Post-COVID-19 Pneumocystis pneumonia cases from Pakistan: an observational study

Background. Concurrent coronavirus disease 2019 (COVID-19) and Pneumocystis jirovecii pneumonia (PJP) has been described in various reports, with a recent study describing a 9.3 % P. jirovecii detection rate in critically ill COVID-19 patients. Methods. Patients with PCR-confirmed PJP following COVID-19 infection who were admitted to Aga Khan University Hospital, Karachi, Pakistan from March 2020–June 2021 were identified through a laboratory database. Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus was performed by RT-PCR Cobas SARS-CoV-2 qualitative assay. P. jirovecii PCR was performed using the RealStar Pneumocystis jirovecii PCR kit. Clinical, radiological and laboratory data for PJP patients were recorded. Results. During the study period, 3707 patients were admitted with COVID-19 at our hospital. P. jirovecii PCR was requested for 90 patients and was positive in 10 (11 %). Five out of 10 patients were discharged from the hospital and later developed cough and dyspnoea. Five patients remained hospitalized with severe COVID-19 and developed PJP. Eight patients in our study received systemic steroids. The trends of lymphocyte counts of all patients showed a lymphocyte count of <1000 mm−3 (<1.0×106 cells µl−1) in the week of PJP diagnosis. Four patients did not survive;one of these patients did not receive co-trimoxazole due to late diagnosis, one patient had concomitant nosocomial pneumonia and bacteraemia with multidrug-resistant Acinetobacter species, and two patients had concomitant aspergillosis. Conclusion. In summary, invasive fungal infections such as PJP should be considered as a complication in COVID-19 patients, with prompt evaluation and management.

Contagion of coronavirus disease-the first family cluster of Pakistan: a case series.

Coronavirus Disease has resulted in public health crisis all over the world. We describe the case series of a family, who travelled together to a mass gathering in Iraq, toured Syria, Lebanon, and Doha and returned to Karachi. The data describes the demographic and clinical features of these six members. There were three males and three females. One developed severe disease and died. Incubation period was between 8-14 days. Four patients were symptomatic, had diabetes mellitus and hypertension; and presented with fever. They also had bilateral airspace opacifications on chest X-ray. Our study describes familial clustering of SARS-CoV-2 and its person-to-person transmission.

Meplazumab in hospitalized adults with severe COVID-19 (DEFLECT): a multicenter, seamless phase 2/3, randomized, third-party double-blind clinical trial.

Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.

VITT with inactivated SARS-CoV-2 vaccine - index case.

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a 73-year-old gentleman who presented with pulmonary embolism and thrombocytopenia, two weeks after receiving inactivated COVID-19 vaccine. He responded well to nonheparin anticoagulation with complete resolution of symptoms and platelet count.

Long Term Impact on Lung Function of Patients With Moderate and Severe COVID-19. A Prospective Cohort Study.

Background: In Pakistan, the cases of COVID-19 have declined from 6000 per day in June to 600 in September 2020. A significant number of patients continue to recover from the disease, however, little is known about the lung function capacity among survivors. We aim to determine the long-term impact on lung function capacity in patients who have survived moderate or severe COVID-19 disease in a resource-poor setting. Methods: This prospective cohort study will be conducted at Aga Khan University Hospital (AKUH), Karachi Pakistan. Patients 15 years and above who have survived an episode of moderate or severe COVID-19, have reverse transcriptase-polymerase chain reaction (RT-PCR) positive for COVID 19 (nasopharyngeal or oropharyngeal) will be included. Patients with a pre-existing diagnosis of obstructive or interstitial lung disease, lung fibrosis, lung cancers, connective tissue disorders, autoimmune conditions affecting the lungs, underlying heart disease, history of syncope and those who refuse to participate will be excluded from the study. Pulmonary function will be assessed using spirometry and diffusion lung capacity for carbon monoxide (DLCO) at 3- and 6-months interval from the time of discharge from the hospital. Additionally, a chest X-ray and CT-chest will be performed if clinically indicated after consultation with the study pulmonologist or Infectious Disease (ID) physician. Echocardiogram (ECHO) will be performed to look for pulmonary hypertension at the 3 month visit and repeated at 6 months in case any abnormality is identified in the initial ECHO. Data analysis will be performed using standard statistical software. The study was approved by the Ethical Review Committee (ERC) of the institution (ERC reference number 2020-4735-11311). Strengths and Limitations of the Study: This cohort study will provide evidence on the long-term impact on lung function among COVID-19 survivors with moderate to severe disease. Such data will be key in understanding the impact of the disease on vital functions and will help devise rehabilitative strategies to best overcome the effects of disease. However, this will be a single-center, study recruiting only a limited number of COVID-19 survivors.

