Secondary HLH: A complication of anaplasmosis infection Free

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory condition. More specifically, there is an improper cytotoxic activation of T lymphocytes or natural killer cells. In the end this results in high serum cytokine levels in the blood and build up of activated T cells and macrophages in target organs including the spleen, liver, lymph nodes, and bone marrow. HLH is typically attributed to an abnormality in CD8+ cells and NK cells which has the effect of steady antigen stimulation and resultant acute immune-mediated tissue damage.

Cytolytic secretory pathway gene abnormalities are the primary cause of primary HLH. Conversely, secondary or acquired HLH can be due to immunologic activation in the setting of infection, malignancy, autoimmune disease or immunodeficiency. With varied causes, a limited number of cases in the literature, the secondary HLH is rarely diagnosed and in turn, the mechanism behind it is yet to be clarified. We report a rare case of secondary HLH in a patient with anaplasmosis.

CASE: A 67-year-old female presented with fever, intermittent dizziness, lightheadedness, and abdominal pain. She had a medical history significant for hypertension. Of note, she recently traveled to the state of Maryland where she had picked an insect off of her skin. Thereafter, she endorsed experiencing symptoms of uncoordination, speech difficulty, and word finding difficulty.

The labs show pancytopenia with 2.12 WBC K/uL, hemoglobin 10.7 g/dL, platelets 25 K/uL. LDH 529 U/L and haptoglobin levels were elevated at 213.0 mg/dL. Ferritin was high at 280,000 ng/mL, iron was 85 ug/dL, TIBC 217 ug/dL, iron saturation 39%, B12 elevated 1410 pg/mL, and folate 18.46 ng/mL. A peripheral blood smear showed normocytic anemia, non-specific poikilocytosis including ovalocytes/elliptocytes/occasional schistocytes. She had elevated liver enzymes AST 123 U/L, ALT 79 U/ and normal levels of alkaline phosphatase 48 U/L and total bilirubin 0.4 mg/dL. Triglycerides were high at 385 mg/dL While the patient did test positive for hepatitis C antibody, the hepatitis C quantification result was unquantifiably low. The NK cell activity was low and serum interleukin 2 receptor test showed a result of 1996.0 pg/ml.

Lyme serologies, a tick-borne panel, HIV panel, and mononucleosis testing were all negative and the patient ultimately tested positive for anaplasma phagocytophilum. Imaging included a CT abdomen and pelvis which showed prominent enhancing gallbladder wall and pericholecystic fluid suspicious for acute cholecystitis. USG and HIDA scan were also negative. CT of the head without contrast, brain/thoracic spine/lumbar spine MRI and with and without contrast, and CSF studies were all negative for acute pathology. She was started on oral doxycycline 100 mg but due to worsening symptoms, ceftriaxone 2 grams twice daily was added due to concerns for neuroboreliosis. Her coordination and overall symptoms improved significantly. Ultimately the patient was transitioned to doxycycline for 14 days upon discharge after significant improvement in her symptoms.

Discussion: HLH secondary to anaplasmosis is very rare. Secondary HLH related to viral infection infection has been found in 29% of reported cases while secondary HLH due to bacterial and parasitic infection accounts for 20% of cases. According to the literature to date, there have been 8 previously reported cases of HLH related to Anaplasmosis infection. Remarkably, patients in all cases received doxycycline while only two patients received HLH targeted treatments. In instances where there is a clear infectious etiology for HLH, prompt diagnosis allows for effective treatment with antimicrobials and avoidance of more targeted HLH therapy.

Neurologic manifestations including imbalance are atypical for anaplasmosis which usually presents with headache. Of particular importance is how the patient's balance symptoms improved significantly after being treated with both ceftriaxone and doxycycline.

Conclusion: Secondary HLH is uncommon and can be due to varying causes including infection, malignancy, or immunodeficiency. Whereas, secondary HLH in the setting of anaplasmosis infection is an even more rare entity. It is imperative that infectious causes of secondary HLH be considered in the differential diagnosis because it signifies a very treatable cause of the HLH and promising outlook for the patient if treated appropriately.