Inborn errors of immunity (primary immunodeficiencies): Overview of management

INTRODUCTION — Inborn errors of immunity (IEIs), formerly called primary immunodeficiency disorders, are a growing group of hundreds of disorders [1]. IEIs range in severity from life-threatening disorders presenting in infancy to less severe disorders diagnosed in adulthood. Most patients with IEIs present with recurrent or chronic infections. Some disorders impact essential immunologic pathways and result in susceptibility to a range of both common and opportunistic pathogens, whereas other disorders may cause susceptibility to a very narrow number of pathogens, with a resulting broad age of presentation [2,3]. A significant number of patients with IEIs do not initially present with infections but rather with failure to thrive, severe atopy, autoinflammatory disease, or autoimmune disease. Others may develop such complications in the course of the disease [4-6].

Management of IEIs therefore differs across the spectrum of severity and depends largely on the specific defect in question. Accurate diagnosis is essential for proper patient management, including tailored screening for known risk factors, targeted pharmacotherapy and biologic use, and consideration of curative therapies such as bone marrow transplantation or gene therapy [7,8]. This topic will provide an overview of the principles of management of IEIs. The suggestions in this topic review are consistent with available practice parameters [2]. General topics related to evaluation and diagnosis of IEIs are found separately:

●(See "Recognition of immunodeficiency in the first three months of life".)

●(See "Newborn screening for inborn errors of immunity".)

●(See "Approach to the child with recurrent infections".)

●(See "Approach to the adult with recurrent infections".)

●(See "Laboratory evaluation of the immune system".)

●(See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

MEASURES TO PREVENT INITIAL INFECTIONS

Isolation measures — Once any severe inborn error of immunity (IEI) is suspected or confirmed, isolation measures should be implemented to prevent the patient from acquiring life-threatening infections [9-11]. This is particularly important for patients who might be candidates for hematopoietic cell transplantation (HCT), because the likelihood of post-HCT survival is improved for patients who have not yet developed any infectious complications of immunodeficiency or in whom infections have been successfully treated (table 1) [12,13]. Patients with profound forms of immunodeficiency, such as severe combined immunodeficiency (SCID), can either be managed carefully at home while awaiting HCT or can be hospitalized in an isolation room. Some immunologists consider the risk of the infant acquiring a nosocomial hospital infection to be greater than the risk of remaining at home, especially if there are no other young children at home who may transmit infections and outside contacts can be avoided. The clinician must weigh the risks and benefits of hospital versus home settings, including the social situation of the family and ease of access to the hospital in case symptoms of infection do appear. If the infant is kept at home, caregivers should receive counseling regarding safe isolation practices. They should not be taken on public outings, and visits to primary care providers should be deferred. Hospitalizations/clinic visits should be planned as to avoid the patient from sitting in busy waiting rooms. Patients instead should be placed directly into a room that has been thoroughly cleaned since the last patient. All staff entering the patient's room should wash hands thoroughly with soap and water and use a mask, gown, and gloves. In the event that hospitalization is preferred or becomes necessary, the patient should be placed into a positive pressure room with high-efficiency particulate air (HEPA) filtration. All staff entering the room should use a mask, gown, and gloves following handwashing. Nonessential staff should avoid entering the room, and the number of visitors should be minimized. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures'.)

Caregiver counseling — Patients, caregivers, and family members should be counseled on ways to minimize transmission of infections. Good handwashing remains paramount. The degree of precaution depends upon the severity of the disorder. For patients with moderate to severe forms of immunodeficiency, caregivers and parents who work, use public transportation, etc, are encouraged to change their clothing and wash hands prior to interacting with the patient. The number of guests/visitors to the home should be minimized. Those who are permitted to visit should have up-to-date vaccinations. (See 'Vaccination of patients, family members, caregivers' below.)

Immune globulin replacement — Immune globulin therapy is used in a variety of IEIs, including primary antibody deficiencies, SCID and combined immunodeficiencies until B cell function is restored, and other specific disorders involving defects in antibody production or function [14]. Prior to the first dose of immunoglobulin replacement, it is prudent to obtain baseline immunoglobulin levels and vaccine titers (if applicable for age). (See "Laboratory evaluation of the immune system", section on 'Measurement of antibody levels' and "Laboratory evaluation of the immune system", section on 'Measurement of antibody function'.)

Immunoglobulin can be replaced intravenously (IVIG) or subcutaneously (SCIg). The route of replacement is often dependent on patient preference unless replacement is needed urgently, in which case the patient should receive IVIG replacement in the hospital or outpatient infusion center to bring immunoglobulin (Ig)G levels into the normal range quickly. Replacement IVIG dosing ranges from 400 mg/kg/dose to 800 mg/kg/dose and is often administered every three to four weeks. The dose of IVIG may be increased to minimize the incidence of infections. Trough IgG levels should be monitored. Meta-analyses suggest that maintaining higher trough levels (>1000 mg/dL) correlates with a reduced risk of pneumonia in adolescents and adults [15,16]. For those patients who prefer SCIg replacement, the starting dose is often 100 to 200 mg/kg/dose and commonly is administered every seven days. The frequency can be modified based on a patient's weight, tolerance, and preference. Specific indications and a detailed discussion of the use of immune globulin therapy are found separately. (See "Immune globulin therapy in inborn errors of immunity" and "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects" and "Subcutaneous and intramuscular immune globulin therapy".)

