22-29 April - World Primary Immune Deficiency Week (PNO)

Early diagnosis of NSAIDs is the basis for successful treatment

Primary immunodeficiency (PNO), covering a large group of genetically determined diseases called innate immune defects, are commonly associated with recurrent infections with a severe course that are difficult to treat. Few people know that symptoms of NSAIDs can include severe allergies, autoimmune diseases in which the immune system destroys the host's own cells, or enlargement of the lymph nodes or spleen.

NSAIDs can be diagnosed at any age - in both children and adults. Time is of the essence in diagnosing the disease, as it is important that patients receive appropriate care as soon as possible. Although we know more and more about NSAIDs, there are still huge underestimations and delays in diagnosing the disease in Poland.

Every year, World PNO Week is celebrated around the world from 22-29 April. This year, the initiative draws attention to the fact that everyone with NSAIDs should have the right care, regardless of age or location.

Tremendous progress in detecting types of PNO genetic defects

Primary immunodeficiencies (PIDs), are a diverse group of diseases, most of which are genetically determined and associated with the malfunction of one or more elements of the immune system. They are classified as rare diseases and some types as ultra-rare. Importantly, both the symptoms and the clinical course may vary, even in patients with the same defect.It is estimated that the prevalence of NSAIDs is as high as 1 per 1 000 people, which would mean 40 000 NSAID patients in Poland, but only about 5 000 cases have been detected so far. The delay in correctly diagnosing the disease in children is on average about 5 years, while in adults it is about 10-11 years.

It is worth noting that in In recent years, the number of diagnosed cases of primary immunodeficiencies has been increasing. Above all, more genetic defects are being detected that determine the occurrence of NSAIDs, and this is possible due to a number of factors, including the availability of diagnostic tools. In particular, the availability of genetic testing should be highlighted - explains Dr hab. n. med. Małgorzata Pac, Prof. IP CZD, Department of Immunology, Institute "Pomnik - Centrum Zdrowia Dziecka" in Warsaw. - An important role is played by other studies of the immune system, such as lymphocyte immunophenotyping by flow cytometry, with assessment of individual lymphocyte subpopulations, their maturation track, etc.

As Prof Pac explains, the latest available update from the International Union of Immunological Societies (IUIS) 2022 mentions 485 genetic defects responsible for NSAIDs. It now appears that there may be more than 500 gene variants underlying NSAIDs. It is worth mentioning that the first classifications initiated by the World Health Organisation took place in the early 1970s, when only 16 immunodeficiencies were distinguished. So progress has been tremendous!

Good care for patients with NSAIDs is determined by a number of factors

Certainly, early diagnosis of primary immunodeficiencies is a key factor in the proper care and the entire diagnostic and therapeutic process of a person with NSAIDs. However, for this to happen, firstly, there must be awareness of the prevalence of this group of diseasesboth among health professionals (GPs, paediatricians, internists, other specialists) and the general public - says Prof Pac.

Second - knowledge of the symptoms of primary immunodeficiencies is crucial. It is commonly thought that NSAIDs are primarily recurrent infections, but the issue turns out to be more complicated. We must also pay attention to their atypical course, to the atypical aetiology of infections, to the appearance of infections despite vaccination, to repeated infections with the same pathogen. Within the group of primary immunodeficiencies, we also encounter non-infectious phenotypes. These are symptoms or diseases of autoimmune origin, which include e.g. cytopenias (e.g. thrombocytopaenia, autoimmune neutropenia), as well as autoimmune diseases affecting other organs, e.g. autoimmune thyroiditis. Non-infectious phenotypes also include lymphadenopathy of unclear aetiology, or enlargement of the spleen and/or liver.

Prof. Pac also draws attention to incidence of cancer, which can either be the result of PNO, as there are immunodeficiencies with a particular predisposition to cancer, or the first symptom of PNO.

Another issue is availability of diagnostic methods and tools, e.g. whether we can assess immunoglobulin levels in patients with recurrent infections at the primary care level. It is also important to be able to interpret the results obtained. It is not enough to look at a parameter - it needs to be related to reference values for specific age groups.

The following should be mentioned as another factor access to an immunologistwhich directs further diagnosis or immediately establishes the diagnosis of PNO. It is also important to accessibility to other specialists - due to the presence of symptoms or diseases from other systems and organs (e.g. autoimmune diseases of various locations) and the need for complex care. Once a proper diagnosis has been made, we need to have guaranteed access to various therapiesdepending on the type of immunodeficiency. Immunoglobulin therapy is most commonly used. It is necessary to be able to choose the route of administration of immunoglobulins and this should be an informed choice, discussed by the patient or their parents (in the case of a child) and by the doctor - emphasises Prof. Pac.

