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Severe combined immunodeficiency (SCID)

Severe combined immune deficiency (SCID) is a life-threatening primary immunodeficiency (PI), with a combined absence of T cell and B cell function. There are at least 20 different genetic variants that can cause SCID.

What is SCID?

Severe combined immunodeficiency (SCID) is one of the most severe types of primary immunodeficiency (PI). Babies born with SCID lack white blood cells called T cells. T cells not only directly attack cells infected with viruses, bacteria, or other microorganisms, but they also cause B cells, another type of white blood cell, to produce antibodies. Essentially, a baby with SCID completely lacks a functional immune system and is extremely vulnerable to severe and life-threatening infections. Without treatment, these children typically do not survive past two years of age.

However, if a child with SCID is diagnosed and treated within the first few months of life before any serious infections develop, their long-term survival rate is more than 90%. 

How is SCID diagnosed?

Babies born with SCID appear healthy at birth but are unable to fight infections. The newborn screening blood test can show if a baby has a low number of T cells, a sign that a baby may have SCID. A lack of T cells is essential to SCID diagnosis, but no or low T cells may also occur in other health conditions.

It takes time to perform a thorough evaluation of a baby found to have no or low T cells. Some laboratory tests come back quickly, while others, like genetic tests, may take weeks or months. Sometimes doctors want to repeat tests over time, in order to try to find any trends in a baby’s cell counts, especially if the numbers are borderline low and/or the baby is not too ill.

Thanks to newborn screening for SCID in all 50 states, most babies with SCID are diagnosed before they develop health problems. However, there are rare types of SCID where some T cells develop but don’t function well that may not be detected by the newborn screening test. In addition, one individual was reported with late-onset adenosine deaminase (ADA) deficiency (ADA-SCID) who had a normal newborn screening test early on. These individuals may not be diagnosed until clinical signs and symptoms of infections appear.

The diagnosis of SCID can also be made before the baby is born through prenatal diagnosis if there has been a previously affected infant in the family and the genetic variant responsible for their condition has been identified. Prenatal diagnosis involves testing the DNA of fetal or placental cells, obtained through chorionic villous sampling (CVS), amniocentesis, or non-invasive means, to see if the SCID-causing genetic variant is present.

What’s the best way to protect a baby with suspected or confirmed SCID?

If a child’s newborn screening blood test shows low T cells, try to stay calm and remember that you are not alone. The clinical immunologist can help you every step of the way during this sometimes confusing and challenging process. They are there to provide you with accurate, scientifically sound information so that you can make well-informed decisions for your child.

Because your baby may have little or no immune system, the most important thing to do right now is to keep your baby from getting sick. Even if the child has not yet been diagnosed, the safest course of action is to assume that they have an immune problem until proven otherwise. 

Ask your immunologist what you should and shouldn’t do while your child is still being evaluated.

  • Check with your doctors immediately if the child develops signs or symptoms of an infection (for example, fever, cough, or diarrhea).
  • Discuss with your immunologist whether or not regular immunizations should be given to your baby. In infants with low lymphocytes, immunizations are often delayed until more is known concerning your baby’s immune system. Live vaccines, such as the rotavirus (oral) vaccine, should be avoided. 
  • Ask your immunologist if breastfeeding is okay or if formula feeding is better for the time being. Breastfeeding can expose the baby to an infection called cytomegalovirus (CMV). CMV can be very harmful, especially if your child needs a hematopoietic stem cell transplant (HSCT). The risk of transmission of CMV through breast milk is significant in any mother who has previously been infected with CMV, even years after exposure to CMV. Many mothers are tested for the CMV antibody during their pregnancy, but a negative result does not guarantee that they have not been exposed to CMV later in pregnancy or after delivery. 
  • If your baby is hospitalized for any reason, be sure that hospital physicians consult with your immunologist before beginning standard treatments. If the infant requires a blood transfusion, the doctors and hospital should use blood that is depleted of white blood cells (or irradiated to destroy any viable lymphocytes) and does not contain any CMV. 
  • Maintain good hygiene, including frequent hand washing or using hand sanitizer.
  • Infants with T cell deficiency should not attend daycare, or be taken into indoor public places such as stores, church, or doctors' offices.
  • Avoid contact with sick people. Make sure to ask your immunologist what to do if your baby has accidental exposure to a sick person, like an older sibling or parent.
  • Limit contact with siblings who attend daycare or school, the possibility of bringing infections into the home represents the greatest danger. Contact with relatives who are not household members should also be limited, especially those with young children. 
  • Although no special diets are helpful, nutrition is nevertheless very important. In some instances, the child with SCID cannot absorb food normally, which in turn can lead to poor nutrition. As a result, in some instances, the child may need continuous intravenous feedings to maintain normal nutrition. 
  • Starting immunoglobulin (Ig) replacement therapy, prophylactic antibiotics, and antiviral and antifungal medications is important. 

Overall, make sure you have good lines of communication with your clinical immunologist and pediatrician. Don’t hesitate to ask questions, and make sure you keep your appointments with your doctors.

Once a child is diagnosed with SCID, reducing the germs the child is exposed to is even more essential. If the doctor recommends that the child stay in the hospital before treatment, then the hospital will put in place procedures to minimize the risk of infection through reverse isolation. If the child is sent home before treatment, healthcare providers can provide instructions to help reduce the chance of infection through at-home isolation procedures.

Reverse isolation in the hospital

If the child stays in the hospital after diagnosis, then the child will typically be in what is known as “reverse isolation.” Reverse isolation is designed to protect the child from other people’s germs, as opposed to protecting other people from a patient who might be sick. When a child with SCID is in the hospital in reverse isolation, visitors who are sick are not allowed in the room.

