- Email: [email protected]
Cutaneous gnathostomiasis: Report of 6 cases with emphasis on histopathological demonstration of the larva
DERMATOPATHOLOGY
Cutaneous gnathostomiasis: Report of 6 cases with emphasis on histopathological demonstration of the larva Alvaro C. Laga, MD, MMSc,a Cecilia Lezcano, MD,a Cesar Ramos, MD,b Humberto Costa, MD,c Cesar Chian, MD,d Cesar Salinas, MD,d Martin Salomon, MD,b,d Manuel del Solar, MD,b and Francisco Bravo, MDb,d,e Boston, Massachusetts, and Lima, Peru Background: Cutaneous gnathostomiasis is an emerging food-borne parasitic zoonosis. Histopathological demonstration of the larva on random biopsy specimen of erythematous plaques is infrequent because of its migrating nature. Objective: We sought to determine whether medical treatment with albendazole or ivermectin increases the diagnostic yield of skin biopsy specimen. Methods: A retrospective chart review was conducted in a private dermatology practice in Lima, Peru. Cases with a clinical diagnosis of nodular migratory panniculitis and pathological diagnosis of eosinophilic panniculitis or gnathostomiasis were reviewed. Only cases with definitive diagnosis confirmed by histopathology or parasite isolation were included in the study. Results: A definitive diagnosis of gnathostomiasis was rendered in 6 of 55 reviewed cases. Histopathological or gross identification of the nematode’s larva was made obtaining a biopsy specimen of papules or pseudofuruncles that developed after oral antiparasitic treatment. Limitations: This is a retrospective case series study and no serologic testing was available. Conclusion: Biopsy of a papule or pseudofuruncle subsequent to oral treatment increases the likelihood of demonstrating the larva on skin biopsy specimen, which allows definitive diagnosis and may have therapeutic benefit. ( J Am Acad Dermatol 2013;68:301-5.) Key words: biopsy; eosinophilic; Gnathostoma; gnathostomiasis; migratory; panniculitis; treatment.
nce confined primarily to Southeast Asia, gnathostomiasis has now spread to the Americas, constituting an important health problem in Mexico, Ecuador, and Peru.1-4 With increased travel and globalization, the disease has been detected at increasing rates in nonendemic areas such as Europe, Africa, Australia, and the United States.5-7 Because of the migrating nature of
O
the parasite, the elusive larva is rarely identified on skin biopsy specimens at initial presentation, with diagnostic and therapeutic implications. Although it has been suggested that medical treatment with albendazole stimulates outward migration of the larva, there are conflicting results in a limited number of studies.8,9 We report 6 cases of cutaneous gnathostomiasis in which the larva was either visualized
From the Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Bostona; Departamento de Dermatologia,b Servicio Universitario de Dermatopatologia,d and Instituto de Medicina Tropical Alexander Von Humboldt,e Universidad Peruana Cayetano Heredia, Lima; and Clinica Anglo-Americana, Lima.c A mentorship award from the American Society of Dermatopathology to Dr Laga supported this work. Conflicts of interest: None declared.
Accepted for publication July 16, 2012. Reprint requests: Alvaro C. Laga, MD, MMSc, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, EBRC 4th Floor, Suite 401b, Boston, MA 02115. E-mail: [email protected]. Published online September 3, 2012. 0190-9622/$36.00 Ó 2012 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2012.07.016
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on skin biopsy specimen or directly isolated from the skin after initial treatment with albendazole or ivermectin, and review the literature with emphasis on how to identify the larva on skin biopsy specimen.
