Acute Interstitial Pneumonitis

family practice grand rounds

Robert L. Blake, Jr., MD, and Sheldon Braun, MD Columbia, M issouri

R. ROBERT BLAKE (Associate Professor o f Family were bibasilar rales and scattered rhonchi and wheezes. D and Community Medicine)-. When we see a patient Her chest x-ray film showed bilateral diffuse interstitial with fever, respiratory symptoms, and pulmonary infil and alveolar infiltrates with no effusion or adenopathy. trates on x-ray film, we usually think of an infectious pro Blood gases on room air were partial arterial oxygen pres cess. The case to be discussed today reminds us that non- sure (Pa02) 50 mmHg, partial arterial carbon dioxide infectious conditions can also present in this way. In ad pressure (PaC02) 29 mmHg, and pH 7.48. Her hematocrit dition to creating an opportunity to focus on the workup was 41 percent and white cell count 13.4 X 103/mL with and treatment of interstitia l lung disease, our management a fairly normal differential. Platelet count, serum electro of this patient involved important psychosocial issues. lytes, glucose, and calcium levels, and findings from renal The patient for discussion today is a 67-year-old woman and hepatic function tests were within normal limits. Sinus who was admitted to the hospital with a four- to five-week tachycardia and right atrial enlargement were demon history of progressive fatigue, generalized weakness, non strated on electrocardiogram. Over the next few days re productive cough, dyspnea on exertion, and anorexia with sults of many laboratory tests were negative, including a 10-lb weight loss. During the immediately preceding routine bacterial cultures and serologic titers for salmo two weeks she had experienced frequent fevers to 101 to nella, tularemia, brucella, mycoplasma, toxoplasma, psit 103 °F with occasional chills. She had been seen several tacosis, legionella, and fungi. Pulmonary function testing times as an outpatient and treated with short courses of revealed reductions in vital capacity, total lung capacity, cefaclor and tetracycline without benefit. Two weeks prior and diffusion capacity consistent with severe restrictive to admission findings on a chest x-ray film had been nor disease. Her antinuclear antibody test was positive with mal. She had a history of multiple respiratory and drug a titer of 1:80 and a speckled pattern, and the rheumatoid allergies and had been taking oral theophylline chronically factor was positive at 1:20. for asthma. She had a remote and poorly documented In the hospital she received oxygen by nasal prongs at history of rheumatoid arthritis but had been free of joint 4 to 5 L/min to maintain her Pa02 between 65 and 80 symptoms for at least ten years. She had smoked cigarettes mmHg. No antibiotics were given. Fever, extreme weak for many years but had stopped six months before ad ness, dyspnea on mild exertion, and anorexia persisted. mission. Also, six months previously she had retired from On the fifth hospital day she underwent open biopsy of a long-term job as a municipal election manager in a small her lung. Histologic examination, using a variety of special town in Indiana and had moved to Columbia to be near stains and electron microscopy, revealed diffused inter a daughter. She had been a widow for many years. At the stitial inflammation with many types of cells, mild fibrosis, time of the onset of her symptoms, she had just returned and no organisms. Results of bacterial, fungal, and viral from a three-month stay in Kuwait, where she was exposed cultures were subsequently negative. A diagnosis of id to birds and to a dust storm but not to contaminated food iopathic interstitial disease was made, and she was started or water. on a daily dose of 1 mg/kg of prednisone. Within one On admission examination, she was a moderately obese week her fever had resolved and her strength, appetite, woman in mild respiratory distress with a respiratory rate and breathing had improved. A month after discharge her of 24/min, a pulse rate of 95 beats per minute, and an symptoms, findings on x-ray examination, and pulmonary oral temperature of 103 °F. The only abnormal findings function tests had greatly improved. Soon after that she moved out of state to live with another daughter. Six months after the hospitalization, the local daughter re Submined, revised, December 10, 1986. ported that her mother was off steroids and doing well.

