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pharmacology
Chronic Steroid and
Immunosuppressant Therapy in
Children
Abraham Gedalia, MD,*
Avinash K. Shetty, MD†
Objectives
After completing this article, readers should be able to:
1. Describe the mechanism of action, list indications for therapy, and discuss the adverse
effects of corticosteroid therapy in children.
2. Delineate the mechanism of action and adverse effects of other immunosuppressive
agents frequently used in children.
3. Discuss the immunization recommendations for children receiving immunosuppressive
therapy.
Introduction
Corticosteroids are the most potent, naturally occurring anti-inflammatory agents known.
Despite more than 50 years of controversy regarding their clinical use, risks, and benefits,
corticosteroids still play a significant role in the management of a wide variety of diseases.
They have reduced the morbidity and mortality significantly in children afflicted with
leukemia, asthma, rheumatic diseases, and other inflammatory disorders. In this article, we
review the mechanism of action, clinical indications, and adverse effects of corticosteroids
and other commonly used immunosuppressive agents in children. We also review immunization recommendations for children receiving immunosuppressive therapy.
Mechanism of Action of Corticosteroids
Corticosteroids have a diverse role in the human body at the physiologic level. The actions
of glucocorticoids include: 1) negative feedback modulation of corticotropin-releasing
factor and adrenocorticotropic hormone; 2) regulation of blood glucose and liver glycogen levels; 3) maintenance of water-electrolyte homeostasis; 4) influence on the metabolism of protein, fat, and purine; 5) maintenance of normal cardiovascular, central nervous
system (CNS), and renal functions; 6) influence on circadian rhythmicity; 7) maintenance
of bone and muscle work capacity; and 8) protection of the body against moderate stress.
Glucocorticoids also have pharmacologic properties that are used in the treatment of
rheumatic and other inflammatory diseases.
Cellular receptors for cortisol are ubiquitous in cell cytoplasm, reflecting the critical role
of the hormone in maintaining cell homeostasis. The type 1 glucocorticoid receptor,
known as the mineralocorticoid receptor, has high affinity for aldosterone. The type 2
glucocorticoid receptor, known as the glucocorticoid receptor, exhibits strong affinity for
dexamethasone. Although the differential function of these two receptors is not understood fully, it is speculated that type 1 receptors primarily regulate basal functions such as
circadian rhythmicity, whereas type 2 receptors respond to stress levels of corticosteroids.
Effect on Inflammation
Corticosteroids suppress inflammation and have immunosuppressive effects that are mediated through inhibition of: 1) the early stages of inflammation such as edema, fibrin
disposition, capillary dilatation, migration of lymphocytes into inflamed tissues, and
phagocytic activity; and 2) the late stages such as proliferation of capillaries and fibroblasts
and the deposition of collagen. Corticosteroids are believed to reduce the production of
arachidonic acid that serves as a substrate for cyclooxygenase-2 without affecting
cyclooxygenase-1.
* Professor of Pediatrics and Head, Division of Pediatric Rheumatology, Louisiana State University Health Sciences Center and
Children’s Hospital, New Orleans, La.
†
Assistant Professor of Pediatrics, Division of Infectious Diseases, Wake Forest University School of Medicine, Winston-Salem, NC.
Pediatrics in Review Vol.25 No.12 December 2004 425
pharmacology corticosteroid and immunosuppressive therapy
Effects on Cytokines and Other Modulators of
the Immune System
Corticosteroids inhibit macrophage and T-helper type 1
cell production of tumor necrosis factor (TNF)-alpha,
interleukin (IL)-1, IL-2, IL-12, interferon-gamma,
granulocyte-macrophage colony-stimulating factor, and
to a lesser extent, IL-4, IL-10, and transforming growth
factor-beta. Both TNF-alpha and IL-1 exert a number of
inflammatory actions, including production of prostaglandin E2 and collagenase, activation of T lymphocytes,
stimulation of fibroblast proliferation, and induction of
hepatic synthesis of acute-phase reactants. Corticosteroids also inhibit the action of humoral regulators of
inflammation, such as platelet-activating factor and macrophage migration inhibition factor. In addition, corticosteroids inhibit expression of adhesion molecules
directly and indirectly through inhibitory effects on cytokines such as TNF-alpha and IL-1.
Effects on Cells of the Reticuloendothelial
System
Through many of the previously noted mediators, corticosteroids inhibit the cellular cascade of inflammation
and immune response at any given level. They cause an
increase in neutrophil and monocyte migration to the
inflammatory site; macrophage antigen presentation to
lymphocytes; and lymphocyte proliferation, activation,
and differentiation to effector cells, particularly T-helper
cells, cytotoxic lymphocytes, natural killer cells, and immature B cells.
effect on immunoglobulin levels or on antigenstimulated antibody production. Under the influence of
corticosteroids, certain activated lymphocyte subpopulations may be susceptible to lysis and apoptosis. Immature
cortical thymic lymphocytes are more sensitive to
corticosteroid-induced apoptosis than are mature lymphocytes.
