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Mucormycosis Peritonitis: More Than 2 Years of Disease-Free Follow-up After Posaconazole Salvage Therapy After Failure of Liposomal Amphotericin B Martin Sedlacek, MD, 1 John G. Cotter, MD, 2 Arief A. Suriawinata, MD, 1,3 Thomas M. Kaneko, MD, MS, 1 Richard A. Zuckerman, MD, MPH, 1,2 Jeffrey Parsonnet, MD, 1,2 and Clay A. Block, MD 1,4 A 57-year-old woman with end-stage kidney disease secondary to autosomal dominant polycystic kidney disease developed peritoneal dialysis–related Mucor peritonitis after her pet cockatoo bit through her transfer set. The infection persisted despite more than 8 weeks of treatment with liposomal amphotericin B. On a compassionate basis, she then received oral posaconazole, 800 mg/d, in divided doses for 6 months. She experienced complete remission and has remained disease free since then, for more than 2 years. We review the medical literature about mucormycosis peritonitis which, albeit rare, carries very high mortality. The treatment of choice is liposomal amphotericin B, which failed in our patient. Our case report suggests that posaconazole is an attractive treatment option in patients with peritoneal dialysis–related Mucor peritonitis. Am J Kidney Dis 51:302-306. © 2008 by the National Kidney Foundation, Inc. INDEX WORDS: Peritoneal dialysis; peritonitis; fungal; Mucor ; mucormycosis; zygomycosis; posaconazole. Z ygomycosis is a rare infection with very high mortality. Previously referred to as mucormy- cosis, zygomycosis most often is caused by organ- isms from the order Mucorales (class Zygomyce- tes), containing a number of species, including species of Rhizopus and Mucor. 1 Few cases of zygomycosis peritonitis related to peritoneal dialy- sis were reported, and most patients died of the disease (Table 1). The incidence of zygomycosis has increased during the last years, particularly in institutions that care for patients with hemato- oncological diseases. Risk factors for zygomycosis include diabetes, ketoacidosis, use of corticoste- roids or deferoxamine, and disruption of the skin barrier by catheters; all these conditions are not infrequent in patients on dialysis therapy. The mor- tality rate for patients with zygomycosis was esti- mated at close to 100% for those with untreated or disseminated disease. Recently, encouraging re- sults were reported with posaconazole therapy, a new triazole antifungal approved by the Food and Drug Administration in 2007 for prophylaxis in immunocompromised hosts. 2 We report more than 2 years of disease-free follow-up in a woman with peritoneal dialysis–related Mucor peritonitis for which amphotericin treatment failed, but that re- sponded to posaconazole salvage therapy used on a compassionate basis. CASE REPORT A 57-year-old woman with autosomal dominant polycys- tic kidney disease was started on peritoneal dialysis therapy in October 2003. She presented with a first episode of peritoneal dialysis–related peritonitis in July 2004 after her pet bird (cockatoo; Fig 1) bit through her transfer set while she was sleeping, and she replaced it with an old nonsterile set that she had kept for sentimental reasons. Her symptoms resolved with empiric treatment with vancomycin and genta- micin, and her initial culture results, including a Calcofluor stain (Sigma Chemicals, St Louis, MO), were negative. Ten days later, fevers, chills, abdominal pain, and cloudiness of the dialysate recurred. This time, the patient had a positive Calcofluor stain result, was hospitalized, and Mucor species grew from her peritoneal fluid (Fig 2). The Tenckhoff catheter was removed, and the patient was treated with high-dose intravenous liposomal amphotericin (10 mg/kg/ d). Initial abdominal computed tomographic (CT) imaging was negative for abscess. A tunneled catheter was placed for hemodialysis therapy. Symptoms resolved, and the patient was discharged on treatment with daily intravenous liposo- mal amphotericin. Two weeks later, the patient presented with right-sided flank pain, fever, and rigors. Abdominal CT scan showed a pelvic abscess that was drained percutaneously. Fever and pain resolved, the patient was discharged, and liposomal From the 1 Dartmouth School of Medicine, 2 Infectious Diseases, 3 Department of Pathology, and 4 Nephrology, Dartmouth-Hitchcock Medical Center, Lebanon, NH. Received June 4, 2007. Accepted in revised form Septem- ber 26, 2007. Address correspondence to Martin Sedlacek, MD, Divi- sion of Nephrology, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756-0001. E-mail: [email protected] © 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5102-0016$34.00/0 doi:10.1053/j.ajkd.2007.09.026 American Journal of Kidney Diseases, Vol 51, No 2 (February), 2008: pp 302-306 302

