key: cord-0715227-31n2ipf8
authors: Haidar, Ghady; Mellors, John W
title: Improving the Outcomes of Immunocompromised Patients with COVID-19
date: 2021-05-05
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab397
sha: 88084bd4dc054f4ec0aab4b22623f8ff4b88c82d
doc_id: 715227
cord_uid: 31n2ipf8

Recent case studies have highlighted that certain immunocompromised individuals are at risk for prolonged SARS-CoV-2 replication, intra-host viral evolution of multiply-mutated variants, and poor clinical outcomes. The immunologic determinants of this risk, the duration of infectiousness, and optimal treatment and prevention strategies in immunocompromised hosts are ill-defined. Of additional concern is the widespread use of immunosuppressive medications (corticosteroids, IL-6 antagonists) to treat COVID-19, which may enhance and prolong viral replication in the context of immunodeficiency. We outline the rationale for four inter-related approaches to usher in an era of evidence-based medicine for optimal management of immunocompromised patients with COVID-19: 1) multicenter pathogenesis and outcomes studies to relate the risk of severe disease to the type and degree of immunodeficiency; 2) studies evaluating immunologic responses to SARS-CoV-2 vaccines; 3) studies evaluating the efficacy of monoclonal antibodies for primary prophylaxis; and 4) clinical trials of novel antiviral agents for the treatment of COVID-19.

A c c e p t e d M a n u s c r i p t 3 Immunocompromised patients are at increased risk for severe and fatal coronavirus disease 2019 (COVID- 19) outcomes. In a multicenter study of over 400 solid organ transplant (SOT) recipients with COVID-19, 78%, 34%, and 27% required hospitalization, intensive care, and mechanical ventilation, respectively [1] . Hematopoietic cell transplant (HCT) recipients also experience high rates of COVID-19-related complications, with up to 15% of patients requiring intubation [2] . Additionally, some studies have shown that mortality rates of SOT and HCT recipients with COVID-19 range between 20% and 30%, respectively [1, 2] , although more recent studies of SOT recipients, including a study showing comparable outcomes between SOT recipients and non-SOT controls [3] , have shown lower mortality rates (4.4-9.6%) [3, 4] . Patients with solid tumors, human immunodeficiency virus (HIV) infection, and primary immunodeficiencies are also at high risk for severe outcomes, intubation, and death [5, 6] . By contrast, data in patients receiving immunosuppression or biologic agents for rheumatological and autoimmune conditions are more reassuring, with many studies showing clinical outcomes similar to those of the general population [5] .

However, the use of the anti-CD20 monoclonal antibody rituximab and specific immunosuppressive medications (.e.g, sulfasalazine, azathioprine, cyclophosphamide, cyclosporine, mycophenolate or tacrolimus) have been associated with worse outcomes compared to the use of methotrexate or disease-modifying anti-rheumatic drugs [7] .

Complementing the clinical outcomes data, several case reports and case series have described prolonged viral replication and evolution of mutated variants in immunocompromised individuals [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] . Although limited in scope, these studies have provided initial insights into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) SARS-CoV-2 in immunocompromised patients, including the extent of viral replication and mutation within the host, the duration of infectious virus shedding, and the potential for transmission to others. Here, we highlight the serious consequences of SARS-CoV-2 infection in immunocompromised patients and recommend actions to fill knowledge gaps, prevent transmission, and ultimately improve patient outcomes.

A c c e p t e d M a n u s c r i p t 4 We identified 14 patients across 10 studies who have been reported to have continued SARS-CoV-2 replication lasting >20 days, with a median duration of 71 days (range 21-143 days), indicating severely impaired ability to clear the infection [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] . Fifty percent (7/14) of patients had an underlying hematological malignancy [8-10, 13, 14] . The remaining predisposing conditions were SOT (N=2) [12, 15] , advanced HIV (CD4 count = 0 cells/mm 3 ) [15] , antiphospholipid syndrome (receiving prednisone, cyclophosphamide, and rituximab) [11] , prostate cancer [17] , rheumatoid arthritis (receiving rituximab) [15] , and Xlinked agammaglobulinemia (N=1 each) [16] . Pneumonia was present in most patients, and SARS-CoV-2 antibody responses were minimal to absent. [8, 9, 11, 13, 14] . Many of these mutations, such as deletions at residues 69-70 and 141-144 of the S-gene NTD and the E484K and N501Y mutations in the RBD would later be identified in late 2020 in the heavily mutated SAR-CoV-2 lineages B.1.1.7, B.1.351 and P.1, first reported in the United Kingdom, South African, and Brazil, respectively [18] . That these variants emerged independently and were first identified in immunocompromised hosts in mid-2020 has led some to propose that their origin was in individuals with prolonged infection. These highly-mutated variants are thought to be transmitted more efficiently because of greater affinity of the mutated Spike proteins to the ACE2 receptor. The mutated variants may also be less sensitive to neutralization by monoclonal antibodies [19] and sera from convalescent donors [14] or from recent A c c e p t e d M a n u s c r i p t 5 vaccinees [20] . It has also been proposed that NTD deletions in the S gene emerged as a result of immune selection following administration of convalescent plasma [14] , though this observation has not been universal [10] .

