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What Is “Severe” COVID-19, and Are the Immunocompromised at Greater Risk?

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Christopher J. Lehmann, MD

Fellow Physician
Section of Infectious Diseases and Global Health
Department of Medicine
University of Chicago Medicine
Chicago, Illinois


Christopher Lehmann, MD, has no relevant conflicts of interest to report.


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Gregory Olson, MD

Clinical Instructor
Fellow

Department of Infectious Diseases
University of Chicago Medical Center
Chicago, Illinois


Gregory Olson, MD, has no relevant conflicts of interest to report.


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Renslow Sherer, MD

Director, International HIV Training Center
Professor of Medicine
University of Chicago
Chicago, Illinois


Renslow Sherer, MD, has no relevant conflicts of interest to report.


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Released: June 10, 2021

This report is dedicated to the medical students and other healthcare trainees around the world who have responded so heroically to the COVID-19 pandemic. In many cases, they accepted great personal risk and far too many developed COVID-19 and died. At the University of Chicago, medical students served 1615 ambulatory patients with COVID-19 in spring 2020, accepting a high degree of personal risk. Their many contributions included staffing free community primary care clinics, developing service innovations such as 3D printing of nasal swabs and low energy positive pressure devices for resource limited settings, and joining other basic and clinical research studies.

One such research study addressed whether immunosuppressed patients—eg, transplant recipients and patients with HIV or cancer—were more likely to die from severe COVID-19 illness. Of the first 401 patients with COVID-19 admitted to our hospital—the University of Chicago—between March and May 2020, 168 (40%) met the standard definition of “severe” illness based on oxygenation levels, and 111 (28%) were immunocompromised.

Several features were of interest in this cohort including the high proportion of Black patients (90%), low use of steroids (6%), high frequency of remdesivir use (31%), low intubation rate (17%), and the 30-day mortality rate of 13% (that compared favorably with early reports from COVID-19 cohorts in New York, Detroit, and the UK).

The investigators found no increase in the incidence of severe illness among the immunocompromised patients compared with other patients. As many analyses have shown, the strongest predictors of severe COVID-19 illness were being older than 70 years of age and/or having comorbidities such as diabetes, hypertension, and chronic kidney disease. The authors concluded that larger cohorts were needed to tease out susceptibility to severe COVID-19 illness among people with each form of immunocompromise in this heterogeneous group.

Larger Cohorts
Data are emerging from such large cohorts. The first report from the Veterans Aging Cohort Study (a cohort of >40,000 veterans with HIV and a 1:2 age/race/site-matched sample controls without HIV) found no evidence of greater mortality, intubation, or hospitalization among 253 patients with HIV (PWH) with SARS-CoV-2 infection compared with others. Recently, another large US cohort of PWH found a greater susceptibility to severe COVID-19 among those with CD4+ cell counts <200 cells/mm³.

The largest multicenter study undertaken so far has examined 2932 PWH, 4633 patients with solid organ transplant, and 111 patients with both. After adjustment for age, sex, race/ethnicity, and comorbidities, the authors found a higher risk of hospitalization in patients with immunocompromise: a 21% higher risk in PWH, a 55% higher risk in people with solid organ transplant, and a 67% higher risk in people with both HIV and a transplant, compared with patients without HIV or solid organ transplant (P ≤.03). Similarly, the risk of mechanical ventilation was 50% greater in PWH, 2 times greater in solid organ transplant recipients, and 3 times greater in patients with both. 

Who Is at Greater Risk for Severe Illness?
Taken together, these studies suggest that the risk of severe COVID-19 varies with and within the specific form of immunosuppression. PWH with higher CD4+ cell counts and stable antiretroviral therapy and survivors of solid organ cancer appear to have no greater risk than the general population. On the other hand, PWH with low CD4+ cell counts, people with solid organ transplant, or people with hematologic malignancies appear to be more susceptible to severe illness and death. Larger cohorts with longer duration of follow-up are still needed to distinguish among other forms of immunosuppression, for example, stem cell transplantation. 

A More Inclusive Definition of Severe Illness
Returning to the first University of Chicago study that I discussed, it is important for us to recognize that even with no greater risk of severe illness, 40% of immunocompromised patients in the University of Chicago cohort had severe illness, and 13% died. An unpublished report from the same University of Chicago cohort has demonstrated that the standard definition that has been developed for COVID-19 severe illness may be flawed because it is an incomplete and limited marker of the severity of acute and chronic SARS-CoV-2 infection and its consequences.

For example, 4 patients in the cohort who were classified as having “moderate” illness died. Of more importance, the standard definition masks the importance of multiorgan illness, specifically extrapulmonary disease. An analysis we did of the patients who developed severe disease demonstrated the high incidence of extrapulmonary in-hospital morbidity (Table). Our findings suggest that a more inclusive definition of “severe” COVID-19 illness would more accurately capture the short-term and long-term morbidity of COVID-19 and the effectiveness of antiviral and immunomodulatory therapies.

The CDC has made a similar case with the description of an adult form of the multisystem inflammatory syndrome in which COVID-19 with fever and little or no respiratory involvement is associated with life-threatening heart disease, with other clinical manifestations including rash, conjunctivitis, neurologic signs and symptoms, abdominal pain, thrombocytopenia, and elevated inflammatory markers. The full breadth of the morbidity and mortality associated with SARS-CoV-2 infection is clearly not limited to the pulmonary system and has so far eluded our current clinical definitions of “severe” COVID-19 illness. To accurately study the efficacy of antiviral and immunomodulatory therapies, it is essential that the full spectrum of COVID-19 illness be deciphered.

Table. COVID-19 Clinical Syndromes by Severity of Illness

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