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Immunodeficiency
Immunodeficiency
Immunodeficiency
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Immunodeficiency
Other namesImmunocompromise, immune deficiency, immunocompromisation
SpecialtyImmunology
MedicationImuran

Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition.[1] Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

In clinical settings, immunosuppression by some drugs, such as steroids, can either be an adverse effect or the intended purpose of the treatment. Examples of such use is in organ transplant surgery as an anti-rejection measure and in patients with an overactive immune system, as in autoimmune diseases. Some people are born with intrinsic defects in their immune system, or primary immunodeficiency.[2]

A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised individual may particularly be vulnerable to opportunistic infections, in addition to normal infections that could affect anyone.[3] It also decreases cancer immunosurveillance, in which the immune system scans the body's cells and kills neoplastic ones. They are also more susceptible to infectious diseases owing to the reduced protection afforded by vaccines.[4][5]

Types

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By affected component

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In reality, immunodeficiency often affects multiple components, with notable examples including severe combined immunodeficiency (which is primary) and acquired immune deficiency syndrome (which is secondary).

Comparison of immunodeficiencies by affected component
Affected components Main causes[8] Main pathogens of resultant infections[8]
Humoral immune deficiency

B cell deficiency

B cells, plasma cells or antibodies
T cell deficiency T cells Intracellular pathogens, including Herpes simplex virus, Mycobacterium, Listeria,[9] and intracellular fungal infections.[8]
Neutropenia Neutrophil granulocytes
Asplenia Spleen
Complement deficiency Complement system
  • Congenital deficiencies

Primary or secondary

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The distinction between primary versus secondary immunodeficiencies is based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it.

Primary immunodeficiency

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Main article: Primary immunodeficiency

A number of rare diseases feature a heightened susceptibility to infections from childhood onward. Primary Immunodeficiency is also known as congenital immunodeficiencies.[11] Many of these disorders are hereditary and are autosomal recessive or X-linked. There are over 95 recognised primary immunodeficiency syndromes; they are generally grouped by the part of the immune system that is malfunctioning, such as lymphocytes or granulocytes.[12]

The treatment of primary immunodeficiencies depends on the nature of the defect, and may involve antibody infusions, long-term antibiotics and (in some cases) stem cell transplantation. The characteristics of lacking and/or impaired antibody functions can be related to illnesses such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency [13]

Secondary immunodeficiencies

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Further information: Immunosuppression

Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging, particular medications (e.g., chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids) and environmental toxins like mercury and other heavy metals, pesticides and petrochemicals like styrene, dichlorobenzene, xylene, and ethylphenol. For medications, the term immunosuppression generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term immunodeficiency generally refers solely to the adverse effect of increased risk for infection.

Many specific diseases directly or indirectly cause immunosuppression. This includes many types of cancer, particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS),[11] caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells, and also impairs other immune system responses indirectly.

Various hormonal and metabolic disorders can also result in immune deficiency including anemia, hypothyroidism and hyperglycemia.

Smoking, alcoholism and drug abuse also depress immune response.

Heavy schedules of training and competition in athletes increases their risk of immune deficiencies.[14]

Causes

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The cause of immunodeficiency varies depending on the nature of the disorder. The cause can be either genetic or acquired by malnutrition and poor sanitary conditions.[15][16] Only for some genetic causes, the exact genes are known.[17]

Immunodeficiency and autoimmunity

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There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation.[18] One example is common variable immunodeficiency (CVID) where multiple autoimmune diseases are seen, e.g., inflammatory bowel disease, autoimmune thrombocytopenia, and autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis, an autosomal recessive primary immunodeficiency, is another example. Low blood levels of red blood cells, white blood cells, and platelets, rashes, lymph node enlargement, and enlargement of the liver and spleen are commonly seen in these patients. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible. In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes are also seen in X-linked agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in chronic granulomatous disease (CGD) as well. CGD is caused by a decreased production of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in patients with midline granulomatous disease; an autoimmune disorder that is commonly seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas. Wiskott–Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency is also sometimes associated with the development of autoimmune and atopic phenomena.

Antibody vulnerability period in children

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The period following birth is critical for the development of a child's immune system. Initially, a newborn relies heavily on passive immunity transferred from the mother, primarily through the placenta and breastfeeding.

As breastfeeding frequency declines, immune protection gradually wanes, making the child more vulnerable and increasingly reliant on their developing immune system. This transitional phase, known as the "antibody vulnerability period", lasts until approximately three to four years of age, during which the child's immune system matures and becomes fully functional.[19]

To combat pathogens, it is important for babies to develop their own specific antibodies recognizing these antigens. And these types of antibodies are known as immunoglobulins. Immunoglobulin G (IgG) is one of them.

Babies are unable to make their own IgG antibodies at birth and rely on maternal transfer of IgG via placenta during the third trimester. Other types of immunoglobulins (IgA, IgM, IgE and IgD) do not cross the placenta. It is believed that IgG is important in protecting babies against infections.[20]

Naturally bioactive Immunoglobulin G is found in breast milk which plays a significant role in early life during the vulnerable period. The Y-shaped structure of Immunoglobulin G allows it to effectively identify and combat pathogens, providing antibody-like protection to the child.[21]

Research indicates that maintaining adequate levels of IgG during early childhood may help mitigate the risks associated with this immune vulnerability. This supplementation can offer a protective boost, enhancing the infant's ability to fend off infections and other health threats during the critical years when their immune system is still developing. The importance of this period underscores the need for targeted nutritional interventions to support overall immune health in young children.

