Elucidating systemic immune responses to acute and convalescent SARS-CoV-2 infection in children and elderly individuals.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), a causative pathogen of the COVID-19 pandemic, affects all age groups. However, various studies have shown that COVID-19 presentation and severity vary considerably with age. We, therefore, wanted to examine the differences between the immune responses of children with COVID-19 and elderly COVID-19 individuals. METHODS: We analyzed cytokines, chemokines, growth factors, and acute phase proteins in acute and convalescent COVID-19 children and the elderly with acute and convalescent COVID-19. RESULTS: We show that most of the pro-inflammatory cytokines (interferon [IFN]γ, interleukin [IL]-2, tumor necrosis factor-α [TNFα], IL-1α, IFNα, IFNß, IL-6, IL-12, IL-3, IL-7, IL-1Ra, IL-13, and IL-10), chemokines (CCL4, CCL11, CCL19, CXCL1, CXCL2, CXCL8, and CXL10), growth factors (vascular endothelial growth factor and CD40L) and acute phase proteins (C-reactive protein, serum amyloid P, and haptoglobin) were decreased in children with acute COVID 19 as compared with elderly individuals. In contrast, children with acute COVID-19 exhibited elevated levels of cytokines- IL-1ß, IL-33, IL-4, IL-5, and IL-25, growth factors-fibroblast growth factor-2, platelet- derived growth factors-BB, and transforming growth factorα as compared with elderly individuals. Similar, differences were manifest in children and elderly with convalescent COVID-19. CONCLUSION: Thus, COVID-19 children are characterized by distinct cytokine/chemokine/growth factor/acute phase protein markers that are markedly different from elderly COVID-19 individuals.

Time Elapsed from onset of symptoms to antituberculosis treatment in children with central nervous system tuberculosis in a tertiary hospital in South India: A mixed-methods pilot study.

A pilot study with a mixed-methods design was conducted to estimate the time for tuberculosis (TB) treatment initiation and associated factors among children with central nervous system-TB (CNS-TB). A total of 38 children were enrolled for the quantitative component, and 20 in-depth interviews were conducted. The median duration (interquartile range) from onset of symptoms to treatment initiation was 23 (11, 55) days. About 44% and 31% of the children presented with Stage II and Stage III of CNS-TB, respectively. The major reasons for delay were symptoms not taken seriously (50%) and too many referrals (21%). About 89% of the families went into catastrophic health expenditure due to the disease. The treatment delay may be due to both patient delay and health system delay. Tailoring approaches to target the pediatric population could further improve early detection and treatment initiation of CNS-TB.

Status of Universal Drug Susceptibility Testing in Pulmonary Tuberculosis Patients Initiated on Treatment in an Urban Setting, South India.

Introduction: Early initiation of drug susceptibility testing (DST) guided anti-tuberculosis treatment benefits the patient in terms of better treatment outcomes and possibly reduces the transmission of tuberculosis (TB) disease in the community. To determine the status of universal DST (UDST) coverage in smear-positive pulmonary TB patients (PTB) initiated on treatment under the TB program in Greater Chennai Corporation. In addition, the barriers and facilitators for UDST were explored. Material and Methods: The data of PTB patients who were initiated on anti-TB treatment from July to December 2019 was abstracted from the NI-KSHAY database of TB Program. The barriers and facilitators for UDST were explored in 5 focus group discussions (FGDs) among the TB program healthcare workers (HCW). UDST coverage was based on the availability of Cartridge-based Nucleic Acid Amplification test (CBNAAT) results in the NI-KSHAY database. Results: The CBNAAT result was available for 1628 (82.6%) of the 1970 smear-positive PTB patients. Non-availability of CBNAAT results was significantly higher among the older age group (>50 years), in female PTB patients, and the Private Sector. Issues with sputum collection, transport of specimens, and receipt of results were highlighted by the HCWs for the non-availability of UDST results. Conclusion: Universal DST coverage in smear-positive PTB patients initiated on treatment in 2019 in Chennai was optimal as per National Strategic Plan for TB elimination UDST target of 80% for the year 2020 but with scope for improvement. The low UDST coverage in the private sector, among female patients and older age groups, needs to be addressed.