Nonimmunomodulatory Effects of
Corticosteroids
Nonimmunomodulatory effects are not related directly
to the immunomodulatory effects of corticosteroids and
can affect the patient adversely. Corticosteroids have a
catabolic effect on protein, leading to its breakdown to
form carbohydrate, which results in a negative nitrogen
balance, muscle wasting, and impaired wound healing.
Growth suppression that occurs in children receiving
chronic steroid therapy is mediated by effects on protein,
bone, and growth hormone. In addition, corticosteroids
stimulate glucose synthesis, diminish its peripheral utilization, and increase glycogen deposition. This facilitates
insulin resistance, impaired glucose tolerance, and occasional overt diabetes. Treatment with high or moderate
doses of corticosteroids in children results in weight gain
due to both fat redistribution and increased appetite. In
addition, sodium and water retention occur in children
receiving long-term steroid therapy. To minimize this
effect, the glucocorticoid analogs used today have been
modified to reduce their mineralocorticoid potency.
Effects on Nonlymphoid Inflammatory Cells
The effect of corticosteroids on neutrophils and other
nonlymphoid cells such as monocytes, macrophages, eosinophils, mast cells, and dendritic cells is significant. The
circulating monocytes and macrophages (including
Langerhans and dendritic cells) are reduced markedly,
and eosinophils significantly diminished from the blood
and sites of allergic reactions. Corticosteroids inhibit
neutrophil migration into inflammatory sites, although
they increase circulating neutrophils by as much as twoto four-fold.
Effects on Lymphocytes
Corticosteroids have a profound effect on cell migration
of lymphocytes. Administration of a single dose of corticosteroid results in a marked but transient lymphopenia
due to redistribution of all lymphocyte populations to
other body compartments, especially to the bone marrow. T lymphocytes are affected more than are B lymphocytes, and low doses of corticosteroids have little
426 Pediatrics in Review Vol.25 No.12 December 2004
Adverse Effects of Corticosteroid Therapy
Although corticosteroids are powerful anti-inflammatory
agents, long-term systemic high-daily dose therapy is
associated with substantial adverse effects (Table 1). The
goal in corticosteroid therapy should be to limit the dose
to the lowest possible level and the duration to the
minimum necessary to achieve clinical disease control.
The adverse effects of corticosteroid therapy are summarized in Table 2. Most of the adverse effects are doserelated and result from prolonged exposure to high doses
of systemic corticosteroids. Short courses of corticosteroids (⬍2 wk), even with high doses, are associated with
minimal risk of toxicity. By contrast, patients receiving
high doses of steroids, such as 1 to 2 mg/kg per day of
prednisone, for 3 months or more eventually suffer significant adverse effects. Withdrawal of therapy after prolonged use of large doses of corticosteroids can result in
acute adrenal insufficiency.
pharmacology corticosteroid and immunosuppressive therapy
Indications for Pharmacologic Doses of
Corticosteroids in Children
Table 1.
Condition
Rheumatic Diseases Group I:
Systemic lupus erythematosus
Juvenile dermatomyositis
Polymyositis
Mixed connective tissue disease
Systemic vasculitis
Wegener granulomatosis
Takayasu arteritis
Polyarteritis nodosa
Rheumatic Diseases Group II:
Juvenile rheumatoid arthritis
Systemic-onset
Polyarticular onset
Pauciarticular onset
Rheumatic Diseases Group III:
Rheumatic fever
Henoch-Schönlein purpura
Kawasaki disease
Nonrheumatic Diseases Group IV:
Inflammatory bowel disease
Crohn disease
Ulcerative colitis
Chronic immune thrombocytopenic purpura
Chronic asthma
Steroid Dose
High
Moderate
Low
Moderate
Generalized Signs and Symptoms
Signs and symptoms of cushingoid appearance (moon
face, truncal obesity, and “buffalo” hump), obesity, and
hypertension are seen commonly among children receiving prolonged moderate- to high-dose steroid therapy
(1 to 2 mg/kg per day for more than 3 mo). Many skin
changes are of minor clinical importance but can be
disturbing to the patient, including acne, hirsutism, hyperpigmentation, skin thinning, and striae.
Growth suppression is one of the most serious adverse
effects associated with prolonged corticosteroid therapy
in children. Young children may develop growth suppression when they have received prolonged therapy
with doses equivalent to 3 mg/d of prednisone or more.
