Cutaneous Acquired Toxoplasmosis in a Child: A Case Report and Review of the Literature Andrew J. Rand, MD,* Andrew B. Buck, MD,* Porcia B. Love, MD,† Neil S. Prose, MD,† and M. Angelica Selim, MD*†
Abstract: Cutaneous toxoplasmosis is a rare and diagnostically challenging entity. Today, the acquired form occurs predominantly in immunocompromised patients with human immunodeﬁciency virus or after hematopoietic stem cell transplantation. We report a case of cutaneous toxoplasmosis in a 6-year-old girl after allogeneic stem cell transplantation for immune-mediated encephalopathy, ﬁrst manifesting at 16 months of age. In the post-transplant setting, she developed a rash consisting of approximately 8 scattered 3–4-mm round, erythematous macules and papules on her back, abdomen, and right shoulder. Sections from a biopsy of a lesion on the back revealed numerous spherules tightly packed within small cystic structures in the epidermis. The diagnosis of cutaneous toxoplasmosis was conﬁrmed by an immunohistochemical stain for Toxoplasma gondii and polymerase chain reaction on the peripheral blood for the T. gondii genome. This case should raise awareness that acquired toxoplasmosis with cutaneous involvement can occur in the pediatric population, particularly in immunocompromised patients after stem cell transplantation. Early diagnosis and treatment of this life-threatening opportunistic infection may improve patient outcomes. Key Words: toxoplasmosis, cutaneous, pediatric, immunocompromised, stem cell transplant (Am J Dermatopathol 2015;37:305–310)
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hematopoietic stem cell transplantation8–11 (Table 1). To the best of our knowledge, acquired biopsy-proven cutaneous toxoplasmosis has not been previously reported in a young child.
CASE REPORT We report a case of toxoplasmosis with cutaneous involvement in a 6-year-old girl after allogeneic stem cell transplant for immune-mediated encephalopathy associated with celiac disease, ﬁrst manifesting at 16 months of age. In the post-transplant setting, while immunocompromised on mycophenolate mofetil and prednisone, she developed a rash consisting of approximately 8 scattered 3–4-mm round, erythematous nonscaling macules and papules on her back, abdomen, and right shoulder (Figs. 1, 2). The examination was negative for mucosal lesions and lymphadenopathy. The ﬁndings were initially interpreted as engraftment syndrome. Punch biopsy of a papule on the back was performed. At low magniﬁcation, the hematoxylin and eosin–stained sections were mostly unremarkable with mild perivascular lymphocytic inﬂammation in the superﬁcial dermis (Fig. 3). Closer inspection of the epidermis revealed numerous spherules (bradyzoites) packed tightly within small cysts in the cytoplasm of keratinocytes (Figs. 4, 5). The bradyzoites were highlighted by an immunohistochemical stain for T. gondii, conﬁrming the diagnosis (Fig. 6). Additionally, polymerase chain reaction (PCR) testing on whole blood showed 4600 DNA copies per milliliter of T. gondii genome, which increased to 12,800 DNA copies per milliliter in 3 days. PCR performed 3 months earlier on cerebrospinal ﬂuid had been negative for T. gondii genome, and thus conversion suggested a new infection. She was treated initially with clindamycin and atovaquone, and then transitioned to clindamycin, pyrimethamine, and leucovorin. The cutaneous lesions began to resolve within 2 days after the start of therapy. No acute neurological changes were noted throughout her hospitalization, and none of the characteristic ring-enhancing brain lesions of toxoplasmosis were seen radiographically. She did, however, develop worsening adenoviremia, pneumonitis, and respiratory failure. Eight days after the diagnostic skin biopsy, the patient was transitioned to DNAR (Do Not Attempt Resuscitation) status and died the next day.
