A Comprehensive Molecular and Clinical Investigation of Approved Anti-HCV Drugs Repurposing against SARS-CoV-2 Infection: A Glaring Gap between Benchside and Bedside Medicine.

The limited availability of effective treatment against SARS-CoV-2 infection is a major challenge in managing COVID-19. This scenario has augmented the need for repurposing anti-virals for COVID-19 mitigation. In this report, the anti-SARS-CoV-2 potential of anti-HCV drugs such as daclatasvir (DCV) or ledipasvir (LDP) in combination with sofosbuvir (SOF) was evaluated. The binding mode and higher affinity of these molecules with RNA-dependent-RNA-polymerase of SARS-CoV-2 were apparent by computational analysis. In vitro anti-SARS-CoV-2 activity depicted that SOF/DCV and SOF/LDP combination has IC50 of 1.8 and 2.0 µM, respectively, comparable to remdesivir, an approved drug for COVID-19. Furthermore, the clinical trial was conducted in 183 mild COVID-19 patients for 14 days to check the efficacy and safety of SOF/DCV and SOF/LDP compared to standard of care (SOC) in a parallel-group, hybrid, individually randomized, controlled clinical study. The primary outcomes of the study suggested no significant difference in negativity after 3, 7 and 14 days in both treatments. None of the patients displayed any worsening in the disease severity, and no mortality was observed in the study. Although, the post hoc exploratory analysis indicated significant normalization of the pulse rate showed in SOF/DCV and SOF/LDP treatment vs. SOC. The current study highlights the limitations of bench side models in predicting the clinical efficacy of drugs that are planned for repurposing.

Indian Guidelines on Nebulization Therapy.

Inhalational therapy, today, happens to be the mainstay of treatment in obstructive airway diseases (OADs), such as asthma, chronic obstructive pulmonary disease (COPD), and is also in the present, used in a variety of other pulmonary and even non-pulmonary disorders. Hand-held inhalation devices may often be difficult to use, particularly for children, elderly, debilitated or distressed patients. Nebulization therapy emerges as a good option in these cases besides being useful in the home care, emergency room and critical care settings. With so many advancements taking place in nebulizer technology; availability of a plethora of drug formulations for its use, and the widening scope of this therapy; medical practitioners, respiratory therapists, and other health care personnel face the challenge of choosing appropriate inhalation devices and drug formulations, besides their rational application and use in different clinical situations. Adequate maintenance of nebulizer equipment including their disinfection and storage are the other relevant issues requiring guidance. Injudicious and improper use of nebulizers and their poor maintenance can sometimes lead to serious health hazards, nosocomial infections, transmission of infection, and other adverse outcomes. Thus, it is imperative to have a proper national guideline on nebulization practices to bridge the knowledge gaps amongst various health care personnel involved in this practice. It will also serve as an educational and scientific resource for healthcare professionals, as well as promote future research by identifying neglected and ignored areas in this field. Such comprehensive guidelines on this subject have not been available in the country and the only available proper international guidelines were released in 1997 which have not been updated for a noticeably long period of over two decades, though many changes and advancements have taken place in this technology in the recent past. Much of nebulization practices in the present may not be evidence-based and even some of these, the way they are currently used, may be ineffective or even harmful. Recognizing the knowledge deficit and paucity of guidelines on the usage of nebulizers in various settings such as inpatient, out-patient, emergency room, critical care, and domiciliary use in India in a wide variety of indications to standardize nebulization practices and to address many other related issues; National College of Chest Physicians (India), commissioned a National task force consisting of eminent experts in the field of Pulmonary Medicine from different backgrounds and different parts of the country to review the available evidence from the medical literature on the scientific principles and clinical practices of nebulization therapy and to formulate evidence-based guidelines on it. The guideline is based on all possible literature that could be explored with the best available evidence and incorporating expert opinions. To support the guideline with high-quality evidence, a systematic search of the electronic databases was performed to identify the relevant studies, position papers, consensus reports, and recommendations published. Rating of the level of the quality of evidence and the strength of recommendation was done using the GRADE system. Six topics were identified, each given to one group of experts comprising of advisors, chairpersons, convenor and members, and such six groups (A-F) were formed and the consensus recommendations of each group was included as a section in the guidelines (Sections I to VI). The topics included were: A. Introduction, basic principles and technical aspects of nebulization, types of equipment, their choice, use, and maintenance B. Nebulization therapy in obstructive airway diseases C. Nebulization therapy in the intensive care unit D. Use of various drugs (other than bronchodilators and inhaled corticosteroids) by nebulized route and miscellaneous uses of nebulization therapy E. Domiciliary/Home/Maintenance nebulization therapy; public & health care workers education, and F. Nebulization therapy in COVID-19 pandemic and in patients of other contagious viral respiratory infections (included later considering the crisis created due to COVID-19 pandemic). Various issues in different sections have been discussed in the form of questions, followed by point-wise evidence statements based on the existing knowledge, and recommendations have been formulated.

