Associate Professor Rohan

AmeratungaAdult and Paediatric Clinical Immunologist and

Allergist

Auckland

8:30 - 9:25 WS #87: Infections in Children - An Immunologist's View

9:35 - 10:30 WS #99: Infections in Children - An Immunologist's View

(Repeated)

The child with recurrent infections

Recurrent infections in children

• Too many

• Too severe

• Too long

• Not responding to treatment

Recurrent Infections in children

Globally

Malnutrition in the world

Childhood deaths in the world

Main categories

• Normal child 50%

• Child with atopy 30%

• Child with chronic disease and/or

anatomical problems 10%

• Immunodeficiency: primary or secondary

10%- detailed features when to suspect

Clinical investigation

• History detailed history incl pregnancy

• Examination

• Investigations- identifying PID

• Lab and imaging studies

Pregnancy history

• Infections

• Drug use legal or illegal

• HIV risk factors

• Tobacco

Birth history

• Length of gestation

• Neonatal complications

• Admission to PICU

• Any complications in hospital

Prematurity

• Increased risk of RSV in the first year

• Difficult to identify which subgroups are at

most risk

• Palivizumab

• Immunoglobulins transferred in the last

trimester

• Increased risk of other infections not as well

documented

Prematurity

• Bronchopulmonary dysplasia

• Still an issue with surfactant, reduced

oxygen, changes in ventilation strategy etc

Cost-effectiveness of palivizumab in New Zealand.Vogel A, McKinlay M, Ashton T, Lennon D, Harding J, Pinnock R,

Graham D, Grimwood K, Pattemore P, Schousboe M.

J Paediatr Child Health 2002 Aug;38(4):352-357

Growth and development

• Chronic disease- poor growth, some PIDS

• Heart and lung disease eg CF

• GI disease eg diarrhoea

Reactions to immunisation

• Adverse reactions to live vaccines eg

rotavirus, BCG

• Polio no longer live

Medications

• Steroids

• immunosuppressives

Family history

• Recurrent infections

• Early deaths

• Unexplained deaths in childhood

• Consanguinity

• Ethnicity

Normal child 50%

• 4-8 infections/yr

• Increased risk: sibling attending daycare

• Overcrowding

• no more than 1 pneumonia or 2 OM in the

first three years of life.

• Generally viral infections

• Complete recovery between infections

Socioeconomic factors and

recurrent infections in children

• The worried well

• Socio-economic status- Overcrowding

• Attendance at daycare

• Number of siblings

• Birth order

• Access to medical care

Socioeconomic factors and

recurrent infections in children

Normal infections

Clinical features of concern

• More than two severe infections/ yr

• 3 respiratory infection incl sinusitis

• Abx > 2 months/yr

• Failure to respond to antibiotics

• Need for IV antibiotics

• Unusual complications eg empyema,

mastoiditis, abscesses

Parental smoking and other risk factors

for wheezing bronchitis in children.Rylander E, Pershagen G, Eriksson M, Nordvall L.

Eur J Epidemiol 1993 Sep;9(5):517-26

• 199 children with wheezing. 309 controls

• Parental smoking rr 1.8

• Strongest association with maternal

smoking and children,18/12

Parental smoking, bronchial reactivity

and peak flow variability in children

Cook, Derek G; Strachan, David P

Thorax 1998;53(4):295-301

Recurrent wheezy bronchitis

and viral respiratory infections.Mertsola J, Ziegler T, Ruuskanen O, Vanto T, Koivikko A, Halonen P.

Arch Dis Child 1991 Jan;66(1):124-9

• 54 pts 1-6 yrs recurrent wheezy bronchitis

• 115 episodes

Mycoplasma 52

Rhinovirus 34

• Associated with parental smoking

Atopic child

• AR mistaken for sinusitis

• Bronchitis vs pneumonia

• PID or anatomical problems can co-exist

with atopy

• Higher risk of atopy with some PIDS

• May have allergen specific IgE tests in PID

Allergy as a cause of

recurrent infections in children

• 5yr old boy with recurrent muco-purulent

nasal discharge.

