Paediatrics JC118: A Child With Recurrent Infections: Primary Immunodeficiencies Flashcards
Recurrent infections
Recurrent infections are common in childhood
- ***8-10 episodes of URTIs per year in young children can be normal —> provided no end organ damage / normal growth + development
- esp. Starting to go to nursery / Many siblings at home
Infections in healthy children are usually:
1. Short duration
2. Self-limited
3. Uncomplicated
4. Healthy in between episodes
Allergy or Recurrent infections?
Features suggestive of allergy:
1. Symptoms with **no fever
2. **Seasonal / Exposure pattern
3. Poor response to antibiotics
4. ***Good response to antihistamine / bronchodilators
5. Prior history of eczema, food allergy / other allergic symptoms
6. Positive family history of allergy
Causes of Recurrent infections
- Non-immunologic defects
- Obstruction to flow
—> Bronchial obstruction due to congenital defect —> Recurrent Pneumonia of ***same lobe
—> Eustachian tube obstruction —> Recurrent Otitis media
—> UT obstruction —> Recurrent UTI
- Damaged barriers
—> Burns, sinus tracts, open fractures —> Pyogenic infections at these sites
—> Mid-line defects, middle ear defects —> Recurrent meningitis (continuation between middle ear / sinuses and CNS)
—> Primary ciliary dyskinesia —> Bronchiectasis + Situs Inversus - Foreign bodies
—> VP shunts, prosthetic valves, central lines —> Recurrent infections at site of foreign body
- Secondary immunodeficiencies
- Iatrogenic (immunosuppressants, cytotoxics, anti-neoplastic drugs)
- Neoplasia (e.g. lymphoma)
- Malnutrition (e.g. zinc deficiency) - Primary immunodeficiencies (PID)
***3. Primary immunodeficiencies (PID)
- Over 400 types
- Incidence: 1 in 2000-5000 live births (4500 babies in China yearly, 80,000 PID patients in China)
- Rare disease
- Prevalence same as France
***Categories:
1. Humoral (Ab) deficiencies (most common)
- XLA
- CVID
- Cellular deficiencies
- Combined deficiencies that affect both humoral + cellular immunity (2nd common)
- SCID - Phagocyte defects
- Complement deficiencies
- Combined immunodeficiencies with associated / syndromic features (3rd common)
- WAS
- DiGeorge’s syndrome
(7. BM failure
8. Phenocopies of PID (inherited genetic defect that produce Ab / cytokines leading to phenotypes ~ to PID))
***Clinical presentations:
1. Infections
2. Autoimmune phenotypes
3. Autoinflammatory phenotypes
4. Haemophagocytosis (Phagocytosis of RBC, WBC, Plt)
5. Lymphoid cancer
6. Allergy
Challenges in the care for rare diseases
Lack precise diagnosis
1. Lack of knowledge + recognition
2. Lack of access to diagnostic tests
Lack of specific treatment
3. Lack of referral network for treatment
4. High cost of drugs + care
5. Inequities in availability of treatment + care
History taking in Recurrent infections
- Documentation is important
- “recurrent pneumonia” may merely reflect frequent URTI / asthma
- CXR findings, isolation of pathogens, blood culture
—> distinguish from allergies - General health history
- ***Past medication
- Steroid therapy (Secondary ID)
- Blood product transfusions (HIV) - Neonatal history, Neonatal hypocalcaemia
- ***neonatal convulsion (DiGeorge syndrome: Hypoparathyroidism) - Immunisation history
- ***Family history (X-linked vs AD vs AR)
- Allergy
- Immunodeficiencies
- Autoimmune syndrome
- Recurrent infections - ***Unexplained death in siblings / other childhood relatives
- Social history
Infectious clues to PID
Vaccination (Live vaccines):
