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Glucocorticoid effects on the immune system

Author: W Winn Chatham, MD
Section Editors: Jordan S Orange, MD, PhD, Kieren A Marr, MD
Deputy Editors: Anna M Feldweg, MD, Sheila Bond, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2020. | This topic last updated: Aug 04, 2020.

INTRODUCTION

Glucocorticoids (corticosteroids) have inhibitory effects on a broad range of immune responses.

Because of their inhibitory effects on multiple types of immune cells, glucocorticoids are
remarkably efficacious in managing many of the acute disease manifestations of inflammatory
and autoimmune disorders [1].

The mechanisms of action of glucocorticoids upon the various effector cells of the immune
system, as well as the effect of glucocorticoids on infection risk and vaccination, will be reviewed
here. The effects of glucocorticoids on other specific physiologic systems are presented
separately:

● (See "Major side effects of systemic glucocorticoids".)

● (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
● (See "Glucocorticoid-induced myopathy".)
● (See "Glucocorticoid effects on the nervous system and behavior".)

GENERAL MECHANISM OF ACTION

Glucocorticoids diffuse passively across the cellular membrane and bind to the intracellular
glucocorticoid receptor. Binding of the drug to this receptor creates a complex, which then
translocates into the nucleus, where it can interact directly with specific DNA sequences
(glucocorticoid-responsive elements [GREs]) and other transcription factors.

Effects on gene transcription — Binding of the receptor to GREs may result in either enhancement
or suppression of transcription of susceptible downstream genes. The anti-inflammatory effects
of glucocorticoids result from the following:
 ● Binding to and blocking promoter sites of proinflammatory genes, such as interleukin (IL)-1-
alpha and IL-1-beta [2].

● Recruiting of transcription factors to promoter sequences of genes coding for anti-

inflammatory gene products including I-kappa-B-alpha, IL-1 receptor-II, lipocortin-1 (annexin
1), IL-10, alpha-2-macroglobulin, and secretory leukocyte-protease inhibitor [3-5].

● Inhibition of the synthesis of almost all known inflammatory cytokines. This is primarily
achieved by competing for or blocking the function of transcription factors, such as nuclear
factor-kappa-B (NF-kB) and activator protein-1 (AP-1), which are required for transcription of
proinflammatory mediators [3,5-8]. This may be mediated in part by glucocorticoid-induced
expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and consequent
dephosphorylation of various proteins that participate in intracellular signaling [8]. These
include Jun N-terminal kinase (interfering with production of c-Jun and AP-1), extracellular
signal-related kinase 1 and 2, and p38 MAPK. Glucocorticoids increase the synthesis of I-
kappa-B-alpha, a protein that traps and thereby inactivates NF-kB [3,5].

Effects on post-translational events — In addition to their effects on gene transcription,

glucocorticoids also inhibit secretion of inflammatory cytokines by affecting post-translational
events [8]. The stability of messenger RNA (mRNA) encoding IL-1, IL-2, IL-6, IL-8, tumor necrosis
factor, and granulocyte-macrophage colony-stimulating factor is diminished in the presence of
glucocorticoids [9].

Noted consequences of the effects of glucocorticoids on gene transcription include the following:

● Upregulating the synthesis of angiotensin-converting enzyme and neutral-endopeptidase

enzymes that degrade bradykinin, which is a vasodilatory peptide central to the generation of
some forms of angioedema [10].

● Suppressing production of inflammatory eicosanoids in phagocytic cells by inducing the

synthesis of lipocortin-1 (annexin 1), macrocortin, and/or lipomodulin, all of which inhibit
phospholipase A2-mediated liberation of arachidonic acid from membrane phospholipids [11-
15].

● Suppressing the synthesis of cyclooxygenase (COX)-2, the inducible isoform of

cyclooxygenase primarily responsible for production of prostaglandins at sites of tissue injury
and inflammation [16]. This effect primarily results from glucocorticoid suppression of NF-kB
transcription. Glucocorticoids do not appear to affect the synthesis of constitutive COX-1.

DOSE RANGES
Some immunologic effects of glucocorticoids are dose-dependent, due primarily to variable
affinity of target genomic sites for the complex of glucocorticoid and glucocorticoid receptor.
High-affinity genomic sites may be affected by low levels of glucocorticoids, with additional genes
affected as the concentration of glucocorticoid increases. Administration of high-dose pulse
glucocorticoids may result in nonspecific general disruption of gene transcription. High-dose pulse
glucocorticoids may also have more rapid effects on leukocyte aggregation, possibly as a
consequence of effects on the expression of leukocyte-adhesion molecules and disruption of
calcium flux across membranes [17,18].

