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34:  Tuberculosis

David Cluck

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Patient presentation.

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Chief Complaint

“I have a cough that won’t go away.”

History of Present Illness

A 63-year-old male presents to the emergency department with complaints of cough/shortness of breath which he attributes to a “nagging cold.” He states he fears this may be something worse after experiencing hemoptysis for the past 3 days. He also admits to waking up in the middle of the night “drenched in sweat” for the past few weeks. When asked, the patient denies ever having a positive PPD and was last screened “several years ago.” His chart indicates he was in the emergency department last week with similar symptoms and was diagnosed with community-acquired pneumonia and discharged with azithromycin.

Past Medical History

Hypertension, dyslipidemia, COPD, atrial fibrillation, generalized anxiety disorder

Surgical History

Appendectomy at age 18

Family History

Father passed away from a myocardial infarction 4 years ago; mother had type 2 DM and passed away from a ruptured abdominal aortic aneurysm

Social History

Retired geologist recently moved from India to live with his son who is currently in medical school in upstate New York. Smoked ½ ppd × 40 years and drinks 6 to 8 beers per day, recently admits to drinking ½ pint of vodka “every few days” since the passing of his wife 6 months ago.

Sulfa (hives); penicillin (nausea/vomiting); shellfish (itching)

Home Medications

Albuterol metered-dose-inhaler 2 puffs q4h PRN shortness of breath

Aspirin 81 mg PO daily

Atorvastatin 40 mg PO daily

Budesonide/formoterol 160 mcg/4.5 mcg 2 inhalations BID

Clonazepam 0.5 mg PO three times daily PRN anxiety

Lisinopril 20 mg PO daily

Metoprolol succinate 100 mg PO daily

Tiotropium 2 inhalations once daily

Venlafaxine 150 mg PO daily

Warfarin 7.5 mg PO daily

Physical Examination

Vital signs.

Temp 100.8°F, P 96, RR 24 breaths per minute, BP 150/84 mm Hg, pO 2 92%, Ht 5′10″, Wt 56.4 kg

Slightly disheveled male in mild-to-moderate distress

Normocephalic, atraumatic, PERRLA, EOMI, pale/dry mucous membranes and conjunctiva, poor dentition

Bronchial breath sounds in RUL

Cardiovascular

NSR, no m/r/g

Soft, non-distended, non-tender, (+) bowel sounds

Genitourinary

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• Case report
• Open access
• Published: 19 November 2022

A case report of persistent drug-sensitive pulmonary tuberculosis after treatment completion

• Sergo A. Vashakidze 1 , 2 ,
• Abivarma Chandrakumaran 3 ,
• Merab Japaridze 1 ,
• Giorgi Gogishvili 1 ,
• Jeffrey M. Collins 4 ,
• Manana Rekhviashvili 1 &
• Russell R. Kempker 4  

BMC Infectious Diseases volume  22 , Article number:  864 ( 2022 ) Cite this article

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Mycobacterium tuberculosis (Mtb) has been found to persist within cavities in patients who have completed their anti-tuberculosis therapy. The clinical implications of Mtb persistence after therapy include recurrence of disease and destructive changes within the lungs. Data on residual changes in patients who completed anti-tuberculosis therapy are scarce. This case highlights the radiological and pathological changes that persist after anti-tuberculosis therapy completion and the importance of achieving sterilization of cavities in order to prevent these changes.

Case presentation

This is a case report of a 33 year old female with drug-sensitive pulmonary tuberculosis who despite successfully completing standard 6-month treatment had persistent changes in her lungs on radiological imaging. The patient underwent multiple adjunctive surgeries to resect cavitary lesions, which were culture positive for Mtb. After surgical treatment, the patient’s chest radiographies improved, symptoms subsided, and she was given a definition of cure.

Conclusions

Medical therapy alone, in the presence of severe cavitary lung lesions may not be able to achieve sterilizing cure in all cases. Cavities can not only cause reactivation but also drive inflammatory changes and subsequent lung damage leading to airflow obstruction, bronchiectasis, and fibrosis. Surgical removal of these foci of bacilli can be an effective adjunctive treatment necessary for a sterilizing cure and improved long term lung health.

Peer Review reports

Mycobacterium tuberculosis treatment has been evolving over the years, especially with the introduction of newer drugs and shorter regimens [ 1 , 2 ]. Apart from the cavitary nature of tuberculous disease, patients who have been treated with current regimens often are given the designation of cure without achieving proper sterilization. Patients who complete the tuberculous regimen are given the definition of cure after they achieve sputum negativity but many of these patients harbor bacilli within cavities that continue to exert their effects on the respiratory system [ 3 ]. The residual changes that occur in patients who have completed medical therapy have been poorly attended to in the literature. Patients that underwent surgical and medical sterilization have been reported to have better pulmonary health in the long term, especially after the removal of cavities [ 4 ].

Here, we report a patient who underwent a complete regimen of medical therapy for pulmonary tuberculosis and later had to have surgical resection of her cavities, which grew tuberculous bacilli even after achieving sputum negativity.

A 33-year-old female from the country of Georgia presented to a tuberculosis dispensary on July 10, 2020, with a temperature of 38° C and symptoms of malaise, productive cough, and night sweats. The patient had no known medical problems. She reported smoking ~ 10 cigarettes daily and denied alcohol or illicit drug use. She had 3 children and her husband was a prisoner being treated for pulmonary tuberculosis. Upon physical examination there were decreased breath sounds in the upper lobes of the lungs with dullness to percussion. The patient had a body mass index (BMI) of 16.3 kg/m 2 . A complete blood count revealed a moderate leukocytosis of 10.2 × 10 9 /L and an erythrocyte sedimentation rate (ESR) of 42 mm/h. Biochemical blood parameters were normal. Sputum testing found a negative acid-fast bacilli (AFB) microscopy, positive Xpert MTB/RIF test (no RIF resistance), and positive culture for Mycobacterium tuberculosis (Mtb). Additionally, drug susceptibility testing (DST) revealed sensitivity to rifampin, isoniazid, and ethambutol. Chest radiography revealed multiple small foci in the upper lobes of both lungs and a cavity in the right lung (Fig.  1 A). The patient was initiated on daily outpatient treatment with three pills of a fixed dosed combination pill containing isoniazid 75 mg, rifampin 150 mg, ethambutol 275 mg and pyrazinamide 400 mg. Treatment was given through directly observed therapy (DOT). She converted her sputum cultures to negative at 2 months and continued rifampin and isoniazid to finish 6 months of treatment. An end of treatment chest x-ray revealed fibrosis and honeycombing in the right upper lung, and fibrosis and dense focal shadows in the 1st and 2nd intercostal spaces of the left lung (Fig.  1 B). The complete treatment timeline is summarized in Fig.  2 .

