TagedEnAnn Allergy Asthma Immunol 130 (2023) 713−717

Contents lists available at ScienceDirect

TagedFiur TagedEn TagedFiur TagedEn

Review

TagedH1Steroid-induced secondary immune deficiencyTagedEn

TagedPS. Shahzad Mustafa, MD*,yTagedEn

TagedP* Rochester Regional Health, Rochester, New York
y
University of Rochester School of Medicine & Dentistry, Rochester, New York

Key Messages
TagedEnP Despite their widespread clinical use, oral corticosteroids (OCSs) are well known to be associated with a myriad of adverse effects, includ-
ing immunosuppression.TagedEn
TagedEnP OCSs exert anti-inflammatory effects by blocking the function of transcription factors, thus inhibiting inflammatory cytokines, and affect-
ing leukocyte function by decreased ability to adhere to vascular endothelium and exit from the circulation, leading to neutrophilia.TagedEn
TagedEnP Prolonged OCS use leads to significant CD4 lymphopenia, and often a decrease in serum immunoglobulin (Ig)G, but has minimal impact on
circulating B cells, serum IgM, or serum IgA levels.TagedEn
TagedEnP Although there are minimal studies to date, individuals treated with prolonged OCS seem to maintain humoral response to various vaccina-
tions, but this area warrants additional research, especially with the emergence of new vaccine platforms, such as messenger RNA vaccines.TagedEn
TagedEnP Individuals treated with prolonged OCS are most at risk for opportunistic infections, especially those with underlying malignancy and his-
tory of bone marrow transplant.TagedEn
TagedEnP Risk mitigation strategies to decrease infectious complications with OCS use include limiting the dose and duration of therapy, appropri-
ately completing a full vaccination series, consideration for passive immunization, and prophylaxis against opportunistic infections.TagedEn

TagedEn
TAGEDPA R T I C L E I N F O TAGEDPA B S T R A C T

Article history:
Received for publication November 28, 2022.
Received in revised form December 29, 2022.
Accepted for publication January 6, 2023.
TagedEn
Despite their widespread clinical use, oral corticosteroids (OCSs) are well known to be associated with a myriad of
adverse effects, including immunosuppression. By inhibiting transcription factors and affecting leukocyte function, pro-
longed OCS use leads to significant CD4 lymphopenia and often a decrease in serum immunoglobulin (Ig)G. Conversely,
OCS use has minimal impact on circulating B cell, serum IgM, or serum IgA levels. Although there is a paucity of litera-
ture, individuals treated with prolonged OCS seem to typically maintain humoral response to various vaccinations
despite hypogammaglobinemia, but this area warrants additional research, especially in the setting of the coronavirus
disease 2019 pandemic. Individuals treated with prolonged OCS use are most at risk for opportunistic infections, espe-
cially those with underlying malignancy and history of bone marrow transplant. Risk mitigation strategies to decrease
infectious complication with OCS use include limiting the dose and duration of therapy, appropriately completing a full
vaccination series, consideration for passive immunization, and prophylaxis against opportunistic infections.
© 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.TagedEn

TagedH1IntroductionTagedEn
T ral corticosteroids (OCSs) are one of the most widely prescribed
agedPO
classes of medications in the world. Prednisone is the most often
prescribed OCS in the United States and the 30th most frequently
prescribed medication based on pharmacy records.1 In 2020, 21 mil-
lion Americans received more than 30 million courses of OCS. More
than 9 million individuals were treated with prednisone specifically,
with 19 million prescriptions filled. OCSs are used by nearly all clini-
cians for a variety of inflammatory and autoimmune indications, for
both acute and chronic management of a wide variety of medical
conditions. In allergy and clinical immunology, OCSs are most fre-
quently prescribed for asthma, but they are also routinely used for

TagedEnAddress correspondence to: S. Shahzad Mustafa, MD, Rochester Regional Health, 222 TagedEnDisclosures: Dr Shahzad Mustafa reports serving on the speaker’s bureau for Genen-
Alexander Street, Suite 3000, Rochester, NY 14607. E-mail: shahzad.mustafa@ tech, AstraZeneca, Regeneron, GlaxoSmithKline, Aimmune, and CSL Behring.
rochesterregional.org. TagedEnFunding: Dr Shahzad Mustafa has no funding sources to report.

