C-reactive protein-based tuberculosis triage testing: a multi-country diagnostic accuracy study.

Rationale: C-reactive protein (CRP)-based tuberculosis (TB) screening is recommended for people with HIV (PWH). However, its performance among people without HIV and in diverse settings is unknown. Objectives: In a multi-country study, we aimed to determine whether CRP meets the minimum accuracy targets (sensitivity ≥90%, specificity ≥70%) for an effective TB triage test. Methods/Measurements: Consecutive outpatient adults with cough ≥2 weeks from five TB endemic countries in Africa and Asia had baseline blood collected for point-of-care CRP testing and HIV and diabetes screening. Sputum samples were collected for Xpert MTB/RIF Ultra (Xpert) testing and culture. CRP sensitivity and specificity (5 mg/L cut-point) was determined in reference to sputum test results and compared by country, sex, and HIV and diabetes status. Variables affecting CRP performance were identified using a multivariate receiver operating characteristic (ROC) regression model. Results: Among 2904 participants, of whom 613 (21%) had microbiologically-confirmed TB, CRP sensitivity was 84% (95% CI: 81-87%) and specificity was 61% (95% CI: 59-63%). CRP accuracy varied geographically, with higher sensitivity in African countries (≥91%) than Asian countries (64-82%). Sensitivity was higher among men than women (87% vs. 79%, difference +8%, 95% CI: 1-15%) and specificity was higher among people without HIV than PWH (64% vs. 45%, difference +19%, 95% CI: 13-25%). ROC regression identified country and measures of TB disease severity as predictors of CRP performance. Conclusions: Overall, CRP did not achieve the minimum accuracy targets and its performance varied by setting and in some sub-groups, likely reflecting population differences in mycobacterial load.

Impact of post-COVID-19 lung damage on pulmonary function, exercise tolerance and quality of life in Indian subjects.

After recovery from COVID-19, there is data to suggest potential long-term pulmonary sequelae and associated impairment of functional capacity. This cross-sectional study was designed to assess the impact on respiratory function in a cohort of Indian subjects. Subjects who had recovered from COVID-19 were recruited. Clinical symptoms, pulmonary function test results, 6-minute walk test (6MWT) results, St George's Respiratory questionnaire (SGRQ) and chest radiographs were obtained. Information on the COVID-19 illness during hospitalization, baseline laboratory biomarkers and the disease severity categories as outlined by WHO (asymptomatic, mild, moderate, severe and critical), were retrieved from the hospital records. The 'COVID pneumonia'(WHO category moderate, severe & critical) group was compared with the 'Mild COVID' (WHO category mild) group and likewise, the WHO category moderate and the WHO category severe/critical groups were compared. In 207 subjects, whose mean age was 48.7 years were assessed after an average of 63 days from onset of symptom, 35% had TLC< 80% (restrictive defect), 8.3% had FEV1/FVC<70% (obstructive defect) and 44.4% had diminished DLCO<80% (diffusing capacity). The 'COVID-19 pneumonia' group when compared to the 'mild COVID-19' group, had lower FVC% (77.85 VS 88.18; P = 0.001), TLC% (79.48 VS 87.91; P = 0.0002), DLCO% (75.30 VS 89.20; P<0.0001) and DLCO/VA% (105.6 VS 111.8; P = 0.032), decreased minimum oxygen saturation (94.89 VS 97.73; P<0.0001) and more subjects had a drop in saturation of ≥ 4% (21.69% VS 4.84%; P = 0.001) during the 6MWT, and a greater mean total SGRQ score (29.2 VS 11.0; P<0.0001). To our knowledge, this is the first such report on Indian subjects. We have shown that post-COVID-19 lung damage leads to significant impairment of lung function, quality of life and effort tolerance.

Evaluation of the Xpert MTB Host Response assay for the triage of patients with presumed pulmonary tuberculosis: a prospective diagnostic accuracy study in Viet Nam, India, the Philippines, Uganda, and South Africa.

