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Cellulitis as First Clinical Presentation of Disseminated Cryptococcosis in Renal Transplant Recipients

Article in Infectious Diseases · February 1994

DOI: 10.3109/00365549409011823 · Source: PubMed

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4 authors, including: Some of the authors of this publication are also working on these related projects: CryptoZim View project Molecular characterization, diagnosis, antifungal susceptibility pattern, pathogenicity and epidemiology of clinically relevant Fusarium species View project Alphons M Horrevorts Canisius-Wilhelmina Ziekenhuis

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Scand J Infect Dis 26: zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 623-626, 1994 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

CASE REPORT

Cellulitis as First Clinical Presentation of Disseminated Cryptococcosis in Renal Transplant Recipients

ALPHONS M. HORREVORTS, FRANS T. M. HWSMANS~, ROLAND J. J. KOOPMAN) and JACQUES F. G. M. MEIS' zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

From the Deparrmenls zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

• f

'Medical Microbiology, 'Internal Medicine and 3Dermatology,

University Hospital Nijmegen, The Netherlands Two renal transplant recipients with cellulitis due to Cryptococcus neoformans are described. The patients were treated empirically for a presumed bacterial erysipelas, but without response. Examination of skin biopsies revealed C. neoformans as the causative organism. In both patients the cellulitis was the presenting clinical manifestation of disseminated cryptococcosis. Therapy with antifungal agents was successful. Disfeminated cryptococcal disease zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

• ccurs mainly in

immunocompromized patients. When left untreated, it nearly always has a fatal course. Early diagnosis and appropriate therapy are therefore essential. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

• A. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

M . Horrevorts, MD, Department o f Medical Microbiology, University Hospital Nijmegen,

P . O .

Box 9101, 6500 HB Nijmegen, The Netherlands

INTRODUCTION Disseminated infection by Cryptococcus neoformans is observed mainly in immunocompro- mized patients and cutaneous involvement occurs in 10- 15% of cases (1). Primary crypto- coccosis zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

• f the skin is very rare and cryptococcal skin disease should therefore be interpreted

as a sign of systemic cryptococcal infection (2). Cryptococcal skin disease can manifest itself

in a variety of ways, each of which is uncharacteristic for C.

neoformans (3). Cellulitis is a very uncommon form (I). We describe 2 patients, both renal transplant recipients, with cellulitis caused by C. neoformans. CASE REPORTS

Case 1

A 31-year-old woman was admitted to the hospital with fever and a lesion of the right lower leg that

resembled erysipelas. The general practitioner had prescribed erythromycin, but without improvement. She had in the past had 2 unsuccessful renal transplants, followed by periods of long-term intermittent hemodialysis and peritoneal dialysis because of a terminal renal insufficiency due to an anti-GBM

• glomerulonephritis. She then underwent a third. successful renal transplantation. Her medication

consisted of prednisone 10 mg and azathioprine 100 mg daily. Four days prior to admission she had felt feverish, without rigors, and had noticed a dry unproductive cough. On examination she appeared moderately ill with a pulse rate of 80 per min and a blood pressure of 120/90

• mmHg. Her temperature

was 39.0C. Examination of heart, lungs and abdomen was unremarkable. On the skin of the right lower leg, there were a few painful, slightly elevated, erythematous patches (Fig. I). Laboratory findings: hemoglobin 90 g/l; leukocyte count 5.2 x 109/1; platelet count 285 x 109/l; serum creatinine was stable at 86 pmol/l. The chest X-ray showed pleural fluid on the left side and 2 circular infiltrates, each with a diameter of IScm, in the right upper lobe. Because the disorder on the right lower leg resembled

• erysipelas. erythromycin was changed to oral penicillin. The patient became subfebrile and started to

complain of headache. A broncheoalveolar lavage and a skin biopsy were performed. Microscopic examination of both showed small yeast cells and cultures yielded C. neoformans. Cerebrospinal fluid (CSF) and urine cultures both grew C. neoformans, whereas blood cultures remained sterile. The cryptococcal antigen titres in the CSF and blood were 4 and 32, respectively. Combination therapy with amphotericin B and 5-fluorocytosine was started. However, as the isolate was resistant to 5-fluorocy- tosine in vitro, therapy was changed to fluconazole 400 mg/day intravenously. Follow-up cultures of zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 1994 Scandinavian University Press. ISSN 0036-5548 Scand J Infect Dis Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 12/09/12 For personal use only.

