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Articles / Journals

Niaid.nih.gov
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Aaaai.org
Primaryimmune.org
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Piduk.org

Gallo, Vera, Laura Dotta, Giuliana Giardino, Emilia Cirillo, Vassilios Lougaris, Roberta D’Assante, Alberto Prandini et al. “Diagnostics of primary immunodeficiencies through next-generation sequencing.”
Frontiers in immunology 7 (2016): 466.

Clinical Updates

Jindal, Ankur Kumar, Rakesh Kumar Pilania, Amit Rawat, and Surjit Singh. “Primary immunodeficiency Disorders in india—A situational review.”
Frontiers in immunology 8 (2017): 714.

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What are Primary Immune Deficiencies?

Primary Immune Deficiencies (PID) or Primary Immune Disorders are a group of rare, genetic disorders (with more than 350 types) which cause dysfunction in the immune system. With a dysfunctional immune system, children and adults with PID are exposed to chronic, life-threatening infections in the respiratory system, ears, eyes, skin, lymphatic system, joints, spinal cord and other internal organs. Depending on the severity, PID is usually diagnosed in infancy, early childhood or adulthood. In some cases, PID can be fatal if the infection is left untreated.

  • PIDs are classified into six groups based on the part of the immune system affected:
  • B cell (antibody) deficiencies
  • T cell deficiencies
  • Combination B and T cell deficiencies
  • Defective phagocytes
  • Complement deficiencies
  • Unknown (idiopathic)
The World Health Organization (WHO) recognizes more than 350 types of PID. The most common types include:
  • Wiscott-Aldrich Syndrome
  • Severe Combined Immunodeficiency Disease (SCID)
  • DiGeorge Syndrome
  • Ataxia-telangectasia
  • Chronic Granulomatous Disease
  • Transient Hypogammaglobulinemia Of Infancy
  • Agammaglobulinemia
  • Complement Deficiencies
  • Selective Iga Deficiency
  • Isolated Igg2 Subclass Deficiency
  • Transient Hypogammaglobulinemia Of Infancy
  • Familial Hemophagocytic Lymphohistiocytosis (Hlh)
  • Autoimmune Lymphoproliferative Syndrome
  • Neutropenia
  • Leukocyte Adhesion Defect (Lad)
  • Disorders of IFNγ-IL12 Pathway
All the above types occur and have been studied in the Indian context.
PIDs can be both x-linked as well as autosomal recessive where both parents are carriers. Some of the x-linked PIDs (passed on from carrier mother to son) include:
  • X-Linked Agammaglobulinemia (XLA)
  • Wiskott-Aldrich Syndrome
  • Severe Combined Immune Deficiency (SCID) caused by mutations in the common gamma chain
  • Hyper IgM Syndrome caused by mutations in CD40 ligand
  • X-Linked Lymphoproliferative Disease
  • Chronic Granulomatous Disease (CGD)
In families where the mother is the carrier of the PID mutation, there is a 50% chance of passing on the disease mutation to the son. Some of the autosomal recessive PIDs (where both parents are carriers) include:
  • Severe Combined Immune Deficiency
  • Chronic Granulomatous Disease
  • Ataxia-Telangiectasia
In families with the autosomal recessive mutation, there is a 25% chance of each child being affected with the disease, 25% chance of a child with a carrier mutation and 25% chance of a child with no carrier/disease mutation.
  • Some of the PIDs can be inherited in an autosomal dominant pattern (50% chance of each child inheriting the disease) where one parent has the disorder:
  • Hyper IgE Syndrome caused by mutations in STAT3 (Jobs syndrome)
  • Hypogammaglobulinemia
  • DiGeorge Syndrome
Genetic counselling is important for families where PID is passed on to the children to ensure that other family members are not carriers. In families where one child is affected with PID, parents can opt for prenatal testing to have a healthy child.

An infant who is born with PID is likely to develop symptoms within a few months. Many babies present with common cold which turns into more severe bronchitis or pneumonia. Some of the signs and symptoms of PIDs include:

  • four or more infections in a year in the eyes, ears, lungs, skin, mouth and genitals
  • infections do not clear up without IV antibiotics
  • severe infections like septicemia and other bacterial infections
  • chronic thrush in the mouth and throat
  • frequent bouts of pneumonia
If the pediatrician suspects PID because the child presents with chronic, untreatable infectioins, he/she may ask for a number of tests:
  • blood tests – to check for normal levels of infection fighting protein (immunoglobulins). Blood tests can also check if the body is producing antibodies which kill bacteria and viruses
  • next-generation sequencing (NGS) and whole exome sequencing (WES) is used when PID is difficult to diagnose because of complex and atypical symptoms
Currently, no permanent cure is available for PID except stem cell transplant for some forms of PID. Treatment is aimed at treating and preventing infections and boosting the immune system. Management of Infections Children and adults with PID have to be managed for infections with interventions like IV antibiotics and hospitalization if required. Long-term antibiotic therapy may be required in some cases where there is a risk of damage to the respiratory system. Medications are used to treat chronic symptoms like fever, sinusitis and chest congestion. Boosting the immune system
  • Immunoglobulin therapy comprises antibody proteins required for the immune system to fight infections. Usually this is in the form of an IV drip and needs to be given every 2-3 weeks
  • Gamma interferon therapy is used to treat chronic granulomatous disease. This is a substance which can fight viruses and stimulate immune system cells. This can be given as an intramuscular injection three times a week
  • Growth factors are used when the immune system lacks white blood cells. Stimulating the production can help prevent and fight infections

Gene therapy has the potential for a permanent cure for PIDs.Gene therapy research for the PIDs began as early as 1990. In gene therapy, the defective genes causing PID are replaced with healthy genes using a vector for delivery. The patient’s stem cells are extracted and the same corrected cells are infused back into the patient. Some form of conditioning with chemotherapy may be required prior to the procedure. The biggest advantage of gene therapy is there is no chance of rejection like in the case of bone marrow/stem cell transplant.

Some of the gene therapy trials for PIDs have cured around 20 children with X-linked severe combined immunodeficiency (X-SCID). In 2000, 14 patients with X-linked chronic granulomatous disease (CGD) underwent gene therapy in centres in the US, Europe and Korea. Currently gene therapy trials for Wiskott–Aldrich syndrome (WAS), X-linked lymphoproliferative disorder (XLP) and two forms of hemophagocytic lymphohistiocytosis (HLH) are in the research phase.

Children and adults with PID can participate in all life activities and must be encouraged to go to regular schools, colleges and participate in social activities. Genetic counselling and psychosocial counselling must be made available whenever required with other supportive measures. While one needs to be careful and avoid unnecessary infections, it does not mean that individuals cannot participate in most life activities.

Individuals with PID must maintain good hygiene at all times by regular bathing and washing of hands with soap and water. A healthy, balanced diet, physical activity, sufficient sleep and avoiding stress can prevent unnecessary infections. All individuals with PID must check with their doctor before taking any vaccinations.

If there is a known case of PID in the family, it is absolutely essential for closest relatives like siblings, uncles, aunts and cousins to test for carrier status.

If a woman with a carrier status is pregnant, prenatal test is essential to determine if the fetus has the disease mutation.