Coronavirus Disease-2019 in The Immunocompromised Host: Christopher D. Bertini JR,, Fareed Khawaja,, Ajay Sheshadri

C o ro n a v i r u s D i s e a s e - 2 0 1 9 i n
t h e I m m u n o c o m p ro m i s e d
Host
a b
Christopher D. Bertini Jr, MD , Fareed Khawaja, MD ,
Ajay Sheshadri, MD, MSc,*
KEYWORDS
COVID-19 SARS-CoV-2 Immunocompromised host Pneumonia
Hematologic malignancy Immunosuppression
KEY POINTS
Immunocompromise refers to a host’s inability to combat infections from a variety of par-
tial or total immune defects and can occur in the setting of diseases such as hematologic
malignancies, immunosuppression use, primary immunodeficiency syndromes, and hu-
man immunodeficiency virus infection.
Hospitalization risk, intensive care unit admission, and mortality are substantially higher
after severe acute respiratory syndrome coronavirus 2 pneumonia in immunocompro-
mised hosts.
Immunocompromised hosts are underrepresented in clinical trials of vaccines and other
treatments, and therefore efficacy data are often inferred or based upon small studies.
Vaccines and treatments are often effective in immunocompromised hosts, but persistent
viral replication due to impaired immunity can hinder the efficacy of these interventions.
INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory virus

that originated in Wuhan, China in 2019. Since that time, SARS-CoV-2 has been
responsible for over 6 million deaths from coronavirus disease-2019 (COVID-19).1
Respiratory viral infections, in general, place an outsized burden on
This article was previously published in Clinics in Chest Medicine 44:2 June 2023.
The authors have nothing to disclose.
a
Department of Internal Medicine, UTHealth Houston McGovern Medical School, 6431 Fannin,
MSB 1.150, Houston, TX 77030, USA; b Department of Infectious Diseases, Infection Control,
and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe
Boulevard, Unit 1469, Houston, TX 77030, USA; c Department of Pulmonary Medicine, The
University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1462, Houston, TX
77030, USA
* Corresponding author.
E-mail address: [email protected]
Twitter: @ajaysheshadri (A.S.)
Infect Dis Clin N Am 38 (2024) 213–228