A (left): Baseline chest X-ray showing a cavity in the right lung and multiple foci in the upper lobes of both lungs. B (right): End of initial treatment chest X-ray, showing fibrosis, local honeycombing and dense focal shadows in both lungs

Patient treatment timeline ( HRZE isoniazid, rifampin, pyrazinamide, ethambutol; HR isoniazid & rifampin; DOTS directly observed therapy, short-course; CT computed tomography; AFB acid fast bacilli)

A follow up chest computed tomography (CT) scan demonstrated a cavity in the right upper lobe measuring 12 × 10 mm in size with a thick and heterogeneous wall and nodules and bronchiectasis in the left lung (Fig.  3 A–D). Based on CT findings and in accordance with National tuberculosis guidelines, the patient was offered surgical resection of the affected portion of the lung. It should be noted that the patient reported no symptoms, complaints, or functional disability before the surgery. Preoperative workup including pulmonary function testing, an echocardiogram, bronchoscopy, and blood chemistries were normal. The patient consented to surgery and underwent a surgical resection of the S1 and S2 segments of the right lung 2 weeks later. Intraoperatively, moderate adhesions were visualized in the S1 and S2 area with a palpable dense formation ~ 3.0 cm in diameter, in addition to a dense nodule. Gross pathology of the resected lesion showed a thick-walled fibrous cavity filled with caseous necrosis (Fig.  4 A) corresponding to the right preoperative CT lesion seen on Fig.  3 A, C.

CT scan (January 11, 2021) showing, A a cavity in the upper lobe of the right lung with heterogeneous thick walls. B S1 and S2 segments of the left lung shows a 23 × 18 mm oval shaped calcified inclusions; C , D areas with calcified, compacted nodules 13 × 20 mm in size with additional traction bronchiectasis

A Gross pathological image of a resected cavity with caseous material from first surgery (S1 & S2 segment of right lung). B The gross pathology from the second surgery showed the presence of a blocked cavity measuring up to 2 cm in diameter filled with caseous material in the S1, S2 and C Tuberculoma in S6 segment

Microbiological analysis on the resected tissue revealed acid-fast bacilli on microscopy, and positive Xpert MTB/RIF and culture results. Mtb grew from the caseous center, inner and outer walls of the cavity and a resected foci located ~ 3 cm from the cavity. DST revealed sensitivity to isoniazid, rifampin, and ethambutol.

Pathological examination of the resected lesion showed findings consistent with fibrocavernous tuberculosis. No postoperative complications were experienced, and the patient reinitiated first-line therapy via DOT on the 2nd postoperative day and was discharged on postoperative day 11.

A follow up CT scan performed after 3 months showed postoperative changes in the right upper lobe, and an unchanged left lung (Fig.  5 A–C). Based on the persistent conglomerate of tuberculomas and multiple small tuberculous foci, growth of Mtb from the previous surgical specimen, and the patient’s social situation (mother of three young children) a second surgery to optimize the chance of cure was recommended. The patient reported no symptoms, complaints, or functional disability before the surgery. Preoperative sputum testing found negative AFB smear microscopy and culture. The patient underwent the second operation on May 18, 2021, in which the S1, S2 and part of the S6 segment of the left lung were resected. Intraoperatively, moderate adhesions seen along with a dense palpable ~ 3 cm mass in the S1 and S2 region and a dense focus in S6.

A – C Follow-up CT scan after first adjunctive surgery showing postoperative changes of the right lung and radiological changes in the left lung, that were unchanged compared to the initial CT. D Final CT scan showing normal postoperative changes with no cavities as previously seen

Microbiological examinations performed on resected tissue revealed positive AFB smear microscopy and Xpert MTB/RIF results and a negative AFB culture. The pathological examination of the surgical samples indicated a variety of destructive changes in addition to ongoing inflammation. The gross specimen of S1 and S2 segments of the left lung showed fibrocavernous tuberculosis shown in Fig.  4 B, which corresponds to the left lung lesion seen on the first preoperative CT in Figs.  3 B and 5 A in the second preoperative CT; the gross specimen of the S6 segment showed progressive tuberculoma seen in Fig.  4 C, which corresponds to the left lung lesion seen on the first preoperative CT in Figs.  3 D and 5 C in the second preoperative CT.

There were no postoperative complications, and tuberculosis (TB) treatment was reinitiated. The patient successfully completed treatment with normalization of clinical and laboratory parameters and a clinical outcome of cure in September 2021, ~ 14 months after beginning treatment. The patient had reported near complete resolution of her symptoms, having a much better ability to perform her daily activities. The patient appreciated the effects surgery had on her recovery and was happy to have gone through that treatment route. A post treatment CT scan demonstrated postoperative changes in the upper segments of both lungs (Fig.  5 D). Results from post treatment lung function testing were all within normal range.

Discussion and conclusions

We present this case to highlight the heterogeneous nature of pulmonary tuberculosis and need for an individualized treatment approach, especially for patients with cavitary disease. Over the last decade, novel diagnostics, drugs, and treatment regimens have revolutionized TB management including a recent landmark clinical trial demonstrating an effective 4-month regimen for drug-susceptible TB [ 1 ]. The move towards shorter regimens is critical to improve treatment completion rates and help meet TB elimination goals. However, during a transition to shorter treatment durations it is imperative that clinicians remain aware of complex and severe pulmonary TB cases that may require longer durations of treatment and adjunctive therapies such as surgery. Supporting evidence comes from a recent landmark study finding persistent inflammation on imaging associated with finding Mtb mRNA in sputum after successful treatment and a meta-analysis demonstrating a hard-to-treat TB phenotype not cured with the standard 6 months of treatment [ 2 , 5 ]. However, regarding recommendations for prolonging treatment beyond 6 months for drug-susceptible pulmonary tuberculosis, ATS/CDC/IDSA recommends (expert opinion) extended treatment for persons with cavitary disease and a positive 2 month culture (our patient would not have met this criteria); World Health Organization (WHO) does not recommend extended treatment for any persons with drug-susceptible TB [ 6 , 7 ]. Accumulating evidence demonstrates surgical resection may be an effective adjunctive treatment in cases with cavitary disease [ 8 , 9 , 10 , 11 , 12 ]. Ultimately, a precision medicine approach towards TB will be able to identify patients who would benefit from short course therapy and those who would benefit from longer therapy and adjunctive treatment including surgery [ 13 ].

Mtb has a unique ability and propensity to induce cavities in humans with various studies showing cavitary lesions in ~ 30 to 85% of patients with pulmonary tuberculosis [ 14 ]. Lung cavities are more common in certain groups including patients with diabetes mellitus and undernutrition such as our patient who had a baseline BMI of 16.3 kg/m 2 [ 15 , 16 ]. Their presence indicates more advanced and severe pulmonary disease as evidenced by their association with worse clinical outcomes. Cavitary disease has been associated with higher rates of treatment failure, disease relapse, acquired drug resistance, and long term-term pulmonary morbidity [ 2 , 17 , 18 , 19 ]. The impact of cavitary disease may be more pronounced in drug-resistant disease as shown in an observational study from our group which found a five times higher rate of acquired drug resistance and eight times higher rate of treatment failure among patients multidrug- or extensively drug-resistant cavitary disease compared to those without [ 20 ].