Taken together, these findings highlight features unique to immunocompromised patients with COVID-19 and underscore deficiencies in the current approach to management. For instance, because immunocompromised individuals can transmit infectious virus for longer than 20 days, a stringent approach to COVID-19 precautions may be prudent in these patients. We recommend that test-based strategies similar to those proposed by revised CDC guidelines [21] be implemented even if the frequency and duration of prolonged infectiousness has yet to be completely characterized, as such interventions have the potential to prevent transmission of SARS-CoV-2 variants to healthcare workers and others. In parallel, research efforts should focus on identifying surrogates for viral replication and infectivity such as cycle threshold values or other biomarkers [22] . In addition, a larger umbrella of studies should be conducted to fill knowledge gaps about the pathogenesis, prevention, and treatment of COVID-19 in immunocompromised patients.

Accordingly, we recommend the rapid implementation of four interconnected research strategies ( Table 1) While administration of the mRNA and adenovirus vector vaccines is expected to be generally safe, there are some concerns that upregulation of immune responses following COVID-19 vaccination in SOT recipients may trigger allograft rejection [23] . Furthermore, the immunogenicity and protective efficacy of these vaccines are likely to be lower than those of immunocompetent individuals, thereby putting vaccinated immunocompromised patients at continued risk for "breakthrough" SARS-CoV-2 infection [23] . [24, 25] . Additionally, a study of 67 hematological malignancy patients who had received two mRNA vaccine doses showed that 46% of individuals failed to produce antibodies against the SARS-CoV-2 Spike protein [26] , a finding which contrasts with the essentially 100% seroconversion rate seen in phase 1 and 2 mRNA vaccine trials of healthy volunteers [27] . In contrast, patients with autoimmune diseases appear to have robust responses to mRNA COVID-19 vaccines, with up to 74% of patients developing antibody responses after one vaccine dose, although the use of anti-CD20 monoclonal antibodies or mycophenolate was associated with vaccine failure [28] . Importantly, in light of current CDC guidance appropriately permitting relaxed precautions among vaccinated and low-risk unvaccinated individuals [29] , immunosuppressed patients should be advised to continue wearing masks and practicing social distancing, regardless of prior COVID-19 or vaccination status.

Since emerging data suggest that immunocompromised patients are not expected to generate robust antibody or memory B-cell responses to COVID-19 vaccines, preventive efforts should be explored that either replace or complement COVID-19 vaccination. An appealing alternative to vaccination is the use of monoclonal antibodies or other direct-acting antivirals to prevent COVID-19. In an unpublished study of over 900 participants residing in or working at nursing homes [30] , the monoclonal antibody bamlanivimab significantly lowered the risk of nursing home residents developing COVID-19. Similar strategies using monoclonal or polyclonal antibodies targeting wild type and mutated SARS-CoV-2 variants A c c e p t e d M a n u s c r i p t 8 should be explored for the primary prevention of COVID-19 in immunocompromised patients. However, the sustainability of this approach may be limited by the emergence and spread of resistance to monoclonal antibodies such as bamlanivimab [31] , which may result in failure of this agent to prevent COVID-19. Consequently, the potential spread of variants with resistance to monoclonal antibody therapy should be vigilantly monitored.

Prophylaxis of immunosuppressed patients with oral agents, such as the novel COVID-19 antiviral molnupiravir (NCT04405739) or repurposed medications such as fluvoxamine (which has shown promise in early COVID-19 treatment trials (NCT04342663)), if shown to be effective in clinical trials, would be an appealing alternative to monoclonal antibody prophylaxis. Although post-exposure prophylaxis against influenza using oseltamivir has been established as standard of care for nearly two decades, studies using oral agents such a hydroxychloroquine for the prevention COVID-19 have not shown efficacy [32, 33] . Additional work in COVID-19 prevention, particularly among vaccine nonresponders, is needed.

