Clinical Immunology: Secondary immunodeficiency, the immunocompromised host and vaccination

• Secondary immunodeficiency: Causes of Secondary Immunodeficiency | Drug-induced Immunosuppression | Secondary Antibody Deficiency | Asplenia and Hyposplenism | Neutropenia and Neutropenic Sepsis
• The immunocompromised host: Infections by Type of Immune Defect | Screening Before Immunosuppression | Prophylaxis in the Immunocompromised | Key Opportunistic Infections
• Vaccination: How Vaccines Work - Types of Vaccine | The UK Immunisation Programme | Vaccinating Immunocompromised People | Contraindications, Allergy and Myths | Passive Immunisation and Post-exposure Prophylaxis
• Revision: Immunocompromise and Vaccines at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🛡️ Secondary immunodeficiency, the immunocompromised host and vaccination - page 3 of the Clinical Immunology chapter. Far more people are immunocompromised by treatment, cancer or chronic illness than by inherited disease - and the numbers grow every year with biologics, chemotherapy and transplantation. Preventing infection (screening, prophylaxis, vaccination) and spotting it early when the usual signs are blunted are everyday skills for every doctor.
Your four questions for every immunocompromised patient: What is the cause and type of immunosuppression? Which infections is this patient at risk of? Have they been screened, vaccinated and given prophylaxis? Is a live vaccine safe for them - or their contacts?

Causes of Secondary Immunodeficiency

• Drugs - corticosteroids, conventional DMARDs, biologics, JAK inhibitors, chemotherapy, transplant immunosuppressants, CAR-T therapy (see below and page 6).
• Haematological cancers - CLL and myeloma (hypogammaglobulinaemia), lymphoma, leukaemia (neutropenia), myelodysplasia.
• Infection - HIV (CD4 depletion), measles (transient "immune amnesia"), EBV, CMV, severe sepsis (immunoparalysis).
• Protein loss - nephrotic syndrome, protein-losing enteropathy, intestinal lymphangiectasia (lymphopenia too), burns.
• Metabolic and chronic disease - diabetes (neutrophil dysfunction - skin, urinary, foot infections, mucormycosis), CKD and dialysis, cirrhosis (spontaneous bacterial peritonitis), malnutrition, alcohol excess.
• Anatomical - asplenia, indwelling lines and devices, breaches in skin and mucosa (burns, mucositis), CSF leak (recurrent pneumococcal meningitis).
• Age - immunosenescence in older people (reduced vaccine responses, shingles, atypical presentations - confusion without fever); prematurity and early infancy.
• Pregnancy - modest changes in cell-mediated immunity (listeria, varicella and influenza severity).
• Thymoma - Good syndrome (hypogammaglobulinaemia, absent B cells, opportunistic infections) in adults.

Drug-induced Immunosuppression

• "High-dose" corticosteroids (Green Book definition for live vaccines) - adults on 40 mg prednisolone or more a day for over a week; children on 2 mg/kg/day for at least a week or 1 mg/kg/day for a month; other guidance (e.g. PCP prophylaxis, shingles vaccine) uses lower thresholds such as 20 mg a day for 4 weeks or more.
• Combinations multiply the risk - e.g. steroids plus another immunosuppressant.

Secondary Antibody Deficiency

• Common causes - CLL, myeloma, lymphoma, rituximab and other B-cell therapies, CAR-T therapy, antiepileptics, nephrotic syndrome, protein-losing enteropathy, thymoma.
• Presentation - recurrent or severe bacterial respiratory infections, bronchiectasis.
• Investigation - IgG, IgA, IgM, protein electrophoresis, free light chains, vaccine responses, lymphocyte subsets (B cells after rituximab), albumin and urine protein.
• Management:
  • Prophylactic antibiotics first (e.g. azithromycin, doxycycline, co-trimoxazole) and vaccinations.
  • Immunoglobulin replacement - NHS England criteria - e.g. low IgG (typically under 4 g/L) with recurrent or severe bacterial infections despite prophylactic antibiotics, or impaired specific antibody responses, after immunology review; reassess regularly (stop if recovers).
• Before rituximab - check baseline immunoglobulins; monitor during long-term therapy (especially repeated courses).
• Serology is unreliable after rituximab (and during immunoglobulin therapy) - use PCR for diagnosis.