Mtb cavities are characterized by a fibrotic surface with variable vascularization, a lymphocytic cuff at the periphery followed by a cellular layer consisting of primarily macrophages and a necrotic center with foamy apoptotic macrophages and high concentrations of bacteria. Historically, each portion of the TB cavity has been conceptualized as concentric layers of a spherical structure due to its appearance on histologic cross-sections. However, recent studies using more detailed imaging techniques have shown most TB cavities exhibit complex structures with diverse, branching morphologies [ 21 ]. A dysregulated host immune response to Mtb is thought to contribute to the development of lung cavities, which may explain why cavitary lesions are seen less frequently among immunosuppressed patients including people living with Human Immunodeficiency Virus (HIV) [ 14 ]. The center of the TB cavity (caseum) is characterized by accumulation of pro-inflammatory lipid signaling molecules (eicosanoids) and reactive oxygen species, which result in ongoing tissue destruction, but do little to control Mtb replication [ 22 ]. Conversely, the cellular rim and lymphocytic cuff are characterized by a lower abundance of pro-inflammatory lipids and increases in immunosuppressive signals including elevated expression of TGF-beta and indoleamine-2,3-dioxygenase-1 [ 22 ]. The anti-inflammatory milieu within these TB cavity microenvironments impairs effector T cell responses, further limiting control of bacterial replication [ 23 , 24 , 25 ].

The combination of impaired cell-mediated immune responses with accumulation of inflammatory mediators at the rim of the caseum leads to ongoing tissue destruction with the potential for long-term pulmonary sequelae. Many with cavitary tuberculosis suffer chronic obstructive pulmonary disease after successful treatment and the risk may be greater in those with multidrug-resistant disease [ 3 , 4 ]. This has led to research into adjunctive treatment with immune modulator therapies with a goal of mitigating the over-exuberant inflammatory response at the interior edge of the cavity to limit tissue damage. In a recent randomized clinical trial, patients with radiographically severe pulmonary tuberculosis treated with adjunctive everolimus or CC-11050 (phosphodiesterase inhibitor with anti-inflammatory properties) achieved better long-term pulmonary outcomes versus those who received placebo [ 26 ]. Such results suggest the inflammatory response can be modified with appropriate host-directed therapies to improve pulmonary outcomes, particularly in those with cavitary tuberculosis.

Tuberculosis cavities not only hinder an effective immune response, but also prevent anti-tuberculosis drugs from achieving sterilizing concentrations throughout the lesion and especially in necrotic regions. The necrotic center of cavitary lesions is associated with extremely high rates of bacilli (up to 10 9 per milliliter), many of which enter a dormant state with reduced metabolic activity. Bacilli in this dormant state may be less responsive to the host immune response and exhibit phenotypic resistance to some anti-tuberculosis drugs thereby preventing sterilization and increasing chances of relapse [ 14 , 27 , 28 ]. The fact that the specimens from our patient’s second surgery were Xpert and AFB positive, but culture negative may indicate the presence of either dead bacilli or metabolically altered(dormant) bacilli that may be alive, but not culturable by standard techniques. Further, genomic sequencing studies have also found distinct strains of Mtb within different areas of the cavity that have varying drug-susceptibilities demonstrating cavities as a potential incubator for drug resistance [ 27 , 29 ].

Emerging literature has started to elucidate the varying abilities of drugs to penetrate into cavitary lesions and the importance of adequate target site concentrations. One notable study found that decreasing tissue concentrations within resected cavitary TB lesions were associated with increasing drug phenotypic MIC values [ 30 ]. Innovative studies using MALDI mass spectrometry imaging have further demonstrated varied spatiotemporal penetration of anti-TB drugs in human TB cavities [ 31 ]. This study found rifampin accumulated within caseum, moxifloxacin preferentially at the cellular rim, and pyrazinamide throughout the lesion, demonstrating the need to consider drug penetration when designing drug regimens in patients with cavitary TB. Computational modeling studies have further demonstrated the importance of complete lesion drug coverage to ensure relapse-free cure [ 32 ]. Furthermore, clinical trials are now incorporating these principles into study design by (1) using radiological characteristics to determine treatment length and (2) incorporating tissue penetration into drug selection and regimen design [ 33 , 34 ]. Beyond tissue penetration, varying drug levels and rapid INH acetylation status can also lead to suboptimal pharmacokinetics and poor clinical outcomes [ 35 , 36 ]. As highlighted in a recent expert document, clinical standards to optimize and individualize dosing need to be developed to improve outcomes [ 37 ].

Available literature points to a benefit of adjunctive surgical resection particularly among patients with drug resistant tuberculosis. A meta-analysis of 24 comparative studies found surgical intervention was associated with favorable treatment outcomes among patients with drug-resistant TB (odds ratio 2.24, 95% CI 1.68–2.97) [ 38 ]. Additionally, an individual patient data meta-analysis found that partial lung resection (adjusted OR 3.9, 95% CI 1.5–5.9) but not pneumectomy was associated with treatment success [ 39 ]. In two observational studies, we have also found that adjunctive surgical resection was associated with high and improved outcomes compared to patients with cavitary disease not undergoing surgery and was associated with less reentry into TB care. It should be noted that all studies of surgical resection for pulmonary TB were observational studies, which may be subject to selection bias, and no clinical trials (very difficult to implement in practice) were conducted to provide more conclusive evidence. Based on available evidence, the WHO has provided guidance to consider surgery among certain hard to treat cases of both drug-susceptible and resistant cavitary disease [ 40 ]. Criteria for surgical intervention included (1) failure of medical therapy (persistent sputum culture positive for M. tuberculosis ), (2) a high likelihood of treatment failure or disease relapse, (3) complications from the disease, (4) localized cavitary lesion, and (5) sufficient pulmonary function to tolerate surgery. For our patient, the severity of disease, lack of improvement of radiological imaging despite appropriate treatment, and high risk of relapse were the main indicators for surgery. Contraindications for surgery included a forced expiratory volume (FEV1) < 1000 mL, severe malnutrition, or patients at high risk for perioperative cardiovascular complications. With strict adherence to indications and contraindications for surgery, an acceptable level of postoperative complications are noted (5–17%) [ 4 , 38 ]. Our results also demonstrate the safety of adjunctive surgery, as our post-operative complication rate (8%) was low with the majority being minor complications [ 41 ].

As our case highlights, patients with persistent cavitary disease at the end of treatment require close clinical follow up and a tailored, individualized plan to determine the best approach for disease elimination and cure. In certain cases, including those with persistent cavitary disease and end of treatment, and where available, surgical resection is an effective adjunctive treatment option that can reduce disease burden and aid anti-tuberculosis agents in providing a sterilizing cure. As we enter an era of welcomed new shorter treatment options for tuberculosis it is imperative for clinicians to be able to identify and recognize complicated TB cases that require prolonged treatment and potentially adjunctive surgery.

Availability of data and materials

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

Abbreviations

Acid fast bacilli

American Thoracic Society

Body mass index

Center for Disease Control

Computed tomography

Directly observed therapy

Drug sensitive tuberculosis

Erythrocyte sedimentation rate

Human Immunodeficiency Virus

Infectious Diseases Society of America

Mycobacterium tuberculosis

• Tuberculosis

World Health Organization

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Acknowledgements

The authors thank the physicians, nurses, and staff at the NCTLD in Tbilisi, Georgia, who provided care for the patient described in this report. Additionally, the authors are thankful for the patient with pulmonary tuberculosis who was willing to have their course of illness presented and help contribute meaningful data that may help future patients with the same illness.

This study did not receive any specific funding.

