Medical Mycology Case Reports 2 (2013) 132–133

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Cutaneous protothecosis in a patient with hypogammaglobulinemia Jason C. Kwong a,b,n, Peter B. Ward b, Paul D. Johnson a a b

Austin Centre for Infection Research, Austin Health, Heidelberg, VIC 3084, Australia Department of Microbiology, Austin Health, Heidelberg, VIC 3084, Australia

art ic l e i nf o

a b s t r a c t

Article history: Received 29 May 2013 Accepted 11 June 2013

Prototheca wickerhamii has been predominantly recognised as a pathogen in immunocompromised hosts with deficits in innate or cellular immunity. The role of specific immunoglobulin against Prototheca in host immunity is uncertain. We describe a case of persistent cutaneous protothecosis in a patient with hypogammaglobulinemia most likely due to common variable immunodeficiency, with clinical response to voriconazole. Crown Copyright & 2013 Published by Elsevier B.V on behalf of International Society for Human and Animal Mycology All rights reserved.

Keywords: Protothecosis Prototheca Hypogammaglobulinemia Common variable immunodeficiency Voriconazole

1. Introduction Prototheca spp. are spherical unicellular organisms best classified as achlorophyllic algae [1]. Most algae are not considered to be pathogenic in humans, though numerous cases of protothecosis have been described in both immunocompromised and immunocompetent human hosts [2]. While defects in innate and cellular immunity appear to predispose towards developing protothecosis, the role of humoral immunity is uncertain.

2. Case A previously well 61 year old Caucasian man presented with a three year history of multiple recurrent ulceronodular skin lesions predominantly on the exposed extremities of his arms and legs. During this time, he had been living and scuba diving in Palau, Micronesia, though had also spent prolonged periods in Eastern Australia and Tasmania, as well as a brief stop in Papua New Guinea prior to developing the lesions. Initial empiric regimens of oral antibiotics, antifungals and steroid injections in Palau were largely unsuccessful, and the patient developed further lesions without evidence of healing in existing lesions. The lesions were excised on multiple occasions, though this did not prevent the formation of new nodules. The patient travelled extensively to seek further advice from a number of physicians. Excision biopsies of the lesions in Hawaii revealed the presence n Corresponding author at: Austin Centre for Infection Research, Austin Health, Heidelberg, VIC 3084, Australia. Tel.: +61 3 9496 6676; fax: +61 3 9496 6677. E-mail addresses: [email protected] (J.C. Kwong), [email protected] (P.B. Ward), [email protected] (P.D. Johnson).

of numerous rounded positively staining organisms with occasional endospores on Gomori-methenamine silver (GMS) and Periodic Acid-Schiff (PAS) staining suggestive of Prototheca spp, although at the time it was uncertain whether this was a recent superinfection or the primary cause of the syndrome. Recurrent lesions subsequently also showed the presence of the organisms on histology, and the patient was commenced on itraconazole 200 mg daily. Despite this, he continued to develop new lesions, some clinically suggestive of Buruli ulcer. He contacted the World Health Organization Collaborating Centre for Mycobacterium ulcerans in Melbourne, but swabs mailed there tested negative for M. ulcerans by PCR and culture. Upon invitation he travelled to Melbourne to seek further opinion, and an excision biopsy of a large new forearm lesion was arranged (day 0). Histopathology again revealed numerous spherical organisms on GMS and PAS staining with internal endospores with a “spoked wheel” appearance suggestive of Prototheca. Cultures on horse-blood agar and Sabouraud dextrose media (without cyclohexamide) demonstrated growth of yeast-like colonies on day +2, which were identified as Prototheca wickerhamii with Biomérieux Viteks2 and APIs Yeast identification, and confirmed by 18S sequencing. In vitro sensitivity testing was conducted using non-validated methods with a Sensititre YeastOnes plate for antifungal susceptibilities (Table 1) as previously described [3]. The patient was commenced on oral voriconazole on day +4 for 3 months (initially 400 mg bd loading, then continued on 200 mg bd) with subsequent resolution of the lesions and no further relapse over the next six months (to day +180). Further testing of the patient's immune function was performed, revealing a global immunoglobulin deficiency consistent with common variable immunodeficiency (CVID), with total IgM 0.2 g/L (0.5–3.0 g/L), IgG 0.8 g/L (7.5–15.6 g/L), and IgA o0.1 g/L (0.8–4.5 g/L). The results were confirmed retrospectively with

2211-7539/$ - see front matter Crown Copyright & 2013 Published by Elsevier B.V on behalf of International Society for Human and Animal Mycology All rights reserved. http://dx.doi.org/10.1016/j.mmcr.2013.06.002

J.C. Kwong et al. / Medical Mycology Case Reports 2 (2013) 132–133

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additional tests performed on serum collected 6 months prior (day −180). Repeat HIV serology was negative, and no other evidence of malignancy other than a superficial basal cell skin carcinoma was identified. T-lymphocyte populations, blood film and serum protein electrophoresis were normal. The patient was referred to an immunologist for confirmation of CVID and consideration of intravenous immunoglobulin infusions.

warranted, as there are currently no guidelines for the performance and interpretation of these methods. Based on interpretations from susceptibility testing of yeasts using the Sensititres plate, the isolate appeared to be most sensitive to voriconazole and amphotericin B, with itraconazole MIC¼ 1.0 mg/L. We also chose voriconazole due to the inferior antifungal activity and evidence of clinical relapse in the patient with itraconazole, as well as ease of administration over amphotericin B. Although the diagnosis was confirmed in our department and laboratory, the patient spent a considerable amount of his own resources seeking a diagnosis and treatment. Protothecosis is generally not suspected on clinical grounds, and diagnosticians must be alert to the characteristic histopathologic appearance and usefulness of supplementary culture media to help establish the diagnosis. Formal guidelines for susceptibility testing have not been established, though a number of agents have been used for treatment with anecdotal clinical success. Although it is unknown whether the hypogammaglobulinemia directly contributed to the development of cutaneous disease in our patient, further investigation may be warranted into the role of immunoglobulin in immunity against and treatment of human protothecosis.

