© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Clin Transplant 2014: 28: 1069–1074 DOI: 10.1111/ctr.12409

Clinical Transplantation

Review Article

Cutaneous histoplasmosis in renal transplant recipients Sun NZ, Augustine JJ, Gerstenblith MR. Cutaneous histoplasmosis in renal transplant recipients.

N. Z. Suna, J. J. Augustineb and M. R. Gerstenblitha a

Abstract: Cutaneous histoplasmosis is a rare entity, although it can be seen in a substantial portion of renal transplant recipients with disseminated disease. The prognosis of disseminated disease is worse than isolated cutaneous involvement, and significant delays in diagnosis are reported. We reviewed reports of cutaneous histoplasmosis with and without dissemination in the setting of renal transplantation to examine incidence, timing of diagnosis, clinical features, and prognosis. Remarkable morphologic variability and the non-specific appearance of skin findings suggest that tissue culture is required for definitive diagnosis. Cutaneous lesions represent an easily accessible source for early diagnosis.

Department of Dermatology, University Hospitals Case Medical Center and b Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA Key words: cutaneous histoplasmosis – disseminated histoplasmosis – Histoplasma capsulatum – renal transplantation Corresponding author: Natalie Z. Sun, MD, Department of Dermatology, University Hospitals Case Medical Center, 11100 Euclid Ave Lakeside 3500, Cleveland, OH 44106, USA. Tel.: +1 216 844 8200; fax: +1 216 844 8993; e-mail: [email protected] Conflict of interest: None. Accepted for publication 21 June 2014

Histoplasma capsulatum is a fungal organism largely endemic to the Ohio and Mississippi River Valleys, parts of Central and South America and Africa, and in most immunocompetent hosts causes an asymptomatic infection of the lungs. The presentation and incidence of cutaneous histoplasmosis largely depend on the host’s state of immunosuppression. In the modern era, cutaneous lesions are rarely seen in immunocompetent hosts. In an early review of cutaneous histoplasmosis by Miller et al. in 1947 (1), prior to the development of renal transplantation, cutaneous disease was seen in nearly half of all reported cases of Histoplasma infection. With the institution of systemic antifungals like amphotericin B, cutaneous disease is generally seen only in the setting of dissemination; in renal transplant patients, estimates of the prevalence of cutaneous lesions in dissemi-

nated disease remained high at nearly 47% according to Farr et al. in 1981 (2). In 1976, Studdard et al. (3) reported an incidence of cutaneous lesions of 6% in two case series of immunosuppressed individuals including renal transplant patients as well as those with hypogammaglobulinemia, leukemia, and lymphoma. Cutaneous lesions in disseminated histoplasmosis are non-specific, and diagnosis cannot be made based on clinical appearance alone. Unequivocal diagnosis requires biopsy and tissue culture to demonstrate the organism. We review the literature for cases of cutaneous involvement with or without dissemination. Methods

We conducted a literature review using the PubMed database using the search terms “cutaneous

1069

Sun et al.

histoplasmosis,” “disseminated histoplasmosis,” and “renal transplantation” for English language articles. Relevant English language articles were included. We reviewed the titles and abstracts identified in the literature search. We also reviewed references from bibliographies of pertinent articles. Results

Our literature review yielded 22 cases of cutaneous histoplasmosis in renal transplant patients, including a patient seen on our inpatient consult service (2–21). The median age in this series was 38 yr, and the majority of cases were reported in males (68%). Regarding the timing of presentation, eight (36%) presented within one yr of transplantation. In two patients, direct transmission of histoplasmosis through cadaveric renal transplantation was implicated, and these patients presented in the early post-transplantation period at around two months (4, 9). The other patients presented out of this one-yr window, with a wide range including up to 29 yr after transplant (Table 1, patient 14). At the time of diagnosis, 16 (73%) received amphotericin B; 13 (59%) also received an azole. Seventeen of these 22 cutaneous histoplasmosis cases, including our patient, occurred in the setting of confirmed disseminated disease (2–18). Table 1 displays the demographic data, time from transplantation to clinical presentation, maintenance immunosuppressants, characteristics of cutaneous findings, other organs with confirmed involvement, treatment medications, and final outcome of these 17 cases. Cutaneous findings varied from cellulitic plaques to panniculitic subcutaneous nodules, mucocutaneous ulcers, papules, and purpura. A representative clinical photograph from our patient is shown (Fig. 1), and the results of Grocott’s methenamine silver stain demonstrated intracellular yeast forms (Fig. 2). In our review, the most commonly reported extracutaneous organs of involvement were lung (65%), kidney (29%), bone marrow (29%), liver (18%), gastrointestinal tract (18%), and spleen (12%). There were only five cases of isolated cutaneous disease after a work-up excluded dissemination (19–22), and these are reported in Table 2. In these patients, both subcutaneous nodules and mucocutaneous ulcerations were reported. The prognosis differed between those with isolated cutaneous disease compared to those with disseminated infection, with 100% survival in individuals with isolated cutaneous disease as compared to 71% in those with disseminated disease.