Individuals differ in their susceptibility to the therapeutic and adverse effects of glucocorticoids.
The proposed mechanisms responsible for this heterogeneity are reviewed separately. (See
"Mechanisms and clinical implications of glucocorticoid resistance in asthma", section on
'Mechanisms of glucocorticoid resistance'.)

Low-to-moderate doses — Low-to-moderate doses of prednisone may be defined as doses up to 1

mg/kg per day of prednisone in children or 40 mg per day in adults, as this is an approximate
threshold at which significant toxicities begin to appear with extended use in most individuals.
Equivalent doses of other glucocorticoids are shown in the table (table 1).

Higher doses — Doses >1 mg/kg per day in children or >40 mg daily in adults can be considered
higher doses for the purpose of immune function. The immunologic effects of higher-dose, short-
term pulse therapy have also been studied. The acute effects of 1 gram of intravenous
methylprednisolone were evaluated in a small study of patients with rheumatoid arthritis who were
given either one or three daily doses of methylprednisolone (1 gram per dose) [19]. Lymphopenia
developed within 2 hours of the dose, peaked at 6 hours, and resolved by 24 hours with both
regimens. Patients were followed for 16 weeks, during which skin test positivity to purified protein
derivative was unaffected, serum immunoglobulin levels were unchanged, and primary antibody
responses to antigens were normal. In vitro, lymphocyte proliferation to mitogens was maximally
suppressed at concentrations of glucocorticoid that would be achieved by the administration of
approximately 1 gram of intravenous methylprednisolone [20].

EFFECTS ON IMMUNE CELLS

Changes in the complete blood count and differential — The administration of glucocorticoids

predictably results in a neutrophilic leukocytosis. The timeframe in which neutrophilia is observed
is inversely proportional to the administered dose, with elevated leucocyte counts noted within
four hours following the initiation of treatment with moderate-to-high doses of glucocorticoids.
(See 'Phagocytes' below.)

In some patients, particularly neonates exposed to betamethasone antenatally, there may be a

slight increase in the percentage of bands on the differential blood count [21]. However, the
appearance of immature neutrophils in the peripheral blood differential is noted only rarely in adult
patients following glucocorticoid administration. As such, the presence of bands or other
immature neutrophils in the peripheral blood of adult patients is best presumed to be evidence of
intercurrent infection [22].

Changes in other cell lines include the following:

● Administration of even low doses of glucocorticoids leads to dramatic reductions in

circulating eosinophils. (See 'Eosinophils' below.)

● Transient minor decreases in monocytes may be observed within one to two hours, often
preceding the increase in neutrophils [23]. (See 'Phagocytes' below.)

● Transient minor reductions in total lymphocytes may also occur acutely, sometimes with more
sustained lymphopenia [24]. However, effects of glucocorticoids on circulating lymphocyte
subsets are variable. (See 'Lymphocytes' below.)

● Glucocorticoids have no immediate direct effects on erythrocyte and platelet counts; however,
sustained use may reverse the anemia and thrombocytosis seen as a consequence of chronic
inflammation.

Changes in cell function and survival

Leukocyte trafficking — Glucocorticoids have profound effects on the cellular functions of

leukocytes and endothelial cells, resulting in reduced ability of leukocytes to adhere to vascular
endothelium and exit from the circulation, leading to a neutrophilia. Entry to sites of infection and
tissue injury is impaired, resulting in suppression of the inflammatory response [24-26]. Reduction
in endothelial adhesion may be due to direct effects of glucocorticoids on expression of adhesion
molecules on both leukocytes and endothelial cells, as well as indirect effects due to the inhibitory
effects of glucocorticoids on transcription of cytokines, such as IL-1 or tumor necrosis factor
(TNF), which upregulate endothelial adhesion molecule expression. The normal process of
leukocyte-endothelial adhesion during inflammation is reviewed separately. (See "Leukocyte-
endothelial adhesion in the pathogenesis of inflammation".)

Phagocytes — Phagocytes are a critical component of the innate immune response, and

glucocorticoids affect the functions of various phagocytic cells, including neutrophils, monocytes,
and macrophages.

● Neutrophils: The main impact of glucocorticoid treatment on neutrophil function is

impairment of migration to sites of inflammation or infection. Neutrophil migration through
the vasculature to sites of inflammation is severely impaired. This, combined with enhanced
release of cells from the bone marrow and inhibition of neutrophil apoptosis, results in
increased numbers of circulating neutrophils [24,27,28].
 In contrast to migration, neutrophil phagocytic responses or bactericidal activities do not
appear to be significantly impaired at low-to-moderate doses of glucocorticoids, although at
high doses, phagocytic function may be inhibited [29-31].