Classes of immunoglobulins (Igs)

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The immune system produces several classes of immunoglobulins (Ig), such as IgA, IgD, IgE, IgG, and IgM. Each class helps protect the body from infection in a different way (see below).[22]

Immunoglobulin Subclasses and Their Properties

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Immunoglobulin Subclasses
Subclass Structure Antigen Binding Sites Crosses Placenta Total Antibody in Serum Fc Binds to Functions
IgM Pentamer 10 No 6% Complement Main antibody of primary responses, best at fixing complement. Monomer form serves as B cell receptor.
IgG Monomer 2 Yes 80% Phagocytes Main blood antibody of secondary responses, neutralize toxins, opsonization. All antibodies are Y shape, only some are dimer (sIgA) or pentamer (IgM). The Y-shaped structure has sites that effectively identify and bind pathogens. Able to suppress more than 99% of the antibody response against the bound antigen.[23]
IgA Dimer 4 No 13% None Secreted into mucus, tears, saliva, colostrum.
IgE Monomer 2 No 0.002% Mast cells and basophils Antibody of allergy and antiparasitic activity.
IgD Monomer 2 No 1% None B-cell receptor.

Diagnosis

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Medical History and Physical Examination: A physician will inquire about past illnesses and family history of immune disorders to identify inherited conditions. A detailed physical examination helps recognize symptoms indicative of an immune disorder. Blood Tests: these tests are instrumental in diagnosing immunodeficiency as they measure: Infection-fighting proteins (immunoglobulins): Essential for robust immune defense, these protein levels are measured to evaluate immune function.[24] Blood cell counts: Deviations in specific blood cells can point to an immune system anomaly. Immune system cells: These assessments are used to measure the levels of various immune cells. Genetic testing involves collecting samples from patients for molecular analysis when there is a suspicion of inborn errors in immunity. Most Primary Immunodeficiency Disorders (PIDs) are inherited as single-gene defects.[25] The key genes associated with immunodeficiency diseases include CD40L, CD40, RAG1, RAG2, IL2RG, and ADA. Here is a summary of some methods utilized to identify genetic anomalies: Sanger Sequencing of Single Genes: Sanger sequencing is widely recognized as the benchmark method for accurately identifying individual nucleotide changes, as well as small-scale insertions or deletions in DNA. It is particularly valuable for confirming known familial genetic variations, for validating findings from next-generation sequencing technologies, and in specific scenarios that require sequencing of single genes. An example is its use to confirm mutations in the Bruton tyrosine kinase (BTK) gene, which are linked to X-linked agammaglobulinemia (XLA)[26] • Targeted Gene Sequencing Panels (tNGS): This technology is ideal for examining genes in specific pathways or for follow-up experiments (targeted resequencing) from whole genome sequencing (WGS). It is rapid and more cost-effective than WGS, and because it allows for deeper sequencing.[27] • Whole Exome Sequencing (WES): is a commonly used method which captures the majority of coding regions of the genome for sequencing, as these regions contain the majority of disease-causing mutations Useful for identifying mutations in specific genes[28] • Trio or Whole-Family Analyses: In some cases, analyzing the DNA of the patient, parents, and siblings (trio analysis) or the entire family (whole-family analysis) can reveal inheritance patterns and identify causative mutations[29]

Treatment

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Available treatment falls into two modalities: treating infections and boosting the immune system.

Prevention of Pneumocystis pneumonia using trimethoprim/sulfamethoxazole is useful in those who are immunocompromised.[30] In the early 1950s Immunoglobulin(Ig) was used by doctors to treat patients with primary immunodeficiency through intramuscular injection. Ig replacement therapy are infusions that can be either subcutaneous or intravenously administered, resulting in higher Ig levels for about three to four weeks, although this varies with each patient.[13]

Prognosis

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Prognosis depends greatly on the nature and severity of the condition. Some deficiencies cause early mortality (before age one), others with or even without treatment are lifelong conditions that cause little mortality or morbidity. Newer stem cell transplant technologies may lead to gene based treatments of debilitating and fatal genetic immune deficiencies. Prognosis of acquired immune deficiencies depends on avoiding or treating the causative agent or condition (like AIDS).

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Immunodeficiency

View on Grokipedia
from Grokipedia
Immunodeficiency is a condition characterized by a deficiency in the immune system's ability to protect against infections and diseases, resulting from the failure or absence of key immune components such as lymphocytes, , or the . These disorders can be broadly classified into primary immunodeficiencies, which are rare genetic conditions inherited from birth that impair immune development or function, estimated to affect hundreds of thousands of people in the United States (with many cases undiagnosed) across more than 550 distinct forms, and secondary immunodeficiencies, which are acquired later in life due to external factors like infections, , immunosuppressive medications, or chronic diseases. Primary immunodeficiencies often manifest in infancy or childhood with recurrent, severe infections from common pathogens, while secondary forms, such as those caused by or use, can lead to opportunistic infections and heightened risks of malignancies or autoimmune disorders. Common symptoms across both types include frequent bacterial, viral, fungal, or parasitic infections that respond poorly to treatment, chronic diarrhea, skin abnormalities such as rashes or infections, and in children. typically involves tests to assess immune cell counts and function, with treatments ranging from immunoglobulin replacement therapy and antibiotics for primary cases to addressing underlying causes like antiretroviral therapy for HIV-related secondary immunodeficiency. Advances in and transplantation have improved outcomes, though early detection remains critical to prevent life-threatening complications.

Overview

Definition

Immunodeficiency is a medical condition characterized by a compromised or absent , resulting in the body's reduced or complete inability to protect against infections and diseases. This state arises from defects in the 's components or functions, leading to heightened vulnerability to that would typically be controlled in healthy individuals. The comprises two primary arms: the , which provides rapid, non-specific defense against a broad range of threats through mechanisms like physical barriers and , and the , which offers targeted, antigen-specific responses that improve with repeated exposure and enable immunological memory. Immunodeficiencies can manifest as quantitative deficiencies, such as reduced numbers of immune cells like lymphocytes or , or qualitative deficiencies, where existing immune elements function abnormally, impairing effective clearance. Common clinical manifestations of immunodeficiency include recurrent or severe infections, opportunistic diseases caused by normally harmless microbes, increased of malignancies due to unchecked cellular proliferation, and sometimes exaggerated allergic responses stemming from dysregulated immune . These immunodeficiencies are broadly classified into primary forms, which are inherent genetic defects, and secondary forms, which develop from external factors.

