Recurrent infections and primary immunodeficiency

A patient with infections that are too many, too severe, too persistent, in unusual locations, or caused by unusual organisms. The threshold is clinical: more than two serious bacterial infections per year in a child, more than one episode of pneumonia, deep abscesses, opportunistic organisms (PCP, CMV in an otherwise well child, disseminated mycobacteria), failure to thrive with infection history, or a family history of similar infections or early death. The diagnostic question is which arm of the immune system is failing, because the pattern of pathogens points to the pattern of immunity affected.

The most useful split is the pathogen pattern → immune arm mapping:

Two anchor questions before any test:

1. Onset: birth and immediately (SCID), first few months (T-cell, combined, agammaglobulinemia after maternal IgG wanes), school years (CGD, hyper-IgE), adult (CVID, late-onset complement).
2. Family history and consanguinity: many PIDs are recessive or X-linked. A sibling who died of "sepsis" or "pneumonia" in infancy is the family-history signal for SCID.

B-cell (antibody) deficiencies

• X-linked agammaglobulinemia (Bruton) (BTK, X-linked): male infants with absent B cells and absent immunoglobulins after maternal IgG wanes (4-6 months). Recurrent sinopulmonary infections with encapsulated bacteria. Enteroviral meningoencephalitis is the feared complication.
• Common variable immunodeficiency (CVID): heterogeneous; usually adult onset. Low IgG + low IgA or IgM + poor vaccine response. Some genes identified (TACI/TNFRSF13B, CTLA4, LRBA, NFKB1, NFKB2), most still genetically unexplained. Autoimmunity (ITP, AIHA) and granulomatous disease are common.
• Selective IgA deficiency: the most common PID; usually asymptomatic. Anaphylactic reaction to IgA-containing blood products is the worst sequela.
• Hyper-IgM syndromes (CD40LG X-linked is most common, AID/AICDA, UNG, CD40): impaired class switching; low IgG and IgA, normal or high IgM. PCP risk (X-linked form has T-cell costimulation defect).

T-cell and combined immunodeficiencies

• Severe combined immunodeficiency (SCID) (multiple genes, severe phenotype):
  • IL2RG (X-linked, most common): "X-SCID," T-/B+/NK-.
  • RAG1, RAG2 (AR): T-/B-/NK+.
  • ADA (adenosine deaminase, AR): T-/B-/NK-; treatable with PEG-ADA, gene therapy, or HSCT; the classic example of a treatable PID where time matters.
  • DCLRE1C (Artemis), JAK3, IL7R, others.
  • All forms detectable by TREC (T-cell receptor excision circle) newborn screening; transplant before infection-related mortality is the goal.
• 22q11.2 deletion syndrome (DiGeorge): thymic hypoplasia → variable T-cell deficiency; conotruncal cardiac defects; hypocalcemia from parathyroid hypoplasia; palatal anomalies; characteristic facies.
• Wiskott-Aldrich syndrome (WAS, X-linked): eczema + thrombocytopenia with small platelets + recurrent infections + lymphoma risk + autoimmunity. The small-platelet finding (MPV < 7 fL) is the discriminating bedside lab.
• Ataxia-telangiectasia (ATM, AR): progressive cerebellar ataxia + oculocutaneous telangiectasias + radiosensitivity + IgA deficiency + lymphoid malignancy + elevated alpha-fetoprotein.
• Hyper-IgE syndrome (Job) (STAT3, AD; DOCK8, AR is a severe variant): recurrent cold staphylococcal abscesses + eczema + retained primary teeth + characteristic facies + scoliosis + minor trauma fractures + very high IgE.
• Chronic mucocutaneous candidiasis (STAT1 gain-of-function, others; APECED with AIRE).

Phagocyte defects

• Chronic granulomatous disease (CGD) (CYBB X-linked most common; NCF1, NCF2, NCF4, CYBA AR): impaired oxidative burst. Catalase-positive organisms (Staph aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, Aspergillus) cause granulomas, abscesses, and lymphadenitis. DHR (dihydrorhodamine) flow cytometry is the functional screen; NBT (nitroblue tetrazolium) is the older version.
• Leukocyte adhesion deficiency (LAD type 1) (ITGB2): delayed umbilical cord separation (> 30 days), neutrophilic leukocytosis, recurrent soft tissue infections without pus.
• Chediak-Higashi syndrome (LYST): partial albinism + giant granules in neutrophils + recurrent infections + bleeding + accelerated phase (HLH-like).

Complement defects

• Terminal complement (C5-C9) deficiencies: recurrent Neisseria meningitidis infections, often at unusual sites or serogroups not covered by routine vaccines.
• Early classical pathway (C1q, C1r, C1s, C4, C2) deficiencies: SLE-like autoimmunity + encapsulated bacterial infections.
• Mannose-binding lectin and lectin pathway deficiencies: variable, often mild.
• Hereditary angioedema (SERPING1 C1 inhibitor deficiency): not an immunodeficiency in the infection sense, but episodic angioedema with abdominal pain attacks; relevant because patients are often misdiagnosed.

Innate immunity

• TLR pathway defects (IRAK-4, MyD88): pyogenic bacterial infections, blunted inflammatory response.
• IL-12 / IFN-γ axis defects (IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1): disseminated atypical mycobacterial or BCG disease.

1. CBC with differential: absolute lymphocyte count (low in SCID), absolute neutrophil count, platelet count, MPV (small platelets in Wiskott-Aldrich), monocyte count (low in GATA2 deficiency).
2. Quantitative immunoglobulins: IgG, IgA, IgM, IgE. Compare to age-matched reference ranges.
3. Specific antibody titers: tetanus, diphtheria, pneumococcal polysaccharide (post-vaccine response is functional, not just quantitative).
4. Lymphocyte subsets by flow cytometry: CD3, CD4, CD8 T cells; CD19 B cells; CD16/56 NK cells. Identifies SCID phenotype (T-/B-/NK-, T-/B+/NK-, etc.) and B-cell absence (XLA).
5. CH50 (classical pathway) and AH50 (alternative pathway): complement screens.
6. DHR oxidative burst by flow cytometry: chronic granulomatous disease.
7. HIV testing: rule out the most common acquired cause.
8. 22q11.2 FISH or chromosomal microarray if clinical features suggest DiGeorge.
9. TREC newborn screen result (or order if not done): SCID screening.
10. Functional T-cell tests (lymphocyte proliferation to mitogens and antigens): T-cell function beyond enumeration.
11. Targeted PID gene panel or trio exome once the phenotype is characterized; many panels cover 300+ genes and are first-line in unclear cases.