Standardization of a stool concentration method for Mycobacterium tuberculosis detection in the pediatric population.

Background: The inability of young children to expectorate sputum and paucibacillary status of Mycobacterium tuberculosis (MTB) increases its diagnostic complexity. In this study, we aimed to standardize a stool concentration method for the detection of MTB and its drug resistance by line probe assay (LPA). Methods: The stool from 10 healthy children spiked with H37Rv in five different dilutions (1:1, 1:10, 1:100, 1:1000, and 1:10,000), and stool from 10 confirmed TB and 54 clinically diagnosed TB children were subjected to an in-house stool concentration protocol. All the processed filtrates were subjected to smear microscopy, solid culture, Xpert ultra testing, and LPA. Results: Of 10 control samples, growth was seen in four samples (neat 1:1). In smear microscopy, bacilli could be seen in eight samples (1:1 and 1:10). Xpert ultra testing could detect MTB in eight samples in all dilutions with different loads. LPA could detect MTB in all samples and dilutions. In microbiologically confirmed children, seven out of 10 stool samples tested were positive. Out of 54 children with clinically diagnosed TB, 4 (7.4%) could be confirmed by microbiological diagnosis. Conclusion: The protocol standardized in this study proves to be better working in the molecular detection of MTB.

Randomised trial to evaluate the effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary tuberculosis: study protocol.

INTRODUCTION: Drug-resistant tuberculosis (DR-TB) is a global public health problem. Patients suffer for months if undiagnosed or treated inadequately, transmitting DR-TB in the community before succumbing to the disease. Early diagnosis, prompt treatment initiation and completion play a significant role in treatment success. However, extended regimens with injectable result in poor treatment adherence and outcomes. Our objective is to evaluate the effectiveness, safety and tolerability of various doses and duration of linezolid (LZD) in combination with bedaquiline (BDQ) and pretomanid (Pa) after 26 weeks of treatment in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary TB. METHODS AND ANALYSIS: A multicentric, randomised pragmatic clinical trial in India will enrol participants in one of the three arms-control arm (arm 1): BDQ, Pa and LZD 600 mg daily for 26 weeks or intervention arms (arm 2): BDQ, Pa and LZD 600 mg for 9 weeks followed by 300 mg for 17 weeks or arm 3: BDQ, Pa and LZD 600 mg for 13 weeks followed by 300 mg for 13 weeks. The primary endpoint is the proportion of patients with favourable outcomes as sustained cure and treatment completion. The secondary endpoint is unfavourable outcomes, including deaths, treatment failure, toxicity/adverse events and lost to follow-up till 48 weeks post-treatment. ETHICS AND DISSEMINATION: The study has been approved by the ethics committees of participating institutes and the National Institute for Research in TB. The trial results will help establish evidence towards a safe and effective dose of LZD that can be used in a fully, all-oral short course regimen for highly DR-TB patients. The results of this study will be shared with the National TB Elimination Programme of the country and the WHO guidelines development group through publications and dissemination meetings. TRIAL REGISTRATION NUMBER: NCT05040126.

Geographic and behavioral differences associated with sexually transmitted infection prevalence among Indian men who have sex with men in Chennai and Mumbai.