Specialized immune globulins — Serum from donors with high titers of antibodies directed against particular infectious organisms may be pooled to prepare special lots of immune globulin with standardized amounts of antibody activity against the pathogen in question or "hyperimmune globulins."

●Cytomegalovirus immune globulin – CytoGam (brand name) is a gamma-globulin preparation using pooled serum from donors with high titers of cytomegalovirus (CMV) antibody. It has been used principally for the prophylaxis of CMV infection in immunosuppressed recipients of solid organ transplants (eg, kidney, lung) [17]. However, this has largely been replaced in these patients by the administration of ganciclovir. CytoGam (brand name) is still used as an adjunct to antiviral drugs in some immunocompromised patients with CMV infection. (See "Prevention of cytomegalovirus infection in lung transplant recipients".)

●Varicella-zoster immune globulin (VariZIG) – Varicella virus is capable of causing severe disease in immunocompromised adults and children. Patients who receive regular infusions of immune globulin are protected and do not require further passive prophylaxis for varicella exposure. In contrast, seronegative adults (those with no history of infection) who are not receiving immune globulin may be given VariZIG if exposed to an infected individual. In such patients, postexposure prophylaxis should be administered within 96 hours of close contact with an individual with varicella infection. (See "Post-exposure prophylaxis against varicella-zoster virus infection".)

Isolation is recommended for any patient with varicella. For immunocompetent patients, a minimum of five days after the appearance of the rash, as long as it remains vesicular, is the recommended period. This corresponds to the time of maximum contagiousness. The rash may remain vesicular longer in immunocompromised hosts, requiring a longer period of isolation. (See "Prevention and control of varicella-zoster virus in hospitals", section on 'Infection control measures'.)

●Anti-respiratory syncytial virus (RSV) antibody – Humanized monoclonal anti-RSV antibodies are used for prevention of RSV infection in certain high-risk groups, including those with primary or secondary immunodeficiency. (See "Respiratory syncytial virus infection: Prevention in infants and children".)

Prophylactic antimicrobial therapy — The use of prophylactic antimicrobials is intended to reduce the frequency and severity of sinopulmonary infections caused by common bacteria [18]. However, other forms of antiviral and antifungal treatments may be necessary in particular disorders. Few studies of the efficacy of prophylaxis in specific immune disorders have been performed, with some notable exceptions (eg, chronic granulomatous disease [CGD]) [19-21]. A survey of American immunologists with clinical focus in IEIs reported that, in the absence of consensus guidelines, approximately 75 percent of practitioners administered prophylactic antibiotics to at least some of their patients with immunodeficiency [22].

There is no standardized approach to the use of prophylactic antimicrobials in patients with immunodeficiency. Example prophylactic regimens are listed in the table (table 2). Prior to initiation of prophylactic antibiotics, it is essential to screen symptomatic patients for active infections. Particular attention should be paid to screening for mycobacterial infection prior to azithromycin use, due to the high risk of resistance development with monotherapy. Baseline screening may also be needed depending on the adverse reaction profile of the considered antibiotic, which could include electrocardiogram (ECG) when using QTc prolonging agents, as well as audiologic testing. (See 'Audiologic care' below.)

●SCID – Patients with SCID or other combined immunodeficiency prior to definitive therapy (hematopoietic stem cell transplant or gene therapy) may receive some combination of antibacterial, antiviral, and/or antifungal prophylaxis as required by their specific diagnoses, exposures, and infection history.

●Specific immune defects – Prophylactic therapy with combinations of antimicrobials may also be required for particular infection susceptibilities associated with specific immune defects. As an example, patients with CGD benefit from prophylactic antibiotics, antifungals, and interferon gamma. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Chronic granulomatous disease: Treatment and prognosis".)

●Mild humoral immune defects – Antibiotic prophylaxis alone is frequently offered to patients with mild hypogammaglobulinemia, selective IgA deficiency, specific antibody deficiency, or IgG subclass deficiency, if they have a history of recurrent infection and are not receiving immune globulin replacement [19,23]. A randomized trial demonstrated comparable efficacy of prophylactic antibiotics versus antibody replacement therapy for specific antibody deficiency, as well as few adverse events with antibiotic prophylaxis [24]. Some patients may require antibiotics only during certain times of the year (eg, over the winter) or only for a few years (eg, until outgrowing transient hypogammaglobulinemia of infancy). In more severely affected patients, prophylaxis may need to be year-round and may last for years. Evidence supporting antibiotic use in this population is lacking. When offered, trials are suggested with careful monitoring of side effects and rate of infections.

●Severe humoral immune defects – Patients with more severe antibody deficiencies receiving immune globulin may still have an increased rate of bacterial infections chronically or at certain times of the year (eg, during the winter) and may also benefit from antibiotic prophylaxis. A randomized trial in patients with primary antibody deficiency demonstrated that azithromycin prophylaxis significantly reduced the rate of pulmonary exacerbations and hospitalizations versus placebo, with no drug-related adverse events or increase in macrolide-resistance bacterial species [19]. Similar effects have been seen in studies of azithromycin prophylaxis in patients with cystic fibrosis or chronic obstructive pulmonary disease.

