Pneumocystis carinii Pneumonia in Primary Brain Tumors John W. Henson, MD; Jai K. Jalaj, MD; Russell W. Walker, Diane E. Stover, MD; Anna O. S. Fels, MD
histologically documented episodes Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen \s=b\ All
of
at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors,
especially during tapering of steroid therapy.
(Arch Neurol. 1991 ;48:406-409)
~Dneumocystis
carinii is
one
of the
most common opportunistic patho¬ gens that causes pneumonitis in immun-
ocompromised patients. There are a va¬ riety of predisposing immunodeficiency states, including hématologie malignant carinii neoplasms.1"" In contrast, pneumonia (PCP) is rare in patients
Accepted for publication October 18,1990. From the Department of Neurology (Drs Henson and Walker) and the Pulmonary Division (Drs Jalaj, Stover, and Fels), Memorial Sloan-Kettering Cancer Center, New York, NY. Dr Jalaj is now in private practice in Fishkill, NY. Reprint requests to Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (Dr Walker).
Patients With
MD;
with solid tumors but may occur in these patients in the setting of corticosteroid therapy.1"1"7 Patients with primary brain tumors often receive high doses of corti¬ costeroids for prolonged periods, in¬ creasing the risk of opportunistic infec¬ tions. To assess the magnitude of this problem in our patients with brain tu¬ mors, we reviewed all cases of PCP in patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY. We determined the percentage of patients with brain tumors in whom PCP developed, the relationship of dexamethasone therapy to PCP, and the clinical features of PCP in this group of patients. PATIENTS AND METHODS
The medical records of all adult patients treated at MSKCC since 1981 for a primary brain tumor and a histologically documented PCP diagnosis were reviewed. Cases were identified from the Memorial Hospital Data Analysis computerized database (containing diagnoses from clinic records of patients re¬ ceiving their treatment at MSKCC, hospital discharge summaries, and autopsy reports) and from bronchoscopy records. To deter¬ mine the size ofthe group at risk for PCP, we used the data analysis database to ascertain the total number of adults (aged s=20 years) treated for a primary brain tumor from 1981 to 1989. Because pediatrie patients with brain tumors at MSKCC are routinely treat¬ ed with prophylactic trimethoprim-sulfamethoxazole during prolonged steroid thera¬ py, we excluded all patients so treated from the group at risk by counting only patients who were at least 20 years old. To be certain that this database contained only patients who had ongoing therapy at MSKCC, 40 pa¬ tients with a diagnosis of glioblastoma multiforme were selected from the group at risk
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for PCP and their records were reviewed for treatment and duration of follow-up. In patients who underwent diagnostic bronchoscopy, bronchial washings and bronchoalveolar lavage were processed for bacte¬ rial, fungal, and mycobacterial staining and culture as previously described.* Cytologie examination was performed on bronchial brushings, washings, and lavage fluids using Papanicolaou and Gram-Weigert stains." Gram-Weigert, Ziehl-Neelsen, and silvermethenamine stains were performed on the transbronchial biopsy specimens in addition to the usual pathologic examination. All lung specimens were extensively examined and cultured, and their pathologic findings re¬ viewed. Pneumocystis carinii pneumonia was diagnosed by the demonstration of cysts in bronchial fluid or lung tissue. RESULTS Patients With PCP
There were 11 histologically docu¬ mented episodes of PCP in 10 patients with primary brain tumors between 1981 and 1989. The cases were distribut¬ ed during this period as outlined in Table 1. Concurrently, 587 adult patients be¬ gan treatment for a primary brain tu¬ mor at MSKCC. Approximately 90% of these 587 had follow-up adequate to identify episodes of PCP (see the follow¬ ing data). Therefore, during the last 8 years, PCP developed in at least 1.7% of our adult patients with brain tumors. There were two patients with clinical¬ ly suspected, but unconfirmed episodes, of PCP and two confirmed episodes in two patients with primary central ner¬ vous system lymphoma who were ex¬ cluded from analysis. Ofthe remaining 10, six patients were men and four were women; their median age was 45 years; and all were white. The tumors were
glioblastoma multiforme (five), anaplastic astrocytoma (three), brain-stem gli¬ oma (one), and medulloblastoma (epi¬
sodes at the ages of 26 and 29 years occurred in this patient). The brain tu¬ mor was in the posterior fossa in six of the patients (medulloblastoma, brainstem glioma, midbrain and thalamic glioblastoma, multifocal anaplastic as¬ trocytoma, cerebellar anaplastic astro¬ cytoma, and cervicomedullary junction
anaplastic astrocytoma).