specimen obtained from a papule or pseudofuruncle that developed after treatment with oral albendazole or ivermectin showed a cross section of third-stage larva of Gnathostoma species, allowing for definitive diagnosis and treatment (Fig 1). In 1 case, an intact METHODS larva consistent with Gnathostoma species was reThis study was performed according to an institucovered by the physician upon physical examination tional review boardeapof a pustule, which also deproved protocol. A veloped after oral treatment. CAPSULE SUMMARY retrospective chart review In the other case, the patient was conducted in a private recovered the larva after noGnathostomiasis is a parasitic infestation dermatology practice in ticing it coming out of a pusdifficult to confirm on random skin Lima, Peru. Cases with a clintule and brought it to the biopsy specimen because of the ical diagnosis of nodular clinic for identification (after migratory nature of the larva. migratory panniculitis and 10 weeks of oral treatment). Prescribing oral treatment may stimulate pathological diagnosis of This last case was not biopdevelopment of a papule or eosinophilic panniculitis or sied before initiation of treatpseudofuruncle containing the larva. gnathostomiasis were rement, as detailed below. viewed. Only cases with deIdentification of the nemaBiopsy of a papule or pseudo furuncle finitive diagnosis confirmed tode’s larva on these 2 latter subsequent to oral treatment increases by histopathology or parasite cases was made based on the likelihood of demonstrating the larva isolation were included in criteria of larval intestinal on skin biopsy specimen, which allows the study. Age, gender, cells or by counting the definitive diagnosis and may have mode of acquisition, treatrows of hooklets in the cetherapeutic benefit. ment, time from medical phalic bulb, as appropritreatment to histopathologic ate.10,11 Table I shows a diagnosis, follow-up period, and outcome were summary of demographic and clinical data from recorded for all patients. Histopathological diagnosis patients with definitive diagnosis of gnathostomiasis; was confirmed by reviewing hematoxylin-eosin sec2 representative histories are detailed below. The tions showing a cross section of third-stage larva, or recovered intact larva subsequently processed for by identification of the whole larva after extrusion light microscopic examination (case 2) measured from the skin. For 1 case (patient 2), the recovered 2.15 mm from cephalic bulb to caudal end and close intact third-stage larva was included in paraffin after examination revealed 4 rows of transverse hooklets. identification and serially sectioned in entirety in Hematoxylin-eosinestained sections examined at transverse fashion to look for diagnostic features at anatomic landmarks as described by different anatomic levels.10 Sirikulchayanonta and Viriyavejakul10 showed a central esophagus and cervical sacs at the upper cervical level, intestine and reproductive organ at RESULTS mid-body level, and intestine and lateral chords at All, 55 patients were given the diagnosis of the caudal end. The average number of nuclei of eosinophilic panniculitis compatible with gnathosintestinal cells was approximately 3 per cell. tomiasis based on clinical presentation, dietary hisCollectively, these findings are most consistent with tory, and histologic findings. A definitive diagnosis of the third larval stage of Gnathostoma species gnathostomiasis was rendered in 6 cases (11%). In (Fig 2).10-14 4 of these cases, the diagnosis was confirmed after identification of third-stage larvae on skin biopsy REPRESENTATIVE CASE HISTORIES specimen. For the other 2 cases, the diagnosis was Case 1 confirmed after positive identification of whole lateA 39-year-old man presented with a 1-month stage larva recovered from pustules. In the remaining history of migratory, red, tender nodules that mi49 cases, only a presumptive diagnosis of gnathosgrated on his face, from the center of the forehead to tomiasis could be rendered based on history, clinical the right supraorbital region (Fig 1). The patient examination, and eosinophilic infiltrates on skin regularly ingested raw fish marinated in lime juice biopsy specimen. Of note, in 5 of 6 cases, an initial (ceviche). An initial 3-mm punch biopsy specimen biopsy specimen before medical treatment showed from the center of his forehead was taken, which eosinophilic panniculitis but no section of the larva. showed an interstitial inflammatory infiltrate rich in In 4 of these cases, a second skin punch biopsy d
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Fig 1. Migratory panniculitis of gnathostomiasis. A and B, Initial biopsy sites (arrowheads) and subsequent papules developing after oral treatment (arrows). C, Dense dermal and subcutaneous inflammatory infiltrate with numerous eosinophils noted on initial biopsy specimens before treatment. D, Section of late-stage larva of Gnathostoma species identified when obtaining biopsy specimen of papule or pseudofuruncle developed after oral treatment. (C and D, Hematoxylin-eosin stains; original magnifications: C and D, 340; D inset, 3400.)
eosinophils. A presumptive diagnosis of gnathostomiasis was made and the patient was prescribed ivermectin (200 g/kg, single dose). One day later the patient returned to the clinic reporting a tender papule. A second punch biopsy specimen was obtained, which revealed prominent dermal lymphoeosinophilic infiltrate and a section of the thirdstage larva of Gnathostoma species. The patient was prescribed albendazole and recovered uneventfully.
weekly for 5 weeks. The cutaneous eruption cleared, but he developed a small papule close to the umbilicus. He was prescribed 5 additional weekly doses of ivermectin, with ensuing disappearance of the papule. He subsequently developed a smaller papule on the left lower quadrant, with a tender central pustule. After 3 days, the patient noticed a larva emerging from the unroofed pustule, which he brought to the clinic.
