Brief overview
- Description: The functioning of the immune system is more or less impaired, either temporarily or permanently.
- Symptoms or consequences: increased susceptibility to infections, infections often more severe and prolonged, infections with “unusual” germs, disturbed immune regulation (with recurrent fever, skin changes, chronic intestinal inflammation, etc.), sometimes increased risk of cancer.
- Causes: Primary (congenital) immunodeficiencies are genetic. Secondary (acquired) immunodeficiencies result from malnutrition, a disease (such as HIV infection, cancer, autoimmune diseases), or medical therapy (e.g., taking immunosuppressants, radiation therapy, surgical removal of the spleen).
- Diagnosis: taking medical history, physical examination, blood tests, immunological and molecular genetic tests, etc.
- Treatment: depending on the type and severity of immunodeficiency. In the case of primary immunodeficiency, for example, by means of antibody infusions or stem cell transplantation. In the case of secondary immunodeficiency, treatment of underlying diseases.
What is immunodeficiency?
Doctors speak of immunodeficiency when the immune system is more or less severely restricted in its ability to function – either temporarily or permanently. It can then no longer perform its tasks optimally. These consist of fighting foreign bodies (such as bacteria, viruses, pollutants) and eliminating damaged or pathologically changed cells (such as cancer cells).
In addition to immunodeficiency and immunodeficiency, the terms immunodeficiency and immunosuppression (immunodepression) also refer to a weakened immune system.
In some cases, however, “immunosuppression” is also used in a narrower sense, namely only for an immune deficiency that results from therapeutic measures. For example, immunosuppressive therapy after organ transplantation aims to suppress the patient’s immune system to such an extent that it does not reject the implanted foreign organ. Read more about therapeutic immunosuppression here.
In addition to medical therapies, various congenital and acquired diseases can also be the reason for an immune deficiency.
How does it manifest itself?
As a rule, immunodeficiencies are accompanied by an increased susceptibility to infections: those affected are more susceptible than immunodeficient individuals to infections with pathogens. For example, they suffer from recurrent respiratory infections.
Because the weakened immune system is also poorly able to resist pathogens that have already invaded the body, the infections are often more severe and prolonged than if the body’s defenses were intact. In the case of bacterial infections, the necessary antibiotic therapy can therefore take a very long time.
Another possible sign of a weakened immune system are infections with opportunistic pathogens. These are germs that can only or predominantly cause an infection when the immune system is weak. A healthy immune system, on the other hand, is able to keep them in check.
One of these opportunistic germs is Candida albicans. This yeast fungus can cause vaginal thrush and thrush, among other things. The protozoan Cryptosporidium parvum – a diarrhea pathogen – also makes its appearance particularly when the immune system is weakened.
Impaired immune regulation is sometimes the only symptom of a primary immunodeficiency – there is not always also an increased susceptibility to infections.
People with an immunodeficiency sometimes also have an increased risk of cancer. For example, combined immunodeficiencies – congenital forms of immunodeficiency – are more likely to develop lymphoma. People infected with HIV are also more susceptible to cancer.
In the next section, you will learn more about the symptoms of selected immunodeficiencies.
What can cause immunodeficiency?
Basically, physicians distinguish between:
- Congenital (primary) immunodeficiency: It is genetically determined.
- Acquired (secondary) immunodeficiency: It is triggered by various underlying diseases or external factors such as certain medications.
Congenital (primary) immunodeficiency.
Primary immunodeficiencies (PID) are very rare. They are based on a genetic defect. This is either inherited from the parents or arises spontaneously during fetal development in the womb.
In both cases, affected individuals are born with the immunodeficiency: elements of their immune system are missing or their function is impaired.
When primary immunodeficiencies manifest themselves
If, on the other hand, primary immunodeficiency is primarily due to impaired antibody formation by B cells (B lymphocytes), this only comes into play somewhat later: after birth, babies benefit for some time from “nest protection,” i.e., from the maternal antibodies (immunoglobulins G) that were transferred to the child during pregnancy. They protect it from infections during the first months of life, but are degraded over time.