● Monocytes and macrophages: Glucocorticoids diminish the production of

monocyte/macrophage-derived eicosanoids and inflammatory cytokines (IL-1, TNF) and also
inhibit macrophage phagocytic and microbicidal function [24,25,32,33]. Clearance of
opsonized bacteria by the reticuloendothelial system is reduced [34]. There is reduced
elaboration of macrophage migration inhibition factor and decreased expression of adhesion
molecules required for transmigration, resulting in reduced accumulation of monocytes and
macrophages in the tissues and a slight increase in circulating levels of these cells [35,36].

Antigen presentation and expression of class II human-leukocyte antigen molecules by

macrophages is downregulated in response to glucocorticoids [37]. This effect, coupled with
the effect of glucocorticoids on dendritic cells, may account for the significant impact of
glucocorticoids on acquired immunity. However, a number of macrophage effector functions
that are associated with inflammatory disorders appear to be refractory to or may actually
increase in the context of treatment with glucocorticoids [38]. Most notable among these are
the expression of major histocompatibility complex class I molecules and the secretion of
chemokines (including CCL5, CXCL1, and CXCL2) involved in leucocyte recruitment [38]. This
observation may partly account for the limited efficacy of glucocorticoids in managing
macrophage-mediated disorders, such as Erdheim-Chester disease, fibrotic lung disease, or
macrophage activation syndromes. The effects of glucocorticoids on dendritic cells are
discussed more below. (See 'Dendritic cells and antigen presentation' below.)

● Natural killer cells: Total numbers of circulating natural killer (NK) cells are not significantly
altered following glucocorticoid administration. However, in a study examining acute effects
of hydrocortisone administration on lymphocyte subsets, numbers of immature NK cells were
noted to decrease, whereas numbers of mature NK cells increased. Notably, sustained
upregulation of NK cell activation genes, including KIR3DL2, KLRC3, KLRD1, and GPR56, were
observed as early as one hour after hydrocortisone infusion [23,39]. (See "NK cell deficiency
syndromes: Clinical manifestations and diagnosis", section on 'Biology of NK cells'.)

Lymphocytes — The administration of glucocorticoids causes an acute lymphopenia that is

maximal at 4 to 6 hours and normalizes by 24 to 48 hours. This is predominantly the result of
redistribution of lymphocytes to bone marrow, spleen, thoracic duct, and lymph nodes [19,24]. T
cells are affected more than B cells, although the effect on T cell subsets is variable.

B cells and immunoglobulin levels — Glucocorticoids do not cause significant acute

changes in the numbers of circulating B cells [23]. With prolonged glucocorticoid administration,
numbers of circulating B lymphocytes may be reduced, although to a much lesser extent than
those of T cells [40]. Although there is significant variability among patients, levels of
immunoglobulin (Ig)G and IgA may decrease by 10 to 20 percent over the first few weeks of
treatment with moderate-to-high dose glucocorticoids given short-term, then return to normal over
weeks to months. IgM levels have not been shown to be affected [41-44]. In vitro exposure of B
cells to therapeutic (10nM) concentrations of dexamethasone has been shown to inhibit IL-4 and
anti-CD40-induced expression of activation-induced cytidine deaminase, the primary regulator of
immunoglobulin gene somatic hypermutation and class-switch recombination in B lymphocytes
[45]. This observation may account for the noted inhibitory effects of glucocorticoids on IgG and
IgA levels relative to the absence of noted effects on IgM levels. Glucocorticoids also increase
immunoglobulin catabolism [46]. In contrast, IgE levels may increase, due to the enhancing effects
of glucocorticoids on IL-4-induced B cell isotype-switching to IgE [47]. (See "Normal B and T
lymphocyte development".)

The following studies have examined the impact of short-term systemic glucocorticoids on
immunoglobulin levels:

● The effect of high-dose, short-term therapy was evaluated in a study of 12 patients with
rheumatoid arthritis, who were given either a single dose of methylprednisolone (1 gram) each
morning for four days or 1 gram three times daily for four days [19]. With both doses, mean
serum IgG levels fell by 10 to 20 percent at one week, then normalized by one month, and
remained normal at four months post-treatment. Another study observed similar changes (20
percent decrease in IgG, which was maximal at two to four weeks after high-dose
methylprednisolone) [48]. IgA dropped 17 percent, with maximal changes at six to eight
weeks.