The mechanism is generalized suppression of cell growth
and division and inhibition of somatomedin C (insulinlike growth factor I) production. Furthermore, growth
failure sometimes is related to the underlying condition.
Organ System-related Adverse Effects
MUSCULOSKELETAL SYSTEM. Patients receiving relatively high doses of steroids (⬎1 mg/kg per day or
⬎30 mg/d) for prolonged periods may develop steroid
myopathy. For patients who have juvenile dermatomyo-
sitis or polymyositis, this might be
misinterpreted as exacerbation of
their underlying disease. However,
patients who have steroid myopRisk of Toxicity
athy generally experience an insidious onset of painless proximal musHigh
cle weakness and have normal
serum levels of muscle enzymes.
Electromyography detects minimal
myopathic changes, and type IIB
fiber atrophy is noted on muscle
biopsy. The acute form has been
reported after short-term highdose corticosteroid therapy. Both
Moderate
proximal and distal muscle weakness can occur, and elevation of serum creatinine phosphokinase or
aldolase levels in conjunction with
Low
rhabdomyolysis may result.
Patients who have rheumatic
diseases, especially systemic lupus
Moderate
erythematosus (SLE) and to a lesser
extent juvenile rheumatoid arthritis
(JRA), are at risk of developing
avascular necrosis (AVN) of the
bone. This risk is increased further
by long-term therapy with corticosteroids (at least 4 to 6 mo of continuous use). AVN
most frequently affects the femoral head, although other
sites, such as the knees and shoulders, may be affected.
This complication has been described with both high
oral doses (2 mg/kg per day) and intravenous pulse
doses (10 to 30 mg/kg per pulse). The exact mechanism
is not known, although both underlying disease and
high-dose steroid therapy (possibly high-dose intravenous administration) play roles.
The development of osteopenia from exogenous corticosteroid use first was described in 1950. Osteoporosis
is related to both the dose and duration of steroid therapy
and appears to involve several mechanisms, including
decreased intestinal absorption of calcium, increased renal calcium loss (that results in secondary hyperparathyroidism), the underlying disease activity (especially in
children who have systemic and polyarticular onsets of
JRA), and reduction of bone formation by direct inhibition of osteoblasts. Bone loss is most rapid during the
first 6 to 12 months of steroid therapy, subsequently
reaching a plateau. Short-term corticosteroid use generally is not associated with osteopenia. In adults, bone loss
often is trabecular rather than cortical, whereas in children it is generalized, affecting both trabecular and corPediatrics in Review Vol.25 No.12 December 2004 427
pharmacology corticosteroid and immunosuppressive therapy
Adverse Effects of
Corticosteroid Therapy
Table 2.
Group I: Generalized signs and symptoms
●
●
Growth suppression in children
Cushingoid feature
Group II: Organ system-related
●
Musculoskeletal
–Myopathy
–Avascular necrosis
–Osteoporosis
● Immune
–Increased risk for infection
● Gastrointestinal
–Peptic ulcer
–Pancreatitis
● Cardiovascular
–Hypertension
–Dyslipoproteinemia
–Atherosclerosis
● Ophthalmologic
–Cataracts
–Glaucoma
● Neuropsychiatric
–Mood changes
–Depression
–Psychosis
–Pseudotumor cerebri
● Dermatologic
–Acne
–Fragile skin and easy bruising
–Hirsutism
–Poor wound healing
● Hematologic
–Lymphopenia
–Neutrophilia
● Endocrine and Metabolic
–Impaired glucose tolerance
–Protein wasting
–Metabolic alkalosis
studied in controlled trials, including the use of vitamin
D, calcitonin, and bisphosphonates. Although these regimens were found to be effective in reducing bone loss,
none demonstrated a significant decrease in the incidence of fractures. Open trials of vitamin D and calcium
in children who have rheumatic diseases receiving longterm steroids have showed benefit.
IMMUNE SYSTEM. Chronic corticosteroid use predisposes patients to bacterial, viral, fungal, and protozoal
infections. In addition, the anti-inflammatory effect of
corticosteroids can mask the signs and symptoms of
infection. Furthermore, diagnostic confusion and inappropriate investigations can result if it is not recognized
that corticosteroids cause neutrophilia and an elevated
total white blood cell count.
