Age of child and type of bugs found important.  SCID and severe DiGeorge can present in first few months of life (failure to thrive, chronic diarrhoea, recurrent viral infections, thrush). Antibody defects tend to present in later childhood; neutrophil problems in between (which goes to show how good your innate immunity is).

On average, a young infant will get 5-6 resp infections per year; if day care + older sibs that goes up to 12/yr.

ESID diagnostic protocol is not particularly simple but does help by starting with clinical presentations. [Clin Exp Immun 2006; 145:204]

• Family history (including autoimmune disease eg SLE, arthritis, thyroid, vitiligo, endocrine glands)
• PMH of 2 invasive, or 1 invasive plus many minor infections
• Lymphopenia: at least 2.5 in baby or infant as rule of thumb.

Age of Presentation:

• Under 6 months: SCID, T cell (DiGeorge, Chronic Mucocutaneous Candidiasis, Wiskott Aldrich)
• 6 months to 5 yr: ataxia telangiectasia, antibody disorders
• Over 5 yr: specific antibody, complement disorders

Typical bugs:

• Bacteria – if gram positive or Haemophilus, think antibody or complement disorder (or SCID, of course). Plus:
  • Staphylococcus – phagocytic (eg Chronic granulomatous disease)
  • Meningococcus – properdin disorder
  • Pneumococcus – spleen, ectodermal dysplasia, IRAK4 deficiency
  • Enteric bacteria – phagocytic, SCID
  • Salmonella – cellular or phagocytic disorder
  • Listeria – SCID
• Viruses – think cellular or SCID, esp CMV and other herpesviruses.
  • HSV – Ataxia Telangiectasia! Mollaret’s meningitis is recurrent chronic meningitis due probably to HSV
  • Enteroviruses – antibody disorder
  • Warts – DOCK8 (with eczema, also molluscum)
• Fungus – which fungus helps you know what the problem is.
  • Aspergillus commonly seen in CGD, in fact CGD appears to be the only condition where lung aspergillus is seen, and A nidulans v specific for CGD).  Whereas candida rarely a problem in CGD unless neonate or heavy steroids for colitis! Rarely in SCID (other bugs out compete!). Having damaged lungs however can create potential for aspergillus infection in other immunodeficiencies eg Hyper IgE.
  • Candida on the other hand is often seen with SCID. Also autosomal dominant Hyper IgE syndrome (also eczema, pneumonia, skin abscesses), and then a range of conditions where it is the main feature:  IL 17 (recruits neutrophils) and IL 23 (pathway includes STAT3, AIRE, DOCK8, CARD9). CARD9 classically associated with CNS infection but now cases of invasive moulds. AIRE associated with autoimmunity viz APECED (see below).
  • Invasive fungal disease also seen in severe congenital neutropenia and Leucocyte Adhesion Disorders but they usually get severe bacterial infections first!  Functional assays can guide treatment eg IFN.
• Cryptosporidium – CD40 ligand
• Pneumocystis jiroveci – SCID, CD40 ligand, phagocyte disorders, ICF (= Immune dysfunction, Centromere instability, Facial dysmorphism; actually a humoral defect. Due to DNA methylation defect hence bizarre chromosomes).  Not just HIV!
• Toxoplasma – SCID
• Mycobacterium incl BCG – cellular and phagocytic disorders
  • IL12, IL23, IFNgamma, and STAT1 disorders – various defects identified, which explain about half of all atypical infections. But these defects have low penetrance, rarely disseminated BCG or TB. Multifocal mycobacterial osteomyelitis and granulomata seem to be particularly troublesome though in those with otherwise mild disease. Also susceptible to salmonella, listeria, CMV and other herpesviruses. NOT staph, aspergillus, burkholderia.
  • NEMO (NF Kappa beta Essential MOdulator) defects affect all manner of nuclear activating cytokines, so are not very organism specific; gram positives or negatives, PCP, CMV, mycobacteria all more likely. Strangely, aspergillus does not appear to be a major problem! Null alleles are lethal so always hypomorphic. X-linked, females sometimes affected if mosaic, so look for incontinentia pigmenti.
• RSV – HIV!
• Chronic recurrent multifocal osteomyelitis = a clinical diagnosis, inflammatory not infective! Self-limiting, rarely persistent bony abnormalities.

