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Pneumocystis Carinii Associated with Polyarteritis and Immunosuppressive Therapy.

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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.
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
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).
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).
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
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).
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.
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.
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Walzer PD, Per1 DP, Krogstad DJ, et al: Pneumocystis
carinii pneumonia in the United States. Epidemiologic,
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Steinberg AD, Plotz PH, Wolff SM, et al: Cytotoxic drugs
in treatment of nonmalignant disease. Ann Intern Med
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Forrest JV: Radiographic findings in Pneumocystis carinii
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Cross AS, Steigbigel RT: Pneumocystis carinii pneumonia
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Kirby HB, Kenamore B, Guckian JC: Pneumocystis ca-
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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
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and management of Pneumocystis carinii pneumonia.
Ann Thorac Surg 14:335-346, 1972
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
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associates, polyarteritis, pneumocystis, immunosuppressive, carinii, therapy
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