Abstract
Adult hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly hyperinflammatory syndrome presenting both diagnostic and therapeutic challenges. HLH may be primary, due to an underlying genetic abnormality, and/or secondary to infection, malignancy, or rheumatologic conditions. We describe a case of HLH-associated severe pulmonary hypertension paralleling Epstein–Barr virus (EBV) reactivation in a 52-year-old male in whom a novel perforin missense mutation was found (PRF1 1517C>T). Although intolerant of standard therapy (HLH-2004 protocol), a 6-week course of anti-CD52 (alemtuzumab) was associated with freedom-from-transfusion from weeks 4 to 13. However, 15 weeks after the onset of salvage therapy, he succumbed to polymicrobial sepsis despite treatment with prophylactic anti-infectives, with necropsy revealing disseminated blastomycosis and relapsed HLH. This case illustrates uncertainties in the relationships between pulmonary hypertension, a newly described PRF1 mutation, and possible pre-existing latent infectious risk factors (such as EBV or Blastomyces) in the pathogenesis and therapeutic perils of adult HLH.
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References
Henter JI, Elinder G, Soder O, et al. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80:428–35.
Horne A, Trottestam H, Arico M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140:327–35.
Morrell DS, Pepping MA, Scott JP, et al. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. 2002;138:1208–12.
Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program. 2009;127–131.
Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.
Gupta A, Tyrrell P, Valani R, et al. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;51:402–4.
Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18:29–33.
Nahum E, Ben-Ari J, Stain J, et al. Hemophagocytic lymphohistiocytic syndrome: unrecognized cause of multiple organ failure. Pediatr Crit Care Med. 2000;1:51–4.
Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis. 2003;36:306–12.
Fox CP, Shannon-Lowe C, Gothard P, et al. Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis. 2010;51:66–9.
Sutherland DR, Kuek N, Azcona-Olivera J, et al. Use of a FLAER-based WBC assay in the primary screening of PNH clones. Am J Clin Pathol. 2009;132:564–72.
Kokame K, Nobe Y, Kokubo Y, et al. FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol. 2005;129:93–100.
Schneider EM, Lorenz I, Muller-Rosenberger M, et al. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood. 2002;100:2891–8.
Kherbeck N, Tamby MC, Bussone G, et al. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin Rev Allergy Immunol. 2011 [Epub ahead of print].
Hashimoto T, Sakata Y, Fukushima K, et al. Pulmonary arterial hypertension associated with chronic active Epstein–Barr virus infection. Intern Med. 2011;50:119–24.
Rimar D, Rimar Y, Keynan Y. Human herpesvirus-8: beyond Kaposi’s. Isr Med Assoc J. 2006;8:489–93.
Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med. 2003;349:1113–22.
Morris CR, Gladwin MT, Kato GJ. Nitric oxide and arginine dysregulation: a novel pathway to pulmonary hypertension in hemolytic disorders. Curr Mol Med. 2008;8:620–32.
Choptiany M, Wiebe L, Limerick B, et al. Risk factors for acquisition of endemic blastomycosis. Can J Infect Dis Med Microbiol. 2009;20:117–21.
Kogawa K, Lee SM, Villanueva J, et al. Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood. 2002;99:61–6.
Molleran Lee S, Villanueva J, Sumegi J, et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet. 2004;41:137–44.
Ueda I, Morimoto A, Inaba T, et al. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol. 2003;121:503–10.
Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367–73.
Balamuth NJ, Nichols KE, Paessler M, et al. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2007;29:569–73.
Filipovich AH, Imashuku S, Henter JI, et al. Healing hemophagocytosis. Clin Immunol. 2005;117:121–4.
Perel Y, Alos N, Ansoborlo S, et al. Dramatic efficacy of antithymocyte globulins in childhood EBV-associated haemophagocytic syndrome. Acta Paediatr. 1997;86:911.
Stephan JL, Donadieu J, Ledeist F, et al. Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A. Blood. 1993;82:2319–23.
Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allogeneic SCT in atypical hemophagocytic lymphohistiocytosis. Nat Rev Clin Oncol. 2010;7:415–20.
Ouachee-Chardin M, Elie C, de Saint Basile G, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center report of 48 patients. Pediatrics. 2006;117:e743–50.
Acknowledgments
We gratefully acknowledge the patient and his family for their permission to share this case, as well as the compassionate access support of the CAMPATH Humanitarian Program of Genzyme (Arlene Nugent, Linda Price, Maria Cavallazzi, Karen Hewitt) for therapeutic anti-CD52.
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Gerard, L.M., Xing, K., Sherifi, I. et al. Adult hemophagocytic lymphohistiocytosis with severe pulmonary hypertension and a novel perforin gene mutation. Int J Hematol 95, 445–450 (2012). https://doi.org/10.1007/s12185-012-1029-6
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DOI: https://doi.org/10.1007/s12185-012-1029-6