1070

Discussion

In our review, we found cutaneous involvement in disseminated histoplasmosis in 17 of 69 cases (25%) in the setting of renal transplantation. This is much higher than the previously reported incidence from cases of patients immunosuppressed due to different etiologies, such as steroid therapy, hypogammaglobulinemia, and chronic lymphocytic leukemia. Renal transplantation thus appears to predispose patients to cutaneous involvement in the setting of dissemination, perhaps reflecting a unique pathophysiology of renal transplantation or the pharmaceutical agents used in this setting. Isolated primary cutaneous disease in renal transplant recipients was only reported in five cases in the English literature, reflecting the rarity of this entity. The 22 cases of cutaneous histoplasmosis reported here with and without disseminated disease presented with heterogeneous morphologies. Therefore, the cutaneous appearance does not appear to predict the occurrence of dissemination. Interestingly, lesions simulating erythema nodosum and erythema multiforme have been described in immunocompetent hosts as a reflection of a reactive phenomenon to the presence of Histoplasma infection; it is not clear whether these may also be seen in patients with depressed immunity. Although generally non-specific and often not subtle, skin lesions can be asymptomatic, without associated pruritus, pain, or other symptoms. In the setting of disseminated disease, when cutaneous lesions are present, they offer a readily accessible source for biopsy for tissue culture diagnosis. Alternatively, tissue can also be submitted for fungal stains such as GMS to demonstrate intracellular organisms. The prognosis of disseminated histoplasmosis is often impacted by the time until diagnosis or treatment, which can be delayed due to constitutional symptoms including weight loss and fever and non-specific symptoms involving multiple organs, including the reticuloendothelial (pancytopenia, enlarged lymph nodes, and hepatosplenomegaly), pulmonary, endocrine (adrenal disease), gastrointestinal (enteritis, intestinal perforation), genitourinary, and musculoskeletal systems (arthralgias). Rarely, cases of meningitis and encephalitis have been reported. A recent multicenter review in solid organ transplant recipients from the Midwest identified a median time from symptom onset until diagnosis of histoplasmosis of 30 d; the majority of these cases had disseminated disease (23). Serum and urine antigen testing are used for diagnosis. The patient from our inpatient

Cutaneous histoplasmosis in renal transplantation Table 1. Cutaneous histoplasmosis in the setting of known disseminated infection in renal transplant patients

Case Sex/Age

Time from transplantation to presentation

Immunosuppressants

Cutaneous findings

Prednisone, Azathioprine Prednisone, Azathioprine

Diffuse purpuraa

Cellulitis in the right thigh and left arm with ulceration Erythematous indurated plaques on arms and legs Cellulitis of the right leg and foot

1 M/39

11 d

2 M/11

6 months

3 M/32

3 yr

Prednisone, Azathioprine

4 M/52

6 months

Prednisone, Azathioprine

5 F/21

10 yr

Prednisone, Azathioprine

6 M/49

6 yr

7 F/30

2 months

Prednisone, Azathioprine Prednisone, Azathioprine

8 M/45

3 yr

Prednisone, Azathioprine

9 F/29

8 yr

Prednisone, Azathioprine, Tacrolimus

Cellulitis of the left thigh

10 M/22

10 months

11 M/23

2, 6 yrb

Prednisone, MMF, Tacrolimus Prednisone, Azathioprine

12 M/60

8 yr

Subcutaneous nodules of the left thigh Subcutaneous nodules of the right forearm and leg Cheek nodule