The interval from the time of tumor
diagnosis to the time of diagnosis of PCP ranged from 3 weeks to 9 years, with a
median of 3 months. Nine tumors were newly diagnosed and two were recur¬ rent, one at 3 years and one at 8.5 years from the original tumor diagnosis. The patient with two episodes of PCP suf¬ fered the second episode during a recur¬ rence 3 years following the original
diagnosis. All patients had received cranial irra¬ diation. Single-agent or combination chemotherapy had been administered before the development of PCP in seven episodes (Table 1), including a nitro-
(lomustine, PCNU [l-(2-chloroethyl)-3-(2,6 dioxo-3-piperadyl)- 1-nitrosureaj, or carmustine), procarbazine hydrochloride, vincristine sulfate, fluorouracil, hydroxyurea, mechlorethamine hydrochloride, and misonidazole. None ofthe five patients who received a nitrosourea had documented pulmonary
Table
1.—Relationship
of Steroid
Therapy
and
Chemotherapy to PCP*
Duration of Duration of Dexamethasone Dexamethasone Dexamethasone Therapy Before Taper Before Dosage at Dexamethesone, Symptoms of Diagnosis of Symptoms of mg/d PCP, mo PCP, mg/d PCP, d Chemotherapy 32 1.5 8 .t Carmustine, Maximum Dosage of
Episode (y) 1(1982)
.
hydroxy¬
.
urea
(1982)
24
2.5
3(1983) 4 (1983) 5 (1984) 6(1985) 7(1986)
28
1.5
92
2.25
24
9.5
32
3.0 1.25
2
63
2
Lomustine, fluorouracit, misonidazole
100
.
.t
20
None
5
24
None
21
12
PCNU
17
12
11
4
Fluorouracil Mechlorethamine
.
hydrochloride,
vincristine
8(1986)
24
3.25
1
8
(1989) (1989) 11(1989)
48
3.25
14
32
16
2.75
5
10
None None
60
Carmustine
9 10 *
are
PCP indicates listed.
96 4.25 .t Pneumocystis carinii pneumonia. Only those drugs in .
tEpisodes occurring
in the absence of
a
.
use
Lomustine, vincristine, procarbazine
at the time of the
diagnosis of PCP
steroid taper.
sourea
toxic reaction from the agent. None of the patients had an identified human immunodeficiency virus risk factor oth¬ er than one patient, who had had a blood transfusion between the first and sec¬ ond episodes of PCP One patient had received trimethoprim-sulfamethoxazole for a urinary tract infection 3 months before the diagnosis of PCP. All of the patients with PCP were re¬ ceiving dexamethasone (Table 1). The duration of steroid therapy before the onset of PCP symptoms ranged from 5 weeks to 9.5 months (median, 2.75 months). The onset of symptoms in eight ofthe 11 episodes occurred while dexa¬ methasone therapy was being tapered. The interval from the initiation of the tapering of steroid therapy to onset of PCP symptoms in these eight ranged from 1 to 63 days (median, 12 days). At the time of diagnosis of PCP, daily dexa¬ methasone dose ranged from 2 to 60 mg. Table 2 summarizes the clinical pre¬ sentations ofthe 11 episodes of PCP. At the time of diagnosis of PCP, pulmonary symptoms had been present from 1 to 30 days (median, 7 days). The most com¬ mon
presenting symptoms
were
dys¬
pnea in eight cases and a nonproductive cough in seven. Fever was present in six of the episodes. In nine episodes in
Table 2.—Clinical Summary of 11
Episodes
of PCP in Patients With Brain Tumors* Chest
Duration of
Roentgenography
Symptoms
Episode
Symptoms
(A-a)02 Gradient, mm Hg
Before PCP Diagnosis, d
NC, F NC, D, F, CP
14
U/L
53
510
69
960 672
51
336
215t
803
NC
PC, D, CP D, F PC, D, F, CP NC, D, F NC, D
at First
LDH,
820
54
30
1284
22
35
419
76
480
Evaluation of
Symptoms Bilateral Infiltrates Bilateral infiltrates Focal infiltrate Diffuse infiltrates Bilateral infiltrates Focal infiltrate Diffuse infiltrates Normal Diffuse infiltrates Bilateral infiltrates
Outcome Recovered
Recovered Recovered Recovered Died Died Recovered Recovered Died Recovered Died
409 NC, CP 10 499 NC, D, F Focal Infiltrate *PCP indicates Pneumocystis carimi pneumonia; (A-a)02, alveolar-arterial oxygen; LDH, lactate dehydroge nase; NC, nonproductive cough; F, fever; D, dyspnea; CP, chest pain; and PC, productive cough. tPatient receiving supplemental oxygen. 10 11
which
arterial blood gas value was increased alveolar-arterial oxygen tension gradient (range, 23.5 to 215 mm Hg; median, 54 mm Hg) was present. One arterial blood gas value was obtained from a patient receiving an
obtained,
an
supplemental oxygen (episode 5, Table 2). Elevated lactate dehydrogenase (LDH) levels ranged from 336 to 1284 U/L
(median,
510
U/L), and
were
pre¬
episode. Serum albumin level ranged from 24 to 38 g/L. Total leukocyte count at diagnosis of PCP ranged from 3.5 to 14.4 x 107L, and ab¬ solute lymphocyte counts ranged from 0.17 to 2.3 107L (median, 0.28 107L; sent in each
lower limit of normal is l.OxlOTL).
