Impact of COVID-19 Pandemic on Clinical Care of Patients and Psychosocial Health of Affected Families with Chronic Granulomatous Disease: an Observational Study from North India.

Day-to-day clinical management of patients with inborn errors of immunity, including chronic granulomatous disease (CGD), has been affected by the coronavirus disease-2019 (COVID-19) pandemic. There is a dearth of information on impact of this pandemic on clinical care of children with CGD and psychological profile of the caretakers. Among the 101 patients with CGD followed up in our center, 5 children developed infection/complications associated with COVID-19. Four of these children had a mild clinical course, while 1 child developed features of multisystem inflammatory syndrome in children (MISC) requiring intravenous glucocorticoids. Parents and caretakers of CGD patients (n = 21) and 21 healthy adults with similar ages and genders were also evaluated on the following scales and questionnaires: COVID-19 Fear Scale (FCV 19S), Impact of Event Scale (IES-R), Depression, Anxiety, and Stress Scale (DASS 21), Preventive COVID-19 Behavior Scale (PCV 19BS), and a "COVID-19 Psychological wellbeing questionnaire." Median age of the parents/caregivers was 41.76 years (range: 28-60 years). Male:female ratio was 2:1. In the study group, 71.4% had higher IES scores compared to 14.3% in controls. The caregivers had a high prevalence of stress, anxiety, avoidance behavior, and depression compared to controls (p < 0.001). Children with CGD have had predominantly mild infection with COVID-19; however, caregivers/parents of these children were at risk of developing psychological distress. The COVID-19 pandemic has brought to light the importance of patients' and caretakers' mental health which needs periodic assessment and appropriate interventions.

Apremilast Add-On Benefits Over Conventional Drugs (ABCD) in Unstable Non-segmental Vitiligo: A 12-Week Single-Center Randomized Controlled Trial.

Background Apremilast is an oral phosphodiesterase-4 enzyme inhibitor that modulates the immune system by increasing intracellular cyclic adenosine monophosphate levels and inhibiting inflammatory cytokines synthesis. We aimed to compare the efficacy and safety of add-on apremilast in combination therapy with standard treatment in patients with unstable, non-segmental vitiligo. Methods The study was a 12-week randomized, controlled, parallel-group, open-labeled trial. The control group received standard treatment (n=15), and the intervention group received 30 mg apremilast twice daily in addition to standard treatment (n= 16). Time to the first sign of re-pigmentation, halt in progression, and change in vitiligo area scoring index (VASI) score is the primary outcomes. Normality was assessed, and appropriate parametric and nonparametric tests were undertaken. Results Thirty-seven participants were randomized into two groups, and analysis was done on thirty-one participants. Over the treatment duration of 12 weeks, the median time to observe the first sign of re-pigmentation was four weeks in the add-on apremilast group compared to seven weeks in the control group (p=0.018). The halt in progression was observed more in the add-on Apremilast group (93.75%) compared to the control group (66.66%) (p=0.08). The VASI score decreased by 1.24 in the add-on apremilast group and 0.05 in the control group (p= 0.754). Parameters including body surface area, dermatology life quality index, and body mass index reduced significantly, while the visual analog scale increased significantly in the add-on apremilast group. However, results were comparable between groups. Conclusions Treatment with add-on apremilast accelerated clinical improvement. It also reduced disease progression and improved the disease index among participants. However, add-on apremilast had a lower tolerability profile than the control group.

Shoulder Injury Related to Vaccine Administration (SIRVA) with COVID-19 vaccination - A case report.

The case report evaluates shoulder injury related to COVID-19 vaccine administration. A 26-year-old female patient presented with shoulder pain, which increased on extension and overhead abduction in routine work. Magnetic resonance imaging (MRI) was done based on which, a diagnosis of shoulder injury related to vaccine administration (SIRVA) was reported. Significant improvement was seen after Non-steroidal anti-inflammatory drugs (NSAIDs), topical diclofenac ointment, and serratiopeptidase tablets. Physical muscle strengthening exercises were advised. Based on Naranjo and World Health Organization (WHO) casualty assessments, the adverse drug reaction (ADR) was categorized under probable. Preventability, Hartwig's scales for severity was assessed, which showed preventability and moderate grade in severity. The total cost (direct and indirect) for management was found to be rupees 7021 and 41,781 in government and private hospital respectively. Thus ADRs not only add to patient suffering but also increase the economic burden. Health care professionals (HCPs) need to be made aware of potentially fatal ADRs associated with the administration of vaccines and should be keen to report such ADRs to drug safety authorities.