●Pneumocystis jirovecii prophylaxis – Prophylaxis for Pneumocystis jirovecii (carinii) pneumonia (PCP) should be administered to patients with moderate to severe T cell deficiency such as SCID, forms of combined immunodeficiency, and in patients receiving potent immunosuppressive therapy. Prophylactic regimens for PCP in primary and secondary immunodeficiency are similar to those administered to patients with human immunodeficiency virus (HIV) infection [25]. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Preventing initial infection'.)

●Antiviral prophylaxis – Prophylaxis against influenza and herpesviruses is indicated in some patients.

Influenza prophylaxis should be considered during influenza season for high-risk immunodeficient patients and for patients in close contact with other persons with influenza. This may include preventive antiviral therapy or, in some instances, full treatment doses. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Seasonal influenza in children: Management" and "Seasonal influenza in children: Prevention with antiviral drugs".)

Herpes simplex virus prophylaxis is indicated in some patients with recurrent mucosal or skin herpes simplex outbreaks in the context of specific immunodeficiencies, including those with defects in natural killer cells or defects in toll-like receptor 3 signaling [26,27]. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and "Toll-like receptors: Roles in disease and therapy".)

In patients with combined immunodeficiencies and a history of varicella infection, long-term suppressive antiviral prophylaxis should be considered, particularly in the setting of prior disseminated varicella.

Patients with combined immunodeficiency with CMV infection may also require prolonged antiviral prophylaxis. (See "Overview of cytomegalovirus infections in children".)

●Antifungal prophylaxis – Antifungal prophylaxis targeting Candida species may be required in disorders with high susceptibility to recurrent fungal infection, such as defects in the interleukin (IL)-12/23/Th17 pathway, or in the presence of anti-cytokine autoantibodies which occur in autoimmune polyendocrinopathy disorder type I. (See "Chronic mucocutaneous candidiasis".)

●Mycobacterial prophylaxis – Prophylaxis against mycobacterial infections is indicated in patients with Mendelian susceptibility to mycobacterial disease, such as defects of the interferon gamma-IL-12 axis, nuclear factor-kappa-B essential modifier (NEMO) deficiency, and others. (See "Mendelian susceptibility to mycobacterial diseases: An overview" and "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

Vaccination of patients, family members, caregivers — It is essential to talk with patients about the benefits and risks of vaccinations. IEI patients can significantly benefit from herd immunity, and therefore vaccination of all caregivers is highly encouraged, when possible and safe. Live vaccines are contraindicated in patients with moderate to severe forms of immunodeficiency, but expert consensus recommends that healthy family members and close contacts receive all vaccines in order to provide secondary protection. The issues surrounding vaccination of patients with IEIs are reviewed in depth separately. (See "Immunizations in patients with inborn errors of immunity".)

Travel recommendations — Because patients with IEIs have increased susceptibility to infections and may have poor responses to vaccination (or be unable to receive live vaccines), patients and their families must take additional travel precautions. In certain locations, it will be necessary to drink only bottled water, to wash or avoid fresh produce, and to avoid eating undercooked food. Medication prophylaxis may be indicated, and it is imperative that all immunocompromised travelers have an emergency treatment plan. Ideally, local experts in IEIs should be identified in case of illness during travel. (See "Travel advice for immunocompromised hosts".)

CAUTION WITH BLOOD PRODUCTS — Patients with suspected or known T cell immunodeficiencies should not be given blood or blood components that may contain viable lymphocytes because of the risk of fatal transfusion-associated graft-versus-host disease. This applies mainly to severe combined immunodeficiencies and other forms of immunodeficiency where T cell function may be severely compromised (eg, Wiskott-Aldrich syndrome, nuclear factor-kappa-B essential modifier [NEMO] deficiency, and complete DiGeorge syndrome [and others]). Any cellular blood products given to these patients must be irradiated. (See "Transfusion-associated graft-versus-host disease", section on 'Immunodeficiency' and "Transfusion-associated graft-versus-host disease", section on 'Prevention'.)

Leukocyte reduction is also highly recommended in order to minimize chances of transmission of cytomegalovirus, which can cause significant disease in individuals who have an underlying T cell defect or have undergone hematopoietic cell transplantation. (See "Overview of cytomegalovirus infections in children", section on 'Immunocompromised hosts'.)

Patients with severe selective IgA deficiency (ie, undetectable levels of serum IgA) also have a potential risk of anaphylaxis to IgA-containing blood products. (See "Selective IgA deficiency: Management and prognosis", section on 'Reactions to blood products'.)

MANAGEMENT OF COMPLICATIONS — Clinicians caring for patients with an inborn error of immunity (IEI) should understand the different ways in which immune dysfunction can present, obstacles that may develop in patients with IEIs, and management strategies for these clinical complications.

Infectious disease — Infections are the most common complication of IEIs and occur even when protective measures are taken. When a suspected bacterial infection develops, attempts should be made to culture and identify the pathogen and initiate antibiotics as rapidly as possible. Immunocompromised individuals do not clear infections or respond to anti-infective therapy as well as immunocompetent individuals, and therefore prolonged antibiotic courses are often required [2]. Standard (short) courses of antibiotics for common infections, such as otitis media, sinusitis, or pneumonia, are often associated with relapse or recurrence of infection in this population. Optimal duration of antimicrobial treatment of immunodeficient patients has not been defined. Experienced clinical immunologists often prescribe courses of antimicrobials that are two to three times longer than standard recommendations. For example, rather than treating acute sinusitis with 10 days of antibiotics, some immunodeficient patients may require a 21-day course (or even up to 28 to 30 days), with careful observation in the initial weeks after treatment to make sure that symptoms do not reappear.