In reverse isolation, the child may be in a room with a special air filtration system. Visitors, including both family and medical staff, must follow a strict handwashing regimen. Visitors must also wear a mask, gloves, and a hospital gown. No food, except for the child’s food, is allowed in the room.

Remember that advocacy in the hospital for your child is an important part of your role as a caregiver. Although doctors decide much of what happens during treatment, you should feel free to discuss all procedures with them. Also, there may be certain situations in which you will need to make sure that protocol is followed. For example, you will want to ensure that staff wash their hands and wear masks and gowns when entering your child’s room if that is what you and the doctor have discussed. Remember, it is your right to do the following when interacting with healthcare workers, including doctors:

  • Ask questions. If you don’t understand the answers, ask them again.
  • Bring up concerns you might have with procedures being performed on your child.
  • Keep a notebook to record information about your child’s care, condition, and recovery.

Isolation at home

If the child stays at home in isolation before treatment, then caregivers must do their best to reduce germs in the home. The child must stay inside, and not venture outside or to public places, as germs thrive in those locations and cannot be controlled or reduced by caregivers.

Children born with SCID are susceptible to infection by all types of germs, including viruses, bacteria, and fungi. Any of these infections are life-threatening and could weaken the child before treatment and make treatment less likely to work. Here are eight simple precautions to prevent the spread of germs in the home.

  1. Wash hands regularly, especially before touching the child. Handwashing with soap and water for at least 20 seconds reduces germs. Be extra careful to wash before and after changing diapers, after going to the bathroom, before preparing food, and after sneezing or coughing.
  2. Do not allow visitors to the home, beyond those who live there.
  3. Do not take the child with SCID out of the house to any enclosed public places like church, shopping, or daycare, until doctors allow the trips.
  4. Siblings should not be allowed to touch the child. If brothers or sisters attend daycare or school, the possibility of them bringing germs into the home represents the greatest threat to the child.
  5. Keep anyone who is sick, even with a cold, away from the child.
  6. Alert the school(s) brothers and sisters that they have a sibling with no immune system and that parents must be contacted if there are any infectious outbreaks at school.
  7. Relocate pets, if possible.
  8. Keep home clean by wiping surfaces with disinfectant.

What causes SCID?

Variants in at least 20 different genes can cause SCID. Although the types of SCID vary with respect to the cause of the immunodeficiency, their laboratory findings, and their pattern of inheritance, infants with any type of typical SCID have severe deficiencies in both T cell and B cell function. The treatment approach will vary with SCID type, so it’s important to know what kind of SCID an individual has.

Types of typical SCID

The most common form of SCID, affecting nearly 30% of all cases, is due to a variant in the interleukin 2 receptor gamma (IL2RG) gene on the X chromosome. IL2RG codes for a protein called the common gamma chain (γc) that is part of several receptors needed for the growth of immune system cells. Changes in IL2RG that cause SCID result in common gamma chain deficiency, leading to very low T cell and NK cell numbers. However, the number of B cells is normal or high (T-, B+, NK- phenotype). Despite the presence of B cells, there is no B cell function, since the B cells have abnormal growth factor receptors on their cell surfaces. 

Common gamma chain deficiency is inherited as an X-linked recessive trait. Generally, only boys have this type of SCID, but girls may carry the IL2RG variant; female carriers usually do not have symptoms. A male with X-linked SCID will pass the gene variant along to his daughters, who will be carriers. He will not pass the gene variant to his sons. A female who is a carrier has a 50% chance of passing the variant along to daughters (who will then be carriers) and to sons (who will then have the disease). However, X-linked SCID can also occur spontaneously without the mother being a carrier.

Another type of SCID is caused by variants in a gene that codes for an enzyme called adenosine deaminase (ADA), leading to ADA deficiency. ADA SCID is the second most common type of SCID, accounting for about 15% of cases. 

The ADA enzyme eliminates a molecule called deoxyadenosine, which is generated when DNA is broken down, from cells. ADA converts harmful deoxyadenosine to a different molecule that is harmless. The absence of this enzyme leads to a buildup of deoxyadenosine within immune cells that causes the cells to die. 

Individuals with this type of SCID have low total immune cell counts because T, B, and NK cells are affected (T-, B-, NK- phenotype). This form of SCID is inherited as an autosomal recessive trait, so both boys and girls can be affected.

Variants in the recombinase activating gene 1 and 2 (RAG1 and RAG2) genes that result in deficiencies in RAG1 and/or RAG2 proteins represent the third most common type of typical SCID. RAG1 and RAG2 are enzymes critical to the development of T and B cells, but not NK cells. Babies with this type of SCID present with low or absent T and B cells, but typically have normal or high NK cells (T-, B-, NK+ phenotype). RAG1 and RAG2 deficiencies are inherited in an autosomal recessive manner, so both boys and girls can be affected.

The fourth most common type of SCID, which accounts for less than 10% of cases, is interleukin 7 receptor (IL7R) deficiency. In this type of SCID, the gene variant prevents the creation of the IL7R chain, which interrupts the signaling for the development of T cells. Infants with this type of SCID have B and NK cells, but no T cells (T-, B+, NK+ phenotype). The numbers of B cells and NK cells are normal, but the B cells don't work because of the lack of T cells. IL7R deficiency is inherited as an autosomal recessive trait, so both boys and girls can be affected.

Another type of SCID is caused by variants in a gene on chromosome 19 that codes for an enzyme called Janus kinase 3 (JAK3). This enzyme is necessary for the function of the common gamma chain (γc or IL2RG). Infants with this type have very similar immune cell counts to those with X-linked SCID, so they are T-, B+, NK-. However, since this form of SCID is inherited as an autosomal recessive trait, both boys and girls can be affected. JAK3 deficiency accounts for less than 10% of cases of SCID.

