Mycopathologia DOI 10.1007/s11046-015-9880-7
Systemic Review of Published Reports on Primary Cutaneous Cryptococcosis in Immunocompetent Patients Lin Du • Yali Yang • Julin Gu • Jianghan Chen Wanqing Liao • Yuanjie Zhu
•
Received: 14 March 2014 / Accepted: 25 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Primary cutaneous cryptococcosis (PCC) has been confirmed as a distinct clinical entity with secondary cutaneous cryptococcosis from systematic infection since 2003. Although it has been confirmed as a distinct clinical entity, little has progressed on PCC in immunocompetent hosts compared to their immunocompromised counterpart. We reviewed the literature on cases of PCC in immunocompetent patients from 2004 to 2014, and 21 cases from 16 reports were identified. Males are more likely to develop PCC infections, with a ratio of 17:4 male to female. These patients were found to be almost all senior population except for patients from Asia. Asymptomatic or moderate itching manifesting in a painful nodule is the most common presentation, although there is no typical clinical manifestation recorded. Upper limbs are the most common site of infection, accounting for 71.4 % of all patients. Of the 12 identified isolates, 6 strains are identified as C. neoformans, 5 as C. gattii, and 1 as C.laurentii. Fluconazole was used in 10 cases; however, only 80 % of the 10 cases could confirm that fluconazole was effective in clearing the infections. Interestingly although not approved as a treatment option,
L. Du Y. Yang J. Gu J. Chen W. Liao Y. Zhu (&) Department of Dermatology and Mycology Center, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China e-mail: [email protected]
Itraconazole was effective in the seven cases it was used to treat cryptococcosis, with a dosage range of 100–400 mg/d and duration from 3 to 6 months. Even though the prognosis of these patients was generally good, more data are need to determine which antifungal azole is the better treatment option and whether primary skin infections could disseminate to systematic infection. Keywords Cryptococcosis Immunocompetent Skin infection
Introduction More than 100 years after it was first identified by Sanfelice [1], the fungi from the genus Cryptococcus continue to cause significant morbidity and mortality worldwide, not only in immunocompromised patients, but also in immunocompetent patients [2]. Cryptococcosis is an opportunistic infection by the fungi of the genus Cryptococcus that can lead to fatal meningitis if left untreated. Although the central nervous system (CNS) is the most common site of cryptococcal infections detected, other sites, such as lung and skin infections, are not rare. Primary cutaneous cryptococcosis (PCC) has been confirmed as a distinct clinical entity with secondary cutaneous infection from systematic cryptococcosis in 2003 [3]. PCC is determined as cryptococcal infection that is only located on the skin.
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PCC is diagnosed both in immunocompromised and immunocompetent hosts, but some marked differences were noticed in the two different groups of host [4]. Among immunocompromised hosts, a subset of PCC patients gave us important clues for the spread of cryptococcosis from the skin to systemic infections [5– 7]. PCC in certain immunocompromised patient populations, such as organ transplant recipients, has been even thoroughly investigated for its epidemiological, clinical, diagnostic and therapeutic features [8, 9]. With the tendency of more and more cryptococcosis reported in immunocompetent host [10], who are ‘‘apparently healthy’’ after thoroughly clinical investigation, little has progressed in recent years to determine the root cause of PCC in these immunocompetent hosts compared to the immunocompromised counterpart. Here, we review the literature on cases of PCC in immunocompetent patients from 2004 to 2014 to dissect the possible factors underlying PCC in immunocompetent hosts.
Materials and Methods A literature search was performed using the PubMed and MEDLINE database. The keywords used included cutaneous cryptococcosis, and publication time was from Jan 2004 to Jan 2014. Only English was searched as the publication language. All searched results were carefully identified by investigators by abstract or original paper to confirm that cases included in this study were primary cutaneous infections and not secondary infections. The hosts were also confirmed as immunocompetent hosts. Definition of immunocompetent host is indicative of patients not having any known predisposing factors or diseases related to cryptococcal infection such as HIV/AIDS or organ transplants, and the tests for these predispositions have been done with negative results per the research articles’ ‘‘Materials and Methods’’. Case definition of PCC [3, 4] was evidenced by records of cutaneous inflammation and identification of genus Cryptococcus, either with culture confirmation and/or histology. We further defined undisseminated infections by negative culture and/or latex agglutination testing in serum, cerebrospinal fluid or radiologic evidence of healed or active cryptococcosis. Cases were excluded if microbiologic identification could not be easily correlated with Cryptococcus.
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Cases were excluded if the patient cannot be easily identified as immunocompetent host.