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Chest roentgenograms at the time of the initial pulmonary evaluation showed either no infiltrate (episode 8), or infil¬ trates that were focal, bilateral (multi¬ focal), or diffuse. A cavitary lesion in addition to infiltrates was seen in one
(episode 3). Fiberoptic bronchoscopy was diag¬ nostic in each ofthe eight cases in which it was performed. Bronchoalveolar la¬ vage analysis was positive for PCP in six of eight patients. A transbronchial biop¬ sy specimen was positive in three of the six patients who had this procedure. Two patients (episodes 10 and 11) were found to have more than one pulmonary pathogen. The first patient (episode 10) case
bronchoscopy because of a nonproductive cough, chest pain, and a persistent infiltrate on chest roentgen¬ ography. Pneumocystis carinii was found in the bronchoalveolar lavage, and fungal elements consistent with As¬ pergillus sp were found invading blood vessels in the transbronchial biopsy specimens. The second patient (episode 11) had autopsy lung cultures and histo¬ logie findings consistent with cytomega¬ underwent
lovirus infection as well as PCP. Three patients did not undergo bronchoscopy but received diagnoses at autopsy. One of these (episode 5) had a fulminant clini¬ cal course and died on the day of admis¬ sion before any procedure could be car¬ ried out; the second (episode 9) was taking anticoagulants and died before the prothrombin time returned to nor¬ mal, preventing bronchoscopy; the third (episode 11) was moribund from progressive tumor when pulmonary symptoms began, and at the family's
bronchoscopy was not performed. Ten episodes were treated with intra¬ venous trimethoprim-sulfamethoxazole. None of these patients had an ad¬ verse reaction to therapy. All were receiving dexamethasone throughout therapy. Four patients (40%) died of PCP Six patients survived seven episodes of PCP; five subsequently died of their tumors. request,
Forty Patients Without PCP It is difficult to determine the exact incidence of PCP in a setting in which patients are often seen in initial evalua¬ tion and then referred back to their point of origin while still receiving cor¬ ticosteroid therapy. Five hundred eighty-seven adult patients with prima¬ ry brain tumors were seen for therapy at MSKCC from 1981 to 1989. The re¬ cords of 40 patients from this group were reviewed to determine how many received ongoing treatment there. Four did not receive therapy at MSKCC or had less than 1 month of follow-up. Therefore, we estimated that 90% ofthe total study group had received ongoing treatment. This would make 1.7% a least estimate ofthe percentage of patients in whom PCP developed. All 40 patients received steroid therapy, with dura¬ tions (to discontinuation of steroid ther¬ apy or to last follow-up) ranging from 3 weeks to 28 months (median, 3.8
months).
COMMENT
The association between PCP and the of high doses of corticosteroids is well documented. Data available in the use
literature suggest that steroids permit reactivation of latent infection by sup¬ pressing the immune system of the host.91" Cellular immunity seems to play the predominant role in the host's de¬ fenses against PCP Many of the under¬ lying diseases in patients with PCP have associated defects of cellular im¬ munity.1'5 Cyclosporine" and dexameth¬ asone both predispose patients to PCP and both inhibit T-lymphocyte prolifer¬ ation by mechanisms affecting interleu¬ kin 2 (T-cell growth factor), a T-helper cell product.*" Single doses of glucocorticoids in humans have been shown to induce peripheral lymphopenia, proba¬ bly by redistribution of lymphocytes from the circulation into other body compartments.14 None of our patients had tests of immunologie function, but peripheral lymphopenia was present in all for whom this information was available. Paradoxically, PCP often becomes clinically apparent when steroid doses are being decreased or withdrawn. Ani¬ mal studies suggest that a tapering of steroid therapy may simply unmask carinii infections that have developed earlier during high-dose steroid admin¬ istration. In a rat model, steroids have depressed the capability of the host to mount an inflammatory response to carinii infection. This inflammatory response appears as the steroid dosage is decreased." Those rats receiving highdose steroids in which PCP developed had scanty alveolar exudates despite the presence of carinii organisms in the lung tissue. When steroids were withdrawn or tapered, intense inflam¬ matory exudates developed. Similarly, rabbits on long-term, stable steroid doses suffer PCP without the character¬ istic proteinaceous alveolar exúdate and interstitial plasma cell infiltration.10 Multiple human studies have con¬ firmed the relationship between de¬ creasing steroid doses and PCP. Fossieck and Spagnolo" observed the appearance of PCP in patients with lung cancer who were receiving tapering doses of steroids. Other investigators have found that of 19 children with can¬ cer in whom PCP developed, 17 had re¬ cently had steroid administration dis¬ continued or were receiving low-dose replacement therapy when the diagno¬ sis of PCP was made.1' Singer et al1" re¬ ported the occurrence of PCP in 11 pa¬ tients (10 with lymphoma or leukemia) who had received steroid therapy. In seven of these patients, PCP developed in the setting of a tapering of steroid therapy. In our series, eight of 11 epi¬ sodes of PCP occurred during a tapering of steroid therapy. The duration of the tapering of steroid therapy before the