BACKGROUND: Non-sputum-based triage tests for tuberculosis are a priority for ending tuberculosis. We aimed to evaluate the diagnostic accuracy of the late-prototype Xpert MTB Host Response (Xpert HR) blood-based assay. METHODS: We conducted a prospective diagnostic accuracy study among outpatients with presumed tuberculosis in outpatient clinics in Viet Nam, India, the Philippines, Uganda, and South Africa. Eligible participants were aged 18 years or older and reported cough lasting at least 2 weeks. We excluded those receiving tuberculosis treatment in the preceding 12 months and those who were unwilling to consent. Xpert HR was performed on capillary or venous blood. Reference standard testing included sputum Xpert MTB/RIF Ultra and mycobacterial culture. We performed receiver operating characteristic (ROC) analysis to identify the optimal cutoff value for the Xpert HR to achieve the target sensitivity of 90% or more while maximising specificity, then calculated diagnostic accuracy using this cutoff value. This study was prospectively registered with ClinicalTrials.gov, NCT04923958. FINDINGS: Between July 13, 2021, and Aug 15, 2022, 2046 adults with at least 2 weeks of cough were identified, of whom 1499 adults (686 [45·8%] females and 813 [54·2%] males) had valid Xpert HR and reference standard results. 329 (21·9%) had microbiologically confirmed tuberculosis. Xpert HR had an area under the ROC curve of 0·89 (95% CI 0·86-0·91). The optimal cutoff value was less than or equal to -1·25, giving a sensitivity of 90·3% (95% CI 86·5-93·3; 297 of 329) and a specificity of 62·6% (95% CI 59·7-65·3; 732 of 1170). Sensitivity was similar across countries, by sex, and by subgroups, although specificity was lower in people living with HIV (45·1%, 95% CI 37·8-52·6) than in those not living with HIV (65·9%, 62·8-68·8; difference of 20·8%, 95% CI 13·0-28·6; p<0·0001). Xpert HR had high negative predictive value (95·8%, 95% CI 94·1-97·1), but positive predictive value was only 40·1% (95% CI 36·8-44·1). Using the Xpert HR as a triage test would have reduced confirmatory sputum testing by 57·3% (95% CI 54·2-60·4). INTERPRETATION: Xpert HR did not meet WHO minimum specificity targets for a non-sputum-based triage test for pulmonary tuberculosis. Despite promise as a rule-out test that could reduce confirmatory sputum testing, further cost-effectiveness modelling and data on acceptability and usability are needed to inform policy recommendations. FUNDING: National Institute of Allergy and Infectious Diseases of the US National Institutes of Health. TRANSLATIONS: For the Vietnamese and Tagalog translations of the abstract see Supplementary Materials section.

Undiagnosed Asthma-COPD overlap among patients diagnosed as Asthma and COPD in a referral hospital, India.

Patients who have features of both Asthma & COPD are now known as Asthma COPD overlap (ACO). Prevalence of ACO based on the Global Initiative for Asthma (GINA) and Global initiative for obstructive lung disease (GOLD) Syndromic Approach is scarce. In this cross-sectional observational study, we recruited physician-diagnosed-pAsthma, pCOPD & pACO by simple random sampling. Clinical features, spirometry, 6-min walk test, Serum Immunoglobulin E, % blood eosinophils and chest x-rays were reviewed. Syndromic approach was applied, and the diagnosis was reclassified accordingly. In all, 877 patients were included (Male = 445, Female = 432). Physician diagnosis for these were: pAsthma-713, pCOPD-157 and pACO-7. They were reclassified using the Syndromic approach as: sAsthma, sCOPD and sACO. The 713 pAsthmatics were reclassified as follows: sAsthma-684 (95.94%), sCOPD-12 (1.68%) and sACO-17 (2.38%). Of the 157 pCOPD patients, 91 (57.96%) were reclassified as sCOPD, 23 (14.6%) as sACO, and 17 (927.38%) as sAsthma. Of the 7 previously diagnosed pACO patients, only 1 (14.28%) was reclassified as sACO, 5 (71.42%) as sAsthma and 1 (14.28%) as sCOPD. sCOPD patients had more exacerbations (52.88% vs 46.34%, p = 0.479), critical care admissions (16.35% vs 7.32%, p = 0.157) and intubations (17.31% vs 9.76%, p = 0.255) compared to sACO patients, the latter had more events than sAsthma patients: exacerbations 46.34% vs 10.11% (p < 0.001), critical care admissions 7.32% vs 1.64% (p = 0.010) and intubations 9.76% vs 1.5% (p < 0.001). The syndromic approach helped us to identify ACO and also more appropriately classified COPD & Asthma. There was a significant difference between physician diagnosis and diagnosis using Syndromic Approach. It revealed considerable misclassification of several Asthmatic and ACO subjects, who could have been denied inhaled corticosteroids, as they were wrongly categorised as COPD by physician diagnosis.

