Primary and Secondary Immunodeficiency

Primary Immunodeficiencies

Primary immunodeficiencies (PIDs) are inherited defects of immune development or function. For USMLE Step 1, classify them by the arm of immunity affected: B-cell/humoral, T-cell/cellular, combined B- and T-cell, phagocyte, and complement disorders. The key clinical principle is that the type of infection predicts the immune defect: encapsulated bacteria suggest antibody or complement deficiency; viral, fungal, and opportunistic infections suggest T-cell deficiency; catalase-positive organisms suggest phagocyte killing defects.

High-yield developmental framework

Maternal IgG crosses the placenta and has a half-life of approximately 21 days; therefore, severe congenital B-cell defects often present after 6 months, when maternal IgG has waned. T-cell defects usually present earlier because cellular immunity is required for control of viruses, fungi, and intracellular pathogens. Normal adult immunoglobulin ranges are approximately: IgG 700–1600 mg/dL, IgA 70–400 mg/dL, IgM 40–230 mg/dL; selective IgA deficiency is classically defined as serum IgA <7 mg/dL with normal IgG and IgM in a patient older than 4 years.

Category	Classic disorders	Typical organisms/findings	Key diagnostic test
B-cell / humoral	X-linked agammaglobulinemia, selective IgA deficiency, CVID, hyper-IgM syndrome	Recurrent sinopulmonary infections with S. pneumoniae, H. influenzae, Giardia	Quantitative immunoglobulins; vaccine antibody titers; flow cytometry for B cells
T-cell / cellular	DiGeorge syndrome	Viral, fungal, mycobacterial infections; hypocalcemic tetany	T-cell count; thymic shadow absent; 22q11.2 deletion testing
Combined	SCID, Wiskott-Aldrich, ataxia-telangiectasia	Severe early infections, chronic diarrhea, failure to thrive	Low T-cell receptor excision circles; lymphocyte subsets
Phagocyte	Chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi	Abscesses, poor wound healing, catalase-positive organisms	Dihydrorhodamine test; neutrophil count; smear morphology
Complement	C1 inhibitor deficiency, C5–C9 deficiency, C3 deficiency	Neisseria; immune complex disease; angioedema	CH50 and AH50 assays

B-cell and antibody deficiencies

X-linked agammaglobulinemia is caused by mutation of Bruton tyrosine kinase (BTK), blocking pre-B-cell maturation. Patients have absent or markedly decreased mature B cells, very low immunoglobulins of all classes, and absent tonsils/lymph nodes. They develop recurrent otitis media, pneumonia, sinusitis, and enteroviral infections after 6 months.

Selective IgA deficiency is the most common primary immunodeficiency, with prevalence about 1:300 to 1:700 in many European-derived populations. It causes mucosal infections, diarrhea due to Giardia lamblia, atopy, autoimmune disease, and anaphylaxis to blood products containing IgA. Many patients are asymptomatic.

Common variable immunodeficiency (CVID) presents later, often in adolescence or adulthood, with low IgG plus low IgA and/or IgM and poor response to vaccines. It is associated with autoimmune disease, bronchiectasis, and increased risk of lymphoma. Hyper-IgM syndrome most commonly results from defective CD40 ligand on T helper cells, impairing class-switch recombination; IgM is normal or high, but IgG, IgA, and IgE are low, causing pyogenic and opportunistic infections including Pneumocystis jirovecii.

T-cell and combined immunodeficiencies

DiGeorge syndrome results from failed development of the 3rd and 4th pharyngeal pouches due to 22q11.2 deletion. Findings include thymic aplasia with T-cell deficiency, hypocalcemia from parathyroid aplasia, conotruncal cardiac defects, abnormal facies, and cleft palate. Live vaccines are contraindicated in severe T-cell deficiency.

Severe combined immunodeficiency (SCID) is a medical emergency of infancy characterized by profound T-cell deficiency with variable B- and NK-cell defects. Causes include X-linked common gamma-chain mutation affecting IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 signaling; adenosine deaminase deficiency, causing toxic deoxyadenosine accumulation; and defects in V(D)J recombination. Newborn screening uses T-cell receptor excision circles (TRECs); low or absent TRECs suggest impaired thymic T-cell production. Treatment is hematopoietic stem cell transplantation; IVIG and antimicrobial prophylaxis are bridges.

Wiskott-Aldrich syndrome is X-linked and due to defective WASp, impairing actin cytoskeleton remodeling. It classically causes thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune disease, and lymphoma. Ataxia-telangiectasia results from ATM mutation causing defective DNA double-strand break repair; findings include cerebellar ataxia, telangiectasias, sinopulmonary infections, elevated alpha-fetoprotein, and radiosensitivity.

