T-Cell Disorders 

Updated: Oct 14, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD 

Overview

Background

This article discusses partial T-cell disorders. For reviews of complete T-cell deficiencies, see the articles titled Severe Combined Immunodeficiency (SCID), Omenn Syndrome, and Cartilage-Hair Hypoplasia. Much remains to be understood about the association of partial T-cell immunodeficiency and immune dysregulation.[1] These heterogeneous disorders are characterized by an incomplete reduction in T-cell number or activity, autoimmunity, inflammatory diseases, and elevated immunoglobulin E (IgE) production.

The nomenclature for T lymphocytes is based on the role of the thymus in the differentiation and maturation of T lymphocytes. The prototypic T-cell disorder in which the thymus is absent, small, or in an aberrant location is DiGeorge syndrome (DGS). Other well-known partial deficiencies in T-cell function include the chromosomal breakage syndromes (CBSs), B-cell and T-cell combined disorders (eg, ataxia telangiectasia [AT]) and Wiskott-Aldrich Syndrome (WAS), which are discussed in separate articles. Similarly, pityriasis lichenoides et varioliformis acuta[2] and other entities linked with or part of T-cell lymphoma spectrum are covered elsewhere.

Partial T-cell disorders typically have limited T-cell defects that predispose patients to more frequent or extensive infections; these disorders often include immune dysregulation that allows autoimmune phenomena, lymphoproliferation, and malignancies. For example, patients with partial DGS rarely lack T-cell function as measured by in vitro T-cell proliferation to nonspecific mitogens. When T-cell function is absent in T-cell disorders, the disorder can be lethal. Conventional clinical management for absent T-cell function consists of immune reconstitution using stem cell or bone marrow transplantation.

Partial T-cell defects commonly cause abnormalities of immune regulation. Thus, T-cell to B-cell communication is defective, with partial defects in antibody production and increased incidence of atopy and autoimmune disorders. Inadequate antibody responses directed against bacterial polysaccharide antigens cause an increased risk for sinopulmonary infections caused by encapsulated organisms. The increased risk for reactive airway disease and thyroiditis in patients with DGS and the high incidence of autoimmune hemolytic anemia in patients with WAS are examples of defective T-cell/B-cell interactions that result in self-reactivity.

T-cell disorders in which autoimmunity and polyendocrinopathy predominate have recently been elucidated, and more will certainly be discovered as pathways for T-cell signal transduction are better understood. Mutations in the CD3+ T-cell complex are associated with autoimmune cytopenias, autoimmune enteropathy, and recurrent sinopulmonary infections. Defects in CD95/Fas and Fas ligand lead to autoimmune cytopenias, lymphadenopathy, and hepatosplenomegaly. A syndrome of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the AIRE gene coding for autoimmune regulator. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome may be associated with reactivation of herpes viruses and activated CD8+ T lymphocytes directed against them.[3] DRESS syndrome may be evident together with another linked with proliferating and activated T cells, hemophagocytic lymphohistiocytosis.

Mutations in the gene coding for Foxp3 at chromosome band Xp11.22 are manifested as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (also termed X-linked syndrome with polyendocrinopathy, immune dysfunction, and diarrhea [XPID]). Mutations in the gene coding for interleukin 2a receptor (IL-2Ra) have similarly caused diarrhea, candidiasis, and lymphoproliferation.

Knockout and transgenic mice have been developed for specific T-cell disorders and are recognized to have helped predict human genetic disorders.

Partial T-cell immunodeficiencies constitute a heterogeneous cluster of disorders characterized by an incomplete reduction in T-cell number or activity. The immune deficiency component of these diseases is less severe than that of the severe T-cell immunodeficiencies and therefore some ability to respond to infectious organisms is retained. Unlike severe T-cell immunodeficiencies, however, partial immunodeficiencies are commonly associated with hyper-immune dysregulation, including autoimmunity, inflammatory diseases, and elevated IgE production. This causative association is counter intuitive. Immune deficiencies are caused by loss-of-function changes to the T-cell component, whereas the coincident autoimmune symptoms are the consequence of gain-of-function changes or loss of regulatory functions.

Partial T-cell immunodeficiencies may also be evident in primary cutaneous γδ T-cell lymphoma, a rare and aggressive cutaneous lymphoma.[4, 5] These cutaneous lymphomas should be distinguished from γδ T-cell–rich variants of pityriasis lichenoides and lymphomatoid papulosis, both of which are benign.[6]

This article details the genetic basis of partial T-cell immunodeficiencies and draws on recent advances in mouse models to propose mechanisms by which a reduction in T-cell numbers or function may disturb the population-dependent balance between activation and tolerance.

One may view immune function as a double-edged sword, with components such as Th17 cells preventing repeated infections yet facilitating autoimmune disorders when dysregulated.[7]

T cells may play important roles in immunity to COVID-19 and in the development of severe disease, with T-cell immunity to COVID-19 mediated through differentiated CD4+ T cells and cytotoxic CD8+ T cells.[8] Abnormally activated T cells and dysregulated T-cell responses may be evident in severe COVID-19.

Pathophysiology

That partial T-cell disorders are associated with immunodeficiency is clear. However, as many as half of patients with these diseases that result in reduced functioning or quantities of T-cells develop autoimmune diseases.[9] The reduction in T-cell quantity or activity in patients with partial T-cell disorders may result in inefficient tolerance mechanisms, which, in turn, predisposes these individuals for the development of autoimmune diseases.[1]

Mature functional T cells undergo differentiation and maturation in the thymus; therefore, the thymus is critical for intact cell-mediated immunity. The thymus also regulates central tolerance by deleting T cells that recognize self-antigens. Thus, defects in the thymic microenvironment, as in DGS, result in poor T-cell function. The ability of T cells to recognize and respond appropriately to antigen depends on a complex pathway of surface glycoproteins and transmembrane molecules involved in signal transduction, many of which can be ascertained by flow cytometry using monoclonal antibodies directed against these antigens.

