This information from Great Ormond Street Hospital (GOSH) explains severe combined immunodeficiency or SCID. SCID is the name given to a group of rare inherited disorders which cause severe abnormalities of the immune system.
This happens when white blood cells, responsible for fighting infection, are missing or working poorly. Their absence or poor function results in serious and often life threatening infections.
Three types of white blood cell can be affected: T and B lymphocytes and natural killer (NK) cells. Not all cases of SCID are identical but all children with SCID have poorly working immune systems and will need protection from infection.
The first case of SCID was reported in 1950 and, following a number of isolated reports of affected children, the term SCID was introduced to describe the syndrome.
Before the advent of modern medication and treatment, most affected babies did not survive beyond their first year. Today doctors understand much more about SCID. Treatment is now available that can reduce the risk of serious infection, and in many cases, cure the disorder.
Blood cells and immunity
Just under half of the volume of blood consists of blood cells which are tiny and can only be seen through a microscope. The rest of the blood volume is plasma, a watery liquid which contains dissolved proteins, sugars, fats, salts and minerals.
There are three main types of cells in the blood: red blood cells, white blood cells and platelets.
It is the white blood cells that play an important role in defending the body against infection. All blood cells are derived from immature cells known as stem cells, sometimes referred to as "mother cells". Some stem cells can be found in the blood, but the richest supply is found in the bone marrow.
The following diagram shows which blood cells are affected in SCID.
Stem cells are cells that are capable of giving rise to all blood cells.
Red blood cells are also known as erythrocytes or red blood corpuscles. They contain haemoglobin which transports oxygen to all parts of the body.
Platelets or thrombocytes play a vital role in blood clotting or coagulation. Low levels of platelets may cause bleeding that is difficult to control.
White blood cells or leukocytes protect the body against infection and fight it when it occurs. There are three main types of white blood cell: granulocytes, monocytes and lymphocytes.
Granulocytes: the most common granulocytes are called neutrophils. They are responsible for isolating and destroying invading bacteria, literally 'swallowing' bacteria. For this reason they are known as phagocytes. Other granulocytes are eosinophils and basophils and play a part in allergic reactions.
Monocytes: these play a role in protecting against certain infections such as fungal infection and tuberculosis (TB) and in cleaning up debris from sites of infection or injury. They can leave the blood stream and are then referred to as tissue macrophages.
Lymphocytes: these play a central role in the immune system.
There are several different types of lymphocytes and these are the blood cells specifically affected in SCID:
- B Cells sometimes referred to as B lymphocytes, recognise and attack germs or foreign attackers. They produce specific antibodies that fight a specific invader. These antibodies are sometimes referred to as gammaglobulins or Immunoglobulins. These work by recognising and binding to infecting organisms, 'marking' them for destruction by other cells in the immune system. There are five main types of antibodies: IgA, IgD, IgE, IgG and IgM, of which IgA, IgG and IgM are the most common.
- T Cells also known as T lymphocytes, also recognise and attack specific germs or foreign attackers. They play an important role in co-ordinating the immune defences and kill organisms by secreting toxic chemicals called lymphokines. T cells are especially important for killing viruses.
- NK Cells or Natural Killer cells are able to kill cells directly. They kill a variety of target cells (such as tumour cells, virus infected cells, transplanted cells).
What causes SCID?
SCID is caused by a defect or mutation in a child's genetic make-up.
It is an inherited condition – passed on in families in the same way as physical characteristics are passed from parent to child.
In the centre of every cell in the body there are 46 string-like structures known as chromosomes. The chromosomes are arranged into 23 matching pairs. For ease of identification the chromosome pairs are numbered according to size from one to 23.
The last pair – number 23 – are the sex chromosomes which determine whether a child is male or female.
Each pair of chromosomes is like a double string of thousands of beads. Each bead is a gene. Each gene is responsible for a certain characteristic (hair colour for instance).
Scientists know that each gene is responsible for producing a particular protein many of which are necessary for the development of a normal immune system.
A defect in one of these genes results in absence of the protein that is necessary for a functioning immune system. There are a number of different genes that can be affected, each causing a different type of SCID.
These important findings now enable doctors to make a much more specific diagnosis
The names given to the different types of SCID are based on the particular protein or gene that is deficient – for example gamma chain deficiency, JAK 3 kinase deficiency, purine nucleoside phosphorylase (PNP) deficiency, adenosine deaminase (ADA) deficiency, MHC class II deficiency or recombinase activating gene (RAG) deficiency.
How is SCID inherited?