Phagocyte and complement defects

Chronic granulomatous disease is usually X-linked NADPH oxidase deficiency. Neutrophils cannot generate reactive oxygen species, causing infections with catalase-positive organisms such as S. aureus, Serratia, Nocardia, Burkholderia cepacia, and Aspergillus. Diagnosis is by abnormal dihydrorhodamine flow cytometry. Prophylaxis may include trimethoprim-sulfamethoxazole and itraconazole; interferon-gamma 50 mcg/m² subcutaneously three times weekly reduces severe infections.

Leukocyte adhesion deficiency type 1 is due to defective CD18 integrins, preventing neutrophil adhesion and diapedesis. Findings include delayed umbilical cord separation beyond 3 weeks, recurrent bacterial infections without pus, impaired wound healing, and marked neutrophilia. Chediak-Higashi syndrome involves defective lysosomal trafficking due to LYST mutation, causing giant granules, partial albinism, neuropathy, and recurrent pyogenic infections.

Complement deficiencies are tested with CH50 for the classical pathway and AH50 for the alternative pathway. C3 deficiency causes severe recurrent pyogenic infections and immune complex disease. C5–C9 terminal complement deficiencies predispose to recurrent Neisseria. C1 inhibitor deficiency causes hereditary angioedema through excess bradykinin, producing nonpitting swelling without urticaria.

Core management principles for Step 1

Primary immunodeficiency management is mechanism-based: replace missing antibody with IVIG 400–600 mg/kg every 3–4 weeks or subcutaneous IgG to maintain protective trough IgG often above 500–700 mg/dL; avoid live attenuated vaccines in severe T-cell defects; use targeted antimicrobial prophylaxis; and consider hematopoietic stem cell transplantation for SCID, severe Wiskott-Aldrich syndrome, and some phagocyte disorders.

Secondary Immunodeficiency

Definition and Core Mechanisms

Secondary immunodeficiency is acquired impairment of host defense caused by an external disease process, therapy, nutritional state, or physiologic stressor. It is more common than primary immunodeficiency and is often reversible if the underlying cause is corrected. Unlike primary immunodeficiencies, which usually reflect inherited defects in a specific immune pathway, secondary immunodeficiency often affects multiple arms of immunity simultaneously: barriers, phagocytes, complement, B cells, T cells, and splenic macrophage function.

High-yield mechanisms include: loss of immune proteins in nephrotic syndrome or protein-losing enteropathy; reduced immune cell production from marrow failure, chemotherapy, radiation, or malnutrition; functional leukocyte impairment in diabetes mellitus and uremia; T-cell suppression by glucocorticoids, calcineurin inhibitors, HIV, and severe protein-calorie malnutrition; and impaired clearance of encapsulated bacteria after splenectomy or functional asplenia.

Cause	Principal Immune Defect	Classic Infection Pattern / Step 1 Association
Malnutrition, especially protein-energy malnutrition	Thymic atrophy, decreased T-cell function, reduced complement and secretory IgA	Recurrent respiratory and gastrointestinal infections; impaired vaccine responses
Diabetes mellitus	Neutrophil chemotaxis and phagocytosis impaired by hyperglycemia; vascular insufficiency	Mucormycosis, malignant otitis externa due to Pseudomonas, skin/soft tissue infections
Nephrotic syndrome	Urinary loss of IgG and complement factors	Increased risk of encapsulated organisms, especially Streptococcus pneumoniae
Splenectomy or functional asplenia, e.g., sickle cell disease	Loss of splenic macrophages and IgM memory B-cell responses	Sepsis from encapsulated organisms: S. pneumoniae, H. influenzae type b, Neisseria meningitidis; Howell-Jolly bodies
Malignancy, especially leukemia, lymphoma, multiple myeloma	Marrow replacement, hypogammaglobulinemia, dysfunctional lymphocytes	Recurrent bacterial infections; myeloma predisposes to pneumococcal infection
Burns, trauma, indwelling catheters	Barrier disruption and innate immune activation followed by immune paralysis	Staphylococcus aureus, Pseudomonas aeruginosa, Candida, polymicrobial infection

Iatrogenic Immunodeficiency

Medications are a major cause of secondary immunodeficiency and are frequently tested by mechanism. Glucocorticoids decrease IL-2 transcription, T-cell proliferation, macrophage activation, and neutrophil adhesion to endothelium; they cause neutrophilia by demargination but reduce tissue migration. A commonly used high-risk threshold is prednisone ≥20 mg/day, or equivalent, for ≥14 days, at which live vaccines are generally avoided. Longer courses, especially ≥20 mg/day for ≥1 month with another immunosuppressive risk factor, increase risk for Pneumocystis jirovecii pneumonia; prophylaxis is classically trimethoprim-sulfamethoxazole double-strength 160/800 mg orally daily or 3 times weekly.