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214 Bertini Jr et al
immunocompromised hosts, and increase the mortality.2 Therefore, there was signif-
icant concern from the outset of the pandemic that SARS-CoV-2 infection would simi-
larly impact immunocompromised patients disproportionately. This review focuses on
the specific impact of COVID-19 on immunocompromised patients.
The term “immunocompromise” describes patients who have an impaired or absent
immune system, limiting a host’s ability to combat pathogens. Immunodeficiencies are
classified as either primary or secondary. Primary immunodeficiencies (PIDs) are
intrinsic to the immune system. Examples include congenital conditions such as se-
vere combined immunodeficiency (SCID), caused by various mutations which can
impact many immune cell lineages, and common variable immune deficiency
(CVID), which is caused by a diverse array of genetic conditions that result in varying
degrees of hypogammaglobulinemia.3 Secondary immunodeficiencies refer to those
acquired through conditions that depress the immune system. These include hemato-
logical malignances, solid and hematopoietic transplantation, infection with the hu-
man immunodeficiency virus (HIV), chronic immunosuppressive medication use,
and others. In these cases, the period of immunocompromise may be limited in dura-
tion; for example, a patient with leukemia may no longer be immunocompromised
once their disease is in remission and leukocyte counts recover, or a patient receiving
biologic immunosuppressive therapy may no longer be immunocompromised once
therapy has completed and enough time has lapsed to allow for immune recovery.
On the contrary, comorbidities that may impact immune function, such as diabetes,
do not necessarily connote an immunocompromised state, but are worthy of consid-
eration because they are often independently associated with poor outcomes after
COVID-19.4,5 Table 1 shows examples of high-risk groups who we consider to be
immunocompromised and their attendant immune deficits.
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 patients with cancer.6 In another study of severe influenza
pneumonia, 12.5% of patients admitted to the ICU were immunocompromised, indica-
tive of a higher propensity toward critical illness after infection.7 Indeed, mortality was
over twofold higher among immunocompromised patients with influenza pneumonia.
Other respiratory viruses also affect the immunocompromised; a recent retrospective
cohort study of 1643 hematopoietic cell transplant (HCT) patients found increased mor-
tality in allogeneic recipients infected with human rhinovirus (HRV) and adenovirus lower
respiratory infections.2 Finally, human herpesvirus-6 (HHV-6) and cytomegalovirus
(CMV) have long been associated with increased mortality amongst HCT recipients.8
Considering that over 500 million cases of COVID-19 have been reported worldwide
since the pandemic began, it is likely that several million immunocompromised hosts
were infected, extrapolating from the estimate that 2.7% of the American adult popula-
tion are immunocompromised.9 Research within this specific vulnerable population has
not been commensurate to the substantial body of literature for COVID-19 in general.
This review will summarize the current scientific literature that discusses the impact
of COVID-19 on immunocompromised hosts. We will discuss mechanisms for
COVID-19’s affinity for the immunocompromised, compare clinical data between immu-
nocompromised and immunocompetent hosts, and examine the evidence supporting
treatment strategies within immunocompromised hosts who develop COVID-19.
MECHANISMS OF IMMUNOCOMPROMISE
The innate immune response is driven by cells such as neutrophils, macrophages, and
natural killer cells. The innate immune response is evolutionarily ancient and is often
COVID-19 in the Immunocompromised Host 215
Table 1
Examples of immunocompromised conditions and possible mechanisms of
immunocompromise
Immunocompromised Mechanism of
Condition Immunocompromise Immune Deficits
Hematologic malignancies Marrow infiltration and Lymphopenia
cytotoxic chemotherapy Neutropenia
Impaired cellular immunity
Impaired humoral immunity
Hematopoietic cell Corticosteroid use, Lymphopenia
transplantation immunosuppressive Neutropenia
medications Impaired cellular immunity
(eg, tacrolimus, Impaired humoral immunity
sirolimus, and ibrutinib)
Solid organ transplant Corticosteroid use, Impaired cellular immunity
(kidney, lung, and heart) immunosuppressive Impaired humoral immunity
medications (eg, tacrolimus,
sirolimus, and cyclosporine)
Human immunodeficiency Apoptosis of T cells Lymphopenia
virus (HIV) Impaired cellular immunity
Autoimmune Use of immunosuppressive agents Lymphopenia
rheumatology (eg, methotrexate, TNF-alpha Impaired cellular immunity
diseases requiring inhibitors, and specific Impaired humoral immunity
immunosuppressive interleukin inhibitors) Impaired innate immunity
drug therapy
Primary Hereditary agammaglobulinemia, Lymphopenia
immunodeficiency defective phagocytosis, Neutropenia
syndromes and impaired leukopoiesis Impaired cellular immunity
Impaired innate immunity
the first defense against many pathogens, including SARS-CoV-2. Impaired innate im-
munity may be correlated with COVID-19 severity. For example, in a study of 84
COVID-19 patients, of whom 44 were critically ill, the presence of immature neutro-
phils, defined by low CD13 expression and characterized by diminished antimicrobial
and phagocytic activity, was associated with a critical illness.10 Similar findings were
seen in monocytes, and the diminished functional capacity of monocytes was corre-
