1142
ARTHRITIS R O U N D S
PNEUMOCYSTIS CARINII ASSOCIATED WITH POLYARTERITIS AND IMMUNOSUPPRESSIVE THERAPY MICHAEL W. BUNG0 and WILLIAM P. BEETHAM, Jr. Pneumocystis carinii characteristically causes pneumonia in patients with immunodeficiency disorders. It occurs most often in patients with malignancy or renal transplants whose immune response has been suppressed by corticosteroids or cytotoxic agents. Individuals with connective tissue disease who receive immunosuppressive drugs become susceptible to Pneumocystis. The incidence of Pneumocystis infection in connective tissue disease is low but may increase if immunosuppressive drugs are used more often. Our patient acquired Pneumocystis pneumonia after immunosuppressive therapy for polyarteritis nodosa. Prompt recognition of this condition is essential now that specific therapy is available. Untreated Pneumocystis infection is usually fatal. Pneumocystis carinii pneumonia is caused by an organism of uncertain classification, probably a protozoan, that characteristically occurs in patients with congenital or acquired immunodeficiency disorders (1-3). It has been observed most frequently in patients with leukemia or other forms of malignant disease who are receiving chemotherapy, and it has been seen with increasing frequency in patients with systemic disease whose immune response has been suppressed by cortiFrom the Department of Medicine, Lahey Clinic Foundation, New England Deaconess Hospital. and Harvard Medical School, Boston, Massachusetts. Michael W. Bungo, M.D.: Resident in Medicine, New England Deaconess Hospital; William P. Beetham, Jr., M.D.: Assistant Professor of Medicine, Harvard Medical School. Address reprint requests to William P. Beetham, Jr., M.D., Department of Medicine, Lahey Clinic Foundation, 605 Commonwealth Avenue, Boston, Massachusetts 02215. Arthritis and Rheumatism, Vol. 20, No. 5 (June 1977)
costeroids or cytotoxic agents. Patients with renal transplants form another high-risk group. Individuals with diffuse connective tissue disease, such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, and polyarteritis nodosa often receive immunosuppressive drugs when conservative measures fail to control the disease and they therefore become susceptible to Pneurnocystis. Its incidence in diffuse connective tissue disease has been low but may increase if immunosuppresive agents are used more frequently in the future. Pneumocystis carinii pneumonia has been reported in 6 patients with systemic lupus erythematosus, in 2 with rheumatoid arthritis, in 1 with Wegener’s granulomatosis, and in 1 with systemic vasculitis (1-4). We report a case of a patient with polyarteritis nodosa in whom Pneumocystis carinii pneumonia developed after therapy with prednisone and cyclophosphamide.
CASE REPORT A 44-year-old man sought medical help for migratory arthralgia in January 1972. Results of lupus erythematosus cell preparation and antinuclear antibody tests were normal, but the latex test for rheumatoid factor gave positive results. Treatment with prednisone was started. Progressive numbness and weakness developed in all four extremities. In June 1972 examination revealed a bilateral foot drop, complete anesthesia below both knees, and atrophy of the muscles in the hands and lower legs. No abnormality was found on examination of the joints. Results of blood urea nitrogen, creatinine determinations, and urinalysis were normal. Biopsies of the right gastrocnemius muscle and sural nerve revealed segmental necrotizing arteritis of small-sized
PNEUMOCYSTIS CA RINII
1143
travenous pyelography revealed normal findings. A urine culture showed no evidence of infection, and the levels of blood urea nitrogen and serum creatinine were normal. Cystoscopy revealed severe hemorrhagic cystitis due to cyclophosphamide, and the drug was discontinued. The patient continued t o experience unexplained exertional dyspnea, but auscultation of the lungs was normal. Congestive heart failure was not evident, and the blood pressure was normal. Radiography of the chest showed no abnormality. Cultures of sputum and skin tests for tuberculosis were negative. Pulmonary function tests revealed a moderate obstructive defect a t the level of the small airways that did not improve with bronchodilators. The residual volume, total lung capacity, and dead space were increased. Resting arterial PO, was 70 mmHg, and the hypoxemia became worse during exercise. Diffusion capacity was only 33% of predicted normal. The patient improved symptomatically and was discharged. Values for pulmonary function tests repeated in 6 weeks were basically unchanged. During this period he continued taking 40 mg of prednisone a day. The patient was hospitalized again in June 1976 because of a nonproductive cough and progressive dyspnea of 3 days’ duration. H e experienced severe dyspnea even at rest with a respiratory rate of 50 breaths a minute; he was not cyanotic and was afebrile. The lungs were clear to auscultation except for a few ronchi in the right lung posteriorly. Arterial PO, was 50 mmHg while the patient was breathing room air, and it improved only slightly with administration of nasal oxygen. A radiograph of the chest revealed a diffuse interstitial
Fig 1. A. Admission radiograph shows fine. homogeneous, granular densities throughout both lungs, most evident in hilar regions. B. Almost complete clearing of pulmonary infiltrates 3 months after admission.