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Page 1: Mucormycosis Peritonitis: More Than 2 Years of Disease-Free Follow-up After Posaconazole Salvage Therapy After Failure of Liposomal Amphotericin B

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Mucormycosis Peritonitis: More Than 2 Years of Disease-Free Follow-upAfter Posaconazole Salvage Therapy After Failure of Liposomal

Amphotericin B

Martin Sedlacek, MD,1 John G. Cotter, MD,2 Arief A. Suriawinata, MD,1,3

Thomas M. Kaneko, MD, MS,1 Richard A. Zuckerman, MD, MPH,1,2 Jeffrey Parsonnet, MD,1,2

and Clay A. Block, MD1,4

A 57-year-old woman with end-stage kidney disease secondary to autosomal dominant polycystickidney disease developed peritoneal dialysis–related Mucor peritonitis after her pet cockatoo bit throughher transfer set. The infection persisted despite more than 8 weeks of treatment with liposomalamphotericin B. On a compassionate basis, she then received oral posaconazole, 800 mg/d, in divideddoses for 6 months. She experienced complete remission and has remained disease free since then, formore than 2 years. We review the medical literature about mucormycosis peritonitis which, albeit rare,carries very high mortality. The treatment of choice is liposomal amphotericin B, which failed in ourpatient. Our case report suggests that posaconazole is an attractive treatment option in patients withperitoneal dialysis–related Mucor peritonitis.Am J Kidney Dis 51:302-306. © 2008 by the National Kidney Foundation, Inc.

INDEX WORDS: Peritoneal dialysis; peritonitis; fungal; Mucor ; mucormycosis; zygomycosis;posaconazole.

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ygomycosis is a rare infection with very highmortality. Previously referred to as mucormy-

osis, zygomycosis most often is caused by organ-sms from the order Mucorales (class Zygomyce-es), containing a number of species, includingpecies of Rhizopus and Mucor.1 Few cases ofygomycosis peritonitis related to peritoneal dialy-is were reported, and most patients died of theisease (Table 1). The incidence of zygomycosisas increased during the last years, particularly innstitutions that care for patients with hemato-ncological diseases. Risk factors for zygomycosisnclude diabetes, ketoacidosis, use of corticoste-oids or deferoxamine, and disruption of the skinarrier by catheters; all these conditions are notnfrequent in patients on dialysis therapy. The mor-ality rate for patients with zygomycosis was esti-ated at close to 100% for those with untreated or

isseminated disease. Recently, encouraging re-

From the 1Dartmouth School of Medicine, 2Infectiousiseases, 3Department of Pathology, and 4Nephrology,artmouth-Hitchcock Medical Center, Lebanon, NH.Received June 4, 2007. Accepted in revised form Septem-

er 26, 2007.Address correspondence to Martin Sedlacek, MD, Divi-

ion of Nephrology, Dartmouth-Hitchcock Medical Center,ne Medical Center Dr, Lebanon, NH 03756-0001. E-mail:[email protected]© 2008 by the National Kidney Foundation, Inc.0272-6386/08/5102-0016$34.00/0

pdoi:10.1053/j.ajkd.2007.09.026

American Journal of Kid02

ults were reported with posaconazole therapy, aew triazole antifungal approved by the Food andrug Administration in 2007 for prophylaxis in

mmunocompromised hosts.2 We report more thanyears of disease-free follow-up in a woman with

eritoneal dialysis–related Mucor peritonitis forhich amphotericin treatment failed, but that re-

ponded to posaconazole salvage therapy used on aompassionate basis.