Results Cases Identified The literature search resulted in identifying 21 cases from 16 reports meeting our definition of PCCs in immunocompetent hosts. The general information, clinical manifestation, mycological test result, diagnoses, and treatment and outcome of these cases were recorded (Table 1). Epidemiological Data All of the 21 cases are from 10 countries on 4 continents: 5 (23.8 %) cases from Europe, 5 (23.8 %) from Asia, 2 (9.5 %) from North America, and 9 (42.9 %) from South America. Of the 21 cases identified as PCCs in this literature search, males are more likely to develop PCC infections (81.0 %), with a ratio of 17:4 to female. Most of all patients identified with PCC were within the senior age group, with a median age of 67 (8–89 years old). However, it is more obvious that patients identified with primary cutaneous Cryptococcus neoformans or gattii infection were all elderly, average age being 58 years old. The average age increased to 71 years old, if we exclude patients from Asia. The average age of the five Asian patients was 34 years old. This age discrepancy was hard to explain, but it may suggest that these patients in Asia may have a genetic predisposition for PCCs. We have demographics for 13 patients, which details employment or living area and conditions. Ten of the 13 (77.0 %) infections could be associated with rural areas, which include poor working or living conditions. While 50 % (8/16) of the recorded patients have a history of exposure with avian excreta or eucalyptus, 42.9 % (9 of 21) patients showed a clear history of trauma before infection. Clinical Manifestation There is no typical clinical manifestation of cutaneous infection of Cryptococcus. Asymptomatic or moderate
8
66
75
58
67
89
67
37
58
71
75
2/[12]
3/[13]
4/[14]
5/[14]
6/[15]
7/[16]
8/[17]
9/[18]
10/[19]
11/[20]
Age
1/[11]
Patient/ [reference] number
F
M
M
M
M
M
F
M
M
M
F
Sex
Housewife in urban area
Handling clothing in poor hygienic condition
Farmer
Forklift driver
Poultry farmer
Collecting firewood
Farmer
Poultry farm business at rural area
Retired carpenter
Rural area
N.A.
Employment/ living area
Brazil
Spain
Italy
Singapore
Brazil
Brazil
(eucalyptus)
N.A.
N
N.A.
N
Y
N.A.
Y
N
Greece
Greece
Y
Y
N
Avian excreta exposure
Brazil
USA
Spain
Country
N
N
Y
Y
Y
Y
N
N
Y
N
N
Trauma
Erythematous plaque
Painful erythematous and edematous, whitlow-like skin
Growing nodule from hand to forearm
Painful nodule
Itching nodule, ulceration, and excoriations
Ulcerated lesion
Painful cellulitis with ulceration
Granulomatous lesion with ulcer
Heat and itching, swelling multiformy lesion
Asymptomatic nodules and ulcer, molluscumlike papules
Asymptomatic growing macule
Clinical manifestation
Forearm
(–)
(–)
(–)
Hand
Thumb of hand
N.A.
N.A.
Forearm
Scalp
N.A.
Forearm
(–)
N.A.
Forearm
Finger
N.A.
Penis
(–)
N.A.
Forearm
Hand
Serum antigen
Lesion location
Table 1 Epidemiological and clinical data of primary cutaneous cryptococcosis in immunocompetent patients
Culture, histology
Culture
Culture, histology
Culture, histology
Culture
Culture, histology
Culture
Culture
Culture, histology
Histology
Culture
Diagnosis evidence
C. neoformans or C. gattii
C. neoformans
C. neoformans
C. gattii
C. neoformans or C. gattii
C. gattii(genotype: VGII)
C. neoformans or C. gattii
C. neoformans or C. gattii
C. gattii, (genotype: VGII)
N.A.
C. laurentii
Cryptococcus speciesa
FCZ: 400 mg/d 3 month with minimal improvement, then AMB 50 mg three times a week for 15 weeks, then ITZ 200 mg/d 6 month
FCZ: 400 mg/d 1 month then 200 mg/d 2 months
ITZ 200 mg/d, 4 months
N.A.
FCZ 450 mg/d, 40 days
ITZ 400 mg/d, 3 months
Surgery and 2 weeks of 200 mg/d FCZ, then 2 weeks of 100 mg/d
FCZ 200 mg/d, 2 weeks
FCZ 800 mg/d, 5 months
ITZ 400 mg/d, 3 months
FCZ 3 mg/kg, 2 weeks
Treatment
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Outcome
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123
35
43
40
81
72
79
70
75
69
17
12/[21]
13/[22]
14/[23]
15/[24]
16/[25]
17/[25]
18/[25]
19/[25]
20/[25]
21/[26]
M
M
F
M
M
M
M
M
M
M
Sex
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
Farmer
N.A.
Driver and helper
Businessman
Employment/ living area
India
Brazil
Brazil
Brazil
Brazil
Brazil
USA
India
Saudi Arabia
China
Country
N
N
Y
N
Y
Y
Y
N.A.
N.A.
N
Avian excreta exposure
N
N
Y
N
Y
Y
Y
N
N
N
Trauma
Nonhealing ulcer
N.A.
N.A.
N.A.
N.A.
N.A.
Asymptomatic nodule
Painless subcutaneous lipoma-like swelling
Nodules
Painless nodule
Clinical manifestation
Toe
Forearm
Forearm
Forearm
Arm ? forearm
Forearm
Forearm
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
(–)
N.A.
Abdominal flank
Culture
Culture, histology
Culture, histology
Culture, histology
Culture, histology
Culture, histology
Culture, histology
Culture
Culture
N.A.
