Immunodeficiencies are disorders of the immune system that are characterized by a reduced or lack of ability to defend against microorganisms, i.e. bacteria, viruses and parasites. Immunodeficiencies are divided into primary (congenital and rare) and secondary (acquired and common).

Primary Immunodeficiencies

They constitute only approximately 5% of all immunodeficiencies. The more severe the immunodeficiencies, the earlier they appear, and the more severe their nature. Primary immunodeficiencies (PID) are a group of over 250 diseases whose essence is the improper functioning of some elements of the immune system. As a result, patients with primary immunodeficiency are much more likely to suffer from serious infections and suffer from many chronic diseases, mainly respiratory diseases. The biggest problem in Poland is still low awareness of the existence of PID and, consequently, a large number of undiagnosed patients. Untreated immune deficiencies can lead to serious chronic complications and even death of the patient.

Preprevalence of Primary Immunodeficiency (PID)

Worldwide, approximately 1 in 10,000 people are affected by PIDs (2–5), a number which is likely underestimated due to “missed” diagnoses. The prevalence of the diseases varies greatly from country to country and is higher than this average in several countries.

So far, almost 300 types of PIDs have been discovered, of which 55-65% of all types of primary immunodeficiencies are antibody deficiencies.

It is estimated that approximately 6 million people in the world probably suffer from Primary Immune Deficiencies.

57 % of Primary Immune Deficiencies are diagnosed among boys/men, and approximately 43 % among girls/women.

Minimum PID prevalence in the United Kingdom is currently 5,90/100 000 and an average incidence of PID between 1980 and 2000 of 7,6 cases per 100 000 UK live births.

Source: The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017

Primary Immunodeficiency – Causes

Genetic mutations (changes) cause primary immunodeficiency. They are usually inherited, or passed down, within families, but can sometimes pop up sporadically. Providers treat primary immunodeficiency by preventing and managing infections and replacing missing or defective immune system components.

Primary Immunodeficiency – Symptoms

The most common symptoms of PID among children are chronic, recurrent infections and increased susceptibility to infections (especially of the respiratory tract). Skin infections, abscess formation and impaired wound healing are also common. Primary Immune Deficiencies may also be accompanied by autoimmune diseases, which are disturbances in the regulation of the human immune system (destruction of own cells and tissues). Such diseases include, for example: sarcoidosis, lupus erythematosus, psoriasis, rheumatoid arthritis or juvenile idiopathic arthritis, most often occurring in children with PID.

Some severe forms of primary immunodeficiencies produce symptoms that become apparent soon after birth. An example of such a condition is Di George syndrome, which causes facial deformities, heart disease and problems with the nervous system, which are observed at birth. Primary immunodeficiencies may also manifest themselves in autoimmune diseases, in which the body is attacked by its own immune system. This is manifested, for example, by a decrease in the number of platelets, arthritis or vitiligo. Most often, the first suspicions about the occurrence of PID arise from serious infections. These are usually severe, recurrent infections that are difficult to treat despite the use of antibiotics. If we suffer from inflammation of the ears, sinuses, bronchi or lungs once again during the year, we should not underestimate it, because it may be a signal that our immune system is not functioning properly.

Primary Immunodeficiency – Diagnosis

When PID is suspected, more detailed tests of the immune system are performed. – They are usually performed gradually to exclude the most severe forms of PID, such as severe combined immunodeficiency (SCID), at the very beginning. First, a blood count with a smear is performed, and then - if necessary - immunoglobulin levels are determined and a number of other specialist tests are performed. A complete blood count is the main indicator of abnormalities related to the immune system, but it is not sufficient to properly diagnose primary immunodeficiency. Blood count results are rather an indication for more accurate tests for specific cell types. Such tests are usually performed by immunologists.

If the patient is diagnosed with an immune deficiency, appropriate treatment may be initiated. Although PID cannot be completely cured, effective therapies improve the health of sick people, significantly reduce the number of infections and allow them to lead an active life, develop a professional career and have a family. The most common method of treatment is immunoglobulin replacement therapy, i.e. subcutaneous or intravenous administration of human immunoglobulin preparations, in most patients throughout their lives.

