Hemophagocytic Lymphohistiocytosis in a 21-year
Hemophagocytic Lymphohistiocytosis in a 21-year-old Patient Salem Assiri, MD; Richard Wang, MS; and Suma Jain, MD Department of Internal Medicine Ochsner Clinic Foundation, New Orleans, LA HPI 21-year-old Caucasian female Presented to her primary care provider with a weeklong history of fever, sore throat, myalgia, arthralgia and non-erythematous, papular rash to the chest and bilateral upper and lower extremities. She was provided symptomatic measures and valacyclovir for fever blisters. Rapid strep test returned negative. Her symptoms worsened, and the rash progressed. HPI She presented to the ED and was treated for dehydration. Her earlier throat cultures returned positive for Group A strep, and she was started on amoxicillin Her symptoms continued to progress, and she returned to the emergency room for further evaluation. History PMHx Asthma Obesity status post uncomplicated laparoscopic gastric sleeve Bronchitis Past Surgical Hx Minor cosmetic surgery on chest Maxillary advancement Gastric sleeve History Family Hx Mother Diabetes Paternal Aunt Diabetes Brother Social Hx Breast cancer Smoking status Never smoker Alcohol use Occassional Physical Exam Vitals: Temp: 101.4 °F (37.3 °C), Pulse: 97 Resp: 18, BP: 101/62 mmHg, SpO2: 91% BMI: 37.87 Constitutional: Well-developed, well-nourished, non-distressed, not diaphoretic, obese Neurological/Psych: AAO x 4, no gross CN deficits, no gross deficits in sensation, strength or tone throughout, no lateralizing or focal findings; normal mood and affect, normal behaviour, thought content and judgement. Exam HEENT: NC/AT, PERRL, EOMI, no scleral icterus OP: exudate with erythema noted to B tonsils Neck: diffuse TTP. No lymphadenopathy, no tracheal deviation, no stridor Cardiovascular: RRR, normal S1/S2, intact distant pulses, no m/r/g, no JVD Pulmonary/Chest wall: CTAB, no Wheezing, rhonchi or crackles GI: S/NT/ND, BS present Exam Musculoskeletal/Skin: Normal ROM, no edema, no atrophy, no tenderness throughout; no c/c/e, nontender, non-erythematous, non-raised papuled noted on LUE and RLE and anterior chest; palmar and plantar erythema GU exam performed in ED: no retained foreign body Admission Labs WBC 14,500 hemoglobin 8.5 hematocrit 25 platelets 87 BUN 12; Cr 1.0 TB 0.4 ALT 14; AST 54 MICU Labs WBC 21,000 BUN/Cr 18/2.1 H/H 11/33 Troponin 0.263 lactic acid 1.1 BNP 968 LDH 1366 ESR 45 CRP 384. Investigations 12-lead ECG: 2D echo: sinus tachycardia with ST elevations in the inferior and anterior leads, consistent with acute pericarditis. an ejection fraction of 25% and diastolic dysfunction. Chest CT: bilateral, patchy consolidative opacities, bilateral small pleural effusion, and trace pericardial effusion. Investigations CT of abdomen and pelvis: Splenomegaly. All blood cultures were no growth, and respiratory viral panel was negative. EBV IgG positive, but IgM and PCR were negative. CMV negative Hospital Course Upon admission to internal medicine for GAS and possible acute rheumatic fever, she continued to spike fevers, desaturated to 80%, and became hypotensive. She was transferred to the MICU for shock and ARDS and possible toxic shock syndrome. Broad-spectrum antibiotics were started, and she was intubated. She received IVIG for toxic shock syndrome with mild to modest improvement in the appearance of maculopapular rash. Dermatology consulted for the maculopapular rash. Skin Biopsy revealed non-specific etiology but thought to be 2/2 drug eruption Hospital Course Developed multi-organ failure (AKI, hepatic failure, DIC, congestive heart failure with elevated troponin and evidence of pericarditis/carditis) Required renal replacement therapy, packed RBC transfusion, FFP, cryoprecipitate and NAC pt cont to spike temperatures and leukcoytosis worsen despite of broad spectrum Antibiotics Rheumatology consulted for Autoimmune disease vs macrophage activation syndrome Pediatric hematology oncology consulted for possible hemophagocytic lymphohistiocytosis (HLH) Hospital Course Subsquent blood work reveals the following Ferritin 26000 ng/mL TG 455 mg/dL Absent NK cell activity soluble CD25 (soluble IL-2 receptor alpha) 13630 pg/mL Some Peripheral smears (hematophagocytosis) Sternal BM biopsy negative for malignancy and no evidence of HLH BM Chromosomal analysis: No clonal abnormality or HLH gene mutation. MDS FISH panel studies were normal HLH diagnosis made based on HLH-2004 guideline criteria Hospital Course Patient started on daily high dose Dexamethasone and biweekly Etoposide Significant improvement noticed, fever subsided, leukocytosis resolved but pt develop neutropenia 2/2 etoposide. Acyclovir and sulfamethoxazole-trimethoprim