Forehead and lumbar region
Diagnosis evidence
Culture
Serum antigen
1:80
Thigh
Lesion location
C. gattii
C. gattii
C. neoformans
C. neoformans or C. gattii
C. neoformans
C. neoformans or C. gattii
C. neoformans or C. gattii
C. neoformans or C. gattii
C.neoformans, serotype D
C.neoformans, serotype A
Cryptococcus speciesa
AMB 10 days (unknown dosage) then FCZ 400 mg/d 3 months
ITZ 200 mg/d 6 months
FCZ 400 mg/d 3 months ? AMB :total 2250 mg
ITZ 100 mg/d 3 months
FCZ 300 mg/d 2 months
ITZ 200 mg/d 4 months
ITZ 400 mg/d, 3 months
FCZ (unknown dosage and time)
N.A.
ITZ 400 mg/d, 3 days, then FCZ 200 mg/d, for 14 days, then ITZ 200 mg/d for 2 months
Treatment
Improved
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Outcome
a C. gattii and C. neoformans were just identified as two different species in recent years while they were thought to be the two varieties of C. neoformans in the past tens of years. When some case reports have just identified them as C. neoformans and no more data to exclude the possibility of C. gattii, we identify the isolate as C. gattii or C. neoformans
FCZ fluconazole, ICZ itraconazole, AMB amphotericin B
Age
Patient/ [reference] number
Table 1 continued
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itching and formation of painful nodules are the most common presentation, while ulcer may become apparent on the basis of the nodule. Forming of cellulitis, mollusum-like papules, granulomata, whitlow, and execration were also reported. Upper limbs (forearm and hand or finger) are the most common site of infection, accounting for 71.4 % (15 cases) of all patients in this study group. Two noncontact site infections were reported in one case. In this case, the noncontact sites were the forehead and lumbar regions.
itraconazole was effective in seven cases, with a dosage range of 100–400 mg/d and duration from 3 to 6 months. Generally, the prognosis for PCC in immunocompetent hosts is good, and 20/21 of the total cases (95.2 %) were treated successfully without spread of the infection. However, there is a report that suggested that an undiagnosed and untreated cutaneous lesion on the toe that persisted for 5 months led to systematic dissemination of cryptococcosis.
Mycological Results
Discussion
Of the 21 cases in this literature review, culture identification was performed in 20/21 cases. The other case was diagnosed by typical histology pertaining to an infection site of the penis. Both histology and culture were the diagnostic evidence in 11 of the 21 (52.4 %) cases to identify PCC. Although some cases have identified the genotype and serotype of the isolates, eight cases in the reports just identified the isolates as C. neoformans, which should include both C. neoformans and C. gattii, according to the new classification. This discrepancy can be explained by the fact that only a few years ago C. gattii and C. neoformans were thought to be different species. Of the 12 identified isolates, 6 strains were identified as C. neoformans (1 as serotype A, 1 as serotype B), 5 were identified as C. gattii (2 as VGNII), and 1 was identified as C. laurentii. Serum antigen test results were recorded in 7/21 cases; only one patient had a low positive titer of 80, while the remaining six tested negative.
Controversy has surrounded the existence of PCC for decades. Since it was confirmed as a distinct clinical entity, PCC in different groups of patients has been reported on a larger scale, especially in immunocompromised patients [5–9]. However, there have been sporadic reports of PCC in immunocompetent hosts, and there is a need to clarify this group of patient populations for understanding dissemination of cryptococcosis. We reviewed the case reports of PCC over the last decade. It is not surprising that more cases seem to be in immunocompromised hosts. After carefully searching the literature, we found only 16 of the 109 searched articles from the database which describe immunocompetent hosts. The previous review [4] showed there were almost the same number articles on PCC patients in the immunocompromised and immunocompetent populations. The increase in incidences may be explained due to the fact that more predisposing factors have been identified for PCCs in recent years, and some of the ‘‘apparently healthy’’ hosts have been identified as immunocompromised. An interesting finding from this review showed that patients from Asia are of a consistently younger population (median age of 34) and then patients found on other continents (median age of 74). Although it seemed like PCCs tend to infect the elderly [4, 5], whose immune system function is thought to decrease with age, it may not be the case for patients infected in Asia. According to recent reports [27–29], the cryptococcal infection in East Asia may be different than other areas in the world. The Asian population demographics suggest that more immunocompetent patients were infected in this region rather than immunocompromised hosts. One explanation for
Treatment and Outcome Nineteen of 21 cases recorded outcome. Of those, fluconazole was used in ten cases (dosage ranged from 200 to 800 mg/d) and the duration of treatment ranged from 2 weeks to 6 months. However, only 80 % of the ten cases could confirm that fluconazole was effective in clearing the infections. One case had a recorded treatment failure after 3 months of treating the infection with 400 mg/d of fluconazole. Interestingly, there is a prominent sign that itraconazole is effective in the treatment of cutaneous cryptococcal infection in the immunocompetent patient population. The data showed that treatment with
