pain control, and quality of life. Corchuelo and colleagues report the successful use of teleconsultation as facilitating the interdisciplinary approach for a patient asymptomatic COVID-19 presenting with Candida albicans, thrush, petechiae, and melanin hyperpigmentation at the gingival level [ 30 ].

Thorough oral examination, while practicing protective measures to avoid viral transmission, is important in addressing oral manifestations of COVID-19. To that end, Bordea and colleagues report a systematic review of guidelines to provide safe and efficacious oral care during the COVID-19 pandemic [ 31 ]. A retrospective study of 47 multisystem inflammatory syndromes in children (MIS-C) positive pediatric patients, who tested positive for COVID-19 infection, concluded that dental care providers play an important role in the early detection of MIS-C and in the identification of oral lesions in MIS-C patients [ 32 ]. They posit, furthermore, that MIS-C incidence is likely to increase as the number of COVID-19 positive cases continues to grow. All things considered, oral healthcare providers can play an important role in the detection and subsequent treatment of oral manifestations following COVID-19 infection.

In conclusion, we affirm that the problems that arise in the oral mucosa in patients with suspected or confirmed SARS-CoV-2 infection should be monitored during the pandemic, as demonstrated in our case of a dorsal tongue ulcer in a COVID-19-positive patient. To prevent such an outcome, awareness programs need to be implemented for the diagnosis and management of clinical symptoms among patients.

Availability of data and materials

The readers can acquire available data and materials in the current study by sending an email to [email protected].

Abbreviations

Polymerase chain reaction

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Faculty of Dentistry, Kabul University of Medical Sciences, Kabul, Afghanistan

Mohammad Bashir Nejabi, Noor Ahmad Shah Noor & Mohammad Yasir Essar

Department of Dermatology, Kabul University of Medical Sciences, Kabul, Afghanistan

Nahid Raufi

Department of Dermatology, Guangdong Provincial Dermatology Hospital, Southern Medical University, Guangzhou, China

Medical Research Center, Kateb University, Kabul, Afghanistan

Mohammad Yasir Essar & Jaffer Shah

Department of Dermatology, Alberoni University, Kapisa, Afghanistan

Ehsanullah Ehsan

Drexel University College of Medicine, Philadelphia, PA, USA

Jaffer Shah

Division of Biology and Medicine, Brown University, Providence, RI, USA

Asghar Shah

Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China

Arash Nemat

Department of Microbiology, Kabul University of Medical Sciences, University Road, Ali Abad, Jamal Mina, 3rd District, Kabul, 1001, Afghanistan

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MBR and NAN performed the initial examination and collected clinical data, MYE provided the clinical dental care of the patient and have continued performing regular clinical follow-up. MBR supervised the clinical dental care of the patient. NR and EE were responsible for the literature search and wrote the paper. JS and AS revised and edited the manuscript and figures. AN provided comprehensive judgment and assisted in editing the final version of the manuscript. All authors read and approved the final manuscript.

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Nejabi, M.B., Noor, N.A.S., Raufi, N. et al. Tongue ulcer in a patient with COVID-19: a case presentation. BMC Oral Health 21 , 273 (2021). https://doi.org/10.1186/s12903-021-01635-8

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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

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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UT Tyler grad wins award for neural net oral presentation at LSUS event

TYLER, Texas (KLTV) - Lucas Vega was recently given the Best Undergraduate Oral Presentation award at LSUS’s ninth annual Regional Scholars Forum.

Vega stopped by the East Texas Now studio to talk about his “A Neural Network Approach To Predict Opioid Misuse Among Previously Hospitalized Patients Using Electronic Health Records” presentation.

“In short ... it’d be nice if we could identify these people early so we could intervene and get them some treatment before, God forbid, they come in and suffer from an overdose,” Vega said. “The problem is, there’s no universal screening method for that because all that exists for that right now are surveys that you have to fill out on paper, and that’s too long for doctors to administer to every single patient.”

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Prevalence of oral manifestations in COVID‐19: A systematic review

Preeti sharma.

1 Department of Oral & Maxillofacial Pathology & Oral Microbiology, Subharti Dental College and Hospital, Swami Vivekanand Subharti University, Meerut Uttar Pradesh, India

Sangeeta Malik

2 Department of Oral Medicine & Radiology, Subharti Dental College and Hospital, Swami Vivekanand Subharti University, Meerut Uttar Pradesh, India

Vijay Wadhwan

Suhasini gotur palakshappa, associated data.

This is a systematic review and data sharing is not applicable to this article as no new data was created in this study. The data for the included studies is presented in Table  1 and Table  2 , while the flow chart for literature search is presented in Figure  1 .

Coronavirus disease 2019 (COVID‐19) is a novel disease caused by a newly identified virus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) causing diverse systemic manifestations. The oral cavity too is not spared and the symptoms appear either independently, concurrently, or sequentially. In view of the rising documented cases of oral lesions of COVID‐19, this systematic review aims to assess the prevalence of oral manifestations in COVID‐19 confirmed individuals. An extensive literature search was conducted in databases like Scopus, Pubmed/Medline, Livivo, Lilacs and Google Scholar and varied oral signs and symptoms were reported as per the PRISMA guidelines. Studies published in English language literature only were included and were subjected to the risk of bias using the Joana Briggs Institute Appraisal tools for prevalence studies, case series and case reports. In a two‐phase selection, 34 studies were included: 21 observational, 3 case‐series and 10 case reports. These observational studies included approximately 14,003 patients from 10 countries. In this review, we explored the most commonly encountered oral and dental manifestations in COVID‐19 and identified that loss of taste acuity, xerostomia and anosmia were frequently reported. Elevated incidence of opportunistic infections like mucormycosis and aspergillosis were reported during the treatment due to prolonged intake of steroids. Immunosuppression and poor oral hygiene led to secondary manifestations like enanthematous lesions. However, it is not clear that oral signs and symptoms are due to COVID‐19 infection itself or are the result of extensive treatment regimen followed [PROSPERO CRD42021258264].

