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Glucocorticoid effects on the immune system

Glucocorticoid effects on the immune system
Author:
W Winn Chatham, MD
Section Editor:
Rebecca Marsh, MD
Deputy Editors:
Anna M Feldweg, MD
Sheila Bond, MD
Literature review current through: Nov 2022. | This topic last updated: Apr 20, 2021.

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 leukocyte 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 leukocyte 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 persons'.)

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 patients without HIV", 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 patients without HIV", 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 "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

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 persons 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 UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

  1. Chatham WW, Kimberly RP. Treatment of lupus with corticosteroids. Lupus 2001; 10:140.
  2. Zhang G, Zhang L, Duff GW. A negative regulatory region containing a glucocorticosteroid response element (nGRE) in the human interleukin-1beta gene. DNA Cell Biol 1997; 16:145.
  3. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995; 270:283.
  4. Almawi WY, Beyhum HN, Rahme AA, Rieder MJ. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J Leukoc Biol 1996; 60:563.
  5. Auphan N, DiDonato JA, Rosette C, et al. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995; 270:286.
  6. Göttlicher M, Heck S, Herrlich P. Transcriptional cross-talk, the second mode of steroid hormone receptor action. J Mol Med (Berl) 1998; 76:480.
  7. Karin M, Liu Zg, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol 1997; 9:240.
  8. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005; 353:1711.
  9. Tobler A, Meier R, Seitz M, et al. Glucocorticoids downregulate gene expression of GM-CSF, NAP-1/IL-8, and IL-6, but not of M-CSF in human fibroblasts. Blood 1992; 79:45.
  10. Borson DB, Gruenert DC. Glucocorticoids induce neutral endopeptidase in transformed human tracheal epithelial cells. Am J Physiol 1991; 260:L83.
  11. Flower RJ, Blackwell GJ. Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation. Nature 1979; 278:456.
  12. Blackwell GJ, Carnuccio R, Di Rosa M, et al. Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids. Nature 1980; 287:147.
  13. Hirata F, Schiffmann E, Venkatasubramanian K, et al. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci U S A 1980; 77:2533.
  14. Kim SW, Rhee HJ, Ko J, et al. Inhibition of cytosolic phospholipase A2 by annexin I. Specific interaction model and mapping of the interaction site. J Biol Chem 2001; 276:15712.
  15. Lew W, Oppenheim JJ, Matsushima K. Analysis of the suppression of IL-1 alpha and IL-1 beta production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone. J Immunol 1988; 140:1895.
  16. Chen CC, Sun YT, Chen JJ, Chiu KT. TNF-alpha-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-gamma 2, protein kinase C-alpha, tyrosine kinase, NF-kappa B-inducing kinase, and I-kappa B kinase 1/2 pathway. J Immunol 2000; 165:2719.
  17. Hammerschmidt DE, White JG, Craddock PR, Jacob HS. Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states. J Clin Invest 1979; 63:798.
  18. Youssef P, Roberts-Thomson P, Ahern M, Smith M. Pulse methylprednisolone in rheumatoid arthritis: effects on peripheral blood and synovial fluid neutrophil surface phenotype. J Rheumatol 1995; 22:2065.
  19. Fan PT, Yu DT, Clements PJ, et al. Effect of corticosteroids on the human immune response: comparison of one and three daily 1 gm intravenous pulses of methylprednisolone. J Lab Clin Med 1978; 91:625.
  20. Fan PT, Yu DT, Targoff C, Bluestone R. Effect of corticosteroids on the human immune response. Suppression of mitogen-induced lymphocyte proliferation by "pulse" methylprednisolone. Transplantation 1978; 26:266.
  21. Barak M, Cohen A, Herschkowitz S. Total leukocyte and neutrophil count changes associated with antenatal betamethasone administration in premature infants. Acta Paediatr 1992; 81:760.
  22. Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J. Prednisone-induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis. Am J Med 1981; 71:773.
  23. Olnes MJ, Kotliarov Y, Biancotto A, et al. Effects of Systemically Administered Hydrocortisone on the Human Immunome. Sci Rep 2016; 6:23002.
  24. Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med 1976; 84:304.
  25. Boumpas DT, Chrousos GP, Wilder RL, et al. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 1993; 119:1198.
