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Alerts, Notices, and Case Reports Alteration of the Natural History of Pneumocystis carinil Infection in Patients With Acquired Immunodeficiency Syndrome Receiving Aerosolized Pentamidine DAVID M. KATES, MD TERENCE G. SPARLING, MD, FRCP(C) NAZMA JETHA, MD, FRCP(C) DAVID R. BURDGE, MD, FRCP(C) Vancouver, British Columbia

Pneumocystis carinii is the most common opportunistic pulmonary infection in patients with the acquired immunodeficiency syndrome (AIDS), but extrapulmonary and disseminated infection remains rare. We report the case of a severely immunocompromised man in whom disseminated P carinii infection developed while he was receiving secondary aerosolized pentamidine prophylaxis. Several factors, including profound immunocompromise and the use of nebulized pentamidine prophylaxis, likely contributed to the development of extrapulmonary pneumocystosis in this patient. We discuss the recent literature concerning disseminated P carinii infectiont8 and comment on the probable pathogenesis and natural history of this infection. Report of a Case

The patient, a 36-year-old man with AIDS, was admitted to hospital in July 1989 for the treatment of P carinii pneumonitis. Seropositivity to the human immunodeficiency vi-

(HIV) had been documented in March 1988, when an initial episode of P carinii pneumonitis was successfully treated with intravenous pentamidine. A regimen of zidovudine (azidothymidine) was started, and in July 1988 he began a program of aerosolized pentamidine prophylaxis using a Fisoneb nebulizer. Five loading doses of 60 mg of pentamidine isethionate were administered over ten days, and he was then maintained on 60 mg by nebulizer every two weeks, receiving a total of 34 treatments. He was readmitted in July 1989 with cough, dyspnea, fever, night sweats, malaise, and weight loss. He was cachectic, febrile, and appeared chronically ill. Oral candidiasis was present, and his spleen tip was palpable 3 cm below the left costal margin. Diminished breath sounds and inspiratory crepitations were noted at the bases of both lungs. The leukocyte count was 1.2 x 109 per liter with 0.7 polymorphonuclear leukocytes and 0.2 lymphocytes. The hemoglobin was 107 grams per liter (10.7 grams per dl) and rus

(Kates DM, Sparling TG, Jetha N, Burdge DR: Alteration of the natural history of Pneumocystis carinii infection in patients with acquired immunodeficiency syndrome receiving aerosolized pentamidine. West J Med 1991 Jun; 154:721-723) From the Department of Medicine (Dr Kates); the Division of Hematology, Department of Medicine (Dr Sparling); the Department of Anatomical Pathology (Dr Jetha); and the Division of Infectious Diseases, Department of Medicine (Dr Burdge), University Hospital-Shaughnessy Site, University of British Columbia, Vancouver. Reprint requests to David R. Burdge, MD, FRCP(C), Division of Infectious Diseases, University of British Columbia, University Hospital-Shaughnessy Site, G61 1, Jean Matheson Pavilion, 4500 Oak St, Vancouver, BC, V6H 3N1.

the platelet count 54 x 109 per liter. Lymphocyte studies showed 0.0 x 109 per liter OKT4 (helper) cells. An arterial blood gas analysis showed a pH of 7.46, a Pco2 of 39 mm of mercury, and a Po2 of 79 mm of mercury with a bicarbonate of 28 mmol per liter and an 02 saturation of 0.96. Serum levels were as follows: total protein, 56 grams per liter; albumin, 25 grams per liter; -y-glutamyltransferase, 73 U per liter (normal, 12 to 53); aspartate aminotransferase, 158 U per liter (normal, 12 to 35); lactate dehydrogenase, 2,059 U per liter (normal, 297 to 537); and creatine kinase, 1,884 U per liter (normal, 60 to 330). Blood cultures were sterile. A lumbar puncture revealed a normal cell count, differential cell count, glucose and protein levels, and the cerebrospinal fluid was negative for cryptococcal antigen. Cerebrospinal fluid cultures for virus, fungi, and acid-fast bacilli were sterile. A VDRL was negative, and a serologic test for Toxoplasma species was negative. A bone marrow aspirate and biopsy were nondiagnostic. An initial abdominal ultrasound examination revealed the spleen to be 14 cm in size, but the results were otherwise normal. A reticular interstitial bilateral infiltrate was seen on chest x-ray films. Bronchoalveolar lavage and brushings revealed numerous cysts of P carinii. Parenteral pentamidine therapy failed, but the patient did respond to parenteral administration of the combination of trimethoprim and sulfamethoxazole with complete clearing on his chest x-ray film and a resolution of pulmonary symptoms. At this point, he was noted to have hepatomegaly, and a repeat ultrasound study (one month after the initial study) showed multiple tiny hyperechoic lesions throughout the liver parenchyma. The spleen measured 15 cm in size, and there were multiple hyperechoic lesions through the spleen, kidneys, and pancreas as well. A liver biopsy specimen revealed multiple caseating granulomata (Figure 1). Stains for acid-fast bacilli and fungi were negative, and cultures were sterile. Cysts of P carinii were demonstrated (Figure 2). Pancytopenia developed with the administration of trimethoprim-sulfamethoxazole. Oral dapsone and trimethoprim therapy was started, and, despite the findings on liver biopsy, the patient improved clinically, gained weight, and

