Eduovisual
Immune System
Common variable immunodeficiency: diagnosis and IVIG
— Prevalence ~1 in 25,000–50,000; bimodal age peak in childhood (school-age) and young adulthood (20s–30s)
— Diagnostic delay averages 5–7 years from symptom onset — a major Step 3 patient-safety point
— Genetic basis identified in only ~10–25% (TACI, ICOS, BAFF-R, CD19, NFKB1, CTLA4) — most cases are sporadic
— Adult with ≥2 serious bacterial infections per year (sinusitis, otitis, pneumonia, bronchitis) over multiple years
— Recurrent encapsulated organism infections: S. pneumoniae, H. influenzae, M. catarrhalis
— Bronchiectasis on chest CT in a non-smoker
— Chronic GI symptoms: giardiasis, norovirus-associated enteropathy, sprue-like illness with negative celiac serologies (because the patient can't make IgA antibodies!)
— Unexplained granulomatous disease, autoimmune cytopenias (ITP, AIHA), splenomegaly, or lymphoid hyperplasia
— B cells are present in normal numbers but fail to class-switch and differentiate into memory B cells and plasma cells
— Result: low IgG plus low IgA and/or low IgM, with poor vaccine response
— T-cell dysfunction coexists in a subset, predisposing to opportunistic and autoimmune complications
Board pearl: A 28-year-old with a third episode of pneumococcal pneumonia in 2 years, chronic sinusitis, and a sister with ITP — order quantitative serum immunoglobulins (IgG, IgA, IgM) before chasing zebras. CVID is the unifying diagnosis hiding behind "recurrent infections plus autoimmunity plus GI symptoms."
— Infection-only phenotype (~50%): recurrent sinopulmonary infections without autoimmune or granulomatous features
— Autoimmune phenotype: ITP, autoimmune hemolytic anemia, pernicious anemia, vitiligo, RA-like arthritis, autoimmune thyroiditis
— Polyclonal lymphoid infiltration: splenomegaly, lymphadenopathy, granulomatous-lymphocytic interstitial lung disease (GLILD)
— Enteropathy phenotype: chronic diarrhea, nodular lymphoid hyperplasia, malabsorption, weight loss
— ≥4 new ear infections/year or ≥2 serious sinus infections/year
— ≥2 pneumonias within 1 year
— Recurrent deep abscesses, persistent thrush after age 1
— Need for IV antibiotics to clear infection
— Family history of primary immunodeficiency
— Frequency, severity, and organisms of past infections (look for encapsulated bacteria, Giardia, Mycoplasma, Campylobacter)
— Response to vaccines as a child — did titers ever develop?
— Travel and exposures (giardiasis from camping/well water is classic)
— Medication history: rule out drug-induced hypogammaglobulinemia from rituximab, anti-epileptics (phenytoin, carbamazepine), corticosteroids, or chemotherapy before labeling as CVID
— Protein-losing states: nephrotic syndrome, protein-losing enteropathy can mimic
Key distinction: XLA (Bruton's) presents in male infants with absent B cells and absent tonsils/lymph nodes; CVID presents later, in both sexes, with normal B-cell numbers but defective antibody production. Always check sex, age of onset, and lymphoid tissue on exam — these three data points front-load the differential before any labs return.
— Adults may appear well between infections; children may show failure to thrive or short stature from chronic illness and malabsorption
— Weight loss and cachexia in enteropathy-dominant disease
— Chronic rhinorrhea, nasal mucosal thickening, perforated tympanic membranes from recurrent otitis, cobblestone posterior pharynx
— Tonsils and adenoids are typically present and may even be enlarged in CVID (contrast with XLA where they are absent)
— Crackles, wheezing, or finger clubbing suggest bronchiectasis — a major morbidity driver
— Tachypnea and hypoxia with diffuse crackles raise concern for GLILD (granulomatous-lymphocytic interstitial lung disease)
— Splenomegaly in ~25% — reflects lymphoid hyperplasia or portal hypertension from nodular regenerative hyperplasia
— Hepatomegaly; nodular regenerative hyperplasia can cause non-cirrhotic portal hypertension
— Diffuse lymphadenopathy — may mimic lymphoma and warrants biopsy if persistent or asymmetric
— Vitiligo, eczema, recurrent skin abscesses, warts (especially if CD4 T-cell dysfunction)
— Oral or genital ulcers can occur in autoimmune subsets
— Inflammatory arthritis (sometimes Mycoplasma- or Ureaplasma-driven septic arthritis)
— Enteroviral meningoencephalitis is a rare but devastating complication — check for cognitive change in long-standing untreated disease
Step 3 management: On the first visit, document height, weight, BMI trajectory, spleen size, lymph node survey, and pulse oximetry as your baseline. These four data points drive your decisions about CT chest (for bronchiectasis/GLILD), abdominal imaging (for spleen/lymph nodes), and nutritional referral. Don't anchor only on infections — CVID is a multisystem disease, and exam findings outside the lungs often dictate the workup pace.
