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To the Editor:

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammation syndrome.1 It is characterized by activation of the mononuclear phagocyte system with uncontrolled proliferation of histiocytes and hemophagocytosis phenomena1, 2 due to dysregulation of the immune response, either primary or acquired. In the primary forms there is a predisposing genetic factor.1 Among secondary causes2 the most important is its association with the development of severe infections, neoplastic or autoimmune diseases (macrophage activation syndrome). While there are a wide variety of microorganisms related to the development of HLH, Epstein–Barr virus (EBV) is the most common3 (primary infection or reactivation), the one with poorer prognosis (therapy with acyclovir is ineffective), and the one benefiting most from early treatment with etoposide.

There are several published cases of development of HLH in inflammatory bowel disease (IBD),4 most of them associated with infections and all under immunosuppressive therapy. There is a predominance of Crohn's disease (CD) over ulcerative colitis. While most infections are due to EBV and cytomegalovirus (CMV), other cases have been published caused by tuberculosis and histoplasmosis. With regard to EBV infection in IBD, there are four cases5–8 described to date, all primoinfections in immunosuppressed patients with high mortality (75%). Of the three out of four patients who died, two of these did not receive therapy with etoposide and the other died despite it.

We report a case of development of HLH in CD associated with primary infection by EBV. The patient was a 24-year-old man who had been diagnosed with ileocolic CD 4 months earlier, treated with infliximab and steroids. After the fourth infusion of infliximab he developed a febrile syndrome lasting for 1 week (39.5°C) with no associated clinical signs. Physical examination revealed a tachycardia of 160 bpm with sustained BP and no other initial findings.

Laboratory tests showed progressive pancytopenia (WBC 600/mm3, neutrophils 300/mm3, hemoglobin 8.6 g/dL, platelets 32,000/mm3), renal impairment with creatinine 4.34 mg/dL, coagulopathy with hypofibrinogenemia (0.3 g/L), severe prolongation of clotting times, and increased D dimer values (35,000 μg/L), hypertriglyceridemia 1235 mg/dL, hyperferritinemia >5000 μg/mL, increased LDH levels (1444 IU/L) with slightly altered liver biochemistry (TB 1.2, GOT 168, GPT 74), PCR 135 mg/dL. Imaging tests showed hepatosplenomegaly and bilateral lung infiltrate. Serology for hepatitis B virus (HBV), HCV, and human immunodeficiency virus (HIV) were negative. IgG and IgM serology for CMV and EBV were negative. Negative PCR for CMV. Positive PCR for EBV with 36,000 copies/mL. Due to the suspicion, a bone marrow study was performed which was not conclusive, despite which treatment was started with dexamethasone, cyclosporine, and etoposide with clinical improvement and normalization of the laboratory parameters, with the patient remaining in remission after 1 year of follow-up.

Additional studies are required to understand the pathophysiological relationship between primoinfection by EBV in patients with immunosuppressed IBD and the development of HLH. It would be recommended to test the serological status of specific immunity against EBV prior to the start of immunosuppression. These patients benefit from specific treatment with etoposide (which has antihistiocytic activity and the capacity to inhibit viral replication) in the early stages of development of HLH associated with primary infection by EBV,3 with a significant reduction in mortality. Although it is a rare syndrome, the need for potent immunosuppressant agents for the treatment of IBD makes it likely that there will be an increased incidence of this disorder in our patients in the coming years. We should thus be prepared for this by familiarizing ourselves with the diagnostic criteria (Table 1) and keeping them in mind at the time of differential diagnosis of febrile syndrome and hepatosplenomegaly and pancytopenia, since patient survival depends on early diagnosis and start of treatment.

Table 1. Diagnostic Guidelines for HLH (Revised)
  • *

    New added diagnostic criteria.

The diagnosis HLH can be established if one of either A or B below is fulfilled
 A) Molecular diagnosis HLH.
 B) Diagnosis criteria for HLH (5 of 9 below)
  1. Fever
  2. Splenomegaly
  3. Cytopenias (minimun 2 of 3 lineages in peripheral blood):
   Hemoglobin < 90 g/L
   Platelets < 100 × 109/L
   Neutrophils <1.0 × 109/L
  4. Hypertriglyceridemia and/or hypofibrinogenemia:
   Fasting triglycerides ≥ 3.0 mmol/L
   Fibrinogen ≤ 1.5 g/L
  5. Hemophagocytosis in bone narrow, spleen or lymph nodes
  6. No evidence of malignancy
  7. Low or absent NK-cell activity*
  8. Ferritin > 500 μg/L*
  9. Soluble CD25 ≥ 2,400 U/mL*

REFERENCES

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  • 1
    Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010; 6: 137154.
  • 2
    Janka GE. Hemophagocytic syndromes. Blood Rev. 2007; 21: 245253.
  • 3
    Rouphael NG, Talati NJ, Vaughan C, et al. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007; 7: 814822.
  • 4
    Uslu N, Demira H, Balta G, et al. Hemophagocytic syndrome in a child with severe Crohn's disease and familial Mediterranean fever. J Crohn's Colitis. 2010; 4: 341344.
  • 5
    Posthuma EFM, Westendorp RGJ, van der Sluys Veer A, et al. Fatal infectious mononucleosis: a severe complication in the treatment of Crohn's disease with azathioprine. Gut. 1995; 36: 311313.
  • 6
    Francolla KA, Altman A, Sylvester FA. Hemophagocytic syndrome in an adolescent with crohn disease receiving azathioprine and infliximab. J Pediatr Gastroenterol Nutr. 2008; 47: 193195.
  • 7
    Siegel CA, Olenec CA, Wartman DG, et al. Hemophagocytic syndrome: a complication of ulcerative colitis or side effect of 6-MP therapy? Am J Gastroenterol. 2004; 99: S134.
  • 8
    N'guyen Y, Andreoletti L, Patey M, et al. Fatal Epstein-Barr virus primo infection in a 25-year-old man treated with azathioprine for Crohn's disease. J Clin Microbiol. 2009; 47: 1252154.

Claudio Trigo Salado MD*, Alvaro Giraldez Gallego MD*, Eduardo Leo Carnerero MD*, Dolores De la Cruz Ramírez MD*, José Manuel Herrera Justiniano MD*, José Luis Márquez Galán PhD*, Manuela Aguilar Guisado MD†, * Digestive UGC, Virgen del Rocío Hospital, Seville, Spain, † Service of Infectious Diseases, Virgen del Rocío Hospital, Seville, Spain.