Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Analysis of human rabies deaths reported at two hospitals in Karachi, Pakistan: a call to save lives by reforming rabies prevention facilities.

BACKGROUND: Rabies is endemic in low- and middle-income countries. It is caused mainly by the bite of a rabid dog and is fatal if not treated effectively and in a timely manner with quality post-exposure prophylaxis. Despite a profusion of private and public healthcare centres in Sindh province, most are ill-equipped to treat dog bites. METHODS: We analysed 129 human deaths from rabies who presented at the emergency departments of two tertiary care hospitals in Karachi over 10 y. Demographic data, time, location of the bite and distance travelled to report symptoms of rabies were recorded. RESULTS: Most victims were male, and children were more often affected; almost none had received post-exposure prophylaxis. A total of 12% of bites were on the face, head or neck. The mean incubation period was 56 d. Most (60%) of the rabies victims travelled long distances, hoping to receive treatment. CONCLUSIONS: Rabies deaths were either due to a lack of awareness or the non-availability of rabies immunobiologicals within easy reach. Public health services must raise awareness, conduct surveillance and provide appropriately spaced centres for free treatment of dog bites. This lethal disease must be prevented at all costs.

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB.

BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.

Implementing 3HP vs. IPT as TB preventive treatment in Pakistan.

BACKGROUND: We assessed treatment uptake and completion for 6 months of isoniazid (6H) and 3 months of isoniazid plus rifapentine weekly (3HP) in a programmatic setting in Pakistan.METHODS: All household contacts were clinically evaluated to rule out TB disease. 6H was used for TB preventive treatment (TPT) from October 2016 to April 2017; from May to September 2017, 3HP was used for contacts aged ≥2 years. We compared clinical evaluation, TPT uptake and completion rates between contacts aged ≥2 years in the 6H period and in the 3HP period.RESULTS: We identified 3,442 contacts for the 6H regimen. After clinical evaluation, 744/1,036 (72%) started treatment, while 46% completed treatment. In contrast, 3,722 contacts were identified for 3HP. After clinical evaluation, 990/1,366 (72%) started treatment, while 67% completed treatment. Uptake of TPT did not differ significantly between the 6H and 3HP groups (OR 1.03, 95%CI 0.86-1.24). However, people who initiated 3HP had 2.3 times greater odds (95% CI 1.9-2.8) of completing treatment than those who initiated 6H after adjusting for age and sex.CONCLUSION: In programmatic settings in a high-burden country, household contacts of all ages were more likely to complete TPT with shorter weekly regimens, although treatment uptake rate for the two regimens was similar.

High tuberculosis prevalence in children exposed at home to drug-resistant tuberculosis.

SETTING: Urban Karachi, Pakistan. OBJECTIVE: To describe the yield of a contact investigation protocol implemented among children living with drug-resistant tuberculosis (DR-TB) patients. DESIGN: We implemented a contact investigation protocol in households of DR-TB patients treated at the Indus Hospital, Karachi, between January 2008 and April 2011. This included a detailed history and physical examination, tuberculin skin test, chest radiograph, smear microscopy and culture of sputum or gastric aspirate specimens, and drug susceptibility testing. Treatment supporters who visited DR-TB patients at home referred all child contacts for baseline evaluation and performed monthly assessments. We evaluated two age groups: 1) children aged <5 years, and 2) those aged 5-14 years. RESULTS: Among 133 children aged <15 years in 40 households, 40.4% (51/125) were moderately to severely underweight (weight-for-age Z-score <-2). Overall, 7.5% (10/133) had TB disease. This proportion was 6.5% (2/31) in those aged <5 years and 7.8% (8/102) in those aged 5-14 years. Seven (7/10) were smear-positive, and 4/10 had culture-confirmed multidrug-resistant Mycobacterium tuberculosis CONCLUSION: We detected a high prevalence of TB in children who live with DR-TB patients, regardless of the age of the child. Child contacts of DR-TB patients are a high-yield population for detecting TB cases.

Change in serum CXCL10 levels during anti-tuberculosis treatment depends on vitamin D status [Short Communication].

Serum levels of the inflammatory C-X-C motif chemokine 10 (CXCL10) are raised in tuberculosis (TB). CXCL10 gene expression is downregulated in monocytes by metabolically active vitamin D3 (1,25dihydroxy vitamin D). Stratification of patients by serum 25hydroxyvitamin D (25[OH]D) levels at baseline showed that treatment-induced decrease in CXCL10 occurred in those with 'insufficient' and 'deficient' but not in those with 'optimal' levels. In the deficient group, 25(OH)D showed an inverse correlation with CXCL10 levels. CXCL10 may thus be a useful biomarker for the follow-up of response to treatment. However, CXCL10 levels should be interpreted taking into account the baseline serum vitamin D levels of the TB patients.

