Immunodeficiency

What is Immunodeficiency?

Immunodeficiency happens when elements of the immune system, such as specific immune cells and proteins, don’t work properly or are absent. This can be primary, like Bruton disease, or secondary, like HIV.

Primary immunodeficiency refers to different disorders related to immune cells and/or proteins:

1. Bruton disease: In this condition, usually found in baby boys around 5-6 months old, there’s something wrong with a gene that affects an important protein in the body. Because of this, the body has a low level of certain important antibodies. Children with this disease often have repeated bacterial infections. Giving large amounts of certain antibodies can help, but severe infections requiring bone marrow transplant can happen.

2. Selective IgA Deficiency: These patients are more likely to have repeated sinus and lung infections due to reduced IgA antibodies, the most common immunoglobulin deficiency.

3. DiGeorge syndrome: This disorder means the body lacks a specific part of the immune system called thymus. This causes more fungal and viral infections. It can be fixed by transplanting a fetal thymus.

4. Chronic Mucocutaneous Candidiasis: With this disorder, the function of certain immune cells is compromised. Patients have normal immunity to most organisms except for Candida fungus. Antifungal treatments can help.

5. Hyper-IgM syndrome: This condition involves bacterial infections from early childhood due to defective immune proteins known as immunoglobulins. Immunoglobulin therapy is recommended.

6. Interleukin-12 receptor deficiency: Mycobacterial infections are frequent due to the lack of a specific immune protein receptor. This treatment involves selected antibiotics.

7. Severe combined immunodeficiency disease (SCID): There is a failure of essential immune cells to develop properly, leading to various infections. Specialized medications can treat infections, and transplants can help fight off infections without needing drugs to suppress the immune system.

Secondary immunodeficiency involves different conditions:

1. Use of Drugs: Steroids can directly impact immune cells and their functions, especially T cells.

2. Nutrient Deficiencies: A lack of important nutrients can impact the immune system, affecting its ability to fight off infections. It requires essential elements like zinc and iron.

3. Obesity: Obesity can lead to impaired immune responses, compromising the body’s natural defense mechanisms.

4. Acquired Immune Deficiency Syndrome (AIDS): AIDS is caused by the human immunodeficiency virus (HIV). It results in immune dysfunction by directly damaging the immune cells, particularly CD4 T cells. The response to antigens becomes decreased, leading to ineffective control of viral replication and infection.

What Causes Immunodeficiency?

Primary immunodeficiency diseases are conditions that happen because of built-in problems with the immune system’s cells, including T cells, complement components, and phagocytes. If you have recurrent pneumonia, which is often caused by bacteria outside the cells, it might suggest a deficiency in your antibodies. On the other hand, recurrent fungal infections could be due to a lack of T lymphocytes, a type of white blood cell that helps protect your body from infections.

Severe combined immunodeficiency disorders (SCID) are severe conditions that usually cause affected children to die in the first two years of life. SCID appears more often in boys and is caused by a defective gene on the X chromosome in more than half of cases. This faulty gene affects a crucial part of the receptors for multiple interleukins, proteins that regulate immune responses. Some forms of SCID are caused by other genetic defects that affect enzymes, leading to problems in DNA synthesis and cell replication. Few SCID cases may stem from mutations in genes referred to as RAG1 or RAG2.

The DiGeorge anomaly is a condition arising from a defect in specific parts of the pharyngeal pouches (cavities in the embryonic stage of development), leading to developmental issues with the thymus, a gland involved in immune responses. Depending on the severity of the defect, there might be a varying degree of T-cell deficiency, which refers to a decreased number of T cells in the body. Infants with this condition often have partial deletions of specific sections of chromosomes, leading to diverse health problems.

In the case of the bare leukocyte syndrome, there’s a mutation in a gene that leads to the absence of class-II MHC molecules that present foreign substances to the immune cells, affecting how the body reacts to infections. Another mutation in a different gene can result in a lack of class-I MHC molecule expression, leading to a deficiency in a particular type of T cells, the CD8+ T lymphocytes.

