Chronic Steroid and Immunosuppressant Therapy in Children

Abstract

After completing this article, readers should be able to: 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.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.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.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.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.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 two- to four-fold.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 effect on immunoglobulin levels or on antigen-stimulated 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 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.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 dose-related 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.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 (insulin-like growth factor I) production. Furthermore, growth failure sometimes is related to the underlying condition.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 dermatomyositis or polymyositis, this might be misinterpreted as exacerbation of their underlying disease. However, patients who have steroid myopathy generally experience an insidious onset of painless proximal muscle 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 high-dose corticosteroid therapy. Both proximal and distal muscle weakness can occur, and elevation of serum creatinine phosphokinase or aldolase levels in conjunction with rhabdomyolysis may result.Patients who have rheumatic diseases, especially systemic lupus 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 cortical 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. Steroid-induced 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 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 long-term steroids have showed benefit.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, high-dose 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.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 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.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.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 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.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, life-threatening 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.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 catheters 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 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 low-dose 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 modification 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.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 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 immunosuppression, 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.