What is hypogammaglobulinemia?
People with an immunoglobulin deficiency are therefore susceptible to infections of all kinds, especially those of the upper and lower respiratory tract. The infections last longer, are more difficult to treat and are more likely to lead to complications. Hypogammaglobulinemia can be the cause of various immunodeficiencies and can be both congenital and acquired.
Hypogammaglobulinemia is a collective term for diseases of the immune system in which patients have too few or no immunoglobulins in their blood. Immunoglobulins are proteins that normally circulate in the blood as antibodies and fight intruders. Such pathogens can be bacteria, viruses, fungi and other pathogens. Due to the immunodeficiency and lack of antibodies, people with hypogammaglobulinemia are particularly susceptible to infections.
Specialized white blood cells are responsible for the production of immunoglobulins (gamma globulins): Plasma cells, which are derived from B lymphocytes. They produce different types of immunoglobulins, which have a variety of functions. These proteins make up a total of around nine to 16 percent of plasma proteins.
Immunodeficiencies – primary or secondary
Hypogammaglobulinemia can be congenital (primary) or acquired in the course of life (secondary). Secondary immunodeficiencies occur much more frequently. The reasons for the lack of immunoglobulins can be tumor diseases, for example of the hematopoietic system. However, infections and medication that suppresses the immune system can also be the cause.
The group of primary immunodeficiencies associated with hypogammaglobulinemia includes many different clinical pictures. The article takes a closer look at these. Some examples:
- Variable immunodeficiency syndrome (common variable immunodeficiency syndrome = CVID)
- Agammaglobulinemia
- Transient (temporary) hypogammaglobulinemia
- IgG subclass deficiency
- Selective IgA deficiency
- Hyper-IgM syndrome
The main symptom of hypogammaglobulinemia is increased susceptibility to infections. Those affected are more likely to have pneumonia, middle ear infections or sinusitis, for example. The diagnosis can be made on the basis of a blood test, in which doctors can detect a lack of the relevant antibodies. Treatment often consists of replacing the missing antibodies, which mainly contain IgG antibodies – either by injection under the skin or into the vein. This means that patients with hypogammaglobulinemia are better protected against infections.
Hypogammaglobulinemia – frequency and age
The frequency of congenital, primary immunodeficiencies is not exactly known. But they tend to be rare diseases. More than 350 different genetic defects are now known to be associated with primary immunodeficiency. Primary and secondary immunodeficiencies can manifest themselves in childhood, but also later in adults. Doctors estimate the following figures for the incidence of some immunodeficiencies that can be associated with hypogammaglobulinemia and age:
- Common Variable Immunodeficiency Syndrome (CVID): approximately one in 25,000 to 50,000 newborns. In principle, CVID can occur at any age – in childhood, adolescence or adulthood. However, there are two peaks in incidence: between the ages of five and ten and between the ages of 20 and 40. Men and women are affected equally often.
- Agammaglobulinemia: approx. 1 in 50,000 to 100,000 newborns. The male sex is almost exclusively affected. The disease usually begins early between the third and sixth month of life.
- Transient hypogammaglobulinemia: A disorder of the immune system that is only temporary. Children between the age of six months and four years are affected.
- IgG subclass deficiency: The frequency is not exactly known because some patients show no symptoms. Although the disease can begin in the first year of life, most people only fall ill after the age of two. Girls are affected just as often as boys.
- Selective IgA deficiency: It is not known how many people suffer from this. Many have no symptoms and therefore do not consult a doctor. However, doctors estimate that the disease affects around 1 in 800 inhabitants.
- Hyper-IgM syndrome: The frequency is approximately 0.2 per 100,000 inhabitants. There are four different types, which are inherited differently. What they all have in common is that the B cells can produce IgM, but no other immunoglobulins (IgG, IgA, IgE).
Hypogammaglobulinemia: causes and risk factors
The causes of hypogammaglobulinemia vary. The lack of immunoglobulins can be congenital (primary). Babies are then born with the immunodeficiency. However, some also acquire the immune deficiency in the course of their lives. Doctors refer to this as secondary hypogammaglobulinemia. The causes can be other diseases, such as cancer.