Abbreviations

1. introduction.

Coronavirus disease 2019 (COVID‐19), caused by a single‐chain RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has resulted in global healthcare crisis, with grave health and socioeconomic impact. 1 , 2 The worst affected countries included United States, India and Brazil, as more than 50% of all the cases were reported from these nations. 3 The primary manifestations of COVID‐19 include pneumonia and acute respiratory distress syndrome, although many organ systems have been affected including the gastrointestinal tract, liver, central nervous systems, blood vessels, heart and kidneys. 4 , 5 , 6 Its transmission through respiratory droplets, aerosols, contact and fomites has facilitated the rapid spread worldwide. 5

The most commonly reported manifestations include symptoms common to other viral infections such as fever, cough, sore throat, myalgia, arthralgia, headache, dyspnoea, and excessive sputum production. However, an increasing number of atypical clinical presentations have been reported, such as gastrointestinal symptoms like anorexia, tremors, nausea, vomiting, and diarrhoea, 1 dermatological manifestations, and chemosensory dysfunctions. 2 COVID‐19 also causes direct injury to myocardial cells mediated by angiotensin‐converting enzyme 2 (ACE2) receptors and additionally by systemic inflammation causing indirect myocyte injury. Thus, myocardial injury, arrhythmias, cardiac arrests, heart failure and coagulation abnormality can manifest as cardiovascular abnormalities in COVID‐19 patients, which may cause serious impairment to the patient. 7 There was a positive and moderate correlation between neutrophil lymphocyte ratio values and clinical outcome of acute ischaemic stroke patients with COVID‐19. 8

Noteworthily, persistent long COVID symptoms like anxiety, prolonged depression, chest pain, palpitations, dizziness and hair loss as well as prolonged neuromuscular symptoms (fatigue, anosmia, headache, myalgia and joint pain) are a cause of grave concern in COVID‐19 patients even after two weeks of recovery. 9 , 10 In a systematic review and meta‐analysis, the authors explored the association between delirium and poor prognosis in COVID‐19 patients and suggested that the delirium in older patients can be an important presenting symptom of COVID‐19 implicating poor outcomes and high risk of mortality. 11

Along with these symptoms, this virus can affect other organs including skin, olfactory system and oral cavity. 6 Various manifestations in the oral cavity such as mucosal ulcerative and vesiculobullous lesions, 1 taste changes, gingivitis, 6 inflammation of the papillae of Wharton's duct, plaques on the tongue, 6 xerostomia, halitosis, parotiditis, 5 are reported in the literature. Oral lesions can be an inaugural sign of Covid‐19 or a warning sign of peripheral thrombosis. 6

In Covid‐19 patients, elevated Interleukin‐6 levels and C‐reactive protein implicate worse clinical outcomes as they cause significant cell damage; thus are a critical factor for shock and multiorgan failure. 12 , 13

SARS‐CoV‐2 invades human cells via the receptor angiotensin converting enzyme II (ACE2). Angiotensin‐converting enzyme 2 receptor is highly expressed in the organs at risk, such as lung, heart, oesophagus, kidney, bladder, and ileum, and located specific cell types (i.e., type II alveolar cells (AT2), myocardial cells, proximal tubule cells of the kidney, ileum and oesophagus epithelial cells, and bladder urothelial cells), which are vulnerable to 2019‐nCoV infection. 14 , 15 Besides high expression of ACE2 receptor on the epithelial cells of the tongue and of the salivary glands, could lead to the development of dysgeusia and oral mucosal ulcerations and necrosis in patients with COVID‐19. 6

Though, some of the oral manifestations may be the initial sign of the disease, however, it is still unclear as to whether these oral lesions are due to coronavirus infection or secondary manifestations resulting from local irritants or deterioration of systemic health/immunosuppression or stress or the side effects of treatment, or a combination of these or just a coexisting finding. 16 , 17 , 18 Protean oral presentations have been documented by various authors globally; therefore, a comprehensive overview on the types and prevalence of various oral manifestations is of current interest.

Furthermore, oral healthcare practitioners are expected to have a thorough knowledge of these oral manifestations as they can be referred to in case of identifying COVID‐19 infection. Thus, this systematic review is relevant and aims to identify and bring together all the available evidence on the prevalence of oral manifestations of covid 19.

2.1. Protocol and registration

The present systematic review protocol was registered at the National Institute of Health Sciences, [PROSPERO, International Prospective Register of Systematic reviews database] under registration CRD42021258264. The data was searched following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta‐analyses). 19 , 20

2.2. Study design

The present systematic review focussed on the prevalence of oral manifestations of COVID‐19 following the Population, Exposure/Intervention, Control, Outcome, Study type strategy.

2.2.1. Participants/population

COVID‐19 patients of all ages with oro‐dental manifestations.

2.2.2. Intervention, exposure

Not applicable, but exposure is COVID‐19.

2.2.3. Comparator/control

Not applicable.

2.2.4. Outcomes

Main outcome.

Oral manifestations in COVID‐19 patients. All types of oral signs and symptoms.

Additional outcomes

• Types and prevalence of oral mucosal manifestations such as infections (fungal, viral, and bacterial). Opportunistic lesions; autoimmune and inflammatory lesions (stomatitis); salivary gland disorders; and other oral symptoms such as dysgeusia, dysosmia.
• Demographic and epidemiological characteristics of patients (age range, gender, ethnicity, habits).

2.2.5. Inclusion criteria

All the observational and cross‐sectional studies on the prevalence of oral manifestations related to COVID‐19. Due to paucity of literature and continuously evolving information on COVID‐19, case series and case reports were also included. Only English language articles published from March 2020 till February 2022 were included in this systematic review. Oral manifestations included taste disorders (dysgeusia, ageusia and hypogeusia), xerostomia, oral mucosal lesions like aphthous ulcers, geographic tongue, candidiasis, Bell's palsy, trigeminal neuralgia, erythema multiforme like lesions, herpes zoster (HZ), herpes simplex, and opportunistic infections like mucormycosis and aspergillosis.