Infection Prevention and Control for ICU during COVID-19 Pandemic: Position Paper of the Indian Society of Critical Care Medicine.

Coronavirus disease-2019 (COVID-19) has very high rates of hospital-related transmission among healthcare workers (HCWs), mandating the need for careful intensive care unit (ICU) designing, optimization of staff resources, implementation of vigorous infection control practices, environmental disinfection, meticulous sample collection, and criteria for staff quarantine. Most of the ICUs are not designed to deal with airborne viral infections and require redesigning for the safety of HCWs and patients. Infection control practices related to the prevention of spread of COVD-19 are unique and are well described. The training of staff on infection control practices reduces the infection rate among HCWs significantly. Adequate staffing not only helps in infection control but also prevents burnout of the staff. In case of infection to HCW, the staff must be assessed systematically, and institute's infection control committee should guide for isolation period as well as return to work based upon standard recommendations. This article focuses on infection control and prevention measures required in ICU during the COVID-19 pandemic. How to cite this article: Sharma J, Nasa P, Reddy KS, Kuragayala SD, Sahi S, Gopal P, et al. Infection Prevention and Control for ICU during COVID-19 Pandemic: Position Paper of the Indian Society of Critical Care Medicine. Indian J Crit Care Med 2020;24(Suppl 5):S280-S289.

Renal Replacement Therapy Practices in India: A Nationwide Survey.

INTRODUCTION: Renal replacement therapy (RRT) is utilized for patients admitted with acute kidney injury and is becoming indispensable for the treatment of critically ill patients. In low middle income and developing country like India, the epidemiological date about the practices of RRT in various hospitals setups in India are lacking. Renal replacement therapy although is being widely practiced in India, however, is not uniform or standardized. Moreover, the use of RRT beyond traditional indications has not only increased but has shifted from the ambit of the nephrologist and has come under the charge of intensivists. AIMS AND OBJECTIVES: The goal of the study was to record perceptions and current practices in RRT management among intensivists across Indian intensive care units (ICUs). MATERIALS AND METHODS: A questionnaire including questions about hospital and ICU settings, availability of RRT, manpower availability, and RRT management in critically ill patients was formed by an expert panel of ICU physicians. The questionnaire was circulated online to Indian Society of Critical Care Medicine (ISCCM) members in October 2019. RESULTS: The facilities in government setups are scarce and undersupplied as compared to private or corporate setups in terms of ICU bed strength and availability of RRT. High cost of continuous renal replacement therapy (CRRT) makes their use restricted. CONCLUSION: Resources of RRT in our country are limited, more in government setup. Improvement of the existing resources, training of personnel, and making RRT affordable are the challenges that need to be overcome to judiciously utilize these services to benefit critically ill patients. HOW TO CITE THIS ARTICLE: Sodhi K, Philips A, Mishra RC, Tyagi N, Dixit SB, Chaudhary D, et al. Renal Replacement Therapy Practices in India: A Nationwide Survey. Indian J Crit Care Med 2020;24(9):823-831.

