Immunomodulating Agents

Background

Coronavirus disease 2019 (COVID–19) is responsible for a worldwide need for hospital care, and a substantial proportion of these patients also need admission to an intensive care unit for escalation of care, which is usually respiratory support. Since the start of the pandemic, many treatments have been tested, all of which having the potential to improve outcome of COVID–19 patients (1-5). Especially within the field of immunomodulating strategies, the number of agents is rapidly increasing. By now, dexamethasone is standard care for all hospitalized COVID–19 patients, and tocilizumab is suggested for critically ill patients with evidence of a hyperinflammatory response (6, 7). It remains uncertain whether immunomodulating strategies like chloroquine and convalescent plasma also have the potential to improve outcomes (8, 9). It is unclear how all these strategies were used during the second wave of the COVID–19 pandemic in the Netherlands, and if these treatments had an association with outcome.

Methods

Design

This is a predefined analysis of the PRoAcT–COVID study, a multicenter, retrospective, observational cohort study in COVID–19 patients with respiratory failure requiring invasive ventilation in hospitals in the Netherlands in the second wave of the national outbreak (10). PRoAcT–COVID is an investigator–initiated study, the study protocol of which was approved by local institutional Review Board of Amsterdam UMC (location ‘AMC’) and registered at clinicaltrials.gov (study identifier NCT04719182).

Patients

Patients were eligible if admitted to an ICU of a participating hospital between September 2020 and January 2021 for COVID–19 confirmed by RT–PCR. The study also enrolled patients outside of ‘physical’ ICUs, in seldom cases a patient received accelerated care from intensivists at other locations within a hospital, like in an operating room, a post–anesthesia care unit or another ‘emergency setting’. Patients were excluded if aged < 18 years. There were no other exclusion criteria.

Exposure

The exposure of interest is use of immunomodulating agents.

Endpoints

The primary endpoint is the practice of immunomodulating strategies, including the incidence, start date, dose, and duration. Secondary endpoints are typical complications in the ICU, including acute renal failure, need for renal replacement therapy, gastro–intestinal bleeding, deep venous thrombosis and pulmonary embolism, and tracheostomy. Other endpoints are duration of high–flow oxygen therapy, noninvasive and invasive ventilation, length of stay in ICU and hospital, and mortality in the ICU, the hospital, and at day 28.

Statistical analysis plan

Descriptive statistics are used to report baseline characteristics. Data are reported as numbers and relative proportions for categorical variables, and as medians with interquartile ranges for continuous variables. To compare baseline characteristics between patients receiving different immunomodulating strategies, a Mann-Whitney U test will be performed for numerical variables and a Fisher’s exact test will be used for categorical variables, if two groups are compared. If more than two groups are compared, a Kruskal Wallis test will be used for numerical variables and a Chi-square test will be used for categorical variables.

For each immunomodulating treatment, incidence, day of start treatment, dose, and duration will be reported. Day of start treatment is defined as number of days between admission and start of treatment. Dose is reported as cumulative dose of treatment per day. This analysis focuses on chloroquine, hydroxychloroquine, interferon, aprepitant, colchicine, immunoglobulin, ivermectin, ruxolitinib, telmisartan, tocilizumab and convalescent plasma.

To determine the association between immunomodulating strategies and mortality, a cox proportional hazards model will be used with center of treatment as shared frailty component. The following variables will be included as covariates: age, gender, body mass index, PaO2, plasma creatinine, medical history of hypertension, heart failure, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, active hematological neoplasia and/or active solid tumor, use of angiotensin converting enzyme inhibitors, use of angiotensin II receptor blockers, fluid balance and heart rate. This analysis will be limited to immunomodulating strategies that were used in more than ten percent of the total number of participants.

A competing risk model will be used to analyse the probability of extubation and probability of ICU discharge. In this competing risk model, death will be treated as the competing event. The same covariates will be included as for the cox proportional hazards model analysis.

All analyses will be run in R v.4.0.4 and a p value < 0.05 will be considered statistically significant.

References

1. Armstrong RA, Kane AD, Cook TM. Outcomes from intensive care in patients with COVID-19: a systematic review and meta-analysis of observational studies. Anaesthesia. 2020;75(10):1340-9.

2. Dennis JM, McGovern AP, Vollmer SJ, Mateen BA. Improving Survival of Critical Care Patients With Coronavirus Disease 2019 in England: A National Cohort Study, March to June 2020. Crit Care Med. 2021;49(2):209-14.

3. Docherty AB, Mulholland RH, Lone NI, Cheyne CP, De Angelis D, Diaz-Ordaz K, et al. Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK. Lancet Respir Med. 2021;9(7):773-85.

4. Lambermont B, Rousseau AF, Seidel L, Thys M, Cavalleri J, Delanaye P, et al. Outcome Improvement Between the First Two Waves of the Coronavirus Disease 2019 Pandemic in a Single Tertiary-Care Hospital in Belgium. Crit Care Explor. 2021;3(5):e0438.

5. Roth GA, Emmons-Bell S, Alger HM, Bradley SM, Das SR, de Lemos JA, et al. Trends in Patient Characteristics and COVID-19 In-Hospital Mortality in the United States During the COVID-19 Pandemic. JAMA Netw Open. 2021;4(5):e218828.

6. Tuinman PR TvdL, Nossent G, Endeman R, Hoeven van der H. Leidraad Corticosteroïden bij de behandeling van COVID-19. Federatie Medisch specialisten. 2020.

7. Vollaard A GE, Lange de D, Boersma W, Linden van der P, Sinha B, Boer de M. [Medical treatment for patients with COVID-19 (infection with SARS-CoV-2)] Stichting Werkgroep Antibioticabeleid. 2021.

8. Cunningham AC, Goh HP, Koh D. Treatment of COVID-19: old tricks for new challenges. Crit Care. 2020;24(1):91.

9. Vollaard A, Gieling EM, van der Linden PD, Sinha B, de Boer MGJ. [Hydroxychloroquine and chloroquine for COVID-19: no evidence of effectiveness]. Ned Tijdschr Geneeskd. 2020;164.

10. Valk CMA, Swart P, Boers LS, Botta M, Bos LDJ, de Abreu MG, et al. Practice of adjunctive treatments in critically ill COVID-19 patients-rational for the multicenter observational PRoAcT-COVID study in The Netherlands. Ann Transl Med. 2021;9(9):813.