2.2.6. Exclusion criteria

All narrative reviews, editorial letters and systematic reviews were excluded. Also, the studies where COVID‐19 positivity was not confirmed in the study subjects and where COVID‐19 patients did not report oral signs and symptoms, were not added for analysis.

2.3. Information sources and search strategy

Our electronic search included the PubMed, Scopus, Web of Science and Embase databases using various key words alternately like COVID‐19, humans, mouth diseases, oral manifestations, prevalence, SARS‐CoV‐2 on 4, 5 and 6 June 2021 and further updated our research on 1 February 2022 across these databases (Appendix Table  1 ). A software reference manager (EndNote X7, Thomson Reuters) was used to collect references and remove duplicate articles.

2.4. Study selection

The article selection was completed by two authors in 2 steps. In step 1, two authors (PS and SM) separately screened the titles and abstracts of all the references through Rayyan software. Only those articles which matched the inclusion criteria were tabbed and the remaining publications were rejected. The concluding decision was taken in consultation with the third author (VW). In step 2, we followed the same selection criteria and only those published full‐text articles were selected which described the prevalence of oral manifestations and oral mucosal lesions in COVID‐19 patients. The same 2 authors were associated independently in step 2. All selected articles were critically and intensely analysed by 3 authors and the new publications were also chosen for selection analysis. If there was any difference of opinion in either of the steps, it was settled by collective consensus among the 3 authors. Eventually, only full‐text articles were preferred and selected for this systematic review.

2.5. Data collection

At the outset, the first (PS) and second (SM) authors extracted the data from the chosen references. An extraction form was developed to list the essential information on the authors, name of the country, year of study, study design, number of subjects, mean age, gender, severity of COVID‐19, clinical features and oral manifestations.

This was followed by the third author (VW) verifying the compiled data and affirmed its accuracy/preciseness/authenticity. If there was disagreement on any issue, it was resolved by discussion and mutual agreement among all the authors. However, final decision was taken by first and second authors. In some articles, if the required information was missing, efforts were made to contact the authors of these publications and the necessary data was filled in the excel sheet.

2.6. Risk of bias within studies

The risk of bias of included studies was assessed by 2 authors (PS and SM) independently using a quality assessment checklist for prevalence studies, case reports and case series adapted by the Joanna Briggs Institute's Critical Appraisal checklist (Munn et al 2015 and Moola et al 2017). In case of difference of opinion, the third author (VW) was consulted. For each article, scoring was concluded only after consultation with all authors, and a study was specified as a high risk of bias when the ‘yes’ score was up to 49%, moderate when 50%–69% and low when >70%. 21 , 22

2.7. Summary measures

In the present systematic review, the chief outcome was the prevalence of all types of oral manifestations in COVID‐19 patients. The additional outcomes included types and prevalence of oral mucosal manifestations, namely, fungal, viral and bacterial infections; autoimmune and inflammatory lesions, salivary gland disorders, neuropathies, taste and smell disturbances, demographic and epidemiological characteristics of patients (age, gender, geographic region, habits).

3.1. Study selection and characteristics

Initially, 3643 records were recognized from databases. After removing duplicate publications, 1732 references were left for title and abstract screening. After analysing all the records, finally 72 full‐text articles were shortlisted for the second phase. Both the authors (PS and SM) completed full‐text reading and excluded 30 articles according to the eligibility criteria. Finally, 34 studies were selected for synthesis, of which 21 were prevalence studies, 10 were case‐reports and three were case series on various oral mucosal lesions in COVID‐19 confirmed individuals. A flow‐chart following PRISMA guidelines is presented in Figure  1 . The oral presentations were widely distributed globally, as cases were reported from Italy, Germany, Belgium, Spain, Turkey, Portugal, Brazil, Mexico, Egypt, UK, Israel, India and US. Only English language articles were identified which were published from March 2020 till February 2022.

Flow‐diagram depicting selection criteria adapted from Preferred Reporting Items for Systematic Reviews and Meta‐analyses

3.2. Risk of bias within studies

All included studies were assessed for risk of bias following Joana Briggs Institute guidelines and the observations are summarised in Table  1 and Table  2 and details are shown in Appendix Table  3 . Prevalence studies, case reports and case series were evaluated with the specified checklist for each study design. 21 , 22

Distinctive features of observational studies included in the systematic review ( n = 21)

Abbreviation: TMJ, temporomandibular joint.

Distinctive features of case series( n = 3) and case reports ( n = 10) included in the systematic review

Abbreviation: PPE, personal protective equipment.

Most prevalence studies ( n  = 15; 71.4%) presented low risk of bias overall, however, six studies (28.5%) had moderate risk of bias. Similarly low risk of bias was observed in almost all case reports ( n  = 9; 90%) and case series ( n  = 2; 66.7%) analysed in this systematic review.

3.3. Synthesis of studies

A total of 14,003 patients from prevalence studies with COVID‐19 were included in this systematic review. For confirmation, Real time reverse transcription polymerase chain reaction test was used for detection of viral RNA.

Olfactory and gustatory disorders were found to be closely associated and were the most commonly reported oral manifestations, followed by xerostomia, anosmia, vesiculobullous lesions and oral ulcers.

Analysis of 21 observational studies on 14,003 patients revealed that there was heterogeneity in the data and it was difficult to draw a conclusive inference of the most prevalent symptom. Nevertheless, 66.7% of the prevalence studies reported primary oral manifestations directly due to COVID‐19 like taste alterations, xerostomia, and salivary gland diseases. One prevalence study conducted showed an increase in the incidence of HZ cases during Covid pandemic times. While four observational studies (19.04%) showed multiple secondary oral manifestations like sialadenitis, dry mouth, mucocutaneous lesions, aphthous ulcers, enanthema, opportunistic infections like mucormycosis, aspergillosis, oral pseudomembranous candidiasis, geographic tongue, coated tongue. Significantly, in at least two questionnaire‐based surveys, Temporomandibular disorders (TMD) were found to be increased, emphasising the psychological impact of COVID‐19.

