Effectiveness of early pharmaceutical interventions in symptomatic COVID-19 patients: A randomized clinical trial.

Objective: We assessed the effectiveness of oral Hydroxychloroquine (HC), Azithromycin (AZ) and Oseltamivir (OS), alone or combined, among patients hospitalized with mildly symptomatic coronavirus infectious disease (COVID-19). Methods: Following the approval of the National Bioethics Committee and prospective registration (clinicaltrials.gov NCT04338698), a multicenter randomized clinical trial of adaptive design was conducted at 10 multispecialty hospitals in Pakistan. Patients were randomized into seven treatment groups. Starting April 15, 2020, consenting, eligible, otherwise healthy adult patients or those with co-morbidities under control, were recruited if they presented with mildly symptomatic COVID-19 (scored 3 on a 7-point ordinal scale anchored between 1 = not hospitalized, able to undertake normal activities, to 7 = death) confirmed by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Two primary outcomes were assessed by day seven: Turning qRT-PCR negative; and clinical improvement of two points from the baseline. Outcome rates were compared using a chi-square test. Multiple imputations were applied to handle missing data. An interim data analysis was carried out on July 19, 2020, following which the study continued without treatment group changes. Data Safety and Monitoring Board advised to stop recruitment due to its futility on January 18, 2021. Results: Of 471 patients randomized, a total of 426 (90.4%) completed the follow-up for primary outcomes. Based on imputed data analyses at day seven: Total qRT-PCR negative cases were 137/471 (29%, 95% CI 25.0 - 33.4). By day seven, a total of 111/471 (23.5%, 95% CI 19.8 - 27.6) showed clinical improvement. No serious or non-serious adverse event was reported. Conclusions: Among patients with mild COVID-19, there was no statistically significant difference in the effectiveness of oral antimalarial, antiviral, or antibiotic treatments.Clinicaltrials.gov ID: NCT04338698.

Consensus statements for influenza awareness, prevention, and vaccination in Pakistan.

INTRODUCTION: Influenza is a serious underestimated viral infection in Pakistan and influenza vaccination and vaccination awareness are low. The current work aimed to develop consensus on influenza epidemiology, prevention, vaccination, and awareness in Pakistan. METHODOLOGY: A systematic literature search was conducted to develop recommendations on influenza vaccines in Pakistan. Experts' feedback was incorporated using the modified Delphi method. A three-step process was used, with 18 experts from different specialties from Pakistan who participated in voting rounds to achieve a minimum 75% agreement level. RESULTS: Pakistan has a low-immunization-rate and is susceptible to serious influenza outbreaks and influenza-related complications. Influenza circulates year-round in Pakistan but peaks during January and February. The subtype A/H1N1 is predominant. The experts urged vaccination in all individuals ≥ 6 months of age and with no contraindications. They highlighted special considerations for those with comorbidities and specific conditions. The experts agreed that the inactivated influenza vaccine is safe and efficient in pregnant women, immunocompromised, and comorbid respiratory and cardiovascular patients. Finally, the experts recommended conducting promotional and educational programs to raise awareness on influenza and vaccination. CONCLUSIONS: This is the first regional consensus on influenza and influenza vaccination in Pakistan with experts' recommendations to increase influenza vaccination and decrease influenza cases and its associated detrimental effects.

Cognitive therapy for depression in tuberculosis treatment: protocol for multicentre pragmatic parallel arm randomised control trial with an internal pilot.

