Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder that occurs almost exclusively in males. This condition mainly affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis.

Glucose-6-phosphate dehydrogenase deficiency.

Background Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. Objectives To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). Search methods We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. Selection criteria We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms. We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. Data collection and analysis We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. Main results We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. Ivermectin doses and treatment duration varied among included studies. We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. Authors' conclusions Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.

Ivermectin for preventing and treating COVID-19

https://macsphere.mcmaster.ca/bitstream/11375/26598/2/How%20COVID-19%20has%20fundamentally%20changed%20clinical%20research%20in%20global%20health.pdf

How COVID-19 has fundamentally changed clinical research in global health.

/pdf/cytokine-storm-in-covid-19-immunopathogenesis-and-therapy-3ef3tqvb.pdf

Cytokine Storm in COVID-19: Immunopathogenesis and Therapy

The outbreak of the coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an evolving global health crisis. Currently, a number of risk factors have been identified to have a potential impact on increasing the morbidity of COVID-19 in adults, including old age, male sex, pre-existing comorbidities, and racial/ethnic disparities. In addition to these factors, changes in laboratory indices and pro-inflammatory cytokines, as well as possible complications, could indicate the progression of COVID-19 into a severe and critical stage. Children predominantly suffer from mild illnesses due to COVID-19. Similar to adults, the main risk factors in pediatric patients include age and pre-existing comorbidities. In contrast, supplementation with a healthy diet and sufficient nutrition, COVID-19 vaccination, and atopic conditions may act as protective factors against the infection of SARS-CoV-2. COVID-19 vaccination not only protects vulnerable individuals from SARS-CoV-2 infection, more importantly, it may also reduce the development of severe disease and death due to COVID-19. Currently used therapies for COVID-19 are off-label and empiric, and their impacts on the severity and mortality of COVID-19 are still unclear. The interaction between asthma and COVID-19 may be bidirectional and needs to be clarified in more studies. In this review, we highlight the clinical evidence supporting the rationale for the risk and protective factors for the morbidity, severity, and mortality of COVID-19. 

/pdf/risk-and-protective-factors-for-covid-19-morbidity-severity-2l4uot5i.pdf

Risk and Protective Factors for COVID-19 Morbidity, Severity, and Mortality

Background
The coronavirus disease 2019 (COVID‐19) pandemic has resulted in substantial mortality. Some specialists proposed chloroquine (CQ) and hydroxychloroquine (HCQ) for treating or preventing the disease. The efficacy and safety of these drugs have been assessed in randomized controlled trials.
Objectives
To evaluate the effects of chloroquine (CQ) or hydroxychloroquine (HCQ) for
1) treating people with COVID‐19 on death and time to clearance of the virus;
2) preventing infection in people at risk of SARS‐CoV‐2 exposure;
3) preventing infection in people exposed to SARS‐CoV‐2.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Current Controlled Trials (www.controlled‐trials.com), and the COVID‐19‐specific resources www.covid‐nma.com and covid‐19.cochrane.org, for studies of any publication status and in any language. We performed all searches up to 15 September 2020. We contacted researchers to identify unpublished and ongoing studies.
Selection criteria
We included randomized controlled trials (RCTs) testing chloroquine or hydroxychloroquine in people with COVID‐19, people at risk of COVID‐19 exposure, and people exposed to COVID‐19.
Adverse events (any, serious, and QT‐interval prolongation on electrocardiogram) were also extracted.
Data collection and analysis
Two review authors independently assessed eligibility of search results, extracted data from the included studies, and assessed risk of bias using the Cochrane ‘Risk of bias’ tool. We contacted study authors for clarification and additional data for some studies. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We performed meta‐analysis using a random‐effects model for outcomes where pooling of effect estimates was appropriate.

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.

Background
Plague is a severe disease associated with high mortality. Late diagnosis leads to advance stage of the disease with worse outcomes and higher risk of spread of the disease. A rapid diagnostic test (RDT) could help in establishing a prompt diagnosis of plague. This would improve patient care and help appropriate public health response.

Objectives
To determine the diagnostic accuracy of the RDT based on the antigen F1 (F1RDT) for detecting plague in people with suspected disease.

Search methods
We searched the CENTRAL, Embase, Science Citation Index, Google Scholar, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov up to 15 May 2019, and PubMed (MEDLINE) up to 27 August 2019, regardless of language, publication status, or publication date. We handsearched the reference lists of relevant papers and contacted researchers working in the field.