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onset of pulmonary symptoms ranged from 1 to 63 days, but seven ofthe epi¬ sodes occurred within 21 days of initia¬ tion ofthe tapering. In all prior studies, PCP was rare among patients with solid tumors. Our findings, however, suggest that this disease occurs in a subset of patients with solid tumors, namely, those with brain tumors. The increased incidence of PCP in patients with primary brain tu¬ mors is most likely due to the fact that they frequently receive high-dose corti¬ costeroids for extended periods. Pa¬ tients with solid tumors that do not arise in the central nervous system who are placed on similar steroid regimens may also be at risk for PCP. In the only other published series of patients with solid tumors who had PCP, three of five pa¬ tients with lung cancer who had PCP had received dexamethasone for brain mé¬ tastases, followed by a tapering of ste¬ roid therapy.'1 Clinicians should have a high index of suspicion for PCP in this selected patient population, particularly because the clinical presentation ofPCP can be subtle and nonspecific. Patients with mild pul¬ monary symptoms in whom the diagno¬ sis of PCP is suspected should be screened carefully. If the chest roent¬ genogram shows diffuse infiltrates, bronchoscopy should be done emergently. Ifthe chest roentgenogram is normal and the patient has mild symptoms, oth¬ er sensitive tests might be helpful to detect interstitial lung disease. These tests include pulmonary diffusing ca¬ pacity,1718 rest and exercise arterial blood gas values,1" or performance of a gallium citrate lung scan.2" If any of these test results are abnormal, one should proceed to bronchoscopy. A se¬ rum LDH measurement may be useful. All the patients in this study had elevat¬ ed levels of LDH. A previous report on patients with acquired immunodeficien¬ cy syndrome (AIDS) who had PCP found that only 7% had normal LDH levels, and levels greater than 450 U/L were highly specific for PCP.21 In this same study, six (75%) of eight patients with¬ out AIDS with PCP had elevated LDH levels. Further investigation is re¬ quired to determine the sensitivity and specificity of this test in the population without AIDS. Confirmation of the di¬ agnosis of PCP depends on the demon¬ stration of the organisms either in lung tissue or in bronchoalveolar lavage fluid. If abnormalities consistent with the diagnosis are found in any of the above tests, further evaluation with bronchos¬ copy, including bronchoalveolar la¬ vage"'22 and transbronchial biopsy,Z3,Z4 is recommended. In more acutely ill pa-
tients, bronchoscopy is recommended to make the
diagnosis as rapidly as pos¬ sible. If bronchoscopy is nondiagnostic, the decision as to whether the patient should have an open-lung biopsy, close follow-up, or empirical therapy depends on the clinical status of the patient and the physician's index of suspicion. In a prospective, randomized study of children with hématologie malignant neoplasms, trimethoprim-sulfamethoxazole provided excellent protection against PCP with minimal toxic reac-
a second study of this popula¬ trimethoprim-sulfamethoxazole prophylaxis had equal efficacy when ad¬ ministered for 3 consecutive days each week when compared with a daily regi¬ men.21' Although the risk of PCP in these studies was much higher than in our patients (PCP developed in 17 ofthe 80 patients in the placebo-treated group), our findings suggest that prolonged ad¬ ministration of high doses of steroids in patients with brain tumors substantial¬ ly increases the risk of PCP.
tion.2' In tion
,
Patients likely to need prolonged, high-dose steroid therapy include those with large postoperative tumor bur¬ dens, those in whom steroid depen¬ dence develops during radiotherapy, and those witb unresectable brain-stem lesions. Such patients undergoing ta¬ pering of steroid therapy are a high-risk subgroup. Given the high mortality of 36%, trimethoprim-sulfamethoxazole prophylaxis should be considered for such patients.
References 1. Burke BA, Good RA. Pneumocystis carinii infection. Medicine. 1973:52:23-51. 2. Sheldon WH. Pulmonary Pneumocystis carinii infection. J Pediatr. 1962;61:780-791. 3. Hartman B, Koss M, Hui A, Baumann W, Athos L, Boylen T. Pneumocystis carinii pneumonia in the acquired immuno-deficiency syndrome (AIDS): diagnosis with bronchial brushings, biopsy and bronchoalveolar lavage. Chest. 1987;87:603\x=req-\ 607. 4. Rifkind D, Faris TD, Hill RB. Pneumocystis carinii pneumonia: studies on the diagnosis and treatment. Ann Intern Med. 1966;65:943-956. 5. Peters SG, Prakash UBS. Pneumocystis carinii pneumonia. Am J Med. 1987;82:73-78. 6. Fossieck BE, Spagnolo SV. Pneumocystis carinii pneumonitis in patients with lung cancer. Chest. 1980;78:721-722. 7. Oster MW, Vizel M, Edsall JR, Barron BA. Case report: Pneumocystis pneumonia in a patient with cervical carcinoma treated with combination
chemotherapy. Gynecol Oncol. 1982;13:262-264. 8. Stover DE, Zaman MB, Hajdu SI, Lange M, Gold J, Armstrong D. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Ann Intern Med. 1984;101:1-7.
9. Frenkel JK, Good JT, ShultzJA. Latent Pneu-
mocystis infection of rats, relapse, and chemotherapy. Lab Invest. 1966:15:1559-1577. 10. Sheldon WH. Experimental pulmonary Pneumocystis carinii infection in rabbits. J Exp
Med. 1959;110:147-160. 11. Hughes WT, Smith B. Provocation of infection due to Pneumocystis carinii by cyclosporin A.
J Infect Dis. 1982;145:767.
