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Case study of a patient with tuberculosis

15 Case study of a patient with tuberculosis Maria Mercer Chapter aims • To provide you with a case study of a patient who has been diagnosed with pulmonary tuberculosis (TB) together with the rationale for care • To encourage you to research and deepen your knowledge of TB Introduction This chapter provides you with an example of the nursing care that a patient with pulmonary TB might require. The case study has been written by a TB nurse specialist and provides you with a patient profile to enable you to understand the context of the patient. The case study aims to guide you through the assessment, nursing action and evaluation of a patient with pulmonary TB together with the rationale for care. Activity In Chapter 1 you were asked to revise the normal anatomy and physiology of the respiratory system (see Montague et al 2005 ) and a brief definition of TB was given. Before reading the case study below, find out how pulmonary TB would affect the respiratory system and what symptoms a patient with TB might present with. The following article may help you: William VG (2006). Tuberculosis: clinical features, diagnosis and management. Nursing Standard 20(22):49–53. Online. Available at: http://nursingstandard.rcnpublishing.co.uk/archive/article-tuberculosis-clinical-features-diagnosis-and-management (accessed July 2011). Patient profile Mr Patel is a 21-year-old gentleman who lives in a shared flat with friends and studies English at a local college. He is a new arrival to the UK having arrived from Bangladesh in October 2009. There are six adults, including Mr Patel, who share a two-bedroom flat. They share three adults to a room. He was referred to accident and emergency (A&E) via his GP with a 2-month history of a productive cough (no episodes of haemoptysis), associated fevers, drenching night sweats, loss of appetite and a 5-kg weight loss. In the last 7 days his symptoms have worsened and warranted the admission via A&E. Assessment on admission Mr Patel has a pyrexia of 38.5°C, he is cachectic and has pleuritic chest pain. His respiratory rate is slightly raised at 18 per minute and he has a tachycardia of 114 beats per minute. Blood pressure is normal. Inflammatory markers – erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) – are raised at 72 mm/h and 65.4 mg/L. A chest X-ray has been reported as abnormal: ‘Patchy shadowing seen in left upper lobe? Pulmonary TB.’ Activity See Appendix 4 in Holland et al ( 2008 ) for possible questions to consider during the assessment stage of care planning. Mr Patel’s problems Based on your assessment of Mr Patel, the following problems should form the basis of your care plan: • Mr Patel has a potential diagnosis of pulmonary TB which can be an infectious disease and public health risk. • Mr Patel feels stigmatised because of respiratory isolation measures and the potential diagnosis of TB. • Mr Patel has a temperature, raised inflammatory markers, a slightly elevated respiratory rate and a tachycardia. • Mr Patel is nutritionally compromised because of a 5-kg weight loss due to anorexia. • Mr Patel has pleuritic chest pain associated with coughing and expectoration of sputum. Mr Patel’s nursing care plans 1. Problem: Mr Patel has an infection. Pulmonary TB is felt to be the primary diagnosis. Goal: To limit transmission of TB to other patients and staff and ensure prompt treatment is commenced. Nursing action Rationale Mr Patel to be isolated in a side room with bathroom facilities with respiratory isolation measures in place immediately The door to the side room must be shut at all times Appropriate face masks (FFP2 or FFP3, depending on risk assessment – refer to infection control/TB policy) should be worn when entering Mr Patel’s room and he should wear the appropriate face mask if he needs to leave the side room for investigations Gloves and aprons do not need to be worn unless handling bodily secretions Liaise with bed managers and infection control team to expedite bed availability as necessary To reduce the risk of TB transmission to other patients and staff Collect three consecutive sputum specimens for acid-fast bacilli (AFB) Send one sputum specimen urgently on day of admission To ascertain diagnosis and ensure the appropriate treatment is commenced promptly Ensure Mr Patel is aware that sputum specimens need to be collected consecutively. Label 3 sputum pots clearly and leave in side room. Instruct Mr Patel to inform the nurse caring for him when the sputum for each day is ready so it can be collected and sent to the Laboratory as soon as possible. To ascertain diagnosis and ensure the appropriate treatment is commenced promptly. Contact the TB nurses to perform a Mantoux test if prescribed by the medical staff. To facilitate prompt diagnosis and obtain specialist nursing advice and support Ensure effective communication with Mr Patel explaining why the above measures are necessary and providing reassurance and support To alleviate fear and anxiety Evaluation:

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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.

• Alcohol Drinking
• Antitubercular Agents / administration & dosage
• Antitubercular Agents / therapeutic use*
• Communication Barriers
• Diabetes Complications
• Drug Therapy, Combination
• Social Support
• Tuberculosis, Multidrug-Resistant / complications
• Tuberculosis, Multidrug-Resistant / drug therapy*
• Tuberculosis, Multidrug-Resistant / nursing*
• United Kingdom
• Antitubercular Agents

• 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

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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

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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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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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Tuberculosis in older adults: case studies from four countries with rapidly ageing populations in the western pacific region

• Alvin Kuo Jing Teo 1 , 2 , 11 ,
• Kalpeshsinh Rahevar 3 ,
• Fukushi Morishita 3 ,
• Alicia Ang 15 ,
• Takashi Yoshiyama 5 ,
• Akihiro Ohkado 5 ,
• Lisa Kawatsu 5 ,
• Norio Yamada 5 ,
• Kazuhiro Uchimura 5 ,
• Youngeun Choi 6 ,
• Zi Chen 7 ,
• Siyan Yi 1 , 8 , 9 ,
• Manami Yanagawa 3 ,
• Kyung Hyun Oh 3 ,
• Kerri Viney 10   na1 ,
• Ben Marais 2 , 11   na1 ,
• Heejin Kim 6   na1 ,
• Seiya Kato 5   na1 ,
• Yuhong Liu 12   na1 ,
• Catherine W.M. Ong 4 , 13 , 14   na1 &
• Tauhid Islam 3   na1  

BMC Public Health volume  23 , Article number:  370 ( 2023 ) Cite this article

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The Western Pacific Region has one of the fastest-growing populations of older adults (≥ 65 years) globally, among whom tuberculosis (TB) poses a particular concern. This study reports country case studies from China, Japan, the Republic of Korea, and Singapore reflecting on their experiences in managing TB among older adults.

Across all four countries, TB case notification and incidence rates were highest among older adults, but clinical and public health guidance focused on this population was limited. Individual country reports illustrated a range of practices and challenges. Passive case finding remains the norm, with limited active case finding (ACF) programs implemented in China, Japan, and the Republic of Korea. Different approaches have been trialled to assist older adults in securing an early diagnosis, as well as adhering to their TB treatment. All countries emphasised the need for person-centred approaches that include the creative application of new technology and tailored incentive programs, as well as reconceptualisation of how we provide treatment support. The use of traditional medicines was found to be culturally entrenched among older adults, with a need for careful consideration of their complementary use. TB infection testing and the provision of TB preventive treatment (TPT) were underutilised with highly variable practice.

Older adults require specific consideration in TB response policies, given the burgeoning aging population and their high TB risk. Policymakers, TB programs and funders must invest in and develop locally contextualised practice guidelines to inform evidence-based TB prevention and care practices for older adults.

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Globally the number of older adults (aged ≥ 65 years) is expected to triple by 2100 [ 1 ]. Life expectancy at birth has gradually increased since the 1950s, [ 1 ] with the number of older adults projected to exceed children aged < 5, across all economies by 2020 [ 2 ]. The Western Pacific Region has one of the fastest-growing populations of older adults globally. In 2019, life expectancy at birth of the population was 4 years above the global estimate of 73.3 years [ 3 ]. Japan, for instance, is the most aged country in the world (average life expectancy 85 years) [ 4 ]. Several other countries in the region, particularly the People’s Republic of China (hereinafter referred to as China), the Republic of Korea, and the Republic of Singapore (hereinafter referred to as Singapore), were estimated to have an increase in the proportion of older adults globally between 2019 and 2050.

Japan has the highest proportion of older adults in the world, at 28% of the total population in 2020, [ 5 ] and the proportion is expected to rise to 38% by 2065 [ 6 ]. China is also undergoing a profound demographic transition. In 2021, the number of older adults reached 191 million, amounting to 13.5% of the total population. The number rose by 4.6% compared to the previous year, [ 7 ] and the increasing trend is likely to persist with the number of older adults expected to exceed 480 million (34.6% of the total population) by 2050 [ 8 ]. Similarly, the demographic transition in the Republic of Korea has seen rapid growth in the older adult population. In 2020, 16% of the total population was ≥ 65 years; this is expected to reach 37% by 2050 [ 9 ]. The older adult population made up 13% of the total population in Singapore in 2020 [ 5 ]. The proportion is projected to rise on the same trajectory as China, Japan, and the Republic of Korea in the next few decades [ 1 ].

Improvements in life expectancy have been attributed to better nutrition, political stability, risk factor reduction and improved healthcare access [ 10 ]. Globally, older adults contributed 26% of the total disease burden (measured in disability-adjusted life years [DALYs]); 38% of the burden in high and upper-middle-income, and 16% in low-and lower-middle-income regions in 2019 [ 11 ]. Non-communicable diseases such as cancer, cardiovascular disease and neurological disorders accounted for most of this burden, but respiratory infections, including tuberculosis (TB), are a major contributor as well [ 11 ]. In fact, TB case notifications and estimated disease incidence rates were highest among older adults in China, Japan, the Republic of Korea, and Singapore (Fig.  1 ) [ 12 ].

The proportion of notified TB cases aged ≥ 65 in Japan, the Republic of Korea, Singapore, China, the Western Pacific region, and globally 2013−2020

Data source: World Health Organization Global TB Programme 2021

With increasing age, progressive immune dysfunction (immunosenescence) increases the risk for TB disease development [ 13 , 14 ]. The convergence of co-morbidities such as diabetes, chronic respiratory disease and undernutrition, and lifestyle behaviour like tobacco smoking also increase TB risk [ 15 , 16 , 17 , 18 ]. Considering the burgeoning aging population in the Western Pacific Region and the limited guidance specific to this population, it is clear that the needs of older adults require greater recognition in TB response policies. This study reports country case studies from China, Japan, the Republic of Korea, and Singapore, reflecting on country-specific experiences in TB diagnosis and management among older adults. The case studies are a part of a broader endeavour, including a narrative review and analysis of epidemiological trends, to understand and document TB management among older adults in the region. The findings from the narrative review (see supplementary materials for methods) were used to support the country-specific experiences reported in the case studies.

TB epidemiology

China has the second-highest TB burden globally. In 2020, China had an estimated 842,000 people with TB (59 per 100,000 population per year), with older adults accounting for a quarter of all cases [ 12 ]. China notified 159,100 cases (19% of all notified cases) among older adults, [ 12 ] and a consistently increasing trend has been observed over the last two decades [ 19 ]. The fifth national TB epidemiological survey performed in 2010 recorded prevalence rates for clinical and bacteriologically confirmed TB as 482 and 138/100,000 population, respectively, among older adults [ 20 ]. The TB prevalence rate in the survey increased with age and peaked in the 75−79 year age group at 866/100,000 population (overall prevalence rate: 442/100,000 population [95% CI 417−469]) [ 20 ]. A subsequent prospective cohort study reported high TB incidence rates, [ 21 ] highlighting the need to prioritise older adults in the TB response. TB-related mortality was also more prevalent among older adults [ 19 ] concentrated in China’s Central and South-Eastern regions, [ 22 ] among lower-income residents from rural areas and in those with comorbidities [ 23 ].

Health system structure and TB services

The Government of China introduced directly observed treatment (DOT) (now known as treatment support), [ 24 ] as a strategy, in 13 provinces in 1991, with a nationwide scale-up by 2001 [ 25 , 26 ]. The National Center for Disease Control (CDC) is responsible for coordination, policymaking, standards and technical guidance, while provincial CDCs conduct TB programs and monitor disease trends at the prefecture and county level.

TB diagnosis and treatment are provided under the free-TB service policy in China [ 27 , 28 ]. The policy is implemented through an integrated model where designated hospitals (specialised centres for infectious diseases and general hospitals with TB departments) provide TB diagnosis and treatment services [ 29 ]. Persons with drug-resistant TB are treated at designated prefectural or provincial-level hospitals [ 29 ]. Primary healthcare providers are responsible for referring older adults presenting with TB symptoms to designated county-level hospitals for diagnostic investigation. They also conduct follow-up, case management and support, and health education activities at the community level [ 29 ]. The private sector is not involved in TB management. This free-TB service policy is supported by funds from the central and local governments [ 29 ]. Expenditures incurred beyond the free-TB service policy are generally covered by other government-linked insurance schemes [ 27 ]. However, the insurance and financial support schemes vary between provinces, resulting in different levels of financial reimbursement.

Despite this policy, catastrophic costs due to TB remain substantial. Studies report that more than 50% of TB patients incurred out-of-pocket payments exceeding 40% of the household’s ‘capacity to pay, [ 30 , 31 ] indicating a need for better financial support plans and packages to be considered. In addition to financial support, social support through better health education, supportive services, and community engagement is important to improve TB treatment adherence and outcomes [ 32 ].

TB case finding

Active case finding (ACF), a provider-initiated systematic screening and testing for TB disease, [ 33 ] has been deployed in conjunction with the annual physical assessments program for older adults since 2015. Such an integrated approach was feasible and effective for TB case detection among older adults, especially those with comorbidities such as diabetes [ 34 , 35 , 36 ]. TB management is carried out by community health service centres under the technical guidance of the National Tuberculosis Plan [ 37 , 38 ].

Institutionalised aged care is a booming sector in China. As of September 2021, more than 2.6 million older adults were living in retirement facilities [ 39 ]. The quality of services provided in these facilities provides is inconsistent, often resulting in over-crowding in poorly ventilated conditions. Consequently, disease outbreaks are common and in one TB outbreak, 40% of the residents were diagnosed with TB disease [ 40 ]. Therefore, amendments to existing legislation regarding infection prevention and control in such facilities should be considered, with relevant TB information provided to residents and staff. ACF should be prioritised with the expansion of the annual physical assessments program.

TB treatment, care and support have been decentralised using various enablers such as the community, family members, local primary healthcare providers, and technology (electronic medication monitor) for people with TB who were clinically stable and non-infectious [ 26 , 41 ]. However, given their advancing age, existing chronic health conditions, and weakened immunity, older adults are prone to stopping treatment (loss to follow-up) and death [ 42 ]. Currently, limited guidance is provided at the country and global levels to address issues encountered by older adults, such as adverse event monitoring and management, drug-drug interactions and treatment adherence.

Traditional Chinese herbal medicines have been used to treat TB and as adjuvants to improve the tolerability of TB treatment. Although not endorsed by the WHO, herbal medicines are widely used in China [ 43 ]. In 2020, a meta-analysis reported some potential benefits, [ 44 ] but unfortunately, the evaluated studies lacked methodological rigour. Given how widely herbal medicines are used in China, especially in older adults, practice guidelines should consider how best to advise and regulate health practitioners.