Then antibodies produced by the child’s own immune system normally take over protection against infection. In some primary immunodeficiencies, however, it is not able to do this – the previously hidden immunodeficiency now becomes apparent.
Babies who are breastfed also receive maternal antibodies – those of the immunoglobulin A class – through their mother’s milk. However, these only exert their protective effect on the mucous membranes of the upper digestive tract (which comes into contact with the mother’s milk). They do not enter the child’s blood, but are broken down in the stomach.
In addition, there are primary immunodeficiencies that manifest themselves later in life – sometimes only in adulthood.
Classification of primary immunodeficiencies
1. combined B- and T-cell defects.
In this group of congenital immunodeficiencies, the development or function of both T lymphocytes (T cells) and B lymphocytes (B cells) is impaired.
This is the case, for example, in severe combined immunodeficiency (SCID). This collective term covers the most severe forms of immunodeficiency. All of them are based on a defect of the T cells. In addition, many forms also lack B cells and/or natural killer cells (NK cells).
After loss of the “nest protection” (see above), the affected children repeatedly contract infections that are often very severe or even fatal. Even childhood diseases such as chickenpox quickly become life-threatening for these children.
2. defined syndromes with immunodeficiency
These include congenital immunodeficiencies within complex genetic syndromes that also affect other organ systems.
One example is DiGeorge syndrome: the immune system of affected children is weakened because the thymus gland is underdeveloped or completely absent. As a result, affected individuals lack functional T cells. Recurrent viral infections are the result.
Wiskott-Aldrich syndrome is also associated with immunodeficiency. First, however, a congenital deficiency of blood platelets (thrombocytes) is noticeable in the children’s blood count. It is the reason why the babies tend to bleed:
Shortly after birth, punctate hemorrhages (petechiae) appear in the skin and mucous membranes. Later, bleeding of the digestive tract or within the skull often occurs. Typical for Wiskott-Aldrich syndrome are also eczemas, which resemble neurodermatitis and usually develop before the 6th month of life.
The immunodeficiency manifests itself from the 2nd year of life with recurrent opportunistic infections. These can manifest as ear infections, pneumonia, or meningitis, for example.
In addition, autoimmune reactions occur more frequently in Wiskott-Aldrich syndrome, for example in the form of vasculitis due to autoimmune causes. The risk of cancer is also increased.
3. defects with reduced antibody production
Sometimes the body cannot produce only one particular class of antibodies. In other immunodeficiencies of this group, the production of several or even all antibody classes is impaired. Examples of such immunodeficiencies are:
Selective IgA deficiency: this is the most common congenital immunodeficiency. Affected individuals lack antibodies of the immunoglobulin A type. However, many do not notice this. Others are prone to respiratory, gastrointestinal and urinary tract infections. In addition, the weakened immune system favors celiac disease-like symptoms, allergies, autoimmune diseases and malignant tumors.
Some affected individuals additionally lack single or multiple subclasses of the antibody class immunoglobulin G. They are then even more frequently plagued by infections.
Common variable immunodeficiency (CVID): Also called variable immunodeficiency syndrome. It is the second most common immunodeficiency. The blood levels of immunoglobulin G and immunoglobulin A are reduced here and often also that of immunoglobulin M. In the affected person this is noticeable.
In those affected, this usually becomes noticeable for the first time between the ages of 10 and 20 – the way in which this occurs varies:
Bruton syndrome (Bruton-Gitlin syndrome, X-linked agammaglobulinemia): People with this primary immunodeficiency cannot make antibodies at all because they lack B lymphocytes.
The underlying genetic defect is inherited via the X chromosome. Therefore, only boys are affected. They have only one X chromosome in their body cells. In girls, on the other hand, there are two, so that there is a “reserve” in case there is a genetic defect on one of the X chromosomes.