Critical components of T-cell antigen recognition include the CD3 complex, CD4, CD8, and the T-cell receptor heterodimers TCRα/ß or TCRg/σ. These molecules act in a coordinated manner to regulate intracellular signaling pathways, which then induce or inhibit the specific immune response. One study generated mice with decreased quantities of immunoreceptor tyrosinase–based activation motifs (ITAMs) in the TCR-CD3 complex. Mice with as little as a 50% reduction in immune-signaling capacity exhibited both partial immunodeficiency and autoimmunity.[10]

Antigen recognition through CD4 depends on antigen presentation by major histocompatibility complex (MHC) class II, whereas CD8 requires antigen presentation by MHC class I. Additional molecules, such as Fas and Fas ligand, mediate apoptosis of T cells that recognize self-antigens. The scurfin protein is a newly identified transcription factor encoded by the FOXP3 gene that is expressed both in the thymus and in peripheral T cells. Foxp3 protein is expressed by regulatory T cells that inhibit proliferation and functions of effector T cells and is thought to be crucial for maintenance of peripheral tolerance. Immune regulation occurs centrally in the thymus and in peripheral T cells, lymphoid tissues, and nonlymphoid tissues (eg, gut, skin).

Defects in cytotoxicity by T cells and natural killer (NK) cells in Chediak-Higashi syndrome (CHS) reflect a global error in packaging of lysosomal enzymes caused by a mutation in the gene coding for lysosomal-trafficking regulator.

For a more detailed discussion of the intricate pathways of T-cell signaling, see the articles on specific T-cell deficiency syndromes listed in Differentials.

Epidemiology

Frequency

Overall frequency of T-cell disorders has been estimated at 1 case per 70,000 people. Specific T-cell disorders are even more infrequent. DGS has an estimated incidence of 1 case per 5,000 live births, but many of these children have minimal immune dysfunction that improves with age. A recent study concluded that the incidence of primary immunodeficiency dramatically increased between 1976-2006.[11] DGS is increasing in incidence due to affected parents bearing their own affected children.[12]

Cutaneous T-cell lymphoma incidence had been increasing steadily in the past quarter century, but it seems to be stabilizing.[13]

Partial T-cell defects are seen in persons of all ethnic backgrounds. This is well established for specific syndromes such as DGS and WAS. Some autosomal recessive disorders are seen more frequently in inbred populations. As mutation analysis becomes more routine, heterozygous mutations have been frequently defined in some disorders, such as AT.

Mortality/Morbidity

Patients with partial T-cell disorders usually have chronic illness from sinopulmonary infections, autoimmune cytopenias, diarrhea, and polyendocrinopathies, especially insulin-dependent diabetes mellitus (IDDM). Depending on the specific mutation, severe disease may cause death in infancy or the patient may survive into middle childhood. Lymphoproliferative disease and malignancy are features of WAS, AT, and immune dysregulation/autoimmunity syndromes.

DGS (partial) is the single T-cell disorder in which the incidence of respiratory and candidal infections often decreases in patients older than 2 years. However, the incidence of hypothyroidism and other autoimmune complications increases in mid childhood. Bone marrow transplantation is the best treatment in patients with WAS and CHS younger than 2 years because outcome studies show higher rates of cure at earlier ages. CHS is difficult to treat once it enters the accelerated phase. Progressive neurologic deterioration is a feature of AT and CHS.

Race

T-cell disorders affect all ethnic populations. Isolated inbred populations in Europe and the Middle East have been identified with a number of rare partial T-cell disorders that were subsequently found to occur sporadically in the United States. Studies of unique large extended families with rare immunodeficiencies have been an important source in documenting clinical manifestations, and these detailed genetic studies have improved understanding of specific gene function.

Sex

Numerous genes regulating immune function are located on the X chromosome. The gene defect in X-linked SCID (mutations in the common γ chain for interleukin [IL]–2, IL-4, IL-7, IL-9, IL-15, and IL-21) is located at chromosome band Xq13. The BTK gene for X-linked agammaglobulinemia is at band Xq21.3. X-linked hyperimmunoglobulin M (XHIM; CD40 ligand deficiency) is caused by mutations at band Xq26.2. X-linked lymphoproliferative disease is caused by mutations in the gene for signaling lymphocyte activation molecule (SLAM)–associated protein at band Xq25. The gene responsible for WAS is located at band Xp11.22, and the gene coding for scurfin (Foxp3), the defect of which causes X-linked polyendocrinopathy and enteropathy (IPEX), is located nearby, between bands Xp11.23 and Xq13.3. In these disorders, only males are affected and females are asymptomatic carriers.

T-cell disorders associated with autosomal chromosomes include DGS at band 22q11 (microdeletion), AT at band 11q22, and CHS at bands 1q42-43. The gene for CD3 complex is localized to chromosome band 11q23. The AIRE gene is on band 21q22.3; AIRE mutation causes APECED. The gene for CD95/Fas is at band 10q23; CD95 deficiency causes one type of autoimmune lymphoproliferative syndrome (ALPS). Targeted next-generation sequencing is a rapid cost-effective method that identified five variants causing five ataxia-telangiectasia in three Chinese probands in one study.[14]

Age

Most T-cell disorders present in early infancy with unusually severe or frequent infections. A search for nonimmunologic features of specific syndromes may aid in the diagnosis of specific syndromes.

DGS can be recognized by facial features and cardiac anomalies at birth. WAS can be diagnosed at birth by the small size of platelets, although the platelet count is within reference range. Clinical manifestations of bleeding and eczema appear within the first weeks to months before infections begin. Clinical phenotypes of WAS widely vary depending on mutations of WAS gene, and a mild form of WAS can present as a chronic thrombocytopenia without features of T-cell immunodeficiency. AT is another T-cell disorder in which noninfectious signs (hypotonia and ataxia) often predate infection. CHS, a global error in intracellular protein transport, is associated with oculocutaneous albinism prior to the onset of recurrent cervical lymphadenopathy and the development of the accelerated phase with bleeding.

 

Presentation

History

Unusually severe common viral infections (eg, respiratory syncytial virus [RSV], enterovirus, rotavirus), mucocutaneous candidiasis, diarrhea, and eczematous or erythrodermatous rashes should prompt suspicion of a T-cell disorder. Failure to thrive and cachexia are late signs of a T-cell defect. Opportunistic infection develops more commonly in an infant who has become wasted, although it may be the presenting illness.

