Immunodeficiency in Children: How to Recognize and Diagnose Hidden Threats

Primary immunodeficiencies (PIDs) are a group of inherited disorders in which one or more components of the immune system fail to function properly. These conditions make children vulnerable to frequent, severe, or unusual infections, and can also manifest as autoimmune disorders, inflammatory processes, and even oncological diseases. Early recognition and timely diagnosis of PIDs are critical for preventing serious complications and improving a child's quality of life.

What are Primary Immunodeficiencies (PIDs) in Children?

PIDs are genetically determined disorders affecting various links of the immune system. Unlike secondary immunodeficiencies, which develop as a result of other diseases or external factors (e.g., HIV infection, chemotherapy), primary immunodeficiencies are congenital. Their spectrum is extremely wide: ranging from relatively mild forms manifesting as a susceptibility to colds, to extremely severe conditions requiring immediate medical intervention. The importance of understanding PIDs lies in the fact that they can mimic other, more common childhood illnesses, which complicates diagnosis and delays the initiation of specific treatment.

Warning Signs: When to Suspect Immunodeficiency?

Suspicion of a primary immunodeficiency should arise when certain clinical signs are present, which can be either obvious or hidden. The Jeffrey Model Foundation has developed 10 warning signs of PIDs to help doctors and parents navigate them. These include:

• 4 or more new ear infections per year;
• 2 or more severe sinus infections per year;
• 2 or more pneumonias per year;
• Failure to thrive [2];
• Recurrent deep skin or organ abscesses;
• Persistent oral thrush or skin fungal infections after 1 year of age;
• Need for intravenous antibiotics to clear infections;
• 2 or more severe infections (meningitis, osteomyelitis, sepsis);
• Family history of PID;
• Adverse reactions to live vaccines.

In addition to these classic signs, there are other manifestations that may indicate a PID:

• Skin manifestations: Eczema and urticaria, especially if they begin in the neonatal period, are accompanied by recurrent infections, chronic lymphadenopathy, or developmental delay, and can be a sign of immunodeficiency [2].
• Chronic lymphadenopathy: Enlarged lymph nodes persisting for a long time are also one of the warning signs [2].
• Mouth ulcers, fever, abdominal pain, arthralgia: These symptoms may indicate rare autoinflammatory conditions, such as A20 haploinsufficiency (HA20), where diagnostic delay can reach nearly a decade [7].
• Gastrointestinal issues: Eosinophilic gastrointestinal diseases (EGIDs) and very early-onset inflammatory bowel disease (VEO-IBD) may be associated with PIDs [1, 3].

Immunodeficiency and Comorbidities: Non-Obvious Connections

PIDs are often not limited to increased susceptibility to infections, but are also closely linked to other diseases, complicating diagnosis:

• Eosinophilic gastrointestinal diseases (EGIDs): Studies show that primary immunodeficiencies may be associated with EGIDs in children. This highlights the need for immunological evaluation in patients with EGIDs to identify possible hidden immune disorders [1].
• Very early-onset inflammatory bowel disease (VEO-IBD): In children under 6 years of age, VEO-IBD often has a more severe course and can be caused by monogenic defects, including primary immunodeficiency genes. Identifying such defects allows for targeted and life-saving therapy [3]. Pediatric IBD may have a broader symptom spectrum and a more severe course than in adults, requiring a special approach to diagnosis [4].
• Autoimmune diseases: Children with type 1 diabetes mellitus are at an increased risk of developing other autoimmune diseases [8]. Autoimmune thyroid diseases, such as Hashimoto's thyroiditis and Graves' disease, can also be associated with genetic syndromes in the pediatric age group [5].
• Liver involvement: Children with IBD may present with asymptomatic liver function test abnormalities, often related to immune liver diseases such as primary sclerosing cholangitis or autoimmune hepatitis [6].

Diagnosis of Primary Immunodeficiencies: From Routine to Genetics

The diagnostic process when PID is suspected involves several stages:

1. Anamnesis and physical examination: The physician carefully gathers information about the frequency and nature of infections, the presence of autoimmune diseases, allergies, developmental delay, and family history. Assessment based on warning signs, such as those proposed by the Jeffrey Model Foundation, is the starting point [1].
2. Basic immunological tests: The first stage involves routine laboratory studies and basic immunological tests. These include determining serum immunoglobulin levels (IgG, IgA, IgM), titers of isohemagglutinins (blood group antibodies), and antibody titers to vaccine antigens (e.g., to HBsAg after hepatitis B vaccination and to rubella) [1].
3. Advanced immunological evaluation: If basic tests or the clinical picture raise serious suspicions, a more in-depth examination is ordered. This may include evaluation of lymphocyte subpopulations (T, B, NK cells), functional phagocyte tests, complement system assessment, and other specialized assays [1].
4. Genetic testing: In cases where clinical data and immunological tests point to a specific type of PID, or in the presence of very early and severe manifestations (e.g., in VEO-IBD), genetic testing may be performed. Identifying monogenic defects is crucial for confirming the diagnosis and selecting targeted therapy [3, 7]. PID diagnosis is established in accordance with the criteria of international societies, such as the European Society for Immunodeficiencies (ESID) [1].

Why is Early Diagnosis So Important?

Timely detection of primary immunodeficiency is critically important for the health and life of a child. Diagnostic delay, which, for instance, can reach nearly a decade in HA20 [7], leads to disease progression, the development of irreversible complications, and reduced treatment efficacy. Early diagnosis allows to:

• Prevent severe, life-threatening infections and their consequences.
• Reduce the risk of developing autoimmune diseases and oncological processes associated with PIDs.
• Initiate targeted therapy that can be life-saving, such as for monogenic defects causing VEO-IBD [3].
• Improve the child's quality of life by providing adequate protection and support for the immune system [2].

Remember that attentiveness to a child's health and seeking prompt medical attention when alarming symptoms appear are the keys to successful diagnosis and treatment of primary immunodeficiencies.

Sources

1. Behind the scenes: Primary immunodeficiencies in pediatric eosinophilic gastrointestinal diseases. https://pubmed.ncbi.nlm.nih.gov/42613804/
2. Eczema and urticaria as manifestations of undiagnosed and rare diseases. https://pubmed.ncbi.nlm.nih.gov/27894451/
3. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition position paper on the evaluation and management of patients with very early-onset inflammatory bowel disease. https://pubmed.ncbi.nlm.nih.gov/32079889/
4. Expert consensus on diagnostic guidelines for pediatric inflammatory bowel disease in Japan. https://pubmed.ncbi.nlm.nih.gov/40603758/
5. Hashimoto's thyroiditis and Graves' disease in genetic syndromes in the pediatric age group. https://pubmed.ncbi.nlm.nih.gov/33557156/
6. Management of abnormal liver tests in children with inflammatory bowel disease. https://pubmed.ncbi.nlm.nih.gov/34261897/
7. Solving the diagnostic puzzle of HA20 in children: challenges of a highly variable clinical and genetic spectrum. https://pubmed.ncbi.nlm.nih.gov/41741169/
8. Frequency of autoimmune diseases in children and adolescents with type 1 diabetes mellitus. https://pubmed.ncbi.nlm.nih.gov/42445886/

The information provided in this article is for reference purposes only and cannot replace professional medical advice. Always consult a qualified specialist for diagnosis and treatment.