Medicine SC064: Why Do I Always Get Sick? Introduction To Immunodeficiencies Flashcards
CSF analysis for meningitis
Acute meningitis: PMN predominant
Subacute, Chronic meningitis: Lymphocytic / Monocytic predominant
Approach to repeated infection
History:
1. Past medical history (Ask from ***birth: Primary / Congenital / Inborn error of immunity)
- History of frequent infections
- Vaccinations according immunisation programme (early challenge to immune system: BCG (live vaccine))
- History of STIs, including Neisseria gonorrhoeae (sensitive to other Neisseria infections?)
- Social history
- Smoker, Social drinker
- Occupation
- Place of residence - ***Family history
- Medical history of family members / Recurrent infections
- Consanguinity
- History of miscarriage
Investigations:
1. 1st line screening tests
- CBC + D/C
- **Absolute lymphocyte count (ALC) + lymphocyte subset (T (CD3, 4, 8), B (CD19, 20), NK cells (CD16, 56)) (different range of paediatric than adult (normal 1.0): paed has higher count)
- **Immunoglobulin profile: IgG/A/M/E
- Serum + Urine Electrophoresis (rule out plasma cell malignancy)
- Autoimmune serology: **C3, **C4 (esp. for Neisseria), **ANA, Anti-ENA +/- Other
- ESR, CRP (body cannot produce APR against pathogen, falsely ↓ ESR if low globulin / fibrinogen / anaemia (low RBC) —> clot drops slowly)
- LRFT
—> Protein (Albumin + **Globulin level (most globulin are IgG))
—> Uraemia affect immune function
- **HIV Ab / Ag
- **Anti-HBs (check whether developed immunity against vaccination) + Anti-A/B isohaemagglutinin (against A / B blood group)
- CXR, CT thorax, Lung function
—> Bronchiectasis
—> TB
—> Good syndrome: Thymoma with immunodeficiency
- 2nd line immunological tests
- Order only based on clinical suspicion
- Complement function tests: CH50 / AH50 (Neisseria really needs complement system (MAC) to kill off) —> Look at complement pathway
—> CH50: test Classical + Lectin pathway —> Opsonisation pathway + Terminal pathway (i.e. MAC formation)
—> AH50: test Alternative pathway —> Inflammation pathway + Terminal pathway (i.e. MAC formation)
—> If both are defective —> indicate problem at Terminal pathway (i.e. MAC formation (C3, C5-9))
(- Lymphocyte subsets (CD3, CD4, CD8, CD16/56, CD19)
- Cell mediated immunity assessment: Lymphocyte proliferation responses to mitogen / antigen
- Humoral immune response assessment (e.g. vaccine titres, Coomb’s test, specific immunoglobulin levels, B + T cell immunophenotyping)
- C1-esterase inhibitor level + function
- Neutrophil function tests (e.g. NBT, DHR)
- Specific molecular / genetic tests + next generation sequencing
1st line investigations (SpC Teaching Clinic)
- Avoid doing all Ab-based test when suspecting Ab-immunodeficiency
- Body cannot mount Ab response due to immunodeficiency
—> High risk of ***false negative of all other specific Ab (e.g. Rickettsia, Q fever, HIV / HBV Ab panel, Rheumat Ab)
- Beware of ***false positive result If on Ig replacement (IVIG)
—> 1000 donors needed for 1 unit of IVIG
—> Chance of +ve anti-HBc, pneumococcal IgG (but in fact the patient was not exposed)
—> takes 6-8 months for IVIG to be cleared from system - Check actual viral Ag (e.g. HBV DNA, HCV RNA, HIV PCR)
- IgA deficiency not CI to IVIG
- Can receive IVIG even IgA deficiency (higher anaphylaxis to blood product, but just relative risk)