— IgG markedly decreased (typically <2 standard deviations below age-adjusted mean, often <400–500 mg/dL)
— IgA and/or IgM also decreased
— Must be confirmed on two separate measurements at least 3 weeks apart
— Measure pre-vaccination titers to pneumococcus (23-valent PPSV23), tetanus, diphtheria, and H. influenzae type b
— Administer vaccines, then recheck titers 4–8 weeks later
— Poor response = failure to mount protective titers to ≥70% of pneumococcal serotypes tested (or <2-fold rise) — this is the functional hallmark of CVID
— Do not give live vaccines (MMR, varicella, yellow fever, LAIV) during workup if hypogammaglobulinemia confirmed
— 24-hour urine protein or spot UPCR — exclude nephrotic syndrome
— Serum protein electrophoresis (SPEP) with immunofixation — exclude multiple myeloma, monoclonal gammopathy, light-chain disease
— CBC with differential — lymphopenia, cytopenias from autoimmune destruction
— Lymphocyte subsets by flow cytometry — confirm B cells are PRESENT (distinguishes from XLA)
— HIV testing — universal in any new immunodeficiency
— Medication review — rituximab causes hypogammaglobulinemia for months to years; anti-epileptics chronic
— Stool studies if GI symptoms: Giardia antigen, Cryptosporidium, C. difficile, calprotectin
— CMP, LFTs, vitamin B12, vitamin D, iron studies (malabsorption screen)
— TSH (autoimmune thyroiditis common)
— Pulmonary function tests (baseline DLCO and spirometry)
Board pearl: A diagnosis of CVID requires all three: low IgG, low IgA or IgM, and poor specific antibody response — in a patient older than 4 years with secondary causes excluded. Missing the vaccine challenge step is the most common error.
— Obtain at baseline in every newly diagnosed CVID patient
— Identifies bronchiectasis (cylindrical, often lower lobe predominant), GLILD (nodules, ground-glass, mediastinal adenopathy), and chronic sinusitis on coronal reformats
— Repeat every 2–5 years or with new pulmonary symptoms
— Spirometry + lung volumes + DLCO — DLCO decline is the earliest GLILD signal
— 6-minute walk if any oxygen desaturation
— Flow cytometry for CD19+ B cells, switched memory B cells (CD27+IgD–IgM–), transitional B cells, CD21-low B cells
— Low switched memory B cells correlate with higher risk of autoimmunity, splenomegaly, and granulomatous disease
— Helps stratify prognosis and guide monitoring intensity
— CD4, CD8 counts; CD4 <200 raises concern for LOCID (late-onset combined immunodeficiency) — manage more aggressively, consider PJP prophylaxis
— Lymphocyte proliferation assays in selected cases
— Send a primary immunodeficiency next-gen sequencing panel in young patients, familial cases, severe phenotypes, or features suggesting CTLA4/LRBA haploinsufficiency (autoimmunity + enteropathy + lymphoproliferation) — these have targeted therapies (abatacept)
— Lymph node biopsy if lymphadenopathy is asymmetric, persistent, or growing (rule out lymphoma — risk is 10–30× general population)
— GI biopsy for chronic diarrhea: shows absent plasma cells in lamina propria, nodular lymphoid hyperplasia, villous blunting
— Lung biopsy (surgical, not transbronchial) for suspected GLILD before immunosuppression
Key distinction: A duodenal biopsy showing villous atrophy with absent plasma cells is CVID enteropathy, not celiac disease — and the patient's celiac serologies will be falsely negative because they can't make IgA-tTG. Always interpret celiac serology in the context of total IgA.