12. Larsson EL. Cyclosporin A and dexamethasuppress T cell responses by selectively acting triggering process. J Immunol. 1980;124:2828-2832. 13. Arya SK, Wong-Staal F, Gallo RC. Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. J Immunol. 1984;133:273-276. 14. Fauci AS, Dale DC. The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest. 1974;53:240-246. 15. Johnson HD, Johnson WW. Pneumocystis carinii pneumonia in children with cancer: diagnosis and treatment. JAMA. 1970:214:1067-1073. 16. Singer C, Armstrong D, Rosen PP, Schottenfeld D. Pneumocystis carinii pneumonia: a cluster of eleven cases. Ann Intern Med. 1975;82:772-777. 17. Nisam M, Wong S, Fallat RJ. Pulse oximetry and diffusing capacity in AIDS patients with Pneumocystis carinii pneumonia. Chest. 1987;92: 134S. Abstract. 18. Sankary RM, Turner J, Lipavsky A, Howes EL, Murray JF. Alveolar-capillary block in patients with AIDS and Pneumocystis carinii pneumonia. Am Rev Respir Dis. 1988;137:443-449. 19. Stover DE, Greeno RA, Gagliardi AJ. The use of a simple exercise test for the diagnosis of Pneumocystis carinii pneumonia in patients with sone
at distinct sites of the
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AIDS. Am Rev Respir Dis. 1989;139:1343-1346. 20. Barron TF, Birnbaum NS, Shane LB, Goldsmith SJ, Rosen MJ. Pneumocystis carinii pneumonia studied by gallium-67 scanning. Radiology.
1985;154:791-793. 21. Zaman MK, White DA. Serum lactate dehy-
drogenase levels and Pneumocystis carinii pneumonia: diagnostic and prognostic significance. Am Rev Respir Dis. 1988;137:796-800. 22. Drew WL, Finley TN, Mintz L, Klein HZ. Diagnosis of Pneumocystis carinii pneumonia by bronchopulmonary lavage. JAMA. 1974;230:713\x=req-\ 715. 23.
Hodgkin JE, Andersen HA, Rosenow EC. Diagnosis of Pneumocystis carinii pneumonia by transbronchoscopic lung biopsy. Chest. 1973; 64:551-554. 24. Springmeyer SC, Silvestri RC, Sale, GE, et al. The role of transbronchial biopsy for the diagnosis of diffuse pneumonias in immunocompromised marrow transplant recipients. Am Rev Respir Dis.
1982;126:763-765.
25. Hughes WT, Kuhn S, Chaudhary S, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med. 1977;297:1419\x=req-\ 1426. 26. Hughes WT, Rivera GK, Schell MJ, Thornton D, Lott L. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med. 1987;316:1627-1632.
histologically documented episodes Pneumocystis carinii pneumonia in adult patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center, New York, NY, since 1981, were retrospectively reviewed. Pneumocystis carinii pneumonia was histologically documented 11 times in 10 patients. During the same 8-year interval, approximately 587 adults were seen \s=b\ All
of
at the center for a brain tumor, 90% of whom received ongoing therapy. Therefore, in at least 1.7% (10/587) of our patients with brain tumors, P carinii pneumonia developed. The median duration of dexamethasone therapy at the onset of P carinii pneumonia symptoms was 2.75 months. Symptoms began during tapering of steroid therapy in eight episodes. Bronchoscopy was diagnostic in the eight cases in which it was performed. Four episodes (40%) were fatal. Trimethoprim-sulfamethoxazole prophylaxis may be indicated in some patients with brain tumors,
especially during tapering of steroid therapy.
(Arch Neurol. 1991 ;48:406-409)
~Dneumocystis
carinii is
one
of the
most common opportunistic patho¬ gens that causes pneumonitis in immun-
ocompromised patients. There are a va¬ riety of predisposing immunodeficiency states, including hématologie malignant carinii neoplasms.1"" In contrast, pneumonia (PCP) is rare in patients
Accepted for publication October 18,1990. From the Department of Neurology (Drs Henson and Walker) and the Pulmonary Division (Drs Jalaj, Stover, and Fels), Memorial Sloan-Kettering Cancer Center, New York, NY. Dr Jalaj is now in private practice in Fishkill, NY. Reprint requests to Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (Dr Walker).
Patients With
MD;
with solid tumors but may occur in these patients in the setting of corticosteroid therapy.1"1"7 Patients with primary brain tumors often receive high doses of corti¬ costeroids for prolonged periods, in¬ creasing the risk of opportunistic infec¬ tions. To assess the magnitude of this problem in our patients with brain tu¬ mors, we reviewed all cases of PCP in patients with primary brain tumors treated at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY. We determined the percentage of patients with brain tumors in whom PCP developed, the relationship of dexamethasone therapy to PCP, and the clinical features of PCP in this group of patients. PATIENTS AND METHODS