Late diagnosis of a partial T-cell defect may occur in patients with DiGeorge syndrome (DGS) when the facial anomalies are subtle and cardiac lesions are absent. These individuals have recurrent respiratory infections consisting of sinusitis and viral infections. In addition, patients have more extensive mucocutaneous candidiasis than anticipated in a healthy host taking antibiotics.

Engrafted maternal T cells rarely may persist, leading to partial constitution of immune function and delayed clinical presentation of SCID.[15]

In patients with ataxia telangiectasia (AT), late diagnosis is often based on the progressive loss of mobility and the appearance of telangiectasia in children aged approximately 4-5 years.

A diagnosis of Wiskott-Aldrich syndrome (WAS) may be delayed until recurrent sinopulmonary infections develop if petechiae and bloody diarrhea are minor and intermittent and if eczema is misinterpreted as severe atopic dermatitis. Additionally, more than 70% of patients with WAS have at least one autoimmune complication.

Patients with Chediak-Higashi syndrome (CHS) are often treated for recurrent otitis, sinusitis, and lymphadenitis caused by staphylococci and streptococci before the massive lymphadenopathy and hepatosplenomegaly make the diagnosis obvious in the accelerated phase.

Epstein-Barr virus (EBV) infection is the predominant lethal infection in X-linked lymphoproliferative disease (XLP), and EBV infection is usually associated with development of the accelerated phase of CHS.

The diagnosis of insulin-dependent diabetes mellitus (IDDM) and diarrhea in a male infant younger than 1 year raises the possibility of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. IDDM and enteropathy are also components of the clinical features in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

Lymphadenopathy and hepatosplenomegaly characterize mutations in the genes coding for CD3 complex and CD95/Fas.

Patients with WAS in whom the immune system is not reconstituted by hematopoietic stem cell transplantation usually die by the third-fourth decade of life from malignancies; lymphoid and CNS tumors are most common.

Patients with AT and Nijmegen breakage syndrome (NBS) are at a higher risk for malignancies, usually lymphoid, that increases with age.

Neurologic disorders are increasingly reported in patients with partial T-cell disorders. Progressive neurologic dysfunction is well known in patients with chromosomal breakage syndromes (CBSs), such as AT, NBS, and in CHS. Patients with DGS have learning and behavioral dysfunction that becomes more apparent at school age. Seizure disorders frequently accompany immune dysregulation/autoimmunity syndromes such as IPEX caused by FoxP3 gene mutation .

Physical

The physical examination features of DGS, WAS, and AT are presented in detail in other respective articles.

Rash often occurs in infants with a T-cell disorder, commonly as a generalized eczema or erythroderma. Urticarial rashes and cutaneous vasculitis are present in CD95/Fas and Fas ligand deficiencies as well as caspase 10 defects. Ectodermal dystrophy characterizes APECED syndrome.

Patients with AT have telangiectasia of the conjunctiva and pinna; these features present after the diagnosis should already have been confirmed by the presence of ataxia and infections. See the images below.

This patient was diagnosed with ataxia telangiecta This patient was diagnosed with ataxia telangiectasia (AT) when she presented at age 6 years. The family was concerned about the increased frequency of sinusitis during the past winter, and she was noted to have poor balance. Findings in her eyes had been explained as conjunctivitis since age 4 years.
A prominent site for telangiectasia in classic ata A prominent site for telangiectasia in classic ataxia telangiectasia is the pinna.
Malformation of the pinna Malformation of the pinna

Candidiasis is a common feature of partial and complete T-cell disorders. In partial T-cell disorders (eg, DGS, WAS, APECED syndrome, IPEX syndrome) dissemination is unlikely, even when the autoimmune disease is treated with immunosuppressive agents. Disseminated invasive candidiasis suggests severe combined immunodeficiency (SCID) or a phagocytic disorder.

Patients with the classic presentation have a complete absence of T cells (ie, SCID) and lack peripheral lymphoid tissue. However, patients with partial T-cell disorders often have palpable lymph nodes.

Lymphadenopathy and hepatosplenomegaly may be progressive in immune dysregulation/autoimmunity syndromes, such as Fas and Fas ligand deficiencies and mutations in the gene coding for CD3 complex. Lymphadenopathy suggests the possibility of lymphoma or leukemia in older patients with WAS and CBSs.

Neurologic deterioration with hypotonia and progressive ataxia may occur before infection, raising a suspicion of immunodeficiency in patients with AT and NBS.

Bleeding in patients with WAS is a result of impaired platelet aggregation with smaller platelet size and numbers of platelets.

In infants, the first sign of WAS is often bloody diarrhea that occurs before petechiae and epistaxis following introduction of solid food.

In the accelerated phase, CHS is accompanied by bleeding.

Causes

Many of the exact functions of the gene products that are mutated in partial T-cell disorders have yet to be elucidated.

For a more complete discussion of the genes responsible for DGS, AT, WAS, and CHS, see Pathophysiology and the specific articles for each disorder.

CHS is caused by mutations in the gene encoding for the lysosomal-trafficking regulator. This mutation leads to abnormal distribution of lysosomal proteins in phagocytes (impairing bactericidal activity), in melanosomes (explaining partial albinism), and in neurologic function and to cytotoxicity by T cells and natural killer (NK) cells, predisposing patients to aberrant responses to EBV and leading to the accelerated phase.

Physical Examination

Cutaneous granulomas are sometimes evident as non-infectious findings may precede the diagnosis of ataxia-telangiectasia, combined variable immunodeficiency, and severe combined immunodeficiency.[16, 17]

 

DDx

Diagnostic Considerations

Partial defects in T-cell function have been ascertained in numerous genetic disorders, particularly Down syndrome and Turner syndrome. These abnormalities help in understanding the clinical infections in these patients, but they play a minor role in the overall problems.

Differential Diagnoses

 

Workup

Laboratory Studies

Partial T-cell disorders are usually difficult to identify using routine screening tests. The absolute lymphocyte count determined by the CBC count is often within reference ranges, although lymphopenia should be sought. In Chediak-Higashi syndrome (CHS), the presence of giant granules in lymphocytic and phagocytic cells confirms a definitive diagnosis by morphologic analysis. Wiskott-Aldrich syndrome (WAS) is characterized by small platelets and variable but often decreased platelet numbers.

In vivo lymphocyte function is assessed by delayed hypersensitivity skin test responses using tetanus and candidal antigens. Anergy is characteristic in patients with ataxia telangiectasia (AT), WAS, and CHS. Patients with chronic mucocutaneous candidiasis have normal responses except for anergy to candidal antigens.

Flow cytometric assessment of T-cell and B-cell populations is essential to categorize partial T-cell disorders. The markers are expanded to include TCRa/b and TCRg/d, CD45RA (ie, "naïve" T cells), CD45RO (ie, "educated" T cells), and activation markers. See Severe Combined Immunodeficiency (SCID) for a table of the lymphocyte profile characteristics for various T-cell disorders.[18]

Patients with AT have decreased numbers of CD4+ T cells, resulting in a decreased CD4/CD8 ratio, whereas patients with WAS have an elevated ratio caused by decreased numbers of CD8 T cells. Patients with AT and CHS have an increased proportion of TCRg/d cells.

Patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome may initially present with strikingly increased levels of T-activation markers. T-cell activation may be detected in CD95/Fas and Fas ligand deficiencies. An elevated population of double-negative CD4-/CD8- T cells that express TCRa/b also characterize these mutations. They often lack intracellular expression of Foxp3.

Assessment of CD3 complex defects is particularly subtle: CD3 expression is present in a normal proportion of T cells, but the intensity (ie, mean fluorescence intensity) is decreased, and TCRa/b expression is low.

In vitro lymphocyte proliferative responses require stimulation with allogeneic lymphocytes, nonspecific mitogens including phytohemagglutinin antigen (PHA), concanavalin A (conA), pokeweed mitogen (PWM), and specific antigens including tetanus and candidal antigens. Partial T-cell defects are most likely to have decreased responses to specific antigens and variable responses to nonspecific mitogens. Mutated CD3 complex lacks lymphoproliferative responses to anti-CD3.

Humoral immunity typically shows nonspecific abnormalities in immunoglobulin class and immunoglobulin G (IgG) subclass levels with relatively preserved antibody function. Classic WAS is accompanied by low immunoglobulin M (IgM) levels, absent isohemagglutinin IgM against the A and B blood group polysaccharides, and poor IgG responses to bacterial polysaccharide antigens.

AT manifests with low-to-absent immunoglobulin A (IgA) levels in 70% of patients, low levels of IgG2 and IgG4, and diminished antibodies to antipolysaccharide antigens.

Low antipolysaccharide antibody responses also occur in patients with immune dysregulation/autoimmunity syndromes (eg, mutations in the genes of CD3, Foxp3, and FASL).

AT is usually diagnosed easily by detecting elevated a-fetoprotein levels in serum. However, patients with other chromosomal breakage syndromes (CBSs), such as NBS and Bloom syndrome, do not demonstrate increased a-fetoprotein levels. These 3 CBSs with immune deficiency (AT, Nijmegen breakage syndrome [NBS], Bloom syndrome) can be diagnosed by assessing spontaneous or induced chromosomal breakage in vitro.

Detection of infectious agents by culture and hematoxylin and eosin (H & E) staining of biopsy material is usually required. Polymerase chain reaction (PCR) techniques for viral detection have become an evaluation mainstay and are performed on body fluids and tissues.

The prevalence and spectrum of T-cell lymphoproliferative disorders in patients with hypereosinophilia was evaluated in 124 consecutive patients in whom seven had the lymphocytic variant of hypereosinophilic syndrome and five had overt T-cell lymphoma. Flow cytometry can be an important screening tool in these patients.[19]

Imaging Studies

Cardiac studies, including echocardiography and catheterization, are appropriate in most patients with DiGeorge syndrome (DGS).

Chest radiography is useful only to confirm the absence of thymic tissue, although the thymus may be involuted in an immunologically healthy host undergoing severe stress or the thymus may be malpositioned in a patient with DGS.

The atrophy in CHS is diffuse in both the brain and the spinal cord in contrast to AT where the cerebellar area is specifically affected.

Other Tests

Mutational analysis is available in specific laboratories for many T-cell deficiency syndromes. These tests must be made available to families to assess carrier status and to perform prenatal diagnosis.

In the past, subtle T-cell dysfunction has been confirmed by delayed rejection of skin grafts in disorders such as AT.

Research studies of autoimmune phenomenon in partial T-cell defects have shown failure to delete T cells that recognize self-antigens. Fas and Fas ligand defects caused by mutations are the prototypic T-cell disorders of this type.

Analysis of additional T-cell functions, such as cytotoxicity in patients with CHS, is only available from specific research laboratories. Such tests are rarely needed to establish the diagnosis.

Procedures

As in complete T-cell defects, obtaining appropriate culture material to identify infectious agents is critical. The most common procedures are bronchoscopy, culture of the sinuses, and biopsies performed in lymph nodes and the liver.

Biopsies of lymphoid tissue are necessary to distinguish lymphoproliferative states from malignancy.

Histologic Findings

The thymus has been studied histologically in patients with DGS and AT. In patients with DGS, the thymus has a wide spectrum of morphology, ranging from apparently intact thymic size and structure to disruption of the medulla and absent Hassall corpuscles to complete thymic absence. Patients with AT have a small thymus, are markedly deficient in thymocytes and Hassall corpuscles, and have poor corticomedullary demarcation. CD3 complex deficiencies show thymic defects similar to those in AT. Histologic analysis has not been available for many partial T-cell disorders until chronic disease and corticosteroid therapy have altered the histologic findings.

Lymphoid hyperplasia is present in Fas and Fas ligand deficiencies and in other immune dysregulation/autoimmunity syndromes. In situ T-cell markers may show excessive CD4+ T cells, a high proportion of CD4-/CD8- T cells, or an imbalance of TCR α/β and TCR γ/δ T cells. The histologic appearance may resemble immunoblastic lymphoma.

The accelerated phase of CHS may be confused with lymphoma or erythrophagocytic lymphohistiocytosis.

 

Treatment

Approach Considerations

Exploration of mutations and analysis of cellular changes related to lymphocyte defects and immune dysregulation has fueled the development of novel treatment options for some primary T-cell disorders that might otherwise by fatal.[20]  It is important to integrate clinical, histopathological, immunohistochemical, and molecular findings in patients with T-cell lymphoid proliferations.[21]

Medical Care

The FDA approved the first therapy to reconstitute immunity in children with congenital athymia in October 2021. Allogeneic processed thymus tissue (Rethymic) is implanted surgically in the quadriceps muscle of the recipient. 

Approval of allogeneic processed thymus tissue was based on 10 prospective single-arm, open-label studies that included 105 patients from 1993 to 2020. Survival rates were analyzed with the longest follow-up period of 25.5 years. In the EAS, Kaplan-Meier estimated survival rates (95% CI) were 77% (0.670–0.841) at 1 year and 76% (0.658–0.832) at 2 years. For patients who were alive at 1 year post implantation, the estimated long-term survival rate was 94% at a median follow-up time of 10.7 years. For the patients in the clinical trials, naïve T-cell levels were measured using flow cytometry at 6, 12, and 24 months after implantation. Patients in the clinical trials started out with very few naïve T cells, but naïve CD4 and CD8 T cells began to reconstitute over the first year, with a durable increase through the second year. Reductions in the number of infections over time during the first 2 years after treatment were statistically significant (p < 0.001).[22]

Sinopulmonary infections with common viral and bacterial agents are characteristic of partial T-cell disorders. Conventional therapy appropriate for the immunologically healthy host is administered, although patients with T-cell defects characteristically have more prolonged and severe clinical courses. Prophylaxis against infection by respiratory syncytial virus (RSV) using RSV-polyclonal immunoglobulin or the humanized monoclonal antibody, palivizumab, is specifically indicated in patients with T-cell disorders. Mucocutaneous candidiasis is more frequent but is conventionally treated in patients, and the disease uncommonly disseminates.

Bone marrow transplantation must be offered early in infancy to patients with Wiskott-Aldrich syndrome (WAS) to ensure better outcome. In addition, transplantation is the only effective treatment in most patients with Chediak-Higashi syndrome (CHS) and is indicated prior to development of the accelerated phase. Patients with DiGeorge syndrome (DGS) rarely have complete absence of T-cell function; these few patients require stem cell reconstitution, usually via bone marrow transplantation.

Routine childhood immunizations are usually indicated because patients with partial T-cell defects, even those with abnormalities in immunoglobulin levels, often respond with adequate specific antibody titers, although the levels may be lower than normal. However, administration of the oral live-attenuated poliovirus vaccine is contraindicated and should be replaced with the inactivated poliovirus vaccine. As a result of the frequency of bacterial sinopulmonary infections, administration of the conjugated pneumococcal vaccine (Prevnar) is particularly important.

Usually, treatment in persons with autoimmune disorders mirrors that for hosts who are immunocompetent. However, infectious complications pose a greater risk in patients with T-cell disorders who receive systemic steroids and other immunosuppressive drugs.

Overproduction of cytokines by T cells and other effector cells of the immune system can be controlled through use of anticytokine monoclonal antibodies, such as anti–tumor necrosis factor (TNF)–α (infliximab), for inflammatory bowel disease.

Insulin-dependent diabetes mellitus (IDDM), hypoadrenalism, hypothyroidism, glomerulonephritis, and autoimmune enteropathy present in patients at unusually young ages, typically in patients younger than 1 year who have immune dysregulation/autoimmunity disorders.

Patients with WAS and older patients who have chromosomal breakage syndromes (CBSs) have a high risk of malignancy. Chemotherapy in patients with ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) is not usually tolerated at conventional doses because of DNA instability. Thus, lower doses and longer intervals between doses are usually used.

Gene therapy is being studied as a possible alternative to allogeneic hematopoietic stem cell transplantation for the treatment of severe combined immunodeficiency (SCID),[23] as well as a treatment for WAS.[24, 25, 26]

Several drugs that block the lymphocyte voltage-gated potassium channel, kv1.3, as well as biologic therapies, are being explored as autoimmune disease treatments.[27, 28]

Graft versus host disease (GVHD) has been prevented successfully in mice through ex vivo selection and expansion of CD4(+)CD25(+) immunoregulatory T cells, specific for recipient alloantigens.[29]

Mesenchymal stem cells have shown some promise in enhancing engraftment and both preventing and treating GVHD in bone marrow transplant recipients.[30]

Antithymocyte globulin has been shown to reduce acute and chronic GVHD in randomized trials.[31]

Surgical Care

With the exception of cardiac procedures in patients with DGS, surgery is not usually required for patients with partial T-cell disorders.

Splenectomy has been used to control autoimmune hemolytic anemia and thrombocytopenia in patients with WAS and immune dysregulation/autoimmunity syndromes. In patients with WAS and Fas and Fas ligand deficiencies, overwhelming postsplenectomy sepsis has occurred despite immunization and antibiotic prophylaxis directed against Streptococcus pneumoniae.

Tumor-stage vulvar mycosis fungoides responded to local low-dose radiotherapy (Bakar et al, 2014).

Consultations

Clinical immunologists and geneticists are integral to the evaluation and treatment in patients with partial T-cell disorders.

Intervention performed by neurologists is important in patients with CBSs and CHS.

Physical therapists and rehabilitation specialists are critical to achieving optimal functioning in patients with CBSs and CHS.

Autoimmune disorders are best controlled with the help of collaboration by hematologists, endocrinologists, and gastroenterologists.

The malignancies in CBSs may require alteration of chemotherapeutic regimens because of the increased DNA instability of host cells.

When a T-cell disorder is suspected, the Immune Deficiency Foundation offers a consultation service for physicians. Laboratories in Seattle (the University of Washington), Boston (Children's Hospital Boston), and New York City (The Jeffrey Modell Foundation) are funded to provide molecular analysis or can assist in contacting other research facilities.

Diet

As with other primary immunodeficiencies, supplemental nutrition can be an essential component of care for the patient with chronic enteropathy or chronic infection.

Unfortunately, many patients remain thin with short stature or become wasted.

Activity

The goal of care is to optimize daily functioning. Care to minimize exposure to certain viruses (eg, RSV, varicella) is important, but complete isolation is not recommended for patients with partial T-cell disorders.

Patients with WAS and CHS who have increased bleeding tendencies must be educated to avoid trauma and, especially, to wear helmets during certain activities.

 

Medication

Medication Summary

Athymia

The FDA approved the first therapy to reconstitute immunity in children with congenital athymia in October 2021. Allogeneic processed thymus tissue (Rethymic) is implanted surgically in the quadriceps muscle of the recipient.[22]  

Partial T-cell deficiencies

Patients with partial T-cell deficiencies often have increased viral and bacterial respiratory infections. Conventional antibiotic therapy is administered for bacterial sinopulmonary infections; these infections are frequent but unlikely to be invasive unless the patient has undergone splenectomy. Individual patients may benefit from prophylaxis against infection by respiratory syncytial virus (RSV) or encapsulated bacteria by antibody replacement using intravenous immunoglobulin (IVIG) or specific anti-RSV antibodies.

By taking advantage of residual T-cell function, immunization against viral and bacterial agents may be efficacious. For example, the conjugated pneumococcal vaccine may induce antibody production that the unconjugated vaccine cannot. Most patients with partial T-cell disorders appear to have adequate immunoglobulin G (IgG) antibody responses to traditionally T-cell dependent antigens (eg, diphtheria, tetanus, pertussis, influenza, conjugated Haemophilus influenzae), although information regarding newer vaccines (eg, hepatitis viruses) is inadequate.

Down-regulation of autoimmune reactions requires therapy with corticosteroids and other immunosuppressive agents. These agents include monoclonal antibodies directed against cytokines (ie, tumor necrosis factor [TNF]-a in autoimmune enteropathy).

Replacement therapy with IVIG in patients with primary immune deficiencies

The overall consensus among clinical immunologists is that a dose of IVIG of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels at greater than 500 mg/dL is desirable. Patients with X-linked agammaglobulinemia with meningoencephalitis require much higher doses (1 g/kg) and, perhaps, intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher doses or shorter intervals may be required.

For replacement therapy in patients with primary immune deficiency, all brands of IVIG are probably equivalent, although the viral inactivation processes (eg, solvent detergent vs pasteurization, liquid vs lyophilized) differ. The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences. Recording all side effects that occur during the infusion is crucial. Monitoring liver and renal function test results periodically, approximately 3-4 times yearly, is also recommended.

The US Food and Drug Administration (FDA) recommends that for patients at risk for renal failure (eg, patients with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, age >65 y, or in those taking nephrotoxic drugs), recommended doses of IVIG should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatments is high, especially in patients with infections and patients who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose administered the next day to achieve a full dose. Treatment should not be discontinued. After achieving serum IgG levels within reference range, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are believed to be related to adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause. Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose), and/or hydrocortisone (6 mg/kg/dose, not to exceed 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued.

Immunoglobulin E (IgE) antibodies to immunoglobulin A (IgA) have been reported to cause severe transfusion reactions in patients with IgA deficiency. A few reports exist of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency that developed IgE antibodies to IgA after treatment with immunoglobulin. However, in actual experience, this response is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Caution should be exercised in patients with IgA deficiency (< 7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see the Table below).

Table. Immune Globulin, Intravenous [32, 33, 34, 35] (Open Table in a new window)

Brand(Manufacturer)

Manufacturing Process

pH

Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)

Parenteral Form and Final Concentrations

IgA Content mcg/mL

Carimune NF

(CSL Behring)

Kistler-Nitschmann fractionation; pH 4 nanofiltration

6.4-6.8

6% solution: 10% sucrose, < 20 mg NaCl/g protein

Lyophilized powder 3%, 6%, 9%, 12%

720

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation

4.6-5.1

0.25M glycine

Ready-for-use liquid 10%

37

Gamunex

(Talecris Biotherapeutics)

Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation

4-4.5

Does not contain carbohydrate stabilizers (eg, sucrose, maltose), contains glycine

Liquid 10%

46

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III; ultrafiltration; pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated

6.4-7.2

5% solution: 0.3% albumin, 2.25% glycine, 2% glucose

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events

Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

Kistler-Nitschmann fractionation; pH 4 incubation; trace pepsin; nanofiltration

6.6

Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl

Lyophilized powder 3%, 6%, 9%, 12%

720

Privigen Liquid 10%

(CSL Behring)

Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration

4.6-5

L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose)

Ready-for use liquid 10%

< 25

Respiratory Syncytial Virus Antibodies

Class Summary

Prevention of RSV infection in immunodeficient infants and children is effective using humanized mouse monoclonal IgG, palivizumab.

Palivizumab (Synagis)

Children with asymptomatic acyanotic congenital cardiac disease may be treated with palivizumab.

Because it is a specific anti-RSV antibody, it does not protect against other respiratory infections.

Immunosuppressive Agents

Class Summary

Patients with immune dysregulation and autoimmunity often benefit from immunosuppression. Commonly used drugs include corticosteroids in combination with cyclosporine or tacrolimus. Cyclophosphamide and azathioprine are administered less commonly. These modalities are usually used in collaboration with hematologists, gastroenterologists, and rheumatologists.

Cyclosporine (Neoral, Sandimmune)

May control autoimmune enteropathy; functions to down-regulate T-cell activation and is used most often to prevent graft rejection of renal, liver, and cardiac transplants; also used as prophylaxis against GVHD.

Tacrolimus (Prograf)

Suppresses humoral immunity (T lymphocyte) activity. Acts via a separate pathway to decrease T-cell activation, similar to cyclosporine; has been effective in autoimmune enteropathy when response to cyclosporine was insufficient or erratic; most extensive experience is as therapy in liver transplantation.