lated with increased risk for septic shock rate and mortality. Impaired type 1 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 contrary, more exuberant
type 1 interferon responses that occur later in the course of infection have been asso-
ciated 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 although the findings indicate that
innate immune impairments are associated with higher COVID-19 severity, these find-
ings require validation in immunocompromised hosts who are evaluated before 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 COVID-19 patients to 166 immunocompromised pa-
tients, lymphopenia was associated with threefold mortality increase in the latter.13
The immunocompromised cohort consisted of patients with autoimmune rheumato-
logic diseases (ARD) (39.2%) as well as patients with hematologic malignancies
(21.1%), solid malignances (19.3%), and solid organ transplant (SOT) recipients
(18.1%). Specifically, CD8 cells may have an important role in determining outcomes
after COVID-19. In a prospective cohort study of 106 patients with cancer, lower pe-
ripheral blood CD8 T-cell counts were correlated with a higher COVID-19 viral load
and associated with higher mortality.14 However, hematologic patients with cancer
with preserved CD8 counts had low viral loads and decreased mortality, even among
patients with impaired humoral immunity. Of note, 23% of patients with hematologic
malignancy had no detectable anti-SARS-CoV-2 T-cell responses. In another cohort
of 79 COVID-19 patients, 36 immunocompromised hosts had significantly fewer
CD31 T -cells and CD31/CD41 T cells compared with 20 patients above age 60
and 23 patients with diabetes.15 T cells from immunocompromised patients produced
less interferon-gamma compared with 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. Further detailing the role CD8 cells play, a retrospective
case-control study of 174 COVID-19 hospitalized patients in Spain showed that pa-
tients admitted to the ICU had lower CD8 counts compared with patients admitted
to the general wards.16 CD4 counts did not vary between ICU and non-ICU admitted
patients. However, in general, the classification of immunocompromise should pre-
cede the infection, and in this study, most of the patients did not have a disease
that would indicate immunocompromise.
In addition to impaired cellular immunity, immunocompromised hosts may have
diminished humoral immunity, defined by an impaired ability to produce pathogen-
specific antibodies against COVID-19 and other pathogens. For example, a study of
103 patients with cancer showed that delayed viral clearance was associated with
loss of antibody production, despite adequate T cell response to infection.17 Pro-
longed viremia was driven by B-cell depletion, potentially indicating that the resolution
of infection depends upon adequate humoral immunity. In a study of lymphoma pa-
tients, B-cell-depleting therapies, such as rituximab, were associated with higher rates
of hospital readmission and persistent SARS-CoV-2 positivity.18 This diminished hu-
moral response may increase the risk in for adverse outcomes; a study of 111 patients
with lymphoma admitted to French hospitals for the treatment of COVID-19 found that
anti-CD20 therapies increased the risk of mortality by over two-fold.19 With regards to
the development of humoral immunity after infection, Wunsch and colleagues15 found
in a cohort of 70 patients with SARS-CoV-2 infection IgG ELISA antibody responses
measured after infection that 16 patients lacked antibodies. Of these 16 patients, 11
were immunocompromised. This lack of humoral immunity can in rare instances
lead to immune escape by SARS-CoV-2 variants.
Long-term shedding of COVID-19 in immunocompromised patients has been well
described in transplant recipients and patients with cancer with B cell depletion.20–24
Many of these cases describe changes in viral spike protein despite repeated treat-
ment with antivirals. For example, one renal transplant patient with COVID-19, over
a 145-day course of infection, SARS-CoV-2 viral spike proteins showed increased
resistance to neutralizing antibodies.20 These mutations have been shown to mimic
variants from Brazil and the United Kingdom, though no clear link between long-
term shedding and the evolution of COVID-19 variants have been identified.20 In
addition to the potential for mutations in the spike protein, resistance to antiviral
agents may also arise in patients with long-term shedding24; this was most recently
described in a cancer patient with B cell depletion.24 These examples cite the risk
long-term shedding of COVID-19 poses in immunocompromised patients and the
need for effective prevention and treatment methods.
Clinical Outcomes After Coronavirus Disease-2019 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.
Immunocompromised patients may have a higher ICU admission rate and longer
hospital lengths of stay. A Turkish retrospective case-control study reported a 22%
ICU admission rate among 156 immunocompromised patients compared with 9%
ICU admission rate among 312 nonimmunocompromised patients between April
2020 and October 2020.25 Length of stay was longer in the immunocompromised
cohort as well. The immunocompromised cohort included people living with HIV
(PLWH), cancer, rheumatologic disease, and those who were on immunosuppressive
medications. Immunocompromised patients may also have higher mortality rates
compared with those in the immunocompetent. For example, a separate Korean retro-
spective cohort study of 871 immunocompromised patients and 5564 nonimmuno-
compromised patients found that immunocompromised patients had a mortality of