Epidemiology

Immunodeficiency encompasses a range of disorders characterized by an increased susceptibility to infections, with primary immunodeficiencies (PIDs) arising from genetic defects and secondary immunodeficiencies resulting from external factors such as infections or medications. Globally, PIDs affect an estimated 1 in 1,200 to 1 in 10,000 individuals, though underdiagnosis remains prevalent, particularly in resource-limited settings, leading to conservative figures of around 6 million cases worldwide. Secondary immunodeficiencies are far more common, driven largely by infection, with approximately 40.8 million people living with globally as of 2024, representing a significant proportion of secondary cases. Incidence rates of PIDs vary by population, with higher occurrences in regions practicing consanguineous marriages, such as parts of the , where rates range from 20% to 50%, significantly elevating the risk of autosomal recessive PID forms compared to non-consanguineous groups. Demographically, PIDs predominantly manifest in pediatric populations, with most diagnoses occurring in children under 18 years due to their congenital nature, whereas secondary immunodeficiencies more frequently affect adults, often linked to chronic conditions like or malignancies. Geographic variations are pronounced, with secondary immunodeficiencies showing elevated prevalence in , where accounts for over 25 million cases—more than 60% of the global total—exacerbated by limited access to antiretroviral therapy and co-endemic infections. Emerging trends highlight the influence of aging populations on secondary immunodeficiencies, as —age-related immune decline—significantly increases infection risks in individuals beyond age 65. Additionally, post-2020 data indicate rises in secondary immunodeficiencies linked to chronic sequelae of severe acute respiratory syndrome coronavirus 2 () infection, including , which has been associated with persistent immune dysregulation, particularly among those with preexisting vulnerabilities. These patterns underscore the need for enhanced surveillance in aging and post-pandemic cohorts to address underreported burdens in developing regions.

Classification

Primary Immunodeficiencies

Primary immunodeficiencies, also known as inborn errors of immunity (IEI), comprise a diverse group of more than 550 inherited disorders arising from genetic defects that compromise the innate and adaptive immune systems. These conditions are predominantly monogenic, stemming from mutations in single genes critical for immune cell development, function, or regulation, as classified by the International Union of Immunological Societies (IUIS). The IUIS framework organizes them into ten phenotypic tables based on the affected immune component, encompassing defects in immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies, and others. Notable examples illustrate the spectrum of these disorders. Severe combined immunodeficiency (SCID) represents a severe form involving profound impairments in T-cell and often B-cell function, rendering infants highly susceptible to opportunistic infections shortly after birth. (XLA), caused by mutations in the BTK gene, leads to a near-complete absence of mature B cells and circulating immunoglobulins, typically manifesting as recurrent sinopulmonary bacterial infections after maternal protection wanes around 6 months of age. (CVID), a more heterogeneous primary disorder, features low serum immunoglobulin levels and poor responses, often presenting with recurrent respiratory infections, gastrointestinal issues, or in childhood or adolescence. Inheritance patterns for primary immunodeficiencies include X-linked recessive, X-linked dominant, autosomal recessive, and autosomal dominant modes, with the specific pattern determining the risk to family members. Autosomal recessive forms predominate in many cases and are significantly more common in regions with high rates, such as the , where parental relatedness elevates the likelihood of inheriting two mutated alleles. has been associated with up to a several-fold increased of autosomal recessive immunodeficiencies compared to non-consanguineous populations. These disorders generally onset in infancy or , characterized by recurrent, severe, or unusual infections involving , viruses, fungi, or , which can lead to or chronic complications if undiagnosed. Unlike secondary immunodeficiencies, which develop later due to environmental or acquired factors, primary forms are congenital and intrinsic to the immune system's genetic makeup.

Secondary Immunodeficiencies

Secondary immunodeficiencies, also known as acquired immunodeficiencies, refer to impairments in immune function that arise after birth due to extrinsic factors disrupting an otherwise normal , such as infections, , pharmacological agents, or malignancies. These conditions increase susceptibility to infections by affecting various immune components, including T cells, B cells, and neutrophils, without involving inherent genetic defects. In contrast to primary immunodeficiencies, which stem from congenital genetic mutations, secondary forms develop in response to environmental or iatrogenic influences. Secondary immunodeficiencies are far more prevalent than primary ones, impacting millions worldwide and representing a significant burden, particularly in vulnerable populations. stands out as the most common cause globally, compromising both innate and adaptive immunity through mechanisms like deficiencies that impair function and production. For example, severe protein-energy affects cellular immunity, leading to higher rates in affected individuals. Iatrogenic cases are especially common among cancer patients, where up to 25% of those with exhibit secondary at diagnosis, rising to 80% over time due to disease progression or therapies. exemplifies a high-impact infectious cause, with approximately 40.8 million people living with the in 2024, resulting in widespread CD4+ T-cell depletion and opportunistic infections. Key examples illustrate the diversity of secondary immunodeficiencies. HIV infection progressively depletes + T cells, leading to acquired immunodeficiency (AIDS) and profound vulnerability to pathogens like . Chemotherapy and other cytotoxic agents induce by suppressing function, causing severe cytopenias that heighten risks of bacterial and fungal infections during treatment cycles. Protein-losing enteropathies, often associated with gastrointestinal disorders, result in excessive loss of immunoglobulins and proteins, culminating in and recurrent infections. These examples highlight how secondary immunodeficiencies target specific immune elements based on the underlying trigger. Unlike many primary immunodeficiencies, secondary forms typically manifest in adulthood or later childhood and offer potential for reversibility when the root cause is effectively managed. For instance, nutritional interventions can restore immune competence in cases, while discontinuing immunosuppressive drugs like corticosteroids often leads to recovery of counts. In , antiretroviral therapy can partially rebuild + T-cell populations, reducing infection risks over time. However, reversibility varies; persistent effects may linger in chronic conditions like malignancies or post-therapy scenarios, necessitating ongoing monitoring and supportive care such as immunoglobulin replacement.

