Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. DISCUSSION: We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. CONCLUSION: Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions.

Signet-Ring Cell Carcinoma Presenting as Hematochezia in a Patient with Crohn's Disease.

Signet-ring cell carcinoma is a rare adenocarcinoma, predominantly affecting the stomach and ovaries. Primary sites elsewhere are rarer. It is recognized that there is an increased cancer risk with the diagnosis of Crohn's disease. We report a patient with Crohn's disease who was diagnosed with signet-ring cell carcinoma in the setting of a Crohn's flare. Diagnosis was made with endoscopy. Treatment included laparoscopic-assisted right hemicolectomy with ileostomy with subsequent chemotherapy as an outpatient.

Complication rate and diagnostic yield of percutaneous native kidney biopsies: A 10-year experience at a Tertiary Care Hospital in Pakistan.

The use of an automated biopsy device, and real-time ultrasound for percutaneous kidney biopsies (PKBs) has improved the likelihood of obtaining adequate tissue for diagnosis and also has reduced the complications associated with the procedure. We aimed to determine the frequency and type of complications associated with PKB and to determine the diagnostic yield. It was a retrospective file-based review of cases who underwent PKB of native kidney between January 2003 and December 2013 at the Aga Khan University Hospital in Karachi, Pakistan. PKBs were performed by trained nephrologists or radiologists using an automated device with a 16/18-gauge needle under real-time ultrasound. The data obtained included age, gender, clinical and histopathological diagnosis, and complications associated with the procedure (minor: hematuria, local infections, and hematoma; major: transfusions, severe infections, surgery, nephrectomy, arteriography, embolism, and death. Yield of the procedure was based on the number of glomeruli obtained. Patients having major complications were compared with the patients who had minor or no complications. A total of 433 native kidney biopsies were performed. The mean age of the patients was 41 ± 15.9 years, and 58% of the patients were male. The main histological findings were membranoproliferative glomerulonephritis (17.6%) followed by focal and segmental glomerulosclerosis (16.4%) and interstitial nephritis (13.9%). Majority of the procedures were performed by nephrologists (67.4%). The overall complication rate was 14.2%. Among those, 21 patients (4.8%) had a major complication while the others had minor complications. Of those who had a major complication, 17 patients required blood transfusion(s) and had hematuria or a major hematoma, three had prolonged hospitalization >24 hours, and one patient required surgical intervention. Only 10 procedures (2.3%) had inadequate tissue to establish the histopathologic diagnosis. PKB under real-time ultrasound guidance is a safe and efficacious procedure to establish the histological diagnosis of the renal disease.

Biosafety Initiatives in BMENA Region: Identification of Gaps and Advances.

INTRODUCTION: The objectives of this study were to identify and assess the impact of capacity-building biosafety initiatives and programs that have taken place in the broader Middle East and North Africa (BMENA) region between 2001 and 2013, to highlight gaps that require further development, and to suggest sustainable ways to build cooperative regional biosafety opportunities. METHODS: A cross-sectional study was conducted with two aspects (1) thorough desktop review of literature for all biosafety/biosecurity-related activities in the study countries, such as seminars, conferences, workshops, policy documents, technology transfer, sustained scientific endeavors between countries, etc. and (2) an online survey of scientists in countries in the region to get first-hand information about biosafety and biosecurity initiatives and gaps in their country. RESULTS: A total of 1832 initiatives of biosafety/biosecurity were recorded from 97 web links; 70.68% (n = 1295) initiatives were focused on raising general awareness among the scientific community about biosafety/biosecurity/biocontainment. The most frequent areas of interest were biorisk management in biomedical and biotechnology laboratories 13% (n = 239), followed by living modified organisms (LMOs) 9.17% (n = 168). Hands-on training accounted for 2.67% (n = 49) of initiatives. Online survey results confirmed desktop review findings; however, the response rate was 11%.

Diuretic induced hyponatremia in hypertensive patients.

Diuretics are the recommended antihypertensive by several international guidelines. This study was designed to determine the association of hyponatremia in hypertensive patients on diuretic therapy. This was a case control study conducted at the Aga Khan University Hospital, Karachi in adult inpatients (> 18 years) who were known hypertensive. Cases were defined as hypertensives with hyponatremia and controls were defined as hypertensives without hyponatremia. Outcome was hyponatremia. Exposed were those using diuretics. Out of 1800 hypertensive patients sampled by the ICD-9-Coding; 1191 (66%) fulfilled the inclusion criteria. Cases n (%) were 553 (46.4) and controls were 638 (53.5). Among 553 cases (%) 180 (32.5) were exposed (on diuretics) and in controls 189 (29.6) were exposed (on diuretics) p=0.15. The association of hyponatremia with diuretic use was not significant with OR=1.11 (95% CI=0.86 - 1.45, p=0.40), after adjusting for chronic kidney disease, ischemic heart disease and chronic liver disease, in the final model. Diuretics were not associated with hyponatremia in hypertensive adult patients in this study.

Reducing transfusion-associated malaria in Pakistan: an algorithmic approach.

Blood transfusions represent a small but significant source of malaria transmission. Most blood banks rely solely on donor questioning to exclude malaria patients from donating blood. No guidelines exist for in vitro screening of donor blood for malaria in endemic areas. Possible laboratory screening techniques include: microscopy; enzyme-linked immunosorbent assay (ELISA) antibody testing; polymerase chain reaction (PCR) testing; and rapid diagnostic antigen tests. However, all these modalities have diagnostic limitations. Based on a best evidence review, we present recommendations using an algorithmic approach to blood screening for malaria in Pakistan. This algorithm considers regional endemicity for malaria, as well as a detailed donor history, in order to decide whether donor blood should be tested with rapid antigen testing. We hope this algorithm will assist in the development of future national guidelines for screening blood for malaria that will reduce the risk of blood-borne transmission.

Abdominal lymphadenopathy: an atypical presentation of enteric fever.

This is a case report of a patient who presented to the Aga Khan University Hospital with generalized abdominal lymphadenopathy and high-grade fever. Due to ambiguous clinical findings, which were suggestive of either abdominal tuberculosis, or a lymphoma, the patient was started on empirical anti-tuberculous treatment due to the endemicity of tuberculosis in this region. The blood culture reports, however, were reported to grow colonies of Salmonella paratyphi A; thus the diagnosis of the patient was changed to enteric fever, and the patient improved on the subsequently started therapy of ceftriaxone 2,000 mg bid. To the best of our knowledge, this is the first reported case of a patient suffering from enteric fever whose primary clinical findings were abdominal lymphadenopathy and fever.