- ∵ Most anti-IgA Ab are IgG isotype —> not cause anaphylaxis, even IgE isotype seldom cause anaphylaxis - Dead / Inactivated vaccinations can be given to patient regardless of immune status (e.g. influenza)
- Only beware of efficacy since immunocompromised patients cannot mount immune response to produce protective effect after vaccination anyway
Primary immunodeficiency (PIDs)
- Aka ***Inborn errors of immunity (IEI) (no longer called immunodeficiency —> some of them are immune dysregulation)
- Increased susceptibility to infections
- Associated with autoimmunity, inflammation + increased risk of malignancy (∵ defective immunosurveillance)
- Possible hereditary + risk in other family members
- Management + Treatment options vary + can be **severely limited without precise diagnosis
—> **Antimicrobial prophylaxis
—> ***Immunoglobulin replacement
—> Targeted therapies
—> HSCT
—> Gene therapy - Rapid advances with Next Generation Sequencing
Classification:
- >400 distinct disorders with >430 different gene defects (still growing)
1. Innate immunity (usually present early)
- Phagocytes
- NK cells
- Complement
- Acquired immunity
- T cells
- B cells
IUIS PID classification:
1. Combined immunodeficiencies (CID)
2. CID with associated / syndromic features
3. Ab deficiencies
4. Immune dysregulation
5. Phagocytic defects
6. Intrinsic + Innate immunity
7. Autoinflammatory disorders
8. Complement deficiencies
9. Bone marrow failure
10. Phenocopies of PID
Role of immunologists
- Screening
- Recognise potential cases
- Selection of initial investigations + working diagnoses
- Acute management
- Appropriate + Timely referral - Diagnosis
- Exclude (first) the reversible, treatable / life-threatening
- Selection of “second line” tests based on clinical presentation, initial investigations, microbiological results - Management
- Replacement therapy
- Antimicrobial prophylaxis
- Treatment of autoimmune, autoinflammatory manifestations
- Disease monitoring + prevention of complications
- ?Transplantation / Gene therapy - Family screening
- Depending on mode of inheritance
- Offspring, siblings, parents
- Preconception counselling
- Prenatal diagnosis
- Early treatment and prevention of complications
General principles to Immunodeficiency
- Not as rare as previously thought: ever-expanding list
- Many patients remain undiagnosed / present later in life
- High index of suspicious for early diagnosis + intervention
- Vigilance of warning signs of PID
- DDx: Exclude **Anatomical + **Functional disorders
- May also present with non-infectious symptoms: **Autoimmunity, **Malignancy
Warning signs of immunodeficiency
記: ***SPUR (Serious, Persistent, Unusual, Recurring)
(SpC Medicine:
Serious: Disproportionately severe
Persistent: Never recovered in same episode
Unusual: e.g. N. meningitidis uncommon by itself
Recur: Recovered and then get infected)
- Disproportionately frequent infections
- Disproportionately severe infections
- Family history
- Unusual clinical presentation
- Unusual microorganisms (e.g. some pathognomonic pathogens)
- Unusual sites of infection (e.g. CNS)
- Clinical phenotype suggestive of syndrome associated with immunodeficiency (e.g. DiGeorge syndrome (SpC Medicine))
- Infections after biologics, chemotherapy, immunosuppressants
***Initial evaluation for immunodeficiency
- Exclude **Secondary causes of immunodeficiency
- DM (affect neutrophil function —> abscesses etc.)
