Radiation pneumonitis successfully treated with inhaled corticosteroids. (Case Report).

Key Words: corticosteroids, pneumonitis, radiation

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Key Points

* Corticosteroids are used to treat radiation pneumonitis.

* Inhaled steroids may be beneficial in lieu of systemic steroids.

* Sporadic radiation pneumonitis can occur outside the radiation field.

Radiation pneumonitis is a well-described complication of chest radiotherapy administered to patients for mediastinal, breast, and lung tumors. Dyspnea, cough, and radiographic infiltrates within the field of radiation are typical symptoms and findings. Systemic corticosteroids are the traditionally accepted treatment, often with good clinical responses reported in a large number of patients. However, no randomized controlled trials exist to support their use. Inhaled steroids have been the mainstay in asthma treatment and have been used to reduce side effects of systemic corticosteroids. Inhaled steroids are being used on an increasing basis to treat other steroid responsive lung diseases such as sarcoidosis. This case report shows inhaled steroids being successfully used to treat radiation pneumonitis.

Discussion

Pneumonitis and fibrosis were first described as a complication of radiotherapy by Groover et al (1) in 1922. Radiation pneumonitis has been reported to occur in from 1 to 34% of patients receiving chest radiation, depending on diagnostic criteria used, with radiographic changes being more common than actual symptoms. (2) Occurrence of pneumonitis is variable depending on the total dose, fractionation, lung volume irradiated, and whether concomitant pneumotoxic chemotherapy is administered. (2-4) Higher radiation doses and greater volumes of lung parenchyma irradiated are associated with a higher incidence of radiation pneumonitis, with symptoms and radiographic changes common after doses above 40 Gy. (3,4) Survival is not adversely affected except in cases of severe radiation pneumonitis. (5)

Symptoms typically develop 1 to 3 months after completion of a course of radiotherapy, with fibrosis occurring at 6 to 12 months. (2) Dyspnea out of proportion to the lung volume irradiated is the most common symptom, occurring in as many as 90% of affected patients. Cough, which is usually nonproductive, occurs in about 50 to 60% of patients and may be severe. A low-grade fever is occasionally reported as well.

Physical findings usually are not prominent but occasionally moist crackles, a pleural friction rub, or evidence of consolidation may be present. (2) A distinct zone defining the radiation port is often present on chest x-rays, but laboratory and radiographic studies are nonspecific. (2,6) Lung biopsy is often needed to rule out other potential diagnoses such as bronchiolitis obliterans with organizing pneumonia, infection, or tumor recurrence. (6)

Cytokine release and direct radiation damage to type II pneumocytes have been implicated as the initial events in radiation pneumonitis. Early histologic findings include increased vascular permeability with alveolar capillary congestion. The alveoli are filled with necrotic alveolar cells and inflammatory cells. The alveolar septa are thickened with an infiltrate of lymphocytes and neutrophils. With time, a fibrous and leukocytic infiltration develops around blood vessels, alveolar ducts, and bronchioles, often obliterating the vessel lumen. Fibrosis is present after 6 months or more with obliteration of normal alveolar architecture. (2,7)

While radiation pneumonitis is often thought to affect only the lung within the zone of irradiation, pathologic changes outside the zone of irradiation, including the contralateral lung, are well described. (2) Gallium scanning reveals bilateral pulmonary inflammation after unilateral radiotherapy. (8) Studies using bronchoalveolar lavage commonly demonstrate a lymphocytosis both within and outside the field of radiation. (9,10) However, less than 10% of such individuals go on to develop a pneumonitis picture. (9,10) The exact mechanism of this "sporadic" radiation pneumonitis is not fully understood but it is thought to be immunologically mediated and possibly involve a hypersensitivity-like reaction. (11,12)

Oral corticosteroids have been the mainstay of therapy for radiation pneumonitis, often with dramatic results. No large human studies exist to support the efficacy of corticosteroids in radiation injury, but the long history of clinical use suggests a response rate as high as 80% in improving symptoms. (2) However, corticosteroids may not influence survival, even in patients who develop severe radiation pneumonitis. (5) Prophylaxis with corticosteroids has not been proven effective, but some studies suggest some benefit. (13) Angiotensin-converting enzyme inhibitors have been shown to inhibit pneumonitis in an animal model, (14) and pentoxifylline may improve radiation-induced skin changes when used with vitamin E. (15) However, no controlled human studies are present to support their use in clinical radiation pneumonitis. Established fibrosis is irreversible and will not improve with corticosteroid therapy.