By Affected Immune Component

Immunodeficiencies can be categorized based on the primary immune component affected, providing a functional framework that highlights the specific arm of the impaired, whether innate or adaptive. This approach complements broader classifications like primary versus secondary etiologies, as defects in immune components can arise congenitally or through acquired factors. Such categorization facilitates targeted diagnostic strategies by linking clinical patterns to underlying immunological vulnerabilities. Defects in innate immunity primarily involve components responsible for immediate, non-specific defenses against pathogens. disorders, for instance, impair the ability of neutrophils and macrophages to engulf and destroy microbes; a representative example is , where neutrophils fail to generate , leading to recurrent bacterial and fungal infections. Complement deficiencies disrupt the cascade that enhances and lyses pathogens—early classical pathway defects like deficiency cause uncontrolled and , while terminal component deficiencies increase susceptibility to encapsulated bacteria such as species. These innate defects often manifest as localized or systemic infections without the broad involvement seen in adaptive failures. Adaptive immunity defects target the antigen-specific responses mediated by . B-cell deficiencies compromise antibody production, resulting in humoral immunodeficiency; common examples include conditions with absent or low immunoglobulins, leading to recurrent sinopulmonary bacterial infections due to poor opsonization and neutralization of extracellular pathogens. T-cell deficiencies hinder cellular immunity, particularly against intracellular viruses, fungi, and opportunistic organisms—disorders like those with thymic exhibit increased vulnerability to viral and fungal infections from impaired T- maturation and function. Combined immunodeficiencies affect both B- and T-cell arms, as in , where profound dysfunction causes life-threatening infections from diverse pathogens shortly after birth. Other categories encompass defects in mucosal barriers or lymphoid organs, which support localized immunity. Mucosal immunity impairments, such as those selectively affecting responses at epithelial surfaces, predispose to chronic candidal infections in the , , and genitals. Lymphoid organ defects, like splenic or thymic aplasia, disrupt and development, amplifying risks from encapsulated bacteria or viruses. Many immunodeficiencies exhibit overlaps across components—for example, certain T-cell defects secondarily impair B-cell function through disrupted T-helper support—emphasizing that this classification aids in identifying dominant impairments for precise evaluation and management.

Causes

Genetic Causes

Primary immunodeficiencies arise from monogenic mutations that disrupt development or function, predominantly through loss-of-function variants that abolish or severely impair protein activity. Gain-of-function mutations, though less common, can also contribute by causing dysregulated signaling, as seen in certain autoinflammatory phenotypes. The advent of next-generation sequencing (NGS) technologies since the early has dramatically accelerated the identification of these causal variants, enabling comprehensive screening of PID gene panels and whole-exome sequencing to uncover novel mutations in undiagnosed cases. As of 2024, the International Union of Immunological Societies recognizes over 550 distinct inborn errors of immunity associated with more than 500 genes. Prominent examples include mutations in the IL2RG gene, which encodes the common gamma chain (γc) shared by receptors for 2, 4, 7, 9, 15, and 21; loss-of-function variants in IL2RG underlie (SCID), leading to profound defects in T-cell, B-cell, and development due to impaired signaling. Similarly, mutations in the BTK gene, encoding , cause by halting B-cell maturation at the pre-B-cell stage, resulting in near-absent circulating B cells and immunoglobulins; over 1,000 distinct BTK mutations have been reported, mostly missense or nonsense leading to protein truncation or instability. Inheritance patterns of primary immunodeficiencies are diverse, with autosomal recessive forms comprising the majority (approximately 65-70%) due to biallelic in consanguineous or outbred populations, X-linked recessive accounting for about 15-20% and primarily affecting males, and the rest autosomal dominant or sporadic. In (CVID), the most prevalent symptomatic PID, polygenic influences predominate, where combinations of common low-penetrance variants in multiple genes (e.g., TACI, BAFF-R) cumulatively impair B-cell function and production, explaining its heterogeneous presentation and late onset. Epigenetic modifications, such as or alterations, play a rare but emerging role in modulating disease expression, particularly in cases of incomplete where identical genotypes yield variable phenotypes; for instance, environmental factors interacting with epigenetic changes may explain why some carriers of PID mutations remain .