3. Discussion

Conflict of interest

Table 1 Antifungal susceptibility testing of the P. wickerhamii isolate using Sensititre YeastOnes. Antifungal agent

MIC (mg/L)

Interpretationa

Amphotericin B Fluconazole Itraconazole Ketoconazole Voriconazole 5-Flucytosine Caspofungin

0.25 4256 1.0 2.0 0.5 4 64 416

Susceptible Resistant Resistant Not interpretable Susceptible Resistant Resistant

a

Interpretation from Sensititre YeastOnes testing of yeasts.

Cutaneous disease with P. wickerhamii predominantly occurs in immunocompromised hosts with innate or cellular immunity deficits (including use of topical or local steroids) [4,5], suggesting that these components of human immunity play important roles in host defence against Prototheca infection [2]. However, infections due to Prototheca species have also been reported in immunocompetent individuals, particularly with the presentation of olecranon bursitis [6]. An in vitro study predominantly investigating the role of polymorphonuclear neutrophils and serum opsonins in killing P. wickerhamii suggested that pooled serum containing specific IgG antibodies to P. wickerhamii had some independent algicidal activity, though optimal conditions required both humoral factors and neutrophils [7]. To our knowledge, this is the first clinical case of protothecosis in the context of isolated hypogammaglobulinemia, though it cannot be completely established whether the patient's infection was directly attributable to this, or whether the two conditions were coincidental by chance. Another recent case occurring in a patient who had received Belimumab for Systemic Lupus Erythematosus implicated humoral immunodeficiency, though the patient had also received steroids and azathioprine [8]. Diagnosis of CVID is based on criteria, including markedly reduced serum IgG with a marked decrease in IgM or IgA, poor response to vaccination, and exclusion of other causes of hypogammaglobulinemia [9]. Although the patient had not completely fulfilled diagnostic criteria, the most likely cause of his persistent hypogammaglobulinemia in the absence of another immunodeficiency or predisposition is CVID. It is possible that another aetiology was responsible for the initial lesions (including CVID), with injections of steroid contributing to the development of cutaneous protothecosis. However, some lesions developed independently of steroid injection, and all of the lesions persisted long after local steroids were ceased. Isolation of P. wickerhamii in our laboratory was facilitated by the earlier identification in Hawaii, allowing us to alert our diagnostic laboratory and histopathologists to this possible diagnosis and to set up media for optimal growth. Many commercial systems can identify Prototheca species from pure cultures, as well as newer molecular diagnostic methods and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) [10]. It is unknown whether routine in-vitro susceptibility testing of Prototheca isolates is

None.

Acknowledgements Written and signed informed consent was obtained from the patient for the publication of this case. References 1 Iacoviello VR, DeGirolami PC, Lucarini J, Sutker K, Williams ME, Wanke CA. Protothecosis complicating prolonged endotracheal intubation: case report and literature review. Clinical infectious diseases: An Official Publication of the Infectious Diseases Society of America 1992;15(6):959–67 (Epub 1992/12/01). 2 Lass-Florl C, Mayr A. Human protothecosis. Clinical Microbiology Reviews 2007;20(2):230–42 (Epub 2007/04/13). 3 Linares MJ, Solis F, Casal M. In vitro activity of voriconazole against Prototheca wickerhamii: comparative evaluation of sensititre and NCCLS M27-A2 methods of detection. Journal of Clinical Microbiology 2005;43(5):2520–2 (Epub 2005/ 05/06). 4 Lu S, Xi L, Qin W, Luo Y, Lu C, Li X. Cutaneous protothecosis: two new cases in China and literature review. International Journal of Dermatology 2012;51 (3):328–31 (Epub 2012/02/22). 5 Todd JR, King JW, Oberle A, Matsumoto T, Odaka Y, Fowler M, et al. Protothecosis: report of a case with 20-year follow-up, and review of previously published cases. Medical Mycology: Official Publication of the International Society for Human and Animal Mycology 2012;50(7):673–89 (Epub 2012/05/ 11). 6 Zhao J, Liu W, Lv G, Shen Y, Wu S. Protothecosis successfully treated with amikacin combined with tetracyclines. Mycoses 2004;47(3–4):156–8 (Epub 2004/04/14). 7 Phair JP, Williams JE, Bassaris HP, Zeiss CR, Morlock BA. Phagocytosis and algicidal activity of human polymorphonuclear neutrophils against Prototheca wickerhamii. The Journal of Infectious Diseases 1981;144(1):72–7 (Epub 1981/ 07/01). 8 Mejia-Otero C, Singh S, Arias Urdaneta L, Sesin C, Chakrabarti A, Mae Miller N, et al. A rare case of Prototheca algaemia in a patient with Systemic Lupus Erythematosus and recent Belimumab infusion. Case Reports in Immunology 2012;2012. 9 Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93 (3):190–7 (Epub 1999/12/22). 10 Murugaiyan J, Ahrholdt J, Kowbel V, Roesler U. Establishment of a matrixassisted laser desorption ionization time-of-flight mass spectrometry database for rapid identification of infectious achlorophyllous green micro-algae of the genus Prototheca. Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases 2012;18 (5):461–7 (Epub 2011/07/26).

Cutaneous protothecosis in a patient with hypogammaglobulinemia.

Prototheca wickerhamii has been predominantly recognised as a pathogen in immunocompromised hosts with deficits in innate or cellular immunity. The ro...
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