Additionally, oral mucosal lesions were presented only in case reports and case series. These included primary manifestations probably caused directly by SARS‐CoV‐2 and secondary manifestations caused as a sequelae and treatment of COVID‐19 infection (Table  2 ). Infection like oral ulcers, angina bullosa hemorrhagica, burning mouth, erythematous macules, plaque‐like changes in the tongue, masticatory muscle pain, acute infectious parotitis and secondary manifestations like facial palsy, enanthema resembling petechiae without erythema, Melkersson‐Rosenthal syndrome, Bell's palsy, parotitis, Guillain‐Barre syndrome, secondary herpetic gingivostomatitis, macroglossia, and trigeminal neuralgia.

While, hospitalised patients were considered as cases of severe COVID‐19, the non‐hospitalised patients were categorised as mild to moderate COVID‐19 cases. Most of the oral presentations were observed during covid‐19 infection period ( n  = In 61.9% of the observational studies, oral manifestations presented in severe cases of COVID‐19). Taste disorders were more commonly observed in severe cases of COVID‐19 (53.8%). At least three cross‐sectional studies (14.3%) observed taste dysfunction and xerostomia during follow‐up after the recovery of COVID‐19.

In one case series, 4 patients presented with angina bullosa hemorrhagica on palatal mucosa, four patients showed facial paralysis and another one patient presented with acute infectious parotitis and malocclusion. There was one patient showing HZ and two patients showing herpes simplex infection. Melkersson‐Rosenthal syndrome was shown by one patient and trigeminal neuralgia was observed in one Covid‐19 patient. In one case report, macroglossia was seen as a sequelae of severe Covid‐19 patient admitted in ICU due to intubation for a prolonged period.

4. DISCUSSION

Many cases on oral manifestations as primary and secondary presentations in COVID‐19, have been reported and published from many countries as case reports, case series, editorial letters and cross‐sectional studies. Nevertheless, there is a scarcity of studies addressing the incidence of oral manifestations in COVID‐19. Dentists may play a very crucial role in the diagnosis of COVID‐19 infection as some oral presentations are the first sign and symptom of this disease. Loss of smell and taste alterations have been reported to be the initial symptoms even before the common signs and symptoms of this disease like dry cough, dyspnoea, sore throat and fatigue appear. Incidentally, taste and smell dysfunctions are also the longest lasting symptoms of SARS‐CoV‐2 infection. 23 , 24 , 25

4.1. Taste impairment

Dysgeusia (altered taste), hypogeusia (diminished sense of taste) and ageusia (complete loss of taste) were the most commonly reported initial symptoms even before the diagnosis of COVID‐19 was confirmed. 26 , 27 , 28 , 29 , 30 The most probable pathogenesis of taste disturbances in COVID‐19 is due to peripheral neurotropism and direct toxicity to taste buds or olfactory epithelium. Other contributory factors may include inadequate saliva, pro‐inflammatory cytokines, angiotensin II accumulation, systemic diseases, hypozincemia, and excessive use of chemicals. 31 , 32 Also, published studies state that angiotensin‐converting enzyme 2 (ACE 2) cell receptors are expressed in abundance on respiratory epithelium and oral mucosa, mainly dorsal surface of the tongue. Incidentally, SARS‐CoV‐2 has a great affinity for these receptors. 31 , 32 Anosmia or loss of smell sensation is very often observed and reported in association with taste disturbance in COVID‐19 patients. Furthermore, it is not easy for the patient to differentiate between taste and smell disorders. It remains ambiguous whether gustatory dysfunction is seen as a result of olfactory dysfunction or it is the primary manifestation of the SARS‐CoV‐2 virus. 30 , 31 , 32 Experimental studies that document the temporal relationship in the commencement of these two symptoms, need to be conducted. It was suggested by the American Academy of Otolaryngology that anosmia, hyposmia and dysgeusia should also be combined in the list of screening tools for COVID‐19 in asymptomatic patients. 33 Considering the published data on the most frequently observed and most significant symptoms of SARS‐CoV‐2 infection, the olfactory and taste dysfunctions were formally acknowledged by The US Centres for Disease Control and Prevention. 34 A systematic review conducted on 40 studies (33 cross‐sectional and 7 case‐reports) which included 10,228 patients concluded that gustatory dysfunction may be the most recognized symptom in COVID‐19 patients and should be considered in the scope of the disease's onset and progression. 35 Additionally, oral mucosal lesions have a high probability of manifesting as coinfections and secondary presentations with various clinical aspects such as white and erythematous plaques, irregular ulcers, small blisters, petechiae, and desquamative gingivitis. 18 A Web‐based questionnaire on 128 COVID‐19 patients was used to report findings in an observational study conducted by Biadsee A et al (2020), 36 which revealed that majority of the patients presented with olfactory and oral disorders like dysgeusia, dry mouth, masticatory muscle pain, burning sensation, plaque‐like changes in the tongue. A new clinical approach to diagnosing COVID‐19 disease was suggested as women manifested with different symptoms than men. Taste dysfunction was the most common reported symptom followed by xerostomia and olfactory dysfunction in a questionnaire‐based survey conducted in an observational study on confirmed COVID‐19 individuals in Italy. 37 In 59 hospitalised COVID‐19 individuals, questionnaire‐based survey revealed that olfactory and taste disorders appeared with equal frequency both before and after the hospital admission. 31 While another observational study, also based on questionnaire‐based survey, emphasised the importance of the close relationship between SARS‐CoV‐2 and oral manifestations and implicated dysgeusia to be the alarming signal for such patients. 38 A systematic review and meta‐analysis found olfactory and gustatory dysfunctions as common symptoms in patients with COVID‐19 and may represent early symptoms in the clinical course of infection. 39 Also, taste and smell dysfunctions were the longest lasting symptoms as they were manifested even after 6 months, as reported in a questionnaire‐based survey conducted in Israel on 103 COVID‐19 patients. 40