Four other forms of SCID are due to variants in genes that code for four of the individual protein chains that make up CD3, another component of the T cell receptor complex. These SCID-causing gene variants result in deficiencies of CD3 delta, epsilon, gamma, or zeta chains. These deficiencies are inherited as autosomal recessive traits and account for less than 5% of individuals with SCID. Both boys and girls can be affected.

Deficiencies in CD3 delta, epsilon, or zeta result in typical SCID, whereas deficiency in CD3 gamma can result in typical SCID or less severe combined immunodeficiency (CID).

There are a group of other autosomal recessive forms of SCID associated with a lack of T and B cells, presence of NK cells, and sensitivity to ionizing radiation like X-rays (radiosensitivity). These types of SCID are caused by variants in genes necessary for repairing DNA, including DCLRE1C (coding for the Artemis protein), PRKDC (coding for the DNA-PKcs protein), NHEJ1 (coding for the cernunnos/XLF protein), and LIG4 (coding for DNA ligase 4). The radiosensitive forms of SCID comprise less than 5% of those with SCID, but they require special consideration in selection of conditioning agents for HSTC to minimize the risk of long-term complications.

Artemis SCID is also known as SCID A or Athabascan-type SCID. This type of SCID is found primarily in the Navajo Nation. Variants in the DCLRE1C gene can also cause Omenn Syndrome.

LIG4 deficiency SCID has a wide range of symptoms including underdeveloped head and brain (known as microcephaly), a malformed face, failure to grow, and developmental delays, along with the lack of immune system.

Cernunnos/XLF deficiency SCID is rare and is characterized by underdeveloped head and brain (known as microcephaly), inability to grow at a normal rate, and lack of T and B cell function.

DNA-PKcs deficiency SCID is extremely rare. In addition to radiosensitivity and absence of T and B cells, individuals with DNA-PKcs deficiency commonly exhibit underdeveloped heads and brains (known as microcephaly).

Reticular dysgenesis SCID is caused by variants in the AK2 gene, which codes for an enzyme that helps cells make energy. It is the most severe form of SCID because the individual not only lacks T and B cells but also lacks neutrophils, making them even more susceptible to infection. Symptoms are present at birth and include deafness, diarrhea, fever, sepsis, failure to thrive, infections, and abscesses.

There are several other genetic defects associated with autosomal recessive inheritance of SCID, including variants in the genes that code for CD45, coronin 1A, and LAT proteins. Furthermore, about 6-10% of individuals with SCID in a recent study did not have an identifiable genetic variant to explain their clinical and laboratory features.

  • CD45 deficiency SCID (T cell negative, B cell positive).
  • Coronin-1a deficiency SCID (T cell negative, B cell positive).
  • LAT deficiency SCID (T cell negative, B cell positive).

Leaky or atypical SCID

In recent years, leaky SCID (also known as atypical or hypomorphic SCID) has been discovered. Leaky SCID occurs when a person has symptoms similar to typical SCID, but with T cell counts that aren’t low enough to qualify as typical SCID. It’s called “leaky” because some T cells “leak” through. Sometimes, children with leaky SCID don’t get diagnosed until they are older—even into adulthood. 

A person with leaky SCID may have a different type of gene variant in the same gene as a person with typical SCID. Variants in RAG1 and/or RAG2 are seen in 40% of those with leaky SCID. 

Omenn syndrome

Omenn syndrome can occur with leaky SCID or with other primary immunodeficiencies with low, but not absent, numbers of T cells. Infants with Omenn syndrome suffer from autoimmune symptoms that are the result of inappropriately activated T cells attacking the body. Symptoms include red and peeling skin, hair loss (alopecia), enlarged lymph nodes (lymphadenopathy), and enlarged liver and/or spleen (hepatosplenomegaly). Omenn syndrome occurs most often in those with RAG1 or RAG2 leaky SCID, but has also been documented in ADA, Artemis, and LIG4 leaky SCID.

What are the clinical signs and symptoms of SCID?

Infants with SCID have no outward appearance to distinguish them from normal newborns and are usually clinically well until they have an infection. 

For those not detected by newborn screening, an excessive number of infections is the most common presenting symptom of infants with typical SCID. These infections are not usually the same sorts of mild infections that children without PI have, such as frequent colds. The infections of an infant with SCID can be much more serious and even life-threatening. They may include pneumonia, severe viral respiratory infections, meningitis, and/or bloodstream infections. 

Infants with SCID are susceptible to routine infections seen in other babies, but they are also at increased risk for infections caused by microorganisms that are usually not harmful in children with normal immunity, including those in or live vaccines. Among the most dangerous is a fungus called Pneumocystis jiroveci that can cause rapidly fatal pneumonia (PCP) if not diagnosed and treated promptly. Up to 20% of people carry P. jiroveci in their lungs without symptoms, and these asymptomatic carriers can spread it to vulnerable people, including babies with SCID.

Another very dangerous organism is the chickenpox virus (varicella). Although chickenpox is annoying and causes discomfort in most children, it usually is limited to the skin and mucous membranes and resolves in a matter of days. In the infant with SCID, chickenpox can be fatal because it doesn't resolve and the virus can go on to infect the lungs, liver, and brain. 

Cytomegalovirus (CMV), which more than 60% of U.S. adults carry in their salivary glands, may cause fatal pneumonia in infants with SCID. Because CMV can be transmitted via breastmilk, mothers of children with suspected or diagnosed SCID are usually advised not to breastfeed. 

Other dangerous viruses for infants with SCID are: 

  • The cold sore virus (herpes simplex). 
  • Cold and flu viruses like adenovirus, respiratory syncytial virus (RSV), rhinovirus, and parainfluenza 3.
  • Epstein-Barr virus (EBV), which causes mononucleosis. 
  • Polioviruses. 
  • Measles virus. 
  • Rotavirus.