CASE REPORT

A 57-year-old woman with autosomal dominant polycys-ic kidney disease was started on peritoneal dialysis therapyn October 2003. She presented with a first episode oferitoneal dialysis–related peritonitis in July 2004 after heret bird (cockatoo; Fig 1) bit through her transfer set whilehe was sleeping, and she replaced it with an old nonsterileet that she had kept for sentimental reasons. Her symptomsesolved with empiric treatment with vancomycin and genta-icin, and her initial culture results, including a Calcofluor

tain (Sigma Chemicals, St Louis, MO), were negative. Tenays later, fevers, chills, abdominal pain, and cloudiness ofhe dialysate recurred. This time, the patient had a positivealcofluor stain result, was hospitalized, and Mucor speciesrew from her peritoneal fluid (Fig 2). The Tenckhoffatheter was removed, and the patient was treated withigh-dose intravenous liposomal amphotericin (10 mg/kg/). Initial abdominal computed tomographic (CT) imagingas negative for abscess. A tunneled catheter was placed foremodialysis therapy. Symptoms resolved, and the patientas discharged on treatment with daily intravenous liposo-al amphotericin.Two weeks later, the patient presented with right-sided

ank pain, fever, and rigors. Abdominal CT scan showed aelvic abscess that was drained percutaneously. Fever and

ain resolved, the patient was discharged, and liposomal

ney Diseases, Vol 51, No 2 (February), 2008: pp 302-306

Page 2: Mucormycosis Peritonitis: More Than 2 Years of Disease-Free Follow-up After Posaconazole Salvage Therapy After Failure of Liposomal Amphotericin B

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Posaconazole Salvage in Mucor PD Peritonitis 303

mphotericin treatment was continued. Results of culturesnd stains from the aspirate remained negative. While receiv-ng liposomal amphotericin, the patient experienced a vari-ty of debilitating symptoms that included weakness, nau-ea, difficulty with balance, and extreme fatigue, whichrompted a decrease in dose to 5 mg/kg/d after 4 weeks, buter symptoms persisted. In October 2004, amphotericinherapy was stopped after more than 8 weeks of treatment.

The patient continued to have intermittent right-sidedank pain without fever or chills. A follow-up abdominal CTcan showed at least 4 intraperitoneal nodules. In November004, the patient underwent open surgical abdominal explo-ation, during which a discrete abscess was identified andrained. Histological examination showed a necrotizingranulomatous reaction. Periodic acid–Schiff with diastaseigestion and Gomori methenamine silver stains was posi-ive for wide ribbon-like aseptate hyphae, consistent with

ucor (Fig 3). After ethical review and informed consentere obtained, the patient was started on treatment with oralosaconazole, 400 mg twice daily, through a compassionaterotocol (Schering-Plough, Kenilworth, NJ). This treatmentas very well tolerated, the patient’s symptoms resolved,

nd her strength and appetite improved. The patient wasntrigued by a “minty taste” of the medication. A follow-upT examination of the abdomen in March 2005 showed 2

emaining abdominal nodules, 1 calcified and 1 decreased inize. Posaconazole therapy was stopped in April 2005 after 6onths of treatment. The patient underwent bilateral laparo-

copic hand-assisted nephrectomy in November 2006 be-

Table 1. Overview of Case Reports of P

Reference, Year Reported Age (y) Sex Predisposin

hanna, 19803-5 NA Male DMakamura, 19896 17 Male Transplant, b

peritonitis,olo, 19897 48 Male Bath in farmranton, 19918 61 Male DM, bacteriaergie, 19929 7 wk Female Acute PD, ca

surgerydam, 199410 47 Male SLEariano, 199611 19 Male Transplant, b

peritonitishan, 200012 65 Male NA

el Rio Perez, 200113 45 Male NA

annini, 200314 43 Male Transplant, bperitonitis

erna, 200315 42 Male Transplant, bperitonitis

onecke, 200616 62 Female Transplant, pcolon

imentel, 200617 39 Female DM

ayak, 200718 62 Male Bacterial peram, 200719 52 Male DM, exit-site

(C

ause of pain related to polycystic kidney disease. On visual t

nspection of the abdominal cavity, no pathological state wasdentified. The patient has remained free of zygomycosisecurrence since November 2004, currently is undergoingemodialysis therapy, and has begun an evaluation for renalransplantation. She donated her pet bird to a friend.

