Hemophagocytic Lymphohistiocytosis in a 21-year-old Patient

1. 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

2. 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.

3. 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.

4. History PMHx Past Surgical Hx Minor cosmetic surgery on chest Maxillary advancement Gastric sleeve • Asthma • Obesity status post uncomplicated laparoscopic gastric sleeve • Bronchitis

5. History Family Hx Social Hx Smoking status Never smoker Alcohol use Occassional • Mother • Diabetes • Brother • Diabetes • Paternal Aunt • Breast cancer

6. 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.

7. 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

8. Exam • Musculoskeletal/Skin: Normal ROM, no edema, no atrophy, no tenderness throughout; no c/c/e, non-tender, 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

9. Admission Labs • WBC 14,500 • hemoglobin 8.5 • hematocrit 25 • platelets 87 • BUN 12; • Cr 1.0 • TB 0.4 • ALT 14; AST 54

10. 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.

11. Investigations • 12-lead ECG: • sinus tachycardia with ST elevations in the inferior and anterior leads, consistent with acute pericarditis. • 2D echo: • an ejection fraction of 25% and diastolic dysfunction. • Chest CT: • bilateral, patchy consolidative opacities, bilateral small pleural effusion, and trace pericardial effusion.

12. 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

13. 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

14. 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 hemophagocyticlymphohistiocytosis(HLH)

15. 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

16. 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

17. 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

18. 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

19. MRI brain

20. 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

21. 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

22. 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).

23. 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.

24. Guidelines set by HLH-2004:

25. 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.

26. 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.

27. Treatment • Therapy based on the HLH-2004 protocol consists of eight weeks of induction therapy with etoposide (VP-16) 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

28. 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.

29. 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).

30. 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.

31. Questions ??