  26. Fauci AS, Murakami T, Brandon DD, et al. Mechanisms of corticosteroid action on lymphocyte subpopulations. VI. Lack of correlation between glucocorticosteroid receptors and the differential effects of glucocorticosteroids on T-cell subpopulations. Cell Immunol 1980; 49:43.
  27. Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J Immunol 1995; 154:4719.
  28. Meagher LC, Cousin JM, Seckl JR, Haslett C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996; 156:4422.
  29. Schleimer RP, Freeland HS, Peters SP, et al. An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4 by purified human neutrophils. J Pharmacol Exp Ther 1989; 250:598.
  30. Jones CJ, Morris KJ, Jayson MI. Prednisolone inhibits phagocytosis by polymorphonuclear leucocytes via steroid receptor mediated events. Ann Rheum Dis 1983; 42:56.
  31. Herzer P, Lemmel EM. Inhibition of granulocyte function by prednisolone and non-steroid anti-inflammatory drugs. Quantitative evaluation with NBT test and its correlation with phagocytosis. Immunobiology 1980; 157:78.
  32. Rinehart JJ, Sagone AL, Balcerzak SP, et al. Effects of corticosteroid therapy on human monocyte function. N Engl J Med 1975; 292:236.
  33. Rinehart JJ, Balcerzak SP, Sagone AL, LoBuglio AF. Effects of corticosteroids on human monocyte function. J Clin Invest 1974; 54:1337.
  34. Atkinson JP, Frank MM. Complement-independent clearance of IgG-sensitized erythrocytes: inhibition by cortisone. Blood 1974; 44:629.
  35. Gerlag DM, Haringman JJ, Smeets TJ, et al. Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis. Arthritis Rheum 2004; 50:3783.
  36. Balow JE, Rosenthal AS. Glucocorticoid suppression of macrophage migration inhibitory factor. J Exp Med 1973; 137:1031.
  37. Gerrard TL, Cupps TR, Jurgensen CH, Fauci AS. Hydrocortisone-mediated inhibition of monocyte antigen presentation: dissociation of inhibitory effect and expression of DR antigens. Cell Immunol 1984; 85:330.
  38. van de Garde MD, Martinez FO, Melgert BN, et al. Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction. J Immunol 2014; 192:1196.
  39. Eddy JL, Krukowski K, Janusek L, Mathews HL. Glucocorticoids regulate natural killer cell function epigenetically. Cell Immunol 2014; 290:120.
  40. Slade JD, Hepburn B. Prednisone-induced alterations of circulating human lymphocyte subsets. J Lab Clin Med 1983; 101:479.
  41. Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on immunoglobulins. J Allergy Clin Immunol 1978; 62:162.
  42. Lack G, Ochs HD, Gelfand EW. Humoral immunity in steroid-dependent children with asthma and hypogammaglobulinemia. J Pediatr 1996; 129:898.
  43. Posey WC, Nelson HS, Branch B, Pearlman DS. The effects of acute corticosteroid therapy for asthma on serum immunoglobulin levels. J Allergy Clin Immunol 1978; 62:340.
  44. Fedor ME, Rubinstein A. Effects of long-term low-dose corticosteroid therapy on humoral immunity. Ann Allergy Asthma Immunol 2006; 97:113.
  45. Benko AL, Olsen NJ, Kovacs WJ. Glucocorticoid inhibition of activation-induced cytidine deaminase expression in human B lymphocytes. Mol Cell Endocrinol 2014; 382:881.
  46. Levy AL, Waldmann TA. The effect of hydrocortisone on immunoglobulin metabolism. J Clin Invest 1970; 49:1679.
  47. Jabara HH, Ahern DJ, Vercelli D, Geha RS. Hydrocortisone and IL-4 induce IgE isotype switching in human B cells. J Immunol 1991; 147:1557.
  48. Butler WT, Rossen RD. Effects of corticosteroids on immunity in man. I. Decreased serum IgG concentration caused by 3 or 5 days of high doses of methylprednisolone. J Clin Invest 1973; 52:2629.
  49. Hamilos DL, Young RM, Peter JB, et al. Hypogammaglobulinemia in asthmatic patients. Ann Allergy 1992; 68:472.
  50. Berger W, Pollock J, Kiechel F, et al. Immunoglobulin levels in children with chronic severe asthma. Ann Allergy 1978; 41:67.
  51. Haynes BF, Fauci AS. The differential effect of in vivo hydrocortisone on the kinetics of subpopulations of human peripheral blood thymus-derived lymphocytes. J Clin Invest 1978; 61:703.
  52. Mathian A, Jouenne R, Chader D, et al. Regulatory T Cell Responses to High-Dose Methylprednisolone in Active Systemic Lupus Erythematosus. PLoS One 2015; 10:e0143689.
  53. Huang H, Lu Z, Jiang C, et al. Imbalance between Th17 and regulatory T-Cells in sarcoidosis. Int J Mol Sci 2013; 14:21463.
  54. Paliogianni F, Ahuja SS, Balow JP, et al. Novel mechanism for inhibition of human T cells by glucocorticoids. Glucocorticoids inhibit signal transduction through IL-2 receptor. J Immunol 1993; 151:4081.
  55. Hanson JA, Sohaib SA, Newell-Price J, et al. Computed tomography appearance of the thymus and anterior mediastinum in active Cushing's syndrome. J Clin Endocrinol Metab 1999; 84:602.