DISCUSSION Case 2 A 43-year-old man from Lima, Peru, presented with a 6-week history of an erythematous plaque on the right upper quadrant. The patient stated frequently eating ceviche, sushi, and sashimi. He was initially prescribed an antibiotic with apparent clinical improvement, but the erythematous plaque reappeared 2 weeks later. A presumptive diagnosis of gnathostomiasis was made, and the patient received ivermectin as a single dose (200 g/kg)
We present 6 cases of cutaneous gnathostomiasis with diagnostic confirmation by identification of the characteristic third-stage larvaeeither in biopsy specimen (4 cases) or by direct identification of the whole larva (2 cases)efrom discrete papules or pustules that developed after initiation of treatment with oral antiparasitic agents. Although single case reports have documented the larva at initial presentation, random biopsy specimens from swollen erythematous areas are of extremely low
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Table I. Demographic and clinical characteristics of 6 patients with cutaneous gnathostomiasis Patient no.
1 2 3 4 5 6
Age, y
Gender
Clinical course*
39 43 44 45 42 12
M M F F F F
1 mo 2 mo 1 mo 6 mo 10 d 1 mo
Lesion site
Treatment
Time to positive biopsy, dy
Face Right side of abdomen Right thigh Right thigh Left flank Left lateral aspect of thorax
Ivermectin Ivermectin Albendazole Albendazole Albendazole Albendazole
1 73 7 30 1 14
Exposure
Raw Raw Raw Raw Raw Raw
fish fish fish fish fish fish
F, Female; M, male. *Symptomatic period before medical treatment. y Time elapsed between initiation of treatment (coincident with initial biopsy specimen) and second (positive) biopsy specimen.
Fig 2. Gnathostoma species. Intact late-stage larva was recovered by patient from pustule that developed subsequent to oral treatment.
diagnostic yield because of the migrating nature of the larva.15-17 A randomized placebo-controlled trial investigating the efficacy of albendazole in Thailand concluded that albendazole stimulates outward migration of Gnathostoma larva in human skin. In this study, Suntharasamai et al8 documented that 3 of 41 (7%) patients in the treatment arm (albendazole) experienced outward migration of the larva as compared with none of 40 patients in the placebo group. Of note, more than 50% of patients in both arms of that trial had cutaneous migratory swellings in the upper extremities, with high predominance in the wrist, hands, or fingers. Not surprisingly, the 3 larvae recovered from patients in the albendazole arm were from lesions in the hands. This observation is important, given that penetration of the skin by advanced third-stage larva has been documented in rodents and cats and has been proposed as a potential mechanism of infection in human beings, particularly people handling raw meats.18 It is certainly possible that patients with this mode of acquisition would become aware of the problem sooner thus enhancing the probability of recovering the larva. Alternatively, it
can be argued that hand lesions may be deemed as more trivial or cause only minor if any concern as compared with facial or truncal eruptions, thus incurring potential for neglect bias. In any event, the overall reported rate of hand lesions from gnathostomiasis in the available literature appears to be well below 50%. Moreover, the duration of the disease before enrollment to that trial (and initiation of treatment) ranged from 7 days to 5 years. In particular, patients from which Gnathostoma larvae were recovered had history of cutaneous migratory swellings for 1, 7, and 20 months before initiation of albendazole. This makes it difficult to establish whether some patients had multiple infestation episodes given that Thailand is an endemic area for gnathostomiasis. The recovery of the 3 larvae from patients in the treatment group of that study occurred on days 8, 9, and 16 after initiation of albendazole. More recently, Nontasut et al9 compared the effectiveness of ivermectin versus albendazole in the treatment of gnathostomiasis. They reported skin outward migration and demonstration of the larva in 1 of 21 (5%) patients in the ivermectin group and 3 of 49 (6%) patients in the albendazole group, but no further details are provided in this study (eg, time of treatment to larva recovery). In agreement with the study by Suntharasamai et al,8 all of our 6 patients presented with nodular migratory panniculitis, and the time from treatment to demonstration of the larva was 12 days on average (median ;11 days). In contrast, none of our patients had lesions on the arms or hands (5 of them had lesions on the trunk and 1 on the face) and all had a history of consuming raw fish. Of interest, the majority of the cases (5/6) reported herein involved consumption of marinated fish (ceviche) in Lima, Peru, where arguably all fish used for such recipe is saltwater fish. This would be in contrast to most cases reported in the literature, which have implicated almost exclusively freshwater fish.19 The Centers for Disease Control and Prevention World Wide Web site page on gnathostomiasis states ‘‘.it is felt that the parasite is not transmitted by eating sushi in the U.S. and Western Europe because typically the
