Primary cutaneous cryptococcosis in a lung transplant recipient.

Abstract: Cryptococcal skin lesions are found in 10 to 15% of patients with disseminated cryptococcosis. Primary skin inoculation by Cryptococcus neoformans is rare but has been reported. We report the first known case of primary cutaneous cryptococcosis in a lung transplant recipient. Our patient, a 57-year-old man, underwent left single-lung transplantation and presented with a nonhealing ulcer 50 months later. Skin histopathology and culture confirmed C neoformans. Serum and cerebrospinal fluid cryptococcal antigen tests were negative. The lesion healed after treatment with fluconazole. To date, disseminated disease is not evident. Primary cutaneous cryptococcosis has been reported in kidney and liver recipients but not in lung transplantation recipients. Nonhealing ulcers in immunocompromised patients mandate aggressive diagnostic procedures. Differential diagnosis of these cutaneous lesions should consider fungi, including C neoformans.

Key Words: amphotericin B, Cryptococcus neoformans, fluconazole, primary cutaneous cryptococcosis, voriconazole

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Cryptococcus neoformans is the only encapsulated fungus that infects humans. The usual mode of infection is by inhalation of infective forms resulting in pulmonary and/or central nervous system cryptococcal infections. Recently, the incidence of cryptococcal infections has been increasing with the advent of human immunodeficiency virus (HIV) and transplantation. The skin is a common site of involvement and, if present, invariably represents disseminated cryptococcosis. Interestingly, a cutaneous lesion, most frequently found in the head and neck regions, might be the initial presenting sign in approximately 10% of patients with disseminated disease. (1-3) However, these lesions may mimic other skin problems, such as bacterial cellulitis, (4-6) skin cancer, (7) molluscum contagiosum, and Kaposi sarcoma, (8) especially in immunocompromised patients. A survey of 17 centers found that organ recipients represented 12% of the non-HIV-infected patients with cryptococcal infections. (9) In transplant populations, cutaneous lesions may actually be more prevalent than in immunocompetent patients. They were the most common presentation in four of six liver recipients with disseminated cryptococcosis. (4) Some physicians believe that the identification of C neoformans in the skin is a secondary sign or a "sentinel" of disseminated disease. (10) Although rare, there are reports of primary cutaneous cryptococcosis (PCC) in both immunocompetent patients and immunocompromised patients such as transplant recipients. (1,5,11-31) We performed a MEDLINE search from 1966 to the present and found no cases of PCC in lung transplant recipients, and describe here the first case of PCC in a lung recipient.

Case Report

A 57-year-old man underwent left single-lung transplantation in June 1995 for emphysema. He received induction immunosuppression with antithymocyte globulin and maintenance immunosuppression with cyclosporine A (CsA), azathioprine, and prednisone. His post-lung transplantation course was complicated by cytomegalovirus infection (treated with ganciclovir), Mycobacterium avium complex necrotizing pneumonia of the native lung (treated with 18 months of ciprofloxacin, clarithromycin, and ethambutol), diabetes mellitus (requiring insulin), and renal insufficiency. Forty-seven months postoperatively, he developed exertional dyspnea with a greater than 20% reduction in the forced expiratory volume in 1 second from his baseline. A bronchoalveolar lavage and transbronchial biopsy showed no signs of infection or acute rejection. He met criteria for the clinical diagnosis of bronchiolitis obliterans syndrome and was treated with antithymocyte globulin for 7 days. His pulmonary mechanics stabilized.

Two months later, a painless nodule developed on his left thigh, which drained spontaneously, became ulcerated, and never healed. There were no fevers, chills, sweats, or weight loss. He denied any cough. His medications included CsA, azathioprine, prednisone, ciprofloxacin, clarithromycin, trimethoprim-sulfamethoxazole, oral ganciclovir, insulin, and terazosin for chronic benign prostatic hypertrophy. He was employed at a lawn care service. There were no known contacts with pigeons or exotic birds and there was no known trauma to the left thigh area.

On physical examination, he was a healthy appearing man. He was afebrile, with normal vital signs. On his left thigh was a 1.5-cm, erythematous, clean-based, punched-out appearing ulcer (Fig. 1A). There were no other cutaneous lesions or lymphadenopathy.