The publication of the RECOVERY trial, which showed a significant reduction in mortality among patients with COVID-19 who received dexamethasone [34] , resulted in a paradigm shift in the medical management of COVID-19, in which immunomodulation and not antiviral therapy has become an accepted clinical practice standard. The concept of immunomodulation has been solidified by clinical trial data demonstrating a mortality benefit of interleukin-6 inhibitor therapy (e.g., tocilizumab or sarilumab) in non-mechanically ventilated critically ill patients with COVID-19. As a result, there has been strong interest in the continued study of immunomodulatory drugs to treat COVID-19. A multitude of immunosuppressive medications are being evaluated (generally as adjuncts to dexamethasone), such as interleukin-1 or tumor necrosis alpha inhibitors, and other cytokine inhibitors and immunomodulators. Current guidelines endorse the use of dexamethasone and IL-6 inhibitor therapy in subgroups of patients with COVID-19 without excluding immunocompromised patients [35] , even though these patients were generally excluded from Studies among immunocompromised hosts should ideally be focused on identifying direct-acting antivirals that markedly reduce SARS-CoV-2 replication, be they small molecules or antibodies. The use of monoclonal antibodies, which are already available for administration to both immunocompromised and immunocompetent patients in the U.S. via an EUA, should now be expanded via clinical trials to encompass settings (e.g., early hospitalization, supplement oxygen requirement in patients with prolonged replication) beyond those outlined in the EUA, with a focus on immunocompromised patients who may benefit the most from them. Although the efficacy of the RNA polymerase inhibitor remdesivir has been questioned due to conflicting data [37, 38] , remdesivir and other antivirals such as molnupiravir (NCT04405739) should also be studied in clinical trials of immunocompromised hosts, who may reap the greatest benefit from such interventions. Indeed, while some have argued that the antiviral oseltamivir may only have modest efficacy against influenza, transplant recipients with influenza who are treated with oseltamivir have a significantly reduced risk of lower tract disease, hypoxemia, intensive care unit admission, and death [39] .

A poignant example of a SARS-CoV-2 antiviral treatment that may benefit immunocompromised patients preferentially over others is convalescent plasma. Although general enthusiasm for convalescent plasma has waned due to contradictory and mostly A c c e p t e d M a n u s c r i p t 10 negative trials, a recent study showed a mortality benefit of convalescent plasma in hematological malignancy patients with COVID-19 [40] . The risk of selecting immune escape variants with convalescent plasma or monoclonal antibodies, or the development of antiviral resistance during therapy should be better defined in larger longitudinal studies. Finally, immunocompromised patients may be ideally suited for the study of adoptive transfer of allogeneic SARS-CoV-2-specific T-cell therapy (NCT04401410). Trials of antivirals in immunocompromised hosts should include quantification and sequencing of SARS-CoV-2 RNA in the respiratory tract and bloodstream to assess the reduction in viral replication and selection of resistant variants.

The fastest way to usher in a new era of evidence-based medicine to manage immunocompromised patients with COVID-19 is to leverage the collective clinical and research expertise of health centers caring for these patients. Only then can we abandon empiricism, intuition-based medicine, and the excessive influence of anecdotal case reports to provide transplant, cancer, and other immunocompromised patients with the best evidence-based care.

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Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study

Inpatient COVID-19 outcomes in solid organ transplant recipients compared to non-solid organ transplant patients: A retrospective cohort

COVID-19 in solid organ transplant recipients: A national cohort study from Sweden

COVID-19 in Immunocompromised Hosts: What We Know So Far

COVID-19 Outcomes Among Persons Living With or Without Diagnosed HIV Infection in New York State

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19

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Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer

Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer

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Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host

Prolonged SARS-CoV-2 shedding and mild course of COVID-19 in a patient after recent heart transplantation

Intractable COVID-19 and Prolonged SARS-CoV-2 Replication in a CAR-T-cell Therapy Recipient: A Case Study

SARS-CoV-2 evolution during treatment of chronic infection

Long term SARS-CoV-2 infectiousness among three immunocompromised patients: from prolonged viral shedding to SARS-CoV-2 superinfection

SARS-CoV-2 positive virus culture 7 weeks after onset of COVID-19 in an immunocompromised patient suffering from X chromosome-linked agammaglobulinemia

A case of extremely prolonged viral shedding: could cell cultures be a diagnostic tool to drive the COVID-19 patients discharge?

The emerging plasticity of SARS-CoV-2

Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

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Comparison of Subgenomic and Total RNA in SARS-CoV-2 Challenged Rhesus Macaques

SARS-CoV-2 Vaccination and Solid Organ Transplant Patients: Data Needed to Inform Safety and Efficacy

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Kidney Transplant Recipients Rarely Show an Early Antibody Response Following the First COVID-19 Vaccine Administration

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When You've Been Fully Vaccinated

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M a n u s c r i p t Observational studies of the risk of opportunistic infections associated with the use of immunomodulatory therapies Clinical trials in immunocompromised patients of antivirals that have activity against SARS-CoV-2 (e.g., small molecules and antibodies)