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more expensive saltwater fish are used..’’20 This notion also appears to be contradicted in a most recent report by Jarell et al,17 who described a patient with gnathostomiasis on the US West Coast with no travel history but an unusually high consumption of raw fish. Whether saltwater fish is a potential source of gnathostomiasis remains a question deserving further inquiry. Our findings are also consistent with those of Magana et al,3 who reported that 42.2% of 946 patients with nodular migratory panniculitis caused by Gnathostoma species had truncal lesions, compared with 23.2% on the upper extremities, and 16% on the head. Isolation and identification of the nematode larva on skin biopsy specimen has important implications, therapeutically and diagnostically. Histopathological demonstration of the late-stage larva allows definitive diagnosis. This is particularly important in endemic areas because of the high prevalence of other parasitoses that may produce a similar clinical syndrome and eosinophilia. The differential diagnosis includes sparganosis, toxocariasis, and onchocerciasis among others. Serologic diagnosis is not currently available except in Thailand, and the clinical use of serology in endemic areas is limited and may reflect exposure status rather than active infection. Regarding treatment, patients in whom the larva is identified on skin biopsy specimen (or removed in toto by direct extrusion) tend to be cured with no recurrences, in contrast to patients who received medical treatment only.21 An overwhelming majority of the reported cases involve a single larva and thus extraction by biopsy or mechanical extrusion is curative. In the series by Menard et al,5 2 of 5 patients treated with albendazole experienced recurrences. In the 6 patients report herein, there were no recurrences at last follow-up (median follow-up time 6.5 years5,12). Our data support the observation that medical treatment provokes outward migration of Gnathostoma species larva in a subset of patients. This outward migration results in a characteristic papule or pseudofuruncle, which upon biopsy specimen is likely to evidence the third-stage larva. We acknowledge that a limitation of our study is selection bias inherent to case series. Notwithstanding, our data are adequate to suggest that instructing patients to come back to the clinic if a papule or pseudofuruncle develops after medical treatment may facilitate identification of the larva upon skin biopsy specimen. This may prove beneficial diagnostically and therapeutically for patients in whom gnathostomiasis is suspected.
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REFERENCES 1. Ligon BL. Gnathostomiasis: a review of a previously localized zoonosis now crossing numerous geographical boundaries. Semin Pediatr Infect Dis 2005;16:137-43. 2. High WA, Bravo FG. Emerging diseases in tropical dermatology. Adv Dermatol 2007;23:335-50. 3. Magana M, Messina M, Bustamante F, Cazarin J. Gnathostomiasis: clinicopathologic study. Am J Dermatopathol 2004;26: 91-5. 4. Diaz Camacho SP, Zazueta Ramos M, Ponce Torrecillas E, Osuna Ramirez I, Castro Velazquez R, Flores Gaxiola A, et al. Clinical manifestations and immunodiagnosis of gnathostomiasis in Culiacan, Mexico. Am J Trop Med Hyg 1998;59:908-15. 5. Menard A, Dos Santos G, Dekumyoy P, Ranque S, Delmont J, Danis M, et al. Imported cutaneous gnathostomiasis: report of five cases. Trans R Soc Trop Med Hyg 2003;97:200-2. 6. Hale DC, Blumberg L, Frean J. Case report: gnathostomiasis in two travelers to Zambia. Am J Trop Med Hyg 2003;68:707-9. 7. McCarthy J, Moore TA. Emerging helminth zoonoses. Int J Parasitol 2000;30:1351-60. 8. Suntharasamai P, Riganti M, Chittamas S, Desakorn V. Albendazole stimulates outward migration of Gnathostoma spinigerum to the dermis in man. Southeast Asian J Trop Med Public Health 1992;23:716-22. 9. Nontasut P, Bussaratid V, Chullawichit S, Charoensook N, Visetsuk K. Comparison of ivermectin and albendazole treatment for gnathostomiasis. Southeast Asian J Trop Med Public Health 2000;31:374-7. 10. Sirikulchayanonta V, Viriyavejakul P. Various morphologic features of Gnathostoma spinigerum in histologic sections: report of 3 cases with reference to topographic study of the reference worm. Southeast Asian J Trop Med Public Health 2001;32:302-7. 