eMedicine Specialties > Pediatrics: General Medicine > Oncology

Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis): Follow-up

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Aug 21, 2009

Follow-up

Further Outpatient Care

  • Supportive care is needed to ensure that the patient with hemophagocytic lymphohistiocytosis (HLH) remains stable until a bone marrow donor can be found. This includes transfusions of RBCs, platelets, and fresh frozen plasma, as well as nutritional support in addition to the treatment protocol.22
  • Patients should be continually monitored for evidence of infection because of their immunosuppressed state. Be aware of the possibility of underlying malignancy.
  • Biopsies and diagnostic cytogenetics may be needed in addition to selective radiographic imaging.12

Complications

  • Complications of individual drugs in the regimen were outlined above (see Medication).
  • Complications due to a subsequent transplant are numerous and include both acute and chronic graft versus host disease, acute inflammatory events, respiratory distress syndrome, and exacerbation of neurologic symptoms.26

Prognosis

  • Although the prognosis varies between studies and with different approaches to treatment, the disease is invariably fatal if not treated. The median survival rate has been reported to be 2-6 months without treatment, but survival time has dramatically improved with the advent of the HLH-94 protocol already discussed.
  • A study of 122 patients from the International Registry for hemophagocytic lymphohistiocytosis found that the overall estimated 5-year survival rate was 21%, with 66% of patients who received bone marrow transplantation (BMT) surviving 5 years versus only 10.1% of patients treated with chemotherapy alone.14 More recent studies have shown that the HLH-94 protocol resulted in an overall survival rate of 55%. Success or failure of an allogeneic BMT is the most important long-term prognostic factor. Unfortunately, many cases are diagnosed late in the course of the disease, after irreversible damage has occurred.
  • Although patients with hemophagocytic lymphohistiocytosis are at high risk for death early in their disease course, steroids, intravenous immunoglobulin (IVIG), or both may be sufficient as first-line therapy for selected patients.27

Patient Education

  • All physicians who treat young patients must be aware of life-threatening diseases such as hemophagocytic lymphohistiocytosis.
  • Pediatricians, dermatologists, and neurologists should especially take note because the presenting symptoms of hemophagocytic lymphohistiocytosis are likely to bring the patient into their offices.
  • Any suspicion warrants a referral to a pediatric hematologic-oncologist who is equipped with the necessary tools to make a rapid diagnosis.

Miscellaneous

Medicolegal Pitfalls

  • Be aware of this disease, both in its typical onset and when it occurs later in life with the initial presentation of CNS symptoms or underlying malignancy rather than the typical triad of a fever, hepatosplenomegaly, and pancytopenia.
  • Cases of hemophagocytic lymphohistiocytosis (HLH) erroneously labeled as child abuse have been reported in the literature.28
  • Failure to make the diagnosis of hemophagocytic lymphohistiocytosis may result in adverse consequences.

Special Concerns

  • Although rare, the disease onset can occur later in life with the initial presentation of CNS symptoms or underlying malignancy rather than the typical triad of a fever, hepatosplenomegaly, and pancytopenia.
  • Physicians should be aware of this atypical presentation and consider hemophagocytic lymphohistiocytosis in their differentials.20
 
Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Nicole L Lacz, MD, and Franklin Desposito, MD, to the original writing and development of this article.



More on Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)

Overview: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Differential Diagnoses & Workup: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Treatment & Medication: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Follow-up: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
Multimedia: Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis)
References
[ CLOSE WINDOW ]

References

  1. Morrell DS, Pepping MA, Scott JP, et al. Cutaneous manifestations of hemophagocytic lymphohistiocytosis. Arch Dermatol. Sep 2002;138(9):1208-12. [Medline].

  2. Feldmann J, Le Deist F, Ouachee-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. Jun 2002;117(4):965-72. [Medline].

  3. Arico M, Allen M, Brusa S, et al. Haemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. Br J Haematol. Oct 2002;119(1):180-8. [Medline].

  4. Imashuku S, Ueda I, Teramura T, et al. Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients. Eur J Pediatr. May 2005;164(5):315-9. [Medline].

  5. Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest. Jan 2006;116(1):182-92. [Medline]. [Full Text].

  6. Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br J Haematol. Mar 2005;128(6):739-50. [Medline].

  7. Rieux-Laucat F, Le Deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med. Jan 20 2005;352(3):306-7; author reply 306-7. [Medline].

