Hemophagocytic lymphohistiocytosis (HLH) is a disorder in which too many infection-fighting cells are produced and activated, causing organ inflammation and damage. If HLH is diagnosed quickly and accurately at a center equipped to manage this complicated disease, a cure is possible. The Children’s Hospital of Philadelphia (CHOP) has a team of experts dedicated to treating HLH.
HLH is not a cancer, but it is treated with some of the same medications as leukemia and lymphoma. To provide the best outcomes for children, CHOP has formed an HLH Treatment Team consisting of oncologists, immunologists, pathologists, neurologists, rheumatologists, clinical pharmacologists and basic scientists. These experts work together to coordinate the care required for a child with HLH.
The HLH Treatment Team helps CHOP pediatricians, and other local physicians, with the diagnosis and treatment of HLH. Because taking action quickly is important to getting the best outcome for children with HLH, the team helps guide physicians through the complex process of ordering the right tests, interpreting their results, diagnosing the disease and deciding on the treatment plan. Together, these services ensure that the patient gets the care he or she needs as quickly as possible.
A suspicion of HLH is raised when children exhibit specific clinical and laboratory manifestations.
The clinical features include high and often prolonged periods of fever, enlargement of the spleen, and at times rash, irritability and/or seizures.
Laboratory features include lowering of the blood counts, elevated levels of chemicals in the blood such as soluble interleukin 2 receptor (sIL-2r), certain cytokines and ferritin. Patients with HLH also often exhibit abnormalities in their immune cells, such as reduced expression of proteins such as perforin, SAP or XIAP, and/or depressed cell functions (reduced cytotoxicity and/or degranulation).
In addition to routine blood work, children suspected to have HLH will undergo specialized diagnostic tests. These include:
These tests will help determine whether your child has HLH, and if so, whether it is primary (familial) or secondary (sporadic) HLH.
For children with primary HLH, the first step is to suppress the overactive immune system, commonly by treatment with a combination of steroids and chemotherapy; the goal is to put the disease in remission.
After this initial treatment, children with familial HLH generally undergo allogeneic stem cell transplantation (replacing their defective immune system with a healthy one from a different person), which offers the best chance of a cure.
For children with secondary HLH, the medical team will try to identify and treat the underlying cause of the HLH (the trigger). Generally, this is sufficient to put the HLH into remission. However, it is sometimes necessary to use steroids and/or chemotherapy, as in the case of primary HLH.
The biggest hurdle in HLH treatment is identifying alternatives for children who don’t respond to currently available combinations of chemotherapy, steroids and stem cell transplantation. HLH experts at CHOP are hard at work in the lab studying the functions of immune cells in HLH patients, trying to identify new genetic causes for familial HLH and testing new drugs that might be effective for patients who experience a relapse or whose HLH does not respond to current treatments.
CHOP is also participating in a multi-site pilot study led by Cincinnati Children’s Hospital, which is evaluating the safety and effectiveness of a novel treatment regimen for patients with HLH. CHOP will open its own in-house clinical trial to test another type of HLH therapy in the spring of 2014. Check back for more information.
CHOP would like to acknowledge the family of Sean Fischel, a young boy who died of HLH. The Fischels have raised nearly $50,000 for HLH research at CHOP. Their support is invaluable in our search to find new, more effective treatment options for children with this disease.
For those children with HLH, our experts offer a variety of services in addition to the many treatment-related recommendations. The team:
Families can also contact the Histiocytosis Association of America for more information and resources.
To refer a patient: Call 267-426-0762 or contact the Cancer Center online.
The HLH Treatment Team works closely with primary care physicians, who are often the first to spot signs of HLH. For these physicians, the team:
Interferon-γ mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice. Canna SW, Wrobel J, Chu N, Kreiger PA, Paessler M, Behrens EM. Arthritis Rheum. 2013 Jul;65(7):1764-75.
Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, Nichols KE, Suppa EK, Kalos M, Berg RA, Fitzgerald JC, Aplenc R, Gore L, Grupp SA. Blood. 2013 Jun 27;121(26):5154-7.
Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, Nichols KE; EBV-HLH Rituximab Study Group. Br J Haematol. 2013 Aug;162(3):376-82. doi: 10.1111/bjh.12386. Epub 2013 May 21.
Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes.
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Rapamycin does not control hemophagocytic lymphohistiocytosis in LCMV-infected perforin-deficient mice. Rothman JA, Das R, Teachey DT, Paessler ME, Nichols KE. Pediatr Blood Cancer. 2011 Dec 15;57(7):1239-43. doi: 10.1002/pbc.23226.
Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, Kambayashi T, Koretzky GA. J Clin Invest. 2011 Jun;121(6):2264-77.
Not all hemophagocytes are created equally: appreciating the heterogeneity of the hemophagocytic syndromes. Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, Kambayashi T, Koretzky GA. J Clin Invest. 2011 Jun;121(6):2264-77.
Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. Rezaei N, Hedayat M, Aghamohammadi A, Nichols KE. J Allergy Clin Immunol. 2011 Jun;127(6):1329-41.e2; quiz 1342-3.
X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, Heath PT, Steward CG, Smith O, O'Meara A, Kerrigan H, Mahlaoui N, Cavazzana-Calvo M, Fischer A, Moshous D, Blanche S, Pachlopnik Schmid J, Latour S, de Saint-Basile G, Albert M, Notheis G, Rieber N, Strahm B, Ritterbusch H, Lankester A, Hartwig NG, Meyts I, Plebani A, Soresina A, Finocchi A, Pignata C, Cirillo E, Bonanomi S, Peters C, Kalwak K, Pasic S, Sedlacek P, Jazbec J, Kanegane H, Nichols KE, Hanson IC, Kapoor N, Haddad E, Cowan M, Choo S, Smart J, Arkwright PD, Gaspar HB. Blood. 2011 Nov 3;118(18):5060.
Pathology of the liver in familial hemophagocytic lymphohistiocytosis. Chen JH, Fleming MD, Pinkus GS, Pinkus JL, Nichols KE, Mo JQ, Perez-Atayde AR. Am J Surg Pathol. 2010 Jun;34(6):852-67.
Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis. Olin RL, Nichols KE, Naghashpour M, Wasik M, Shelly B, Stadtmauer EA, Vogl DT. Am J Hematol. 2008 Sep;83(9):747-9.
Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis. Balamuth NJ, Nichols KE, Paessler M, Teachey DT. J Pediatr Hematol Oncol. 2007 Aug;29(8):569-73.
Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy. Milone MC, Tsai DE, Hodinka RL, Silverman LB, Malbran A, Wasik MA, Nichols KE. Blood. 2005 Feb 1;105(3):994-6. Epub 2004 Oct 19.
Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Arico M, Imashuku S, Clementi R, Hibi S, Teramura T, Danesino C, Haber DA, Nichols KE. Blood. 2001 Feb 15;97(4):1131-3.
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