11. Akahane H, Sano M, Kobayashi M. Three cases of human gnathostomiasis caused by Gnathostoma hispidum, with particular reference to the identification of parasitic larvae. Southeast Asian J Trop Med Public Health 1998;29:611-4. 12. Diaz Camacho SP, Diaz Camacho SP, Willms K, Ramos MZ, del Carmen de la Cruz Otero M, Nawa Y, Akahane H. Morphology of Gnathostoma spp isolated from natural hosts in Sinaloa, Mexico. Parasitol Res 2002;88:639-45. 13. Almeyda-Artigas RJ, Bargues MD, Mas-Coma S. ITS-2 rDNA sequencing of Gnathostoma species (Nematoda) and elucidation of the species causing human gnathostomiasis in the Americas. J Parasitol 2000;86:537-44. 14. Bravo F, Mohanna S. A woman with a migratory rash. Clin Infect Dis 2008;47(391):425-6. 15. Crowley JJ, Kim YH. Cutaneous gnathostomiasis. J Am Acad Dermatol 1995;33:825-8. 16. Chappuis F, Farinelli T, Loutan L. Ivermectin treatment of a traveler who returned from Peru with cutaneous gnathostomiasis. Clin Infect Dis 2001;33:E17-9. 17. Jarell AD, Dans MJ, Elston DM, Mathison BA, Ruben BS. Gnathostomiasis in a patient who frequently consumes sushi. Am J Dermatopathol 2011;33:e91-3. 18. Rusnak JM, Lucey DR. Clinical gnathostomiasis: case report and review of the English-language literature. Clin Infect Dis 1993;16:33-50. 19. Herman JS, Chiodini PL. Gnathostomiasis, another emerging imported disease. Clin Microbiol Rev 2009;22:484-92. 20. Parasites-Gnathostomiasis (Gnathostoma infection). Centers for Disease Control and Prevention. Available from: URL: http://www.cdc.gov/parasites/gnathostoma/faqs.html. Accessed April 5, 2012 21. Feinstein RJ, Rodriguez-Valdes J. Gnathostomiasis, or larva migrans profundus. J Am Acad Dermatol 1984;11:738-40.
Cutaneous gnathostomiasis: Report of 6 cases with emphasis on histopathological demonstration of the larva Alvaro C. Laga, MD, MMSc,a Cecilia Lezcano, MD,a Cesar Ramos, MD,b Humberto Costa, MD,c Cesar Chian, MD,d Cesar Salinas, MD,d Martin Salomon, MD,b,d Manuel del Solar, MD,b and Francisco Bravo, MDb,d,e Boston, Massachusetts, and Lima, Peru Background: Cutaneous gnathostomiasis is an emerging food-borne parasitic zoonosis. Histopathological demonstration of the larva on random biopsy specimen of erythematous plaques is infrequent because of its migrating nature. Objective: We sought to determine whether medical treatment with albendazole or ivermectin increases the diagnostic yield of skin biopsy specimen. Methods: A retrospective chart review was conducted in a private dermatology practice in Lima, Peru. Cases with a clinical diagnosis of nodular migratory panniculitis and pathological diagnosis of eosinophilic panniculitis or gnathostomiasis were reviewed. Only cases with definitive diagnosis confirmed by histopathology or parasite isolation were included in the study. Results: A definitive diagnosis of gnathostomiasis was rendered in 6 of 55 reviewed cases. Histopathological or gross identification of the nematode’s larva was made obtaining a biopsy specimen of papules or pseudofuruncles that developed after oral antiparasitic treatment. Limitations: This is a retrospective case series study and no serologic testing was available. Conclusion: Biopsy of a papule or pseudofuruncle subsequent to oral treatment increases the likelihood of demonstrating the larva on skin biopsy specimen, which allows definitive diagnosis and may have therapeutic benefit. ( J Am Acad Dermatol 2013;68:301-5.) Key words: biopsy; eosinophilic; Gnathostoma; gnathostomiasis; migratory; panniculitis; treatment.
nce confined primarily to Southeast Asia, gnathostomiasis has now spread to the Americas, constituting an important health problem in Mexico, Ecuador, and Peru.1-4 With increased travel and globalization, the disease has been detected at increasing rates in nonendemic areas such as Europe, Africa, Australia, and the United States.5-7 Because of the migrating nature of
O
the parasite, the elusive larva is rarely identified on skin biopsy specimens at initial presentation, with diagnostic and therapeutic implications. Although it has been suggested that medical treatment with albendazole stimulates outward migration of the larva, there are conflicting results in a limited number of studies.8,9 We report 6 cases of cutaneous gnathostomiasis in which the larva was either visualized
From the Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Bostona; Departamento de Dermatologia,b Servicio Universitario de Dermatopatologia,d and Instituto de Medicina Tropical Alexander Von Humboldt,e Universidad Peruana Cayetano Heredia, Lima; and Clinica Anglo-Americana, Lima.c A mentorship award from the American Society of Dermatopathology to Dr Laga supported this work. Conflicts of interest: None declared.