TB prevention

The ramp-up of TB response through nationwide expansion of treatment support (historically known as directly observed treatment [DOT]) and improvement of disease reporting and referral system saw a 28% and 65% reduction in the prevalence of pulmonary TB and smear-positive TB, respectively, between 1990 and 2010 in China [ 45 ]. As the risk of infection and transmission decreases, it is expected that reactivation will be the main driver of TB disease occurrence as the population ages in the coming decades [ 46 , 47 ]. China has around 350 million people with TB infection, [ 48 ] however, screening for TB infection and the uptake of TB preventive treatment (TPT) among at-risk groups is limited. Incorporation of TB infection screening into the annual health assessment could improve awareness regarding TB infection and uptake of TPT among at-risk groups but requires further evaluation for feasibility and safety [ 49 ].

The estimated TB incidence in Japan has declined from 36 to 12/100,000 population per year from 2000 to 2020 [ 12 ]. The treatment coverage (notification rate as a proportion of the estimated incidence) was approximately 85%, with 69% reported among older adults (43% among those ≥ 80 years) [ 12 , 50 ]. The median age of a person notified with TB in 2020 was 77 years [ 50 ]. While the number and rate of TB cases have decreased in the last decade, the proportion of older adults among new cases has increased from 48% to 2000 to 59% in 2010 and 69% in 2020 [ 50 ]. Although this is mainly driven by reactivation, multiple outbreaks with transmission in health and aged-care facilities have been reported [ 51 , 52 ]. Despite increased rates of disease, TB mortality among older adults has declined from > 10 to < 5 deaths per 100,000 population in recent years [ 53 ]. Nevertheless, the highest number of TB deaths occurred among older adults in Japan [ 53 ].

The Ministry of Health, Labour, and Welfare of Japan comprises 18 departments, bureaus, and offices that oversee public health, workplace safety and sanitation, medical services, and health insurance [ 54 ]. Access to healthcare in Japan is facilitated by a universal health insurance scheme with population-wide coverage. While approximately 80% of the health facilities are privately owned, they are regulated by the government, and payment for services is controlled by the ministry under the insurance scheme [ 54 ]. These facilities provide direct medical care for people with TB, including in-patient care during TB treatment. Meanwhile, the public health centres provide other aspects of TB response such as screening for TB disease and infection, contact investigation, surveillance, and community-based treatment support [ 55 ]. National TB surveillance data are managed by the Research Institute of Tuberculosis [ 55 ].

TB care is covered by national health insurance and public subsidies at about 70% and 25%, respectively. The remaining 5% is paid out-of-pocket, but a public assistance fund can be used to offset costs for those who cannot afford it [ 55 ]. Medical expenses incurred during hospitalisation are wholly covered by health insurance and public subsidies. Given the rising need for dedicated and specialised care for older adults, a long-term care insurance scheme was introduced in 2020 to support those in need, as well as their family members [ 54 ].

In Japan, TB among older adults has historically been detected passively at outpatient and inpatient health facilities [ 56 , 57 ]. TB case finding among older adults in the health facilities were facilitated by the presence of comorbidities and routine follow-up for other health conditions, thus increasing the likelihood of care-seeking at the onset of TB symptoms and, subsequently, screening for TB [ 58 ]. However, case finding in such settings hinge on a clinician’s awareness of the need to screen for TB. On presentation to health facilities, TB diagnosis among older adults has historically been difficult due to atypical presentation in older adults. For example, one study reported that > 40% of older adults with TB presented with atypical features of TB in Japan [ 59 ]. The non-specific symptoms and low awareness of TB [ 60 ], especially in intermediate TB burden settings such as Japan, could lead to delayed diagnosis.

In addition, community-based ACF programs targeting older adults have been recommended and implemented [ 61 ]. Currently, these programs prioritise older adults ≥ 80 years for TB screening using mobile chest x-rays in the community. For institutionalised older adults, those aged ≥ 65 are offered annual TB disease screening to prevent outbreaks in aged-care facilities. Before admission to an aged-care facility, TB screening using chest radiography has also been implemented to facilitate the early detection of TB disease [ 62 ]. This obligation is also extended to frontline workers in health and aged-care facilities and welfare facilities.

Treatment of drug-susceptible TB in Japan generally follows the standard 6-month regimen [ 55 ] . However, a 9-month regimen without pyrazinamide (2 months of isoniazid, rifampicin, and ethambutol, followed by isoniazid and rifampicin for 7 months) is widely prescribed for older adults, particularly those aged ≥ 80, and the national guidelines did not recommend pyrazinamide for older adults with TB until 2018 [ 63 ]. While recent studies have reported that the pyrazinamide-based regimens do not lead to significantly higher rates of treatment discontinuation, liver injuries, and death than regimens without pyrazinamide, [ 63 , 64 ] the proportion of those receiving the standard 6-month regimen with pyrazinamide declines with age, particularly for those aged ≥ 75 years [ 50 ].

The overall treatment success rate of drug-susceptible TB was 66% in Japan in 2019 [ 50 ] . The treatment success rate among people with TB < 65 years was 82%, and the rate decreased among the older age groups (65−74 years; 76%, 75−84 years; 65%, ≥85 years; 46%) [ 50 ]. The low treatment success rate among older adults has been ascribed to a high death rate during TB treatment. In 2019, 33% of older adults with TB died during treatment, and > 60% died of non-TB-related causes [ 50 ]. Japan has a comprehensive treatment support strategy for people with TB disease or TB infection (TPT). For those who require in-patient care, treatment support that comprises patient education is provided in the hospital. Upon discharge, an individual support plan for community-based treatment support is developed based on the person’s risk of non-adherence, and the frequency and means of medication support are determined. A treatment support conference is held to evaluate and review the plan. Through a patient-centred care approach, treatment support may be provided by health professionals in the local community, community health workers and volunteers, or family members.

Tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) are used to diagnose TB infection in Japan; both tests are covered by national health insurance. TB infection has been a notifiable condition since 2006 [ 50 ]. While there are no policies to actively screen older adults as a priority group for TB infection, notification of TB infection among older adults ≥ 65 has gradually increased since 2010 [ 50 ]. In 2020, approximately 49% of older adults with TB infection were detected via contact investigation, [ 50 ] a national policy to facilitate early detection of TB disease and infection and prevent onward transmission. There was also an increasing number of older adults diagnosed with TB infection in the hospital due to TB infection testing carried out before treating other medical conditions such as rheumatoid arthritis [ 65 ]. Nevertheless, the lower sensitivity of IGRA among older adults remains a concern. A 2017 study in Japan reported discrepancies between IGRA positivity rates and the corresponding estimated prevalence of TB infection among older adults, highlighting the utility and applicability of IGRA in this population [ 66 ]. Furthermore, providing TPT for older adults remains controversial among clinicians due to the risk of adverse events.

• Republic of Korea

In 2020, in the Republic of Korea, there was an estimated TB incidence was 25,000 people with incident TB (49 per 100,000 population per year); 94% of these were notified to the national authorities, of which 49% were aged ≥ 65 [ 12 ]. [ 12 ] While the number of people with TB has steadily declined in the last decade, the proportion of older adults among new TB patients has risen (19.2% in 2001 and 49.1% in 2020) [ 67 ] . In 2020, the TB notification rate among older adults aged 65−69 was 58 per 100,000 population; the rate increased with age and peaked among those aged ≥ 80 years at 235 per 100,000 population [ 67 ]. TB mortality among older adults ≥ 65 was 13.8 per 100,000 population in 2020, the lowest rate recorded since 2001. However, of all TB-related deaths, 82.5% involved those aged ≥ 65, and the proportion has been above 80% since 2016 (2001; 58.0%, 2010; 72.1%). Despite the decline in overall TB burden and mortality rates, the course is predicted to reverse after 2032 (TB incidence) and 2026 (TB deaths) due to increasing trends among older adults, particularly those aged ≥ 80 69 .

The Ministry of Health and Welfare is the national policymaking and governing body for public health and medical services in the Republic of Korea [ 70 ]. The ministry also oversees the national health insurance scheme, a compulsory scheme that confers health care coverage and benefits for the entire population [ 70 ]. The Korean Disease Control and Prevention Agency (KDCA) is responsible for disease surveillance, public health response, disease prevention, and research and oversees the National TB Elimination Project [ 70 ]. While policies regarding TB prevention and care are established by the government, the private sector’s involvement in TB care began in the 1990s and was formalised in 2011 through the public-private mix model [ 71 ].

TB care in the public and private sectors is covered by national health insurance. A 10% co-payment scheme was in place until 2016 [ 71 ]. Since 2017, all expenses incurred during TB care, including hospitalisation, isolation orders (movement restriction to prevent further transmission), and an allowance for dependents, are included in the policy, thereby minimising out-of-pocket payments for people affected by TB. Interventions such as contact investigation and the screening of close contacts for TB disease and infection are also covered by health insurance. While there is specific funding for TB interventions targeted at older adults in the Republic of Korea, the budget only amounted to 1.8% of the total budget for the national TB control program in 2018 [ 71 ].

Since the inception of the national TB control program in the 1960s, early detection and treatment of TB has been a mainstay of TB policies, including for older adults [ 71 ]. In 2020, the TB incidence rate detected through TB screening among older adults ≥ 65 using mobile chest x-ray machines in 17 regions and provinces was 75 per 100,000, 1.9 times higher than the general population’s rate [ 72 ]. This high detection rate prompted KDCA to implement nationwide TB screening among older adults in the community and aged-care facilities as a key strategy to detect TB early in this group.

With an increasingly aging population and the growth in the proportion of women in the labour market, the number of older adults living in institutionalised settings has also increased proportionally, partly due to the introduction of long-term care insurance, which covers home and institutional care services, assistive equipment such as walker and wheelchair, and cash benefits [ 73 ]. In fact, the number of recipients of long-term care insurance increased three-fold between 2008 and 2019 [ 74 ]. Using mobile chest x-ray, TB screening among older adults ≥ 65 in long-term care facilities in 17 regions and provinces resulted in an incidence rate of 66 per 100,000 in 2020 [ 72 ].

Drug-susceptible TB in the Republic of Korea is treated using the standard 6-month regimen [ 75 ]. Partly due to concerns about potential pyrazinamide hepatotoxicity, there is ongoing work to optimise TB treatment among older adults through establishing an adverse events monitoring system, managing adverse events, and developing biomarkers that may predict diagnostic and therapeutic responses [ 76 ].

Overall, the TB treatment success rate has been sitting at approximately > 80% over the last two decades [ 12 ]. However, the treatment success rate among older adults was lower than the general population at approximately 70% between 2012 and 2015 [ 77 ]. Treatment support remains the main treatment administration option. Video-observed therapy and support through a comprehensive support centre for older adults living alone had been trialled with some success. Preliminary data showed higher treatment success rate among older adults enrolled in the programme [ 78 ]. Other incentives have been implemented, such as providing food, daily necessities, and medical accompaniment service for older adults who have trouble remaining on treatment. Furthermore, an approach to assess the vulnerability of people with TB, particularly older adults, with customised case management and linkage with social welfare services have also been implemented.

A comprehensive epidemiologic and contact investigations protocol is in place to screen at-risk populations for both TB disease and infection. TB disease and infection screening is mandatory for healthcare and nursery workers and teachers. Other at-risk groups, such as people living with HIV, those with silicosis, organ transplant recipients, and patients with kidney disease on dialysis, are recommended to be screened for TB infection. For household contacts of persons with TB, chest x-ray investigations and TB infection workups (TST/IGRA, but not mandatory) will be offered (covered by health insurance). TPT (3HP [isoniazid-rifapentine once-weekly for 3 months], 3RH [rifampicin-isoniazid daily for 3 months], or 4R [rifampicin daily for 4 months) is offered to those eligible for it. However, there is no policy to screen older adults for TB infection. In a 2016 study conducted across 11 regions, 40% of those aged ≥60 tested positive for TB infection using IGRA [ 79 ]. Considering the potentially high prevalence of TB infection and risk for reactivation among older adults, [ 80 ] a systematic approach to TB infection screening and TPT administration in this population is warranted.

An estimated 2700 people were affected by TB in 2020 (46 per 100,000 population per year); 89% of these (2400) were notified to the national authorities in 2020. [ 12 ] Of the 2400 people with TB, approximately 57% were Singapore citizens and permanent residents [ 81 ]. The TB incidence rate has been approximately 40 per 100,000 since the late 1990s and may be attributed to migration (about 30−50% of the cases were detected among short and long-term visitors, including work pass holders and students) and an aging population [ 82 , 83 ]. In 2020, older age groups (≥60) made up a significant proportion of the TB notifications both among Singaporean-born (58%) and foreign-born (46%) individuals [ 81 ]. While reactivation of past infections could sustain the TB epidemic among older residents, outbreaks in aged-care facilities have also been reported. Overall, TB mortality rates have remained < 1 per 100,000 population in the past few years [ 12 ]. However, the TB mortality rate among older adults ≥70 was higher at 5.1 per 100,000 population in 2018 [ 84 ].

The Ministry of Health (MOH) Singapore initiated the national TB program, named Singapore TB Elimination Program (STEP), to strengthen TB response efforts by detecting and treating TB disease and infection and preventing drug-resistance TB in 1997 [ 82 ]. STEP manages a notification registry and a treatment surveillance system to monitor TB notification and treatment outcomes. The TB Control Unit (TBCU) is the referral centre for TB management in Singapore, responsible for treatment support, contact investigation, and the administration of TPT. Both public and private hospitals can offer TB diagnosis and treatment. Referrals for TB diagnosis and treatment can be made by primary care physicians in public, private, and community-based organisations (such as the Singapore Anti-Tuberculosis Association).

Singapore’s health system is financed through subsidies, a national health savings account (MediSave), a basic national health insurance scheme (MediShield) for hospitalisation and treatment bills, and an endowment scheme for individuals who have exhausted other means of payment [ 85 ]. For citizens and permanent residents, TB diagnosis and treatment costs are covered by the health financing system. Non-residents, such as those holding long-term work visas, are not covered by these schemes and must rely on employer coverage, private health insurance, or out-of-pocket payment for TB screening and diagnosis costs. TB medications are provided to all at no cost.

TB is diagnosed by passive case finding when a person presents with symptoms or a chest x-ray for other medical conditions (yet suggestive of TB) [ 86 ]. TB screening is conducted for foreigners applying for work or long-term visas and during the visa renewal process using chest radiography [ 86 ]. The same approach applies to everyone regardless of age. There are currently no specific interventions targeting TB screening among older adults. Some aged-care facilities may enquire about the date and information of the last chest x-ray or require a chest x-ray to be conducted before admission. However, this policy is inconsistent.

Treatment of drug-susceptible TB in Singapore follows the standard 6-month regimen (2 months of isoniazid, rifampicin, ethambutol, and pyrazinamide followed by isoniazid and rifampicin for 4 months) [ 86 ]. However, for older adults who may be unlikely to tolerate pyrazinamide, a 9-month regimen comprising ethambutol, rifampicin, and isoniazid for 2 months (intensive phase), followed by rifampicin and isoniazid for 7 months (continuation phase) is used [ 86 ]. It is required by law under the Infectious Diseases Act for all clinicians to report treatment progress and the outcomes of people with TB to the MOH [ 86 ].