Other clinical problems:

• Cardiac – Digeorge
• Eosinophilia and eczema – Hyper IgE, IPEX, Wiskott Aldrich, DOCK8
• inflammatory bowel disease – CGD, IPEX, CVID, CD40 ligand.
• Rash in SCID (=GVHD)
• Liver abscesses – 50% will have CGD in UK.
• pneumatocoele – Hyper IgE
• Absent thymus on CXR (pleurae appear to meet in middle) – DiGeorge, SCID
• Bruising/bleeding – Wiskott Aldrich
• Abnormal nails, hair, teeth (eg conical incisors), skin (erythroderma), sweat glands – Ectodermal dysplasia, or Cartilage-Hair (= immune osseous dysplasia, due to RNA processing defect, short limbed dwarfism, variable combined defect esp human herpesviruses. Predisposed to lymphoma). X-linked recessive anhidrotic type ectodermal dysplasia presents early in life, but NEMO defects found with abnormal teeth alone (see above). Often get surprisingly little inflammatory response with infections, at least milder ones.  Also APECED (just candida).
• Coarse facies – Hyper IgE, esp extra/irregular teeth, ICF, but lots of other syndromes of course
• Persistent vaccination nodule – CGD!
• Albinism – Chediak Higashi (patches in retina or skin) and related. Incontinentia pigmenti suggests mosaicism, so girl may have X-linked disorder.
• Late walking, unsteadiness, drooling – ATA (telangiectasia later, esp eye)
• Diplegia/dysarthria – PNP def
• Bird head – DNA repair defect (like Seckels, developmental delay)
• Erythrophagocytosis/lymphoma/aplastic/persistent EBV – X linked lymphoproliferative disorder
• Late cord detachment = neutrophil or leucocyte adhesion defect
• Autoimmunity – CVID, CD40 ligand, APECED (ectodermal dystrophy, chronic mucocutaneous candidiasis), IPEX (enteropathy, x-linked)
• Cytopenias – ALPS, DNA repair and autoimmunity in CD40 ligand.
• Granulomas – CDG, CVID

History

Consanguinity.

Examination

Scars, nails, creases.

Tests

Always test for HIV!

IgG will be maternal in first 6 months of life.  IgM reaches adult levels in toddlerhood.  IgG in young childhood.  IgA only in adolescence – often low in young children, deficiency only diagnosed after age 4.  Immunoglobulin levels can be high in HIV, Digeorge, CGD.

IgG subsets are controversial – not great evidence that they are responsible for increased infections. High IgM can indicate a problem with class switching eg Hyper IgM syndrome.

Lymphocyte counts:

Functional abs – pneumo often worse response esp polysacch.

Subsets – EDTA, fresh, room temp (else CD4 drops – “fridge AIDS”).   CD3 are T cells, which then subdivide into CD4 and CD8 T-helper cells. CD19 and 21 are B cells, CD56 are NK cells. CD4 numbers should exceed CD8 – reversed ratio seen in HIV. A specific NK problem has been described with increased susceptibility to herpesviruses and papillomaviruses. Abnormal NK numbers also seen in Chediak-Higashi, CD40 ligand and NEMO (?).  Low CD4 seen in steroids, sepsis, Digeorge, CVID, Ataxia telangiectasia, Coeliac.

If subsets normal, look at proliferation studies (signalling problem rather than maturation problem).

A total hemolytic complement (CH50 or CH100) screening assay looks for defects in the complement pathway. AH50 or AH100 tests the alternative pathway. [C3/C4 are not enough!]

[Peds 11.127.810]