Immunodeficiency diseases: Early diagnosis to extend a patient’s life span with more than 30 years

This resulted in sick leave, ward care periods, and intensive care periods. The later the disease is discovered, the more time it has to damage the body.

Thanks to research,

• a diagnosis is reached now on average in less than 7 years,
• the patient receives timely antibody therapies and
• for a patient who is selected correctly, the treatment can extend their life span with more than 30 years.

For many patients and their symptoms, a diagnosis cannot be reached or there is none. These mysteries can only be solved through research.

• Research on immunodeficiency diseases started in Finland in the 1970s.
• In the early 21st century, Finland’s first clinic for adults with immunodeficiencies was established at HUS.
• Now, all university hospitals already have good expertise to treat these patients.
• Our service system is aware of the patient group in question.

The diverse symptoms of hereditary immunodeficiency disorders

Hereditary immunodeficiency disorders are most often immune system dysfunctions occurring in several different organs and caused by a single gene defect.

The symptoms usually begin between the ages of 0 and 30 and progress in an insidious manner over the years. Most commonly, they are exceptional susceptibility to infections, such as recurrent respiratory infections, ear infections, pneumonia and sepsis, meningitis and joint infections. In addition, frequent, severe bacterial infections and sometimes also atypical tissue and general infections as well as other organ or generalized inflammatory diseases occur.

The later the immunodeficiency disease is discovered, the more time it has to damage to the body

The later the disease is discovered, the more it has time to cause damage, and the lower the quality of life or shorter the life span of the patient. In addition, the diseases predispose the patient to infections if left untreated, and even if treated, to autoimmune diseases, other inflammatory symptoms, cancers or sometimes also severe atopy that starts during the childhood years.

Identification and treatment of congenital immunodeficiencies require specialized knowledge, but there is no single specialty for them. In Finland, as in the entire European region, several immunodeficiency diseases have been previously diagnosed 10–20 years too late. Patients have not received effective medication for their disease in a timely manner, which has resulted in sickness-related absences, inpatient care periods and intensive care periods, and many have a significantly reduced life span. As a rule, healthcare services did not recognize adult-onset immunodeficiency diseases.

Research on immunodeficiency diseases addresses the blind spots in medicine

It was difficult to get funding for immunodeficiency research at first, because financiers make their decisions based on published articles. However, the study of immunodeficiency diseases diagnosed in adulthood caught momemtum with research funding from HUS and the government.

Based on the study results, decision-makers were convinced that an organized system for the diagnostics and effective treatment of these patients must be created along with clinical pathways.

There are more immunodeficiency patients in Finland than anywhere else in the western world

In the early 21st century, Finland’s first clinic for adults with immunodeficiencies was established at HUS, and the time of specialists familiar with the topics was reserved for treating these patients. At that time, 20 years ago, not much was known about this disease group in Finland and even around the world. Since then, it has been shown that there are more patients in this group of diseases in Finland than anywhere else in the western world. Only cultures favoring marriages between cousins diagnose these diseases more frequently than in the Finnish population.

Thanks to research,

• more than 485 hereditary immunodeficiency diseases are now known,
• it is known that many immunodeficiency diseases are most common in Finland in the world,
• our service system is aware of the group of patients in question,
• many people get a diagnosis much faster than before: in less than seven years, when the delay was previously 10–20 years or even 50 years,
• the patient receives timely antibody therapy or a stem cell transplant, and
• medical treatment can prolong the patient’s life by more than 30 years.

Training is organized to maintain knowledge of research and treatment for immunodeficiency

There are now appointments available for immunodeficient patients in all university hospitals, and the central hospitals have also acquired competence for this area. Skill in caring for these patients is maintained through training and virtual meetings where problems are resolved. Newborn infants will also be screened for the most severe immunodeficiencies already at the maternity hospital (a SCID screen).

Steps in diagnosing an immunodeficiency disease

The diagnosis of congenital immunodeficiency is made by a physician experienced in the topic in a specialized medical care unit. Diagnosing very rare immunodeficiencies often requires special examinations that are difficult to obtain in Finland. Before further studies, as guided by the clinical picture, it is recommended that genetic testing is requested, including an extensive panel of immunodeficiency genes, evaluation of all genes coding proteins, or evaluation of the entire genome. These provide guidance for the laborious further investigations.