Due to a defect in cell-mediated immunity, patients
receiving prolonged high (but not low) doses of steroids,
especially when administered in divided daily doses, are
prone to tuberculosis, fungi, Pneumocystis carinii pneumonia (PCP), and toxoplasmosis. A purified protein
derivative skin test should be performed prior to the
initiation of prolonged high-dose corticosteroid treatment. Complications of varicella infection also may occur. Except for herpesviruses, most viruses are not a
major threat during corticosteroid treatment. Although
humoral defense mechanisms are less impaired, highdose steroids can be a risk for more frequent and severe
pyogenic infections, particularly bacteremia, with organisms such as Staphylococcus aureus, group A Streptococcus,
and Eschericia coli. This effect appears to be related to the
decreased migration of polymorphonuclear leukocytes to
the sites of infection and inhibition of chemotaxis. Very
high doses of steroid inhibit phagocytosis and intracellular killing, thus predisposing to infections with intracellular pathogens such as Listeria monocytogenes and Salmonella, Brucella, and Legionella sp.
Group III: Effects from withdrawal of steroid therapy
●
Adrenal insufficiency
tical bone. In adults, large cumulative doses of corticosteroids (⬎10 to 30 g) result in significant bone loss, and
alternate-day dosing may not be protective. Steroidinduced osteoporosis has been studied to a lesser extent
in children. There are no reliable biochemical markers to
predict the significance of bone loss, although bone
densitometry can be used to screen high-risk children
and planned for 6 to 12 months after the initiation of
therapy. Several methods of preventing and treating
steroid-induced osteoporosis in adult patients have been
428 Pediatrics in Review Vol.25 No.12 December 2004
GASTROINTESTINAL SYSTEM. Corticosteroids may increase the risk of peptic ulceration, especially when combined with nonsteroidal anti-inflammatory drugs, although the data supporting this association have been
based on retrospective studies and meta-analyses. The
data often are confounded by the simultaneous use of
both drugs in patients who have more severe diseases.
Corticosteroids may mask the signs and symptoms of
intra-abdominal catastrophes (such as intestinal perforation), leading to delayed diagnosis and subsequent increased morbidity and mortality.
The association of corticosteroid use with pancreatitis
is not well established. Many of the reported cases have
pharmacology corticosteroid and immunosuppressive therapy
occurred with concomitant drug use (such as azathioprine or hydralazine) or as a result of complication (eg,
vasculitis) due to an underlying disease such as SLE.
CARDIOVASCULAR SYSTEM. The primary cardiovascular adverse effect seen in children receiving corticosteroid
therapy is hypertension, probably related to sodium retention and increased antidiuretic hormone activity and
plasma renin levels. Other adverse effects of corticosteroids include hyperlipidemia and accelerated coronary
atherosclerosis.
OCULAR SYSTEM. The frequency of posterior subcapsular cataracts in patients receiving prolonged high-dose
corticosteroids is greater than that seen in idiopathic
Cushing syndrome. The risk of developing cataracts is
more significant when the steroid dose is 0.3 mg/kg per
day (9 mg/m2 per day) or more administered for longer
than 1 year. In children, prednisone doses of 20 mg/d
for 4 years or more were associated with cataracts. An
earlier report suggested that younger patients and children develop cataracts in a shorter time and with lower
doses of corticosteroids than do older patients.
CNS. CNS adverse effects include a wide range of
psychiatric symptoms from changes in mood, such as
emotional lability, euphoria, insomnia, and depression,
to psychosis. A study in adults found mood changes to be
the most common psychiatric adverse effect, developing
in almost 90% of patients receiving steroid therapy. Most
of the reactions occurred within the first 5 days of therapy, although delayed reactions after many weeks were
observed. Psychosis is more frequent in patients who
have idiopathic Cushing syndrome than in those receiving corticosteroids. A prospective study on the adverse
effects of intermittent intravenous corticosteroid
(30 mg/kg per dose) therapy in 213 children who had
rheumatic diseases revealed behavioral changes in 10%;
these abnormalities included alterations in mood, hyperactivity, sleep disturbances, and psychosis. In some cases,
the CNS changes may be attributed to the underlying
disorder, such as SLE. Behavioral abnormalities usually
resolve when corticosteroids are withdrawn.
Pseudotumor cerebri (benign intracranial hypertension) has been described rarely with corticosteroid use,
often noted following rapid tapering of the corticosteroid dose. Patients typically present with persistent
headaches; visual symptoms may be absent, although
papilledema is evident. The diagnosis is based on
increased cerebrospinal fluid pressure during lumbar
puncture.
Adverse Effects Associated With Withdrawal
of Corticosteroid Therapy
Withdrawal of short-term corticosteroid therapy (days or
a few weeks) is not associated with symptoms of adrenal
insufficiency. However, sudden withdrawal of prolonged
and high-dose therapy may result in serious, lifethreatening adrenal insufficiency with possible circulatory collapse and death. Manifestations may include high
fever in the absence of infection, hypotension, nausea,
vomiting, diarrhea, confusion, hyponatremia, hyperkalemia, hypoglycemia, and eosinophilia. In addition to the
duration and dose of corticosteroid therapy, studies in
adults revealed that the risk of hypothalamic pituitary
adrenal axis (HPA) suppression depends on the mode of
administration; suppression is the highest with divided
daily doses and lowest with alternate-day dosing. The
recovery of the HPA axis following discontinuation of
the steroid therapy is related inversely to the duration of
the preceding steroid therapy. Children receiving prolonged steroid therapy who encounter serious infections,
trauma, and surgery are at risk for HPA axis suppression
and need steroid supplementation to prevent addisonian
crisis.