9.6%, over four times higher than the 2.3% mortality rate observed in immunocompe-
tent patients.26 Immunocompromised patients included those with HIV/AIDs, malig-
nancy, SOT, and immunosuppressive medication use. Smaller cohort studies have
also shown a mortality rate three to four times higher in immunocompromised
patients.25
Immunocompromised patients who are mechanically ventilated often present with
more severe acute respiratory distress syndrome (ARDS). For example, a retrospec-
tive cohort of 1594 patients with COVID-19, of whom 166 were immunocompromised,
found that the mean Sap02/Fi02 ratio was 251 in immunocompromised patients,
compared with 276 in immunocompetent patients.13 Mild ARDS (Sap02/
FiO2 >235 mm Hg) occurred in 42.3% of the immunocompetent grouped, compared
with 33.7% of the immunocompromised group, and moderate ARDS (Sap02/
FiO2 >160 mm Hg) occurred in 25.6% of the immunocompetent group compared
with 33.1% of the immunocompromised group. No significant difference was
observed in the rate of severe ARDS (Sap02/FiO2 <100 mm Hg) between the two
groups. Immunocompromised patients had higher mortality, and among immunocom-
promised patients, older age, the presence of ARDS, and severe lymphopenia were
predictors of mortality. These studies show the shift to a higher disease severity
among COVID-19 patients.
Hematologic malignancy
Patients with hematologic malignancy have been shown to have high rates of hospi-
talization for COVID-19. For example, a European multicenter analysis of 3801 pa-
tients with hematologic malignancies who developed COVID-19 reported a
hospitalization rate of 74%.27 Other studies have also reported high hospitalization
rates; for example, Mato and colleagues28 reported a 25% admission rate among
174 patients with chronic lymphocytic leukemia (CLL). ICU admission rate has high as
18% have been observed, with a median length of stays as long as 15 days.27 Mortal-
ity is often high in hematologic patients with cancer. For example, in 174 patients with
CLL, 33% of patients died during the analysis.28 Similarly, a study of 3801 patients
with hematologic malignancies showed a mortality rate of 31%, with the highest found
in patients with AML or myelodysplastic syndrome (w40%).27 Smaller cohort studies
have confirmed a case fatality rate of about 40% among patients with hematologic
malignancy. Lastly, patients with hematologic malignancies often require vasopressor
support and renal replacement; in a cohort of patients with CLL, 27% required vaso-
pressor support and 11% required hemodialysis.28 Reassuringly, survival in patients
with CLL may be improving with newer variants.29
Solid malignancy
Several studies have shown that solid malignancy COVID-19 patients have a high hos-
pitalization rate. A French retrospective cohort study of 212 solid tumor patients with
cancer, of whom about 75% were undergoing active treatment of cancer, found a
similar 70% rate of hospitalization, but a lower rate of ICU admission (12%).30 Half
of this cohort had undergone chemotherapy in the first 3 months, and overall mortality
was 30%.
Furthermore, Dai and colleagues31 showed an ICU admission rate of 20% for 105
hospitalized patients with cancer, compared with 8% in 536 non-patients with cancer,
and ICU survivors with cancer had a mean 27-day length of stay compared with 17 in
ICU survivors without cancer. The cancer cohort in this study included patients with
lung, breast, thyroid, blood, cervical and esophageal cancer. In addition, death
occurred in 11% of the cancer cohort compared with 4% in the noncancer cohort.
Of all the cancers, hematologic and lung cancers had the highest mortality rates at
33% and 18%, respectively. This suggests that though patients with lung cancer usu-
ally do not meet the definition of immunocompromise, their risk of death is substan-
tially higher than in non-patients with cancer. Though it is not clear how lung cancer
increases mortality in patients with COVID-19, it is possible that this is either due to
the extent of preexisting lung disease or a direct effect from smoking.32 Further
work is necessary to understand the mechanisms driving increased in mortality in
lung patients with cancer with COVID-19.
In general, patients with hematologic and lung cancers or metastatic cancers had
more severe COVID-19 illness. To wit, Dai and colleagues31 found that 10% of patients
with cancer required mechanical ventilation, compared with less than 1% of non-
patients with cancer. The authors also found that patients with cancer had higher rates
of renal replacement therapy and extracorporeal membrane oxygenation compared
with non-patients with cancer, in addition to symptoms such as fever or chest pain.
Risk factors that have been reported to correlate with disease severity in immuno-
competent patients have been validated in patients with cancer.33 For example, a Chi-
nese comparative study showed that old age, d-dimer, elevated tumor necrosis factor
(TNF) alpha and N terminal pro-brain natriuretic peptide (pro-BNP) may be correlated
worsening hypoxemia in solid and hematological patients with cancer admitted with
COVID 19.34 Furthermore, in an analysis of 218 solid and hematologic patients with
cancer, D-dimer levels were twice as high in patients with cancer who died; serum
lactate and lactate dehydrogenase were also higher among decedents.35 Further-
more, CRP and ferritin have been shown to be higher in immunocompromised patients
compared with immunocompetent patients.25 This suggests that serum biomarkers
which correlate with disease severity in non-patients with cancer are also applicable
to patients with cancer.
Hematopoietic cell transplantation

