Why Some People Get Sick Over and Over: The Hidden Genetic Reason Behind Primary Immunodeficiencies

If you or a loved one seems to catch every infection that comes around, struggles with infections that won't clear up, or has a family history of serious illness, there might be a genetic explanation. Primary immunodeficiencies (PIDs) are genetic disorders that compromise the immune system from birth, making people vulnerable to infections that healthy immune systems easily fight off. These conditions are far more common than most people realize, affecting an estimated 1 in every 2,000 people officially diagnosed—though researchers believe the true number could be 10 to 20 times higher when all types and variants are considered.

The immune system is your body's defense network, made up of organs, cells, and proteins working together to protect you from harmful invaders. It has two main operating systems: the innate immune system, which provides non-specific protection from birth, and the adaptive immune system, which learns to recognize specific threats as you encounter them. When genetic mutations disrupt either system, the result can be devastating.

What Are the Warning Signs That Someone Might Have a Primary Immunodeficiency?

PIDs often go undiagnosed because their symptoms mimic common childhood illnesses or adult health problems. However, certain patterns should raise red flags. In children, key warning signs include four or more new ear infections in a single year, two or more severe sinus infections annually, two months or longer of antibiotic treatment without improvement, two or more cases of pneumonia in one year, difficulty growing and gaining weight normally, recurrent deep abscesses, persistent mouth ulcers or fungal skin infections, and a family history of immunodeficiencies.

Adults with PIDs show slightly different patterns. These include two or more ear infections per year, two or more severe sinus infections annually, one pneumonia per year for more than one year, chronic diarrhea with weight loss, and recurrent viral infections. The key difference is that adults often have fewer infections overall, but the ones they do get tend to be more severe or persistent.

How Do Genetic Tests Help Diagnose These Conditions?

Genetic diagnosis is essential because it reveals the specific mutation causing the immunodeficiency, which directly shapes treatment decisions. The International Union of Societies for Immunology has classified PIDs into 10 main categories based on which part of the immune system is affected. Understanding which category applies to a patient allows doctors to provide personalized management and dramatically improve outcomes.

The 10 main types of primary immunodeficiencies include:

• Combined Immunodeficiencies: Defects in T lymphocytes that affect both cellular and humoral immunity, with severe combined immunodeficiency (SCID) being the most serious form, often called "bubble boy" disease, which is fatal within two years without treatment.
• Combined Immunodeficiencies with Syndromic Features: Immune system defects paired with abnormalities in other organs or body systems, such as DiGeorge syndrome, which includes cardiac malformations and facial differences.
• Antibody-Predominant Immunodeficiencies: The most common PIDs worldwide, accounting for approximately half of all cases, including selective IgA deficiency and common variable immunodeficiency.
• Immune Dysregulation Diseases: Conditions characterized by autoimmune manifestations where the immune system attacks the body's own tissues, requiring immunosuppressant treatment.
• Congenital Defects in Phagocytic Cells: Mutations affecting neutrophils and macrophages, which are responsible for engulfing and destroying pathogens.
• Defects in Innate Immunity: Genetic alterations that expose patients to serious infections from mycobacteria, viruses, and fungi.
• Autoinflammatory Diseases: Conditions characterized by abnormal stimulation of the innate immune system, causing recurrent inflammatory episodes with fever.
• Complement System Defects: Rare genetic alterations affecting proteins that help immune cells find and destroy microorganisms, increasing susceptibility to infections and autoimmune diseases.
• Phenocopies of Congenital Immunodeficiencies: Recently identified PIDs where the genetic alteration is somatic, meaning it is not inherited from parents.
• Bone Marrow Failure: A heterogeneous group of diseases resulting from dysfunction of blood-forming cells in the bone marrow.

Early diagnosis through genetic testing is critical because untreated PIDs can lead to serious, prolonged, and sometimes life-threatening infections. Beyond infections, people with PIDs face increased risk of allergies, autoimmune diseases, and cancer. Without proper identification and treatment, infections recur repeatedly, and patients become increasingly vulnerable.

The challenge is that many PIDs are underdiagnosed. Some appear during the first years of life, while others manifest in adulthood—either because they were missed during childhood or because they are late-onset forms. When someone presents with two or more characteristic signs of a PID, initiating a genetic study is essential to determine whether an underlying immunodeficiency is responsible.

If you notice a pattern of frequent, severe, or unusually persistent infections in yourself or a family member, discussing genetic testing with your doctor could be the first step toward a diagnosis that changes everything. Early identification enables personalized treatment plans that can prevent serious complications and dramatically improve quality of life.