Additionally, SARS‐CoV‐2 causes activation of cytokines triggering apoptosis of cells as well as abnormal cell turnover. Consequently, it results in loss of taste buds and failure of differentiation of different types of taste cells manifesting taste dysfunctions in COVID‐19 patients. SARS‐CoV‐2 also affects the peripheral gustatory neurons, causing direct damage of ACE‐2 expressing cells of the peripheral taste neurosensory chemoreceptors and the cranial nerves VII, IX, or X, which are responsible for gustation. It is also hypothesised that zinc imbalance in these patients leads to infection & inflammation of taste buds with SARS‐CoV‐2 causing acute hypozincemia due to zinc chelation and alteration in zinc haemostasis, resulting in taste disturbances. Taste dysfunctions also occur secondary to smell dysfunction, medications and reduced sialic acid concentration. 5

In concordance with other studies, majority of the prevalence studies included in our systematic review observed taste dysfunction and xerostomia as the most common symptom reported early before the manifestation of other symptoms of Covid‐19.

4.2. Oral mucosal lesions

Aphthous ulcers, muco‐cutaneous lesions, erosions, plaque‐like lesions, geographic tongue, candidiasis, mucormycosis, angina bullosa hemorrhagica, herpes zoster ulcers, herpes simplex reactivation (HSV‐1) associated ulcers, sialadenitis have been reported in COVID‐19 suspected individuals as well as confirmed cases. The pathogenesis of occurrence of oral mucosal lesions in COVID‐19 is still not clear. Many published studies report that the oral lesions are manifested as a result of reduced immunity in COVID‐19 patients, or as consequent manifestation of the treatment administered for COVID‐19. 41 , 42 , 43 , 44 , 45 , 46 , 47 It is hypothesised that ulcers and erosions are observed clinically due to direct damage to oral mucosa caused by binding of SARS‐CoV‐2 with oral epithelial cells (keratinocytes and non‐keratinocytes). Therefore, there is increased cell permeability and entry of SARS‐CoV‐2 inside epithelial cells. Also, inflammation may be localised or systemic leading to production of inflammatory cytokines and TNF‐α, causing chemotaxis of neutrophil to inflammatory site of oral mucosa, causing aphthous ulcers. Inflammation in SARS‐CoV‐2 can also cause vasculitis, thrombotic vasculopathy, drug eruption and can also present as non‐specific ulcers, erosions, vesiculobullous lesions and mucositis. 5 Noteworthily, acute infection, medication, neglected oral hygiene, stress and deterioration of systemic health also causes immune system suppression, which leads to manifestation of vesiculobullous lesions, non‐specific oral ulcers, eruptions, recurrent oral herpes simplex virus (HSV‐1) infection (Herpes gingivostomatitis). 5 Different studies have published various oral manifestations which are listed below.

4.3. Muco‐cutaneous manifestations

An observational study carried out on 666 confirmed cases of COVID‐19 patients in Spain, revealed that oral manifestations like transient lingual papillitis, glossitis with lateral indentations, aphthous ulcers, glossitis with patchy depapillation and mucositis, enanthema, candidiasis and burning sensation were observed. Noteworthily, taste disturbances like dysgeusia was frequently associated in this viral infection. The authors concluded that almost half of patients with mild to moderate COVID‐19 infection admitted in a field‐hospital during a 2‐week period show muco‐cutaneous findings. Therefore, oral cavity is frequently involved and must be examined thoroughly under the appropriate conditions to prevent contagion risk. 48

Acute infection, medication, neglected oral hygiene, stress, deterioration of systemic health causes immune system suppression, which leads to manifestation of vesiculobullous lesions, non‐specific oral ulcers, eruptions, recurrent oral herpes simplex virus (herpes simplex reactivation) infection (Herpes gingivostomatitis). 41 , 42

In the present systematic review, almost all these oral lesions were observed during COVID‐19 infection period except the TMD which were the long‐lasting symptoms manifesting even after the recovery of the infection.

4.4. Aphthous ulcers

In a retrospective cross‐sectional study, medical records were reviewed of COVID‐19 patients, and the prevalence of aphthous ulcers was 0.64% compared with 0.148% in the hospital population that served as the control group, implicating a strong association between COVID‐19 and aphthous ulcers. 45

Mild to moderate cases of COVID‐19 infection were associated with oral symptoms like ulcerations, xerostomia, oral pain and pain in the jaw bones in an observational study carried out using online questionnaire on 573 patients. 47

4.5. Herpes zoster

According to an observational study conducted on 8695 patients in Brazil, there was an increase in HZ cases during the COVID‐19 pandemic, which suggests a correlation between these diseases. A case was reported with left facial HZ with intraoral mucosal lesions and hypogeusia in Brazil, implicating the emergence of the latent infection by varicella zoster virus (VZV) under a rare presentation. This illustrates that retrograde reactivation of VZV could be induced in a young immunocompetent COVID‐19 patient. 49

Physical intraoral and extraoral examination of a 39 ‐year old Brazilian COVID‐19 patient showed facial HZ with intraoral mucosal lesions. Thus, the retrograde reactivation of VZV was probably induced in this young immunocompetent patient, indicating the rare possibility of the impact of COVID‐19. 50

4.6. Herpetic gingivostomatitis

COVID‐19 infection and prolonged hospitalisation could cause stress and immunosuppression leading to secondary herpetic gingivostomatitis, as observed in a 46 ‐year old confirmed COVID‐19 patient who was hospitalised in intensive care unit, showing multiple sharply circumscribed ulcerations of the oral mucosa covered by yellow‐grey membranes. Intraoral examination of COVID‐19 patient showed lesions in the median lower lip semimucosa and severe pruritus which persisted clinically for 14 days, and was clinically diagnosed as herpes simplex infection. 51