Asplenia and Hyposplenism

• Causes - splenectomy (trauma, ITP, haematological disease), sickle cell disease (autosplenectomy in childhood), coeliac disease, IBD, alcoholic liver disease, splenic irradiation, congenital asplenia, amyloidosis, GVHD.
• Film - Howell–Jolly bodies, target cells, Pappenheimer bodies, raised platelets.
• Risk - overwhelming post-splenectomy infection (OPSI) - rapid, fulminant sepsis (mortality up to 50%) with encapsulated bacteria - Streptococcus pneumoniae (commonest), Haemophilus influenzae type b, Neisseria meningitidis; also Capnocytophaga canimorsus (dog bites), severe malaria and babesiosis. Highest risk in the first 2 years, children, and those with underlying immune disease - but lifelong.
• Prevention (Green Book; BSH 2011):
  • Vaccines - pneumococcal, Hib/MenC (or as per current schedule), MenACWY, MenB, annual influenza, COVID-19 - ideally at least 2 weeks before elective splenectomy, or 2 weeks after emergency splenectomy.
  • Prophylactic antibiotics - phenoxymethylpenicillin (or a macrolide if penicillin allergic) - offer lifelong, especially in the first 2 years, under 16s, over 50s and those with poor vaccine response or previous invasive pneumococcal disease.
  • Emergency "standby" antibiotics (e.g. amoxicillin) to start at the first sign of fever while seeking urgent medical help.
  • Patient education and an alert card; malaria prophylaxis and avoidance when travelling; urgent antibiotics after animal bites.

Neutropenia and Neutropenic Sepsis

• Neutropenia - neutrophils under 1.5 × 10⁹/L; severe under 0.5 - high infection risk, especially if prolonged (over 7 days).
• Causes - chemotherapy (commonest), drugs (clozapine, carbimazole and propylthiouracil - agranulocytosis, sulfasalazine, co-trimoxazole, methotrexate, azathioprine, antiepileptics), viral infection, sepsis, B12 or folate deficiency, autoimmune (SLE, Felty's syndrome), marrow infiltration, myelodysplasia, aplastic anaemia, large granular lymphocyte leukaemia, Duffy-null associated neutrophil count (benign).
• Neutropenic sepsis (NICE CG151) - temperature over 38°C or signs of sepsis with neutrophils 0.5 × 10⁹/L or less in someone having anticancer treatment:
  • A medical emergency - assess immediately; empirical IV piperacillin–tazobactam within 1 hour of arrival (don't wait for the neutrophil count - treat suspected neutropenic sepsis); don't routinely add an aminoglycoside.
  • Blood cultures (peripheral and from any central line), lactate, FBC, U&E, LFTs, urine and sputum culture, chest X-ray if respiratory signs.
  • Risk stratify (e.g. MASCC score) - low-risk patients may switch to oral antibiotics or outpatient care.
  • Fever may be absent (steroids, older people) - act on sepsis signs.
• Prolonged neutropenia - add antifungal cover if fever persists (invasive Aspergillus - CT chest, galactomannan); G-CSF in selected patients.
• Agranulocytosis on carbimazole - warn patients to report sore throat, mouth ulcers or fever; check FBC and stop the drug if neutropenic.

Infections by Type of Immune Defect

• Atypical presentation is common - fever and inflammatory signs may be blunted; CRP may be low (IL-6 blockade); infections may disseminate rapidly - low threshold for imaging, cultures and empirical treatment.

Screening Before Immunosuppression

• Before starting biologics, JAK inhibitors, high-dose or prolonged steroids, chemotherapy or transplant:
  • Tuberculosis - history (previous TB, contacts, travel or birth in high-incidence country), IGRA (QuantiFERON or T-SPOT) and/or chest X-ray; treat latent TB (e.g. 3 months of rifampicin and isoniazid, or 6 months of isoniazid) before or alongside starting anti-TNF (usually at least 1 month first).
  • Hepatitis B - HBsAg and anti-HBc: if HBsAg positive - antiviral treatment (entecavir or tenofovir); if anti-HBc positive and HBsAg negative (past infection) - prophylaxis or monitoring depending on the drug (prophylaxis with rituximab - high risk of reactivation).
  • Hepatitis C and HIV serology.
  • Varicella zoster IgG (if no history of chickenpox or shingles) - vaccinate if non-immune before immunosuppression (live vaccine - at least 4 weeks before).
  • Strongyloides serology if from an endemic area (tropics) - treat with ivermectin before high-dose steroids (risk of hyperinfection syndrome).
  • Baseline - FBC, U&E, LFTs, immunoglobulins (before rituximab), pregnancy test, cervical screening up to date (HPV risk).
• Update vaccinations before starting - pneumococcal, influenza, COVID-19, shingles (Shingrix - non-live), HPV, hepatitis B where indicated; live vaccines at least 4 weeks before.
• Skin check - skin cancer risk with azathioprine, transplant drugs and some biologics.