DISCUSSION T. gondii is a protozoan parasite that infects humans and virtually all other warm-blooded animals worldwide.12 Humans acquire it primarily by ingestion of contaminated food and water, or in utero. The prevalence of Toxoplasma infection in humans varies widely between and within countries, ranging from 10% to 80%. Seroprevalence is low (10%–30%) in North America, Northern Europe, and Southeast Asia; moderate (30%–50%) in Central and Southern Europe; and high in Latin America and tropical African www.amjdermatopathology.com |
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Rand et al
TABLE 1. Cases of Cutaneous Toxoplasmosis Reported in the Literature in the Last 3 Decades
Leyva et al , 1986
8 9 10
Associated Clinical Conditions
Systemic/ Neurologic Involvement
Physical Exam Findings
CML in blast phase, after Multiple 1-cm palpable purpuric nodules on the scalp, right bone marrow transplant forearm, back, and bilateral groin areas Hirschmann and Chu4, 27/M Heroin addict with AIDS Numerous 0.5–1.0-cm red, blanching, nontender, nonpruritic 1988 papules on face, trunk, legs, and arms, but not palms and soles Mawhorter et al16, 1992 50/M Immune competent Prominent 5–15-mm macular and papular lesions. Purpuric changes involving palms, soles, and rest of body Fernandez et al21, 1994 60/M Immune competent Blanchable erythema of all areas except the mucous membranes, midback, axillae, and genitalia. The neck, elbows and knees were licheniﬁed Unknown HIV infection Unknown Rabaud et al6, 1994 Arnold et al3, 1997 12/F Undergoing induction Maculopapular skin rash chemotherapy for lymphoma 37/M Refractory ALL, after Greater than 50 nonvesicular, pleomorphic papular skin lesions Lee et al10, 2005 bone marrow transplant on extremities, torso, abdominal wall, and face; these lesions were discrete with no accompanying induration or central necrosis 31/F AML, after bone marrow 5–6 scattered purplish papules (0.5–0.8 cm in diameter) on the Amir et al11, 2008 transplant legs, slightly raised, with mild hyperemia and indistinct borders Vidal et al8, 2008 16/M ALL, after bone marrow Subtle papular erythematous rash on back and chest transplant Fong et al5, 2010 49/M HIV infection Multiple hard and painful nodular lesions on both arms, hands, and a few on the chest. The nodules were nontender and variable in size (0.5–3 cm in diameter) 60/F Aplastic anemia Multiple disseminated small vesicles with little surrounding Zimmermann et al7, 2013 erythema on face, arms, legs, back, and abdomen (Our case) 6/F Immune-mediated 8, 3–4-mm macules and papules on back, abdomen, and right encephalopathy, after shoulder bone marrow transplant
Age/ Gender, Yr 53/M
Skin Biopsy Findings Organisms found within epidermal keratinocytes (at all levels), both singularly and in cysts, with dermal involvement. No inﬂammatory reaction Moderate perivascular inﬁltrate, predominantly neutrophilic in the superﬁcial and deep dermis. Leukocytoclastic vasculitis in the superﬁcial dermis. No organisms were seen T. gondii not identiﬁed, even with immunoperoxidase cytochemistry Parakeratosis of stratum corneum with collections of neutrophils overlying epidermal acanthosis with spongiosis. Also seen was a superﬁcial perivascular lymphocytic inﬁltrate with scattered eosinophils The organism was identiﬁed Extensive mixed septal and lobular panniculitis with predominantly lymphohistiocytic inﬁltrates and scattered neutrophils. There were scattered extracellular Toxoplasma tachyzoites and rare intracellular tachyzoites within dermal histiocytes. No cysts were identiﬁed
Ancillary Diagnostic Studies Electron microscopy revealed protozoan organisms within the cytoplasm of keratinocytes and macrophages Bone marrow biopsy revealed a nodular inﬁltrate of histiocytes containing Toxoplasma organisms. Toxoplasma dye test was markedly elevated at 1:800
Yes/No Yes/No Yes/No
Yes/Yes Yes/Yes No/No
Pyrimethamine, sulfamethoxazole, and folinic acid (leukovorin) Sulfadiazine and pyrimethamine
Indirect immunoﬂuorescence antibody (IgM Pyrimethamine and and IgG) assay was positive trimethoprim– for T. gondii sulfamethoxazole Toxoplasma IgM and IgG titers were Antibiotics for diagnostic of acute infection secondary impetigo
Giemsa stain conﬁrmed the presence of the organism T. gondii conﬁrmed by IHC staining
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Cutaneous Toxoplasmosis: A Case Report
TABLE 1. (Continued ) Cases of Cutaneous Toxoplasmosis Reported in the Literature in the Last 3 Decades Case No. 7
Skin Biopsy Findings Multiple T. gondii bradyzoites in keratinocytes and endothelial cells