4.7. Angina bullosa hemorrhagica

Four confirmed cases of COVID‐19 were physically examined where prominent lesions were angina bullosa hemorrhagica, vascular‐like purple macule on palatal mucosa, burning mouth, dysgeusia and erythematous macules. Therefore, it is significant to remember that oral mucosal lesions in COVID‐19 subjects could resemble reactive, vascular and immunologic disorders, making it essential to differentiate them to arrive at a correct diagnosis to effectively manage such patients. 52

4.8. Salivary gland involvement

Patients with COVID‐19 frequently show salivary gland involvement due to ACE‐2 expression in minor salivary glands which is reportedly higher as compared to the lungs, thus making the salivary glands susceptible to SARS‐CoV‐2 viral infection. 28

Extraoral and intraoral physical examination was conducted in an observational study on 122 patients in Italy. The most prevalent oral findings were salivary gland ectasia, dry mouth, masticatory muscle weakness, temporomandibular joint abnormalities, dysgeusia, anosmia, facial tingling, trigeminal neuralgia, facial asymmetry. 53 The authors concluded that oral manifestations persisted in the vast majority of survivors even after clinical recovery and thus oral cavity could be the likely target of COVID‐19. Atypical presentations of COVID‐19 like acute infectious parotitis, malocclusion due to inflammation surrounding muscles of mastication, are being increasingly recognized. Emergency Department clinicians must have a high suspicion for COVID‐19 among any patient presenting with infectious symptoms or viral associated illnesses and don available personal protective equipment accordingly for the initial evaluation. 54

Intraparotid lymphadenitis could lead to parotid inflammation during COVID‐19 as three patients showed parotitis characterised by ear pain, retromandibular oedema, sticky saliva and pain during mastication. 55

A questionnaire‐based survey was carried out on 58 COVID‐19 hospitalised patients, which found xerostomia as the most prevalent symptom, followed by gustatory dysfunction. This suggested that salivary gland‐related symptoms and disorders are highly prevalent in COVID‐19 patients. 56

4.9. Facial palsy

Cases have been observed and published where facial palsy was the first symptom observed in SARS‐CoV‐2 patients and it was suggested that peripheral facial palsy should be added to the spectrum of neurological manifestations associated with COVID‐19. 57 In another 35‐ year old pregnant Portuguese patient, Bell's palsy showed involuntary drooling and there was deviation of the left side labial commissure, suggesting that the neurological symptoms could be the first and only manifestation and, also, pregnancy may illustrate a higher susceptibility for peripheral facial palsy in this viral infection. 58

Another COVID‐19 patient reported with bilateral facial nerve palsy with unresponsive blink reflex involving both eyes and Guillain‐Barre syndrome. This implied that neurological manifestations may be directly or indirectly linked to SARS‐CoV‐2 infection. 59

4.10. Trigeminal neuralgia

Paroxysmal lancinating pain was found in the right VI region that lasted a few seconds and was triggered by a light touch of the skin at a specific point on the scalp in a 65‐year old patient, suggesting SARS‐CoV‐2 as a possible aetiology of secondary trigeminal neuralgia. However, more studies are needed to establish the neuropathology of this viral infection. 60

4.11. Melkersson‐Rosenthal syndrome

In a 51‐year old hospitalised female patient, the right lower lip was hyperaemic and showed firm oedema extending towards the jaw, right facial paralysis and fissured tongue, suggestive of Melkersson‐Rosenthal syndrome. It was concluded that activated mast cells may play a significant role in the pathogenesis of COVID‐19 infection, as they release cytokines in the lungs and may be a probable etiological factor for this presentation. 61

4.12. Fungal infections

There was a significant increase in the incidence of angio‐invasive maxillofacial fungal infections in diabetic patients treated for SARS‐CoV‐2 with a strong association with corticosteroid administration. In a retrospective observational study carried out on 18 COVID‐19 hospitalised patients, mucormycosis was observed in 16 patients while aspergillosis was found in one patient and another one patient revealed a mixed fungal infection. 62 Oral pseudomembranous candidiasis was the most frequently observed oral presentation, followed by geographic tongue and taste alteration, in 27 COVID‐19 positive children in a retrospective study conducted in Italy. 63

Opportunistic fungal infections like candidiasis, mucormycosis and aspergillosis are seen due to immunosuppression caused by the acute infection, heavy medication, poor oral hygiene and debilitated systemic health. 5

4.13. Macroglossia

Severe, persistent macroglossia was observed following a prolonged course of prone positioning for treatment of a 40 year old COVID‐19 patient. 64

4.14. Temporomandibular disorders

Psychological impact of COVID‐19 cannot be neglected as it is leading to aggravation TMD, bruxism and anxiety in COVID‐19 patients even after recovery. 65

5. LIMITATIONS

There are some limitations of this systematic review which must be emphasised. Firstly, there are only few studies on the prevalence of oral findings; most of the oral manifestations are reported as either case reports or letters to editor. Secondly, there is no clear distinction between the primary and secondary manifestations of COVID‐19 and it is still a dilemma that oral presentations are merely incidental findings or caused by the SARS‐CoV‐2 virus itself. Most importantly, in most of the studies, there is no categorisation of the severity of COVID‐19 infection as mild, moderate or severe at the time of investigation, which further despises the causative factors for oral manifestations. Additionally, due to high risk of contamination in such patients, many oral findings may have been under reported. In the present systematic review, many observational studies are based on the Questionnaires or web based questionnaires, which are not reliable for a conclusive diagnosis. Due to deficient high quality prevalence studies on oral manifestations in COVID‐19, meta‐analysis was not conducted for this systematic review, which is a major limitation of this review.