13 F/22

5 yr

14 M/81

29 yr

15 M/47

2 months

16 F/42

9 yr

17 M/54

3 yr

Prednisone, MMF, Tacrolimus Prednisone, MMF, Sirolimus Prednisone, Azathioprine Prednisone, MMF, Tacrolimus Prednisone, MMF, Cyclosporine

Prednisone, MMF, Tacrolimus

Erythematous indurated plaques of the chest

Tongue ulcer Subcutaneous nodules of right thigh and chest Tongue ulcer

Other involved organs

Treatments

Outcomes

References

Blood, liver, spleen Liver, GI, kidney, gall bladder, pericardium, lung, bone marrow Lung



Death

(4)

Amphotericin B

Death

(5)

Amphotericin B

Survived

(6)

Blood, lung

Amphotericin B

Death

(7)

Blood, lung, ascites, joint fluid Lung, kidney

Amphotericin B

Death

(2)

Amphotericin B, Itraconazole Amphotericin B, Ketoconazole

Survived

(8)

Survived

(9)



Death

(10)

Fluconazole, Liposomal Amphotericin B, Itraconazole Amphotericin B, Itraconazole

Survived

(11)

Survived

(12)

Kidney

Amphotericin B, Ketoconazole

Survived

(14)

Lung, epiglottiis

Liposomal amphotericin B, Itraconazole Liposomal amphotericin B, Itraconazole Itraconazole

Survived

(13)

Survived

(15)

Survived

(16)

Amphotericin B, Voriconazole

Survived

(17)

Lung

Voriconazole, Itraconazole

Survived

(18)

Lung, GI

Itraconazole

Survived

Reported here

Kidney

Bone marrow, lung, liver, spleen Kidney, GI

Bone marrow

Lip and nares ulcers

Bone marrow, blood

Ecchymosis of right palm Crusted papules of the lip and nasal ala Subcutaneous nodules of the thighs and right forearm Erythematous indurated papule of the angle of the mouth

Lung, joint fluid Lung, bone marrow

M, male; F, female; GI, gastrointestinal; MMF, mycophenolate mofetil. a Unclear whether purpura was related to drug toxicity, marrow replacement, unmasking of latent immunothrombocytopenic purpura, hypersplenism, etc. b Patient presented twice for symptoms related to H. capsulatum: initial presentation for subcutaneous nodules; subsequently with positive urine cultures for H. capsulatum.

1071

Sun et al.

Fig. 2. Grocott’s methenamine silver stain of papule showing intracellular yeast forms of Histoplasma capsulatum (40X magnification).

Fig. 1. Ulcerated pink papule involving the left oral commissure prior to biopsy.

consultation service presented with a negative urinary antigen and positive serum antigen. A multicenter study of diagnostic tests found antigenuria in 91.8% of 158 patients with disseminated disease and antigenemia in 100% of 31 patients with disseminated disease. Positive antigenuria was correlated with severity of disease, including whether the patient was hospitalized, or required

intensive care, and the degree of immunosuppression, with higher rates seen in AIDS, in cases where blood cultures were positive, and in ICU patients; the authors concluded that serum and urine antigen testing were likely to be of similar high sensitivity in disseminated disease (24). Of note, once a urine antigen is positive, it may remain persistently positive, despite adequate treatment and no signs of clinical relapse. Treatment in the majority of reviewed cases of disseminated disease included amphotericin B, with a substantial subset of patients receiving an

Table 2. Cutaneous histoplasmosis without evidence of dissemination in renal transplant patients

Case Sex/Age

Time from transplantation to presentation

1 M/45

11 months

2 F/27

6 months

3 M/31

10 yr

4 M/37

14 yr

5 F/49

18 yr

Immunosuppressants

Cutaneous findings

Methyl prednisolone, Azathioprine Methyl prednisolone, Azathioprine

Subcutaneous nodule of left axilla Subcutaneous nodules of abdomen, arms and legs Diffuse swelling with ulceration of fingers Ulceration of the gingiva, hard and soft palate and oropharynx Cellulitic plaque of the left arm