The treatment success rate was 79% in 2019, [ 12 ] and the treatment success rate among older adults was not known at the time of writing. Different forms of treatment support have been implemented to support treatment. Outpatient treatment support is implemented at all the 18 public polyclinics and the TBCU. People with TB disease can choose to have their treatment administered at the nearest public health facility. In a 2016 study among adults with TB in Singapore, 72% of respondents reported that they could accept the schedule of facility-based treatment support [ 87 ]. However, 45% perceived the arrangement to be disruptive to their work, school, and social activities [ 87 ]. The results were not age disaggregated. While not specific to older adults, incentive-based intervention to encourage treatment adherence among people with TB from the lower-income bracket has shown promise compared to the non-intervention group in Singapore [ 88 ]. Other forms of treatment support, such as administration in aged-care facilities and through outreach for recipients who have mobility issues or are frail, have been implemented [ 86 ]. Self-administered treatment is also used in Singapore, especially for those treated in the private sector. However, there are no data on self-administered treatment among older adults.

The STEP strategy includes contact investigation to identify close contacts of persons with bacteriologically confirmed TB [ 86 ]. Testing for TB infection is recommended for high-risk groups if there is an intention to treat with TPT [ 86 ]. IGRA is the preferred test for TB infection; variable TPT options are available, including 6 H (isoniazid daily for 6 months), or 4R (daily rifampicin for 4 months) [ 86 ]. Although TB infection has been estimated to affect up to 30% of older adults in Singapore, [ 81 ] there is no policy or specific guideline regarding TPT use for older adults. The risk of adverse events associated with TPT remains a concern, and further studies are needed.

Summary and conclusion

The four case studies presented exemplify the range of practices and challenges in managing TB among older adults in the Western Pacific Region. Here we summarise the key findings and action points based on country experiences:

While passive case finding remains the mainstay intervention contributing to TB case detection in older adults, routine ACF has been implemented in China, Japan, and the Republic of Korea. The optimal use of ACF requires further consideration and assessment in different contexts.

A person-centred approach to TB care was identified as a key theme in all four countries. Nevertheless, limited guidance is available at the country and global levels to address issues older adults encounter (e.g., adverse event monitoring and management, consideration of drug-drug interactions, and treatment adherence). Existing evidence (and evidence gaps) related to the optimal management of older adults with TB require systematic review and guideline development.

There is a lack of standardisation in the approach to TB infection testing and TPT provision. It is important to generate the necessary evidence to inform benefit-risk estimates for managing TB infection among older adults.

The use of traditional medicines is culturally deeply rooted among older adults in this region. Their complementary use in TB care should be explored and carefully considered.

A summary of the approaches implemented by the four countries is outlined in Fig.  2 .

TB management among older adults in China, Japan, the Republic of Korea, and Singapore

TB management experiences were mapped based on three main domains: case finding and detection, treatment, and prevention. The relevant policies and interventions are tagged to the respective implementing countries. Areas shaded in grey represent cross-cutting interventions that extend beyond the older adult population. Treatment support was historically known as directly observed treatment (DOT)

Abbreviations: TB; tuberculosis, TPT; TB preventive treatment, CN; China, JP; Japan, KR; Republic of Korea, SG; Singapore

Cross-cutting challenges

The COVID-19 pandemic has severely disrupted access to TB care. with an 18% decrease in TB disease notifications globally [ 89 ]. Health services for older people were often more severely.

affected and TB services in South-East Asia and the Western Pacific Regions were highly impacted [ 12 ]. Of the four countries included in this study, TB notification data for 2020 and 2021 were lower than 2019 [ 12 , 90 ].

In addition to key risk factors for TB such as living in crowded and poorly ventilated conditions, indoor air pollution and tobacco smoking, [ 91 ] older adults also have age-associated immune dysfunction, financial resources constraints, and frequent comorbidities [ 92 ]. Caring for older adults with TB can be difficult and complex cases may require referral to appropriate specialty care. Service integration between relevant specialties should facilitate better care for older adults with TB. TB diagnosis in older adults is further complicated by challenges related to cognitive impairment, communication challenges and difficulties in obtaining quality sputum samples [ 93 , 94 ]. Dementia, which primarily affects older adults, has been associated with difficult TB diagnosis and poor adherence to TB treatment in the absence of tailored treatment support [ 95 ].

TB-related stigma (perceived and experienced) remains pervasive in many communities [ 96 ]. While systematic assessment of TB-related stigma among older adults has not been conducted, older adults in China have reported unwillingness to seek TB care due to fear of discrimination and self-isolation because of stigma [ 32 , 97 ]. Anecdotally, aged care facilities in Japan were reluctant to accept returning residents after hospital admission for TB care due to fear and stigma, while unwillingness to be screened for TB has also been ascribed to stigma.

The high standards of living and well-being may have shaped the notion that TB is not a significant concern, rendering a lower index of TB suspicion, including among healthcare workers [ 98 ]. A recent cross-sectional study conducted among older adults in Shenzhen, China, reported that > 70% of the respondents were aware of TB as a contagious disease, its symptoms, and preventive measures. Yet, less than half knew that TB was curable, and only one-third were willing to be screened for TB if they were to develop suspicious symptoms [ 99 ].

Considering that aging populations is a global phenomenon that implies a heightened TB risk, particularly in areas with historically high rates of TB, policymakers and funders must invest more to deliver and generate the evidence required to inform optimal TB prevention and care initiatives in older adults.

Data Availability

Data used for this case study comprised published literature, reports, and co-authors’ experience in managing TB among older adults in their respective settings.

Change history

07 june 2023.

A Correction to this paper has been published: https://doi.org/10.1186/s12889-023-15576-0

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Acknowledgements

We would like to thank Jeffery Cutter, Jun Yang Tay, and Shera Tan of the Singapore TB Program for verifying the section on Singapore’s experience.

The author(s) received no specific funding for this work.

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Kerri Viney, Ben Marais, Heejin Kim, Seiya Kato, Yuhong Liu, Catherine W.M. Ong and Tauhid Islam are joint senior authors.

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Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore

Alvin Kuo Jing Teo & Siyan Yi

Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

Alvin Kuo Jing Teo & Ben Marais

World Health Organization, Regional Office for the Western Pacific, Manila, Philippines

Kalpeshsinh Rahevar, Fukushi Morishita, Manami Yanagawa, Kyung Hyun Oh & Tauhid Islam

Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore, Singapore

Catherine W.M. Ong

Research Institute of Tuberculosis, Anti-Tuberculosis Association, Tokyo, Japan

Takashi Yoshiyama, Akihiro Ohkado, Lisa Kawatsu, Norio Yamada, Kazuhiro Uchimura & Seiya Kato

Korean National Tuberculosis Association, Seoul, Republic of Korea

Youngeun Choi & Heejin Kim

Office of International Cooperation, Innovation Alliance on Tuberculosis Diagnosis and Treatment, Beijing, China

KHANA Center for Population Health Research, Phnom Penh, Cambodia

Center for Global Health Research, Public Health Program, Touro University California, Vallejo, CA, USA

Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland

Kerri Viney

The University of Sydney Institute for Infectious Diseases (Sydney ID) and the Centre of Research Excellence in Tuberculosis (TB-CRE), Sydney, NSW, Australia

Beijing Chest Hospital, Capital Medical University, Beijing, China

Infectious Diseases Translational Research Programme, Department of Medicine, National University of Singapore, Singapore, Singapore

Institute of Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore

Division of Infectious Diseases, Department of Medicine, Woodlands Health, Singapore, Singapore

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KR, FM, TI, and SY conceptualised the study. AA, TY, AO, LK, NY, KU, YC, ZC, SK, YL, and CWMO contributed to the country experiences reported in this study. AKJT collated the information. AKJT, BM, KV, KR, FM, MY, and KHO wrote the initial draft. All authors critically reviewed the manuscript and approved the final version.

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Correspondence to Kalpeshsinh Rahevar .

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Teo, A., Rahevar, K., Morishita, F. et al. Tuberculosis in older adults: case studies from four countries with rapidly ageing populations in the western pacific region. BMC Public Health 23 , 370 (2023). https://doi.org/10.1186/s12889-023-15197-7

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Stigma, depression, and quality of life among people with pulmonary tuberculosis diagnosed through active and passive case finding in Nepal: a prospective cohort study

• Kritika Dixit 1 , 2 ,
• Bhola Rai 1 ,
• Tara Prasad Aryal 1 ,
• Noemia Teixeira de Siqueira-Filha 3 ,
• Raghu Dhital 1 ,
• Manoj Kumar Sah 1 ,
• Ram Narayan Pandit 1 ,
• Govinda Majhi 1 ,
• Puskar Raj Paudel 1 ,
• Jens W. Levy 4 ,
• Job van Rest 4 ,
• Suman Chandra Gurung 1 , 5 ,
• Gokul Mishra 5 ,
• Knut Lönnroth 2 ,
• Stephen Bertel Squire 5 , 6 ,
• Kristi Sidney Annerstedt 2 ,
• Laura Bonnett 7 ,
• Ahmad Fuady 8 ,
• Maxine Caws 1 , 5 &
• Tom Wingfield   ORCID: orcid.org/0000-0001-8433-6887 2 , 5 , 6  

BMC Global and Public Health volume  2 , Article number:  20 ( 2024 ) Cite this article

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The psychosocial consequences of tuberculosis (TB) are key barriers to ending TB globally. We evaluated and compared stigma, depression, and quality of life (QoL) among people with TB diagnosed through active (ACF) and passive (PCF) case-finding in Nepal.

We prospectively recruited adults with TB diagnosed through ACF and PCF in four districts of Nepal between August 2018 and April 2019. Participants were interviewed at 8–12 weeks (baseline) and 22–26 weeks (follow-up) following treatment initiation. TB stigma was measured using an adapted Van Rie Stigma Scale (0 = no stigma to 30 = highest stigma). Depression was measured using a locally-validated Patient Health Questionnaire (PHQ-9). Mild and major depression were indicated by  PHQ-9 scores 5–9 and ≥ 10, respectively. QoL was measured using the EuroQoL 5-Dimension 5-level (EQ-5D-5L) from 0 to 1 (optimal QoL); and self-rated health from 0 to 100 (optimal self-rated health).

We recruited 221 participants (111 ACF; 110 PCF) with a mean age of 48 years (standard deviation [SD] =  ± 16), of whom 147/221 (67%) were men. The mean TB stigma score was 12 (SD = 7.3) at baseline and 12 (SD = 6.7) at follow-up. The most commonly perceived elements of TB stigma at baseline were that people with TB experienced guilt (110/221, 50%) and feared disclosure outside their household (114/221, 52%). Self-rated health and EQ-5D-5L scores increased from baseline to follow-up (69.3 to 80.3, p  < 0.001; 0.92 to 0.9, p  = 0.009). Nearly one-third of participants (68/221, 31%) had mild or major depression at baseline. The proportion of participants with major depression decreased from baseline to follow-up (11.5% vs. 5%, p  = 0.012). There was a moderate, significant positive correlation between depression and stigma scores ( r  = 0.41, p  < 0.001). There were no differences found in TB stigma, self-rated health, QoL, or prevalence of mild/major depression between ACF and PCF participants.

Conclusions

We found a substantial, persistent, and clustered psychosocial impact among adults with TB diagnosed through both ACF and PCF strategies in Nepal. These findings suggest an urgent need to develop effective, evidence-based psychosocial support interventions with the potential to be integrated with existing ACF strategies and routine TB service activities.

Peer Review reports

Tuberculosis (TB) remains a major public health problem and the leading cause of death owing to a single infectious disease. In 2022, an estimated 10.6 million people developed TB, 40% of whom were never notified of National TB Programs (NTPs) and 80% of whom lived in low- and middle-income countries (LMICs) [ 1 ]. Being ill with TB and having delayed diagnosis and care are associated not only with negative economic impacts, such as catastrophic costs [ 2 , 3 , 4 , 5 ], but also deleterious psychological and social (herein termed psychosocial) consequences including stigma, depression, and poor quality of life [ 6 , 7 , 8 , 9 ]. In short, the current biomedical approach focused on TB diagnostics and therapeutics is proving insufficient to achieve the END TB strategy goal of TB elimination. Broader strategies including active case finding (ACF) and holistic, person-centered support are required [ 10 , 11 , 12 ].

Stigma is recognized as one of the most important challenges to accessing TB care and becoming cured, particularly among key vulnerable populations with intersectoral barriers to health. There are several different types of TB-related stigma, including anticipated, perceived, enacted, experienced, or internalized stigma. People with TB may experience anticipated or perceived stigma where they fear being devalued when diagnosed with TB or have self-stigma resulting from internalized negative messages that are associated with TB in the community. Enacted or experienced stigma occurs when people with TB experience stigmatizing behavior from families, communities, and healthcare workers [ 13 ]. Such stigmatizing behaviors or actions can be associated with social isolation, broken marriages, discrimination, non-disclosure of TB diagnosis, and depression [ 7 , 14 , 15 , 16 ]. TB-related stigma can also hinder care-seeking behavior [ 17 , 18 , 19 , 20 ], delay diagnosis, and lead to adverse TB treatment outcomes including death [ 21 ]. For these reasons, stigma was cited as a key issue requiring comprehensive political, legal, and programmatic actions in the political declaration signed by member states during the United Nations High-Level Meeting on the Fight Against Tuberculosis in 2023. These actions included increased research and investment to understand and address the issues fueling TB stigma in affected communities [ 22 ].

TB and depression have a bidirectional relationship [ 23 , 24 ]. A meta-analysis reported a pooled estimated prevalence of depression among people with TB of 45.2% [ 25 ]. Another meta-analysis found that people with TB and depressive symptoms had a three-fold, four-fold, and nine-fold increased risk of death, adverse TB treatment outcomes, and loss to follow-up respectively [ 8 ]. It is clear that TB and depression are syndemic and compound negative socioeconomic and health outcomes among those affected [ 23 , 26 , 27 ].

Stigma, depression, and quality of life (QoL) are known to be intricately related. There is evidence that depression, stigma, and low QoL exhibit clustering at the individual level [ 28 , 29 ], which can, collectively, have an adverse effect on TB treatment adherence and outcomes [ 30 ]. Stigma can be a precursor to depression and having depression can impede individuals’ capacity to engage in daily activities and mitigate stigmatizing thoughts and actions [ 28 , 30 , 31 ]. QoL is lower in people with TB than those without, for multifactorial reasons which include a complex interplay of physical illness, financial burden, and psychosocial consequences of the disease. Lower quality of life at treatment initiation can predict adverse TB treatment outcomes [ 32 ]. Therefore, understanding these complex consequences of TB together can elucidate the drivers and the magnitude of the impact on treatment outcomes. This new knowledge will inform the design of improved person-centered approaches to TB care delivery which are recognized as an essential component of the WHO End TB Strategy goals [ 22 ].