and medium-sized vessels characteristic of polyarteritis nodosa. The patient continued to take prednisone, 45 mg daily, and cyclophosphamide (Cytoxan), 150 mg daily, was started. Motor and sensory symptoms improved markedly during that year and allowed the patient to walk with only mild difficulty, but some numbness persisted in the lower legs. After 2 years of cyclophosphamide therapy, the patient felt well except for periodic muscular cramps in his legs. The Westergren sedimentation rate was normal. He was taking 15 mg of prednisone and 150 mg o f cyclophosphamide daily. By March 1975 he had undergone bilateral cataract extractions. At this time the Westergren sedimentation rate was 45 mm/hour, and he still had residual numbness in both feet and weakness of dorsiflexion in his right foot. In January 1976 he was hospitalized because of exertional dyspnea and hematuria of 2.5 weeks’ duration. The Westergren sedimentation rate had risen to 65 mm/hour. In-
Fig 2. Pneumocystis carinii in intraalveolar exudate (methenamine silver, x 4000).
I144
B U N G 0 AND BEETHAM
infiltrate in both lungs with a ground-glass appearance (Figure IA). Blood, urine, and throat and sputum cultures showed no pathogens. Skin tests for tuberculosis, histoplasmosis, and candida were negative with a positive streptokinase-streptodornase test for control. On the evening of admission, the patient underwent fiberoptic bronchoscopy which revealed nonspecific inflammation of the bronchial wall. A transbronchial biopsy was performed but failed to obtain parenchymal tissue. Administration of pentamidine isethionate, 300 mg daily intramuscularly, was begun empirically, for suspected Pneumocystis carinii. Several days later, the patient underwent open lung biopsy which confirmed the diagnosis of Pneumocystis carinii pneumonia (Figure 2). Pentamidine was continued for 12 days. Pyrimethamine and sulfadiazine were added to the regimen on the sixth day and continued until discharge. Prednisone was gradually decreased from 60 mg to 20 mg daily at the time of discharge. Sixteen days after admission, revision of a previous gastrectomy was accomplished for a perforated stomal ulcer, without complication. Chest radiography showed significant clearing about 2 weeks after completion of pentamidine therapy. When discharged, he was markedly improved and continued to do well on follow-up examination 3 months later. A radiograph of the chest 3 months after admission showed almost complete clearing of pulmonary infiltrates (Figure 1B).
