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.
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