The medical records of all adult patients treated at MSKCC since 1981 for a primary brain tumor and a histologically documented PCP diagnosis were reviewed. Cases were identified from the Memorial Hospital Data Analysis computerized database (containing diagnoses from clinic records of patients re¬ ceiving their treatment at MSKCC, hospital discharge summaries, and autopsy reports) and from bronchoscopy records. To deter¬ mine the size ofthe group at risk for PCP, we used the data analysis database to ascertain the total number of adults (aged s=20 years) treated for a primary brain tumor from 1981 to 1989. Because pediatrie patients with brain tumors at MSKCC are routinely treat¬ ed with prophylactic trimethoprim-sulfamethoxazole during prolonged steroid thera¬ py, we excluded all patients so treated from the group at risk by counting only patients who were at least 20 years old. To be certain that this database contained only patients who had ongoing therapy at MSKCC, 40 pa¬ tients with a diagnosis of glioblastoma multiforme were selected from the group at risk
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for PCP and their records were reviewed for treatment and duration of follow-up. In patients who underwent diagnostic bronchoscopy, bronchial washings and bronchoalveolar lavage were processed for bacte¬ rial, fungal, and mycobacterial staining and culture as previously described.* Cytologie examination was performed on bronchial brushings, washings, and lavage fluids using Papanicolaou and Gram-Weigert stains." Gram-Weigert, Ziehl-Neelsen, and silvermethenamine stains were performed on the transbronchial biopsy specimens in addition to the usual pathologic examination. All lung specimens were extensively examined and cultured, and their pathologic findings re¬ viewed. Pneumocystis carinii pneumonia was diagnosed by the demonstration of cysts in bronchial fluid or lung tissue. RESULTS Patients With PCP
There were 11 histologically docu¬ mented episodes of PCP in 10 patients with primary brain tumors between 1981 and 1989. The cases were distribut¬ ed during this period as outlined in Table 1. Concurrently, 587 adult patients be¬ gan treatment for a primary brain tu¬ mor at MSKCC. Approximately 90% of these 587 had follow-up adequate to identify episodes of PCP (see the follow¬ ing data). Therefore, during the last 8 years, PCP developed in at least 1.7% of our adult patients with brain tumors. There were two patients with clinical¬ ly suspected, but unconfirmed episodes, of PCP and two confirmed episodes in two patients with primary central ner¬ vous system lymphoma who were ex¬ cluded from analysis. Ofthe remaining 10, six patients were men and four were women; their median age was 45 years; and all were white. The tumors were
glioblastoma multiforme (five), anaplastic astrocytoma (three), brain-stem gli¬ oma (one), and medulloblastoma (epi¬
sodes at the ages of 26 and 29 years occurred in this patient). The brain tu¬ mor was in the posterior fossa in six of the patients (medulloblastoma, brainstem glioma, midbrain and thalamic glioblastoma, multifocal anaplastic as¬ trocytoma, cerebellar anaplastic astro¬ cytoma, and cervicomedullary junction
anaplastic astrocytoma).
The interval from the time of tumor
diagnosis to the time of diagnosis of PCP ranged from 3 weeks to 9 years, with a
median of 3 months. Nine tumors were newly diagnosed and two were recur¬ rent, one at 3 years and one at 8.5 years from the original tumor diagnosis. The patient with two episodes of PCP suf¬ fered the second episode during a recur¬ rence 3 years following the original
diagnosis. All patients had received cranial irra¬ diation. Single-agent or combination chemotherapy had been administered before the development of PCP in seven episodes (Table 1), including a nitro-
(lomustine, PCNU [l-(2-chloroethyl)-3-(2,6 dioxo-3-piperadyl)- 1-nitrosureaj, or carmustine), procarbazine hydrochloride, vincristine sulfate, fluorouracil, hydroxyurea, mechlorethamine hydrochloride, and misonidazole. None ofthe five patients who received a nitrosourea had documented pulmonary
Table
1.—Relationship
of Steroid
Therapy
and
Chemotherapy to PCP*
Duration of Duration of Dexamethasone Dexamethasone Dexamethasone Therapy Before Taper Before Dosage at Dexamethesone, Symptoms of Diagnosis of Symptoms of mg/d PCP, mo PCP, mg/d PCP, d Chemotherapy 32 1.5 8 .t Carmustine, Maximum Dosage of
Episode (y) 1(1982)
.
hydroxy¬
.
urea
(1982)
24
2.5
3(1983) 4 (1983) 5 (1984) 6(1985) 7(1986)
28
1.5
92
2.25
24
9.5
32
3.0 1.25
2
63
2
Lomustine, fluorouracit, misonidazole
100
.
.t
20
None
5
24
None
21
12
PCNU
17
12
11
4
Fluorouracil Mechlorethamine
.
hydrochloride,
vincristine
8(1986)
24
3.25
1
8
(1989) (1989) 11(1989)
48
3.25
14
32
16
2.75
5
10
None None
60
Carmustine
9 10 *
are
PCP indicates listed.
96 4.25 .t Pneumocystis carinii pneumonia. Only those drugs in .
tEpisodes occurring
in the absence of
a
.
use
Lomustine, vincristine, procarbazine
at the time of the
diagnosis of PCP
steroid taper.