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Thoracic Surgery Department, National Center for Tuberculosis and Lung Diseases, 50 Maruashvili, 0101, Tbilisi, Georgia

Sergo A. Vashakidze, Merab Japaridze, Giorgi Gogishvili & Manana Rekhviashvili

The University of Georgia, Tbilisi, Georgia

Sergo A. Vashakidze

Tbilisi State Medical University, Tbilisi, Georgia

Abivarma Chandrakumaran

Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

Jeffrey M. Collins & Russell R. Kempker

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SAV: Conceptualization; Data collection and interpretation; Scientific Writing including initial draft preparation and manuscript revision and editing. AC: Data interpretation; Table and Figure preparation; Literature review; Scientific Writing including initial draft preparation and manuscript revision and editing. MJ: Data collection; Scientific Writing including manuscript review and editing. GG: Data collection; Scientific Writing including manuscript review and editing. JMC: Data interpretation; Scientific Writing including manuscript review and editing. MR: Data interpretation; Scientific Writing including manuscript review and editing. RRK: Conceptualization; Literature review; Scientific Writing including manuscript review and editing. All authors read and approved the final manuscript.

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Vashakidze, S.A., Chandrakumaran, A., Japaridze, M. et al. A case report of persistent drug-sensitive pulmonary tuberculosis after treatment completion. BMC Infect Dis 22 , 864 (2022). https://doi.org/10.1186/s12879-022-07836-y

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A case study of a patient with multidrug-resistant tuberculosis

Affiliation.

• 1 Community nurse working in South West England.
• PMID: 30048191
• DOI: 10.12968/bjon.2018.27.14.806

In this case study, a nurse presents her reflections on the challenges of supporting a patient through his treatment journey for multidrug-resistant tuberculosis. The patient has significant comorbidities and social issues, such as diabetes and homelessness. There was also a language barrier. All these aspects made the management of his treatment challenging. The medication side effects and his lifestyle were also a barrier to full engagement. The same multidisciplinary team was involved with the patient and, despite the obstacles, he seemed willing to engage with treatment and the team.

Keywords: Comorbidities; Language barrier; Multidisciplinary team; Multidrug-resistant tuberculosis; Pulmonary TB; Under-served population.

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Racial and Ethnic Disparities in Tuberculosis—the Cost of Neglect

• 1 Institute for Social Research, University of Michigan, Ann Arbor
• 2 Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland
• Original Investigation Estimated Health and Economic Outcomes of Racial and Ethnic Tuberculosis Disparities Nicole A. Swartwood, MSPH; Yunfei Li, ScD; Mathilda Regan, PhD; Suzanne M. Marks, MPH; Terrika Barham, PhD; Garrett R. Beeler Asay, PhD; Ted Cohen, DPH; Andrew N. Hill, PhD; Charles R. Horsburgh Jr, MD; Awal D. Khan, PhD; Donna Hubbard McCree, PhD; Ranell L. Myles, PhD; Joshua A. Salomon, PhD; Julie L. Self, PhD; Nicolas A. Menzies, PhD JAMA Network Open

The recent study by Swartwood et al 1 examines the health and societal costs of continued racial and ethnic inequities in both tuberculosis (TB) cases and deaths among US-born persons in the US. The authors employ a rigorous statistical approach to estimate the cost of TB-related racial and ethnic inequities with respect to the number of cases and deaths associated with racial and ethnic inequities in TB, quality-adjusted life years lost, and actual US dollars spent as a result of the continued inequities in TB in the US. They reported that under a scenario where the current racial and ethnic inequities in TB incidence and deaths continue during the period of 2023 to 2035, an estimated 45% of all TB cases and deaths among US-born persons will be associated with racial and ethnic inequities, and an even greater proportion of cases and deaths among racialized minority populations will be associated with such inequities. The health consequences associated with such inequities would cost the US nearly $1 billion.

While there is a prevailing paradigm that TB in the US is not a major public health problem because of its low prevalence, Swartwood et al 1 remind us of the cost of neglecting infectious disease burden in US communities, the allowance of which furthers the marginalization and targeting of society’s most vulnerable. For nearly 3 decades, TB incidence and deaths have been declining in the US. 2 However, in the past 4 years, those declines have started to stagnate, and cases have increased. 2 TB in the US has evolved from a disease that was all-pervasive at the turn of the 19th century to one that disproportionately affects society’s most marginalized and vulnerable populations.

In recent decades, the assumption in many public health circles has been that TB in the US is primarily a product of importation, from either travelers or immigrants who acquire a latent infection outside of the US and then experience reactivation of the infection once in the US. 3 Studies have demonstrated, though, that a significant proportion of cases in the US can be attributed to recent transmission of TB occurring in the US among US-born persons. 2 , 4 And while there are striking social inequities in who is infected with TB generally, the inequities are noticeably pronounced when examining those cases attributable to recent transmission alone. A 2016 study showed, for example, that being classified in a racialized minority population, experiencing homelessness, or reporting a substance use disorder were all associated with a higher likelihood of being a case of recent transmission rather than reactivation of latent infection. 5

As an infectious disease, TB can serve as a necessary roadmap for the consequences of inaction and inattention to infectious diseases, particularly for respiratory infections that thrive in population-dense, close-quartered environments. For decades, TB has targeted those who are most marginalized in US society, allowing it to appear somewhat invisible to the mainstream population but never disappearing altogether. When new infectious diseases emerge, TB often rears its head again, an interaction of immune and social suppression, as was the case with both HIV/AIDS and now COVID-19. Without continued action and attention, TB will continue this same pattern, and as Swartwood et al 1 show, there are considerable societal costs associated with continued inequities in TB.

For this reason, we contend that TB reminds us more broadly of the cost, both in terms of actual lives as well as societal costs, of ignoring infectious disease in the US. In a time when the public has collectively grown weary of dealing with emerging and evolving infectious diseases, TB serves as a salient harbinger of the cost of ignoring these diseases. To further extend the findings in Swartwood et al, 1 we highlight 2 key areas that those involved in infectious disease research, control, and treatment can target to improve our understanding of the inequities in infectious disease burden and shed light on how we can develop strategies to address such inequities.

Development of Robust Surveillance Systems for Infectious Diseases

The US has a critical need for more robust surveillance systems for infectious disease. As has been demonstrated since the start of the COVID-19 pandemic, there are factors at the individual, neighborhood, and state level that contribute to which populations are most at risk for outbreaks and any downstream effects. Improved surveillance systems that can monitor disease outbreaks, of both existing and emerging infectious pathogens, and that can link with neighborhood-level socioeconomic data and state-level policies could drastically alter our ability to understand disease transmission and control in real-time. Such systems could be designed to shed light on who, where, and what factors contribute to outbreak occurrence, what might lead to disease persistence, and what decisions or community attributes (ie, access to care facilities or housing resources) result in disease control. Surveillance systems designed with a goal of improving health equity in mind could effectively identify which populations are most at risk and allocate resources accordingly.

Political Will and Resources

Even in the presence of robust surveillance systems, it is critical that the political will and resources be available to address infectious disease control and elimination. These efforts should remain a priority even when disease burden is only among a minority of individuals, specifically those who have less access to resources and therefore a higher likelihood of disease persistence. As has been proven through successful infectious disease management programs globally, like the US President’s Emergency Plan for AIDS Relief, investing in infectious disease control among those who are most vulnerable improves our collective ability to address gaps in treatment or health care access with an aim toward societal progress. The provision of resources to those who lack access not only prevents further disease transmission but also promotes resiliency among the communities affected, improving quality of life among populations that may already be experiencing stressors from multiple facets of structural oppression and disadvantage. Political will and resources are needed to acknowledge and address the continued burden of infectious diseases that marginalized populations face.