Primary immunodeficiencies: Causes
- Variable immunodeficiency syndrome (CVID): The blood serum of those affected contains few or no immunoglobulins. The number of B lymphocytes, which produce the antibodies, is usually normal. However, the cells do not mature properly and can therefore produce little or no immunoglobulins. The exact causes and mechanism of development of CVID are unknown. However, genes, infections and various environmental factors probably play a role. Together, these lead to hypogammaglobulinemia.
- Agammaglobulinemia: The cause is a defect on the X chromosome – parents pass the change on to their children. Men only have one X chromosome, whereas women have two – the female sex can therefore usually compensate for the defect. Agammaglobulinemia is found almost exclusively in men.
- Transient hypogammaglobulinemia: This immunodeficiency disappears again when the immune system is fully mature – it is therefore a temporary and transient immunodeficiency. The causes are still largely unknown.
- IgG subclass deficiency: IgG accounts for around 75 percent of the immunoglobulin in the serum of healthy people. IgG subclass deficiency is more common in people with other immune system disorders. Many people often suffer from a lack of IgA at the same time. The causes of IgG subclass deficiency are still virtually unclear. Researchers were able to identify a genetic mutation in some families.
- Selective IgA deficiency: Researchers have not yet clarified the causes of selective IgA deficiency. Although those affected cannot produce IgA, the immune system otherwise functions without any problems. They can also produce the other immunoglobulins. Although IgA is very important in mucosal immunology, most patients with reduced IgA do not suffer more frequently from infections. The function of IgA is then presumably compensated for by IgM antibodies.
- Hyper-IgM syndrome: those affected have too much IgM but too few other immunoglobulins in their blood. There are four different types, which are inherited in different ways. The B cells can produce the immunoglobulin IgM, but not the other immunoglobulins IgG, IgA and IgE. The cause of the most common form of hyper-IgM syndrome is a defect or deficiency of a specific protein on the surface of the T cells. This type is inherited on the X chromosome and therefore almost exclusively affects males.
Symptoms: Hypogammaglobulinemia increases the risk of infection
The symptoms of hypogammaglobulinemia vary from person to person. The type, number and severity of the symptoms depend on the type of hypogammaglobulinemia. Some only experience mild symptoms or none at all, so that a doctor never diagnoses the disease. Others, on the other hand, experience more intense symptoms that affect their health, everyday life and quality of life.
What they all have in common, however, is that the lack of immunoglobulins reduces the effectiveness of the immune system. This makes it easier for bacteria, viruses, fungi and other pathogens to cause illness. The infections occur more frequently, last longer, are usually more severe and often cause complications. Doctors have developed certain criteria for children and adults that are considered warning signs of hypogammaglobulinemia and make it more likely.
Immunodeficiencies: Warning signs in children
The most important alarm signs in children are
- Two or more pneumonia (pneumonia) within one year, diagnosed by X-ray
- Sinusitis that occurs several times in a row or permanently
- Eight or more purulent middle ear infections per year
- Two or more infections of internal organs, for example meningitis, septic arthritis (joint inflammation caused by bacteria), blood poisoning (sepsis)
- Vaccination complications after live vaccinations, especially BCG (vaccine against tuberculosis), rotavirus and polio
- Fungal infections (Candida = yeast) on the skin, mucous membranes or nails after the first year of life
- Infections with unusual bacteria or other microorganisms
- Unclear skin redness or inflammation (erythema, eczema) in newborns and young infants
- Recurrent deep skin or organ abscesses
- Failure to thrive in infancy – with and without chronic diarrhea
- Treatment with antibiotics for non-resistant bacteria without effect
- Congenital immunodeficiencies in close relatives
Immunodeficiencies: Warning signs in adults
These alarm signs may indicate an immunodeficiency in adults:
- Existing immunodeficiencies in the family
- four or more infections per year that have been treated with antibiotics, for example ear infections, pneumonia, sinusitis or bronchitis
- Infections that keep coming back or that doctors have to treat with antibiotics for a very long time
- Two or more serious bacterial infections, such as meningitis or osteomyelitis, sepsis
- Two or more pneumonia cases within three years diagnosed in an X-ray examination
- Infections in unusual areas of the body or caused by pathogens that are normally harmless
In principle, the infections and thus the symptoms of hypogammaglobulinemia can affect many organs of the body – depending on the type of immunodeficiency: upper and lower respiratory tract, ears, skin, eyes, gastrointestinal tract, urinary tract (bladder, renal pelvis) or the joints. Sometimes complications and consequential damage also occur due to the lack of antibodies.