DISCUSSION

Peritoneal dialysis–related Mucorales peritoni-is is a rare occurrence, and medical knowledgehus is restricted to anecdotal case reports. In theiterature, we were able to identify 15 publishedases (Table 1).3-19 The first case reported in theiterature was observed at Toronto Western Hos-ital and mentioned in several publications.3-5

his patient not only survived, but was able toesume peritoneal dialysis therapy, a success thatas never duplicated.Of note, Zygomycetes were identified byeans of culture of the peritoneal dialysis fluid

n nearly all cases. This is remarkable becausen other fluid sites (blood, cerebrospinal fluid,putum, and bronchial lavage), culture yield isxtremely low, and the diagnosis is usuallyontingent on histopathologic examination.1

istological invasion by wide ribbon-like asep-

eal Dialysis–Related Mucor Peritonitis

r Culture Result Tissue Confirmation

Mucor Nol Rhizopus from postmortem

culturesAutopsy

Rhizopus from PD fluid Nonitis Rhizopus from PD fluid Autopsy

Mucor from PD fluid No

Mucor NAl Fungus from PD fluid Lymph node biopsy

Absidia corymbifera fromPD fluid

No

Zygomyces from PD fluid NA

l Mucor from PD fluid Removed abscess

l Zygomyces from PD fluid Yes

ed Rhizopus from peritonealplaque

Yes

Cunninghamellabertholletiae

No

Rhizopus from PD fluid Non Zygomyces from catheter tip Wound tissue

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Page 3: Mucormycosis Peritonitis: More Than 2 Years of Disease-Free Follow-up After Posaconazole Salvage Therapy After Failure of Liposomal Amphotericin B

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ic in the appropriate clinical context (Fig 3).n positive cultures, Mucorales show vigorousrowth in vitro and are known as a “lid lifter,”

Table 1 (Cont’d). Overview of Case Reports

Catheter Removal Therapy Dose

es NA NAA Ampho B NA

es Ampho B NAes Ampho B 500 mg totales Ampho B 0.25 mg/kg/d

es Ampho B NAes Ampho B NA

A NA NA

A Ampho B and 5flucytosine

NA

es Liposomal ampho B 5 mg/kg 3 times/

es Liposomal ampho B 5 mg/kg/d for tot

A Ampho B 50 mg/d

es Voriconazole 200 mg 2 times/

es Liposomal ampho B 1,000 mg totales Ampho B NA

Abbreviations: Ampho B, amphotericin B; DFO, deferonformation not available; PD, peritoneal dialysis; SLE, syst

bFigure 1. Pet cockatoo nibbling on home dialysis equip-ent. (Published with permission from patient.)

hich we observed in the culture from ouratient (Fig 2). This property can lead to thehairy pus” sign in patients with mucocutane-us involvement, in which direct visualizationf lesions can help make the diagnosis.20 Peri-oneal mold-like plaques were described in thease reported by Monecke et al.16 Neverthe-ess, in up to half the cases, zygomycosis isiagnosed postmortem.Diabetes mellitus with ketoacidosis is a known

redisposing risk factor for zygomycosis. It is tempt-ng to speculate that the high glucose content thatrovides the osmotic driving force of peritonealialysate may be related to the apparent greaterield of peritoneal dialysis fluid cultures comparedith other body fluid cultures. Use of deferox-

mine was associated strongly with zygomycosis,urportedly by acting as a siderophore to the fun-us. Several cases in hemodialysis patients werettributed to this agent in the past. Only 1 of the 15ase reports in peritoneal dialysis patients showedxposure to deferoxamine.