From the Department of Family and Community Medicine, and the Department RESIDENT: Was bronchoscopy performed? of Internal Medicine, University of Missouri-Coiumbia, Columbia, Missouri. Re- DR. BLAKE: We considered bronchoscopy but did not quests for reprints should be addressed to Dr. Robert L. Blake, Jr., Department of Family and Community Medicine, M-222 Health Sciences Center, University do this procedure for several reasons. She gave a history of Missouri-Coiumbia, Columbia, MO 65212. of allergy to “caine” drugs, which we confirmed by talking

1987 Appleton & Lange

the JOURNAL OF FAMILY PRACTICE, VOL. 24, NO. 3: 243-248, 1987 243 ACUTE INTERSTITIAL PNEUMONITIS

the world and can be stirred up by sand storms. People TABLE 1. CAUSES OF NONINFECTIOUS INTERSTITIAL exposed to such storms can receive a relatively large in LUNG DISEASE oculum of organisms and are at risk for acute disease. Inorganic Dusts Her exposure to a lot of birds raised the possibility of Silica psittacosis, which can present with this kind of clinical Asbestos picture. Beryllium Cadmium Dr. Braun helped us manage this patient and will dis Hypersensitivity Pneumonitis cuss interstitial lung disease. Farmer’s lung DR. SHELDON BRAUN (Director o f the Division of Bagassosis Pulmonary Medicine): This patient illustrates many of Air-conditioner lung the common clinical and pathological features of diffuse Turkey handler’s lung Malt worker’s lung interstitial pneumonitis. The hallmark symptom is dys Drugs pnea, which initially occurs with exertion and progresses Busulfan over a variable time until it is present even at rest. Fever, Bleomycin chills, nonproductive cough, and generalized weakness Cyclophosphamide may occur, but frequently dyspnea progresses insidiously Penicillin without other symptoms. Dry, crackling rales in the lower Nitrofurantoin Sulfonamides lung fields are early findings. As the disease progresses, Diphenylhydantoin (phenytoin) digital clubbing and cyanosis can occur, and in the late Gold stage signs of cor pulmonale may develop. The findings Methysergide on chest x-ray film are often normal early in the course, Gases, Fumes, Poisons but later a reticulonodular interstitial pattern is present. Oxygen toxicity Sulfur dioxide In end-stage disease a honeycomb radiographic appear Chlorine ance may be found. Pulmonary function testing shows a Paraquat restrictive pattern with a reduction in diffusion capacity, Collagen Vascular Disorders and moderate to severe hypoxemia is present. The PaC02 Rheumatoid arthritis is usually reduced, but may rise in the terminal stages. Systemic lupus erythematosus Etiologically, interstitial lung disease is heterogeneous. Progressive systemic sclerosis Polymyositis A partial list of noninfectious causes is displayed in Table Miscellaneous 1. Before discussing this differential diagnosis, however, Sarcoidosis I would like to review briefly the sequence of pathological Histiocytosis-X changes involved in this process.1 Radiation The lung has a limited way of responding to the variety Vasculitis Lymphangitic malignancy of infectious, immunologic, and toxic insults that it may Neurofibromatosis experience. The initial reaction is cellular; an assortment Tuberous sclerosis of neutrophils, lymphocytes, and macrophages collect in Familial pulmonary fibrosis the edematous interstitium and exude into the alveolar Amyloidosis spaces. In the next stage the inflammatory cell infiltrate persists, alveolar epithelial cells regenerate and proliferate, and fibroblasts appear and begin to deposit collagen. As the alveolitis progresses, alveolar epithelial cells undergo to her previous physician. Consequently, bronchoscopy metaplastic changes, becoming cuboidal in shape, and would have had to have been performed under general there is increasing fibrosis and decreasing inflammatory anesthesia. We felt that tissue was needed for a diagnosis. cell infiltration in the alveolar walls. In the late stage the With a diffuse pulmonary process such as this, transbron- alveolar walls are thickened by extensive fibrous tissue, chial needle biopsy often does not get sufficient tissue. We and alveolar-capillary gas exchange is greatly impaired. thought that an open biopsy would be the best approach. In general, these pathologic changes are etiologically non She tolerated it well, and we obtained enough tissue for specific. The time course of this process varies from a few good examination. weeks to many years. RESIDENT: What was the significance of the exposure The shortness of breath characteristic of this disorder to a dust storm in Kuwait? is probably caused by the decreasing compliance of the DR. BLAKE: One of the diagnostic considerations lung. With the evolving interstitial inflammation and fi when she was admitted was an acute fungal infection. brosis, the lungs become progressively more stiff, increas The Histoplasma organism is widely distributed around ing the work of breathing.