INTRODUCTION AND OBJECTIVES: There is an unmet need to develop high-quality evidence addressing tuberculosis (TB)-related mental health comorbidity, particularly in the context of lower-middle-income countries. This study aims to examine the effectiveness and cost-effectiveness of cognitive behavioural therapy (CBT) versus enhanced treatment as usual (ETAU) in improving depressive symptoms in people with TB and comorbid depression, enhancing adherence with anti-TB treatment (ATT) and its implementation in the real-world setting of Pakistan. METHODS: We will conduct a pragmatic parallel arm randomised control trial with an internal pilot. A brief psychological intervention based on CBT has been developed using a combination of qualitative and ethnographic studies. The inbuilt pilot trial will have a sample size of 80, while we plan to recruit 560 (280 per arm) participants in the definitive trial. Participants who started on ATT within 1 month of diagnosis for pulmonary and extrapulmonary TB or multidrug resistant TB (MDR-TB) and meeting the criteria for depression on Patient Health Questionnaire-9 (PHQ-9) will be randomised with 1:1 allocation to receive six sessions of CBT (delivered by TB healthcare workers) or ETAU. Data on the feasibility outcomes of the pilot will be considered to proceed with the definitive trial. Participants will be assessed (by a blinded assessor) for the following main trial primary outcomes: (1) severity of depression using PHQ-9 scale (interviewer-administered questionnaire) at baseline, weeks 8, 24 and 32 postrandomisation and (2) ATT at baseline and week 24 at the end of ATT therapy. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Keele University Research Ethics Committee (ref: 2023-0599-792), Khyber Medical University Ethical Review Board (ref: DIR/KMU-EB/CT/000990) and National Bioethics Committee Pakistan (ref: No.4-87/NBC-998/23/587). The results of this study will be reported in peer-reviewed journals and academic conferences and disseminated to stakeholders and policymakers. TRIAL REGISTRATION NUMBER: ISRCTN10761003.

A comparative absorption study of sucrosomial® orodispersible vitamin D3 supplementation vs. a reference chewable tablet and soft gel capsule vitamin D3 in improving circulatory 25(OH)D levels in healthy adults with vitamin D deficiency-Results from a prospective randomized clinical trial.

Background: Vitamin D (Vit D) deficiency (VDD), associated with diverse health conditions, is commonly treated with Vit D3 supplements. However, the gastrointestinal (GI) absorption of Vit D3 in different formulations has not been well studied. Objective: We aimed to compare the absorption of an innovative phospholipids-sucrester matrix biodelivery vehicle-based (sucrosomial®) orodispersible Vit D3 preparation against a reference chewable tablet and soft gel capsule (SGC) Vit D3 formulations in Vit D-deficient healthy adults. Methods: In study 1, 25 subjects were randomized to receive a weekly single dose of 200,000 IU of sucrosomial® Vit D3 (n = 12) or chewable tablet Vit D3 (n = 13) for 3 weeks. In study 2, 20 subjects were randomized to receive a single dose of 200,000 IU every other week of sucrosomial® Vit D3 (n = 10) or SGC Vit D3 (n = 10) for 6 weeks. Circulatory 25-hydroxyvitamin D3 [25(OH)D] levels were reassessed after 2, 3, and 6 weeks in study 1 and after 4 and 6 weeks in study 2. Results: In study 1, after 2 weeks, circulatory 25(OH)D levels increased significantly in both Vit D3 treatment groups (p < 0.0001) but improved markedly in the sucrosomial® Vit D3 group, with no further considerable change after 3 and 6 weeks in both groups. Overall, at all three follow-ups, sucrosomial® Vit D3 treatment achieved significantly higher and sustained 25(OH)D levels (p < 0.001). In study 2, after 4 weeks, both Vit D3 treatment groups showed significant improvement in circulatory 25(OH)D levels (p < 0.0001) but substantially higher in the sucrosomial® group with statistically significant differences between the two treatment groups (p = 0.02). At the 6-week follow-up, only subjects in the sucrosomial® Vit D3 group showed a further increase in circulatory 25(OH)D levels (p = 0.049), but no further significant changes in the levels of the SGC Vit D3 group (p = 0.062), showing a statistically significant difference between the two treatment groups (p = 0.002). The Vit D3 treatment was well tolerated by all participants, and no treatment-emergent effects or serious adverse events were reported. Conclusion: Our results suggest that the sucrosomial® Vit D3 preparation absorbs efficiently in the GI system, achieving adequately higher and sustained circulatory Vit D levels in VDD, and thus can effectively contribute to the body protection against VDD-associated health conditions. Clinical trial registration: clinicaltrials.gov, identifier: NCT05706259.

National Registry of Interstitial Lung Disease from Pakistan.

