Summary

Combined immunodeficiency (CID) is the name given to a group of rare, inherited disorders of the immune system. The major problem in CID is that specialised white blood cells, known as T cells, do not function properly or there are not enough of them. Antibody production is usually also impaired, which is why the term ‘combined’ is used.

T cells are essential for protection against many infections: viruses, bacteria and fungi. They are also important in controlling inflammation and preventing cancer. If T cells are completely missing then severe CID (SCID) results, producing a characteristic pattern of illness in babies.

Different types of CID are named based on the particular protein or gene that is affected or sometimes the doctor(s) who first described it. Some of the better-known types include Wiskott-Aldrich syndrome, DOCK8 deficiency and recombination-activating gene (RAG) deficiency.

The information describes some of the common clinical features of CID in children.

Not all patients are affected in the same way and sometimes the diagnosis is not made until adulthood. Treatment is now available that can reduce the risk of serious infection, manage autoimmunity or overgrowth of white blood cells and, in some cases, cure the disorder.

Continuing developments and improvements are transforming the lives of children with CID. Better diagnostic techniques and genetic technology, better treatments and better medications enable many children with CID to live healthy lives pending curative therapy, such as stem cell transplant. It is likely that new treatments, such as gene therapy, will continue to develop and become applicable to more types of CID.

Children with CID may seem well at birth and for the first few months or years of life. This is because they are partly protected by antibodies passed from mother to baby across the placenta during the last few months of pregnancy. They also have partially functional immunity of their own and may be able to respond to some extent to vaccinations and germs they encounter.

CID can affect children in many different ways. They are likely to suffer infections more frequently than other infants. Ordinary problems, such as coughs and colds, may seem more severe and last longer than would be expected, requiring repeated and prolonged courses of treatment. Skin rashes (such as eczema), a wheezy chest or breathlessness and even food allergies may be present. Sometimes children with CID may have a poor appetite, have chronic diarrhoea and fail to grow and gain weight normally, even if no definite infection is found.

CID can make it difficult for children to deal with some common viruses (for example, chickenpox and the glandular fever virus (caused by Epstein-Barr Virus (EBV)). Germs in the environment that don’t cause disease in healthy individuals can sometimes cause serious and life-threatening illness in a child with CID. In particular, Pneumocystis jirovecii, Aspergillus and Cytomegalovirus can cause severe infection (most frequently pneumonia). Cryptosporidium (sometimes found in drinking water) can cause severe diarrhoea and sometimes liver disease in children with CID. Thrush in the mouth and/or nappy area may be severe and persistent.

Apart from infections, some children with CID cannot regulate their immune system correctly. They may not be able to ‘turn down’ an immune response triggered by infection, so ending up with a vicious cycle of fever and inflammation called haemophagocytic lymphohistiocytosis (HLH). The immune system might also get turned against the child’s own body, resulting in autoimmune diseases, such as arthritis, bowel problems or a low blood count.

CID is usually an inherited condition, passed on in families in a similar way to physical characteristics, such as eye colour. It is caused by a mistake (or ‘mutation’) in a child’s genetic makeup. Immunodeficiency UK has a separate information leaflet devoted to the genetics of primary immunodeficiency.

Specialists in genetics and genetic counselling are also on hand to talk through the inheritance of CID with you if needed.

The immune system relies on a large number of genes for its normal development. In children affected by CID, a defect in one or more of these genes results in the absence or malfunction of a protein necessary for the normal functioning of the immune system. Different types of CID are named based on the particular protein or gene that is affected or sometimes the doctor(s) who first described it. Some of the better-known types include Wiskott-Aldrich syndrome, DOCK8 deficiency and recombination-activating gene (RAG) deficiency. It is helpful to know the exact cause: (a) because in some conditions there may be specific treatments available, and (b) to allow accurate genetic counselling for future pregnancies.

In the UK there are several specialist paediatric immunology centres that can diagnose and often treat CID. Care is usually shared between the specialist centre and paediatricians in the local centre and other specialities, such as gastroenterologists or lung specialists, as well as the child’s family doctor (GP).