- **HIV (medico-legal)
- Protein-losing states (e.g. anorexic, nephrotic syndrome)
- CKD (uraemia affect immune function)
- Malignancy (lymphoma, leukaemia, paraneoplastic syndrome, malnutrition)
- **Immunosuppression (chemotherapy)
- **Drugs (steroid)
- ***Structural defects (e.g. basal skull defect in recurrent meningitis) - Warning signs
- ***SPUR infections
- Family history (>=3 generations: siblings (include cousins) + offspring (include miscarriage) + parents (include aunties, uncles)) + Consanguinity (for autosomal recessive)
—> infections, cancers (e.g. lymphoma), early death of unknown cause + age of death
- Childhood history
- Immunisation history + adverse reactions to vaccinations - Salient history (to identify **“Phenotype”)
- Age of presentation (earlier —> more likely primary)
- Gender
- Progression of symptoms
- **Pattern of pathogens (e.g. Neisseria —> Complement problem, Haemophilus —> Ab problem, Viral —> T cell)
- Location of infections (for anatomical defects)
- Features of immune dysregulation (e.g. RA, ITP)
- Investigation results
- Family history: Plot family tree (3 generation)
- ***Consider immunology referral - 1st line investigations + 2nd line investigations
Antibody immunodeficiencies
- Most common form of primary or secondary immunodeficiency (50% of all immunodeficiency)
Examples:
1. Agammaglobulinemia
2. Common Variable Immunodeficiency (CVID)
3. B-cell depleting therapies (Monoclonal Ab)
4. **B-cell malignancies
- B-cell lymphoma
- Chronic lymphocytic leukemia (CLL)
- Multiple myeloma (MM)
5. **Drugs (check baseline Immunoglobulin profile before initiation + check every 3-6 months to screen for hypogammaglobulinaemia esp. for stronger immunosuppression e.g. Rituximab)
- Anti-epileptics (e.g. Carbamazepine, Phenytoin, Valproate)
- Immunosuppressants (e.g. Steroids, Azathioprine)
- Monoclonal Ab (e.g. Rituximab)
Clinical features:
1. Recurrent sinopulmonary (“idiopathic” bronchiectasis) + GI infections (chronic diarrhoea) (∵ lack of IgA lining mucosal membrane, lack of IgG in blood)
- esp. Encapsulated bacteria (***NHS: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis) (∵ require Ab for opsonisation), Giardia (pathognomonic for CVID), enteroviruses
- Autoimmune cytopenias (e.g. ITP, AIHA), ILD, IBD
Treatment:
1. Ig replacement (IGRT)
2. Prophylactic antibiotics
Immunoglobulin therapy
- Ig derived from pool of plasma donors (>1000)
- Mostly ***IgG only (other Ig isotypes negligible) —> NOT give to patients with IgA / IgM deficiency
- Routes:
—> IVIG
—> SCIG
—> IMIG (obsolete) - Specific types of Ig: Hyperimmune globulin (specific Ab) (for rabies), Anti-D Ig (for HDN)
Main indications:
1. Ig replacement
- Protection against infection
- Primary / Secondary Ab deficiencies
- ~0.4-0.5 g/kg per month
- Immunomodulatory
- Suppression of inflammation
- Neurology, rheumatology, haematology, renal, transplantation, infections
- ~1-2 g/kg per dose
NB: ***Most serology tests become inaccurate after Ig replacement (e.g. Anti-HBs)
—> Save serum of patient before Ig replacement for baseline serology test
IVIG vs SCIG:
- IV: Once per month
—> in hospital
—> supraphysiological dose (lead to high globulin level —> risk of ***thrombosis, MI, stroke)
- SC: Once per week, daily push, facilitated SCIG
—> more physiological: avoid trough levels / peak levels (∵ more frequent doses), gradual absorption through SC
—> more convenient: home therapy, fewer admissions (lower infection risk)
—> easier: not require IV access
—> safer: fewer systemic adverse reactions
—> cost: ?more cost effective (even though drug cost is higher but better QoL, less days off, better productivity, fewer hospital beds / admissions required)
Summary
- Primary immunodeficiencies are not as “rare”
- Never encountered vs Never diagnosed
- Vigilance is important for potential cases, otherwise easily overlooked
- Exclude **Secondary causes first —> Consider **Disease phenotypes
—> Pattern of pathogens
—> Types of infection / immunodysregulation
—> Age of onset
—> Gender
—> Family history
—> Preliminary investigations - 1st line +/- 2nd line investigations if indicated
- Timely referral to immunologists
SpC Teaching Clinic:
- Secondary immunodeficiencies are overlooked and undertreated
- Antibody deficiencies commonly associated with B-cell depletion / immunosuppression, lymphoproliferative disorders and other drugs
- Likely more prevalent with novel biologics and B cell therapies
- Diagnosis dependent on physician vigilance and awareness
- Secondary immunodeficiency may be reversible… but many are not!!!