1. BCG (lead to ***BCG dissemination)
- SCID (severe combined ID)
- CGD (chronic granulomatous disease)
- MSMD / STAT1 (Mendelian susceptibility to mycobacterial diseases / STAT1 deficiency —> prone to atypical mycobacterial infections e.g. BCG, environmental mycobacteria, salmonella + BCG osteomyelitis)
- OPV
- SCID
- XLA (Agammaglobulinemia)
—> cannot clear polio virus vaccine —> revert back to virulent —> ***Paralytic polio - Rotavirus vaccine
- SCID (***severe diarrhoea) - Rubella vaccine
- ***Chronic skin granuloma in primary T-cell deficiency
Physical examination in Recurrent infections
- Growth
- Growth chart
- ***Failure to thrive (weight crossing centiles to way down below 3rd centile) - Mucocutaneous surfaces
- ***Candidiasis (suspect T cell immune defects e.g. DiGeorge syndrome, SCID) - Lymphatic tissue
- **Too much (CGD: lymphadenopathy)
- **Too little (SCID: no LN, XLA: small absent / tonsils (∵ tonsils full of B cells)) - Lung
- ***Bronchiectasis
- Finger clubbing - Hepatosplenomegaly
- Arthritis
- Neurologic examination
- Ataxia (Ataxia telangiectasia: conjunctiva, earlobes for telangiectasia —> PID due to DNA repair defect) - Nails
- Dysplastic (Dyskeratosis congenita: part of BM failure syndrome —> PID) / Candidiasis (Chronic mucocutaneous candidiasis due to STAT1 deficiency) - Skin
- **Poor wound healing / scar (indicate Leukocyte deficiency: leukocyte cannot move out from blood vessels to soft tissue)
—> paper thin skin + dysplastic
- **Skin infections / abscess (CGD / congenital neutropenia)
Clinical features suggestive of PID
- ***Failure to thrive
- ***Family history
- Chronic / Recurrent infections
- Recurrent abscesses
- Unusual opportunistic infections
- Chronic diarrhoea
- Incomplete response to anti-infective treatment
- Vaccine-associated paralytic polio
- Disseminated BCG infection
- Unusual autoimmune features
Warning signs of PID (not too sensitive / specific):
1. **Failure to thrive
2. **Family history of PID
3. >=8 new ear infections within 1 year
4. >=2 serious sinus infections within 1 year
5. >=2 months on antibiotics with little effect
6. >=2 pneumonias within 1 year
7. Recurrent deep skin / organ abscesses
8. Persistent thrush in mouth / skin
9. Need for IV Antibiotics to clear infections
10. >=2 deep-seated infections
***Association between infecting pathogens + Most likely type of ID
Bacteria
1. Encapsulated bacteria: Ab deficiency
- Pneumococcus
- Hib
2. Staphylococcus: Neutrophil deficiency
3. Meningococcus (Neisseria meningitidis): Complement deficiency
4. Salmonella: Th1 cytokines (e.g. IFNγ, IL12) (MSMD), Neutrophil deficiency
5. Pseudomonas: Neutrophil deficiency
6. Mycobacteria (typical / atypical): Th1 cytokines (e.g. IFNγ, IL12) (MSMD)
Protozoa
1. Cryptosporidium: T cells (esp. CD40-L deficiency)
2. Giardia lamblia: Ab (XLA, get duodenal aspirate to diagnosis giardiasis)
Fungi
1. Candida albicans: T cells, Neutrophil
2. Aspergillus: Neutrophil (CGD)
3. Pneumocystis: CD40-L, T cells deficiency
Viruses
1. Enterovirus (polio, echovirus): Ab deficiency (XLA) (unknown reason, echoviral chronic meningoencephalitis)
(記: XLA susceptible to Bacteria + Enterovirus infection)
2. Herpes viruses (EBV, CMV): T-cell deficiency
Other
1. Mycoplasma: Ab
- Ab deficiency: X-linked Agammaglobulinaemia
- X-linked inheritance
- ***Btk protein defect
- Recurrent Sinopulmonary infections (Pneumococcus, Hib), Meningitis (Enterovirus), Diarrhoea (Giardiasis), Arthritis (∵ delayed treatment)