Systemic corticosteroids are associated with numerous side effects including osteoporosis, adrenal suppression, and increased susceptibility to infection. Inhaled steroids minimize these systemic side effects and are routinely used in the treatment of asthma. Inhaled steroids are being used on an increasing basis to treat bronchiolitis obliterans with organizing pneumonia (BOOP) and sarcoidosis, diseases traditionally treated with systemic steroids. (16)

While dyspnea was not the dominant symptom in this patient, it may have been masked by the severity of the cough and the patient's sedentary lifestyle. Our patient clearly demonstrated a requirement for corticosteroids to maintain control of her symptoms, as a prednisone taper to less than 25 mg per day resulted in relapse of her intractable cough. The addition of inhaled steroids to her regimen allowed her prednisone medication to be tapered off completely with resolution of significant steroid-induced side effects, and improvements in FVC gained while using prednisone were maintained while on inhaled steroids. While the hypothalamic-pituitary-adrenal axis was not evaluated, institution of inhaled steroids alleviated the intolerable systemic effects experienced by this patient on oral steroids.

While radiation pneumonitis is the most likely diagnosis in this patient, we also entertained other possible diagnoses. This patient demonstrated no airflow obstruction on spirometry measurement and had no improvement in symptoms with inhaled [beta]-agonists, making the diagnosis of asthma unlikely. BOOP is often seen as a complication of radiation pneumonitis. This patient's clinical and radiographic presentation as well as her response to steroid therapy is consistent with BOOP. However, lung biopsy did not demonstrate organizing pneumonia in the terminal bronchioles or alveolar spaces characteristic of BOOP. Instead, biopsy revealed fibrosis and inflammation consistent with radiation pneumonitis.

Conclusion

We report the successful use of inhaled steroids as a replacement for oral steroids in a patient with radiation pneumonitis. Relatively high doses of inhaled steroids were needed to maintain control of her symptoms, but the intolerable side effects of systemic steroids were eliminated. Radiation pneumonitis may be another in a growing list of diseases with good responses to more locally directed treatment.

Accepted August 22, 2002.

References

(1.) Groover TA, Christie AC, Merritt EA. Observations on the use of the copper filter in the treatment of deep-seated malignancies. South Med J 1922;15:440-444.

(2.) Movsas B, Raffin TA, Epstein AH, Link CJ Jr. Pulmonary radiation injury. Chest 1997;111:1061-1076.

(3.) Gross NJ. Pulmonary effects of radiation therapy. Ann Intern Med 1977;129:127-136.

(4.) Roach M III, Gandara DR, Yuo HS, Swift PS, Kroll S, Shrieve DC, et al. Radiation pneumonitis following combined modality therapy for lung cancer: Analysis of prognostic factors. J Clin Oncol 1995;13:2606-2612.

(5.) Inoue A, Kunitoh H, Sekine I, Sumi M, Tokuuye K, Saijo N. Radiation pneumonitis in lung cancer patients: A retrospective study of risk factors and the long-term prognosis. Int J Radiat Oncol Blot Phys 2001;49:649-655.

(6.) Libshitz HI, Southard ME. Complications of radiation therapy: The thorax. Semin Roentgenol 1974;9:41-49.

(7.) Rosiello, RA, Merrill, WW. Radiation-induced lung injury. Clin Chest Med 1990;11:65-71.

(8.) Morgan GW. Breit SN. Radiation and the lung: A reevaluation of the mechanisms mediating pulmonary injury. Int J Radiat Oncol Biol Phys 1995;31:361-369.

(9.) Arbetter KR, Prakash UB, Tazelaar HD, Douglas WW. Radiation-induced pneumonitis in the "nonirradiated" lung. Mayo Clin Proc 1999;74:27-36.

(10.) Roberts CM, Fouleher E, Zaunders JJ, Bryant DH, Freund J, Cairns D, et al, Radiation pneumonitis: A possible lymphocyte-mediated hypersensitivity reaction. Ann Intern Med 1993;118:696-700.