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younger PCC immunocompetent patients in Asia may be linked to ethnicity or endemic problems. But that is beyond the scope of our review due to the small sample size. Although trauma and exposure history to Cryptococcus-contaminated materials in this review looked almost the same as that determined by Christianson [4], most of the PCC cases could be attributed to poor living conditions where hygiene is inferior to that of more developed countries. It is not possible to diagnose PCC on a specific clinical manifestation, because a diversity of skin lesions and most everybody site that could be exposed and affected by cryptococcal infection has been reported in the literature. Culture and histology are still the gold criteria for diagnoses of cryptococcosis; however, some reports suggested that fine-needle aspiration maybe helpful to make a quick and easy diagnosis [22, 23]. Before we come to discuss ideology of the infecting Cryptococcus strains, we have to take into account what was thought to be a variety of C. neoformans. With better genetic tools, it is now evident that C. gattii is a distinct species from C. neoformans. The classification of C. gattii and C. neoformans as distinct species is based on phylogenetic studies and the absence of genetic recombination in matings between isolates of each species [30]. Because eight cases just identify the infective strain as ‘‘C. neoformans’’ in terms of the old classification system, the change of strain name has led to hard to identify them as C. gattii and C. neoformans. The 12 identified isolates showed almost equal amounts of C. neoformans (6) and C. gattii (5), with a first report of infection by C. laurentii. However, this review differs from trends reported before 2004 [4, 5]. C. neoformans serotype D was the likely pathogen for this group of patients that acquired PCC. In our review, we found only one isolate identified as serotype D, while more C. gattii infections were identified including two further classified as VGII genotype. This result is more aligned with the ideology that C. gattii is thought to be the main isolate in immunocompetent hosts diagnosed with cryptococcosis [30]. Therapy for PCC in this group of patients seemed successful in most cases we found from the last 10 years in terms of survival and recovery from cryptococcosis. One report showed dissemination from primary skin infection to CNSs is possible when
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treatment is not administered early. Although fluconazole was still the choice of treatment in accordance to the current guideline and effective in many cases of our review, one case report showed that even after 3 months of 400 mg/d fluconazole, there was minimal improvement in a patient. Subsequently the outlying patient was cured by treatment with amphotericin B, with a dosage of 50 mg three times a week for 15 weeks. Interestingly, the treatment regimens differ from the previous decade [3, 4]. It is now current practice to use itraconazole as an alternative of treatment for PCC in immunocompetent hosts. There were seven cases treated with itraconazole, and all showed successful outcome, while few were reported in the previous decade. Although it is difficult to confirm if itraconazole or fluconazole is a better therapy for treatment because small numbers of these patients, it seems reasonable that treatment with azole drugs over an extended period of time is the therapy of choice when patients are diagnosed with PCC. Acknowledgments Part of this work was supported by China National Nature and Science Foundation (Number: 30600540). We would like to acknowledge Dr Shu Hui Chen from NIAID, NIH, who has contributed scientific discussions, English and proper grammar, and syntax for this paper. Conflict of interest
None.
References 1. Sanfelice F. Contributo alle morfologia e biologia dei blastomiceti che si sviluppano nei succhi di alcuni frutti. Ann Isto Igiene R Univ Roma. 1894;4:463–95. 2. Ricardo M, La Hoz La, Pappas PG. Cryptococcal infections: changing epidemiology and implications for therapy. Drugs. 2013;73(6):495–504. 3. Neuville S, Dromer F, Morin O, et al. Primary cutaneous cryptococcosis: a distinct clinical entity. Clin Infect Dis. 2003;36(3):337–47. 4. Christianson JC, Engber W, Andes D. Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts. Med Mycol. 2003;41(3):177–88. 5. Lu HC, Yang YY, Huang YL, et al. Disseminated cryptococcosis initially presenting as cellulitis in a rheumatoid arthritis patient. J Chin Med Assoc. 2007;70(6):249–52. 6. Rerolle JP, Szelag JC, Diaconita M, et al. Intracranial granuloma and skull osteolysis: complication of a primary cutaneous cryptococcosis in a kidney transplant recipient. Am J Kidney Dis. 2005;46(6):e113–7. 7. Hafner C, Linde HJ, Vogt T, et al. Primary cutaneous cryptococcosis and secondary antigenemia in a patient with
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long-term corticosteroid therapy. Infection. 2005;33(2): 86–9. Biancheri D, Kanitakis J, Bienvenu AL, et al. Cutaneous cryptococcosis in solid organ transplant recipients: epidemiological, clinical, diagnostic and therapeutic features. Eur J Dermatol. 2012;22(5):651–7. Sun HY, Alexander BD, Lortholary O, et al. Cutaneous cryptococcosis in solid organ transplant recipients. Med Mycol. 2010;48(6):785–91. Kronstad JW, Attarian R, Cadieux B, et al. Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box. Nat Rev Microbiol. 2011;9(3):193–203. Molina-Leyva A, Ruiz-Carrascosa JC, Leyva-Garcia A, et al. Cutaneous Cryptococcus laurentii infection in an immunocompetent child. Int J Infect Dis. 2013;17(12): e1232–3. Narva´ez-Moreno B, Bernabeu-Wittel J, Zulueta-Dorado T, et al. Primary cutaneous cryptococcosis of the penis. Sex Transm Dis. 2012;39(10):792–3. Lea˜o CA, Ferreira-Paim K, Andrade-Silva L, et al. Primary cutaneous cryptococcosis caused by Cryptococcus gattii in an immunocompetent host. Med Mycol. 2011;49(4):352–5. Spiliopoulou A, Anastassiou ED, Christofidou M. Primary cutaneous cryptococcosis in immunocompetent hosts. Mycoses. 2012;55(2):e45–7. Pasa CR, Chang MR, Hans-Filho G. Post-trauma primary cutaneous cryptococcosis in an immunocompetent host by Cryptococcus gattii VGII. Mycoses. 2012;55(2):e1–3. Nasser N, Nasser Filho N, Vieira AG. Primay cutaneous cryptococcosis in an immunocompetent patient. An Bras Dermatol. 2011;86(6):1178–80. Lingegowda BP, Koh TH, Ong HS, et al. Primary cutaneous cryptococcosis due to Cryptococcus gattii in Singapore. Singap Med J. 2011;52(7):e160–2. Pau M, Lallai C, Aste N, et al. Primary cutaneous cryptococcosis in an immunocompetent host. Mycoses. 2010;53(3):256–8. Allegue F, de Lis MP, Pe´rez-Alvarez R. Primary cutaneous cryptococcosis presenting as a whitlow. Acta Derm Venereol. 2007;87(5):443–4.