Introduction Interstitial lung disease (ILD) is a heterogeneous group of over 200 parenchymal lung diseases with a myriad of etiologies. Interstitial lung disease registries from around the world show varying prevalence and incidence of these diseases. The aim of this study was to determine the epidemiology and characteristics of ILD in Pakistan. Methods This web-based registry, which is the first multicenter registry of ILD from Pakistan, recruited patients from 10 centers of five major cities between January 2016 and March 2019. Results A total of 744 patients were enrolled in the registry. The five most frequent ILDs were idiopathic pulmonary fibrosis (IPF) 34.4%, hypersensitivity pneumonitis (HP) - 17.7%, idiopathic nonspecific interstitial pneumonitis (iNSIP) - 16.8%, connective tissue disease-associated ILD (CTD-ILD) - 16.3%, and sarcoidosis - 9.1%. Conclusion Idiopathic pulmonary fibrosis is the most prevalent ILD in Pakistan, followed by HP and iNSIP. An ongoing prospective registry with longitudinal follow-up will help us further elaborate on the clinical characteristics, treatment, and survival outcome of patients with ILD.

Clinical Characteristics, Mortality and Associated risk factors in COVID-19 patients reported in ten major hospitals of Khyber Pakhtunkhwa, Pakistan.

BACKGROUND: COVID-19 is an ongoing public health issue across the world. Several risk factors associated with mortality in COVID-19 have been reported. The present study aims to describe clinical and epidemiological characteristics and predictors of mortality in hospitalized patients from Khyber Pakhtunkhwa, a province in Pakistan with highest COVID-19 associated case fatality rate. METHODS: This multicentre, retrospective study was conducted in hospitalized COVID-19 patients who died or discharged alive until 1st May 2020. Data about sociodemographic characteristics, clinical and laboratory findings, treatment and outcome were obtained from hospital records and compared between survivors and non-survivors. Statistical tests were applied to determine the risk factors associated with mortality in hospitalized patients. RESULTS: Of the total 179 patients from the 10 designated hospitals, 127 (70.9%) were discharged alive while 52 (29.1%) died in the hospital. Overall, 109 (60.9%) patients had an underlying comorbidity with hypertension being the commonest. Multivariate logistics regression analysis showed significantly higher odds of in-hospital death from COVID-19 in patients with multiple morbidities (OR 3.2, 95% CI 1.1, 9.1, p-value=0.03), length of hospital stay (OR 0.8, 95% CI 0.7, 0.9, p-value <0.001), those presenting with dyspnoea (OR 4.0, 95% CI 1.1, 14.0, p-value=0.03) and oxygen saturation below 90 (OR 9.6, 95% CI: 3.1, 29.2, p-value <0.001). CONCLUSION: Comorbidity, oxygen saturation and dyspnoea on arrival and length of stay in hospital (late admission) are associated with COVID-19 mortality. The demographic, clinical and lab characteristics could potentially help clinician and policy makers before potential second wave in the country.

Risk factors for multi-drug resistant tuberculosis in patients at tertiary care hospital, Peshawar.

OBJECTIVE: To determine the frequency of common risk factors for multi-drug resistant tuberculosis in patients presented at a tertiary care hospital, Peshawar. STUDY DESIGN: Cross-sectional, observational study. PLACE AND DURATION OF STUDY: Pulmonology Department, Khyber Teaching Hospital, Peshawar, from December 2006 to October 2007. METHODOLOGY: Patients with positive AFB culture and sensitivity results and found resistant to both rifampicin and isoniazid with or with resistance to other first line anti-tuberculosis drugs, were recruited from both Pulmonology Ward and Outpatient Department (OPD). Informed verbal consent was taken and a questionnaire administered to all participants of the study. Information regarding demographics, education status, occupation, monthly household income, AFB C/S, details of past history of tuberculosis and family history of TB or Multi-Drug Resistant (MDR-TB) was recorded. Data was analyzed on SPSS version 11. RESULTS: A total of 30 patients of MDR-TB were interviewed. Male (n=17) and female (n=13) ratio was 1.3:1. Mean age was 34.2+/-15.3 years. Ninety-two percent female and 52.9% male were uneducated. In 56.7%, monthly income was less than 5,000 rupees and in 40% between 5,000-10,000 rupees. All patients had previous history of Antituberculous Treatment (ATT), in which 20% had undertaken ATT course once, 53.3% twice and 26.7% thrice in the past. In the study group, 13 (43.3%) patients had not completed their first ATT course and 11 of them were receiving ATT from a general practitioner (GP) at that time. Seven (23.3%) patients had family history of TB but no one had documented MDR-TB in the family. Resistance to RH was present in all patients; moreover, 56.7% had resistance to RHEZ+S. CONCLUSION: The most common factors in the study group were previous history of tuberculosis, repeated courses of ATT, prescribed by different clinicians and unsupervised treatment by a GP during the initial course of ATT.