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:
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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.
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.
Treatment and management
There is no need for specific treatment for asymptomatic children but some patients may need prophylactic antibiotics if they experience recurrent infections. A proportion of children will develop Common Variable Immunodeficiency Disorder and therefore long-term follow up maybe appropriate.
Specific antibody deficiency (SPAD)
A condition that is identified when there is inadequate response to polysaccharide antigens in a patient with normal immunoglobulin levels, IgG subclasses and responses to protein antigens. In young children, an inadequate response to polysaccharide stimuli is physiological and improves with age as the immune system matures. Recurrent or severe rhinosinusitis and bronchopulmonary infections due to Streptococcus pneumoniae, Haemophilus influenzae and others are the main findings at presentation.
Transient hypogammaglobulinemia of infancy (THI)
IgG is actively transported across the placenta and the term newborn infant is protected by the maternal IgG for the first few months of life. These antibodies break down and are undetectable from 6–9 months. As the child’s own immunoglobulin production starts slowly, there is a physiological nadir at around 4–6 months of age and during this period, the bacterial infection risk increases. Eventually immunoglobulin levels increase and IgM is the first major class to reach adult levels, followed by IgG and then IgA during puberty. THI is common and has an incidence of around 1 in 100 births. It is a clinical diagnosis usually given retrospectively in a child with:
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persistently low immunoglobulin levels
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no evidence of other primary immunodeficiency
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normalisation of immunoglobulin levels by 2 years
Prophylactic antibiotics may be required, and immunoglobulin replacement is reserved for children presenting with significant infections.
Secondary antibody deficiencies
Low levels of immunoglobulins can be the result of other, nonimmune conditions. These may need to be considered and excluded in some children presenting with recurrent infections. The conditions include:
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excessive protein losses (nephrotic syndrome, inflammatory bowel disease, extensive burns)
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medication—carbamazepine, phenytoin, valproic acid, corticosteroids
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chronic infections—HIV, congenital CMV, rubella, EBV
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malignancies—lymphoma
Combined immunodeficiencies
This is a diverse group of conditions leading to a spectrum of severity in presentations, ranging from increased susceptibility to opportunistic infections from the first months of life through to less severe infections in later childhood. Those with the condition are also at risk of autoimmune disease and malignant disease. Examples of these conditions include:
Severe combined immunodeficiency (SCID)
Maternal antibodies passed through the placenta and offer some protection initially, but as levels fall, infections develop and the infant usually presents within the first 6 months of life with:
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persistent mucocutaneous candidiasis
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opportunistic and viral infections
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chronic diarrhoea
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growth retardation
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lack a thymic shadow on CXR
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absent peripheral lymphoid tissue
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lymphopenia
Symptomatic vaccine-strain rotavirus infection is common in babies who are later diagnosed with SCID.
Management
Infection prevention measures must be started with some urgency if a diagnosis of SCID is considered. Placing the baby in protective isolation and commencing prophylactic antimicrobial agents are paramount. Pneumocystis prophylaxis and antifungal medication are used in all patients whilst passive immunity is offered with immunoglobulin replacement therapy. Urgent referral to regional bone marrow transplant centre is required.
All live vaccines are contraindicated and the inactivated vaccines are unlikely to be effective but safe to give. Household contacts need to be up to date with all the inactivated immunisations and live vaccinations are strictly avoided in all close contacts.
Caution is required if blood, platelet or plasma transfusions are needed. Only CMV negative and leuco-depleted irradiated products can be used. Haemopoietic stem cell transplantation is curative although it has an associated morbidity and risk of mortality.
From September 2021, a pilot newborn screening program for SCID will be introduced into UK clinical practice. The dried blood spot will be used to measure small circular DNA pieces (TRECs) formed during T cell development. Absent or very low TRECs suggest a SCID-like condition and appropriate measures would need to be instigated until the diagnosis is confirmed.
Combined immunodeficiencies
A heterogenous group of very rare conditions which present with SCID-like infections and a predisposition to malignant and autoimmune disease. A variety of syndromes are also associated with combined immunodeficiency and these include Wiskott-Aldrich syndrome, ataxia telangiectasia and chromosome 22q11.2 deletion (Di George syndrome, velo-cardio-facial syndrome).