6. CONCLUSION

In this systematic review, the most frequently observed oral presentations were taste alterations, followed by xerostomia and vesiculobullous lesions. Though, increasing number of patients are reporting oral manifestations in COVID‐19, but, it still remains ambiguous whether they are directly due to the deadly infection or are merely seen as secondary presentation during the treatment. In the current scenario of rapidly changing and new mutated strains of COVID‐19 virus, more high‐quality prevalence studies are required to be conducted to find a causal relationship between oral symptoms and this highly contagious virus. Noteworthily, dental professionals can play a key role in the early diagnosis of this viral infection.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTION

Preeti Sharma conducted the literature search and contributed to conception, data acquisition, analysis, interpretation and design of the first draft. Sangeeta Malik conducted the literature search (independent screening and selection of publications) and contributed to conception, data acquisition, analysis. Vijay Wadhwan contributed to conception, data acquisition, analysis and critically revised the manuscript and provided advice to improve the manuscript. Suhasini Gotur Palakshappa and Roli Singh also contributed to the literature search, data acquisition, analysis and critically revised the manuscript. All authors have read the submitted manuscript and agree to be accountable for all aspects of the work.

Supporting information

Supporting Information S1

ACKNOWLEDGEMENTS

None. No funding was received for this study.

Sharma P, Malik S, Wadhwan V, Gotur Palakshappa S, Singh R. Prevalence of oral manifestations in COVID‐19: a systematic review . Rev Med Virol . 2022;e2345. 10.1002/rmv.2345 [ PMC free article ] [ PubMed ] [ CrossRef ]

DATA AVAILABILITY STATEMENT

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Traws pharma’s icar poster highlights potency of covid-19 candidate.

Differentiated resistance profile positions Traws’ program as a potential class leader

NEWTOWN, Pa., May 23, 2024 (GLOBE NEWSWIRE) -- Traws Pharma, Inc. (“Traws” or “Traws Pharma”), a clinical stage biopharmaceutical company developing oral small molecules for respiratory viral diseases and cancer, today announced presentation of a poster at the annual International Conference on Antiviral Research (ICAR2024) which is being held from May 20 th to May 24 th in Gold Coast, Australia. The poster highlights positive results of preclinical experiments using patient isolates of COVID19 virus to define the resistance profile of ratutrelvir, formerly known as travatrelvir or TRX01, Traws’ ritonavir-free Mpro protease inhibitor for COVID19, currently in Phase 1 single and multiple ascending dose (SAD/MAD) escalation studies.

“We are very pleased to present the results of resistance studies for ratutrelvir at ICAR2024. Resistance studies are an important part of establishing a differentiation profile for an antiviral agent. Our initial data indicate that ratutrelvir has superior activity compared to nirmatrelvir against a range of omicron variants, based on a comparison of EC 50 . We believe the results presented at ICAR provide additional positive data to indicate that ratutrelvir has a differentiated resistance profile compared to nirmatrelvir,” said Werner Cautreels, Ph.D., Chief Executive Officer of Traws Pharma.

Dr. Cautreels continued, “Some resistance mutations are common to both drugs but a large part of resistance to nirmatrelvir was not seen with ratutrelvir. Together, ratutrelvir’s differentiated resistance profile, promising pharmacokinetic effects, potential to be used without ritonavir and the accelerated pace of Phase 1 enrollment put the compound on track to advance to Phase 2 studies in H2 2024 and position ratutrelvir as a potential class-leading therapy for COVID- 19.”

C. David Pauza, Ph.D., Chief Scientific Officer, Virology at Traws Pharma said, “Understanding the patterns of resistance mutations gives us the ability to identify circulating viruses that may already be resistant to individual antiviral agents; selecting the right drug can be guided by this information. The resistance studies presented at ICAR compared ratutrelvir to nirmatrelvir, the only Mpro inhibitor approved in the U.S. Our data suggest that ratutrelvir exhibited greater activity compared to nirmatrelvir against wild type Mpro, and remained active against Mpro variants with specific mutations that are associated with nirmatrelvir resistance.”

Dr. Pauza added, “An important finding was that critical mutations accounting for much of the resistance to nirmatrelvir were not found using ratutrelvir, indicating important differences between the two compounds. These differences were most apparent when the nirmatrelvir-resistant mutants P252L or T304I were involved in drug resistance, as these mutations were not observed after ratutrelvir selection.

The data were reported in a poster entitled, “ Travatrelvir, an inhibitor of SARS-CoV-2 Main Protease now in Phase 1 Clinical Trials: in vitro Drug Resistance Compared to Nirmatrelvir ” (Abstract 356V) presented at ICAR by Bhargava Teja Sallapalli, Master of Veterinary Science, Department of Veterinary Medicine, Virginia-Maryland School of Veterinary Medicine, College Park Maryland et al. The poster can be found on the Scientific Presentations section of the Traws Investor Relations web page.

About Ratutrelvir, the Phase 1 Program and Planned Next Steps

Ratutrelvir (also previously known as 83-0060) was designed as an inhibitor of the SARS-CoV-2 Mpro (3CL protease). It has demonstrated in vitro activity against the original strain of the virus as well as the delta and omicron variants and is more active than nirmatrelvir (PAXLOVID®, Pfizer’s Mpro inhibitor) in preclinical studies. Also in preclinical studies, ratutrelvir did not require co-administration with a human cytochrome P450 (CYP) inhibitor, such as ritonavir, and so it is expected to avoid associated drug:drug interactions, potentially permitting wider patient use. The drug candidate’s pharmacokinetic (PK) profile may enable a once daily, treatment regimen and reduce the likelihood of viral rebound.

The Phase 1 study will evaluate single and multiple ascending doses of ratutrelvir in a double-blinded, placebo-controlled clinical trial to assess safety, tolerability, and pharmacokinetics. Subjects will be randomized 3:1 in five fasted and one fed single ascending dosing (SAD) cohorts and two multiple ascending dosing (MAD) cohorts. Topline data from the study, which is being conducted in Australia (NCT06402136), and the initiation of an international Phase 2 study in subjects with moderate to severe COVID19, are expected to take place in H2 2024.

