PRIMARY IMMUNODEFICIENCY DISEASE IN CHILDREN

In a nutshell, the immune system defends the body from infectious agents and foreign materials through different mechanisms. One type of response to infections is called the innate or natural immunity, which uses specialized cells and substances (that are already intrinsic to the body), to eradicate the invading organisms. These can involve “ingesting” the offending organism, or secreting substances that alert and “call for help” from surrounding cells.

The second type of response, known as the acquired or adaptive immunity, makes use of T cells and B cells that first require exposure to specific microorganisms. These special types of cells constantly undergo small changes in their genetic material as they learn distinct structures from invading organisms and use these to identify and eradicate future infections.

What is an immunodeficiency?

Simply put, an immunodeficiency is a defect in one or more components of the immune system, causing errors in body defenses. This can cause an affected individual to become more prone to infections or become much more ill when hit with mild infections.

Defects in the immune system may be roughly divided into primary and secondary immunodeficiencies. This article focuses on the causes and different types of primary immunodeficiencies.

What is a primary immunodeficiency?

Primary immunodeficiencies are weaknesses in the immune system caused by inherited errors in the genetic code. These conditions are more commonly seen in children.Children with primary immunodeficiencies are often predisposed to severe infections, autoimmune disorders, blood disorders, and even some types of cancer.

What are signs of an underlying immunodeficiency?

The most common sign of a possible primary immunodeficiency is a history of recurrent infections from the upper and lower respiratory tract. The well-known list of 10 warning signs of primary immunodeficiency have detected around 30% of cases. For children, these warning signs are as follows:

1. Four or more new ear infections within one year
2. Two or more serious sinus infections within one year
3. Two or more months on antibiotics with little effect
4. Two or more pneumonias within one 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 septicemia
10. A family history of primary immunodeficiency

Other signs include infection/s in multiple areas of the body that may be increasing in frequency and becoming more severe as new infections crop up. Some children experience infections that last much longer than usual. A history of severe symptoms in response to a typically mild infection, needing hospital admission or intravenous antibiotics, may also indicate a possible primary immunodeficiency. Other children may also experience gastrointestinal or skin conditions.

Types of Primary Immunodeficiency

Antibody Disorders (B-Cell Defects)

B-cells, also referred to as B lymphocytes, are immune cells that create antibodies when exposed to antigens. Antibodies are molecules that identify infectious agents, allowing these foreign organisms to be targeted or attacked by other immune cells. B cells may also produce cytokines.

Antibody disorders are the most common type of primary immunodeficiency. In this condition, B cells are either absent, or present but in abnormal amounts or quality. Symptoms appear later than expected due to the protective nature of maternal antibodies that infants receive while inside the womb. Once these antibodies wane at around 5 to 7 months of age, there is no mountable immune response to infectious triggers.

Symptoms may start to appear as early as 3 months of age, which are usually recurrent bacterial infections of the ears, lungs, and sinuses. This is because bacteria with a specialized capsule, which B cells normally eradicate in the body, commonly cause these types of infections.

Common bacteria such as staphylococci and streptococci, as well as enterovirus, Giardia and Cryptosporidia can easily attack the immune system. Infants may develop recurrent lung infections, malabsorption and gastrointestinal symptoms, arthritis, and even infections of the central nervous system, such as meningoencephalitis. There is some risk of developing certain malignancies, such as lymphomas and thymomas.

T-cell Defects

T-cells, also known as T lymphocytes, are immune cells created in the bone marrow. They migrate to the thymus, then through the bloodstream, to arrive at the spleen, lymph nodes, appendix, and tonsils. T cells play various roles in immunity, such as secreting cytokines and directly killing infected or dysregulated cells.

In T-cell defects, T lymphocytes may be present or absent. Because these cells are important in the development of B cell functions, T-cell defects can lead to B-cell defects as well.

This condition usually starts when a child turns 2 to 6 months old. Some types of bacteria, viruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as certain fungi like Candida and Pneumocystis are the common causes of infection in this type of immunodeficiency.