Prednisone (Deltasone)

Prototypic corticosteroid drug; doses of other corticosteroids should be converted to prednisone equivalents; patients with immune dysregulation/autoimmunity syndromes receive chronic therapy over years and, thus, must be monitored for long-term toxicities, especially hypertension, cataracts, and osteoporosis; prednisolone is preferred in patients with hepatic disease because prednisone is converted to prednisolone in the liver.

Cyclophosphamide (Cytoxan, Neosar)

Traditional alkylator chemotherapeutic agent effective in various rheumatologic diseases (eg, systemic lupus erythematosus); individual patients with autoimmune hemolytic anemia and autoimmune enteropathy also have responded to therapy; specific dosage depends on the autoimmune disorder type and should be chosen in consultation with a specialist in that disease.

Azathioprine (Imuran)

Lengthy experience is available in the use of this drug for long-term management of inflammatory bowel disease and renal disease caused by autoimmunity; efficacy in immune dysregulation/autoimmunity is not as well documented; may allow administration of lower-dose corticosteroids.

Vaccines

Class Summary

Sinopulmonary infections in children with T-cell disorders are common. Immunization of children against S pneumoniae infection is an important consideration.

Pneumococcal 7-valent conjugate vaccine (Prevnar)

Sterile solution of saccharides of capsular antigens of S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F individually conjugated to the diphtheria CRM197 protein. These 7 serotypes have been responsible for >80% of invasive pneumococcal disease in children < 6 y in the United States. S pneumoniae also accounts for 74% of penicillin-nonsusceptible S pneumoniae (PNSP) and 100% of pneumococci with high-level penicillin resistance. Customary age for first dose is 2 mo, but can be given as young as 6 wk. Preferred sites of IM injection are anterolateral aspect of the thigh in infants or deltoid muscle of upper arm in toddlers and young children. Do not inject vaccine in gluteal area or areas in which a major nerve trunk or blood vessel may be located.

Ideally, it should be administered at ages 2 mo, 4 mo, and 6 mo, with a booster dose at 12-15 mo for a total of 4 injections. The following is a guideline for vaccinating infants and toddlers who do not meet this schedule: The number of 0.5-mL doses administered in infants receiving the first dose at age 7-11 mo is 3 (4 wk apart; third dose after first birthday), in children aged 12-23 mo is 2 (2 mo apart), and in children aged >24 mo through 9 y is 1.

Minor illnesses, such as a mild upper respiratory tract infection, with or without low-grade fever, are not generally contraindications.

Pneumococcal vaccine polyvalent (Pneumovax-23, Pnu-Imune 23)

Polyvalent vaccine used for prophylaxis against infection from S pneumoniae. Used in populations at increased risk of pneumococcal pneumonia (ie, age >55 y, chronic infection, asplenia, immunocompromised state).

Tumor Necrosis Factor Inhibitors

Class Summary

TNF is a cytokine in which 2 forms have been identified with similar biologic properties. TNF-α or cachectin is produced predominantly by macrophages, and TNF-β or lymphotoxin is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that contributes to symptoms. Infliximab (Remicade), was the first one approved by FDA belonging to this category. Since then, 3 more TNF inhibitors are approved by FDA: etanercept (Enbrel), adalimumab (Humira), and certolizumab (Cimzia). They may be used for controlling autoimmune complications but clinical data for their use are limited in the diseases described in this paper.

Infliximab (Remicade)

Neutralizes cytokine TNF-α and inhibits it from binding to TNF-α receptor. Consult gastroenterologist for use.

Regenerative Therapy

Class Summary

Surgically implanted allogeneic processed thymic tissue is intended to reconstitute immunity in children who are athymic.

Allogeneic processed thymus tissue (Rethymic)

Indicated for immune reconstitution in pediatric patients with congenital athymia. 

 

Follow-up

Further Outpatient Care

Otitis media, sinusitis, and mucocutaneous candidiasis are common infections that are treated on an outpatient basis. Conventional antibiotics and antifungal agents are administered but may require longer courses.

Treat eczematous rashes with conventional topical corticosteroids and emollients. Topical tacrolimus has recently been shown to be effective in controlling atopic dermatitis.

Neurologic dysfunction can occur in patients with ataxia telangiectasia (AT), CHS, and immune dysfunction/autoimmunity syndromes. Among these dysfunctions are seizure disorders that require anticonvulsant drug administration.

Further Inpatient Care

Bronchiolitis caused by respiratory syncytial virus (RSV), adenovirus, parainfluenza, and influenza is more severe and more likely to result in hospitalization. Conventional treatment includes use of oxygen, bronchodilator therapy, and deep suctioning.

Patients with DiGeorge syndrome (DGS) may require hospitalization for cardiac evaluation.

Bleeding diatheses in patients with Wiskott-Aldrich syndrome (WAS) and Chediak-Higashi syndrome (CHS) usually require inpatient treatment.

Bone marrow transplantation and other stem cell reconstitution are performed in specialized hospital units.

Thymus transplantation is a promising investigational therapy for athymic infants.[36]

Transfer

Treatment in most patients requires a team effort that includes a clinical immunologist and other subspecialists.

Bone marrow transplantation units usually assume the primary care role for patients undergoing stem cell reconstitution.

Deterrence/Prevention

Currently, mutation analysis is used to identify most infants with and carriers of partial T-cell disorders. Complete a familial mutation analysis in order to offer prenatal diagnosis.

Remarkably, a delayed diagnosis of DiGeorge syndrome may occur in someone aged 70 years or older.[37] It may be not so rare a disorder but simply one that is infrequently unrecognized.[38]

Adult T-cell leukemia/lymphoma (ATLL), which develops after long-term chronic infection with human T-cell lymphotropic virus type-1 (HTLV-1), has 3 major routes of viral transmission: (1) mother-to-child transmission through breastfeeding; (2) sexual transmission, predominantly from men to women; and (3) cellular blood components.[39] There is no preventive vaccine against HTLV-1 infection, but one should try to interrupt HTLV-1 transmission with prevention. Mother-to-child transmission through the replacement of breastfeeding can have a significant impact.

