Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials

EClinicalMedicine · 2024 · 8 citations

• Medicine
• Intensive care medicine
• Internal medicine

Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Immunogenetics associated with severe coccidioidomycosis

JCI Insight · 2022 · 52 citations

• Medicine
• Immunology
• Computational biology

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial

The Lancet · 2022 · 165 citations

• Medicine
• Internal medicine
• Surgery

Coronavirus Disease 2019–Associated Invasive Fungal Infection

Open Forum Infectious Diseases · 2021 · 108 citations

• Medicine
• Immunology
• Intensive care medicine

Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19-associated fungal infections.

Coccidioidomycosis

Infectious Disease Clinics of North America · 2021 · 91 citations

• Medicine
• Intensive care medicine
• Dermatology

Investigation of nosocomial SARS-CoV-2 transmission from two patients to healthcare workers identifies close contact but not airborne transmission events

Infection Control and Hospital Epidemiology · 2020 · 25 citations

• Computer Science
• Medicine
• Virology

OBJECTIVE: To describe the pattern of transmission of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) during 2 nosocomial outbreaks of coronavirus disease 2019 (COVID-19) with regard to the possibility of airborne transmission. DESIGN: Contact investigations with active case finding were used to assess the pattern of spread from 2 COVID-19 index patients. SETTING: A community hospital and university medical center in the United States, in February and March, 2020, early in the COVID-19 pandemic. PATIENTS: Two index patients and 421 exposed healthcare workers. METHODS: Exposed healthcare workers (HCWs) were identified by analyzing the electronic medical record (EMR) and conducting active case finding in combination with structured interviews. Healthcare coworkers (HCWs) were tested for COVID-19 by obtaining oropharyngeal/nasopharyngeal specimens, and RT-PCR testing was used to detect SARS-CoV-2. RESULTS: Two separate index patients were admitted in February and March 2020, without initial suspicion for COVID-19 and without contact or droplet precautions in place; both patients underwent several aerosol-generating procedures in this context. In total, 421 HCWs were exposed in total, and the results of the case contact investigations identified 8 secondary infections in HCWs. In all 8 cases, the HCWs had close contact with the index patients without sufficient personal protective equipment. Importantly, despite multiple aerosol-generating procedures, there was no evidence of airborne transmission. CONCLUSION: These observations suggest that, at least in a healthcare setting, most SARS-CoV-2 transmission is likely to take place during close contact with infected patients through respiratory droplets, rather than by long-distance airborne transmission.

