Ehrlichia-Induced Hemophagocytic Lymphohistiocytosis: A Case Series

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially fatal hyperinflammatory syndrome. There are familial forms (primary HLH), typically presenting in childhood, and sporadic forms (secondary HLH), often presenting in adults. Many cases of HLH are in response to infectious pathogens. While Epstein Barr virus, HIV, and bacterial infections are the dominant non malignancy related causes linked with HLH, there are scattered case reports of other uncommon pathogens associated with HLH. We describe the clinical and laboratory findings from a series of 5 cases of Ehrlichia-induced HLH.

Methods: We have reviewed diagnoses of HLH in adolescents and adults treated at Barnes-Jewish Hospital in St. Louis from June 2001 through June 2014. The diagnosis of Ehrlichia was made by PCR testing on peripheral blood. HLH diagnosis was based on the 2004 Histiocyte Society Criteria for HLH. Five of the following 8 criteria should be met: 1) fever ≥ 38.5⁰C; 2) splenomegaly; 3) cytopenia of two or three lines: ANC < 1 × 10³/µL, hemoglobin < 9 g/dL, platelet count < 100 × 10³/µL; 4) hypertriglyceridemia ≥ 265 mg/dL or hypofibrinogenemia ≤ 150 mg/dL; 5) hyperferritinemia ≥ 500 µg/L; 6) increased soluble IL-2 receptor ≥ 2,400 U/mL; 7) low/absent natural killer (NK) cell activity; and 8) pathology showing hemophagocytosis (bone marrow, spleen, or lymph nodes).

Results: Among 77 confirmed HLH cases, we identified Ehrlichia chaffeensis to be the causative agent of secondary HLH in 5 cases. Table 1 summarizes the initial characteristics of patients. All patients were Caucasian with a median age of 52 years (range, 16-62). Four patients were female and one male. All patients presented during summer time. Four patients reported recent history of tick bites. All patients were febrile on presentation. Hyperferritinemia was striking and median peak ferritin was 10002 µg/L (range, 2863-85517). Bone marrow biopsy was performed on 4 patients, 3 of which showed hemophagocytosis.

Two patients had neurologic symptoms and they tested positive for Ehrlichia chaffeensis on cerebrospinal fluid. Doxycycline was administered on day 2, 1, 3, 1, and 1 of admission (respectively for patients 1 through 5). In addition to doxycycline, Patient 1 received rifampin and dexamethasone, Patient 2 received methyprednisolone, and Patients 4 and 5 received dexamethasone. After a median follow up of 7.3 months (range, 1.7-35.8), all patients were alive and none had recurrence of HLH.

We identified an additional 4 cases of Ehrlichia infection presenting with fever, cytopenia(s), and high ferritin. These patients fulfilled 4 of the HLH diagnostic criteria. Al patients responded to doxycycline.

Conclusion: Ehrlichia can trigger HLH and should be on the differential diagnosis of critically ill patients presenting with fever and hyperferritinemia, especially during warm weather when tick bites are more likely in areas endemic with Ehrlichia. Although HLH is often fatal, the prognosis of Ehrlichia-induced HLH is quite good with early diagnosis and prompt initiation of treatment.

* CNS involvement with Ehrlichia

^ Patients 1, 2, 3 and 4 had bone marrow biopsy. Pathology testing was not performed on lymph node or spleen.

Abbreviations: F, female; M, male, Y, yes; N, no; N/P, not performed; ANC, absolute neutrophil count