Predictors of mortality among hospitalized patients with COVID-19: A single-centre retrospective analysis.

Background: The severity of disease and mortality due to coronavirus disease (COVID-19) was found to be high among patients with concurrent medical illnesses. Serum biomarkers can be used to predict the course of COVID-19 pneumonia. Data from India are very scarce about predictors of mortality among COVID-19 patients. Methodology: In the present retrospective study of 65 RT-PCR confirmed COVID-19 patients, we retrieved data regarding clinical symptoms, laboratory parameters, and radiological grading of severity. Further, we also collected data about their hospital course, duration of stay, treatment, and outcome. Data analysis was done to compare the patient characteristics between survivor and non-survivor groups and to assess the predictors of mortality. Results: The mean age of the study population was 56.23 years (SD, 12.91) and most of them were males (63%); 81.5% of patients survived and were discharged, whereas 18.5% of patients succumbed to the disease. Univariate analysis across both groups showed that older age, diabetes mellitus, higher computed tomogram (CT) severity score, and raised levels of laboratory parameters viz, D-dimer, CPK-MB (creatine kinase), and lactate dehydrogenase (LDH) were associated with increased mortality among hospitalized patients. On multivariate analysis, elevated levels of serum D-dimer (odds ratio, 95% CI: 10.98, 1.13-106.62, p = 0.04) and LDH (odds ratio, 95% CI: 19.15, 3.28-111.87, p = 0.001) were independently associated with mortality. Conclusion: Older patients, diabetics, and patients with high CT severity scores at admission are at increased risk of death from COVID-19. Serum biomarkers such as D-dimer and LDH help in predicting mortality in COVID-19 patients.

Mechanisms of Immune Dysregulation in COVID-19 Are Different From SARS and MERS: A Perspective in Context of Kawasaki Disease and MIS-C.

Coronaviruses have led to three major outbreaks to date-Severe Acute Respiratory Syndrome (SARS; 2002), Middle East Respiratory Syndrome (MERS; 2012) and the ongoing pandemic, Coronavirus Disease (COVID-19; 2019). Coronavirus infections are usually mild in children. However, a few children with MERS had presented with a severe phenotype in the acute phase resulting in progressive pneumonic changes with increasing oxygen dependency and acute respiratory distress requiring ventilatory support. A subset of children with a history of SARS-CoV-2 infection develops a multisystem hyper-inflammatory phenotype known as Multisystem Inflammatory Syndrome in Children (MIS-C). This syndrome occurs 4-6 weeks after infection with SARS-CoV-2 and has been reported more often from areas with high community transmission. Children with MIS-C present with high fever and often have involvement of cardiovascular, gastrointestinal and hematologic systems leading to multiorgan failure. This is accompanied by elevation of pro-inflammatory cytokines such as IL-6 and IL-10. MIS-C has several similarities with Kawasaki disease (KD) considering children with both conditions present with fever, rash, conjunctival injection, mucosal symptoms and swelling of hands and feet. For reasons that are still not clear, both KD and MIS-C were not reported during the SARS-CoV and MERS-CoV outbreaks. As SARS-CoV-2 differs from SARS-CoV by 19.5% and MERS by 50% in terms of sequence identity, differences in genomic and proteomic profiles may explain the varied disease immunopathology and host responses. Left untreated, MIS-C may lead to severe abdominal pain, ventricular dysfunction and shock. Immunological investigations reveal reduced numbers of follicular B cells, increased numbers of terminally differentiated CD4+T lymphocytes, and decreased IL-17A. There is still ambiguity about the clinical and immunologic risk factors that predispose some children to development of MIS-C while sparing others. Host-pathogen interactions in SARS, MERS and COVID-19 are likely to play a crucial role in the clinical phenotypes that manifest. This narrative review focuses on the immunological basis for development of MIS-C syndrome in the ongoing SARS-CoV-2 pandemic. To the best of our knowledge, these aspects have not been reviewed before.