There are two main ways in which SCID can be inherited. These are autosomal recessive type inheritance and X-Linked inheritance.
Autosomal Recessive Type Inheritance
Everyone is a carrier of around three to five different genetic disorders. In most cases a person never knows about them because the fault lies in one gene of one chromosome and the other healthy half of the pair switches on to compensate for the faulty one.
A problem only arises if a person’s partner carries the same faulty gene as they do, and their child inherits both faulty chromosomes.
If coincidentally both parents carry the same faulty gene, there is a 25 per cent chance of the child inheriting the two affected copies (and therefore developing SCID), a 25 per cent chance of inheriting the two unaffected copies (in which case there are no problems) and a 50 per cent chance of inheriting one faulty gene from either one of the parents - making the child a carrier.
Because undetected gene mistakes may be found in several family members, autosomal recessive inheritance is most common in children whose parents are related to each other.
Approximately 60 per cent of all cases of SCID are inherited in this way.
In X-Linked SCID (otherwise known as gamma chain deficiency) the faulty gene is carried on the X chromosome (one of the sex chromosomes).
Females have two X chromosomes, men have one X and one Y. A mother will pass on one of her X chromosomes to the baby while a father will pass on either an X or Y chromosome determining the sex of the child.
If the mother has an affected gene on one of her X chromosomes there is a 50 per cent chance that her child will inherit the affected one, and a 50 per cent chance of inheriting the unaffected one.
If the affected gene is inherited and the child is a girl, the father's healthy X chromosome will compensate for the affected one passed on by her mother and the girl will be a carrier.
If the child is a boy, the father will have passed on his Y chromosome which is not able to compensate for the affected X chromosome and the child will have SCID. This means only boys will inherit X-Linked SCID, girls can only be carriers.
If a mother carries the affected gene for X-Linked SCID, there is a 25 per cent chance of having either: an unaffected boy; an affected boy; an unaffected girl or a carrier girl (see diagram below). Approximately 40 per cent of all cases of SCID are thought to be caused in this way.
Figure 1: Autosomal Recessive Inheritance
Figure 2: X-Linked Inheritance
What are the signs and symptoms of SCID?
Sometimes, babies seem well at birth and for the following weeks. This is probably because they are partly protected by antibodies passed from mother to baby across the placenta during the last few months of pregnancy.
The first signs of SCID generally occur within the first three to six months.
As the baby's immune system is not working properly, they will become highly susceptible to infection.
The baby may suffer infections more frequently than other children – run of the mill problems such as coughs and colds will seem more severe and last longer than would usually be expected, requiring repeated and prolonged courses of treatment.
The more common childhood infections such as thrush (candida), chicken pox (varicella), measles virus (rubella) and cold sore virus (herpes simplex) can also be dangerous for a baby with SCID and may even be life threatening.
Germs in the environment which children are often exposed to, but do not cause disease if the immune system is healthy, can be devastating for a child with SCID.
In particular pneumocystis carinii (PCP), aspergillus, cytomegalovirus and cryptosporidium are examples of infections that can cause severe pneumonia, liver disease and severe diarrhoea in children with SCID.
As a result of repeated infections, the baby may not feed well and may not gain weight as fast as expected.
Many infants with SCID suffer from chronic diarrhoea even when an infection cannot be identified, and this also contributes to poor weight gain.
Skin rashes are common, and may be caused by candida infection (thrush), or sometimes by a reaction in the skin caused by maternal blood cells which have crossed the placenta at birth.
How SCID normally diagnosed?
Before parents know their baby has SCID they many seek help from their GP because of repeated infections, poor weight gain or feeding problems.
If parents or the GP are worried about a possible problem, the doctor usually makes a referral to a local paediatrician.
Sometimes the first indication that something is wrong can be a serious life threatening infection which causes a rapid deterioration in the baby’s condition.
It may be necessary for the baby to be admitted to an intensive care unit for emergency treatment. During the course of routine investigations, SCID may be suspected.
Depending on the type of SCID, it may be possible to diagnose or at least suspect the disorder by performing a simple blood test known as a full blood count. However, it will be necessary to perform more specialised immune blood tests to confirm this.
Once SCID is suspected, the child will be referred to a specialist centre.
How is SCID initially treated?
There are two specialist centres in the country that treat children with SCID - GOSH and at Great North Children’s Hospital in Newcastle. Treatment will begin when the child is referred to one of these centres.
The immediate priorities will be to provide an environment which protects from infection, the appropriate tests and assessments made and initial treatment given.