244 THE JOURNAL OF FAMILY PRACTICE, VOL. 24, NO. 3, 1987 acute interstitial pneumonitis

Turning now to the workup of these patients, it is im tious pulmonary inflammation. The yield from trans- portant to try to ascertain a specific cause of the condition. bronchial biopsy is frequently inadequate. An open-lung A careful, detailed history is crucial to this goal. Attention biospy obtains a sufficient amount of tissue for complete should be directed to drug exposure; such commonly used testing and is usually the best approach. Tissue exami medications as nitrofurantoin, phenytoin, and penicillin nation is frequently not necessary to establish a diagnosis can produce interstitial pneumonitis. In a patient with of silicosis or asbestosis. These diagnoses can be based on this disorder all nonessential drugs should be stopped. A a good history of exposure and characteristic radiographic complete occupational history is important to detect pre findings. vious exposure to silica, asbestos, cotton dust, and chem In most cases of interstitial lung disease, a specific cause icals or fumes. As exposure to silica or asbestos may have cannot be determined despite a comprehensive history occurred decades before the onset of disease, the inquiry and extensive laboratory workup. We are left with the should cover an individual’s entire occupational history. label idiopathic. Such was the case with this patient. Detailed questioning about occupational exposures, If possible, the treatment of interstitial lung disease hobbies, and leisure time activities is important in iden should be specific, for example, avoiding the inciting an tifying hypersensitivity pneumonitis.2 This diverse con tigen in hypersensitivity pneumonitis. There is no specifii dition is mediated by an immunologic response to an in therapy for pneumoconiosis. While we lack evidence from haled antigen, which can be one of a multitude of foreign randomized controlled clinical trials, there is considerable proteins, including molds and animal excreta. Farmer’s clinical experience supporting the therapeutic role of cor lung is the prototype of this process, and several dozen ticosteroids for idiopathic disease.4 The efficacy of steroids disease entities, such as pigeon breeder’s disease and air- seems to be related to the histologic appearance of the conditioner lung, have been described. A consistent tem lung tissue. Favorable responses are more likely during poral relationship between certain activities or exposures the stage of cellular alveolitis and are less likely with in and the onset of symptoms is the best clue to the presence creasing fibrosis. Experience suggests that in some patients of one of these hypersensitivity pneumonitides. Typically, steroids reverse the cellular inflammation, prevent fibrosis, fever, chills, and dyspnea develop four to six hours after and restore normal alveolar structure and function. The the exposure, and diffuse interstitial infiltrates are found prognosis is poor in the presence of extensive fibrosis. on the chest roentgenogram. Evidence supporting the di Azathioprine (Imuran) and cyclophosphamide may help agnosis includes the presence of serum-precipitating an in some patients who have not responded to steroids, but tibodies and the induction of symptoms by an inhalation there is really little we can do for end-stage fibrotic, hon challenge. The provocative challenge test can be danger eycombed lungs. ous, however, and often is not necessary for the diagnosis. This patient’s histologic picture was fairly favorable, Interstitial lung disease can be a component of a sys with a florid cellular reaction and only a little fibrosis temic disease. In a patient with a malignancy, lymphan- focally. She received the usual dosage of 1 mg/kg of pred gitic spread in the lung is a cause of interstitial abnor nisone and seems to have enjoyed an excellent response. malities. Collagen vascular disorders can produce inter We began to gradually reduce her steroids at the time she stitial pneumonitis3; however, pulmonary involvement is moved, one month after hospital discharge. In monitoring unusual in the absence of other evidence of disease. Al the response to therapy, we follow symptoms, results on though this patient did have a vague history of rheumatoid chest x-ray examination, and pulmonary function tests. arthritis and had a positive antinuclear antibody test and RESIDENT: Dr. Braun, what are the characteristic ra rheumatoid factor with low titers, there was nothing else diographic lung findings with silicosis and asbestosis? to support a diagnosis of a collagen vascular disorder. It DR. BRAUN: In addition to the diffuse interstitial pat is not uncommon for patients with idiopathic interstitial tern, interstitial nodules are found with silicosis and pneumonitis to have low titers of antinuclear antibodies pleural plaques are found with asbestosis. and rheumatoid factor. RESIDENT: What is the role of bronchopulmonary In a patient such as the one under discussion today, it lavage in the workup of these patients? is important to exclude the possibility of an infectious DR. BRAUN: Bronchoalveolar lavage can be of diag process. First, the infection may be treatable and, second, nostic value in some situations.5 In normal nonsmokers, the treatment for the interstitial disease may exacerbate 80 to 95 percent of cells recovered on lavage are alveolar the infection. A wide variety of viral, bacterial, fungal, macrophages, 5 to 10 percent are lymphocytes, and less and parasitic diseases can produce an interstitial radio- than 1 percent are polymorphonuclear leukocytes. With graphic pattern. In this case extensive culturing and se idiopathic pulmonary fibrosis, the total cell count is in rologic testing were done searching for an infection. As is creased and a larger proportion are polymorphonuclear frequently the case, examination of lung tissue was nec cells. With sarcoidosis and hypersensitivity pneumonitis, essary to establish conclusively the diagnosis of noninfec- there is an increased proportion of lymphocytes. The sug-