Upregulated type I interferon responses in asymptomatic COVID-19 infection are associated with improved clinical outcome.

Understanding key host protective mechanisms against SARS-CoV-2 infection can help improve treatment modalities for COVID-19. We used a blood transcriptome approach to study biomarkers associated with differing severity of COVID-19, comparing severe and mild Symptomatic disease with Asymptomatic COVID-19 and uninfected Controls. There was suppression of antigen presentation but upregulation of inflammatory and viral mRNA translation associated pathways in Symptomatic as compared with Asymptomatic cases. In severe COVID-19, CD177 a neutrophil marker, was upregulated while interferon stimulated genes (ISGs) were downregulated. Asymptomatic COVID-19 cases displayed upregulation of ISGs and humoral response genes with downregulation of ICAM3 and TLR8. Compared across the COVID-19 disease spectrum, we found type I interferon (IFN) responses to be significantly upregulated (IFNAR2, IRF2BP1, IRF4, MAVS, SAMHD1, TRIM1), or downregulated (SOCS3, IRF2BP2, IRF2BPL) in Asymptomatic as compared with mild and severe COVID-19, with the dysregulation of an increasing number of ISGs associated with progressive disease. These data suggest that initial early responses against SARS-CoV-2 may be effectively controlled by ISGs. Therefore, we hypothesize that treatment with type I interferons in the early stage of COVID-19 may limit disease progression by limiting SARS-CoV-2 in the host.

C. auris and non-C. auris candidemia in hospitalized adult and pediatric COVID-19 patients; single center data from Pakistan.

We compared candidemia due to Candida auris and other non-C.auris cases in hospitalized COVID-19 patients over a period of 9 months at our institution. Candidemia cases in all admitted patients (with or without COVID-19) from April to December 2020 were identified. Electronic records were accessed to record clinical data of COVID-19 patients with candidemia. For statistical analysis, independent samples Mann-Whitney U test was used for continuous and Fisher's exact test was used for categorical variables.A total of 26 candidemia cases (four C.auris, 22 non-C.auris) in 2438 admitted COVID-19 (10.7 per 1000 admissions) and 59 candidemia cases (six C.auris, 53 non-C.auris) in admitted non-COVID patients (8.2 per 1000 admission) were identified. The proportion of C.auris candidemia in COVID-19 and non-COVID-19 patients was 15.4 and 10%, respectively. 4/26 of COVID-19 candidemia patients were aged ≤ 15 years (10 months--15 years). Comparison of C.auris and non-C. auris candidemia cases reveal significant difference in prior antifungal exposure, present in 100% C. auris candidemia versus 27% non-C. auris candidemia patients (P-value 0.014). Although not statistically significant, C. auris candidemia patients had a longer stay in hospital before candidemia (20 vs. 9 days), higher isolation rate of multidrug resistant bacteria (100 vs. 50%), increased rate of prior colonization of Candida species (50 vs. 14%) and lower mean beta-d-glucan levels (48.73 pg/ml vs. 138.146 pg/ml). Both C. auris and non-C. auris COVID-19 patients had similar mortality rate (67 vs. 65%). A significant number of critically ill COVID-19 patients developed candidemia in our study highlighting the need for prompt diagnosis and management. LAY SUMMARY: 26 candidemia cases (4 Candida auris;22 non-C. auris) in COVID-19 patients (April-December 2020) are reported from Pakistan. Compared to non-C. auris, C. auris candidemia patients had higher prior antifungal exposure, longer hospital stay, higher rates of MDR bacteria and Candida colonization.