In some immunodeficiencies there is the possibility of targeted treatment, such as haematopoietic cell transplantation. In the care of a person with NSAIDs, accessibility to gene therapy, to immunosuppressive treatment, to modern biological drugs, to enzyme therapy is also important.

The aim of treatment in immunodeficiencies is primarily to improve the patient's quality of life. Treatment is primarily aimed at preventing various infections and life-threatening complications. In some primary immunodeficiencies (e.g. Bruton's agammaglobulinaemia), therapy must be lifelong. - states Prof Pac.

Early diagnosis of NSAIDs as a basis for successful treatment

Primary immunodeficiencies are usually diagnosed in childhood. It is important to remember that a child, especially at the nursery/pre-school stage, has the right to be sick very often, up to 10-12 times a year, and if the number of infections decreases over time and their course is milder, there is usually no cause for concern. However, when the infections are unusual, severe and/or complicated, often requiring hospital treatment because they are difficult to manage at home, and other health problems occur, e.g. poorly responsive allergies or autoimmune diseases (thrombocytopaenia, neutropenia), such a child should definitely go to an immunologist with suspected immunodeficiency - explains Prof. Sylwia Kołtan, MD, PhD, National Consultant in Clinical Immunology, Department of Paediatrics, Haematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun. - The parent and the child go to a GP, paediatrician or to an allergist, haematologist or pulmonologist, and it is these doctors who should be most vigilant and mindful of the fact that children may have NSAIDs. This is the first and most important step. The doctor who thinks about this will look for answers and himself - before referring the child to an immunologist - will interview parents, including past illnesses, serious infections or NSAIDs in the family, perform a physical examination, order initial laboratory tests, i.e. blood count with smear, proteinogram and tests for IgG, IgE gammaglobulin levels, IgA. Unfortunately, the latter test is chargeable (free of charge to the patient mogn these are performed in hospital or at an immunology clinic), which significantly increases the time for the GP to 'catch the patient'.

Prof Koltan also points out that although infections are a very common manifestation of NSAIDs, their absence is not at all proof that the immune disorder is not present. The occurrence of allergic or autoimmune problems, neoplastic diseases, chronic enlargement of the liver, spleen, lymph nodes, the appearance of gastroenterological problems - these are also reasons to wonder whether the common denominator is not precisely immune deficiency. In such patients, NSAIDs are usually diagnosed late, and by the time this happens, they may have been managed for years by different doctors or come to an immunologist by chance.

The consequences of delayed diagnosis are largely irreversible and result in permanent organ damage or the development of chronic diseases. Depending on which organs these diseases are concentrated in, there may be complications that can no longer be cured. We can only try to treat them in such a way that they cause the patient as little discomfort as possible. An example of this is late-onset humoral immunodeficiency, which is the most common in our country and which can result in the development of chronic sinusitis or bronchial dilatation. Although the patient will be treated very successfully with immunoglobulin transfusions, chronic sinusitis will remain a lifelong problem for him or her, and bronchial dilatation will not regress - Prof Koltan explains. - Early diagnosis is therefore the basis not only for good treatment, but also for prevention and proper functioning in the natural environment, in the family, at school.

According to Prof. Koltan, a lot has already been done in Poland with regard to the care of patients with NSAIDs. In most provinces there are centres that diagnose and treat children with immunodeficiencies. We have drug programmes for patients with antibody deficiencies, i.e. treatment with intravenous and subcutaneous immunoglobulin preparations. The latter form of therapy is accessible to most children and has the great advantage of being delivered at home. Children with the most severe diseases of the immune system also have sufficient access to haematopoietic cell transplantation, and at a high level. In addition, there is the possibility of treating autoinflammatory syndromes.

What we have a problem with is the lack of adequate funding for highly advanced genetic testing, which unfortunately results in diseases, especially extremely rare diseases that cannot necessarily be detected by basic immunological testing, being diagnosed very late or not at all. Therefore, it is not possible to provide targeted therapies for these rare diseases - notes Prof Koltan. - I would still dream of neonatal screening for selected most severe immunodeficiencies, primarily severe combined immunodeficiency, has been implemented in Poland. I know that there are plans to do so and work is already being undertaken on this.