Secondary immunodeficiencies (SpC Teaching Clinic)
Multifactorial (Disease vs Medication):
Disease:
***B-cell lymphoproliferative diseases
1. CLL
2. Multiple myeloma
3. Lymphoma
Medication:
1. **B-cell depleting therapies
2. **Conventional immunosuppression
Predominant humoral defect (B cell):
1. Bacteria: **Encapsulated NHS (Strep pneumonia, Neisseria meningitidis, Haemophilus influenzae), Salmonella, Campylobacter jejuni, Pseudomonas aeruginosa
2. Virus: **Enterovirus (meningoencephalitis), echovirus
3. Parasite: ***Giardia lamblia
Predominant cellular defect (T cell):
1. Bacteria: **Intracellular organisms (Mycobacteria, Listeria monocytogenes), Gram negative bacteria (Salmonella)
2. Virus: Herpesviridae (CMV, EBV, VZV), RSV, Enterovirus, HPV
3. Fungi: Candida albicans, Aspergillus fumigatus, **Pneumocystis jirovecii
4. Parasite: Cryptosporidium, Toxoplasma gondii
B-cell targeted therapy (BCTT)
- Rituximab: Chimeric monoclonal antibody against CD20 (pre-B and mature-B)
- B cell depletion lasts ***~6-12 months
- Variable: disease and patient dependent (longer for AAV?)
- Plasma cells are main source of IgG (>95%) but do not express CD20
- Risk factors: elderly, concomitant immunosuppression
- Stem cells, pro-B-cells and plasma cells that do not express CD20 are spared, which allows for B cell recovery after anti-CD20 therapy
- Hypogammaglobulinemia due to prolonged depletion of plasma cell precursors
- Secondary Ab def in **40% of lymphoma (四成), and **25% in autoimmune diseases (四份一) (EXAM)
Overarching principles:
- Patients and their parents / carers should be specifically informed about possibility + implications of developing hypogammaglobulinaemia secondary to BCTTs
- There should be a locally agreed pathway for patients to report infections
- Health-care professionals using BCTTs should be aware of local referral pathways for hypogammaglobulinaemia and its complications
- Commencement of IGRT and its route of administration, should follow a shared decision-making process between patient, clinician supervising the care of the underlying autoimmune disease and a Clinical Immunology service
Recommendations:
1. Decision to start IGRT should be informed by:
- **Degree of hypogammaglobulinaemia
- **SPUR infections
- Demonstration of **impaired Ab responses to polysaccharide Ag
- **Poor response to Antibiotic prophylaxis
- Predisposing factors for developing clinically significant hypogammaglobulinaemia include pre-existing low IgG level (<400) + previous / concomitant ***immunosuppressive therapies
- Patients who have **hypogammaglobulinaemia + **SPUR infections (or Asymptomatic but IgG ***<3g/L) should be referred to Clinical immunology service for assessment
-
**Ig levels should be measured **prior to commencement of BCTT + repeated every ***6-12 months for the duration of BCTT + a minimum of 1 year after stopping treatment, may be appropriate to monitor for longer in selected patients
(- Alternatively monitor CD19 (NOT CD20 since rituximab may be mistaken for CD20 in a machine —> abnormally high CD20)
Primary vs Secondary Immunodeficiencies (SpC Revision)
Primary immunodeficiency (PID):
- Inherent dysfunctions of immune system
- Genetic in general
- Hereditary / Arising from de novo mutations
Secondary / Acquired immunodeficiency (SID):
- Secondary to other conditions / pathologies
- Potential causes include variety of factors affecting immune function
- e.g. Lymphoproliferative diseases, malignancies, medications (e.g. chemotherapy), infections (e.g. HIV), advanced age, malnutrition, protein-losing states