Abnormal laboratory studies included a glucose level of 191 mg/dL (normal, 70-110 mg/dL), a creatinine level of 2.3 mg/dL (normal, 0.5-1.4 mg/dL), and a hemoglobin of 10.3 g/dL (normal, 14-18 g/dL). The white blood cell count was normal. A chest radiograph showed a residual ill-defined opacity in the right upper lobe, which was unchanged from previous studies. A surface culture of the thigh ulcer resulted in a heavy growth of C neoformans. A skin biopsy specimen showed a moderate neutrophilic and chronic inflammatory infiltrate amid granulation tissue, and there were forms that had a central nucleus surrounded by a zone of clearing consistent with a nonstaining cryptococcal capsule. A Gomori methenamine silver stain showed many cryptococcal organisms (Fig. 2). Although the patient was asymptomatic, a lumbar puncture was performed to rule out central nervous system infection. The cerebrospinal fluid (CSF) glucose level was mildly elevated, but all other CSF parameters were normal. Cryptococcal antigen tests of the CSF and serum were negative. The patient was treated with oral fluconazole 200 mg/d for 2 months. The skin lesion resolved with therapy (Fig. 1B).

Discussion

C neoformans is a polysaccharide-encapsulated yeast-like fungus. It reproduces by narrow-based budding. It is ubiquitous and saprophytic in nature. It is frequently found in pigeon or bird droppings and in soil. C neoformans can grow at 37[degrees]C and is the species responsible for causing disease in humans. The typical portal of entry of Cryptococcus is through inhalation of infective particles into the respiratory system. (3) The skin may be another portal of entry, by direct inoculation; however, reports are rare and controversial. (1,5,11-31) Evidence for primary inoculation has been supported in many animal models. Dissemination from the skin entry can occur, especially if a high inoculum is injected or concomitant steroids are administered. (32) Glaser and Garden (11) published a report of a healthy medical student who developed a local cryptococcal infection without developing HIV infection after an inadvertent needle-stick contaminated with blood of a patient with acquired immunodeficiency syndrome and disseminated cryptococcal disease. This case proves that primary skin infection in humans occurs.

[FIGURE 1 OMITTED]

Noble and Fajardo (13) have suggested criteria for PCC. The criteria include a lesion confined to the skin and subcutis, a positive culture for Cryptococcus, a biopsy specimen with organisms consistent with Cryptococcus, and no clinical evidence of systemic disease for at least 4 weeks. To secure a diagnosis of PCC, infection at other possible sites must be ruled out. These include pulmonary, central nervous system, urinary, and disseminated disease. A positive cryptococcal antigen test implies dissemination. Several types of lesions have been reported in PCC, including nodules, (18) vesicles, (12) ulcers, plaques, (31) and cellulitis. (6) These infections may appear identical to bacterial infections, with warmth, erythema, and induration, and must be differentiated on the basis of biopsy or culture. (6)

[FIGURE 2 OMITTED]

PCC has also been reported in transplant recipients. Iacobellis et al (12) reported the first case in a renal transplant patient in 1979. The patient was packing fruit and developed a vesicle on his right arm. Both biopsy and culture were positive for Cryptococcus. The serum cryptococcal antigen and CSF cryptococcal antigen were negative. The patient was treated with amphotericin B (570 mg total) with resolution. (12)

An interesting aspect of Cryptococcus in transplant patients is the possible antifungal properties of CsA. CsA was first recognized for its antimicrobial activity in vitro, but when tested in vivo, it was too immunosuppressive to be clinically useful. Although in vitro data support CsA's anti-cryptococcal activity, studies in animal models are conflicting. (33) It is unclear whether this made a difference in our patient.

Because so few patients have been diagnosed with PCC, no clinical data are available regarding treatment. We feel that the therapeutic approach to PCC should be based on the immune status of the patient. In the immunocompetent patient, resection, (26,30) topical antifungal therapy, (24,30) and systemic antifungal therapy (1,18,31) have each been reported to be effective. In the immunocompromised patient, systemic dissemination is a concern. Noble and Fajardo (13) have reported one patient with lymphoma who was treated with topical amphotericin B 3% ointment without benefit and then underwent resection of the PCC lesion. Several months later, the serum cryptococcal antigen became positive and the patient required systemic therapy. He died as a result of metastatic cancer with no evidence of disseminated cryptococcosis at autopsy. This case highlights the possibility of dissemination despite apparent local control. Therefore, we advocate systemic therapy for PCC in the transplant population. The systemic therapies available include amphotericin B, lipid formulations of amphotericin B, fluconazole, and itraconazole. (34) New therapeutic options may soon be available. In vitro testing of voriconazole with cryptococcal isolates demonstrates that it has better activity than either itraconazole or fluconazole. (35-36) Caspofungin has been released recently in the United States but should not be used as a single agent for the treatment of Cryptococcus. In vitro data suggest caspofungin is relatively ineffective against C neoformans. (37-39)

When a skin lesion is caused by Cryptococcus, disseminated disease and/or a primary site of infection should be excluded. Excisional biopsy should be considered in those patients who are severely immunocompromised or not responding to therapy. The optimal length of therapy is unknown, but we suggest 6 to 8 weeks of systemic therapy, with close clinical follow-up.