Published: September 10, 2024. doi:10.1001/jamanetworkopen.2024.31908

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Noppert GA et al. JAMA Network Open .

Corresponding Author: Grace A. Noppert, PhD, Institute for Social Research, University of Michigan, 426 Thompson St, Ann Arbor, MI 48104 ( [email protected] ).

Conflict of Interest Disclosures: None reported.

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Noppert GA , Hegde ST. Racial and Ethnic Disparities in Tuberculosis—the Cost of Neglect. JAMA Netw Open. 2024;7(9):e2431908. doi:10.1001/jamanetworkopen.2024.31908

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Tuberculosis: current challenges and beyond

Raquel villar-hernández.

1 Institut d'Investigació Germans Trias i Pujol, Barcelona, Spain

2 Genome Identification Diagnostics GmbH (GenID), Straßberg, Germany

15 Contributed equally as first authors

Arash Ghodousi

3 Vita-Salute San Raffaele University, Milan, Italy

Olha Konstantynovska

4 V.N. Karazin Kharkiv National University, Kharkiv, Ukraine

Raquel Duarte

5 EPI Unit, Instituto de Saúde Pública da Universidade do Porto, Porto, Portugal

6 Unidade de Investigação Clínica da Administração Regional de Saúde do Norte, Porto, Portugal

7 Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

8 Serviço de Pneumologia, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal

Christoph Lange

9 Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany

10 German Center for Infection Research (DZIF) Partner Site Borstel-Hamburg-Lübeck-Riems, Borstel, Germany

11 Respiratory Medicine and International Health, University of Lübeck, Lübeck, Germany

12 Cluster of Excellence Precision Medicine in Chronic Inflammation, Kiel, Germany

13 Department of Medicine, Karolinska Institute, Stockholm, Sweden

Mario Raviglione

14 Centre for Multidisciplinary Research in Health Science, University of Milan, Milan, Italy

Despite being a preventable and curable disease, tuberculosis (TB) is still a major global health threat and the second leading cause of death due to an infectious agent worldwide. All the efforts invested to end TB have resulted overall in rather slow decreases in TB incidence and mortality rates, which have been further negatively affected by the ongoing coronavirus disease 2019 (COVID-19) pandemic. While the majority of targets of the End TB Strategy remain off track, and we have not yet overcome the disruptions caused by the COVID-19 pandemic, recent conflicts such as the ongoing war in Ukraine are threatening the decrease of the burden of TB even further. To get back on track and get closer to ending TB, we need urgent, global, well-structured and committed multi-sectoral actions that go beyond national and global TB programmes with the support of deep investments in research and facilitation of equitable and rapid implementation of innovation worldwide.

Short abstract

Although preventable and curable, TB is still a major global health threat. The recent #COVID19 pandemic and other conflicts have left an unsettling scenario for #TB. We need urgent, united and effective multi-sectoral responses to #EndTB. https://bit.ly/40gpBrG

Introduction

Tuberculosis (TB) represents a major global health threat that, despite being preventable and treatable, is the 13th leading cause of death worldwide and the second leading infectious killer after coronavirus disease 2019 (COVID-19) [ 1 , 2 ]. In the past decades, the TB burden has been slowly decreasing; however, with the emergence of COVID-19 and the current political conflicts, including the war in Ukraine, proper functioning of healthcare services and TB control programmes are threatened, and the milestones set by the international health community to end TB remain unreached. In this viewpoint article, we discuss some of the challenges faced when tackling TB and the proposed strategy to end it.

Global TB burden

With 10.6 million estimated new cases, 1.6 million deaths and 1.7 billion latently infected in 2021, TB remains a major global health concern [ 1 ]. Although able to affect anyone anywhere, in low- and middle-income countries TB stands as the eighth and seventh most common cause of death, respectively, and these countries bear the burden of 80% of all TB cases [ 2 ]. In 2020, the World Health Organization (WHO) regions of South-East Asia and Africa accounted for more than two-thirds of all new TB cases (43% and 25%, respectively), with 46% of deaths estimated in South-East Asia and 39% in Africa [ 2 ]. Furthermore, ∼450 000 new cases worldwide are multidrug-resistant TB (MDR-TB)/rifampicin-resistant TB, 78% being MDR-TB. The highest MDR-TB rates are detected in Belarus, Russia and Moldova, with 38%, 35% and 33% of new TB cases, respectively, followed by Kyrgyzstan and Tajikistan with 29% and Kazakhstan and Ukraine with 27%, meaning that one out of three new TB cases are MDR-TB [ 3 ]. Although still a major concern, MDR-TB has remained stable in the past years, representing <5% of TB cases. Finally, 8% of TB cases globally are HIV-associated; three-quarters of these are found in Africa, with a high incidence also in Russia and Ukraine [ 3 ].

During the past years, the TB burden has been slowly decreasing at a rate of 1.5–2% per year [ 2 ]. Such low speed is due to many factors. Firstly, there is a large TB (latent) infection pool, which, together with risk factors for active disease, global ageing, slow and insufficient case detection, low cure rates and drug resistance, favours the slow incidence decline. Furthermore, TB is tightly linked to social-economic determinants. The main vulnerable people are those living in poor, crowded and poorly ventilated conditions; those living with HIV, diabetes, malnutrition, alcohol abuse, and drug and tobacco use; and migrants, refugees, prisoners, ethnic minorities and marginalised populations. The higher the gross domestic product (GDP) the lower the TB incidence, whilst the higher the level of undernutrition, the higher the incidence [ 1 ]. Moreover, other major disruptive events like the current pandemic and political conflicts greatly slow down the decline of TB burden.

The three layers

The determinants affecting TB burden may be classified into three layers of challenges that can be addressed within national TB programmes, the general health sector and beyond health; the latter are faced through good performance of sectors addressing undernutrition, poor living conditions, discrimination and marginalisation ( figure 1 ). To end TB, a multi-sectoral approach involving all stakeholders, all government departments, the private sector, community engagement and survivor groups is required. This approach should consider good health and well-being secured by national TB programmes and the general health system, together with different sectors of development within the framework of the Sustainable Development Goals (SDGs) addressing the variety of determinants affecting TB. In this regard, the Western Pacific Regional Framework to End TB has classified TB interventions into three layers: essential TB functions, health system foundation (bold policies), and health beyond health [ 4 ]. This classification reflects the global health approach that foresees the engagement of sectors beyond health to reach a health outcome such as TB burden decline.

The three layers of tuberculosis (TB) challenges and actions. MDR: multidrug-resistant. Adapted from [ 4 ].

The COVID-19 pandemic and war

Besides general challenges, certain unforeseen events greatly disrupt TB burden control actions. Since the end of 2019, COVID-19 has severely hit the global healthcare system and, subsequently, national and global TB programmes [ 5 , 6 ]. By reducing healthcare facilities and services, and reallocating human resources, diagnostic platforms and budgets, by the end of 2020 the pandemic had already caused a 20% decrease in TB detection and proper treatment, an 18% drop in case notifications, and an increase in TB deaths for the first time since the early 2000s [ 2 ]. According to the latest Global TB Report, there was a partial recovery in case notifications to 6.4 million in 2021, similar to that recorded in 2016–2017 [ 1 ].

