History
Patients with severe combined immunodeficiency (SCID) may present with multiple severe or recurrent illnesses during the first months of life. Initially, growth appears normal, but failure to thrive with severe emaciation ensues secondary to diarrhea and chronic infections. In the past, SCID was often diagnosed after children acquired serious infections, such as pneumonia due to P jiroveci (carinii). Today, most infants should be recognized before the development of failure to thrive or Pneumocystis infection.
Within the first 3 months of life, infants with SCID present with persistent and recurrent diarrhea, otitis media, thrush, and respiratory infections (see the image below). In this setting, a thorough medical and family history, with particular attention to recurrent infections, should be obtained. The history should include questions about the following:
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Family history of consanguinity
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Sibling death in infancy (eg, multiple deaths during infancy due to infection or unexplained deaths in male infants) or previous miscarriages in the mother
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Family history of SCID or other primary immunodeficiency
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Poor feeding and poor weight gain
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Chronic diarrhea
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Previous infections, especially pneumonia
See the image below.
This patient presented with fever and paralysis of his left arm 3 months after receiving his third oral poliovirus vaccine. Past history included chronic thrush presenting in the absence of antibiotic therapy or breastfeeding at 2 months, chronic diarrhea from 4 months, and recurrent otitis media. He was at the 90th percentile for height and weight, similar to his parents. Major histocompatibility complex (MHC) class II deficiency was diagnosed by immunologic tests.
Diarrhea may be caused by rotavirus, adenovirus, and enterovirus. Cryptosporidiosis is also reported frequently. Diarrhea resembling Crohn disease complicates some types of SCID, such as major histocompatibility complex (MHC) class II deficiency.
Patients with SCID have repeated infections, which are typically more severe than comparable infections occurring in children with normal immunity. The frequency may be greater than 8 per year. Patients may require antibiotics for longer than 2 months; at times, intravenous (IV) antibiotics may be necessary. Patients with SCID may have recurrent deep skin or organ abscesses.
Mucocutaneous candidiasis is often more severe than expected and is resistant to treatment. Bacterial otitis media and pneumonia are common. Viral infections caused by varicella zoster virus (VZV), herpes simplex virus (HSV), respiratory syncytial virus (RSV), rotavirus, adenovirus, enterovirus, parainfluenza virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are seen. Asking the mother about risk factors for HIV infection is important; infants with transplacental HIV infection may present in much the same fashion as SCID.
Dismissing an infant’s death caused by an overwhelming common bacterial or viral infection without further investigation is a mistake. Whenever an infant with a history of unusually frequent and severe common infections dies of infection, an autopsy should be performed to assess lymphoid and thymic tissue. Peripheral blood lymphocytes can survive for several days; thus, blood should be saved for assessment of T-cell and B-cell markers by flow cytometry and for responses to mitogens.
Defects in the cell-mediated immune system become more apparent because breastfeeding may mask the humoral immune defects during the early neonatal period. T-cell defects, such as candidiasis affecting the esophagus, may occur. For example, cytomegalovirus (CMV) infection, measles, and varicella, which are usually self-limited, infect the lungs and the brain, resulting in life-threatening pneumonia, meningitis, and sepsis. Pulmonary involvement with P jiroveci (carinii) pneumonia (PCP) can also be severe.
Autoimmune phenomena, especially hemolytic anemia and neutropenia, are more common in CD3 deficiency and MHC class II mutations. The absolute lymphocyte count is less than 3000/μL, and the proliferative response of the lymphocytes to mitogens activation is less than 10% of control values.
Physical Examination
Physical findings are multisystemic. The abnormal findings are primarily related to the various superimposed infections or to graft-versus-host disease (GVHD) rather than to SCID itself. The patient may present with the following:
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Failure to thrive, manifesting as decreased weight, height, and head circumference
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Dehydration from chronic diarrhea
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Recurrent, painful otitis media, which may be more severe than typical, is common
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Eczematous rash from GVHD, which may be mistaken for atopic dermatitis, especially in Omenn syndrome
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Increased respiratory rate and effort and crepitations secondary to pneumonia (especially PCP)
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Fever from sepsis, systemic fungal infections, or generalized herpes
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Absent lymphatic tissue, including tonsils; lack of recognizable peripheral lymphoid organs should raise suspicion of SCID in children with multiple aggressive infections
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Lymphadenopathy and hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome
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Neurologic sequelae and developmental regression (loss of developmental milestones), especially in purine nucleotide phosphorylase (PNP) deficiency (the cause of which is genetic, not infectious); neurologic perturbation also occurs secondary to central nervous system (CNS) infection
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Abdominal findings, including tenderness secondary to gastrointestinal (GI) infections and hepatomegaly from viral hepatitis
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Candidiasis
Infants with SCID have an extensive and diverse group of cutaneous disorders. Recurrent skin abscesses are present. Extensive candidiasis in the mouth and diaper area may persist beyond the neonatal period and may involve the rest of the skin. Severe seborrheic dermatitis is observed over the scalp, ears, and nasolabial folds. Intractable eczemalike dermatitis is noted. Impetigo and severe skin infections with deep ulcers in the perineum, tongue, and buccal mucosa are observed. Recurrent furunculosis may develop.