Detection of mycobacterial CFP-10 (Rv3874) protein in tuberculosis patients by gold nanoparticle-based real-time immuno-PCR.

Aim: Timely and reliable diagnostic test for tuberculosis (TB) is immediately required. Attempts were made to improve the technology and diagnostic potential of real-time immuno-PCR (RT-I-PCR). Methods: We designed gold nanoparticle (GNP)-based RT-I-PCR (GNP-RT-I-PCR) assay for the detection of Mycobacterium tuberculosis CFP-10 (Rv3874) protein in clinical samples of TB patients. Results: A wide quantitative detection range of CFP-10 was found to be 0.5-5 × 104 pg/ml in bodily fluids of TB patients, which can evaluate the progression of disease. Moreover, sensitivities of 83.7 and 76.2% were observed in pulmonary (n = 49) and extrapulmonary TB (n = 42) patients, respectively, with specificities of 93.5-93.8% (n = 63). Conclusion: Conjugation of detection antibodies and oligonucleotides to functionalized GNPs of GNP-RT-I-PCR is relatively easier, compared with streptavidin-biotin/succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate system employed in RT-I-PCR. Our assay also showed better diagnostic performance than RT-I-PCR, which may provide a viable platform for the development of an efficient TB diagnostic test.

Indian Society of Critical Care Medicine Position Statement for Central Venous Catheterization and Management 2020.

BACKGROUND AND PURPOSE: Short-term central venous catheterization (CVC) is one of the commonly used invasive interventions in ICU and other patient-care areas. Practice and management of CVC is not standardized, varies widely, and need appropriate guidance. Purpose of this document is to provide a comprehensive, evidence-based and up-to-date, one document source for practice and management of central venous catheterization. These recommendations are intended to be used by critical care physicians and allied professionals involved in care of patients with central venous lines. METHODS: This position statement for central venous catheterization is framed by expert committee members under the aegis of Indian Society of Critical Care Medicine (ISCCM). Experts group exchanged and reviewed the relevant literature. During the final meeting of the experts held at the ISCCM Head Office, a consensus on all the topics was made and the recommendations for final document draft were prepared. The final document was reviewed and accepted by all expert committee members and after a process of peer-review this document is finally accepted as an official ISCCM position paper.Modified grade system was utilized to classify the quality of evidence and the strength of recommendations. The draft document thus formulated was reviewed by all committee members; further comments and suggestions were incorporated after discussion, and a final document was prepared. RESULTS: This document makes recommendations about various aspects of resource preparation, infection control, prevention of mechanical complication and surveillance related to short-term central venous catheterization. This document also provides four appendices for ready reference and use at institutional level. CONCLUSION: In this document, committee is able to make 54 different recommendations for various aspects of care, out of which 40 are strong and 14 weak recommendations. Among all of them, 42 recommendations are backed by any level of evidence, however due to paucity of data on 12 clinical questions, a consensus was reached by working committee and practice recommendations given on these topics are based on vast clinical experience of the members of this committee, which makes a useful practice point. Committee recognizes the fact that in event of new emerging evidences this document will require update, and that shall be provided in due time. ABBREVIATIONS LIST: ABHR: Alcohol-based hand rub; AICD: Automated implantable cardioverter defibrillator; BSI: Blood stream infection; C/SS: CHG/silver sulfadiazine; Cath Lab: Catheterization laboratory (Cardiac Cath Lab); CDC: Centers for Disease Control and Prevention; CFU: Colony forming unit; CHG: Chlorhexidine gluconate; CL: Central line; COMBUX: Comparison of Bedside Ultrasound with Chest X-ray (COMBUX study); CQI: Continuous quality improvement; CRBSI: Catheter-related blood stream infection; CUS: Chest ultrasonography; CVC: Central Venous Catheter; CXR: Chest X-ray; DTTP: Differential time to positivity; DVT: Deep venous thrombosis; ECG: Electrocardiography; ELVIS: Ethanol lock and risk of hemodialysis catheter infection in critically ill patients; ER: Emergency room; FDA: Food and Drug Administration; FV: Femoral vein; GWE: Guidewire exchange; HD catheter: Hemodialysis catheter; HTS: Hypertonic saline; ICP: Intracranial pressure; ICU: Intensive Care Unit; IDSA: Infectious Disease Society of America; IJV: Internal jugular vein; IPC: Indian penal code; IRR: Incidence rate ratio; ISCCM: Indian Society of Critical Care Medicine; IV: Intravenous; LCBI: Laboratory confirmed blood stream infection; M/R: Minocycline/rifampicin; MBI-LCBI: Mucosal barrier injury laboratory-confirmed bloodstream infection; MRSA: Methicillin-resistant Staphylococcus aureus; NHS: National Health Service (UK); NHSN: National Healthcare Safety Network (USA); OT: Operation Theater; PICC: Peripherally-inserted central catheter; PIV: Peripheral intravenous line; PL: Peripheral line; PVI: Povidone-iodine; RA: Right atrium; RCT: Randomized controlled trial; RR: Relative risk; SCV/SV: Subclavian vein; ScVO2: Central venous oxygen saturation; Sn: Sensitivity; SOP: Standard operating procedure; SVC: Superior vena cava; TEE: Transesophageal echocardiography; UPP: Useful Practice Points; USG: Ultrasonography; WHO: World Health Organization. HOW TO CITE THIS ARTICLE: Javeri Y, Jagathkar G, Dixit S, Chaudhary D, Zirpe KG, Mehta Y, et al. Indian Society of Critical Care Medicine Position Statement for Central Venous Catheterization and Management 2020. Indian J Crit Care Med 2020;24(Suppl 1):S6-S30.