https://doi.org/10.1016/j.anai.2023.01.010
1081-1206/© 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
TagedEn714 TagedFiur
S.S. Mustafa / Ann Allergy Asthma Immunol 130 (2023) 713−717

urticaria and angioedema, chronic rhinosinusitis with nasal polypo-

sis, and even common variable immunodeficiency for complications
such as granulomatous and lymphocytic interstitial lung disease.
Despite their widespread clinical use, OCSs are well known to be
associated with a myriad of adverse effects, including, but not limited
to, adrenal suppression, osteoporosis, hyperglycemia, neuropsychiat-
ric manifestations, cataracts, glaucoma, and immunosuppression.2
The purpose of this review is to discuss the mechanisms of action of
OCS, and their resulting impact on immune function, with a focus
on both cellular immunity and humoral immunity. The review will
also discuss strategies to minimize the negative impact of OCS
on immune function and unmet needs and potential for future
research.TagedEn

TagedH1Mechanism of Action and Short-Term Immune EffectsTagedEn

TagedPOCSs have both glucocorticoid and mineralocorticoid effects, with
each form having slightly unique properties. Furthermore, the
absorption and efficacy of OCS vary among individuals, as do their
adverse effects. OCSs passively diffuse across the cellular membrane
and bind to the intracellular glucocorticoid receptor, creating a com-
plex that translocates into the nucleus and interacts directly with
DNA sequences and various transcription factors.3 This complex
inhibits the synthesis of numerous inflammatory cytokines by block-
ing the function of various transcription factors, including nuclear
factor kappa B (NF-kB) and activator protein-1 (AP-1), which are
required for the transcription of proinflammatory mediators. More- Figure 1. Immune defects associated with chronic OCS use. Ig, immunoglobulin; OCS,
oral corticosteroid.TagedEn
over, OCSs exert anti-inflammatory effects by blocking the action of
proinflammatory genes, such as interleukin (IL)-1-alpha and IL-1-
beta. OCSs decrease the peripheral function of leukocytes and the
also be affected by even short courses (5-10 days) of OCS, with tran-
numbers of lymphocytes, monocytes, basophils, and eosinophils.
sient decreases lasting up to several weeks.12 Levels of IgM and IgA
After these initial effects, OCSs decrease the expression of additional
are less affected, and frequently remain in the reference range
inflammatory mediators, such as prostaglandins, leukotrienes, and
despite OCS use.13 A close-to-normal serum IgA level may help differ-
platelet-activating factor. A key role of OCS is their ability to affect
entiate between cases of primary and secondary immunodeficiency,
neutrophil function by reducing their adherence to the vascular
because individuals with secondary immunodeficiency (ie, because
endothelium. By affecting the release of cytokines such as tumor
of OCS use) typically have preserved IgA levels, whereas those with
necrosis factor and IL-1, OCSs are able to inhibit the function of mac-
primary immune defects tend to have decreased or absent IgA.14,15
rophages and other antigen-presenting cells by limiting chemotaxis,
Although OCS use frequently causes mild to moderate decreases in
and thus bactericidal activity. OCS-induced leukocytosis results from
IgG levels, severe hypogammaglobinemia, frequently considered an
the reduced ability of leukocytes to adhere to the vascular endothe-
IgG level below 400 mg/dL, warrants additional evaluation for other
lium and exit from the circulation, leading to neutrophilia, thus
causes of immunodeficiency.TagedEn
impairing entry into sites of infection and tissue injury. Neutrophilia
also results from an increase in liberation of mature polymorphonu-
clear leukocytes from the bone marrow into circulation, along with
decreased apoptosis.4 Of note, in the setting of OCS use and resulting TagedH1Vaccine ResponsesTagedEn
leukocytosis, it is essential to closely monitor for clinical signs of
TagedPEven in the setting of OCS-induced hypogammaglobinemia, indi-
infections, such as fever and left shift with peripheral white blood
viduals seem to maintain adequate response to vaccination (Table 1).