624 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA A . zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

M.

Horreuorts et al. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

%and J Infect Dis 26

F i g . zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

• 1. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

Cutaneous skin lesion in a renal transplant recipient. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

T h e

biopsy revealed Cryptococcus neoformans. CSF, urine and skin biopsies remained sterile, although cryptococci were still visible in smears of skin biopsies even after 5 weeks of treatment. Combination therapy was given for 7.5 weeks after which amphotericin B was stopped (cumulative dose 1.6 g), but fluconazole was continued in a dose of zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

100 mg

• rally twice daily for 6 months. 11 weeks after admission, the patient was discharged in good condition

with healed skin lesions. Cryptocmal antigen titres in CSF and blood had become negative. However, the abnormalities on the pulmonary X-ray were unchanged. Three months after stopping medication, a control pulmonary X-ray showed that the infiltrates i n the upper right side of the lung had progressed. Therefore blood CSF, urine and bronchoalveolar lavage were taken for culture, but none yielded C. neoformans. Eventually a dorsal segment of the upper lobe of the right lung was removed. Histopathological examination revealed no abnormalities other than fibrotic consolidation and cultures proved negative for C. neoformans. Case 2 A 66-year-old woman was admitted to the hospital because of repeated episodes of high fever. A few months prior to admission she had been given antibiotics repeatedly by her general practitioner for an erysipelas-like skin lesion on the left lower leg. Several weeks prior to admission she had begun to complain

• f headache. During the last days, vomiting and fever >

39°C developed. Her medical history recorded a double-sided hydronephrosis due to junctura stenosis for which she underwent nephrectomy in 1939 (left) and again in 1982 (right). In 1982 a period of long-term, intermittent hemodialysis followed. In 1985 she received a cadaveric renal transplant. She was receiving maintenance immunosuppressive therapy with prednisone 10 mg and azathioprine 150 mg daily. She also suffered from diabetes mellitus type 11. On physical examination, a moderately ill, slightly somnolent and dehydrated patient was seen with a temperature of 38.4"C, a pulse rate of 108 per min and a blood pressure of 14/85 m H g . Meningeal signs were absent and fundoscopic examination showed no papilledema. The skin of the left lower leg displayed erythema (5 by 5 an). Laboratory findings: hemoglobin 152 g/l; leukocyte count 10.6 x 109/l; platelet count 392 x I09/l; serum creatinine was stable at 84 pmolfl. The pulmonary X-ray showed no

• abnormalities. Blood, CSF, urine and skin biopsies were taken for culture. CSF examination revealed a

leukocyte count of 800 x 106/1, an increased albumin concentration of 3 g/l, and a decreased glucose concentration of 3.8 mmol/l (blood glucose of 14.6 mmol/l). An India ink preparation of the CSF proved positive for yeasts and C. neoformans was isolated from CSF, skin biopsies and urine, while blood and sputum remained negative. Cryptococcal antigen titres in CSF and blood were 64 and 512, respectively. Scand J Infect Dis Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 12/09/12 For personal use only.

Scand J Infect Dis 26 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

Cryptococcal celluiitis zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

i n renal transplants

625

Therapy was started with fluconazole 400 mg administered zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA i.v. once a day. After 10 days, ampho- tericin B was added at a dose of 0.6mg/kg/day, because the patient was deteriorating and follow-up cultures of CSF, skin biopsies and urine still yielded growth of C. neoformans. CSF and urine cultures became sterile I week after adding amphotericin B, and the skin biopsies after 3.5 weeks’ treatment. The condition of the patient improved slowly as did the skin lesion. Amphotericin B was administered for 4 weeks to a cumulative dose 1.2 g. After 2 months of i.v. administration, fluconazole was given orally at a dose of 200 mg/day. Cryptococcal antigen titres in CSF and blood had then decreased to 0 and 256, respectively. The patient was discharged 10 weeks after admission. The administration

• f fluconazole was

continued for 6 months and zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

up until now, 4 years later, she is well, with no recurrence of the

cryptococcosis.