Comparison of clinical characteristics and outcomes between COVID-19 pneumonia and H1N1 influenza.

INTRODUCTION: The COVID-19 pandemic has been likened to the 2009 H1N1 influenza pandemic. We aim to study the similarities and differences between patients hospitalized with COVID-19 and H1N1 influenza in order to provide better care to patients, particularly during the co-circulation of Influenza A Subtype H1N1 and SARS-CoV-2. MATERIAL AND METHODS: A retrospective cohort study was conducted in order to compare clinical characteristics, complications, and outcomes of hospitalized patients with PCR-confirmed H1N1 influenza pneumonia and COVID-19 at a tertiary care center in Karachi, Pakistan. RESULTS: A total of 115 patients hospitalized with COVID-19 were compared with 55 patients with H1N1 Influenza A pneumonia. Median age was similar in both COVID-19 patients (54 years) and in patients with H1N1 influenza (59 years), but there was male predominance in COVID-19 patients (OR = 2.95; 95% CI: 1.12-7.79). Patients with COVID-19 pneumonia were 1.34 (95% CI: 1.14-1.62) times more likely to have a greater duration of illness prior to presentation compared to H1N1 influenza patients. COVID-19 patients were 4.59 times (95% CI: 1.32-15.94) more likely to be admitted to a general ward compared to H1N1 pneumonia patients. Moreover, patients with COVID-19 were 7.62 times (95% CI: 2.42-24.00) more likely to be treated with systemic steroids compared to patients with H1N1 pneumonia. The rate of nosocomial infections as well as mortality was similar in both H1N1 and COVID-19 pneumonia. CONCLUSION: Our study found a male predominance and longer duration of illness in hospitalized patients with COVID-19 compared to H1N1 influenza patients but no difference in outcomes with either infection.

Risk factors for bacterial infections in patients with moderate to severe COVID-19: A case-control study.

Adverse outcomes in coronavirus infection disease-19 (COVID-19) patients are not always due to the direct effects of the viral infection, but often due to bacterial coinfection. However, the risk factors for such bacterial coinfection are hitherto unknown. A case-control study was conducted to determine risk factors for bacterial infection in moderate to critical COVID-19. Out of a total of 50 cases and 50 controls, the proportion of cases with severe/critical disease at presentation was 80% in cases compared to 30% in controls (p < 0.001). The predominant site was hospital-acquired pneumonia (72%) and the majority were Gram-negative organisms (82%). The overall mortality was 30%, with comparatively higher mortality among cases (42% vs. 18%; p = 0.009). There was no difference between procalcitonin levels in both groups (p = 0.883). In multivariable logistic regression analysis, significant independent association was found with severe/critical COVID-19 at presentation (AOR: 4.42 times; 95% CI: 1.63-11.9) and use of steroids (AOR: 4.60; 95% CI: 1.24-17.05). Notably, 64% of controls were administered antibiotics despite the absence of bacterial coinfection or secondary infection. Risk factors for bacterial infections in moderate to critically ill patients with COVID-19 include critical illness at presentation and use of steroids. There is widespread empiric antibiotic utilization in those without bacterial infection.

Clinical characteristics and outcomes of COVID-19: Experience at a major tertiary care center in Pakistan.