● In a study of 21 children and adults with asthma who required systemic glucocorticoid
therapy for a mean of eight days, 8 received high-dose intravenous methylprednisolone, and
13 received lower doses of oral prednisone. IgG, IgM, IgA, and IgE levels were compared with
a control group of 20 patients (with or without asthma) who did not require glucocorticoids
[43]. Doses ranged from 20 to 250 mg of prednisone (or equivalent) per day. Of the 21
patients who received glucocorticoids, 15 showed a reduction in IgG of 10 to 15 percent,
which was maximal at two to four weeks after the start of therapy. Levels were approaching
normal by eight weeks. IgA changed in a similar manner, and IgM did not change. IgE was
higher in the treated patients throughout the study. Another study of nine patients with
asthma treated with an average dose of 17 mg of prednisone daily for 15 days found a 22
percent decline in IgG levels and a decline in IgA levels, with no change in IgM, similar to the
previous study [41].

The impact of long-term glucocorticoid therapy is less well-studied, but it appears that a subset of
patients on chronic glucocorticoid therapy can become hypogammaglobulinemic [42,49,50].

● In a study of 253 children hospitalized for severe asthma, the mean IgG level of the group was
25 percent lower than normal, a statistically significant difference [50]. The mean IgM level of
 the group was 10 percent higher, and the mean IgA level was normal. The lowest IgG levels
were in steroid-dependent patients, with one-third of this subset having levels <2 standard
deviations below the normal mean.

● In a study of 101 unselected adults with asthma of all severities, the mean IgG of the group
was lower than normal, but the difference was not statistically significant [49]. Mean IgA and
IgM levels were not different from normal. Twelve individuals were hypogammaglobulinemic,
with serum IgG <600 mg/dL (range 315 to 595) [49]. These patients did not have more
sinopulmonary infections. Hypogammaglobulinemia was most strongly associated with an
average daily dose of ≥5 mg for at least two years.

Response to pneumococcal vaccination may serve to differentiate hypogammaglobulinemia due

to humoral immune deficiency from that due to prolonged glucocorticoid therapy, when this
determination may be clinically required. (See 'Impact on vaccination' below.)

T cells — In the low-to-moderate dose range, glucocorticoids have variable effects on T

lymphocyte subsets. Following glucocorticoid administration, total T cells may be slightly reduced
in the circulation, with immature, naïve CD4+ T cells affected more than mature CD4+ effector and
memory subsets, T helper (Th)17+ T cells, and CD8+ effector T cells, all of which have been
observed to transiently increase following administration of hydrocortisone [23,51]. The
percentages of circulating T regulatory cells have been shown to increase in patients with lupus
and also in patients with sarcoidosis treated with intravenous methylprednisolone or prednisone,
respectively [51-53]. At higher doses, glucocorticoids produce a rapid depletion of most circulating
T cells due to a combination of effects including:

● Enhanced circulatory emigration [24]

● Inhibition of interleukin (IL)-2, a principal T cell growth factor, and IL-2 signaling [54]
● Impaired release of cells from lymphoid tissues
● Induction of apoptosis [55-60]

Glucocorticoids also inhibit the acute generation of both Th1- and Th2-derived cytokines by
activated T cells, although the inhibitory effect on expression of Th1 cytokines appears to be
greater [61]. Thus, treatment with glucocorticoids may be associated with a shift in the expression
of Th2-derived cytokines relative to Th1 cytokines (table 2) [62,63].

Delayed-type hypersensitivity reactions — The effect of glucocorticoids on delayed-type

hypersensitivity (DTH) responses is variable. Glucocorticoids may result in cutaneous anergy,
primarily due to the failure of inflammatory cells to be recruited to the site of the reaction [64].
However, another report of six patients treated with high-dose methylprednisolone found no effect
on DTH responses [19]. Similarly, long-term, low-dose methylprednisolone (4 mg daily for 36 years)
had no effect on one patient's DTH responses in a case report [44].
 Eosinophils — Glucocorticoids promote eosinophil apoptosis (the opposite of their effect on
neutrophil apoptosis) either directly or by attenuating synthesis of IL-5, a cytokine that promotes
eosinophil survival [28,65]. Following glucocorticoid administration, circulating levels of
eosinophils are markedly and rapidly reduced [66]. This is mediated in part by sequestration of
eosinophils in extravascular tissues, possibly due to the preferential upregulation of the CXC
chemokine receptor 4 [67]. Glucocorticoids have variable inhibitory effects upon the degranulation
of eosinophils that are dependent upon the activating ligand and the glucocorticoid used in the
assay [68].

