Immunodeficiency (Primary and Secondary)

Primary immunodeficiency syndromes

• Mostly these are inherited single-gene disorders that present in infancy in early childhood with the exception of common variable immunodeficiency which usually occurs in adults.¹
• Mutations/deletions of genes governing stem cell differentiation have been identified and over 150 disorders have been identified.²
• They are sometimes classified according to which component is faulty (T cells, B cells, phagocytic cells or complement) or according to individual clinical syndromes.
• The overall incidence of symptomatic primary immunodeficiency is estimated to be 1/10,000.³
• About 80% of patients are less than 20 years old when diagnosed, because the majority of cases are inherited or congenital. 70% occur in males due to X-linked inheritance in many syndromes.
• B-cell defects account for 50% of primary immunodeficiency,
• T-cell defects for 30%, phagocytic deficiencies 18% and complement deficiencies 2%. Knowledge about the function and diversity of B-cells in health and disease has now become quite detailed but there is still much to learn.⁴

One study found that the four commonest primary immunodeficiencies seen in paediatric practice apart from physiologic hypogammaglobulinaemia of infancy, were transient hypogammaglobulinaemia of infancy (THI), IgG subclass deficiency, partial antibody deficiency with impaired polysaccharide responsiveness (IPR) and selective IgA deficiency IgAD.⁵

• Antibody deficiency syndromes: this is a group of conditions characterised by an inability to produce antibodies in sufficient quantity or of sufficient quality.⁶
  • Common variable immunodeficiency: this is a heterogenous syndrome characterised by various degrees of hypogammaglobulinaemia, commonly associated with autoimmunity.⁷ The genetic mutations which cause this condition have been identified in some patients in considerable detail.⁸ Gender-associated differences in some types of B cells have been noted.⁹ Flow cytometry (a method of counting, examining, and sorting microscopic particles suspended in a stream of fluid)¹⁰ has been helpful in identifying sub-groups and as a screening technique for mutations.¹¹
  • Thymoma and hypogammaglobulinaemia: this is characterised by low numbers of B cells and a distinctive type of T cells.¹²
  • X-linked (Bruton's agammoglobulinaemia): the agammaglobulinaemia is an X-linked immunodeficiency in which there is a failure to produce mature B lymphocyte cells. The defect in this disorder is a fault in the enzyme in Bruton tyrosine kinase, a key regulator in B-cell development.¹³ Novel genetic defects have been found.¹⁴
  • Selective IgA deficiency: occurs in about 1/400 people.¹⁵ There is a selective severe deficiency or total absence of IgA in serum and body secretions.¹⁶
• Major defects in cellular immunity: cell-mediated immunity can be subject to a number of genetic defects affecting the function of the T-cells.¹⁷
  • Thymic aplasia (Di George syndrome): there are genetic defects of the thymus and often the parathyroid glands and heart, associated with T-cell dysfunction and significant immune deficiency.¹⁸
  • Severe combined immunodeficiency disease: this is in fact a group of rare congenital diseases in which there is severe and usually fatal immune deficiency. It has gained the attention of the media in the past and has been known as 'bubble boy disease'.¹⁹
  • Inherited syndromes associated with immunodeficiency: a wide range of inherited immunodeficiency conditions has been identified, many involving a single gene.²⁰

Secondary immunodeficiencies

Due to the eclectic list of causes, it is difficult if not impossible to obtain exact epidemiological data encompassing all secondary immunodeficiency. It is known that the two current epidemics of AIDs and tuberculosis have caused global increases in the condition per se. Secondary immunodeficiency is also common in people who are hospitalised for various diseases.¹⁵

• Lymphoreticular malignancy: chronic lymphatic leukaemia and myeloma are both associated with hypogammaglobulinaemia. it also occurs in patients treated for leukaemia with bone marrow transplants.
• Drugs: these particularly include cytotoxic drugs and immunosuppressants including steroids.
• Viruses: HIV affects T-cells. Other viral diseases, such as congenital rubella infection and cytomegalovirus, can affect antibody production.³
• Nutritional: the commonest cause worldwide is protein-calorie malnutrition and deficiencies of vitamins and trace elements, particularly vitamin A, zinc and selenium.
• Metabolic: prolonged metabolic disorders associated with liver and kidney failure compromise immunity (this occurs in 10% of patients on continuous ambulatory peritoneal dialysis).
• Trauma: some degree of immunodeficiency may be seen following major surgery or severe trauma.
• Protein Loss: loss of immunoglobulin can result from a number of conditions including nephrotic syndrome, protein-losing enteropathy and intestinal lymphangiectasia.