BCG vaccination impact on mortality and recovery rates in COVID-19: A meta-analysis.

COVID-19 is a pandemic caused by SARS-CoV-2 virus which is a very worrisome public health emergency. In this study, we compared the mortality rate and recovery rate in countries with and without BCG vaccination policy. The data of mortality of COVID-19 was extracted from worldometer (https://www.worldometers.info/coronavirus/) on 26th July 2020. The data of countries where BCG vaccination is being done for all individuals is taken from BCG world atlas (http://www.bcgatlas.org/index.php), updated in 2017. BCG vaccination policy recommended countries are intervention group versus countries without BCG vaccination policies which are regarded as control group. Pooled analysis of countries with and without BCG vaccination policy revealed mortality rate of 1.31% (95%CI - 1.31% to 1.32%; I2 = 100%, p<0.01) and 3.25% (95%CI - 3.23% to 3.26%; I2 = 100%, p<0.01), respectively. The recovery rates in two country groups were found to be 72.60% (95%CI - 72.57% to 72.63%) and 55.94% (95%CI - 55.90% to 55.98%), respectively. 52 individuals need to be BCG vaccinated to prevent one death (NNT = 52). In BCG vaccination program countries, there is statistically and clinically significant less mortality (p<0.001) as compared to countries without BCG policy. Our findings corroborate the hypothesis that BCG vaccination may provide protection from COVID-19. High quality evidence from randomised controlled trials are required to establish causality between BCG vaccination and protection from severe COVID-19.

Does Bacille Calmette-Guérin Vaccination Provides Protection against COVID-19: A Systematic Review and Meta-analysis.

BACKGROUND: Lower morbidity and mortality in few geographic locations on the globe suffering with SARS-CoV-2 has been associated with the existing or previously followed long-standing Bacille Calmette-Guérin (BCG) vaccination policy among infants. However, does it hold true that today after years of BCG vaccination, few adults have better prognosis or is it just confounding due to differential disease burden, population density, testing facilities, or improper reporting. The purpose was to evaluate and correlate this effect systematically. METHODS: Detailed electronic search for randomized controlled trials (RCTs) and observational studies in PubMed, Cochrane Library, and ClinicalTrials.gov for eligible studies was performed. RESULTS: One hundred and fourteen studies were yielded on search strategy and 28 observational studies were finally included for analysis. From our results, we can say that BCG vaccination causes a decrease in COVID-19 incidence and mortality. However, these results must be interpreted cautiously as lot of confounding factors were present in included studies, which can affect the outcome. CONCLUSION: The evidence of BCG vaccination for the protection against COVID-19 cannot be ruled out as evidence from many studies support the hypothesis, but the evidence of well-conducted RCTs and observational studies can strengthen the evidence. REGISTRATION NUMBER: PROSPERO (International Prospective Register of Systematic Reviews) database (CRD42020204466).

Non-SARS, non-MERS human coronavirus infections and risk of Kawasaki disease: a meta-analysis.

Aim: To study the association between non-SARS, non-MERS human coronavirus (HCoV) infections and Kawasaki disease (KD). Methods: Meta-analysis of observational studies published until 1 May 2021. Results: Out of 571 papers retrieved through database search, 10 provided data of 17,732 children. Age ranged from 2 months-14.9 years with 66% being male and 71% being complete KD. Compared with controls, there was an increased risk of developing KD in those detected to have HCoV infection (OR: 2.3 [95% CI: 1.06-4.99]; p = 0.03). The GRADE evidence for all outcomes was of 'low-certainty'. Conclusion: A 'low certainty' of evidence suggests an increased risk of KD in children infected with HCoV. We need multi-center, prospective studies to support or refute this finding. PROSPERO protocol registration: CRD42021251582.

Flashback and lessons learnt from history of pandemics before COVID-19.