Secondary immunodeficiency can be caused by particular medications and viral infections. For instance, HIV causes AIDS, which is a condition that significantly weakens the immune system and makes affected individuals susceptible to other infections and cancers.

Poor nutrition can also cause secondary deficiency, for example, protein-energy malnutrition can affect cell-mediated immunity and phagocytosis, which means how well your immune cells can consume foreign bodies. Essential nutrients like Zinc, Iron, vitamins B6 and B12, selenium, and copper are necessary for the immune system to work well, and their deficiency can have diverse effects on immunity. Chronic conditions such as cancer, burns, chronic kidney disease, multiple traumas, and chronic infections can also lead to nutritional deficiency and hence, a compromised immune system.

Risk Factors and Frequency for Immunodeficiency

In Korea, from 2001 to 2005, 152 patients were found to have primary immunodeficiencies (PID), a group of disorders where part of the body’s immune system is missing or doesn’t function correctly. This equated to 11.25 cases for every million children. The most common types of PID were deficiencies in the production of antibodies, which help your body fight off bacteria and viruses, accounting for 53.3% of cases. The second most frequent PID issue was related to phagocytes, a type of immune cell that eats up harmful bacteria, making up 28.9% of cases.

This pattern was also evident in other countries. For example, Sweden reported similar findings between 1974 and 1979 with the majority of their 201 reported cases being antibody deficiencies (45%), followed by phagocytic disorders (22%). Similarly, in Taiwan, most of the 37 PID patients identified between January 1985 to October 2004 had problems with antibody production (46%). Studies in South Africa and Singapore between 1983-2009 and 1990-2000 respectively showed a similar trend.

The frequency of common variable immunodeficiency (CVID), where the body can’t produce enough antibodies, varies across the globe. This can lead to an increased risk of infections.

On another note, secondary immunodeficiency, the most common one being caused by HIV, leads to acquired immunodeficiency syndrome. The prevalence of HIV varies worldwide. As of 2016, around 37 million people were living with HIV globally, with 20.9 million undergoing antiretroviral therapy (ART) in 2017. The widespread use of ART has curbed the number of people dying from HIV-related diseases, reflecting a 45% decrease since 2005. Despite this, certain populations remain at high risk, including men who have sex with men, prison inmates, drug users, sex workers, transgender individuals, patients receiving blood transfusions, and babies born to HIV-infected mothers.

Signs and Symptoms of Immunodeficiency

Immunodeficiency disorders are conditions where your immune system doesn’t work properly, which can make you more likely to get infections. Some people might be born with these disorders, while others might get them due to health conditions or treatments. If you have an immunodeficiency disorder, you might experience different symptoms and medical issues.

Common history and background factors include:

• Being male
• Frequently getting infections
• Getting infections from unusual or opportunistic microorganisms
• Frequently taking antibiotics without getting better
• Having internal inflammation or infections
• Having blood issues like anemia and a low platelet count

During a medical exam, a doctor might find:

• Different types of infections, like sinus or lung infections, middle ear infections, meningitis, septicemia, and arthritis
• Fever or cough
• Tiredness or weakness
• Signs of poor nutrient absorption in your intestines
• Bronchiectasis, a condition where the airways in your lungs get larger and cause breathing problems
• Signs of autoimmunity or a graft versus host reaction
• Tonsillitis, skin infections, or serious reactions like acute suffocation
• Failures of multiple organs, such as the liver and kidneys, or physical issues like asymmetrical eye sockets and a cleft palate
• Sore throats, eye infections, or skin abnormalities

Additionally, a doctor might find:

• Enlarged liver or spleen
• Various types of cancer
• Eczema or failure to grow properly
• Diarrhea or diseases like tuberculosis
• Blood problems, like unusual bleeding or anemia
• Short height, swelling in your throat (laryngeal edema), or problems with coordination (ataxia)
• Unusual skin features, like telangiectasia, which are small, visible blood vessels, or opportunistic cancers like Kaposi’s sarcoma

The list goes on to include issues such as:

