r 2010 John Wiley & Sons A/S Transplant Infectious Disease . ISSN 1398-2273
Case report
Periumbilical parasitic thumbprint purpura: Strongyloides hyperinfection syndrome acquired from a cadaveric renal transplant
J.A.Weiser, B.E. Scully,W.A. Bulman, S. Husain, M.E. Grossman. Periumbilical parasitic thumbprint purpura: Strongyloides hyperinfection syndrome acquired from a cadaveric renal transplant. Transpl Infect Dis 2011: 13: 58^62. All rights reserved Abstract: Periumbilical parasitic thumbprint purpura may be a presenting sign of hyperinfection strongyloidiasis in the immunocompromised host.We report a case of fatal hyperinfection strongyloidiasis acquired from a cadaveric renal allograft, diagnosed by the pathognomonic periumbilical thumbprint purpuric eruption, con¢rmed by skin biopsy and laboratory testing.
Periumbilical parasitic thumbprint purpura is a recognizable sign of Strongyloides stercoralis hyperinfection syndrome in the immunocompromised host (1). It usually represents endogenous reactivation of an infection acquired in the distant past from an endemic location. We report a fatal case of Strongyloides hyperinfection syndrome acquired from a cadaveric renal transplantation, diagnosed by the pathognomonic skin rash and con¢rmed by skin biopsy and laboratory testing.
Case report A 68 -year-old man with hypertensive renal failure underwent a right renal cadaveric transplant in March 2009. In June 2009, he was found to have cytomegalovirus (CMV) viremia and leukopenia and was treated with ¢lgrastim
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J.A. Weiser1, B.E. Scully2, W.A. Bulman3, S. Husain1,4, M.E. Grossman1,5 Departments of 1Dermatology, 2Medicine, Infectious Disease, 3 Medicine, Pulmonary and Critical Care, 4Division of Dermatopathology, 5Dermatology Consultation Service, Columbia University Medical Center, New York, New York, USA Key words: Strongyloides; purpura; transplantation; strongyloidiasis; renal transplant; periumbilical thumbprint purura Correspondence to: Jessica A. Weiser, MD, Department of Dermatology, Columbia University Medical Center, 161 Fort Washington Avenue, 12th floor, New York, NY 10032 USA Tel: 1 1 212 305 5317 Fax: 1 1 212 795 1859 Email:
[email protected] Received 24 December 2009, revised 13 March 2010, accepted for publication 30 March 2010 DOI: 10.1111/j.1399-3062.2010.00516.x Transpl Infect Dis 2011: 13: 58–62
and valganciclovir. Two weeks later he complained of lowgrade fevers, nausea, and generalized malaise. In the emergency room he had 4 episodes of co¡ee-ground emesis and gastric lavage was positive for blood. He developed acute respiratory distress requiring intubation. Dense consolidation with air bronchograms involving both lower lobes and the posterior segments of both upper lobes, as well as di¡use ground-glass opacity throughout both lungs concerning for aspiration pneumonia was seen on chest x-ray. He was started on Cytogams (CMV intravenous immunoglobulin), levo£oxacin, and meropenem, in addition to oseltamivir empirically for H1N1 strain of in£uenza despite negative in£uenza nasopharyngeal swab enzyme immunoassay, and subsequent negative in£uenza polymerase chain reaction (PCR) assay. He developed septic shock requiring vasopressor support and dropping hemoglobin levels necessitating transfusions. The patient resided in northeastern United States with his wife and was an avid gardener. His travel history
Weiser et al: Strongyloides purpura after renal transplant
included 2 business trips to Puerto Rico approximately 20 years prior, each 1^2 days duration, but otherwise he had not left the continent. Dermatology was consulted on hospital day 3 for a purpuric rash on the patient’s trunk. He was febrile (temperature 38.61C/101.41F), with bilateral scleral and conjunctival hemorrhage, and extensive purpuric macules and patches (thumbprint purpura) over his anterior abdominal wall (Fig. 1), £anks, and proximal thighs. He had a linear array of purpuric macules extending up the ventral penile shaft onto the suprapubic abdomen (Fig. 1). Endotracheal tube suction aspirates, bronchoalveolar lavage specimens, and nasogastric tube aspirates contained innumerable larvae of S. stercoralis (Fig. 2A, B). The patient was started on albendazole 400 mg per rectum twice daily (b.i.d.) within hours of the initial dermatology consultation; he was unable to tolerate any oral medications because of his substantial gastric outputs. Skin biopsy from the purpuric patches on his abdomen demonstrated larvae throughout the dermis and within the dermal vessels, associated with extravasated erythrocytes (Fig. 3); there was no in£ammatory in¢ltrate. Bronchoalveolar lavage demonstrated bloody secretions throughout the tracheobronchial tree suggestive of pulmonary hemorrhage. On hospital day 3 he grew multidrug-resistant Acinetobacter baumannii from his sputum cultures and his antibiotics were changed from meropenem to ampicillin-sulbactam according to organism sensitivities. His declining renal function necessitated continuous veno-venous hemo¢ltration. The decision was made to discontinue all immunosuppressive agents in the setting of disseminated Strongyloides infection and gram-negative sepsis. On hospital day 6 his gastric outputs diminished and he was started on oral albendazole
Fig. 1. On initial examination the patient demonstrated numerous purpuric macules and patches resembling thumbprints, in a periumbilical distribution.