The list of 10 warning symptoms suggestive of the disease among children, developed by experts from the European Immunodeficiency Society and the Jeffrey Modell Foundation, is helpful in diagnosing Primary Immunodeficiencies. The occurrence of 2 of the 10 symptoms described above should be a disturbing indication that the doctor may suspect that the patient has one of the Primary Immunodeficiencies.

Warning symptoms that may suggest primary immunodeficiencies in children

  1. Four or more ear infections (inflamations) within a year
  2. Two or more sinus infections in a year
  3. Antibiotic therapy for 2 months or longer with little improvement
  4. Two or more pneumonias in a year
  5. No weight gain, stunted growth
  6. Recurrent deep skin or organ abscesses
  7. Chronic oral or skin mycosis in children after 1 year of age
  8. The need for long-term treatment of the infection with intravenous antibiotics
  9. Two or more serious infections such as sepsis, inflammation of the brain, bones, skin
  10. Family history indicating the occurrence of PID

Primary Immunodeficiency – Therapy

Treatment must go in two directions (1) be directed at treating the deficiencies as far as possible and (2) combating infections and other diseases resulting from immune deficiencies.

Managing infections

• Treating infections. Infections require rapid and aggressive treatment with antibiotics. Treatment might require a longer course of antibiotics than is usually prescribed. Infections that don't respond may require hospitalization and intravenous (IV) antibiotics.

• Preventing infections. Some people need long-term antibiotics to prevent respiratory infections and permanent damage to the lungs and ears. Children with primary immunodeficiency might not be able to have vaccines containing live viruses, such as oral polio and measles-mumps-rubella.

• Immunoglobulin therapy. Immunoglobulin consists of antibody proteins needed for the immune system to fight infections. It can either be injected into a vein through an intravenous (IV) line or inserted underneath the skin (subcutaneous infusion). treatment is needed every few weeks, and subcutaneous infusion is needed once or twice a week.

Treatment to reinstitute the immune system

• Stem cell transplantation. Stem cell transplantation offers a permanent cure for several forms of life-threatening immunodeficiency. Normal stem cells are transferred to the person with immunodeficiency, which results in a typically functioning immune system. Stem cells can be harvested through bone marrow, or they can be obtained from a placenta at birth (cord blood banking). The stem cell donor — usually a parent or other close relative — must have body tissues that are a close biological match to those of the person with primary immunodeficiency. Even with a good match, however, stem cell transplants don't always work. The treatment often requires that functioning immune cells be destroyed using chemotherapy or radiation before the transplants, leaving the transplant recipient temporarily even more vulnerable to infection.

In the case of the most severe immune deficiencies, such as SCID (severe combined immunodificiency), bone marrow transplantation is used.

• Gene therapy. This type of treatment involves taking stem cells from the person with primary immunodeficiency, correcting the gene in the cells and then returning the corrected stem cells back to the person via an intravenous infusion. With gene therapy, there is no need to find a suitable donor, as the person's own cells are used. Currently, this treatment is used to treat only a few primary immunodeficiencies, but clinical trials are underway for many other types.

Typically, patients with primary immunodeficiencies must take medications for the rest of their lives, but this does not prevent them from functioning normally. A person with PID can and should lead a normal life. There are no contraindications for her to go to school, study or work. Of course, you need to remember to take certain precautions to minimize the risk of infection, but that's basically it.

It should be noted that in the case of primary immunodeficiencies, the diagnosis of the disease and the directions of treatment should be determined by an immunologist, and the therapy is carried out on a daily basis by a family doctor.