• The commonest presenting feature and the one which usually raises the possibility of immunodeficiency is frequent infections. Recurrent respiratory infections are common, but this is by no means pathognomonic as every GP will be aware of the 'sickly child' who seems to acquire infections from his or her siblings frequently.
• The development of severe, persistent recurrent bacterial infection is a better pointer. A common scenario is repeated episodes of sore throat or upper respiratory tract infection which lead to sinusitis, chronic otitis and bronchitis. Another feature is the ease with which complications develop. For example, bronchitis progresses to pneumonia, bronchiectasis and respiratory failure.
• Opportunistic infections are common, such as Pneumocystis jiroveci (carinii) or cytomegalovirus, especially in patients with T-cell deficiencies. Infection of the skin and mucous membranes occur frequently, including resistant thrush, oral ulcers and periodontitis. Conjunctivitis, pyoderma, severe warts, alopecia, eczema and telangiectasia are also prominent features.
• Common gastrointestinal symptoms include diarrhoea, malabsorption and failure to thrive. The diarrhoea is usually noninfectious, although a range of organisms, including rotavirus, Giardia lamblia, rotavirus, Cryptosporidium spp and cytomegalovirus may be involved.
• Less commonly, haematological abnormalities such as autoimmune haemolytic anaemia, leucopenia, or thrombocytopenia can occur.
• Neurological problems such as seizures and encephalitis and autoimmune conditions such as vasculitis and arthritis are also sometimes seen. There is also a higher incidence of gastric carcinoma and liver disease.
• Paradoxically, autoimmune diseases can be associated with primary immunodeficiencies.²¹

History¹⁵

• If the condition is suspected a family history should be sought. There may be a familial tendency to early death, similar disease, autoimmunity, allergy, early malignancy or intermarriage.
• A history of adverse reactions to immunisations or complications of viral infections may be signficant.
• Enquiry should be made about the frequency of previous antibiotic prescriptions and any history of relevant surgery (e.g. splenectomy, tonsillectomy, adenoidectomy).
• A history of radiation therapy to the thymus or nasopharynx may also be a pointer to the diagnosis.

Examination

• Patients with immunodeficiency often look ill on presentation, with pale skin, general malaise, cachexia and a distended abdomen. Various skin manifestations may be apparent such as rashes, vesicles, pyoderma, eczema and telangectasia.
• The eyes may be inflamed and infected.
• Signs of chronic ENT disease, such as scarred eardrums, encrusted nostrils and postnasal drip may be evident.
• There may be a chronic cough with crepitations in both lungs.
• Hepatomegaly and splenomegaly may be detected in the abdomen.
• In infants, crusting around the anus may be a sign of chronic diarrhoea. Delayed developmental milestones or ataxia may be evident.

• Specialist tests are often required to elucidate the exact diagnosis, but screening tests can be done in primary care. These should include full blood count, IgG, IgM and IgA levels and tests to confirm the presence and type of any infection. A systematic review called for screening in patients with recurrent infections, irrespective of age.²²
• An elevated ESR is a pointer to chronic infection,and chest and sinus X-rays may confirm the source.
• Appropriate microbiological swabs should be taken, as dictated by the clinical picture.
• More advanced investigations might include assays of lymphocyte response, antibody response to immunisation of diphtheria, tetanus and pneumococcus polysaccharides, phagocytosis assay and quantitation of individual complement components.³

• General measures include making sure that patients have a healthy lifestyle and are protected as far as possible from infection. This includes having regular dental checks and their own accommodation. There may be an element of social isolation and psychological issues may need to be addressed.
• If there is any evidence of antibody response, the standard regime of killed vaccines should be given. Live vaccines are contraindicated in T-cell deficiency.
• Bacterial and fungal infection should be recognised and treated early. Swabs should be taken before treatment so that empirical treatment failures can be rectified rapidly. Continuous prophylactic antibiotics may be appropriate in some circumstances. Chest infections may require physiotherapy and lung exercises.
• Antiviral therapies such as amantidine and ramantadine may be life-saving in the management of viral infections.
• Intravenous or subcutaneous immunoglobulin replacement is the first-line treatment for most immunoglobulin deficiency states.^23,24 Subcutaneous therapy is preferred by many patients because it is more convenient and they can be more independent.²⁵ Immunoglobulin replacement is contraindicated in selective IgA deficiency as serious anaphylactic reactions can be caused. Fortunately, selective IgA deficiency is a relatively mild disease and usually responds to general support measures and appropriate treatment of infections.
• The best treatment for T-cell deficiency conditions is bone marrow transplant, if a donor can be found.
• Other treatment options, some of which are still in the experimental phase, include cytokines (e.g. interferon-alpha²⁶), thymic transplants,²⁷ gene therapy,²⁸ and stem cell transplantation.²⁹

Most primary immunodeficiencies are genetic in origin and therefore lifelong. Some conditions such as selective IgA deficiency have a good prognosis. Many patients have a normal lifespan, especially if the condition is diagnosed early and infections are treated regularly.²² The prognosis in other conditions such as severe combined immunodeficiency is less optimistic. Many patients suffer from chronic illness and require intensive treatment.

The prognosis in secondary immune deficiency depends on the underlying cause. Many conditions secondary to acute disease resolve when the underlying pathology is treated. Even in chronic disease, the prognosis has improved with robust and early treatment of bacterial infection and advances in antiviral therapy such as highly active antiretroviral therapy (HAART) in AIDS.³⁰

Prevention of primary immunodeficiency depends on the identification and genetic counselling of likely carriers in families with a positive history.¹⁵ Prenatal diagnosis using such techniques as cultured amniotic cells or foetal blood may be possible for some disorders such as severe combined immunodeficiency. X-linked disorders may be excluded by sex determination.³¹ Few large random controlled trials exist and international pooling of information is required to identify areas for future research.²²