• Lack of lymph nodes
• Bleeding
• Thymus gland issues
• Unusual facial features
• Recurrent abscesses
• Unhealthy weight loss (cachexia)
• Oral candidiasis (fungal infection)
• Symptoms resembling lupus
• Swelling (angioedema)
• Malnutrition
• Heart issues
• Low body temperature (hypothermia) or septic shock

Along with:

• Weakness (asthenia)
• Loss of appetite
• Weight loss
• Headache
• Convulsions
• Allergic reactions (anaphylaxis)
• Hypoparathyroidism or obesity

There can also be mental, developmental, and growth problems, such as:

• Mental retardation
• Dwarfism
• Slow growth in the womb (intrauterine growth retardation)
• Physical abnormalities, like albinism or cafe-au-lait spots
• Skeletal issues, like osteoporosis, fractures, scoliosis, or hyperextensible joints
• Poor wound healing

Furthermore, a doctor might notice:

• Adrenal disease or diabetes
• Thyroiditis (inflammation of the thyroid gland)
• Thickening of the skin on the palms and soles (palmoplantar hyperkeratosis)
• Issues with the urinary or genital organs
• Swelling and redness in veins (venous telangiectasias)
• Problems with bone development (chondrodysplasia)
• Amyloidosis, a condition where abnormal proteins build up in your organs
• Issues with the mouth, like periodontitis (gum inflammation) or delayed separation of the umbilical cord

These disorders can be complex and impact many different parts of the body. If you or a loved one has these symptoms, especially recurrent or persistent infections, it’s important to seek medical advice.

Testing for Immunodeficiency

When a doctor suspects a patient is experiencing problems with their immune system, they may perform various tests to help make a diagnosis. Various tests including analyzing the amounts and activity of certain immune cells and proteins in the blood are required. These immune cells are antibodies and T and B-lymphocytes (a type of white blood cell that plays a key role in our immune response).

One way doctors check immune health is by measuring the levels of different types of antibodies called immunoglobulins (proteins that help fight off infections). These include types such as IgG, IgM, IgA, and IgE. Moreover, they might look at how these antibodies respond to certain vaccines or infections like tetanus, diphtheria, and polio as well as natural exposures like rubella, measles, and chickenpox.

Another part of the immune system that may be tested is the phagocytic function. In simpler terms, the doctor may examine how well certain types of your white blood cells are able to consume and destroy harmful bacteria or infected cells. They may also evaluate aspects of your immune response known as the complement system, which involves a series of proteins that cooperate with antibodies and phagocytes to protect the body from infection.

Further tests may look at the body’s reaction to its own cells. The presence of anti-nuclear antibodies (ANA) and other similar markers can indicate autoimmune conditions, where the immune system mistakenly attacks healthy tissue.

Besides these, other tests involve taking cultures of body fluids such as blood, urine, or sputum (mucus coughed up from the lungs) to look for the presence of pathogens (like bacteria or viruses). Additionally, doctors might perform tests to evaluate the clotting function of the blood and conduct imaging tests like X-rays or CT scans to identify any physical abnormalities linked to immunodeficiency.

In a nutshell, the checklist to diagnose an immune deficiency disorder is long and complex because doctors have to investigate different parts of the immune response to piece together an accurate, holistic picture of what’s happening in the body.

Treatment Options for Immunodeficiency

Immunoglobulin therapy is a treatment often used for conditions where the immune system is weakened or not functioning properly, such as X-linked agammaglobulinemia, certain lupus-like syndromes, and transient hypogammaglobulinemia of infancy.

Transfer factor, which is a preparation made from white blood cells, has been found useful in treating a variety of diseases, including pneumonia in people with suppressed immune systems, Behcet’s disease, recurrent viral infections in those with weakened immune systems, and Wiskott-Aldrich syndrome, a rare genetic disorder.

Antibiotics can prove helpful in fighting off infections in people with weakened immune systems due to conditions like HIV/AIDS, chronic mucocutaneous candidiasis (a fungal infection), severe combined immunodeficiency diseases, and nutrient deficiencies like lack of zinc and iron.