Secondary Immunodeficiencies

Otherwise known as acquired immunodeficiencies, they are much more common than primary immunodeficiencies. Secondary immunodeficiencies most often occur in diseases such as diabetes, sickle cell anaemia, rubella, leukaemia, chicken pox and various bacterial infections. The cause of secondary immunodeficiency can be malnutrition, surgery, burns or organ transplants and the administration of immunosuppressive drugs. Other causes can be diseases of the haematopoietic system, as well as autoimmune diseases. It can also be caused by HIV (Human Immunodeficieny Virus). AIDS, a disease caused by HIV, is also referred to as Acquired Immunodeficiency Syndrome. The result of HIV infection is a decrease in the number of lymphocyte-T cells, which makes the body more susceptible to diseases which, with normal immunity, pose no threat, but which can be fatal for HIV-positive people. Patients very often have atypical pneumonias, fungal infections, tumours and defects in the nervous system that eventually lead to death. Secondary immunodeficiencies are acquired and most often caused by iatrogenic disorders. The use of various immunosuppressive drugs, anti-cancer drugs or certain antibiotics further reduces immunity.

A number of situations in which immune disorders/deficiencies occur are summarised below.

Immune disorder of the elderly

Related to cellular immunity

  •   Gradual decline in the number of T lymphocytes after the age of 70
  •   An increase in the number of CD4 lymphocytes and a decrease in the number of CD8 lymphocytes
  •   Residual thymus function
  •   Increase in CD45RO expression, decrease in CD45RA expression
  •   Decrease in the expression of IL-2, IL-4 and INF-γ
  •   Weakening of the proliferative response of lymphocytes after stimulation with PHA and ConA
  •   Reducing the frequency of positive DTH reactions and weakening their intensity

Related to humoral immunity

  •   Decrease in IgM, IgE and IgD levels, increase in IgG levels
  •   Decrease in the titer of natural antibodies
  •   Increased titer of autoantibodies and anti-idiotypic antibodies
  •   Decrease in the number of CD5(-) B cells and increase in CD5(+) B cells after the age of 70
  •   Increased synthesis of IL-4, IL-5, IL-6, increased INF-γ activity

Immune disorders in renal failure

  •   Prolonged tolerance to allogeneic transplant
  •   Increased susceptibility to infections
  •   Increased cases of neoplasia
  •   Incorrect reaction to vaccines against viral infections (flu, hepatitis)

Immune disorders in uremia

  •   Chronic protein and calorie deficiency (insufficient supply, absorption disorders, excessive loss)
  •   Deficiencies of Zn, vitamins B6 and E
  •   Iron overload (ferritin over 500 mcg/l)
  •   Low- and high-molecular-weight uremic toxins
  •   Chronic dialysis therapy

Immune disfunction after surgery

  •   Occurrence of cutaneous anergy
  •   Decrease in IgG and IgM (preoperatively) against bacterial endotoxins
  •   A large decrease (>50%) in the number of lymphocytes on the 1st day after the procedure
  •   Increased neutrophil activity on the 1st - 2nd day
  •   Decrease (20-30%) of activated monocytes
  •   Increased IL-6 concentration

Drug-induced immune disorders

          After treatment with cytostatics

  •      Late neutropenia 35 – 45 days (irreversible damage to the myeloid stem cell)
  •      Early neutropenia 7 – 14 days (reversible damage to the myeloid stem cell)

          With other drugs - the drug (hapten) triggers abnormal destruction of granulocytes

          After long-term use of glucocorticosteroids - inhibition of granulocyte function

Effect of glucocorticosteroids

  •   Apoptosis of lymphocytes activated by allo- and autoantigens
  •   Reducing the expression of MCH antigens and adhesion molecules on cell surfaces
  •   Inhibition of nitric oxide synthase induction in macrophages
  •   Impaired function of cytotoxic lymphocytes and NK cells
  •   Inhibition of monocyte and macrophage functions

Infections complicating immunosuppressive treatment

  •   Cytomegalovirus (CMV) infection - in 80% of the population in youth it is asymptomatic, symptoms occur with reduced immunity
  •   Acute varicella zoster virus (VZV) infection
  •   Acute herpes virus infection (Herpes Simplex Virus – HSV)
  •   Tuberculosis and mycobacterioses
  •   Fungal infections (candida, cryptococcus, aspergillus)
  •   Pneumocystis pneumonia or PCP is a fungal infection

Stress and Immunity

Experimental studies on animals under stress show a decrease in cellular response indexes.