India has one of the largest numbers of men who have sex with men (MSM) globally; however, geographic data on sexually transmitted infection (STI) prevalence and associations with sexual behavior are limited. Six-hundred and eight MSM in Chennai and Mumbai underwent screening for a behavioral trial and were assessed for bacterial STIs (syphilis, chlamydia, gonorrhea), HIV, and past-month self-reported condomless anal sex (CAS). Mumbai (37.8%) had a greater prevalence of any STI than Chennai (27.6%) (prevalence ratio [PR] = 1.37, 95% CI: 1.09, 1.73). This pattern also emerged for gonorrhea and chlamydia separately but not syphilis. Conversely, Mumbai MSM reported lower rates of CAS (mean = 2.2) compared to Chennai MSM (mean = 14.0) (mean difference = -11.8, 95% CI: -14.6, -9.1). The interaction of city by CAS on any STI prevalence (PR = 2.09, 95% CI: 1.45, 3.01, p < .0001) revealed that in Chennai, higher rates of CAS were not associated with STI prevalence, but in Mumbai they were (PR = 2.49, 95% CI: 1.65, 3.76, p < .0001). The higher prevalence of bacterial STIs but lower frequency of CAS in Mumbai (versus Chennai), along with the significant interaction of CAS with city on STI rates, suggests that there are either differences in disease burden or differences by city with respect to self-reported assessment of CAS. Regardless, the high prevalence rates of untreated STIs and condomless sex among MSM suggest the need for additional prevention intervention efforts for MSM in urban India.

Tuberculosis screening in household contacts of pulmonary tuberculosis patients in an urban setting.

BACKGROUND: Household contacts (HHC) of tuberculosis (TB) patients are at risk of TB infection and disease. The study assessed the utility of "Household contact card and register" for screening of HHC of pulmonary TB (PTB) patients for TB and explored the reasons for HHC not being screened and followed-up. METHODS: The "Household contact card and register" was implemented by the Health Care Workers (HCW) of the TB Control Programme in Chennai District for screening HHC of index PTB patients initiated on treatment between June and August, 2018. Contacts were required to be screened within 2 months of treatment initiation of the index patient. Details collected included age, gender, smoking, alcohol use, immunosuppressive conditions and TB treatment. Symptom screening along with chest radiograph and or sputum examination was attempted. Follow-up TB screening at 6 and 12 months were performed. Screening of HHC was compared pre and post implementation phase. Proportions were computed for the data analysed. RESULTS: HHC information was documented for 93% (1268/1364) of Index PTB patients. The main reasons of non-listing of HHC in 96 PTB patients were HCW non-availability or non-co-operation of the HHC. There were 2150 (80%) contacts who were screened for TB. Inconvenient time, feeling healthy, stigma, out-station visit were the main reasons for 537 contacts not undergoing TB screening. Anti-TB treatment was initiated in 21 (1%) of contacts diagnosed with TB. Preventive therapy was initiated in 59% (81/138) of contacts aged <6 years. The screening of HHC improved from 36% to 80% during the implementation phase. Follow-up TB screening at 12 months was performed in 50% of HHC and 2 incident TB cases were identified. CONCLUSION: "Household contact card and register" is a useful tool for HCWs for TB screening in HHC of PTB patients. Reasons for non-adherence to contact screening needs to be addressed.

Idiopathic intracranial hypertension associated with anaemia, secondary to antiretroviral drug in a human immunodeficiency virus positive patient.

Papilledema in a patient with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome is an alarming finding. Any condition giving rise to raised intracranial tension (ICT) can cause papilledema, and in these patients, it could be secondary to opportunistic infections like meningitis to neoplasm. We report a case of a 28-year old female with HIV on antiretroviral therapy, who presented to us, with papilledema. Her fundus examination revealed superficial hemorrhages and Roth's spots along with papilledema. Patient was diagnosed with idiopathic intracranial hypertension (IIH), and all other possible systemic associations were ruled out. Her blood tests showed severe anemia. The papilledema and retinal changes resolved with treatment of anemia. This is a rare presentation of IIH in HIV positive patient due to anemia, secondary to zidovudine adverse effect.

Ocular lesions in 1,000 consecutive HIV-positive patients in India: a long-term study.