Conclusion

We report the first known case of PCC in a lung transplant recipient. His occupation as a professional gardener placed him at risk for skin inoculation leading to PCC. He was treated with oral fluconazole for 2 months and was cured. There is no clinical or laboratory evidence of dissemination after 16 months of follow-up. PCC is a rare and controversial entity within the spectrum of cryptococcal disease. Optimal treatment is unclear. However, in a transplant or immunocompromised patient, systemic therapy may be warranted to prevent dissemination. These patients require close follow-up. Most importantly, any nonhealing skin lesion in a transplant patient mandates biopsy and culture for proper diagnosis so that the appropriate therapy may be administered expeditiously.

Those who think they know it all are very annoying to those of us who
do.
--Robert K. Mueller

Accepted April 21, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9707-0692

References

1. Antony SA, Antony SJ. Primary cutaneous Cryptococcus in nonimmunocompromised patients. Cutis 1995;56:96-98.

2. Cawley EP, Grekin RH, Cutis AC. Torulosis: A review of the cutaneous and adjoining mucous membrane manifestations. J Invest Dermatol 1950;14:327-344.

3. Diamond RD. Cryptococcus neoformans, in Mandell GL, Bennett JE, Dolin R (eds): Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 1995, ed 4, pp 2331-2340.

4. Singh N, Gayowski T, Wagener MM, et al. Clinical spectrum of invasive cryptococcosis in liver transplant recipients receiving tacrolimus. Clin Transplant 1997;11:66-70.

5. Mayers DL, Martone WJ, Mandell GL. Cutaneous cryptococcosis mimicking Gram-positive cellulitis in a renal transplant patient. South Med J 1981;74:1032-1033.

6. Anderson DJ, Schmidt C, Goodman J, et al. Cryptococcal disease presenting as cellulitis. Clin Infect Dis 1992;14:666-672.

7. Lui H, McLeod WA, Wood WS. An ulcerated plaque in a gay man: Cutaneous cryptococcosis. Arch Dermatol 1993;129:499, 501-502.

8. Pema K, Diaz J, Guerra LG, et al. Disseminated cutaneous cryptococcosis: Comparison of clinical manifestations in the pre-AIDS and AIDS eras. Arch Intern Med 1994;154:1032-1034.

9. Pappas P, Perfect J, Henderson H, et al. Cryptococcosis in non-HIV infected patients: A multicenter survey. Infectious Diseases Society of America, 35th annual meeting, San Francisco, CA, 1997 (Abstract 128).

10. Sarosi GA, Silberfarb PM, Tosh FE. Cutaneous cryptococcosis: A sentinel of disseminated disease. Arch Dermatol 1971;104:1-3.

11. Glaser JB, Garden A. Inoculation of cryptococcosis without transmission of the acquired immunodeficiency syndrome. N Engl J Med 1985;313:266 (letter).

12. Iacobellis FW, Jacobs MI, Cohen RP. Primary cutaneous cryptococcosis. Arch Dermatol 1979;115:984-985.

13. Noble RC, Fajardo LF. Primary cutaneous cryptococcosis: Review and morphologic study. Am J Clin Pathol 1972;57:13-22.

14. Vogelaers D, Petrovic M, Deroo M, et al. A case of primary cutaneous cryptococcosis. Eur J Clin Microbiol Infect Dis 1997;16:150-152.

15. Bohne T, Sander A, Pfister-Wartha A, et al. Primary cutaneous cryptococcosis following trauma of the right forearm. Mycoses 1996;39:457-459.

16. Goonetilleke AK, Krause K, Slater DN, et al. Primary cutaneous cryptococcosis in an immunocompromised pigeon keeper. Br J Dermatol 1995;133:650-652.

17. Naka W, Masuda M, Konohana A, et al. Primary cutaneous cryptococcosis and Cryptococcus neoformans serotype D. Clin Exp Dermatol 1995;20:221-225.