added for prophylaxis Extubated and kidney function recovered Subsequently developed SVT and became HD unstable Echocardiogram revealed significant pericardial effusion and tamponade physiology Hospital Course Pericardiocentesis performed and yeild > 1 L bloody pericardial fluid. Cytology negative for HLH or malignancy Pt cont to recover Stepped down to pediatric hematology Subsequently developed seizure and found to be in status epilepticus Intubated and admitted to neurocritical care AEDs started Hospital Course MRI brain revealed Extensive relatively symmetrical T2/flair signal abnormality within the parenchyma primarily within the sub cortical white matter DDX CNS involvement of lymphohistiocytosis vs posterior reversible encephalopathy Intrathecal methotrexate initiated Alemtuzumab added for HLH salvage treatment Repeated MRI showed resolving the white matter lesions MRI brain Hospital Course Subsequently pt develop maculpapular rash on the extremities which rapidly progressed to the entire body Skin biopsies were consistent with SJS/TEN SJS/TEN thought to be 2/2 drug eruption All blood cultures were negative CSF: WBC 1, RBC 820, glucose 55, protein 50 CSF cytology negative for HLH or malignancy Bactrim, acyclovir, keppra and Onfi (clobazam) held Pt exhibited improvement in her mental status but skin lesions cont to get worse Transferred to burn center Differential Diagnosis Infection/sepsis Malignancies (leukemia, lymphoma, other solid tumors) Drug reaction with eosinophilia and systemic symptoms (DRESS) Autoimmune lymphoproliferative syndrome (ALPS) Adult Still's Disease Macrophage activating syndrome Diagnosis of HLH While initially thought to be due to infection (positive strep throat culture and positive ASO titers), the diagnosis of HLH was considered. A sternal bone marrow was obtained which was negative for malignancy (no comment on hematophagocytosis but apparently few histiocytes although some peripheral blood smears showed hematophagocytosis). Etiology: Hemophagocytic lymphohistiocytosis (HLH) A rare, aggressive syndrome of excessive inflammation and tissue destruction due to abnormal immune activation Primarily a pediatric disease Manifests as either a familial disorder or a sporadic condition Both forms are associated with a variety of triggers, typically an infection. In this patient’s case, secondary to Group A strep infection. Guidelines set by HLH-2004: Diagnostic Reasoning According to the guidelines set by HLH-2004, she fit the diagnostic criteria for HLH even without having hematophagocytosis in the bone marrow. She fulfilled at least 5 of the criteria with Fever Splenomegaly Hypertriglyceridemia Ferritin greater than 10000 microgram/L Soluble CD25 (soluble IL-2 receptor) greater than 2400 U/ml Also demonstrated a sixth criteria with a platelet count less than 100 x 109 and a hemoglobin less than 10 g/dL. Treatment Can include a combination of chemotherapy, immunotherapy and steroids. Antibiotics and antiviral drugs may also be used. Treatments may be followed by a bone-marrow or stem-cell transplant in patients with persistent or recurring HLH. Treatment Therapy based on the HLH-2004 protocol consists of eight weeks of induction therapy with etoposide (VP16) and dexamethasone, with intrathecal therapy for those with CNS involvement. Etoposide (VP-16) is given at a dose of 150 mg/m2 for adults, and 5 mg/kg for children weighing <10 kg. Dose is given twice weekly for the first two weeks, and once weekly for weeks three through eight. Dexamethasone is the preferred corticosteroid because it can cross the blood-brain barrier. Given intravenously or orally and tapered over the eight-week induction Treatment The major modifications of the HLH-2004 protocol (trial from 2004 to 2011) are to begin cyclosporin simultaneously with etoposide and to add hydrocortisone to the intrathecal methotrexate, but results are not yet available. Prognosis Without therapy, mortality of patients with HLH is high Those with an inherited mutation in an HLH gene have a survival of approximately two months without treatment. Patients treated on the HLH-2004 protocol had a median survival of 54 percent at 6.2 years (249 patients, median age eight months). Reference Henter, J.-I., Horne, A., Aricó, M., Egeler, R. M., Filipovich, A. H., Imashuku, S., Ladisch, S., McClain, K., Webb, D., Winiarski, J. and Janka, G. (2007), HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer, 48: 124–131. doi: 10.1002/pbc.21039 McClain, K. Treatment and prognosis of hemophagocytic lymphohistiocytosis. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2014. Questions ??
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