Leukoerythroblastic reaction in a patient with <scp>COVID</scp>‐19 infection

American Journal of Hematology · 2020 · 99 citations

• Medicine
• Internal medicine
• Gastroenterology

A 46-year-old previously healthy female developed flu-like symptoms several days prior to presenting to a local hospital. The patient did not note a recent travel history, specifically denying travel to China. Sick contact exposure was not known. Chest X-ray and computed tomography of the chest showed findings concerning for lobar pneumonia. Subsequent radiology studies showed worsening lung findings along with worsening respiratory symptoms necessitating intubation and ventilation. She was transferred to a university hospital due to the need for an elevated level of care. Upon arrival to the university hospital, it was confirmed that the patient was positive for the novel Corona virus disease 2019 (COVID-19). Her initial complete blood count (CBC) showed a normal leukocyte count (7.3 × 103/μL) with lymphopenia (200/μL), normocytic anemia (hemoglobin = 10.4 g/dL), and a normal platelet count (213 × 103/μL). Three days after admission to the university hospital (approximately one week after initial hospital admission) the patient developed leukocytosis (14.1 × 103/μL), with a left-shifted population of neutrophilic cells, prompting peripheral blood smear evaluation. Mild monocytosis (900/μL) along with the persistent lymphopenia was also noted. The peripheral blood smear was consistent with a leukoerythroblastic picture with normocytic anemia with occasional nucleated red blood cells (Image 1A), mild anisocytosis, and rare dacrocytes. Schistocytes were absent. Neutrophilia with left shifted myeloid cells, including occasional myelocytes and rare promyelocytes were noted (Image 1B-D). Lymphopenia was confirmed with many smudge cells seen. Platelets were adequate with some large platelets seen. Leukoerythroblastic reactions, defined as immature erythroid and immature myeloid cells circulating in the peripheral blood, are uncommon. Leukoerythroblastic blood findings are typically seen in disorders associated with bone marrow fibrosis including myelofibrosis and other myeloproliferative disorders, and cancers with metastatic disease to the bone marrow. Leukoerythroblastosis can rarely be seen in viral infections such as parvovirus.1, 2 Corona virus disease 2019 (COVID-19) is an infectious viral disease caused by a pathogen named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).3 Note, COVID-19 has created a public health emergency in many countries, including the United States, and is expected to continue to spread. Few strains of corona virus are known to cause flu-like upper respiratory illnesses in humans, but the current strain, SARS-CoV-2, was not known to cause any human illnesses prior to this outbreak. Thus, very little information about COVID-19's pathogenic role in humans is known. Other coronaviruses have been previously found responsible for infection in both animals and humans, including the viruses responsible for the Middle East Respiratory Syndrome (MERS-CoV)4 and severe acute respiratory syndrome (SARS-CoV).5 Most of the patient morbidity and mortality attributable to COVID-19 has been reported in Wuhan, China.6 Other patients with symptoms of severe infection have now been reported in South Korea, Italy, German, and Iran among others. Following the recent availability of COVID-19 testing, it is likely the number of diagnosed cases will significantly increase. Our understanding of this novel virus continues to evolve. The spectrum of disease, clinical manifestations, and pathophysiology underpinning this infection will be further elucidated over the coming months. Although we are only reporting the findings of a single patient with COVID-19, our aim is to describe the unusual finding of leukoerythroblastosis in this viral infection. We cannot definitively conclude that our findings are secondary to infection with COVID-19. However, following clinical improvement, the neutrophilia has resolved with the other blood findings slowly improving. With our description of these findings, it is our hope to avoid additional work-up and diagnostic testing in other patients with COVID-19, as well as contribute to our understanding of this novel infection.

Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium

The Journal of Infectious Diseases · 2020 · 157 citations

• Political Science
• Medicine
• Microbiology

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.

Natural History of Disseminated Coccidioidomycosis: Examination of the Veterans Affairs–Armed Forces Database

Clinical Infectious Diseases · 2020 · 42 citations

• Medicine
• Internal medicine
• Immunology

BACKGROUND: The natural history of non-central nervous system (non-CNS) disseminated coccidioidomycosis (DCM) has not been previously characterized. The historical Veterans Affairs (VA)-Armed Forces coccidioidomycosis patient group provides a unique cohort of patients not treated with standard antifungal therapy, allowing for characterization of the natural history of coccidioidomycosis. METHODS: We conducted a retrospective study of 531 VA-Armed Forces coccidioidomycosis patients diagnosed between 1955-1958 and followed to 1966. Groups were identified as non-DCM (462 patients), DCM (44 patients), and CNS (25 patients). The duration of the initial infection, fate of the primary infection, all-cause mortality, and mortality secondary to coccidioidomycosis were assessed and compared between groups. RESULTS: Mortality due to coccidioidomycosis at the last known follow-up was significantly different across the groups: 0.65% in the non-DCM group, 25% in the DCM group, and 88% in the CNS group (P < .001). The primary fate of pulmonary infection demonstrated key differences, with pulmonary nodules observed in 39.61% of the non-DCM group, 13.64% of the DCM group, and 20% of the CNS group (P < .001). There were differences in cavity formation, with 34.20% in the non-DCM group, 9.09% in the DCM group, and 8% in the CNS group (P < .001). Dissemination was the presenting manifestation or was concurrent with the initial infection in 41% and 56% of patients in the non-CNS DCM and CNS groups, respectively. CONCLUSIONS: This large, retrospective cohort study helps characterize the natural history of DCM, provides insight into the host immunologic response, and has direct clinical implications for the management and follow-up of patients.