INTRODUCTION: Limited data exist on clinical characteristics and outcomes of hospitalized COVID-19 patients in low-middle income countries. We aimed to describe the clinical spectrum and outcomes of hospitalized COVID-19 patients at a tertiary-care center in Karachi, Pakistan. METHODOLOGY: We conducted an observational study of adult COVID-19 patients hospitalized between February-June 2020. Patients with a discharge diagnosis of COVID-19 and PCR positivity were included. We created logistic regression models to understand association of clinical characteristics with illness severity and in-hospital mortality. RESULTS: The study population comprised 445 patients [67% males, median age 53 (IQR 40-64) years]. Majority of patients (N = 268; 60%) had ≥ 1 co-morbid [37.5% hypertension, 36.4% diabetes]. In-hospital mortality was 13%. Age ≥ 60 (aOR] =1.92; 95 %CI = 1.23-3.03), shortness of breath (aOR=4.43; 95% CI=2.73-7.22), CRP ≥150mg/L (aOR:1.77; 95% CI=1.09-2.85), LDH ≥ 500 I.U/L (aOR:1.98; 95% CI=1.25-3.16), Neutrophil-to-Lymphocyte ratio (NLR) ≥5 (aOR:2.80; 95%CI = 1.77-4.42) and increase in serum creatinine (aOR:1.32; 95%CI=1.07-1.61) were independently associated with disease severity. Septic shock (aOR: 13.27; 95% CI=3.78-46.65), age ≥ 60 (aOR: 3.26; 95% CI=1.07-9.89), Ferritin ≥ 1500ng/ml (aOR: 3.78; 95% CI=1.21-11.8), NLR ≥ 5 (aOR: 4.04; 95% CI=1.14-14.35) and acute kidney injury (aOR: 5.52; 95% CI=1.78-17.06) were independent predictors of in-hospital mortality. CONCLUSIONS: We found multiple predictors to be independently associated with in-hospital mortality, except diabetes and gender. Compared to reports from other countries, the in-hospital mortality among COVID-19 patients was lower, despite a high burden of co-morbidities. Further research is required to explore reasons behind this dichotomy.

Vitamin D and COVID-19: is there a role?

The COVID-19 pandemic requires a rapid understanding of the pathogenesis of the spectrum of the disease and factors associated with varied clinical presentations. Immune dysregulation with a cytokine storm (CS) progressing to ARDS with resemblance to sHLH is suggested as a main cause of tissue injury. Low levels of vitamin D were observed in COVID-19 cases with higher incidence of mortality in 20 European countries, increased risk of severity in COVID-19 contributing to ARDS or fulminant myocarditis and micro vascular thrombosis is proposed. Vitamin D may be protective against acute respiratory tract infections, as it regulates the inflammatory cytokine response of respiratory epithelial cells and macrophages, suppress CS and other manifestations seen in SARS-Cov-2. Hence, it is suggested as one of the therapies in SARS-CoV-2 infection. Major research gaps are identified globally in clinical management and this relationship. There is an imperative requisite to understand the interplay of markers in SARS-CoV-2, its risk factors and potential role of vitamin D to improve clinical outcome by pandemic of COVID-19. We therefore perform this review for understanding the pathophysiology of SARS-CoV-2 infections and the role of vitamin D in combating it.

Role of awake prone positioning in patients with moderate-to-severe COVID-19: an experience from a developing country.

There is limited evidence on the efficacy of awake prone positioning (PP) in non-ventilated patients with COVID-19 who have hypoxemia. We, therefore, aim to describe our experience with the use of early proning in awake, non-intubated patients with confirmed COVID-19. In our retrospective observational study, 23 patients with confirmed positive PCR test results for Severe Acute respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and hypoxemia that required oxygen therapy with or without non-invasive ventilation were treated with PP. Patients were classified into mild, moderate and severe COVID-19 disease. There were no targeted number of hours for proning per day and patients were kept in prone position according to their tolerance. The primary outcome measure was the avoidance of intubation and secondary outcomes were in-hospital mortality, length of hospital stays and complications related to PP. The mean (standard deviation) age of our cohort was 54.5 (11.7) years, and the majority were males (21/23, 91.3%). Sixty-one per cent (14/23) of the patients were suffering from severe disease and 82.6% (19/23) had bilateral lung involvement with interstitial infiltrates. Majority of the patients were prone positioned for a median of 6 days (IQR 4 - 8). Only one patient required transfer to ICU for mechanical ventilation and subsequently died due to severe ARDS. All 22 patients showed progressive improvement in oxygen requirement and PF ratio, mostly after 3-5 days of proning. The mean length of hospital stay was 12 days. All patients, except one, were discharged in stable conditions, on room air or on a minimal oxygen requirement of 1-2 liters. No major complication of PP was recorded. Awake prone positioning is a valuable and safe therapeutic adjunct that can be applied in patients with moderate-to-severe COVID-19. It can also be included in the home-based management protocols of COVID-19 to improve patient outcomes and mitigate the burden on health care facilities.