Mast cells and basophils — Glucocorticoids have been shown in vitro to inhibit both production
of cytokines and degranulation by mast cells. The noted inhibition of inflammatory cytokine
production by mast cells appears to occur through suppression of gene transcription as described
for other leukocytes. The inhibition of mast cell degranulation by glucocorticoids has been shown
to be time-dependent, mediated through the upregulation of inhibitory regulators of signaling, such
as src-like adapter protein-1 [69-71].

Dendritic cells and antigen presentation — Glucocorticoids induced a marked reduction in

circulating dendritic cells in humans [72]. This effect appears to be mediated at least in part by
glucocorticoid-induced apoptosis of resident dendritic and/or CD34+ precursor-derived CD14+
dendritic cells [73]. Given the central antigen-presenting function of dendritic cells in stimulating
naïve T cells, treatment with glucocorticoids may impair the development of immunity to newly
encountered antigens. (See 'Impact on vaccination' below and 'Infection risk' below.)

INFECTION RISK

Systemic glucocorticoid therapy is associated with an immediate increase in the risk of infection,
especially with common bacterial, viral, and fungal pathogens, due to its dose-dependent inhibitory
effects on phagocyte function. In addition to glucocorticoid dose, the intensity of therapy and
several patient-specific factors influence infection risk. In contrast to systemic therapy, inhaled
and topical corticosteroids are usually not implicated in increased risk of systemic infections. The
side effects of inhaled and topical corticosteroids are reviewed elsewhere. (See "Major side
effects of inhaled glucocorticoids" and "Topical corticosteroids: Use and adverse effects", section
on 'Adverse effects'.)

Dose and intensity of therapy — Infection risk is directly related to glucocorticoid dose. The risk
begins to normalize as soon as high-dose therapy is complete. In contrast, the effects on
phagocytic cell function with longer-term, low-dose use are minimal, but there may be some
inhibition of adaptive immune responses with increasing duration of therapy. For these reasons,
glucocorticoid-sparing therapies and alternate-day dosing are advisable when possible.
Patient-specific factors — Patient-specific factors that may influence infection risk include
underlying disease(s), the presence of concomitant immunosuppressive therapies [74,75], and
whether the patient is hospitalized. When used in combination with other immunosuppressive
drugs, as in recipients of solid organ transplants, there is a risk of both newly acquired infections
and reactivation of latent viral infections. These infectious complications are discussed in more
detail elsewhere. (See "Infection in the solid organ transplant recipient".)

Older patients and those with lower functional status are also at higher risk for infection [76]. In
addition, patients taking glucocorticoids may not manifest signs and symptoms of infection as
clearly, due to the inhibition of cytokine release and associated reduction in inflammatory and
febrile responses. This can impair early recognition of infection.

Types of infections — Common viral (mainly herpes viruses), bacterial (Staphylococcus aureus and
others), and fungal (mainly Candida species) pathogens are encountered with greater frequency in
a dose-dependent manner during therapy with glucocorticoids.

● Herpes zoster may occur more commonly among patients taking low-dose glucocorticoids. In
an analysis of >28,000 patients with rheumatoid arthritis, glucocorticoid therapy (prednisone
≥7.5 mg/day) was a significant independent risk factor for development of herpes zoster [77].
The use of zoster vaccines in patients receiving glucocorticoids is discussed separately. (See
"Vaccination for the prevention of shingles (herpes zoster)", section on 'Immunocompromised
hosts'.)

● Tuberculosis is a concern in patients receiving moderate-to-high doses of glucocorticoids for

prolonged periods of time. This is discussed in more detail in related topics. (See "Prophylaxis
of infections in solid organ transplantation", section on 'Screening for latent tuberculosis' and
"Prevention of infections in hematopoietic cell transplant recipients".)

● Reactivation of latent Strongyloides stercoralis infection can occur in patients receiving

glucocorticoids, leading to a hyperinfection syndrome that can be fatal.

● Other helminthic or protozoan infections are unusual, except in areas of the world where they
are endemic (eg, Plasmodium falciparum). (See "Malaria: Epidemiology, prevention, and
control".)