Antifungal drugs are often used for conditions like DiGeorge syndrome, severe combined deficiency diseases, and chronic granulomatous disease. They are also helpful for people with weakened immune systems due to obesity, HIV/AIDS, or the use of immunosuppressors, which are medications that suppress the immune system.

Antiviral drugs are used for conditions such as severe combined deficiency diseases, recurring viral infections in those with weakened immune systems, and HIV/AIDS. They are also beneficial for certain transplant recipients.

Immunosuppressors are used in treatment of diseases like systemic lupus erythematosus and Wiskott-Aldrich syndrome. They are also used when there are deficiencies in the immune system.

Transplanting bone marrow can be an effective course of treatment for conditions like RAG-1/RAG-2 SCID (a severe combined immunodeficiency disease), Wiskott-Aldrich syndrome, acute leukemia, and others. DiGeorge syndrome can be treated using thymus transplantation.

In advanced stages of cancer, cytokines, which are proteins that help direct the immune response, are often utilized. Examples include Interleukin-2, Interleukin-7, and Interleukin-12 among others.

Nutritional supplements such as vitamins A, C, E and B6, as well as iron, zinc, selenium, and copper, can provide essential support for those with conditions like primary immunodeficiency with malnutrition, graft-versus-host reaction, and diseases with impaired cell-mediated immunity. They are also helpful in addressing recurrent and chronic bacterial infections, as well as complications arising from burns.

The Bruton Tyrosine Kinase inhibitor Ibrutinib, which is currently in Phase III Clinical Trials, has potential in treating conditions like chronic lymphocytic leukemia and small lymphocytic lymphoma.

Interferon gamma, a type of protein produced by the immune system, has shown promising activity against conditions like chronic granulomatous disease, bladder carcinoma, melanoma, and Chagas disease. It’s also used in the treatment of HIV/AIDS and cryptococcal meningitis, an infection of the brain caused by a type of fungus.

What else can Immunodeficiency be?

These disorders are illnesses that occur due to different types of bacterial infections. Some common examples include pneumonia, meningitis, ear infections, diarrhea, bladder infections, blood infections, bone infections, skin infections, eye infections, liver inflammation, and stomach flu. Sometimes, a parasite called Giardia lamblia can also cause problems with nutrient absorption in the intestines. These conditions typically begin in early childhood and include a variety of immune disorders such as:

• X-linked agammaglobulinemia
• IgG selective deficiencies
• Transient hypogammaglobulinemia of infancy
• Common variable immunodeficiency
• Hyper-IgM syndrome
• Certain types of Severe Combined Immunodeficiency Diseases (SCID)

Each of these disorders can be identified to reach a proper diagnosis:

• X-linked agammaglobulinemia typically occurs in male infants around 5-6 months old, usually once the immunity they obtained from their mother starts to fade. It’s characterized by low levels of antibodies in the blood and DNA studies can reveal genetic mutations specific to this condition.
• Transient hypogammaglobulinemia of infancy is similar, but is caused by the immune system not being fully developed yet. This condition typically stops causing recurrent bacterial infections once the infants’ bodies start making their own antibodies.
• IgG selective deficiencies lead to recurring bacterial infections. Doctors can identify this by finding low or absent levels of specific antibodies in the blood. This can often be corrected with treatments that include receiving antibodies.
• Common variable immunodeficiency can cause recurring bacterial or viral infections, but these usually start to appear after children have grown up. Doctors will try to rule out all other causes of antibody deficiencies before they diagnose this condition.
• Hyper-IgM syndrome features recurring bacterial infections found in X-linked agammaglobulinemia. cause is different: a genetic mutation affects the immune cells, interfering with the body’s ability to produce the right kinds of antibodies. Genetic testing can help diagnose this condition.
• Severe Combined Immunodeficiency Diseases (SCID) also lead to frequent bacterial infections. However, patients with SCID can also suffer from cancer and recurring viral, fungal, parasitic and opportunistic infections. This helps doctors rule out SCID as the cause.

What to expect with Immunodeficiency

People with B-cell deficiencies typically have a better chance of recovery if they receive treatments such as intravenous immunoglobulins (medicines given directly into the blood) every few weeks and subcutaneous infusion (fluid administered into the skin) once or twice per week.