Allergic diseases in India - Prevalence, risk factors and current challenges.

Epidemiological studies have shown a rise in the prevalence of allergic diseases in India during the last two decades. However, recent evidence from the Global Asthma Network study has observed a decrease in allergic rhinitis, asthma and atopic dermatitis in children. Still, with a population over 1.3 billion, there is a huge burden of allergic rhinitis, asthma and atopic dermatitis, and this is compounded by an unmet demand for trained allergy specialists and poor health service framework. There is wide variation in the prevalence of allergic diseases between different geographical locations in India, and the reasons are unclear at present. This may at least in part be attributable to considerable heterogeneity in aero-biology, weather, air pollution levels, cultural and religious factors, diet, socioeconomic strata and literacy. At present, factors enhancing risks and those protecting from development of atopy and allergic diseases have not been well delineated, although there is some evidence for the influence of genetic factors alongside cultural and environmental variables such as diet, exposure to tobacco smoke and air pollution and residence in urban areas. This narrative review provides an overview of data from India regarding epidemiology, risk factors and genetics and highlights gaps in evidence as well as areas for future research.

Accuracy of Xpert MTB/RIF Ultra for the diagnosis of tuberculosis in adult patients: a retrospective cohort study.

OBJECTIVES: The value of the "trace" result in Xpert Ultra for diagnosing active tuberculosis (TB) remains unclear. Our study evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) (Cepheid, Sunnyvale, USA) over Xpert MTB/RIF (Xpert) (Cepheid, Sunnyvale, USA) and mycobacterial culture when compared with a composite reference standard (CRS). METHODS: A retrospective single-center observational study was conducted in a tertiary care hospital in South India. Over three months, patients (aged ≥15 years) data on Xpert Ultra tests and mycobacterial culture of pulmonary and extrapulmonary samples were extracted from their electronic medical records. Patients were defined as TB cases based on the CRS criteria. Sensitivity, specificity, positive and negative predictive values of diagnostic tests were calculated by comparing them to the CRS. RESULTS: Xpert Ultra was more sensitive (87.8%) than Xpert (72.1%) and culture (44.1%). The specificity of Xpert Ultra was lower (98.1%) than those of Xpert (100%) and culture (100%). The sensitivity (92%) and specificity (100%) of Xpert Ultra were highest when performed on pus samples. CONCLUSIONS: Xpert Ultra with the trace category is superior to the conventional Xpert, and mycobacterial culture in identifying TB.

Treatment of COVID-19 Acute Respiratory Distress Syndrome With a Tabletop Noninvasive Ventilation Device in a Respiratory Intermediate Care Unit.

Objective: To study the outcomes of noninvasive ventilation (NIV) administered through a tabletop device for coronavirus disease 2019 acute respiratory distress syndrome in the respiratory intermediate care unit (RIMCU) at a tertiary care hospital in India. Patients and Methods: We retrospectively studied a cohort of hospitalized patients deteriorating despite low-flow oxygen support who received protocolized management with positive airway pressure using a tabletop NIV device in the RIMCU as a step-up rescue therapy from July 30, 2020 to November 14, 2020. Treatment was commenced on the continuous positive airway pressure mode up to a pressure of 10 cm of H2O, and if required, inspiratory pressures were added using the bilevel positive air pressure mode. Success was defined as weaning from NIV and stepping down to the ward, and failure was defined as escalation to the intensive care unit, the need for intubation, or death. Results: In total, 246 patients were treated in the RIMCU during the study period. Of these, 168 received respiratory support via a tabletop NIV device as a step-up rescue therapy. Their mean age was 54 years, and 83% were men. Diabetes mellitus (78%) and hypertension (44%) were the commonest comorbidities. Treatment was successful with tabletop NIV in 77% (129/168) of the patients; of them, 41% (69/168) received treatment with continuous positive airway pressure alone and 36% (60/168) received additional increased inspiratory pressure via the bilevel positive air pressure mode. Conclusion: Respiratory support using the tabletop NIV device was an effective and economical treatment for coronavirus disease 2019 acute respiratory distress syndrome. Further studies are required to assess the appropriate time of initiation for maximal benefits and judicious utilization of resources.