400 mg b.i.d. and ivermectin 18 mg daily in addition to the rectally administered albendazole. The renal transplantation team contacted the organ donor registry. Our patient received his deceased donor transplant from a 57-year-old Honduran woman who was thought to have died of status asthmaticus but had no history of asthma. Given our patient’s lack of risk factors for Strongyloides exposure and negative S. stercoralis immunoglobulin G antibody titer, the donor serum was tested, at our request, and was found to be S. stercoralis antibody positive. The two other organ recipients from this donor, a liver and a kidney, were also tested and found to have negative Strongyloides serologies but were prophylactically treated with anthelmintic agents. On hospital day 9, our patient’s clinical picture continued to decline and he was started on veterinary formulation ivermectin (200 mcg/kg), administered as 18 mg divided into 2 equal doses subcutaneously every 48 h. His purpuric patches, which had become con£uent during his intensive care unit course, began to regress centrally with treatment, but his gastric aspirates, tracheal aspirates, and stool samples remained persistently positive for S. stercoralis until hospital day 24. Despite broad-spectrum antibiotic, antiviral, antifungal, and anthelmintic treatment, he continued to have worsening CMV viremia as evidenced by rising CMV PCR copy number, septic shock, and cardiac complications. He died on hospital day 28.
Discussion We report a case of Strongyloides hyperinfection syndrome in an immunosuppressed solid organ transplant recipient 3 months after acquiring the nematode from the transplanted kidney. The manifestations of disseminated S. stercoralis infection were indistinguishable from symptoms in a typical host, producing minimal or no symptoms until the immune system became compromised and latent disease could develop into life-threatening infection. The signs of disseminated strongyloidiasis in the immunosuppressed host may be atypical. Eosinophilia may be absent in the debilitated or corticosteroid-treated host (1), so the presence of eosinophilia in these patients should prompt a vigorous search for parasitic infection. Strongyloides hyperinfection should be suspected with unexplained and/or persistent bacteremia with enteric organisms despite appropriate antibiotic therapy (2); nonspeci¢c gastrointestinal complaints such as abdominal pain without distension, nausea, vomiting, or diarrhea; nonspeci¢c pulmonary signs including cough, wheezing, hemoptysis; and transient interstitial in¢ltrates (3). Other indications that raise concern for strongyloidiasis include concurrent
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Weiser et al: Strongyloides purpura after renal transplant
A
B
Fig. 2. Aspirates from the nasogastric tube (A) and from bronchoalveolar lavage (B) demonstrated numerous rhabditiform and ¢lariform larvae of Strongyloides stercoralis.
infection with or prior therapy for other intestinal parasites, and history of residence or travel to an endemic area, even many years prior. Di¡use alveolar hemorrhage associated with strongyloidiasis in the setting of solid organ transplant has been rarely reported. Damage to the alveolar wall capillaries by invasion of the S. stercoralis larvae results in bleeding into the alveolar spaces (4), a process that may be exacerbated by cytotoxic chemokines released by the larvae (5).The parasite itself may piggyback bacteria to the lung and directly cause infection and in£ammation (2). Intubation and the institution of positive pressure ventilation causes retrograde venous
Fig. 3. Skin biopsy from a purpuric patch on the abdomen demonstrated numerous larvae throughout the dermis and within dermal blood vessels, associated with extravasated erythrocytes (hematoxylin & eosin, 10 magni¢cation).