With an increasing frequency of infectious disease outbreaks, the COVID-19 pandemic causing mortality around the world and the threat of similar future events looming large, mankind is faced with the herculean task of counteracting such threats with the best possible strategies and public health decisions. It is key that such decisions should be guided by previous examples of similar health emergencies. Here we review some of the significant infectious disease outbreaks, including epidemics and pandemics occurring worldwide in the past including their impact at population and global levels, unique challenges presented by each and the measures taken by authorities worldwide as well as the crucial lessons each epidemic or pandemic provided. This review highlights that throughout history measures such as contact tracing, quarantine and isolation have been incredibly effective in limiting an outbreak in its severity, thus ensuring accurate information flow to the public is as essential as limiting the spread of misinformation. With global populations rising, surveillance for emerging and re-emerging pathogens will play an immense role in preventing future epidemics or pandemics. And finally that even though for novel strains or pathogens, although vaccines are thought to be an irreplaceable defense, but their development and distribution in time to curb an epidemic has seldom been witnessed and remains an important challenge for the future. Hence, we conclude that looking at these past examples not only highlights the important knowledge gained for the strategies to devise, but also the mistakes that can be avoided in the way forward.

A comprehensive insight on the COVID-19 vaccine candidates.

The world is currently facing a pandemic triggered by the novel corona virus (SARS - CoV2), which causes a highly infectious infection that predominantly affects the lungs, resulting in a variety of clinical symptoms some cases may be asymptomatic while others may result in to severe respiratory disorder, if the infection is left unattended it may result in multi-organ failure and eventually death of the patient. The transmission of infection is by droplet and fomites of the infected person. The incubation period of virus is from 2 to 14 days. Most common symptoms resemble flu-like but later progress to pneumonia along with dyspnoea and worsening of oxygen saturation, thus requiring ventilator support. The diagnostic modalities include Reverse transcriptase real time PCR (Quantitative Reverse transcriptase polymerase chain reaction) which is recommended method used for diagnosis of the COVID-19 infection using oro-pharyngeal or nasopharyngeal swabs of the patients. Recently serological tests for antigen and antibody detection has been approved by ICMR. Till now, nine COVID-19 vaccines are granted emergency approval for prevention and for the management of infection symptomatic and supportive measures are being adopted. Globally major pharmaceutical firms are engrossed for development of a potent vaccine candidate. This review highlights on various vaccine candidates under clinical trials.

Systematic review and meta-analysis of efficacy and safety of hydroxychloroquine and chloroquine in the treatment of COVID-19.

Repurposed drugs like hydroxycloroquine (HCQ) and chloroquine (CQ) are being tested for potential therapeutic role in COVID-19. We aimed to evaluate efficacy and safety of HCQ and CQ in COVID-19. Using PubMed, EMBASE, medRxiv, Google Scholar, clinicaltrials.gov, electronic search was carried out to identify relevant articles till June 2020 with re-evaluation in last week of November 2020. Observational and interventional clinical studies comparing efficacy of CQ or HCQ to standard management or other drug/s for SARS-CoV-2 infection patients were included. Cochrane review manager version 5.3 was used for synthesis of meta-analysis results. For randomized controlled trials, risk of bias was assessed using Cochrane Collaboration risk of bias assessment tool, version 2.0 (ROB-2). ROBINS-I was used for quality assessment of observational studies. Overall evidence quality generated by review was graded as per GRADE Recommendation. A total of 903 studies were screened. Nineteen studies were included in synthesis of meta-analysis with total of 4,693, 1,626, and 6,491 patients in HCQ/CQ, HCQ/CQ + AZ and control groups, respectively. HCQ/CQ treatment was associated with significantly increased rates of virological cure (OR = 2.08, 95%CI = 1.36-3.17; P = 0.0007) and radiological cure (OR = 3.89, 95%CI = 1.35 - 11.23; P = 0.01) compared to control. HCQ/CQ had no difference in unadjusted mortality rate (unadjusted OR = 0.98 95% CI = 0.70-1.37, P = 0.89, random effect model) and adjusted hazard ratio for mortality (adjusted HR = 1.05, 95%CI = 0.86--1.29; P = 0.64). However, a significant increase in odds of disease progression (OR = 1.77, 95%CI = 1.46-2.13; P < 0.00001) and QT prolongation (OR = 11.15, 95%CI = 3.95-31.44; P < 0.00001) was noted. The results with HCQ/CQ and azithromycin combination were similar to HCQ/CQ mono-therapy. In the light of contemporary evidence on effectiveness of HCQ/CQ, judicious and monitored use of HCQ/CQ for treatment of COVID-19 patients is recommended in low to middle income countries with emphasis on no mortality benefit. Registration number of Systematic review. Register in PROSPERO database: cRD42020187710.

