A Case of Fingernail Onychomycosis Due to Aspergillus Flavus

Med. Mycol. J. Vol.Med. 57E, Mycol. E 21− J. Vol. E 25, 57（No. 2016 2）, 2016 E21 ISSN 2185 − 6486

Short Report A Case of Fingernail Onychomycosis due to Aspergillus flavus

Hiromitsu Noguchiઃ, ઄, ઇ, Masataro Hiruma઄, Azusa Miyashitaઅ, Koji Makinoઆ, Keishi Miyataઇ and Hironobu Ihnઅ

Noguchi Dermatology Clinic ઄Ochanomizu Institute for Medical Mycology & Allergology અDepartment of Dermatology & Plastic Surgery, Faculty of Life Sciences, Kumamoto University આDivision of Dermatology, National Hospital Organization Kumamoto Medical Center ઇDepartment of Immunology, Allergy & Vascular Biology, Kumamoto University

ABSTRACT

A 56-year-old woman on insulin therapy for diabetes visited our clinic due to whitish discoloration on the right index finger. Despite topical application of 1% lanoconazole solution, the lesion grew, causing paronychia. Direct microscopy revealed non-dermatophyte molds. Based on the morphological features and genetic analysis of the isolate, the pathogen was identified as Aspergillus flavus. The patient was diagnosed with proximal subungual onychomycosis due to A. flavus. Following itraconazole pulse therapy, she was cured in 6 months. To our knowledge, this is the first reported case of fingernail onychomycosis due to A. flavus in Japan. Key words：Aspergillus flavus, onychomycosis, non-dermatophyte nail infection

our experience with an extremely rare case of Introduction fingernail onychomycosis due to Aspergillus flavus, along with a review of other reported Approximately 90% of onychomycosis cases cases of onychomycosis due to Aspergillus are caused by dermatophytes, while Candida species in Japan. species and non-dermatophyte filamentous fungi, including Aspergillus species, Acremonium spe- Case report cies, Fusarium species, Scopulariopsis brevi- caulis, and Scytalidium dimidiatum, are responsi- The patient was a 56-year-old female nurse ble for the remaining approximately 10% of whose hobby was gardening. In February 2014, cases1）. Onychomycosis due to Aspergillus spe- she noticed a whitish discoloration on the inside of cies is rare, accounting for less than 2% of all the nail fold of her right index finger, which had cases; it is often difficult to diagnose because it expanded to cover the entire nail plate by May presents a clinical picture similar to that of tinea 2014. A family doctor removed the nail, but she unguium2）. Studies of 15,000 patients with onycho- visited our clinic after the diseased nail re-grew mycosis in Canada revealed that, among finger- from the nail fold. At presentation in September nail cases, dermatophytes were responsible for 2014, a whitish discoloration was observed in the 70% of the cases and Candida species for 30%, radial half of the nail plate of her right index finger, and no non-dermatophyte molds were isolated with fragile and broken nail margins. The full from diseased fingernails1, 3）. We herein describe length of the nail was 14.2 mm, and the discolored

Address for correspondence : Hiromitsu Noguchi Noguchi Dermatology Clinic, Namazu1834-1, Kamimashiki-gun Kashima-machi, Kumamoto, 861-3101, Japan Received : 24, December 2015, Accepted: 15, March 2016 E-mail : [email protected] E22 Medical Mycology Journal Volume 57, Number 2, 2016

Fig. 1．Clinical picture at presentation. The discolored nail area accounted for 55.0% of the nail surface（a）. Clinical picture after 2 months of topical application of 1% lanoconazole solution. The discolored nail accounted for 82.2% of the total area（b）. Clinical picture 3 months after completion of the 3-month pulse therapy with ITCZ（c）.

Fig. 2．Non-dermatophyte fungal elements were found by direct microscopy of the diseased nail.（a）. Colonies formed after 10 days of culture in Sabouraud glucose agar at 25℃（b）. Slide culture shows conidial heads each consisting of a vesicle and radially arranged conidia（c）. area measured 87.8 mm2, accounting for 55.0% of 2.5 to 5μm, which were entangled with infiltrative the total surface area（Fig. 1a）. Topical applica- growth（Fig. 2a）. The primary culture was done tion of 1% lanoconazole solution was continued with Sabouraud cycloheximide-chloramphenicol for 2 months, but the discolored area increased to agar at first visit and 1 month later without 82.2%. There was concomitant paronychia, accom- stopping topical treatment. At second visit three panied by slight tenderness（Fig. 1b）. Tinea was samples were taken and yielded separate col- not found in her toenails. Peripheral blood ex- onies. No other colonies were seen on the culture. amination showed no abnormalities in blood Ten-day culture of the isolates in Sabouraud count, liver function, or renal function. However, glucose agar at 25℃ yielded raised colonies with a the patient, who had been on insulin therapy for 8 fluffy surface, having a yellowish white color in years because of diabetes, had a fasting blood the center and white color on the periphery sugar level of 111 mg/dl and HbA1c of 8.0%. （Fig. 2b）. Slide culture showed conidial heads Direct microscopy of the discolored nail re- each consisting of a vesicle and radially arranged vealed septate hyphae ranging in diameter from conidia（Fig. 2c）, suggesting onychomycosis due Med. Mycol. J. Vol. 57（No. 2）, 2016 E23