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migration of larvae into the periumbilical portosystemic anastamoses. Transmigration of the ¢lariform Strongyloides larvae across the vascular endothelium into the dermal connective tissue with associated red blood cell extravasation produces the characteristic thumbprint purpura, a term ¢rst used by Bank et al. (6). The unique vascular distribution of the skin lesions in these patients closely parallels that of the caput medusae seen in chronic liver disease with portal hypertension and retrograde £ow toward the umbilicus (7). This easily recognizable pattern of periumbilical purpura that resembles multiple thumbprints allows the clinician to diagnose Strongyloides hyperinfection syndrome, which can be con¢rmed by microscopic examination of the nasogastric aspirates, bronchopulmonary lavage specimen, or skin biopsy. The skin biopsy readily demonstrates Strongyloides ¢lariform larvae in and around blood vessels and throughout the dermis in association with extravasated red blood cells. The absence of an in£ammatory response to the larvae accounts for the eruption being nonpalpable. Kidney allografts have been reported to transmit bacterial infection (8), mycobacterial infections (9), viral infections (10, 11), in addition to Toxoplasma gondii (12), Aspergillus fumigatus (13), Cryptococcus neoformans (14), and S. stercoralis. Most solid organ transplant centers, including ours, do not routinely screen donors or recipients for prior Strongyloides exposure.There are at least 3 reports in the literature speculating that Strongyloides hyperinfection syndrome has resulted from donor organ infection and obligatory immunosuppression (15^17 ). In 1981, Hoy et al. (15) described Strongyloides hyperinfection syndrome in 2 renal transplant recipients who received allografts from the same cadaveric donor thought to have Strongyloides
Weiser et al: Strongyloides purpura after renal transplant
hepatitis on autopsy. Huston et al. (17 ) reported a case of Strongyloides hyperinfection after a cadaveric renal allograft in a 61-year-old woman, with no risk factors, born in South Korea who immigrated to New York at an early age. The organ donor was from Puerto Rico where Strongyloides infection is endemic (17 ). Palau and Pankey (16) described a 49 -year-old man who underwent a cadaveric renal transplant for hypertensive renal failure who had no risk factors for Strongyloides exposure except lifetime residence in Louisiana. Eight days after discontinuation of cyclosporine from his immunosuppressive regimen the patient developed disseminated strongyloidiasis (16). No Strongyloides studies were performed on the renal allograft or the donor in this case or in the case reported by Huston and colleagues Our patient had no history of Strongyloides exposure, and received his cadaveric renal allograft from a Honduran woman subsequently found to have positive Strongyloides serologies. These cases raise the question of pre-transplantation screening for Strongyloides of both donors and recipients. Fatal infection could be prevented through the treatment of strongyloidiasis before initiation of immunosuppression, or through the use of prophylactic anthelmintic therapy in allograft recipients. Immunosuppression regimens including cyclosporine may be advantageous, given the paucity of strongyloidiasis reported in organ transplant patients receiving this medication. The anthelmintic properties of cyclosporine have been demonstrated in mouse models, with comparable clinical e¡ects (18, 19). Treatment of strongyloidiasis in the transplant patient can be challenging. In clinical trials, ivermectin is more e¡ective than thiabendazole and albendazole, is better tolerated, and is considered ¢rst-line therapy (20). Although oral ivermectin is the only form that is US Food & Drug Administration-approved for human use, e¡ective treatment has also been demonstrated with rectal administration (21) and subcutaneous injection of veterinary ivermectin (22, 23), as we used in our patient. Although our patient’s disease was fatal, he cleared the Strongyloides larvae from his stool and gastric and pulmonary aspirates after receiving parenteral ivermectin.The optimal duration of therapy remains uncertain but more frequent administration or prolonged courses of treatment are needed to clear the parasite from all body £uids, especially in patients with hyperinfection syndrome and/or continued immunosuppression. Despite the rapid diagnosis of Strongyloides hyperinfection syndrome and institution of anthelmintic therapy, our patient succumbed to his illness. Many factors may contribute to a fatal outcome from Strongyloides hyperinfection including viral co-infection (i.e., CMV), which may amplify the severity of opportunistic parasitic infections, profound immunosuppression from pulse-dosed corticosteroid ther-
apy of acute transplant rejection, and sudden discontinuation of cyclosporine with loss of its anthelmintic e¡ects.