Chest-X-ray-Based Scoring, Total Leukocyte Count, and Neutrophil-to-Lymphocyte Ratio for Prediction of COVID-19 in Patients with Severe Acute Respiratory Illness.

OBJECTIVE: This study aimed to use chest-X-ray (CXR)-based scores along with total leukocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) in the prediction of coronavirus disease 2019 (COVID-19) in patients presenting with clinical features of severe acute respiratory illness (SARI). MATERIAL AND METHODS: This is a retrospective study involving all patients who presented with clinical features of SARI and who had undergone bedside chest X-ray (CXR), hemograms with TLC, NLR, and reverse transcriptase-polymerase chain reaction (RT-PCR) at our institute from May 1 to June 30, 2020. RESULTS: Of 204 patients, 115 tested RT-PCR-positive and 89 tested negative. The patients who presented with SARI, using CXR-based score of 4 or more, TLC of less than 8,700 cells/µL, and NLR of <7 had a statistically significant area under the curve (p<0.001) for diagnosing COVID-19. The sensitivity and specificity of the CXR score was 80.8% and 73.0%, of TLC was 70.1% and 74.7%, and of NLR was 70.1% and 59.0%, respectively, in diagnosing COVID-19 alone. The specificity further increased to 90.4% when we used the CXR score with NLR and to 92.8% when we used the CXR score with TLC. The post-test odds ("rule in" disease) of a positive test for having the disease were 3, 2.77, and 1.71 times with the use of either CXR score, TLC, or NLR criteria, respectively; whereas, combined use of CXR score and NLR increased the post-test odds by 5.53 times, and combination of CXR score with TLC increased the post-test odds by 7.5 times. CONCLUSION: CXR score with TLC and NLR can predict COVID-19 infection among those who presented with features of SARI. This may help in the early isolation of the patient until the RT-PCR report becomes available.

Efficacy and safety of remdesivir in COVID-19 caused by SARS-CoV-2: a systematic review and meta-analysis.

OBJECTIVES: Evaluation of remdesivir, an RNA polymerase inhibitor, for effectiveness in adults with COVID-19. DATA SOURCES: Electronic search for eligible articles of PubMed, Cochrane Central and clinicaltrials.gov was performed on 20 September 2020. PARTICIPANTS AND STUDY ELIGIBILITY CRITERIA: Only randomised controlled trials (RCTs) evaluating efficacy of remdesivir in COVID-19 were included for meta-analysis. INTERVENTIONS: Remdesivir was compared with standard of care. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was mortality and secondary outcomes were time to clinical improvement and safety outcomes like serious adverse events, respiratory failure. STUDY APPRAISAL AND SYNTHESIS METHODS: Data synthesis was done with Cochrane review manager 5 (RevMan) V.5.3. Cochrane risk of bias V.2.0 tool was used for methodological quality assessment. The GRADE pro GDT was applied for overall quality of evidence. RESULTS: 52 RCTs were screened and 4 studies were included in analysis, with total of 7324 patients. No mortality benefit was observed with remdesivir versus control group (OR=0.92 (95% CI 0.79 to 1.07), p=0.30, moderate quality evidence). Significantly higher rates of clinical improvement (OR=1.52 (95% CI 1.24 to 1.87), p<0.0001, low quality) and faster time to clinical improvement (HR=1.28 (95% CI 1.12 to 1.46), p=0.0002, very low quality) was observed with remdesivir versus control group. Significant decrease was found in the risk of serious adverse events (RR=0.75 (95% CI 0.62 to 0.90), p=0.0003, low quality); however, no difference was found in the risk of respiratory failure (RR=0.85 (95% CI 0.41 to 1.77), p=0.67, very low quality evidence) with remdesivir. CONCLUSIONS: As per the evidence from current review, remdesivir has shown no mortality benefit (moderate quality evidence) in the treatment of COVID-19. From a cost-benefit perspective, it is our personal opinion that it should not be recommended for use, especially in low and lower middle income countries. TRIAL REGISTRATION NUMBER: PROSPERO registration number: CRD42020189517.