cells because of the release of band neutrophils, which is rare in OCS-
Lack et al16 revealed that 7 children with OCS-dependent asthma and
induced leukocytosis.5TagedEn
hypogammaglobinemia ranging from IgG level of 275 to 443 mg/dL
maintained adequate antibody response to both peptide and polysac-
charide antigens, including a neoantigen, bacteriophage ɸX174, sug-
TagedH1Immune Defects of Chronic Oral Corticosteroid UseTagedEn
gesting maintained humoral function despite abnormal IgG levels. In
TagedPThe administration of OCS results in the redistribution of lympho- another small study comparing vaccine response in 3 groups of adult
cytes to the bone marrow, spleen, and lymph nodes, and acute lym- patients, (OCS-treated people with asthma who had low levels of IgG,
phopenia can be detected within hours of exposure, which will OCS-treated people with asthma who had normal levels of IgG, and
normalize in 24 to 48 hours.6 Subsequently, CD4 T-cell lymphopenia people with asthma who had never been treated with OCS), all
is the most common immune defect associated with chronic OCS groups equally responded to vaccination to tetanus toxoid, influenza,
use.7 Although OCSs do not cause significant acute changes in the and pneumococcal polysaccharide vaccine (PPSV23). There was no
numbers of circulating B cells,8 hypogammaglobinemia is frequently difference in magnitude of IgG response between the groups.17 Simi-
noted in the setting of OCS use (Fig 1). There are multiple proposed larly, Lahood et al18 compared 14 patients with asthma on predni-
mechanisms leading to hypogammaglobinemia with OCS use, includ- sone 10 to 35 mg to 14 patients with asthma not on chronic OCS, and
ing down-regulation of genes contributing to immunoglobulin syn- both groups had similar IgG levels in the reference range, with similar
thesis, decreased immunoglobulin synthesis because of increased response to PPSV23. In contrast, children with nephrotic syndrome
apoptosis of B-cell subsets along with plasma cells, and increased treated with OCS had lower IgG level to PPSV23 but still had
immunoglobulin catabolism.9-11 Immunoglobulin (Ig)G levels can increased IgG level as compared with baseline, and this difference
 TagedEnS.S. Mustafa / Ann Allergy Asthma Immunol 130 (2023) 713−717
TagedEnTable 1
Summary of Studies Evaluating Vaccine Responses While on OCS
Population Vaccine
Children with OCS-dependent asthma Bacteriophage ɸX174
Tetanus
Diphtheria
Haemophilus influenza type B
Pneumococcal polysaccharide
Adults with OCS-dependent asthma Tetanus
Influenza
Pneumococcal polysaccharide
Adults with OCS-dependent asthma Pneumococcal polysaccharide
Children with OCS-dependent nephrotic syndrome Pneumococcal polysaccharide
Adults with rheumatologic illness Influenza
Adults with OCS-dependent pulmonary disease Influenza
Children and adults with asthma Influenza
Adults with chronic inflammatory conditions mRNA COVID-19
Abbreviations: COVID-19, coronavirus disease 2019; mRNA, messenger RNA; OCS, oral corticosteroid.
could potentially be explained by urinary protein losses rather than
dysfunction in humoral immunity.19TagedEn
TagedPIn regard to influenza vaccination, Herron et al20 compared 32
healthy controls with 62 patients with rheumatologic disease treated
with OCS and found similar seroconversion in both groups, but the
OCS-treated patients had a lower magnitude of response as com-
pared with non−OCS-treated counterparts. A more recent study con-
cluded that adult patients with pulmonary conditions treated with
OCS (stable daily dose of prednisone 2.5-60 mg daily for more than
30 days) had similar antibody response to inactivated influenza virus
vaccination as a matched cohort not treated with chronic OCS.21 The
results of the largest study to date evaluated 294 individuals with
asthma and suggest that OCS use may decrease the magnitude of
humoral response to the influenza vaccine.22TagedEn
TagedPLast, in the setting of the coronavirus disease 2019 (COVID-19)
pandemic, a prospective observational cohort study of 186 partici-
pants strongly suggested that the 17 individuals treated with chronic
OCS of an average dose of prednisone 6.5 mg (range 1-20 mg daily)