Acquired Causes

Acquired causes of immunodeficiency encompass a range of external factors that disrupt immune function after birth, distinct from genetic origins and contributing to secondary immunodeficiencies. These triggers include infections, therapeutic interventions, nutritional deficits, chronic illnesses, and physiological changes like aging, often leading to increased susceptibility to opportunistic infections through mechanisms such as depletion or impaired signaling. The severity and duration of typically correlate with the intensity and persistence of the exposure, as seen in dose-dependent effects from medications or pathogens. Infectious agents represent a primary category of acquired immunodeficiency, with human immunodeficiency virus (HIV) being the most prevalent cause globally, resulting in acquired immunodeficiency (AIDS). HIV targets CD4+ T lymphocytes by binding its envelope glycoprotein gp120 to the receptor on these cells, triggering viral entry, replication, and progressive depletion of helper T cells essential for coordinating immune responses. This leads to profound cellular immunodeficiency, with CD4 counts often falling below 200 cells/μL in advanced stages, heightening risks for infections like . Similarly, virus induces transient but severe immunosuppression lasting weeks to months post-infection, primarily through direct infection of lymphocytes and dendritic cells via its receptor CD150 (SLAM), which suppresses by inhibiting T-cell proliferation and cytokine production such as interleukin-12. This viral interference with and adaptive responses explains the elevated mortality from secondary bacterial infections in measles cases, particularly in unvaccinated children. Iatrogenic causes arise from medical treatments intended for other conditions but inadvertently suppress immunity. Immunosuppressive drugs, such as corticosteroids, exert their effects by activating glucocorticoid receptors in immune cells, which translocate to the nucleus to inhibit pro-inflammatory gene transcription, including cytokines like IL-1, IL-6, and TNF-α, thereby reducing T-cell activation and neutrophil migration. High-dose or prolonged use, common in autoimmune diseases, can lead to opportunistic infections in up to 20-30% of patients. Biologic agents targeting tumor necrosis factor (TNF), such as infliximab or adalimumab, block this cytokine's role in granuloma formation and macrophage activation, increasing susceptibility to intracellular pathogens like Mycobacterium tuberculosis; meta-analyses show a 1.5-2-fold higher risk of serious infections compared to non-biologic therapies. Chemotherapy and radiation therapy further contribute by inducing lymphopenia: alkylating agents and antimetabolites damage rapidly dividing hematopoietic cells, while ionizing radiation depletes circulating lymphocytes through apoptosis and bone marrow suppression, with studies reporting grade 3-4 lymphopenia in over 70% of patients receiving thoracic radiation, correlating with poorer survival in cancers like lung carcinoma. Beyond infections and treatments, other acquired factors include , chronic diseases, and aging. , the leading global cause of secondary immunodeficiency, impairs T-cell maturation and function; for instance, —prevalent in protein-energy malnutrition—reduces thymic hormone production and T-lymphocyte differentiation, as evidenced by decreased + counts and heightened rates in affected populations. Chronic diseases exacerbate this: diabetes mellitus compromises innate immunity via hyperglycemia-induced dysfunction and delayed , with diabetic patients facing 2-3 times higher risks from pathogens like . Renal failure induces uremia-related by accumulating toxins that inhibit T-cell signaling and , contributing to a 10-20% annual rate in dialysis patients. Aging, through , manifests as acquired immune decline with thymic reducing naïve T-cell output and promoting oligoclonal expansions of T cells, alongside chronic (inflammaging) that elevates baseline vulnerability in those over 65. Dose-response relationships are evident in scenarios like prolonged antibiotic therapy, where extended courses (e.g., >14 days) disrupt diversity, fostering that weakens mucosal barriers and systemic immunity, as observed in increased difficile colitis rates post-broad-spectrum use.

Pathophysiology

Mechanisms of Immune Dysfunction

Immunodeficiencies impair immune responses through disruptions at the cellular and molecular levels, leading to defective pathogen recognition, clearance, and adaptation. At the cellular level, dysregulation of in T-cells contributes to immune dysfunction, as seen in (ADA) deficiency where accumulation of (dATP) triggers excessive thymic , reducing mature T-cell numbers and impairing adaptive immunity. Similarly, impaired in neutrophils underlies conditions like (CGD), where mutations in components, such as gp91phox, prevent the oxidative burst necessary for killing ingested microbes, resulting in recurrent bacterial and fungal infections. On the molecular front, defects in signaling pathways, exemplified by JAK-STAT disruptions in primary immunodeficiencies, hinder T- and natural killer (NK)-cell development; for instance, JAK3 mutations block IL-2 and IL-4 receptor signaling by failing to phosphorylate STAT proteins, thereby arresting lymphocyte maturation. Antibody production failures further exacerbate deficits, as in (XLA) caused by (Btk) mutations that halt B-cell maturation at the pre-B stage, leading to absent circulating immunoglobulins. Systemic consequences of these cellular and molecular impairments include lymphopenia, which compromises immune by reducing the pool of circulating lymphocytes available to detect and respond to antigens. In severe combined immunodeficiencies (SCIDs), such as X-linked SCID due to IL2RG mutations, profound T-cell lymphopenia diminishes cytotoxic and helper functions, allowing opportunistic infections to evade detection and proliferate unchecked. Unresolved infections from these defects often provoke chronic inflammation, as phagocytic failures in CGD lead to persistent microbial remnants that sustain formation and tissue damage through prolonged release and immune cell recruitment. Feedback loops amplify dysfunction, particularly through persistent antigen stimulation that exhausts immune reserves. In (XLP), mutations in SH2D1A () result in uncontrolled T- and B-cell proliferation following Epstein-Barr virus (EBV) exposure, leading to hyperactivation followed by exhaustion of lymphocyte pools due to chronic antigenic drive and dysregulation. This exhaustion manifests as reduced proliferative capacity and effector function in remaining T-cells, perpetuating vulnerability to secondary infections and further depleting adaptive immunity.

Relationship with Autoimmunity

Immunodeficiency and exhibit a paradoxical relationship, where defects in immune function can paradoxically lead to aberrant self-reactive responses due to failures in immune regulation. In primary immunodeficiencies (PIDs), genetic disruptions often impair both protective immunity against pathogens and mechanisms that maintain self-tolerance, resulting in autoimmune manifestations that may precede or complicate infectious susceptibility. This overlap is evident in syndromes where single-gene mutations disrupt central or peripheral tolerance, highlighting how immunodeficiency can foster autoimmunity through dysregulated activity. Key mechanisms include the loss of regulatory T-cells (Tregs), which are essential for suppressing autoreactive T-cells and maintaining . For instance, in the gene, which encodes a critical for Treg development and function, cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked () syndrome, leading to severe multi-organ such as , , and enteropathy alongside profound immunodeficiency. Additionally, chronic infections in immunodeficient states can trigger via molecular mimicry, where microbial antigens structurally resemble self-antigens, eliciting cross-reactive immune responses that breach tolerance; bystander activation and effects from persistent pathogens further exacerbate this process. Representative examples illustrate this link in specific PIDs. In (CVID), a heterogeneous PID characterized by , autoimmune cytopenias such as immune and occur frequently due to B-cell dysregulation and impaired Treg function. Similarly, selective IgA deficiency, the most common PID, is associated with autoimmune thyroiditis, where antithyroid antibodies develop in a subset of patients, reflecting breakdowns in mucosal and systemic tolerance. These autoimmune complications often manifest as non-infectious features in PIDs. Autoimmunity affects 20-30% of patients with PIDs, with higher rates in certain subgroups; for example, up to 22% of CVID patients experience autoimmune manifestations, rising to 50% in those with granulomatous disease. This bidirectional association extends beyond primary defects, as autoimmune diseases can secondarily exacerbate immunodeficiency—for instance, through the production of neutralizing autoantibodies against cytokines like interferons or , which impair innate and adaptive responses, or via immunosuppressive therapies that further compromise immune competence.