sourea
toxic reaction from the agent. None of the patients had an identified human immunodeficiency virus risk factor oth¬ er than one patient, who had had a blood transfusion between the first and sec¬ ond episodes of PCP One patient had received trimethoprim-sulfamethoxazole for a urinary tract infection 3 months before the diagnosis of PCP. All of the patients with PCP were re¬ ceiving dexamethasone (Table 1). The duration of steroid therapy before the onset of PCP symptoms ranged from 5 weeks to 9.5 months (median, 2.75 months). The onset of symptoms in eight ofthe 11 episodes occurred while dexa¬ methasone therapy was being tapered. The interval from the initiation of the tapering of steroid therapy to onset of PCP symptoms in these eight ranged from 1 to 63 days (median, 12 days). At the time of diagnosis of PCP, daily dexa¬ methasone dose ranged from 2 to 60 mg. Table 2 summarizes the clinical pre¬ sentations ofthe 11 episodes of PCP. At the time of diagnosis of PCP, pulmonary symptoms had been present from 1 to 30 days (median, 7 days). The most com¬ mon
presenting symptoms
were
dys¬
pnea in eight cases and a nonproductive cough in seven. Fever was present in six of the episodes. In nine episodes in
Table 2.—Clinical Summary of 11
Episodes
of PCP in Patients With Brain Tumors* Chest
Duration of
Roentgenography
Symptoms
Episode
Symptoms
(A-a)02 Gradient, mm Hg
Before PCP Diagnosis, d
NC, F NC, D, F, CP
14
U/L
53
510
69
960 672
51
336
215t
803
NC
PC, D, CP D, F PC, D, F, CP NC, D, F NC, D
at First
LDH,
820
54
30
1284
22
35
419
76
480
Evaluation of
Symptoms Bilateral Infiltrates Bilateral infiltrates Focal infiltrate Diffuse infiltrates Bilateral infiltrates Focal infiltrate Diffuse infiltrates Normal Diffuse infiltrates Bilateral infiltrates
Outcome Recovered
Recovered Recovered Recovered Died Died Recovered Recovered Died Recovered Died
409 NC, CP 10 499 NC, D, F Focal Infiltrate *PCP indicates Pneumocystis carimi pneumonia; (A-a)02, alveolar-arterial oxygen; LDH, lactate dehydroge nase; NC, nonproductive cough; F, fever; D, dyspnea; CP, chest pain; and PC, productive cough. tPatient receiving supplemental oxygen. 10 11
which
arterial blood gas value was increased alveolar-arterial oxygen tension gradient (range, 23.5 to 215 mm Hg; median, 54 mm Hg) was present. One arterial blood gas value was obtained from a patient receiving an
obtained,
an
supplemental oxygen (episode 5, Table 2). Elevated lactate dehydrogenase (LDH) levels ranged from 336 to 1284 U/L
(median,
510
U/L), and
were
pre¬
episode. Serum albumin level ranged from 24 to 38 g/L. Total leukocyte count at diagnosis of PCP ranged from 3.5 to 14.4 x 107L, and ab¬ solute lymphocyte counts ranged from 0.17 to 2.3 107L (median, 0.28 107L; sent in each
lower limit of normal is l.OxlOTL).
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Chest roentgenograms at the time of the initial pulmonary evaluation showed either no infiltrate (episode 8), or infil¬ trates that were focal, bilateral (multi¬ focal), or diffuse. A cavitary lesion in addition to infiltrates was seen in one
(episode 3). Fiberoptic bronchoscopy was diag¬ nostic in each ofthe eight cases in which it was performed. Bronchoalveolar la¬ vage analysis was positive for PCP in six of eight patients. A transbronchial biop¬ sy specimen was positive in three of the six patients who had this procedure. Two patients (episodes 10 and 11) were found to have more than one pulmonary pathogen. The first patient (episode 10) case
bronchoscopy because of a nonproductive cough, chest pain, and a persistent infiltrate on chest roentgen¬ ography. Pneumocystis carinii was found in the bronchoalveolar lavage, and fungal elements consistent with As¬ pergillus sp were found invading blood vessels in the transbronchial biopsy specimens. The second patient (episode 11) had autopsy lung cultures and histo¬ logie findings consistent with cytomega¬ underwent
lovirus infection as well as PCP. Three patients did not undergo bronchoscopy but received diagnoses at autopsy. One of these (episode 5) had a fulminant clini¬ cal course and died on the day of admis¬ sion before any procedure could be car¬ ried out; the second (episode 9) was taking anticoagulants and died before the prothrombin time returned to nor¬ mal, preventing bronchoscopy; the third (episode 11) was moribund from progressive tumor when pulmonary symptoms began, and at the family's
bronchoscopy was not performed. Ten episodes were treated with intra¬ venous trimethoprim-sulfamethoxazole. None of these patients had an ad¬ verse reaction to therapy. All were receiving dexamethasone throughout therapy. Four patients (40%) died of PCP Six patients survived seven episodes of PCP; five subsequently died of their tumors. request,
Forty Patients Without PCP It is difficult to determine the exact incidence of PCP in a setting in which patients are often seen in initial evalua¬ tion and then referred back to their point of origin while still receiving cor¬ ticosteroid therapy. Five hundred eighty-seven adult patients with prima¬ ry brain tumors were seen for therapy at MSKCC from 1981 to 1989. The re¬ cords of 40 patients from this group were reviewed to determine how many received ongoing treatment there. Four did not receive therapy at MSKCC or had less than 1 month of follow-up. Therefore, we estimated that 90% ofthe total study group had received ongoing treatment. This would make 1.7% a least estimate ofthe percentage of patients in whom PCP developed. All 40 patients received steroid therapy, with dura¬ tions (to discontinuation of steroid ther¬ apy or to last follow-up) ranging from 3 weeks to 28 months (median, 3.8
months).