Since 2019, severe immune deficiencies, such as SCID syndrome, have been screened from a newborn’s blood with a heel prick sample at HUS and Southwest Finland, and since then screening has spread throughout Finland.

Even if the patient’s examination results are within normal, the physician treating the patient will consult an infectious disease specialist or a pediatrician if the patient has repeated

• low IgG values or persistent low blood white cell counts for no obvious reason,
• serious infections, or
• exceptional pathogens, or
• exceptional cluster of other inflammatory diseases.

Research discovers more forms of immunodeficiency diseases

Over the course of more than twenty years, research has taken big steps forward. In recent years, Finnish researchers have also been involved in discovering new immunodeficiency genes and completely new phenotypes for known primary immunodeficiencies.

Finns have been genetically isolated from the rest of the world for a long time, so Finns have an abnormally high prevalence of immunodeficiency diseases. By the end of 2021, a total of 485 new immunodeficiencies had been confirmed, of which approximately 90 have already been identified in the Finnish population. There are more significant antibody deficiencies in Finland than in any other developed country, i.e. at least 8 cases per 10, 000 people. Among other things, the prevalence of common variable immunodeficiency (CVI), AICDA mutations, APECED syndrome and cartilage-hair hypoplasia, with the genetic cause still often open, is most frequent in the Finnish population when assessed by country.

Different mutations in the same gene can cause completely different clinical pictures

New immunodeficiencies include, for example, NFKB1, BACH2, and CEBPE gene mutations in transcription factors causing misregulation of the immune system. Different mutations in the same gene can cause completely different clinical pictures with differing mechanisms, even giving the gene tasks that it does not normally have.

In collaboration with researchers from other university hospitals, HUS researchers have also surprisingly often found immunodeficiency diseases in Finns caused by heterozygous NFKB1 gene mutations (variants) with differing expressions. Mutations work by different mechanisms on the functioning of the immune system and cause a wide range of clinical pictures, such as recurrent respiratory infections, joint infections and/or fever, abdominal pain and ulcers in the mucous membranes of the mouth, gastrointestinal tract, and genitals. In the future, research will guide the development of medical treatment and the understanding that all people with familial Behçet’s disease should be genetically screened.

Predominantly inherited BACH2 mutations are associated with a number of autoimmune and immune-mediated diseases; celiac disease, Crohn’s disease, asthma, and type 1 diabetes

In addition, changes in the CEBPE gene were found in HUS to also cause CAIN, a recessively inherited autoinflammatory immunodeficiency. Changes in the performance of the CEBPE gene affected the translation of more than 460 genes (“transcription”). This explained the reason for patients’ fever and other autoinflammatory symptom complex, and targeted treatment with anakinra could be effective.

New findings at HUS also include that the predominantly inherited BACH2 mutations are associated with a number of autoimmune and immune-mediated diseases, such as celiac disease, Crohn’s disease, asthma, and type 1 diabetes The low level of functioning BACH2 protein in patients’ B cells perhaps explains their problems with class-switching antibodies and the resulting susceptibility to infection.

Among other things, a new gene called RHOG was recently found in a Finnish person, causing a pathogen-independent general inflammation, a hereditary hemophagocytic lymphohistiocytosis, if left untreated. The disease leads to death in early childhood. In addition, the gene responsible for the refractory immunodeficiency HYOU1 was found. What is common with these is that there are targeted treatments that will save the patient’s life.

The immunodeficiency diseases affecting the Finns must be investigated in Finland

Although the current sequencing methods covering the entire exome (protein-coding genes) and genome have made it easier to find rare but previously undescribed genetic changes, it still requires years of basic medical research to confirm disease connection.

The long-term basic medical research can not only identify new forms of disease, but also find out more about the molecular-level mechanisms and disease connections caused by the mutation, thus speeding up and specifying both diagnosis and treatment.

Diseases and mutations concentrated in Finland are not frequently studied elsewhere, but instead it requires local research expertise and local resources. The plan is that, at the end of the research project, all the accumulated research material will be incorporated into a biobank, if the patient has given their consent.