Fevers, sore throat

and jaundice...
16 year old female
• History of migraines on topimax presents with acute
scleral icterus, fevers, sore throat, and abdominal pain
HPI
• 2 weeks prior to admission: AOM and acute tonsillitis at
urgent care, cefuroxime X 10 days with improvement in
symptoms
• 2 days prior to admission: fevers, malaise, headache
(baseline), abdominal pain, nausea/vomiting
• Day of admission: Fever, headache, “yellow eyes”,
continued diffuse abdominal pain and nausea/vomiting
Physical exams on day of
admission:
• Vital trend: tachycardia and initial afebrile but rapidly
febrile to 40 on admission
• 1st PE: well-appearing, no scleral icterus, no
organomegaly
• 2nd PE: well-appearing, slight yellow tinge of face, no
scleral icterus
• 3rd PE: ill-appearing but nontoxic, bilateral scleral icterus,
jaundice of the face and chest, hepatosplenomegaly
• Otherwise normal exam
 CBC: WBC = 2.6; differential 0% Band forms, 69%
Neutrophils, 22% Lymphocytes, 8% Monocytes, 0%
Eosinophils, ANC 1800; Hgb = 13, Hct = 36.3, Platelet =
34
Retic Count 1.36%

Initial labs CMP Na = 132, K = 3.3, Cl = 103, CO2 = 19, BUN = 7, Cr =

0.61, Glucose = 97, Ca = 8.8, Protein = 6.9, Albumin =
3.9, Bilirubin = 5.5 (Indirect 1.3, Direct 4.2), Alk. Phos. =
160, ALT = 187, AST = 171Urinalysis: negative
LDH 849 PTT 42, INR 1.4, PT 17.6 Monospot Positive
Rapid Strep Negative b-hCG negative
 ID: sepsis 2/2 bacteremia/fungemia, Infectious
mononucleosis (EBV, CMV), malaria, babesia, HIV

Heme/onc: Leukemia (Tcell, NK, anaplastic large

cell), lymphoma, solid organ, HLH

GI: pancreatitis, cholangitis, primary or secondary

Differential biliary cirrhosis, PSC, hepatitis, Gilbert syndrome

Rheum: SLE, MAS, autoimmune

lymphoproliferative syndrome

Drugs: DRESS
 Hospital course

DOA #1: Tmax 40.2 with continued abdominal pain, nausea/vomiting partially
responsive to zofran, unchanged jaundice

Complete abdominal US: hepatitis with hepatosplenomegaly and small ascites and
gallbladder contraction and mild nonspecific indistinct gallbladder wall thickening.

Chest xray: Normal, no mediastinal mass

Labs: worsening transaminitis, thrombocytopenia, hyponatremia

DOA #2: Tmax 39.8, abdominal fullness and pain, no appetite, worsening
cytopenias
Heme/Onc consultation

• Bone marrow aspirate: Normocellular marrow 90% with trilinear hematopoiesis,

myeloid and megakaryocytic hyperplasia and decreased erythroids, prominent
hemophagocytosis
• Peripheral smear:
• Moderate normocytic normochromic anemia
• Mild leukopenia with many atypical/reactive appearing lymphocytes and left
shifted granulocytes with toxic changes
• Marked thrombocytopenia
Hemophagocytic
lymphohistiocytosis (HLH)
 Definition: Potentially fatal hyperinflammatory condition
characterized by highly stimulated but ineffective immune
response
• Protein defect in formation of the immunologic synapse→ persistent
activation of macrophages and cytotoxic T cells
• Associated with severe infections, malignancies, rheumatologic disorders and
metabolic disease - EBV is the most common cause of infection associated
HLH

Incidence: primarily a pediatric syndrome, approximately 1

HLH child in 3000 admitted will have HLH (peds tertiary centers),
largest peds hospital in Texas: 1 in 100,000.

Classification: Primary (genetic) vs secondary (acquired)--

Secondary HLH pathogenesis remains largely unclear

Genetic HLH: Large portion of involved genes yet unknown. All

of the known genetic abnormalities lead to defects in proteins
of the cytolytic secretory pathway - Can present at any age
Classification of HLH and
Underlying Disorders
Madkaikar M, Shabrish S, Desai M.
Current Updates on Classification,
Diagnosis and Treatment of
Hemophagocytic Lymphohistiocytosis
(HLH).
Indian J Pediatr. 2016
May;83(5):434-43. Review.
PubMed PMID: 26872683.
 • Pathogenesis not well understood
• Clinical manifestations a result of:
1. Hyperactivation of CD8+ T
Lymphocytes and macrophages
2. Proliferation, ectopic migration, and
infiltration of these cells into organs
3. elevated pro-inflammatory cytokines
Clinic Features causing progressive organ dysfunction
• Clinic features: prolonged fever, HSM,
bleeding, skin rash, CNS changes, jaundice
• Lab findings: bi/pan-cytopenias,
coagulopathy, hyperlipidemia,
hypofibrinogenemia, hyperferritinemia,
transaminitis, hyperlipidemia,
hypoalbuminemia, hyponatremia
Diagnostic Criteria
• Sen ES, Steward CG, Ramanan AV.
• Diagnosing haemophagocytic
syndrome.
• Arch Dis Child. 2017
Mar;102(3):279-284.
• Review.
• PubMed PMID: 27831908.
Our patient...

• Ferritin >40,000 ng/ml

• sIL2 56,900 pg/ml
• Triglycerides 309 mg/dL
• Albumin dropped <3g/dL on DOA 1-2
• Fibrinogen low at 121 mg/dL
• Increased MCF of perforin and granzyme B in NK cells
Treatment
Madkaikar M, Shabrish S, Desai M.
Current Updates on Classification,
Diagnosis and Treatment of
Hemophagocytic Lymphohistiocytosis
(HLH).
Indian J Pediatr. 2016
May;83(5):434-43. Review.
PubMed PMID: 26872683.