Prophylaxis in the Immunocompromised

• Pneumocystis pneumonia (PCP) prophylaxis - co-trimoxazole (e.g. 480 mg daily or 960 mg three times weekly) - for:
  • HIV with CD4 under 200 cells/mm³.
  • Solid organ and stem cell transplant recipients.
  • Prolonged high-dose steroids, especially with another immunosuppressant (e.g. prednisolone 20 mg or more for 4 weeks or more plus another agent).
  • Cyclophosphamide and rituximab regimens (e.g. ANCA vasculitis), purine analogues (fludarabine), ALL treatment, alemtuzumab, some CAR-T and lymphoma regimens.
  • Alternatives - atovaquone, dapsone (check G6PD), nebulised pentamidine.
• Antiviral - aciclovir or valaciclovir (HSV and VZV) in stem cell transplant, bortezomib and some chemotherapy; valganciclovir or letermovir (CMV) after transplant; HBV prophylaxis with rituximab if anti-HBc positive.
• Antifungal - fluconazole or posaconazole (prolonged neutropenia in AML, stem cell transplant, GVHD).
• Antibacterial - penicillin (asplenia, complement deficiency), levofloxacin in selected neutropenic patients, azithromycin (bronchiectasis), meningococcal prophylaxis with eculizumab.
• Strongyloides - ivermectin before steroids if at risk.
• Food safety - avoid unpasteurised dairy, soft cheeses, pâté, raw eggs and undercooked meat (Listeria, Salmonella, Toxoplasma); safe water (Cryptosporidium).

Key Opportunistic Infections

• Pneumocystis jirovecii pneumonia - subacute breathlessness, dry cough, desaturation on exertion, few chest signs; chest X-ray may be normal or show bilateral perihilar ground-glass change; raised LDH and beta-D-glucan; diagnosis by PCR or immunofluorescence on induced sputum or BAL; treat with high-dose co-trimoxazole plus prednisolone if hypoxic (PaO₂ under 9.3 kPa - HIV); faster and more severe in non-HIV patients.
• Cytomegalovirus - fever, cytopenias, hepatitis, pneumonitis, colitis, retinitis (HIV with CD4 under 50) - CMV PCR; ganciclovir, valganciclovir.
• Varicella zoster - disseminated or multidermatomal shingles, varicella pneumonitis - IV aciclovir.
• Tuberculosis - reactivation with anti-TNF, steroids, transplant, HIV - often extrapulmonary or disseminated; IGRA may be falsely negative.
• Invasive fungal infection - Aspergillus (prolonged neutropenia, transplant - nodules with halo sign on CT, galactomannan - voriconazole), Mucor (DKA, neutropenia - rhino-orbital-cerebral necrosis - surgery and amphotericin), Cryptococcus (meningitis - HIV, transplant), invasive candida (lines, abdominal surgery).
• Progressive multifocal leukoencephalopathy (JC virus) - subacute focal neurology, cognitive decline; MRI white matter lesions; CSF JC virus PCR - natalizumab, rituximab, HIV - stop the drug (natalizumab - plasma exchange); IRIS risk.
• Listeria - meningitis or bacteraemia in pregnancy, older people and the immunosuppressed - amoxicillin (cephalosporins don't cover it).
• Strongyloides hyperinfection - after steroids in people from endemic areas - Gram-negative sepsis and meningitis, larva currens - ivermectin.
• EBV - post-transplant lymphoproliferative disorder (see page 6).

How Vaccines Work - Types of Vaccine

• Herd immunity - high coverage protects those who can't be vaccinated (e.g. MMR coverage of 95% needed for measles).
• Live vaccine spacing - two live vaccines should be given on the same day or 4 weeks apart (some exceptions); immunoglobulin or blood products can block live vaccines (MMR, varicella) for up to 3–11 months.