A study of 382 HCT recipients in Europe during the first few months of the pandemic
showed a mortality of 22% in allogeneic transplant recipients and 28% in autologous
transplant recipients; children had a mortality of 7%, lower than adults but exponen-
tially higher than the mortality observed in children who were not HCT recipients.36,37
Older age and more severe immunodeficiency were associated with a higher chance
for death. Furthermore, an observational cohort study of 86 HCT recipients in Brazil
showed that 70% required hospitalization and 14% required ICU admission.38 Mortal-
ity in this cohort was 30%, with a 34% mortality rate among the 62 adult patients
compared with 21% in the 24 pediatric patients. In general, large studies of HCT re-
cipients who are infected with SARS-CoV-2 are lacking.
Solid organ transplant

SOT recipients also have poorer outcomes after COVID-19. In over 17,000 patients
with SOT, of whom 1682 developed COVID-19, COVID-19 increased the rate of death
by nearly ten-fold, and SOT recipients hospitalized with COVID-19 were about 2.5
times more likely to die than those hospitalized with non-SARS-CoV-2 pneumonia.39
In-hospital mortality among those who developed COVID-19 was 17%, and 21%
required ICU admission. SOT recipients with COVID-19 had an increased length of
stay (LOS) compared with SOT patients with non-COVID-19 pneumonia (6 vs.
4 days). Similar to the general population, certain comorbidities increase hospitaliza-
tion risk in SOT recipients. For example, a case-control series of 47 SOT recipients
found that chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and hyper-
tension (HTN) were more prevalent in the hospitalized patients compared with the non-
hospitalized control group.40
In 49 advanced heart failure (HF) patients admitted for COVID-19, heart transplant
(HTx) patients had worse mortality compared with left ventricular assist device
(LVAD) and HF patients.41 Specifically, mortality for the HTx group was 18.9%
compared with 12.5% for LVAD and 11.5% for HF, respectively. Similarly, HTx pa-
tients, who are often on immunosuppressive medications, have been shown to have
higher ICU LOS compared with HF patients. Kidney transplant recipients (KTx)
show similar vulnerability to COVID-19. An international registry of 9845 KTx recipients
reported that 144 patients required hospitalization.42 The mortality rate was 32%; 29%
were intubated and 52% developed acute kidney injury. Lymphopenia, elevated
lactate dehydrogenase and elevated procalcitonin were all correlated with increased
mortality. Outcomes may be more severe among lung transplant (LTx) recipients, as a
French cohort analysis of 35 LTx patients with COVID-19 reported a hospitalization
rate of 88.6%.43 42% were admitted to the ICU, and 52% required mechanical venti-
lation. 14% of the 35 LTx patients died after COVID-19.
People living with human immunodeficiency virus