Dermal edema, extravasated erythrocytes, necrotic collagen, and scattered karyorectic debris. Viable neutrophils and other inﬂammatory cells were not seen. Small cysts containing tiny parasites (bradyzoites) were seen singly in the epidermis, skin appendages including follicular epithelium and sweat glands and ducts, and in endothelial cells in the dermis. In addition, tiny free parasites (tachyzoites) were seen lying haphazardly in the dermis 9 Cell-poor interface dermatitis with occasional necrotic keratinocytes. T. gondii bradyzoites and tachyzoites were identiﬁed within the epidermal keratinocytes 10 Numerous granulomas and foci of macrophages with intracellular and extracellular organisms in the dermis. These organisms were crescent-shaped, resembling the zoites of T. gondii 11 Intracytoplasmic particles with the shape of parasites were detected in epidermal keratinocytes. Bradyzoites and tachyzoites were mostly intracytoplasmic and occasionally extracellular 12 Numerous spherules tightly packed within (Our case) small cystic structures (bradyzoites) in the epidermis
Ancillary Diagnostic Studies
T. gondii conﬁrmed by IHC staining
Clindamycin and pyrimethamine
Pretransplant serology positive for Unknown Toxoplasma IgG. The parafﬁn-embedded skin biopsy, stored CSF sample from postadmission day 16, and a post-admission day 37 CSF sample were positive for T. gondii by PCR
Outcome Death, probably from systemic inﬂammatory response related to engraftment syndrome Death from multiple organ failure
T. gondii conﬁrmed by IHC staining. Pyrimethamine and Recovery Pretransplant serological testing was sulfadiazine. Daily positive for T. gondii, with Toxoplasma granulocyte IgG measuring 406 mg/mL and IgM transfusions for 3 days negative T. gondii was conﬁrmed by electron Sulfadiazine and The existing lesions microscopy. PCR analysis of skin biopsy pyrimethamine failed to respond to was positive. Serological tests for antitherapy and new Toxoplasma IgG and IgM were negative lesions appeared T. gondii detected by IHC staining and PCR Unknown analysis of skin biopsy
T. gondii detected by IHC staining on skin biopsy and PCR testing on whole blood
Initially clindamycin and atovaquone, then clindamycin, pyrimethamine, and leucovorin
Death from respiratory failure secondary to multiple infections
Death with adenoviremia, pneumonitis, and respiratory failure
AIDS, acquired immune deﬁciency syndrome; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; CSF, cerebrospinal ﬂuid; F, female; HIV, human immunodeﬁciency virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IHC, immunohistochemical; M, male; PCR, polymerase chain reaction.
Cutaneous toxoplasmosis may occur in both congenital and acquired infection, including acute and reactivated forms.12 It is uncommon, occurring in less than 10% of acquired infections.16 The frequency is thought to be greater in severe or disseminated infections and in immunocompromised hosts.16,17 However, in a French National Survey in 1994 of extracerebral toxoplasmosis in 199 HIV-infected patients in 37 hospitals, only 1 had biopsy-proven cutaneous infection.6 Acquired cutaneous toxoplasmosis was ﬁrst described by Pinkerton et al18–20 in 1940–1941. A thorough review of the literature yielded only 11 reported cases in the last 3 decades. All but 2 cases16,21 of cutaneous toxoplasmosis were reported in patients with known immunosuppression, including 3 with HIV infection,4–6 1 with aplastic anemia,7 1 undergoing induction chemotherapy for lymphoma,3 and 4 after bone marrow transplantation8–11 (Table 1). Cutaneous involvement in congenital toxoplasmosis has been reported; it was ﬁrst described by Magarinos Torres in 1928, in a 2-day-old newborn child with congenital encephalomyelitis, myocarditis, and myositis.20 Acquired cutaneous www.amjdermatopathology.com |
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FIGURE 1. A 4 mm round, erythematous non-scaling papule (arrowhead) on the abdomen. Approximately 8 of these lesions were identified on the abdomen, back, and right shoulder.
toxoplasmosis in children has also been reported. In 1950, a case of erythema chronicum migrans (partially bullous) and meningitis in an immunocompetent 7-year-old boy was attributed to toxoplasmosis based on positive serology, although skin biopsy was not performed.22 Herein, we have described the youngest patient in the literature with acquired, biopsy-proven cutaneous toxoplasmosis, diagnosed in a 6-year-old girl after unrelated cord blood transplant for immune-mediated encephalopathy.
FIGURE 3. Punch biopsy of the skin with mild perivascular lymphocytic inflammation in the superficial dermis (hematoxylin and eosin, scale bar = 200 mm).
FIGURE 2. Scattered 3–4-mm round, erythematous nonscaling papules (arrowheads) on the flank. Approximately 8 of these lesions were identified on the abdomen, back, and right shoulder.