Complications

Each partial T-cell disorder has specific complications.

While patients with DGS are most likely to have fewer complications at an older age, the risk for malignancy increases with age in patients with WAS and AT.

Patients with AT and CHS develop progressive neurologic dysfunction as they age.

Insulin-dependent diabetes mellitus (IDDM), enteropathy, or pulmonary disorders can be fatal in many patients with dysregulation/autoimmunity syndromes as patient's age.

Splenectomy can be clinically effective in patients with WAS and Fas or Fas ligand deficiencies over the short term, but fatal sepsis is unpredictable.

Female carriers of AT have increased risk for breast cancer.

Prognosis

Outcome in patients with partial T-cell deficiencies have improved with better supportive care and improved techniques for bone marrow transplantation. For example, the mean age of survival has increased in patients with WAS. Although stem cell reconstitution offers the possibility of complete cure, control of infections and bleeding increased the mean age of survival from early childhood (in the 1970s) to the third decade of life (in the 1990s).

Longer survival in patients with AT and CHS is compromised by progressive neurologic deterioration. In patients with CHS, the rates of deafness and blindness are high. In both disorders, patients often become confined to a wheelchair.

Some children spontaneously correct immunoglobulin abnormalities during the first decade of life, even with a severe primary immunodeficiency.[40] Guidelines for the diagnosis and management of primary immunodeficiency have been established.[11] They may have had a delay in maturation of immunoglobulin synthesis.

Multivariate analysis of pediatric T-cell lymphoblastic lymphomas showed mutational status of NOTCH1/FBXW7 to be a promising marker for early therapeutic stratification and N/F(mut) to be an independent factor for good prognosis.[41]

Solitary mycosis fungoides appears to have a favorable prognosis.[42] However, long-term follow up is desirable. The peripheral blood CD4:CD8 ratio may be a biomarker for favorable response to radiation treatment.[43]

Patient Education

Inform families of patients with partial T-cell disorders regarding the risks of infection so they can institute appropriate steps to avoid exposure to infection. Inform families that bacille Calmette-Guérin vaccine (BCG) and live poliovirus vaccine are contraindicated.

Genetic counseling is an essential part of medical care for the family. Parents must be informed of the 25% risk that an affected infant will be born to parents each carrying autosomal recessive gene mutations and the 50% risk that an affected male infant will be born to mothers carrying X-linked mutations.

Adequate informed consent for stem cell reconstitution must review (1) the high risk for life-threatening infection during the immunosuppressive regimen used in preparation for stem cell reconstitution, (2) the risk that the graft will fail, and (3) the risk of graft versus host disease (GVHD). Although successful complete immune reconstitution from bone marrow transplantation is reported using fully matched related and unrelated donors or haploidentical parents, the graft may fail or patients may develop GVHD posttransplant. Other forms of stem cell reconstitution that can be offered include stem cell transplantation. Gene therapy is expected to become an option.[26]

The following organizations are among those providing educational services and support for families:

Immune Deficiency Foundation

40 W Chesapeake Avenue. Suite 308

Towson, MD 21204

Telephone: (800) 296-4433

Email: idf@primaryimmune.org

This organization is an important resource for education and for support for patients and families with any primary immunodeficiency disease. Some states have local chapters.

The Primary Immunodeficiency Resource Center

747 Third Avenue

34th Floor

New York, NY 10017

Telephone: 800-JEFF-844

Email: info@jmfworld.org

This organization provides support and raises funds.

 

Questions & Answers

Overview

What are T-cell disorders?

What is the pathophysiology of T-cell disorders?

What is the prevalence of T-cell disorders in the US?

What is the global prevalence of T-cell disorders?

What is the mortality and morbidity associated with T-cell disorders?

What are the racial predilections of T-cell disorders?

What are the sexual predilections of T-cell disorders?

Which T-cell disorders are associated with autosomal chromosomes?

At what age do T-cell disorders typically present?

Presentation

Which clinical history findings are characteristic of T-cell disorders?

Which physical findings are characteristic of T-cell disorders?

What causes T-cell disorders?

What does a finding of cutaneous granulomas indicate in the physical exam for T-cell disorders?

DDX

Which genetic disorders are associated with T-cell disorders?

What are the differential diagnoses for T-Cell Disorders?

Workup

What is the role of lab tests in the workup of T-cell disorders?

What is the role of imaging studies in the workup of T-cell disorders?

What is the role of mutational analysis in the workup of T-cell disorders?

What is the role of cytotoxicity analysis in the workup of T-cell disorders?

What is the role of biopsy in the workup of T-cell disorders?

Which histologic findings are characteristic of T-cell disorders?

Treatment

How are T-cell disorders treated?

What is the role of surgery in the treatment of T-cell disorders?

Which specialist consultations are beneficial to patients with T-cell disorders?

Which dietary modifications are used in the treatment of T-cell disorders?

Which activity modifications are used in the treatment of T-cell disorders?

Medications

What is the role of medications in the treatment of T-cell disorders?

What is the role of IV immunoglobulin replacement in the treatment of T-cell disorders?

Which medications in the drug class Tumor Necrosis Factor Inhibitors are used in the treatment of T-Cell Disorders?

Which medications in the drug class Vaccines are used in the treatment of T-Cell Disorders?

Which medications in the drug class Immunosuppressive Agents are used in the treatment of T-Cell Disorders?

Which medications in the drug class Respiratory Syncytial Virus Antibodies are used in the treatment of T-Cell Disorders?

Follow-up

How are common infections treated in patients with T-cell disorders?

How are eczematous rashes treated in patients with T-cell disorders?

How is neurologic dysfunction treated in T-cell disorders?

When is inpatient care indicated for the treatment of T-cell disorders?

When is patient transfer indicated for the treatment of T-cell disorders?

What is the role of mutational analysis in the prevention of T-cell disorders?

How are T-cell disorders prevented?

What are the possible complications of T-cell disorders?

What is the prognosis of T-cell disorders?

What is included in patient education about T-cell disorders?