Focus on the quality of life of children with primary immunodeficiency diseases
1. Dr. Osmonova Gulnaz Zhenishbaevna
2. Ganesh Soni
3. Manish Yadav
(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
2. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
3. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
Introduction
Primary immunodeficiency disease (PID) is a group of clinical syndromes caused by congenital factors (mostly genetic factors) resulting in defects in immune organs, immune cells and immune molecules, leading to the absence or reduction of immune response and resulting in low immune function against infection. PID seriously threatens the life of children and affects their quality of life. In 2017, the International Union of Immunologic Societies (IUIS) updated the disease classification of PID, which is still divided into 9 major categories of diseases (combined immunodeficiency diseases, combined immunodeficiency with related or syndromic features, immunodeficiency mainly with antibody deficiency, immune dysregulation diseases, congenital white blood cell number and function defects, innate immunodeficiency, autoinflammatory diseases, complement deficiency and phenotypical immunodeficiency), which includes 354 diseases and involves 344 pathogenic genes [1]. Although the incidence of each individual PID is not high, the total number of patients affected by the 354 diseases is still a large group. Furthermore, PID often occurs in childhood, so timely diagnosis and proper treatment are crucial for improving the quality of life for children with PID and enhancing the overall health and quality of life of children in my country. With advancements in science and technology, significant progress has been made in the diagnosis and treatment of PID in recent years, leading to a marked improvement in the survival rate of children with PID. Further improving the quality of life for these children warrants attention from pediatric rheumatologists.
I. Understanding the disease and early diagnosis
Early diagnosis and timely treatment are the most important measures to improve the prognosis and quality of life of children with PID. In recent years, the advancement of immunology and molecular biology techniques has made early diagnosis of PID possible. However, the most crucial factor is the clinicians' understanding of PID. The early clinical manifestations of PID are diverse, and patients may be distributed across various subspecialties of pediatrics and other related disciplines such as dermatology, otolaryngology, and ophthalmology. This requires doctors in all relevant departments to understand the early clinical manifestations of PID, identify them early, recognize the possibility of PID when encountering suspicious cases, and conduct relevant examinations in a timely manner to make early diagnosis and treatment of PID possible. Carneiro-Sampaio et al. [2] proposed 12 warning signs for suspected PID in infancy: severe and persistent fungal, viral and bacterial infections; adverse reactions after vaccination with live attenuated vaccines, especially BCG; persistent diabetes or other autoimmune diseases or inflammatory manifestations; sepsis-like manifestations without etiological findings; various severe skin diseases; persistent diarrhea; congenital heart disease (especially conus medullaris); delayed umbilical cord shedding (>30 days); family history of PID or a family history of infants who died from infection; persistent low lymphocyte count (<2.5×10⁹/L) or other blood cell counts (neutropenia), leukocytosis without obvious signs of infection; hypocalcemia with or without seizures; lack of thymus shadow on chest X-ray. Based on my country’s experience in PID diagnosis and treatment and clinical data from some PID diagnosis and treatment centers, and after extensive consultation with peers, the Immunology Group of the Pediatrics Branch of the Chinese Medical Association proposed in 2015 the following possible early clues that strongly suggest PID: recurrent respiratory infections, early infant infections with growth disorders, recurrent purulent infections of the skin, mucous membranes and internal organs, rare and extremely severe infections in early life, recurrent infections with the same pathogen, autoimmune or chronic inflammation, and the appearance of various special manifestations of immunodeficiency syndromes (such as early-onset refractory thrombocytopenia, severe skin eczema, ataxia and telangiectasia, bone dysplasia and hypopigmentation, etc.) [3].