I

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I

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8

Figure 1.-A liver biopsy specimen shows a loosely formed granuloma with central necrosis (between two arrowheads) (hematoxylin and eosin, original magnification x 200).

ALERTS, NOTICES, AND CASE REPORTS

722

ABBREVIATIONS USED IN TEXT = AIDS acquired immunodeficiency syndrome HIV = human immunodeficiency virus

fPlm.l

f-,

.i

U ..

'::.!

Aolzt-.

11;

Figure

2.-A

Pneumocystis

of the necrotic

carinii cyst (open arrow)

in

zone seen

Figure

1

is shown at the periphery (Grocott stain, original magnification x

400).

discharged home. Because of gastrointestinal intolertrimethoprim was discontinued and he has subsequently been maintained on a regimen of oral dapsone, 100 mg daily, and clindamycin, 450 mg four times a day. Followwas

ance,

up ultrasound studies of the abdomen have shown

no

appre-

change in the multiple hyperechoic lesions in the liver, spleen, and kidneys. His course has been complicated by gradual weight loss and cytomegalovirus chorioretinitis, but he remains alive with a reasonable quality of life ten months after the hospital discharge. ciable

Discussion

Extrapulmonary and disseminated infection with Pneumocystis carinii remains rare, and several large autopsy series failed to find the organism outside of the lungs.',"0 When reported, extrapulmonary pneumocystosis has usually occurred in patients with overwhelming pulmonary infection.' Two of

us

(T.G.S. and D.R.B.) and colleagues have recently

reported the occurrence of disseminated P carinii infection in a severely compromised AIDS patient with no evidence of pulmonary involvement, and Hardy and co-workers have reported a similar case.' In both of these cases, the patients were receiving secondary prophylactic aerosolized pentamidine These two cases, and the further case reported herein, join a series of recent reports of extrapulmonary P carinii infection, all of which have occurred in patients re-

therapy.

ceiving prophylactic

aerosolized

Shelhammer

associates

and

successful treatment

as

pentamidine.~-, have

shown that

judged clinically

even

P carinii cysts are not eradicated from therefore not surprising that recurrences of P carinii monia are common in the absence of some form of

cally,

with

radiographithe lungs.'2 It is

and

pneu-

prophy-

lactic

therapy.

Various

the recurrence rate

prophylactic measures have pneumonitis, including

of the

decreased the

use

of

zidovudine trimethoprim-sulfamethoxazole, pyrimethamine, sulfadoxine, dapsone, and parenteral pentamidineu.y Aerosolized pentamidine has also been shown to be effective prophylactically against recurrent P carinii pneumonia and for this imdihas recently been recommended for routine oral