ACF programs involve systematic screening for TB, often among targeted high-risk or multiple disadvantaged groups such as close contacts, poor and marginalized populations, and drug users outside of healthcare settings, in order to promptly diagnose people with TB and link them to care [ 33 ]. ACF represents an opportunity for early evaluation and intervention to address the psychosocial and economic needs of people with TB to improve their health and broader outcomes, including QoL. Nevertheless, this opportunity is often missed during the implementation of existing ACF programs, which rarely include psychosocial and economic indicators and instead commonly focus on a single outcome indicator: the yield of additional TB cases.

Nepal is a lower–middle-income country in South Asia where the prevalence of TB is 416 cases per 100,000 population [ 34 ]. The prevalence is similar to other high TB burden countries including India, Bangladesh, and Pakistan [ 1 ]. Due to the high prevalence of both TB and multidimensional poverty in Nepal, the psychosocial consequences of TB are likely to be more severe in groups with lower socioeconomic status [ 35 ]. These effects are also further amplified in groups with intersectional disadvantages resulting from factors such as ethnicity, caste, multimorbidity including HIV, diabetes, and undernutrition, and historical marginalization [ 1 , 36 , 37 ]. Our previous research in Nepal has shown that people with TB diagnosed through ACF incurred lower TB-related direct costs during pre-treatment and intensive periods than those diagnosed through passive-case finding (PCF) [ 4 , 5 ]. However, the impact or potential impact of these existing ACF programs on psychosocial indicators such as stigma, depression, and quality of life, remains unknown. The psychosocial impacts of TB could be hypothesized to be higher among people diagnosed via ACF strategies because ACF interventions usually reach people with lower socioeconomic status and barriers to healthcare access [ 5 ]. Therefore, ACF programs could be an ideal opportunity to integrate psychosocial interventions for those most vulnerable to the severe psychosocial consequences of TB. Moreover, while a handful of qualitative studies have explored stigma, depression, and quality of life as barriers to TB care in Nepal [ 14 , 38 , 39 ], there have been no quantitative studies examining the longitudinal psychosocial impact of TB in people with TB diagnosed through ACF and PCF.

We aimed to fill this knowledge gap to inform the development of an integrated psychosocial and economic intervention to support TB-affected households in Nepal.

Study design

This was a prospective longitudinal cohort study to evaluate the economic and psychosocial consequences of TB in Nepal [ 40 ]. It was nested within the larger IMPACT TB project ( www.impacttbproject.org ,) to generate evidence on community-based ACF models in Nepal [ 4 , 5 , 41 ]. From July 2017 to June 2019, the IMPACT TB study implemented community-based ACF in the study site districts including social contact tracing and mobile case-finding camps using rapid molecular testing with GeneXpert or smear microscopy [ 4 , 5 ]. People with pulmonary bacteriologically confirmed, drug-sensitive TB diagnosed through ACF were defined as ACF participants. People who self-presented to public TB services in the study site districts without having received any ACF or other community-based TB outreach activities, and who were subsequently diagnosed with drug-sensitive pulmonary TB and notified to the Nepal National TB Programme (NTP), were defined as PCF participants [ 4 ]. For both ACF and PCF participants, the Nepal NTP delivered a 6-month treatment regimen for drug-sensitive TB by daily Directly Observed Treatment Short-course (DOTS) at government TB health centers [ 42 ]. The detailed process of participant selection and recruitment to IMPACT TB has been published elsewhere [ 5 ].

Between April 2018 and January 2019, a sub-sample of IMPACT TB ACF participants and unmatched PCF participants were consecutively recruited to a longitudinal cohort study and completed additional interviews during their treatment about the economic and psychosocial consequences of TB. A follow-up of this nested cohort was completed in October 2019 and the findings of the economic consequences of TB, including catastrophic costs, are reported elsewhere [ 5 ].

The study was implemented in Nepal by a well-established and TB-focused Nepalese non-government organization, Birat Nepal Medical Trust, in the Chitwan, Mahottari, Dhanusha, and Makwanpur districts of Nepal.

These districts all share high TB burden and poverty levels but are geographically diverse: Chitwan, Mahottari, and Dhanusha districts are plains regions sharing a border with India; Makwanpur is a mid-hill district with a remote population and poor road and transportation infrastructure [ 43 ] (Fig.  1 ).

Study site districts in Nepal

Eligibility criteria

Eligible participants were adults aged 18 years or above with drug-sensitive bacteriologically confirmed drug-sensitive pulmonary TB who were recruited to the IMPACT TB project between April 2018 and January 2019 and diagnosed by either ACF or PCF [ 5 ]. People with rifampicin-resistant or multidrug-resistant TB or those diagnosed and/or treated in the private sector were not eligible to participate in the IMPACT TB cost survey due to limited time and budget availability and therefore also excluded from this study.

Procedures and data sources

The data were collected longitudinally using an adapted, piloted, and validated version of the WHO TB Patient Cost Survey [ 5 ] with additional exploratory questions on perceptions of TB stigma, depression, and quality of life [ 40 ]. Community Health Workers (CHWs) from the IMPACT TB project administered the survey in the local language using face-to-face interview techniques during participant household visits at 8–12 weeks (herein termed “Baseline”) and 22–26 weeks (herein termed “Follow-up”) following treatment initiation.

Before obtaining a participant’s signature (or thumbprint) to indicate consent, interviewers verbally read the contents of the patient information sheet and consent form and provided an opportunity for participants to ask questions. Participants were invited to have another person of their choosing present to witness the consent, or to discuss the study with other family members before granting consent. In place of signature, participants were able to provide a thumbprint to give consent, a common and legally recognized form of signature to documents in Nepal.

Variables and measurements

The study used measures of TB stigma, depression, and QoL as outcomes of interest to estimate the psychosocial impact of TB among participants [ 44 ]. To contextualize and evaluate the differences in levels of TB stigma, depression, and quality of life among participants between baseline and follow-up and between ACF and PCF participants, we used the minimal clinically important difference (MCID) [ 45 , 46 ]. MCID is used to report the nominal detectable change in the outcome of interest that is considered to be significant or meaningful in clinical settings [ 47 ]. Where MCID was not available in the published literature, we followed Redwood et al.’s pragmatic analysis strategy of calculating the MCID as 1.96 times the standard error of the measurement [ 44 ].

Stigma was measured by adapting the validated Van Rie Stigma Scale to the Nepali context [ 48 ]. The questionnaire comprised ten questions with responses on a 5-point Likert Scale of “strongly disagree” (assigned 0 points), “disagree” (assigned 1 point), “neither disagree nor agree” (assigned 1.5 points), “agree” (assigned 2 points), and “strongly agree” (assigned 3 points). The “neither agree nor disagree” response and the associated 1.5 points assigned were not included in the original Van Rie Stigma Scale but were perceived by our project team to be necessary to assess the utility of the scale in Nepal and ensure participants were not obliged to give a polarized response. Total stigma scores ranged from 0 (no stigma) to 30 (highest levels of stigma). We used the only published data on the MCID stigma scale from Redwood et al., which estimated it to be 4.30 in a sample of 84 people with DS-TB and 315 people with DR-TB in Vietnam [ 44 ]. In addition to summarizing the stigma score as a continuous variable, we also summarised stigma as a binary indicator of the proportion of participants responding “agree” or “strongly agree” vs “neither agree nor disagree”, “disagree”, and “strongly disagree” for each stigma scale domain.

In this study, the project team initially reviewed the Van Rie Stigma Scale together. We opted to combine questions about the “community perspectives towards TB” and “patient perspectives towards TB” for multiple reasons. First, the project team wanted to measure perceptions of stigma at both the individual level and community level. Second, this study was part of a larger longitudinal study evaluating the health, psychosocial, and economic impact on people with TB diagnosed through ACF and PCF. In the planning stages, the team was cognizant of the length of the survey and wanted to balance robust data collection with a reduction in participant time and responder fatigue; in addition, first-person questions (“I feel…”, “I experience….”) were felt by the project team to be overly sensitive, probing, and with the potential to cause distress in the study site settings. To address these issues, we purposefully selected third-person (“Some people in the community…”, “Some people with TB….”) stigma questions, which we felt to be most socio-culturally pertinent and sensitive at the individual and community level in Nepal, to also facilitate a more concise section of the survey. The questions were initially employed among 10 participants, and tested for clarity and completeness.

Depression was measured using an adapted version of the Patient Health Questionnaire (PHQ-9), which has been validated in Nepal [ 49 , 50 ]. The adapted tool uses an initial screening question about low mood, which translates literally in English to “Have you experienced heart-mind problems over the past 2 weeks?”. In Nepali, the term is known as ‘ manko samasya’ which relates to the problem in the organs of emotion (heart) and memories (mind) and includes conditions such as sadness and negative memories [ 50 ]. Participants answering “No” are not asked any further questions and are presumed to have a PHQ-9 score of 0. Participants answering “Yes” go on to answer the full PHQ-9 questions related to symptoms of depression. We included eight PHQ-9 questions. During the piloting of the questionnaire, the study team reached a consensus that the question “How often in the past 2 weeks have you been having bad thoughts about your own self, feeling like being responsible for your own failure or having let your family down?” could cause distress for participants in the local context. Therefore, the question was not administered during implementation due to the lack of mental health services to provide further expert counseling with qualified mental health professionals being rare outside of Kathmandu. Possible responses were on a four-point scale of “0: not at all”, “1: sometimes”, “2: usually”, and “3: always”. Total PHQ-9 score in this study ranged from 0 (no depression) to 24 (highest depression). As has been demonstrated to be highly sensitive and specific in other settings, the scores were categorized into no depression (scores between 0 and 4), mild depression (scores between 5 and 9), and major depression (scores ≥ 10 and above) [ 49 ]. Based on the relevant available literature, the MCID for the PHQ-9 scale was five [ 46 ].

• Quality of life

To assess the quality of life, we adapted the EQ-5D-5L index tool, which uses five dimensions of quality of life: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression and a visual analog scale that includes a self-health rating [ 51 ]. Each question includes a five-category response scale from 1: no problem, 2: slight problem, 3: moderate problem, 4: severe problems, 5: being unable. Since an existing set of scores were not available for Nepal, we applied the sets from the most geographically and socioculturally proximate country, India, and totaled to get a utility score, from 0 (lowest quality of life) to 1 (highest quality of life) [ 52 ]. Nepal and India are among the 30 high TB burden countries with a high prevalence of stigma, poverty rates, and low literacy. Other published value sets either represented high or middle-income countries and therefore were not appropriate for our study. Similarly, the health rating was measured on a visual analog scale of 0 to 100 based on participants’ self-reported health. The participants were asked to label an appropriate point that best defined their health condition that day with a mark on the scale printed in the questionnaire with 0 indicating the worst health and 100 indicating the best health of the participant [ 51 ]. Despite a thorough review of the literature, no evidence of MCID estimates relating to EQ-5D-5L among people with TB was identified. Therefore, we used an MCID from a study on people with TB in South Africa which used the EQ-5D-3L index for people with TB as 0.07 [ 53 ]. The questions were initially employed among 10 participants, and tested for clarity and completeness.

Sample size calculation and sampling

There was no formal sample size calculation for this study on the psychosocial impact of TB. The participant sample size was calculated for the TB Patient Cost Survey performed within the IMPACT-TB project, which was based on the prevalence of catastrophic costs among TB-affected households identified by ACF vs PCF. Previous TB PCS have suggested that a sample size of 100 people with TB and their households provides a representative distribution of TB-affected household-level costs [ 54 , 55 , 56 ]. To compensate for potential attrition, we aimed to consecutively recruit 110 PCF and 110 ACF participants respectively during the study period. The sample size of 220 participants, 110 PCF and 110 ACF was sufficient to detect a mean difference of 3.7 in levels of stigma, 1.5 in levels of depression, and 0.10 in quality of life with a power of 0.8 and an alpha value of 0.05.

Statistical methods

The study adhered to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines [ 57 ]. The study used descriptive statistics to summarize the participants’ socio-demographic details, comorbid conditions, depression, stigma, and quality of life and compare these data at baseline, follow-up, and the change over time for ACF participants, PCF participants, and the overall cohort. The proportion of missing responses to each question on psychosocial impact including TB stigma, depression, and quality of life, was calculated. Van Rie stigma scale domain responses shown in the supplementary files, demonstrated full completion of stigma questions with no missing responses and < 4% of responses being “neither agree nor disagree”. Similarly, the full responses to each PHQ-9 question, shown in the Additional file 1 : Table S2, showed high rates of completion with 2/221 (0.9%) and 4/221 (1.8%) of participants not fully completing the PHQ-9 at baseline and follow-up respectively.

Continuous data were summarised by mean and standard deviation and compared: ACF vs PCF participants at baseline, follow-up, and change from baseline to follow-up using the two group Student’s t -test; and change from baseline to follow-up among ACF participants, among PCF participants, and all participants using the Repeated Measures ANOVA test. Discrete variables that depict sociodemographic and clinical characteristics were expressed in proportion and percentage and compared between ACF and PCF participants at baseline, follow-up, and the change between baseline and follow-up using the chi-square test. Spearman’s coefficient was used to evaluate the correlation between stigma and depression scores and the p value of the correlation had Bonferroni adjustment. Data were analyzed using Stata Version 15. P values of < 0.05 were considered statistically significant.

Demographic characteristics

Of 221 people invited, 100% were recruited and completed the survey, of whom 111 and 110 were diagnosed through ACF and PCF strategies respectively (Table  1 ). The mean age was 48 years (SD =  ± 16.0) and two-thirds (67%) of participants were male, consistent with the known gender ratio of TB cases in Nepal. Over half of the participants (54%) were illiterate and without formal education, of whom 46% were female. Almost 40% were unemployed at baseline. Comorbid conditions were reported among 11% of participants. ACF participants had lower education levels, were poorer, and were more likely to live in crowded housing than PCF participants (Table  1 ).

The psychosocial impact of TB

Table  2 summarizes TB stigma scores, PHQ-9 scores, EQ-5D-5L scores, and self-rated health at baseline and follow-up and compares the change from baseline to follow-up among all participants, ACF participants, and PCF participants. Table  3 summarises and compares the baseline, follow-up, and change between baseline and follow-up TB stigma scores, PHQ-9 scores, and EQ-5D-5L scores, among ACF vs PCF participants.

The mean TB stigma scores at baseline and follow-up for all participants were 12.0 (SD = 7.3) and 12.0 (SD = 6.7), respectively, with a change from baseline to follow-up of 0.0 (SD = 5.7, Table  2 ). There were no significant differences or differences greater than the MCID threshold found in the change between baseline and follow-up TB stigma scores of all participants, ACF participants, and PCF participants (Table  2 ) or in the change between baseline and follow-up TB stigma scores of ACF vs PCF participants (Table  3 ).

