key: cord-0855946-ym7rtqyx
authors: Jakharia, Niyati; Subramanian, Aruna; Shapiro, Adrienne E.
title: COVID-19 in the Immunocompromised Host, including People with HIV
date: 2022-02-01
journal: Infect Dis Clin North Am
DOI: 10.1016/j.idc.2022.01.006
sha: 38cdaf0cbd46867cfbe35ce77a3eb86a1ca9a621
doc_id: 855946
cord_uid: ym7rtqyx

This review describes the incidence, epidemiology, and risk factors for mortality of COVID-19 in immunocompromised patients, including persons with HIV. We describe various preventive measures including vaccines and their effectiveness and the role of monoclonal antibodies for pre-exposure prophylaxis. We also review the different treatment options for immunocompromised individuals, including antivirals, monoclonal antibodies and immunomodulators. Lastly, we describe the impact of COVID-19 on transplantation and continuity care of this population.

preventing severe disease in PWH, but vaccines might have lower efficacy in immunosuppressed PWH. Many questions remain regarding the relative immunogenicity of different vaccine types (mRNA, Ad5 vector, Ad26 vector, protein subunit, whole inactivated) for PWH, particularly PWH with CD4+ cell count <350/mm 3 or untreated HIV with persistent HIV viremia, the persistence of vaccine-induced immunity, and the optimal dosing and boosting interval for vaccines. Studies such as the recently-initiated CoVPN 3008 protocol, evaluating the immunogenicity of the Moderna mRNA-1273 vaccine in sub-Saharan Africa in countries with a high prevalence of HIV, are well-poised to answer some of these questions, but additional global cohorts of vaccinated PWH should be engaged to assess immunologic markers while we await clinical and immunologic outcomes. 38 Also critical to preventing COVID-19 and severe disease in PWH, is additional research into use and indications for prophylactic therapies, including new oral antivirals and neutralizing monoclonal antibodies, and identifying the PWH who would most benefit from these preventive therapeutics (e.g. CD4+ cell count thresholds, other historical immune indicators).

Finally, post-COVID sequelae, ("long COVID" or "post-acute sequelae of SARS-CoV-2," PASC) characterized by persistent neuropsychiatric, cardiovascular, pulmonary, and other symptoms dysregulated immune system that leads to severe systemic effects. The immunosuppression in this population may impair development of T cell immunity to SARS-CoV2 virus. 50 Prolonged viral shedding has been observed beyond day 30 in transplant patients. SARS-CoV2 plasma viral load has also been associated with mortality in the kidney transplant population. 51 Immunosuppressive therapies may help with curbing severe immune responses in the late phases of 52 The effect of immunosuppressive therapies varies with the type and intensity, and phase of illness. Most centers practice reduction or holding immunosuppression (RIS). Most retrospective cohort studies did not reveal any significant impact of immunosuppression on mortality. 41,46,53 , except within a liver transplant cohort in which mycophenolate-containing regimens were an independent risk predictor of severe disease (RR =3.94), especially at doses of > 1000mg/day .44 However, these were retrospective studies, and must be interpreted with caution. The impact of type and degree of immunosuppression on the course of COVID-19 still remains unclear. Further randomized controlled trials are needed to address this question. 54

The mortality in the Solid Organ Transplant population has ranged in various studies from 6-27% (Table 1 ). The various risk factors associated with mortality in this population are increasing age (>60 years), chronic heart failure, chronic lung disease, obesity, lymphopenia, mycophenolate containing regimens for immunosuppression, and lung transplantation. 41, 42, 44, 53 In the lung transplant population, chronic lung allograft dysfunction was an independent J o u r n a l P r e -p r o o f predictor of mortality. 55 The rate of hospitalization for COVID-19 in SOT recipients is also high, ranging from 30-89%. Acute kidney injury (AKI) has been reported in 24-52% of patients. A meta-analysis showed that age, male sex, diabetes mellitus, hypertension, chronic kidney disease and cardiovascular disease are associated with AKI in transplant patients, and also leads to increased mortality. 56 The reported rate of rejection associated with SARS-CoV-2 infection is low: 1.5-6%. 

Remdesivir is an inhibitor of viral RNA based RNA polymerase, which is essential for viral replication of SARS-CoV2. ACTT-1 (Adaptive COVID-19 treatment trial) showed reduced time to clinical recovery in patients with severe COVID, especially on supplemental oxygen. 62 The WHO Solidarity trial did not show any decrease in the in-hospital mortality in hospitalized patients compared to the standard of care. 63 There was no significant difference in the outcomes between a 5 vs 10-day course of remdesivir. 64 Treatment for SOT populations with remdesivir J o u r n a l P r e -p r o o f does not differ from the general population, although some consider the extended 10 day course for patients without improving clinical status, due to risk for increased duration of viral replication in this population.