20. Yuge S, Bastazini Ju´nior I, Coelho MC, et al. Cutaneous cryptococcosis in an immunocompetent host. Acta Derm Venereol. 2006;86(2):165–6. 21. Xiujiao X, Ai’e X. Two cases of cutaneous cryptococcosis. Mycoses. 2005;48(4):238–41. 22. Al-Marzooq YM, Chopra R, Al-Mommatten MI, et al. Fineneedle aspiration diagnosis of primary cutaneous cryptococcosis in an immunocompetent patient: a case report. Diagn Cytopathol. 2005;32(4):219–21. 23. Kumar P, Saran RK, Gondal R, et al. Smear morphology of cryptococcosis presenting as a subcutaneous swelling in healthy adults: a report of three cases. Cytopathology. 2005;16(3):143–6. 24. Werchniak AE, Baughman RD. Primary cutaneous cryptococcosis in an elderly man. Clin Exp Dermatol. 2004; 29(2):159–60. 25. Marques SA, Bastazini I Jr, Martins AL, et al. Primary cutaneous cryptococcosis in Brazil: report of 11 cases in immunocompetent and immunosuppressed patients. Int J Dermatol. 2012;51(7):780–4. 26. Tilak R, Prakash P, Nigam C, et al. Cryptococcal meningitis with an antecedent cutaneous Cryptococcal lesion. Dermatol Online J. 2009;15(9):12. 27. Chen J, Varma A. Diaz MR, Cryptococcus neoformans strains and infection in apparently immunocompetent patients China. Emerg Infect Dis. 2008;14:755–62. 28. Chau TT, Mai NH, Phu NH, et al. A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam-high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease. BMC Infect Dis. 2010;9(10):199. 29. Lee SJ, Choi HK, Son J, et al. Cryptococcal meningitis in patients with or without human immunodeficiency virus: experience in a tertiary hospital. Yonsei Med J. 2011;52(3): 482–7. 30. Kronstad JW, Attarian R, Cadieux B, et al. Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box. Nat Rev Microbiol. 2011;9(3):193–203.
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Systemic Review of Published Reports on Primary Cutaneous Cryptococcosis in Immunocompetent Patients Lin Du • Yali Yang • Julin Gu • Jianghan Chen Wanqing Liao • Yuanjie Zhu
•
Received: 14 March 2014 / Accepted: 25 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Primary cutaneous cryptococcosis (PCC) has been confirmed as a distinct clinical entity with secondary cutaneous cryptococcosis from systematic infection since 2003. Although it has been confirmed as a distinct clinical entity, little has progressed on PCC in immunocompetent hosts compared to their immunocompromised counterpart. We reviewed the literature on cases of PCC in immunocompetent patients from 2004 to 2014, and 21 cases from 16 reports were identified. Males are more likely to develop PCC infections, with a ratio of 17:4 male to female. These patients were found to be almost all senior population except for patients from Asia. Asymptomatic or moderate itching manifesting in a painful nodule is the most common presentation, although there is no typical clinical manifestation recorded. Upper limbs are the most common site of infection, accounting for 71.4 % of all patients. Of the 12 identified isolates, 6 strains are identified as C. neoformans, 5 as C. gattii, and 1 as C.laurentii. Fluconazole was used in 10 cases; however, only 80 % of the 10 cases could confirm that fluconazole was effective in clearing the infections. Interestingly although not approved as a treatment option,
L. Du Y. Yang J. Gu J. Chen W. Liao Y. Zhu (&) Department of Dermatology and Mycology Center, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China e-mail: [email protected]
Itraconazole was effective in the seven cases it was used to treat cryptococcosis, with a dosage range of 100–400 mg/d and duration from 3 to 6 months. Even though the prognosis of these patients was generally good, more data are need to determine which antifungal azole is the better treatment option and whether primary skin infections could disseminate to systematic infection. Keywords Cryptococcosis Immunocompetent Skin infection
Introduction More than 100 years after it was first identified by Sanfelice [1], the fungi from the genus Cryptococcus continue to cause significant morbidity and mortality worldwide, not only in immunocompromised patients, but also in immunocompetent patients [2]. Cryptococcosis is an opportunistic infection by the fungi of the genus Cryptococcus that can lead to fatal meningitis if left untreated. Although the central nervous system (CNS) is the most common site of cryptococcal infections detected, other sites, such as lung and skin infections, are not rare. Primary cutaneous cryptococcosis (PCC) has been confirmed as a distinct clinical entity with secondary cutaneous infection from systematic cryptococcosis in 2003 [3]. PCC is determined as cryptococcal infection that is only located on the skin.