Since vaccines that infants receive for chickenpox, measles, and rotavirus contain live but weakened virus, infants with SCID can contract viral infections from these immunizations. If the newborn screen for SCID is abnormal or someone in the family has had or currently has SCID, these vaccines should not be given until SCID has been ruled out in the new baby. This is especially a problem for the rotavirus vaccine, which is routinely given when babies are 6-8 weeks old. A baby with SCID may not have had any infections by that time, and would not be diagnosed except by newborn screening.

Fungal infections may be very difficult to treat. For example, candida infections of the mouth, known as thrush, are common in most babies but usually resolve by themselves or with oral medication. In contrast, for the child with SCID, oral thrush may improve, but it either doesn’t go completely away or recurs as soon as the medication is stopped. The diaper area may also be involved. Occasionally, candida pneumonia, abscesses, esophageal infection, or even meningitis may develop in infants with SCID.

Persistent diarrhea resulting in failure to thrive is a common problem in children with SCID. It can lead to severe weight loss and malnutrition. Diarrhea may be caused by the same bacteria, viruses, or parasites that affect other children. However, in the case of SCID, the organisms are very difficult to get rid of once they become established.

The skin may also be involved in children with SCID. The skin may become chronically infected with the same candida fungus that infects the mouth and causes thrush. Infants with SCID may also have a rash that is mistakenly diagnosed as eczema but is actually caused by their mother's T cells, which enter the baby's circulation before birth, reacting against the baby's tissues. This reaction is called graft-versus-host disease (GVHD) due to maternal T cell engraftment.

In individuals with leaky SCID, the clinical presentation may occur later in life and symptoms can be highly variable and mimic symptoms of combined immunodeficiency. Autoimmunity and invasive granulomatous lesions (where immune cells clump together and create tiny nodules at the site of infection) are common as these individuals age.

How is SCID treated?

In all types of SCID, individuals have a severe reduction in the number of T cells, which are a type of white blood cell. Treatments for SCID like hematopoietic stem cell transplant (HSCT) and gene therapy fix the individual’s immune system by replacing their blood-forming cells, which allows their body to make functional T cells. In the case of enzyme replacement therapy (ERT), which is only an option for ADA-SCID, the treatment provides a working version of the ADA protein, which breaks down the toxin that kills these individuals’ T cells.

If a child with SCID is diagnosed and treated within the first few months of life, before any serious infections develop, their long-term survival rate is more than 90%. Once an infection develops in a baby with SCID, it may reduce the effectiveness of treatment or cause organ or tissue damage that treatment cannot undo. 

Most children with SCID are treated with hematopoietic stem cell transplant (HSCT), also known as a bone marrow transplant, because it works for many types of SCID and has been performed successfully for decades. HSCT is the current standard of care for SCID in the medical community. 

In HSCT, doctors take healthy blood-forming cells from a donor and give them to the baby with SCID through an infusion. The blood-forming cells grow and divide, providing the child with a functioning immune system.

HSCT is a months-long process that requires a lengthy hospital stay. Once in the hospital, a baby will first undergo a number of tests and other procedures to get ready for HSCT. Importantly, the doctors will determine the best match to provide blood-forming cells for the HSCT. This person will be the donor. 

Next, the baby will undergo the treatment itself. Following HSCT, the baby will undergo months of immune system monitoring to determine if the HSCT was successful. With HSCT, there can be a number of complications, and sometimes the HSCT needs to be repeated.

Read about HSCT

Gene therapy is another possible SCID treatment, but it is still in clinical trials and is not yet a U.S. Food and Drug Administration (FDA)-approved treatment for any form of SCID. 

In all cases of SCID, there is a severe reduction in the number of T cells. With gene therapy, doctors take the baby’s hematopoietic, or blood-forming, stem cells out, put a functional copy of the SCID-causing gene into those cells, and then infuse the corrected cells back into the baby. The cells with the corrected gene make copies of themselves and create an immune system for the baby. 

Currently, gene therapy trials are available for ADA-SCID, Artemis SCID, Rag1-deficient SCID, and X-linked SCID. Families of children who choose gene therapy must enroll in a clinical trial.

Learn about gene therapy

Conditioning may be used to prepare your child's immune system to receive treatment. 

Key Points

  • Conditioning is used to make space in your child’s bone marrow for new stem cells and/or suppress your child’s immune system.
  • The goal of conditioning is to reduce the chance of treatment complications and improve short and long-term health outcomes.
  • Conditioning can have side effects and long-term risks.
  • For some children with SCID, conditioning may not be appropriate. Your child’s need for conditioning may depend on several factors. 
  • There are many approaches to treatment and conditioning. There is not one ‘right’ way that leads to a successful outcome.
  • Together, you and your child’s doctors should review the options available and decide whether to use conditioning.

What Is Conditioning?

Conditioning describes a pre-treatment that may be given to a child before a hematopoietic stem cell transplant (HSCT) or gene therapy. Conditioning means that your child may receive chemotherapy and/or other drugs to prepare your child to receive the new stem cells. The goal is to increase the chance of your child having a successful outcome.

Why Is Conditioning Sometimes Used?

The goal of conditioning is to lower the risk of possible treatment complications and improve your child’s short-term and long-term health outcomes. Conditioning may reduce the impact of these possible complications:

  • Graft/transplant rejection: Your child’s immune system, even if it doesn’t work very well, might notice the new stem cells as different and kill them.
  • Failure of new stem cells to engraft: The new stem cells might not find a place to land in your child’s marrow and, therefore, may not give rise to the different types of immune cells.
  • New stem cells partially engraft: The new stem cells may engraft and start working to make T-cells with the help of the thymus, but fail to engraft in the bones, where B-cells are made. If this happens your child may still need lifelong immunoglobulin (IG) replacement therapy (i.e., frequent injections of plasma that contain antibodies to help fight infections), antibiotics, or other ongoing therapy to help the immune system.