Accepted for publication July 16, 2012. Reprint requests: Alvaro C. Laga, MD, MMSc, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, EBRC 4th Floor, Suite 401b, Boston, MA 02115. E-mail: [email protected]. Published online September 3, 2012. 0190-9622/$36.00 Ó 2012 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2012.07.016
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on skin biopsy specimen or directly isolated from the skin after initial treatment with albendazole or ivermectin, and review the literature with emphasis on how to identify the larva on skin biopsy specimen.
specimen obtained from a papule or pseudofuruncle that developed after treatment with oral albendazole or ivermectin showed a cross section of third-stage larva of Gnathostoma species, allowing for definitive diagnosis and treatment (Fig 1). In 1 case, an intact METHODS larva consistent with Gnathostoma species was reThis study was performed according to an institucovered by the physician upon physical examination tional review boardeapof a pustule, which also deproved protocol. A veloped after oral treatment. CAPSULE SUMMARY retrospective chart review In the other case, the patient was conducted in a private recovered the larva after noGnathostomiasis is a parasitic infestation dermatology practice in ticing it coming out of a pusdifficult to confirm on random skin Lima, Peru. Cases with a clintule and brought it to the biopsy specimen because of the ical diagnosis of nodular clinic for identification (after migratory nature of the larva. migratory panniculitis and 10 weeks of oral treatment). Prescribing oral treatment may stimulate pathological diagnosis of This last case was not biopdevelopment of a papule or eosinophilic panniculitis or sied before initiation of treatpseudofuruncle containing the larva. gnathostomiasis were rement, as detailed below. viewed. Only cases with deIdentification of the nemaBiopsy of a papule or pseudo furuncle finitive diagnosis confirmed tode’s larva on these 2 latter subsequent to oral treatment increases by histopathology or parasite cases was made based on the likelihood of demonstrating the larva isolation were included in criteria of larval intestinal on skin biopsy specimen, which allows the study. Age, gender, cells or by counting the definitive diagnosis and may have mode of acquisition, treatrows of hooklets in the cetherapeutic benefit. ment, time from medical phalic bulb, as appropritreatment to histopathologic ate.10,11 Table I shows a diagnosis, follow-up period, and outcome were summary of demographic and clinical data from recorded for all patients. Histopathological diagnosis patients with definitive diagnosis of gnathostomiasis; was confirmed by reviewing hematoxylin-eosin sec2 representative histories are detailed below. The tions showing a cross section of third-stage larva, or recovered intact larva subsequently processed for by identification of the whole larva after extrusion light microscopic examination (case 2) measured from the skin. For 1 case (patient 2), the recovered 2.15 mm from cephalic bulb to caudal end and close intact third-stage larva was included in paraffin after examination revealed 4 rows of transverse hooklets. identification and serially sectioned in entirety in Hematoxylin-eosinestained sections examined at transverse fashion to look for diagnostic features at anatomic landmarks as described by different anatomic levels.10 Sirikulchayanonta and Viriyavejakul10 showed a central esophagus and cervical sacs at the upper cervical level, intestine and reproductive organ at RESULTS mid-body level, and intestine and lateral chords at All, 55 patients were given the diagnosis of the caudal end. The average number of nuclei of eosinophilic panniculitis compatible with gnathosintestinal cells was approximately 3 per cell. tomiasis based on clinical presentation, dietary hisCollectively, these findings are most consistent with tory, and histologic findings. A definitive diagnosis of the third larval stage of Gnathostoma species gnathostomiasis was rendered in 6 cases (11%). In (Fig 2).10-14 4 of these cases, the diagnosis was confirmed after identification of third-stage larvae on skin biopsy REPRESENTATIVE CASE HISTORIES specimen. For the other 2 cases, the diagnosis was Case 1 confirmed after positive identification of whole lateA 39-year-old man presented with a 1-month stage larva recovered from pustules. In the remaining history of migratory, red, tender nodules that mi49 cases, only a presumptive diagnosis of gnathosgrated on his face, from the center of the forehead to tomiasis could be rendered based on history, clinical the right supraorbital region (Fig 1). The patient examination, and eosinophilic infiltrates on skin regularly ingested raw fish marinated in lime juice biopsy specimen. Of note, in 5 of 6 cases, an initial (ceviche). An initial 3-mm punch biopsy specimen biopsy specimen before medical treatment showed from the center of his forehead was taken, which eosinophilic panniculitis but no section of the larva. showed an interstitial inflammatory infiltrate rich in In 4 of these cases, a second skin punch biopsy d
d
d
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Fig 1. Migratory panniculitis of gnathostomiasis. A and B, Initial biopsy sites (arrowheads) and subsequent papules developing after oral treatment (arrows). C, Dense dermal and subcutaneous inflammatory infiltrate with numerous eosinophils noted on initial biopsy specimens before treatment. D, Section of late-stage larva of Gnathostoma species identified when obtaining biopsy specimen of papule or pseudofuruncle developed after oral treatment. (C and D, Hematoxylin-eosin stains; original magnifications: C and D, 340; D inset, 3400.)