Mycobacterium tuberculosis Sonicate-Induced IFNγ, CXCL10 and IL10 can Differentiate Severity in Tuberculosis.

Improved tools are required to study immunopathogenesis of tuberculosis (TB). Mycobacterium tuberculosis antigen-stimulated T cell-based assays can detect TB but are less effective when responses are compromised such as in severe disease. We investigated immune responses to M. tuberculosis whole sonicate (MTBs), recombinant antigens ESAT6 and CFP10 in whole blood cells of healthy endemic controls (EC, n = 42) and patients with pulmonary (PTB, n = 36) or extrapulmonary (ETB, n = 41) disease. Biomarkers of T cell activation (IFNγ) or modulation (IL10) and chemokines, CXCL9, CXCL10 and CCL2, secretion were measured. MTBs, ESAT6 and CFP10 all induced IFNγ responses in TB. ESAT6-induced IFNγ was elevated in TB as compared with EC. MTBs stimulated the highest IFNγ levels but did not differentiate between TB and EC. However, MTBs-induced CXCL10 (P = 0.004) was reduced, while IL10 (P < 0.001) was raised in TB as compared with EC. Between sites, MTBs-induced CCL2 (P = 0.001) and IL10 secretion was higher in PTB than ETB (P < 0.001). In comparison of disease severity, MTBs-induced IFNγ (P = 0.014) and CXCL10 (P = 0.022) levels were raised in moderate as compared with far advanced PTB. In ETB, MTBs-induced IL10 levels were greater in less-severe (L-ETB) than in severe disseminated (D-ETB) cases, P = 0.035. Within the L-ETB group, MTBs-induced IFNγ was greater in patients with tuberculous lymphadenitis than those with pleural TB (P = 0.002). As immune responses to MTBs were differentially activated in TB of different sites and severity, we propose the utility of MTBs-induced IFNγ, CXCL10 and IL10 as biomarkers in TB.

Predictors of delayed culture conversion in patients treated for multidrug-resistant tuberculosis in Pakistan.

Culture conversion is an interim monitoring tool for treatment of multidrug-resistant tuberculosis (MDR-TB). We evaluated the time to and predictors of culture conversion in pulmonary MDR-TB patients enrolled in the community-based MDR-TB management program at the Indus Hospital in Karachi, Pakistan. Despite strict daily directly observed therapy, monthly food incentives and patient counseling, the median time to culture conversion was 196 days (range 32-471). The cumulative probabilities of culture conversion by 2, 4, 6 and 12 months were respectively 6%, 33%, 47%, and 73%. Smoking, high smear grade at baseline and previous use of second-line drugs delayed culture conversion.

Trauma, stressful life events and depression predict HIV-related fatigue.

Despite the fact that fatigue is a common and debilitating symptom among HIV-infected persons, we know little about the predictors of fatigue in this population. The goal of this cross-sectional study was to examine the effects of early childhood trauma, recent stressful life events and depression on intensity and impairment of fatigue in HIV, over and above demographic factors and clinical characteristics. We studied 128 HIV-infected men and women from one southern state. The median number of childhood traumatic events was two and participants tended to have at least one moderate recent stressful event. Multiple regression findings showed that patients with less income, more childhood trauma, more recent stressful events and more depressive symptoms had greater fatigue intensity and fatigue-related impairment in daily functioning. Recent stresses were a more powerful predictor of fatigue than childhood trauma. None of the disease-related measures (e.g. CD4, viral load, antiretroviral medication) predicted fatigue. Although stress and trauma have been related to fatigue in other populations, this is the first study to examine the effects of traumatic and recent stressful life events on fatigue in an HIV-infected sample.

Measuring fatigue in people living with HIV/AIDS: psychometric characteristics of the HIV-related fatigue scale.

In the era of life-prolonging antiretroviral therapy, chronic fatigue is one of the most prevalent and disabling symptoms of people living with HIV/AIDS, yet its measurement remains challenging. No instruments have been developed specifically to describe HIV-related fatigue. We assessed the reliability and construct validity of the HIV-Related Fatigue Scale (HRFS), a 56-item self-report instrument developed through formative qualitative research and designed to measure the intensity and consequences of fatigue as well as the circumstances surrounding fatigue in people living with HIV. The HRFS has three main scales, which measure fatigue intensity, the responsiveness of fatigue to circumstances and fatigue-related impairment of functioning. The functioning scale can be further divided into subscales measuring impairment of activities of daily living, impairment of mental functioning and impairment of social functioning. Each scale demonstrated high internal consistency (Cronbach's alpha=0.93, 0.91 and 0.97 for the intensity, responsiveness and functioning scales, respectively). The HRFS scales also demonstrated satisfactory convergent validity when compared to other fatigue measures. HIV-Related Fatigue Scales were moderately correlated with quality of nighttime sleep (rho=0.46, 0.47 and 0.35) but showed only weak correlations with daytime sleepiness (rho=0.20, 0.33 and 0.18). The scales were also moderately correlated with general mental and physical health as measured by the SF-36 Health Survey (rho ranged from 0.30 to 0.68 across the 8 SF-36 subscales with most >0.40). The HRFS is a promising tool to help facilitate research on the prevalence, etiology and consequences of fatigue in people living with HIV.