FDA granted emergency use authorization for both these antivirals in December 2021.

Nirmatrelvir is a SARS CoV-2 protease inhibitor that inhibits viral replication. It is administered with ritonavir, which inhibits CYP3A4, and raises nirmatrelvir levels to a therapeutic range. In the EPIC-HR trial, ritonavir-boosted nirmatrelvir (Paxlovid) reduced the risk of hospitalization or death by 88% compared to placebo in nonhospitalized high-risk adults with laboratoryconfirmed SARS-CoV-2 infection and within 5 day of symptom onset. 65 However, this drug must be used with caution in transplant population due to the drug interactions between ritonavir and calcineurin inhibitors (CNI). In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death by 30% compared to placebo in high-risk adults within 5 days of symptom onset, and the recommendations for its use in SOT recipients do not differ from the general population. 66

Various monoclonal antibodies to the spike protein of SARS-CoV-2 have received emergency use authorization (EUA) by the US Food and drug administration (FDA) for treatment of nonhospitalized patients with COVID-19, who are at a high risk of progression to severe disease.

Real-world experience in SOT patients showed a decrease in hospitalization and respiratory failure compared to patients who did not receive mAb ( be appropriate depending on circulating variants of concern (VOC).

The Food and Drug Administration issued an emergency use authorization (EUA) for treatment of hospitalized patients with COVID with convalescent plasma from donors who have recovered from COVID-19 which contains antibodies to SARS-CoV2. In immunocompromised patients,

there are only few case series and retrospective studies that suggest some benefit however, and randomized controlled trials are lacking. 73, 74 In a double blind, placebo controlled RCT, administration of high titer (greater than 1:1000 anti-SARS-CoV-2 antibodies) convalescent plasma to older adults within 72 hours of onset of mild symptoms of COVID, led to relative risk reduction of development of severe COVID by 48%. 75 In December 2021, the US FDA extended the EUA for convalescent plasma to include immunocompromised non-hospitalized patients.

J o u r n a l P r e -p r o o f COVID-19 associated systemic inflammation results from cytokine release. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that is released by various cells during systemic inflammation. It is hypothesized that modulating or inhibiting these levels may reduce the severity of COVID-19 infection.

A large multi-center randomized controlled trial (RECOVERY) showed decreased 28-day mortality in hospitalized patients with COVID-19, on supplemental oxygen or invasive mechanical ventilation, who received 10 days of dexamethasone (an anti-inflammatory agent). 76 Tocilizumab and sarilumab, monoclonal antibodies to IL-6 receptor, are used in management of certain rheumatological disorders and cytokine release syndrome related to CAR-T therapy. In the RECOVERY and REMAP-CAP trials, tocilizumab was reported to have mortality benefit in COVID patients with respiratory decompensation, requiring oxygen or non-invasive ventilation. 76, 77 However, these trials did not include SOT patients. These drugs must be used with caution in the SOT population due to an increased risk of secondary infections.

Janus kinase (JAK) inhibitors prevent phosphorylation of proteins that lead to immune activation and inflammation. The COV-BARRIER trial showed a decrease in the 28-day mortality and the ACTT-2 trial showed improved time to recovery in patients who received baricitinib with remdesivir. 78, 79 At this time, there is insufficient evidence to recommend for or against the use of these immunomodulators in immunocompromised patients. 

Various studies showed that vaccine effectiveness in immunocompromised patients was lower compared to immunocompetent ( J o u r n a l P r e -p r o o f (Table 4) . 

There was a decline in transplantation all over the world during the first several months of pandemic, for various reasons. 50 Early in the pandemic, there was a national decline in the number of transplants by 35% from January to April 2020. There was also an increase in the waitlist deaths by 26%. These changes were more significant in regions with high COVID-19

burden. The largest reduction was seen in kidney (42%) and lung (40%) transplant patients. 98 A survey was conducted to understand the impact of COVID-19 on transplant activity on organ transplants in 111 centers across the US. Complete suspension of live kidney and liver transplantation was reported by 71% and 67%. Many centers were limiting their transplants to higher acuity patients. Some transplants were limited by supplies, personnel and capacity. In person outpatient visits were limited by 98% of respondents, lab draws were stopped/limited by 20%. 96% reported using telemedicine. 99 There was also a decline in the availability of ICU beds since they were occupied by the critically ill COVID patients. Pre-transplant COVID screening measures for donors and recipients were implemented by most centers. There was an 11% decline in donor organ authorization by families from March to May 2020. Donor cause of death due to substance abuse increased by 35% and trauma decreased by 5% in that time period. 100

The transplantation societies have issued guidance for safe donation and transplantation practices, and there is an increased use of telemedicine for outpatient care to minimize hospital exposure.

