Age: 5.0
Sex: F
Vaccine: VARCEL
Symptoms: Varicella virus test positive
Clinical narrative: This literature marketed report was received from author referring to 5 year old female patient. Background: Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening disorder characterized by an overwhelming hyper-inflammatory state. HLH is categorized as primary or familial HLH (FHLH) when there is a family history of HLH or a known underlying genetic defect. Infection and rheumatologic illness are the two most common settings of secondary HLH in children. Herpes family viruses, including Epstein-Barr virus (EBV) and cytomegalovirus, are frequent causes of infection-associated HLH. Although infections alone can lead to secondary HLH, there are also the common trigger for overwhelming immune activation in familial HLH, thereby making the evaluation for an underlying primary genetic disease an important aspect of the overall management for this disorder. Clinically, patients with FHLH or secondary FHLH typically present with high-grade fever, splenomegaly, progressive cytopenias, liver dysfunction, coagulopathy, or neurological symptoms. Current management of HLH involves corticosteroid treatment along with other agents such as etoposide, anti-thymocyte globulin, or alemtuzumab, aimed at controlling the hyperinflammatory state. Long-term management of patients with primary/familial HLH includes definitively correcting the underlying genetic defect with allogeneic hematopoietic stem cell transplantation. In both primary and secondary HLH, management of associated infection is important, but even in infection-associated HLH, some form of immune suppressive or immune modulatory therapy is often necessary to manage the hyperinflammatory state. This case refers to a 5-year-old female patient who presented to her physician with a history of fever, jaundice, epistaxis. She also complained of generalized fatigue. Past medical and family histories were non-contributory. On an unknown date, the patient was vaccinated with VARIVAX (Merck) in the right upper extremity. On an unknown date (reported as two weeks after VARIVAX (Merck) administration) patient developed symptoms. On an unknown date, diagnostic testing revealed pancytopenia and hepatitis, with a peak alanine transaminase (ALT) of 1712 unit/L. She was transfused with platelets for her ongoing epistaxis and transferred to a tertiary care facility for further management. On physical examination at the facility, she appeared ill but non-toxic. Additional findings included mild pallor, scleral icterus, petechiae and mild hepatomegaly. Laboratory evaluations were remarkable for pancytopenia with hemoglobin of 8.3 g/dL, platelet count of 137,000/mcL (following her recent transfusion) which decreased to 37K/mcL over the next 4 days, and a neutrophil count of 3.96K /mcL that decreased to zero over the next 2 weeks. ALT remained elevated at 1938 unit/L. Serological tests did not revealed evidence of an underlying viral hepatitis. Ultrasound imaging was notable for an enlarged liver. Patient soon developed vesicles on her right upper extremity and shoulder in a non-dermatomal pattern. The lesions remained localized to the right upper extremity. A vesicle was unroofed from the rash and the fluid tested positive for varicella by polymerase chain reaction (PCR). Further analysis revealed the virus to be vaccine strain varicella. A set of four fixed markers, all located in ORF62, were identified that were unique to the VARIVAX (Merck). In addition, two markers located in ORF38 and ORF54 distinguished a subset of clade 2 isolates. The parental strain from which vaccine was derived has the profile of the minority subclade of clade 2, and also serves to distinguish vaccine from wild type. The patient contained markers at these positions that clearly identify it as VARIVAX (Merck). A liver biopsy was performed and showed diffuse portal and lobular hepatocellular inflammation with prominent lymphohistiocytic infiltrate. A bone marrow aspirate and biopsy performed to evaluate pancytopenia revealed a hypocellular marrow and hemophagocytosis. On an unknown date, VARIVAX (Merck) strain varicella caused a vesicular rash in a non-classical distribution that included the entire vaccinated limb, without leading to widespread lesions or remaining confined to a single dermatome, as observed with shingles. The vaccine strain of virus also triggered HLH. Additional immunologic testing revealed an elevated level of soluble interleukin-2 receptor, 12,701 U/mL, and absent natural killer cell function. Triglycerides were elevated at 309 mg/dL. No mutations were identified in the genes known to cause familial HLH, including PRF1, STXBP2, STX11, UNC130, and RAB27A. On an unknown date, patient was started on 10 mg/m2 of dexamethasone for the short term treatment of HLH. Additionally, she was started on intravenous acyclovir to treat her underlying infection and her lesions improved. Simultaneously, she received alemtuzumab for treatment for HLH, and subsequently underwent allogeneic hematopoietic cell transplantation. Varicella lesions crusted over 21 days from presentation. Outcome of events was reported as resolving. The author considered that there was a positive causal relation between the events, non-dermatomal vesicular rash to right upper extremity, pancytopenia and hemophagocytic lymphohistiocytosis and VARIVAX (Merck). Upon internal review, the event pancytopenia was determined to be medically significant. Additional information has been requested.