to Aspergillus species. The base sequence of the contamination. Shemer A et al.7） suggest that internal transcribed spacer 1 region of the when NDM infection is found in the first culture, ribosomal RNA gene of the isolate had 100% the patient should be re-examined in a subse- （237/237 bp）homology to A. flavus ATCC strain quent visit, wherein three separate samples are （accession: JX535495）; thus, the isolate was taken from the affected nail. If NDM is confirmed in identified as A. flavus. Moreover, the minimum all three cultures, the diagnosis of NDM is inhibitory concentrations（MIC）of the isolate were: established. Our case satisfied these new criteria. micafungin ≤ 0.015μg/ml, amphotericin B 1μg/ml, Onychomycosis due to Aspergillus species 5- fluorocytosine 4μg/ml, fluconazole 64μg/ml, occurs in less than 2% of cases and rarely itraconazole（ITCZ）0. 125 μ g/ml, voriconazole involves fingernails1, 2）. Table 1 shows reported 0.125μg/ml, and miconazole 0.125μg/ml. cases of onychomycosis due to Aspergillus The patient was treated by pulse therapy species in Japan. There have been 20 cases, consisting of 3 courses of 400 mg ITCZ/day for 7 including ours, since 1980. The mean age of the days per month. In April 2015, i.e., 3 months after patients is 48.9 ± 13.5 years. Patients were pre- completing therapy, the nail discoloration dis- dominantly female, with 19 women（95.0%）against appeared（Fig. 1c）. There has been no recurr- 1 man（5.0%）. Underlying disease was present in 4 ence to date, 9 months later. （20.0%）patients. The affected site was the fingernail in 4（20.0%）andthe toenail in 16（80.0%）cases; Discussion thus, involvement of fingernails was relatively rare. The clinical manifestations8） included distal Aspergillus species are among the most ubi- and lateral subungual onychomycosis（DLSO）in quitous fungi commonly isolated from the living 14（70. 0%）cases, PSO in 3（15. 0%）, superficial environment worldwide, and are important white onychomycosis（SWO）in 2（10. 0%）, total pathogens for opportunistic infection mainly of dystrophic onychomycosis（TDO）in1（5.0%）, and the respiratory organ. In pulmonary aspergillosis, onychomycosis accompanied by paronychia in 5 A. flavus is frequently isolated, second to A. cases（25.0%）. The causative fungus was A. niger fumigatus; it produces aflatoxin, the most potent in 5（25. 0%）cases, A. terreus in 5（25. 0%）, A. carcinogen found in nature4）. Diabetes, peripheral sydowii in 4（20. 0%）, A. flavus in 4（20. 0%）, A. vascular disease, orthopedic trauma, and adv- fumigatus in 1（5.0%）, and A. ochraceus in 1 case anced age are the most important underlying （5.0%）. ITCZ was effective in 6（60. 0%）of 10 conditions in onychomycosis due to Aspergillus patients whose clinical course was described. species, although no risk factors are evident in Onychomycosis due to A. flavus has been half of cases. The most characteristic clinical rarely reported. In Japan, there have been only 4 manifestation is proximal subungual onychomy- cases, including ours, and the other 3 were cosis（PSO）accompanied by painful paronychia reported only as abstracts that lacked many without pus discharge2）. Our case was also a case details. These 4 patients are female, with a mean of PSO accompanied by paronychia in a diabetic age of 53. 5 ± 3. 7 years, and 2 had underlying patient. The lesion twice extended to cover disease. The affected sites included the toenail in almost the entire nail plate, i.e., before removal of 3 and the fingernail in 1 case. The clinical the nail at another clinic and after visiting our manifestations were DLSO and PSO in 2 cases hospital, within a period of 3 months, indicating a each. Our case was the first and only one to rapid progression unlike that of tinea unguium. involve the fingernail. Overseas reports of The diagnosis of non-dermatophyte mold（NDM） onychomycosis due to A. flavus have also been onychomycosis requires more stringent criteria rare2）, but A. flavus was the most frequent than that of dermatophytes. The classical 6 main causative non-dermatophyte mold in Iran, re- criteria are identification of the NDM in the nail by ported in 12（37.5%）of 32 cases9）. In Japan, 3 of microscopy, isolation in culture, repeated isola- the 4 cases occurred in Kochi, Nagasaki, and tion in culture, inoculum counting, failure