Prednisone, Azathioprine Prednisone, Azathioprine Prednisone, MMF

Other known-to-be involved organs

Treatments

Outcomes

References

1

Amphotericin B

Survived

(20)

2

Amphotericin B

Survived

(20)

3

Amphotericin B

Survived

(21)



Amphotericin B, Itraconazole

Survived

(19)

4

Itraconazole

Survived

(22)

M, male; F, female; MMF, mycophenolate mofetil. 1. Work-up to rule out dissemination included a negative chest X-ray, no clinical hepatosplenomegaly, normal liver enzymes, normal bone marrow aspirate, negative liver biopsy, and culture for Histoplasma spp. 2. Work-up to rule out dissemination included a negative chest X-ray, normal liver enzymes, negative blood, and urine cultures, normal lumbar puncture. Liver-spleen scan showed hepatosplenomegaly with homogeneous uptake of isotope. 3. Bilateral swelling of hands with ulcerations on multiple digits. Work-up to rule out dissemination included negative chest X-ray, normal liver enzymes, and renal function; repeat presentation nine months later with wrist swelling and joint biopsy was negative for fungal organisms; a bone marrow biopsy at that time showed a single granuloma without fungus. 4. Work-up to rule out dissemination included a negative chest X-ray, thoracic computed tomography scan, and unspecified blood laboratory work, which were normal or negative.

1072

Cutaneous histoplasmosis in renal transplantation additional triazole such as itraconazole or voriconazole. The Infectious Diseases Society of America recommends treatment of moderately severe to severe progressive disseminated histoplasmosis with liposomal amphotericin B for 1–2 wk followed by oral itraconazole for at least 12 months; lifelong suppressive therapy may be required for patients who remain persistently immunocompromised (25). As described above, there are cases of relapse noted in the literature, albeit in a minority of patients. In our report, case 11 initially presented with subcutaneous nodules two yr after transplantation, was treated with amphotericin B and discharged on oral ketoconazole then readmitted four yr later with chronic organ rejection (14). He was treated with increasing doses of immunosuppressants, and H. capsulatum was subsequently recovered from a urine culture. The duration of ketoconazole treatment was unclear. In summary, cutaneous findings can be seen in renal transplant patients with and without disseminated histoplasmosis, although the lesions themselves are often asymptomatic and non-specific. Cutaneous histoplasmosis is remarkably heterogeneous, and a high index of clinical suspicion should be maintained. Early diagnosis can be achieved through dermatologic consultation with skin biopsy of lesions for tissue culture and special fungal stains. Treatment typically results in positive outcomes for isolated cutaneous disease. In cases of cutaneous disease in the setting of dissemination, outcomes have been increasingly favorable in the last two decades with the advent and use of triazoles. Acknowledgements The authors wish to thank Ji Buethe, MD, for assistance with obtaining the images presented in this manuscript.

Authors’ contributions

N.Z. Sun drafted, critical revised, and approved the article; J.J. Augustine was involved in critical revision and approval of the article; M.R. Gerstenblith was involved in concept/design, critical revision, and approval of the article. References 1. MILLER HE, KEDDIE FM, JOHNSTONE HG et al. Histoplasmosis; cutaneous and mucomembranous lesions, mycologic and pathologic observations. Arch Derm Syphilol 1947: 56: 715. 2. FARR B, BEACHAM BE, ATUK NO. Cutaneous histoplasmosis after renal transplantation. South Med J 1981: 74: 635.