End of life in the intensive care unit: knowledge and practice of clinicians from Karachi, Pakistan.

BACKGROUND: With improvements in the care of critically ill, physicians are faced with obligations to provide quality end-of-life care. Barriers to this include inadequate understanding of the dying patient and withdrawal or limitation of care. The objectives of this study were to document the comprehensions of physicians and nurses regarding the recognition and practice of end-of-life care for critically ill patients placed on life support in the intensive care unit. METHODS: This was a cross-sectional study carried out at three hospitals in Karachi. Chi-squared analysis and one-way ANOVA were used to compare differences in response between the groups. RESULTS: One hundred and thirty-seven physicians and critical care nurses completed the survey. 'Brain death' was defined as an 'irreversible cessation of brainstem function' by 85% respondents, with 50% relying on specialty consultation. Withdrawal of life support is practised by 83.2%; physicians are more likely (Chi square test P-value < 0.001) to withdraw mechanical ventilation, compared with nurses who would withdraw vasopressors (P-value 0.006). In a do not resuscitate patient, 72.3% use vasopressors, 83% initiate haemodialysis and 17.5% use non-invasive ventilation; 72.6% consult Hospital Ethics Committees; 16% respondents never withdraw life support; 28.3% considered it their responsibility to 'sustain life at all costs' and only 8% gave religious beliefs as a reason. CONCLUSIONS: There are confusions in the definition of brain death, end-of-life recognition and indications and processes of withdrawal of life support. There are discrepancies between physicians' and nurses' perceptions and attitudes. Clearly, teaching programmes will need to incorporate cultural and religious differences in their ethics curricula.

Stroke-associated pneumonia: microbiological data and outcome.

INTRODUCTION: Pneumonia is a common complication after acute stroke. It affects the outcome adversely. However, data regarding microbiology of stroke-associated pneumonia and its effect on outcome is scarce. METHODS: Stroke-associated pneumonia was identified through chart review of all ICD-9 identified adult stroke patients admitted to our hospital over a period of four years (1998-2001). The demographical, laboratory, radiological, microbiological data and outcome of patients with stroke-associated pneumonia were recorded and analysed. RESULTS: 443 patients with stroke were admitted over the four-year period and 102 (23 percent) had stroke-associated pneumonia. Their ages range from 28 to 100 (mean 64+/-14) years. 69 (68 percent) were men. Median length of stay was nine days compared to four days for all stroke patients. 68 (67 percent) patients manifested pneumonia within 48 hours and 34 (33 percent) after 48 hours of admission. Yield of tracheal aspirate cultures was 38 percent and that of chest radiographs was 25 percent. Pseudomonas aeruginosa and Staphylococcus aureus were the most common organisms (12 percent each) followed by Streptococcus pneumoniae and Klebsiella pneumoniae (4 percent each). Patients with infiltrates on chest radiographs were more likely to have positive tracheal aspirate cultures (p-value is 0.003). 35 patients (34 percent) expired during hospital stay. Positive chest radiographs and tracheal aspirates were independent predictors of prolonged hospital stay (p-value is less than 0.005). CONCLUSION: Pneumonia is a common medical complication of stroke. It is associated with a high mortality and prolongs the hospital stay. The yield of chest radiographs and tracheal aspirates is low. However, these are independent predictors of prolonged hospital stay. Pseudomonas aeruginosa and Staphylococcus aureus are most common organisms in stroke-associated pneumonia.

Reducing ventilator-associated pneumonia rates through a staff education programme.

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in patients on mechanical ventilation and results in increases in mortality, prolonged hospitalization and costs. Preventive measures for VAP are well-documented and evidence-based, yet remain poorly implemented in most intensive care units. We undertook an observational pre and post-intervention study to assess whether an educational programme focusing on preventive practices for VAP could reduce the incidence. Six hundred and seventy-seven adult patients, mechanically ventilated for >48 h were included in the study population. An evidence-based guideline for preventive practices at the bedside was developed and disseminated to the intensive care unit staff. VAP incidence rates before and after implementation of the educational programme were compared. VAP infection rates reduced by 51%, from a mean of 13.2+/-1.2 in the pre-intervention period to 6.5+/-1.5/1000 device days in the post-intervention period (mean difference 6.7; 95% CI: 2.9-10.4, P =0.02). A multidisciplinary educational programme geared towards intensive care unit staff can successfully reduce the incidence rates of VAP. Further studies will be needed to assess the impact on broader outcome measures such as costs or mortality.