Tocilizumab for COVID-19 Acute Respiratory Distress Syndrome: Outcomes Assessment Using the WHO Ordinal Scale.

Introduction Cytokine release syndrome in COVID-19 is characterized by hyperinflammation, which manifests as acute respiratory distress syndrome (ARDS), multiorgan failure, and high inflammatory parameters. Tocilizumab, an interleukin 6 (IL-6) antagonist has been used in COVID-19 ARDS with conflicting results from different parts of the world. Objective To study the treatment outcomes with tocilizumab in patients with COVID-19 ARDS and hyperinflammation using the World Health Organization (WHO) COVID-19 ordinal scale. Methods An observational study was conducted from Feb 2020 to May 2020 on COVID-19 ARDS patients with hyperinflammation. Results A total of 244 patients with COVID-19 were admitted, out of which 107 had ARDS. Thirty patients had both ARDS and hyperinflammation and received tocilizumab. The mean age was 62.5 years (SD: 13.5) and the majority were male (83%). The mean CRP pre-treatment was 217.5 mg/L and post 48 to 72 hours of tocilizumab treatment was 98.5 mg/L. Twenty-one patients (70%) also received concomitant intravenous (IV) methylprednisolone. Of the 30 patients, seven died and 20 recovered. Ten patients required intensive care unit admission and nine developed nosocomial infections. COVID-19-associated aspergillosis was diagnosed in three patients post tocilizumab treatment. Mortality was significantly higher in patients who developed a nosocomial infection and who required intermittent positive pressure ventilation (IPPV). Post-treatment, clinical improvement was observed in patients who had a median score of 5 on the WHO ordinal scale. Conclusion Our study supports the use of tocilizumab in COVID-19 ARDS patients with a pre-treatment median WHO ordinal severity score of 5 and recommends the monitoring of nosocomial infections and opportunistic infections.

COVID-19-associated pulmonary aspergillosis (CAPA) in patients admitted with severe COVID-19 pneumonia: An observational study from Pakistan.

BACKGROUND: Invasive aspergillosis is a well-known complication of severe influenza pneumonia with acute respiratory distress syndrome (ARDS). However, recent studies are reporting emergence of aspergillosis in severe COVID-19 pneumonia, named as COVID-19-associated pulmonary aspergillosis (CAPA). METHODS: A retrospective observational study was conducted in patients with severe COVID-19 pneumonia from February 2020 to April 2020. Patients ≥18 years of age with clinical features and abnormal chest imaging with confirmed COVID-19 by RT-PCR for SARS-CoV-2 were included. CAPA was diagnosed based on clinical parameters, radiological findings and mycological data. Data were recorded on a structured proforma, and descriptive analysis was performed using Stata ver 12.1. RESULTS: A total of 147 patients with confirmed COVID-19 and 23 (15.6%) patients requiring ICU admission were identified. Aspergillus species were isolated from tracheal aspirates of nine (39.1%) patients, and of these, five patients (21.7%) were diagnosed with CAPA and four (17.4%) had Aspergillus colonisation. The mean age of patients with CAPA was 69 years (Median age: 71, IQR: 24, Range: 51-85), and 3/5 patients were male. The most frequent co-morbid was diabetes mellitus (4/5). The overall fatality rate of COVID-19 patients with aspergillosis was 44% (4/9). The cause of death was ARDS in all three patients with CAPA, and the median length of stay was 16 days (IQR: 10; Range 6-35 days). CONCLUSION: This study highlights the need for comparative studies to establish whether there is an association of aspergillosis and COVID-19 and the need for screening for fungal infections in severe COVID-19 patients with certain risk factors.