DISCUSSION Human cryptococcosis was first described by the German dermatologist Buschke in 1895 (4). It is caused by C. neoformans and is seen mainly in immunocompromized patients. Skin involvement occurs in some 10-15% of the cases and includes ulcers, acneiform papules or pustules, ecchymoses, granulomata, gummas, abscesses, vesicles. Cellulitis is the rarest presentation (3). In renal transplant recipients, infections caused by C. neoformans occurs almost exclusively in the late post-transplant period from about 4 months after transplanta- tion and onwards (5). The reported incidence varies from 0.8 to 5.8% and use of high doses

• f immunosuppressive drugs leads to a higher risk of infection (6, 7). C. neoformans is

considered to be the main cause of subacute or chronic meningitis in these patients. Meningitis is often preceded by several weeks of headache and fever (5, 8). In about a third

• f the patients a period of coughing is noted and some also suffer from pulmonary infection

(5). Other predilection sites of C. neoformans include the urinary tract, bones and the skin (5, 6). Some 20-30% of transplant recipients with cryptococcal infection will have skin lesions weeks to months prior to the development of central nervous system (CNS) disease zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA ( 5 ) . Any renal transplant patient with a documented cryptococcal infection at any site should undergo lumbar puncture to exclude CNS involvement, since CNS involvement determines the intensity and duration of treatment zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

(5). In addition to our 2 cases, 11 other recipients of

renal transplant with cellulitis caused by C. neoformans have been reported (1-3, 9-12). Inclusive of our 2 patients, it concerns 10 male and 3 female patients varying in age from 31 to 66 years, all taking immunosuppressive drugs. 11 patients had received a transplant from a deceased donor. The time of manifestation of the disease varied from 1 to 10 years after

• transplantation. Two patients developed cellulitis after a trauma zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

( 10, 12). The cellulitis appeared to be restricted mainly to the extremities, especially the legs. One patient also suffered from cellulitis on the skin of the abdomen (12). In 8 patients C. neoformans was also recovered from more than 1 site, most commonly from CSF and sputum. Cryptococcal antigens were detected in the blood of 8 and in the CSF of 3 patients. 11 patients had been treated initially with antibacterial agents, without improvement, when specific examination revealed C. neoformans. Disseminated cryptococcosis appeared to be present in 8 patients, whereas cellulitis alone was present in 2 renal transplant recipients (2, 12). Five patients were treated with amphotericin B, 6 further in combination with 5-fluorocytosine and 2 (our 2 cases) in combination with fluconazole. The cumulative dose and duration of treatment with amphotericin B varied from 570 to 1,970 mg and from 16 days to 8 weeks, respectively. Five patients died, 1 as a direct result of the cryptococcal infection (12). In the treatment of acute AIDS-related cryptococcal meningitis, fluconazole has been as effective as amphotericin B and, as maintenance therapy, even better than amphotencin B

(13, 14). Our second case was initially treated with fluconazole alone, but because follow-up

cultures of CSF still demonstrated growth of C . neoformans, amphotericin B was added. Maintenance therapy did not seem necessary, since none of our patients and none of the

Scand J Infect Dis Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 12/09/12 For personal use only.