Specific IEIs increase risk for specific types of infection. Often these infections present in patients of certain age ranges, in predictable locations. As such, one can use epidemiologic data and knowledge of the mechanistic deficit to help predict causative organisms and direct treatment. Appropriate and timely treatment of infection is imperative to better clinical outcomes.

●Patients with cellular, complement, or antibody defects are at increased risk of bacterial infections. Examples include increased risk for patients with a late complement deficiency to develop Neisseria infections [28], and patients with chronic granulomatous disease (CGD) to develop Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, and Nocardia species [29]. Specific risk may be elevated during particular times of year (eg, during the winter). Chronic gastrointestinal infections with bacteria such as Campylobacter jejuni or salmonella can occur.

●Fungal infections are more common in children with some IEIs, including CGD (Aspergillus), X-linked hyper IgM syndrome (Pneumocystis jirovecii, Cryptococcus), chronic mucocutaneous candidiasis, CARD9 deficiency, and in patients with tumor necrosis factor (TNF) autoantibodies. (See "Chronic granulomatous disease: Treatment and prognosis" and "Primary humoral immunodeficiencies: An overview" and "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Treatment' and "Hyperimmunoglobulin M syndromes".)

●Children with disorders in the category of Mendelian susceptibility to mycobacterial disease, such as defects of the interferon gamma-interleukin-12 axis and nuclear factor-kappa-B essential modifier (NEMO) deficiency, are at increased risk for mycobacterial infections. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

●Parasitic infections due to Giardia or Cryptosporidium species can cause chronic gastrointestinal infections in common variable immunodeficiency (CVID) as well as combined immunodeficiency disorder. Cryptosporidium in particular has been described to cause severe biliary disease in patients with X-linked hyper-IgM disorder and related orders. (See "Hyperimmunoglobulin M syndromes", section on 'Clinical manifestations'.)

●Severe and recurrent viral infections are found in children with defects in T cells, natural killer cells, or innate pathogen signaling. Herpesviruses such as cytomegalovirus, Epstein-Barr virus, and varicella-zoster virus can cause severe visceral disease in these patients, and screening for these viruses by polymerase chain reaction (PCR) is suggested [30,31]. Adenovirus infection can be similarly severe and warrants screening in the setting of gastrointestinal or respiratory symptoms [32]. Chronic gastrointestinal infections due to norovirus or enterovirus can occur in the patients with CVID or combined immunodeficiency disorders and can result in chronic diarrhea and wasting [2,33]. Recurrent mucosal or skin disease due to herpes simplex virus 1 and 2 and human papillomavirus virus (HPV) can also occur and warrant vigilance and testing of skin eruptions [34]. In some diseases characterized by susceptibility to HPV infection, the underlying genetic defect may not be restricted to the immune system but also involve keratinocytes, as in the case of epidermodysplasia verruciformis but also in X-linked and JAK3 deficiency [35]. (See "Toll-like receptors: Roles in disease and therapy" and "Seasonal influenza in children: Management" and "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)

Both culture and molecular-based testing should be undertaken in the workup of any potential infection in a patient with an IEI. Culture has the advantage of allowing susceptibility testing, but, as many atypical organisms are fastidious, PCR and next-generation sequencing (NGS)-based methods of pathogen detection are recommended for guidance of therapy.

Pulmonary disease — Pulmonary disease is a leading cause of morbidity and mortality in patients with IEIs. In addition to pulmonary infections, other manifestations include bronchiectasis, granuloma formation, interstitial lung disease, bronchiolitis obliterans, and mediastinal adenopathy. Screening for pulmonary complications is essential in moderate to severe forms of IEIs and depends on both regular pulmonary functional testing and imaging. Previous studies have demonstrated that functional testing alone lacks sensitivity in detecting interstitial pathology [36]. There are no guidelines regarding the ideal timing or modality of screening imaging in absence of symptoms in different IEIs. Treatment of lung disease is focused on the underlying etiology, with cautious attention to infection risk, and often includes inhaled glucocorticoids, physiotherapy, and immunosuppression in the setting of inflammatory disease. (See "Pulmonary complications of primary immunodeficiencies".)

Gastrointestinal disorders — Gastrointestinal disorders are commonly found concomitantly in patients with IEIs [37,38]. Manifestations include infection, autoimmune inflammation, malabsorption, granuloma formation, and lymphoproliferative disorders. Primary treatment efforts should focus on the type of IEI and underlying gastrointestinal disorder. These patients typically require aggressive, extended antibiotic and/or immune modulating therapy (table 3). Moreover, surgical intervention may be required to help manage obstruction due to abscesses, granulomas, or lymphoid hyperplasia. (See "Gastrointestinal manifestations in primary immunodeficiency".)