  8. Menasche G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. Feb 2005;203:165-79. [Medline].

  9. zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. Mar 15 2005;14(6):827-34. [Medline]. [Full Text].

  10. Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol. Sep 2001;114(4):761-9. [Medline].

  11. Malloy CA, Polinski C, Alkan S, et al. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. Jul 2004;24(7):458-60. [Medline].

  12. Sung L, King SM, Carcao M, et al. Adverse outcomes in primary hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. Oct 2002;24(7):550-4. [Medline].

  13. Ericson KG, Fadeel B, Andersson M, et al. Sequence analysis of the granulysin and granzyme B genes in familial hemophagocytic lymphohistiocytosis. Hum Genet. Jan 2003;112(1):98-9. [Medline].

  14. Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. Feb 1996;10(2):197-203. [Medline].

  15. [Guideline] Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. Feb 1991;18(1):29-33. [Medline].

  16. Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. Apr 1991;80(4):428-35. [Medline].

  17. Su NW, Chen CK, Chen GS, Hsieh RK, Chang MC. A case of tuberculosis-induced hemophagocytic lymphohistiocytosis in a patient under hemodialysis. Int J Hematol. Apr 2009;89(3):298-301. [Medline].

  18. Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of haemophagocytic lymphohistiocytosis. Expert Opin Pharmacother. Sep 2001;2(9):1437-48. [Medline].

  19. Hafsteinsdottir S, Jonmundsson GK, Kristinsson Jr, et al. Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation. Acta Paediatr. 2002;91(8):974-7. [Medline].

  20. Clementi R, Emmi L, Maccario R, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. Sep 15 2002;100(6):2266-7. [Medline].

  21. Macheta M, Will AM, Houghton JB, Wynn RF. Prominent dyserythropoiesis in four cases of haemophagocytic lymphohistiocytosis. J Clin Pathol. Dec 2001;54(12):961-3. [Medline].

  22. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. Oct 1 2002;100(7):2367-73. [Medline].

  23. Emmenegger U, Spaeth PJ, Neftel KA. Intravenous immunoglobulin for hemophagocytic lymphohistiocytosis?. J Clin Oncol. Jan 15 2002;20(2):599-601. [Medline].

  24. Thompson PA, Allen CE, Horton T, Jones JY, Vinks AA, McClain KL. Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. May 2009;52(5):621-5. [Medline].

  25. Cooper N, Rao K, Gilmour K, et al. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. Feb 1 2006;107(3):1233-6. [Medline].

  26. Filipovich AH. Life-threatening hemophagocytic syndromes: current outcomes with hematopoietic stem cell transplantation. Pediatr Transplant. Dec 2005;9 Suppl 7:87-91. [Medline].

  27. Gupta AA, Tyrrell P, Valani R, Benseler S, Abdelhaleem M, Weitzman S. Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution. J Pediatr Hematol Oncol. Feb 2009;31(2):81-4. [Medline].

  28. Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics. May 2003;111(5 Pt 1):e636-40. [Medline].

  29. Chen RL, Lin KH, Lin DT, et al. Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. Feb 1995;89(2):282-90. [Medline].

  30. Goransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet. Mar 2001;68(3):590-7. [Medline].

  31. Pradalier A, Teillet F, Molitor JL, Drappier JC. [Macrophage activation syndrome, hemophagocytic syndrome]. Pathol Biol (Paris). Sep 2004;52(7):407-14. [Medline].

  32. Schmidt MH, Sung L, Shuckett BM. Hemophagocytic lymphohistiocytosis in children: abdominal US findings within 1 week of presentation. Radiology. Mar 2004;230(3):685-9. [Medline]. [Full Text].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

lymphohistiocytosis, hemophagocytic lymphohistiocytosis, HLH, familial hemophagocytic lymphohistiocytosis, FHL, familial erythrophagocytic lymphohistiocytosis, FEL, primary hemophagocytic lymphohistiocytosis, primary HLH, secondary hemophagocytic lymphohistiocytosis, secondary HLH, acquired hemophagocytic lymphohistiocytosis, acquired HLH, infection-associated hemophagocytic syndrome, IAHS, reactive HLH, hepatosplenomegaly, pancytopenia, lymphadenopathy, ascites, gallbladder wall thickening, treatment, diagnosis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA
Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.