What Are The Types Of Conditioning?

There are two major categories of conditioning: 1) conditioning drugs that target stem cells, and 2) conditioning drugs that target the immune cells.  They have different goals. Children may have one or both types of conditioning before treatment.

Drugs that target stem cells

This type of conditioning uses chemotherapy drugs to reduce the number of stem cells in your child’s bone marrow. Doctors may call this “myelosuppression.” While this seems like a bad thing, the goal is to make space in your child’s bone marrow for the new stem cells to engraft. There are several intensities of myelosuppressive conditioning that could be used before transplant. They use the same drugs. The difference is the dose of drugs and how many drugs are used. The three categories of myelosuppressive conditioning include:

  • Myeloablative conditioning (MAC): This type of conditioning uses a higher dose of chemotherapy drugs aimed at completely getting rid of your child’s stem cells. Successful MAC makes plenty of empty space in your child’s bone marrow for new stem cells to land and start to work. In general, MAC has the best chance to fully replace the bone marrow with new stem cells to achieve a fully functioning immune system that can fight off infections. However, this approach does not always work in every patient and comes with more severe side effects and higher risks.
  • Reduced-intensity conditioning (RIC): This type of conditioning uses lower doses of chemotherapy drugs to achieve full replacement of your child’s stem cells but with less toxicity. Successful RIC makes enough empty space for donor stem cells to land and start to work. Use of RIC means less severe side effects and lower risks. But because RIC uses lower doses, there is a greater chance when compared with MAC that replacement of your child’s stem cells is incomplete. This means your child’s immune system might not be fully functioning after the transplant. For example, your child might still need lifelong IG treatment.
  • Low-dose conditioning: This type of conditioning uses very low doses of chemotherapy drugs and is more commonly used in gene therapy.

Drugs that target immune cells

This type of conditioning uses drugs to reduce the T and B cells in your child’s immune system. Doctors may call this “immunosuppression.” While this seems like a bad thing, the goal is to protect the new stem cells from being attacked by your child’s immune cells. There are two categories of immunosuppressive drugs:

  • Antibody-based drugs: Antibody-based drugs use antibodies to target the child’s immune cells to decrease risk of graft rejection.  Examples include Alemtuzumab (CAMPATH), ATG (Anti-thymocyte globulin).
  • Chemotherapy drugs: Chemotherapy drugs are used to kill immune cells, but not stem cells. Examples include Cyclophosphamide and Fludarabine.

What Are The Side Effects Of Conditioning?

Short-term side effects are temporary and subside when the treatment starts working. Long-term side effects may appear months or years after conditioning. In addition, some short-term side effects may become chronic and last a long time.

Short-Term Side Effects

Below are some possible short-term side effects of conditioning. These side effects may be mild to severe.

  • The chemotherapy and/or other drugs used for conditioning may affect your child’s mouth, throat, and intestines.
  • Your child could have sores on those areas which can lead to pain, drooling, nausea, vomiting, or diarrhea.
  • Your child may have a harder time eating because of mouth sores, which could result in the need for a feeding tube.
  • Conditioning will reduce the number of all your child’s blood cells for several weeks. This includes immune cells, red blood cells, and blood-clotting cells (platelets).
  • When your child has a reduced number of immune cells, he/she is at an increased risk for infection.
  • Your child may have blood clotting problems or become anemic, which is when your child feels tired and weak because of having fewer red blood cells.
  • Your child’s vital organs, such as the brain, lungs, kidney, and liver, may be harmed. Sometimes these complications can be treated with medication.

Long-Term Side Effects

Below are some possible long-term side effects of conditioning. Any one of these complications is infrequent, but parents should know that sometimes they do occur.  

  • Chronic problems from harm to your child’s vital organs, such as the brain, lungs, kidney, and liver. Sometimes these complications can be treated with medication.
  • Bone growth suppression, which may result in shortened stature as an adult
  • Endocrine abnormalities such as growth hormone deficiency, hypothyroidism (underactive thyroid), ovarian and testicular dysfunction
  • Reduced fertility
  • Increased risk of cancer
  • Developmental delay or problems with learning
  • Issues with development and arrangement of teeth
  • The vast majority of children with SCID survive conditioning and treatment, but there is a risk of life-threatening complications related to conditioning

What Are The Outcomes Of Treatment With Or Without Conditioning?

The most successful outcome is when your child has a fully functioning immune system that can fight off infections. For HSCT, doctors will measure your child’s level of chimerism to determine how well your child’s immune system is functioning. Chimerism is the percentage of healthy donor cells versus the child’s own cells. After transplant, the doctor will measure chimerism in your child’s blood as an indicator of how well your child’s cells have been replaced with the donor cells. After transplant, some children have 100% replacement of the blood and bone marrow with donor cells, which is called full donor chimerism. Mixed chimerism means that there is a mixture of the child’s cells and the donor’s cells. In general, the more donor cells are in the bone marrow, the better the child’s immune system works. In some cases, having low chimerism may mean that your child’s doctor may consider another transplant.

In the case of gene therapy, doctors test your child’s stem cells after they are treated with a vector to see how well the vector got incorporated into the cells. This test is called vector copy number (VCN). The VCN is the average number of copies of the vector in each cell. If the VCN is less than 1, for example 0.5, this means that, on average, there are 0.5 copies of the vector per cell. In other words, some cells have the vector while others do not. If the VCN is greater than 1, for example 2 or 3, this means that, on average, there are 2 or 3 copies of the vector per cell. Most gene therapies for SCID are currently being studied through clinical trials, and these studies set a goal for what the VCN should ideally be to improve the symptoms of the disease. To sustain your child’s immune system, your child’s VCN number should come close to the goal set by the study.

Conditioning may help achieve the right degree of chimerism or VCN.