— Stratify by phenotype (infection-only vs autoimmune vs lymphoproliferative vs enteropathy) — each subset has different monitoring and therapy needs
— Stratify by organ damage at baseline (bronchiectasis on HRCT, GLILD, splenomegaly with cytopenias)
— Stratify by IgG trough goal based on infection frequency and lung disease
— Immunoglobulin replacement therapy (IgRT) — IVIG or SCIG — cornerstone for nearly all symptomatic patients
— Aggressive treatment of acute infections with culture-directed antibiotics, often longer courses (10–14 days for sinopulmonary)
— Prophylactic antibiotics in selected patients (e.g., azithromycin 3×/week) with breakthrough infections despite adequate IgG troughs
— Vaccination of household contacts with inactivated influenza yearly (no live vaccines around the patient if also on immunosuppression)
— Avoid live vaccines in the patient
— Hypogammaglobulinemia + recurrent infections + impaired vaccine response → start IgRT
— Hypogammaglobulinemia + no infections yet ("asymptomatic CVID") + preserved vaccine response → may observe with close follow-up
— Traditional target: >500 mg/dL
— Modern target: individualized "biologic trough" — the level at which the patient stops having infections; often 700–1000 mg/dL, higher (>1000) in patients with bronchiectasis
— Immunology (primary), pulmonology (bronchiectasis/GLILD), GI (enteropathy), hematology (cytopenias), infectious disease (resistant infections)
Step 3 management: Confirm CVID → start IgRT → reassess infection frequency and trough at 3–6 months → escalate dose or switch route (IV ↔ SC) if breakthrough infections continue. Lung CT and PFTs every 2–3 years anchor the long-term plan. CVID is a chronic disease requiring lifelong replacement and multidisciplinary follow-up — frame it that way for the patient at diagnosis.
— 400–600 mg/kg every 3–4 weeks IV is the standard starting dose
— Adjust by trough IgG drawn just before next infusion — uptitrate dose or shorten interval to achieve infection-free state
— Onset: troughs stabilize after ~3–6 months of regular dosing
— 100–200 mg/kg weekly subcutaneously, or facilitated SCIG (with hyaluronidase) every 2–4 weeks
— Advantages: home administration, steadier serum levels (no peak-trough fluctuation), fewer systemic reactions, no IV access required
— Disadvantages: local site reactions (swelling, redness), weekly burden
— Preferred for patients with prior severe IVIG reactions, poor venous access, or who travel often
— Acetaminophen + diphenhydramine 30 min before infusion
— Hydrocortisone for patients with prior reactions
— Slow initial infusion rate; advance per protocol
— Headache (most common) — aseptic meningitis in severe cases; slow rate and hydrate
— Flushing, myalgia, low-grade fever, nausea during infusion
— Anaphylaxis — especially in IgA-deficient patients with anti-IgA antibodies — use IgA-depleted preparations if anti-IgA IgE confirmed
— Thromboembolism — VTE and arterial events; risk highest with high-dose, rapid infusion, dehydration, elderly, prior VTE — ensure hydration, slower rate
— Hemolysis — from anti-A/anti-B isoagglutinins; check Hgb after high doses
— Acute kidney injury — sucrose-stabilized products (now rare); maintain hydration
— Transfusion-related acute lung injury (TRALI) — rare
— IgG trough every 3 months until stable, then every 6 months
— CBC, BUN/creatinine, LFTs periodically; pre-infusion vitals
Board pearl: A CVID patient on IVIG who develops a severe anaphylactic reaction → check for selective IgA deficiency with anti-IgA antibodies and switch to an IgA-depleted product or SCIG, which has lower anaphylaxis risk. Hydration before infusion is the single best prevention for headache, AKI, and thromboembolism.