The diagnosis of cutaneous toxoplasmosis is not straightforward. The presence of symptoms mimicking but unrelated to systemic toxoplasmosis may confound the diagnosis. This was true for our patient, who had several nonspeciﬁc neurological problems from 16 months of age, including developmental regression, gait ataxia, left-sided hemiparesis, and seizures. However, the negative PCR test for the T. gondii genome 3 months before the positive PCR test and skin biopsy conﬁrms that she acquired toxoplasmosis during her hospitalization (after allogeneic stem cell transplantation) and that the chronic neurological symptoms, attributed to immune-mediated encephalopathy, were unrelated to toxoplasmosis. The classic neurological manifestations of toxoplasmosis, including ring-enhancing intracranial lesions and chorioretinitis, may raise the suspicion for cutaneous involvement of toxoplasmosis, but they are not always present. In the past 3 decades, only 4 of 11 other reported cases of cutaneous toxoplasmosis showed neurological involvement (Table 1). This was also true for our patient, who showed neither acute neurological changes nor enhancing brain lesions by computed tomography during her hospitalization. The physical ﬁndings of cutaneous toxoplasmosis are variable and nonspeciﬁc. In congenital infection, skin lesions are usually hemorrhagic or necrotic papules found primarily on the trunk.12 In acquired infection, a maculopapular erythematous rash involving the trunk is most common.17 When the extremities are involved, the palms and soles are usually spared. However, cutaneous lesions have also been reported as papulopustular, vesicular, nodular, morbilliform, purpuric, lichenoid, vegetative,
FIGURE 5. Numerous spherules (bradyzoites, arrows) packed tightly within small cysts in the cytoplasm of epidermal keratinocytes (hematoxylin and eosin, scale bar = 50 mm).
(8–30 mm, intracellular colonies of zoites that give parasitized cells an irregular shape).12,17 T. gondii must be distinguished from morphologically similar organisms including Histoplasma capsulatum, Leishmania, Trypanosoma, and others. These organisms tend to elicit a different inﬂammatory response. H. capsulatum, for example, usually produces a granulomatous reaction in immunocompetent hosts.17 Yeast forms of H. capsulatum are surrounded by a small halo (from shrinkage artifact) and are positive for Gomori methenamine silver stain. Leishmania and Trypanosoma species may be distinguished from T. gondii by identifying kinetoplasts. The recommended diagnostic tools for T. gondii are the immunohistochemical stain on parafﬁn-embedded tissue and PCR for the T. gondii genome in the peripheral blood. Other serologic testing and electron microscopy are of limited utility. In a patient recovering from bone marrow transplantation, cutaneous toxoplasmosis must be distinguished from engraftment syndrome, graft-versus-host disease (GVHD), and drug toxicity, as well as other opportunistic infections.8 This can be very challenging with signiﬁcant implications for prognosis and treatment. Toxoplasmosis is usually distinguished from these other entities by, for example, the absence of interface dermatitis with satellitosis (as seen in GVHD) and the lack of abundant eosinophils (as in a drug reaction). In one reported case, however, T. gondii confounded the www.amjdermatopathology.com |
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and Steven Conlon for expert help with microscopic photography.