Lymphoproliferative and malignant disease — Patients with many forms of IEIs are at increased risk for malignancies secondary to a number of different factors, including immune dysregulation, genetic predisposition, and impaired viral clearance [39]. Moreover, those who develop malignancies do so at younger ages than their immunocompetent peers. Defects in DNA repair mechanisms, such as occur in ataxia telangiectasia, Bloom syndrome, Artemis deficiency, and related disorders are associated with high rates of malignancy. In the presence of combined immunodeficiency, chronic infection with oncogenic viruses such as Epstein-Barr virus (EBV) or HPV can lead to malignancies. Whereas latent infection with EBV is normally controlled by a robust T cell-mediated response, impaired cytotoxic T cell function could allow development of EBV-driven lymphoproliferative disease (EBV-LPD). In EBV-LPD, EBV-infected B cells may infiltrate secondary lymphatics as well as solid organs and is usually associated with marked elevation of EBV viral load [40,41]. A more detailed discussion of this disorder in transplant patients is found separately. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Clinical manifestations'.)

Certain IEIs are also associated with specific malignancies, such as dermatofibrosarcoma protuberans in adenosine deaminase (ADA) deficiency. Screening for EBV and HPV is recommended in IEIs with impaired antiviral response. In radiation sensitivity disorders, strict avoidance of radiation exposure is recommended, and other imaging modalities should be utilized when necessary [42]. When necessary, standard cancer therapy and transplantation protocols often require modification, given increased toxicity risks in IEI patients. (See "Malignancy in inborn errors of immunity" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Radiation-sensitive SCID due to DNA repair defects'.)

Hypersensitivity disorders — Atopic disease, with sensitivity to foods, medications, and/or environmental allergens, is seen in a variety of antibody deficiencies, diseases of immune dysregulation, and other categories of immunodeficiency. Severe eczema is a frequent manifestation in forms of IEI with immunodysregulatory features, including Job syndrome, Wiskott-Aldrich syndrome, IPEX syndrome, and Omenn syndrome. Drug hypersensitivity may complicate patients requiring chronic antibiotics and other long-term therapies. Non-IgE-mediated mechanisms of food intolerance and reactions to environmental exposures may also occur. (See "Clinical manifestations of food allergy: An overview" and "An approach to the patient with drug allergy".)

Autoimmunity — Autoimmunity is increasingly recognized as a disease manifestation in many IEIs [5,43-47]. Patients with defects in innate, humoral, and cellular immunity are all at risk for autoimmune disease, though the absolute risk of autoimmunity varies by disease. Autoimmunity in the setting of an IEI can impact multiple organ systems and can include endocrinopathy, hepatitis, vitiligo, autoimmune enteropathy, systemic lupus erythematosus (SLE), and cytopenias (table 3). Management of autoimmunity is often similar to that utilized in broader populations of patients with similar autoimmune disorders, though in some cases first-line therapies may need to be altered depending on specific infectious precautious for that specific population. Genetic diagnosis may also aid in guiding therapy for autoimmunity based on the affected pathway. A more comprehensive review of autoimmunity in IEIs is found separately. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Clinicians evaluating patients with new-onset autoimmune disorders should be suspicious of an IEI, especially if the presentation is atypical in age of onset, severity, or if the patient has multiple autoimmune manifestations. Patients who carry an IEI diagnosis should be aware of autoimmune sequelae related to their disorder, and regular screening is recommended. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Endocrinopathies — Children with certain IEIs may show symptoms of endocrine dysregulation very early in life. Typically, this presents as type 1 diabetes mellitus and/or thyroiditis. However, growth hormone deficiencies and adrenal dysregulation have also been described. Infections and other metabolic imbalances can produce emergent events and abrupt decompensation. As such, management requires an aggressive, personalized, multidisciplinary approach, with focus on infection control, metabolic support, and immune modulation. (See "Causes of primary adrenal insufficiency (Addison disease)" and "Neonatal diabetes mellitus" and "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

IMMUNE RECONSTITUTION — Depending upon the disorder present, immunologic reconstitution may be possible in the form of hematopoietic cell transplantation (HCT), enzyme replacement, thymic transplantation, or gene therapies.

Hematopoietic cell transplantation — HCT has been used as the primary curative therapy for severe inborn errors of immunity (IEIs) for over 50 years (table 1) [12,48,49]. Approaches to HCT and overall risk have changed substantially over the past two decades, with more potential donor sources, greater targeting of preparative chemotherapy regimens, and improved supportive care [12,48]. Approach to transplantation in pediatric and adult patients is covered in detail separately. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

General considerations include:

●Available donor options

●Patient health prior to transplant, with particular focus on infections, nutritional status, and general organ function

●Whether a disorder is limited to the hematopoietic compartment, such that HCT would be more likely to be truly curative and lead to significant improvement in the quality of life

A genetic diagnosis is helpful but not required for HCT. Genetic diagnosis is particularly important for disorders involving radiosensitivity (such as ataxia telangiectasia or radiosensitive severe combined immunodeficiency [SCID] including Artemis, ligase IV, and Cernunnos deficiencies), as these disorders impart higher risk of immediate and long-term toxicities from alkylating agents that are commonly used in preparative regimens. Genetic diagnosis is also helpful in the setting of immunodysregulatory disorders, many of which are associated with transplant risks including graft rejection and inflammatory complications such as hemophagocytic lymphohistiocytosis. Knowledge of previous experience in transplantation of a specific disorder can guide the discussion of whether to pursue HCT, as well as best approaches with regard to donors, preparative regimens, and post-transplant screening and management.