THE JOURNAL OF FAMILY PRACTICE, VOL. 24, NO. 3, 1987 245 “Do not substitute” necessary.” or not substitute” “Medically “Do ______Be sure to write a complete prescription. a complete Be towrite sure prescription writing only writing Do Not Substitute Not Do ADDRESS ' NAME Tel. 000-0000 The cut out "V " design is a registered trademark of Roche Products Inc. Products Roche of trademark aregistered is design " "V out cut The Roche Products Inc., Manati, Puerto Rico 00701 Puerto Manati, Inc., Products Roche Specify “Dispense as written” or as written” Specify “Dispense Copyright c 1986 by Roche Products Inc. All rights reserved. rights All Inc. Products Roche 1986by c Copyright Are you Are t a The One You Know Best Know You One The for it? for i half a half This half This Stmfrd G Mndlstn, M.D. Mndlstn, Stmfrd G Anytown, UAnytown,S A.00000 10 Main Street 2 m g 5 m g 10 mg 10 g m 5 g m DATF

so soon after coming to live in Columbia. In addition to addition In Columbia. in live to coming after soon so She had some guilt feelings about her mother getting sick getting mother her about feelings guilt some had She verydifficult forher was daughter.several time years. This forfamily her and daughter the for caring been Ihad but was happening to her. She gradually adjusted to the sitthe to adjusted gradually She her. to happening was over whatcontrol some had she which in ways devised we uation and ended up coping fairly well. fairly coping up ended and uation nurses, the and worker social a of help the for herWith reasons feelings. the into insight good had She anger. and treat instituting and diagnosis a establishing in delay the ment. We spent a lot of time addressing her frustration her addressing time of lot a spent We ment. by compounded was anger Her physicians. and nurses, family,her on vented she which anger, considerable ated cre hospitalization and illness the by engendered loss control ofinevitable The dependent. and disabled being like chosocial stressors may well have played a role in the in role a played have process. causal well psy may These stressors factors. and chosocial events of confluence a was ably there prob Givencausation, did. disease she of model when sick multifactorial the became lady this of types how or these why that evidence interesting some is there extended family. She did not like being sick; she didnot she sick; being like not did She family. extended in herinfluential was and her job in authority and power diffi real some faced we challenge, diagnostic the with stressors may impair immune function.8 We don’t knowdon’t We function.8 immune impair may stressors elucidated, be to remain risk this mediating changesmechanisms While thesuch problems.7 health of of risk increased an accumulation confers an that evidence erable symptoms. He had the acute devastating form of pul of Rich.6 and form Hamman devastating by described fibrosis acute monary the had He symptoms. cyclophospha then and steroids with therapy aggressive Despitefibrosis. extensive showed biopsy lung His worse. iomn. h aprnl hd noe considerable enjoyed had apparently She socialen her over vironment. control of lot a exerting to been has ac customed who woman independent strong-willed, aShe illness.is her to reaction psychological her with culties struggle we did only Not her. for oared that team the for eie, oe, n taee oesa. hr i consid is There overseas. traveled and She had moved, events. retired,had she life stressful sick, many became she experienced recently time the At today. presented ie h ws ed ihn w mnh o h onsetof the of months two within dead was he mide, gettingkept that weakness and breath of develshortness He oped course. progressive rapidly a had practice our disease on occasion. Two years ago a 60-year-old man in60-year-old a ago years Two occasion. on disease encounter this to going is physician family busy rare.The however, I do not think this is practical. is this think not do I however, assess the and disease discomfort and the expense the of of affectBecause of treatment. becourse may a the lavages monitor repeated to that way made been has gestion ACUTE INTERSTITIAL PNEUMONITIS INTERSTITIAL ACUTE I did not know the patient prior to her hospitalization, her to prior patient the know not I did hs ain psd infcn mngmn problems management significant posed patient This I would like to make a few comments about the the patient about comments afew make to like Iwould DR. BLAKE: Idiopathic interstitial pneumonitis is notpneumonitis interstitial Idiopathic BLAKE: DR. H ORA FFML RCIE O.2,N. 3,1987NO. 24, VOL. PRACTICE, FAMILY OF JOURNAL THE continuedonpage 248