— Acute infections: prolonged courses (often 2–3× standard duration), culture-directed when possible
— Empiric coverage for encapsulated organisms; add atypical coverage (azithromycin, doxycycline) for chronic bronchiectasis exacerbations
— Consider Mycoplasma/Ureaplasma in septic arthritis and chronic urethritis — they don't gram-stain and need PCR
— Azithromycin 250–500 mg three times weekly — preferred in bronchiectasis (anti-inflammatory + antimicrobial); check QTc and LFTs, screen for NTM before starting
— Alternatives: TMP-SMX, amoxicillin
— PJP prophylaxis (TMP-SMX) if CD4 <200 (LOCID phenotype) or on chronic steroids/immunosuppression
— Daily airway clearance (chest physiotherapy, oscillatory PEP device, hypertonic saline nebs)
— Annual sputum cultures for bacteria, mycobacteria, fungi
— Pulmonary rehab if exercise-limited
— Consider when symptomatic, progressive DLCO decline, or significant radiographic burden
— Rituximab + azathioprine is a commonly used combination; abatacept if CTLA4 haploinsufficiency
— Steroids alone often inadequate
— ITP/AIHA: corticosteroids first-line, then IVIG (already being given), then rituximab; splenectomy generally avoided (infection risk in already-immunodeficient host)
— Treat infections (Giardia → metronidazole/tinidazole; norovirus chronic carriage difficult)
— Budesonide for steroid-responsive enteropathy
— Heightened risk of non-Hodgkin lymphoma (especially MALT) and gastric adenocarcinoma — low threshold for EGD with biopsy in dyspepsia or weight loss; H. pylori eradication aggressive
CCS pearl: Admit the febrile CVID patient with new infiltrate → blood and sputum cultures, broad-spectrum antibiotics covering encapsulated organisms and atypicals, IV fluids, IVIG if due, CT chest, pulmonology consult. Don't forget to check last IgG trough and consider giving IVIG during the admission if overdue.
— CVID can be diagnosed at any age; new diagnoses in the 6th–7th decade are not rare and often missed for years
— Higher thromboembolic risk with IVIG: pre-existing atherosclerosis, immobility, hypercoagulable comorbidities
— Strategy: lower infusion rates, smaller divided doses, aggressive hydration, consider SCIG over IVIG to avoid peak hyperviscosity
— Screen and treat cardiovascular risk factors aggressively — chronic inflammation accelerates atherosclerosis
— IVIG is not contraindicated but requires caution: osmotic nephrosis from sucrose-stabilized products is now historical (current products use glycine, proline, maltose)
— Maintain euvolemia; check creatinine before and after infusion in CKD stage 3+
— Avoid rapid infusion in eGFR <60
— SCIG is preferred in advanced CKD — no renal clearance concern, steadier levels
— Adjust antibiotic doses (TMP-SMX, aminoglycosides) per renal function
— CVID itself can cause nodular regenerative hyperplasia (NRH) with non-cirrhotic portal hypertension — surveillance LFTs, platelets, and abdominal imaging
— Avoid hepatotoxic antibiotics where possible; monitor LFTs on azithromycin prophylaxis
— IVIG safe in hepatic dysfunction; product is plasma-derived and pathogen-inactivated
— Falls risk during infusion (especially after diphenhydramine premedication) — use non-sedating alternatives like cetirizine
— Deprescribe anticholinergics
— Vaccinate household contacts annually (flu, COVID, pertussis) — herd protection is critical
— Repeated IV access in elderly veins is challenging — transition to SCIG is often the right answer at the first sign of access failure rather than placing a port
Step 3 management: In the elderly CVID patient with CKD, atrial fibrillation, and prior DVT, default to SCIG weekly rather than IVIG monthly — same efficacy, lower thrombosis and AKI risk, no peak-trough swings, and home-based reduces clinic burden. This is a high-yield Step 3 transitions-of-care decision.