18. Ng WF, Loo KT. Cutaneous cryptococcosis: Primary versus secondary disease--Report of two cases with review of literature. Am J Dermatopathol 1993;15:372-377. [Erratum: Am J Dermatopathol 1994 Apr; 16(2):227.]

19. Cusini M, Cagliani P, Grimalt R, et al. Primary cutaneous cryptococcosis in a patient with the acquired immunodeficiency syndrome. Arch Dermatol 1991;127:1848-1849 (letter).

20. Salm R, Groth D, Kappe R, et al. Primary cutaneous cryptococcosis after microtrauma of the right index finger. Mycoses 1988(Suppl 1):88-92.

21. Butler WP, Kaufer GI. Primary cutaneous cryptococcosis successfully treated with outpatient amphotericin B and 5-fluorocytosine. NITA 1985;8:295-297.

22. Baes H, Van Cutsem J. Primary cutaneous cryptococcosis. Dermatologica 1985;171:357-361.

23. Sussman EJ, McMahon F, Wright D, et al. Cutaneous cryptococcosis without evidence of systemic involvement. J Am Acad Dermatol 1984;11:371-374.

24. Bee OB, Tan T, Pang R. A case of primary cutaneous cryptococcosis successfully treated with miconazole. Arch Dermatol 1981;117:290-291.

25. Rao TV, Rao KS, Satyanarayana CV. Primary cutaneous cryptococcal granuloma in a child. J Pediatr Surg 1976;11:267-268.

26. Abdel-Fattah A, Zeid MS, Ghaly AF. Primary cutaneous cryptococcosis in Egypt. Int J Dermatol 1975;14:606-609.

27. Handa S, Nagaraja, Chakraborty A, et al. Primary cutaneous cryptococcosis in an immune competent patient. J Eur Acad Dermatol Venereol 1998;10:167-169.

28. Micalizzi C, Persi A, Parodi A. Primary cutaneous cryptococcosis in an immunocompetent pigeon keeper. Clin Exp Dermatol 1997;22:195-197.

29. Bellosta M, Gaviglio MR, Mosconi M, et al. Primary cutaneous cryptococcosis in an HIV-negative patient. Eur J Dermatol 1999;9:224-226.

30. Hurwich BJ, Domonkos AN. Primary cutaneous cryptococcosis: Seroimmunologic and fluorescent antibody studies. N Y State J Med 1970;70:1075-1079.

31. Burlage AM, Fuller P, Mikolich DJ, et al. Cutaneous cryptococcus in a nonimmunocompromised host. Infect Dis Clin Pract 1997;6:410-412.

32. Sethi KK, Salfelder K, Schwarz J. Experimental cutaneous primary infection with Cryptococcus neoformans (Sanfelice) Vuillemin. Mycopathol Mycol Appl 1965;27:357-368.

33. High KP. The antimicrobial activities of cyclosporine, FK506, and rapamycin. Transplantation 1994;57:1689-1700.

34. Saag MS, Graybill RJ, Larsen RA, et al; Infectious Diseases Society of America. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710-718.

35. Pfaller MA, Zhang J, Messer SA, et al. In vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of Cryptococcus neoformans from the United States and Africa. Antimicrob Agents Chemother 1999;43:169-171.

36. Espinel-Ingroff A. In vitro activity of the new triazole voriconazole (UK-109,496) against opportunistic filamentous and dimorphic fungi and common and emerging yeast pathogens. J Clin Microbiol 1998;36:198-202.

37. Abruzzo GK, Flattery AM, Gill CJ, et al. Evaluation of the echinocandin antifungal MK-0991 (L-743,872): Efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis. Antimicrob Agents Chemother 1997;41:2333-2338.

38. Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998;36:2950-2956.

39. Feldmesser M, Kress Y, Mednick A, et al. The effect of the echinocandin analogue caspofungin on cell wall glucan synthesis by Cryptococcus neoformans. J Infect Dis 2000;182:1791-1795.

RELATED ARTICLE: Key Points

* Although rare, primary skin inoculation can result in primary cutaneous cryptococcosis.

* Nonhealing skin lesions in immunosuppressed patients warrant an aggressive diagnostic workup to ensure appropriate treatment.

Katherine L. Baumgarten, MD, Vincent G. Valentine, MD, FCCP, and Julia B. Garcia-Diaz, MD, MS

From the Departments of Infectious Disease and Transplant Surgery, Ochsner Clinic Foundation, New Orleans, LA.

There is no financial disclosure or proprietary interest to declare for this manuscript.

Address correspondence to Katherine L. Baumgarten, MD, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121. Email: [e-mail]