The UK Immunisation Programme

• Childhood programme (the schedule changed in 2025–2026 - check the current Green Book and UKHSA schedule):
  • Infancy - 6-in-1 vaccine (diphtheria, tetanus, pertussis, polio, Hib, hepatitis B), rotavirus (oral - first dose by 15 weeks, course complete by 24 weeks), MenB, pneumococcal conjugate.
  • Around 1 year and 18 months - MMR (now combined with varicella as MMRV from 2026), MenB and pneumococcal boosters, further 6-in-1 dose.
  • Pre-school - 4-in-1 booster (DTaP/IPV).
  • Children's nasal flu (LAIV) annually from age 2 through school years.
  • Adolescents - HPV (single dose at 12–13 for all), Td/IPV and MenACWY at about 14.
• Pregnancy - pertussis (from 16 weeks - ideally by 32 weeks), influenza (any stage), RSV (from 28 weeks - protects the baby), COVID-19.
• Adults:
  • Influenza - annually for 65 and over, clinical risk groups, health and social care workers, pregnant women, carers.
  • Pneumococcal - at 65, and for clinical risk groups.
  • Shingles - Shingrix (2 doses) - for people turning 65 and older age cohorts, and the severely immunosuppressed (from age 18 or 50 - check current eligibility).
  • RSV - older adults (from 75; the eligible cohort may change).
  • COVID-19 - seasonal boosters for older people and the immunosuppressed.
• Selective programmes - BCG for infants at higher TB risk, hepatitis B for babies of infected mothers, travel vaccines, occupational vaccines (hepatitis B for healthcare workers).

Vaccinating Immunocompromised People

• Inactivated vaccines are safe - give influenza, pneumococcal, COVID-19, Shingrix and others; responses may be reduced - give before starting immunosuppression where possible (at least 2 weeks before).
• Live vaccines are contraindicated in severe immunosuppression (Green Book chapter 6), including:
  • High-dose steroids (and for at least 3 months after stopping).
  • Biologics and JAK inhibitors, high-dose methotrexate, azathioprine, mycophenolate, ciclosporin, tacrolimus (and for 3–12 months after, depending on drug - longer after rituximab).
  • Chemotherapy (and for at least 6 months after), stem cell transplant (at least 24 months and no GVHD), solid organ transplant.
  • HIV with low CD4 (MMR and varicella may be given if CD4 is above a threshold).
  • Primary immunodeficiency affecting T cells or antibodies.
• Babies exposed to biologics in utero (e.g. infliximab, adalimumab in the third trimester) - avoid live vaccines (BCG, and seek advice on rotavirus) in the first months of life - usually until 6–12 months.
• Household contacts - should be vaccinated, including MMR, varicella, rotavirus (good hand hygiene with nappies) and influenza (inactivated or LAIV - avoid LAIV contact with severely immunocompromised people, e.g. after stem cell transplant).
• Re-vaccination - after stem cell transplant the whole schedule is repeated.
• Asplenia and complement deficiency - extra pneumococcal, meningococcal (MenACWY and MenB) and Hib vaccines (see above).

⚠️ Safety Pearl: Before giving a live vaccine (MMR, varicella, BCG, yellow fever, rotavirus, nasal flu, oral typhoid), always ask about immunosuppressive drugs, cancer treatment, transplant, immunodeficiency and pregnancy - and for babies, about biologics taken by the mother in pregnancy. Disseminated vaccine-strain infection can be fatal.

Contraindications, Allergy and Myths

• True contraindications (any vaccine) - confirmed anaphylaxis to a previous dose of the same vaccine or to a component (e.g. gelatin, neomycin, polyethylene glycol in mRNA vaccines).
• Live vaccine contraindications - significant immunosuppression and pregnancy (avoid pregnancy for 1 month after MMR or varicella - though inadvertent vaccination is not a reason for termination).
• Postpone for acute febrile illness (not minor illness).
• Not contraindications - minor illness without fever, prematurity (vaccinate at the usual chronological age), asthma, eczema, hay fever, family history of vaccine reactions or allergy, stable neurological conditions, antibiotics, breastfeeding, a pregnant household contact, previous history of the disease (for most), recent surgery.
• Egg allergy - MMR is safe (grown in chick fibroblast culture - give in primary care); influenza vaccines (very low ovalbumin) can be given to most egg-allergic people, including those with previous anaphylaxis to egg (hospital setting only if severe anaphylaxis needing intensive care); yellow fever vaccine - specialist advice.
• Vaccine anaphylaxis - rare (about 1 per million doses) - all vaccinators must be trained and have adrenaline available; observation times per Green Book.
• Myths - MMR does not cause autism (the original study was fraudulent and retracted); vaccines don't overload the immune system.
• Recording and reporting - record batch numbers; report suspected adverse reactions through the MHRA Yellow Card scheme.

