Portal de Periódicos da CAPES

When oral corticosteroids are essential for persistent severe asthma

2010; Elsevier BV; Volume: 125; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2009.12.979

1097-6825

Paul A. Greenberger,

Respiratory and Cough-Related Research

When oral corticosteroids are indicated for patients with asthma, the response to treatment should be anticipated and weighed against potential risks or side effects. This discussion is focused on the immune effects of systemic corticosteroids. In some patients with persistent severe asthma, it might be impossible to achieve effective control of asthma without oral corticosteroids. As outpatients, patients can begin to respond within 1 to 2 hours of initiation of prednisone as part of an action plan, whereas other patients might require 6 to more than 48 hours or longer to begin to improve. The half-life of prednisone is between 1 and 3 hours, and anti-inflammatory effects from oral or intravenous corticosteroids occur promptly. CD4+ T-lymphocyte and peripheral blood eosinophil numbers decrease in the first few hours. Peripheral blood eosinophil numbers can decrease from 10% on admission to less than 2% in 8 to 24 hours after oral or intravenous corticosteroids in patients admitted for acute severe asthma (status asthmaticus) who have not received oral corticosteroids as an outpatient. Sputum eosinophilia decreases substantially in the first 48 hours. It can be expected that patients have tissue eosinophilia without peripheral blood eosinophilia. There are many clinically useful and anti-inflammatory effects of corticosteroids in the treatment of asthma, examples of which are presented in Table I.Table ISelected examples of clinical and anti-inflammatory actions of corticosteroids in asthma∗Adapted from Greenberger PA. Asthma. In: Grammer LC, Greenberger PA, editors. Patterson's allergic diseases. 7th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2009. p. 333-88.Clinical Increases β2-adrenergic receptor density Decreases sputum and blood eosinophil numbers Decreases expired nitric oxide levels Reduces recidivism to the emergency department Improves oxygenation and time to discharge after hospitalization Partially inhibits early and late bronchoconstriction responses to allergen after 1 week of inhaled or oral corticosteroidAnti-inflammatory Regenerates bronchial epithelium Reduces numbers of eosinophils and mast cells in respiratory epithelium and lamina propria Decreases production of superoxide anions by eosinophils Activates the glucocorticoid receptor in the cytoplasm with translocation into the nucleus Decreases histone acetyltransferase activity, which reduces “unwinding” of chromatin (DNA-histone) and transcription Increases histone deacetylase activity, causing transcriptional repression of inflammatory genes Supports expression of FOXP3 mRNA in CD4+CD25+ Treg cells Decreases the stability of mRNA transcriptsFOXP3, Forkhead box protein 3; Treg, regulatory T.∗ Adapted from Greenberger PA. Asthma. In: Grammer LC, Greenberger PA, editors. Patterson's allergic diseases. 7th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2009. p. 333-88. Open table in a new tab FOXP3, Forkhead box protein 3; Treg, regulatory T. Alternatively, when a patient with severe, corticosteroid-dependent asthma is admitted for acute severe asthma despite receiving 40 to 60 mg of prednisone daily for 5 to 7 days as part of an action plan and peripheral blood eosinophils of 8% to 10% are recorded, the disappearance of eosinophils within 8 to 24 hours of receiving intravenous or supervised oral steroids suggests nonadherence with prednisone and not severe corticosteroid-dependent asthma. A 53-year-old woman was hospitalized with acute severe asthma. She had a history of asthma for more than 20 years and reported allergic rhinitis symptoms. She denied childhood symptoms suggestive of asthma or atopic dermatitis. She had smoked a total of 10 pack-years of cigarettes and none in 20 years. A high-resolution computed tomographic examination of the lungs was obtained because during the hospitalization, cystic bronchiectasis of the upper lobes, middle lobe, and lingula and some areas of atelectasis were unexpectedly revealed. Allergic bronchopulmonary aspergillosis (ABPA) was confirmed with a total IgE concentration of 1,412 kU/L (upper range of normal, 417 kU/L), an IgE–Aspergillus fumigatus index of 4.6 (normal, <2.0), and an IgG–A fumigatus index of 3.1 (normal, <2.0). Precipitating antibodies to A fumigatus were identified. The patient had positive skin prick test responses to A fumigatus, Penicillium species, Alternaria species, house dust mite, cat dander, and cockroach. On intradermal testing, she had positive results to trees and grasses. She was still wheezing on examination a week after discharge despite 60 mg of prednisone each morning, 500 μg of fluticasone propionate/50 μg of salmeterol twice daily, 2 inhalations from an albuterol inhaler 3 times daily, 10 mg of montelukast, and nasal fluticasone, lansoprazole, cetirizine, aspirin, moxifloxacin, and hydrochlorothiazide. During the hospitalization, complete pulmonary function tests were performed. Her initial FEV1 was 1.53 L (63%), with