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IEI

FIRS

PID

HLH

MAS

Triple I

Sepsis

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TRIPLE I� (Intrauterine Inflammation or Infection or both)

In 2015, NICHD recommended replace ‘chorioamnionitis’ with ‘Triple I

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  • Consonni S, Salmoiraghi E, Vaglio Tessitore I, Pintucci A, Vitale V, Calzi P, Moltrasio F, Locatelli A. Intra-Amniotic Inflammation or Infection: Suspected and Confirmed Diagnosis of "Triple I" at Term. Children (Basel). 2023 Jun 26;10(7):1110. doi: 10.3390/children10071110
  • Peng CC, Chang JH, Lin HY, Cheng PJ, Su BH. Intrauterine inflammation, infection, or both (Triple I): A new concept for chorioamnionitis. Pediatr Neonatol. 2018 Jun;59(3):231-237. doi: 10.1016/j.pedneo.2017.09.001.

Term

Meaning

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Triple I

Intrauterine Inflammation, Infection, or both

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Suspected Triple I

Fever + 1 clinical sign

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Confirmed Triple I

Suspected + lab/histologic confirmation

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Fetal Inflammatory Response Syndrome (FIRS)

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  • Giovannini et al. Infection Induced Fetal Inflammatory Response Syndrome (FIRS): State-of- the-Art and Medico-Legal Implications-A Narrative Review. Microorganisms. 2023;11(4):1010.

Fetal infection or injury

Systemic activation of fetus's innate immune system

Release of cytokines and chemokines

Multiorgan impairment

Neonatal mortality and morbidity

FIRS

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Redline Staging and grading of triple I

  • Stage 1 (mild):
    • Chorionic vasculitis/umbilical phlebitis (vein involvement)

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  • Stage 2 (moderate):
    • Neutrophils in one or both umbilical arteries (arteritis)
    • Involvement of the umbilical vein ±
    • Fading or degeneration of the vascular smooth muscle cells

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  • Stage 3 (severe):
    • Necrotizing funisitis
    • Concentric umbilical perivasculitis (neutrophils & eosinophils)
    • Mineralization of umbilical vessels ±

Redline R.W., Faye-Petersen O., Heller D., Qureshi F., Savell V., Vogler C., Society for Pediatric Pathology, Perinatal Section, Amniotic Fluid Infection Nosology Committee Amniotic infection syndrome: Nosology and reproducibility of placental reaction patterns. Pediatr. Dev. Pathol. 2003;6:435–448. doi: 10.1007/s10024-003-7070-y.

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Jung et al. The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications. Seminars in fetal & neonatal medicine. 2020;25:101146.

FIRS diagnosis

  • Placenta: histologically
  • U. cord: IL-6 (>11 pg/ml) 
  • Neonates:
    • IL-6
    • IL-8
    • CXCL10
    • IL-1β
    • TNF

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HLH & Sepsis

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Hemophagocytic lymphohistiocytosis (HLH)

  • Rare but life-threatening hyperinflammatory syndrome
  • Immune dysregulation involving
    • Defects in cytotoxic pathways of natural killer (NK) cells and/or cytotoxic T lymphocytes (CTLs)
    • Leading to hypercytokinemia
    • Accumulation of activated macrophages/ histiocytes in organs and tissues
  • Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2;127(22):2672-81, editorial can be found in Blood 2016 Jun 2;127(22):2655.

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Hemophagocytic lymphohistiocytosis (HLH)

  • Can mimic or coexist with neonatal sepsis
  • Incidence of neonatal HLH: 1 in 50,000 to 150,000
  • Ethnicity
  • Slight male preponderance 
  • Consanguinity, 10% of familial HLH (fHLH) is nHLH
  • 20% to 40% of FHLH cases result from mutations at the fHLH2 loci within the perforin gene (PRF1) on chromo some 10q22.1

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  • Balakumar N, Sendi P, Totapally BR. Epidemiology and Outcomes of Neonatal Hemophagocytic Lymphohistiocytosis. Front Pediatr. 2022 Apr 26;10:848004.
  • Lincoln Kranz, Wyatt Hahn, Whitney Thompson, Roland Hentz, Nathan L. Kobrinsky, Paul J. Galardy, Jacob R Greenmyer; Neonatal Hemophagocytic Lymphohistiocytosis: Scoping Review and Analysis of 205 Cases. Blood 2023; 142 (Supplement 1): 5350. doi: https://doi.org/10.1182/blood-2023-182092
  • Josef McLean, Roia Katebian, Eugene Suh, Kamran Mirza, Sachin Amin; Neonatal Hemophagocytic Lymphohistiocytosis. Neoreviews June 2019; 20 (6): e316–e325. https://doi.org/10.1542/neo.20-6-e316

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When to suspect HLH in a neonate with sepsis

  • Clinicians should consider HLH in neonates with
    • Unexplained fever, hepatosplenomegaly, and pancytopenia.
    • Sepsis is not improving despite appropriate antibiotics and supportive care
    • Multiple organ systems are involved
    • Unusual lab findings (especially with cytopenia and elevated ferritin)
  • McLean J, Katebian R, Suh E, Mirza K, Amin S. Neonatal hemophagocytic lymphohistiocytosis. Neoreviews. (2019) 20:e316–25. 10.1542/neo.20-6-e316