Quantitative detection of a cocktail of mycobacterial MPT64 and PstS1 in tuberculosis patients by real-time immuno-PCR.

AIM: There is an urgent need to design a reliable diagnostic test for tuberculosis (TB). METHODS: Real-time immuno-PCR (RT-I-PCR) assay was devised for the quantitative detection of a cocktail of mycobacterial MPT64 (Rv1980c) and PstS1 (Rv0934) in TB patients. RESULTS: A broad dynamic range of 0.95 pg/ml-95 ng/ml of MPT64+PstS1 was detected in TB patients. In smear-positive (n = 59) and smear-negative (n = 42) pulmonary TB cases, sensitivities of 93.2 and 83.3% were observed, respectively with 92.8% specificity, whereas a sensitivity of 77.9% and a specificity of 91.3% were observed in extrapulmonary TB cases (n = 86). Furthermore, significantly reduced MPT64+PstS1 concentrations (p < 0.001) were noticed in patients on therapy by RT-I-PCR as compared with untreated patients. CONCLUSION: Our RT-I-PCR assay revealed high sensitivity especially for the rapid diagnosis of smear-negative pulmonary TB and paucibacillary extrapulmonary TB samples, which could also monitor the dynamics of disease in patients on therapy.

Immuno-PCR, a new technique for the serodiagnosis of tuberculosis.

Rapid and accurate diagnosis of tuberculosis (TB) is essential to control the disease. The conventional microbiological tests have limitations and there is an urgent need to devise a simple, rapid and reliable point-of-care (POC) test. The failure of TB diagnostic tests based on antibody detection due to inconsistent and imprecise results has stimulated renewed interest in the development of rapid antigen detection methods. However, the World Health Organization (WHO) has emphasized to continue research for designing new antibody-based detection tests with improved accuracy. Immuno-polymerase chain reaction (I-PCR) combines the simplicity and versatility of enzyme-linked immunosorbent assay (ELISA) with the exponential amplification capacity and sensitivity of PCR thus leading to several-fold increase in sensitivity in comparison to analogous ELISA. In this review, we have described the serodiagnostic potential of I-PCR assays for an early diagnosis of TB based on the detection of potential mycobacterial antigens and circulating antibodies in body fluids of TB patients.