Pediatric Considerations

Immunoglobulin Development

Immunoglobulin development in children begins and continues postnatally, providing essential during periods of vulnerability. Fetal B cells first produce IgM around 10-12 weeks of , marking the initial antibody response independent of maternal transfer, as IgM does not cross the . Maternal IgG, the predominant immunoglobulin transferred transplacentally, starts accumulating in the from approximately the 13th week of and reaches peak levels in the third trimester, offering passive protection against pathogens. At birth, IgG levels are comparable to maternal levels, but these decline rapidly postnatally due to a of about 30 days, reaching a around 3-6 months of age. Endogenous IgG synthesis by the infant's B cells gradually increases from the first weeks of life, compensating for the waning maternal antibodies and peaking at near-adult levels by age 5-6 years. The five major immunoglobulin classes each play distinct roles in pediatric immune maturation, with their production patterns evolving to meet developmental needs. IgM serves as the primary response antibody, forming pentamers for effective early agglutination and complement activation during initial infections. IgG provides long-term immunity, crossing the and dominating the serum response after class switching, with its subclasses enabling targeted protection. IgA is crucial for mucosal immunity, secreted at secretory sites like the respiratory and gastrointestinal tracts to prevent adhesion, though its serum levels remain low until later childhood. IgE mediates allergic responses and defense against parasites, with production increasing postnatally but often remaining minimal in early infancy. IgD functions primarily in B-cell activation and maturation on the cell surface, with limited soluble roles in children. IgG subclasses—IgG1, IgG2, IgG3, and IgG4—exhibit specialized properties that mature differentially in children, influencing susceptibility to specific infections. IgG1, comprising 60-70% of total IgG, predominates in responses to viral proteins and toxins, facilitating opsonization and complement , and reaches near- levels (about 60-70% of concentrations) by age 1 year, with full levels by 5-7 years. IgG2, about 20-30% of IgG, is key for antibody responses to antigens from encapsulated like , but its production lags, with serum levels reaching concentrations by 7-10 years, though functional responses to polysaccharides mature around age 2-3 years, contributing to higher infection risks in young children. IgG3, effective against certain viruses and toxins with strong complement-fixing ability, and IgG4, involved in responses, both develop more variably, with levels increasing up to 7-8 years and plateauing thereafter to support overall humoral balance. Aberrant immunoglobulin development in children can manifest as primary immunodeficiencies, with selective IgA deficiency being the most common, affecting approximately 1 in 600 individuals and impairing mucosal barrier defenses against respiratory and gastrointestinal pathogens. This condition arises from impaired terminal differentiation of IgA-secreting plasma cells, often but associated with increased autoimmune and allergic risks in affected children. Other deficiencies, such as transient of infancy, delay endogenous IgG production beyond the typical timeline, prolonging reliance on maternal antibodies and heightening vulnerability during the first year. These developmental aberrations underscore the importance of timely B-cell maturation for pediatric immune competence.

Vulnerability Periods in Infants

In infants with immunodeficiency, distinct windows of immune immaturity during early life significantly elevate the risk of severe and recurrent infections, as the has not yet achieved full functionality. These vulnerability periods stem from the gradual of , particularly the reliance on and transition from maternal antibodies to endogenous production. During the neonatal period (0-28 days), protection depends almost exclusively on transplacentally transferred maternal IgG, which provides passive against systemic pathogens. This limited repertoire heightens susceptibility to perinatal infections, including early-onset Group B (GBS) disease, a major cause of and in term and preterm infants. Similarly, (HSV) infections represent a critical threat, with maternal IgG antibodies serving as the primary barrier against disseminated , which can lead to high mortality if breached in immunodeficient cases. The 3- to 6-month period marks a physiological in total serum IgG levels, occurring as maternal IgG wanes (halving every 30 days) while the infant's own IgG synthesis remains insufficient to compensate fully. In the context of immunodeficiency, such as transient hypogammaglobulinemia of infancy, this decline amplifies risks for bacterial infections, exemplified by invasive disease from type b, which exploits impaired opsonization and . The immunoglobulin maturation process, involving delayed B-cell activation and class switching, contributes to this transitional vulnerability. From 6 to 24 months, endogenous IgA production—vital for mucosal immunity in the respiratory and gastrointestinal tracts—develops slowly, with serum levels remaining low (often 10-20% of adult values) and secretory IgA detectable but immature until at least 1-2 years of age. Concurrently, IgG2 subclass concentrations, which predominate in responses to polysaccharide capsules of , exhibit a quantitative defect, reaching only partial adult equivalence by age 2 and full maturity by 5-10 years. These delays render immunodeficient infants particularly prone to infections by encapsulated such as and , as well as respiratory viruses, due to suboptimal antibody-mediated clearance at mucosal surfaces and in the bloodstream. Management of these periods requires tailored strategies to mitigate risks without exacerbating immunodeficiency. Inactivated can be administered per standard schedules to bolster specific immunity, but live attenuated (e.g., oral or ) must be contraindicated in severe immunodeficiencies to avoid vaccine-strain dissemination and severe disease.