Newborn screening is of great significance for the early diagnosis of PID. Reports show that the transplant survival rate of children with severe combined immunodeficiency (SCID) under 3.5 months of age is 94%, which is significantly higher than that of older children or children with secondary infections [4]. At present, the methods of newborn screening have become increasingly mature. Quantitative PCR detection of T-cell receptor excision circles (TREC) can screen for some PID with abnormal T-cell development, with a specificity of up to 95% [5]. Kapa excision circles (κ-deleting recombination excision circles (KREC)) can also screen for some B-cell developmental defects such as X-linked agammalobulinemia (XLA) [6]. The United States and Europe began to carry out newborn PID screening in 2008 and gradually popularized it. In the past 10 years, the 2-year survival rate of SCID patients diagnosed by newborn screening and treated with hematopoietic stem cell transplantation (HSCT) has reached 90% [7]. Currently, provinces and cities in my country such as Shanghai, Chongqing, and Zhejiang have begun exploring newborn PID screening. It is hoped that these preliminary studies and practices can promote the spread of this work in my country, enabling more children with PID to receive treatment at the optimal time, improve their prognosis, and enhance their quality of life.
II. Timely and appropriate treatment.
Advances in medical science have made some diseases caused by gene mutations treatable. Since there are many types of PID and varying degrees of severity, appropriate treatment methods should be selected for different diseases. For severe and early-onset diseases, timely diagnosis and bone marrow stem cell transplantation can significantly improve the prognosis of 65% to 75% of children, with disease-free survival time of more than 4 years [2]. Children without complications such as infection have a significantly reduced risk of receiving HSCT [8]. More than 300 cases of PID have been treated with HSCT in Chongqing, Shanghai, Shenzhen and other places in my country, including SCID, Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD), etc., and satisfactory results have been achieved, with an overall success rate of 65% to 85%. Currently, the indications for bone marrow transplantation for PID include SCID, hemophagocytic lymphohistiocytic hyperplasia syndrome, X-linked polysecreting gland disease-enteropathy-immune dysregulation syndrome, severe phagocytic abnormalities such as leukocyte adhesion defects, severe congenital neutropenia, CGD, DiGeorge syndrome (DGS), WAS, and innate immune abnormalities such as hypohidrotic ectodermal dysplasia with immunodeficiency caused by NEMO gene mutations. Advances in gene technology have also brought greater hope for the treatment of PID, especially new gene editing technologies such as CRISPR-Cas9, which have been successfully used for targeted repair of PID mutant genes. Currently, clinical trials of gene editing technology are being conducted in SCID, CGD, and WAS, and preclinical studies are also underway in X-linked hyper-IgM syndrome and XLA. Thymus transplantation has also been successfully used for children with complete DGS and forkhead protein N1 deficiency.
Some PID patients, after early identification and diagnosis, can also be well controlled with medication, or maintain good health and significantly improve their quality of life. Examples include the use of human gamma globulin replacement therapy for XLA and interleukin-1 antagonists for cryopyrin-associated periodic syndromes (CAPS).
III. Regular follow-up visits and standardized treatment
For children with PID, in addition to early diagnosis, selection of specific HSCT treatment and possible gene therapy, supportive treatments such as prophylactic use of immunoglobulin G (IgG), prophylactic use of antibiotics, and drug control of autoinflammatory disease (AID) are equally important.
1. Application of prophylactic IgG:
IgG replacement therapy is the most cost-effective and simple treatment measure in the treatment of PID. Regular and correct application can prevent most children with PID from recurrent infections and the resulting disease deterioration and progression, and significantly improve the quality of life of children with PID. The International PID Patient Organization conducted a survey on the treatment and life satisfaction of PID patients. 300 health-related quality of life questionnaires from 21 countries showed that the satisfaction rate of PID patients receiving IgG replacement therapy was 76%, which illustrates the importance of this replacement therapy; however, it was also found that only 53% (intravenous injection) and 45% (subcutaneous injection) of patients received this replacement therapy. IUIS once recommended that all PID patients with severe IgG deficiency and/or antibody production defects should receive IgG replacement therapy. The Chinese Journal of Pediatrics also published a review article in 2017 entitled "Further Strengthening Immunoglobulin G Replacement Therapy for Primary Immunodeficiency Diseases". However, at present, India's understanding of the importance of IgG replacement therapy for children with PID and the principles and protocols of its application is still insufficient, and the popularization of standardized application of IgG replacement therapy for children with PID is far from satisfactory. To this end, the "Expert Consensus on Immunoglobulin G Replacement Therapy for Primary Immunodeficiency Diseases", jointly written by the Immunology Group of the Pediatrics Branch of the Chinese Medical Association and the Editorial Board of the Chinese Journal of Pediatrics and published in this journal, provides a detailed introduction to the indications, application principles, recommended application regimens, adverse reactions and precautions for IgG replacement therapy in children with primary immunodeficiency diseases. Of course, issues such as whether or how to extend the dosing interval, whether the dosing time can be improved, and how to make the application more convenient need to be addressed and further improved in practice.