eosinophils. A presumptive diagnosis of gnathostomiasis was made and the patient was prescribed ivermectin (200 g/kg, single dose). One day later the patient returned to the clinic reporting a tender papule. A second punch biopsy specimen was obtained, which revealed prominent dermal lymphoeosinophilic infiltrate and a section of the thirdstage larva of Gnathostoma species. The patient was prescribed albendazole and recovered uneventfully.
weekly for 5 weeks. The cutaneous eruption cleared, but he developed a small papule close to the umbilicus. He was prescribed 5 additional weekly doses of ivermectin, with ensuing disappearance of the papule. He subsequently developed a smaller papule on the left lower quadrant, with a tender central pustule. After 3 days, the patient noticed a larva emerging from the unroofed pustule, which he brought to the clinic.
DISCUSSION Case 2 A 43-year-old man from Lima, Peru, presented with a 6-week history of an erythematous plaque on the right upper quadrant. The patient stated frequently eating ceviche, sushi, and sashimi. He was initially prescribed an antibiotic with apparent clinical improvement, but the erythematous plaque reappeared 2 weeks later. A presumptive diagnosis of gnathostomiasis was made, and the patient received ivermectin as a single dose (200 g/kg)
We present 6 cases of cutaneous gnathostomiasis with diagnostic confirmation by identification of the characteristic third-stage larvaeeither in biopsy specimen (4 cases) or by direct identification of the whole larva (2 cases)efrom discrete papules or pustules that developed after initiation of treatment with oral antiparasitic agents. Although single case reports have documented the larva at initial presentation, random biopsy specimens from swollen erythematous areas are of extremely low
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Table I. Demographic and clinical characteristics of 6 patients with cutaneous gnathostomiasis Patient no.
1 2 3 4 5 6
Age, y
Gender
Clinical course*
39 43 44 45 42 12
M M F F F F
1 mo 2 mo 1 mo 6 mo 10 d 1 mo
Lesion site
Treatment
Time to positive biopsy, dy
Face Right side of abdomen Right thigh Right thigh Left flank Left lateral aspect of thorax
Ivermectin Ivermectin Albendazole Albendazole Albendazole Albendazole
1 73 7 30 1 14
Exposure
Raw Raw Raw Raw Raw Raw
fish fish fish fish fish fish
F, Female; M, male. *Symptomatic period before medical treatment. y Time elapsed between initiation of treatment (coincident with initial biopsy specimen) and second (positive) biopsy specimen.
Fig 2. Gnathostoma species. Intact late-stage larva was recovered by patient from pustule that developed subsequent to oral treatment.