DISCUSSION This case report dramatically shows the complications associated with the use of immunosuppressive drugs. The patient required bilateral cataract removal at a relatively young age, probably as a result of prolonged use of steroids. After taking cyclophosphamide for 3.5 years, the patient had severe hemorrhagic cystitis, which is one of the commonest complications of cyclophosphamide therapy. Subsequently, extensive pneumonia due to Pneumocystis carinii developed. This is a n opportunistic infection facilitated by the immunosuppressive effects of steroids and cyclophosphamide. Finally, a perforated stomal ulcer developed, after the prolonged use of steroids. The onset of Pneumocystis carinii pneumonia may be slow or acute. The commonest symptoms are dyspnea, tachypnea, and a nonproductive cough. Cyanosis is often present, and blood gases usually show decreased oxygen saturation. Auscultation of the lungs is frequently normal, but scattered rales or ronchi may be heard. The chest radiograph characteristically shows fine, homogeneous, granular densities throughout both lungs, which have a hazy, ground-glass appearance most evident in the hilar region. Hilar adenopathy is usually absent, but unusual presentations of localized nodular densities, paramediastinal sparing, lobar con-
solidations, and pleural effusions have been described ( 5 , 6 ) . The radiographic appearance of the lungs, however, is nonspecific, and histologic examination of sputum or lung tissue is necessary to identify the characteristic cysts (2). Bronchoscopy should be performed promptly, and bronchial brushings should be obtained and examined for Pneumocystis. Percutaneous lung biopsy sometimes provides a satisfactory specimen for analysis. If these procedures are negative and the patient is in satisfactory condition, open lung biopsy should be performed for definitive diagnosis. Microscopic review of lung parenchyma containing Pneumocystis has shown hyperplasia of alveolar epithelial cells and diffuse interstitial infiltration by inflammatory cells (2). In epidemic forms of Pneumocystis associated with malnutrition, the plasma cell is the predominant inflammatory cell, whereas in immunodeficient disorders, lymphocytes and macrophages predominate. A characteristic honeycomb appearance may occur when masses of cysts fill the central portions of the alveoli; less often, however, cysts may appear in alveolar or interlobular septae. Giemsa, Gomori methenamine silver, or G r a m and Weigert stain is used to demonstrate cysts in biopsy material. Oxygen therapy can be an important aid to other therapeutic measures in Pneumocystis carinii pneumonia. If started early, therapy with pentamidine, or pyrimethamine (Daraprim) and sulfadiazine may be successful ( I ,2,7,8). Recently, trimethoprim plus sulfamethoxazole (Septra) has also been reported to be effective in the treatment of Pneumocystis carinii (9). If sputum and bronchial washings are negative for Pneumocystis and the patient is too ill for open lung biopsy, a trial of drug therapy should be started whenever Pneumocystis infection is strongly suspected. Untreated Pneumocystis carinii pneumonia is uniformly fatal ( 10).
ACKNOWLEDGMENTS The authors thank Joseph L. Andrews Jr., M.D., and the staff of the Pulmonary Function Laboratory, Interstitial Lung Disease Project, New England Deaconess Hospital, who performed and analyzed the pulmonary function studies.
REFERENCES Western KA, Perera DR, Schultz MG: Pentamidine isethionate in the treatment of Pneumocystis carinii pneumonia. Ann Intern Med 73:695-702, 1970 Burke BA, Good RA: Pneumocystis carinii infection. Medicine 52:23-51, 1973 Walzer PD, Per1 DP, Krogstad DJ, et al: Pneumocystis
PNEUMOCYSTIS CARINII
4.
5. 6. 7.