626 A. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

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Horrevorts et al. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

Scand J zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

I n f a t

Dis zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 26 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

renal transplant patients described before (1-3, 9-12) had had a relapse of cryptococcal disease after cessation of treatment, in contrast to patients with AIDS in whom a high relapse rate is observed (3, IS). However, it is advisable to monitor the patient for at least a year after completion of the antimycotic therapy (3). Untreated disseminated cryptococcosis is almost invariably a fatal disease. Timely diagno- sis and appropriate treatment are therefore of the utmost importance. Cryptococcal cellulitis can be mistaken for a bacterial erysipelas and a delay in appropriate diagnosis can lead to high morbidity and mortality rates. As the cellulitis may be the first manifestation of a disseminated rather than a localized disease, an exhaustive examination (including a lumbar puncture) is indicated in any renal transplant recipient who presents with cellulitis. REFERENCES

I . Shrader SK. Watts JC, Dancik JA, Band JD. Disseminated cryptococcosis presenting as cellulitis

• 2. lacobellis FW, Jacobs MI, Cohen RP. Primary cutaneous cryptococcosis. Arch Dermatol 115:
• 3. Anderson DJ, Schmidt C, Goodman J, Pomeroy C. Cryptococcal disease presenting as cellulitis.

Clin Infect Dis zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

1 4 666-672, 1992.

• 4. Buschke A. Uber eine durch Coccidien hervorgerufen Krankheit des Menschen. Dtsch Med

Wochenschr 21: 14, 1895.

• 5. Rubin RH. Infection in the renal and liver transplant patient. In: Rubin RH, Young LS, eds.

Clinical approach to infection in the compromised host. New York: Plenum Publishing Corporation,

• 6. Gallis HA, Berman RA, Cate TR, Hamilton JD, Gummells, Stickel DL. Fungal infection following
• 7. Sampaio M, lanhez LE, Sabbaga E. Protective effect of cyclosporin in human renal posttransplant
• 8. Elshout van den FJJ, Huysmans FTM, Muytjens HL, Koene RAP. Cryptococcus neoformans
• 9. Mayers DL, Martone WJ, Mandell GL. Cutaneous cryptococcosis mimicking gram-positive cellulitis zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
• 10. Jennings, HS, Bradsher RW, McGee ZA, Johnson HK, Alford RH. Acute cryptococcal cellulitis in
• 11. Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine 6 2 98-109, 1983.
• 12. Carlson KC, Mehlmauer M, Evans S, Chandrasoma P. Cryptococcal cellulitis in renal transplant
• recipients. J Am Acad Dermatol 17: 469-472, 1987.
• 13. Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, Thompson SE, Sugar

AM, Tuazon C, Fisher JF, Hyslop N, Jacobson JM, Hafner R, Dismukes WE, The NIAID Mycoses Study Group, AIDS Clinical Trials Group. Comparison of amphotedcin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 326: 83-89, 1992.

• 14. Powderly WG, Saag MS, Cloud GA, Robinson P, Meyer RD, Jacobson JM, Graybill JR, Sugar

AM, McAuliffe VJ, Follansbee SE, Tuazon CU, Stern JJ, Feinberg J, Hafner R, Dismukes WE, The NIAID AIDS Clinical Trials Group, NIAID Mycoses Study Group. A controlled trial of flucona- zole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 326: 793-798, 1992.

• 15. Bozzette S, Larsen RA, Chiu J, Leal MAE, Jacobson J, Rothman P, Robinson P, Gilbert G,

McCutchan JA, Tilles J, Leedom JM, Richman DD, California Collaborative Treatment Group. Placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med 324: 580-584, 1991. with necrotizing vasculitis. J Clin Microbiol 2 4 860-862, 1986. 984-985, 1979. 557V621, 1988. renal transplantation. Arch Intern Med 135: 1163-1 172, 1975.

• cryptococcosis. Transplant Proc 24: 309 1-3092, 1992.

meningitis following renal transplantation. Neth J Med 31: 183- 190, 1987. in a renal transplant patient. South Med J 7 4 1032-1033, 1981. renal transplant recipients. South Med J 74: 1150-1 153, 1981. Submitted March 2. 1994; accepted May 1, 1994 Scand J Infect Dis Downloaded from informahealthcare.com by Radboud Universiteit Nijmegen on 12/09/12 For personal use only.

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