The impaired antibody formation becomes apparent from about six months of life, as soon as the nest protection fades. The children are then susceptible to severe recurrent infections, for example in the form of bronchitis, sinusitis, pneumonia and “blood poisoning” (sepsis).
Children from the age of two onwards often contract chronic meningitis, triggered by echoviruses.
4. diseases with disorders of immune regulation
Here, genetic defects are present that disrupt the complex regulation of immune reactions via various mechanisms.
In affected infants, there is an uncontrolled rapid proliferation of activated lymphocytes and macrophages. These immune cells secrete large quantities of pro-inflammatory messenger substances known as cytokines. As a result, the children develop a high fever. The liver and spleen enlarge (hepatosplenomegaly).
The levels of two or all three types of blood cells – red blood cells, white blood cells, platelets – drop (bicytopenia or pancytopenia). The increasing deficiency of neutrophil granulocytes (a subgroup of white blood cells) promotes severe bacterial infections as well as fungal infections, which are often fatal.
Other possible symptoms include swollen lymph nodes, jaundice (icterus), tissue swelling (edema), skin rashes (exanthema), and neurological signs such as epileptic seizures.
In addition to the familial (genetic) form of the disease, there is also an acquired (secondary) form of hemophagocytic lymphohistiocytosis. Its trigger may be, for example, an infection.
5. defects in the number and/or function of phagocytes.
A primary immunodeficiency affecting the oxygen-dependent metabolism of phagocytes is septic granulomatosis. It is the most common phagocyte defect.
Typical symptoms of this hereditary disease are recurrent purulent infections with various bacteria as well as yeast infections. Chronic infections often develop, which are accompanied by the formation of encapsulated pus foci (abscesses), for example on the skin and bones.
6. defects of the innate immunity
Innate immunity is based on mechanisms and structures that unspecifically defend against pathogens and other foreign substances. These include phagocytes, various proteins (such as acute phase proteins), and the skin and mucous membranes (as barriers to the outside world).
Defects in this innate immunity also result in immune deficiency, for example in the rare disease epidermodysplasia verruciformis:
Read more about epidermodysplasia verruciformis in the article Human papillomavirus (HPV).
7. autoinflammatory syndromes
In these diseases, excessive immune reactions cause inflammatory processes in the body and recurrent episodes of fever.
This disease mechanism underlies, for example, familial Mediterranean fever. In this rare disease, genetic changes (mutations) are present in the gene that contains the blueprint for the protein pyrin. This protein plays an important role in the regulation of substances that cause inflammation.
As a result, those affected repeatedly suffer from acute fever, which subsides on its own after one to three days. In addition, there is pain caused by the inflammation of serous membranes such as the pleura or peritoneum (chest pain, abdominal pain, joint pain, etc.). Some affected individuals also develop a skin rash and/or muscle pain.
8. complement defects
Genetic defects in the blueprints of such complement factors cause immune deficiency, which can manifest itself in different ways. For example, in the case of a factor D defect, the immune system can only defend itself with difficulty against bacteria of the genus Neisseria. These pathogens can cause meningitis, among other things.
In the case of a C1r defect, on the other hand, a clinical picture develops that is similar to systemic lupus erythematosus. In addition, affected individuals are prone to infections with encapsulated bacteria (such as Neisseria).
Learn more about the complement system here.
9. phenocopies of primary immunodeficiencies
To understand the term phenocopy, one must first know what “genotype” and “phenotype” mean. Genotype is the combination of hereditary traits on which a trait is based. The visible characteristics of this trait are called phenotype.
During pregnancy, the action of external factors interacting with certain hereditary traits can cause the formation of a trait to change – in such a way that the external appearances look like those of a different genotype. This is what physicians call a phenocopy.
Acquired (secondary) immunodeficiency
Much more common than a primary immunodeficiency is a secondary immunodeficiency. It can have several causes:
Medical treatments
The immune system can be specifically weakened with immunosuppressive drugs. This is done, for example, in the case of autoimmune diseases (e.g. multiple sclerosis) or after a transplant. In the first case, the aim is to bring the malfunctioning immune system under control; in the second, to prevent rejection of the implanted foreign tissue.