use

cation by both the Centers for Disease Control"3 and Health and Welfare Canada. 14 Minimal systemic toxicity and documented efficacy in the setting of secondary prophylaxis have also resulted in the recent recommendation that primary prophylaxis with aerosolized pentamidine be initiated in all HIVinfected patients with low OKT4 (helper) cell counts."3 Pharmacokinetic studies by Conte and Golden,15 Montgomery and colleagues,16 and Salamone and Cunha"7 have shown that the concentration of pentamidine in bronchoalveolar lavage fluid following aerosolized administration is high- 10 to 75 times greater than drug levels achieved with intravenous infusion-following inhalation therapy. The half-life of the drug in bronchial fluid is prolonged; detectable levels have been observed in one patient as long as 115 days following the completion of a two-week course of therapy. Systemic absorption is minimal, and accumulation in plasma has not been observed. This pharmacokinetic finding appears to support the hypothesis that aerosolized pentamidine suppresses pulmonary disease but might allow for the dissemination of the organism. I It is noteworthy that in both cases of disseminated pneumocystosis that we have reported, patients have been severely immunocompromised, as reflected by OKT4 (helper) cell counts of 0.0 x 109 per liter (present case) and 0.017 x 109 per liter.1 It may be that aerosolized pentamidine is not the sole factor resulting in dissemination and that profound immunocompromise must also be present. Unfortunately, the majority of reported cases of extrapulmonary P carinii infection do not include documentation of CD4 + cell counts. It will be relevant to observe whether dissemination also occurs in less compromised patients receiving aerosolized pentamidine, such as those receiving primary pneumocystis prophylaxis. Further study is required before it can be concluded that the severely immunocompromised state is a necessary cofactor for the development of disseminated P carinii infection. The natural history of extrapulmonary P carinii infection is not yet clear. In both of our patients, the infection has been indolent, and they have remained well for several months following diagnosis. Optimal modalities of therapy are also unknown, and it remains to be seen whether prolonged systemic therapy alters the natural history of the infection. In all severely immunocompromised patients who are receiving aerosolized pentamidine therapy, the diagnosis of disseminated pneumocystosis must be considered when systemic symptoms or hepatosplenomegaly or lymphadenopathy develop. Liver and lymph node biopsies are helpful in establishing the diagnosis. We anticipate that disseminated pneumocystosis will be seen more frequently with the increasing use of aerosolized pentamidine prophylaxis. Innovative prophylactic regimens that include systemic prophylaxis (perhaps in combination with aerosolized pentamidine) deserve further consideration and study. REFERENCES 1. Sparling TG, Dong SR, Hegedus C, Burdge DR: Aerosolized pentamidine and disseminated infection with Pneumocystis carinii. Ann Intern Med 1989; 111:442 2. Hardy WD. Northfelt DW, Drake TA: Fatal, disseminated pneumocystosis in a patient with acquired immunodeficiency syndrome receiving prophylactic aerosolized pentamidine. Am J Med 1989; 87:329-331 3. Poblete RB, Rodriguez K, Foust RT, Reddy KR, Saldana MJ: Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989; 110:737-738 4. Piot DF, Gathe J, Del Junco GW, Stool EW, Trujillo JR: Splenic pneumocystosis-Poster MBP377, In Abstracts, Vth Intemational Conference on AIDS. Montreal, Quebec, 1989, p 284

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5. Ward DJ: Disseminated granulomatous pneumocystosis in a patient receiving aerosolized pentamidine prophylaxis-Poster MBP378, In Abstracts, Vth International Conference on AIDS. Montreal, Quebec, 1989, p 284 6. Raviglione MC, Mariuz P, Sugar J, Mullen MP: Extrapulmonary Pneumocystis infection (Letter). Ann Intern Med 1989; 1 1 1:339 7. Richie TL, Yamaguchi E, Virani NA, Quinn BD, Chaisson RE: Extrapulmonary Pneumocystis infection (Letter). Ann Intern Med 1989; 111:339-340 8. Dyner TS, Lang W, Busch DF, Gordon PR: Intravascular and pleural involvement by Pneumocystis carinii in a patient with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989; 111:94-95 9. Unger PD, Rosenblum M, Krown SE: Disseminated Pneumocystis carinii infection in a patient with acquired immune deficiency syndrome. Hum Pathol 1988; 19:113-1 16 10. Bamett RN, Hull JG, Vortel V, Schwarz J: Pneumocystis carinii in lymph nodes and spleen. Arch Pathol 1969; 88:175-180 11. Berman SM, Shah B, Wylie FA, Dacosta-Iyer M, McRae DM: Disseminated Pneumocystis carinii in a patient receiving aerosolized pentamidine prophylaxis. West J Med 1990; 153:82-86 12. Shelhammer JH, Ognibene FP, Macher AM, et al: Persistence of Pneumocystis carinii in lung tissue of acquired immunodeficiency syndrome patients treated for pneumocystis pneumonia. Am Rev Respir Dis 1984; 130:1161-1165 13. Centers for Disease Control: Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989; 38(Suppl S-5):1-9 14. Health and Welfare Canada. Aerosol pentamidine. Dear Doctor 1989 Jul 10, pp 1-5 15. Conte JE Jr, Golden JA: Concentrations of aerosolized pentamidine in bronchoalveolar lavage, systemic absorption, and excretion. Antimicrob Agents Chemother 1988; 32:1490-1493 16. Montgomery AB, Debs RJ, Luce JM, et al: Selective delivery of pentamidine to the lungs by aerosol. Am Rev Respir Dis 1988; 137:477-478 17. Salamone FR, Cunha BA: Update on pentamidine for the treatment of Pneumocystis carinii pneumonia. Clin Pharm 1988; 7:501-5 10