The child will normally be admitted to a room or an area with ‘filtered air’ (to remove germs). The child will usually be restricted to this room and will not be able to mix with other children or go to the playroom. This can be one of the most difficult aspects of SCID. No baby likes to be separated from those closest to them. Parents will be able to stay with the baby and will be encouraged to continue to feed, care for and play with them as much as they want.
Parents will be told about the ways that they can avoid passing on infection, such as washing hands thoroughly. It may be necessary to keep visitors to a minimum. Soon after admission it will be necessary to perform further blood tests to confirm the diagnosis of SCID.
It is possible to examine all the different blood cells and determine which cells are missing or working poorly. More specialised tests will be carried out to determine the precise genetic abnormality. A range of investigations will be necessary to see if the baby has any undetected infection and will include chest x-rays, scans and samples of blood, urine, faeces, and mucous from the throat.
Most children with SCID will have similar symptoms and will receive the same treatments whatever the type of SCID. If the child is having many blood tests and needs a number of intravenous medications, or intravenous nutrition, it is usual to put in a central line (sometimes called a central venous catheter). This is a latex tube which is put into a large vein and fixed to the skin surface usually on the chest, under general anaesthetic. It requires a small operation to put it in, but it allows blood to be taken and medicine to be given without the need for any needles.
The child will need antibiotics, anti-viral and anti-fungal medicines to protect against serious infection. Most medicines can be given in the form of syrups. If the baby has an infection it may be necessary to give the medicines into a vein, through a drip.
Immunoglobulin (antibody) therapy
The child will not be able to produce enough natural antibody to fight infection. It is possible to replace some of the missing antibody by giving treatment with immunoglobulin.
Immunoglobulin is a solution of purified human antibodies which have been removed from normal blood donations. It provides temporary protection against infection and it is given either intravenously (into a vein) or subcutaneously (injection into the skin). The child will receive regular immunoglobulin therapy from the time of diagnosis up until approximately six months after a bone marrow transplant. Because it is derived from donor blood, giving immunoglobulin carries a small risk of transmitting viruses. Parents will have the chance to discuss immunoglobulin therapy in more detail and the method by which it will be given with the immunologist or nurse specialist caring for the child before treatment starts.
The child may need blood, platelet or plasma transfusions. It is important that these treatments are given, but precautions need to be taken first. If the child needs a transfusion, they will receive specially prepared ‘irradiated’ blood. Irradiating donor blood preserves the red blood cells and platelets but removes any immune cells which may cause a bad reaction. The donor blood will also be screened to ensure it does not contain a virus called cytomegalovirus (CMV) - which could cause problems for a child with SCID. The child’s blood, platelet or plasma transfusion will be labelled “CMV negative” and “irradiated”.
CMV and breast feeding
CMV is a very common virus in the general population with approximately 50 to 80 per cent of adults in the UK being positive for the virus. It is spread through bodily fluids such as saliva, urine and breast milk. In most cases CMV doesn’t cause any symptoms, but if you do experience symptoms they are similar to flu like symptoms which includes high temperature, sore throat and swollen glands.
Once you have had CMV, the virus stays in your body but is inactive and doesn’t cause any further problems. CMV can be serious for infants with SCID and antiviral medications are used to treat the infection. If a mother is breast feeding a child with SCID, a blood test will be taken from the mother to see if she is CMV positive as we know the virus can be transmitted in the breast milk. During this time, we will support mothers to express their milk until we have the blood test result, which normally takes 24 to 48 hours. Unfortunately, if the result is positive we advise against breastfeeding due to the risk of transmitting CMV to the baby. We recommend the baby commences formula milk feeds.
It is possible that despite all efforts to maintain sufficient feeding, a baby may need some extra calories, vitamins and minerals. These can be given in special drinks or medicines. If the baby has difficulty taking enough feed they may need to be given extra feeds through a naso-gastric tube (a tube inserted into the stomach through the nose). If the baby is still not tolerating feeds it may be necessary to give feeding called TPN (total parenteral nutrition), in which all the nutrients and calories are given intravenously, directly through a drip into a vein.
Repeated hospitalisation, separation from extended family, blood tests and uncomfortable procedures will contribute to a great deal of stress and anxiety and even guilt for parents of a child with SCID. Ask about support groups and counselling services. As part of the hospital’s regular care for families there is a team psychologist and team social worker who can offer help with particular problems.
It may be possible for the child to go home for a period of time before they need further treatment. The ward staff will contact local doctors and community nurses beforehand to make arrangements if any particular treatments need to be given. Parents are always able to ring the hospital and speak to an immunologist or a nurse if they are worried at any time.