had significantly decreased antibody response to 2 doses of messen-
ger RNA (mRNA) vaccination against COVID-19.23 Similarly, Deepak
et al24 concluded that in patients with chronic inflammatory disease,
OCS use with prednisone leads to a 10-fold reduction in humoral
response to 2 mRNA doses of vaccination against COVID-19. Interest-
ingly, the blunted vaccine response to mRNA vaccination against
COVID-19 was independent of dose, with effect noted in some
patients on less than prednisone 5 mg daily. OCS use had the most
pronounced effects on mRNA vaccine response when combined with
other immunosuppression agents, and effects were variable with
other vaccinations, such as influenza vaccine. Thus, mRNA-based
COVID-19 vaccination may be more susceptible to the immunosup-
pressive effects of OCS as compared with other vaccine platforms.
The American College of Immunization Practices guidelines consider
any individual on more than prednisone 20 mg/d (or the equivalent)
for more than 2 weeks to be moderately to severely immune compro-
mised.25 These individuals should discuss the benefits of vaccination
against COVID-19 vs delaying vaccination until a lower dose of OCS
can be achieved. Individuals on chronic OCS are eligible for passive
preexposure prophylaxis against COVID-19 with tixagevimab/cilgavi-
mab (Evusheld), which has emergency use authorization by the US
Food and Drug Administration for people who are moderately to
severely immunocompromised and potential inability to mount an
adequate response to COVID-19 vaccines. However, efficacy of tixage-
vimab/cilgavimab is waning because of the emergence of COVID-19
variants. Despite the literature to date being reassuring that OCS use
does not significantly blunt humoral immune response, more
research is necessary to better understand the effects of dose and
715
Humoral response in OCS-treated individuals References
Adequate antibody responses to both peptide and Lack et al,16 1996
polysaccharide vaccines
Adequate antibody responses to both peptide and Katz et al,17 1988
polysaccharide vaccines
Adequate antibody response Lahood et al,18 1993
Decreased antibody response Spika et al,19 1982
Adequate rates of seroconversion, but decreased Herron et al,20 1979
magnitude of antibody response
Adequate antibody response Kubiet et al,21 1996
Possibly decreased magnitude of antibody Hanania et al,22 2004
response
Significantly decreased antibody response Deepak et al,23 2021
duration of OCS use on specific vaccine responses and humoral
immunity. The current studies are small in numbers, focus almost
exclusively on humoral rather than cellular response, and have no
information regarding long-term memory or impact on clinical out-
comes.TagedEn
TagedH1Infectious ComplicationsTagedEn
TagedPDespite the seemingly minimal impact on immune parameters,
use of OCS has been consistently related to an increased risk of clini-
cally meaningful infectious complications. High-dose OCS use (typi-
cally considered prednisone 20 mg daily or the equivalent for more
than 1 month) clearly increases the risk of opportunistic infections,
such as Pneumocystis jirovecii. Individuals on these doses of OCS are
susceptible to viral infections such as atypical mycobacterial infection
and cytomegalovirus infection, fungal infections, including endemic
mycoses, cryptococcosis, aspergillosis, and candidiasis.26,27 The risk
of these invasive fungal and viral infections is greatest in bone mar-
row transplant recipients receiving OCS.28 O’Donnell et al29 retro-
spectively reviewed 331 allogeneic bone marrow recipients and
found that the major risk factor for candidemia or aspergillosis was
treatment with prednisone (0.5-1mg/kg/d). Furthermore, several
studies from the Fred Hutchinson Cancer Research Center and Uni-
versity of Washington found not only an increased risk of invasive
mold infections (including Aspergillus and Zygomycetes) but also an
increased risk of death from these infections in bone marrow trans-
plant patients receiving high-dose corticosteroids.30,31 Herpes zoster
may also occur more frequently among individuals on OCS, and even
at lower doses. In an analysis of more than 28,000 patients with rheu-