Tropical Fevers in Indian Intensive Care Units: A Prospective Multicenter Study.

BACKGROUND AND AIMS: Infections in tropics often present as undifferentiated fevers with organ failures. We conducted this nationwide study to identify the prevalence, profile, resource utilization, and outcome of tropical fevers in Indian Intensive Care Units (ICUs). MATERIALS AND METHODS: This was a multicenter prospective observational study done in 34 ICUs across India (July 2013-September 2014). Critically ill adults and children with nonlocalizing fever >48 h and onset < 14 days with any of the following: thrombocytopenia/rash, respiratory distress, renal failure, encephalopathy, jaundice, or multiorgan failure were enrolled consecutively. RESULTS: Of 456 cases enrolled, 173 were children <12 years. More than half of the participants (58.7%) presented in postmonsoon months (August-October). Thrombocytopenia/rash was the most common presentation (60%) followed by respiratory distress (46%), encephalopathy (28.5%), renal failure (23.5%), jaundice (20%), and multiorgan failure (19%). An etiology could be established in 365 (80.5%) cases. Dengue (n = 105.23%) was the most common followed by scrub typhus (n = 83.18%), encephalitis/meningitis (n = 44.9.6%), malaria (n = 37.8%), and bacterial sepsis (n = 32.7%). Nearly, half (35% invasive; 12% noninvasive) received mechanical ventilation, a quarter (23.4%) required vasoactive therapy in first 24 h and 9% received renal replacement therapy. Median (interquartile range) ICU and hospital length of stay were 4 (3-7) and 7 (5-11.3) days. At 28 days, 76.2% survived without disability, 4.4% had some disability, and 18.4% died. Mortality was higher (27% vs. 15%) in patients with undiagnosed etiology (P < 0.01). On multivariate analysis, multiorgan dysfunction syndrome at admission (odds ratio [95% confidence interval]-2.8 [1.8-6.6]), day 1 Sequential Organ Failure Assessment score (1.2 [1.0-1.3]), and the need for invasive ventilation (8.3 [3.4-20]) were the only independent predictors of unfavorable outcome. CONCLUSIONS: Dengue, scrub typhus, encephalitis, and malaria are the major tropical fevers in Indian ICUs. The data support a syndromic approach, point of care tests, and empiric antimicrobial therapy recommended by Indian Society of Critical Care Medicine in 2014.

Diagnosis of tuberculosis based on the detection of a cocktail of mycobacterial antigen 85B, ESAT-6 and cord factor by immuno-PCR.

Attempts were made to enhance the sensitivity of immuno-PCR assay based on the detection of cocktail of mycobacterial antigen 85B (Rv1886c), ESAT-6 (Rv3875) and cord factor (trehalose 6,6'-dimycolate) in pulmonary and extrapulmonary TB patients. Detection of Ag85B was found to be superior to the detection of cocktail in TB patients.

Comparative Evaluation of Several Gene Targets for Designing a Multiplex-PCR for an Early Diagnosis of Extrapulmonary Tuberculosis.

PURPOSE: Diagnosis of extrapulmonary tuberculosis (EPTB) poses serious challenges. A careful selection of appropriate gene targets is essential for designing a multiplex-polymerase chain reaction (M-PCR) assay. MATERIALS AND METHODS: We compared several gene targets of Mycobacterium tuberculosis, including IS6110, devR, and genes encoding MPB-64 (mpb64), 38kDa (pstS1), 65kDa (hsp65), 30kDa (fbpB), ESAT-6 (esat6), and CFP-10 (cfp10) proteins, using PCR assays on 105 EPTB specimens. From these data, we chose the two best gene targets to design an M-PCR. RESULTS: Among all gene targets tested, mpb64 showed the highest sensitivity (84% in confirmed cases and 77.5% in clinically suspected cases), followed by IS6110, hsp65, 38kDa, 30kDa, esat6, cfp10, and devR. We used mpb64+IS6110 for designing an M-PCR assay. Our M-PCR assay demonstrated a high sensitivity of 96% in confirmed EPTB cases and 88.75% in clinically suspected EPTB cases with a high specificity of 100%, taking clinical diagnosis as the gold standard. CONCLUSION: These M-PCR results along with the clinical findings may facilitate an early diagnosis of EPTB patients and clinical management of disease.

