The risk for severe COVID 19 in patients with autoimmune and/or inflammatory diseases: First wave lessons

Abstract Data regarding the risk for severe COVID19 in patients with autoimmune or inflammatory diseases are scarce. To estimate the risk of those patients to develop a more severe COVID19 infection All active patients and those with dermatologic and/or rheumatologic autoimmune/inflammatory diseases were identified in a single tertiary center. The charts of those tested positive for COVID19 between 1 March 2020 and 31 May 2020 reviewed including demographics, co‐morbidities, and medications. COVID19 outcome of those with dermatologic and/or rheumatologic autoimmune/inflammatory diseases were compared to COVID19 infected matched controls without an autoimmune/inflammatory background. Overall, 974 of 381 268 active patients were tested positive for COVID19, including 35 out of 13 225 with dermatologic and/or rheumatologic autoimmune/inflammatory diseases. No statistically significant difference in severity of COVID19 infection or mortality rate was found. The rate of asymptomatic, mild, moderate, severe/critical and fatal COVID19 infection was 11.4%, 37.1%, 22.8%, 11.4%, and 17.1%, respectively, for the patients with autoimmune diseases and 17.8%, 45.8%, 10.9%, 6.8%, and 18.4%, respectively for the controls . Patients with autoimmune/inflammatory diseases seem not to develop a more severe COVID19 infection than controls.


| INTRODUCTION
The COVID-19 pandemic, caused by the SARS CoV2 virus, is an ongoing worldwide medical challenge. The lack of specific treatment or vaccine has led to epidemiological research efforts in order to characterize patients at risk for developing severe infection. 1,2 So far, the established risk groups for higher severity and mortality rate of COVID-19 infection are elderly people and those with underlying medical co-morbidities such as hypertension and obesity. 3,4 Patients with autoimmune and/or inflammatory diseases (AID) are a group of special interest regarding their risk for severe COVID19 as they are considered at a potential increased risk of infection because of their underlying disease coupled with the immunosuppressive therapy needed to control it. 5 On the other hand, some immunomodulatory drugs used to treat different autoimmune diseases are being studied as treatments for severe COVID19 infection 6 rendering patients on these therapies protected, in theory at least, from developing the "cytokine storm" associated with this virus.
Thus, human CoV infections might have a dual influence: while they may trigger an immune response leading to viral clearance in the early stages of the infection, at later stage the secondary immune response may be exaggerated ("cytokine storm"), leading to pneumonitis, acute respiratory distress syndrome, organ failure, and potentially death. 7 The current data regarding the risk of patients with AID to contract the SARS CoV2 virus and/or develop severe disease are insufficient and guidelines on treating patients with AID 8,9 are based on limited experience from current and past pandemics alongside theoretical assumptions. Autoimmunity and/or immune-suppression has not, to date, been implicated as a risk factor for contracting SARS CoV2 10 or for severer COVID19 infection. 1 The largest series to date includes 600 patients from multiple countries with autoimmune rheumatic diseases 11 have shown that the majority of those patients recover from COVID-19. In this series older age, comorbidities and prednisone use ≥10 mg/day were associated with higher odds of hospitalization. On the other hand, anti-TNFα treatment was associated with reduced odds of hospitalization suggesting in fact that anticytokine therapy may have a protective role from severe COVID-19 infection.
In the current study, we describe a cohort of patients with AID from a single institution and compare those of them infected with SARS CoV2 to patients without AID, infected during the same period.

| MATERIALS AND METHODS
This was a single center study performed at the Sheba Medical Center-a 1400 bed tertiary hospital located in central Israel, where 381 268 patients were actively treated and/or followed up over the last 2 years. A subset of patients with a diagnosis of dermatologic and/or rheumatologic AID, commonly treated with immunosuppressive medications were defined. Their data collected from the comput- moderate-presence of the pulmonary infiltrate; severe-breath rate over 30/minute or O 2 saturation < 93% or Pao 2 /FIO 2 < 300 or pulmonary infiltrate progression to more than 50% of the lungs in 24-48 hours; critical-need for ventilation and/or vasopressors and/or ECMO support.
Institutional review board approval was obtained and patient consent was waived due to the non-interventional nature of the study.
Quantitative and parametric parameters were compared using a two-tailed t test and Fisher's exact test, respectively. To assess variables associated with severe COVID19, a multivariate Cox proportional hazards regression model was applied. An exploratory decision  infection was age, contributing almost 60% to the prediction in our cohort, followed by diabetes, malignancy and obesity, with other variables contributing less than 5% each. When using different subgroups created by the decision tree model to calculate the OR for severe/critical or fatal COVID19 according to the presence or absence of an AID, we did not find a statistically significant increased risk in patients with an AID.

| DISCUSSION
The established risk groups for higher severity and mortality rate of COVID-19 infection are elderly people and those with underlying medical co-morbidities. 3,4 Most rheumatologic and several cutaneous immunemediated diseases, are treated with biologic and non-biologic immunosuppressive and immune-modulatory drugs increasing the risk for various infectious diseases. 5 Thus, at least theoretically, those patients are at higher risk of infection and/or worse course of the COVI19 disease. In addition, AID patients have a higher incidence of comorbidities, for example, metabolic syndrome and ischemic heart disease putting them at increased risk for severe infection. 13,14 Recommendations from dermatology and rheumatology societies so far 8,9,[15][16][17] mostly suggested COVID-19 infected patients to discontinue or postpone immunosuppressive or biologic therapy, while the decision to stop or withhold treatment in the uninfected, was left to the treating physician judgment. Those recommendations based on limited experience from current and past pandemics, and mostly on intuition taking into account the mechanism of immune-modulatory therapy with a possible dual influence. 7 Our study suggests that having an AID per se is not, by itself, a risk factor for acquiring COVID19 infection since only 35 of 13 225 (0.3%) active AID patients in our institution were diagnosed. It is true, that asymptomatic and mild cases might have been missed. However, the latter would have no clinical, but only epidemiological significance.
It is also possible (though unlikely due to the local medical system structure) that a small number of our infected patients were diagnosed outside our center. Similarly, the AID patients could possibly be more precocious, compared to general population, thus having a lower chance to be infected and/or to acquire a smaller amount of COVID Further large-scale studies and meta-analyses are needed in order to clarify the risk of patients with AIDs and/or immune-modulatory therapy for severe COVID19.

CONFLICT OF INTEREST
None of the corresponding authors has any conflict of interest or funding sources related to this article.

AUTHOR CONTRIBUTIONS
All authors have made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data and been involved in revising it critically and given final approval of the version to be published. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work appropriately investigated and resolved.

DATA AVAILABILITY STATEMENT
Data derived from public domain resources.