  •   Decrease in the number of lymphocytes
  •   Quantitative disorders of subpopulations
  •   Decrease in NK cell activity
  •   Decrease in the proliferative response to the antigen
  •   Phagocytosis disorders

Chronic stress → hypothalamus → pituitary gland → sympathetic system → ACTH, catecholamines, opioids → decreased IL2 production

Immune Disorders due to Ionising Radiation

  •   Total body irradiation = Total Lymphoid Irradiation
  •   The greatest excitability of dividing cells, e.g. lymphocytes stimulated by alloantigen
  •   Th lymphocytes more sensitive than Ts lymphocytes
  •   Macrophages and NK cells relatively resistant to irradiation

Immune disorders and certain cancers

The immune system performs immunological surveillance that prevents cancer by early detection and destruction of atypical cells. Immunosuppression and impaired immunity may lead to viral infections, which in turn may contribute to the development of a number of cancer diseases:

  •       Non-Hodgkin lymphomas (Epstein-Barr Virus – EBV)
  •       Kaposi sarcoma (human immunodeficiency virus – HIV)
  •       Skin cancer and rectal cancer (human papilloma virus – HPV)
  •       Primary liver cancer (hepatitis B virus – HBV)

Humoral Immune Disorders in the Course of Cancer

  •   Cytokines (mainly TGF-beta transforming growth factor) secreted by cancer cells (oat cell carcinoma, mesothelioma, Hodgkin's disease)
  •   Prostaglandins (mainly PGE2) secreted by macrophages (head and neck cancer)
  •   Gangliosides produced, i.a., by macrophages, erythrocytes, liver cells

Cellular Immune Disorders in the Course of Cancer


  •   Reduction in the number of lymphocytes
  •   Decrease in the population of CD4 lymphocytes
  •   Decrease or reversal of CD4/CD8 ratio
  •   Weakened NK cells activity

Local (Cancer region, regional lymph nodes):

  •   Reduction in the number and dysfunction of mononuclear cells

Immune Disorders in the Course of Famine Disease

Fortunately, in our country and in Europe, hunger disease practically does not occur spontaneously. It may manifest itself in the course of other severe and long-term diseases, including: in the course of cancer, tuberculosis, pneumonia, severe diarrhea. Hunger disease is typical of war-affected regions and sub-Saharan Africa. In Europe in the 20th century, there were regions affected by famine, e.g. the great famine in Ukraine in 1932 - 1933, and famine in Nazi concentration camps or in the Nazi ghettos for Jews. In the course of starvation disease, a number of body disorders occur, including those in the immune system.

  •   Impaired cellular response
  •   Impaired phagocytosis
  •   Impaired production of cytokines, antibodies and complement system proteins
  •   Atrophy of the thymus and thymus-dependent lymph node zones

Other Secondary Immune Disorders

  •   In the course of infection (HIV, HTLV1 (Human T-cell Leukemia Virus), measles virus, tuberculosis
  •   Nutritional deficiencies (zinc, iron, vitamins A, E, B, folic acid)
  •       Endocrinopathy (hyperthyroidism, Cushing's disease, diabetes, hyperparathyroidism)
  •   Conditions after injuries, after extensive burns, deep hypothermia
  •   Protein loss (exudative enteropathies, nephrotic syndrome)
  •   Alcoholism, drug addiction

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The European Medicines Agency (EMA) has approved gene therapy for the treatment of severe combined immunodeficiency due to adesine deaminase deficiency (ADA-SCID), which is the result of a genetic mutation - reports New Scientist. You can read about gene therapy, what it is and its prospects, on the website News Medical Life Sciencies


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