Anticonvulsants, which are used to treat epileptic seizures, can also impair the immune system.
The same side effect is known from cytostatic drugs. Physicians administer these agents to cancer patients as chemotherapy. Cancer treatment by means of radiation therapy can also be the cause of secondary immunodeficiency if the radiation in the bone marrow impairs the formation of blood cells and thus of important immune cells (white blood cells).
Cancer
Various cancers can affect elements of the immune system, i.e., weaken the body’s defenses in a direct way.
Malignant lymphomas (“lymph gland cancer”) as well as plasmocytoma or multiple myeloma originate from certain types of leukocytes. As a result, immunodeficiency develops here as well.
Infections
Various pathogens can weaken the immune system. A well-known example is HI viruses (HIV). The final stage of the HIV infection, which cannot be cured but can be controlled with medication, is the disease AIDS.
Epstein-Barr viruses (EBV) can also be responsible for a secondary immunodeficiency. They trigger glandular fever. They are also involved in the development of various cancers. These include Burkitt’s lymphoma (a representative of the non-Hodgkin’s lymphomas) and some Hodgkin’s diseases.
Measles viruses can also cause a weakened immune system, even some time after the disease has been overcome. Flu viruses (influenza A and B viruses) also temporarily dampen the effectiveness of the body’s defenses.
Systemic inflammatory diseases
Secondary immunodeficiency is also possible in other inflammatory autoimmune diseases such as rheumatoid arthritis and sarcoidosis.
Protein loss
Sometimes people develop immunodeficiency because they lack protein. The body needs the building blocks of proteins – amino acids – for the formation of immune cells, among other things.
In various diseases, the body can lose excessive amounts of protein through frequent diarrhea – with resulting immune deficiency. This can happen, for example, in chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis), celiac disease and intestinal tuberculosis.
However, immunodeficiency due to a large loss of protein can also be the result of a kidney disease, such as a disease of the renal corpuscles (glomerulopathy).
Large protein losses can also occur through extensive burns, which can lead to immune deficiency, among other things.
Other causes of secondary immunodeficiencies
Malnutrition is the most common cause of acquired immune deficiency worldwide. For strong defenses, the body needs sufficient protein, vitamins and minerals (e.g. copper, zinc), among other things.
In any case, those affected are susceptible to severe infections, which can even be life-threatening. The spleen is an important part of the immune system.
Other possible causes of secondary immunodeficiency include:
- Alcohol embryopathy (fetal alcohol syndrome, FAS): prenatal damage to a child caused by maternal alcohol consumption during pregnancy.
- Diabetes (diabetes mellitus)
- Liver disease
How is immunodeficiency diagnosed?
Immunodeficiency may be suspected, for example, if someone has infections with striking frequency, these often run a complicated course and are slow to heal. More detailed information on the medical history (anamnesis) helps the doctor to get to the bottom of the cause.
For example, it is important to know how often and which infections someone has had recently and how they progressed. Information on autoimmune diseases and abnormalities in the thorough physical examination (such as skin rashes or a palpably enlarged spleen) can also be informative for the physician.
Warning signs for primary immunodeficiencies
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Children |
Adults |
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pathological susceptibility to infection (ELVIS – see below) |
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disturbed immune regulation (GARFIELD – see below) |
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Failure to thrive |
Weight loss, usually with diarrhea |
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conspicuous family history (e.g. immunodeficiencies, pathological susceptibility to infections, lymphomas in close blood relatives) |
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Lack of antibodies (hypogammaglobulinemia), lack of neutrophil granulocytes (neutropenia), lack of platelets (thrombocytopenia) |
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Genetic evidence of primary immunodeficiency or positive neonatal screening for primary immunodeficiency |
ELVIS
ELVIS parameters indicate pathological susceptibility to infection due to a primary immunodeficiency:
E for pathogens: infections with opportunistic pathogens (e.g. pneumonia caused by Pneumocystis jirovecii) indicate a weakened immune system. The same applies to recurrent severe infections with “common” pathogens (such as pneumococci).