— IVIG/SCIG is safe and continued throughout pregnancy — IgG actively transports across placenta, protecting the neonate
— Increase IgRT dose in 2nd and 3rd trimesters because of plasma volume expansion and active fetal IgG transport — often 25–50% dose increase to maintain troughs
— Monthly trough monitoring; aim for stable or rising IgG
— Avoid live vaccines (rubella, varicella, MMR) — give before pregnancy if not immune
— TdaP at 27–36 weeks (inactivated, safe), influenza (inactivated)
— Counsel: maternal autoimmune disease may flare; obstetric infection risk modestly increased — coordinate with MFM
— Maternal IgG (from IVIG) crosses placenta and gives neonate passive protection for ~4–6 months
— Test infant immunoglobulins around 6–12 months if family history of PID; genetic counseling offered (most CVID is sporadic, but monogenic forms with autosomal dominant inheritance like NFKB1, CTLA4 exist)
— Diagnosis after age 4 (younger infants have physiologic hypogammaglobulinemia — "transient hypogammaglobulinemia of infancy")
— Growth and nutrition tracking essential; chronic infection causes failure to thrive
— Immunization strategy: inactivated vaccines yes (assess response), live vaccines avoided if active immunodeficiency
— School/daycare: reasonable to attend; emphasize hand hygiene and prompt evaluation of febrile illness
— CVID does not impair fertility directly, but chronic illness and autoimmunity may
— Hormonal contraception is fine; estrogen + IVIG both confer modest thrombosis risk — consider progestin-only or non-hormonal in high-risk patients
— Refer if monogenic mutation identified or strong family history; prenatal/preimplantation diagnosis available for known mutations
Board pearl: A pregnant CVID patient at 28 weeks has an IgG trough of 480 mg/dL (previously 750 pre-pregnancy). The correct action is to increase IVIG dose by ~25%, not to switch products or stop therapy. Plasma volume expansion is the answer.
— Recurrent sinopulmonary infections leading to bronchiectasis in 30–60% of long-standing untreated patients — the dominant driver of pulmonary morbidity and mortality
— Chronic Giardia, norovirus, Campylobacter enteritis
— Mycoplasma/Ureaplasma septic arthritis and genitourinary infections
— Enteroviral meningoencephalitis (rare, devastating)
— Pneumocystis in LOCID subset
— ITP, AIHA, autoimmune neutropenia (Evans syndrome possible)
— Pernicious anemia, autoimmune thyroiditis, vitiligo
— Inflammatory arthritis, sicca syndrome
— Paradox: low antibodies but high autoimmunity — reflects loss of immune regulation
— Non-Hodgkin lymphoma — risk 10–30× general population, especially extranodal MALT lymphomas
— Gastric adenocarcinoma — markedly increased; EBV/H. pylori interplay; screen with EGD in dyspepsia and consider periodic surveillance
— Polyclonal lymphoid hyperplasia mimicking lymphoma — biopsy when in doubt
— GLILD — restrictive disease with DLCO decline; associated with worse mortality
— Bronchiectasis with chronic Pseudomonas colonization in late disease
— Pulmonary hypertension secondary to chronic lung disease
— Chronic enteropathy with malabsorption, B12 deficiency
— Nodular regenerative hyperplasia (NRH) — non-cirrhotic portal hypertension, splenomegaly, thrombocytopenia, varices
— Increased risk of cholangiopathy
— IVIG: thromboembolism, AKI, aseptic meningitis, hemolysis, anaphylaxis (anti-IgA)
— Long-term immunosuppression for autoimmunity adds infection risk
— Lymphoma, chronic lung disease, liver disease — not acute infection in IgRT-treated patients
Key distinction: Mortality in treated CVID is driven by malignancy and chronic organ damage, not acute sepsis — IgRT dramatically reduces infections but doesn't prevent autoimmunity, GLILD, or cancer. Counsel patients that lifelong surveillance matters as much as infusions.