diagnostic yield because of the migrating nature of the larva.15-17 A randomized placebo-controlled trial investigating the efficacy of albendazole in Thailand concluded that albendazole stimulates outward migration of Gnathostoma larva in human skin. In this study, Suntharasamai et al8 documented that 3 of 41 (7%) patients in the treatment arm (albendazole) experienced outward migration of the larva as compared with none of 40 patients in the placebo group. Of note, more than 50% of patients in both arms of that trial had cutaneous migratory swellings in the upper extremities, with high predominance in the wrist, hands, or fingers. Not surprisingly, the 3 larvae recovered from patients in the albendazole arm were from lesions in the hands. This observation is important, given that penetration of the skin by advanced third-stage larva has been documented in rodents and cats and has been proposed as a potential mechanism of infection in human beings, particularly people handling raw meats.18 It is certainly possible that patients with this mode of acquisition would become aware of the problem sooner thus enhancing the probability of recovering the larva. Alternatively, it
can be argued that hand lesions may be deemed as more trivial or cause only minor if any concern as compared with facial or truncal eruptions, thus incurring potential for neglect bias. In any event, the overall reported rate of hand lesions from gnathostomiasis in the available literature appears to be well below 50%. Moreover, the duration of the disease before enrollment to that trial (and initiation of treatment) ranged from 7 days to 5 years. In particular, patients from which Gnathostoma larvae were recovered had history of cutaneous migratory swellings for 1, 7, and 20 months before initiation of albendazole. This makes it difficult to establish whether some patients had multiple infestation episodes given that Thailand is an endemic area for gnathostomiasis. The recovery of the 3 larvae from patients in the treatment group of that study occurred on days 8, 9, and 16 after initiation of albendazole. More recently, Nontasut et al9 compared the effectiveness of ivermectin versus albendazole in the treatment of gnathostomiasis. They reported skin outward migration and demonstration of the larva in 1 of 21 (5%) patients in the ivermectin group and 3 of 49 (6%) patients in the albendazole group, but no further details are provided in this study (eg, time of treatment to larva recovery). In agreement with the study by Suntharasamai et al,8 all of our 6 patients presented with nodular migratory panniculitis, and the time from treatment to demonstration of the larva was 12 days on average (median ;11 days). In contrast, none of our patients had lesions on the arms or hands (5 of them had lesions on the trunk and 1 on the face) and all had a history of consuming raw fish. Of interest, the majority of the cases (5/6) reported herein involved consumption of marinated fish (ceviche) in Lima, Peru, where arguably all fish used for such recipe is saltwater fish. This would be in contrast to most cases reported in the literature, which have implicated almost exclusively freshwater fish.19 The Centers for Disease Control and Prevention World Wide Web site page on gnathostomiasis states ‘‘.it is felt that the parasite is not transmitted by eating sushi in the U.S. and Western Europe because typically the
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more expensive saltwater fish are used..’’20 This notion also appears to be contradicted in a most recent report by Jarell et al,17 who described a patient with gnathostomiasis on the US West Coast with no travel history but an unusually high consumption of raw fish. Whether saltwater fish is a potential source of gnathostomiasis remains a question deserving further inquiry. Our findings are also consistent with those of Magana et al,3 who reported that 42.2% of 946 patients with nodular migratory panniculitis caused by Gnathostoma species had truncal lesions, compared with 23.2% on the upper extremities, and 16% on the head. Isolation and identification of the nematode larva on skin biopsy specimen has important implications, therapeutically and diagnostically. Histopathological demonstration of the late-stage larva allows definitive diagnosis. This is particularly important in endemic areas because of the high prevalence of other parasitoses that may produce a similar clinical syndrome and eosinophilia. The differential diagnosis includes sparganosis, toxocariasis, and onchocerciasis among others. Serologic diagnosis is not currently available except in Thailand, and the clinical use of serology in endemic areas is limited and may reflect exposure status rather than active infection. Regarding treatment, patients in whom the larva is identified on skin biopsy specimen (or removed in toto by direct extrusion) tend to be cured with no recurrences, in contrast to patients who received medical treatment only.21 An overwhelming majority of the reported cases involve a single larva and thus extraction by biopsy or mechanical extrusion is curative. In the series by Menard et al,5 2 of 5 patients treated with albendazole experienced recurrences. In the 6 patients report herein, there were no recurrences at last follow-up (median follow-up time 6.5 years5,12). Our data support the observation that medical treatment provokes outward migration of Gnathostoma species larva in a subset of patients. This outward migration results in a characteristic papule or pseudofuruncle, which upon biopsy specimen is likely to evidence the third-stage larva. We acknowledge that a limitation of our study is selection bias inherent to case series. Notwithstanding, our data are adequate to suggest that instructing patients to come back to the clinic if a papule or pseudofuruncle develops after medical treatment may facilitate identification of the larva upon skin biopsy specimen. This may prove beneficial diagnostically and therapeutically for patients in whom gnathostomiasis is suspected.
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