Enzyme replacement and metabolic therapy — Several IEIs stem from defects in cell metabolism that impair development or survival of lymphocytes.

●Adenosine deaminase (ADA) deficiency accounts for roughly 20 percent of SCID and can be treated via enzyme replacement with recombinant ADA stabilized with polyethylene glycol (PEG-ADA), which is administered intramuscularly once to twice weekly [50]. PEG-ADA enzyme replacement therapy permits partial immune reconstitution by detoxification of immunotoxic metabolites and permits adequate T cell and B cell function to permit response to inactivated vaccines. However, progressive lymphopenia and waning function have been reported with long-term use, and accordingly it is recommended primarily as a bridge to other definitive therapies [51]. (See "Adenosine deaminase deficiency: Treatment and prognosis", section on 'Stabilization/bridge therapy with enzyme replacement therapy' and "Adenosine deaminase deficiency: Treatment and prognosis", section on 'Longer-term ERT'.)

●Rare defects in B12/folate intracellular metabolism are associated with combined immunodeficiency and may be treated via lifelong B12 or folate supplementation therapy [52,53].

Thymic transplantation — Transplantation of thymic tissue has been successfully performed in infants with complete DiGeorge syndrome and Forkhead box N1 (FOXN1) deficiency [54]. (See "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis", section on 'Cultured thymic transplant'.)

Gene therapy — Gene therapy is feasible and effective in several severe immunodeficiency disorders that are limited to hematopoietic cell lineages. This has been performed by transduction of autologous hematopoietic stem cells with a vector containing the corrected gene product, which is then administered to the patient as an autologous bone marrow transplant. Early phase I trials of gene therapy using gamma-retroviral vectors to treat SCID, Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD) demonstrated immune reconstitution after engraftment but were complicated by multiple cases of leukemia and myelodysplastic syndrome stemming from insertional oncogenesis [55,56]. Advances in vector engineering have seemingly minimized this risk, and current self-inactivating lentiviral vectors have been used successfully to treat patients with X-linked and ADA SCID, WAS, and CGD in phase I trials with no reported incidence of leukemia [57-59]. One gamma-retroviral gene therapy product for treatment of ADA-SCID is approved in Europe. (See "Overview of gene therapy for inborn errors of immunity".)

ISSUES DURING THE CORONAVIRUS PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has presented significant challenges for patients with inborn errors of immunity (IEIs), their families, and their medical providers.

IEIs and the risk of COVID-19 disease — International cohort studies demonstrated that most IEIs do not impart significant risk of severe COVID-19 disease [60,61]. In a 2022 series of 63 patients (39 children and 24 adults) with various IEIs, investigators retrospectively collected data on clinical course and treatment [62]. Patients had a range of IEIs, consistent with the prevalence of different disorders in the population, and 60 percent were vaccinated. When infected with SARS-CoV-2 (mostly Omicron), 90 percent of patients had a mild clinical course and 10 percent had moderate to severe disease. One child with multiple comorbidities died.

However, some IEIs do impart higher risk. Lymphopenia as well as low serum immunoglobulins correlated with risk of hospitalization and severe disease in these same studies [60,61]. In addition, defects in type I interferon signaling, either due to autoantibodies to type I interferons or congenital defects in type I interferon pathways, were associated with a dramatic risk of severe COVID-19 disease [63,64]. Accordingly, this population requires careful monitoring and early treatment of infection. (See "Toll-like receptors: Roles in disease and therapy", section on 'Severe COVID-19'.)

Access to care during the COVID-19 pandemic — Telehealth consultations have been an integral part of patient care, especially for patients with IEIs, to decrease infection exposure and associated concerns. Published surveys show that over half of patients with IEIs have used telemedicine resources to receive medical care [65].

Vaccination against COVID-19 — Multiple small studies of the efficacy of COVID-19 vaccinations in immunodeficient populations have been performed. To date, patients with B cell aplasia have predictably mounted no antibody responses to COVID-19 vaccinations, whereas patients with other antibody deficiency syndromes mount variable responses in comparison to healthy donors. Conversely, the majority of IEI patients demonstrate T cell responses to spike protein vaccines. COVID-19 vaccines have been safe and generally well tolerated in IEI patients and therefore are recommended for all eligible individuals.

Treatment of COVID-19 in IEI patients — Most patients with IEIs who develop COVID-19 infection require only supportive care, although consideration of treatment with antiviral pharmacotherapy (nirmatrelvir-ritonavir) is worthwhile, particularly in patients with multiple risk factors. (See "COVID-19: Management in children" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

HEALTH MAINTENANCE — Health maintenance in patients with IEIs includes dental, audiologic, and vision care and screening for complications from infections, inflammatory disorders, and medications.

Dental care — Certain IEIs carry increased risk for dental disease, including caries, periodontitis, and tooth loss (figure 1) [66]. Granulocyte function is particularly essential for dental health; accordingly, functional defects in neutrophils as well as Th17 CD4⁺ T cells place patients at elevated risk of dental disease [67]. Certainly, immunologic pathways are also essential for bone metabolism, such as the receptor activator of nuclear factor-kappa-B (RANK), and defects in these pathways may impair tooth formation. Routine dental visits at least twice annually are essential for patients with IEIs. Antibiotic prophylaxis is generally not required for routine dental work.