Selection criteria
We included cross‐sectional studies that assessed the accuracy of the F1RDT for diagnosing plague, where participants were tested with both the F1RDT and at least one reference standard. The reference standards were bacterial isolation by culture, polymerase chain reaction (PCR), and paired serology (this is a four‐fold difference in F1 antibody titres between two samples from acute and convalescent phases).

Data collection and analysis
Two review authors independently selected studies and extracted data. We appraised the methodological quality of each selected studies and applicability by using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool. When meta‐analysis was appropriate, we used the bivariate model to obtain pooled estimates of sensitivity and specificity. We stratified all analyses by the reference standard used and presented disaggregated data for forms of plague. We assessed the certainty of the evidence using GRADE.

Main results
We included eight manuscripts reporting seven studies. Studies were conducted in three countries in Africa among adults and children with any form of plague. All studies except one assessed the F1RDT produced at the Institut Pasteur of Madagascar (F1RDT‐IPM) and one study assessed a F1RDT produced by New Horizons (F1RDT‐NH), utilized by the US Centers for Disease Control and Prevention. We could not pool the findings from the F1RDT‐NH in meta‐analyses due to a lack of raw data and a threshold of the test for positivity different from the F1RDT‐IPM.

Risk of bias was high for participant selection (retrospective studies, recruitment of participants not consecutive or random, unclear exclusion criteria), low or unclear for index test (blinding of F1RDT interpretation unknown), low for reference standards, and high or unclear for flow and timing (time of sample transportation was longer than seven days, which can lead to decreased viability of the pathogen and overgrowth of contaminating bacteria, with subsequent false‐negative results and misclassification of the target condition).

F1RDT for diagnosing all forms of plague

F1RDT‐IPM pooled sensitivity against culture was 100% (95% confidence interval (CI) 82 to 100; 4 studies, 1692 participants; very low certainty evidence) and pooled specificity was 70.3% (95% CI 65 to 75; 4 studies, 2004 participants; very low‐certainty evidence).

The performance of F1RDT‐IPM against PCR was calculated from a single study in participants with bubonic plague (see below).
There were limited data on the performance of F1RDT against paired serology.

F1RDT for diagnosing pneumonic plague

Performed in sputum, F1RDT‐IPM pooled sensitivity against culture was 100% (95% CI 0 to 100; 2 studies, 56 participants; very low‐certainty evidence) and pooled specificity was 71% (95% CI 59 to 80; 2 studies, 297 participants; very low‐certainty evidence).

There were limited data on the performance of F1RDT against PCR or against paired serology for diagnosing pneumonic plague.

F1RDT for diagnosing bubonic plague

Performed in bubo aspirate, F1RDT‐IPM pooled sensitivity against culture was 100% (95% CI not calculable; 2 studies, 1454 participants; low‐certainty evidence) and pooled specificity was 67% (95% CI 65 to 70; 2 studies, 1198 participants; very low‐certainty evidence).

Performed in bubo aspirate, F1RDT‐IPM pooled sensitivity against PCR for the caf1 gene was 95% (95% CI 89 to 99; 1 study, 88 participants; very low‐certainty evidence) and pooled specificity was 93% (95% CI 84 to 98; 1 study, 61 participants; very low‐certainty evidence).

There were no data providing data on both F1RDT and paired serology for diagnosing bubonic plague.

Authors' conclusions
Against culture, the F1RDT appeared highly sensitive for diagnosing either pneumonic or bubonic plague, and can help detect plague in remote areas to assure management and enable a public health response. False positive results mean culture or PCR confirmation may be needed. F1RDT does not replace culture, which provides additional information on resistance to antibiotics and bacterial strains.

Rapid diagnostic tests for plague.

Objectives
This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:

To assess the diagnostic accuracy of near‐patient tests for G6PD deficiency in people undergoing treatment or prophylaxis with primaquine or tafenoquine for malaria; or in people at risk of or susceptible to malaria.

Secondary objectives
To investigate sources of heterogeneity, namely the following.

Age: adults versus children

Sex: male versus female

Reported prevalence of G6PD (high versus low)

Malaria endemicity (endemic versus non‐endemic)

Geographic location (continent of residence; that is, Africa, Asia, or other continent)

Reference standard used (adjusted male median, median G6PD, laboratory standard)

Type of blood used (venous versus capillary)

To compare the accuracy of each type of test.

Martha Chaplin

Papers

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.

Rapid diagnostic tests for plague.

Glucose‐6‐phosphate dehydrogenase deficiency near‐patient tests for tafenoquine or primaquine use with Plasmodium vivax malaria