matoid arthritis, OCS use (prednisone ≥7.5 mg/d) was a significant
independent risk factor for development of herpes zoster.32TagedEn
TagedPIn addition to opportunistic infections, prolonged use of OCS has
been suggested to increase the risk of bacterial infection. Many of
these studies have found a dose response, with infectious complica-
tions arising at higher doses of OCSs, and typically more than predni-
sone 10 mg daily or the equivalent. A meta-analysis of 71 clinical
trials involving more than 2000 patients randomly allocated to OCS
therapy found the overall rate of infectious complications to be sig-
nificantly higher in patients using OCSs vs control subjects (8% con-
trol group, 12.7% in OCS group [risk ratio, 1.6; 95% confidence
interval, 1.3-1.9; P < .001]). However, the rate of infections was not
increased in patients given a daily dose of less than 10 mg or a cumu-
lative dose of less than 700 mg of prednisone.33 In patients with
rheumatoid arthritis, prednisone use increased the risk of pneumonia
hospitalization, also in a dose-dependent manner (hazard ratio 1.7
TagedFiurTagedEn716
Figure 2. Risk mitigation for infectious complications. OCS, oral corticosteroid.TagedEn
[95% confidence interval, 1.5-2.0]), after adjustment for covariates.
The hazard ratios with doses of less than or equal to 5 mg/d, greater
than 5 to 10 mg/d, and greater than 10 mg/d were 1.4, 2.1, and 2.3,
respectively.34 In an even larger meta-analysis of more than 8700
patients, bacterial sepsis occurred 1.5 times more frequently in
patients using OCS than in those using placebo (P < .01). Similar to
other reports, the mean daily dose was the equivalent of 35 mg of
prednisone and the mean total dose was 2200 mg of prednisone for
these patients.35TagedEn
TagedH1Strategies for Risk MitigationTagedEn
TagedPGiven the risk of infectious complications with OCS use, strategies
to mitigate this risk should be considered (Fig 2). Limiting the duration
of therapy is an important first step, hopefully facilitated by an
expanding arsenal of steroid-sparing medical therapies. The cumula-
tive dose of OCS should also be minimized. A goal dose of prednisone 5
to 10 mg daily is likely to have less immunosuppressive effects as com-
pared with higher doses. Administration of OCS on an alternate-day
schedule may also minimize immunosuppression, as it has been found
to decrease the negative impact on leukocyte function.36 Although vac-
cine responses are likely maintained at lower doses of OCS, all indi-
cated vaccinations should be administered before initiation of
prolonged courses of OCS use if possible. Conversely, if OCS doses are
being tapered, non-urgent vaccines may be deferred until lower doses,
in hopes of maximizing humoral response. For individuals at high risk
of secondary immunodeficiency and suboptimal vaccine response, one
should consider passive immunization. For COVID-19, tixagevimab/cil-
gavimab (Evusheld) should be considered. In individuals with more
severe immune compromise, such as those with significant hypogam-
maglobinemia and impaired vaccine responses who are experiencing
recurrent bacterial infections, immunoglobulin replacement therapy
may be indicated. By extrapolating studies from individuals with
human immunodeficiency virus and acquired immunodeficiency syn-
drome, individuals on prednisone 20 mg daily for more than 1 month
should receive prophylaxis against Pneumocystis jirovecii.37TagedEn
TagedH1ConclusionTagedEn
TagedPDespite their widespread clinical utility, OCS must be used cau-
tiously and sparingly because of a myriad of adverse effects, including
immunosuppression and increased risk of infectious complications.
Lymphopenia and hypogammaglobinemia are common, but humoral
immunity generally remains intact, as evidenced by intact vaccine
S.S. Mustafa / Ann Allergy Asthma Immunol 130 (2023) 713−717
responses. For individuals requiring prolonged use of OCS, clinicians
must implement strategies to minimize the risk of infections, such as
thoughtful timing of vaccinations, prophylaxis against opportunistic
infections, and consideration of passive immunization.TagedEn
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