- ***Panhypogammaglobulinaemia + Absent B cells
—> but variable presentations (may have near normal IgG but not functional (i.e. absent isohaemagglutinin e.g. absent Anti-B in group A blood)) - Require regular ***IVIG infusion
- Do not present until 2-3 months of life (∵ body still have mother IgG)
- Complications: ***Bronchiectasis
Other Ab deficiency:
1. **AR hyper-IgM syndrome
2. **Common variable immunodeficiency (susceptible to Autoimmune disease + Lymphoma as well)
3. Selective IgA deficiency
4. IgG subclass deficiency
5. Transient hypogammagloublinaemia of infancy
- Ab deficiency: Common variable immunodeficiency (CVID)
- Common in west, less in east (could be related to HLA distribution)
- ***Low Serum IgG, A, E
- ***Impaired capacity to produce specific Ab
- Infections, Autoimmunity, Lymphoma
- Complications: Bronchiectasis, ***Interstitial lung disease (∵ immune dysregulation, altered CD4:8 ratio, dysfunctional T cells —> Granulomatous lymphocytic ILD (GLILD))
ESID definition:
1. >=1 of following
- Increased infection susceptibility
- **Autoimmune manifestations
- **Granulomatous disease
- ***Unexplained polyclonal lymphoproliferation
- Affected family member with Ab deficiency
AND
- ***Marked ↓ of IgG + IgA +/- IgM
- measured at least twice, <2 SD of normal concentrations for their age
AND
- > =1 of following
- Poor Ab response to vaccines / Absent isohaemagglutinins / Both (i.e. absence of protective concentrations despite vaccination)
- Low number of switched memory B cells (<70% of age-related normal value)
AND
- Secondary causes of hypogammaglobulinaemia excluded
- Diagnosis established after 4th year of life
- No evidence of profound T-cell deficiency
- Combined immunodeficiencies with associated / syndromic features
***Wiskott-Aldrich syndrome
- Prone to Lymphoma (EBV), IBD
Classical phenotype:
- ***Triad
1. Eczema
2. Thrombocytopenia (petechiae, intracerebral haemorrhage)
- small platelets of 3-5 fL (normal 7-10 fL) (SpC Paed)
3. Recurrent infection
Other phenotypes (1 gene —> many diseases):
- X-linked thrombocytopenia (no infection, little eczema): ↑ in number of missense mutations —> correlated with XLT phenotype at the time of presentation
- X-linked neutropenia
Impaired T cell immunity
***DiGeorge’s syndrome
Patterns of infection:
- Failure to thrive
- Chronic diarrhoea
- Thrush
- ***Viral, Fungal opportunistic infections
Clinical presentations:
1. **Hypocalcaemia (Low Ca Low pH) —> Muscle cramps
2. **Low T cells (babies have low but adequate T cells for live vaccines)
3. Abnormal facies with prominent ears, small chin, short philtrum
4. ***Pcychiatric + Learning issues
5. Conotruncal heart defects
Investigation:
- **FISH: chromosome **22q deletion
- Hyper-IgE syndrome
AD inheritance, STAT3 loss-of-function mutation
Pathophysiology (wiki):
- Abnormal ***neutrophil chemotaxis due to decreased production of IFNγ by T cells
Clinical features:
1. **Coarse facies
2. **High IgE (but less allergies / anaphylaxis than expected ∵ not those IgE that give rise to allergies)
3. **Retained primary teeth
4. Minimal trauma fractures, scoliosis
5. **Mucocutaneous candidiasis
6. Pneumatoceles with secondary infections (cavity in the lung parenchyma filled with air)
7. Prolonged bronchopleural fistulae after lung resection
8. **Eczema (SpC Paed)
9. Retroauricular fissures
10. Severe folliculitis of the axillae and groin
11. **Cutaneous cold staphylococcal abscesses
12. Candidiasis of the nails