Both survival and the chance for your child having a fully functioning immune system that can fight off infection depend on many factors based on your child's situation, including:

  1. How old your child is at the time of treatment
  2. What type of SCID your child has (genetic type)
  3. In HSCT, the type of donor match
  4. Whether your child has conditioning before treatment, and if so, what type
  5. Your child’s health before treatment

    Talk to your doctor about your child’s possible outcomes after treatment. Your doctor’s experience and knowledge may allow him/her to give you information more targeted to your child.

How Do Doctors Decide Whether To Recommend Conditioning?

Treatment can be successful with and without conditioning. Treatment is very individualized to the needs of each child. There is not one specific "recipe" or standard. Each patient's personal risks and current medical condition should be evaluated by their doctor. Using this information, doctors will recommend whether conditioning is the best option or not.

In general, conditioning may be recommended when:

  • The child has some immune function, such as those with leaky or atypical SCID
  • The donor is not related to your child
  • The child has certain types of SCID, such as ADA or RAG-1/RAG-2

In general, conditioning may NOT be recommended when:

  • The donor is a fully matched sibling
  • The child has an active infection
  • The child is very young (under 2 months of age) or small (e.g., was born prematurely)

    When conditioning is not used, the chances of a child achieving a fully functioning immune system are generally less. The child may need more treatment or have more infections. Some doctors plan for a staged approach. The doctor might do a transplant without conditioning at a young age, knowing that it is likely the child will need a second transplant down the road or lifelong IG replacement therapy.

How Are Parents Or Legal Guardians Involved In Choices About The Use Of Conditioning?

As parents or legal guardians of a child with SCID, you are the ultimate decision-makers about your child’s care. Talk to your child’s doctor about all available treatment options. Similarly, you and your child’s doctor should discuss the potential benefits and risks of conditioning.

Parents’ involvement in making a choice about using conditioning may vary. Some parents want to decide along with the doctor. Others want the doctors to make the decision about the use of conditioning given their expertise. A doctor may strongly recommend that conditioning be used or not used based on his or her best judgment and current research guidelines, the child’s specific situation, and sometimes the hospital’s standard practice.

If parents have concerns about their doctor’s approach, they may be able to get a second opinion from a different doctor. Personal considerations, like a family’s ability to travel, the child’s insurance coverage, and the urgency of the timing of the HSCT, could affect whether parents are able to seek a second opinion at another treatment center. If a family has such restrictions, they may still be able to have another SCID expert provide a consultation by phone or videoconference.

Questions To Ask Your Child’s Doctor

Below are some suggested questions you can discuss with your child’s doctor to determine if conditioning is the best choice.

If conditioning IS used:

  1. What side effects may be most problematic for my child?
  2. What are the risks of conditioning for my child?
  3. Long term, do the potential benefits of conditioning outweigh the potential risks?
  4. For my child, is conditioning the best choice?

If conditioning is NOT used:

  1. How likely is it that HSCT will lead to a fully functioning immune system for my child?
  2. What are the chances that my child will need another transplant later in life or lifelong IG treatment?
  3. How likely is it that my child’s body will reject the transplant?

Remember: There is no right or wrong approach. Transplants can be successful with and without conditioning. There are many factors that play a role in the decision-making about when to use conditioning. Although existing data supports general guidelines for when to use conditioning and when to avoid it, doctors and researchers do not yet have enough data to develop consensus guidance and standards of care.

Support For Parents

You may feel worried or frustrated when doctors cannot guarantee that using conditioning will lead to a more successful transplant for your child than not using conditioning, or vice versa. It is natural to be worried or frustrated. Families often say that going through a treatment when there is a lot of uncertainty is one of the hardest parts of their child’s journey with SCID.

Some parents manage uncertainties by reaching out to other SCID families to learn about their experiences with treatment. Parents often join social media groups, such as the SCID, Angels for Life Foundation on Facebook to connect to SCID families or to look for more information. Others lean on family and friends to deal with uncertainties.

Some parents decide to look for second opinions about their child’s treatment by reaching out to multiple doctors. Other families find that turning to social workers helps them to address their questions and uncertainties.

These are a few examples of the ways in which families deal with uncertainty in their SCID journey. You may pick a different strategy that works best for your family.

Remember: Conditioning may make a transplant more successful by increasing the chances of complete replacement of your child’s immune cells with donor cells. But on the other hand, use of conditioning comes with side effects and the potential for serious risks of its own. Together, you and your child’s doctors should review the options available and decide whether to use conditioning based on the balance of benefits and risks.

For children and adults with ADA-SCID, PEG-ADA, an enzyme replacement therapy (ERT) treatment manufactured under the name Revcovi, is available.

Persons with ADA-SCID lack an important enzyme that helps their immune system function. In ERT, individuals with ADA-SCID receive at least weekly intramuscular injections of the missing enzyme. These injections allow the immune system to function. After a few lessons, caregivers can give the person with ADA-SCID the injection at home without needing the help of a doctor or nurse.

ERT use is an important temporary step in treating persons with ADA-SCID, even if they plan to get a more permanent treatment, like an HSCT, soon. This is because even short-term ERT use can rapidly reduce the level of certain toxins that have built up in the body in the absence of the ADA enzyme. These toxins kill white blood cells, including T cells, and cause SCID.

Giving a baby ERT before HSCT increases the number of T cells in the baby, decreasing the risk of infection until definitive treatment is given.

In some cases, ERT is used over a much longer period of time (months to years), although there is agreement among doctors that HSCT or gene therapy is the preferred treatment in the long term. The length of time using ERT and the timing for the stopping of ERT may differ depending on whether the individual undergoes gene therapy or HSCT. Doctors will discuss this with the individual and any caregivers.

