Case Presentation: A 43 year old female with no significant past medical history presented to the emergency department after developing subjective fevers, myalgias, arthralgias, and malaise one week after a hiking trip in northern Minnesota. She had a fever of 39.2℃ and splenomegaly with no rash. Pertinent labs showed a hemoglobin of 12.1 g/dL (11.6-15.0 g/dL), platelets of 177,000/mL (157,000-371,000/mL), AST of 308 U/L (8-43 U/L), and ALT of 266 U/L (7-45 U/L). She was admitted and started on doxycycline on day 3 after testing positive for Lyme disease. Despite this, she continued to have fevers as high as 40.0℃ with worsening tachycardia and respiratory distress that persisted despite the addition of ceftriaxone. Labs on day 6 now showed a hemoglobin of 9.9 g/dL, platelets of 80,000/mL, AST of 640 U/L, and ALT of 408 U/L. Additional investigation showed a ferritin of 59,150 mcg/L (11-307 mcg/L), fibrinogen of 119 mg/dL (200-430 mg/dL), LDH of 1907 U/L (122-222 U/L), and triglycerides of 426 mg/dL (<150 mg/dL). A thorough rheumatologic, infectious, and malignancy work-up including autoimmune serologies, blood cultures, viral and fungal serologies, testing for other tick-borne infections, and a PET scan was negative. Given the constellation of fevers, bicytopenia, splenomegaly, hypertriglyceridemia, and striking hyperferritinemia, a presumptive diagnosis of hemophagocytic lymphohistiocytosis (HLH) secondary to Lyme disease was made. She was treated with 1 gram of methylprednisolone daily for 5 days beginning on day 8. She underwent bone marrow, liver, and spleen biopsies, all of which showed hemophagocytosis with no evidence of lymphoproliferative disease. She improved significantly following steroids with resolution of fevers and reduction in her ferritin. She completed 2 weeks of doxycycline for Lyme disease and began HLH specific treatment with etoposide and dexamethasone on day 14. She was discharged to home on day 20 where she completed 2 months of etoposide and dexamethasone. She continues to do well with normalization of all laboratory parameters.
Discussion: HLH is a rare, life-threatening syndrome of excessive immune activation. It occurs in individuals who experience an inflammatory trigger, the most common of which include malignancy, autoimmune disease, and infection. Viral infections, including EBV and CMV, are the most common infectious triggers, with bacterial infections being far less common. The most widely used diagnostic criteria are the HLH-2004 criteria, which require 5 of the following 8 features: fever ≥38.5℃, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis on biopsy, absent or low NK cell activity, elevated soluble CD25, and ferritin >500 mcg/L. An elevated ferritin can be extremely useful, as one study showed that a ferritin >10,000 mcg/L had a specificity of 96% for HLH. Treatment includes correcting the underlying trigger and use of etoposide and dexamethasone in critically ill patients. Bone marrow transplant can be done in refractory or relapsed disease.
Conclusions: We have presented a case of HLH triggered by Lyme disease, a trigger that has not been previously well described. Hospitalists are often the first provider to care for patients with underlying HLH. Checking a ferritin in patients manifesting features of HLH is crucial, as detecting hyperferritinemia can help lead to early recognition of HLH. This can result in early involvement of specialty teams and disease-specific treatment, all of which improve patient outcomes.