1145
carinii pneumonia in the United States. Epidemiologic, diagnostic, and clinical features. Ann Intern Med 808393, -1 974 Steinberg AD, Plotz PH, Wolff SM, et al: Cytotoxic drugs in treatment of nonmalignant disease. Ann Intern Med 76:619-642, 1972 Forrest JV: Radiographic findings in Pneumocystis carinii pneumonia. Radiology 103539-544, 1972 Cross AS, Steigbigel RT: Pneumocystis carinii pneumonia presenting as localized nodular densities. N Engl J Med 29 1:83l-832, 1974 Kirby HB, Kenamore B, Guckian JC: Pneumocystis ca-
rinii pneumonia treated with pyrimethamine and sulfadiazine. Ann Intern Med 75505-509, 1971
8. Western KA, Krogstad DJ, Walzer PD: Informational material for physicians: Pentamidine isethionate. HEW Public Health Service C D C Publication, 1971 9. Lau W K , Young LS: Co-trimoxazole treatment of Pneumocystis carinii pneumonia in adults. N Engl J Med 295:716-718, 1976 10. Geelhoed G W , Levin BJ, Adkins PC, et al: The diagnosis and management of Pneumocystis carinii pneumonia. Ann Thorac Surg 14:335-346, 1972
DISCUSSION JOHN S. SERGENT It is important to remind ourselves that rheumatology remains a rather primitive specialty, in which most of the diseases are poorly defined and for which the therapy is imperfect. It is especially important to point out the tremendous and unpredictable power at our disposal when we elect to treat disease by altering the host’s immune response. As Decker has pointed out (l), our ignorance is so great that we can present plausible arguments for either immunosuppression or immunostimulation in the same disease! Nevertheless, in the real world we are faced with diseases in which we have evidence that immunologic factors may be playing a pathogenetic role, and the only tools we have at our disposal are agents that alter this immune response. Therefore, aware of the fact that medical historians of the future will be amused by our efforts even as we are amused by the blood-letters and fever therapists of the past, we proceed to use cortiJohn S. Sergent, M.D.: Chief of Rheumatology, Vanderbilt University, Nashville, Tennessee 37232.
costeroids and immunosuppressive drugs. In calling attention to a treatable but potentially fatal complication of such therapy, the article by Bungo and Beetham is a welcome contribution. In another light, however, the article is bothersome. The last few years have seen a tremendous increase in our knowledge of the potential causes of necrotizing vasculitis in man. Obviously the authors were not trying to discuss the problem of vasculitis, but merely to point out complications of its therapy. Nevertheless, it is abundantly clear that simply demonstrating a vasculitis by biopsy does not establish a diagnosis any more than does a biopsy demonstrating pneumonitis or glomerulonephritis. Today it would be unthinkable to report on “complications of therapy for pneumonitis,” because readers would immediately recognize that the entities compared (e.g. Pneumocystis pneumonia and pneumococcal pneumonia) are simply not comparable. Such is the case, I would submit, for polyarteritis nodosa. In an era when most diseases were defined morphologically (e.g. glomerulonephritis), a diagnosis
ARTHRITIS R O U N D S
PNEUMOCYSTIS CARINII ASSOCIATED WITH POLYARTERITIS AND IMMUNOSUPPRESSIVE THERAPY MICHAEL W. BUNG0 and WILLIAM P. BEETHAM, Jr. Pneumocystis carinii characteristically causes pneumonia in patients with immunodeficiency disorders. It occurs most often in patients with malignancy or renal transplants whose immune response has been suppressed by corticosteroids or cytotoxic agents. Individuals with connective tissue disease who receive immunosuppressive drugs become susceptible to Pneumocystis. The incidence of Pneumocystis infection in connective tissue disease is low but may increase if immunosuppressive drugs are used more often. Our patient acquired Pneumocystis pneumonia after immunosuppressive therapy for polyarteritis nodosa. Prompt recognition of this condition is essential now that specific therapy is available. Untreated Pneumocystis infection is usually fatal. Pneumocystis carinii pneumonia is caused by an organism of uncertain classification, probably a protozoan, that characteristically occurs in patients with congenital or acquired immunodeficiency disorders (1-3). It has been observed most frequently in patients with leukemia or other forms of malignant disease who are receiving chemotherapy, and it has been seen with increasing frequency in patients with systemic disease whose immune response has been suppressed by cortiFrom the Department of Medicine, Lahey Clinic Foundation, New England Deaconess Hospital. and Harvard Medical School, Boston, Massachusetts. Michael W. Bungo, M.D.: Resident in Medicine, New England Deaconess Hospital; William P. Beetham, Jr., M.D.: Assistant Professor of Medicine, Harvard Medical School. Address reprint requests to William P. Beetham, Jr., M.D., Department of Medicine, Lahey Clinic Foundation, 605 Commonwealth Avenue, Boston, Massachusetts 02215. Arthritis and Rheumatism, Vol. 20, No. 5 (June 1977)
costeroids or cytotoxic agents. Patients with renal transplants form another high-risk group. Individuals with diffuse connective tissue disease, such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, and polyarteritis nodosa often receive immunosuppressive drugs when conservative measures fail to control the disease and they therefore become susceptible to Pneurnocystis. Its incidence in diffuse connective tissue disease has been low but may increase if immunosuppresive agents are used more frequently in the future. Pneumocystis carinii pneumonia has been reported in 6 patients with systemic lupus erythematosus, in 2 with rheumatoid arthritis, in 1 with Wegener’s granulomatosis, and in 1 with systemic vasculitis (1-4). We report a case of a patient with polyarteritis nodosa in whom Pneumocystis carinii pneumonia developed after therapy with prednisone and cyclophosphamide.