a 5% increase to 1.60 L (65%) after albuterol. The forced vital capacity (FVC) was 2.25 L (69%), with an 11% increase to 2.48 L (77%). The diffusion capacity of the lung for carbon monoxide was 18.4 mL/mm Hg/min (82%). Nevertheless, when she was examined as an outpatient after high-dosage corticosteroids, her outpatient FEV1 was 1.34 L (58%), and her FVC was 1.95 L (60%). The FEV1/FVC ratio was 68%, which is similar to values when she was hospitalized. The history of hospitalizations for asthma previously, continued wheezing, dyspnea, and the finding of ABPA indicated the need for prednisone at least for the next 3 months administered on an alternate-day schedule. The patient asked whether “steroids would damage my immune system.” It should be stated that the patient was treated with omalizumab in the next year, and the control of her asthma was improved. However, she was not able to be tapered completely from prednisone, with a controlling dosage of 10 to 15 mg on alternate days. Antibody production from influenza immunization is preserved in patients receiving doses of oral corticosteroids2Kunisaki K.M. Janoff E.N. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses.Lancet Infect Dis. 2009; 9: 493-504Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar, 3Kubiet M.A. Gonzalez-Rothi R.J. Cottey R. Bender B.S. Serum antibody response to influenza vaccine in pulmonary patients receiving corticosteroids.Chest. 1996; 110: 367-370Crossref PubMed Scopus (51) Google Scholar and inhaled/intranasal corticosteroids for asthma/rhinosinusitis. Influenza vaccination is considered T cell dependent, but adequate clinical protection can be achieved despite oral corticosteroids being administered for severe asthma. When larger doses of daily prednisone are used, as in other conditions, the results are similar.4Lu Y. Jacobson D.L. Ashworth L.A. Grand R.J. Meyer A.L. McNeal M.M. et al.Immune response to influenza vaccine in children with inflammatory bowel disease.Am J Gastroenterol. 2009; 104: 444-453Crossref PubMed Scopus (137) Google Scholar For example, in children with inflammatory bowel disease receiving “corticosteroids at 0.7 mg/kg/day,” there was no reduction in 4-fold increases in antibody responses to influenza A.4Lu Y. Jacobson D.L. Ashworth L.A. Grand R.J. Meyer A.L. McNeal M.M. et al.Immune response to influenza vaccine in children with inflammatory bowel disease.Am J Gastroenterol. 2009; 104: 444-453Crossref PubMed Scopus (137) Google Scholar The administration of oral tacrolimus or a TNF-α inhibitor did not compromise the seroprotection to influenza A, but there was a nonsignificantly lower response for influenza B when a TNF-α inhibitor was administered.4Lu Y. Jacobson D.L. Ashworth L.A. Grand R.J. Meyer A.L. McNeal M.M. et al.Immune response to influenza vaccine in children with inflammatory bowel disease.Am J Gastroenterol. 2009; 104: 444-453Crossref PubMed Scopus (137) Google Scholar Neither daily nor alternate-day prednisone has been found to suppress responses to pneumococcal vaccination,5Lahood N. Emerson S.S. Kumar P. Sorensen R.U. Antibody level and response to pneumococcal vaccine in steroid-dependent asthma.Ann Allergy. 1993; 70: 289-294PubMed Google Scholar, 6Gelinck L.B.S. van der Bijl A.E. Visser L.G. Huizinga T.W.J. van Hogezand R.A. Rijkers G.T. et al.Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine.Vaccine. 2008; 26: 3528-3533Crossref PubMed Scopus (58) Google Scholar which, although considered T cell independent, does involve some T cell–dependent polysaccharides. In a study of patients with rheumatoid arthritis, ankylosing spondylitis, or Crohn disease, it took the combination of methotrexate and a TNF-α inhibitor to diminish response rates to pneumococcal vaccination.6Gelinck L.B.S. van der Bijl A.E. Visser L.G. Huizinga T.W.J. van Hogezand R.A. Rijkers G.T. et al.Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine.Vaccine. 2008; 26: 3528-3533Crossref PubMed Scopus (58) Google Scholar Results in patients receiving methotrexate, azathioprine, or prednisone did not differ from those in control subjects.6Gelinck L.B.S. van der Bijl A.E. Visser L.G. Huizinga T.W.J. van Hogezand R.A. Rijkers G.T. et al.Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine.Vaccine. 2008; 26: 3528-3533Crossref PubMed Scopus (58) Google Scholar In summary, regarding the patient with severe asthma and ABPA who required inhaled, intranasal, and oral corticosteroids, influenza and pneumococcal immunizations should result in adequate seroprotection and clinical responses. In a classic study by Fauci and Dale,7Fauci A.S. Dale D.C. Alternate-day prednisone therapy and human lymphocyte subpopulations.J Clin Invest. 1975; 55: 22-32Crossref PubMed Scopus (134) Google Scholar prednisone administered at doses as high as 100 mg on alternate days did not suppress delayed cutaneous hypersensitivity responses to a panel of tuberculin, Candida species, mumps, and streptokinase-streptodornase. It did not matter whether the testing was conducted on the prednisone day or a nonpredisone day. The authors demonstrated profound transient lymphopenia in the first 4 hours that returned to normal the next day.7Fauci A.S. Dale D.C. Alternate-day prednisone therapy and human lymphocyte subpopulations.J Clin Invest. 