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COVID-19 in the Immunocompromised Host

Synopsis: Immunocompromised hosts, which encompass a diverse population of persons with malignancies, HIV disease, solid organ and hematologic transplants, autoimmune diseases, and primary immunodeficiencies, bear a significant burden of the morbidity and mortality due to COVID-19. Immunocompromised patients who develop COVID-19 have more severe illness, higher hospitalization rates, and higher mortality rates than immunocompetent patients. There are no well-defined treatment strategies that are specific to immunocompromised patients and vaccines, monoclonal antibodies, and convalescent plasma are variably effective. This review focuses on the specific impact of COVID-19 in immunocompromised patients and the gaps in knowledge that require further study.

Immunocompromised hosts are at considerable risk for a variety of infections. For example, bacterial pneumonia has been estimated to account for 30% of intensive care unit (ICU) admissions in cancer patients 6 . In another study of severe influenza pneumonia, 12.5% of patients admitted to the ICU were immunocompromised, indicative of a higher propensity interferon responses measured in the peripheral blood were also associated with severe illness in 50 patients with COVID-19 of variable severity 11 . On the other hand, more exuberant type 1 interferon responses that occur later in the course of infection have been associated with a worsening of lung injury, indicating that these innate immune responses may have salutary or harmful roles depending upon when they occur within the course of disease 12 . Of note, these studies were conducted in immunocompetent hosts and were performed during an acute infection, and while the findings indicate that innate immune impairments are associated with higher COVID-19 severity, these findings require validation in immunocompromised hosts who are evaluated prior to the onset of disease.
Cellular, or cell-mediated, immunity, typically refers to host response involving T-cells, though notably many innate immune cells also have a direct cell-mediated anti-pathogen response. In many immunocompromised hosts, cellular immunity can be impaired and lead to worsened outcomes after COVID-19. In a study comparing over 1400 immunocompetent  In another cohort of 79 COVID-19 patients, 36 immunocompromised hosts had   significantly fewer CD3+ T -cells and CD3+/CD4+ T cells compared to 20 patients above age 60   and 23 patients with diabetes 15 . T-cells from immunocompromised patients produced less interferon-gamma compared to elderly patients, but there was no difference in interferon production between diabetic and immunocompromised patients. However, this study included patients with renal disease and cirrhosis as part of its definition of immunocompromised hosts.

Clinical outcomes after COVID-19 infection in immunocompromised hosts
Immunocompromised patients generally develop more severe illness after SARS-CoV-2 infection than immunocompetent patients. However, the studies discussed here need to be interpreted in the context of which variants dominated during the time of study and the availability of vaccines and effective therapies. We will discuss COVID 19 disease severity in the immunocompromised and considerations amongst different types of immunocompromised patients. ICU admission by 32%, acute kidney injury by 81%, and venous thromboembolism by 74%, but did not increase the risk for mechanical ventilation or death 49 . Severe outcomes were more J o u r n a l P r e -p r o o f common for patients on glucocorticoids, but not DMARDs (disease modifying antirheumatic drugs). In a study of 52 patients with systemic ARD, of whom 75% were on immunosuppressive therapy and 31% on biologic therapies, the requirement for mechanical ventilation was threefold higher in patients with rheumatologic disease compared to matched controls. However, mortality was indistinguishable between the two groups. Similar to other patients, a greater number of comorbidities increases the likelihood of severe COVID-19 in patients with ARD. For example, in patients with inflammatory bowel disease with two or more comorbidities, such as heart disease, diabetes, and kidney disease, severe COVID-19 was more common than in patients with one or zero comorbidities 50 .

vii) Primary Immunodeficiency
Little data exists for patients who have non-HIV immunodeficiency. In an Italian case series of 7 patients with primary immunodeficiencies, 6 were hospitalized and 3 were admitted the ICU 51 . Of the hospitalized patients at time of publication, 1 patient died in hospital, three were discharged and two were still being treated. The length of stay ranged between 3 days to 25 days.

Treatment
In general, there is a paucity of randomized controlled trial data examining the efficacy of anti-SARS-CoV-2 treatments in immunocompromised hosts. For example, in a recent randomized controlled trial of high-risk individuals who developed COVID-19 and were randomized to nirmatrelivir/ritonavir or placebo, fewer than 30 patients met any criteria for immunocompromise as we outline above 52 . Most data comes from observational or case-control studies. In this section, we will discuss studies that show the efficacy of antiviral, monoclonal J o u r n a l P r e -p r o o f antibodies, and convalescent plasma to treat, preempt, or prevent COVID-19 in immunocompromised patients.
Little data exists regarding antiviral therapy and its efficacy specifically in the immunocompromised. One challenge with the use of antiviral therapy is that the kinetics of viral replication necessitate prompt therapy in order to ensure an adequate outcome 53 ; there is no clear evidence that replication is more rapid in immunocompromised hosts, despite the possibility due to impaired innate and cellular immunity. In one series of 31 ARD patients treated with nirmatrelivir/ritonavir (29) and molnupilavir during the first 5 days of COVID-19 diagnosis, no patients were hospitalized, but most (94%) were fully vaccinated 54  For example, in a propensity score-matched analysis of 112 patients with hematologic malignancies, most of whom received other non-plasma therapies, the use of convalescent plasma decreased mortality by 63% among patients who were exposed to anti-CD20 antibodies in the sub-group of patients with B-cell neoplasms 63  weeks. An inferior response to SARS-CoV-2 vaccination in immunocompromised patients has been shown in other studies. For example, an Austrian prospective cohort studied antibody J o u r n a l P r e -p r o o f response to COVID-19 vaccination in 15 healthy controls compared this to 74 patients previously treated with rituximab 67 . All healthy patients developed antibodies, but only 39% of the rituximab group developed antibodies to spike proteins following vaccination.
Lastly, COVID-19 hospitalization following vaccination, commonly referred to as "breakthrough cases," are more frequent in the immunocompromised. For example, an American study of 45 vaccine breakthrough COVID-hospitalizations reported that 44% were immunocompromised, and an Israeli cohort of 152 hospitalized fully vaccinated patients reported that 40% were immunocompromised 68,69 . Of the 60 immunocompromised fully vaccinated patients in the Israeli cohort, 18 had a poor outcome, which was defined as either requiring mechanical ventilation or death. Knowing that the prevalence of immunocompromise in the United States is around 2%, it follows that breakthrough infection seems to occur much more frequently among immunocompromised patients. Two studies prove this point more definitively.
In a study of 6,860 cases of breakthrough COVID-19 after vaccination, patients with hematologic malignancies had over a four-fold higher risk for breakthrough infection 70 , with the highest rates seen in patients with leukemia or myeloma. Proteasome inhibitors and other immunomodulators significantly increased the risk for breakthrough infection. Similarly, in a study of over 45,000 patients with cancer, primarily with solid tumors, the overall incidence of breakthrough COVID-19 was 13.6%. 71 Mortality rate may be higher after breakthrough infection in immunocompromised patients. A cohort study of 54 fully vaccinated hematologic and solid