While still struggling with COVID-19 consequences, the Russian invasion of Ukraine on 24 February 2022 put this situation at greater risk, especially given the severity of TB burden in both countries. Besides the terrible losses of lives due to their direct effects, wars and conflicts disrupt basic pillars of society such as education, economy, nutrition and access to social and healthcare services, resulting in devastating and long-lasting consequences. Since the invasion began, hundreds of buildings have been destroyed, thousands of civilians have died, and >7.7 million refugees have left Ukraine for neighbouring countries (according to the United Nations (UN) and UN Refugee Agency), causing Europe's largest refugee crisis since World War (WW) II. Looking back, during WWI, TB deaths increased greatly [ 7 ], and TB was considered the major health disaster of WWII [ 8 ], where malnutrition, overcrowding and health services disruption, among others, caused a major increase in TB deaths [ 9 ]. Although anti-TB drugs were not available until the end of WWII, the negative effects of these conflicts on TB have also been seen in later historical warfare events. During the civil war in Guinea-Bissau (June 1998 to May 1999), a three-fold increase in TB mortality during the first 6 months of war was attributed to treatment interruption [ 10 ]. Due to the Syrian crisis, starting in 2011, a sharp increase in TB cases was registered in neighbouring countries, attributed to the mass movement of refugees [ 11 ]. Additionally, with respect to the previous conflict in 2014 in Ukraine, one of the countries with the highest MDR-TB rates worldwide (>7000 new cases per year [ 3 ]), an almost two-fold increase of MDR-TB cases was documented in 2016 (post-war) versus 2014 (pre-war) (25% versus 14% of total TB cases, respectively) [ 12 , 13 ]. At the moment, according to official statistics [ 14 , 15 ], the numbers of newly diagnosed TB cases and patients on treatment are similar to those in the same time span, when comparing 2021 with 2022 data. This may be evidence for the hidden epidemic of TB in Ukraine due to undiagnosed and/or delayed diagnosed cases and the lack of data in the military conflict and occupied territory zones, respectively [ 14 , 15 ]. Therefore, the current war in Ukraine will undoubtedly have negative consequences for TB control and require additional efforts from neighbouring countries on refugee patient follow-ups.

The End TB Strategy

To decrease TB burden, global targets have been established in the context of the End TB Strategy of the WHO, the UN's SDGs, and the High-Level Meeting at the UN General Assembly in 2018. Approved by the WHO's World Health Assembly in 2014, the Strategy aims to “end TB” by 2030/2035 [ 16 ], ensuring equitable access to high-quality diagnosis, treatment, care and prevention for everyone affected by TB, without the risk of incurring catastrophic expenditure or social repercussions. The Strategy is based on three pillars: 1) integrated, patient-centred care and prevention; 2) bold policies and supportive systems; and 3) intensified research and innovation. These pillars are built upon four fundamental principles to be respected by all countries adopting the Strategy: 1) government stewardship and accountability, with monitoring and evaluation; 2) building a strong coalition with civil society and communities; 3) protecting and promoting human rights, ethics and equity; and 4) adaptation of the strategy and targets at country level, with global collaboration.

To evaluate the progression of the Strategy, certain milestones are set [ 16 ], which unfortunately are far from reached [ 1 , 2 ]. Although TB incidence has been falling by 2% per year since 2015, the overall decrease by 2020 was 11% instead of the intended 20% [ 2 ]. Importantly, due to the disruptions caused by COVID-19, the situation has worsened, with only 5.8 of the 9.9 million estimated cases in 2020 being reported and treated, resulting in a gap of 4.1 million missing TB cases [ 2 ]. Additionally, mortality increased by 5.6% in 2020 compared to 2019, leaving an overall 9.2% mortality decrease by 2020, far from the intended 35%. Thus, all targets to end TB are off track, except for that regarding people living with TB/HIV receiving TB preventive treatment [ 1 , 2 ]. To get back on track we need to accelerate development of new diagnostics, including new point-of-care tests for infection and disease, and explore further global digital health initiatives and artificial intelligence approaches, new drugs that are safer and easier to use, shorter treatment regimens, and effective pre- and post-exposure vaccines. Moreover, implementation capacity and urgency in transferring tools and technology to the most affected countries must be built. Taking the direction of enhanced collaboration within the health sector and beyond, policy makers and healthcare providers should further focus their efforts towards a system approach and universal health coverage to ensure that vertical, disease-specific efforts are progressively evolving towards harmonised, comprehensive and integrated methods while preserving the essential elements of an effective TB prevention, care and control strategy [ 17 ]. An example of an integrated approach is the adoption of a multi-disease diagnostic platform to detect several diseases through a single tool, thus facilitating detection, increasing the chances of successful screening, and perhaps avoiding the consequences of unidirectional reallocation of resources when facing pandemics such as COVID-19 [ 6 ]. Coupling more research investments with facilitation of equitable and rapid implementation of innovations is therefore a paradigm to advance TB response.

Conclusions

Despite the efforts to end TB, incidence and mortality rates are decreasing rather slowly, leaving TB as a major global health threat. This situation has been further affected by COVID-19 and other conflicts including the war in Ukraine, leaving an unsettling scenario for TB worldwide. Once again, we will be reminded that “war is the enemy of health” [ 18 ], that TB is tightly linked to social determinants and poverty, and that strong reliable multi-sectoral interventions are needed urgently to address it. Besides sound health practices and good performance of TB services, bold policies need to be a key focus in combating TB. Without adequate nutrition, universal health coverage and social protection, we will be unable to improve TB outcomes. In the absence of a global health approach that engages sectors devoted to poverty alleviation, social protection, nutrition, clean energy, sustainable cities, gender equality, equity in societies, etc ., we will not reach any target. Although a great part of the success in eliminating TB will depend on the immediate action taken by South-East Asian and African countries, global action is necessary as TB does not respect borders: “TB anywhere is TB everywhere”, as an old slogan used to say. To reach the set targets and end TB, having united, well-structured, reliable, accountable and effective multi-sectoral responses is crucial. Additionally, going beyond TB programmes and the healthcare sector, addressing the lack of social protection while mitigating crucial social determinants is also pivotal to end TB.

This article has been corrected according to the author correction published in the June 2023 issue of Breathe .

Disclaimer: This communication reflects the authors’ view and neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained therein.

Conflicts of interest: The authors have no conflicts of interest to disclose.

Support statement: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 101007873. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA, Deutsches Zentrum für Infektionsforschung e.V. (DZIF), and Ludwig-Maximilians-Universität Munich (LMU). EFPIA/AP contribute to 50% of funding, whereas the contribution of DZIF and the LMU University Hospital Munich has been granted by the German Federal Ministry of Education and Research.

Tuberculosis

On this page, coping and support, preparing for your appointment.

To diagnosis a tuberculosis (TB) infection, your health care provider will do an exam that includes:

• Listening to you breathe with a stethoscope.
• Checking for swollen lymph nodes.
• Asking you questions about your symptoms.

Your health care provider will order tests if:

• Tuberculosis is suspected.
• You were likely exposed to a person with active tuberculosis (TB) disease.
• You have health risks for active TB disease.

Your provider will determine whether a skin test or blood test is the best option.

A tiny amount of a substance called tuberculin is injected just below the skin on the inside of one forearm. Within 48 to 72 hours, a health care worker will check your arm for swelling at the injection site. The size of the raised skin is used to determine a positive or negative test.