COVID-19 may more severely affect PLWH who have uncontrolled HIV as compared
with their well-controlled counterparts. For example, in an Italian study of 69 PLWH, 38
hospitalized patients had an average nadir CD4 count of 167 compared 399 in those
who were not hospitalized.44 However, the hospitalization rate remains high even
among PLWH on antiretroviral therapy (ART). In a large Spanish cohort of 77,590
PLWH on ART, 63% of the 236 PLWH diagnosed with COVID-19 required hospitaliza-
tion.45 Of those 151 hospitalized patients, the ICU admission rate was about 9% and
the mortality rate was 11%. Of the 15 PLWH admitted to the ICU, the mortality rate
was 33%. The median LOS for 116 patients who survived to hospital discharge was
7 days. Similar to the general population and other immunocompromised patients,
age and number of comorbidities were highly correlated with hospitalization, ICU
admission, and death rates.
Autoimmune rheumatologic disease

Patients with rheumatologic illness are also at high risk for severe complications from
COVID-19. For example, a cohort of 58,052 Danish patients with inflammatory rheu-
matologic diseases had a 50% higher probability of admission compared with the
general Danish population of 4.5 million.46 The risk was 30% higher for patients with
rheumatoid arthritis and over 80% higher for patients with vasculitis. However, the
use of immunosuppressive agents (TNF-alpha inhibitors and steroids) surprisingly
did not impact admission rate. Hospitalized patients with rheumatoid arthritis, partic-
ularly those with lung or cardiovascular disease, may have the more severe infection
than hospitalized patients without ARD. In a case-control study comparing 2,379 pa-
tients with ARD to those without, ARD increased the risk of hospitalization by 14%,
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.47 Severe out-
comes were more 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 require-
ment for mechanical ventilation was threefold higher in patients with rheumatologic
disease compared with 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 pa-
tients 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.48
Primary immunodeficiency
Little data exist for patients who have non-HIV immunodeficiency. In an Italian case
series of seven patients with PIDs, six were hospitalized, and three were admitted
the ICU.49 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 be-
tween 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.50 Most data comes
from observational or case-control studies. In this section, we will discuss studies
that show the efficacy of antiviral, monoclonal antibodies, and convalescent plasma
to treat, preempt, or prevent COVID-19 in immunocompromised patients.
Little data exist regarding antiviral therapy and its efficacy specifically in the immu-
nocompromised. One challenge with the use of antiviral therapy is that the kinetics of
viral replication necessitate prompt therapy to ensure an adequate outcome51; 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,52 and no comparator arm was studied. Little efficacy data is available
for remdesivir in immunocompromised hosts; a case study suggested that remdesivir

can reduce viral load in immunocompromised patients with persistent infections.53 A
recent randomized, double-blind, placebo-controlled trial found that a 3-day course of
remdesivir in non-hospitalized patients with COVID-19 with high-risk conditions
reduced the risk for hospitalization or death by 87%; however, only 4% of patients
were immunocompromised.54 Given the possibility of prolonged viral replication, mul-
tiple courses or longer courses of remdesivir may be necessary in immunocompro-
mised hosts, but prospective studies comparing these strategies to usual care are
necessary. In general, the evidence for the efficacy of antiviral therapy in immunocom-
promised hosts is lacking, but antiviral therapies are reasonable to use given the high
probability of adverse outcomes in immunocompromised hosts.
It is unclear as to whether anti-inflammatory drugs are as effective in immunocom-
promised COVID-19 patients as in the general population. For example, a multicenter
cohort study of 80 KTx patients showed that the mortality rate among patients treated
with the interleukin-6 inhibitor tocilizumab was around 33%,55,56 whereas the overall
mortality rate for KTx patients with COVID-19 has been estimated to be around
24%. However, it is likely there is a selection bias as sicker patients tend to be treated
with monoclonal antibodies, and prospective studies with appropriate controls are
lacking. Similarly, studies regarding the use of the interleukin-6 inhibitor sarilumab
have also excluded patients on immunosuppressive medications. The Infectious Dis-
ease Society of America (IDSA) does not promote nor discourage the use of tocilizu-
mab and sarilumab in immunocompromised due to lack of available evidence.57 Janus
Kinase Inhibitors such as baricitinib have not been well studied in the immunocompro-
mised. Both the RECOVERY trial and COV-BARRIER trial showed that baricitinib
reduced risk of death in COVID-19 patients; however, only RECOVERY included
immunocompromised patients, whereas COV-BARRIER excluded them.58,59 The
IDSA points out that data supporting the use of Janus kinase inhibitors in immunocom-
promised hosts is lacking.
COVID-19 convalescent plasma (CCP) has been used in immunocompetent pa-
tients with variable evidence for efficacy. Although this may be useful in immunocom-
promised patients who cannot generate a humoral response, high-quality
randomized, placebo-controlled trials have shown no benefit.60 Lower quality studies
have suggested efficacy under some circumstances. For example, in a propensity
score-matched analysis of 112 patients with hematologic malignancies, most of
whom received other nonplasma therapies, the use of convalescent plasma
decreased mortality by 63% among patients who were exposed to anti-CD20 anti-
bodies in the subgroup of patients with B-cell neoplasms.61 Transfusion reactions
were rare. A Swedish cohort of 28 immunocompromised COVID-19 patients showed
that 46% had clinical improvement by at least one score one WHO scale on week after
convalescent plasma administration.62 No comparator arm was studied. The United
States Food and Drug Administration Emergency Use Authorization authorizes CCP
use in patients with immunosuppressive conditions, but data is limited and caution
is necessary when extrapolating data from immunocompetent hosts.57
VACCINATION
Vaccinations are effective for reducing mortality in immunocompromised patients. For