Combined immunodeficiencies with syndromic features
Wiskott-Aldrich syndrome is X-linked recessive and presents with bleeding of varying severity due to thrombocytopenia, eczema and combined immunodeficiency with sinopulmonary and skin infections. Investigations demonstrate low platelets, T cell lymphocytopenia with normal IgG and low IgM values. Treatment is initially supportive but stem cell transplant can be curative. Children should have irradiated and CMV negative transfusions.
Ataxia telangiectasia is autosomal recessive and usually presents with progressive neurological features, particularly ataxia. Telangiectases can be seen in the bulbar conjunctiva and skin. There may be a history of recurrent infections particularly sinopulmonary infections. Immunological investigations commonly show lymphopenia, reduced IgA levels and raised alpha-fetoprotein. The treatment is supportive with some patients requiring prophylactic antibiotics or immunoglobulin replacement therapy
Chromosome 22q11.2 deletion (Di George syndrome, Velo-Cardio-Facial Syndrome) leads to a variable T cell lymphopenia due to the absence of a thymus. In complete Di George syndrome, the immune deficiency is comparable to that of SCID and can be managed with thymic transplantation. Treatment of milder presentations of immunodeficiency is supportive. Other aspects of management are to be found in Chapter 25 Endocrinology and Chapter 27 Neurodevelopmental Medicine.
Complement deficiencies
These are rare inherited disorders where the child is at risk of encapsulated bacterial infections and may also develop some types of autoimmune disease such as SLE. Those patients with an increased susceptibility to infections are managed with antimicrobials and additional vaccinations.
Abnormalities of neutrophil function
Congenital neutropenia
A neutropenia of less than 0.5 x 10 9 /l that persists for over 3 months is diagnostic of congenital neutropenia if other causes for secondary neutropenia have been excluded. The infections present early, in the first year of life, affecting skin, GI mucosa and respiratory tract. Examples of the various types of congenital neutropenia include:
Severe congenital neutropenia (SCN)
Presentation of SCN is with severe pyogenic infections, usually within the first few months of life along with severe neutropenia, mild anaemia and hypergammaglobulinaemia. The prognosis, however, has improved significantly following the introduction of G-CSF therapy. SCN predisposes to myelodysplastic syndrome and acute myeloid leukaemia.
Cyclical neutropenia
In this condition, the neutropenia lasts for 3 to 6 days, every 21 days and the affected child usually presents in the first year of life with recurrent infections, fever, recurrent malaise and stomatitis. Bacterial causes may not always be identified. Cyclical neutropenia is not associated with increased risk of blood dyscrasias.
Schwachman-Diamond syndrome (SDS)
The condition is inherited as an autosomal recessive disorder that affects both the number and the movement of neutrophils into inflammatory sites. Presentation includes:
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diarrhoea and growth retardation
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bone marrow failure—intermittent neutropenia, anaemia, thrombocytopenia
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steatorrhea due to exocrine pancreatic insufficiency
Full blood count, bone marrow aspirate and faecal elastase would support the diagnosis and genetic testing would identify the specific gene defects. Supportive measures and G-CSF significantly reduces the infection burden whilst a bone marrow transplant may be considered in children who are severely affected. Pancreatic enzyme replacement and fat-soluble vitamin supplementation are usually required.
Chronic granulomatous disease (CGD)
CGD results from defects in phagocytes, and in those with a positive family history the condition invariably follows an X-linked pattern of inheritance. It usually presents in early childhood, before the age of five years with a susceptibility to bacterial and fungal infections, growth retardation and impaired wound healing. It should be considered and excluded in young children who present with inflammatory bowel disease. The affected individuals have normal responses to virus infections. Neutrophil function testing (currently DHR assay is preferred) is undertaken and those with a positive result require specific genetic test to confirm the diagnosis. Current treatment includes lifestyle advice on how to avoid fungal spores and antibiotic and antifungal prophylaxis and this has led to a marked improvement in prognosis. Bone marrow transplantation may be considered and is curative and has high success rates.
Autoimmune disorders
These conditions have a common aetiology and develop when the immune system of the individual is directed at host tissue. The target of the immune attack is usually very specific but the consequences of the tissue injury will be widespread. Coeliac disease, diabetes mellitus type 1 and Addison disease are all examples of autoimmune disease with specific tissue destruction and a systemic impact. Autoimmune conditions have identifiable abnormalities of the immune response to host antigens and the process includes abnormalities of T- and B-cell function ( Table 15.1 ).