CASE REPORT A 44-year-old man sought medical help for migratory arthralgia in January 1972. Results of lupus erythematosus cell preparation and antinuclear antibody tests were normal, but the latex test for rheumatoid factor gave positive results. Treatment with prednisone was started. Progressive numbness and weakness developed in all four extremities. In June 1972 examination revealed a bilateral foot drop, complete anesthesia below both knees, and atrophy of the muscles in the hands and lower legs. No abnormality was found on examination of the joints. Results of blood urea nitrogen, creatinine determinations, and urinalysis were normal. Biopsies of the right gastrocnemius muscle and sural nerve revealed segmental necrotizing arteritis of small-sized
PNEUMOCYSTIS CA RINII
1143
travenous pyelography revealed normal findings. A urine culture showed no evidence of infection, and the levels of blood urea nitrogen and serum creatinine were normal. Cystoscopy revealed severe hemorrhagic cystitis due to cyclophosphamide, and the drug was discontinued. The patient continued t o experience unexplained exertional dyspnea, but auscultation of the lungs was normal. Congestive heart failure was not evident, and the blood pressure was normal. Radiography of the chest showed no abnormality. Cultures of sputum and skin tests for tuberculosis were negative. Pulmonary function tests revealed a moderate obstructive defect a t the level of the small airways that did not improve with bronchodilators. The residual volume, total lung capacity, and dead space were increased. Resting arterial PO, was 70 mmHg, and the hypoxemia became worse during exercise. Diffusion capacity was only 33% of predicted normal. The patient improved symptomatically and was discharged. Values for pulmonary function tests repeated in 6 weeks were basically unchanged. During this period he continued taking 40 mg of prednisone a day. The patient was hospitalized again in June 1976 because of a nonproductive cough and progressive dyspnea of 3 days’ duration. H e experienced severe dyspnea even at rest with a respiratory rate of 50 breaths a minute; he was not cyanotic and was afebrile. The lungs were clear to auscultation except for a few ronchi in the right lung posteriorly. Arterial PO, was 50 mmHg while the patient was breathing room air, and it improved only slightly with administration of nasal oxygen. A radiograph of the chest revealed a diffuse interstitial
Fig 1. A. Admission radiograph shows fine. homogeneous, granular densities throughout both lungs, most evident in hilar regions. B. Almost complete clearing of pulmonary infiltrates 3 months after admission.
and medium-sized vessels characteristic of polyarteritis nodosa. The patient continued to take prednisone, 45 mg daily, and cyclophosphamide (Cytoxan), 150 mg daily, was started. Motor and sensory symptoms improved markedly during that year and allowed the patient to walk with only mild difficulty, but some numbness persisted in the lower legs. After 2 years of cyclophosphamide therapy, the patient felt well except for periodic muscular cramps in his legs. The Westergren sedimentation rate was normal. He was taking 15 mg of prednisone and 150 mg o f cyclophosphamide daily. By March 1975 he had undergone bilateral cataract extractions. At this time the Westergren sedimentation rate was 45 mm/hour, and he still had residual numbness in both feet and weakness of dorsiflexion in his right foot. In January 1976 he was hospitalized because of exertional dyspnea and hematuria of 2.5 weeks’ duration. The Westergren sedimentation rate had risen to 65 mm/hour. In-
Fig 2. Pneumocystis carinii in intraalveolar exudate (methenamine silver, x 4000).