T-cell deficiencies like DiGeorge syndrome generally have a less favorable outcome. But, if a thymus transplant (a procedure where a healthy thymus is transplanted in place of a defective one) is successfully done, the chances of a better recovery increase.

Severe Combined Immunodeficiency (SCID) has the least positive outlook unless a successful bone marrow transplant (where healthy marrow is placed into a patient) has been carried out.

Immunodeficiency disorders that come with congenital disabilities (conditions present from birth) can be treated with surgery and further improved by using immunotherapy (a type of treatment that helps the immune system fight diseases).

To improve the quality of life for patients with these primary immunodeficiencies, long-term treatment with medications that fight against bacteria, viruses, and fungi is necessary.

Most primary immunodeficiencies are rare, hence each patient’s treatment needs to be individually tailored, especially if caused by gene mutations or a missing enzyme. Currently, promising outcomes are being observed with the use of gene therapy and stem cell transplantation.

In the case of secondary immunodeficiency disorders like HIV/AIDS, long-term treatment with antiretroviral drugs (medicines that stop the virus from multiplying) is needed, as well as preventative treatment for fungal infections.

If patients are malnourished, measures need to be put in place to provide a balanced diet that’s high in proteins and includes all necessary vitamins, minerals, and other nutrients.

For drug-related immunodeficiencies, the prognosis varies, mainly in patients with autoimmune disorders, inflammatory diseases, and organ transplants.

Similarly, the prognosis for patients with malignancies (cancers) depending on the type of cancer, its progression and severity, and the response to various treatment methods such as chemotherapy, radiotherapy, and even the use of natural products.

Possible Complications When Diagnosed with Immunodeficiency

There are various severe and sometimes life-threatening complications that can be caused by different harmful agents such as bacteria, viruses, fungi, and parasites. Other tragic outcomes can be opportunistic cancers which take advantage of an impaired immune system, or septic shock, which is a severe infection that spreads throughout the body.

Unfortunately, other conditions include an extreme allergic reaction known as anaphylactic shock, disorders that prevent blood from clotting properly, and cardiac failure (heart failure). Some may also experience acute or chronic kidney failure, difficulty in proper breathing or respiratory insufficiency, and the malfunction of multiple organs.

Several potential complications may also arise during pregnancy such as an underdeveloped baby in the womb, or more tragically, a fetal demise. Those with systemic lupus erythematosus or other systemic rheumatic disorders are also at risk. These complications also extend to endocrine gland disorders, congenital disabilities, or disorders that are present from birth, and metabolic disturbances.

Neurological complications can include seizures or coma, while chemical imbalances in the body can lead to conditions known as acidosis or alkalosis. Sadly, these complications can result in premature death.

• Life-threatening infections caused by harmful agents
• Opportunistic cancers
• Septic shock
• Anaphylactic shock
• Bleeding disorders
• Cardiac failure
• Acute and chronic kidney failure
• Respiratory problems
• Multiple organ failure
• Issues during pregnancy
• Situations associated with systemic lupus erythematosus and other systemic disorders
• Endocrine gland disorders
• Congenital disabilities
• Metabolic disturbances
• Neurological complications
• Acidosis/alkalosis
• Premature death

Preventing Immunodeficiency

People with genetic or uncommon immune system disorders need to know that there’s a chance they could have children who also have these medical problems. They also need to understand the different treatment options available for these disorders. Additionally, they should be aware of the need for monitoring during pregnancy and the possibility of therapeutic abortion if required. These individuals also need to be advised about the importance of preventing children from inbreeding.

People with HIV/AIDS can still start a family, but they should know how important it is to regularly check their HIV load and CD4 count throughout pregnancy, delivery, and while breastfeeding. Based on these results, they can then be treated to prevent HIV from being passed onto the baby. They should also consider lifestyle changes and habits to reduce the risk of passing on the HIV virus and lowering the amount of virus in the body. This includes safe practices like using condoms, abstaining from sex, and avoiding the use of injectable drugs.