1975; 55: 22-32Crossref PubMed Scopus (134) Google Scholar Inhaled fluticasone propionate administered at a dosage of 800 μg/d for 28 days without systemic corticosteroids did not suppress delayed cutaneous hypersensitivity to a panel of tuberculin, tetanus, Candida species, and mumps.8England R.W. Nugent J.S. Grathwohl K.W. Hagan L. Quinn J.M. High-dose fluticasone and delayed hypersensitivity testing.Chest. 2003; 123: 1014-1017Crossref PubMed Scopus (10) Google Scholar It has been suggested in some but not all studies that there is an increased risk of suprainfections in patients receiving prednisone, with the risk increasing at a daily dosage of as little as 7.5 mg9Ruiz-Irastorza G. Olivares N. Ruiz-Arruza I. Martinez-Berriotxoa A. Egurbide M.V. Aguirre C. Predictors of major infections in systemic lupus erythematosus.Arthritis Res Ther. 2009; 11: R109Crossref PubMed Scopus (234) Google Scholar or greater than 10 mg.1Greenberger P.A. Asthma.in: Grammer L.C. Greenberger P.A. Patterson's allergic diseases. 7th ed. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia2009: 333-388Google Scholar, 2Kunisaki K.M. Janoff E.N. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses.Lancet Infect Dis. 2009; 9: 493-504Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar, 10Stuck A.E. Minder C.E. Frey F.J. Risk of infectious complications in patients taking corticosteroids.Rev Infect Dis. 1989; 11: 954-963Crossref PubMed Scopus (650) Google Scholar However, alternate-day prednisone, even in doses as high as 100 mg, has not been associated with an increased risk of major suprainfections.7Fauci A.S. Dale D.C. Alternate-day prednisone therapy and human lymphocyte subpopulations.J Clin Invest. 1975; 55: 22-32Crossref PubMed Scopus (134) Google Scholar In recent years, identifying patients who have not received anticytokine therapies or immunosuppressive treatments that can cause neutropenia (<1,000/μL) or lymphopenia (<1,000/μL) makes interpretation of the literature focusing on the risk of infections from oral corticosteroids more challenging. In any event, localized oral candidiasis is a recognized complication of orally inhaled corticosteroids with or without concurrent antibiotic treatment. Candida species–induced bacteremia or sepsis would suggest concurrent severe neutropenia or uncontrolled hyperglycemia if it occurred in a patient receiving long-term moderate- to high-dose daily prednisone for asthma. A serious disruption in the immune system from a medication could result in increased risk of malignancy, but the data do not support such a convincing connection with use of prednisone, especially in doses used for the treatment of asthma. In a case-control study of patients with bladder cancer, prolonged oral corticosteroid use was reported as a risk factor.11Dietrich K. Schned A. Fortuny J. Heaney J. Marsit C. Kelsey K.T. et al.Glucocorticoid therapy and risk of bladder cancer.Br J Cancer. 2009; 101: 1316-1320Crossref PubMed Scopus (51) Google Scholar The critical dose of prednisone was 50 mg daily but not less than 10 mg or 10 to 49 mg, making any generalizability questionable. In summary, prednisone administered in doses recommended for asthma either as alternate-day with intermittent daily courses or as a single low dose each morning does not impede protective humoral immunity or delayed cutaneous hypersensitivity responses or predispose to the risks of major infection or neoplasms. For additional information about the clinical pharmacology of corticosteroids and potential adverse effects, the reader is referred to an excellent recent review.12Spahn J.D. Covar R. Szefler S.J. Glucocorticoids: clinical pharmacology.in: Adkinson Jr., N.F. Bochner B.S. Busse W.W. Holgate S.T. Lemanske Jr., R.F. Simons F.E.R. Middleton's allergy: principles & practice. 7th ed. Mosby Elsevier, Philadelphia2008: 1575-1589Google Scholar What are some “teaching points” regarding the use of prednisone in a patient with persistent allergic asthma and an unexpected diagnosis of ABPA who questions the benefits compared with the risks of prednisone on the immune system? The addition of recommended doses of inhaled/intranasal corticosteroids should not contribute to major untoward or damaging effects on the immune system. Low-dose single-morning prednisone is an option for some patients who require prednisone. The use of lower doses of single-dose, morning daily prednisone is quite safe from major adverse effects but might result in mild Cushingoid facies, hyperglycemia, or hypertension. Thus it is preferred to attempt to manage patients with alternate-day prednisone along with appropriate avoidance measures, treatment of comorbidities, pharmacotherapy, and potentially allergen immunotherapy or immunomodulatory treatment. If oral steroid administration does not improve the patient's overall status, it is necessary to review the diagnoses; extent of adherence; comorbidities, including allergic rhinitis, chronic rhinosinusitis, gastroesophageal reflux, and possibly B-lymphocyte function; and optional other treatment modalities and to identify the minimal effective dosage of oral corticosteroid required.