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After reading this chapter you should:
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primary and secondary immunodeficiency
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understand the presentation and management of autoimmune disorders
The impact of an infection depends on many factors including those of the host, those of the infecting organism and those of the environment including access to medical care. Recurrent infection is seen frequently in paediatric practice and there is often a need to assess whether this is a result of deficiencies within the individual.
Common causes for recurrent infection include:
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disruption in physical barrier of the host—cystic fibrosis, skin trauma, foreign bodies
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structural anomalies and dysfunction—CSF leaks, swallow dysfunction
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host immunodeficiency
Systemic immunodeficiency can present in many ways with some being overwhelming and catastrophic whilst others are indolent and subtle. Immunodeficiency diseases can be grouped by the underlying aetiology:
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primary immunodeficiencies
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antibody immunodeficiencies
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T-cell and combined immunodeficiencies
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phagocytic disorders
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secondary immunodeficiency
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treatment related
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immunodeficiencies as part of a syndrome
Primary immunodeficiencies
Primary abnormalities of the immune system can have significant and devastating consequences for a child or young person, and certain features of an illness raise the prospect of an underlying immunodeficiency. These infections include those which are Serious, Persistent, Unusual and Recurrent (SPUR). Those presenting with recurrent infections should be assessed for underlying primary immunodeficiency when two or more of the following signs are present:
Practice Point—consider immunodeficiency if:
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four or more ear infections in a year
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two or more severe sinus infections in a year
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two or more months of antibiotic treatment with little effect
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two or more pneumonias per year
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insufficient weight gain or growth delay
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recurrent deep skin or organ abscesses
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persistent mouth thrush or fungal skin infection
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need for iv antibiotics to clear infections
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two or more deep-seated infections
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family history of primary immunodeficiency
Other important indicators can be found in the family history, especially early infant deaths, other individuals affected by immunodeficiency, history of autoimmunity and malignancy.
Antibody immunodeficiencies
Children with these conditions are unable to produce protective antibodies, and this can be evident from birth or manifest later in life. There may be a deficiency in the level of one or more of the immunoglobulin classes, the IgG subclasses or in the response to polysaccharide antigens, and there are some children who present with combinations of all these abnormalities. In those children where the genetic defect has been identified, the mutation usually affects genes that regulate the B-cell development or the immunoglobulin genes themselves.
Conditions include
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X-linked agammaglobulinaemia
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common variable immunodeficiency disorder
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selective IgA deficiency
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specific antibody deficiency (SPAD)
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transient hypoglobulinaemia of infancy (THI)
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secondary antibody deficiencies
Clinical presentation
Patients with antibody deficiencies typically present with:
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recurrent sinopulmonary infections (otitis media, sinusitis, bronchopneumonia)
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chronic diarrhoea with Giardia lamblia infection
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skin infections are also common
Viral infections are normally cleared as T cell function is usually intact.
Investigations
Initial assessment will include leucocyte count, lymphocyte subsets, immunoglobulin levels and functional antibodies to tetanus, Haemophilus influenzae type b , pneumococcal serotypes. HIV serology would also be important.
Treatment and management
In general, the aim of managing patients with a humoral deficiency, is to support growth and development and prevent organ damage, especially bronchiectasis. This is achieved by treating comorbidities, treating infections with antibiotics and ensuring appropriate immunisations, if indicated. In more severe or recurrent infections, prolonged prophylactic antibiotics would be appropriate and immunoglobulin replacement therapy may be necessary.
X-linked agammaglobulinaemia
X-linked agammaglobulinaemia (XLA) is caused by abnormal development of B cells and presents with near absence of these cells. It is caused by a mutation in Bruton’s Tyrosine Kinase (BTK) gene although this is a spontaneous mutation in about 60% of the children.
Clinical presentation
XLA usually presents after the first 4–6 months of life, following the decline in maternal IgG. Half of children become symptomatic in the first year of life and 95% by the age of 5 years. XLA is only seen in boys although autosomal recessive agammaglobulinemia has the same clinical picture as XLA and affects both boys and girls. Patients with XLA are also found to be more frequently affected by sensorineural hearing loss and eczema and have a higher risk of malignancy compared to the unaffected population.
Susceptibility to infections is the common presentation, especially chronic sinopulmonary infections from encapsulated pyogenic bacteria. Gastroenteritis with chronic diarrhoea from salmonella and campylobacter are also seen.
Investigations
The laboratory findings include hypogammaglobulinaemia or agammaglobulinaemia, an absence, or significant reduction, of B cells and a deficient response to immunisations. There is usually an absence of the BTK protein and the diagnosis is confirmed with genetic studies.
Treatment and management
Timely diagnosis and initiation of immunoglobulin replacement is paramount in reducing the burden of infection. General supportive care with appropriate inactivated vaccines and antibiotics for acute infections is the basis of ongoing care.
Clinical Scenario
An 18-month-old boy was referred to the General Paediatric team with concerns regarding recurrent ear infections. The family reported at least 10 courses of antibiotics over the previous year, with recurrent ear discharge and tympanic membrane perforations. He had one hospital admission for chest infection which was treated with oral antibiotics and oxygen. He was fully vaccinated for his age and was the first child of healthy unrelated parents.
On examination, he did not appear dysmorphic and he had atrophic tonsils.
Initial investigations revealed normal full blood count with normal lymphocyte and neutrophil count; however, his lymphocytes subsets showed slightly elevated CD3 T cells, normal numbers NK cells and absent CD19 B cells. He had a panhypoglobulinaemia with IgG <0.5 g/l (lower normal for age 3.7 g/l), IgA and IgM undetectable. His vaccination responses to tetanus, H. influenza b and pneumococcal serotypes were very low.
The child was commenced on prophylactic antibiotics and immunoglobulin replacement with presumed diagnosis of X-linked agammaglobulinaemia. Genetic testing confirmed the diagnosis.
Common variable immunodeficiency disorder (CVID)
A heterogeneous group of conditions with a significant decrease in IgG and at least in one of the IgM or IgA classes. Diagnosis in those under 4 years is difficult to establish as the picture can be indistinguishable from Transient Hypoglobulinaemia of Infancy in this age group. Children have susceptibility to infections of the sinopulmonary tract, skin and gastrointestinal tract whilst some patients develop a coeliac-like enteropathy with villous atrophy. Patients with CVID have increased risk to develop malignancies, especially lymphomas and stomach cancers.
Treatment and management
General supportive and monitoring measures for infection prevention and treatment with immunoglobulin replacement.
Selective IgA deficiency
This is the most common primary immunodeficiency and presents with an isolated deficiency of IgA with normal levels of the other immunoglobulin subclasses. Due to physiological delay in the onset of IgA production, the diagnosis can only be made with confidence after the sixth year of life when IgA levels become stable. The T cell–mediated immunity is intact in most of the patients.
Clinical presentation
Most patients are asymptomatic and the low IgA is incidental finding, often in the process of coeliac screening.
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