— Fever >38.5°C in a CVID patient — treat as immunocompromised host until proven otherwise
— New hypoxia or worsening dyspnea (rule out pneumonia, GLILD flare, PE)
— New severe headache during/after IVIG — aseptic meningitis vs sinus venous thrombosis
— New unilateral leg swelling, chest pain — IVIG-associated VTE
— Hematochezia, melena, weight loss — GI malignancy workup
— Pneumonia with hypoxia, hemodynamic instability, multilobar involvement, or failure of outpatient antibiotics
— Suspected bacteremia or sepsis — lower threshold than immunocompetent patients
— Severe cytopenias (ITP with bleeding, AIHA with hemodynamic compromise)
— Severe enteritis with dehydration, electrolyte derangement, or unable to tolerate POs
— IVIG anaphylaxis or other severe transfusion-like reaction
— Septic shock requiring vasopressors
— Respiratory failure requiring HFNC, NIV, or intubation
— Severe AKI from IVIG with volume overload
— Massive PE or stroke from IVIG-associated thrombosis
— Immunology for all admissions — confirms diagnosis, guides IgRT timing
— Pulmonology for any respiratory presentation
— Infectious disease for atypical, opportunistic, or resistant organisms
— Hematology for cytopenias or thrombotic events
— GI for chronic diarrhea or suspected lymphoma/NRH
— Blood cultures × 2, sputum culture, urine culture, viral PCR (influenza, RSV, COVID, CMV if T-cell concerns)
— CT chest with contrast (PE protocol if dyspnea + IVIG history)
— Empiric broad-spectrum antibiotics within 1 hour of sepsis recognition
— Check last IgG trough; give IVIG if overdue
— VTE prophylaxis (CVID patients are at higher baseline risk)
CCS pearl: A CVID patient admitted with pneumonia → cultures → empiric ceftriaxone + azithromycin → check IgG trough → consider IVIG dose during admission if due → pulmonology consult → discharge with PCP follow-up in 1 week and immunology in 2–4 weeks with repeat HRCT planned.
— BTK mutation; male infants; onset 6–12 months as maternal IgG wanes
— Absent B cells on flow, absent tonsils/lymph nodes/adenoids
— All Ig classes profoundly low
— Treatment is IgRT, similar principle to CVID
— Isolated low IgA with normal IgG and IgM
— Usually asymptomatic; some have mucosal infections, atopy, autoimmunity (celiac)
— Risk of anaphylaxis with IVIG due to anti-IgA antibodies
— Subset progresses to CVID over years — monitor IgG annually
— Defective class-switching: elevated IgM, low IgG/IgA
— X-linked form (CD40L deficiency): opportunistic infections (PJP, Cryptosporidium), neutropenia
— Treatment: IgRT + PJP prophylaxis ± HSCT
— Normal total immunoglobulins but poor vaccine response
— Recurrent sinopulmonary infections; manage with antibiotics ± IgRT in severe cases
— CVID phenotype + low CD4 count + opportunistic infections — manage like CVID plus PJP prophylaxis
— Thymoma + hypogammaglobulinemia in adults — always check chest imaging in new-onset adult hypogammaglobulinemia
— Thymectomy does not reverse the immunodeficiency; IgRT lifelong
Key distinction: Adult-onset hypogammaglobulinemia → always get a chest CT to look for thymoma (Good syndrome) before settling on CVID. Missing thymoma means missing a surgically addressable comorbidity (myasthenia, pure red cell aplasia) even though it doesn't fix the antibody defect.
— Multiple myeloma: paradoxical hypogammaglobulinemia from suppression of non-clonal Ig despite monoclonal M-spike — SPEP + immunofixation is mandatory before diagnosing CVID
— Chronic lymphocytic leukemia (CLL): hypogammaglobulinemia in 25–70%; recurrent infections; IgRT indicated if symptomatic
— Non-Hodgkin lymphoma, Waldenström macroglobulinemia
— Rituximab and other anti-CD20 agents — hypogammaglobulinemia can persist for months to years after the last dose
— Anti-epileptics: phenytoin, carbamazepine, valproate, lamotrigine
— Chronic corticosteroids (high dose, prolonged)
— Mycophenolate, methotrexate, calcineurin inhibitors
— Newer biologics: ibrutinib, idelalisib
— Always reconcile meds before labeling CVID
— Nephrotic syndrome — check urine protein/creatinine; albumin will also be low
— Protein-losing enteropathy — Ménétrier, lymphangiectasia, severe IBD
— Burns, exudative skin disease
— Key: albumin is usually also low in these — pure CVID has normal albumin
— HIV (especially advanced)
— Chronic EBV, CMV, parvovirus B19 in some hosts
— Splenectomy doesn't cause hypogammaglobulinemia but impairs encapsulated organism response
— Aplastic anemia, post-HSCT
— SPEP/IFE, UPCR, albumin, HIV, medication review, CBC with flow if abnormal lymphocytes, age-appropriate cancer screening
Board pearl: A 68-year-old with recurrent pneumonias and IgG 320 mg/dL — CLL until proven otherwise. Send a CBC with differential and peripheral smear; flow cytometry will clinch it. Treating with IgRT is appropriate, but the underlying malignancy diagnosis changes everything about prognosis, monitoring, and chemotherapy planning.