A generalized herpetic dermatitis may also be noted. Cutaneous manifestations of GVHD may also be present from maternally derived T cells that are reacting host cells in the absence of opposing host T cells. Such manifestations include the following:
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In the acute setting, a maculopapular or morbilliform rash can occur and progress to erythroderma and exfoliative dermatitis
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In chronic GVHD, lichenoid or sclerodermoid lesions are described
The dermatologic disorders of incontinentia pigmenti and hypohidrotic ectodermal dysplasia are associated with severe pneumococcal infections and progressive bronchiectasis, even with immunoglobulin (Ig) replacement.
Dermatophytosis is uncommon in SCID patients, although a case has been described with widespread tinea corporis due to Trichophyton mentagrophytes. [34] Children with Artemis-deficient SCID additionally suffer from numerous oral and genital ulcers. Some patients with a mild form of JAK3-deficient SCID may present with extensive cutaneous transitory warts.
Adenosine deaminase (ADA) deficiency is accompanied by abnormalities to ribs and vertebrae caused by defects in cartilaginous structures.
Sparse hair, abnormal dentition, and osteopetrosis are other manifestations in SCID patients. Hypomorphic heterozygous mutations in IKBA causes autosomal dominant ectodermal dysplasia with immunodeficiency (AD-EDA-ID) with impaired nuclear factor kappa B (NFκB) signaling pathways; however, this defect also causes severely impaired T-cell receptor (TCR) signaling with the resultant clinical phenotype of SCID.
Unique features of Omenn syndrome and the Omennlike syndrome caused by GVHD include erythroderma, lymphoid hyperplasia, hypereosinophilia, and hepatosplenomegaly. Growing numbers of leaky SCID mutations have been shown to manifest Omenn syndrome; accordingly, this syndrome is now considered to consist of dysregulated inflammatory processes revealed in leaky SCID.
Complications
Patients are at risk for infections from inadequate immune reconstitution from bone marrow transplantation (BMT) or enzyme replacement. Opportunistic infections usually follow more common infections. P jiroveci and fungal pneumonias cause death in classic cases. CMV, VZV, and HSV infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other enteroviruses precludes stem cell reconstitution.
Ensure that the child does not receive any live virus vaccines until after BMT engraftment, especially polio or bacille Calmette-Guérin (BCG) vaccine. Vaccinating children with SCID is not only futile, because they cannot make antibody, but also dangerous, because they can develop disease (eg, poliomyelitis) from attenuated viruses and may even die after exposure to these vaccines.
Graft failure with BMT and posttransplant GVHD are well recognized, although both have decreased with improved BMT preparatory techniques. GVHD) may ensue if the blood products given before BMT are not depleted of white blood cells by filtration or irradiation. Ensure that all blood products are also negative for CMV to avoid systemic CMV disease.
Gene therapy has been associated with virus-induced malignancies. Cancer, usually non-Hodgkin lymphoma, is seen in patients with cartilage-hair hypoplasia who survive beyond early childhood.
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This patient presented with fever and paralysis of his left arm 3 months after receiving his third oral poliovirus vaccine. Past history included chronic thrush presenting in the absence of antibiotic therapy or breastfeeding at 2 months, chronic diarrhea from 4 months, and recurrent otitis media. He was at the 90th percentile for height and weight, similar to his parents. Major histocompatibility complex (MHC) class II deficiency was diagnosed by immunologic tests.
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This patient with an autosomal recessive type of severe combined immunodeficiency died of cytomegalovirus pneumonia when aged 22 months after prior infections that included recurrent otitis, pneumonia, and oral thrush. A CMV inclusion body is pictured in the upper left of the photo.
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Histologically, the thymus in severe combined immunodeficiency usually lacks Hassall corpuscles and is depleted of lymphocytes. In this photo, a Hassall corpuscle is identified to the right of center.
Tables
Genetic Disease Causing SCID |
T-Cell Defect |
B-Cell Defect |
NK-Cell Defect |
Inheritance Pattern |
Reticular dysgenesis |
Yes |
Yes |
Yes |
Autosomal recessive |
ADA deficiency |
Yes |
Yes |
Yes |
Autosomal recessive |
RAG1 and RAG2 deficiency |
Yes |
Yes |
No |
Autosomal recessive |
TCR and BCR recombination gene deficiency |
Yes |
Yes |
No |
Autosomal recessive |
Common γ chain deficiency |
Yes |
No |
Yes |
X-linked |
JAK3 deficiency |
Yes |
No |
No |
Autosomal recessive |
IL-7Ra deficiency |
Yes |
No |
No |
Autosomal recessive |
Omenn syndrome |
Yes |
No |
No |
Autosomal recessive |
ZAP-70 kinase |
CD4+ present |
No |
No |
Autosomal recessive |
CD4+ lymphopenia |
CD8+ present |
No |
No |
Autosomal recessive |
MHC II deficiency |
CD8+ present |
No |
No |
Autosomal recessive |
p56lck deficiency |
CD8+ present |
No |
No |
Autosomal recessive |
ADA = adenosine deaminase; BCR = B-cell receptor; JAK = Janus-associated kinase; MHC = major histocompatibility complex; RAG = recombination-activating gene; SCID = severe combined immunodeficiency; TCR = T-cell receptor, ZAP = ζ chain-associated protein. |
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