Six of 15 patients experienced an episode of

ritoneal Dialysis–Related Mucor Peritonitis

Outcome Autopsy Return to PD

Alive No YesDeath 5 d Yes No

Death 20 d No NoDeath after 1 mo Yes NoDeath 20 d No No

Alive No NADeath 45 d No No

NA No NA

Death 2 y later from MI No NA

12 wk Alive after 5 mo No No

k Alive after 5 mo No No

Death 47 d No No

d Alive after 6 mo No Planned

Death 8 mo from MI No NoTreatment refused 3 wk No No

e; DM, diabetes mellitus; MI, myocardial infarction; NA,pus erythematosus.

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Page 4: Mucormycosis Peritonitis: More Than 2 Years of Disease-Free Follow-up After Posaconazole Salvage Therapy After Failure of Liposomal Amphotericin B

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Posaconazole Salvage in Mucor PD Peritonitis 305

les peritonitis, often within a relatively shortime, as in our patient. Prior bacterial peritonitishus seems to constitute a risk factor for Mucor-les peritonitis.

Outcome information was available in 14 of5 cases: 7 patients died of the infection within7 days, and 3 patients died of myocardial infarc-ion at 1 month, 8 months, and 2 years. Only 1 ofhese patients underwent autopsy with a postmor-em diagnosis of invasive zygomycosis. Survivalas reported in 5 patients with follow-up of 5 tomonths. Interestingly, there was initial improve-ent with treatment in some patients, but recur-

ence of the disease after 4, 6, and 8 weeks. Twof the survivors were treated with liposomalmphotericin, which was also used in 1 patient

Figure 2. “Lid-lifting” growth of Mucor species in cul-ure of peritoneal dialysate.

Figure 3. (Left) Periodiccid–Schiff with diastase diges-ion and (right) Gomori methe-amine silver stains show wideibbon-like aseptate hyphae in

eritoneal implant, consistentith Mucor infection.

ho did not survive. Because reporting biasavors favorable outcome and there was onlyhort follow-up in the survivors and no autopsiesn unrelated deaths, mortality likely is greaterhan the 50% that these cases suggest.

We speculate that the cockatoo was a likelyource of the infection in our patient becauseany fungi are found on feathers and skin of

ealthy birds, especially if soiled. Although weo not have direct proof in our case, molecularvidence for zoonotic transmission of Cryptococ-us neoformans from a pet cockatoo to a renalransplant recipient was reported.21

Liposomal amphotericin B at the highest toler-ted dose in conjunction with surgical debride-ent was identified as the treatment of choice,hich failed in our patient. Posaconazole is aighly lipophilic triazole that inhibits sterol 14�-emethylation, resulting in faulty fungal mem-rane synthesis. It is available only orally and isell absorbed and extensively distributed in tis-

ues. Several encouraging reports of salvageherapy with posaconazole recently appeared,ncluding survival from disseminated disease thatitherto had close to 100% mortality.2 Our pa-ient experienced complete remission withosaconazole after more than 8 weeks of liposo-al amphotericin B treatment failed. She re-ains well more than 2 years off therapy.osaconazole has since been approved by theood and Drug Administration for prophylaxis in

mmunocompromised persons, and additional

Page 5: Mucormycosis Peritonitis: More Than 2 Years of Disease-Free Follow-up After Posaconazole Salvage Therapy After Failure of Liposomal Amphotericin B

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herapeutic trials currently are underway. Ourase report suggests that posaconazole, 800 mg/drally in divided doses, is an attractive treatmentption in patients with peritoneal dialysis–elated Mucor peritonitis.

ACKNOWLEDGEMENTSSupport: Posaconazole was provided on a compassionate

asis by Schering-Plough (Kenilworth, NJ).Financial Disclosure: None.