Drug/Class	Mechanism	High-Yield Infectious Risk
Glucocorticoids	↓ NF-κB/AP-1 signaling, ↓ IL-2, lymphocyte apoptosis, impaired macrophages	PJP, herpesvirus reactivation, bacterial and fungal infections
Calcineurin inhibitors: cyclosporine, tacrolimus	Block calcineurin-dependent NFAT activation → ↓ IL-2 transcription	Opportunistic viral and fungal infections in transplant patients
Antimetabolites: methotrexate, azathioprine, mycophenolate	Inhibit nucleotide synthesis and lymphocyte proliferation	Marrow suppression; viral reactivation; poor vaccine response
Rituximab	Anti-CD20 monoclonal antibody → B-cell depletion for approximately 6–12 months; half-life about 18–22 days	Hypogammaglobulinemia, hepatitis B reactivation, impaired humoral vaccine responses
TNF-α inhibitors: infliximab, adalimumab, etanercept	Disrupt macrophage activation and granuloma maintenance	Reactivation tuberculosis, histoplasmosis, coccidioidomycosis
Eculizumab/ravulizumab	Anti-C5 → blocks terminal complement complex C5b-9	Marked susceptibility to Neisseria; meningococcal vaccination required

Laboratory Classification and Practical Thresholds

Secondary immunodeficiency is evaluated by identifying which immune compartment is abnormal. Useful screening tests include complete blood count with differential, quantitative immunoglobulins, lymphocyte subsets, complement activity, and HIV testing when appropriate. Normal adult absolute neutrophil count is approximately 1,500–8,000/µL. Neutropenia is classified as mild 1,000–1,500/µL, moderate 500–1,000/µL, and severe <500/µL; risk of invasive bacterial and fungal infection rises sharply below 500/µL, especially when prolonged for >7 days. Normal serum IgG is approximately 700–1,600 mg/dL; low IgG in nephrotic syndrome, myeloma therapy, or rituximab exposure predicts recurrent sinopulmonary bacterial infection.

Prevention Principles: Vaccines and Prophylaxis

Prevention is highly testable. Patients with anatomic or functional asplenia should receive vaccines against encapsulated bacteria: pneumococcal conjugate vaccine, meningococcal ACWY and B vaccines, and H. influenzae type b vaccine. When splenectomy is elective, vaccination is ideally completed ≥14 days before surgery; if not possible, give after recovery, commonly ≥14 days postoperatively. Live attenuated vaccines are generally contraindicated in severe T-cell immunodeficiency, after hematopoietic stem cell transplant until immune reconstitution, and during significant immunosuppressive therapy. Inactivated vaccines are safer but may be less immunogenic, particularly during B-cell depletion or chemotherapy.

For Step 1, the key organizing principle is to match the acquired defect with the pathogen: T-cell defects predispose to viral, fungal, and intracellular infections; B-cell or complement loss predisposes to encapsulated bacteria; neutropenia predisposes to pyogenic bacteria and molds such as Aspergillus; and asplenia predisposes to overwhelming sepsis from encapsulated organisms.

HIV/AIDS

Human immunodeficiency virus (HIV) is an enveloped, positive-sense, single-stranded RNA retrovirus in the Lentivirus genus. HIV-1 causes most infections worldwide; HIV-2 is less transmissible, progresses more slowly, and is concentrated in West Africa. AIDS is the late clinical syndrome of HIV infection, defined by severe cellular immunodeficiency: CD4+ T-cell count <200 cells/µL or the presence of an AIDS-defining illness regardless of CD4 count.

Virology and Pathogenesis

HIV primarily infects CD4+ T lymphocytes, macrophages, and dendritic cells. Viral entry requires binding of envelope glycoprotein gp120 to CD4, followed by binding to a chemokine coreceptor: CCR5 early in infection, especially on macrophages and memory T cells, or CXCR4 later, especially on T cells. gp41 mediates fusion of the viral envelope with the host cell membrane.

1. Entry: gp120 binds CD4 and CCR5/CXCR4; gp41 mediates fusion.
2. Reverse transcription: viral reverse transcriptase converts RNA into double-stranded DNA; this enzyme is error-prone, causing high mutation rates and drug resistance.
3. Integration: viral integrase inserts proviral DNA into the host genome.
4. Transcription/translation: host machinery produces viral proteins and genomic RNA.
5. Budding and maturation: viral protease cleaves gag-pol polyproteins, producing infectious virions.