3. STUDDARD J, SNEED WF, TAYLOR MR Jr et al. Cutaneous histoplasmosis. Am Rev Respir Dis 1976: 113: 689. 4. HOOD AB, INGLIS FG, LOWENSTEIN L, DOSSETOR JB, MACLEAN LD. Histoplasmosis and thrombocytopenic purpura: transmission by renal homotransplantation. Can Med Assoc J 1965: 93: 587. 5. PARK RK, GOLTZ RW, CAREY TB. Unusual cutaneous infections associated with immunosuppressive therapy. Arch Dermatol 1967: 95: 345. 6. OLIVERO JJ, LOZANO-MENDEZ J, GHAFARY EM et al. Mitigation of amphotericin B nephrotoxicity by mannitol. Br Med J 1975: 1: 550. 7. DAMAN LA, HASHIMOTO K, KAPLAN RJ et al. Disseminated histoplasmosis in an immunosuppressed patient. South Med J 1977: 70: 355. 8. SRIDHAR NR, TCHERVENKOV JI, WEISS MA et al. Disseminated histoplasmosis in a renal transplant patient: a cause of renal failure several years following transplantation. Am J Kidney Dis 1991: 17: 719. 9. WONG SY, ALLEN DM. Transmission of disseminated histoplasmosis via cadaveric renal transplantation: case report. Clin Infect Dis 1992: 14: 232. 10. SMAK GREGOOR PJ, VAN SAASE JL, VD INGH HF et al. Disseminated histoplasmosis in a haemodialysis patient on immunosuppression after graft failure. Nephrol Dial Transplant 1996: 11: 542. 11. MCGUINN ML, LAWRENCE ME, PROIA L et al. Progressive disseminated histoplasmosis presenting as cellulitis in a renal transplant recipient. Transplant Proc 2005: 37: 4313. 12. BHOWMIK D, DINDA AK, XESS I et al. Fungal panniculitis in renal transplant recipients. Transpl Infect Dis 2008: 10: 286. 13. RAPPO U, BEITLER JR, FAULHABER JR et al. Expanding the horizons of histoplasmosis: disseminated histoplasmosis in a renal transplant patient after a trip to Bangladesh. Transpl Infect Dis 2010: 12: 155. 14. PASQUALOTTO AC, OLIVEIRA FM, SEVERO LC. Histoplasma capsulatum recovery from the urine and a short review of genitourinary histoplasmosis. Mycopathologia 2009: 167: 315. 15. LO MM, MO JQ, DIXON BP et al. Disseminated histoplasmosis associated with hemophagocytic lymphohistiocytosis in kidney transplant recipients. Am J Transplant 2010: 10: 687. 16. MAKOL A, WIELAND CN, YTTERBERG SR. Articular involvement in disseminated histoplasmosis in a kidney transplant patient taking azathioprine. J Rheumatol 2011: 38: 2692. 17. JOHNSTON RB Jr, THAREJA S, SHENEFELT PD. Disseminated histoplasmosis in a renal transplant patient. Cutis 2013: 91: 295. 18. ROSADO-ODOM VM, DAOUD J, JOHNSON R et al. Cutaneous presentation of progressive disseminated histoplasmosis nine years after renal transplantation. Transpl Infect Dis 2013: 15: E64. 19. MOTTA AC, GALO R, LOURENCß O AG et al. Unusual orofacial manifestations of histoplasmosis in renal transplanted patient. Mycopathologia 2006: 161: 161. 20. KING RW Jr, KRAIKITPANITCH S, LINDEMAN RD. Subcutaneous nodules caused by Histoplasma capsulatum. Ann Intern Med 1977: 86: 586. 21. PETERSON PK, DAHL MV, HOWARD RJ et al. Mucormycosis and cutaneous histoplasmosis in a renal transplant recipient. Arch Dermatol 1982: 118: 275. 22. MARQUES SA, HOZUMI S, CAMARGO RM, CARVALHO MF, MARQUES ME. Histoplasmosis presenting as cellulitis

1073

Sun et al. 18 years after renal transplantation. Med Mycol 2008: 46: 725. 23. GRIM SA, PROIA L, MILLER R et al. A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation. Transpl Infect Dis 2012: 14: 17. 24. HAGE CA, RIBES JA, WENGENACK NL et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis 2011: 53: 448.

1074

25. WHEAT LJ, FREIFELD AG, KLEIMAN MB et al.; INFECTIOUS DISEASES SOCIETY OF AMERICA. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007: 45: 807.

Cutaneous histoplasmosis in renal transplant recipients.

Cutaneous histoplasmosis is a rare entity, although it can be seen in a substantial portion of renal transplant recipients with disseminated disease. ...
308KB Sizes 0 Downloads 4 Views