REFERENCES1. Spellberg B, Edwards J, Ibrahim A: Novel perspec-

ives on mucormycosis: Pathophysiology, presentation andanagement. Clin Microbiol Rev 18:556-569, 20052. Greenberg RN, Mullane K, van Burik JAH, et al:

osaconazole as salvage therapy for zygomycosis. Antimi-rob Agents Chemother 50:126-133, 2006

3. Khanna R, Oreopoulos DG, Vas S, McCready W,ombros N: Fungal peritonitis in patients undergoing chronic

ntermittent or continuous ambulatory peritoneal dialysis.roc EDTA 17:291-296, 19804. Amair P, Khanna R, Leibel B, et al: Continuous ambu-

atory peritoneal dialysis in diabetics with end-stage renalisease. N Engl J Med 306:625-630, 19825. Eisenberg ES, Leviton I, Soeiro R: Fungal peritonitis

n patients receiving peritoneal dialysis: Experience with 11atients and review of the literature. Rev Infect Dis 8:309-21, 19866. Nakamura M, Weil WB, Kaufman DB: Fatal fungal

eritonitis in an adolescent on continuous ambulatory perito-eal dialysis: Association with deferoxamine. Pediatr Neph-ol 3:80-82, 1989

7. Polo JR, Luno J, Menarguez C, Gallego E, Robles R,ernandez P: Peritoneal mucormycosis in a patient receiv-

ng continuous ambulatory peritoneal dialysis. Am J Kidneyis 13:237-239, 19898. Branton MH, Johnson SC, Brooke JD, Hasbargen JA:

eritonitis due to Rhizopus in a patient undergoing continu-us ambulatory peritoneal dialysis. Rev Infect Dis 13:19-21,9919. Fergie JE, Fitzwater DS, Einstein P, Leggiadro RJ:ucor peritonitis associated with acute peritoneal dialysis.

ediatr Infect Dis J 11:498-500, 1992 2

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ions. Clin Infect Dis 19:67-76, 199411. Mariano F, Rossano C, Goia F, Cottino R, Dogliani N,

avalli PL: Systemic mucormycosis in dialysis: Computedomography picture and histologic lesions. Minerva Urolephrol 48:51-54, 199612. Khan ZU, Chugh TD: Invasive fungal infections in

uwait. Indian J Chest Dis Allied Sci 42:279-287, 200013. del Rio Perez O, Santin Cerezales M, Manos M, Rufi

igau G, Udiol Munte F: Mucormycosis: A classical infec-ion with a high mortality rate. Report of 5 cases. Rev Clinsp 201:184-187, 200114. Nannini EC, Paphitou NI, Ostrosky-Zeicher L: Perito-

itis due to Aspergillus and Zygomycetes in patients under-oing peritoneal dialysis: Report of 2 cases and review of theiterature. Diagn Microbiol Infect Dis 46:49-54, 2003

15. Serna JH, Wanger A, Dosekun AK: Successful treat-ent of mucormycosis peritonitis with liposomal amphoteri-

in B in a patient on long term peritoneal dialysis. Am Jidney Dis 42:E14-E17, 200316. Monecke S, Hochauf K, Gottschlich B, Ehricht R: A

ase of peritonitis caused by Rhizopus microsporus. Mycosis9:139-142, 200617. Pimentel JD, Dreyer G, Lum GD: Peritonitis due to

unninghamella bertholletiae in a patient undergoing ambu-atory peritoneal dialysis. J Med Microbiol 55:115-118,00618. Nayak S, Satish R, Gokulnath, Savio J, Rajalakshmi

: Peritoneal mucormycosis in a patient on CAPD. Perit Dialnt 27:216-217, 2007

19. Ram R, Swarnalatha G, Prasad N, Venkata K, Dakshi-amurty V: Exit site infection due to Zygomycosis resultingn abdominal wall necrosis in a continuous ambulatoryeritoneal dialysis patient. Nephrol Dial Transplant 22:266-67, 200720. Bouza E, Munoz P, Guinea J. Mucormycosis: An

merging disease? Clin Microbiol Infect 12:S7-S23, 2006suppl 7)

21. Nosanchuk JD, Shoham S, Fries BC, Shapiro DS,evitz SM, Casadevall A: Evidence of zoonotic transmis-ion of Cryptococcus neoformans from a pet cockatoo to anmmunocompromised patient. Ann Intern Med 132:205-208,

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