to isolate Kumamoto, cities located south of the 34°north a dermatophyte in culture, and histology5）. Be- latitude and having annual mean air temperatures cause these criteria are too rigorous and difficult of 16℃ or higher. Climate presumably influences to employ in practice, Gupta AK et al.6） recom- infection with this fungus. mend using at least 3 of the criteria to rule out Because the fingernail was affected in our E24 Medical Mycology Journal Volume 57, Number 2, 2016 topical unchanged SLE topical unknown （−）（−）（−） ITCZ（−） ITCZ（−） unknown ITCZ（−） unknown ITCZ（−） melanychia effective ITCZ（−） melanychia effective ITCZ melanychia effective topical ineffective melanychia ITCZ effective effective （−）（−） untreated topical（−） almost cured （−）（−） untreated （−） topical（−） ITCZ unknown （−） topical effective ITCZ improved topical ineffective unknown diabetes ITCZ effective sarcoidosis unknown unknown enteropathy protein-losing species in Japan , ITCZ: itraconazole Aspergillus A. niger A. niger A. niger A. niger A. sydowii A. ochraceus A. sydowii A. flavus A. terreus A. terreus A. fumigatus A. flavus A. flavus A. niger A. terreus A. flavus A. sydowii A. sydowii A. terreus A. terreus A. : Aspergillus Paronychia Strain Underlying disease Treatment Outcome Remarks TDO （−） Clinical manifestation and toes all fingers Table 1．Reported cases of onychomycosis due to 68 F left toe I DLSO （+） 49 F right toe I PSO （−） Age Sex Affected site report Year of Reference Higashi N 2008 DLSO: distal and lateral subungualSWO: onychomycosis, superficial PSO: white proximal onychomycosis, subungual TDO: onychomycosis, total dystrophic onychomycosis, Ito K 2005 1 Honma K 1980 54 F 2 Watanabe S 1983 35 F right finger V DLSO （−） 3 Noda T4 Nakagawa T5 1994 1993 Nakashima6 Y 1995 Wakeyama 347 24 E Hiruma F 19988 52 F M Tenma9 F M 66 right finger I left toe 2000 Higashi I N F right toe I 2000 44 DLSO 2004 all F 35 toes SWO 51 DLSO F right （+） toe I F bilateral toes I DLSO （−）（−） left toe DLSO SWO I （−）（−） DLSO （−）（−） 1314 151617 Takahata Y18 Hagiya Y19 2007 Yamada A20 54 33 2011 Our Case M F 2012 57 72 right 53 toe 2015 right I F toe 56 F I F 57 F right finger left I toe F DLSO I right DLSO toe I right toe I right finger DLSO I （−） DLSO （−） DLSO DLSO PSO （+）（−）（−）（+）（+） 12 28 F all toes SWO （−） 10 Saruta T11 2004 56 F left toe I DLSO （−） No. Case Med. Mycol. J. Vol. 57（No. 2）, 2016 E25 patient, 1% lanoconazole solution was applied Leffell DJ, Wolff K ed）, vol.2, pp.2277-2297, McGraw- topically for 2 months; however, this treatment Hill, New York, 2012. was ineffective. A 47-year-old woman with TDO 2）Negroni R: Onychomycosis due to Aspergillus species. In Aspergillosis: from diagnosis to preven- due to A. flavus of the fourth fingernail reportedly tion 1st ed（Pasqualotto AC ed）, pp. 961-971, did not respond to a 5-month oral treatment of 200 Springer, Heidelberg, 2010. mg/day ketoconazole, but was cured by 100 3）Gupta AK, Jain HC, Lynde CW, Macdonald P, mg/day ITCZ for 5 months10）. In our case, we Cooper EA, Summerbell RC: Prevalence and conducted 3 courses of pulse therapy, with each epidemiology of onychomycosis in patients visit- course consisting of oral administration of 400 ing physiciansOoffices: a multicenter canadian survey of 15,000 patients. J Am Acad Dermatol 43: mg/day ITCZ for 7 days followed by 3 weeks off 244-248, 2000. treatment, because ITCZ is indicated for treat- 4）Chen SCA, Sorrell TC, Meyer W: Aspergillus and ment of mycosis due to Aspergillus species in Penicillium. In Manual of Clinical Microbiology 11th Japan and because the MIC for the patient isolate ed（Jorgensen JH, Pfaller MA, Carroll KC, Funke was 0.125μg/ml. The patient responded well to this G, Landry ML, Richter SS, Warnock DW ed）, pp. therapy. Onychomycosis of the fingernail causes 2030-2056, ASM Press, Heidelberg, 2015. 5）English MP: Nails and fungi. Br J Dermatol 94: 697- a marked decrease in the patientOs quality of life. 701, 1976. Therefore, careful, mycology-based diagnosis is 6）Gupta AK, Drummond-Main C, Cooper EA, Brint- necessary to properly treat this condition. nell W, Piraccini BM, Tosti A: Systematic review of nondermatophyte mold onychomycosis: diagno- Acknowledgements sis, clinical types, epidemiology, and treatment. 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