Recurrent COVID-19 infection in a case of rituximab-induced hypogammaglobulinaemia.

Patients with immunodeficiency are at an increased risk of recurrent COVID-19 infection. They may lack the natural immune response that usually confers long-lasting immunity. Here, we present our experience managing one such patient, who had a COVID-19 infection twice, 5 months apart. He had a positive SARS-CoV-2 real-time reverse transcription polymerase chain reaction (RT-PCR) and computed tomography (CT) thorax with classical findings of COVID-19 on both occasions. He had multiple negative RT-PCR tests and two CT scans without COVID-19 features between these two infections. While the antibody response to the first infection was not detectable, the response to the second infection was robust. Live attenuated vaccines are contraindicated in patients with immunodeficiency, and other vaccines may not elicit an adequate immune response. A high index of suspicion for recurrent COVID-19 is warranted in this group of patients.

Practical management of suspected hypersensitivity reactions to anti-tuberculosis drugs.

Tuberculosis (TB) is the commonest cause of death by a single infectious agent globally and ranks amongst the top ten causes of global mortality. The incidence of TB is highest in Low-Middle Income countries (LMICs). Prompt institution of, and compliance with, therapy are cornerstones for a favourable outcome in TB and to mitigate the risk of multiple drug resistant (MDR)-TB, which is challenging to treat. There is some evidence that adverse drug reactions (ADRs) and hypersensitivity reactions (HSRs) to anti-TB drugs occur in over 60% and 3%-4% of patients respectively. Both ADRs and HSRs represent significant barriers to treatment adherence and are recognised risk factors for MDR-TB. HSRs to anti-TB drugs are usually cutaneous and benign, occur within few weeks after commencement of therapy and are likely to be T-cell mediated. Severe and systemic T-cell mediated HSRs and IgE mediated anaphylaxis to anti-TB drugs are relatively rare, but important to recognise and treat promptly. T-cell-mediated HSRs are more frequent amongst patients with co-existing HIV infection. Some patients develop multiple sensitisation to anti-TB drugs. Whilst skin tests, patch tests and in vitro diagnostics have been used in the investigation of HSRs to anti-TB drugs, their predictive value is not established, they are onerous, require specialist input of an allergist and are resource-dependent. This is compounded by the global, unmet demand for allergy specialists, particularly in low-income countries (LICs)/LMICs and now the challenging circumstances of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This narrative review provides a critical analysis of the limited published evidence on this topic and proposes a cautious and pragmatic approach to optimise and standardise the management of HSRs to anti-TB drugs. This includes clinical risk stratification and a dual strategy involving sequential re-challenge and rapid drug desensitisation. Furthermore, a concerted international effort is needed to generate real-time data on ADRs, HSRs, safety and clinical outcomes of these interventions.

An appraisal of allergic disorders in India and an urgent call for action.

India is the second most populous country in the world with a population of nearly 1.3 billion, comprising 20% of the global population. There are an estimated 37.5 million cases of asthma in India, and recent studies have reported a rise in prevalence of allergic rhinitis and asthma. Overall, 40-50% of paediatric asthma cases in India are uncontrolled or severe. Treatment of allergic rhinitis and asthma is sub-optimal in a significant proportion of cases due to multiple factors relating to unaffordability to buy medications, low national gross domestic product, religious beliefs, myths and stigma regarding chronic ailment, illiteracy, lack of allergy specialists, and lack of access to allergen-specific immunotherapy for allergic rhinitis and biologics for severe asthma. High quality allergen extracts for skin tests and adrenaline auto-injectors are currently not available in India. Higher postgraduate specialist training programmes in Allergy and Immunology are also not available. Another major challenge for the vast majority of the Indian population is an unacceptably high level of exposure to particulate matter (PM)2.5 generated from traffic pollution and use of fossil fuel and biomass fuel and burning of incense sticks and mosquito coils. This review provides an overview of the burden of allergic disorders in India. It appraises current evidence and justifies an urgent need for a strategic multipronged approach to enhance quality of care for allergic disorders. This may include creating an infrastructure for education and training of healthcare professionals and patients and involving regulatory authorities for making essential treatments accessible at subsidised prices. It calls for research into better phenotypic characterisation of allergic disorders, as evidence generated from high income western countries are not directly applicable to India, due to important confounders such as ethnicity, air pollution, high rates of parasitic infestation, and other infections.