Adults also suffer from primary immunodeficiencies

Among the almost 500 disease entities detected is common variable immunodeficiency (CVID). Its phe first symptoms can occur even in people of advanced age. The oldest patient at our clinic in Gdansk is 50 years old, while the literature shows that in Poland and Europe there are people as old as 80 years old - says Dr Marcin Ziętkiewicz, MD from the Department of Rheumatology, Clinical Immunology, Geriatrics and Internal Medicine at the Medical University of Gdańsk.

It can also happen that immunodeficiency is not diagnosed in childhood, but already in adulthood. This is because in a child, the manifestation of the disease may be very mild, almost imperceptible, and only become more severe years later.

According to Dr Ziêtkiewicz, the big danger for adults is that it is difficult to get the idea that a person aged, for example, 40 years could be burdened with a primary immunodeficiency. Such patients are often referred from doctor to doctor for 10 years to no avail. What should make an adult think about the functioning of their own immune system is covered in the 10 warning signs. They are similar to those in children, but the frequency of occurrence differs. And while eight infections a year in a child is not unusual, in an adult it should already raise concern.

Generally, NSAIDs are associated with recurrent infections and a severe course of the disease that cannot be easily treated with standard therapies. The causative agent here are pathogens that pose no risk to healthy people. If an adult suddenly falls ill and we find that the cause is a bacterium that is common in the environment and does not cause harm to most people, it means there is something wrong with the patient's immune system. My adult patients in whom we diagnosed immune deficiencies often developed infections where they finished one antibiotic because they had pneumonia, and after two weeks they started taking another one - explains Dr Ziętkiewicz.

In the diagnosis of NSAIDs, the role of the general practitioner (GP) is crucial, as it is usually the GP that the patient goes to first. The management pathway is the same as in children, i.e. the doctor should first take a history and order a blood count with smear and concentration tests for the main immunoglobulin classes, because 50% immunodeficient patients have problems with their production or function.

The primary treatment used for people with impaired antibody production or function is immunoglobulin replacement therapy, financed as part of the drug programme. In most patients in Poland, it is administered subcutaneously. Such treatment, after appropriate training by medical staff, can also be self-administered at home - by the patient himself or his carer.

Primary immunodeficiency knowledge portal

For those seeking knowledge about NSAIDs, for patients and their relatives, the following has been created educational portal , which is a compendium of knowledge on this disease entity. The website features articles, videos and infographics, prepared in a friendly and understandable way in collaboration with experts in clinical immunology and paediatrics. You can also read the stories of people with NSAIDs.

World Primary Immunodeficiency Week activities are supported by medical experts in clinical immunology, family medicine and paediatrics, as well as patient organisations. The activities are initiated by the Association for People with Immunodeficiencies "Immunoprotect" and partnered by the Institute for Patient Rights and Health Education, the National Forum for Rare Disease Therapy - ORPHAN and the Dream Immunity Foundation. Takeda is a patron of the celebrations.

Warning signs of PNO IN CHILDREN:

1. 4 or more new ear infections per year.
2. 2 or more new sinus infections per year.
3. 2 or more pneumoniae per year.
4. Failure to gain weight or stunting of normal development.
5. Use of antibiotics for 2 months or longer with little effect.
6. Persistent oral thrush or fungal infections on the skin.
7. 2 or more deep tissue infections, including septicaemia.
8. Recurrent, deep abscesses of the skin and other organs.
9. PNO in family history.
10. The need for intravenous antibiotics to treat the infection.

Warning signs of PNO IN ADULTS:

1. Recurrent invasive infections (2 or more pneumonia, recurrent septicaemia, abscesses, meningitis).
2. Opportunistic infections or those caused by atypical pathogens (e.g. pneumocystis pneumonia).
3. Poor response to prolonged or repeated antibiotic therapy, especially intravenous antibiotics.
4. Chronic diarrhoea with or without signs of colitis.
5. Low serum IgG levels, chronic lymphopenia, neutropenia or thrombocytopenia.
6. Prolonged or recurrent, atypical or refractory oral lesions (aphthae and ulcers) or skin rashes (erythema, telangiectasias, recurrent pimple/glandular/rubular rashes).
7. Chronic lymphoid tissue enlargement, generalised lymphadenopathy, splenic enlargement of unclear cause or undetectable lymph nodes and tonsils.
8. Positive family history of PNO, autoimmune diseases, leukaemia or lymphoma.