In addition, researchers suspect that high levels of toxins cause or contribute to secondary issues that can result from ADA-SCID in some cases. While many persons with ADA-SCID may experience few or no secondary issues, some patients have liver problems, bone issues, skin tumors, or neurological problems. Neurological problems include hearing loss, learning disabilities, attention-deficit/hyperactivity disorder (ADHD), fine motor skill impairment, nystagmus (uncontrolled rapid eye movement), abnormal walking, and epilepsy. Getting rid of toxins as early as possible may reduce the chances or severity of secondary issues.

One of the drawbacks is that ERT requires once or twice weekly injections into the muscle. In addition, the treatment is lifelong if the individual does not undergo HSCT or gene therapy and includes side effects such as coughing, vomiting, anemia, skin-related problems, and cancer of the immune system.

A guide for parents and caregivers

  • SCID, or severe combined immunodeficiency, is a life-threatening genetic condition diagnosed when blood is taken and tested through newborn screening.
  • Babies with SCID have no functioning immune system.
  • SCID is caused by genetic variants in the genes of cells responsible for the functioning of the immune system cells and close to 20 variants have been identified so far.
  • Most types of SCID are hereditary, though some develop spontaneously.
  • Babies with SCID have few or no T cells, which prevents B cell function—T cells activate B cells and kill infected cells; B cells provide antibodies to fight infection.
  • A child with SCID is extremely susceptible to serious illnesses such as severe viral respiratory infection, meningitis, bloodstream infections, skin infections, intestinal tract infections, chicken pox, cytomegalovirus, cold sore virus, adenovirus, rhinovirus, parainfluenza virus, mononucleosis, polio, measles, and rotavirus.
  • Infections in babies with SCID are fatal within the first year of life if the child is not treated.
  • Babies with SCID must be kept in isolation to reduce exposure to germs. The main way to control germs is to wash or sanitize hands before touching a baby with SCID.
  • Treatment for SCID is a bone marrow transplant, or gene therapy through clinical trials. In bone marrow transplant, the child with SCID receives stem cells from a donor, which create an immune system; in gene therapy, the child’s own cells are altered to create an immune system.
  • A treatment for SCID does not “cure” the condition; it simply provides the child with a working immune system that may or may not continue to function in the future.
  • Babies with SCID receive immunoglobulin, or Ig, therapy, which is made from plasma from blood provided by donors. Plasma contains antibodies the child needs to fight infection.
  • The Ig therapy is administered either intravenously or subcutaneously on a regular basis, such as weekly or monthly, depending on the child’s condition.
  • The incidence of SCID is 1 in about 58,000 children, or 76 children annually, in the U.S.

What is SCID?

SCID, or severe combined immunodeficiency, is a set of genetic disorders that results in a lack of an immune system. Most babies born with SCID produce no T cells, resulting in no B cell function. With no operating T or B cells, the baby lacks natural defenses against germs, and is highly susceptible to bacteria, viruses, and fungi. The condition is fatal if not treated within the first year or two of life. There are close to 20 different genetic variants that cause SCID.

What are the symptoms of SCID?

Often, when the baby is first born, there are no outward symptoms. Sometimes a baby with SCID is born with an infection or presents with one quickly after birth. As the baby develops, common symptoms of SCID are respiratory infections, yeast infections, meningitis, sepsis, failure to thrive, diarrhea, ear and sinus infections, skin rashes, and liver infections.

How is SCID diagnosed?

SCID is diagnosed through a TREC test performed on blood obtained during the newborn screening. A TREC, or T cell excision circle, assay that yields low or no TRECs means there are few or no T cells and is a strong indicator of SCID. Further testing for SCID includes a complete blood count and flow cytometry. Infants with SCID are referred to an immunologist.

How is SCID treated?

The most common treatment for SCID is a bone marrow transplant, which provides the baby with an immune system through donor cells. Gene therapy, a treatment option still in clinical trials, uses the baby’s own corrected cells to build an immune system. Babies with ADA-SCID may benefit from enzyme replacement therapy, but that treatment is only temporary. Almost all babies with SCID will receive antibiotics and immunoglobulin therapy. Early treatment for SCID, within the first few months of life, is essential before infection develops in the baby and compromises their chances of recovery.

What’s the best way to protect a baby with SCID?

Babies with SCID should be kept in isolation and come into contact with as few people as possible in order to reduce exposure to germs. The best way to prevent the spread of germs is to wash or sanitize hands every time before touching the baby.

How prevalent is SCID?

It’s currently estimated that SCID occurs in 1 out of 58,000 births, or 76 cases annually. SCID occurs in babies of all races and ethnicities, however, higher numbers of cases do occur in certain populations such as the Navajo Nation and among Amish and Mennonite communities. SCID affects both boys and girls, but the most common type, X-linked, only occurs in boys.

Hospital stays will be required for testing, treatment, and, if needed, recovery time from infections. Long hospital stays can take their toll on families, but there are steps families can take to reduce the stress. From knowing what to expect to making the best use of time in the hospital, families can minimize the effects of daily life in the hospital.

Length of stay

After caregivers receive a diagnosis of SCID for their baby, they should understand that their stay in the hospital could be a long one, though all cases differ with circumstances.

While the baby is waiting for treatment, some doctors allow the family to go home after a few days, if the family can start isolation measures at home. Other doctors may keep the baby in isolation at the hospital until treatment is administered.

Factors that may influence whether or not a baby may return home before treatment include:

  • Does the baby have an infection?
  • Do other young children reside in the home where the baby will live?

Treatment and recovery will require at least two months at the hospital but could take several months or more depending on any complications. In some cases, doctors do allow patients to spend part of their recovery time at home if they live within 30 minutes of the hospital. Also, in some cases, if travel time to the hospital takes more than 30 minutes, part of the recovery time may be spent in a temporary home nearby until the doctors approve departure from the area. Hospitals differ on the residential resources that they offer. For example, some may have residences specifically for families with children who are ill.

