Infectious Complications of Cell-Mediated Immunity Other Than AIDS: Primary Immunodeficiencies

Definition

SCID, which occurs in about 1 in 58,000 live births in the US, is an inherited severe immunodeficiency with marked impairment of the de novo production by the thymus of peripheral antigenically naïve (CD45RA ^high CD45RO ^low ) T cells. The profound T-cell lymphopenia is either due to reduced intrathymic production (most etiologies) or, rarely, to a block in their egress from the thymus to the periphery [coronin 1A ( CORO1A ) deficiency]. ^, The “combined” term in SCID reflects the fact that severe T-cell deficiency invariably compromises B-cell function, regardless of whether B cells are present in normal numbers, which they are in a number of common etiologies. This is because CD4 T-cell help for B-cell antibody production in the form of surface CD40 ligand and secreted cytokines—such as IL-21—is required for most antigens. In addition, in some forms of SCID, the B cells that are present may have intrinsic functional defects—such as a lack of responsiveness to the cytokine IL-21—that further compromise B-cell function. There is variable loss of NK cell numbers and other ILCs, depending on the specific defect ( Table 105.1 ). ^{, ,}

Specific Gene Defects and Their Inheritance Pattern

SCID can be due to single X-linked or biallelic AR gene defects ^{, , ,} (the specific genes involved are indicated in italics in the text and Table 105.1 ) or, less commonly, to heterozygosity for gain-of-function mutations that inhibit hematopoietic cell function (e.g., certain Rac2 deficiency cases) or chromosomal abnormalities (e.g., complete DiGeorge syndrome secondary to heterozygosity for the 22q11.2 deletion). Most types of SCID caused by monogenic defects are hematopoietic cell autonomous so that the disease can be cured by hematopoietic stem cell (HSC) transplantation or HSC-based gene therapy. X-linked SCID, the most common form of these hematopoietic cell autonomous defects, comprises about 50% of cases of SCID in most series and is due to deficiency of the common gamma chain gene (also known as the IL-2 receptor gamma chain gene [ IL2RG ]) encoded in the Xq13.1 region. The common gamma chain protein (CD132), along with the IL-7Rα chain (CD127), comprises the specific receptor for the cytokine IL-7, and a lack of functional IL-7 receptors on developing thymocytes results in their arrested development. ^, Deficiency of the common gamma chain protein also results in the loss of functional surface receptors for IL-2, IL-4, IL-9, IL-15, and IL-21 and compromises the ability of IL2RG -deficient B cells to receive IL-21−mediated help for immunoglobulin production. Thymocyte deficiency of Janus kinase-3 ( JAK3 ), which is associated with the cytoplasmic domain of the common gamma chain, results in a form of SCID similar to IL2RG deficiency—except for an AR rather than an X-linked inheritance pattern. ^, SCID with an AR inheritance pattern also can be due to defects in the ability of the thymocyte TCRs to transmit intracellular survival or activation signals (e.g., deficiencies of CD3-δ [ CD3D ], CD3-ε [ CD3E ], TCR-zeta [ CD247 ], zeta-associated protein of 70-kilodaltons kinase [ ZAP70 ], sarcoma homology 2 domain-containing leukocyte protein of 76 kilodaltons ( SLP76 ), CD45 , or the proteins encoded by ORAI1 or STIM1 molecules that are involved in calcium signaling); defective thymocyte rearrangement of TCR genes (deficiencies of recombination activating gene proteins encoded by RAG1 and RAG2 , Artemis ( DCLRE1C ), Cernunnos ( NHEJ1 ), DNA ligase IV ( LIG4 ), or DNA-dependent protein kinase catalytic subunit ( PRKDC ); increased thymocyte death from toxic effects of accumulated purine metabolites (deficiency of adenosine deaminase [ ADA ] or purine nucleoside phosphorylase [ PNP ]); a failure of the development of bone marrow hematopoietic cell precursors that normally colonize the thymus and give rise to thymocytes (reticular dysgenesis due to deficiency of adenylate kinase 2 [ AK2 ]); and impaired expression of MHC class II molecules (deficiency of transcription factors encoded by RFXAP , RFXANK , RFX5 , or CIITA ), which are required for the intrathymic development of CD4 T cells from CD4 ⁺ CD8 ⁺ thymocytes as well as antigen presentation to mature peripheral CD4 T cells.