The teeth, gums, and tongue should be brushed at least twice daily and preferably after every meal. Sugar-free gum may be beneficial. Flossing should also be done at least once per day. Electric toothbrushes are recommended. Sugary drinks should be avoided. Fluoridated toothpaste should be used, and, for patients susceptible to dental caries, a prescription high-dose fluoridated toothpaste should be considered. Of note, routine dental x-rays should be avoided in patients with forms of IEI associated with radiosensitivity, including ataxia telangiectasia, Artemis deficiency, and related disorders.

Audiologic care — All patients with IEIs should have baseline audiologic screening, with further testing depending on their disease, exposures, and symptoms. Hearing loss can be a potential risk to many patients with IEIs due to infections or medication toxicities. Cytomegalovirus is a risk in patients with cellular immunodeficiency and is a leading cause of hearing loss. Aminoglycosides are known to be potential causes of ototoxicity, whereas other antibiotics including vancomycin and macrolides such as erythromycin and azithromycin are associated with lower risk of hearing loss, which is often described to be reversible. Certain IEIs also have intrinsic risk of hearing loss. Adenosine deaminase deficiency has been associated with an elevated risk of sensorineural hearing loss after bone marrow transplantation [68]. Autoinflammatory disorders such as Muckle-Wells syndrome and neonatal-onset multisystemic inflammatory disorder (NOMID) have high risk of hearing loss, which may be partially reversible with targeted therapy. One study found that 38 percent of a group of 47 children with either X-linked or autosomal recessive agammaglobulinemia or common variable immunodeficiency had hearing loss [69].

Vision screening — All patients with IEIs should have baseline ophthalmologic examinations, with further testing depending on their disease, exposures, and symptoms. Patients with IEIs are at risk for eye infections as well as inflammatory complications that may impact vision. Infections with many herpesviruses (cytomegalovirus, herpes simplex virus 1 and 2, and varicella zoster) can cause retinitis and/or uveitis. Toxoplasmosis can similarly cause chorioretinitis. Bacterial or fungal chorioretinitis may also occur in the setting of disseminated infection. Many autoinflammatory disorders are also associated with uveitis, such as familial Mediterranean fever, chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome, NOMID, and tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS) [70]. Diseases involving granulomatous inflammation, such as chronic granulomatous disease, may also be associated with retinal disease.

FAMILY AND PSYCHOSOCIAL SUPPORT

Mental and emotional health — Integration of individuals with inborn errors of immunity (IEIs) into normal social spheres is desired, but it is often challenging due to frequent illness, hospitalization, and consequent isolation. Cognitive, neurologic, and developmental problems may be particular issues in individuals with certain disorders, such as adenosine deaminase deficiency (ADA), DiGeorge syndrome, and others [71]. Patient support groups may be helpful, and neurologic, psychiatric, and social treatment and support should be sought early [72]. Primary humoral immunodeficiency has also been significantly associated with risk of multiple mental health disorders, as well as risk of suicide, highlighting the critical importance of mental health screening in the IEI population [73]. A general discussion of the needs of children with chronic illnesses is found separately. (See "Children and youth with special health care needs".)

Genetic testing and counseling — A geneticist or genetic counselor may be helpful in situations where there is ambiguity or uncertainty in the approach toward genetic diagnosis or its interpretation and is beneficial for education of the patient and family regarding the implications of specific findings. Parental genetic sequencing should be offered to families of children with a suspected IEI, to confirm variant phase (cis/trans) and aid in interpretation of pathogenicity. All families tested should be offered genetic counseling to review the test results and potential clinical and hereditary implications.

Genetic testing in the diagnosis of IEIs is discussed in detail separately. (See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome" and "Laboratory evaluation of the immune system", section on 'Advanced genomic studies for all forms of IEIs'.)

Resources for patients, families, and clinicians — A variety of resources are available via the internet for clinicians and patients and their families, which can help with both diagnosis and management:

●Immune Deficiency Foundation (IDF) (https://primaryimmune.org/) – IDF has a Consulting Immunologist Program (CIP) to connect health care providers who have questions about patients with known or suspected immunodeficiency with immunology experts experienced in diagnosing and managing these disorders. The site contains many additional resources for providers and patients, including a free handbook for patients and families, which contains chapters on living with immunodeficiency and navigating health insurance (intended for a United States audience).

●American Academy of Allergy, Asthma, and Immunology (AAAAI) (https://www.aaaai.org/) – Resources for patients and providers; "ask the expert" feature for clinicians.

●European Society for Immunodeficiencies (ESID) (https://esid.org/) – Resources primarily directed toward clinicians.

●Jeffrey Modell Foundation/Primary Immunodeficiency Resource Center (https://info4pi.org/) – Resources for clinicians and patients.

●US Immunodeficiency Network (USIDNET) (https://usidnet.org/) – Oriented toward researchers in immunodeficiency; includes a registry of specific disorders.

●An independent searchable database ("Immunodeficiency Search") (https://www.immunodeficiencysearch.com/) – Primarily directed toward clinicians; includes lists and tables of immunodeficiency disorders, clinical algorithms, and diagnostic laboratory resources.

●National Library of Medicine (NLM) (available online as PubMed) (https://www.nlm.nih.gov/) – Includes nearly all of the world's medical articles on all diseases and treatments including articles on immunodeficiency. Many can be downloaded free of charge. Mostly for clinicians and researchers.

