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Severe combined immunodeficiency disorder (SCID)-Full Text
Outline:
• Introduction
• Epidemiology
• Etiology
• Pathophysiology
• Histopathology
• Clinical presentation
• Evaluation and diagnosis
• Differential diagnosis of SCID
• Prognosis of SCID
• Management
• Complications
• References
Introduction:
Combined immunodeficiency disorder is due to T and B lymphocyte deficiency. The disorder is characterized by recurrent infections occurring early in life due to multiple organisms both ordinary and opportunistic pathogens. The most severe form of this disorder is known as Severe combined immunodeficiency disease (SCID) which is a group of potentially life threatening disorders. The disorder may be autosomal, sporadic, or the X-linked. More than 20 genetic defects were found in SCID. About 1 in 40,000 to 75,000 per live birth are diagnosed as SCID. Manifestations begin at the age of 6 months or earlier with multiple recurrent infections that may lead to early death in the severe form of the disease.
SCID is classified into T-B- SCID or T-B + SCID phenotypes based on B cell status whether defected or not. Further sub-classification is based on the natural killer cells status. Immunotherapy may not always be available to treat the manifestations of SCID. In 1968, the first successful bone marrow transplant from healthy HLA-matched sibling was performed to a male infant. Over years, research in allogeneic hematopoietic cell transplantation (HCT) was performed with progress in reaching effective treatment and restoration of T cell numbers and function form both matched siblings and alternative donors. Different methods of treatment have been used including Haplo-identical parental bone marrow or mobilized peripheral blood hematopoietic stem cells (PBSC) depleted of T cells in addition to closely matched bone marrow or cord blood from donors. For adenosine deaminase (ADA) deficient SCID, enzyme replacement therapy (ERT) was developed. Moreover, an autologous hematopoietic cell correction by gene therapy (GT) was developed for ADA deficient and X-linked SCID.
Early treatment can improve the outcome by avoiding infectious complication which can be achieved by newborn screening program. However, it is a rare disease without family history in apparently healthy newborns.
Epidemiology:
In 2003, a public awareness and physician education about primary immunodeficiency were implemented by the Jeffrey Modell Foundation. A population-based newborn screening for SCID and T cell deficiency over 96% of the US newborns.
About 89% of patients were 6 months of age and presented with the first symptoms. Recurrent pneumonia was reported in 66% of the cases, failure to thrive in 60%, and chronic diarrhoea in 35% of patients.
A study in the US showed that the incidence of SCID is about in 58,000 live births. Consanguinity increases the incidence of autosomal-recessive SCID.
Etiology:
-Reticular dysgenesis due to stem cell deficiency may lead to T-B-NK-SCID.
-Adenosine deaminase (ADA) deficiency may cause toxic metabolites in T,B, and NK cells leading to T-B-NK-SCID phenotype.
- RAG1/2 enzymes to snip DNA for VDJ rearrangement for TCR and BCR in addition to Artemis deficiency that causes failure of DNA repair after RAG1/2 snips. Both causes may lead to T-B-NK+ SCID (RAG1/2 defect).
-SCID may be X-linked and due to common gamma chain deficiency leading to absent Interleukin (IL) receptor for cytokines therefore leading to T-B+NK- SCID.
-Jak 3 kinase deficiency may also lead to T-B+NK- SCID.
-Lack of IL-7 alpha chains leading to IL-7 deficiency and therefore leading to failure of T cell differentiation Which may cause T-B+NK+ SCID.
-Failure of CD3 activation and defective signal transduction such as ZAP-70 deficiency may also lead to T-B+NK+ SCID.
-MHC class I deficiency which is known as “bare lymphocyte syndrome” is caused by defect in TAP-2 transcription leading to failure of MHC class I expression may cause T+B+NK+ SCID.
- MHC class II deficiency which is caused by defected MHC class II proteins transcription may also lead to T+B+NK+ SCID.
-Leaky-SCID is due to hypomorphic mutations in classical genes of SCID which is less severe phenotype presents with infections in addition to autoimmunity.
Pathophysiology:
Mutations in the genes of T and B cell functions are the main cause of SCID. B cell function depends on T cells as it requires signals from T cells for antibodies production. Therefore, profound T cell abnormalities can lead to B cell abnormalities and functional deficiency. NK cell can be protective in cases of T and B cell deficiency as its development is not related to T and B cells. Detection of the presence of these immunity cells especially NK cells can be used for assessment of the severity and prognosis of SCID.
Histopathology:
Histopathologic studies of SCID through mictoscopic examination show the following:
-Absence of lymphoid cells in the stroma of thymus gland.
-Absence of Hassall's corpuscles.