Other Immunosuppressive Drugs
Besides corticosteroids, several other classes of immunosuppressive drugs are used routinely by pediatric rheumatologists, oncologists, nephrologists, and transplant
surgeons and include cytotoxic/antiproliferative agents
(eg, azathioprine, 6-mercaptopurine, chlorambucil, cyclophosphamide), calcineurin inhibitors (eg, cyclosporine, tacrolimus), and antimetabolites (eg, methotrexate,
mycophenolate mofetil). All current immunosuppressive
agents target T-cell activation and cytokine production,
clonal expansion, or both (Table 3). These agents produce cytotoxicity through their effect on rapidly dividing
cells such as the malignant cells as well as normal cells of
the immune system, primarily T lymphocytes.
Children receiving chronic immunosuppressive therapy should be monitored closely for serious adverse
effects (Table 4). When used in chemotherapeutic doses
for management of cancer, the cytotoxic agents may
cause significant bone marrow and immune suppression,
leading to life-threatening infections. Therefore, any febrile child who has an absolute neutrophil count of fewer
than 500 cells/mm3 associated with myelosuppressive
chemotherapy must be considered septic. The degree
and duration of neutropenia remain the most critical
factors predictive of infection. The status and type of
underlying malignancy, degree of disruption of host
defenses, and presence of indwelling central venous cathPediatrics in Review Vol.25 No.12 December 2004 429
pharmacology corticosteroid and immunosuppressive therapy
Table 3.
Mechanism of Action of Immunosuppressive Agents
Mechanism of Action
Agents
Molecular Target
Molecular Effect
Corticosteroids
Cytosolic receptors
Heat shock proteins
Azathioprine
Purine nucleotide analogue
Cyclosporin A
Cyclophilin, calcineurin
Tacrolimus (FK 506)
FKBP-12
Calcineurin
Sirolimus
FKBP-12
p70 S6 kinase
Mycophenolate
Inosine monophosphate
dehydrogenase enzyme
Blocks transcription of cytokine genes (eg, interleukins
(IL) 1, 2, 3, 5; tumor necrosis factor-alpha;
interferon-gamma)
Inhibits purine synthesis
Blocks DNA and RNA synthesis
Inhibits the transcription factor nuclear factor of
activated T cells (NFAT)
Inhibits IL-2-dependent growth of activated
lymphocytes
Inhibits NFAT
Inhibits IL-2-dependent growth of activated
lymphocytes
Inhibits DNA and protein synthesis; inhibits several
cytokines
Inhibits B-cell synthesis
Blocks de novo purine mofetil pathway
Blocks inosine monophosphatase
Inhibits T cells and B cells
FKBP-12⫽FK506 binding protein.
eters are other important factors that influence the risk
and type of infection encountered. It is important to note
that the classic signs of infection generally are absent in
affected patients.
The initial evaluation of a patient who has febrile
neutropenia involves a meticulous physical examination,
with particular attention paid to the skin, perirectal area,
and other mucous membrane sites. Blood cultures
should be obtained promptly, and the patient should be
started on broad-spectrum intravenous antibiotics that
provide excellent coverage against gram-positive pathogens, most notably staphylococci and alpha-hemolytic
streptococci, as well as gram-negative enteric organisms
such as Enterobacteriaceae and Pseudomonas aeruginosa.
Patients are hospitalized until they have become afebrile
for at least 24 to 48 hours and blood, urine, or cerebrospinal fluid cultures are negative. If fever continues beyond 1 week despite broad-spectrum antibiotic therapy,
empiric use of amphotericin B may be indicated for
treatment of fungal infection, including that caused by
Candida and Aspergillus sp.
Children who have lymphomas and those who are
maintained on steroids as part of consolidation therapy
appear to be at increased risk for the development of
PCP. The incidence of PCP has been reduced drastically
with the routine use of trimethoprim-sulfamethoxazole
prophylaxis.