● Opportunistic infections with organisms of low pathogenicity usually occur only in patients
with very significant immunosuppression, such as those receiving prolonged glucocorticoids
in addition to other immunosuppressant drugs or those with underlying immunosuppressive
conditions (eg, hematologic malignancy). Pneumocystis jirovecii (formerly Pneumocystis
carinii) pneumonia is associated with the use of glucocorticoids, both with chronic use of
moderate doses and short-term use of high doses. Indications for prophylaxis against P.
jirovecii are discussed separately. (See "Treatment and prevention of Pneumocystis
pneumonia in HIV-uninfected patients", section on 'Indications'.)
 Magnitude of increased risk — Studies of chronic glucocorticoid therapy (prednisone in most
studies) in patients with rheumatoid arthritis, systemic lupus erythematosus, and other
autoimmune disorders provide some information about the magnitude of the increased risk [77-
80]:

● A meta-analysis of controlled trials in which glucocorticoids or placebo were given reported

that infection occurred significantly more often with steroid therapy (12.7 versus 8.0 percent
with placebo, relative risk [RR] 1.6) [78]. The infection rates were significantly increased only in
patients given an average dose of prednisone of more than 10 mg/day; increased infection
rates were not observed when the cumulative prednisone dose remained <700 mg over the
duration of the study. It was also noted that doses <10 mg/day when given over very extended
periods (eg, 5 mg/daily for two years), even when the cumulative dose reached into the gram
range, was not associated with an increased relative risk of infection. A dose dependence was
noted in both the glucocorticoid- and placebo-treated groups, suggesting that the activity of
the underlying disease is also a risk factor for infection.

● Similar findings were noted in a study of 223 patients with lupus who were not receiving other
immunosuppressive agents [79]. The risk of infection rose from 1.5-fold at an average
prednisone dose below 10 mg/day to over eightfold in patients receiving doses above 40
mg/day. However, patients receiving higher doses also had more severe underlying disease.

● Prednisone use increased the risk of pneumonia hospitalization in a dose-dependent manner

among patients with rheumatoid arthritis (hazard ratio [HR] 1.7 [95% CI 1.5-2.0]), after
adjustment for covariates [80]. The HRs with doses ≤5 mg/day, >5 to 10 mg/day, and >10
mg/day were 1.4, 2.1, and 2.3, respectively.

One study suggests that even short-term outpatient glucocorticoid use is associated with an
increased risk of sepsis, although the absolute risk appears to be low. A retrospective cohort study
and self-controlled case series that used a nationwide dataset of private insurance claims in the
United States assessed the risk of sepsis in 327,452 adults aged 18 to 64 years, who received at
least one outpatient prescription for short-term use (<30 days) of oral glucocorticoids over a three-
year period [81]. The median number of days of use was 6 (interquartile range 6 to 12 days), with
47.4 percent receiving treatment for 7 or more days. The most common indications for use were
upper respiratory tract infections, spinal conditions, and allergies. Within 30 days of starting
glucocorticoid therapy, there was an increase in rate of sepsis (incidence rate ratio 5.30; 95% CI
3.80-7.41), which diminished over the subsequent 60 days. The increased risk persisted at
prednisone-equivalent doses of <20 mg/day (incidence rate ratio 4.02). However, the absolute risk
of sepsis in glucocorticoid recipients remained low. For patients who had a clinic visit, the risk of
hospital admission for sepsis during the 5- to 90-day period after the visit was 0.05 percent in
glucocorticoid users compared with 0.02 percent in nonusers.
 Measures to reduce risk — There are several strategies to help reduce the risk of infection
associated with glucocorticoid therapy.

Locally acting glucocorticoids — When possible, glucocorticoids should be administered

locally rather than systemically. Examples include topical corticosteroids for cutaneous disease,
intra-articular administration (triamcinolone) for joint inflammation, inhaled therapy for
inflammatory respiratory disease, and use of oral agents with high, first-pass metabolism
(budesonide) for intestinal inflammation. Locally acting preparations minimize infection risk, as
well as the systemic adverse effects, of glucocorticoid therapy.

Alternate-day dosing — The infection risk may be significantly lessened by the use of short-
acting preparations (such as prednisone) given every other day (table 1) [24]. In one retrospective
report of 70 patients with various inflammatory conditions treated with alternate-day prednisone at
mean doses of 45 to 60 mg daily, none developed serious infections [24]. Strategies to reduce the
side effects of glucocorticoids are reviewed in more detail elsewhere. (See "Pharmacologic use of
glucocorticoids", section on 'Alternate-day administration' and "Pharmacologic use of
glucocorticoids", section on 'Minimizing glucocorticoid side effects'.)