example, a retrospective British study examining vaccine efficacy in SOT patients
including 39260 double vaccinated patients, 1141 single vaccinated patients and
3080 unvaccinated patients showed a 20% reduction in risk of death in vaccinated pa-
tients.63 However, vaccination may not effectively decrease risk of positive SARS-
CoV-2 test, as the risk-adjusted infection incidence rate was 1.29. Moreover, although
two doses of ChAdOx1-S vaccines reduced the risk of death, similar efficacy was not
observed with BNT162b2.
However, vaccines may be less effective for the immunocompromised compared
with the immunocompetent. For example, one comparison prospective study detailing
humoral immune response between 54 immunocompetent patients and 57 immuno-
compromised patients showed that some immunocompromised patients, namely pa-
tients with PIDs and rheumatologic disease, show declining immunity to COVID-19 as
time progresses after two administrations of BNT162b2 vaccine.64 Among the immu-
nocompetent patients, PLWH and CKD patients, all had detectable antibodies at
2 weeks and 3 months post vaccination. The mean CD4 count for the PLWH was
254. However, subgroup analysis showed that 50% of the rheumatologic patients
and 94.5% of the (PID) group had antibodies at two 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 response to
COVID-19 vaccination in 15 healthy controls compared this to 74 patients previously
treated with rituximab.65 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 vacci-
nated patients reported that 40% were immunocompromised.66,67 Of the 60 immuno-
compromised 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 immuno-
compromised 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,68 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%.69 Mortality rate may
be higher after breakthrough infection in immunocompromised patients. A cohort
study of 54 fully vaccinated hematologic and solid tumor patients with cancer who
developed breakthrough COVID-19 reported a 65% hospitalization rate, 19% ICU
admission rate and 13% mortality rate,70 not markedly different from adverse event
rates among unvaccinated patients with cancer.
Pre-Exposure Prophylaxis
A preexposure prophylaxis strategy may be effective to mitigate COVID-19 severity in
the immunocompromised. The PROVENT trial is a 2:1 randomized double-blind pla-
cebo-controlled study of 5197 patients investigating the use of tixagevimab and cilga-
vimab, a cocktail of two monoclonal antibodies that bind to non-overlapping sites from
the SARS-CoV-2 spike protein, in preventing symptomatic COVID-19 in the at-risk pa-
tients, such as those with chronic obstructive pulmonary disease, immunocompro-
mise, or elderly. Results show that the medication has a 77% risk reduction
compared with placebo and 83% reduction at 6 months analysis.71 As a result, the In-
fectious Diseases Society of America guidelines and US Food and Drug Administra-
tion agree about its use for the immunocompromised to provide further protection.
However, only 7.4% of the cohort had any cancer, only 3.3% were receiving immuno-
suppressive therapies, and only 0.5% had a PID; therefore, these results are not
necessarily indicative of efficacy in all immunocompromised hosts. Nevertheless,
the use of tixagevimab and cilgavimab is reasonable given the frequent lack of humor-
al response to vaccination in immunocompromised hosts.
Post-Acute Sequelae of Coronavirus Disease-2019