Early recognition of exposure to varicella in children
430 Pediatrics in Review Vol.25 No.12 December 2004
receiving immunosuppressive therapy is critical. Physical
contact with the skin lesions of herpes zoster (“shingles”)
can transmit infection, leading to visceral dissemination
in immunocompromised patients, especially those receiving corticosteroid therapy. Prophylactic intervention
with varicella-zoster immunoglobulin (VZIG) within
96 hours of exposure is recommended in immunocompromised children who have no history of varicella, regardless of serologic tests. VZIG can prevent or attenuate
the disease manifestations of varicella in susceptible contacts at high risk of infection. Patients who develop
chickenpox, either with or without VZIG, must be
treated promptly with intravenous acyclovir. Early treatment, especially within 24 hours of the onset of rash,
prevents fatalities.
In addition to cancer chemotherapy, cytotoxic agents
(eg, cyclophosphamide, methotrexate) also are used
commonly for inflammatory rheumatic and renal disorders. For these indications, the doses typically are lower,
and adverse effects, when noted, often are less profound
and less common. For example, methotrexate in a lowdose regimen of 0.3 to 1.1 mg/kg per week (10 to
25 mg/m2 once weekly dosing) is used most frequently
as a disease-modifying antirheumatic drug in JRA. Minor
adverse effects, such as oral mucous membrane lesions,
may occur. Two primary adverse effects may be noted:
bone marrow suppression (relatively rare) and hepatotoxicity (mostly mild). Both resolve with dose modifica-
Skin cancer, alopecia
Gonadal suppression,
myelodysplasia,
oncogenesis,
opportunistic infections
Miscellaneous
Pulmonary fibrosis
Gastrointestinal
intolerance
Dermatologic
Hepatic
Pulmonary
Gastrointestinal
Neurologic
Syndrome of inappropriate
antidiuretic protein
secretion
Cystitis, bladder cancer
Cardiovascular
Renal
Metabolic
Bone marrow suppression
Cyclophosphamide
Teratogenicity,
opportunistic
infections
Pneumonitis
Gastrointestinal
intolerance,
stomatitis
Hepatotoxicity
(fibrosis, cirrhosis)
Accelerated nodulosis
Bone marrow
suppression
Methotrexate
Pneumonitis
Gastrointestinal
intolerance, oral
ulcers, pancreatitis
Hepatotoxicity,
cholestasis
Hair loss, skin rash
Bone marrow
suppression
Azathioprine
Hypertrichosis, brittle
fingernails
Gingival hypertrophy
Hepatotoxicity, cholestasis
Gastrointestinal intolerance
Tremor, seizures,
paraesthesias
Hemolytic uremic syndrome,
macrocytosis
Hypertension
Tubular atrophy, interstitial
fibrosis, hyperkalemia
Dyslipidemia, reduced
glucose tolerance
Cyclosporine
Adverse Effects of Commonly Used Immunosuppressive Agents
Hematologic-oncologic
Table 4.
Opportunistic
infections
Gastrointestinal
intolerance
Bone marrow
suppression
Mycophenolate
pharmacology corticosteroid and immunosuppressive therapy
Pediatrics in Review Vol.25 No.12 December 2004 431
pharmacology corticosteroid and immunosuppressive therapy
tion or temporary discontinuation of methotrexate. Pulmonary toxicity has been reported in adults. Careful
clinical observation and periodic safety laboratory checks
that include a complete blood count and liver profile are
mandatory to detect toxicity.
Intravenous immune globulin (IVIG) therapy is used
in a number of childhood inflammatory diseases, including idiopathic thrombocytopenic purpura, Kawasaki disease, and some cases of juvenile dermatomyositis and
systemic-onset JRA. IVIG therapy usually is safe and well
tolerated when administered appropriately. Fever, chills,
nausea, and headaches are common, and anaphylactoid
reaction and aseptic meningitis can occur rarely.
Finally, several novel biologic agents (eg, TNF-alpha
inhibitors) have been developed for managing rheumatic
disorders and inflammatory bowel disease (IBD). The
proinflammatory cytokines, particularly TNF-alpha and
IL-1-beta, play a major role in the signaling of inflammation, especially the production of metalloproteinases that
leads to pannus formation and joint destruction in patients who have rheumatoid arthritis. Etanercept (for
JRA) and infliximab (for IBD) are approved by the
United States Food and Drug Administration for use in
children. The most common adverse effects are increased
risk of mild-to-moderate upper respiratory tract infection
and, in the case of etanercept, local skin reaction at
injection sites, which has occurred in about 30% of
patients. Recent reports of infliximab-associated tuberculosis activation in adults are reminders that data on
long-term exposure are needed to understand fully the
safety profile of these newer agents.