References 1. Kalb RE, Grossman ME. Periumbilical purpura in disseminated strongyloidiasis. JAMA 1986; 256: 1170^1171. 2. Orlent H, Crawley C, Cwynarski K, et al. Strongyloidiasis pre and post autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 2003; 32: 115^117. 3. Morrell MR, Dallas J, Kollef MH. A 50 -year-old woman with abdominal pain and respiratory failure 3 months after kidney transplantation. Chest 2008; 134: 442^446. 4. Kinjo R,Tsuhako K, Nakazato I, et al. Extensive intra-alveolar haemorrhage caused by disseminated strongyloidiasis. Int J Parasitol 1998; 28: 323^330. 5. Gupta S, Jain A, Fanning TV, et al. An unusual cause of alveolar hemorrhage post hematopoietic stem cell transplantation: a case report. BMC Cancer 2006; 6: 1^5. 6. Bank DE, Grossman ME, Kohn SR, Rabinowitz AD. The thumbprint sign: rapid diagnosis of disseminated strongyloidiasis. J Am Acad Dermatol 1990; 23: 324^326. 7. Grossman ME. Cutaneous manifestations of infection in the immunocompromised host. Baltimore: Lippincott Williams & Wilkins, 1995: 143^148. 8. Dong RL, Boyd PJR, Eykyn S. Staphylococcus aureus transmitted in transplanted kidneys. Lancet 1975; 2: 243^245. 9. Siu YP,Tong MK, Leung KT,Yung CY. Successful kidney retransplantation in a patient with previous allograft kidney tuberculosis. Transpl Infect Dis 2004; 6: 132^135. 10. Betts RF, Freeman RB, Douglas RG, et al. Transmission of cytomegalovirus infection with renal allografts. Kidney Int 1975; 8: 387^394. 11. Yango A Jr, Morrissey P, Gohh R,Wahbeh A. Donor-transmitted parvovirus infection in a kidney transplant recipient presenting as pancytopenia and allograft dysfunction. Transpl Infect Dis 2002; 4: 163^166. 12. Rogers NM, Peh CA, Faull R, Pannell M, Cooper J, Russ GR.Transmission of toxoplasmosis in two renal allograft recipients receiving an organ from the same donor. Transpl Infect Dis 2008; 10: 71^74. 13. Linden E, Restrepo D, Dikman S, et al. Aspergillus infection limited to renal allograft: case report and review of literature.Transpl Infect Dis 2006; 8: 177^181. 14. Ooi BS, Chen BTM, Lin CH, et al. Survival of a patient transplanted with a kidney infected with Cryptococcus neoformans. Transplantation 1971; 11: 428^429. 15. Hoy WE, Roberts NJ, Bryson MF, et al. Transmission of strongyloidiasis by kidney transplant? Disseminated strongyloidiasis in both recipients of kidney allografts from a single cadaver donor. JAMA 1981; 246: 1937^1939. 16. Palau LA, Pankey GA. Strongyloides hyperinfection in a renal transplant recipient receiving cyclosporine: possible Strongyloides stercoralis transmission by kidney transplant. Am J Trop Med Hyg 1997; 57: 413^415. 17. Huston JM, Eachempati SR, Rodney JR, et al. Treatment of Strongyloides stercoralis hyperinfection-associated septic shock and acute respiratory distress syndrome with drotrecogin alfa (activated) in a renal transplant recipient. Transpl Infect Dis 2009; 11: 277^280. 18. McLauchlan PE, Roberts HC, Chappell LH. Mode of action of cyclosporin A against Hymenolepis microstoma (Cestoda): relationship between cyclophilin binding and drug-induced damage. Parasitology 2000; 121: 661^670.
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19. Armson A, Cunningham GA, Grubb WB, et al. Murine strongyloidiasis: the e¡ects of cyclosporin A and thiabendazole administered singly and in combination. Int J Parasitol 1995; 25: 533^535. 20. RoxbyAC, Gottlieb GS, Limaye AP. Strongyloidiasis in transplant patients. Clin Infect Dis 2009; 49: 1411^1423. 21. Tarr PE, Miele PS, Peregoy KS, et al. Rectal administration of ivermectin to a patient with Strongyloides hyperinfection syndrome. Am J Trop Med Hyg 2003; 68: 453^455.
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22. Marty FM, Lowry CM, Rodriguez M, et al. Treatment of human disseminated strongyloidiasis with parenteral veterinary formulation of ivermectin. Clin Infect Dis 2005; 41: 5^8. 23. Pacanowski J, Dos Santos M, Roux A, et al. Subcutaneous ivermectin as a safe salvage therapy in Strongyloides stercoralis hyperinfection syndrome: a case report. Am J Trop Med Hyg 2005; 73: 122^124.