With regards to specific items from the TB stigma scale at baseline, a sizeable proportion of participants reported that people with TB experienced guilt and fear of disclosure: 110/221 (50%) participants agreed ‘some people with TB feel guilty about having TB’; and 114/221 (52%) agreed ‘some people with TB fear telling people outside of their household’. A fifth of participants 47/221 (21%) agreed that ‘some people with TB fear telling their household that they have TB disease’ (Fig.  2 a), with more men (72%) than women (28%) in agreement. Between baseline and follow-up, among all participants (Fig.  2 a), ACF participants (Fig.  2 b), and PCF participants (Fig.  2 c), there was minimal reduction in the prevalence of TB stigma across most of the 10 items of the scale. Among PCF participants, the proportion of participants who agreed with questions including ‘Some people prefer not to have individuals with TB living in their community’, ‘Some people keep their distance from individuals with TB disease’, ‘Some people feel uncomfortable when they are close to an individual with TB’, and ‘Some people with TB feel hurt with the way other people react when they learn they have TB, did not change between baseline and follow-up (Fig.  2 c). Detailed participants’ responses reporting the Van Rie stigma scale at baseline and follow-up for ACF and PCF participants are presented in Additional file  1 : Table S1.

The blue color represents the percentage of people reporting ‘strongly agree’ or ‘agree’ with the items of the Van Rie stigma scale at the baseline period. The orange-brown color represents the percentage of people at the baseline period reporting ‘strongly agree’ or ‘agree’ with the items of the Van Rie stigma scale for the follow-up period of the study

Among all participants, 70/221 (32%) and 64/221 (29%) had a positive PHQ-9 depression screening question at baseline and follow-up, respectively, and went on to complete the remaining PHQ-9 questions (Additional file  1 : Table S2). The mean PHQ-9 depression scores of all participants were 2.9 (SD = 4.4) and 2.4 (SD = 4.0) at baseline and follow-up, respectively ( p  = 0.07, Table  2 ).

Depression scores decreased significantly between baseline and follow-up among ACF participants (3.3 [SD = 4.7] baseline vs 2.0 [SD = 3.8] follow-up, p  = 0.004) but not among PCF participants (2.6 [SD = 4.2] vs 2.8 [SD = 4.1], p  = 0.73, Table  2 ). Changes in depression scores between baseline and follow-up were more pronounced among ACF participants than PCF participants, (change − 1.2 [SD = 4.4] vs 0.15 [SD = 4.5], p  = 0.02, Table  2 ).

There were no differences greater than the MCID threshold found in the change between baseline and follow-up depression scores of all participants, ACF participants, and PCF participants (Table  2 ) or in the change between baseline and follow-up depression scores of ACF vs PCF participants (Table  3 ).

When the scores were categorized into three levels (no depression, mild depression, and major depression), we found nearly one-third of participants (68/221, 31%) had some form of depression at baseline, with 43/221 (19.5%) having mild and 25/221 (11.5%) major depression (Table  4 ). Among all participants, there were significant changes in the proportional distribution of no, mild, and major depression between baseline and follow-up ( p  = 0.012, Table  4 ). The proportion with major depression decreased (25/221 [11.5%] at baseline vs 11/221 [5%] at follow-up) and there was a concomitant increase in those with mild depression (43/221 [19.5%] vs 49/221 [22%]) and no depression (153/221 [69%] vs 161/221 [73%], Table  4 ). Changes in the proportional distribution of no, mild, or major depression did not reach significance when analyzed by sub-group of ACF ( p  = 0.067) or PCF ( p  = 0.084) diagnosis (Table  4 ).

There were no significant differences found between the proportion distribution of no, mild, or major depression among ACF vs PCF participants at baseline, follow-up, or change between baseline and follow-up (Table  5 ).

Among those who screened positive for depression, there was a moderate, significant positive correlation between depression scores and stigma scores at baseline ( r 0.41, p  < 0.001) but no association at the follow-up ( p  = 0.9). (Additional file  2 : Figure S1) The most prevalent issues reported in the disaggregated PHQ-9 responses included lack of appetite and energy (Additional file  1 : Table S2).

At baseline, 3% of the participants reported having severe problems or being unable to walk or self-care; approximately 2% of participants reported having severe problems or being unable to do usual activities and 4% reported having anxiety. Similarly, at baseline, among ACF and PCF participants, a higher proportion of participants from the ACF group reported having severe problems or being unable for four dimensions except pain or discomfort. At follow-up, less than 1% reported having severe problems or being unable for all the five dimensions of EQ-5D-5L. Similarly, none of the PCF participants reported having severe problems or being unable to for the four dimensions except anxiety and depression (Additional file  1 : Table S3).

The self-reported mean health rating for all participants improved by 11.3 points from 69.0 (SD = 15.0) at baseline to 80.3 (SD = 13.6) at follow-up ( p  < 0.001, Table  2 ). The mean EQ-5D-5L score for all participants increased by 0.05 from 0.92 (SD = 0.18) at baseline to 0.97 (SD = 0.07, p  = 0.009) at follow-up. Among both ACF and PCF groups, self-reported health rating (both p  < 0.001) and EQ-5D-5L scores (ACF p  < 0.003; PCF p  = 0.002) increased between baseline and follow-up (Table  2 ). However, there were no significant differences in self-reported health rating or EQ-5D-5L among ACF vs PCF at baseline, follow-up, or the change between baseline and follow-up (Table  3 ). There were no differences greater than the MCID threshold found in the change between baseline and follow-up EQ-5D-5L and self-rated health scores of all participants, ACF participants, and PCF participants (Table  2 ) or in the change between baseline and follow-up EQ-5D-5L and self-rated health scores of ACF vs PCF participants (Table  3 ).

The disaggregated data for the responses across the five domains of the EQ-5D-5L are shown in the Additional file  1 : Table S3.

To our knowledge, this is the first study to measure the perception of TB stigma, depression, and quality of life longitudinally among people with TB and to compare these between people diagnosed with TB through ACF and PCF. Nearly one-third of participants had mild or major depression at baseline. The proportion of participants with major depression decreased between baseline and follow-up and, amongst ACF but not PCF participants, the depression score decreased between baseline and follow-up. Most of the items on the stigma scale decreased at follow-up for both ACF and PCF participants. TB stigma and depression scores were positively correlated. Self-reported quality of life and EQ-5D-5L scores improved between baseline and follow-up for all participants but no differences in quality of life were found between ACF and PCF participants. These findings emphasise the stark psychosocial consequences of TB and highlight ACF activities as an early point-of-contact with vulnerable people with TB, which currently represents a missed opportunity to intervene and improve psychosocial outcomes.

There is strong evidence that TB remains a severely stigmatized disease, especially within high-burden communities in LMICs [ 19 ]. In this cohort of people with TB in Nepal, TB stigma, especially related to guilt and fear of disclosure outside of the household, was prevalent and persistent throughout TB treatment, regardless of whether participants were diagnosed through ACF or PCF. This finding contradicts other studies that reported a reduction in TB stigma over time, more often at the continuation phases of TB treatment. For example, cross-sectional studies conducted in Ethiopia among people with TB found that individuals in the intensive phase of TB treatment were more likely to report TB stigma than those in the continuation phase [ 58 , 59 ]. Longitudinal studies on stigma associated with diseases such as HIV also have shown that stigma, particularly internalized stigma is higher following diagnosis and gradually decreases over time [ 60 ]. Zambian and South African TB and HIV Reduction (ZAMSTAR) study also showed a reduction in levels of internalized stigma over the treatment course [ 61 ]. This is also in concordance with an article by Earnshaw et al. that describes how people may be able to overcome their stigmatized status over time when the severity of symptoms begins to gradually wane [ 62 ]. Interventions that aim to reduce stigma during the early stages of treatment are therefore important for curable diseases like TB. However, there is a paucity of evidence globally and in Nepal that determines the underlying cause for the persistence of TB-related stigma in communities, and warrants future research.

In our longitudinal cohort, we did not find significant differences in the stigma scores between our baseline interview conducted during the intensive phase and our follow-up interview conducted during the continuation phase. Nevertheless, we found a high proportion of participants reporting TB stigma, including guilt and fear of disclosure, which persisted throughout both phases. This is important because TB-related stigma has been shown to contribute to diagnostic or treatment delay, non-adherence to TB medications, and adverse TB treatment outcomes [ 19 , 21 ]. There were no differences between TB stigma scores among participants diagnosed through ACF or PCF at any time point or across time points. Although ACF represents a prime opportunity to promptly identify and address stigma among TB-affected households, it is notable that TB stigma has also been found to be a barrier to the successful implementation of ACF programs [ 63 , 64 , 65 ]. This should be taken into account in the design and implementation of any ACF program aiming to incorporate TB stigma reduction activities within the interventions.

The 10-item adapted TB stigma scale had very low non-response or equivocal response rates. Half of the cohort was in agreement that people with TB fear telling people outside their household about their disease status. Of perhaps greater concern, a fifth of participants agreed that people with TB fear even telling people within their own household about their illness, which reflects the highly stigmatized nature of TB in Nepali society. It is well recognized that people with TB report hiding their illness [ 7 , 66 , 67 ] and that such non-disclosure is associated with stigma, fear and isolation, worsening depression, delayed diagnosis, developing drug-resistant TB, and sustained transmission [ 31 , 68 , 69 , 70 , 71 ]. Our findings are concurrent with other studies that found that people with TB are more likely to disclose their disease to people within their household than non-household members, although more men than women in our cohort reported fear of disclosure within their households [ 68 , 72 ]. The perception that people with TB feel guilt due to their disease which was prevalent among our cohort, has been reported in other studies including a cross-sectional study in Kathmandu Valley, Nepal [ 7 , 31 , 73 ].

Based on our findings related to TB stigma, we have since developed and piloted a complex psychosocial and economic intervention, a component of which aims to support people to recognize, cope, and challenge the stigma associated with TB [ 74 ]. The stigma intervention is a locally made animated video about TB stigma, which is shown during household visits and at mutual support “TB Clubs”, which are knowledge- and experience-sharing events led by TB survivors to which all TB-affected household members are invited [ 75 ]. We will evaluate the effect of this video on the major stigma domains identified in our study, enhance pre-existing emotional support of the affected person by their household and inform the design of TB stigma reduction intervention in communities.

The intensive phase of TB treatment, nearly one-third of our cohort had mild (20%) or major (12%) depression, which is in line with the existing body of evidence of an association between TB and depression [ 23 , 25 ]. Similarly, comparable to a study in Malaysia, our study showed depression persisted even at the end of TB treatment [ 76 ]. A study by Ambaw et al. showed untreated depression at the initiation of treatment, is associated with poor quality of life and increased disability at the end of treatment [ 77 ]. We also found that, among people with mild or major depression, depression scores correlated positively with stigma scores, suggesting a clustering of the psychosocial consequences of TB. Our study adds to the scant literature on the longitudinal measurement of depression: in our cohort, the distribution of no, mild, and major depression changed significantly between the baseline and follow-up interviews, with major depression decreasing by more than half. This suggests that earlier psychosocial support interventions combined with stigma reduction programs could be effective in reducing the impact of TB on mental health and internalized stigma. A similar reduction in the magnitude of depression was seen in two longitudinal studies conducted in India [ 78 , 79 ]. Rouf et al. also reported that people with TB who experienced depression persisting after the intensive phase had a higher likelihood of adverse TB treatment outcomes including treatment failure [ 79 ]. An analysis of 48 LMICs showed that having comorbid depression and TB was associated with an increase in problems related to sleep, self-care, mobility, and pain [ 23 ], all measures of quality of life.

In our study, the prevalence of depression among people with TB at baseline (end of intensive phase) and follow-up (end of continuation phase) was higher than other cross-sectional studies conducted in Nepal (10%) and China (18%) but similar to Nigeria (28%) and Vietnam (25%) [ 44 , 80 , 81 , 82 ]. The differences in depression prevalence across countries may relate to the time point during TB treatment at which the depression scale was applied and also to sociodemographic differences including urban or rural location, age, gender, inadequate social support, and low education status [ 83 ]. For example, the majority of participants in our study were aged 55 years and above, an age group which has been shown in Ethiopia and Nigeria to have higher rates of depression compared to younger age groups [ 84 , 85 ]. Nevertheless, our findings of prevalent depression among people with TB coupled with a lack of integrated mental health screening programs in Nepal represent a significant challenge for Nepal’s NTP [ 86 ].

We found a significant decrease in depression scores between baseline and follow-up among ACF participants. This could be due to increased contact, support, and informal counseling from experienced community health workers for those diagnosed with ACF. To our knowledge, this is the only quantitative data to evaluate the impact of ACF on depression. A previous qualitative study and scoping review reported ACF interventions benefitted people with TB through trust, good communication, and addressing fear and stigma [ 64 , 87 ]. This highlights the need to strengthen resources to integrate community-proven ACF activities, such as household TB screening, with concomitant screening for and management of mental illness (such as counseling and psychological therapies) as part of routine NTP activities, to reduce depression and address mental health issues associated with TB [ 88 , 89 ].

We observed that the quality of life of people with TB, whether measured by EQ-5D-5L utility tool or self-rated health, improved between the intensive and continuation phases of treatment for ACF, PCF, and all participants. This is consistent with other evidence including a longitudinal study from Pakistan [ 9 , 90 ]. Although our findings do not show differences in quality of life between the ACF and PCF participants, ACF has been found as an effective strategy to improve quality of life [ 91 ].

Similar to our findings, longitudinal studies conducted in Peru by Datta et al. and in Canada by Bauer et al. showed the quality of life at treatment initiation is lower than for those without TB [ 32 , 92 ]. Datta et al. also found the quality of life increased to a level similar to people without TB after 6 months of TB treatment [ 32 ]. However, a study in South Africa reported that, even at the end of TB treatment, quality of life was worse for people with TB than those without TB [ 53 ]. We also observed that the EQ-5D-5L score during the intensive phase was higher among our cohort than in a study conducted in South Africa [ 53 ]. Studies have shown that family and social support for people with TB improves their quality of life [ 93 , 94 ].

The proportion of participants reporting problems for the five levels in EQ-5D-5L was lower in our longitudinal study compared to that in Pakistan [ 90 ]. This could be due to the difference in the time period of the interview (2 months in Pakistan versus 2–3 months for our study) and/or the use of the EQ-5D-5L versus EQ-5D-3L tool. The time period during which quality of life is measured is important as the quality of life improves as treatment progresses and the differences in the levels of the tool may differ in the self-reported severity of the illness.

Stigma, depression, and quality of life

Our study found that a high proportion of people with TB perceived TB stigma. The association between stigma and depression is well established and individuals having internalized or TB stigma have a higher likelihood of having depression [ 30 ]. This suggests that psychosocial support programs including stigma reduction interventions, especially when implemented early in treatment, could be effective in mitigating the impact of TB on mental health and internalized stigma. The study found that the proportion of participants with major depression decreased during the follow-up period. The reasons for this improvement during follow-up are likely to be multi-factorial, including improved physical health due to treatment, decreased financial stress on the household due to a return to income-generating activities, and reduced out-of-pocket medical expenditure compared to the diagnostic phase of the illness, decreased fear of mortality from TB, and other inter-related factors. Therefore, it is important to design comprehensive health programs that support overcoming the negative health effects of stigma and depression for people with TB.

