(Elena) Hsieh, MD - Clinical Immunology Society

An Infant in Septic Shock:Immunodeficiency vs.Infection?Elena Hsieh, MDAllergy and ImmunologyStanford University

History• ID: 4mo old, ex-full term boy, intermittent feversfor 2 months• Chief Complaint: progressively worse abdominaldistention, non-bilious emesis• Social History: No travel. No sick contacts.• Family History: Healthy sibling. Parents denyconsanguinity, but both from village in Michoacan,Mexico. Maternal cousin died of unknown cause asan infant

Initial Clinical Course• Physical Exam: Shotty cervical LAD bilaterally,hepatosplenomegaly, anasarca, no rashes• Labs: Metabolic acidosis, leukocytosis, DIC• Paracentesis: cx + bacillus IV antibiotics• Change of mental statusintubation and ionotropicsupport PICU• LP: WBC 11 (polys 1, lymph 68, mono 31), glucose75, protein 318, RBC 15

Brain MRIAbdominal & PelvicMRI

Differential Diagnosis13.212.598PMNs: 3%Bands: 16%35.3Lymphs: 40%• Possible diagnoses?• Additional laboratory testing?• Additional imaging studies?

Laboratory Results• CRP: 4.70.6• QUIGs: IgG 271, IgA 40, IgM 36• T&B Cell SubsetsAbsolutePercentLymph 2804 65CD3+ 505 18CD19+ 84 3CD4_+ 365 13CD8+ 140 5CD3-/16+56+2159 77

Differential Diagnosis• ID work up negative (EBV, CMV, parvo,HSV, HIV, blood, urine, stool cultures)• What are the possible diagnoses now?• Any additional work up?

Laboratory Results• Ferritin: 3928• Soluble IL2R: 17155• Triglycerides: 201• NK Cell FunctionNK %CytotoxicityResultNormal50:1 26 >2025:1 22 >1012:1 14 >56:1 11 >1NK Lyticunits17.7 >2.6CD16/56 % 67 2-13Bone Marrow Biopsy

Differential for HemophagocyticHistiolymphocytosis (HLH)Familial HLHPrimary HLH% of Familial HLHcasesProtein/GeneFHL1 ? UnknownFHL2 20-40 Perforin/PRF1FHL3 10-30 (Scandinavian) MUNC13-4/UNC13DFHL4 10-20 (Kurdish) Syntaxin-11/STX11FHL5 ? MUNC18-2/STXBP2Immunodeficiency Incidence Protein/GeneXLPXFLHGriscelli syndromeType 240%-60% withidentified mutationRareSAP/SH2D1AXIAP/BRIC4RAB27AChediak-Higashi

Differential for HemophagocyticHistiolymphocytosis (HLH)Secondary HLHInfectionsVirusesBacteriaParasitesFungiNon-infectionsMalignancyRheumatology(MAS)TherapyCommon Inciting AgentsAdenovirus, enterovirus, hespesvirus (HSV, CMV,EBV, HHV-6, HHV-8, VZV), HIV, influenza, measles,parvovirus B19Mycobacterium tuberculosis, Brucella, Coxiella,rickettsioses, gram-negative/positive bacteremiaPlasmodium, LeishmaniaHistoplasma capsulatum, Penicillium, FusariumLymphoma, pre-B ALLJIA, SLE, KawasakiCommon Inciting AgentsHAART, BMT, solid organ transplant, chemotherapy

Griscelli Syndrome• Autosomal recessive• Hypopigmentation: partial albinism• Neurologic involvement: usually due tolymphohistiocytic infiltration• Absence of giant granules in histology differentiatesit from Chediak-Higashi• Mutations– Type 1 (MYO5A unconventional myosin): noimmunodeficiency or HLH, neurological symptoms– Type 2 (RAB27A GTP binding protein of Ras family):HLH with neurologic involvement– Type 3 (MLPH melanophilin): albinism alone, noimmunodeficiency or neurologic complications

Clinical Course After Diagnosis• RAB27 homozygous mutation• HLA 10/10 matched related BMT with motheras the donor (she was positive for trait butnegative for disease)• BMT complications: GVHD grade II withmucositis, hypertension, and prolonged treatmentwith antimicrobials• Died 3 mo post transplant, with embolic eventsleading to renal and cardiac failure

References• Janka GE. Familial and AcquiredHemophagocytic Lymphohistiocytosis. Annu.Rev. Med. 2012. 63:233–46• Henter et al. HLH-2004: Diagnostic andTherapeutic Guidelines for HemophagocyticLymphohistiocytosis. Pediatr Blood Cancer2007;48:124–131