Prophylaxis against Pneumocystis jirovecii — Indications for prophylaxis against P. jirovecii

are discussed separately. (See "Treatment and prevention of Pneumocystis pneumonia in HIV-
uninfected patients", section on 'Indications'.)

IMPACT ON VACCINATION

A small number of studies have evaluated the ability of patients receiving glucocorticoid therapy
to respond to vaccination. Glucocorticoid dose and duration, as well as the patient's underlying
state of health or disease, impact the response to vaccination.

Low-to-moderate doses — The majority of available studies evaluated patients receiving low-to-

moderate doses of glucocorticoids for the management of chronic disease (ie, doses of less than
1 mg/kg per day of prednisone in children or less than 40 mg per day in adults) and found that
responses to pneumococcal and influenza vaccines were mostly adequate. Thus, administration
of killed or attenuated vaccines can proceed normally for patients on low-to-moderate doses of
glucocorticoids.

● Pneumococcal vaccine remains immunogenic in most patients on glucocorticoid therapy for

renal, pulmonary, or rheumatic diseases, although antibody titers may be reduced [42,82].

● A small study compared pneumococcal vaccination responses in 14 steroid-dependent

asthmatics and 14 control asthmatics and found no differences in the strength of response
[83]. The doses of glucocorticoids taken by these patients ranged from 10 to 35 mg daily or
every other day.
 ● Influenza vaccination is effective in most patients receiving chronic glucocorticoid therapy for
rheumatologic or pulmonary disorders, although some patients have lower antibody titers
[84,85]. The significance of lower immunization-induced antibody titers with regard to
infection prevention is unclear, and dose thresholds for glucocorticoid use with regard to
vaccination success have not been established. Patients receiving glucocorticoids should be
given the inactivated influenza vaccine rather than the live-attenuated influenza vaccine.

In patients who do show evidence of impaired vaccine response, removal of chronic, low-dose
glucocorticoid treatment may result in improved antibody production [44].

Higher doses — For the purposes of immune response to vaccines, the Advisory Committee on
Immunization Practices (ACIP) considers doses of prednisone equivalent to ≥2 mg/kg of body
weight or ≥20 mg/day for patients weighing >10 kg, when administered for ≥14 consecutive days
to be thresholds above which vaccine responses may be suppressed [86]. When possible, it is
therefore preferable to wait until the patient has transitioned to lower doses of glucocorticoids or
stopped therapy altogether to administer killed or attenuated vaccines. Live vaccines are
discussed below. (See 'Avoidance of live vaccines' below.)

Avoidance of live vaccines — The Infectious Diseases Society of America has published

recommendations for vaccination of patients with chronic inflammatory diseases on
immunosuppressive medications. (See "Nonpharmacologic therapies and preventive measures for
patients with rheumatoid arthritis", section on 'Vaccinations'.)

Live-virus vaccines can be administered to patients (provided there are no other contraindications,
such as severe immunodeficiency) who are receiving glucocorticoid therapy when administration
is [86]:

● Short term (eg, less than 14 days)

● Low-to-moderate dose (eg <20 mg of prednisone or equivalent per day or <2 mg/kg body
weight per day for a young child)
● Long-term, alternate-day treatment with short-acting preparations
● Maintenance physiologic doses (replacement therapy)
● Topical (skin or eyes), inhaled, or given as an intra-articular, bursal, or tendon injection

For patients receiving brief courses of high-dose glucocorticoids (ie, ≥14 days), live-virus
vaccination should be deferred for at least one month after discontinuation [86].

The administration of various vaccines in transplant candidates and recipients, as well as other
special patient populations is reviewed in detail separately.

● (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

● (See "Immunizations in solid organ transplant candidates and recipients".)
● (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
 ● (See "Immunizations during pregnancy".)
● (See "Immunizations in patients with HIV".)
● (See "Immunizations in patients with end-stage kidney disease".)
● (See "Immunizations for patients with chronic liver disease".)
● (See "Immunizations in patients with primary immunodeficiency".)

SUMMARY AND RECOMMENDATIONS

● Glucocorticoids diffuse across the cell membrane and bind to the intracellular glucocorticoid
receptor to form a complex that translocates into the nucleus. This complex interacts with
DNA, resulting in altered transcription of various glucocorticoid-responsive genes. Post-
translational events are also affected. (See 'General mechanism of action' above.)

● Doses of less than 1 mg/kg per day of prednisone in children or less than 40 mg per day in
adults can be considered low-to-moderate. (See 'Dose ranges' above.)