Most parents are delighted to get home, but it can be a worrying time. Anxiety about catching or passing on an infection can make life very stressful. The hospital team, nurses and support groups can provide families with all the information they need to protect the child from infection, keep the house clean and cope with a child’s diet and medication.
Babies with SCID also have to avoid some vaccinations which may be dangerous. A child should not have live vaccines such as polio vaccination, measles mumps and rubella (MMR) or BCG. Children vaccinated in the UK now receive killed polio vaccine, so this should not be a problem but if your child or another family member has received live polio vaccine due to vaccination in another country, then the doctors should be made aware.
The child will be receiving regular immunoglobulin treatment and this will provide protection against a number of germs including diphtheria, pertussis and tetanus (DPT). The normal triple vaccination programme is therefore unnecessary while the child receives regular immunoglobulin therapy.
What happens next in the treatment of SCID?
Bone Marrow Transplant (BMT) offers the only long-term ‘cure’ for SCID at present. The aim is to replace the faulty immune system with an immune system from a healthy donor. Healthy bone marrow is rich in stem cells, from which all the cells of the immune system develop, and it is possible to take bone marrow from a healthy individual and give it by transfusion into the child with SCID.
A BMT 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. A BMT does involve a number of risks, and complications can arise - some of which are temporary, others of which can be life-threatening. Parents will have the opportunity to discuss this in detail with an immunologist and BMT consultant on a number of occasions.
Early during the child’s stay in hospital, blood will be collected from members of the family to determine the tissue type of each of member. If a family member is found to have an identical tissue type to the affected baby, they will be selected to be the bone marrow donor. If there is no suitable family donor, an unrelated donor will be sought from the world-wide donor panels.
Donating bone marrow involves having a general anaesthetic but it is a relatively minor procedure, involving minimal risk to the donor. Before the BMT can be arranged the donor will meet members of the transplant team who will ensure that they have ample opportunity to see the BMT unit, discuss worries and to ask questions. The BMT will usually be carried out in a room on the BMT unit and the donor will be admitted a few days before the chemotherapy drugs are given.
It is usually necessary for the affected child to have chemotherapy drugs to prepare the body to receive a new immune system. Chemotherapy is given to reduce the chance of rejection of the new bone marrow by the child’s own immune cells. If a perfectly matched bone marrow donor has been found within the immediate family then chemotherapy is not always necessary. In most other circumstances, some form of chemotherapy will be given.. Not all children will receive exactly the same drug combinations. There are a number of side effects related to chemotherapy.
Now, more than ever, developments and improvements are being made that are transforming life for children with SCID. Better diagnostic techniques and genetic technology, better treatments and better medications enable children with SCID to proceed through bone marrow transplant safely. The future too holds some exciting developments.
Gene therapy is currently undergoing clinical trials in selected patients and has been successful in correcting or ‘curing’ a small number of children affected by X-linked SCID and the ADA form of SCID. It may also be available soon for some other genetic forms of SCID. Gene therapy aims to correct the underlying genetic abnormality causing SCID. For the child, gene therapy is a relatively straightforward procedure and if successful would offer a cure.
The process being tested involves taking stem cells from an affected child’s blood or bone marrow and then, under laboratory conditions, manipulating and correcting these cells using complex gene technology. Once corrected, the cells are returned a few days later by transfusion into the child. As in a bone marrow transplant, these new stem cells find their way to the bone marrow where they start to produce healthy immune cells. This is known as somatic gene therapy – altered genetic material is only present in the child’s own immune cells and cannot be passed on to offspring.
People worry about the idea of gene therapy because of the possibilities of eugenics (generating an improved population through selection of its best characteristics for breeding). Manipulating genes that can be passed on to offspring is known as germ line gene therapy and is not permitted by law. If there is a family history of SCID, it may be possible to offer genetic counselling and pre-natal diagnosis for future pregnancies.
Newborn screening for SCID
Typically, infants with SCID who do not have a positive family history are only diagnosed after problems with serious infection occur. Early diagnosis of SCID has been shown to significantly improve survival (over 90 per cent). This is because infants can be started on preventative medications and measures are taken to protect infants from developing serious infections from birth. While much work is being undertaken towards introducing newborn screening for SCID worldwide, the United States remains the only country to have an established screening programme for SCID. This is not currently available in the UK. However, we continue to work closely with the UK National Screening Committee (UKNSC) and we hope a national screening programme for SCID will be approved in the UK in the near future.