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Clinical features

  • Hydrops fetalis
  • Hypothermia > hyperthermia
  • Rash
    • Petechiae
    • Purpura
    • Erythroderma
  • Neurological manifestations including seizures
  • Sepsis like manifestation

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  • Lincoln Kranz, Wyatt Hahn, Whitney Thompson, Roland Hentz, Nathan L. Kobrinsky, Paul J. Galardy, Jacob R Greenmyer; Neonatal Hemophagocytic Lymphohistiocytosis: Scoping Review and Analysis of 205 Cases. Blood 2023; 142 (Supplement 1): 5350. doi: https://doi.org/10.1182/blood-2023-182092

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Diagnosing HLH

  • CBC with Differential
  • Ferritin
  • Triglycerides
  • Fibrinogen
  • Liver Function Tests
  • LDH
  • CRP/ESR
  • Coagulation profile
  • Chest X-ray / CT

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  • Bone Marrow Aspiration/Biopsy
  • CSF Analysis
  • Neuroimaging (MRI)
  • Soluble IL-2 receptor (sCD25)
  • NK Cell Activity
  • Blood cultures
  • Viral PCRs (EBV, CMV, etc.)
  • Genetic Testing

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Diagnosing HLH !

  • Ferritin >10,000 ng/mL : highly suggestive but not specific.
  • Hemophagocytosis: is supportive but not required if other criteria are met.
  • Always combine clinical picture with labs.
  • A deteriorating neonate with sepsis-like signs, cytopenias, and high ferritin: strong HLH suspect

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Management

  • Supportive
  • Specific
  • Definitive

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Macrophage Activation Syndrome (MAS)

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Cytokine Storm Syndrome

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Macrophage activation syndrome (MAS)

  • MAS is a life-threatening hyperinflammatory syndrome and is caused by a severely dysregulated immune response.

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  • MAS / Cytokine storm syndrome: combinations of

    • Genetic predisposition
    • Inflammatory state
    • Triggering infectious agents
    • Autoimmune (mothers who are SSA- and/or SSB-positive)

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  • Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ. Genetic defects in cytolysis in macrophage activation syndrome. Curr Rheumatol Rep. 2014;16(9):439
  • Griffin G, Shenoi S, Hughes GC. Hemophagocytic lymphohistiocytosis: an update on pathogenesis, diagnosis, and therapy. Best Pract Res Clin Rheumatol. 2020;34(4):101515.

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MAS & HLH : Part Of A Spectrum

  • Shared clinical features
  • Similar immune dysregulation
    • Uncontrolled activation of cytotoxic T cells and macrophages.
    • Excessive cytokine production (IL-1, IL-6, IFN-γ, etc.).
  • Overlap in triggers
    • Genetic HLH mutations become symptomatic when exposed to a trigger
    • Blurred lines between "genetic" and "acquired”

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  • Bracaglia C, Prencipe G, De Benedetti F. Macrophage activation syndrome: different mechanisms leading to a one clinical syndrome. Pediatr Rheumatol Online J. 2017;15(1):5.
  • Heijstek, V., Habib, M., van der Palen, R. et al. Macrophage activation syndrome in a newborn: report of a case associated with neonatal lupus erythematosus and a summary of the literature. Pediatr Rheumatol 19, 13 (2021).

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MAS & HLH : Part Of A Spectrum

  • Levels of IL-18
    • Markedly increased in MAS
    • Moderately elevated in familial HLH
    • Reflects the extent of macrophage activation (main source of IL-18)
    • Levels of IL-18 correlate with levels of ferritin

IL-18 ≈ serum Ferritin

  • MAS responds to HLH-directed therapy (like steroids, etoposide, or IL-1 inhibitors) reinforcing the shared pathway

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Bracaglia C, Prencipe G, De Benedetti F. Macrophage activation syndrome: different mechanisms leading to a one clinical syndrome. Pediatr Rheumatol Online J. 2017;15(1):5.

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2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization Collaborative Initiative

  • Arthritis & Rheumatology, Volume: 68, Issue: 3, Pages: 566-576, First published: 28 August 2015, DOI: (10.1002/art.39332)

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Inborn Error of Immunity (IEI)

PRIMARY IMMUNE DEFICIENCY (PID)

  • Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Picard C, Puck J, Torgerson TR, Casanova JL, Sullivan KE. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020 Jan;40(1):24-64. doi: 10.1007/s10875-019-00737-x. Epub 2020 Jan 17. Erratum in: J Clin Immunol. 2020 Jan;40(1):65. doi: 10.1007/s10875-020-00763-0. PMID: 31953710; PMCID: PMC7082301.
  • Kim VHD, Upton JEM, Derfalvi B, Hildebrand KJ, McCusker C. Inborn errors of immunity (primary immunodeficiencies). Allergy Asthma Clin Immunol. 2025 8;20(Suppl 3):76.