Rapidly-progressive bronchiolitis obliterans organising pneumonia.

Bronchiolitis obliterans organising pneumonia is a clinicopathological syndrome characterised by indolent course of flu-like illness followed by cough, dyspnoea and fever, and responds well to steroid treatment. We describe a 76-year-old woman who presented with a short three-day history and progressed rapidly to respiratory failure. She was successfully treated with high-dose steroids.

The kinetics and spectral studies of the in situ polyaniline film formation.

The chemical oxidation of aniline with ammonium persulfate (APS) in an aqueous acidic solution to form polyaniline (PANI) films has been studied using the quartz crystal microbalance (QCM) technique. The kinetics of the film formation was investigated. The reaction exhibited half-order with respect to APS and first-order to aniline. The effect of temperature on the growth rate of PANI films was studied. The activation energy is 39.79 kJ/mol. This is in agreement with the corresponding one determined for the chemical polymerization of PANI in the bulk. The UV-visible spectra of the PANI films grown onto a glass support immersed into the bulk solution were measured. The absorption of the PANI film with time was also studied and compared to the growth of the PANI film thickness using the QCM technique.

The association of relapsing polychondritis and myelodysplastic syndrome: report of three cases.

Myelodysplastic syndrome is a group of clonal stem cell disorders characterized by cytopenias, including anemia. Rheumatologic manifestations have been reported in patients with myelodysplastic syndrome, including the rare disorder of relapsing polychondritis, which seems to occur more frequently than would be expected by chance. We describe three older males with relapsing polychondritis, who developed myelodysplastic syndrome, and we review the clinical features of the previously reported cases. Most of these patients are epidemiologically and prognostically similar to those with myelodysplastic syndrome alone, leading to speculation that relapsing polychondritis may be a paraneoplastic manifestation of myelodysplastic syndrome. These cases illustrate the need for greater awareness by physicians of the association between these two entities, and a thorough evaluation of hematologic abnormalities in patients, especially older patients, with relapsing polychondritis.

An epidemic of Dengue fever in Karachi--associated clinical manifestations.

Dengue is a mosquito borne disease with worldwide distribution. Depending on virulence factors and host immune status, infection can manifest as a severe but non fatal viral syndrome or a rapidly progressive and a frequently fatal haemorrhagic fever. During the course of an outbreak of viral fever in Karachi, Pakistan from June, 1994 to September, 1995, we studied 145 cases admitted at the Aga Khan University Hospital. 43% of the cases were between the age group of 20-30 years, majority of these being male (75%). Amongst the clinical signs and symptoms, the most frequent findings were fever, vomiting and abdominal pain. Spontaneous hemorrhagic manifestations occurred in 66 patients and of these petechiae and mucosal bleed were the commonest, that is, 42% and 38% respectively. At presentation thrombocytopenia (platelet count < or = 50,000) per cubic millimeter) was present in 78%, leucopenia (white cell count < 4,000 per cubic millimeter) in 34%. Apart from one patient who died from hemorrhagic shock on the 5th day of admission, the remaining patients recovered and their platelet counts normalized on an average in 9 days. This is the first reported epidemic in Karachi of dengue infection.

Rhinocerebral invasive mycosis: occurrence in immunocompetent individuals.

We report the computed tomographic appearance of invasive fungal disease of the paranasal sinuses in 13 patients. Coronal and axial computed tomographic images were obtained in each patient and data were analysed. Eight patients had Aspergillus flavus infection, four had Mucormycosis, and one had mixed Candida and Mucor. Our experience was different from that of other workers in many respects. All of our patients were immunocompetent. On radiological imaging by computed tomography, ethmoid sinuses were involved in 85% of our patients. In previously reported series maxillary sinuses were most frequently affected. Calcification in the inflammatory mass was not encountered in any of our patients, whereas this feature was present in many reported cases. Features in our patients that were similar to other studies were contrast enhancement, extension of the disease into the orbit and cranial cavity and a high mortality. The clinical course and radiological features of invasive mycosis simulate malignancy. Certain features that may help to differentiate invasive fungal infection from malignancy are discussed. We conclude that invasive fungal infection can affect immunocompetent individuals and should be considered in the differential diagnosis in appropriate clinical settings.