(11.) Martin C, Romero S, Sanchez-Paya J, Massuti B, Arriero JM, Hemandez L. Bilateral lymphocytic alveolitis: A common reaction after unilateral thoracic irradiation. Eur Respir J 1999;13:727-732.

(12.) Prakash U. Radiation-induced injury in the "nonirradiated" lung. Eur Respir J 1999;13:715-717.

(13.) Pagel J, Mohom M, Kloetzer KH, Fleck M, Wendt TG. The inhalation versus systemic prevention of pneumonitis during thoracic irradiation. Strahlenther Onkol 1998;174:25-29.

(14.) Delanian S, Balla-Mekias S, Lefaiz J. Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 1999;17:3283-3290.

(15.) Molteni A, Moulder JE, Cohen EF, Ward WF, Fish BL, Taylor JM, et al. Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blocker, Int J Radiat Biol 2000;76:523-532.

(16.) Paramothayan NS, Jones PW. Corticosteroids for pulmonary sarcoidosis. Cochrane Database Syst Rev 2002;2:CD001114.

RELATED ARTICLE: Case Report

A 48-year-old woman presented for medical evaluation with a 3-week history of cough, productive of yellow-green sputum, refractory to two courses of oral antibiotics. A chest x-ray revealed a 17 X 15-cm mass in the right anterior mediastinum (Figs. 1 and 2). The patient underwent a computed tomography (CT)-guided transthoracic biopsy, and a diagnosis of thymoma was made. At surgery, extracapsular extension with tumor adherent to all three lobes of the right lung and pleural invasion was found. The patient underwent right upper and right lower lobe wedge resections with a complete right middle lobectomy as well as pleural and pericardial resections. Postoperatively, 45 Gy of adjuvant radiotherapy in 25 fractions was administered to the mediastinum and tumor bed.

The patient did well until 3 months later, when she presented to her radiation oncologist with severe, intractable cough and copious sputum production. She characterized her sputum as thick and white, 1/2-1 cup in volume per day. No hemoptysis, chills, sweats, or fever was noted. The cough was refractory to albuterol, narcotic cough syrup, and antibiotic therapy, and it was interfering significantly with sleep and daily activities. Her examination revealed egophony anteriorly on the right and chest x-ray showed an ill-defined "haze" in the right mid and upper lung fields (Fig. 3). A CT scan revealed consolidation with extensive air bronchograms primarily in the anterior segment of the right upper lobe (Fig. 4). Bronchoscopy revealed no endobronchial lesions and transbronchial biopsy revealed no growth on cultures and nonspecific chronic bronchitis. Open biopsy of the right upper lobe revealed fibrosis with ongoing inflammation consistent with radiation fibrosis and ongoing pneumonitis.

The patient was started on 60 mg of prednisone and showed significant improvement in her symptoms. She was able to sleep through the night and decreased use of narcotic cough syrup. Forced vital capacity (FVC) increased from 46 to 58% of predicted capacity without signs of airflow obstruction or a bronchodilator response. Prednisone treatment was tapered over 3 months to 20 mg at which point the patient had recurrence of her cough and sputum production and a decline in FVC. A prednisone burst of 40 mg was given again with rapid improvement in symptoms. However, the patient desired an alternative to prednisone due to emotional turmoil, mood swings, and weight gain attributed to the drug. Therefore, treatment with 220 [micro]g of fluticasone was started 2 puffs twice daily (BID), and the oral prednisone was slowly tapered. As prednisone treatment was decreased to 10 mg, the cough worsened and the fluticasone was increased to 3 puffs BID. This permitted complete discontinuation of the prednisone and significant improvement in systemic steroid-related symptoms. An attempt was made by the patient to reduce the dose of the fluticasone to 2 puffs BID, however, the patient had a recurrence of her cough, which resolved with an increase in the fluticasone back to the 3 puffs BID previously prescribed. The patient still requires inhaled steroids 18 months after their initiation to control her symptoms.

From the Department of Internal Medicine-Pulmonary, Allergy, Critical Care, University of New Mexico School of Medicine, Albuquerque, NM.

Reprint requests to Richard E. Crowell, MD, Department of' Internal Medicine-Pulmonary, Allergy, Critical Care, University of New Mexico, 2211 Lomas Blvd. NE, 5-ACC, Albuquerque, NM 87131-5271.

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