The reason for the baby having to be within a 30-minute drive of the hospital is because doctors must:

  • Monitor recovery through bloodwork and other tests daily, several times a week, or weekly. 
  • Address any complications that arise. 
  • Be able to treat the baby quickly if there is an emergency.   

There could also be multiple hospital stays, depending on whether or not the baby develops infections or other health problems.

Isolation measures at either location—at the hospital or in short-term housing—could go on for several months following treatment. The reason for this is that it could take several months after treatment to ensure that the treatment worked well enough to allow the baby to move further away from the hospital.

Even after being allowed to return home outside of the 30-minute travel time to the hospital, isolation measures may have to continue at the family's house while recovery continues.

Isolation at the hospital

When a child is diagnosed with SCID, and admitted to the hospital for treatment, the child must be kept in isolation. Isolation is necessary to reduce the spread of germs, and thus reduce the chance of infection.

Families may also find themselves in emotional isolation because visitors are not allowed in the baby’s room. Only primary caretakers, such as parents, are cleared for entrance into the baby’s room. Visits to the baby from siblings, extended family, and friends may be severely restricted because of the risk of germs.

Even so, there are ways that families can make the most of their time in the hospital and do their best to reduce stress and remain calm and rested. Below are some tips for life in the hospital.

  • Work out a schedule in which the main caretakers are given a break each day to either go to a different location in the hospital or leave the hospital for a walk, shopping, or visiting with other family members, especially children. Mental health breaks are essential and should be taken.  
  • Consider exercising during breaks; go for runs or walks or visit the gym.   
  • The main caretakers should make sure they get adequate rest and food. Important decisions must be made regarding the child, and the caretaker must be ready to understand information and make informed decisions regarding the child’s care.   
  • Keep a notebook on hand to record the baby’s condition, medical information provided by the doctor, and any questions for the medical staff. Caregivers may also want to keep a separate daily journal to write down their thoughts and feelings about their experiences.   
  • Be intentional with time when interacting with the baby. Despite the challenge of SCID, the baby is still undergoing intellectual and physical developmental progress and needs interaction from his or her caregivers. Feed the baby, read the baby stories, provide the baby with tummy time, and give the baby books and toys for play. Interact with the baby as normally as possible to avoid developmental delays in the future.   
  • Meet with the hospital social worker, or bone marrow transplant coordinator, to discuss topics such as financial assistance, employment issues, temporary housing, discounted travel, and other general suggestions for navigating time in the hospital, as well as time after the hospital.   
  • Use technology to reach out to support groups. Speak with other parents who have experienced the same journey and get their advice.   
  • Meet with the hospital chaplain. Hospital chaplains are trained to speak with people from all religious backgrounds or none at all. Their role is to listen and to respond with comfort to families.
  • What is the difference between newborn screening and confirmatory testing?
  • What signs or symptoms of SCID should I be looking for?
  • How should I protect my baby while awaiting the diagnosis?
  • Does my child need to be isolated from other people, or can friends and family visit?
    • Can I breastfeed?
    • Should my child get any vaccines?
  • What type of SCID does my child have?
  • What causes SCID?
  • How is SCID treated?
  • How can I get connected to others who can support me and my family (e.g., mental health services, family support groups)?
  • What treatment options are available for my child’s type of SCID?
  • What new or emerging treatment options, such as a clinical trial, might be available for my child?
  • What are the risks and benefits of each treatment option available for my child’s type of SCID?
  • Will my child need pre-treatment conditioning before treatment?
  • What are the different types and intensities of chemotherapy?
  • What are the potential side effects and long-term risks of chemotherapy?
  • Are there types of pre-treatment conditioning other than chemotherapy that are options for my child?
  • How much of my child’s treatment will my insurance/Medicaid plan cover?
  • How many children with SCID have been treated at this facility and what is the success rate?
  • How long can I expect my child to be hospitalized during treatment?
  • Can I stay with my child during and after treatment?
    • What can I expect during the hospital stay?
    • Who can I talk to about family support resources while my child is in the hospital?
  • How will you monitor if the treatment is working?
  • What are the possible short- and long-term complications of my child’s treatment?
  • Will my child need to take medication after the treatment?
  • How long will my child need to stay in isolation after we return home from the hospital?
    • What activities can I do with my baby during the isolation period?
    • When can I introduce my child to friends and family?
    • When can I do activities in public with my baby?
    • Can we have a pet in our home?
  • Are there support groups for me where I can meet other families whose child with SCID has gone through treatment?
  • How often should we follow up with our healthcare team?
    • What kinds of lab tests will my child get to monitor the long-term success of the treatment?
    • Who will be my primary contact on the healthcare team after we are discharged?
    • What role does my child’s pediatrician play now that we are home?
    • Who do I contact first if my child gets sick?
  • Are there resources to help us explain my child’s SCID to the pediatrician?
  • What type of precautions should family members take around my child with SCID?
  • What cleaning protocols should we implement at home?
  • Is there anything we should consider before enrolling my child who has SCID, or my other children, in school or childcare?
  • When can my child with SCID get vaccines?
    • What type of vaccines can my baby get post-treatment and when?
    • What type of vaccines can members of my family get?

Download a copy of questions for your healthcare team.

Other organizations that support SCID patients and families

SCID Angels for Life

SCID logo

SCID Angels for Life is a non-profit organization that increases awareness, benefits research and provides parent and family education for those affected by Severe Combined Immune Deficiency (SCID).

National Organization for Rare Disorders

NORD logo

The National Organization for Rare Disorders (NORD) is a non-profit organization that provides information, programs, and services for thousands of rare medical conditions, including primary immunodeficiencies.


This informational website for those affected by adenosine deaminase severe combined immune deficiency (ADA-SCID) was developed by Chiesi USA and intended for residents of the United States. 

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA