INTRODUCTION — The prevalence of primary immunodeficiency (PID) is estimated at approximately 1 in 2000 live births, and more than 300 distinct disorders have been identified [1,2]. The molecular defects underlying many of these disorders are now understood . Each year, new disorders are identified, and milder variants of known PIDs are recognized in patients surviving into adolescence and adulthood. A number of new medical therapies have provided dramatic improvements in life expectancy and quality of life for immunodeficient individuals, and their care is becoming increasingly complex.
The management of patients with PID begins with early identification and diagnosis. Families with affected children require counseling about the risk of the same disorder occurring in future children. If an affected pregnancy is identified, measures to prevent infection and plan for curative therapies begin at birth. Affected adults may seek information about family planning. Topics related to detection and diagnosis of PID are found separately:
●(See "Syndromic immunodeficiencies".)
This topic will provide an overview of the principles of management of PID. The suggestions in this topic review are consistent with practice parameters for the management of PID .
EARLY INVOLVEMENT OF AN EXPERT — In newborns or young infants with suspected immunodeficiency, early consultation with a pediatric immunologist is highly recommended, whenever possible . Many immunodeficiencies that present in early infancy are potentially life-threatening. In addition, routine interventions, especially administration of live vaccines or untreated blood products, can result in devastating complications. The immediate management of a neonate who may have immunodeficiency, including isolation to prevent infection and safe vaccination and feeding, is presented in detail separately. (See "Recognition of immunodeficiency in the newborn period".)
For older children and adults with suspected immune disorders, an immunologist should also be consulted, whenever possible, to assist with diagnosis and ongoing care . The specific diagnostic studies required depend on the particular diagnosis, treatment, and complications. These are discussed individually for specific disorders.
Resources for clinicians and patients — 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) – 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) – Resources for patients and providers; "ask the expert" feature for clinicians.
●European Society for Immunodeficiencies (ESID) – Primarily directed toward clinicians.
●Jeffrey Modell Foundation/Primary Immunodeficiency Resource Center – Resources for clinicians and patients.
●US Immunodeficiency Network (USIDNET) – Oriented toward researchers in immunodeficiency; includes a registry of specific disorders.
●An independent searchable database ("Immunodeficiency Search") – Primarily directed toward clinicians; includes lists and tables of immunodeficiency disorders, clinical algorithms, and diagnostic laboratory resources.
●International Patient Organization for Primary Immunodeficiencies (IPOPI) – Directed mainly toward patients and families.
ISSUES OF IMMEDIATE IMPORTANCE FOR NEWBORNS AND INFANTS — If PID is suspected in a newborn or infant, particular care is required with the administration of blood products and with vaccinations.
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 (SCID) and other forms of immunodeficiency where T cell function may be severely compromised (eg, Wiskott-Aldrich syndrome, X-linked hyperimmunoglobulin M syndrome, nuclear factor [NF]-kappa-B essential modifier (NEMO) deficiency, and complete DiGeorge syndrome [and others]). Any cellular blood products given to these patients must be leukoreduced or irradiated. (See "Transfusion-associated graft-versus-host disease", section on 'Immunodeficient states' and "Transfusion-associated graft-versus-host disease", section on 'Prevention'.)
Blood products should also be tested for cytomegalovirus (CMV), a virus that can cause significant disease in immunocompromised individuals who have an underlying T cell defect or have undergone transplantation. (See "Overview of cytomegalovirus infections in children", section on 'Immunocompromised hosts'.)
Safe vaccination — Patients with severe PIDs should not be given live viral or live bacterial vaccines, as these may cause disseminated infection, as discussed in detail separately. (See "Immunizations in patients with primary immunodeficiency".)
CONFIRMATION OF THE DIAGNOSIS — In patients of all ages, it is essential that the diagnosis of PID be as well-documented as possible with appropriate diagnostic procedures. This is important for the following reasons:
●Patients often require lifetime therapy (eg immune globulin, repeated courses of antimicrobials, other biologics), which confer some risk to the patient and considerable expense.
●In the United States and some other countries, documentation is required for reimbursement of costly therapies by insurers.
●The diagnosis of PID may impact future employment, military service, family planning, and insurability.
●Patients may be candidates for genetic counseling either to assist parents of infants in planning for future childbearing or for older patients planning their own families. (See 'Genetic counseling' below.)
Patients who are referred to immunology experts for care should have any previous diagnoses re-evaluated to assure that the correct diagnosis has been assigned. In some older patients, more accurate molecular diagnostic testing will have become available since the original diagnosis was made. In other cases, the diagnosis may be incorrect and therapies (eg, immune globulin) may need to be discontinued so that testing can be repeated.
INFECTION PREVENTION AND TREATMENT — The prevention of infections in patients with PID involves avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy, and sometimes specialized immune globulins. When infections do occur, broader spectrum and more prolonged antibiotics are often required.
Avoidance — One of the goals of medical therapy is to optimize the individual's function and integration into society. Children and adults with mild forms of immunodeficiency should be encouraged to participate in all usual activities. Normal school attendance should be the goal for children with immunodeficiency, although some experts advise against the placement of infants and young children in large institutional day care settings where there is a well-documented higher rate of infectious illness [3,4]. Concern about infections also applies to adults in whom placement in institutional settings is a consideration .
There are several routine measures patients and families can take to reduce exposure to others with potentially contagious illnesses:
●Instructions in proper handwashing and use of alcohol-based disinfectants should be provided to patients and their families (see "Infection prevention: Precautions for preventing transmission of infection", section on 'Hand hygiene'). Patient information is available in topics about avoidance of the common cold. (See "Patient education: The common cold in children (Beyond the Basics)" and "Patient education: The common cold in adults (Beyond the Basics)".)
●Co-sleeping among family members should be minimized, and immunization of family members and close contacts (against influenza, for example) is encouraged. (See "Immunizations in patients with primary immunodeficiency".)
●Careful attention should be paid to patient's oral hygiene and dental health. (See 'Dental care' below.)
●The safety of the patient's drinking water should be considered. Private wells and public sources may be contaminated with giardia or cryptosporidium. The latter is resistant to chlorination. Some advocate use of filtration systems or bottled water, although this issue has not been extensively investigated.
●Social integration is always desirable, and it is a goal of therapy to make this as easy and successful as possible. While exposure to infectious illnesses is relatively high in crowded environments such as shopping malls or in school, nevertheless, with reasonable precautions, most patients with primary immunodeficiency do not require "isolation" nor must they strictly avoid these areas. One possible exception may be large institutional daycare or preschool settings, where the high rate of hand-to-mouth contact may be difficult to manage.
Vaccination — The issues surrounding vaccination of patients with PID are reviewed in depth separately. (See "Immunizations in patients with primary immunodeficiency".)
Treating acute infections — Immunocompromised individuals do not clear infections or respond to anti-infective therapy as well as immunocompetent individuals . Many practitioners prescribe standard (short) courses of antibiotics to treat common infections, such as otitis media, sinusitis, or pneumonia, in immunodeficient patients. This often leads to rapid relapse or recurrence of infection and further morbidity, including permanent scarring and loss of function. 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.
Prophylaxis should be considered for patients who relapse quickly after prolonged courses of antimicrobials.
Prophylactic antimicrobial therapy — In most cases, the use of prophylactic antimicrobials is intended to reduce the frequency and severity of sinopulmonary infections caused by common bacteria. However, other forms of antiviral and antifungal treatments may be necessary in particular disorders. There is no standardized approach to the use of prophylactic antimicrobials in patients with immunodeficiency. Rigorous studies of the efficacy of prophylaxis in specific immune disorders are lacking, with a few notable exceptions (eg, chronic granulomatous disease [CGD]). A survey of American immunologists with clinical focus in PID reported that, in the absence of consensus guidelines, approximately 75 percent of practitioners administered prophylactic antibiotics to at least some of their immunodeficiency patients . This proportion was significantly greater than among immunologists who saw only a few PID patients.
●Patients with severe combined immunodeficiency or other combined immunodeficiency prior to definitive therapy (stem cell transplant) may receive some combination of antibacterial, antiviral, and/or antifungal prophylaxis as required by their specific diagnoses, exposures, and infection history.
●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".)
●Antibiotic prophylaxis alone is most consistently offered to patients with mild hypogammaglobulinemia, selective immunoglobulin A deficiency (sIgAD), or immunoglobulin G (IgG) subclass deficiency, who are not receiving immune globulin [7,8]. Some patients may require antibiotics only during certain times of the year (eg, over the winter) or only for a few years. In more severely affected patients, prophylaxis may need to be year-round and may last for years.
●Patients with more severe antibody deficiencies receiving immune globulin may 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. However, there are no published controlled studies of the benefits of antibiotic prophylaxis in this population.
●Antiviral (herpesvirus family) 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. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis" and "Toll-like receptors: Roles in disease and therapy".)
●Prophylaxis against mycobacterial infections is indicated in disorders where these types of organisms are commonly encountered, including those in the category of Mendelian susceptibility to mycobacterial disease (MSMD), such as defects of the interferon-gamma-interleukin-12 axis, NEMO deficiency, and others. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)
Representative regimens — Regimens of antibacterial prophylaxis applied in the care of immunodeficient patients were initially derived from a series of immunocompetent patients with recurrent otitis media [9-11]. A general principal, at least at the initiation of therapy, is the use of approximately one-half of a therapeutic dose. However, depending on circumstances, full therapeutic doses may also be used:
●For children – Options include one of the following:
•Amoxicillin (10 to 20 mg/kg per day as a single dose or given twice daily for a total dose of 40 mg/kg daily)
•Azithromycin (10 mg/kg per week or 5 mg/kg every other day)
If these options are not effective:
•Clarithromycin (7.5 mg/kg per day or twice daily)
•Amoxicillin-clavulanate (20 mg/kg per day as a single dose or twice daily)
•Doxycycline (for children >8 years of age) (25 to 50 mg daily or twice daily)
●For adults – Options include one of the following:
•Amoxicillin (500 to 1000 mg daily or twice daily)
•Azithromycin (500 mg per week or 250 mg every other day)
If these options are not effective:
•Clarithromycin (500 mg daily or twice daily)
•Amoxicillin-clavulanate (875 mg or 1000 mg daily or twice daily)
•Doxycycline (100 mg daily or twice daily)
At some centers, it is common practice to "rotate" or periodically change antibiotics to avoid the development of resistance to a specific drug . The frequency with which antibiotics are rotated varies from monthly to every six months. However, studies have not been performed to compare rotation with the use of one agent for an extended period of time, and so the best approach is not known.
Prevention of Pneumocystis jirovecii pneumonia — Prophylaxis for Pneumocystis jirovecii (carinii) pneumonia (PCP) should be administered to patients with severe combined immunodeficiencies (SCID) and patients receiving potent-immunosuppressive therapy. PCP prophylaxis is also indicated in some other immunodeficiencies, such as X-linked hyperimmunoglobulin M syndrome. (See "Primary humoral immunodeficiencies: An overview".)
Prophylactic regimens for PCP in primary and secondary immunodeficiency are similar to those administered to patients with human immunodeficiency virus (HIV) infection. (See "Treatment and prevention of Pneumocystis infection in HIV-infected patients", section on 'Treatment'.)
Immune globulin replacement — Immune globulin therapy is used in a variety of PID disorders, including primary antibody deficiencies, combined immunodeficiencies prior to transplantation and until B cell function is restored, and other specific disorders involving defects in antibody production or function. Specific indications and a detailed discussion of the use of immune globulin therapy are found separately. (See "Immune globulin therapy in primary immunodeficiency" 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 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) . However, this has largely been replaced in these patients by the administration of ganciclovir. Cytogam is still used as an adjunct to antiviral drugs in some immunocompromised patients with CMV infection. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant recipients" and "Prevention of cytomegalovirus infection in lung transplant recipients".)
●Varicella-zoster immune globulin – Varicella virus is capable of causing severe disease in immunocompromised adults and children. Patients who are receiving 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) may be given varicella-zoster immune globulin (VariZIG). 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 – Palivizumab is a humanized monoclonal anti-RSV antibody used for prevention of RSV infection in certain high-risk groups. It may be administered for this purpose to patients with primary or secondary immunodeficiency. (See "Respiratory syncytial virus infection: Prevention", section on 'Immunoprophylaxis'.)
●Others – Other immune globulin products are formulated for the prevention of specific infections following certain high-risk exposures including:
•Tetanus immune globulin (TIG)
•Hepatitis B immune globulin (HBIG)
•Human rabies immune globulin (HRIG)
•Vaccinia immune globulin (VIG-IV; for complications of smallpox immunization)
BIOLOGIC THERAPIES — A variety of "biologic" reagents have been developed as therapeutics to modulate immune function in different clinical settings, including inflammatory disorders, autoimmune disease, and malignancy. Many of these drugs are monoclonal antibodies directed against cell surface and/or soluble proteins. Others are "fusion proteins" made by joining a portion of a cell surface or soluble protein with another distinct molecule (such as the Fc portion of immunoglobulin G [IgG]) that gives the resulting fusion product distinct biologic properties. Many of these drugs have applications in immunodeficiency disorders. Several are listed in the table (table 1).
IMMUNE RECONSTITUTION — The two modalities that offer potential cures for some PIDs are hematopoietic cell transplantation (HCT) and gene therapy. In some cases, planning for these interventions begins immediately after birth, while in others, there is an initial period of waiting to observe the patient's clinical course. A specialist in immunodeficiency should be involved as early as possible to help guide these decisions. (See 'Early involvement of an expert' above.)
Hematopoietic cell transplantation — Hematopoietic cell transplantation (HCT) provides patients with certain PIDs with healthy, tissue-matched hematopoietic stem cells (HSCs) that can differentiate into mature functional immune cells. Human-leukocyte antigen (HLA) typing should be undertaken as soon as a diagnosis of severe combined immunodeficiency (SCID) or other immunodeficiency potentially correctable by HCT is established. The risks of HCT are reduced in patients who have not yet developed infectious complications of immunodeficiency [13-15]. Furthermore, the thymus microenvironment may deteriorate over time and be less capable of supporting T cell development. (See "Hematopoietic cell transplantation for primary immunodeficiency".)
Gene therapy — Gene therapy has the potential to correct an inherited PID by introducing a functional copy of the patient's defective gene into the appropriate cells. HSCs are removed from the affected patient, genetically modified ex vivo by adding a correct gene copy that integrates into chromosomal DNA and then returned to the patient as an autologous HCT. In addition, there are several related techniques that are under development for specific disorders. (See "Gene therapy for primary immunodeficiency".)
Thymic transplantation — Transplantation of thymic tissue 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'.)
VIGILANCE FOR ASSOCIATED DISORDERS — Clinicians caring for patients with PID should understand the different ways in which immune dysfunction can present and the complications that may develop in patients with PID:
●Infectious diseases. (See 'Infection prevention and treatment' above.)
●Autoimmune processes, such as cytopenias, endocrinopathies, and enteropathies. (See "Autoimmunity in patients with primary immunodeficiency".)
●Gastrointestinal disorders, including autoimmune, infectious, and lymphoproliferative disorders. (See "Gastrointestinal manifestations in primary immunodeficiency".)
●Lymphoproliferative and malignant diseases. (See "Malignancy in primary immunodeficiency".)
●Hypersensitivity disorders to inhaled allergens, foods, and medications – Atopic disease of variable severity with sensitivity to both food and/or environmental allergens is seen in a variety of antibody deficiencies, diseases of immune dysregulation, and other categories of immunodeficiency. Drug hypersensitivity may complicate patients requiring chronic antibiotics and other long-term therapies. Non-immunoglobulin E (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".)
OTHER ISSUES — Although there have been significant advances in the treatment of PID and more children are surviving into adulthood, patients routinely suffer decrements in quality of life that are similar to those associated with other serious chronic diseases . Successful treatment and careful health maintenance may mitigate some of the burden of these diseases. This requires the coordinated efforts of both primary care providers and various specialists.
