​Work on primary immunodeficiency is improving diagnosis and treatment of these under recognised disorders, and helping researchers gain a better understanding of these patients' susceptibility to bacterial infections such as TB.

Primary immunodeficiency diseases (PIDs), which are due primarily to genetic deficits in the immune system response, render patients susceptible to various infections. They are traditionally regarded as rare diseases, and this is true of the very severe forms: these occur only in one in several hundred thousand infants.

Dr Monika Esser, Head of the Immunology Unit at Stellenbosch University and the National Health Laboratory Service (NHLS) at Tygerberg, says, however, that: "It's becoming clearer that highly selective immunodeficiencies against certain strains of bacteria (such as TB), are far more common than was previously thought."

With moderate to severe PID, incidence is much higher, rising to about one in 10 000 people in South Africa. Yet, says Esser, "The level of awareness in South Africa of PID is shockingly low."

"In cases of very severe immunodeficiency early in life, children may die from overwhelming infection without ever being diagnosed. And even where one child has had a significant immunodeficiency, the same genetic deficiency is often missed in a sibling. We need better training in the clinical setting to recognise PID s."

PID often not diagnosed

It's now known that PID can manifest in adolescence and adulthood, although such cases are regularly missed: the condition is perceived as a chronic infection while the underlying immune deficit goes undetected. Diagnosis is often very delayed, sometimes for a decade or more. The later the diagnosis, the greater the likelihood of organ damage. Unexplained recurrence of infections, or unusual infections, are red flags for PID.

The majority of well-recognised PID s are due to antibody deficiencies against bacteria, and can be screened for effectively using inexpensive blood tests. Also, because the main defects are antibody-related, these can be treated effectively with immunoglobulin (plasma products from donated blood that contain disease-fighting antibodies). Even very severe immunodeficiencies, if recognised early, can potentially be cured with stem cell transplants.

Drs Craig Kinnear and Marlo Möller are using PID in their work with the TB Host Genetics Research Group in the Division of Molecular Biology and Human Genetics. Their interest lies in identifying susceptibility genes and factors for tuberculosis – why some people with TB infection develop the disease and others do not. PID can act as a tool to help answer this question.

Kinnear explains: "Some patients have a form of PID where a particular gene mutation makes them more susceptible to TB. In the general population, many genes are involved in TB susceptibility, and the picture is further complicated by environmental factors. Whereas in these PID patients, it's a simplified genetic situation."

"The aim is to identify the disease-causing mutations in this form of PID, because these genes are also good candidates as TB susceptibility genes in the general population. We then compare those genes in a group of TB patients to a group of individuals who don't have TB, to see if there are subtle differences – which genetic factors are comparatively more common in the TB group."

Diagnosis a benefit of the study

An important benefit of the study is that it provides PID patients and their families with a diagnosis. When the researchers find a disease-causing mutation in a patient, they can use the information to screen family members for those same mutations.

"A baby gets a BC G vaccination against TB a day after birth; if there's a mutation present that lowers tolerance, dissemination of the live vaccine can occur. This can be avoided if we can predict that an infant will likely react poorly to the vaccine," says Kinnear.

Knowledge of specific mutations also informs treatment, which differs depending on severity. Not all patients need stem cell or immunoglobulin therapy; some can be managed with measures such as prompt treatment of infections, prophylactic antibiotics and hygiene precautions.

Photo: Drs Monika Esser (left), Craig Kinnear and Marlo Möller.

This article was originally published in the Faculty of Medicine and Health Sciences' annual publication.