• Requiring up to 12 Rx antibiotics per year

• Symptoms worse in winter

• Frequent sneezing and rhinorrhoea

• Other family members also atopic

• Strongly +ve spt tests to HDM, cats

Allergy as a cause of

recurrent infections in children

• Allergy treatment HDM prevention

measures

• Combination of Butacort and Loratadine

• Reduction in frequency of infections and

rhinitis symptoms

• Allergen-specific immunotherapy

The prevalence of atopic disorders in children

with chronic otitis media with effusion.Alles R, Parikh A, Hawk L, Darby Y, Romero JN, Scadding G

Pediatr Allergy Immunol 2001 Apr;12(2):102-6

• 209 chronic OME cases from an ENT clinic

• 89% had allergic rhinitis (hx, spts)

• cf 20% prevalence of allergic rhinitis

Child with chronic disease 10%

• Barrier failure

• Inadequate respiratory clearance

• Obstruction

• CV problems

• Foreign body

• Resistant organism

• Continuous reinfection eg contaminated

water

Host factors important in defense

• Skin

• Mucous membranes

• Lysozyme

• Digestive enzymes

• Respiratory mucous clearance mechanisms

Generalised anatomical factors predisposing

to recurrent infections in children

• Skin defects eg burns, eczema

• Multiple mechanisms: barrier loss,

nutritional compromise, secondary immune

defects, use of antibiotics, nosocomial

infections, immobility

• Infections in multiple anatomical areas

Cystic fibrosis

• Most patients identified by neonatal screening

• Can present later

• Children can look relatively well

• Nasal polyps in children

• Chronic cough, chronic sputum production,

clubbing

• Sweat testing +/- genetic testing

• Genetic testing

Localised anatomical factors predisposing to

recurrent infections in children

• Localised defects eg Bronchial obstruction

• Most infections in the same system and

same location

• Infections may be slow to respond to Rx

• There may be localised complications eg

bronchiectasis.

• Investigations and management focused on

correcting the anatomical defect.

Lobar pneumonia

Localised anatomical factors predisposing to

recurrent infections in children

• Localised defects eg enlarged adenoids

• Frequent URTIS and OME

• ENT referral if suspected.

• Surgery +/- tympanostomy tubes

Localised anatomical factors predisposing to

recurrent infections in children

• Localised defects eg chronic tonsillitis

• ENT referral

• Removal if indicated

• Frequent cause of ill health, URTIS,

abdominal symptoms etc

• Foreign bodies- unilateral nasal symptoms

The immune response to cancer

Infections in cancer

• Destruction of the immune system esp Leukemia

• Drugs- chemotherapy

• Radiotherapy- multiple mechanisms

• Localised obstruction eg Ca bronchus

• Malnutrition

• Probably worse with hematological malignancy

Suspected immunodeficiency 10%

• Family history of immunodeficiency or unexplained early

death (eg, before age 30 years)

• Failure to gain weight or grow normally (failure to thrive)

• Need for intravenous antibiotics and/or hospitalization to

clear infections

• Six or more ear or respiratory tract infections/ year

• Two or more serious sinus infections or pneumonias within

one year

• Four or more new ear infections within one year

• Two or more episodes of sepsis or meningitis in a lifetime

• Two or more months of antibiotics with little effect

• Recurrent or resistant oral or cutaneous candidiasis

• Recurrent deep skin or organ abscesses

• Infection caused by an unusual microbe and/or in an unusual location

• Complications from a live vaccine (eg, rotavirus, varicella, and BCG vaccines)

• Chronic diarrhea

• Nonhealing wounds

• Extensive skin lesions

• Persistent lymphopenia (age dependent)

• Unexplained autoimmunity or fevers

• Granulomas

• Hemophagocytic lymphohistiocytosis (HLH)