-Fetal appearance of thymus gland.
-The presence of multiple Giardia lamblia in the gastrointestinal tract mainly in the mucosa of the jejunum due to defective immunity against multiple intestinal parasites.
-Biopsy of intestinal tract may show absence of plasma cells.
-Lymph node biopsy reveals severe depletion, absence of follicle formation, absence of cortico-medullary differentiation.
Clinical presentation:
-Symptoms of SCID present in the first few weeks or months of life mainly 6 months of age or even before with multiple recurrent infections whether ordinary with bacteria or opportunistic infection with viral, fungal or protozoal organisms.
-Infection with Cytomegalovirus (CMV) may affect liver, intestine, lung, heart, retina, and central nervous system.
-Immune dysregulation whether autologous (Omenn syndrome) or allogeneic (maternal GvHD) T cells
-Recurrent respiratory infections caused by multiple viruses such as Respiratory Syncytial Virus, Adenovirus, Myxovirus) and Frequent cough
-Severe pneumonias requiring mechanical ventilation caused by Pneumocystis jirovecii (PJP)
-Bronchiectasis
-Recurrent tonsillitis and sore throat, Aphthous stomatitis
-Oral candidiasis
-Arthritis
-Extensive cutaneous infections, Recurrent abscess
-Infection of internal organs
-Using multiple antimicrobials without improvement
-Lymphopenia, Anemia, Thrombocytopenia with bleeding
-Failure to thrive and short stature, Malnutrition, loss of weight
-Autoimmunity and Graft versus host reaction
-Bacteremia, Septicemia
-Fever or Hypothermia, Malaise, Anorexia, Cachexia
-Symptoms of meningitis, convulsions, headache, Late-onset primary encephalopathy, Microcephaly, Mental retardation
-Purulent conjunctivitis
-Skin manifestations including pyodermatitis, Eczema, Pruritus, Erythroderma
-Intestinal malabsorption, Chronic diarrhea due to intestinal infections with Rota-, Noro or Adenovirus
-Tuberculosis, Granuloma
-Lymphoproliferative disorders, Lymphocytic interstitial pneumonitis
-Hypoparathyroidism, Dwarfism, Thymic aplasia or hypoplasia, Thyroiditis
-Exocrine pancreatic insufficiency
-Mutiple maignencies
-Cardiac abnormalities such as cardiac murmur and conotruncal malformation
-Intrauterine growth retardation, Hydrops fetalis, Fetal demise, Delayed cord separation,
-Glomerulonephritis, hemolytic-uremic syndrome, Urinary sepsis, Urogenital abnormalities
-Amyloidosis
-Angioedema, Cafe-au-lait spots, Albinism, Vasculitis
-Poor wound healing, Nail dystrophy
-Hearing impairment, deafness
-Osteoporosis and fractures, Scoliosis, Chondrodysplasia
-Serositis, Periodontitis
-Denture abnormalities
-Myopathy, Tetany, Lupus-like syndrome
-Macroglossia
-Venous telangiectasias of trunk and limbs
-Atypical infection or following chronic swelling or ulceration at the injection site of live attenuated vaccines such as Bacille Calmette-Guérin (BCG) or Rotavirus vaccines, require further investigations to exclude T-lymphocyte deficiency.
According to the genes affected, the presentation varies as the following:
-ADA deficiency: patients present with bone abnormalities (cupping of osteochondral junctions), alveolar proteinosis
-DNA repair defects: patients present with delayed neurological development and microcephalia
-Hypomorphic mutations of SCID: patients present with Omenn syndrome (lymphadenopathy, hepato-/splenomegaly, eosinophilia, generalized exanthema, intractable diarrhea, and alopecia)
Evaluation and diagnosis:
Immunological studies:
-Assessment of immunoglobulins: Quantitative Serum Immunoglobulins (IgG including IgG1, IgG2, IgG3, and IgG4, IgM, IgA, IgE)
-Assessment of antibody activity
-Assessment of post-immunization IgG antibodies (Diphtheria and Tetanus toxoid, Polio, and Pneumococcal polysaccharide)
-Assessment of post-exposure IgG antibodies ( Measles, Rubella, Varicella zoster)
-Assessment of isohemagglutinins (IgM): Anti-type A blood, Anti-type B blood
-Heterophile antibody
-Immunodiagnosis of infectious diseases (hepatitis B, hepatitis C, HIV, HTLV and dengue)
-Serum protein electrophoresis
-Anti-streptolysin O titer
-Total lymphocyte count
-B lymphocytes (CD19 and CD20)
and T-lymphocyte counts (CD3, CD4, and CD8)
-CD4/CD8 ratio
-NK cell count and function
-Lymphocyte stimulation assays (Phorbol ester and ionophore, Phytohemagglutinin, Antiserum to CD3)
-Assessment of Phagocytic function and activity "Nitroblue tetrazolium (NBT) test"
-Assessment of the complement system
-Immunoprecipitation tests, ELISA, or Western blotting to detect C3 and C4 serum levels, Factor B serum and C1 inhibitor serum levels
-Haemolytic assays (CH100, CH50, AH50)
Microbiological studies:
>Bacterial culture, PCR
>Cerebrospinal fluid culture and analysis
>Nasopharyngeal swab
>Sputum culture and PCR
>Urine testing for sepsis, proteinuria
>Stool culture
Autoimmune Studies:
-Anti-nuclear antibodies (ANA), anti-ds DNA, rheumatoid factor, anti-histones, anti-neutrophil, anti-RBC, antiplatelet
Coagulation tests:
-Prothrombin time, Thrombin time, Bleeding time
-Fibrinogen level
-Factor V assay
Other investigations:
-CT scan, Chest x-ray, Diagnostic ultrasound
-Bone marrow biopsy
-DNA testing
-Blood chemistry, Levels of cytokines, Complete blood cell count
-Histopathological studies
-Liver function test
-Tuberculin test
-Fluorescent in situ hybridization (FISH)
-Tumour markers
Genetic diagnosis:
Genetic testing of SCID is required for antenatal and genetic counselling. Some types of SCID especially radiosensitive types show higher toxicity to alkylator-based chemotherapeutic agents used in the treatment (pretransplant program) so genetic testing is necessary for those cases.
New-born screening:
1-Assessment of T cell receptor excision circles (TRECs):
The process of TRECs production performed briefly through the following steps:
-Each T cell has its own receptor (TCR) to recognize foreign antigens bound to its MHC molecule.
-In thymocytes, rearrangement of DNA gene and linear re-assembly to produce large number of unique TCRs with combination of TCR elements with each cell. Specific enzymes produce double strand breaks at specific sequences.
-Unique rearranged T cell receptors are produced after cutting and ligation of the DNA.
-Maturation of T cell precursors that express TCRs leading to the release of diverse repertoire of naïve T cells into peripheral blood.
-Some of the excised DNA fragments of the TCR are ligated at their ends to produce circular DNA by-products called T cell receptor excision circles (TRECs).
Using TRECs as a screening method:
An effective and immediate method used in the United States to detect SCID new-borns is through assessment of T cell receptor excision circles (TRECs) in the residual dried blood spots (DBS). Amplification of DNA isolated from the dried blood spots is performed through PCR, and then used to detect TRECs that act as a marker for naïve T cells. During T cell receptor recombination process, TRECs are the by-products from the process. To provide efficient interventions for infants with T cell insufficiency, determination of appropriate cut-off levels for TRECs is required. If the screening results are positive, laboratory investigations are required to determine the type of SCID. New-born screening (NBS) improved the prognosis of SCID over the last 10 years. Screening allows early detection and avoiding various complications as well as early therapy through HSCT or gene therapy. It also provides information about the incidence and the spectrum of the disorder and reflects certain aspects of the population. However, some types of SCID such as ZAP70 defect, MHC class II deficiency, and Late-onset ADA deficiency have been reported to have normal TREC levels.
2-Assessment of kappa-receptor excision circles (KREC):
Detection of delayed-onset ADA SCID and B cell lymphopenia can be performed through assessment of kappa-receptor excision circles (KREC).
Other methods for screening that were suggested before:
3-A simple complete blood count (CBC):
Previously, it was suggested that a simple CBC and differential can be used to detect lymphopenia and many cases of SCID. However, leaky SCID cases with oligo clonal T cell expansion (Omenn syndrome) and SCID cases with maternal T cell engraftment can not be detected using this simple method.
4-Flow cytometry with liquid blood samples:
Another method for screening of SCID that was suggested if flow cytometry with liquid blood samples but it is expensive to obtain liquid blood sample for every infant instead of using the dried samples (DBS).
5-Protein assays for T cell specific markers:
It was suggested that protein assay for specific T cell markers such as CD3 chains can be used as screening method for SCID. Low amount of protein that can be obtained from DBS samples limited the efficiency of this method.
6-Detection of DNA sequence:
New mutations in SCID frequently occur, therefore gene sequencing is not suitable as a primary screening test for SCID.
Differential diagnosis of SCID:
-Other forms of combined immunodeficiency including agenesis of the thymus or T cell deficiency (e.g., DiGeorge syndrome or CHARGE syndrome)
-Wiskott-Aldrich syndrome
-Malabsorption syndromes
-HIV/AIDS
-Zeta-chain-associated protein 70 deficiency
-Calcium channel deficiencies
-NF-kappa-B essential modifier (NEMO) deficiency
Prognosis of SCID:
The outcomes of SCID are extremely poor. Performing a successful transplantation or gene therapy may improve the outcomes. Long-term antimicrobial agents are required for the management which is mainly personalized management based on genetic studies.
Management:
Management of SCID includes bone marrow transplant, gammaglobulins, antimicrobial treatment, gene therapy, and other treatment options.
1-Bone marrow transplant:
Bone marrow transplant may improve the outcomes of some types of SCID including ADA-SCID, Wiskott-Aldrich syndrome, RAG1/2 SCID, and Artemis SCID.
2-Gammaglobulins:
Gammmaglobulin may be used in various sub-types of SCID including Artemis SCID, ADA-SCID, MHC class II deficiency, RAG1/2 SCID, Bare lymphocyte syndrome, CD3 SCID, Jak 3 kinase deficiency, and X-linked SCID.
3-Supportive care:
Once SCID is suspected, isolation of patient to avoid infections and initiation of Trimethoprim/sulfamethoxazole as prophylaxis for PJP, as well as Ig replacement therapy. Long-term Ig replacement therapy may be required in about 25% in absence of donor B-lymphocyte engraftment.
Many centers recommend stopping breastfeeding as the main source of Cytomegalovirus (CMV) infection is breastfeeding unless proved negative CMV screening test.
4-Antimicrobial treatment:
Antimicrobial drugs include antibiotics, antifungal, antiviral, and antiparasitic.
Other treatment options including:
Transfer factor, vitamins, anti-inflammatory drugs, irradiated blood transfusions, and cytokines (e.g., IL-2 and gamma interferon).
5-Gene therapy:
Gene therapy emerged long time ago. Since the discovery of the biology of retroviruses, researchers used them as vectors to integrate a transgene into targeted cells Transduction of hematopoietic stem cells (HSCs) was first performed using murine retroviruses. The first indication for allogeneic HSC transplantation and the first disorder corrected by gene therapy was SCID. Treatment with allogeneic HSCT leads to correction of the T cell deficiency on the long-term and is considered the definitive treatment of SCID. Gene therapy was first used to correct adenosine deaminase (ADA) deficiency sub-group of SCID but failed due to poor technology. Understanding the genes defects in SCID and the pathophysiology of the disease helped to perform successful gene therapy. Due to graft-versus-host disease (GvHD), transplant from non-genoidentical donors in the early 1990s led to high mortality and morbidity rates.
Survival rates after HCT are between 85 and 90% recently. Matched sibling donor (MSD) is the main factor improving the survival after HSCT. The survival rate after HSCT with a MSD is usually >90%. Other factors affecting the survival after HSCT include genotype, age, race/ethnicity, and infection at HSCT. Survival in RAG mutations was better compared to DCLRE1C mutations (The Artemis gene) after HSCT.
Conditioning regimen is required to provide normal B-lymphocyte function post-HSCT in patients with deficient RAG1, RAG2, and DCLRE1C due to residual Natural Killer (NK) cell function and to avoid the inhibition of donor progenitor engraftment which is caused by thymic and bone marrow components and thus require emptying. It is also used non-functional B-lymphocytes such as JAK3 and IL2RG. The conditioning regimen in HSCT may be associated with chemotherapy-induced toxicity and increase the incidence of GvHD. Due to the long-term toxicity of conditioning regimen associated with DNA repair defects, anti-stem cell monoclonal antibody may be required. The conditioning regimen with myeloablative agents enables stem cell engraftment and allows better reconstitution of T and B lymphocytes. Better prognosis was found with T and B lymphocyte reconstitution.
A two-step approach can be used in case of active infection at transplantation: the first HCT is performed without conditioning regimen and after recovery from infection another HCT with conditioning regimen is performed. If conditioning regimen used in the first step in the presence of infection, it will be associated with poor prognosis.
In ADA-deficient SCID, enzyme replacement by PEG-ADA may be used as a short term therapy until definitive treatment by HSCT or gene therapy through providing sufficient T-lymphocyte function to prolong the survival.
Complications of SCID:
Complications of SCID include life-threatening infections caused by multiple organisms, septic shock, anaphylactic shock, opportunistic malignancy, multi-organ failure, acute and chronic renal failure, cardiac failure, respiratory insufficiency, metabolic disturbances (e.g., acidosis, alkalosis), endocrinopathy, bleeding disorders, neurological complications ( e.g., seizures, coma), congenital disabilities, and premature death.
References:
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