Safety and Effectiveness Outcomes From a 14-Country Cohort of Patients With Multi-Drug Resistant Tuberculosis Treated Concomitantly With Bedaquiline, Delamanid, and Other Second-Line Drugs.

BACKGROUND: Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs. METHODS: We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented. RESULTS: Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure. CONCLUSIONS: Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.

Histopathological and microbiological findings and diagnostic performance of GeneXpert in clinically suspected tuberculous lymphadenitis.

OBJECTIVES: The primary objective was to determine the association between histopathological and microbiological findings in patients clinically suspected to have tuberculous lymphadenitis. A secondary objective was to assess the diagnostic utility of GeneXpert in lymph node specimens. METHOD: This was a single-centre prospective cohort study, performed in the Infectious Disease Clinic at The Indus Hospital. Three hundred and forty-one adult patients with chronically enlarged, accessible lymph nodes were enrolled after obtaining verbal consent, between February 2013 and April 2016. Tissue specimens were processed for histopathology, acid-fast bacillus (AFB) microscopy, AFB culture, and GeneXpert. Based on these results, anti-tuberculosis therapy (ATT) was prescribed. Clinical characteristics and treatment outcomes were recorded. RESULTS: There were 297 evaluable patients; 74.4% were diagnosed with tuberculous lymphadenitis (TBLA), 6.7% with a malignancy, and 12.8% with reactive nodes. TBLA was diagnosed on suggestive histopathology in 89.6% of cases, followed by GeneXpert (32.6%), mycobacterial culture (26.6%), and AFB smear positivity (12.5%). The sensitivity of GeneXpert was 65.7% when assessed against AFB culture. Drug resistance was displayed by 8.2% of GeneXpert-positive cases and 11.7% of culture-positive cases. The majority of TBLA patients (88.7%) responded favorably to ATT. CONCLUSIONS: In light of laboratory evidence, a quarter of patients suspected of TBLA had an alternative diagnosis, highlighting its importance in avoiding over-treatment and diagnostic delays in malignancy. Although sensitivity is poor, the demonstration of drug resistance by both GeneXpert and AFB culture represents a useful tool to guide treatment.

Leprosy manifesting with type 2 leprae reaction in a patient presenting with chronic fever: A case report.

Leprosy is a chronic granulomatous disease involving the skin and nerves, leading to a debilitating condition. Leprosy has been controlled in most parts of the world; therefore physicians are not very well versed in the recognition, management and assessment of this disease. The protean manifestations of leprosy often lead to delays in diagnosis and increase the morbidity. We present a case of a 33-year-old male with fever, lymphadenopathy, nodular skin lesions, uveitis and arthritis. Lymphnode, bonemarrow and skin biopsy revealed 3+ AFB smear with negative AFB cultures, leading to the diagnosis of leprosy. The course of illness was complicated by flare of Erythema Nodosum Leprosum (ENL).

Unusual case of non-resolving necrotizing pneumonia: A last resort measure for cure.

To our knowledge, this is an unusual case of a community-acquired pneumonia (CAP) with sepsis secondary to Streptococcus pneumoniae that required lung resection for a non-resolving consolidation. A 74 year old previously healthy woman, presented with acute fever, chills and pleuritic chest pain in Emergency Department (ED). A diagnosis of CAP was established with a Pneumonia Severity Index CURB-65 score of 5/5. In the ER, she was promptly and appropriately managed with antibiotics and aggressive supportive therapy. She remained on ten days of intravenous antibiotics. However, 48 hours post antibiotic course, she returned to ER with fever and signs of sepsis. Despite timely and appropriate management, the consolidated lobe remained the focus of sepsis for over four weeks. The patient recovered after the offending lobe was resected. Histopathology of the lung tissue revealed acute and chronic inflammation. However, no malignancy, bacterial infection or broncho-pleural fistula was found. Eighteen months post-surgery, the patient remains well.

Expression of M. tuberculosis-induced suppressor of cytokine signaling (SOCS) 1, SOCS3, FoxP3 and secretion of IL-6 associates with differing clinical severity of tuberculosis.

BACKGROUND: Appropriate immune activation of T cells and macrophages is central for the control of Mycobacterium tuberculosis infections. IFN-γ stimulated responses are lowered in tuberculosis (TB), while expression of Suppressor of Cytokine Signaling (SOCS) molecules - 1 and 3 and CD4+CD25+FoxP3+T regulatory cells is increased. Here we investigated the association of these molecules in regard to clinical severity of TB. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with pulmonary TB (PTB, n = 33), extra-pulmonary TB (ETB, n = 33) and healthy endemic controls (EC, n = 15). Cases were classified as moderately advanced or far advanced PTB, and less severe or severe disseminated ETB. M. tuberculosis -stimulated IFN-γ, SOCS1, SOCS3 and FoxP3 gene expression and secretion of Th1 and Th2 cytokines was measured. Statistical analysis was performed using Mann-Whitney U, Wilcoxon Rank and Kruskal Wallis non-parametric tests. RESULTS: In un-stimulated PBMCs, IL-6 (p = 0.018) and IL-10 (p = 0.013) secretion levels were increased in PTB while IL-10 was also increased in ETB (p = 0.003), all in comparison with EC. M. tuberculosis-stimulated IL-6 (p = 0.003) was lowered in ETB as compared with EC. SOCS1 mRNA expression in M. tuberculosis stimulated PBMCs levels in moderately advanced PTB (p = 0.022), far advanced (p = 0.014) PTB, and severe ETB (p = 0.009) were raised as compared with EC. On the other hand, SOCS1 mRNA titers were reduced in less severe ETB, in comparison with severe ETB (p = 0.027) and far advanced PTB (p = 0.016). SOCS3 mRNA accumulation was reduced in far advanced PTB (p = 0.007) and FoxP3 mRNA expression was increased in less severe ETB as compared with EC (p = 0.017). CONCLUSIONS: The lowered SOCS1 mRNA levels in patients with less severe extra-pulmonary TB as compared to those with more severe ETB and PTB may lead to elevated IFN-γ pathway gene expression in the latter group. As localized ETB has shown to be associated with more effective Th1 immunity and adaptive responses, this suggests a role for SOCS1 in determining disease outcome in extra-pulmonary TB.

BCG vaccination is associated with decreased severity of tuberculosis in Pakistan.

Vaccination with Bacille Calmette-Guérin (BCG) is given at birth to protect against tuberculosis (TB) in Pakistan. The country ranks 6th amongst high-burden countries worldwide and has an incidence of 231/100,000 pyopulation. This was a cross-sectional multi-center hospital-based study. TB patients (n=218) with pulmonary (PTB, n=120) or extrapulmonary (ETB, 98) were recruited, and the presence of a BCG vaccination scar was documented. Cases were further classified into minimal, moderate and advanced PTB or less severe (L-ETB) or severe disseminated (D-ETB) disease. The association of age, gender and severity of TB infections with BCG vaccination of the individual TB cases was investigated. No difference was found of the BCG vaccination status of PTB and ETB cases, or in relation to age or gender. Patients under 29years of age comprised the largest group. There were more females with ETB than PTB. The largest group within ETB comprised those with tuberculous lymphadenitis (LNTB, 39%). A significantly greater number of LNTB cases had received BCG vaccinations than had those with pleural (unilateral) TB (p=0.004), and tuberculous meningitis (p=0.027) groups. Also, there were more immunized patients with pulmonary as compared with pleural disease (p=0.001). LNTB represents localized granulomatous disease and the observation of higher vaccination rates in this group suggests that BCG has protected against more severe forms of TB in this high-burden region.