Passive Immunisation and Post-exposure Prophylaxis

• Passive immunisation - ready-made antibodies - immediate but short-lived protection (weeks to months).
• Examples:
  • Chickenpox exposure in non-immune immunosuppressed people, pregnant women and neonates - oral aciclovir (or valaciclovir) from day 7 to 14 after exposure is now first line for most; VZIG for selected groups (e.g. some neonates, those unable to take oral treatment) - UKHSA guidance.
  • Measles exposure - human normal immunoglobulin (HNIG) for immunosuppressed people (IV), non-immune pregnant women and infants under 9 months (within 6 days); MMR within 72 hours for eligible contacts.
  • Hepatitis B - HBIG plus vaccine for babies of HBsAg-positive mothers (within 24 hours) and after high-risk exposure in non-responders.
  • Tetanus-prone wounds - human tetanus immunoglobulin plus vaccine depending on wound and vaccination status.
  • Rabies - vaccine plus rabies immunoglobulin (infiltrated into the wound) for high-risk exposures in unvaccinated people.
  • RSV - nirsevimab (long-acting monoclonal antibody) for high-risk infants; palivizumab previously.
  • Hepatitis A - vaccine (or HNIG for some contacts).
  • Botulism and diphtheria - antitoxin.
• Post-exposure antibiotics - meningococcal contacts (ciprofloxacin), pertussis contacts in high-risk settings (macrolide).
• HIV post-exposure prophylaxis - within 72 hours (ideally hours) after high-risk exposure.
• Neonatal passive immunity - maternal IgG crosses the placenta (boosted by vaccination in pregnancy - pertussis, influenza, RSV, COVID-19).

Immunocompromise and Vaccines at a Glance

Spot the Diagnosis

Exam-style Scenarios

1. A 58-year-old woman with rheumatoid arthritis is starting adalimumab. She was born in India and had a TB contact as a child. IGRA is positive; chest X-ray is normal.
Answer: Latent TB infection - treat before anti-TNF.

• Exclude active TB (symptoms, chest X-ray, sputum if indicated).
• Treat latent TB (e.g. 3 months rifampicin + isoniazid, or 6 months isoniazid) - start adalimumab after at least 1 month if needed (specialist).
• Also check HBsAg, anti-HBc, HCV, HIV, VZV; update inactivated vaccines.

2. A 22-year-old has an emergency splenectomy after a road traffic collision.
Answer: Prevent overwhelming post-splenectomy infection.

• Vaccines from 2 weeks after surgery - pneumococcal, Hib/MenC, MenACWY, MenB, annual influenza.
• Prophylactic phenoxymethylpenicillin (at least 2 years, ideally lifelong) plus standby amoxicillin.
• Education, alert card, travel and malaria advice, urgent care after animal bites.

3. A 65-year-old man with lymphoma had R-CHOP chemotherapy 9 days ago. He feels unwell; temperature 38.4°C, HR 112, BP 98/60.
Answer: Neutropenic sepsis (probable).

• IV piperacillin–tazobactam within 1 hour - don't wait for the neutrophil count.
• Blood cultures (peripheral and line), lactate, FBC, U&E, LFTs, urine, chest X-ray; fluids; sepsis bundle.
• Acute oncology/haematology input; consider G-CSF and antifungal therapy if fever persists.

4. A 45-year-old woman with lupus nephritis on prednisolone 30 mg and mycophenolate develops progressive breathlessness and a dry cough over a week. SpO₂ 95% at rest, 86% on walking.
Answer: Pneumocystis jirovecii pneumonia.

• CT chest (ground glass), LDH, beta-D-glucan, induced sputum or BAL for PCP PCR.
• High-dose co-trimoxazole (check FBC, potassium, renal function) plus steroids if hypoxic.
• Secondary prophylaxis afterwards; she should have been on prophylaxis.

5. A 30-year-old woman on rituximab for vasculitis is a household contact of a child with chickenpox. She has no history of chickenpox; VZV IgG negative.
Answer: Significant exposure in a non-immune immunosuppressed person.

• Oral aciclovir or valaciclovir from day 7 to day 14 after exposure (UKHSA) - VZIG only in selected cases.
• Advise to report any rash urgently - IV aciclovir if chickenpox develops.
• No live varicella vaccine while immunosuppressed; consider when immunosuppression ends.