GUEST BLOG: Severe Combined Immunodeficiency Explained

Primary immunodeficiencies (PIDs) are inherited flaws in the immune system that cause a part of the immune system to be missing or not work. Patients are born with these genetic flaws and, although some disorders present at birth or in early childhood, the disorders can affect anyone, regardless of age or gender. Some affect a single part of the immune system; others may affect more than one part of the immune system, e.g. SCID or Severe Combined Immunodeficiency.  People affected by PIDs have parts of their immune systems missing or not working. This leaves them with reduced or no natural defence against germs such as bacteria, fungi and viruses, which surround us every day.

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Due to the fact that the immune system has such an important role to play to protect us from infections, any defect in the immune system can lead to infections that occur more often than is normal.   Therefore patients with PIDs mostly suffer from infections affecting various parts of the body, the upper respiratory tract like ear, nose and throat, the lungs, gastrointestinal tract, skin, joints, brain or spinal cord etc.  These infections can be caused by unusual organisms and it may be prolonged infections, it may be difficult to treat and they often come back.  Some PIDs affect growth and facial features and some causes autoimmune disorders such as rheumatoid arthritis and some may increase the risk to develop cancers.

Although more than 300 different PIDs have been described, the most ominous of these is SCID, considered as the most severe immunodeficiency. The diagnosis of which constitutes a life-threatening paediatric emergency.

SCID typically presents in early infancy and results in profound immune deficiency that renders the body utterly susceptible to infection.

Patients with SCID acquire infections instantly from contact with seemingly healthy people, or airborne spread of organisms or organism in water or food. People with a normal immune system, will not get sick or just contract a slight illness from these, but these children may die from these infections. This is why we nurse these children in isolation. Think of the scenario of the Boy in the Plastic bubble a 1976 American made-for-television drama film inspired by the lives of David Vetter and Ted DeVita, who lacked effective immune systems. Or more recently the movie Bubble Boy released in 2001 and Directed by Blair Hayes regarding a young man born without immunities.

If children with SCID go undiagnosed, most will die before the age of 1 year, sometimes 2 years of age. The only curative treatment is a bone marrow transplant, or nowadays gene transplant therapy (still under trial).  The sooner the diagnosis is made, the better the chance of survival.  The ideal is diagnosis at birth.

There are other PIDs that will also require bone marrow transplant, but many others do not require this. Some PID’s can be treated with immunoglobulin replacement therapy, where donors’ antibodies are given to a patient for passive protection against organisms.

Overall, serious PIDs has an incidence in the region of 1/10000, one can expect around 6000 patients to have PIDs in SA of whom only 340 are placed on the SA registry to date. SCID may be as frequent as 1/50000 in the population (latest figures on TREC screening in the US).  We see variations of SCID, however, especially with the advent of modern genetic testing; it may therefore be more frequent and present with milder forms and can even be diagnosed in adolescence and adulthood!

SCID and PIDs in general are under diagnosed in SA and also underreported. Once diagnosed it is important that these patients be put on the SA PID registry and that they come in contact with PiNSA (Primary immunodeficiency network of SA). PiNSA is a voluntary Non-Profit Organisation (NPO) South African patient driven association dealing with PIDs, affiliated with the international society for PIDs, IPOPI. Their vision is to ensure that people with Primary Immunodeficiency in South Africa receive optimal treatment and support.

They depend on donations to help save lives.

Website: http://www.pinsa.org.za

What are the alarm bells for alerting a doctor or parent that a child might have a PID?

There is a simple acronym that has been implemented worldwide and also endorsed by PiNSA: SPURR.  It is easy to remember, one just think of our popular SA family restaurant.  Any patient presenting with infections that are:

Severe

Persistent

Unusual

Recurrent

Runs in the family

The Jeffrey Modell Foundation Medical advisory board also developed 10 warning signs of PID:

10 Warning signs of PID

1.   Four or more new ear infections within 1 year.

2.   Two or more serious sinus infections within 1 year.

3.   Two or more months on antibiotics with little effect.

4.   Two or more pneumonias within 1 year.

5.   Failure of an infant to gain weight or grow normally.

6.   Recurrent, deep skin or organ abscesses.

7.   Persistent thrush in mouth or fungal infection on skin.

8.   Need for intravenous antibiotics to clear infections.

9.   Two or more deep-seated infections including septicaemia.

10.   A family history of PID.

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How can my doctor diagnose PIDs?

The earlier the underlying diagnosis of a PID is made, the less damage will be done and, often, the easier it is to treat the disease successfully.

There are some basic screening tests that he/she can do, also in state sector, to enable them to at least make a working diagnosis. These tests are affordable, and widely available in all laboratories.  Worldwide a step wise approach is followed to diagnose these disorders. Your doctor is welcome to read the article (van den Berg S, van Rooyen C, Green RJ. We can do more to identify patients with Primary Immunodeficiencies. Current Allergy & Clinical Immunology March 2017;30(1):46-53) or to contact me at 012-678-0614.

In South Africa I believe we CAN do more to identify and handle PIDs. We have constructed a checklist for medical professionals:

1.   Be aware that they exist.

2.   Know the red flag signs (SPURR, 10 warning signs).

3.   Know the sentinel organisms; these are mostly unusual in immune competent patients.

4.   Know which diagnostic tests to order (contact your Pathologist if uncertain)

5.   Consider immunodeficiency when interpreting abnormal pathology tests undertaken for other reasons.

6.   Aim to identify patients prior to the onset of clinical symptoms, e.g. Newborn screening (TREC and KREC PCR at birth on babies’ blood).

7.   Training of pre- and postgraduate medical students in Immunology.

8.   Access to specialised care. There are a handful of specialists (paediatricians and physicians in SA) with special interest in PIDs that can manage these children and adults appropriately.

9.   Aim to make a definitive diagnosis. We have most of the specialised tests (including genetic testing) available in the private laboratory sector to assist in making the final diagnosis.

10.   Reporting patients with PID on the SA PID registry.

11.   Draft dedicated guidelines for patients to get access to lifesaving immunoglobulin therapy and bone marrow transplants (when indicated).

Screening for SCID:

Newborn screening (NBS) has the potential to identify diseases and disorders before symptoms appear and before serious complications arise. Early detection allows treatment that may prevent development of serious health problems or even death.

Early diagnosis of SCID has a significant impact on survival, as it allows the start of supportive treatments and prevention of infections. It also means that a search for matched donors can begin earlier.

Data from transplants in the first month of life are associated with ∼92% chance of survival regardless of donor type or type of SCID. Long-term immune function is also better when transplanted in the first month of life.

How would a NBS for SCID work?

Since all patients with SCID have reduced normal T cell development, it follows that the detection of low numbers of naive early T cells (measured by low TRECs on PCR) can aid SCID diagnosis. This test can be performed on a heel-prick or blood specimen taken directly after birth.


Written by: Dr. Sylvia van den Berg, Clinical Pathologist