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

Brother Diabetes

Paternal Aunt

Breast cancer

Social Hx 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, 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

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:

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.

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 (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

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.

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