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IEI

  • At birth or early infancy
  • 1/1000 to 1/10000
  • Males > females (5:1)

Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27:497–502. doi: 10.1007/s10875-007-9103-1

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Index of suspicion / IEI Screening�(Risk factors and/or clinical features)

  • Family history
  • Syndromic look (abnormal facies)
  • Infection at any location
  • Infection after live vaccines (e.g., rotavirus, BCG, oral polio, etc.)
  • Failure to thrive
  • Chronic diarrhea
  • Abdominal distention
  • Lymphadenopathy
  • Hepatosplenomegaly

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  • Lung or cardiac problems
  • Mucosal diseases, e.g., thrush, mouth sores, and ulcerations
  • Skin rashes
  • Pigmentary disorders
  • Alopecia
  • Bleeding
  • Petechiae
  • Melena
  • Late separation of umbilical cord
  • O’Connell AE. Primary immunodeficiency in the NICU. Neoreviews 2019;20:e67–78.

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Preliminary Evaluation for IEI in the Newborn

  • Leukopenia <4000 / uL
  • ANC <1500 / uL
  • Platelets <150
  • Eosinophilia
  • ALC < 3000 / Ul
  • Ig levels

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  • Immune flowcytometry
    • NK cells CD3 – CD16+ / 56+
    • T cells
      • T lymphocytes (CD3+)
      • T helper (CD3+ CD4+)
      • T cytotoxic(CD3+ CD8+)
    • B cells
      • CD19+ or CD20+
  • Lymphocyte proliferation assay (PHA & anti-CD3)

Ozdemir O. Primary immunodeficiency diseases in the newborn. North Clin Istanb 2021;8(4):405–413.

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IEI �in �neonates

Innate immune system

Complement deficiencies

Phagocytic diseases

Immunoregulatory Disorders

Cellular/combined immunodeficiencies

Antibody deficiencies

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Antibody deficiencies

  • Recurrent RTI, diarrhea, fever, FTT
  • Physiologic Hypogammaglobulinemia of Infancy (PHI)
    • Maternal transferred IgG inutero
    • Roughly 3–6 months of age
    • Serum IgG levels <400 mg/Dl
  • Congenital agammaglobulinemia
    • Usually asymptomatic
    • Decreased IgG after several months

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�Cellular/combined immunodeficiencies (CID)�

  • SCID
  • Others
    • Di George  
          • Conotruncal cardiac anomalies
          • Hypoplastic thymus
          • Hypocalcemia

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    • Wiskot Aldrich syndrome (WAS)
          • Eczema
          • Thrombocytopenia
          • Immune deficiency
    • X-linked hyperimmunoglobulin M syndrome (HIGM)
        • Recurrent sinopulmonary infections
        • Recurrent diarrhea
        • Higher susceptibility to Pneumocystis jirovecii (PCP) pneumonia. 

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    • Chronic mucocutaneous candidiasis

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Phagocytic diseases

  • Congenital neutropenia disorders
  • Chronic granulomatous disease (CGD)
  • Leukocyte adhesion deficiency (LAD)
      • Delayed umbilical cord separation
      • Recurrent bacterial infections of the skin and mucosal membranes
      • Leukocytosis
  • Presentation as
    • Bacterial (e.g., S. aureus, P aeruginosa, N asteroides, and S typhi)
    • Fungal (e.g., Candida and Aspergillus species)
    • Abscess, abnormal wound healing, dermatitis/eczema, and stomatitis
    • Necrotizing pneumonia

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Immunoregulatory Disorders

  • Hemophagocytic lymphohistiocytosis (HLH)
  • X-linked (IPEX) syndrome / Immune dysregulation

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          • Enteropathy
          • Endocrinopathy
          • Eczematous dermatitis

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Innate immune defects in newborn

  • NF-kappa-B essential modulator defects
  • Toll-like receptor defects (MyD88 and IRAK4 deficiencies)
  • Congenital asplenia
  • Natural killer cell deficiencies
  • Mendelian susceptibility to mycobacterial diseases

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Autoinflammatory Disorders

          • Fevers
          • Rash
          • Joint inflammation (arthropathy), ± CNS involvement

 

  • No Infection but inflammation
  • Neonatal-Onset Multisystem Inflammatory Disorder (NOMID)
  • Cryopyrin-associated periodic syndromes (CAPS)
  • Muckle-Wells Syndrome (MWS) milder course of NOMID
  • Familial Cold Autoinflammatory Syndrome (FCAS): A milder CAPS disorder with cold-induced fever and rash. 

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Complement Deficiencies

  • Positive family history
  • Encapsulated bacterial infections (streptococci, meningococci, or H. influenzae type B)
  • Classical pathway (C1q, C4, and C3)
  • Alternative pathway (properdin, factor B)
  • Complement deficiencies cause decreased ability to lyse bacteria, defective chemotaxis, and lesser enrollment of leukocytes to infection sites and poorer phagocytic (opsonizing) capacity.

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Bone Marrow Failures

  • Fanconi anemia
  • Myelodysplasia

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Thanks