BACKGROUND: Ocular lesions in patients on highly active antiretroviral therapy (HAART) have shown changes in disease prevalence and pattern. Although they have been described in the Western population, there are not many such studies in the HAART era from India. This study aims to present the clinical profile, systemic correlation, and visual outcome in HIV-positive patients in relation to HAART in comparison with pre-HAART Indian studies and current Western data. Ocular findings and systemic correlation in 1,000 consecutive patients with HIV seen at a tertiary eye care center were analyzed. This study uses a prospective observational case series design. RESULTS: Age range of the patients was 1.5 to 75 years. Ocular lesions were seen in 68.5% of the patients (cytomegalovirus (CMV) retinitis was the commonest). The commonest systemic disease was pulmonary TB. Mean interval between HIV diagnosis and onset of ocular lesions was 2.43 years. CD4 counts range from 2 to 1,110 cells/mm3. Immune recovery uveitis (IRU) was seen in 17.4%. Interval between HAART initiation and IRU was 4 months to 2.5 years. Recurrence of ocular infection was seen in 2.53% (post-HAART) and > 20% (pre-HAART). Overall visual outcome showed improvement in about 14.3% and was maintained in 71.6% of the patients. CONCLUSIONS: CMV retinitis is the commonest ocular opportunistic infection in India, even in the HAART era. Newer manifestations of known diseases and newer ocular lesions are being seen. In contrast to Western studies, in our patients on HAART, ocular lesions do not always behave as in immunocompetent individuals. Ocular TB needs to be kept in mind in India, as well as other neuro-ophthalmic manifestations related to cryptococci, especially in gravely ill patients. Occurrence and frequency of various ocular opportunistic infections in developing nations such as India have significant variations from those reported in Western literature and need to be managed accordingly.

Safety, Tolerability, and Efficacy of Second-Line Generic Protease Inhibitor Containing HAART after First-Line Failure among South Indian HIV-Infected Patients.

INTRODUCTION: We describe the safety, tolerability, and efficacy of protease inhibitor (PI) containing highly active antiretroviral therapy (HAART) among patients switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART from a clinical setting in South India. METHODS: We assessed a prospective cohort of 91 HIV-infected patients with at least 12 months of clinical follow-up on second-line ritonavir-boosted PI-based therapy between August 2003 and December 2008. RESULTS: More than three fourths of patients met the World Health Organization (WHO) criteria for immunological failure at the time of switch. The median time to switch was 758 days. Patients demonstrated consistent increases in their CD4 counts during the first 12 months, by which time the median CD4 count was 322 cells/mm(3). The most common adverse events within the first year after switch were nausea (14.8%), lipodystrophy (10.4%), and peripheral neuropathy (7.0%). Patients switching to atazanavir (ATV)-based regimens compared to those switching to indinavir (IDV)-based regimens had similar immunological and clinical outcomes. CONCLUSIONS: Given the therapeutic success of using second-line PI-containing HAART after experiencing treatment failure, further efforts must be taken to expand access to second-line HAART so that more patients can benefit from these drugs.

High frequency of clinically significant mutations after first-line generic highly active antiretroviral therapy failure: implications for second-line options in resource-limited settings.

Continuation of failed highly active antiretroviral therapy regimens can lead to the accumulation of mutations that may limit options for second-line treatment. We studied the pattern of drug resistance mutations among 138 Indian patients who experienced failure of nonnucleotide reverse-transcriptase-containing first-line highly active antiretroviral therapy. This study demonstrates a high frequency of drug resistance mutations in human immunodeficiency virus-infected Indians who experience immunologic treatment failure and suggests the need for viral load monitoring.

Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients.

To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available.

Atypically distributed cutaneous lesions of Norwegian scabies in an HIV-positive man in South India: a case report.

INTRODUCTION: Immune-compromised subjects, especially those with underlying HIV disease, are prone to be infected with Norwegian scabies, where the cutaneous lesions are classically distributed over the extremities. CASE PRESENTATION: We report the case of an HIV-positive 16-year-old man with severe crusted Norwegian scabies initially misdiagnosed as a dermal fungal infection. The patient had extensive, generalized, thick, hyperkeratotic, crusting, yellowish papule lesions distributed on the entire body from his scalp to his toes.The patient was started with Ivermectin and topical Permethrin, which eventually resulted in complete resolution. Interestingly, despite quarantining efforts, one of the patient's acquaintances and a healthcare worker acquired the symptoms of itching. CONCLUSION: This atypical presentation of Norwegian scabies emphasizes the need to include scabies in the differential diagnosis when HIV-infected patients present with crusted, generalized cutaneous lesions.