About Traws Pharma, Inc.

Traws Pharma is a clinical stage biopharmaceutical company developing oral small molecule therapies for the treatment of respiratory viral diseases and cancer. The viral respiratory disease program includes an oral inhibitor of the SARS-CoV-2 Mpro (3CL protease), ratutrelvir, and tivoxavir marboxil, a new oral antiviral drug candidate for influenza which targets the influenza cap-dependent endonuclease and has shown activity in cell-based assays against drug resistant viruses as well as against avian flu.

In the cancer program, Traws is developing the novel, proprietary multi-kinase CDK4-plus inhibitor narazaciclib for refractory endometrial cancer and potentially other cancers. Narazaciclib targets pathways involved in the development of resistance to CDK inhibitors.

Traws Pharma is committed to delivering novel compounds for unmet medical needs using state-of-the-art drug development technology. With a focus on product safety and a commitment to patients in need or that are specifically vulnerable, we build solutions for important medical challenges, aiming to alleviate the burden of viral infections and cancer.

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• Published: 16 May 2024

Effects of post-COVID-19 vaccination in oral cavity: a systematic review

• Anubhuti Sood   ORCID: orcid.org/0000-0001-9550-695X 1 ,
• Sreevatsan Raghavan 1 ,
• Deepika Mishra 2 &
• Harsh Priya 3  

Evidence-Based Dentistry ( 2024 ) Cite this article

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• Dental epidemiology
• Oral diseases

SARS-CoV-2 virus and its variants continue to be on a rampage worldwide. Several vaccines are being marketed to control their spread and reduce severity of symptoms in the affected. Various adverse events are being reported following the vaccine administration and therefore this systematic review investigated the oral adverse events post-COVID-19 vaccination.

Materials and methods

A systematic search of five databases was conducted. Case reports, case series and observational studies describing oral lesions/oral adverse effects (outcome) following anti-SARS-CoV-2 vaccination (exposure) in humans were included. Quality assessment of the studies was done using Joanna Briggs Institute Critical Appraisal tools. A working classification was developed from reported final diagnosis.

The systematic review included 18 individual cases. Majority of oral lesions occurred following BNT162b2 vaccination with average age of occurrence at 59.94 years. 67% of the affected individuals were female, with hypertension being the most common comorbidity.

Immune-mediated oral events have a propensity of occurrence following COVID-19 vaccination. mRNA-based vaccinations may have an affinity for causing oral adverse effects. It might be due to the immune dysregulation caused by these vaccinations.

The female, geriatric population and older individuals with co-morbidities might have an increased affinity to develop oral lesions post-COVID-19 vaccination.

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Data availability.

The data is available on request to corresponding author.

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Translational Health Science and Technology Institute, Faridabad, India

Anubhuti Sood & Sreevatsan Raghavan

Division of Oral Pathology and Microbiology, Centre for Dental Education and Research, All India Institute of Medical Sciences, Delhi, India

Deepika Mishra

Department of Public Health Dentistry, Centre for Dental Education and Research, All India Institute of Medical Sciences, Delhi, India

Harsh Priya

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Conceptualization: [Anubhuti Sood]; Methodology: [Anubhuti Sood and Harsh Priya]; Formal analysis and investigation: [Anubhuti Sood, Harsh Priya, Sreevatsan Raghavan and Deepika Mishra]; Writing—original draft preparation: [Anubhuti Sood]; Writing—review and editing: [Sreevatsan Raghavan, Harsh Priya and Deepika Mishra]; Supervision: [Harsh Priya and Deepika Mishra].

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Sood, A., Raghavan, S., Mishra, D. et al. Effects of post-COVID-19 vaccination in oral cavity: a systematic review. Evid Based Dent (2024). https://doi.org/10.1038/s41432-024-01014-6

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Received : 06 November 2023

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Published : 16 May 2024

DOI : https://doi.org/10.1038/s41432-024-01014-6

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Oral manifestations of COVID-19 disease: A review article

Affiliations.

• 1 Department of Dermatology, Kerman University of Medical Sciences, Kerman, Iran.
• 2 Leishmaniasis Research Center, Afzalipour Hospital, Kerman University of Medical Sciences, Kerman, Iran.
• PMID: 33236823
• PMCID: PMC7744903
• DOI: 10.1111/dth.14578

Dysgeusia is the first recognized oral symptom of novel coronavirus disease (COVID-19). In this review article, we described oral lesions of COVID-19 patients. We searched PubMed library and Google Scholar for published literature since December 2019 until September 2020. Finally, we selected 35 articles including case reports, case series and letters to editor. Oral manifestations included ulcer, erosion, bulla, vesicle, pustule, fissured or depapillated tongue, macule, papule, plaque, pigmentation, halitosis, whitish areas, hemorrhagic crust, necrosis, petechiae, swelling, erythema, and spontaneous bleeding. The most common sites of involvement in descending order were tongue (38%), labial mucosa (26%), and palate (22%). Suggested diagnoses of the lesions were aphthous stomatitis, herpetiform lesions, candidiasis, vasculitis, Kawasaki-like, EM-like, mucositis, drug eruption, necrotizing periodontal disease, angina bullosa-like, angular cheilitis, atypical Sweet syndrome, and Melkerson-Rosenthal syndrome. Oral lesions were symptomatic in 68% of the cases. Oral lesions were nearly equal in both genders (49% female and 51% male). Patients with older age and higher severity of COVID-19 disease had more widespread and sever oral lesions. Lack of oral hygiene, opportunistic infections, stress, immunosuppression, vasculitis, and hyper-inflammatory response secondary to COVID-19 are the most important predisposing factors for onset of oral lesions in COVID-19 patients.

Keywords: COVID-19; aphthous; gingivostomatitis; manifestation; oral.

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Publication types

• COVID-19* / complications
• Mouth Diseases / etiology*