V for progression: Infections that persist for an unusually long time (protracted course) or respond only inadequately to antibiotics (in the case of a bacterial cause) are also a possible indication of a pathological immune deficiency.
It is also suspicious if the attenuated pathogens of a live vaccine (e.g. MMR vaccination) trigger an illness and this progresses with complications.
I for intensity: Serious infections (so-called “major infections”) are particularly common in primary immunodeficiency. These include inflammations of the lungs, meninges and bone marrow, “blood poisoning” (sepsis), and invasive abscesses (encapsulated foci of pus) from so-called “minor infections” such as otitis media, sinusitis and bronchitis.
Such “minor infections” can also – if they are persistent or recurrent – indicate a primary immunodeficiency.
S for sum: If someone has an infection very often, this also raises the suspicion of a weakened immune system that is particularly susceptible to disease.
GARFIELD
The acronym GARFIELD summarizes parameters that are typical for a disturbed immune regulation – another leading symptom of primary immunodeficiencies:
G for granulomas: The first manifestation of a primary immunodeficiency may be small-hoarded tissue nodules (granulomas) that are not accompanied by tissue destruction (necrosis) and consist of certain cells (epithelioid cells). They form especially in the lungs, lymphoid tissue, intestines, and skin.
A for autoimmunity: The impaired immune regulation in primary immunodeficiencies can also be reflected in autoimmune reactions, i.e. attacks by the immune system against the body’s own tissue.
Very often, blood cells are attacked, resulting in a significant reduction in their number (autoimmune cytopenia). The thyroid gland is also a frequent target of attack by a misguided immune system (autoimmune thyroiditis or Hashimoto’s thyroiditis).
Other examples of autoimmune consequences of an immune defect are rheumatoid arthritis, vasculitis, liver inflammation (hepatitis), celiac disease, hair loss (alopecia), white spot disease (vitiligo), type 1 diabetes and Addison’s disease.
E for eczematous skin diseases: Eczematous skin lesions are found in many primary immunodeficiencies. These often appear early (soon after birth) and are difficult to treat.
L for lymphoproliferation: This term refers to the pathological enlargement of the spleen, liver and lymph nodes or the development of tertiary lymphoid tissue, especially in the lungs and digestive tract. Lymphoid tissue is referred to as tertiary if it newly develops in the vicinity of inflammation.
D for chronic intestinal inflammation: Sometimes congenital immunodeficiencies present first with chronic intestinal inflammation. Immunodeficiency is especially likely to be a cause in chronic diarrhea that occurs early in life and/or is difficult to treat.
Blood tests
The various leukocyte groups and other blood cells can be examined under the microscope using a blood smear. To do this, a drop of blood is spread thinly on a glass plate (microscope slide).
Then a specialist takes a closer look at the blood cells under the microscope. Some immunodeficiencies are associated with typical changes in blood cells. For example, in the congenital immunodeficiency Chediak-Higashi syndrome, large granules (giant granules) are found inside neutrophil granulocytes.
Serum electrophoresis can be used to analyze the protein composition in blood serum. In this process, the proteins contained in the serum, which include the antibodies (immunoglobulins), are divided into different fractions according to their size and electrical charge and measured. This helps, for example, in cases of suspected immunodeficiency associated with a lack of antibodies.
However, serum electrophoresis can only determine antibodies as a whole – without differentiating between the various antibody classes. For this, direct immunoglobulin determination is necessary (see next section).
Immunological examinations
Sometimes special immunological tests are also indicated. For example, one can measure the different subclasses of IgG antibodies. Or vaccine antibodies can be determined to learn more about the functioning of many elements of the immune system. Functional tests on phagocytes (“scavenger cells”) are also possible.