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drawn up, and he spoke with effort. There was no headache, nausea, vomiting, tinnitus, diplopia, or visual, mental, or sphincteric disturbances preceding or during the attacks, nor were any residual sensory or motor deficits noted. When these attacks had first started, the patient went to an emergency department. No episodes were witnessed there, and the results of an examination were normal. A diagnosis of "muscle spasm: no neurologic disease" was made, and he was instructed to consult a neurologist should the episodes continue. The episodes were initially only a few seconds in duration and occurred once to three times per day, but over a month's time they increased in severity and frequency, lasting 15 to 60 seconds and occurring as often as three times per hour. While originally benign, they became troublesome to the patient, interfering with his driving and at one point causing him to drop a beverage glass. His medical history included a period of several months of diplopia at age 12, requiring "visual training classes," but resolving without medical or surgical therapy. He had sustained minor injuries in vehicular accidents, but his only operation was a tonsillectomy at age 7. His habits included two-packs-per-day tobacco smoking and moderate daily alcohol use. No medications or street drugs were being taken. On general physical examination, no abnormalities were noted. His mental state was notable for anxiety, inappro-

Tonic Spasms in Multiple Sclerosis Anatomic Basis and Treatment LAWRENCE S. HONIG, MD, PhD PHILIP H. WASSERSTEIN, MD Stanford, California BRUCE T. ADORNATO, MD Palo Alto, Califomia

TONIC SPASMS are among several paroxysmal symptoms of multiple sclerosis. Although first described decades ago, they are frequently misdiagnosed, and they have not been well localized. We present the case ofa 31-year-old man with the sole complaint of stereotyped, left-sided, painful tonic spasms primarily affecting the arm, with less involvement of leg and face. Hyperventilation reliably precipitated the spasms.

Report of a Case The patient, a 31-year-old right-handed man, was seen because for six weeks he had had intermittent "muscle spasms" involving the left side of his body. They typically began in the left shoulder and progressed distally to the arm, hand, and fingers. There was simultaneous involvement of his left hip and leg. The feeling of muscle tension was accompanied by uncontrollable shaking and spasmodic movements of the affected parts, with the fingers "going every which wayautomatically." In addition, a pins-and-needles tingling sensation that was unpleasant and painful developed in the left limbs. The left side of the face was involuntarily (Honig LS, Wasserstein PH, Adornato BT: Tonic spasms in multiple sclerosis-Anatomic basis and treatment. West J Med 1991 Jun; 154:723-726) From the Department of Neurology and Neurological Sciences, Stanford University Medical Center. Stanford, California. Reprint requests to Lawrence S. Honig, MD, Department of Neurology and Neurological Sciences (H-3 160), Stanford University Medical Center, Stanford, CA 943055235.

Figure 1.-Brain magnetic resonance imaging: Spin-echo sequences include a proton-weighted first-echo (TR = 2,000, TE = 20 milliseconds) image (A) that shows a right internal capsule abnormality with greatly increased signal intensity on a T2-weighted second-echo (TR = 2,000, TE = 80 milliseconds) image (B) but no signal abnormality on a Ti-weighted (TR = 800, TE = 20 milliseconds) image (C). Two months later, the lesion size and signal intensity are decreased, as shown in a

T2-weighted image (D).