PCOM Library / Hot Topics in Research / Internal Medicine / Archive for "Infectious Disease"

Category: Infectious Disease

Hot Topics: Antimalarial Drug Decreases Covid-19 Patient Survival

Jackie Werner Hot Topics in Research, Infectious Disease, Pharmaceutical Sciences

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis. The Lancet. https://doi.org/10.1016/S0140-6736(20)31180-6.

Background

Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

Methods

We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation).

Findings

96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.

Interpretation

We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

Hot Topics: Loss of Smell May Mean Less Severe COVID-19

Jackie Werner Hot Topics in Research, Infectious Disease

Self‐reported olfactory loss associates with outpatient clinical course in Covid‐19

Yan CH, Faraji F, Prajapati DP, Ostrander BT, DeConde AS. Self-reported olfactory loss associates with outpatient clinical course in covid-19. Int Forum Allergy Rhinol. 2020. https://doi.org/10.1002/alr.22592.

Background

Rapid spread of the SARS‐CoV‐2 virus has left many health systems around the world overwhelmed, forcing triaging of scarce medical resources. Identifying indicators of hospital admission for Covid‐19 patients early in the disease course could aid the efficient allocation of medical interventions. Self‐reported olfactory impairment has recently been recognized as a hallmark of Covid‐19 and may be an important predictor of clinical outcome.

Methods

A retrospective review of all patients presenting to a San Diego Hospital system with laboratory‐confirmed positive Covid‐19 infection was conducted with evaluation of olfactory and gustatory function and clinical disease course. Univariable and multivariable logistic regression were performed to identify risk factors for hospital admission and anosmia.

Results

A total of 169 patients tested positive for Covid‐19 disease between March 3 and April 8, 2020. Olfactory and gustatory data were obtained for 128/169 (75.7%) subjects of which 26/128 (20.1%) required hospitalization. Admission for Covid‐19 was associated with intact sense of smell and taste, increased age, diabetes, as well as subjective and objective parameters associated with respiratory failure. On adjusted analysis, anosmia was strongly and independently associated with outpatient care (aOR 0.09 95% CI: 0.01‐0.74) while positive findings of pulmonary infiltrates and/or pleural effusion on chest radiograph (aOR 8.01 95% CI: 1.12‐57.49) was strongly and independently associated with admission.

Conclusions

Normosmia is an independent predictor of admission in Covid‐19 cases. Smell loss in Covid‐19 may associate with a milder clinical course.

Hot Topics: Race and Class Affect COVID-19 Risk

Jackie Werner Hot Topics in Research, Infectious Disease, Public Health

Disparities in the Population at Risk of Severe Illness From COVID-19 by Race/Ethnicity and Income

Raifman M, Raifman J. Disparities in the population at risk of severe illness from COVID-19 by race/ethnicity and income. American Journal of Preventive Medicine. 2020. https://doi.org/10.1016/j.amepre.2020.04.003.

Identifying those at heightened risk of severe illness from novel coronavirus disease 2019 (COVID-19) is essential for modeling disease, designing return-to-work criteria, allocating economic assistance, advancing health equity, and limiting morbidity and mortality. The U.S. Centers for Disease Control and Prevention has identified criteria associated with risk of severe complications from COVID-19 infection. Structural inequities have shaped racial, ethnic, and income disparities for many of these criteria. To date, there has been limited analysis of the proportion of the population at risk in the U.S. based on these criteria, or risk factors by race/ethnicity or income. Preliminary national data on cases by race/ethnicity suggest that disparities in hospitalization are already developing. Quantifying disparities in risk is important for allocating resources to prevent, identify, and treat COVID-19-related severe illness and limit diverging outcomes for already vulnerable subgroups.

Hot Topics: Existing Drugs May Fight Coronavirus

Jackie Werner Hot Topics in Research, Infectious Disease

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen PI, Ianevski A, Lysvand H, et al. Discovery and development of safe-in-man broad-spectrum antiviral agents. Int J Infect Dis. 2020. https://doi.org/10.1016/j.ijid.2020.02.018

Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and re-emerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 119 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.

Hot Topics: Color-Changing Bandages Treat Infection

Jackie Werner Hot Topics in Research, Infectious Disease

Colorimetric Band-aids for Point-of-Care Sensing and Treating Bacterial Infection

Sun Y, Zhao C, Niu J, Ren J, Qu X. Colorimetric band-aids for point-of-care sensing and treating bacterial infection. ACS Cent Sci. 2020. https://doi.org/10.1021/acscentsci.9b01104.

Sensing bacterial infections and monitoring drug resistance are very important for the selection of treatment options. However, the common methods of sensing resistance are limited by time-consuming, the requirement for professional personnel, and expensive instruments. Moreover, the abuse of antibiotics causes the accelerated process of bacterial resistance. Herein, we construct a portable paper-based band-aid (PBA) which implements a selective antibacterial strategy after sensing of drug resistance. The colors of PBA indicate bacterial infection (yellow) and drug resistance (red), just like a bacterial resistance colorimetric card. On the basis of color, antibiotic-based chemotherapy and Zr-MOF PCN-224-based photodynamic therapy (PDT) are used on site to treat sensitive and resistant strains, respectively. Eventually, it takes 4 h to sense, and the limit of detection is 104 CFU/mL for drug-resistant E. coli. Compared with traditional PDT-based antibacterial strategies, our design can alleviate off-target side effects, maximize therapeutic efficacy, and track the drug resistance in real time with the naked eye. This work develops a new way for the rational use of antibiotics. Given the low cost and easy operation of this point-of-care device, it can be developed for practical applications.