Molecular genetic testing
In some cases of congenital (primary) immunodeficiencies, molecular genetic testing is also necessary. However, diagnosis cannot be based on such genetic tests alone, for two reasons:
First, one and the same genetic defect can manifest itself with quite different symptoms. Thus, there is no strict correlation between genetic defect and symptomatic appearance. On the other hand, similar symptomatic manifestations can be based on defects in different genes.
Physicians therefore always interpret the results of molecular genetic tests only in conjunction with other findings (e.g. immunological tests).
Molecular genetic testing may also be useful in close relatives of patients with primary immunodeficiencies.
Depending on the individual case, physicians often perform further examinations. This can be an HIV test, for example, to determine or rule out HIV infection as the cause of an acquired immune deficiency. Or they measure protein excretion in the urine in case increased protein loss weakens the immune system.
How can immunodeficiency be treated?
Whether and how physicians treat an immunodeficiency depends primarily on its cause and severity.
Treatment of primary immunodeficiencies
Primary immunodeficiencies are not curable in most cases. However, early and appropriate treatment can improve the quality of life of those affected – and sometimes even save lives!
Most primary immunodeficiencies are due to a lack of antibodies. To compensate, many affected individuals are dependent on immunoglobulin replacement therapy for the rest of their lives: They regularly receive ready-made antibodies, either as an infusion directly into a vein or as an infusion or injection (syringe) under the skin.
Researchers hope to cure severe primary immunodeficiencies by means of gene therapy. In principle, this involves replacing defective genes with functional genes. However, this is still largely the subject of research.
However, gene therapy is already available in some countries for certain cases of severe combined immunodeficiency (SCID) – namely, for patients in whom the immunodeficiency is due to a change (mutation) in the gene that contains the blueprint for the enzyme ADA (adenosine deaminase). Due to the genetic defect, affected individuals lack this enzyme, which impairs the formation of lymphocytes. This results in a severe, life-threatening immune deficiency.
This is usually attempted to be counteracted with a transplantation of blood stem cells. However, if such treatment is not possible, the administration of a gene therapy agent may be considered. It is produced individually for each patient from cells previously taken from the patient’s bone marrow. In the laboratory, scientists use gene therapy to insert a functioning ADA gene into these cells.
The gene therapy drug for the treatment of ADA-SCID is approved in the EU, but not (so far) in Switzerland.
Treatment of secondary immunodeficiencies
If an immunodeficiency is caused by a disease, it must be treated appropriately.
However, a cure is not always possible, for example in the case of HIV infection. However, those affected should take medication at an early stage and for the long term to keep the AIDS pathogens in check. This can prevent the progression of the acquired immune deficiency and even strengthen the body’s defenses again. Read more about HIV therapy here.
Long-term treatment is also important for other chronic diseases that put a strain on the immune system (systemic lupus erythematosus, chronic inflammatory bowel disease, etc.).
Other diseases that are associated with a weakened immune system, on the other hand, are only temporary and sometimes even heal on their own (possibly supported by symptomatic measures). This is the case, for example, with measles and influenza.
Preventive measures for immunodeficiency
Sometimes doctors prescribe preventive medications against infections in the case of immunodeficiency, as they are used to treat such infections: Antibiotics (against bacterial infections), antifungals (against fungal infections), antivirals (against viral infections).
To reduce the risk of infection, people with a weakened immune system should avoid crowds as much as possible (e.g., crowded subways). They should also, if possible, stay away from contagious patients (e.g. children with measles or flu patients).
It also makes sense in the case of an immunodeficiency to pay attention to appropriate hygiene. This includes, for example, regular hand washing. This is particularly important after using public transport.
Vaccinations are also highly advisable in the case of immunodeficiency. Many infections can quickly become dangerous if the immune system is weakened. However, some vaccinations are critical or strictly forbidden in the case of immunodeficiency. You can find out more about this and the particularities of vaccination in immunodeficiency in the article Immunosuppression and vaccination.