I144
B U N G 0 AND BEETHAM
infiltrate in both lungs with a ground-glass appearance (Figure IA). Blood, urine, and throat and sputum cultures showed no pathogens. Skin tests for tuberculosis, histoplasmosis, and candida were negative with a positive streptokinase-streptodornase test for control. On the evening of admission, the patient underwent fiberoptic bronchoscopy which revealed nonspecific inflammation of the bronchial wall. A transbronchial biopsy was performed but failed to obtain parenchymal tissue. Administration of pentamidine isethionate, 300 mg daily intramuscularly, was begun empirically, for suspected Pneumocystis carinii. Several days later, the patient underwent open lung biopsy which confirmed the diagnosis of Pneumocystis carinii pneumonia (Figure 2). Pentamidine was continued for 12 days. Pyrimethamine and sulfadiazine were added to the regimen on the sixth day and continued until discharge. Prednisone was gradually decreased from 60 mg to 20 mg daily at the time of discharge. Sixteen days after admission, revision of a previous gastrectomy was accomplished for a perforated stomal ulcer, without complication. Chest radiography showed significant clearing about 2 weeks after completion of pentamidine therapy. When discharged, he was markedly improved and continued to do well on follow-up examination 3 months later. A radiograph of the chest 3 months after admission showed almost complete clearing of pulmonary infiltrates (Figure 1B).
DISCUSSION This case report dramatically shows the complications associated with the use of immunosuppressive drugs. The patient required bilateral cataract removal at a relatively young age, probably as a result of prolonged use of steroids. After taking cyclophosphamide for 3.5 years, the patient had severe hemorrhagic cystitis, which is one of the commonest complications of cyclophosphamide therapy. Subsequently, extensive pneumonia due to Pneumocystis carinii developed. This is a n opportunistic infection facilitated by the immunosuppressive effects of steroids and cyclophosphamide. Finally, a perforated stomal ulcer developed, after the prolonged use of steroids. The onset of Pneumocystis carinii pneumonia may be slow or acute. The commonest symptoms are dyspnea, tachypnea, and a nonproductive cough. Cyanosis is often present, and blood gases usually show decreased oxygen saturation. Auscultation of the lungs is frequently normal, but scattered rales or ronchi may be heard. The chest radiograph characteristically shows fine, homogeneous, granular densities throughout both lungs, which have a hazy, ground-glass appearance most evident in the hilar region. Hilar adenopathy is usually absent, but unusual presentations of localized nodular densities, paramediastinal sparing, lobar con-
solidations, and pleural effusions have been described ( 5 , 6 ) . The radiographic appearance of the lungs, however, is nonspecific, and histologic examination of sputum or lung tissue is necessary to identify the characteristic cysts (2). Bronchoscopy should be performed promptly, and bronchial brushings should be obtained and examined for Pneumocystis. Percutaneous lung biopsy sometimes provides a satisfactory specimen for analysis. If these procedures are negative and the patient is in satisfactory condition, open lung biopsy should be performed for definitive diagnosis. Microscopic review of lung parenchyma containing Pneumocystis has shown hyperplasia of alveolar epithelial cells and diffuse interstitial infiltration by inflammatory cells (2). In epidemic forms of Pneumocystis associated with malnutrition, the plasma cell is the predominant inflammatory cell, whereas in immunodeficient disorders, lymphocytes and macrophages predominate. A characteristic honeycomb appearance may occur when masses of cysts fill the central portions of the alveoli; less often, however, cysts may appear in alveolar or interlobular septae. Giemsa, Gomori methenamine silver, or G r a m and Weigert stain is used to demonstrate cysts in biopsy material. Oxygen therapy can be an important aid to other therapeutic measures in Pneumocystis carinii pneumonia. If started early, therapy with pentamidine, or pyrimethamine (Daraprim) and sulfadiazine may be successful ( I ,2,7,8). Recently, trimethoprim plus sulfamethoxazole (Septra) has also been reported to be effective in the treatment of Pneumocystis carinii (9). If sputum and bronchial washings are negative for Pneumocystis and the patient is too ill for open lung biopsy, a trial of drug therapy should be started whenever Pneumocystis infection is strongly suspected. Untreated Pneumocystis carinii pneumonia is uniformly fatal ( 10).