Diagnosis

Clinical Evaluation

The clinical evaluation of suspected immunodeficiency begins with a detailed to identify patterns suggestive of immune dysfunction. Key elements include a family history of recurrent infections, early deaths, or known immunodeficiencies, which points toward primary immunodeficiencies, particularly in cases of or X-linked inheritance. Infection patterns are scrutinized, such as more than four severe infections per year, including recurrent , , or , often requiring prolonged antibiotic courses with limited response. , characterized by poor weight gain or growth despite adequate nutrition, is a common historical red flag, especially in pediatric patients with underlying or combined defects. Symptoms prompting evaluation typically involve recurrent or severe infections beyond typical childhood illnesses. Recurrent sinopulmonary infections, such as chronic or , are hallmark features of antibody deficiencies like . Chronic diarrhea, often due to persistent gastrointestinal pathogens like , and recurrent skin abscesses from bacteria such as suggest humoral or phagocytic impairments. Infections by unusual or opportunistic pathogens, including pneumonia or persistent viral infections like , raise suspicion for T-cell or combined immunodeficiencies. Physical examination provides critical clues through observable signs of immune compromise. The absence of or tonsillar tissue is a classic finding in conditions like , reflecting profound B-cell deficiency. Oral thrush or , particularly if recurrent and unresponsive, indicates T-cell dysfunction, as seen in . In hyper-IgE syndrome, eczematous rashes combined with recurrent staphylococcal abscesses and skeletal abnormalities are distinctive. or may signal chronic infections or lymphoproliferative issues, while signs of , such as or , can coexist in certain primary immunodeficiencies. Red flags in the clinical assessment that strongly suggest include early-onset infections before six months of age, unexplained , or a history of , which warrant heightened suspicion and prompt referral. These findings, aligned with established classification systems, help differentiate primary from secondary causes and guide targeted investigation.

Laboratory Testing

Laboratory testing plays a crucial role in confirming and characterizing immunodeficiencies by providing objective measures of components and function. Initial evaluations often begin with basic screening tests to identify abnormalities in counts and levels, followed by more specialized assays to assess cellular immunity, functional responses, and underlying genetic or infectious causes. These tests are typically prompted by clinical histories of recurrent infections or suggestive symptoms, guiding the selection of appropriate immunological investigations. A (CBC) with differential is a fundamental initial test, often revealing lymphopenia, which indicates reduced numbers of lymphocytes and suggests possible T-cell or combined immunodeficiencies. Quantitative measurement of serum immunoglobulins, including IgG, IgA, IgM, and IgE, is performed using nephelometry, a light-scattering technique that detects antigen-antibody complexes to quantify protein levels; low levels may point to humoral immunodeficiencies such as . For cellular immunity assessment, flow cytometry enumerates lymphocyte subsets, including T cells (CD3+), B cells (CD19+ or CD20+), and natural killer (NK) cells (CD16+/CD56+), providing absolute counts and percentages to identify defects like severe combined immunodeficiency or DiGeorge syndrome. Lymphocyte proliferation assays evaluate T-cell function by measuring DNA synthesis (via tritiated thymidine incorporation or dye dilution) in response to mitogens like phytohemagglutinin, antigens, or anti-CD3/CD28 stimulation; diminished responses indicate impaired cellular immunity. Functional testing includes evaluation of antibody responses to vaccines, such as measuring pre- and post-vaccination titers to using (ELISA), where a failure to achieve a four-fold increase or protective levels (>0.1 IU/mL) suggests specific antibody deficiency. activity is assessed via the CH50 assay, which quantifies total hemolytic complement through the classical pathway; absent or low CH50 (<30% of normal) indicates deficiencies in components C1 through C9. Advanced testing for primary immunodeficiencies often involves whole (WES), which analyzes coding regions of approximately 20,000 genes to identify pathogenic variants in over 550 known immunodeficiency-associated genes, aiding in precise molecular . In cases of suspected acquired immunodeficiency, such as infection, plasma viral load is measured by quantitative (RT-PCR) to detect and quantify copies per milliliter, with levels above 10,000 copies/mL indicating active replication and immune compromise.

Management

Treatment Strategies

Treatment strategies for immunodeficiency aim to restore immune function, prevent infections, and address underlying causes, tailored to the specific type and severity of the immune defect. plays a key role in guiding therapy selection, ensuring interventions match the identified immune deficiency. For primary immunodeficiencies involving antibody defects, such as (CVID) or , immunoglobulin replacement therapy is the cornerstone of management. Intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) provides by replenishing deficient antibodies, typically administered at doses of 400-600 mg/kg per month, divided according to the route and interval (e.g., every 3-4 weeks for IVIG or weekly for SCIG). This approach significantly reduces infection rates and improves in affected patients. Antimicrobial prophylaxis is essential to mitigate opportunistic infections in immunodeficient individuals at high risk. Trimethoprim-sulfamethoxazole (TMP-SMX), the first-line agent for pneumonia (PJP) prevention, is dosed at one double-strength tablet (160 mg trimethoprim/800 mg sulfamethoxazole) daily in adults and children capable of swallowing tablets. Antifungal prophylaxis, such as , may be used for those with prolonged or T-cell defects to prevent or other fungal infections. These measures are particularly critical in severe cases like (SCID) prior to definitive therapy. Advanced curative therapies are available for certain genetic immunodeficiencies. for SCID allows early diagnosis, enabling (HSCT) as the standard treatment, offering potential cure by replacing defective immune cells; early intervention (within 3.5 months of birth) achieves overall survival rates exceeding 90% at 3 years post-transplant. represents a targeted option for specific forms, such as adenosine deaminase-deficient SCID (ADA-SCID); Strimvelis, an ex vivo retroviral correcting the ADA gene in autologous hematopoietic stem cells, received approval in 2016 for patients lacking suitable donors. As of 2025, long-term studies of lentiviral for ADA-SCID report overall survival of 100% and event-free survival of 95-96% in treated children, with no serious complications. Disease-specific treatments address secondary immunodeficiencies by targeting their etiology. In HIV-associated immunodeficiency, combination antiretroviral therapy () suppresses , restores + T-cell counts, and prevents progression to AIDS; current guidelines recommend initiating ART immediately upon diagnosis for all patients. For iatrogenic secondary immunodeficiencies caused by immunosuppressive drugs (e.g., in organ transplant recipients or autoimmune diseases), management involves dose optimization or discontinuation when feasible, alongside supportive therapies like immunoglobulin replacement if production is impaired.