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PCC is diagnosed both in immunocompromised and immunocompetent hosts, but some marked differences were noticed in the two different groups of host [4]. Among immunocompromised hosts, a subset of PCC patients gave us important clues for the spread of cryptococcosis from the skin to systemic infections [5– 7]. PCC in certain immunocompromised patient populations, such as organ transplant recipients, has been even thoroughly investigated for its epidemiological, clinical, diagnostic and therapeutic features [8, 9]. With the tendency of more and more cryptococcosis reported in immunocompetent host [10], who are ‘‘apparently healthy’’ after thoroughly clinical investigation, little has progressed in recent years to determine the root cause of PCC in these immunocompetent hosts compared to the immunocompromised counterpart. Here, we review the literature on cases of PCC in immunocompetent patients from 2004 to 2014 to dissect the possible factors underlying PCC in immunocompetent hosts.
Materials and Methods A literature search was performed using the PubMed and MEDLINE database. The keywords used included cutaneous cryptococcosis, and publication time was from Jan 2004 to Jan 2014. Only English was searched as the publication language. All searched results were carefully identified by investigators by abstract or original paper to confirm that cases included in this study were primary cutaneous infections and not secondary infections. The hosts were also confirmed as immunocompetent hosts. Definition of immunocompetent host is indicative of patients not having any known predisposing factors or diseases related to cryptococcal infection such as HIV/AIDS or organ transplants, and the tests for these predispositions have been done with negative results per the research articles’ ‘‘Materials and Methods’’. Case definition of PCC [3, 4] was evidenced by records of cutaneous inflammation and identification of genus Cryptococcus, either with culture confirmation and/or histology. We further defined undisseminated infections by negative culture and/or latex agglutination testing in serum, cerebrospinal fluid or radiologic evidence of healed or active cryptococcosis. Cases were excluded if microbiologic identification could not be easily correlated with Cryptococcus.
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Cases were excluded if the patient cannot be easily identified as immunocompetent host.
Results Cases Identified The literature search resulted in identifying 21 cases from 16 reports meeting our definition of PCCs in immunocompetent hosts. The general information, clinical manifestation, mycological test result, diagnoses, and treatment and outcome of these cases were recorded (Table 1). Epidemiological Data All of the 21 cases are from 10 countries on 4 continents: 5 (23.8 %) cases from Europe, 5 (23.8 %) from Asia, 2 (9.5 %) from North America, and 9 (42.9 %) from South America. Of the 21 cases identified as PCCs in this literature search, males are more likely to develop PCC infections (81.0 %), with a ratio of 17:4 to female. Most of all patients identified with PCC were within the senior age group, with a median age of 67 (8–89 years old). However, it is more obvious that patients identified with primary cutaneous Cryptococcus neoformans or gattii infection were all elderly, average age being 58 years old. The average age increased to 71 years old, if we exclude patients from Asia. The average age of the five Asian patients was 34 years old. This age discrepancy was hard to explain, but it may suggest that these patients in Asia may have a genetic predisposition for PCCs. We have demographics for 13 patients, which details employment or living area and conditions. Ten of the 13 (77.0 %) infections could be associated with rural areas, which include poor working or living conditions. While 50 % (8/16) of the recorded patients have a history of exposure with avian excreta or eucalyptus, 42.9 % (9 of 21) patients showed a clear history of trauma before infection. Clinical Manifestation There is no typical clinical manifestation of cutaneous infection of Cryptococcus. Asymptomatic or moderate
8
66
75
58
67
89
67
37
58
71
75
2/[12]
3/[13]
4/[14]
5/[14]
6/[15]
7/[16]
8/[17]
9/[18]
10/[19]
11/[20]
Age
1/[11]
Patient/ [reference] number
F
M
M
M
M
M
F
M
M
M
F
Sex
Housewife in urban area
Handling clothing in poor hygienic condition
Farmer
Forklift driver
Poultry farmer
Collecting firewood
Farmer
Poultry farm business at rural area
Retired carpenter
Rural area
N.A.
Employment/ living area
Brazil
Spain
Italy
Singapore
Brazil
Brazil
(eucalyptus)
N.A.
N
N.A.
N
Y
N.A.
Y
N
Greece
Greece
Y
Y
N
Avian excreta exposure
Brazil
USA
Spain
Country
N
N
Y
Y
Y
Y
N
N
Y
N
N
Trauma
Erythematous plaque
Painful erythematous and edematous, whitlow-like skin
Growing nodule from hand to forearm
Painful nodule
Itching nodule, ulceration, and excoriations
Ulcerated lesion
Painful cellulitis with ulceration
Granulomatous lesion with ulcer
Heat and itching, swelling multiformy lesion
Asymptomatic nodules and ulcer, molluscumlike papules
Asymptomatic growing macule
Clinical manifestation
Forearm
(–)
(–)
(–)
Hand
Thumb of hand
N.A.
N.A.
Forearm
Scalp
N.A.
Forearm
(–)
N.A.
Forearm
Finger
N.A.
Penis
(–)
N.A.