It is also interesting to note the findings that despite the decrease in depression towards the end of treatment, stigma persisted for both ACF and PCF groups. Stigma has been associated with years of education, poor knowledge regarding TB and its transmission, perceived risks of transmission, poverty, and socioeconomic class [ 19 , 30 ]. In our study, more than half of our participants did not have basic literacy and are poor which might be the reason for enduring stigma in this cohort. Thus, further study is needed to measure other factors that cause stigma and depression for people with TB and develop better people-centric TB care.

Strengths and limitations

This is the first longitudinal study measuring TB stigma, depression, and quality of life among people with TB during TB treatment in Nepal. It is also one of the few studies that compared participants diagnosed with TB from ACF and PCF strategies. The findings will contribute to informing researchers and policymakers aiming to design and develop locally appropriate psychosocial interventions to improve the health, mental health, and quality of life of people with TB in low- and middle-income countries like Nepal.

The study has several limitations. This was a formative and opportunistic study taking part within a larger program of research including an ACF study with an associated TB Patient Costs survey. Due to logistical, time, and budgetary constraints, the study was unpowered and unmatched, which may have introduced selection bias. Indeed, by their very nature, ACF interventions are aimed at identifying people with TB who may be more vulnerable and less able to access healthcare, which was reflected in the baseline socioeconomic differences in our ACF and PCF cohort. Therefore, the finding of no difference in the psychosocial consequences of TB among ACF vs PCF participants, apart from the change in depression scores between baseline and follow-up in ACF vs PCF participants, should be interpreted with caution. To overcome this issue of selection bias, we have since completed recruitment and follow-up of the randomized-controlled “ASCOT” pilot trial of a socioeconomic intervention, including TB-stigma reduction activities, during which we longitudinally measured levels of stigma, depression, and quality of life [ 74 ]. Another limitation of our study was the use of adapted versions of PHQ-9, Van Rie Stigma Scale, and EQ-5D-5L tools. The removal, due to the issue related to the potential to cause distress identified during piloting, of a question from the PHQ-9 scale, meant the maximum possible score was 24 rather than 27. This change could have potentially resulted in a small underestimation of the prevalence and severity of depression in our cohort, underlining the main finding that depression is highly prevalent among TB cases in Nepal. At the time the study was being conducted, there were no formal mental health services available in the districts or a mechanism for referral of people identified as having major depression to mental health services further afield. Our staff used an informal referral pathway which we recognized needed to be systematised. We have since developed a referral pathway to address this issue, which has been successfully used during the subsequent ASCOT pilot trial [ 74 ]. The Van Rie Stigma Scale was also adapted to be more concise and to remove questions perceived as potentially insensitive but, in future research, we aim to formally validate the psychometric properties of the scale in Nepal, as we have done in other settings including Indonesia [ 95 , 96 , 97 ]. Similarly, the EQ-5D-5L tool is a simple tool appropriate for field studies, but as a consequence, it is also a rather ‘blunt’ tool for measuring physical changes in quality of life for drug-sensitive TB. We adapted our weighted EQ-5D-5L score from an Indian quality of life dataset that had used EQ-5D-3L, which may have meant contextual and measurement differences were introduced, which we did not evaluate within this study. The use of MCID values to contextualize differences in psychosocial impact was limited by a scarcity of evidence on MCIDs in this field. Nevertheless, the use of MCID values by researchers and implementers appears to be growing and they will be refined further as more robust evidence becomes available to inform the parameters [ 44 ]. Finally, there is the possibility that longitudinal administration of tools measuring the psychosocial impact of TB could have introduced desirability bias amongst participants in their responses at follow-up interviews. However, conversely, we believe the longitudinal study design would reduce recall bias compared to the standard cross-sectional studies that have been reported in this field. The longitudinal design has added value in measuring multiple psychosocial impacts of TB during the course of treatment for the first time in Nepal [ 31 , 44 , 72 , 73 , 98 ].

Our findings show a substantial, persistent, and clustered psychosocial impact of TB in Nepal. One-third of people with TB had some form of depression and levels of depression were reduced amongst ACF but not PCF participants. TB diagnosis provides an opportunity to evaluate and identify people who would benefit from support through holistic psychosocial interventions, which could be integrated with ACF strategies and routine TB services.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Email: [email protected]. This is because the ethical approval for the study that was received in both the UK and Nepal specified the publication of findings in peer-reviewed journals and presentation through public engagement activities and made no specific mention of making the data publicly available. This was also not stated in any study documents including the protocol, consent forms, or participant information leaflets.

Abbreviations

• Active case finding

Birat Nepal Medical Trust

Directly Observed Treatment Short-course

Low- and middle-income countries

Liverpool School of Tropical Medicine

Minimal Clinically Important Difference

National Tuberculosis Program

• Passive case finding

Patient Cost Survey

People with tuberculosis

• Tuberculosis

Van Rie Stigma Scale

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Acknowledgements

We would like to acknowledge the National Tuberculosis Control Center, Nepal Health Research Council, Health Directorate of Madhesh Province and Bagmati Province, and all related health centers and staff for their contribution and collaboration with this study. We are also grateful to all the Community Health Supervisors from Chitwan, Makwanpur, Mahottari, and Dhanusha districts for engaging with people with TB care throughout the study period. Most importantly, we thank people with TB for their generous time and for sharing their experiences in this study.

TW is supported by grants from: the Wellcome Trust, UK (Seed Award, grant number 209075/Z/17/Z); the Department of Health and Social Care (DHSC), the Foreign, Commonwealth & Development Office (FCDO), the Medical Research Council (MRC) and Wellcome, UK (Joint Global Health Trials, MR/V004832/1); the Medical Research Council (Public Health Intervention Development Award “PHIND”, APP2293); and the Medical Research Foundation (Dorothy Temple Cross International Collaboration Research Grant, MRF-131–0006-RG-KHOS-C0942). Authors KD, BR, TPA, NTSF, RD, MKS, RNP, GM, PRP, JWL, JvR, SCG, GM, KL, BS, KSA, MC are supported by IMPACT TB: European Union, Horizon 2020 grant number 733174.

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Kritika Dixit, Bhola Rai, Tara Prasad Aryal, Raghu Dhital, Manoj Kumar Sah, Ram Narayan Pandit, Govinda Majhi, Puskar Raj Paudel, Suman Chandra Gurung & Maxine Caws

Department of Global Public Health, WHO Collaborating Centre On TB and Social Medicine, Karolinska Institutet, Stockholm, Sweden

Kritika Dixit, Knut Lönnroth, Kristi Sidney Annerstedt & Tom Wingfield

Department of Health Sciences, University of York, York, UK

Noemia Teixeira de Siqueira-Filha

KNCV Tuberculosis Foundation, The Hague, Netherlands

Jens W. Levy & Job van Rest

Centre for Tuberculosis Research, Departments of International Public Health and Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK

Suman Chandra Gurung, Gokul Mishra, Stephen Bertel Squire, Maxine Caws & Tom Wingfield

Tropical and Infectious Disease Unit, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK

Stephen Bertel Squire & Tom Wingfield

Institute of Population Health, University of Liverpool, Liverpool, UK

Laura Bonnett

Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

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Contributions

K.D. wrote the first draft. K.D., B.R., T.P.A., M.K.S. and R.N.P. collected data. K.D. and T.W. performed the analysis. K.S.A, L.B., A.F., M.C. and T.W. reviewed the first draft and provided comments. K.D., B.R., R.D., K.L., S.B.S., M.C. and T.W. are responsible for study conception and design. K.D., N.T.S.F., R.D., P.R.P., J.W.L., J.vR., S.C.G., G.M., K.L., S.B.S., M.C. and T.W. were responsible for overall project administration. All authors read and approved the final manuscript.

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Correspondence to Tom Wingfield .

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The study conformed to the principles outlined in the Declaration of Helsinki. The study received ethical approval from the University of Liverpool, UK (approval number 2436) and Nepal Health Research Council (approval number 320/2018). Participants were provided with a leaflet that detailed the objective, duration, risks and benefits of participating in the study [ 99 ]. Written informed consent was obtained from all the participants.

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Supplementary Information

Additional file 1: table s1..

Participants responses in percentage reporting the van Rie stigma scale at baseline and follow-up. Table S2. Participants responses in percentage reporting for each Patient Health Questionnaire question at baseline and follow-up. Table S3. Participants responses in percentage reporting the experience of quality of life at baseline and follow-up.

Additional file 2: Figure S1.

Correlation between baseline depression and stigma scores amongst participants who screened positive for depression ( n =71).

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Dixit, K., Rai, B., Aryal, T.P. et al. Stigma, depression, and quality of life among people with pulmonary tuberculosis diagnosed through active and passive case finding in Nepal: a prospective cohort study. BMC Global Public Health 2 , 20 (2024). https://doi.org/10.1186/s44263-024-00049-2

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Received : 18 July 2023

Accepted : 23 February 2024

Published : 24 March 2024

DOI : https://doi.org/10.1186/s44263-024-00049-2

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Suitability of reduced dose glucocorticoids therapy regimen for antibody-associated vasculitis patients with TB: a retrospective study

• Original Article
• Published: 27 March 2024

Cite this article

• Rui Wen 1   na1 ,
• Jingni Xiao 1   na1 ,
• Ning Ding 2 ,
• Yong Zhong 3 , 4 ,
• Qiong Yuan 1 ,
• Jiali Li 1 ,
• Qi Wang 1 ,
• Hebin Xie 5   na2 &
• Jiao Qin 1 , 6   na2  

Immunosuppressive therapy is the major treatment approach for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Due to impaired cellular immunological function and the use of glucocorticoids and immunosuppressants, AAV patients are predisposed to opportunistic infections, including tuberculosis (TB). This retrospective study aims to analyze the clinical characteristics of patients with AAV and TB and explore suitable glucocorticoid regimens for them. So as to provide a basis for future clinical guidelines and have important value for guiding clinical treatment.

This study retrospectively reviewed 58 AAV patients (18–80 years old) with TB admitted to Changsha Central Hospital Affiliated with the University of South China from 2016.1 to 2023.4 Patients were divided into standard-dose and reduced-dose glucocorticoid groups before retrospectively analyzing their medical records.

A total of 58 AAV patients with TB were enrolled, with 15 dying throughout the monitoring period. Through analysis data, compared with the standard-dose group, the reduced group had less proteinuria and hematuria. In survival analysis, the reduced-dose glucocorticoid group had lower mortality than the standard-dose group ( P  = 0.03); however, no significant difference was noted in the use of immunoglobulin ( P  = 0.39), tuberculosis activity ( P  = 0.64), and age stratification ( P  = 0.40). The BVAS score before treatment and 6 months post-treatment suggest that the two regimens cause the same risk of ESKD ( P  > 0.05).

In conclusion, the reduced glucocorticoid dose group can achieve the same curative effect as the standard dose group and has less damage to the kidney in hematuria and proteinuria. Therefore, the reduced glucocorticoid dose treatment regimen may be more suitable for AAV patients with TB.

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Data availability

The data sets used and/or analyzed during the present study were availed by the corresponding author upon reasonable request.

Abbreviations

Coronary heart disease

Chronic Obistructive Pulmonary Disease

End Stage Kidney Disease

Birmingham vasculitis activity score

• Tuberculosis

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This research was supported by the Hunan Provincial Natural Science Foundation Youth Foundation (Grant No. 2020JJ5611 and No. 2020JJ8044), Hunan Provincial Health Commission Foundation (Grant No. 202203052625), Changsha Central Hospital Subject of South China University (Grant No. YNKY202101), Scientific research Project of Education Department of Hunan Province (Grant No.22A0321), Hunan Provincial Science and Technology Department Project (Great No. kzd21074 and 2021SK53410).

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Rui Wen and Jingni Xiao contributed equally to this work.

Hebin Xie and Jiao Qin contributed equally to this work.

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The Affiliated Changsha Central Hospital, Department of Nephrology, Hengyang Medical School, University of South China, Changsha, Hunan, 410004, China

Rui Wen, Jingni Xiao, Qiong Yuan, Jiali Li, Qi Wang & Jiao Qin

The Affiliated Changsha Central Hospital, Department of Emergency, Hengyang Medical School, University of South China, Changsha, Hunan, 410004, China

Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China

Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, Hunan, China

The Affiliated Changsha Central Hospital, Department of drug clinical trial institutions, Hengyang Medical School, University of South China, Changsha, Hunan, 410004, China

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Rui Wen, Jingni Xiao, Qin Jiao, and Hebin Xie. The first draft of the manuscript was written by Rui Wen and Jingni Xiao, and Ning Ding, Yong Zhong, Qiong Yuan, Jiali Li and Qi Wang commented on previous versions of the manuscript. All authors read and approved the final manuscript. Jiao Qin and Hebin Xie contributed equally to this manuscript. Rui Wen and Jingni Xiao contributed equally to this manuscript.

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Wen, R., Xiao, J., Ding, N. et al. Suitability of reduced dose glucocorticoids therapy regimen for antibody-associated vasculitis patients with TB: a retrospective study. Eur J Clin Microbiol Infect Dis (2024). https://doi.org/10.1007/s10096-024-04807-w

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Scientists close in on TB blood test which could detect millions of silent spreaders

Scientists have taken a major step towards developing a blood test that could identify millions of people who spread tuberculosis unknowingly.

A breakthrough study has discovered a group of biological markers that are found in high levels among infectious patients.

The researchers hope the findings will pave the way for a simple test that can diagnose and stop the spread of the estimated 10 million cases annually.

Tuberculosis, or TB, is the world's deadliest infectious disease and kills more than one million people each year, according to World Health Organisation data.

Scientists from the University of Southampton, working with experts worldwide, carried out the most detailed analysis ever undertaken of blood markers for the bacterial infection.

The study, published in the Journal of Clinical Investigation Insight , used a novel technique that identified a set of six proteins that are highly accurate in pinpointing TB.

Lead author Dr Hannah Schiff, a respiratory expert at Southampton, said as many as three million cases were missed last year, mostly in developing countries.

She added: "TB remains a global catastrophe because our efforts to control the spread are hindered by inadequate testing, which is slow and reliant on specialist equipment and labs.

"A third of people who get infected go undiagnosed and remain infectious.

"In our study, we combined a new measurement technique with deep mathematical analysis to identify these six new markers of TB disease.

"It could lead to a transformative alternative to diagnosing the condition -- a simple test that detects proteins in the bloodstream whose levels differ between people with TB, healthy individuals, and those suffering from other respiratory illnesses."

TB spreads through inhaling tiny droplets from coughs or sneezes of infected people -- and, while it mostly affects the lungs, it can devastate any part of the body.

Cases in the UK increased to around 5,000 last year, and are expected to continue rising in 2024, according to the UK Health Security Agency.

The University of Southampton study was undertaken with experts from the University of Cape Town in South Africa and Cayetano Heredia University in Lima, Peru.

It was published for world TB day, on 24 March, which is held to raise awareness and to step up efforts to end the global Tuberculosis pandemic.

The study was funded by the UK Medical Research Council and the National Institute for Health and Care Research (NIHR) Southampton Biomedical Research Centre.

Academics leading the investigation studied proteins found in the blood of people with active TB in Africa and South America.