Hypogammaglobulinemia: diagnosis with us
Hypogammaglobulinemia often begins in childhood. Parents then notice that their child suffers more frequently from infections, which also last longer, are more severe and take longer to treat. Sometimes, however, the lack of immunoglobulins only becomes apparent in adolescence or adulthood. Always consult a doctor if you or your child suffer from recurrent infections.
We will first ask you or your parents about your medical history (anamnesis). We ask the following questions, for example:
- What symptoms are present?
- When did they first appear?
- How intensively are they pronounced?
- In which parts of the body do the symptoms manifest themselves?
- Are more frequent infections known? Which ones and how often per year?
- Is an underlying disease known, for example an allergy, atopic disease or autoimmune disease?
- Are there immunodeficiencies in the family?
- Are you or your child taking medication? If yes: Which ones and since when?
Primary immunodeficiency: diagnosis with “ELVIS”
Doctors also use the list of warning signs for children and adults when diagnosing hypogammaglobulinemia. They can also use the abbreviation “ELVIS” to find out if there is a pathological susceptibility to infection:
- E = Pathogen: Affected persons have infections with unusual pathogens that rarely lead to serious illness in people with an intact immune system. Examples are: Pneumonia caused by the fungus Pneumocystis jirovecii or the cytomegalovirus (CMV), blood poisoning caused by Candida (yeast fungi), intestinal and/or biliary tract infection caused by Cryptosporidia or Microsporidia (both are unicellular parasites) or disseminated infection caused by non-tuberculous mycobacteria. Severe infections with common pathogens such as pneumococci or herpes simplex viruses (HSV) can also indicate a primary immunodeficiency.
- L = Localization: Infections that affect different parts of the body or change location more frequently. Unusual sites of infection can also be an indication. Examples: Brain abscess caused by molds (Aspergillus spp.) or liver abscess caused by Staphylococcus aureus.
- V = Progression: A protracted course of infections or if treatment with antibiotics does not work are characteristics of a primary immunodeficiency. The same applies if complications occur after live vaccinations with an attenuated pathogen. Examples: Measles-mumps-rubella, chickenpox or rotavirus vaccination.
- I = Intensity: The severity of an infection can provide clues. Doctors distinguish between “major infections” such as pneumonia and meningitis, meningitis, blood poisoning or bone and bone marrow inflammation (osteomyelitis) and “minor infections” – these include middle ear and sinus infections, bronchitis or superficial skin abscesses. Major infections usually predominate in primary immunodeficiency.
- S = Sum: The number of infections is meant here. However, this parameter is only meaningful if the infection has actually been diagnosed by X-ray. Subjectively perceived infections can distort the picture.
Hypogammaglobulinemia: prevention, early detection, prognosis
No special measures for the prevention of hypogammaglobulinemia are known. Because in many cases the causes of the lack of antibodies are unknown, you cannot prevent it. Sometimes several factors have to interact to cause hypogammaglobulinemia, such as genes and environmental factors – and you usually have no influence on these.
There are also no special measures for the early detection of immunoglobulin deficiency. The following therefore applies in general: always consult a doctor yourself or with your child if infections occur frequently and are protracted and severe.
Course and prognosis of hypogammaglobulinemia
The course and prognosis of hypogammaglobulinemia cannot be generally predicted. The type of disease and its severity play a role. Some have hardly any or only minor symptoms, while others experience severe courses with complications. It is important for the course and prognosis to diagnose the antibody deficiency in good time and to treat it early and adequately.
Hypogammaglobulinemia: treatment with immunoglobulins
Hypogammaglobulinemia can be treated well in many cases. Doctors usually replace the missing immunoglobulins with medication. The treatment is also called antibody replacement therapy. This compensates for the lack of antibodies and the organism is better protected against infections with bacteria, viruses, fungi and other pathogens. However, congenital immunodeficiency cannot be cured.
Transient hypogammaglobulinemia, on the other hand, is only temporary and often resolves itself once the child’s immune system has matured. Sometimes only a temporary administration of immunoglobulins is necessary. An IgG substance class deficiency in children can also normalize with increasing age.