Forearm
Hand
Serum antigen
Lesion location
Table 1 Epidemiological and clinical data of primary cutaneous cryptococcosis in immunocompetent patients
Culture, histology
Culture
Culture, histology
Culture, histology
Culture
Culture, histology
Culture
Culture
Culture, histology
Histology
Culture
Diagnosis evidence
C. neoformans or C. gattii
C. neoformans
C. neoformans
C. gattii
C. neoformans or C. gattii
C. gattii(genotype: VGII)
C. neoformans or C. gattii
C. neoformans or C. gattii
C. gattii, (genotype: VGII)
N.A.
C. laurentii
Cryptococcus speciesa
FCZ: 400 mg/d 3 month with minimal improvement, then AMB 50 mg three times a week for 15 weeks, then ITZ 200 mg/d 6 month
FCZ: 400 mg/d 1 month then 200 mg/d 2 months
ITZ 200 mg/d, 4 months
N.A.
FCZ 450 mg/d, 40 days
ITZ 400 mg/d, 3 months
Surgery and 2 weeks of 200 mg/d FCZ, then 2 weeks of 100 mg/d
FCZ 200 mg/d, 2 weeks
FCZ 800 mg/d, 5 months
ITZ 400 mg/d, 3 months
FCZ 3 mg/kg, 2 weeks
Treatment
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Outcome
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123
35
43
40
81
72
79
70
75
69
17
12/[21]
13/[22]
14/[23]
15/[24]
16/[25]
17/[25]
18/[25]
19/[25]
20/[25]
21/[26]
M
M
F
M
M
M
M
M
M
M
Sex
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
Farmer
N.A.
Driver and helper
Businessman
Employment/ living area
India
Brazil
Brazil
Brazil
Brazil
Brazil
USA
India
Saudi Arabia
China
Country
N
N
Y
N
Y
Y
Y
N.A.
N.A.
N
Avian excreta exposure
N
N
Y
N
Y
Y
Y
N
N
N
Trauma
Nonhealing ulcer
N.A.
N.A.
N.A.
N.A.
N.A.
Asymptomatic nodule
Painless subcutaneous lipoma-like swelling
Nodules
Painless nodule
Clinical manifestation
Toe
Forearm
Forearm
Forearm
Arm ? forearm
Forearm
Forearm
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
(–)
N.A.
Abdominal flank
Culture
Culture, histology
Culture, histology
Culture, histology
Culture, histology
Culture, histology
Culture, histology
Culture
Culture
N.A.
Forehead and lumbar region
Diagnosis evidence
Culture
Serum antigen
1:80
Thigh
Lesion location
C. gattii
C. gattii
C. neoformans
C. neoformans or C. gattii
C. neoformans
C. neoformans or C. gattii
C. neoformans or C. gattii
C. neoformans or C. gattii
C.neoformans, serotype D
C.neoformans, serotype A
Cryptococcus speciesa
AMB 10 days (unknown dosage) then FCZ 400 mg/d 3 months
ITZ 200 mg/d 6 months
FCZ 400 mg/d 3 months ? AMB :total 2250 mg
ITZ 100 mg/d 3 months
FCZ 300 mg/d 2 months
ITZ 200 mg/d 4 months
ITZ 400 mg/d, 3 months
FCZ (unknown dosage and time)
N.A.
ITZ 400 mg/d, 3 days, then FCZ 200 mg/d, for 14 days, then ITZ 200 mg/d for 2 months
Treatment
Improved
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Outcome
a C. gattii and C. neoformans were just identified as two different species in recent years while they were thought to be the two varieties of C. neoformans in the past tens of years. When some case reports have just identified them as C. neoformans and no more data to exclude the possibility of C. gattii, we identify the isolate as C. gattii or C. neoformans
FCZ fluconazole, ICZ itraconazole, AMB amphotericin B
Age
Patient/ [reference] number
Table 1 continued
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itching and formation of painful nodules are the most common presentation, while ulcer may become apparent on the basis of the nodule. Forming of cellulitis, mollusum-like papules, granulomata, whitlow, and execration were also reported. Upper limbs (forearm and hand or finger) are the most common site of infection, accounting for 71.4 % (15 cases) of all patients in this study group. Two noncontact site infections were reported in one case. In this case, the noncontact sites were the forehead and lumbar regions.
itraconazole was effective in seven cases, with a dosage range of 100–400 mg/d and duration from 3 to 6 months. Generally, the prognosis for PCC in immunocompetent hosts is good, and 20/21 of the total cases (95.2 %) were treated successfully without spread of the infection. However, there is a report that suggested that an undiagnosed and untreated cutaneous lesion on the toe that persisted for 5 months led to systematic dissemination of cryptococcosis.
Mycological Results
Discussion
Of the 21 cases in this literature review, culture identification was performed in 20/21 cases. The other case was diagnosed by typical histology pertaining to an infection site of the penis. Both histology and culture were the diagnostic evidence in 11 of the 21 (52.4 %) cases to identify PCC. Although some cases have identified the genotype and serotype of the isolates, eight cases in the reports just identified the isolates as C. neoformans, which should include both C. neoformans and C. gattii, according to the new classification. This discrepancy can be explained by the fact that only a few years ago C. gattii and C. neoformans were thought to be different species. Of the 12 identified isolates, 6 strains were identified as C. neoformans (1 as serotype A, 1 as serotype B), 5 were identified as C. gattii (2 as VGNII), and 1 was identified as C. laurentii. Serum antigen test results were recorded in 7/21 cases; only one patient had a low positive titer of 80, while the remaining six tested negative.