ACUTE INTERSTITIAL PNEUMONITIS

continued from page 246 past. It helped to explain a certain overprotectiveness and her concern about her mother, she was very worried about excessive anxiety that I had perceived in her. This is an the health of her two teenage sons. They had had exten example of the accumulation of important pieces of in sive contact with their grandmother early in the course formation that occurs as a physician takes care of a family of her illness. The daughter was concerned that the disease over time. was contagious and that the boys were at risk of developing it. This fear persisted despite reassurances and several ex aminations of the boys. Even when the noninfectious na References ture of the disease was established, this intense worry per sisted and resulted in several middle-of-the-night calls to 1. Crystal RG, Gadik JE, Ferrans VJ, et al: Interstitial lung disease: Current concepts of pathogenesis, staging and therapy. Am J Med me to report some symptom. Finally, during the course 1981; 70:542-568 of a session with the daughter and her husband, the basis 2. Salvaggio JE, Karr RM: Hypersensitivity pneumonitis: State of the for this anxiety was revealed. She acknowledged a long art. Chest 1979; 75:270-274 term fear that one of her children was fated to die before 3. Hunninghake GW, Fauci AS: Pulmonary involvement in the collagen reaching adulthood. The fear derived from the fact that vascular diseases. Am Rev Respir Dis 1979; 119:471-503 4. Crystal RG, Bitterman PB, Rennard SI, et al: Interstitial lung disease both her mother and her sister had a child who had died. of unknown cause: Disorders characterized by chronic inflammation She had never admitted this fear to anyone before. The of the lower respiratory tract (Part II). N Engl J Med 1984; 310: three of us spent a lot of time discussing this fear. Inter 235-244 estingly, in the days following this disclosure, she did not 5. Crystal RG, Bitterman PB, Rennard SI, et al: Interstitial lung disease of unknown cause: Disorders characterized by chronic inflammation express any concerns about her sons contracting her of the lower respiratory tract (Part I). N Engl J Med 1984; 310: mother’s illness. With this long-term concern ventilated 154-166 and perhaps diminished, she was then able to prepare 6. Hamman L, Rich AR: Acute diffuse interstitial fibrosis of the lungs. effectively for the home-based care that her mother would Johns Hopkins Med J 1944; 74:177-212 require. 7. Rahe RH, Arthur RJ: Life change and illness studies: Past history and future directions. J Human Stress 1978; 4:3-15 This disclosure put into perspective some of the medical 8. Bartrop RW, Luckhurst E, Lazarus L, et al: Depressed lymphocyte encounters that I had had with her and her sons in the function after bereavement. Lancet 1977; 1:834-836

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248 THE JOURNAL OF FAMILY PRACTICE, VOL. 24, NO. 3,1987