— Inactivated vaccines yes: influenza yearly, COVID per current schedule, pneumococcal (PCV20 or PCV15→PPSV23), TdaP, HPV, shingles (Shingrix, recombinant — safe)
— Live vaccines NO (MMR, varicella, yellow fever, LAIV, oral typhoid, BCG)
— Vaccine response may be poor but partial protection valued; household contacts should be fully vaccinated (and household members can receive live vaccines safely)
— Prompt evaluation and culture-directed antibiotics for breakthrough infections
— Reserve prophylactic azithromycin for those with bronchiectasis or breakthrough infections despite adequate troughs
— Annual EGD or per symptoms for gastric cancer surveillance (especially with H. pylori, atrophic gastritis, pernicious anemia)
— Standard age-appropriate screening: colonoscopy, mammography, cervical, lung (if smoker)
— Low threshold for lymph node biopsy if persistent or growing
— Daily airway clearance in bronchiectasis
— Annual or biennial PFTs; HRCT every 2–5 years or with new symptoms
— Pulmonary rehab and smoking avoidance (active and passive)
— Vitamin D and calcium repletion (malabsorption + chronic steroids if used)
— DEXA every 2 years if on chronic steroids or with prior fragility fracture
— Depression, anxiety, and "infusion fatigue" common — screen at follow-up visits
— Patient support organizations (IDF, IPOPI) for community and education
— IgRT is expensive ($30,000–80,000+/year); ensure prior authorization, copay assistance, and continuity through insurance transitions — a major Step 3 transition-of-care issue
Step 3 management: At every annual visit, audit five domains: infections (frequency, organisms), IgG trough, pulmonary function, autoimmune/malignancy surveillance, and psychosocial/access. Missing any one is how patients silently decompensate between visits.
— Immunology visits every 3 months for first year, then every 6 months once stable on IgRT
— Primary care: continue routine preventive care, vaccinations, age-appropriate cancer screening
— Pulmonology: at diagnosis, then yearly or biennial depending on lung disease severity
— GI: as needed for symptoms; surveillance EGD discussed individually
— IgG trough every 3 months until stable, then every 6 months; before each IVIG dose
— CBC, CMP every 6 months (LFTs, renal function, cytopenias)
— TSH yearly (high autoimmune thyroid prevalence)
— B12, vitamin D, iron studies yearly (malabsorption)
— Quantiferon and HIV periodically if on immunosuppression
— HRCT chest every 2–5 years or with new symptoms
— PFTs with DLCO yearly in those with lung disease, every 2–3 years otherwise
— Abdominal ultrasound for splenomegaly, liver evaluation as clinically indicated
— Maintain an infection log (date, symptoms, organism, antibiotic, response) — invaluable at visits
— Recognize early infection signs and seek prompt evaluation
— Hydrate well before/after IVIG; report headache, leg swelling, chest pain immediately
— Travel counseling: ensure IgRT supply, avoid live vaccines (yellow fever workaround documents), water/food precautions for giardiasis
— Pulmonary rehab in bronchiectasis or post-pneumonia deconditioning
— Nutrition referral for enteropathy and malabsorption
— Physical activity encouraged; reduce sedentary behavior to lower VTE risk
— Vaccinate household contacts (inactivated for everyone; live vaccines for contacts are fine — patient does not catch vaccine virus from contact in vast majority of cases)
— Hand hygiene in the home, especially during respiratory illness seasons
Board pearl: "When should I check the next IgG trough?" — answer is just before the next IVIG infusion, not in between. Trough is the lowest serum level and the actionable number for dose titration.
