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Med (N Y) ; 3(4): 233-248.e6, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1882364


Background: Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15). Methods: Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1ß, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints. Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1ß, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients. Conclusions: In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic. Funding: ECSA-2020-009; Elaine Galwey Research Bursary.

COVID-19 , Respiratory Distress Syndrome , alpha 1-Antitrypsin Deficiency , COVID-19/complications , Humans , Interleukin-10/therapeutic use , Interleukin-6/therapeutic use , Interleukin-8/therapeutic use , Respiratory Distress Syndrome/drug therapy , alpha 1-Antitrypsin/therapeutic use , alpha 1-Antitrypsin Deficiency/drug therapy
J Mycol Med ; 32(2): 101252, 2022 May.
Article in English | MEDLINE | ID: covidwho-1665312


BACKGROUND AND AIMS: Published studies on coronavirus disease 19 (COVID-19) associated rhino-orbito-cerebral mucormycosis (CAROCM) were primarily descriptive. Therefore, we aimed to identify features of COVID-19 that could predispose to CAROCM and explore the pathogenic pathways. PATIENTS AND METHODS: This retrospective hospital-based study was done during the first (March 2020 - January 2021) and the second (February 2021 - June 2021) waves of the COVID-19 pandemic. Subjects were grouped into four categories: first-wave CAROCM (n-4); second-wave CAROCM (n-27); first-wave non-mucor COVID (n-75), and second-wave non-mucor COVID (n-50). Data elements included age, gender, comorbidities, COVID-19 severity, steroid therapy, peak values of interleukin-6 (IL-6), serum ferritin and D-dimer, nadir values of absolute lymphocyte count (ALC), absolute neutrophil count (ANC) and platelet count (Pl. C). RESULTS: Thirty-one patients of CAROCM were included. The mean (SD) age was 51.26 (11.48) years. 27 (87.1%) were aged ≥ 40 years and males. Severe COVID-19 was seen more often in the second wave than the first wave (P-0.001). CAROCM group was significantly younger (P-0.008) and showed a higher incidence of uncontrolled diabetes (P-0.001) and renal dysfunction (P-0.004) than non-mucor COVID. While IL-6, ferritin and D-dimer were significantly elevated in CAROCM than non-mucor COVID, clinical severity, ANC, ALC and Pl. C showed no significant difference. CONCLUSION: CAROCM is seen often in middle-aged diabetic males with uncontrolled hyperglycaemia, diabetic ketoacidosis, renal dysfunction and those infected by more transmissible delta variants and treated with steroids. IL-6, D-dimer, serum ferritin are more often elevated in CAROCM and might play a pathogenic role.

COVID-19 , Diabetic Ketoacidosis , Kidney Diseases , Mucormycosis , COVID-19/complications , Ferritins/therapeutic use , Humans , Interleukin-6/therapeutic use , Kidney Diseases/epidemiology , Male , Middle Aged , Mucormycosis/drug therapy , Pandemics , Retrospective Studies , SARS-CoV-2 , Virulence Factors