Progressive disease results from both direct viral cytopathic effects and immune-mediated destruction of infected CD4+ cells. Normal CD4 count is approximately 500–1500 cells/µL. As CD4 cells decline, patients lose cell-mediated immunity, predisposing to intracellular pathogens, fungi, viruses, and certain malignancies. A CCR5-Δ32 homozygous genotype confers strong resistance to R5-tropic HIV entry; heterozygosity slows progression.

Clinical Course and Staging

Stage	Typical Findings	Key Step 1 Associations
Acute HIV	2–4 weeks after exposure: fever, pharyngitis, rash, lymphadenopathy, myalgias, aseptic meningitis	Very high viral load; p24 antigen and HIV RNA positive before antibodies
Clinical latency	Often asymptomatic; persistent generalized lymphadenopathy may occur	Ongoing viral replication in lymphoid tissue; gradual CD4 decline
AIDS	CD4 <200 cells/µL or AIDS-defining disease	Opportunistic infections and tumors; high mortality without ART

High-yield AIDS-defining illnesses include Pneumocystis jirovecii pneumonia, esophageal candidiasis, toxoplasmosis of the brain, cryptococcal meningitis, disseminated Mycobacterium avium complex, cytomegalovirus retinitis, Kaposi sarcoma due to HHV-8, primary CNS lymphoma due to EBV, and invasive cervical carcinoma due to HPV.

Diagnosis

Current screening uses a fourth-generation HIV-1/2 antigen-antibody immunoassay, which detects both HIV antibodies and p24 antigen. The window period is shortened to about 2–3 weeks. Reactive screening is followed by an HIV-1/HIV-2 differentiation immunoassay. If results are discordant or acute infection is suspected, obtain HIV RNA nucleic acid testing, which can become positive about 10 days after infection. Viral load is reported as copies/mL and is used to monitor treatment response; CD4 count assesses immune status and opportunistic infection risk.

CD4 Thresholds and Opportunistic Infection Prophylaxis

CD4 Count	Risk	Typical Prophylaxis
<200 cells/µL	Pneumocystis jirovecii pneumonia	Trimethoprim-sulfamethoxazole, commonly 1 double-strength tablet daily
<100 cells/µL	Toxoplasma gondii encephalitis if IgG positive	Trimethoprim-sulfamethoxazole also covers toxoplasmosis
<50 cells/µL	Disseminated Mycobacterium avium complex	Azithromycin 1200 mg weekly if not promptly starting effective ART

Antiretroviral Therapy

Guidelines recommend ART for all patients with HIV, regardless of CD4 count. The landmark START trial showed that immediate ART at CD4 counts >500 cells/µL reduced serious AIDS-related and non-AIDS events compared with deferred therapy. Effective ART typically reduces viral load to <50 copies/mL; “undetectable = untransmittable” applies when viral suppression is sustained.

Class	Mechanism	High-Yield Toxicities/Associations
NRTIs: tenofovir, emtricitabine, lamivudine, abacavir, zidovudine	Nucleoside/nucleotide analogs; inhibit reverse transcriptase after phosphorylation; terminate DNA chain	Tenofovir: renal tubular injury, ↓ bone density; abacavir: HLA-B*57:01 hypersensitivity; zidovudine: macrocytic anemia
NNRTIs: efavirenz, rilpivirine, nevirapine	Bind reverse transcriptase allosterically; do not require phosphorylation	Efavirenz: neuropsychiatric effects, vivid dreams; nevirapine: hepatotoxicity, rash
Integrase inhibitors: dolutegravir, bictegravir, raltegravir	Block integration of viral DNA into host genome	Generally first-line; cation interactions reduce absorption
Protease inhibitors: darunavir, atazanavir, ritonavir	Prevent cleavage of viral polyproteins, producing immature noninfectious virions	Metabolic syndrome, lipodystrophy; ritonavir/cobicistat inhibit CYP3A4 as pharmacokinetic boosters
Entry/fusion agents: maraviroc, enfuvirtide	Maraviroc blocks CCR5; enfuvirtide blocks gp41-mediated fusion	Maraviroc requires CCR5-tropism testing

Common first-line regimens combine two NRTIs with an integrase strand transfer inhibitor, for example bictegravir/tenofovir alafenamide/emtricitabine once daily or dolutegravir plus tenofovir/emtricitabine. Poor adherence promotes resistance because HIV replicates rapidly and reverse transcriptase lacks proofreading.

Prevention and Special Concepts

Pre-exposure prophylaxis for high-risk HIV-negative individuals commonly uses daily tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg. Post-exposure prophylaxis should begin as soon as possible, ideally within hours and no later than 72 hours, and is continued for 28 days. Immune reconstitution inflammatory syndrome occurs after ART initiation when recovering immunity mounts an inflammatory response to latent or partially treated infections, classically tuberculosis, MAC, or cryptococcus.