Health maintenance — Regular medical follow-up and adherence to treatment regimens are critical for optimal outcomes . Primary care providers play an important role in initial detection, ensuring appropriate anticipatory guidance and care, and in coordination and integration of care among multiple specialty providers for these complex patients. Denial and other psychosocial factors (family dysfunction, poverty) can impede care and must be treated or mitigated as much as possible. (See "Unipolar depression in adult primary care patients and general medical illness: Evidence for the efficacy of initial treatments".)
Mental and emotional health — Integration of individuals with PID 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 also be specific associations with PIDs, such as adenosine deaminase (ADA) deficiency, DiGeorge syndrome, and others. Patient support groups may be helpful, and neurologic, psychiatric, and social treatment and support should be sought early .
Dental care — Oral hygiene is extremely important in patients with PID . Oral health is often impaired in patients with PID, and problems may affect tooth development (mineralization), eruption and shedding, inflammation, and infection. These are summarized in the figure (figure 1).
Audiologic care — Sensorineural hearing loss occurs in a relatively high percentage of children with primary antibody deficiencies. 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 . Possible contributing factors include recurrent bacterial otitis media, exposure to neurotoxic antibiotics, certain viral infections, and central nervous system infections. Audiologic evaluation should be considered in children with antibody disorders to maximize educational and interpersonal functioning.
GENETIC 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 education of the patient and family regarding the implications of specific findings. Referral should be made in any situation where the provider is not able to offer the necessary information or expertise.
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: Primary immunodeficiencies".)
SUMMARY AND RECOMMENDATIONS
●The management of patients with primary immunodeficiency (PID) begins with early identification and diagnosis. For infants with suspected severe forms of PID, isolation measures and precautions with vaccination and feeding are necessary. For patients of any age with possible PID, a clinician with experience in diagnosing and treating immunodeficiency should be involved when possible to assist in accurate diagnosis and to formulate an ongoing plan of care. Several online resources are also available for both clinicians and patients. (See 'Early involvement of an expert' above.)
●Patients with suspected or known severe T cell immunodeficiencies should not be given blood or blood components that may contain viable lymphocytes because of the risk of fatal graft-versus-host disease. All such products should be leukoreduced or irradiated. Blood products should also be tested for cytomegalovirus (CMV). These precautions apply mainly to severe combined immunodeficiencies (SCID) and other forms of immunodeficiency where T cell function may be severely compromised. (See 'Caution with blood products' above.)
●Patients with severe PIDs should not be given live viral or live bacterial vaccines, as these may cause disseminated infection, as discussed in detail separately. (See "Immunizations in patients with primary immunodeficiency".)
●The prevention of infections in patients with PID involves avoidance measures, vaccination, prophylactic antibiotics, immune globulin therapy, and sometimes specialized immune globulins. When infections do occur, broader spectrum and more prolonged antibiotics are often required. (See 'Infection prevention and treatment' above.)
●Hematopoietic cell transplantation (HCT) and gene therapy offer potential cures for some PIDs. In some cases, planning for these interventions begins immediately after birth, while in others, there is an initial period of waiting to observe the patient's clinical course. (See 'Immune reconstitution' above.)
●Immune disorders often present with increased susceptibility to infections, but other manifestations of immune dysregulation include autoimmunity, malignancy, and hypersensitivity, all of which may be seen to varying degrees in different PIDs. Clinicians caring for these complex patients should be vigilant for the associated disorders that may arise. (See 'Vigilance for associated disorders' above.)
●Integration of individuals with PID 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. Mental health care, dental and oral care, and often audiologic evaluation and care are also important. Primary care providers are essential for guidance about health maintenance, as well as coordination and integration of the care provided by various specialists. (See 'Other issues' above.)
●Families with affected children require counseling about the risk of the same disorder occurring in future children and adult patients often seek advice about family planning. If an affected pregnancy is identified, measures to prevent infection and plan for potentially curative therapies begin at birth. (See 'Genetic counseling' above.)