Assessment of allergenicity to fungal allergens of Rohtak city, Haryana, India.

Fungal spores are known as one of the important bioparticles causing allergic manifestation in human beings. Hence, knowledge of season and prevalence of the airborne allergens to which the patients are exposed is a prerequisite for proper diagnosis and treatment of allergic disorders in hypersensitive individuals. Keeping this in view, aerial survey was performed in the atmosphere of Rohtak city for 2 consecutive years (March 2008-February 2010), using a volumetric petri plate sampler. A total of 45 fungal spore types were recorded during the survey period. In the present study, February-April and July-November were identified as the peak seasons for Rohtak city. Cladosporium was the main contributor to the total fungal load with 25.14% followed by Alternaria (18.05%), Aspergillus niger (7.66%), Curvularia (5.31%), and Epicoccum (5.29%). Fifteen dominant viable fungal spore types were represented in the form of a fungal calendar. An attempt has also been made to assess the allergenicity of some of the fungal types recorded from the atmosphere of Rohtak city. The magnitude of variations observed in markedly positive skin reactions (2+ and above) varied from 17.3 to 2.3%. Penicillium oxalicum showed a markedly positive reaction in maximum number of patients (26; 17.3%) followed by Rhizopus nigricans (23; 15.3%). ELISA was performed with the sera of patients showing markedly positive skin reactions and the sera were classified into four groups based on percent binding. The majority of the sera showed 0-15% binding to different antigenic extracts, while sera showing >60% binding were least in number. Greater than 30% binding was observed against antigens of Rhizopus nigricans, Epicoccum purpurascens, Penicillium oxalicum, Curvularia lunata, Aspergillus flavus, Candida albicans and Neurospora sitophila. The concordance between positive skin reaction and serum-specific IgE antibodies ranged from 16.7 to 69.2%.

Tropical fevers: Management guidelines.

Tropical fevers were defined as infections that are prevalent in, or are unique to tropical and subtropical regions. Some of these occur throughout the year and some especially in rainy and post-rainy season. Concerned about high prevalence and morbidity and mortality caused by these infections, and overlapping clinical presentations, difficulties in arriving at specific diagnoses and need for early empiric treatment, Indian Society of Critical Care Medicine (ISCCM) constituted an expert committee to develop a consensus statement and guidelines for management of these diseases in the emergency and critical care. The committee decided to focus on most common infections on the basis of available epidemiologic data from India and overall experience of the group. These included dengue hemorrhagic fever, rickettsial infections/scrub typhus, malaria (usually falciparum), typhoid, and leptospira bacterial sepsis and common viral infections like influenza. The committee recommends a 'syndromic approach' to diagnosis and treatment of critical tropical infections and has identified five major clinical syndromes: undifferentiated fever, fever with rash / thrombocytopenia, fever with acute respiratory distress syndrome (ARDS), fever with encephalopathy and fever with multi organ dysfunction syndrome. Evidence based algorithms are presented to guide critical care specialists to choose reliable rapid diagnostic modalities and early empiric therapy based on clinical syndromes.

Silicosis with bilateral spontaneous pneumothorax.

Presentation with simultaneous bilateral pneumothorax is uncommon and usually in the context of secondary spontaneous pneumothorax. The association of pneumothorax and silicosis is infrequent and most cases are unilateral. Bilateral pneumothorax in silicosis is very rare with just a few reports in medical literature.