Likely owing to variable expressivity of null mutations, AR SCID also can occur in a number of genetic causes of combined deficiency involving T cells and B cells in which most patients have a milder phenotype. For example, SCID also can occur in some cases of immunodeficiency with multiple intestinal atresias due to biallelic mutations of the TTC7A gene, which encodes a cytoplasmic protein that may be involved in phosphatidyl inositol signaling. Rarely, some genetic immunodeficiencies may result in substantial or even normal numbers of peripheral naïve T cells that have profound functional impairments, resulting in a SCID clinical presentation. For example, caspase recruitment domain 11 (CARD11) deficiency, in which damaging biallelic mutations in CARD11 result in the normal production of T cells by the thymus that have profound defects in TCR activation of the NF-κB pathway, resulting in a SCID presentation.

A few types of SCID are mainly due to thymic epithelial cell abnormalities resulting in a secondary perturbation of thymocyte differentiation and proliferation. These include complete DiGeorge syndrome, which occurs in about 1%–2% of cases of the hemizygous interstitial chromosome 22q11.2 deletion. Biallelic mutations of CHD7 (CHARGE syndrome: c oloboma, h eart defect, a tresia choanae, r etarded growth and development, g enital hypoplasia, e ar anomalies/deafness) also rarely can result in a complete DiGeorge syndrome−like clinical presentation. ^, Biallelic mutations of the gene encoding the forkhead box N1 (FoxN1) transcription factor also results in SCID due to perturbed thymic epithelial development. ^, Finally, SCID due to biallelic mutations encoding the PAX1 transcription factor appear to also reflect a thymic epithelial cell autonomous defect that is not treatable using HSC transplantation. ^, These forms of SCID are currently treatable only by the allogeneic transplantation of thymic epithelium. ^,

Characteristic Infections

Even with the widespread adoption of neonatal screening for SCID, it remains important for the clinician to be aware of the frequent initial presentation of SCID so that the diagnosis can be confirmed rapidly and potentially life-saving clinical management be considered. SCID disorders typically manifest early in infancy with infections caused by opportunistic organisms or with severe or protracted infections caused by common pathogens, especially viruses. ^{, ,} The infectious complications of SCID are similar regardless of the particular genetic defect and reflect a failure of T cells and, in some cases, NK cells to control and ultimately eliminate intracellular viruses in lymphatic and other tissues. Infections due to adenovirus, enterovirus, parainfluenza and influenza viruses, respiratory syncytial virus (RSV), and herpesviruses, such as cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV), can be severe, with marked pulmonary, hepatic, or central nervous system involvement. ^{, ,} Failure to thrive is a prominent manifestation in most patients and usually is due to persistent gastroenteritis from common pathogens, such as rotavirus, adenovirus, enteroviruses, or norovirus. SCID patients also have increased risk for complications from live vaccines, such as disseminated infection after receipt of the bacille Calmette-Guérin (BCG) vaccine or chronic diarrhea due to persistent vaccine-acquired rotavirus infection.

Fungal infections, which are suggestive of severe CD4 T-cell immune deficiency, include persistent and severe mucocutaneous candidiasis and Pneumocystis jirovecii pneumonia (PJP). Pneumocystis infection always should prompt a comprehensive search for SCID or another primary immunodeficiency involving CD4 T cells.

Severe bacterial infections with pathogens that have a predominant intracellular presence, such as Legionella, Listeria, Mycobacterium (e.g., after vaccination with BCG), and Salmonella can occur and illustrate the requirement for CD4 T-cell−mediated immunity in control of these pathogens. Other gram-negative bacteria, such as Pseudomonas, Serratia, Klebsiella, and Escherichia coli, also have been reported as causes of infection even before hematopoietic cell transplantation, and this may be explained by defects in Th17 cells affecting neutrophil immunity or neutropenia that is part of certain etiologies of SCID (e.g., reticular dysgenesis). Some cases of SCID can be complicated before transplantation by the hemophagocytic lymphohistiocytosis syndrome, which can include neutropenia that increases the risk for invasive bacterial disease, such as gram-negative septicemia. As maternally derived immunoglobulin G (IgG) level decreases over the first several months of life, patients develop marked and persistent hypogammaglobulinemia and have increased risk for recurrent sinopulmonary infections from encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae.