— Document discussion of blood-product nature (pooled from thousands of donors, pathogen-inactivated but not zero-risk), thromboembolism, anaphylaxis (especially in IgA-deficient patients), aseptic meningitis, AKI, hemolysis, and TRALI
— Consent should specify product and route; switching products may require renewed consent
— Some patients (e.g., Jehovah's Witnesses) may decline plasma-derived products — IgRT is a fractionated plasma product
— Discuss alternatives openly; respect autonomy while ensuring patient understands the elevated infection risk without therapy
— Document the conversation, the decision, and the safety plan (aggressive antibiotic strategy, prophylaxis)
— Pediatric to adult transition: structured handoff to adult immunology; risk of lapsed therapy during gap years
— Hospital to home: ensure IgRT not interrupted by admission; communicate trough timing and next infusion to outpatient team
— Insurance changes: prior authorizations often lapse — proactive coordination prevents missed doses
— Provider turnover: every CVID patient should have a written care summary listing diagnosis, IgRT product/dose/route, IgG trough goal, complications, and consultant team
— Two-patient identifier and product label match before every infusion (right product, right patient, right dose)
— Monitor vitals at baseline, during rate escalations, and after — anaphylaxis can occur even after years of tolerance
— Emergency epinephrine, oxygen, and resuscitation equipment available
— Genetic testing results have implications for family members; counsel on cascade testing, GINA protections
— Disclose to school/employer only with patient consent; ADA accommodations may be appropriate
— Vaccine reactions, severe IVIG adverse events to FDA MedWatch
— Tuberculosis, certain infections per state requirements
Step 3 management: When a CVID patient changes insurance and there is a gap in IVIG coverage, the correct action is to engage the manufacturer patient-assistance program and clinic social work immediately and consider bridging SCIG from samples — not to simply delay infusion. Missed doses → infections → preventable harm.
Board pearl: If a stem mentions recurrent encapsulated infections + autoimmune cytopenia + chronic diarrhea + bronchiectasis — there's only one answer that ties them together: CVID. Order quantitative immunoglobulins.
— 26-year-old with 4th pneumonia in 3 years, chronic sinusitis, normal CD4, normal HIV. → Quantitative immunoglobulins is the next step. Answer = CVID, start IVIG after vaccine challenge.
— 32-year-old with ITP, recurrent otitis, IgG 380. → CVID; vaccine response testing confirms; start IgRT.
— 40-year-old with chronic diarrhea, weight loss, negative celiac serology with low total IgA. → Duodenal biopsy shows villous atrophy with absent plasma cells → CVID enteropathy. Don't repeat celiac serology — it's falsely negative.
— Patient on IVIG develops anaphylaxis on third infusion. → Check for selective IgA deficiency with anti-IgA antibodies → switch to IgA-depleted product or SCIG.
— 60-year-old new hypogammaglobulinemia, recurrent infections, mediastinal mass on CXR. → Get chest CT → thymoma → Good syndrome, not CVID.
— Older adult with hypogammaglobulinemia and lymphocytosis with smudge cells. → CLL (do flow cytometry), not CVID — but still may need IgRT.
— CVID patient at 28 weeks with falling IgG trough. → Increase IVIG dose — do not stop or switch.
— Which vaccine is contraindicated? → Live vaccines (MMR, varicella, LAIV, yellow fever, BCG). Inactivated influenza and Shingrix (recombinant zoster) are OK.
— Elderly patient develops DVT 5 days post-IVIG → IVIG-associated thrombosis; manage with anticoagulation; for future doses use slower rate, hydration, and consider SCIG transition.
— CVID with recurrent exacerbations despite adequate IgG trough → add azithromycin three times weekly prophylaxis (after ruling out NTM and QTc check).
— Don't rush to splenectomy — risk of overwhelming encapsulated infection in already-immunodeficient host; use rituximab/steroids first.
Key distinction: The Step 3 question often hinges on the next best step — quantitative immunoglobulins is the screening test, vaccine response is the confirmatory test, and secondary causes must be excluded before labeling CVID. Don't skip any of the three.
CVID is an adult-onset primary immunodeficiency defined by low IgG plus low IgA or IgM with impaired vaccine response after exclusion of secondary causes, treated with lifelong immunoglobulin replacement (IVIG or SCIG) titrated to an infection-free state, with multidisciplinary surveillance for bronchiectasis, GLILD, autoimmunity, and lymphoma/gastric cancer.
Board pearl: When in doubt on Step 3 — "recurrent encapsulated bacterial infections in an adult with low IgG" — order quantitative immunoglobulins, exclude secondary causes, do the vaccine challenge, and start IgRT. That sequence wins the question every time.