Little is known about the transmissibility of SARS-CoV-2 virus during organ transplantation. All 

COVID-19 has had a major impact on the SOT population. While we have developed policies and practices for better management during this pandemic, there is still a need for better preventive measures due to the depressed immune response in this vulnerable population.

There is also a need for better therapeutic agents for management of this infection. There are still some uncertainties about some practices such as management of immunosuppression, vaccine responses, role of immunomodulators, which need to be studied.

Epidemiology:

Much of the data regarding natural history of disease in HCT patients was gathered early in the In the series from Turkey, HCT recipients on immunosuppressive agents had a higher mortality rate than those who were not receiving exogenous immunosuppression (33% vs 11.5%). 108 

A few studies of antibody response to 2 doses of mRNA vaccines after HCT helped inform the years, vaccination within 6 months of HCT, or use of anti-thymocyte globulin during conditioning all were associated with lack of response to vaccination in this group. 111 As in J o u r n a l P r e -p r o o f other populations not expected to mount adequate vaccine responses, use of authorized anti-SARS-CoV-2 mAbs for pre-exposure prophylaxis may be warranted.

Vaccination should be delayed for 3 months following HCT or CAR-T therapy to maximize vaccine efficacy, according to National Comprehensive Cancer Network (NCCN)guidelines.

European Society for Blood and Marrow Transplantation (EBMT) guidelines recommend waiting for at least 3 months in high transmission areas, and preferably for 6 months if the transmission is low. It is also recommended to repeat the vaccine series if vaccinated prior to HCT.

Currently, the CDC, and international societies including the NCCN, CIBMTR, and EBMT all recommend a 3rd dose of mRNA vaccine for those who received 2 doses of an mRNA SARS-CoV-2 vaccine after transplant, after a minimum 4-week interval from the prior dose. 112, 113 Boosters continue to be recommended following completion of the initial series, as in nonimmunocompromised persons.

A survey study of 101 patients post-HCT was done to assess their supportive care needs.

Largely, there were unmet physical and psychological needs of the patients. Compliance with exercise programs was low. Women had more unmet psychological needs compared to men and measures of their quality of life (QoL) were low. 114 A cross-sectional analysis of 205 patients undergoing HCT enrolled in a supportive care trial found that enrollment during COVID-19 was J o u r n a l P r e -p r o o f not associated with pre-HCT symptoms of depression, anxiety, PTSD, fatigue, or QoL impairment. During the COVID-19 era, patients reported negative implications such as increased isolation, increased family and caregiver distress, and positive implications such as engagement in meaningful activities and increased support from caregivers. 115 Telehealth services can be helpful to provide increased support and interventions to meet patient needs and reduce distress.

In a large registry (COVID-19 and Cancer Consortium) of 928 cancer patients with confirmed SARS-CoV2 infection, the factors that were associated with increased 30-day mortality were increased age, male sex, co-morbidities, smoking and having active cancer. Type of cancer or chemotherapy were not associated with mortality. 116 Another prospective observational study of COVID patients with active cancer and symptomatic COVID-19 reported mortality of 28%.

Risk of death was associated with advancing age, male sex, and presence of co-morbidities such as hypertension and cardiovascular disease. There was no significant effect of chemotherapy, immunotherapy or radiation therapy on mortality. 117 In a recent report from COVID-19 Global Rheumatology Alliance physician registry, of 2869 people with COVID-19 on disease modifying anti-rheumatic drugs (DMARDS), 21% required hospitalization and 5.5% died. Patients on rituximab or JAK (Janus Kinase) inhibitors had higher rates of hospitalization and deaths compared to TNF alpha inhibitors. 118 An international registry (SECURE-IBD) to record outcomes of COVID-19 in patients with inflammatory bowel disease (IBD) of 525 patients, 31% were hospitalized and 3% died. Risk factors for severe

Risk Factors for Coronavirus Disease

Death in a Population Cohort Study from the Western Cape Province, South Africa

COVID-19 Susceptibility and Outcomes Among People Living With HIV in San Francisco

COVID-19 Testing Results by HIV Status

Persistent SARS-CoV-2 infection and intra-host evolution in association with advanced HIV infection