Immunizations for Children Receiving
Immunosuppressive Therapy
Recipients of immunosuppressive therapy for management of collagen vascular diseases, malignancy, or transplantation are at increased risk of various infectious diseases, some of which can be prevented by vaccines. Such
children also may be more susceptible to adverse effects
from live virus vaccines, although serious complications
have been reported only rarely. Several factors must be
considered in the immunization of children receiving
chronic steroid or other immunosuppressive therapy. In
general, live vaccines, either viral or bacterial (eg, measles,
mumps, and rubella; oral polio vaccine; and varicella) are
contraindicated in recipients of high doses of systemic corticosteroids or other immunosuppressive therapy. Live vaccines are not administered until the underlying malignancy
is in remission and immunosuppressive therapy has been
discontinued for at least 90 days.
The safety and effectiveness of vaccines in children
432 Pediatrics in Review Vol.25 No.12 December 2004
receiving corticosteroid therapy are determined by the
frequency and route of administration, the underlying
condition, and the concurrent administration of other
immunosuppressive agents. In previously healthy children, the minimal immunosuppressive dose and duration
of systemic corticosteroids are not well defined. Based on
expert guidelines developed by the American Academy
of Pediatrics (AAP), individuals receiving chronic steroid
therapy are considered immunocompromised if they receive prednisone or an equivalent at a dose of at least
2 mg/kg per day (or a total dose of at least 20 mg/d for
children weighing more than 10 kg) administered daily
or on alternate days for 14 or more days.
The AAP recommendations for use of live-virus vaccines in previously healthy children receiving corticosteroids are summarized in Table 5. Previously healthy
children who are being treated with topical, locally instilled, or inhaled corticosteroids; children receiving
physiologic corticosteroid therapy without other immunodeficiency; and children who are being treated with
low-to-moderate doses of systemic corticosteroids administered daily or on alternate days can receive live
vaccines safely during steroid treatment. Live-virus vaccines are contraindicated for children receiving high
doses of systemic steroids administered daily or on alternate days for 14 days or more until steroid therapy has
been discontinued for at least 1 month. In addition,
children who have underlying conditions that are considered to suppress the immune system and who are receiving systemic or local corticosteroids should not receive
live-virus vaccines except in special circumstances.
Inactivated vaccines (eg, diphtheria, tetanus, acellular
pertussis; hepatitis B; inactivated poliovirus; Haemophilus influenzae type b; pneumococcal; and influenza) are
safe and are recommended routinely for children receiving immunosuppressive therapy. However, high-dose
immunosuppressive therapy may inhibit an adequate immune response to inactivated vaccines. The ability to
mount an adequate immune response to inactivated vaccines usually develops 3 to 12 months after discontinuation of immunosuppressive therapy. Children who have
received vaccines during the period of immunosuppressive therapy should be reimmunized after therapy is
discontinued. Influenza vaccine is recommended
strongly for most immunosuppressed patients during the
influenza season. For children who have cancer, influenza vaccine may be administered 3 to 4 weeks after
chemotherapy is stopped if the absolute neutrophil
and lymphocyte counts are greater than 1,000/mm3.
When possible, immunization series should be completed before procedures that require or induce immu-
pharmacology corticosteroid and immunosuppressive therapy
Immunization of Children and Adolescents Receiving
Corticosteroid Therapy
Table 5.
Treatment Category and
Duration
Dose of Prednisone
or Equivalent
Topical therapy
Inhaled therapy
Local injections
Vaccine
Contraindications*
None
None
None
Avoid live vaccines until steroids discontinued
for >1 mo if prolonged topical therapy
results in clinical or laboratory evidence of
systemic immunosuppression
May receive live-virus vaccines during
corticosteroid treatment
May receive live-virus vaccines during
corticosteroid treatment
Physiologic maintenance
Replacement doses
None
Low or moderate dose, daily
or alternate day
<2 mg/kg per day or
<20 mg/d if
weight >10 kg
>2 mg/kg per day or
>20 mg/d if
weight >10 kg
None
>2 mg/kg per day or
>20 mg/d if
weight >10 kg
All live vaccines
High dose, <14 d, daily or
alternate day
High dose, >14 d, daily or
alternate day
Comments
May receive live-virus vaccines immediately
after steroids are discontinued; some
experts recommend a 2-wk delay after
discontinuing steroids prior to
administering live-virus vaccines
May receive live vaccines after steroids
discontinued for >1 mo
*Live viral vaccines: measles-mumps-rubella, oral polio vaccine, varicella.
From: American Academy of Pediatrics. Immunization in special clinical circumstances: immunocompromised children. In: Pickering LK, ed, 2000 Red Book:
Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2000:56 – 64.
nosuppression, such as organ transplantation or chemotherapy.
