approach to immunodeficiency

Secondary immunodeficiency (medications, HIV, malignancy, protein loss) vastly outnumbers primary immunodeficiency in adults. The culprit organisms and infection site point to which arm of immunity is affected. Workup centres on excluding secondary causes, quantifying immunoglobulin levels, and checking vaccine responses — advanced testing belongs to immunology.

classification

secondary immunodeficiency — far more common in adults

Category	Examples
Medications	Corticosteroids, methotrexate, cyclosporine, rituximab, anti-CD19 CAR-T, antiepileptics (phenytoin, carbamazepine, valproate, levetiracetam, lamotrigine), antipsychotics (clozapine, chlorpromazine)
Infections	HIV, measles, EBV, COVID-19, mycobacteria
Malnutrition	Macronutrient deficiency/malabsorption, micronutrient deficiency (zinc, selenium, vitamins A, C, D, E)
Protein loss	GI (protein-losing enteropathy), renal (nephrotic syndrome, CKD)
Extremes of age	Prematurity, immunosenescence/inflammaging
Haematologic malignancy	CLL, multiple myeloma

Most common cause in developed countries → medications
Most common cause worldwide → malnutrition

primary immunodeficiency (inborn errors of immunity)

Rare in adults. Common variable immunodeficiency (CVID) is the most frequently diagnosed primary immunodeficiency in adulthood.

when to suspect

Recurrent bacterial sinopulmonary infections (ideally with imaging confirmation)
Invasive or severe meningococcal disease
Opportunistic infections (PJP, CMV, disseminated fungal)
Unexplained bronchiectasis
Recurrent deep-seated abscesses
Autoimmunity or lymphoma in the setting of recurrent infections (some primary immunodeficiencies present this way)

Bacterial sinopulmonary infections matter more than viral URTIs when considering immunodeficiency. Always confirm with imaging when possible.

pattern recognition — organism → immune defect

Immune defect	Typical infections	Key organisms
Humoral (B cell)	Recurrent sinopulmonary infections, otitis media, chronic diarrhoea, bronchiectasis	Encapsulated bacteria (S. pneumoniae, H. influenzae), Giardia, Salmonella, Campylobacter
Combined (T cell ± B cell)	Opportunistic infections (same spectrum as HIV/AIDS)	PJP, CMV, Cryptosporidium, Mycobacteria, Candida
Phagocyte (neutrophil)	Recurrent invasive skin/soft tissue infections, deep abscesses, pneumonia	Catalase-positive organisms: S. aureus, GNB, Aspergillus, Nocardia
Complement / asplenia	Invasive infections with encapsulated organisms	Neisseria (especially meningococcal), S. pneumoniae

initial assessment

for all patients

History — thorough medication review (immunosuppressants, antiepileptics, antipsychotics), infection timeline, autoimmune disease, malignancy
CBC with differential and smear — lymphopaenia, neutropaenia, autoimmune cytopaenias, Howell-Jolly bodies (asplenia)
Metabolic — liver enzymes, creatinine, HbA1c
Protein loss screen — serum total protein, albumin, urinalysis (proteinuria)
Infection screen — HIV Ag/Ab, HBV, HCV
Paraprotein screen — SPEP with immunofixation, free light chains

HIV is a can’t-miss diagnosis. Test every patient being worked up for immunodeficiency — no exceptions.

immunologic testing

Quantitative immunoglobulins — IgG, IgA, IgM
- IgE and IgG subclasses are not helpful in the initial workup
Vaccine responses — tetanus (protein antigen) and pneumococcal (protein + polysaccharide) titres
Complement — CH50 and AH50 if complement defect suspected (recurrent Neisseria)
Lymphocyte subsets — T/B/NK flow cytometry (CD3, CD4, CD8) — can usually defer to outpatient immunology

Immunoglobulin levels and lymphocyte counts are unreliable during acute illness or hospitalisation. Rarely diagnose or start specific treatment for immunodeficiency during an admission — abnormal values often normalise after recovery.

diagnostic algorithm

Recurrent/unusual infections
       │
       ▼
History + medications + CBC/diff/smear + metabolic + HIV/HBV/HCV
       │
       ▼
SPEP/immunofixation + FLC → rule out myeloma/lymphoproliferative
       │
       ▼
Quantitative Ig (IgG, IgA, IgM)
       │
       ├─ Low Ig → vaccine responses (tetanus, pneumococcal)
       │           → refer immunology (? CVID)
       │
       ├─ Normal Ig → consider complement (CH50/AH50),
       │              phagocyte defects, T cell disorders
       │              → refer immunology
       │
       └─ Secondary cause identified → treat underlying cause

practical tips for IM residents

Before starting rituximab, ocrelizumab, or IVIG → get baseline IgG/IgA/IgM (enables monitoring for secondary hypogammaglobulinaemia)
CD4 thresholds for prophylaxis — same principles as HIV:
- CD4 < 200 cells/µL → PJP prophylaxis (TMP-SMX)
- CD4 < 100 cells/µL → consider toxoplasmosis prophylaxis
- CD4 < 50 cells/µL → MAC prophylaxis (azithromycin)
Secondary >> primary — always ask: could we have caused this?
Immunocompromised patient with infection → treat empirically and aggressively rather than watch and wait
Febrile neutropaenia — follow neutropaenic sepsis protocols; do not delay antibiotics

what NOT to do

Do not order IgE or IgG subclasses as part of initial workup — low yield, high confusion
Do not diagnose primary immunodeficiency during acute illness — recheck once recovered
Do not send specialised tests (neutrophil oxidative burst, lymphocyte proliferation) without immunology involvement
Do not delay HIV testing — it alters every subsequent management decision
Do not attribute recurrent viral URTIs alone to immunodeficiency — focus on bacterial sinopulmonary infections with imaging