●International Patient Organization for Primary Immunodeficiencies (IPOPI) (https://ipopi.org/) – Directed mainly toward patients and families.

TRANSITION OF CARE — With diagnostic and treatment advances, more children with inborn errors of immunity are living longer lives, generating a subsequent need to transition from pediatric to adult health care management [74]. This has wide implications for health care maintenance and coordination among multiple, new health care professionals. A patient will need to have adequate guidance and time to become self-sufficient and transition successfully.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Measures to prevent infections – The management of patients with inborn errors of immunity (IEIs), previously called primary immunodeficiency disorders, begins with early identification and diagnosis. Efforts to prevent initial infections are critical for infants suspected of having severe forms IEI, such as severe combined immunodeficiency (SCID), and important for patients of any age. Specific measures include:

•Infants with possible SCID must be isolated to prevent infections until immune reconstitution can take place. Isolation can either occur at home or in-hospital. (See 'Isolation measures' above.)

•Counseling on ways to minimize transmission of infections should be provided to patients, caregivers, and family members. (See 'Caregiver counseling' above.)

•Prophylaxis for Pneumocystis jirovecii (carinii) pneumonia should be administered to patients with moderate to severe T cell deficiency such as SCID, forms of combined immunodeficiency, and in patients receiving potent immunosuppressive therapy. (See 'Prophylactic antimicrobial therapy' above.)

•Immune globulin replacement is given to patients with a variety of IEIs, including primary antibody deficiencies, SCID and combined immunodeficiencies until B cell function is restored, and other specific disorders involving defects in antibody production or function. (See 'Immune globulin replacement' above.)

•Other prophylactic antibiotics are appropriate for specific IEIs such as chronic granulomatous disease and some patients with antibody deficiency (table 2). Use of antibiotics in this way is not standardized and should be evaluated on a case-by-case basis. Prior to initiation of prophylactic antibiotics, it is essential to screen symptomatic patients for active infections. (See 'Prophylactic antimicrobial therapy' above.)

•Live vaccines are contraindicated in patients with moderate to severe IEIs, but healthy family members and close contacts should receive all vaccines in order to provide secondary protection. (See "Immunizations in patients with inborn errors of immunity".)

●Treatment of infections – Infections are the most common complication of IEIs, and both culture and molecular-based testing should be undertaken to identify the responsible organisms. Immunocompromised patients often require broader spectrum and prolonged courses of antibiotics to eradicate infections, compared with immunocompetent patients, with observation in the initial weeks after treatment to make sure that symptoms do not reappear. (See 'Infectious disease' above.)

●Risk of malignancies – Patients with many forms of IEIs are at increased risk for malignancies secondary to a number of different factors, including immune dysregulation, genetic predisposition, radiation sensitivity, and impaired viral clearance. Those who develop malignancies do so at younger ages than their immunocompetent peers. When necessary, standard cancer therapy and transplantation protocols often require modification, given increased toxicity risks in IEI patients. (See "Malignancy in inborn errors of immunity" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Radiation-sensitive SCID due to DNA repair defects'.)

●Risk of autoimmunity – Autoimmunity is increasingly recognized as a disease manifestation in many IEI disorders and can include endocrinopathies (especially type 1 diabetes mellitus and/or thyroiditis), hepatitis, vitiligo, autoimmune enteropathy, systemic lupus erythematosus (SLE), cytopenias, and hypogonadism (table 3). Patients with these IEIs often develop these disorders at younger ages than immunocompetent individuals. (See 'Autoimmunity' above.)

●Options for immunologic reconstitution – Immunologic reconstitution may be possible in several IEI disorders in the form of hematopoietic cell transplantation (HCT), enzyme replacement, thymic transplantation, or gene therapies (see 'Immune reconstitution' above):

•HCT has been used as the primary curative therapy for severe IEIs for over 50 years. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

•Enzyme replacement therapy is useful in adenosine deaminase (ADA) deficiency and rare defects in B12/folate metabolism. (See "Adenosine deaminase deficiency: Treatment and prognosis", section on 'Stabilization/bridge therapy with enzyme replacement therapy' and "Adenosine deaminase deficiency: Treatment and prognosis", section on 'Longer-term ERT'.)

•Thymic transplant has been successfully performed in infants with complete DiGeorge syndrome and Forkhead box N1 (FOXN1) deficiency. (See "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis", section on 'Cultured thymic transplant'.)

•Gene therapy is feasible and effective in several severe IEIs that are limited to hematopoietic cell lineages, including X-linked and ADA SCID and others. (See 'Gene therapy' above.)

●Health maintenance – Health maintenance in patients with IEIs includes dental, audiologic, and vision care and screening for complications from infections, inflammatory disorders, and medications. (See 'Health maintenance' above.)

●Psychosocial care – Integration of individuals with IEIs into normal life activities is desirable but may be challenging due to frequent illness and hospitalization and the resulting isolation. Cognitive, neurologic, and developmental problems may be present. Patient support groups can be helpful, and neurologic and psychiatric care as well as social support should be sought early. In addition, a variety of resources are available via the internet for clinicians and patients and their families. (See 'Family and psychosocial support' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, E Richard Stiehm, MD, Vanessa Bundy, MD, PhD, and Kristen Barbieri, PA-C, MSHS, who contributed to earlier versions of this topic review.