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Secondary Immunodeficiency & Immunity Across the Lifespan

Name: Secondary Immunodeficiency & Immunity Across the Lifespan
Creator: Veli Bakalov, MD

The everyday causes of immune failure, from preterm infants to the elderly

Immunology·Immunodeficiency & Host Defense·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Acquired causes (drugs, diabetes, uremia, cirrhosis, malnutrition, protein loss, B-cell cancers, HIV, burns) far outnumber primary immunodeficiency; malnutrition leads worldwide.
Glucocorticoids cause neutrophilia by demargination with lymphopenia and eosinopenia, block NF-κB and AP-1, and at prolonged high doses predispose to PJP (TMP-SMX prophylaxis).
ANC <500/μL: gram-negatives including Pseudomonas first (empiric antipseudomonal β-lactam for fever), then invasive Aspergillus and Candida if neutropenia persists.
Diabetes impairs neutrophil chemotaxis and phagocytosis: rhinocerebral mucormycosis in DKA and Pseudomonas malignant otitis externa.
Nephrotic syndrome, protein-losing enteropathy, CLL and myeloma lower functional IgG, so encapsulated bacteria recur.
Maternal IgG crosses the placenta via FcRn, mostly in the third trimester, so preterm infants are deficient; infant IgG bottoms out at 3–6 months.
IgM cannot cross the placenta, so elevated cord-blood IgM indicates congenital infection.
Children under 2 respond poorly to polysaccharide antigens; conjugate vaccines recruit T-cell help.
Immunosenescence (thymic involution, fewer naive T cells, inflammaging) weakens vaccine responses: give high-dose or adjuvanted influenza vaccine at ≥65 and recombinant zoster vaccine at ≥50.

Acquired immune compromise

Scale. Primary immunodeficiencies are rare; drugs (glucocorticoids, chemotherapy, biologics, transplant immunosuppressants), chronic disease, malnutrition, cancer, HIV and burns account for the vast majority of immunocompromised patients, and protein-energy malnutrition is the leading cause worldwide. The damaged arm predicts the organisms.

Common acquired causes

Cause	Main defect	Typical infections
Glucocorticoids	Lymphopenia, cytokine suppression, weak T-cell immunity	Pneumocystis, TB reactivation, Strongyloides hyperinfection
Chemotherapy	Neutropenia, mucositis	Gram-negatives incl. Pseudomonas; later Aspergillus, Candida
Diabetes	Poor neutrophil chemotaxis, adherence, phagocytosis, killing	Mucormycosis, malignant otitis externa, emphysematous pyelonephritis, foot infections
Cirrhosis	Low complement, Kupffer-cell dysfunction, portosystemic shunting	Spontaneous bacterial peritonitis, Vibrio vulnificus
Malnutrition	Thymic atrophy, T-cell dysfunction	Severe measles, TB
Nephrotic syndrome, protein-losing enteropathy, CLL, myeloma	Low functional IgG	Encapsulated bacteria (S. pneumoniae, H. influenzae)
Burns	Lost barrier, protein leak, neutrophil dysfunction	Pseudomonas, S. aureus wound sepsis

Glucocorticoids and chemotherapy

Steroids and the blood count. Within hours, neutrophils rise because they detach from vessel walls (less adhesion-molecule expression), leave the marrow faster and die more slowly. Lymphocytes (redistribution and apoptosis), eosinophils, monocytes and basophils all fall.

Steroid mechanism. The glucocorticoid receptor blocks NF-κB (partly by inducing IκB) and AP-1, shutting down IL-1, IL-2, IL-6 and TNF-α transcription, and induces annexin A1, which inhibits phospholipase A2. The resulting T-cell defect makes Pneumocystis pneumonia the classic risk of prolonged high doses, prevented with TMP-SMX.

Chemotherapy. Cytotoxic drugs destroy dividing marrow precursors and mucosal epithelium. Risk climbs steeply once the absolute neutrophil count (ANC) falls below 500/μL and with each day it stays there: first gram-negative bacilli including Pseudomonas, so fever demands an immediate antipseudomonal β-lactam (cefepime, piperacillin-tazobactam or a carbapenem); after about a week, invasive Aspergillus (septate, acute-angle hyphae; halo sign on CT) and Candida.

<500/μLANC defining severe neutropenia; fever is an emergency

≥20 mg × ≥4 wkdaily prednisone exposure that usually prompts PJP prophylaxis

Chronic disease, malnutrition and low antibody

Diabetes. Hyperglycemia cripples neutrophils, and neuropathy and vascular disease add tissue damage. Rhinocerebral mucormycosis (Rhizopus, Mucor: broad nonseptate hyphae, black necrotic eschar) and malignant otitis externa (Pseudomonas in older diabetics) are the signature infections.

DKA favors Mucorales: acidosis frees iron from transferrin, and deferoxamine acts as a siderophore these molds can use.

Uremia and cirrhosis. Uremia impairs neutrophil and lymphocyte function and blunts vaccine responses, so dialysis patients receive higher-dose hepatitis B vaccine. Cirrhosis cuts complement synthesis, weakens Kupffer-cell clearance and shunts portal blood past the liver, so gut bacteria (E. coli, Klebsiella) seed ascites and raw-shellfish Vibrio vulnificus can cause fulminant sepsis.

Malnutrition. Protein-energy malnutrition shrinks the thymus, lowers T-cell numbers and function (cutaneous anergy), and reduces complement and secretory IgA. Zinc deficiency adds T-cell dysfunction and vitamin A deficiency weakens mucosal barriers.

Low functional antibody. Nephrotic syndrome spills IgG and factor B into urine (pneumococcal peritonitis in children); protein-losing enteropathy such as intestinal lymphangiectasia leaks IgG and lymphocytes into the gut. In CLL and multiple myeloma, polyclonal antibody falls even when a monoclonal spike raises total protein; infection is a leading cause of death, and IVIG helps selected patients with recurrent infections.

Immunity at the start of life

Third trimesterFcRn actively transports maternal IgG, the only isotype that crosses
Birthterm IgG near maternal level; preterm infants deficient
3–6 monthsphysiologic nadir as maternal IgG decays before infant production rises
Later infancythe infant's own IgG steadily climbs

Transient hypogammaglobulinemia of infancy. A deeper or prolonged nadir that resolves on its own in early childhood; vaccine responses are usually preserved. Breast milk supplies secretory IgA for the gut but does not raise serum IgG.

Cord-blood IgM. IgM does not cross the placenta and is the first isotype the fetus makes, so high total or pathogen-specific IgM in cord or neonatal blood signals congenital (TORCH) infection, whereas neonatal IgG mostly reflects the mother's antibody.

Polysaccharide antigens. T-independent responses rely on marginal-zone B cells that stay functionally immature until about age 2, so infants respond poorly to capsules of S. pneumoniae, Hib and N. meningitidis. Conjugate vaccines link the polysaccharide to a protein carrier, recruiting T-cell help for class switching, affinity maturation and memory.

Immunity in old age

Immunosenescence. Thymic involution shrinks the naive T-cell pool, memory T cells become oligoclonal, B-cell responses weaken, and chronic low-grade inflammation with raised IL-6 and TNF-α (inflammaging) develops. The results are weaker vaccine responses, reactivation of VZV and latent TB, and more severe influenza and pneumococcal disease.

Vaccine adaptations. Adults ≥65 receive high-dose, adjuvanted or recombinant influenza vaccine, and adults ≥50 receive the adjuvanted recombinant zoster vaccine.

Infection in older adults often presents without fever or leukocytosis; delirium or a fall may be the only clue.