They compared the biomarkers to those found in healthy people and patients with lung infections, identifying 118 proteins that differed significantly between the groups.

The experts then narrowed these down to the six proteins that, they said, can be used to distinguish contagious patients with TB from people in good health or with lung conditions.

The findings are a roadmap to developing a TB test that is as simple as the lateral flows used during Covid, said study co-director Dr Diana Garay-Baquero, also from Southampton.

She added: "The new markers we discovered are truly exciting, but the important work now is to develop these into tests that can be used for the millions of people who are transmitting TB without knowing it.

"As the Covid-19 pandemic confirmed, we ignore highly infectious airborne diseases at our peril."

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Materials provided by University of Southampton . Note: Content may be edited for style and length.

Journal Reference :

• Hannah F. Schiff, Naomi F. Walker, Cesar Ugarte-Gil, Marc Tebruegge, Antigoni Manousopoulou, Spiros D. Garbis, Salah Mansour, Pak Ho Wong, Gabrielle Rockett, Paolo Piazza, Mahesan Niranjan, Andres F. Vallejo, Christopher H. Woelk, Robert J. Wilkinson, Liku B. Tezera, Diana Garay-Baquero, Paul Elkington. Integrated plasma proteomics identifies tuberculosis-specific diagnostic biomarkers . JCI Insight , 2024; DOI: 10.1172/jci.insight.173273

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Intensifying new initiatives for TB case-finding in Nigeria

Abuja ‒ Around a year ago, Mallam Mainasara Mohammad, a resident of Makera,  a locality in Kebbi State, Nigeria, became increasingly worried about his son, nine-year-old Yusuf. The child had been coughing for weeks, had difficulty sleeping and unable to attend school.

“I took him to the health centre after I heard on the radio that the government  conducts  free tests for people coughing for more than two weeks,” says Mohammad. After a chest x-ray and a sputum test using a specialized system called GeneXpert, which provides rapid tuberculosis (TB) diagnosis and an antibiotic sensitivity test, Yusuf was diagnosed with drug-resistant TB.

He was immediately treated with combination TB medicines for six months. In addition, Yusuf’s family members were screened for TB and given a course of anti-TB medicines to prevent the development of the disease. The medicine was provided at no cost to the family.

“We would go to the hospital every week to collect the TB treatment. This allowed the health workers to follow up on Yusuf’s progress,” says Mohammed.” I am happy my son is now better and  has resumed school.”

Nigeria has the highest TB burden in Africa. The disease kills 268 people in the country every day. Yet TB cases are under-reported, increasing the high risk of transmission. It is estimated that one missed case can transmit TB to 15 people in a year.

The gap in case detection is mostly among children, due to some health workers at facility and community level not sufficiently skilled to detect childhood TB, as well as a lack of awareness among families and communities. TB services are also not fully integrated into routine children’s health services, such as nutrition and immunization programmes.

To  intensify TB case-finding in the country, Nigeria’s National Tuberculosis, Buruli Ulcer and Leprosy Control Programme, and its partners including World Health Organization (WHO), have been implementing various innovative strategies, including a TB drive across the 36 states and Federal Capital Territory. A special childhood TB case-finding testing week was conducted in May 2023.

According to provisional data, over 361 000 TB cases were reported in Nigeria in 2023, 9% of these in children. Overall, this marked a 26% increase in the number of cases compared with 2022.

“The drive showed the importance of TB case-finding in the community, especially among children, and marks the beginning of continuing active surveillance for TB in line with WHO standards,” says Kebbi State TB programme manager, Dr Sheu Gele. “Intensive mobilization and TB awareness creation among community and health practitioners, including community-health workers and paediatricians, has paid off,” he adds.

Community sensitization is carried out in communities with a high burden of TB, guided by the data and a hotspot mapping tool. Community health workers collaborate with local community organizations to engage community gatekeepers, conduct community entrance meetings and engage community mobilizers to assist with active case-finding.

WHO has supported the national TB programme to adopt evidence-based strategies for case-finding, including training health workers. During 2023 and the first three months of 2024, with funding from The Global Fund to Fight AIDS, TB and Malaria, WHO has trained 242 health workers to improve TB case detection, reporting and treatment of patients across five states. In addition, in January 2024, at the request of Borno State’s governor, WHO conducted a 10-day training of 60 TB supervisors from 27 local government areas in the state.

Furthermore, WHO has facilitated the roll out of the six-month treatment regimen for drug-resistant TB, and is currently piloting the use of a “treatment decision” algorithm. This aims to standardize clinical assessment and decision-making to enhance TB case detection among children.

“WHO is committed to work with the Government of Nigeria and all partners who are committed to ending TB. While it is highly contagious, TB is preventable and treatable. We must rally together to quickly detect and treat TB cases to kick this disease out of Nigeria,” says Dr Walter Kazadi Mulombo, WHO Representative in Nigeria.

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• v.8(11); 2002 Nov

Two Cases of Pulmonary Tuberculosis Caused by Mycobacterium tuberculosis subsp. canetti

Jean miltgen.

* Hôpital d’instruction des armées Laveran, Marseille, France

Marc Morillon

Jean-louis koeck.

† Hôpital d’instruction des armées Val de Grâce, Paris, France

Anne Varnerot

‡ Institut Pasteur, Paris, France

Jean-François Briant

Gilbert nguyen, denis verrot, daniel bonnet, véronique vincent.

We identified an unusual strain of mycobacteria from two patients with pulmonary tuberculosis by its smooth, glossy morphotype and, primarily, its genotypic characteristics. Spoligotyping and restriction fragment length polymorphism typing were carried out with the insertion sequence IS6110 patterns. All known cases of tuberculosis caused by Mycobacterium canetti have been contracted in the Horn of Africa.

The Mycobacterium tuberculosis complex includes the following mycobacteria, which are characterized by a slow growing rate: M. tuberculosis, M. africanum, M. bovis, and M. microti ( 1 ). In recently published reports of two cases of lymphatic node tuberculosis (TB), the strains were recognized as belonging to a new taxon of M. tuberculosis ( 2 , 3 ). These isolates were characterized by a highly particular growing pattern, and the colonies appeared smooth and glossy. A complete genetic study of these strains led to their integration into the M. tuberculosis complex. This strain, identified as M. tuberculosis subsp. canetti or, more simply, M. canetti, was first isolated in 1969 by Georges Canetti from a French farmer. The strain was preserved at the Pasteur Institute where its antigenic pattern was studied extensively. We report two cases of pulmonary TB caused by this strain. The two patients had also lived in East Africa.

In September 1998, a 36-year-old male soldier in the French Foreign Legion with hemoptysis was sent back to France from Djibouti. He expectorated bloody sputum after running and on a few other occasions. His medical history was not unusual. When the patient was hospitalized, 2 weeks after the initial symptoms, he began to experience progressive fatigue. He did not experience fever, weight loss, night sweats, anorexia, cough, dyspnea, or chest pain, and did not produce sputum.

Results of the clinical examination were normal. The Mantoux test, performed with 10 IU of purified tuberculin (Aventis-Pasteur-MSD, Lyon, France), yielded a maximum transverse diameter of induration of 15 mm. Laboratory values were normal ( Table ). The chest X-ray showed a triangular consolidation of the left upper lobe with blurred limits and small cavitary lesions. No other contiguous mediastinohilar anomalies were visible. A computed tomographic scan confirmed the cavitary syndrome: three excavated nodular images showed radiating spicules within a micronodular infiltrate. Bronchoscopy showed a moderate inflammation of airway mucosa, especially in the left upper lobe. Biopsy specimens exhibited nonspecific inflammation.

A bronchial washing smear from the left upper lobe was positive for acid-fast bacilli. Serologic tests for HIV-1 and HIV-2 were negative. No evidence of disease was found elsewhere; the patient did not experience bone pain. Results of neurologic and ophthalmologic examinations were normal; no lymphadenopathy or hepatosplenomegaly were found and the genitalia were normal. Auscultation revealed no pericardial fremitus; no ascitic fluid was detected. The urinary sediment contained <1,000 red blood cells/L and <5,000 leukocytes/L. Antituberculosis chemotherapy was begun with four drugs: rifampicin, isoniazid, ethambutol, and pyrazinamide. Cultures revealed a strain identified as M. tuberculosis subsp. canetti that was susceptible to all primary antituberculous drugs. Therefore, rifampicin and isoniazid were continued for 3 more months for a total treatment period of 6 months. The patient’s response to treatment was favorable, and he remained asymptomatic.

A 55-year-old male soldier in the French Foreign Legion, who returned from Djibouti, was hospitalized in September 1999 after his chest x-ray showed abnormal findings. He was a nurse and had been occasionally in charge at the Djibouti Hospital for 2 years. His medical history was unremarkable. Eight months before he returned to France, he experienced asthenia, anorexia, and a weight loss of 3 kg. The symptoms resolved spontaneously after 2 months, and he had been asymptomatic since then. He had no history of cough, sputum production, hemoptysis, dyspnea, fever, or night sweats.

Results of a clinical examination and of laboratory studies were normal ( Table ), except for hypereosinophilia. Serologic tests for schistosomiasis, hydatidosis, distomiasis, amebiasis, toxocariasis, and trichinosis were negative, and parasites were not found in stool samples. Thoracic radiographs performed when he came back from Djibouti showed parenchymal consolidation of the right upper lobe with small cavities. Sputum was not produced. A gastric aspirate smear was negative for acid-fast bacilli, and a bronchial aspiration smear was positive for acid-fast bacilli. HIV serology was negative, and no other site of the infection was found. Drug therapy was initiated with rifampicin, isoniazid, ethambutol, and pyrazinamide for 2 months. Cultures of bronchial aspirates were positive within 14 days; later, cultures of two gastric aspirates were positive for acid-fast bacilli. An M. tuberculosis subsp. canetti isolate was identified, which was susceptible to all primary antituberculous drugs. The treatment was then extended for 4 months with rifampicin and isoniazid. The patient's response to treatment was favorable.

The following methods were used to identify the etiologic agent. First, the samples were decontaminated with N-acetyl-L-cysteine/NaOH. Acid-fast bacilli were detected by auramine staining, the positive smears also were stained with Ziehl-Nielsen stain. The samples were then seeded onto Löwenstein-Jensen and Coletsos slants and also into a liquid system, the BBL Mycobacterial Growth Indicator Tube (MGIT, BD Diagnostic Systems, Sparks, MD).

The mycobacteria were identified by using a specific DNA probe (Gen-Probe, Gen-Probe Incorporated, San Diego, CA) and by performing the usual biochemical tests (nitrate reduction, 68°C catalase resistance, niacin production).

The Pasteur Institute of Paris used two methods for typing: restriction fragment length polymorphism (RFLP) analysis and spoligotyping. In RFLP analysis, after digestion of the M. tuberculosis strain's genomic DNA with PvuII restriction enzyme and agarose gel migration, the DNA was transferred on a membrane, according to the Southern method, and then hybridized with an insertion sequence IS6110 probe ( 4 ). In the spoligotyping method, after DNA direct repeat amplification, the labeled polymerase chain reaction product was used as a probe to hybridize with 43 synthetic spacer oligonucleotides (DNA sequences derived from the direct repeat [DR] region of M. tuberculosis, H37Rv and M. bovis BCG P3), which were attached to a carrier membrane ( 5 ). The sensitivity to antituberculous drugs was determined by the indirect proportion method.

MGIT results were positive for the two cultures in 9 and 12 days, respectively. On Löwenstein-Jensen slants, the cultures were positive in 12 and 14 days, respectively. The white, smooth, and glossy colonies were characteristic of M. tuberculosis subsp. canetti ( Figure 1 ). The two strains had the same phenotypic and genotypic pattern; 68°C catalase was negative, and they reduced nitrate, as do other M. tuberculosis species, but they did not produce niacin. The DNA probe, Gen-Probe, confirmed that these strains belonged to the M. tuberculosis complex.

Colony morphology on Löwenstein-Jensen slants, showing M. canetti and M. tuberculosis strains. (A) Colonies of M. tuberculosis are rough, thick, wrinkled, have an irregular margin, and are faintly buff-colored. (B) M. canetti exhibits smooth, white and glossy colonies.

These strains contained two copies of IS6110. Spoligotyping showed that they shared only 2 of the 43 oligonucleotides reproducing the spacer DNA sequences of M. tuberculosis, H37Rv and M. bovis BCG P3. This profile is characteristic of M. tuberculosis subsp. canetti ( Figure 2 ).

(A) IS6110 hybridization patterns of PvuII-digested genomic DNA. Lane 1, Mycobacterium tuberculosis Mt 14323 (reference strain). Lane 2, M. canetti strain NZM 217/94. Lanes 3 and 4, the strains isolated from French legionnaires with pulmonary tuberculosis (TB). (B) Spoligotyping patterns. Lane 1, M. tuberculosis H37Rv (reference strain). Lane 2, M. canetti strain NZM 217/94. Lanes 3 and 4, the strains isolated from French legionnaires with pulmonary TB.

In 1997, van Soolingen reported a case of lymph node TB in a 2-year-old Somali child on the child’s arrival in the Netherlands in 1993 ( 2 ). In 1998, Pfyffer described abdominal lymphatic TB in a 56-year-old Swiss man (who lived in Kenya) with stage C2 HIV infection ( 3 ). These strains of M. canetti (So93 from the Somali child and NZM 217/94 from the Swiss man) have been studied extensively. In culture they grow faster than other strains in the M. tuberculosis complex. The So93 strain expands by one rough colony for every 500 smooth colonies. They appear smooth, white, and glossy because of the high amount of lipooligosaccharides in the membrane ( 6 ); the So93 rough colonies lack this amount ( 2 ).

Two copies of the IS6110 insertion sequence were found in the NZM 217/94 and So93 genome. This fingerprint matched none of the 5,000 other strains preserved in the laboratory of van Soolingen (Bilthoven, the Netherlands) ( 2 ). The strains we observed also showed two copies of IS6110.

So93, NZM 217/94, and our two strains share only 2 of 43 identical repeated sequences that have been observed by spoligotyping. Study of the IS6110 RFLP patterns and of the spacer DNA sequences of the DR locus confirmed that M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canetti represent a closely related group of mycobacteria that are clearly distinct from other mycobacterial species. In the M. tuberculosis complex, M. canetti appears to be the most divergent strain ( 2 ).

We believe that this is the first published report of pulmonary disease caused by M. canetti. Our two cases confirm that M. canetti is able to involve lungs, like any other other member of the M. tuberculosis complex and is able to affect immunocompetent subjects. The clinical features of these two pulmonary cases of TB caused by M. canetti are not specific.

TB caused by M. canetti appears to be an emerging disease in the Horn of Africa. A history of a visit to the region should cause this strain to be considered promptly. As travel to this area becomes more frequent, and mycobacterial identification techniques improve, the number of diagnosed cases will likely increase.

Acknowledgments

We thank Michel Fabre for the photographs and Jan Eskandari for his translation of this article.

Dr. Miltgen is assistant head of the Pneumology Department at the Hôpital d’Instruction des Armées of Marseilles, where he specializes in tropical diseases.

