Respiratory presentation of PIDs

Dr Somwe Wa Somwe Paediatrician Department of Paediatrics and Child Health UTH

The heterogeneity of the PIDs, the variability of their clinical manifestations, inconsistence between genotype and phenotype, and involvement of whatever organ or tissue supports the interdisciplinary character of these diseases, which requires multidisciplinary approach in their management.

In children, respiratory symptoms are typical initial presentation of various PIDs.

General clinical course of PIDs and different approaches in establishment of the diagnosis (Adapted from Lindegren ML et al)

The most important PIDs associated with respiratory complications in children.

Mild PIDs Severe PIDs Transient hypogammaglobulinaemia Common variable of infancy immunodeficiency

Selective deficiency of IgA Severe CID

Deficiencies of IgG sub-classes Congenital neutropenias

Deficiencies of specific antibodies X-linked

agammaglobulinaemia

Deficiency of mannose-binding Hyper-IgE syndromes lectin DNA-repair defects

Warning signs for PIDs in children

1. ≥ 4 Ear infections in 12 months

2. ≥ 2 Serious sinus infections in 12 months

3. ≥ 2 Pneumonias in 12 months

4. Recurrent, deep skin or organ abscesses

5. Persistent thrush in the mouth or skin fungal infection

Warning signs for PIDs in children, cont

6. ≥ 2 Deep-seated infections (septicaemia, meningitis, osteomyelitis,…)

7. ≥ 2 months on antibiotics with little or no effect

8. Need for intravenous antibiotics to clear infections

9. Failure to thrive

10. Positive family history of PID

(Adapted according to Arkwright and Gennery, 2011)

Warning signs for PIDs in adults

1. ≥ 4 Infections treated with antibiotics per year (Otitis, bronchitis, sinusitis or pneumonia)

2. Recurrent infections or infections requiring long-term antibiotic therapy

3. ≥ 2 Serious bacterial infections (Osteomyelitis, meningitis, septicaemia or cellulitis)

4. ≥ 2 Pneumonia during last 3 years

5. Infections caused by atypical bacteria in unusual location

6. Positive family history of PID

Respiratory manifestations and complications of PIDs in childhood with estimated average frequency

Respiratory manifestationFrequency

1. Respiratory infections (Rhinosinusitis, otitis media, ↑↑↑ bronchitis and pneumonia)

2. Complications and consequences of respiratory infections ↑↑

(Bronchiectasis, lung abscesses, empyema, pneumatoceles)

3. Airway structural abnormalities ↑↑ (Bronchial wall thickening and air trapping)

4. Interstitial lung diseases (LIP) ↑

5. Lymphoproliferative diseases (Lymphoma, benign Rare lymphoproliferative diseases and lymphadenopathy)

Simplified classification of the respiratory manifestations of PIDs

Pathophysiological substrates of the development of respiratory complications of PIDs

Infectious manifestations of PIDs

1. Predominantly humoral deficiencies

• IgA deficiency• IgG sub-classes deficiency• Specific Ig deficiency• CVID• XLA (Bruton)• Hyper-IgE syndrome• Hyper- IgM syndrome

Predominantly humoral deficiencies, cont

Characterised by recurrent and prolonged respiratory

infections:

• Rhinosinusitis• Otitis media• Bronchitis• Bronchiectasis• Pneumonia

Respiratory infections in PIDs are SPUR (Severe, Persistent, Unusual, atypical, opportunistic micro-organisms and Recurrent). Onset of symptoms is usually beyond 6 months of age after maternal IgG have disappeared.

2. Combined and other well defined PIDs a. Severe combined immunodeficiency (SCID)

Severe recurrent respiratory infections

P jiroveciiCMVAdenovirusParainfluenzae type 3RSV can lead to persistent bronchiolitis

Combined and other well defined PIDs, cont

b. Hyper-IgE syndrome (Job syndrome)

Recurrent sino-pulmonary infections

S aureusS pneumoniaeH influenzae

May lead to bronchiectasis (P aeruginosa)

Pneumatoceles are another complication (Aspergillus

and scedosporium spp)

Combined and other well defined PIDs, cont

c. Hyper-IgE syndrome

Recurrent pneumonias

Encapsulated bacteriaCMVHistoplasmaP jiroveciiC albicansC neoformans

3. Phagocytic immunodeficiencies

Predominantly chronic granulomatous disease and congenital neutropenias

Common pathogens

S aureus P aeruginosaK pneumoniae Aspergillus sppAerobacter spp C albicans

Others are Burkholderia and Serratia spp

Difficult to treat, slow to resolve, recurrent pneumonias.

4. Complement immunodeficiencies

These diseases are generally underdiagnosed and underreported.

C1 C4 deficiencies lead to pyogenic infections

C5 C9 deficiencies predispose to Neisseria spp infections

C3 deficiency will particularly cause recurrent pneumonias.

There is an association with hereditary angioedema which is potentially life-threatening when occuring in the larynx.

Non-infectious respiratory complications of PIDs

Recurrent bacterial pulmonary infections may cause the following

Air trapping Atelectasis Bronchial wall thickening Bronchiectasis

1. Bronchiectasis

Major causes

• Cystic fibrosis• Primary ciliary dyskinesia• Primary immunodeficiencies

CVID up to 73% XLA from 17 to 76% Selective IgA deficiency IgG sub-classes deficiency

Mainly cylindrical type, bilateral and diffuse Affecting middle and lower lobes Proximal bronchi

Early detection and aggressive management are required.

2. Interstitial lung disease and PIDs

CVID may cause granulomatous lymphocytic interstitial lung disease (GLILD) which may present as

Lymphocytic interstitial pneumonia Follicular bronchiolitis Granulomatous lung disease Organising pneumonia Pulmonary lymphoid hyperplasia

Development of GLILD may be associated with infections such as

HHV8EBVCMV

Interstitial lung disease and PIDs, cont

ILD usually results from immune dysregulation.It has a poor prognosis.There is increased prevalence of

lymphoproliferative disorders.ILD is asymptomatic at the initial stage, hence

screening at risk patients is very important.

3. Respiratory tract tumours in PIDs

There is a strong association with EBV. CVID and Wiskott-Aldrich syndrome patients are at greater

risk.

Some of the tumours areLeiomyomaPulmonary adenocarcinomaThymomaLymphoma (NHL)

These tumours must be differentiated from benign

lymphoproliferative diseases.

4. Other respiratory complications of PIDs

Allergies Primary pulmonary hypertension Pulmonary alveolar proteinosis Cor pulmonale Respiratory insufficiency

Examination and investigations in a child with recurrent, severe and prolonged respiratory infections

Examination:

• Plot weight and height on growth chart

• Respiratory examination including clubbing and chest wall deformity

• Look for lymphadenopathy and/or hepatosplenomegaly

• Examine mouth/mucous membranes? candidal infection

• ENT and full systemic examination, including skin

Investigations to consider:

First line:

FBC and WBC differential IgG and IgG subclasses, IgA, IgM Specific antibodies to Tetanus, HiB and pneumococcus

(repeat levels one month after any boosters)

Second line:

Lymphocyte subsets Neutrophil oxidative burst if indicated Simple spirometry (if more than 5 years) Plain chest radiograph High resolution computerized tomography of chest Bronchoscopy

References

1. Milos J et al. Pulmonary manifestations of primary immunodefciency disorders in children. Frontiers in Pediatrics,July 2014, Volume 2, Article 77.

2. Woodsford M A M, Spencer D A and Cant A J. Symposium: Respiratory Medicine. Immune deficiency and the lung. Paediatrics and Child Health, 2010, 21:5, pp 213-218.