This test is seeing if your immune system reacts, or has made an antibody, to tuberculosis. A positive test indicates you likely have either a latent TB infection or active TB disease. People who had a TB vaccination might get a positive test even if they have no infection.

A negative test means that your body didn't react to the test. It doesn't necessarily mean you don't have an infection.

Blood tests

A sample of blood is sent to a lab. One lab test finds out whether certain immune system cells can "recognize" tuberculosis. A positive test shows that you have either a latent TB infection or active TB disease. Other tests of the blood sample can help determine if you have active disease.

A negative result means you likely do not have a TB infection.

A chest X-ray can show irregular patches in the lungs that are typical of active TB disease.

Sputum tests

Your health care provider may take a sample of the mucus that comes up when you cough, also called sputum. If you have active TB disease in your lungs or voice box, lab tests can detect the bacteria.

A relatively quick laboratory test can tell if the sputum likely has the TB bacteria. But it may be showing bacteria with similar features.

Another lab test can confirm the presence of TB bacteria. The results often take several weeks. A lab test also can tell if it's a drug-resistant form of the bacteria. This information helps your health care provider choose the best treatment.

Other lab tests

Other lab tests that may be ordered include:

• Breath test.
• Procedure to remove sputum from your lungs with a special tube.
• Urine test.
• Test of the fluid around the spine and brain, called cerebrospinal fluid.

More Information

• Chest X-rays

If you have a latent TB infection, your health care provider may begin drug treatments. This is especially true for people with HIV/AIDS or other factors that increase the risk of active TB disease. Most latent TB infections are treated for three or four months.

Active TB disease may be treated for four, six or nine months. Specialists in TB treatment will determine which drugs are best for you.

You will have regular appointments to see if you're improving and to watch for side effects.

Take all of the drugs

It is important to take every dose as instructed. And you must complete the full course of treatment. This is important for killing the bacteria in your body and preventing new drug-resistant bacteria.

Your public health department may use a program called directly observed therapy (DOT). With directly observed therapy (DOT), a health care worker visits you at home to watch you take your dose of drugs.

Some health care departments have programs that let you take your drugs on your own. The Centers for Disease Control and Prevention has printable forms you can use to keep track of your daily doses.

Most common TB drugs

If you have a latent TB infection, you might need to take only one or two types of drugs. Active TB disease requires taking several drugs. Common medications used to treat tuberculosis include:

• Rifampin (Rimactane).
• Rifabutin (Mycobutin).
• Rifapentine (Priftin).
• Pyrazinamide.
• Ethambutol (Myambutol).

You may be prescribed other drugs if you have drug-resistant tuberculosis or other complications from your illness.

Medication side effects

Most people can take TB drugs without serious side effects. If you have serious side effects, your care provider may ask you to stop taking a drug. You may have to change the dose of a drug.

Talk to your health care provider if you experience any of the following:

• Upset stomach.
• Loss of appetite.
• Severe diarrhea.
• Light-colored stool.
• Dark urine.
• Yellowish skin or eye color.
• Changes in vision.
• Dizziness or trouble with balance.
• Tingling in hands or feet.
• Easy bruising or bleeding.
• Unexplained weight loss.
• Unexplained tiredness.
• Sadness or depression.
• Joint pain.

It is important for you to list all drugs, dietary supplements or herbal remedies you take. You may need to stop taking some of these during your treatment.

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The long treatment plan for tuberculosis can be challenging. Anger or frustration are normal. Talking to someone, such as a therapist, might help you develop coping strategies.

You are likely to start with an appointment with your health care provider. You may be referred to a doctor who specializes in treating infectious diseases.

What you can do

When you make the appointment, ask if there's anything you need to do in advance. Make a list of:

• Your symptoms, including any that may seem unrelated to the reason for which you scheduled the appointment, and when they began.
• Key personal information, including recent life changes or international travel.
• All medications, vitamins or supplements you take, including doses.
• Questions to ask your doctor.

For tuberculosis, some basic questions to ask your doctor include:

• What's the most likely cause of my symptoms?
• Do I need tests?
• What treatments are available? Which do you recommend?
• What if the treatment doesn't work?
• How long do I have to stay on the treatment?
• How often do I need to follow up with you?
• I have other health problems. How can I best manage these conditions together?

What to expect from your doctor

Be prepared to answer the following questions during your appointments:

• What symptoms have you had?
• When did your symptoms begin?
• Do you have HIV or AIDS?
• Have you been around anyone with active TB disease?
• Were you born in another country?
• Have you traveled in another country?
• Were you vaccinated against tuberculosis as an infant?
• Have you ever had tuberculosis or a positive TB skin test?
• Have you ever taken medicine for TB ? If so, what kind and for how long?
• What kind of work do you do?
• How much alcohol do you drink?
• Do you inject drugs?
• What drugs, dietary supplements or herbal remedies do you take?

Mar 22, 2023

• Tuberculosis (TB). Merck Manual Professional Version. https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb. Accessed Jan. 4, 2023.
• Bennett JE, et al. Mycobacterium tuberculosis. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Jan. 4, 2023.
• Drug-resistant TB. Centers for Disease Control and Prevention. https://www.cdc.gov/tb/topic/drtb/default.htm. Accessed Jan. 4, 2023.
• Questions and answers about tuberculosis. Centers for Disease Control and Prevention. https://www.cdc.gov/tb/publications/faqs/tb-qa.htm. Accessed Jan. 4, 2023.
• AskMayoExpert. Tuberculosis. Mayo Clinic; 2022.
• Extrapulmonary tuberculosis (TB). Merck Manual Professional Version. https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/extrapulmonary-tuberculosis-tb. Accessed Jan. 4, 2023.
• Bacterial meningitis. Centers for Disease Control and Prevention. https://www.cdc.gov/meningitis/bacterial.html. Accessed Jan. 24, 2023.
• TB disease burden. Global Tuberculosis Report. World Health Organization. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022/tb-disease-burden/2-1-tb-incidence. Accessed Jan. 25, 2023.
• Treatment regimens for latent TB infection. Centers for Disease Control and Prevention. https://www.cdc.gov/tb/topic/treatment/ltbi.htm. Accessed Jan. 26, 2023.
• Treatment for TB disease. Centers for Disease Control and Prevention. https://www.cdc.gov/tb/topic/treatment/tbdisease.htm. Accessed Jan. 26, 2023.
• Rizza SA (expert opinion). Mayo Clinic. Feb. 7, 2023.
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Related Posts

September 10, 2024

Expert Perspective

Can Molecular Tests Revolutionize Tuberculosis Control?

Tuberculosis (TB) remains a significant global health challenge. In 2022, about 1.3 million people died from TB, while an estimated 10.6 million people contracted the disease. 1 TB disproportionately impacts people in low- and middle-income countries, 2 where healthcare resources are limited. However, new tests offer hope for better disease control.

Regional Impact of TB

TB is a major health concern in the Middle East and North Africa (MENA), 1  where research shows a high prevalence (42%) of latent TB infections. 3 If not treated, latent tuberculosis infections can progress to active TB, contributing to the spread of the disease.