Transformational Effect of COVID Pandemic on Postgraduate Programme in Oral and Maxillofacial Surgery in India-A Trainee Perspective.

Background and purpose: The purpose of the survey was to evaluate transformation in mode of teaching during the COVID pandemic on a postgraduate program in oral and maxillofacial surgery in India. Methods: A standardised e-questionnaire was created on Google Forms™ and was shared using emails and WhatsApp™. A total of 103 postgraduate students of oral and maxillofacial surgery from different universities participated in this cross-sectional survey. The collected data were analysed using bivariate and multivariate analysis. Results: A total of 95.1% of postgraduates in the survey believed that their overall regular speciality work was deprived during first 5 months of COVID. 90.3% participants accepted that webinar/online teaching program become more beneficial for their academics. But 78.1 % participants think that because of overburdening of these academic sessions, they have reduced the enthusiasm in attending them. Conclusion: This survey highlighted the intense negative impacts of this pandemic on the postgraduate program from the eyes of the trainees themselves. This triggers us to hasten this process of medical education transformation in a way to cope with any such calamity with minimal consequences.

Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management.

Multisystem inflammatory syndrome (MIS-C) is a pediatric hyperinflammation disorder caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It has now been reported from several countries the world over. Some of the clinical manifestations of MIS-C mimic Kawasaki disease (KD) shock syndrome. MIS-C develops 4-6 weeks following SARS-CoV-2 infection, and is presumably initiated by adaptive immune response. Though it has multisystem involvement, it is the cardiovascular manifestations that are most prominent. High titres of anti-SARS-CoV-2 antibodies are seen in these patients. As this is a new disease entity, its immunopathogenesis is not fully elucidated. Whether it has some overlap with KD is still unclear. Current treatment guidelines recommend use of intravenous immunoglobulin and high-dose corticosteroids as first-line treatment. Mortality rates of MIS-C are lower compared to adult forms of severe COVID-19 disease.

Kawasaki disease and influenza-new lessons from old associations.

Kawasaki disease (KD), an enigmatic medium vessel vasculitis, presents as an acute febrile illness predominantly affecting young children. KD appears to be a hyper-inflammatory response elicited by environmental or infectious agents (including respiratory viruses) in genetically predisposed individuals. Numerous reports from the current era of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have described the occurrence of KD/KD-like illness in close temporal proximity to SARS-CoV-2 infection or exposure. Notably, KD has been reported in association with H1N1-pdm09 virus that caused the previous pandemic a decade ago. Non-H1N1 influenza infections as well as influenza vaccination have also been reported to trigger KD. Herein, we report a case of H1N1-pdm09 influenza who developed KD. We review the published literature on influenza infection or vaccination triggering KD. This may help in a better understanding of the KD/KD-like illness associated with SARS-CoV-2. Besides, we also evaluate the safety of aspirin in influenza-triggered KD as aspirin administration in children with influenza is associated with the risk of development of Reye syndrome.

Cardiovascular Involvement in Kawasaki Disease Is Much More Than Mere Coronary Arteritis.

Kawasaki disease (KD) is now a common cause of acquired heart disease in children. Coronary artery involvement is the most serious complication in children with KD. Several non-coronary complications have now been identified in this condition but these are often overlooked. Myocarditis is an integral component of KD and may be more common than coronary artery abnormalities. Pericardial involvement and valvular abnormalities have also been observed in patients with KD. KD shock syndrome is now being increasingly recognized and may be difficult to differentiate clinically from toxic shock syndrome. Endothelial dysfunction has been reported both during acute stage and also on follow-up. This may be a potentially modifiable cardiovascular risk factor.