Household contacts of immunosuppressed children
should be vaccinated to protect the patient. However,
oral live polio vaccine should be avoided in close contacts
of immunocompromised children because it may infect
the patient. If indicated, siblings and household contacts
should receive measles, mumps, and rubella and influenza vaccines because there is no transmission of vaccine
strains. In addition, varicella vaccine is recommended for
susceptible household contacts because transmission of
vaccine strains is rare and severe disease is unlikely, even
in compromised hosts. Pediatricians should consult with
infectious disease specialists when considering immunizations for children receiving immunosuppressive therapy. Readers are referred to the 2003 edition of the Red
Book for expert guidance regarding immunization practices in immunocompromised children, including those
who have primary and secondary (acquired) immune
deficiencies, those receiving chronic corticosteroid therapy, and transplant recipients.
References
American Academy of Pediatrics. Immunization in special clinical
circumstances: immunocompromised children. In: Pickering
LK, ed. 2000 Red Book: Report of the Committee on Infectious
Diseases. 25th ed. Elk Grove Village, Ill: American Academy of
Pediatrics; 2000:56 – 64
Ansell BM. Overview of side effects of corticosteroid therapy. Clin
Exp Rheumatol. 1991;9:19 –20
Boumpas DT, Chrousos GP, Wilder RL, et al. Glucocorticoid
therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med. 1993;119:1198 –1208
Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med.
1976;84:304
Klein-Gitelman MS, Pachman LM. Intravenous corticosteroids:
adverse reactions are more variable than expected in children.
J Rheumatol. 1998;25:1995–2002
Laredo A, Rodriguez RS, Murillo L. Cataracts after short-term
corticosteroid treatment. N Engl J Med. 1972;286:160
Loeb JN. Corticosteroids and growth. N Engl J Med. 1976;295:547
Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with
polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000;
342:763–769
McFarland E. Immunizations for the immunocompromised child.
Pediatr Ann. 1999;28:487– 496
Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl
J Med. 1992;326:1473
Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335:1206
Pearce D, Yamamoto KR. Mineralocorticoid and glucocorticoid
receptor activities distinguished by nonreceptor factors at a
composite element. Science. 1993;259:1161–1165
Saag KG, Emkey R, Schnitzer T, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis.
N Engl J Med. 1998;339:292–299
Pediatrics in Review Vol.25 No.12 December 2004 433
pharmacology corticosteroid and immunosuppressive therapy
Schleimer RP. An overview of glucocorticoid anti-inflammatory
actions. Eur J Clin Pharmacol. 1993;45(suppl):S3
Segal BH, Sneller MC. Infectious complications of immunosuppressive therapy in patients with rheumatic diseases. Rheum Dis
Clin North Am. 1997;23:219 –237
Stuck AE, Minder CE, Frey EJ. Risk of infectious complications
in patients taking glucocorticoids. Rev Infect Dis. 1989;11:
954
The American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendation for the prevention and the
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Rheum. 2001;44:1496 –1503
PIR Quiz
Quiz also available online at www.pedsinreview.org.
10. A 6-year-old boy is receiving oral steroid therapy for outpatient management of asthma. An absolute
increase of which of the following white blood cells will be observed on his complete blood count?
A.
B.
C.
D.
E.
Basophils.
Eosinophils
Lymphocytes.
Monocytes.
Neutrophils.
11. A 7-year-old girl who has frequent exacerbations of dermatomyositis has been treated with
corticosteroids for 6 months. Which of the following metabolic effects can be attributed to steroid
therapy?
A.
B.
C.
D.
E.
Decreased production of somatomedin C.
Hypoglycemia.
Metabolic acidosis.
Positive nitrogen balance.
Salt wasting.
12. A 4-year-old boy who has acute lymphocytic leukemia is undergoing induction therapy with vincristine,
prednisone, and asparaginase. He has had no previous history of chickenpox or varicella vaccination. His
2-year-old sister was just diagnosed with chickenpox. Which of the following is the most appropriate
management for the boy?
A.
B.
C.
D.
E.
Administration of acyclovir therapy and varicella vaccine now.
Administration of intravenous immune globulin and acyclovir therapy now.
Administration of varicella vaccine now and acyclovir therapy if lesions develop.
Administration of varicella-zoster immune globulin now and acyclovir therapy if lesions develop.
Observation and reassurance, with administration of acyclovir if lesions develop.
13. A 12-year-old girl who has diffuse proliferative lupus nephritis has received 30 mg of prednisone daily for
the last 2 months. Which of the following vaccines is most likely to cause serious adverse effects in this
girl?
A.
B.
C.
D.
E.
Haemophilus influenzae type b conjugate vaccine.
Influenza vaccine.
Measles, mumps, rubella vaccine.
Tetanus and diphtheria toxoid.
23-valent pneumococcal vaccine.
434 Pediatrics in Review Vol.25 No.12 December 2004