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Frequency of opportunistic pathogens in Covid-19 and their impact on clinical outcome

Projectomschrijving

Een infectie veroorzaakt door herpesvirussen of de schimmel Aspergillus in de long kunnen voorkomen bij patiënten met ernstig COVID-19. Het blijft onduidelijk hoe vaak dit voorkomt en of dit invloed heeft op de ernst van de ziekte.

Doel

Doel van deze studie is om te onderzoeken hoe vaak een infectie met herpesvirussen of de schimmel Aspergillus voorkomt bij ernstig COVID-19, en of dit invloed heeft op de ernst van de ziekte.

Onderzoeksopzet

Een belangrijke oorzaak voor het ontstaan van ernstig COVID-19 is een schadelijke ontstekingsreactie. In de pandemie werd bekend dat remming van deze ontstekingsreactie gunstig was voor patiënten met ernstig COVID-19. Het risico van deze behandelingen is dat er mogelijk een verhoogde vatbaarheid ontstaat voor herpesinfecties en schimmelinfecties. Middels dit onderzoek willen we antwoord krijgen op hoe vaak een infectie met herpesvirussen of de schimmel Aspergillus voorkomt bij ernstig COVID-19 en of dit invloed heeft op de ernst van de ziekte. Deze uitkomsten zijn nodig om vervolgens te kunnen onderzoeken of het behandelen van deze infecties bij patiënten met COVID-19 zinvol is.

Context

Dit onderzoek is 1 van de studies op het gebied van onderzoek naar optimale medisch-specialistische zorg bij COVID-19. De onderzoeken hebben als doel het beantwoorden van belangrijke kennishiaten op gebied van behandeling. ZonMw faciliteert deze onderzoeken in het COVID-19 deelprogramma Behandeling om een bijdrage te leveren aan het bevorderen van optimale zorg voor COVID-19. De kennishiaten zijn geïdentificeerd door de Multidisciplinaire Wetenschapscommissie COVID-19 van de Federatie Medisch Specialisten (FMS).

Uitvoerende partijen

Radboudumc, Amsterdam UMC – locatie AMC, Erasmus MC

Meer informatie

Hoofdaanvrager: F.L. van de Veerdonk (Radboudumc)
Projectleider en penvoerder: P.E. Verweij (Radboudumc)

Verslagen


Samenvatting van de aanvraag

RESEARCH QUESTION and HYPOTHESIS: With the increased use of immunosuppressive agents to treat Covid-19 we hypothesize a rise in opportunistic infections caused by herpes viruses (Cytomegalovirus (CMV) and Herpes Simplex virus (HSV)) and Aspergillus. The question is what the frequency is of opportunistic infections in patients with severe Covid-19 that underwent BAL and whether this has impact on clinical outcome. DESIGN: We will address our aims through case banked BAL and blood sample collections and information from health records. STUDY POPULATION/DATA SOURCES: The proposal will merge initiatives from UMCs and Radboudumc-RIVM resulting in a total of 6 UMCs (Amsterdam, Rotterdam, Leiden, Utrecht, Groningen and Nijmegen) and 9 non-academic hospitals (Maasstad, Amphia, Ikazia, Medisch Spectrum Twente, Medische Centrum Leeuwarden, Gelre ziekenhuis, Deventer Ziekenhuis, Ziekenhuis Gelderse Vallei and Ziekenhuis Rivierenland). Clinical data, and data from BAL and plasma analysis will be collected and analyzed. INTERVENTION, OUTCOMES and DATA ANALYSIS are structured in 3 workpackages (WPs): WP1: To determine the frequency of opportunistic pathogens in the lower respiratory tract in ventilated patients with Covid-19. Background: In this WP we will investigate how often and to what extend HSV, CMV and Aspergillus are present in BALs collected from patients with Covid-19 in the ICU. Intervention: For CMV and HSV: viral loads in BALs will be determined by qPCR, and a subset will be analyzed for % HSV/CMV positive cells and cell types positive for HSV/CMV. For fungal diagnostics we will determine: Aspergillus culture, BAL galactomannan (GM), Aspergillus PCR, azole resistance PCR. In serum HSV/CMV load and GM, Beta-D glucan and Aspergillus PCR will be performed. Outcome: Identification of four groups: 1. No evidence for opportunistic infection, 2) HSV and/or CMV, 3) Aspergillus and 4) both HSV and/or CMV and Aspergillus. We will also have determined the frequency of HSV/CMV and/or Aspergillus in BAL in Covid-19 patients in the ICU. WP2: To define whether immunosuppressive therapy and disease profiles based on host-pathogen factors (HPFs) are associated with the risk of opportunistic infection. Background: Here we will investigate all the factors that we propose to be contributing to the opportunistic infection (figure 1). This includes predisposing factors, SARS-CoV-2 virus itself, the host immune response, and immunomodulatory treatment. Intervention: Determine viral loads of SARS-CoV-2 in BALs, collection of systemic host parameters: lymphocyte count, neutrophils, monocytes, ferritin, D-Dimer, CRP and procalcitonine. Evaluate systemic and local host response using Luminex panels (R&D Systems) on plasma and BAL with 63 biomarkers including: TNF, IL-6, IL17 and caspase dependent inflammatory pathways, endothelial injury, alveolar type 1 and 2 injury. This data will then further be categorized into 3 groups reflecting the immunomodulatory treatment periods, namely without dexamethasone or IL-6 blockade, with only dexamethasone, and with dexamethasone and IL-6 Blockade. Outcome: Quantify the association between host-pathogen factors and the development of opportunistic infections in patients with or without immunosuppression. WP3: To explore whether opportunistic infections and these disease profiles are associated with worse clinical outcome. Background: A key question is whether the opportunistic infections are associated with worse clinical outcome. We will also investigate whether immunosuppression contributes to increased frequency of opportunistic infection and if opportunistic infections are associated with specific disease profiles determined by host-pathogen factors, and how much these factors contribute to clinical outcome. Intervention: We will analyze the data collected from WP2 and WP3 and compare the different groups as described in WP1 and WP2 for clinical outcome including length of stay in the ICU and mortality. Since outcomes in the ICU are determined not only by respiratory status, we will take the sequential organ failure score (SOFA) into account as covariate. Outcome: Quantify the association between HSV, CMV and CAPA with clinical outcomes. To identify a mediating effect of host-pathogen factors and immunosuppressive treatment on this association. SAMPLE SIZE CALCULATION and DATA-ANALYSIS: We aim to collect BAL samples from 100 patients without immunosupression, 350 patients with dexamethasone, and 100 patients with dexamethasone and Il-6 blockade. During the 1st period bronchoscopy was largely restricted due to the risk of aerosolization. For statistical Analysis we will seek expert guidance but in short, incidence of the different outcomes will be estimated using Kaplan-Meier methods and factors associated with these outcomes will be evaluated using multivariate Cox proportional hazards regression.

Onderwerpen

Kenmerken

Projectnummer:
10430102110011
Looptijd: 88%
Looptijd: 88 %
2022
2024
Onderdeel van programma:
Projectleider en penvoerder:
Prof. dr. P.E. Verweij
Verantwoordelijke organisatie:
Radboud Universitair Medisch Centrum