Preventive Measures

Preventive measures for individuals with immunodeficiency focus on reducing exposure to pathogens and supporting overall immune health through targeted strategies. Vaccinations play a central role, with inactivated vaccines recommended over live attenuated ones to minimize infection risk; for example, the inactivated polio vaccine (IPV) is preferred instead of the oral polio vaccine (OPV) due to the potential for vaccine-derived in immunocompromised patients. Guidelines advise adjusting timing for infants with immunodeficiency, often delaying or modifying schedules based on the specific immune defect to ensure safety and efficacy. Live vaccines, such as measles-mumps-rubella (MMR) or varicella, are generally contraindicated in severely immunocompromised individuals to prevent disseminated disease. Hygiene and infection control practices are essential to limit opportunistic infections. Regular handwashing with soap and water, or alcohol-based sanitizers when soap is unavailable, significantly reduces transmission of bacteria and viruses in daily activities. Immunodeficient individuals should avoid crowded places during peak respiratory illness seasons and practice respiratory etiquette, such as covering coughs and sneezes, to prevent airborne pathogen exposure. Pet-related precautions include avoiding contact with animal feces; for instance, pregnant or immunocompromised persons should not handle cat litter boxes to prevent toxoplasmosis, a protozoal infection that can be severe in this population, with daily litter scooping recommended if unavoidable. Well-maintained pets and avoidance of reptiles or birds, which carry Salmonella, further mitigate zoonotic risks. Nutritional interventions address common deficiencies that exacerbate immune dysfunction. supplementation is advised for those with low levels, as it supports innate and adaptive immune responses and may reduce the incidence of respiratory infections; studies show that daily supplementation lowers acute risk in deficient individuals. In cases of secondary immunodeficiency like , correcting can enhance immunologic recovery alongside antiretroviral therapy. A balanced diet rich in fruits, , and proteins is encouraged, with supplements tailored to identified deficiencies to avoid excess intake. Screening and monitoring enable early intervention to prevent complications. For primary immunodeficiencies, which are often genetic, family is recommended to assess risks, guide reproductive decisions, and facilitate carrier testing for relatives. In secondary immunodeficiencies such as , regular monitoring of counts helps track immune status and informs prophylaxis against opportunistic infections, with guidelines suggesting testing every 3-6 months or more frequently if counts are low. These measures, adapted to the underlying immunodeficiency type, promote long-term health by preempting severe infections.

Prognosis

General Outcomes

Immunodeficiency disorders encompass a range of conditions that impair the immune system's ability to fight infections, leading to varied outcomes depending on the specific type and the timeliness of intervention. In (SCID), an untreated condition results in approximately 90% mortality by age 2 due to overwhelming infections. (HSCT), when performed early, achieves long-term survival rates exceeding 80%, with studies reporting up to 94% five-year survival in infants transplanted before 3.5 months of age. For acquired immunodeficiencies like , untreated typically progresses to AIDS within about 10 years, severely compromising immune function and leading to life-threatening opportunistic infections. With antiretroviral therapy (ART), approaches that of the general , particularly when initiated early and adhered to consistently. Common complications across immunodeficiencies include chronic lung diseases, such as , which arise from recurrent infections and contribute to long-term respiratory impairment. Malignancies, notably , pose significant risks; for instance, patients with (CVID) face a lymphoma prevalence of around 4%, far exceeding general rates. Malignancies occur at approximately 1.4-fold higher rate in primary immunodeficiencies compared to the general , with lymphomas showing much higher risks (8- to 10-fold). Quality of life in immunodeficient patients improves substantially with early , enabling timely interventions that reduce frequency and severity. However, persistent and associated complications often limit daily functioning, leading to higher rates of hospitalization and reduced overall well-being compared to healthy individuals.

Influencing Factors

Timely plays a pivotal role in modifying prognosis for immunodeficiencies, particularly through newborn screening programs for (SCID). These programs enable early detection before life-threatening infections occur, leading to improved survival rates post-hematopoietic transplantation, with studies showing enhancements from approximately 74% to 96% overall survival in screened populations. By 2023, SCID newborn screening had been implemented in more than 20 countries worldwide, including all U.S. states, most Canadian provinces, and several European nations such as the , , and , facilitating proactive interventions that significantly reduce early mortality. Access to healthcare resources profoundly influences outcomes, with stark disparities evident in low-resource settings where undiagnosed and untreated primary immunodeficiencies result in elevated mortality. In developing countries, where diagnostic facilities and immunoglobulin replacement therapies are often limited, a substantial proportion of cases—estimated at 70-90% globally—remain undiagnosed, leading to fatal infections in many patients before adulthood. For instance, untreated primary cases in these regions face mortality rates approaching 50% or higher due to recurrent severe infections, underscoring the need for equitable to bridge these gaps. Comorbidities such as and malignancies adversely affect in primary immunodeficiencies by exacerbating immune dysregulation and increasing treatment complexity. Autoimmune manifestations, common in conditions like (CVID) and (ALPS), heighten the risk of lymphomas by 8-10-fold through impaired and chronic inflammation, thereby reducing overall survival. Similarly, malignancies, which occur at a 2-fold higher rate in primary immunodeficiencies compared to the general population, represent a leading , particularly non-Hodgkin lymphomas in CVID, complicating immune surveillance and therapeutic responses. Age at onset further modulates , with earlier presentation in infancy—such as in SCID—associated with more severe disease and poorer outcomes if not promptly addressed, whereas later-onset forms like adult CVID generally permit longer survival with management. Recent advances in have transformed prognosis for certain previously fatal primary immunodeficiencies, extending survival in conditions like Wiskott-Aldrich syndrome (WAS). Lentiviral hematopoietic stem cell corrects the underlying WASp deficiency, achieving sustained immune reconstitution and clinical benefits in patients followed for up to 9 years, with 7 of 9 patients achieving long-term survival and reduced rates of infections, , and bleeding episodes. This approach has enabled discontinuation of supportive therapies like immunoglobulin replacement in multiple cases, marking a shift from historical high mortality to improved quality of life and longevity. As of November 2025, the EMA has recommended approval for Waskyra, the first for WAS, enhancing treatment options and long-term outcomes.

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