Post-acute Sequelae of COVID-19 (PASC) refer to a range of ongoing health problems
that people experience usually in the weeks and months following SARS-CoV-2 pneu-
monia,.72 PASC refers to symptoms that are not explained by an alternative diagnosis,
including fatigue, shortness of breath, anosmia, chest pain, diarrhea, and fever.73,74 In
immunocompromised patients, persistent respiratory symptoms and fatigue may be
the most common.74 These symptoms can persist for an extended period of time
and, in some cases, may persist indefinitely.
PASC presents unique challenges to immunocompromised patients. A study of
1557 COVID-19 survivors with cancer showed that 15% reported PASC symptoms
at a median of 44 days after COVID-19 diagnosis, suggesting a higher incidence
than in the general population.74 The study also reported a higher hospitalization
rate and mortality rate due to PASC, but this must be interpreted in the context of other
factors related to cancer, such as the discontinuation of cancer treatment which was
independently associated with mortality. Lastly, the analysis revealed a few character-
istics that were more frequent in the 234 patients with PASC as compared with the
1323 patients without PASC. Compared with patients without COVID-19 sequalae,
a larger portion of the PASC group was male (54.5% vs 47.2%), over the age 65
(55.1% vs 48.1%), and had two or more comorbidities (48.4% vs 36.4%).74
One possibility for why immunocompromised patients may experience PASC is the
possibility of delayed viral clearance. Some reports have shown that immunocompro-
mised patients may display persistent viral infection well after initial COVID-19 diag-
nosis. For example, in addition to prior examples, one follicular lymphoma patient
showed an increase in SARS-CoV-2 viral load 54 days after symptoms onset, whereas
another patient receiving showed persistent RT-PCR (reverse transcription polymer-
ase chain reaction) positivity 238 days following SARS-Cov-2 diagnosis.53,75 A recent
report suggested that the presence of spike proteins could be associated with PASC;
in a recent study of 37 PASC patients, 84% had evidence of circulating spike protein,
as compared with 0 in 26 recovered COVID-19 patients.76 Whether the circulating
spike protein represents active SARS-CoV-2 replication or simply viral remnants is un-
clear. Further work is needed to understand PASC in patients with or without
immunocompromise.
SUMMARY
COVID-19 often results in more severe infections in immunocompromised patients.

Hospitalization rate, disease severity, and mortality rates are generally higher for the
immunocompromised, especially those with hematologic malignancies, SOT recipi-
ents, and patients with ARD. Treatment strategies for these patients are similar to
those in the immunocompetent, but high-quality data are lacking. Vaccinations are
recommended but less effective in immunocompromised patients. As the pandemic
continues, the vulnerability of immunocompromised patients should garner the atten-
tion of the medical and scientific communities. Studies focusing on immunocompro-
mised patients will help illuminate the best strategies to mitigate harms in these high-
risk patients.
CLINICS CARE POINTS
Immunocompromised patients have often develop severe SARS-CoV-2 pneumonia, and the
threshold to escalate the level of care should be low given the possibility for rapid
deterioration.
Despite the possibility of inferior rates of response to vaccination, vaccinatiion is
recommended in most immunocompromsied patients.
Though most antiviral and anti-inflammatory agents have not been specifically tested in
immunocompromised hosts, these should be initiated early given the possibility for clinical
worsening without prompt intervention.
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C o ro n a v i r u s D i s e a s e - 2 0 1 9 i n

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory virus

Infect Dis Clin N Am 38 (2024) 213–228

be impaired and lead to worsened outcomes after COVID-19. In a study comparing

Clinical Outcomes After Coronavirus Disease-2019 Infection in

Hematopoietic cell transplantation

Solid organ transplant

People living with human immunodeficiency virus

Autoimmune rheumatologic disease

for remdesivir in immunocompromised hosts; a case study suggested that remdesivir

Vaccinations are effective for reducing mortality in immunocompromised patients. For

Post-Acute Sequelae of Coronavirus Disease-2019

COVID-19 often results in more severe infections in immunocompromised patients.

CLINICS CARE POINTS

1. WHO. WHO Coronavirus disease (COVID-19) dashboard In:2022. Available at:

inflammatory bowel diseases: results from an international registry. Gastroenter-

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