ACKNOWLEDGMENTS The authors thank Joseph L. Andrews Jr., M.D., and the staff of the Pulmonary Function Laboratory, Interstitial Lung Disease Project, New England Deaconess Hospital, who performed and analyzed the pulmonary function studies.
REFERENCES Western KA, Perera DR, Schultz MG: Pentamidine isethionate in the treatment of Pneumocystis carinii pneumonia. Ann Intern Med 73:695-702, 1970 Burke BA, Good RA: Pneumocystis carinii infection. Medicine 52:23-51, 1973 Walzer PD, Per1 DP, Krogstad DJ, et al: Pneumocystis
PNEUMOCYSTIS CARINII
4.
5. 6. 7.
1145
carinii pneumonia in the United States. Epidemiologic, diagnostic, and clinical features. Ann Intern Med 808393, -1 974 Steinberg AD, Plotz PH, Wolff SM, et al: Cytotoxic drugs in treatment of nonmalignant disease. Ann Intern Med 76:619-642, 1972 Forrest JV: Radiographic findings in Pneumocystis carinii pneumonia. Radiology 103539-544, 1972 Cross AS, Steigbigel RT: Pneumocystis carinii pneumonia presenting as localized nodular densities. N Engl J Med 29 1:83l-832, 1974 Kirby HB, Kenamore B, Guckian JC: Pneumocystis ca-
rinii pneumonia treated with pyrimethamine and sulfadiazine. Ann Intern Med 75505-509, 1971
8. Western KA, Krogstad DJ, Walzer PD: Informational material for physicians: Pentamidine isethionate. HEW Public Health Service C D C Publication, 1971 9. Lau W K , Young LS: Co-trimoxazole treatment of Pneumocystis carinii pneumonia in adults. N Engl J Med 295:716-718, 1976 10. Geelhoed G W , Levin BJ, Adkins PC, et al: The diagnosis and management of Pneumocystis carinii pneumonia. Ann Thorac Surg 14:335-346, 1972
DISCUSSION JOHN S. SERGENT It is important to remind ourselves that rheumatology remains a rather primitive specialty, in which most of the diseases are poorly defined and for which the therapy is imperfect. It is especially important to point out the tremendous and unpredictable power at our disposal when we elect to treat disease by altering the host’s immune response. As Decker has pointed out (l), our ignorance is so great that we can present plausible arguments for either immunosuppression or immunostimulation in the same disease! Nevertheless, in the real world we are faced with diseases in which we have evidence that immunologic factors may be playing a pathogenetic role, and the only tools we have at our disposal are agents that alter this immune response. Therefore, aware of the fact that medical historians of the future will be amused by our efforts even as we are amused by the blood-letters and fever therapists of the past, we proceed to use cortiJohn S. Sergent, M.D.: Chief of Rheumatology, Vanderbilt University, Nashville, Tennessee 37232.
costeroids and immunosuppressive drugs. In calling attention to a treatable but potentially fatal complication of such therapy, the article by Bungo and Beetham is a welcome contribution. In another light, however, the article is bothersome. The last few years have seen a tremendous increase in our knowledge of the potential causes of necrotizing vasculitis in man. Obviously the authors were not trying to discuss the problem of vasculitis, but merely to point out complications of its therapy. Nevertheless, it is abundantly clear that simply demonstrating a vasculitis by biopsy does not establish a diagnosis any more than does a biopsy demonstrating pneumonitis or glomerulonephritis. Today it would be unthinkable to report on “complications of therapy for pneumonitis,” because readers would immediately recognize that the entities compared (e.g. Pneumocystis pneumonia and pneumococcal pneumonia) are simply not comparable. Such is the case, I would submit, for polyarteritis nodosa. In an era when most diseases were defined morphologically (e.g. glomerulonephritis), a diagnosis
