An Uncommon Presentation of Adult Hemophagocytic Lymphohistiocytosis with Severe Pulmonary Hypertension

Adult hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening hyperinflammatory syndrome that presents both diagnostic and therapeutic challenges. HLH may be primary and related to an underlying genetic abnormality or secondary to infection, malignancy, or rheumatologic condition. We describe a case of HLH in a latently EBV-/CMV-/HBV-immune 52-year old male co-presenting with severe pulmonary hypertension and a novel heterozygous perforin missense exon mutation. He was intolerant of the HLH 2004 protocol but responded to salvage alemtuzumab therapy, which was then followed seven weeks later by a fatal polymicrobial sepsis.

This previously healthy 52 year-old male developed the insidious onset of acral paresthesia and exertional dsypnea over a two year period. Seven months prior to admission, he was treated as an outpatient for suspected H1N1 infection, followed by the development of spontaneously-resolving superior oblique nerve palsy, with the EMG/NCS correlate of demyelinating polyneuropathy and secondary axonal loss. His dyspnea progressed, and he presented to hospital with fevers, weight loss, and respiratory distress requiring mechanical ventilation. His course in the intensive care unit was complicated by nephrotic range azotemia (Cr >200 umol/L), cryptogenic hepatitis (transaminases >1000 IU/ml), and splenomegaly. Hematologic investigations initially revealed an isolated thrombocytopenia that was IVIg and steroid refractory, followed by hemolytic anemia with oxidative blood film abnormalities, and an initial bone marrow biopsy devoid of hemophagocytosis. Rheumatologic serologies (ANA, ENA, C3, C4, p-ANCA, c-ANCA, ds-DNA, anti-GBM) and microbiologic studies (HIV, Monospot, and indices of reactivation of HBV or CMV) were negative. Other causes of peripherally destructive cytopenias were also ruled out (DAT, PNH flow cytometry, APLA, ADAMTS13, methemoglobin, G6PD, PK normal).

Four weeks after admission, worsening pancytopenia and unexplained fevers prompted a second bone marrow examination, which demonstrated hemophagocytosis with an EBV reactivation viral load of 7 × 10⁵/ml. Meeting clinicopathologic diagnostic criteria for HLH, the HLH 2004 protocol was thus initiated. Within 7 days, treatment-limiting nephrotoxicity and hepatotoxicity developed, prompting discontinuation of cyclosporine and dose-reduction of etoposide. Hepatic biopsy revealed drug-induced sinusoidal necrosis without lymphohistiocytic infiltration. Worsening HLH prompted the next-line use of anti-CD52 monoclonal therapy (alemtuzumab), which associated with the onset of freedom from transfusion within 35 days. Over the six week course of therapy, clinical, biochemical, and hematologic manifestations continued to improve. In parallel with sildenafil, the pulmonary hypertension was also dramatically alleviated. He thus remained in a transfusion-free remission for 55 days until day 105 after diagnosis.

Fevers then recurred, with polymicrobial sepsis complicated by disseminated intravascular coagulation, respiratory failure, and hematopathologic evidence of macrophage re-activation. The goals of care were changed to comfort measures and the patient succumbed. Autopsy revealed disseminated blastomycosis with relapsed HLH. Perforin gene sequencing identified a novel heterozygous exon missense single nucleotide polymorphism 1517A>C (His506Pro).

This is an extraordinary case of adult EBV-reactivation-associated HLH presenting with severe pulmonary hypertension, a novel perforin gene mutation, intolerance towards the HLH-2004 protocol, and responsiveness to alemtuzumab. Fatal secondary infections, including the discovery of disseminated blastomycosis, presaged or provoked the concomitant relapse of HLH. The relevance of the unique perforin mutation or the co-infection with Blastomyces with respect to the atypical features of this HLH presentation remains unknown.

Off Label Use: Alemtuzumab (anti-CD52) was used off-label in the salvage management of hemophagocytic lymphohistiocytosis (HLH).