ACKNOWLEDGMENTS The authors thank Joseph Geradts, MD, for skillful translation of German text into English, and Susan Reeves
1. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363: 1965–1976. 2. Weiss LM, Dubey JP. Toxoplasmosis: a history of clinical observations. Int J Parasitol. 2009;39:895–901. 3. Arnold SJ, Kinney MC, McCormick MS, et al. Disseminated toxoplasmosis. Unusual presentations in the immunocompromised host. Arch Pathol Lab Med. 1997;121:869–873. 4. Hirschmann JV, Chu AC. Skin lesions with disseminated toxoplasmosis in a patient with the acquired immunodeﬁciency syndrome. Arch Dermatol. 1988;124:1446–1447. 5. Fong MY, Wong KT, Rohela M, et al. Unusual manifestation of cutaneous toxoplasmosis in a HIV-positive patient. Trop Biomed. 2010;27: 447–450. 6. Rabaud C, May T, Amiel C, et al. Extracerebral toxoplasmosis in patients infected with HIV. A French National Survey. Medicine (Baltimore). 1994;73:306–314. 7. Zimmermann S, Hadaschik E, Dalpke A, et al. Varicella-like cutaneous toxoplasmosis in a patient with aplastic anemia. J Clin Microbiol. 2013; 51:1341–1344. 8. Vidal CI, Pollack M, Uliasz A, et al. Cutaneous toxoplasmosis histologically mimicking graft-versus-host disease. Am J Dermatopathol. 2008; 30:492–493. 9. Leyva WH, Santa Cruz DJ. Cutaneous toxoplasmosis. J Am Acad Dermatol. 1986;14:600–605. 10. Lee SA, Diwan AH, Cohn M, et al. Cutaneous toxoplasmosis: a case of confounding diagnosis. Bone Marrow Transplant. 2005;36:465–466. 11. Amir G, Salant H, Resnick IB, et al. Cutaneous toxoplasmosis after bone marrow transplantation with molecular conﬁrmation. J Am Acad Dermatol. 2008;59:781–784. 12. Lupi O, Bartlett BL, Haugen RN, et al. Tropical dermatology: tropical diseases caused by protozoa. J Am Acad Dermatol. 2009;60:897–925; quiz 926–898. 13. Robert-Gangneux F, Darde ML. Epidemiology of and diagnostic strategies for toxoplasmosis. Clin Microbiol Rev. 2012;25:264–296. 14. Jones JL, Kruszon-Moran D, Sanders-Lewis K, et al. Toxoplasma gondii infection in the United States, 1999–2004, decline from the prior decade. Am J Trop Med Hyg. 2007;77:405–410. 15. Barry MA, Weatherhead JE, Hotez PJ, et al. Childhood parasitic infections endemic to the United States. Pediatr Clin North Am. 2013;60: 471–485. 16. Mawhorter SD, Effron D, Blinkhorn R, et al. Cutaneous manifestations of toxoplasmosis. Clin Infect Dis. 1992;14:1084–1088. 17. Nelson A, Hofman P, Lemons-Estes F. Protozoal and algal infections. In: Barnhill R, ed. Dermatopathology: Third Edition: McGraw-Hill Medical; 2010:517–529. 18. Pinkerton H, Weinman D. Toxoplasma infection in man. Arch Pathol. 1940;30:374–392. 19. Pinkerton H, Henderson RG. Adult toxoplasmosis: a previously unrecognized entity simulating the typhus-spotted fever group. JAMA. 1941; 116:807–814. 20. Binazzi M. Historical aspects of cutaneous toxoplasmosis. Int J Dermatol. 1986;25:401–404. 21. Fernandez DF, Wolff AH, Bagley MP. Acute cutaneous toxoplasmosis presenting as erythroderma. Int J Dermatol. 1994;33:129–130. 22. Schirduan M. Verdacht auf Toxoplasmose bei Meningitis nach Erythema chronicum migrans bullosum [in German]. Arch Dermatol Syph. 1950;192: 256–260. 23. Justus J. Cutaneous manifestations of toxoplasmosis. Curr Probl Dermatol. 1972;4:24–47. 24. Binazzi M, Papini M. Cutaneous toxoplasmosis. Int J Dermatol. 1980; 19:332–335. 25. Topi G, D’Alessandro Gandolfo L, Giacalone B, et al. Acquired cutaneous toxoplasmosis. Dermatologica. 1983;167:24–32. 26. Binazzi M. Proﬁle of cutaneous toxoplasmosis. Int J Dermatol. 1986;25: 357–363.
FIGURE 6. Immunohistochemical stain for T. gondii highlighting bradyzoites in the epidermis (T. gondii stain, scale bar = 50 mm).
diagnosis by eliciting a reaction pattern similar to that seen in GVHD.8 Evidence of damage to other organs like the gastrointestinal tract and liver may support GVHD, and a history of exposure to new medications suggests drug toxicity. Most cases of disseminated toxoplasmosis in stem cell transplant recipients are diagnosed after death. In the literature, there is only 1 case of a bone marrow transplant recipient who survived with appropriate treatment after toxoplasmosis was diagnosed on a skin biopsy.8 Although our 6-year-old patient died of unrelated respiratory complications 9 days after her diagnostic skin biopsy, she received appropriate treatment for toxoplasmosis, followed by resolution of her cutaneous lesions and no acute neurological changes. We wish to raise awareness that acquired cutaneous toxoplasmosis can occur in the pediatric population, particularly among immunocompromised bone marrow transplant recipients. The physical ﬁndings are variable, and the disease may present without its classic systemic ﬁndings. We hope that this report will facilitate early diagnosis and appropriate treatment in the future, so that the morbidity and mortality associated with this life-threatening opportunistic infection may be minimized.