COVID-19: Prolonged viral shedding in an HIV patient with literature review of risk factors for prolonged viral shedding and its implications for isolation strategies. Clin Case Rep

Brief Report: Virologic and Immunologic Outcomes for HIV Patients With Coronavirus Disease

A High Percentage of People With Human Immunodeficiency Virus (HIV) on Antiretroviral Therapy Experience Detectable Low-Level Plasma HIV-1 RNA Following Coronavirus Disease 2019 (COVID-19)

HIV-1 Infection Does Not Change Disease Course or

Inflammatory Pattern of SARS-CoV-2-Infected Patients Presenting at a Large Urban Medical Center

Description of COVID-19 in HIV-infected individuals: a single-centre, prospective cohort. Lancet HIV

Outcomes of COVID-19 in solid organ transplant recipients: A matched cohort study

Remdesivir for the Treatment of Covid-19 -Final Report

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for molnupiravir

Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial. The Lancet Infectious Diseases

Monoclonal Antibody Therapy for COVID-19 in Solid Organ Transplant Recipients

Use of anti-spike monoclonal antibodies in kidney transplant recipients with COVID-19: Efficacy, ethnic and racial disparities

Anti-SARS-CoV-2 Monoclonal Antibodies in Solid-organ Transplant Patients

Early Monoclonal Antibody Administration Can Reduce Both Hospitalizations and Mortality in High-Risk Outpatients with COVID-19

Treatment of immunocompromised COVID-19 patients with convalescent plasma

Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

Dexamethasone in Hospitalized Patients with Covid-19

Interleukin-6 receptor antagonists in critically ill patients with Covid-19

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial

Safety and Reactogenicity of 2 Doses of SARS-CoV-2

Vaccination in Solid Organ Transplant Recipients

Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients

Humoral and cellular immune response and safety of two-dose SARS-CoV-2 mRNA-1273 vaccine in solid organ transplant recipients

Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults -Nine States

Clinical effectiveness of COVID-19 vaccination in solid organ transplant recipients

Two Doses of SARS-CoV-2 Vaccines Reduce Risk of Death Due to COVID-19 in Solid Organ Transplant Recipients: Preliminary Outcomes From a UK Registry Linkage Analysis

Effectiveness of SARS-CoV-2 vaccination in fully vaccinated solid organ transplant recipients

Breakthrough COVID-19 Infections After mRNA Vaccination in Solid Organ Transplant Recipients in Miami

Risk of Breakthrough SARS-CoV-2 Infections in Adult Transplant Recipients

COVID-19 after two doses of mRNA vaccines in kidney transplant recipients

Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients

Three Doses of an mRNA

Covid-19 Vaccine in Solid-Organ Transplant Recipients

Antibody Response After a Third Dose of the mRNA

SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses

Cellular and Humoral Immune Responses After 3 Doses of BNT162b2 mRNA SARS-CoV-2 Vaccine in Kidney Transplant

Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial

Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19

Fact sheet for healthcare providers: emergency use authorization (EUA) of REGEN-COV (casirivimab and imdevimab)

Early Impact of COVID-19 on Solid Organ Transplantation in the United States

Early impact of COVID-19 on transplant center practices and policies in the United States

Organ donation during the COVID-19 pandemic

Donor to recipient transmission of SARS-CoV-2 by lung transplantation despite negative donor upper respiratory tract testing

A call to routinely test lower respiratory tract samples for SARS-CoV-2 in lung donors

Early success transplanting kidneys from donors with new SARS-CoV-2 RNA positivity: A report of 10 cases

COVID-19 in recipients of allogeneic stem cell transplantation: favorable outcome

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

COVID-19 and stem cell transplantation

results from an EBMT and GETH multicenter prospective survey

COVID-19 in hematopoietic cell transplant recipients

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation

and 2 Doses of BNT162b2 mRNA Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant

Antibody responses to SARS-CoV2 vaccination in allogeneic hematopoietic stem cell transplant recipients

Screening supportive care needs, compliance with exercise program, quality of life, and anxiety level during the COVID-19 pandemic in individuals treated with hematopoietic stem cell transplantation

Distress in a Pandemic: Association of the

Coronavirus Disease-2019 Pandemic with Distress and Quality of Life in Hematopoietic Stem Cell Transplantation

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study

Seet AM COVID-19 Global Rheumatology Alliance, et al Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry

But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry

Effect of IBD medications on COVID-19 outcomes: results from an international registry

A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia

COVID-19 infection in 10 common variable immunodeficiency patients in New York City