Controversy has surrounded the existence of PCC for decades. Since it was confirmed as a distinct clinical entity, PCC in different groups of patients has been reported on a larger scale, especially in immunocompromised patients [5–9]. However, there have been sporadic reports of PCC in immunocompetent hosts, and there is a need to clarify this group of patient populations for understanding dissemination of cryptococcosis. We reviewed the case reports of PCC over the last decade. It is not surprising that more cases seem to be in immunocompromised hosts. After carefully searching the literature, we found only 16 of the 109 searched articles from the database which describe immunocompetent hosts. The previous review [4] showed there were almost the same number articles on PCC patients in the immunocompromised and immunocompetent populations. The increase in incidences may be explained due to the fact that more predisposing factors have been identified for PCCs in recent years, and some of the ‘‘apparently healthy’’ hosts have been identified as immunocompromised. An interesting finding from this review showed that patients from Asia are of a consistently younger population (median age of 34) and then patients found on other continents (median age of 74). Although it seemed like PCCs tend to infect the elderly [4, 5], whose immune system function is thought to decrease with age, it may not be the case for patients infected in Asia. According to recent reports [27–29], the cryptococcal infection in East Asia may be different than other areas in the world. The Asian population demographics suggest that more immunocompetent patients were infected in this region rather than immunocompromised hosts. One explanation for
Treatment and Outcome Nineteen of 21 cases recorded outcome. Of those, fluconazole was used in ten cases (dosage ranged from 200 to 800 mg/d) and the duration of treatment ranged from 2 weeks to 6 months. However, only 80 % of the ten cases could confirm that fluconazole was effective in clearing the infections. One case had a recorded treatment failure after 3 months of treating the infection with 400 mg/d of fluconazole. Interestingly, there is a prominent sign that itraconazole is effective in the treatment of cutaneous cryptococcal infection in the immunocompetent patient population. The data showed that treatment with
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younger PCC immunocompetent patients in Asia may be linked to ethnicity or endemic problems. But that is beyond the scope of our review due to the small sample size. Although trauma and exposure history to Cryptococcus-contaminated materials in this review looked almost the same as that determined by Christianson [4], most of the PCC cases could be attributed to poor living conditions where hygiene is inferior to that of more developed countries. It is not possible to diagnose PCC on a specific clinical manifestation, because a diversity of skin lesions and most everybody site that could be exposed and affected by cryptococcal infection has been reported in the literature. Culture and histology are still the gold criteria for diagnoses of cryptococcosis; however, some reports suggested that fine-needle aspiration maybe helpful to make a quick and easy diagnosis [22, 23]. Before we come to discuss ideology of the infecting Cryptococcus strains, we have to take into account what was thought to be a variety of C. neoformans. With better genetic tools, it is now evident that C. gattii is a distinct species from C. neoformans. The classification of C. gattii and C. neoformans as distinct species is based on phylogenetic studies and the absence of genetic recombination in matings between isolates of each species [30]. Because eight cases just identify the infective strain as ‘‘C. neoformans’’ in terms of the old classification system, the change of strain name has led to hard to identify them as C. gattii and C. neoformans. The 12 identified isolates showed almost equal amounts of C. neoformans (6) and C. gattii (5), with a first report of infection by C. laurentii. However, this review differs from trends reported before 2004 [4, 5]. C. neoformans serotype D was the likely pathogen for this group of patients that acquired PCC. In our review, we found only one isolate identified as serotype D, while more C. gattii infections were identified including two further classified as VGII genotype. This result is more aligned with the ideology that C. gattii is thought to be the main isolate in immunocompetent hosts diagnosed with cryptococcosis [30]. Therapy for PCC in this group of patients seemed successful in most cases we found from the last 10 years in terms of survival and recovery from cryptococcosis. One report showed dissemination from primary skin infection to CNSs is possible when
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treatment is not administered early. Although fluconazole was still the choice of treatment in accordance to the current guideline and effective in many cases of our review, one case report showed that even after 3 months of 400 mg/d fluconazole, there was minimal improvement in a patient. Subsequently the outlying patient was cured by treatment with amphotericin B, with a dosage of 50 mg three times a week for 15 weeks. Interestingly, the treatment regimens differ from the previous decade [3, 4]. It is now current practice to use itraconazole as an alternative of treatment for PCC in immunocompetent hosts. There were seven cases treated with itraconazole, and all showed successful outcome, while few were reported in the previous decade. Although it is difficult to confirm if itraconazole or fluconazole is a better therapy for treatment because small numbers of these patients, it seems reasonable that treatment with azole drugs over an extended period of time is the therapy of choice when patients are diagnosed with PCC. Acknowledgments Part of this work was supported by China National Nature and Science Foundation (Number: 30600540). We would like to acknowledge Dr Shu Hui Chen from NIAID, NIH, who has contributed scientific discussions, English and proper grammar, and syntax for this paper. Conflict of interest
None.
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