COMMENT
The association between PCP and the of high doses of corticosteroids is well documented. Data available in the use
literature suggest that steroids permit reactivation of latent infection by sup¬ pressing the immune system of the host.91" Cellular immunity seems to play the predominant role in the host's de¬ fenses against PCP Many of the under¬ lying diseases in patients with PCP have associated defects of cellular im¬ munity.1'5 Cyclosporine" and dexameth¬ asone both predispose patients to PCP and both inhibit T-lymphocyte prolifer¬ ation by mechanisms affecting interleu¬ kin 2 (T-cell growth factor), a T-helper cell product.*" Single doses of glucocorticoids in humans have been shown to induce peripheral lymphopenia, proba¬ bly by redistribution of lymphocytes from the circulation into other body compartments.14 None of our patients had tests of immunologie function, but peripheral lymphopenia was present in all for whom this information was available. Paradoxically, PCP often becomes clinically apparent when steroid doses are being decreased or withdrawn. Ani¬ mal studies suggest that a tapering of steroid therapy may simply unmask carinii infections that have developed earlier during high-dose steroid admin¬ istration. In a rat model, steroids have depressed the capability of the host to mount an inflammatory response to carinii infection. This inflammatory response appears as the steroid dosage is decreased." Those rats receiving highdose steroids in which PCP developed had scanty alveolar exudates despite the presence of carinii organisms in the lung tissue. When steroids were withdrawn or tapered, intense inflam¬ matory exudates developed. Similarly, rabbits on long-term, stable steroid doses suffer PCP without the character¬ istic proteinaceous alveolar exúdate and interstitial plasma cell infiltration.10 Multiple human studies have con¬ firmed the relationship between de¬ creasing steroid doses and PCP. Fossieck and Spagnolo" observed the appearance of PCP in patients with lung cancer who were receiving tapering doses of steroids. Other investigators have found that of 19 children with can¬ cer in whom PCP developed, 17 had re¬ cently had steroid administration dis¬ continued or were receiving low-dose replacement therapy when the diagno¬ sis of PCP was made.1' Singer et al1" re¬ ported the occurrence of PCP in 11 pa¬ tients (10 with lymphoma or leukemia) who had received steroid therapy. In seven of these patients, PCP developed in the setting of a tapering of steroid therapy. In our series, eight of 11 epi¬ sodes of PCP occurred during a tapering of steroid therapy. The duration of the tapering of steroid therapy before the
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onset of pulmonary symptoms ranged from 1 to 63 days, but seven ofthe epi¬ sodes occurred within 21 days of initia¬ tion ofthe tapering. In all prior studies, PCP was rare among patients with solid tumors. Our findings, however, suggest that this disease occurs in a subset of patients with solid tumors, namely, those with brain tumors. The increased incidence of PCP in patients with primary brain tu¬ mors is most likely due to the fact that they frequently receive high-dose corti¬ costeroids for extended periods. Pa¬ tients with solid tumors that do not arise in the central nervous system who are placed on similar steroid regimens may also be at risk for PCP. In the only other published series of patients with solid tumors who had PCP, three of five pa¬ tients with lung cancer who had PCP had received dexamethasone for brain mé¬ tastases, followed by a tapering of ste¬ roid therapy.'1 Clinicians should have a high index of suspicion for PCP in this selected patient population, particularly because the clinical presentation ofPCP can be subtle and nonspecific. Patients with mild pul¬ monary symptoms in whom the diagno¬ sis of PCP is suspected should be screened carefully. If the chest roent¬ genogram shows diffuse infiltrates, bronchoscopy should be done emergently. Ifthe chest roentgenogram is normal and the patient has mild symptoms, oth¬ er sensitive tests might be helpful to detect interstitial lung disease. These tests include pulmonary diffusing ca¬ pacity,1718 rest and exercise arterial blood gas values,1" or performance of a gallium citrate lung scan.2" If any of these test results are abnormal, one should proceed to bronchoscopy. A se¬ rum LDH measurement may be useful. All the patients in this study had elevat¬ ed levels of LDH. A previous report on patients with acquired immunodeficien¬ cy syndrome (AIDS) who had PCP found that only 7% had normal LDH levels, and levels greater than 450 U/L were highly specific for PCP.21 In this same study, six (75%) of eight patients with¬ out AIDS with PCP had elevated LDH levels. Further investigation is re¬ quired to determine the sensitivity and specificity of this test in the population without AIDS. Confirmation of the di¬ agnosis of PCP depends on the demon¬ stration of the organisms either in lung tissue or in bronchoalveolar lavage fluid. If abnormalities consistent with the diagnosis are found in any of the above tests, further evaluation with bronchos¬ copy, including bronchoalveolar la¬ vage"'22 and transbronchial biopsy,Z3,Z4 is recommended. In more acutely ill pa-
tients, bronchoscopy is recommended to make the
diagnosis as rapidly as pos¬ sible. If bronchoscopy is nondiagnostic, the decision as to whether the patient should have an open-lung biopsy, close follow-up, or empirical therapy depends on the clinical status of the patient and the physician's index of suspicion. In a prospective, randomized study of children with hématologie malignant neoplasms, trimethoprim-sulfamethoxazole provided excellent protection against PCP with minimal toxic reac-
a second study of this popula¬ trimethoprim-sulfamethoxazole prophylaxis had equal efficacy when ad¬ ministered for 3 consecutive days each week when compared with a daily regi¬ men.21' Although the risk of PCP in these studies was much higher than in our patients (PCP developed in 17 ofthe 80 patients in the placebo-treated group), our findings suggest that prolonged ad¬ ministration of high doses of steroids in patients with brain tumors substantial¬ ly increases the risk of PCP.
tion.2' In tion
,
Patients likely to need prolonged, high-dose steroid therapy include those with large postoperative tumor bur¬ dens, those in whom steroid depen¬ dence develops during radiotherapy, and those witb unresectable brain-stem lesions. Such patients undergoing ta¬ pering of steroid therapy are a high-risk subgroup. Given the high mortality of 36%, trimethoprim-sulfamethoxazole prophylaxis should be considered for such patients.
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