Suggested citation for this article: Miltgen J, Morrillon M, Koeck J-L, Varnerot A, Briant J-F, Nguyen G. Two cases of pulmonary tuberculosis caused by Mycobacterium tuberculosis subsp. canetti. Emerg Infect Dis [serial online] 2002 Nov [date cited]. Available from http://www.cdc.gov/ncidod/EID/vol8no11/02-0017.htm

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Taxpayers Were Overcharged for Patient Meds. Then Came the Lawyers.

A group of politically connected lawyers teamed up to go after insurers and made millions from one of the largest Medicaid settlements in history.

By Shalina Chatlani

Shalina Chatlani examined the health care system in Mississippi as a part of The Times’s Local Investigations Fellowship .

In 2018, when Mike DeWine was Ohio’s attorney general, he began investigating an obscure corner of the health care industry.

He believed that insurers were inflating prescription drug prices through management companies that operated as middlemen in the drug supply chain. There were concerns that these companies, known as pharmacy benefit managers, or P.B.M.s, were fleecing agencies like Medicaid, the government-run health insurance program for the poor.

Three years later, after Mr. DeWine became governor of Ohio, the state announced an $88 million settlement with one of the nation’s largest insurance companies, Centene.

The case led to a nationwide reckoning for the company, as attorneys general in one state after another followed Ohio’s lead, announcing multimillion-dollar settlements and claiming credit for forcing Centene to reform its billing practices.

On the surface, it appeared that these settlements, which now total nearly $1 billion, were driven by state governments cracking down on a company that had ripped off taxpayers.

But a New York Times investigation, drawing on thousands of pages of court documents, emails and other public records in multiple states, reveals that the case against Centene was conceived and executed by a group of powerful private lawyers who used their political connections to go after millions of dollars in contingency fees.

The lawyers were first hired in Ohio, without competitive bidding. Then, they gathered evidence against Centene of questionable billing practices across the country.

Using information they acquired from Centene and other sources, they negotiated with the company to set the basic framework of an agreement that could be applied in other states. With that in hand, they approached attorneys general in multiple states and made a compelling offer: hire them, at no direct cost to taxpayers, and recoup millions of dollars Centene had already set aside.

So far, the lawyers have been awarded at least $108 million in fees.

The Centene case is just one example in a thriving industry that allows private lawyers to partner with elected attorneys general and temporarily gain powers usually reserved for the government. Under the banner of their state partners, these lawyers sue corporations and help set public policy while collecting millions of dollars in fees, usually based on a percentage of whatever money they recoup. The practice has become standard fare in the oversight of major industries, shifting the work of accountability away from legislators and regulators to the opaque world of private litigation.

Private lawyers do not have to publicly defend the deals they make or prove how aggressively they went after a company accused of wrongdoing. Nearly all their work happens in secret, especially if companies settle before the stage of a lawsuit when evidence is filed with the court.

The lawyers do not even have to disclose who worked on a case or who was paid, so the public may be left unable to monitor potential conflicts of interest even as the lawyers pursue litigation on behalf of the people.

The Centene case was organized by the Mississippi-based law firm Liston & Deas along with at least three other firms, several with close ties to former Gov. Haley Barbour of Mississippi, who was once considered one of the most influential Republican power brokers in the nation.

The lawyers included Paul Hurst, who served as Mr. Barbour’s chief of staff when he was governor and who married into Mr. Barbour’s family, and David H. Nutt, one of the richest men in Mississippi, who amassed a fortune funding state lawsuits against tobacco companies. Cohen Milstein, a huge national law firm with deep experience in contingency work for state attorneys general, was also part of the venture.

Though he is not listed in any government contracts as a lawyer of record, Mr. Barbour himself was a member of the legal team when Liston & Deas vied for the contract in Ohio.

At the time, Mr. Barbour also worked for Centene as a federal lobbyist .

Even now, close to three years after Centene signed its first settlements, no one has fully explained Mr. Barbour’s role in the case for the company. There is no way for the public to know whether he influenced the outcome or to measure whether Centene paid its full share, because the data used to calculate what Centene overcharged remains hidden from the public under provisions designed to protect attorney work product.

Mr. Barbour and other lawyers said that the former governor worked on the case for less than a year when the group was examining several insurance companies, and that he cut ties when Centene emerged as the primary target. Mr. Barbour said he informed Centene and his colleagues about the development and was never involved in negotiations or legal matters. He continued representing Centene as a lobbyist, he said, but his role in the case on behalf of the company was as “more of an observer.”

The lawyers said that Mr. Barbour was never paid for his work and that the settlement was not influenced by Mr. Barbour’s connections to Centene or to the lawyers who remained. They said each state attorney general reviewed Centene’s billing practices when deciding whether to enter a settlement agreement.

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In recent years, P.B.M.s have been widely criticized , including by members of Congress, who have held multiple hearings and proposed legislation. The Centene settlements stand as the most successful attempt to hold a company operating in the industry accountable.

Liston & Deas and its partner law firms uncovered that Centene had arranged discounts with CVS Caremark on certain drugs and then pocketed the savings instead of passing them on to Medicaid. In some states, they revealed that Centene layered on unnecessary management fees that it had not disclosed. Although Centene settled without admitting guilt, the company agreed to be more transparent in how it sets reimbursement rates.

The lawyers noted that they spent several years investigating Centene and negotiating with the company at their own risk, saving states the cost of building a case.

Mr. Nutt, one of the lawyers who pursued the case, said states were happy with the terms of the settlements.

“Almost every one of those states audited to determine if our damage model was fair,” Mr. Nutt said.

“The formula was based on a triple damages model that we developed. And everybody was quite satisfied with it, because it was three times what anybody could have proven in court.”

Hiring Outside Counsel

For most of their history, state attorneys general were largely focused on advising state officials on legal matters and representing local agencies in court.

That changed drastically almost 30 years ago, when states came together to sue tobacco companies and won a $206 billion settlement to cover the cost of medical care related to smoking. The lawsuit helped redefine the role of the attorney general as one of the most powerful positions in state government and a natural place to start a political career.

Through high-profile lawsuits against corporations, an attorney general could directly affect policy and build a reputation as a champion of the people.

But complex litigation against large companies can require years of investigation and legal work, with no guarantee of success. Increasingly, states have turned to private lawyers willing to work on contingency as a way to stretch limited resources.

The rise of contingency fee cases kicked off a new wave of lobbying across the nation. Law firms looking for contracts have poured money into attorney general election campaigns and sponsored conferences at high-priced resorts, where private lawyers mingle with attorneys general and pitch their latest ideas for lawsuits.

Many states have capped how much lawyers can be paid in contingency fees and have increased oversight of private firms working for the government. But there remains concern about undue political influence and potential conflicts of interest.

“In theory, there’s an incentive to have the settlement be as big as possible, and of course that’s great for the state,” said Paul Nolette, a professor at Marquette University who has studied how the role of attorneys general has changed over time.

But in reality, lawyers have an incentive to recover the largest amount of money in the shortest amount of time, which could pressure them to water down settlements and compromise on punitive measures, Dr. Nolette said.

“I think that does raise some questions about how forcefully A.G.s and private attorneys are prosecuting a particular case,” he said.

Several experts said that contingency cases had recouped billions of dollars on behalf of the public and had become a critical way to regulate the behavior of powerful industries and large corporations.

But inviting private lawyers to help set public policy has inherent risks, they said.

Private lawyers may be more likely to have conflicts of interest because they generally represent many businesses and individuals, not just the citizens of a state.

And unlike most attorneys general, private lawyers are not elected officials. They are not generally governed by open records laws or subject to public pressure, as from legislators setting their budgets.

In the Centene case, Mr. Barbour’s associations with both Centene and the private lawyers raise “important questions” about who controlled the case to make sure it was pursued in the best interests of states that settled, said Kathleen Clark, a professor of legal ethics at Washington University in St. Louis.

“Did state A.G.s proactively pursue these cases, or did they passively accept the ‘free money’ or ‘easy money’ of the proposed settlements that the law firms had already negotiated with Centene?” Ms. Clark asked.

Christina Saler, a partner at Cohen Milstein, said Mr. Barbour’s early association with the legal team was not a conflict of interest because Mr. Barbour withdrew from the case before lawyers started investigating Centene.

“After Mr. Barbour’s disassociation, we had no further contact with Mr. Barbour on this matter,” she said.

A Well-Connected Team

Mr. Barbour’s involvement in the Ohio case against P.B.M.s illustrates the potential for favoritism when states hire private lawyers.

Mr. Hurst noted the involvement of Mr. Barbour when seeking the contract in Ohio, according to emails acquired from the Ohio attorney general’s office through a public records request.

In a June 22, 2018, email exchange, just a few days before the state hired Liston & Deas, Mr. Hurst recalled meeting with the attorney general’s staff in Ohio.

Mr. Hurst went on to note that members of his team had worked with Governor Barbour while he was in office and that they all “continue to work together now.”

In an email a week later, an assistant attorney general shared Mr. Barbour’s cell number with Mr. DeWine, saying that Mr. Barbour had shared it so he could “call him about this case anytime.”

Mr. Barbour, who had served two terms as governor of Mississippi, was a former chairman of the Republican Governors Association and a former chairman of the Republican National Committee. Known as a prolific fund-raiser , he was credited with bringing in hundreds of millions of dollars to support Republican candidates across the nation.

In 1991, Mr. Barbour co-founded BGR Group, a lobbying firm that quickly became one of the most influential in Washington.

Mr. Barbour had known Mr. DeWine since he was first elected to the Senate in 1995.

Two decades later, when Mr. DeWine was in the midst of a hard-fought campaign for governor, Mr. Barbour’s close associates solicited him for the legal work on the Centene case. In October 2018, less than three months after Mr. DeWine hired Liston & Deas, he traveled to Washington to visit Mr. Barbour’s lobbying firm for several hours, according to calendar records.

At the time, Mr. Barbour and others at BGR were registered lobbyists for Centene.

Mr. Barbour has never been named in state contracts as one of the private lawyers on the case in Ohio or anywhere else. His involvement has rarely, if ever, been publicly reported.

Ms. Saler, of Cohen Milstein, said there was no need to inform state officials because Mr. Barbour had not been involved in the Centene portion of the case and had exited the venture several years before states hired the lawyers.

At least four law firms were involved in the case in two or more states, according to retainer agreements and financial records showing broadly how settlement funds were disbursed.

According to Max Littman, a former data analyst with HealthPlan Data Solutions, the analytics firm that helped identify Centene’s overcharges in Ohio, one important role for many of the lawyers was to use their connections as they presented the overcharges to various states.

Mr. Littman, who said he worked closely with the legal team, described the dynamic: Liston & Deas, with roots in a deeply red state, would approach Republican attorneys general, and Cohen Milstein, “who were our Democrats,” would focus on Democratic states.

When The Times asked for records showing Liston & Deas’s qualifications to be hired to represent the State of Ohio, the attorney general’s office said no records existed. Cohen Milstein and other law firms had submitted such documentation in the past when seeking contracts in Ohio.

Settling With States

In June 2021, nearly three years after Ohio hired its outside counsel, two states announced the first settlements with Centene on the same day: Ohio would get $88 million, Mississippi $55 million.

After that, Centene settled in one state after another, often with just months between announcements.

In fact, Centene had already set aside $1.1 billion to handle all subsequent cases. The company estimated the amount after early discussions with the private lawyers that did not involve the state attorneys general who would later work with them.

With a settlement in hand and an estimate of how much each state could collect, the private lawyers had a powerful pitch. The team also had the option to file whistle-blower lawsuits, which can advance without a state attorney general’s having to hire outside counsel.

The team pursued whistle-blower lawsuits in Texas, California and Washington.

In Texas, the whistle-blower lawsuit came with a benefit for Attorney General Ken Paxton: Under Texas law , his office is allowed to recoup “reasonable attorney’s fees” for work associated with such cases. It collected nearly $25 million in legal fees on the Centene case while spending just 561 hours on it, financial records show. That comes out to more than $44,000 per hour of work. The Texas attorney general’s office declined to comment.

Ms. Saler said all the state attorneys general decided their own strategies in reaching settlements with Centene based on the best interest of taxpayers in their states.

In states that hired the lawyers on contingency, the attorney general closely reviewed Centene’s billing practices. But no state has revealed whether its own overcharge calculations matched those of the private lawyers.

State officials who hired Liston & Deas and the other firms knew that the lawyers had previously negotiated with Centene. But in a vast majority of states, officials did not explicitly address that fact when talking publicly about the settlements.

In addition, Liston & Deas and most of the states the firm worked for have not revealed exactly how much Centene overcharged for drugs or how settlement amounts were calculated. A few states have offered sparse descriptions, which vary widely.

The New Hampshire attorney general’s office wrote in its settlement announcement that Centene’s activities had a “$2.4 million negative financial impact.” Centene agreed to pay the state nearly 10 times that amount.

The attorney general’s office in Washington, one of the few states where officials agreed to discuss basic details about the settlement with The Times, said the $33 million it recovered amounted to treble damages.

A news release from the California attorney general’s office said the state recovered double its damages, for a total settlement of more than $215 million.

As of last month, Centene had settled in at least 19 states. The Liston & Deas website says Centene will ultimately pay about $1.25 billion to 22 states.

A Sweetheart Deal?

Some observers believe Centene would have faced stricter penalties if the federal government had taken up the case instead of private lawyers hopscotching from one state to the next.

Several experts in health care fraud litigation and whistle-blower cases said the best way to recoup money for taxpayers would have been to file a federal whistle-blower case, similar to what the lawyers did in state court in Texas and California.

A federal case could have triggered the involvement of the Justice Department, which might have investigated Centene more thoroughly. And a federal case probably would have gotten more attention and media coverage, required more transparency and taken longer to complete, the experts said.

Mr. Hurst and other lawyers in the case said they had not filed any type of federal action against Centene.

A spokesperson for the Justice Department confirmed that it had inquired about the P.B.M. and Centene cases in Ohio, but no further federal action was taken. The department declined further comment.

Mary Inman, a lawyer at Whistleblower Partners L.L.P. with decades of experience, said one of the reasons Liston & Deas wound up in state court might have been that its case relied on whistle-blowers the federal government was unlikely to approve.

The whistle-blower in Texas was Mr. Hurst. In California, the whistle-blower was Matthew McDonald, a lawyer at David Nutt & Associates and the son of Bryan McDonald, who worked in Mr. Barbour’s administration when he was governor.

Ms. Inman said whistle-blowers are typically insiders with firsthand knowledge of wrongdoing who share information at some risk to themselves, not lawyers who gain information while on the job.

“It’s very unusual,” Ms. Inman said. “And it’s something that I, as a longtime lawyer in this space, I would not want to do because atmospherically and reputationally it doesn’t look great.”

Mr. Barbour said he believes everyone walked away from the settlements happy — including executives at Centene. As evidence, he cited the company’s stock performance.

“I can’t speak for them, but if I had agreed to pay a big settlement and my stock went up after the first day, I would think it was a pretty good settlement,” Mr. Barbour said.