● Glucocorticoid administration results in a neutrophilic leukocytosis, smaller elevations in

monocytes, dramatic reductions in circulating eosinophils, and lesser reductions in
lymphocytes. (See 'Changes in the complete blood count and differential' above.)

● Glucocorticoids have profound effects on the cellular functions of leukocytes and endothelial
cells, resulting in reduced ability of leukocytes to adhere to vascular endothelium and exit
from the circulation. Entry to sites of infection and tissue injury is impaired, resulting in
suppression of the inflammatory response. (See 'Leukocyte trafficking' above.)

● Neutrophil phagocytic responses or bactericidal activities do not appear to be significantly

impaired at low-to-moderate doses of glucocorticoids, although at high doses, phagocytic
function may be inhibited. Glucocorticoids impair a variety of T cell functions, and moderate-
to-high doses induce T cell apoptosis. T regulatory cell functions may be less affected than
other T cell subsets. B cells are less affected, and antibody production is largely preserved,
although a mild-to-moderate decrement in immunoglobulin (Ig)G may develop in some
patients with high doses given acutely and with chronic use. (See 'Changes in cell function
and survival' above and 'B cells and immunoglobulin levels' above.)

● Systemic glucocorticoid therapy is associated with a dose-dependent increase in the risk of

infection. Patients are most often affected by common viral, bacterial, and fungal pathogens.
Opportunistic infections are less common and are mainly a concern in patients taking other
immunosuppressive agents or with diseases causing immunocompromise. In contrast to
systemic therapy, inhaled and topical corticosteroids are usually not implicated in increased
risk of infections. (See 'Infection risk' above.)
 ● Live vaccines should be avoided in patients receiving higher-dose glucocorticoids. (See
'Avoidance of live vaccines' above.)

● Responses to vaccines are preserved in most patients on chronic low-to-moderate doses of

glucocorticoids for renal, pulmonary, or rheumatologic diseases, although the titers may be
reduced in some individuals. In contrast, vaccine response may not be adequate in patients
who are receiving protracted courses of high dose steroids, are seriously ill, have
malignancies, or are immediately post-transplantation. (See 'Impact on vaccination' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge E Richard Stiehm, MD, who contributed
as a Section Editor to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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. ACIP recommendations are available at: https://www.cdc.gov/vaccines/hcp/acip-recs/gener

al-recs/immunocompetence.html (Accessed on December 13, 2018).

Topic 3986 Version 21.0

GRAPHICS

Glucocorticoid dosing (upper limit of moderate daily dose range)

Duration of action
Glucocorticoid Adults Children
(hours)

Prednisone 40 mg 1 mg/kg 12 to 36

Prednisolone 40 mg 1 mg/kg 12 to 36

Methylprednisolone 31 mg 0.8 mg/kg 12 to 36

Hydrocortisone 160 mg 4 mg/kg 8 to 12

Cortisone acetate 200 mg 5 mg/kg 8 to 12

Dexamethasone 6 mg 0.15 mg/kg 26 to 72

Graphic 111230 Version 1.0

T cell cytokine secretion profiles

Th1
IL-2

IL-3

IFN-gamma

TNF

Th2
IL-4

IL-5

IL-6

IL-9

IL-10

IL-13

Th17
IL-17

Treg
TGF-beta

IL-10

Th: T helper cell (types 1, 2, and 17); IL: interleukin; IFN: interferon; TNF: tumor necrosis factor; Treg: T regulatory cell; TGF: transforming-
growth factor.

Graphic 63847 Version 7.0

Contributor Disclosures
W Winn Chatham, MD Nothing to disclose Jordan S Orange, MD, PhD Patent Holder: Children's Hospital of
Philadelphia [Genetic diagnosis]. Consultant/Advisory Boards: ADMA Biologics [Therapeutic immune globulin
(IVIG)]; CSL Behring [Therapeutic immune globulin (IVIG, SCIG)]; Grifols [Therapeutic immune globulin (IVIG,
SCIG)]; Takeda [Therapeutic immune globulin (IVIG, SCIG)]; Enzvyant [Thymic Transplantation]. Kieren A Marr,
MD Equity Ownership/Stock Options: MycoMed Technologies [Fungal diagnostics]. Patent Holder: MycoMed
Technologies [Diagnostics, antifungals]. Grant/Research/Clinical Trial Support: Merck [Antifungals, fungal
infections]. Consultant/Advisory Boards: Amplyx; Cidara Therapeutics [Antifungals, fungal infections]; Merck
[Antifungals, Caspofungin, posaconazole]. Anna M Feldweg, MD Nothing to disclose Sheila Bond,
MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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