Initial management

The immediate priorities are to treat any current infection, prevent new infections and perform appropriate tests and assessments. Other complications, such as autoimmunity, may require specific treatment. Depending on the severity and type of condition, it may be appropriate to think about treatments designed to fix the faulty immune system permanently.

Simple measures to prevent infection in more severely affected children include drinking cooled, boiled water instead of water straight from the tap. If a child with CID is exposed to chickenpox or shingles, especially for the first time, they may need an urgent injection and/or medicine to protect them, so contact your healthcare team straight away.

Vaccination

In many cases, vaccines will already have been given before the diagnosis of CID is made. Most of these are completely safe and do not cause problems. Some live vaccines might need to be avoided, particularly BCG, rotavirus, measles/ mumps/rubella (MMR) and chickenpox (VZV, not in the routine immunisation schedule in the UK, but routinely given in other countries).

Immunoglobulin (antibody) therapy

Children affected by CID often have problems producing antibodies, leaving them vulnerable to infection. This can be corrected by immunoglobulin therapy, made from a solution of human antibodies. Further information about immunoglobulin treatment can be found in a range of our leaflets.

Repeated chest infections, often before the diagnosis of CID is made, can lead to scarring and widening of the airways (bronchiectasis). In this situation, children usually benefit from regular physiotherapy. This helps to clear secretions and prevent infection from taking hold. Expert physiotherapists can often teach parents to do this and older children can do physiotherapy for themselves.

Depending on the particular problems in individual children, other treatments may also be needed. These will be discussed in detail with your immunology doctors and nurses.

A new diagnosis of CID can be worrying. Anxiety about catching or passing on an infection can make life very stressful. The hospital team, nurses and support groups will provide families with guidance on protecting the child from infection, keeping the house clean and coping with diet and medication. Parents are always able to ring the hospital and speak to an immunologist or a nurse if they are worried at any time.

Genetic counselling

In many cases, the genetic cause of CID can now be identified. This means that accurate genetic counselling is available for the immediate and extended family and that prenatal diagnosis, or even pre-implantation diagnosis in highly selected cases, is possible for future pregnancies.

Haematopoietic stem cell transplantation

In some cases, haematopoietic stem cell transplant (HSCT) (including bone marrow transplant, BMT) offers the potential for a long-term cure of CID. This treatment is most well-established for defined types of CID that are known to be life-limiting because of predictably severe complications.

HSCT aims to replace the faulty immune system with an immune system from a healthy donor. Stem cells, from which all the cells of the immune system develop, can be obtained from healthy bone marrow, or in some cases from umbilical cord blood or donor blood.

The healthy stem cells can be given by transfusion into a vein to a child with CID.

HSCT is not an operation like a heart or kidney transplant. Stem cells contained in the donor bone marrow are able to find their way from the bloodstream to the child’s bone marrow, where they start to produce healthy blood cells. HSCT does involve a number of risks, and complications can arise afterwards – some of which are temporary, others of which can be life-threatening. Further information about HSCT/BMT will be provided by the BMT centre, and families will have the opportunity to discuss their concerns in detail with an immunologist and BMT
consultant on several occasions.

Gene therapy

Gene therapy aims to correct the underlying genetic abnormality by replacing the faulty gene in immune cells with a normal copy. It is currently undergoing clinical trials in selected patients who have certain specific conditions.

Thymic transplantation

Rarely, CID happens not because of a problem with the T cells themselves but because of missing or faulty tissue in an organ called the thymus, where T cells develop. The most common condition affecting thymus development is called 22q11 deletion syndrome (also known as DiGeorge syndrome). In the small fraction (<1%) of DiGeorge patients whose thymus is completely missing, thymic transplant may need to be considered. This treatment is available at Great Ormond Street Hospital in the UK and at Duke University Medical Center in USA. Further information about 22q11 deletion syndrome is available from the support organisation Max Appeal!

What does this mean for the future?

Continuing developments and improvements are transforming the lives of children with CID. Better diagnostic techniques and genetic technology, better treatments and better medications enable many children with CID to live healthy lives pending curative therapy, such as stem cell transplant. It is likely that new treatments, such as gene therapy, will continue to develop and become applicable to more types of CID.

You can download our information booklet here.