Children are commonly malnourished with poor weight gain, diarrhea, and fungal infections. In rare and very severe cases, immunization with BCG and chickenpox vaccines may not work well. Administering vaccines in children with T-cell defects may or may not be done, as the decision is made by qualified doctors on a case-to-case basis.

Severe combined immunodeficiency (SCID) is the most severe type of T-cell defect. Infants with this condition are undernourished with a very low weight for age, insufficient food intake, diarrhea, chronic skin or blood conditions, and repeated severe infections.

Phagocytic Disorders

Neutrophils are a type of white blood cell that attack microorganisms by ingestion or release of enzymes. On the other hand, monocytes are another type of white blood cell that engulfs foreign organisms, although much of its functions are not yet well established.

Any abnormalities in neutrophils or monocytes are classified as phagocytic disorders. Neutrophils in this disorder are unable to produce hydrogen peroxide, a substance necessary for neutralizing some invasive bacteria and fungi. Children with this condition present with recurrent skin infections, including abscesses, and severe fungal infections.

Chronic granulomatous disease is the most common type of phagocytic disorder. Symptoms include problems in wound healing, granuloma formation, and infections affecting the skin, lungs, liver, bones, and lymph nodes. Another type of phagocytic disorder called leukocyte adhesion deficiency is seen in infants in their first month of life. This is characterized by ulcers around the anus, and a delay in falling off and separation of the umbilical cord from the navel.

Complement Defects

The complement system is a set of proteins found in the blood, that help activate other immune cells, hone in and detect harmful organisms, and promote inflammation in affected areas.

Complement disorders are rare, comprising only 2-3% of primary immunodeficiency cases. Like antibody disorders, children with this condition are easily infected by organisms with a specialized capsule, such as streptococci, Neisseria meningitidis, and Haemophilus influenzae. Conditions such as arthritis, bloodstream infections and meningitis are common in this disorder.

Living with a Primary Immunodeficiency

Children diagnosed with primary immunodeficiencies need special care and benefit from an early diagnosis. Since they are at risk for autoimmune disorders, blood disorders and some types of cancer, a complete medical evaluation can help detect the specific type of immunodeficiency and any associated conditions a child may have.

An important aspect in managing a child with this disorder is to ensure proper infection control and prevention. This includes proper handwashing measures, regular dental hygiene, appropriate exercise, and diet, as well as adequate sleep. Children with primary immunodeficiency should avoid close contact with potentially sick people and persistently stressful triggers or situations. Appropriate vaccinations should be completed when possible.

There are various treatment options for primary immunodeficiency, depending on the type involved. These include antibiotics, immunoglobulin therapy, growth factors, interferon-gamma therapy, stem cell transplants, or gene therapies.

Summary

Primary immunodeficiencies are due to inherited defects in the immune system. Various symptoms include infections of the ear, sinuses, and the lungs. Children may have diarrheal or skin symptoms and are often malnourished. Timely diagnosis and proper care of children with primary immunodeficiencies can help prevent severe infections and provide a better quality of life.

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References:

• Kliegman, R.M. et al. (2020). Part 13 Immunology. Nelson Textbook of Pediatrics 21st edition. Elsevier.
• Chinn, I.K., & Orange, J.S. (2019). Immunodeficiency Disorders. Pediatrics in Review May 2019, 40 (5) 229-242.
• Reust, C.E. (2013). Evaluation of Primary Immunodeficiency Disease in Children. Am Fam Physician. 2013 Jun 1;87(11):773-778.
• Primary Immunodeficiency (PI) (2020). Office of Science (OS), Office of Genomics and Precision Public Health. Centers for Disease Control and Prevention. Taken from: https://www.cdc.gov/genomics/disease/primary_immunodeficiency.htm
• Leonardi, L. et al. (2020). Update in primary immunodeficiencies. Acta Biomed. 2020; 91(Suppl 11): e2020010.
• O’Sullivan, M. D. & Cant, A.J. (2012). The 10 warning signs: a time for a change?. Curr Opin Allergy Clin Immunol 2012, 12:588–594.
• Chronic Granulomatous Disease. American Academy of Allergy, Asthma & Immunology. Taken from: https://www.aaaai.org/conditions-treatments/primary-immunodeficiency-disease/chronic-granulomatous-disease

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