Case Presentation: A 70-year-old man with history of chronic lymphocytic leukemia presented with fevers and chills. Vital signs on admission were significant for fever (104.5oF) and tachycardia (127 beats per minute). Lab results showed AKI (Cr 2.0 mg/dL), elevated lactate of 4.1 mmol/L, and bandemia (30%). Blood and urine cultures were positive for extended spectrum beta-lactamase E. Coli. Patient was started on meropenem and vancomycin. Despite broad-spectrum antibiotics, he continued to have persistent fevers. Extensive workup including CT chest/abdomen/pelvis, tagged WBC scan, and V/Q scan were all negative. Subsequent labs revealed pancytopenia (WBC 0.2 k/uL, Hemoglobin 6.6 g/dL, Platelets 26 k/uL), hypertriglyceridemia (674 mg/dL), high ferritin (>100K ng/mL), elevated interleukin-2 (17,590 pg/mL), and low natural killer cells (CD4 75 per uL, CD8 49 per uL). Given his history of malignancy and these lab findings, there was concern for hemophagocytic lymphohistiocytosis (HLH). He was started on high dose prednisone and etoposide as per the HLH-94 protocol. Despite treatment, he continued to clinically decline, developed disseminated intravascular coagulation, and expired.
Discussion: HLH is a life-threatening disorder caused by an overactive immune system that leads to multiorgan system failure and death. HLH results from genetic, infectious or malignancy related factors. The estimated annual incidence of HLH is 1 in 800,000 persons/year. Of these up to 27% are malignancy related, with hematologic malignancies being the most common. Typically, natural killer cells (NKC) and cytotoxic lymphocytes (CTL) regulate activated macrophages. HLH is caused by a two-fold dysregulation in this process. Over activation of macrophages results in excessive release of cytokines. In addition, NKCs and CTLs fail to inhibit this cytokine storm thus leading to extensive tissue damage. Diagnosis of HLH requires five of the following eight criteria to be met: fever (>7 days), splenomegaly, cytopenia of > 2 cell lines, hypertriglyceridemia/hypofibrinogenemia, low NKC activity, elevated ferritin, elevated interleukin-2 levels, and biopsy proven hemophagocytosis. Hemophagocytosis however, is neither pathognomonic nor required for the diagnosis of HLH. Treatment is guided by the HLH-94 protocol. This therapy includes etoposide and dexamethasone (tapered over eight weeks), with the addition of intrathecal methotrexate and hydrocortisone in patients with neurological manifestations. Even with early recognition and treatment, mortality rates remain high with about fifty-percent median survival rate.
Conclusions: Here we present a fatal case of secondary HLH. HLH is often a diagnostic challenge due to its non-specific symptoms and its resemblance to the provoking illness. Although exceedingly rare, it is important for internists to recognize this constellation of symptoms as it continues to carry a high mortality rate. Early recognition is critical for the prompt and appropriate treatment of these patients.