Migration and crowded living conditions often worsen the spread of TB in the MENA region. For instance, mass gatherings like the Hajj pilgrimage offer opportunities for TB transmission. A 2023 study found 0.7% of non-hospitalized and 2.9% of hospitalized pilgrims tested positive for TB, with significant cases from South Asia and Africa. 4 The study highlights the need for better TB screening and awareness to avoid missed cases.

Challenges & Gaps in TB Management

The COVID-19 pandemic disrupted prior gains in TB management, resulting in increased TB incidence rates between 2020 and 2021, versus declines of about 2% per year for most of the past two decades. COVID-19-related disruptions resulted in a staggering half million excess deaths from TB. 1 Although there was a major global recovery in new TB diagnoses in 2022, TB remained a leading cause of death from an infectious disease, second only to COVID-19 in 2022. Additionally, global TB targets set for 2018-2022 at the first UN high-level meeting on TB were largely missed, and END TB Strategy targets were not met. 1 These statistics indicate a dire situation in need of action.

Missed cases during the Hajj pilgrimage provide one example of the diagnostic gap in TB. In 2022, the World Health Organization (WHO) estimated that 3.1 million people fell ill with TB but weren’t diagnosed or reported. 1   Without a diagnosis, patients not only go without treatment but are also more likely to spread the illness to others.

Advancements in TB Diagnostics

Recent years have seen significant advancements in TB testing, which are vital for effective disease management. The WHO updated its guidelines in 2024, recommending diagnostic tools for TB relevant to various testing scenarios, including moderate and low-complexity automated nucleic acid amplification tests (NAATs) for the detection of TB and drug resistance, antigen detection tests, and line probe assays. 5 One of the critical updates is the inclusion of targeted next-generation sequencing tests for drug-resistant TB (DR-TB). These tests can identify resistance to a broad list of drugs, informing treatment recommendations.

Automated Nucleic Acid Amplification Tests

The Xpert ® MTB/RIF and Xpert MTB/RIF Ultra tests are recommended as initial diagnostic tests for TB and rifampin resistance detection. 5 These molecular tests detect TB bacterial DNA and rifampicin resistance genes directly from sputum samples. Rifampicin is a critical first-line drug for TB treatment, and resistance to it can indicate multidrug-resistant TB (MDR-TB), which is more complex to treat.

The WHO recommendation of such tests for detection in sputum rather than smear microscopy/culture and phenotypic drug susceptibility testing provides guidance towards simple, accurate, and accessible options to meet testing needs, even in resource-limited environments.

Xpert MTB/XDR is the only test in the new WHO-designated class “Low complexity automated NAATs for the detection of resistance to isoniazid and second-line anti-TB agents.” 5 This new class of diagnostics is intended for use as a reflex test in Tb-positive specimens, offering rapid drug susceptibility information. WHO notes that “Results are available in under 90 minutes, leading to faster time to results than the current standard of care, which includes LPAs and culture-based phenotypic DST.” 5

While the Xpert tests were the first ever WHO-endorsed tests for TB and rifampin resistance detection, 6 several other molecular tests from various manufacturers are now included as WHO-recommended tools in the fight against TB. 5 Given the magnitude of the TB crisis, continued innovation, development, and mechanisms to broaden access are crucial.

The Role of Molecular Diagnostics

Molecular diagnostics have revolutionized TB management. Traditional methods, such as smear microscopy and culture, can be time-consuming and less accurate than molecular tests. The impact of front-line tests such as Xpert MTB/RIF Ultra has been widely reported, providing fast, accurate, and accessible results in developed as well as resource-limited settings. 7-10 Yet, less than half of the 7.5 million people newly diagnosed with TB in 2022 received a WHO-recommended rapid diagnostic test. 1

Modern molecular tests are being designed for use in laboratory environments and decentralized settings where care is provided. Such flexibility increases adoption within communities, allowing more patients to be reached. Recent advancements in drug resistance detection by molecular tests allow healthcare facilities to follow recommended treatment algorithms, which specify testing to determine and initiate appropriate therapy. These transitions will help close the diagnostic gap, allowing TB to be diagnosed earlier, more accurately, and more broadly than with traditional methods.

 A Path Forward

Dr. Tedros Adhanom Ghebreyesus, Director-General of the WHO has observed that “If the pandemic has taught us anything, it’s that with solidarity, determination, innovation and the equitable use of tools, we can overcome severe health threats. Let’s apply those lessons to tuberculosis. It is time to put a stop to this long-time killer. Working together, we can end TB.” These words ring true as a vital call to action. With continued improvements in diagnostic testing, greater access to recommended molecular tools, and sustained commitment to close the diagnostic gap, the goal of TB elimination remains in sight.

1. Global Tuberculosis Report 2023 [Internet]. [cited 2024 Jul 2]. Available from: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023

2. Tuberculosis - Our World in Data [Internet]. [cited 2024 Jul 2]. Available from: https://ourworldindata.org/tuberculosis

3. Barry M. Prevalence of latent tuberculosis infection in the middle east and north africa: A systematic review. Pulm Med. 2021 Jan 28;2021:6680651.

4. Yezli S, Yassin Y, Mushi A, Maashi F, Abdelmalek NM, Awam AH, et al. Undiagnosed and missed active pulmonary tuberculosis during mass gatherings: a prospective cross-sectional study from the Hajj pilgrimage. Eur J Clin Microbiol Infect Dis. 2023 Jun;42(6):727–40.

5. WHO consolidated guidelines on tuberculosis: Module 3: Diagnosis – Rapid diagnostics for tuberculosis detection. Geneva: World Health Organization; 2024.

6. Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system: policy statement [Internet]. [cited 2024 Jul 2]. Available from: https://www.who.int/publications/i/item/9789241501545

7. Opota O, Zakham F, Mazza-Stalder J, Nicod L, Greub G, Jaton K. Added Value of Xpert MTB/RIF Ultra for Diagnosis of Pulmonary Tuberculosis in a Low-Prevalence Setting. J Clin Microbiol. 2019 Feb;57(2).

8. Saavedra B, Mambuque E, Nguenha D, Gomes N, Munguambe S, García JI, et al. Performance of Xpert MTB/RIF Ultra for tuberculosis diagnosis in the context of passive and active case finding. Eur Respir J. 2021 Dec 23;58(6).

9. Zifodya JS, Kreniske JS, Schiller I, Kohli M, Dendukuri N, Schumacher SG, et al. Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis. Cochrane Database Syst Rev. 2021 Feb 22;2:CD009593.

10. Choi HW, Miele K, Dowdy D, Shah M. Cost-effectiveness of Xpert® MTB/RIF for diagnosing pulmonary tuberculosis in the United States. Int J Tuberc Lung Dis. 2013 Oct;17(10):1328–35. 

September 12, 2024

Impact Story

PCR Screening at a British Hospital Enables Timely Infection Control

Royal Liverpool and Broadgreen University Hospitals NHS Trust in the U.K. solve the problem of long TAT times for CPE testing using on-demand PCR testing from Cepheid.

September 11, 2024

Danish HCV Testing Program Improves Patient Management & Access

A Danish mobile service features a mobile HCV RNA POC testing facility that brings HCV testing, using the GeneXpert® system, to a population that is often not reached through traditional healthcare pathways.

Cepheid Expands in India to Support Global Efforts in Fight Against TB

Cepheid opens new manufacturing facility in Banglore, India to support global efforts to win against tuberculosis.