Hot Topics: Neurotoxin Targets Malaria Mosquitos

Jackie Werner Hot Topics in Research, Infectious Disease

A neurotoxin that specifically targets Anopheles mosquitoes

Contreras E, Masuyer G, Qureshi N, et al. A neurotoxin that specifically targets anopheles mosquitoes. Nature Communications. 2019;10(1):2869. https://doi.org/10.1038/s41467-019-10732-w.

Clostridial neurotoxins, including tetanus and botulinum neurotoxins, generally target vertebrates. We show here that this family of toxins has a much broader host spectrum, by identifying PMP1, a clostridial-like neurotoxin that selectively targets anopheline mosquitoes. Isolation of PMP1 from Paraclostridium bifermentans strains collected in anopheline endemic areas on two continents indicates it is widely distributed. The toxin likely evolved from an ancestral form that targets the nervous system of similar organisms, using a common mechanism that disrupts SNARE-mediated exocytosis. It cleaves the mosquito syntaxin and employs a unique receptor recognition strategy. Our research has an important impact on the study of the evolution of clostridial neurotoxins and provides the basis for the use of P. bifermentans strains and PMP1 as innovative, environmentally friendly approaches to reduce malaria through anopheline control.

Hot Topics: Online Intervention May Decrease HIV Risk

Jackie Werner Hot Topics in Research, Infectious Disease, Psychology and Psychiatry

Acceptability and Preliminary Efficacy of an Online HIV Prevention Intervention for Single Young Men Who Have Sex with Men Seeking Partners Online: The myDEx Project

Bauermeister JA, Tingler RC, Demers M, et al. Acceptability and preliminary efficacy of an online HIV prevention intervention for single young men who have sex with men seeking partners online: The myDEx project. AIDS and Behavior. 2019. https://doi.org/10.1007/s10461-019-02426-7.

Prevention of new cases of HIV among young gay, bisexual and other men who have sex with men (YGBMSM; ages 18–24) remains a priority. We developed and pilot tested an online intervention (myDEx) using a pilot randomized trial design with 180 online-recruited single YGBMSM who reported recent unprotected anal intercourse, self-reporting as HIV negative or status-unaware, and who met sexual partners through online dating applications. myDEx participants reported higher overall satisfaction (d = 0.46) and willingness to recommend the intervention to friends (d = 0.48) than controls. myDEx participants were less likely to report foregoing condoms to achieve an emotional connection with a partner (d =0 .43), and more likely to report greater emotional regulation during their partner-seeking behaviors (d = 0.44). myDEx participants reported fewer partners with whom they had condomless receptive anal sex (d = 0.48). Our pilot results demonstrate the potential of the myDEx intervention, suggesting that a larger efficacy trial may be warranted in the future.

Hot Topics: Flu Vaccine Antibodies Inhibit Two Viral Proteins

Jackie Werner Hot Topics in Research, Infectious Disease

Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies

Kosik I, Angeletti D, Gibbs JS, et al. Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies. J Exp Med. 2019. dx.doi.org/10.1084/jem.20181624.

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice, likely due at least in part to NA-mediated inhibition of FcγR-dependent activation of innate immune cells by Ab bound to virions. Food and Drug Administration–approved NA inhibitors enhance anti-stem–based Fc-dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.

Hot Topics: New Drug Found Effective for Influenza

Jackie Werner Hot Topics in Research, Infectious Disease, Pharmaceutical Sciences

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379(10):913-923. https://doi.org/10.1056/NEJMoa1716197.

BACKGROUND

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

METHODS

We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

RESULTS

In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.

CONCLUSIONS

Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed.

Hot Topics: Flu May Be Spread By Breathing

Jackie Werner Hot Topics in Research, Infectious Disease

Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community

Yan J, Grantham M, Pantelic J, et al. Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community. Proc Natl Acad Sci USA. 2018. doi: 10.1073/pnas.1716561115

Little is known about the amount and infectiousness of influenza virus shed into exhaled breath. This contributes to uncertainty about the importance of airborne influenza transmission. We screened 355 symptomatic volunteers with acute respiratory illness and report 142 cases with confirmed influenza infection who provided 218 paired nasopharyngeal (NP) and 30-minute breath samples (coarse >5-µm and fine ≤5-µm fractions) on days 1–3 after symptom onset. We assessed viral RNA copy number for all samples and cultured NP swabs and fine aerosols. We recovered infectious virus from 52 (39%) of the fine aerosols and 150 (89%) of the NP swabs with valid cultures. The geometric mean RNA copy numbers were 3.8 × 104/30-minutes fine-, 1.2 × 104/30-minutes coarse-aerosol sample, and 8.2 × 108 per NP swab. Fine- and coarse-aerosol viral RNA were positively associated with body mass index and number of coughs and negatively associated with increasing days since symptom onset in adjusted models. Fine-aerosol viral RNA was also positively associated with having influenza vaccination for both the current and prior season. NP swab viral RNA was positively associated with upper respiratory symptoms and negatively associated with age but was not significantly associated with fine- or coarse-aerosol viral RNA or their predictors. Sneezing was rare, and sneezing and coughing were not necessary for infectious aerosol generation. Our observations suggest that influenza infection in the upper and lower airways are compartmentalized and independent.