• Lymphoma in infancy

• Features typical of syndromic PIDs

Suspected immunodeficiency

Primary immune deficiency

Stem

cell

Hematopoeisis

BM

Thymus

CD4

CD8

IgG

IgA

IgM

antigenX

XXX

XX

XTh1

Th2

X

• B cell defects- Bruton’s, CVID, XLA

• T cell defects- di George

• Combined defects- SCID, XHIM

• Other well-defined disorders- WAS

• Complement defects

• Phagocytic defects- CGD

• Disorders of innate immunity- TLRs

• Autoinflammatory disorders- FMF, TRAPS

• Disorders of Apoptosis- ALPS

• Phenocopy

WHO classification of

primary immune deficiency

Patients with PID by Reported Diagnosis

Source: IDF Patient Survey N=2815

12%

1%

1%

34%

24%

17%

8%

4%

4%

2%

2%

0% 10% 20% 30% 40%

Common Variable

IgG Subclass

IgA Subclass

X-Linked Agamma

Severe Combined

CGD

Hyper IgM

DiGeorge

Wiskott-Aldrich

Ataxia

Other

When to suspect primary immune deficiency

• Increased # of infections

• Unusual organisms

• Unusual site of infections

• Failure to respond as predicted

• Failure to thrive/ growth retardation

• Other clinical features

• Family history

Times Hospitalized before Diagnosis

None

30%

One

17% 2-5

32%

6-10

10%

11-20

6%

21+

5%

Source: IDF Patient Survey N=2,708

Possible presentations of PID

• ID: Rec bacterial, fungal, viral infections

• GI: Chronic diarrhea with Giardia, Crypto

• Chest: Bronchiectasis, bronchitis

• Rheum: SLE (comp), Oligoarthritis

• ENT: Sinusitis, otitis media

• Endo: Mucocutaneous Candidiasis

• Haem: AIHA, tcp, lymphoma

• Onc: Lymphoma, SCC

Recognition of PIDs

• Institution of correct therapy

• Prevention of complications

• Addressing issues related to chronic disease

(marriage, work, school, support IDFNZ)

• Genetic implications for family members

Health Status: Before and

After Treatment

28%

29%

16%4%

4%

11%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Year Before Diagnosis Last Year on IVIG

Good

Very Good

Excellent

Why Patient was Initially Tested for PID

7%

1%

66%

6%

11%

8%

0% 20% 40% 60% 80%

Family History

Routine Checkup

Repeated Infections

Unusual Infection

Overwhelming Infection

Other

PID: Typical history

• 2yr old boy

• Recurrent chest infections since 6 mo

• Frequent OM

• Family history: 2 uncles died at 1 yr of age

• OE/ Absent tonsils

• Inx IgG 1.2 g/l

• No response to specific vaccines

Some examples of primary immune deficiencies

• T cell (HIV), diGeorge

• B cell Bruton’s, CVID

• Combined SCID, XHIM,

• Complement C1inh

• Neutrophil CGD, LAD

T cell immune defects

• T cell immune defects eg diGeorge

syndrome

• Infections: viral, fungal, parasitic, protozoal

• Impaired growth in children

B cell immune defects

• B cell immune defects eg XLA (Brutons)

• Infections: bacterial, protozoal, (viral)

• Normal growth in children

Chronic sinusitis

Chronic sinusitis

Bronchiectasis

Giardia

IVIG

Screening tests for immune deficiency

• FBC ESR

• Blood film

• Immunoglobulins

• Specific antibodies: proteins eg tetanus toxoid

• Specific antibodies: carbohydrates blood group

• HIV test

Interpretation of immunoglobulin levels

• Age of the child

• Prematurity

• Concurrent infections

• Medication

• Lab-lab variations

Interpretation of immunoglobulin levels

Advanced tests for PID

• Vaccine responses

• Flow cytometry

• Electron microscopy

• Molecular diagnosis

Summary: An approach to the child

with recurrent infections

• Accurately document the numbers of infections

• Are the infections localised to 1 organ system?

• Are they localised to one anatomical location?

• Are there obvious predisposing factors? Incl smk

• Failure to thrive/ growth retardation?

• Unusual features of the infections

• Relevant Family history

Main categories

• Normal child 50%

• Child with atopy 30%

• Child with anatomical problems 10%

• Immunodeficiency: primary or secondary

10%