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A chance at life for immune-deficient babies
Author: Wilma Stassen
Published: 17/06/2017

Every year a number of babies are born in South Africa with genetic defects that prevent their immune systems from developing, and in the most severe cases leaving them totally defenceless against infection.

Protected in the womb, they grow into healthy new-born babies until they are exposed to the outside world, where they are powerless against the onslaught of viruses and bacteria that "normal" babies can cope with. Even the vaccines they receive at birth may turn against them and spread throughout their bodies – causing illness, rather than preventing it.

Severe Combined Immunodeficiency (SCID), the most severe form of primary immunodeficiency (PID), is a medical emergency. "These children have a severely impaired immune system from birth and usually die before their first birthday," says paediatric immunology specialist, Prof Monika Esser, Head of the National Health Laboratory Unit at Tygerberg Hospital. She also works with the Department of Paediatrics and Child Health at Stellenbosch University's Faculty of Medicine and Health Sciences (FMHS). "Unless you put them in a sterile bubble, they just can't survive."

David Vetter

This was actually the case with David Vetter, a boy who was born in 1971 with this severe form of PID. Immediately after his birth at Texas Children's Hospital he was placed in a germ-free plastic chamber, or "bubble". He spent most of his life in similar sterile environments and his case attracted the attention of the media, who dubbed him "Bubble Boy". David died at the age of 12 from Burkitt's lymphoma caused by a dormant virus, Epstein-Barr, which he acquired from a bone-marrow transplant.

PID and its genetic causes were only discovered relatively recently. Before the advent of antibiotics in the early 1900s people, and children in particular, used to die rapidly from infections. Only after the introduction of antibiotics it became apparent that some people were more susceptible to infections than others.

PID covers a wide spectrum of disorders in which a part of the body's immune system is lacking or functioning improperly, or in rarer cases not functioning at all. Most cases of PID develop early in life – generally within the first few months or years of life, but in severe cases it will manifest within a few weeks after birth.

The first sign of PID is an unusual susceptibility to infection. "Severe, persistent, unusual, recurrent infections or unusual features of autoimmunity occur from early in life," Esser explains.

There are many common health issues in South Africa that make children more susceptible to infection and which have to be ruled out before PID can be diagnosed. "We have to screen very carefully for underlying or precipitating causes. If there are other causes for being immune impaired, like HIV, severe malnourishment, premature birth or other risk factors such as anatomic malformations, then obviously you are also going to have an excess of infections."

Genetic screening for severe PID at birth is becoming routine in many developed countries, but this is not envisaged to become a priority in South Africa with its shortages of financial and human resources in the healthcare system for more common diseases. This means that most cases of SCID in South Africa are diagnosed late or not at all, unless there is a family history of infant death due to severe infections.

Stem cell transplant

The only treatment option for severe cases of PID is a stem cell transplant. For it to succeed, it should be performed at the youngest possible age and before the child acquires any infections or is given live vaccines at birth. However, the diagnosis is usually made once the child already starts showing susceptibility to infection – frequently only after multiple infections – unless the doctors are made aware of a family history or a previous genetic diagnosis of the disease.

This was the case with Vetter's parents, who previously lost a son to severe PID and were warned by physicians that any future male child they conceive would have a 50% chance of also inheriting the disease. So when David was born, doctors were ready to place him in a sterile environment. Sadly for him the knowledge about transplantation and rejection of donor tissue was just in its infancy then.

Tygerberg success

A similar story played out in January 2016 when a woman from Cape Town arrived at Tygerberg Hospital (the academic hospital linked to the FMHS) to deliver her baby. On admission to the maternity ward, she presented a doctor's letter stating that she had previously lost a baby to severe PID and that any future children are at risk of the condition.

"Immediately after birth this infant had to be isolated to minimise exposure to germs in the environment, but that's no easy task. Ideally you need special rooms with sophisticated ventilation, specialised cleaning et cetera, but we don't have all of this at Tygerberg Hospital. The infection control team, with the help of the ward staff, isolated the child in a single room with restricted access to necessary staff only, provided special nursing services that required wearing gloves and masks at all times, and gave special cleaning instructions for anything the child received. Importantly, the new-born received no live vaccines at birth. Also the mom was kept with the child at all times to cocoon and breastfeed, which provided the child with antibodies against infection which he could not produce on his own," Esser recounts.

Blood tests confirmed that the child had severe PID and the Bone Marrow Registry and the transplant team at Groote Schuur Hospital were contacted for tissue typing and donor search for a transplant. The isolation continued while waiting for these results and the baby was given bacterial, fungal and viral prophylaxis, as well as immunoglobulin replacement infusions, to ward off infection until a more permanent solution could be found.

The solution had to come in the form of a stem cell transplant, but with a bone marrow donor list of only about 75 000 for the whole country, no match could be found. Since international bone marrow donor searches are very expensive and lengthy procedures, doctors were left with only one option to give this baby the best chance at life – performing a half-match stem cell transplant with cells harvested from his mother.

"If this is performed very early – preferably before two months of age or earlier – and the child is free of infection and has sustained no organ damage, a good outcome is expected even with a half-identical donor and moderate immune suppression to prevent rejection," Esser explains.

Currently there are only two facilities in the country's public sector where these transplants are performed on infants, resulting in long waiting times.

"International figures show that children who undergo transplants under the age of two months have the best survival rate, and with every day that passes the chance for a successful transplant wanes as the chance for infection increases."

Finally, just about one month after he took his first breath, the boy received a stem cell transplant. His mother's half-matched cells engrafted in his bone marrow and developed a new immune system.

"The transplant was a huge success and a normal immune system was reborn. The child has since been discharged from hospital and is thriving." He only received moderate immune suppression, which doctors believe he eventually might be able to stop altogether.

Very early diagnosis, meticulous nursing care and infection control and prompt access to transplantation saved this child's life – but sadly this is not the case for the great majority of babies with severe PID. Most are diagnosed when they are already struggling with persistent, recurring infections, fail to thrive or after early death. Low awareness of this disease, even in the medical fraternity, results in diagnoses usually being missed, despite obvious warning signs.

"We often make excuses in a country like South Africa endemic with TB, HIV, you name it, and say the child is just overexposed, especially if he or she is from a poor socioeconomic background."

Basic tests

According to Esser there is also a misunderstanding that very advanced immunology laboratories are required for a diagnosis. "The first thing the doctor should ask, is 'why are these infections happening?', 'is this unusual?', 'is there a relevant family history?' Then some first line investigations should be done. You can arrive at a provisional diagnosis with some very basic tests and confirm a definite molecular diagnosis at a later stage."

The warning signs for PID are: when an HIV-negative child disseminates with live vaccines; has persistently low lymphocyte counts; or the presence of certain organisms, especially those which would not be expected to cause illness in someone with normal immunity.

A South African registry was established in 2008 to create a database of all types of PID patients in order to record and profile these hereditary conditions and with increasing awareness help facilitate early diagnosis to ensure the best possible outcomes for PID patients, especially babies born with this condition. Less severe forms of PID can be treated or improved with immune replacement therapy, but best outcome and prevention of organ damage also depend on the earliest diagnosis.

According to Esser SCID causes terrible suffering for both parents and children. "The related morbidity and mortality are inevitable in these children if they are not diagnosed and treated early. And it can all be avoided and cured by means of early diagnosis and a successful transplant."

Caption: Prof Monica Esser

Photo by Luigi Bennett