Routine neonatal screening for SCID using Guthrie card blood spots for measurement of signal joint T-cell receptor excision circles (sjTRECs) is now being carried out in all US states, Puerto Rico, and the Navajo Nation. ^, Results typically are available by 3 weeks of age, after which confirmed SCID patients can be put into some form of protective isolation and begun on prophylactic antimicrobial agents to prevent infections (e.g., for PCP) and immunoglobulin replacement therapy. However, because CMV frequently is acquired during vaginal delivery or by breastfeeding, the current screening cannot prevent the postnatal acquisition of CMV in all cases of SCID.

In addition to infectious complications, some infants with SCID develop a skin rash and other organ dysfunction, such as hepatitis and gastrointestinal inflammation, from graft-versus-host-disease (GvHD). GvHD is mediated by T cells acquired transplacentally from the mother or from unirradiated blood transfusions, especially whole blood or platelets. Such maternally derived T cells also can cause hemophagocytic syndrome in untransplanted SCID patients. Severe GvHD also should be distinguished from Omenn syndrome (OS), a form of SCID that classically is due to biallelic hypomorphic (i.e., not null) mutations of either RAG1 or RAG2 . It also can occur in cases of SCID due to a number of other gene deficiencies involving T cells , including IL2RG , LIG4 , IL7R , ADA , DCLRE1C , AK2 , ZAP70 , CHD7 , and CARD11 . Patients with OS often have extensive erythroderma, which resembles primary dermatologic conditions (such as Netherton syndrome), lymphadenopathy, hepatosplenomegaly, and failure to thrive. OS due to hypomorphic RAG mutations typically includes marked peripheral eosinophilia, highly elevated serum levels of IgE, increased levels of CD4 T cells producing Th2-type cytokines (IL-4, IL-5, and IL-13), and markedly reduced peripheral CD8 T cells and B cells.

About one third of patients with complete DiGeorge syndrome have an atypical course in which an OS-like syndrome of erythroderma—which may be accompanied by enteritis and hepatitis—occurs starting at several months of age. The OS-like syndrome coincides with the appearance of increased numbers of circulating oligoclonal T cells that are produced by the infant (and not the mother). These T cells are highly activated, express memory/effector markers, (i.e., CD45RO ^high CD45RA ^low ), and appear to be autoreactive against the skin, gastrointestinal tract, liver, and potentially other organs.

Diagnosis

A history of other family members who experienced severe or recurrent infections in infancy or who died of unknown cause is suggestive of the diagnosis. However, a substantial number of cases of SCID—even of X-linked disease—result from new mutations, so that the family history is not informative. Because SCID usually is due to severe thymic hypoplasia, there typically is a reduced or absent thymic shadow on imaging studies. Exceptions can include CORO1 or CARD11 deficiency. In cases of early-onset ADA deficiency, a plain chest radiograph may reveal the rachitic-like flaring of the costochondral junctions. On physical examination, peripheral lymph node tissue typically is reduced, although there are exceptions—such as in OS—in which lymphadenopathy and hepatosplenomegaly are common. In a minority of cases, findings point to a specific disorder (e.g., the absence of hair in deficiency of FOXNI , or the characteristic facies and congenital heart disease typical of DiGeorge syndrome; see Table 105.1 ).