2. Application of prophylactic antibiotics:
Because of the abnormal immune function of children with PID, infections are usually serious and fatal, and cover a variety of sources of infection, especially opportunistic pathogens, which are difficult to identify and treat. Therefore, infection is an important factor affecting the prognosis of children with PID. The quality of treatment of PID children with concurrent infections directly affects their quality of life. To this end, the Immunology Group of the Pediatrics Branch of the Chinese Medical Association and the Editorial Board of the Chinese Journal of Pediatrics jointly formulated the "Expert Consensus on Anti-infective Treatment and Prevention of Primary Immunodeficiency Diseases", which put forward suggestions on the pathogens, treatment and prevention of different types of PID complicated with infection. The aim is to draw the attention of pediatricians of different specialties to the treatment of PID children with concurrent infections, promote the standardized anti-infective treatment of PID children, and provide a good opportunity and conditions for further radical treatment of PID children.
3. Drug treatment for autoimmune and inflammatory states:
Although most AIDs have clear gene abnormalities and defects (monogenous AIDs), with the elucidation of the signaling pathways in their pathogenesis, the disease can still be controlled and long-term remission can be maintained with the corresponding cytokines or inhibitors of the signaling pathways, which has significantly improved the quality of life of the children. This issue of "Drug Treatment of Monogenic Autoinflammatory Diseases" provides a more detailed and systematic summary of the inhibitors of different cytokines involved in different pathogenesis mechanisms of AID and their application in AID. It is hoped that with the attention of pediatricians and pediatric rheumatologists, appropriate treatment can be given to children with AID in a timely manner to improve their prognosis.
Conclusion
In conclusion, it is hoped that all pediatricians and related specialists will increase their vigilance regarding PID in their daily clinical work, conduct preliminary laboratory tests on suspected cases, and refer them to immunology specialists for consultation. This will ensure that these children receive timely diagnosis and appropriate treatment options under the guidance of immunology specialists, with standardized treatment, regular follow-up, and efforts to improve the diagnosis and treatment level of PID in India, thereby maximizing the improvement of these children's quality of life. Of course, improving the quality of life for these children should also include raising public awareness of PID and mobilizing the entire society to provide comprehensive guidance and assistance in various aspects, including their learning, mental health, and future employment
References
1.Robert A. Good – Known as one of the “fathers of modern immunology”; performed the first successful bone marrow transplant for immunodeficiency.
2. Max D. Cooper – Discovered B and T lymphocytes; major contributor to understanding immune system disorders.
3.H. Buckley – Pioneer in treating Severe Combined Immunodeficiency (SCID) in children.
4. Luigi D. Notarangelo – Leading expert in primary immunodeficiency and genetic immune disorders.
5. Jean-Laurent Casanova – Known for research on genetic causes of childhood infectious diseases.
6. Alain Fischer – Key figure in gene therapy for pediatric immunodeficiency.
7. Charlotte Cunningham-Rundles – Expert in primary immune deficiency diseases.
8. Hans D. Ochs – Known for research on Wiskott-Aldrich syndrome and pediatric immune disorders