  56. Cohen JJ, Duke RC. Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol 1984; 132:38.
  57. Lanza L, Scudeletti M, Puppo F, et al. Prednisone increases apoptosis in in vitro activated human peripheral blood T lymphocytes. Clin Exp Immunol 1996; 103:482.
  58. Webster JC, Huber RM, Hanson RL, et al. Dexamethasone and tumor necrosis factor-alpha act together to induce the cellular inhibitor of apoptosis-2 gene and prevent apoptosis in a variety of cell types. Endocrinology 2002; 143:3866.
  59. McKinley L, Alcorn JF, Peterson A, et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol 2008; 181:4089.
  60. Ramesh R, Kozhaya L, McKevitt K, et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 2014; 211:89.
  61. Franchimont D, Louis E, Dewe W, et al. Effects of dexamethasone on the profile of cytokine secretion in human whole blood cell cultures. Regul Pept 1998; 73:59.
  62. Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function*. Annu Rev Immunol 2000; 18:309.
  63. Visser J, van Boxel-Dezaire A, Methorst D, et al. Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro. Blood 1998; 91:4255.
  64. BOVORNKITTI S, KANGSADAL P, SATHIRAPAT P, OONSOMBATTI P. Reversion and reconversion rate of tuberculin skin reactions in correction with the use of prednisone. Dis Chest 1960; 38:51.
  65. Wallen N, Kita H, Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J Immunol 1991; 147:3490.
  66. Andersen V, bro-Rasmussen F, Hougaard K. Autoradiographic studies of eosinophil kinetics: Effects of cortisol. Cell Tissue Kinet 1969; 2:139.
  67. Nagase H, Miyamasu M, Yamaguchi M, et al. Glucocorticoids preferentially upregulate functional CXCR4 expression in eosinophils. J Allergy Clin Immunol 2000; 106:1132.
  68. Kita H, Abu-Ghazaleh R, Sanderson CJ, Gleich GJ. Effect of steroids on immunoglobulin-induced eosinophil degranulation. J Allergy Clin Immunol 1991; 87:70.
  69. Andrade MV, Hiragun T, Beaven MA. Dexamethasone suppresses antigen-induced activation of phosphatidylinositol 3-kinase and downstream responses in mast cells. J Immunol 2004; 172:7254.
  70. Nakamura R, Okunuki H, Ishida S, et al. Gene expression profiling of dexamethasone-treated RBL-2H3 cells: induction of anti-inflammatory molecules. Immunol Lett 2005; 98:272.
  71. Park SK, Beaven MA. Mechanism of upregulation of the inhibitory regulator, src-like adaptor protein (SLAP), by glucocorticoids in mast cells. Mol Immunol 2009; 46:492.
  72. Shodell M, Shah K, Siegal FP. Circulating human plasmacytoid dendritic cells are highly sensitive to corticosteroid administration. Lupus 2003; 12:222.
  73. Woltman AM, Massacrier C, de Fijter JW, et al. Corticosteroids prevent generation of CD34+-derived dermal dendritic cells but do not inhibit Langerhans cell development. J Immunol 2002; 168:6181.
  74. Strangfeld A, Eveslage M, Schneider M, et al. Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 2011; 70:1914.
  75. Chen JY, Wang LK, Feng PH, et al. Risk of Shingles in Adults with Primary Sjogren's Syndrome and Treatments: A Nationwide Population-Based Cohort Study. PLoS One 2015; 10:e0134930.
  76. Sakuma Y, Katoh T, Owada K, et al. Initial functional status predicts infections during steroid therapy for renal diseases. Clin Nephrol 2005; 63:68.
  77. Pappas DA, Hooper MM, Kremer JM, et al. Herpes Zoster Reactivation in Patients With Rheumatoid Arthritis: Analysis of Disease Characteristics and Disease-Modifying Antirheumatic Drugs. Arthritis Care Res (Hoboken) 2015; 67:1671.
  78. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 1989; 11:954.
  79. Ginzler E, Diamond H, Kaplan D, et al. Computer analysis of factors influencing frequency of infection in systemic lupus erythematosus. Arthritis Rheum 1978; 21:37.
  80. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 2006; 54:628.
  81. Waljee AK, Rogers MA, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 2017; 357:j1415.
  82. Spika JS, Halsey NA, Fish AJ, et al. Serum antibody response to pneumococcal vaccine in children with nephrotic syndrome. Pediatrics 1982; 69:219.
  83. Lahood N, Emerson SS, Kumar P, Sorensen RU. Antibody levels and response to pneumococcal vaccine in steroid-dependent asthma. Ann Allergy 1993; 70:289.
  84. Herron A, Dettleff G, Hixon B, et al. Influenza vaccination in patients with rheumatic diseases. Safety and efficacy. JAMA 1979; 242:53.
  85. Kubiet MA, Gonzalez-Rothi RJ, Cottey R, Bender BS. Serum antibody response to influenza vaccine in pulmonary patients receiving corticosteroids. Chest 1996; 110:367.
  86. ACIP recommendations are available at: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html (Accessed on December 13, 2018).
Topic 3986 Version 26.0

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