In most cases of SCID, a complete blood count reveals a reduced absolute lymphocyte count (ALC) for age. This finding in early infancy never should be ignored—even in a well-appearing infant—because it can lead to an early diagnosis of immunodeficiency. A severely reduced ALC is typical of forms of SCID that result in an arrest of both naïve T-cell and B-cell development, such as null mutations of RAG or ADA deficiency. A less severely decreased ALC is characteristic of forms of SCID due to defects of IL7R because this spares human B-cell and NK- cell development ( Table 105.1 ). However, the ALC in some forms of SCID can be normal (e.g., some cases of X-linked SCID, MHC class II deficiency, and ZAP-70 deficiency) or even increased (e.g., some cases of ZAP-70 deficiency and most cases of OS). Normal or increased counts may reflect a compensatory increase in one lymphocyte population that masks the loss of another (e.g., the absolute increase in circulating numbers of CD4 T cells masking the absence of CD8 T cells in ZAP-70 deficiency) or a pathologic expansion (e.g., the marked expansion of a small population of activated CD4 T cells with a limited αβ TCR repertoire in OS or of CD4 T cells or CD8 T cells in maternal engraftment or in atypical complete DiGeorge syndrome). In these pathologic expansions, these oligoclonal T-cell populations uniformly express memory/effector markers (CD45RO) rather than the CD45RA isoform of naïve T cells. ^{, ,} Gene defects in which there is retention of residual function—such as in certain cases of IL2RG mutations—may also result in ALCs that are normal or even elevated. Therefore—regardless of the result of the ALC or T-cell subset analysis—if SCID is suspected clinically, it is critical to enlist the help of a clinical immunologist so that appropriate tests can be performed to evaluate lymphocyte subpopulations (e.g., surface phenotype by flow cytometry) and T-cell function (e.g., mitogen- and antigen-induced proliferation, flow cytometric analysis of cytokine secretion capacity), specific gene sequencing, αβ TCR repertoire analysis, and determination of whole blood level TCR excision circles if this has not already been performed as part of neonatal screening.

Treatment

After SCID is diagnosed and appropriate blood samples for total and antigen-specific immunoglobulin levels have been obtained, immune globulin intravenous (IGIV) usually is administered pending a definitive treatment plan. All live vaccines, including oral poliovirus vaccine, rotavirus vaccine, measles, mumps rubella (MMR) vaccine, varicella vaccine, vaccinia, BCG, and attenuated influenza vaccine and oral Salmonella Typhi vaccine, are contraindicated. IGIV therapy obviates the benefit of vaccination with “killed” vaccines (e.g., inactivated poliovirus vaccine) by providing passive antibody. Therefore, inactivated or protein/polysaccharide component vaccines, although safe in SCID and other immunodeficiencies, typically are not administered after IGIV therapy is begun. All infants identified as having SCID by means of newborn screening should be evaluated for CMV infection, which can be transmitted to the infant during vaginal delivery or through human milk. Detailed approaches used by expert clinicians for prophylaxis of herpesviruses, RSV, PCP, and fungal infections of infants with SCID are available. For most etiologies of SCID, the early transplantation of HSCs contained in bone marrow, peripheral blood, or cord blood—ideally from an HLA-matched relative—is standard treatment for immune reconstitution. For IL2RG SCID, clinical gene therapy trials are ongoing and use self-inactivating lentiviral vectors for the transduction of autologous bone marrow leukocytes enriched in CD34 ⁺ HSCs. The transduced bone marrow leukocytes are administered to recipients that receive low-dose intravenous busulfan to improve the engraftment of the transduced HSCs into the bone marrow microenvironment. Recently published results for 8 infants with X-linked SCID, suggest that these newer retroviral vectors are safe and effective (based on immune reconstitution and the clearing of opportunistic infections) and are at a low risk to cause dysregulation of endogenous genes near the lentiviral insertion sites that could lead to oncogenesis. This contrasts with the early IL2RG gammaretroviral vector therapy for X-linked SCID that was started in 1999 and 2000 and in which insertional oncogenesis occurred in 6 out of 20 gene therapy recipients. For SCID due to ADA deficiency, specific enzyme replacement with polyethylene glycol−associated ADA (pegademase [Adagen]) should be started in consultation with a clinician experienced in its use for SCID. These ADA-SCID infants should then be evaluated for treatment either using allogeneic HSC transplantation, ideally with an HLA-matched family donor, or lentivirus-mediated autologous HSC gene therapy if available. The excellent efficacy and safety (no cases of oncogenesis) of retroviral gene therapy observed in more than 100 patients with SCID due to ADA deficiency makes this an equal alternative to allogeneic HSC transplantation.

Adenosine Deaminase and Purine Nucleoside Phosphorylase Deficiency (Late Onset)

ADA, or PNP deficiency, should be considered in HIV-negative patients of any age, including adults in whom there is unexplained lymphopenia and recurrent infections. Notable infections include recurrent sinopulmonary disease, pneumonia, bacteremia, severe local papilloma infections, and recurrent herpes zoster. Late-onset infections associated with allergic or autoimmune hematologic disorders (e.g., immune thrombocytopenia, autoimmune hemolytic anemia) suggest partial enzyme defects.