Continuing Education Activity

Severe combined immunodeficiency disease (SCID) is an inherited primary immunodeficiency disorder that presents by six months of age with opportunistic infections caused by bacteria, viruses, fungi, and protozoa. It is one of the most serious primary immunodeficiency disorders with early death due to disturbed or absent T and B cell functions. This activity outlines the evaluation and management of severe combined immunodeficiency disease and highlights the role of the interprofessional team in improving outcomes for those with the disease.

Objectives:

• Describe the pathophysiology of severe combined immunodeficiency disease.

• Outline the history and physical exam of a patient with severe combined immunodeficiency disease.

• Summarize the treatment options for severe combined immunodeficiency disease.

• Identify the importance of improving care coordination among the interprofessional team in counseling the parents of those with severe combined immunodeficiency disease.

Introduction

Patients with combined immunodeficiency disorder (T and B lymphocyte deficiency) present with recurrent infections usually early in life. These patients are susceptible to infection by many organisms. Immunotherapy sometimes is not available to treat these recurrent infections. Severe combined immunodeficiency disease (SCID) is the most severe expression among the combined immunodeficiency disorders. The onset of the clinical manifestations occurs by 6 months of age or before, with bacterial, viral, fungal and protozoal infections. Also, these infections may lead to early death in severe combined immunodeficiency disease, differentiating this condition from other forms or combined immunodeficiency. 

Both T and B cell functions are disturbed or absent entirely in severe combined immunodeficiency disease. Autosomal, sporadic, or the X-linked form may affect the neonate, and without treatment, patients rarely survive beyond one year of age before succumbing to opportunistic infections.[1][2][3]

Etiology

Some causes and examples of SCID[4][5]:

1. T-B-NK- SCID can be seen in reticular dysgenesis caused by a lack of stem cells. A similar phenotype (T-B-NK-) occurs in adenosine deaminase (ADA) deficiency, and defective ADA genes cause it leads to toxic metabolites in T, B, and NK cells.  
2. T-B-NK+ SCID (RAG1/2 defect) can cause SCID due to RAG1/2 enzymes to snip DNA for VDJ rearrangement for TCR and BCR. A similar phenotype is Artemis deficiency characterized by a failure to repair DNA after RAG1/2 snips.   
3. T-B+NK- SCID can be X linked and due to absent IL receptor for a range of cytokines due to lack of common gamma chain. A similar phenotype named Jak 3 kinase deficiency is caused by a lack of Jak 3 kinase to follow signal via IL-R binding.     
4. T-B+NK+ SCID is the phenotype of IL-7 deficiency when there are no IL-7 alpha chains that lead to the failure of T cell differentiation. A similar phenotype is present in CD3 activation failure, characterized by defective signal transduction, e.g., ZAP-70 deficiency.    
5. T+B+NK+ MHC failure is a phenotype that has two conditions: MHC class I deficiency (bare lymphocyte syndrome) and MHC class II deficiency. The first condition is caused by failure to express MHC class I caused by a defect in TAP-2 transcription. The second condition is due to a defect in transcription of MHC class II proteins.

Epidemiology

The Jeffrey Modell Foundation implemented public awareness and physician education about primary immunodeficiencies, including severe combined immunodeficiency disease beginning in 2003. The network has implemented population-based newborn screening for SCID and T cell lymphopenia, covering 96% of the total newborns in the US.[6]

The majority of the patients (89%) presented with the first symptoms within six months of age. The clinical manifestations observed were recurrent pneumonia (66%), followed by failure to thrive (60%) and chronic diarrhea (35%).[1]

One US study reported the incidence of SCID as 1 in 58,000 live births.[7]  Consanguineous relationships have been shown to have a higher incidence of autosomal-recessive SCID.[8]

Pathophysiology

Genetic mutation is the root cause of SCID.  Specifically, the genes which are responsible for the function of T and B cells are affected in SCID.  Profound T-cell abnormalities can prevent B cells from functioning normally because the B cells require signals from T cells to produce appropriate antibodies.  Therefore, in some instances, SCID may be present with only T cell dysfunction.  Natural killer (NK) cells develop separately from T and B cells and can provide a degree of protection in individuals with T and B cell dysfunction.  Assessing for the presence of NK cells helps determine the severity and prognosis of the SCID.

Histopathology

In SCID, microscopic examination of the thymic stroma reveals an absence of lymphoid cells, as well as the absence of Hassall's corpuscles.  In essence, the thymus gland has a fetal appearance.

Additionally, numerable Giardia lamblia can present in the gastrointestinal tract, specifically over the mucosa of the jejunum. The lack of protective immunity results in an inability to fight against these intestinal parasites.[9]

Biopsy of lymph nodes (if detectable) shows severe depletion, without cortico-medullary differentiation or follicle formation. Biopsy of the intestinal tract may demonstrate a complete absence of plasma cells.

History and Physical

Major immunological features of severe combined immune deficiency include the following[9]:

• Present in the first few weeks or months of life 
• Primarily viral or fungal infections although bacterial and protozoal infections do occur  
• Frequent respiratory infections   
• Oral candidiasis 
• Failure to thrive 
• Lymphopenia (often overlooked)     
• Infections by rare microorganisms       
• Opportunistic infections      
• Recurrent infections        
• Frequent use of antimicrobials without noticeable improvement      
• Infection and inflammation of internal organs      
• Blood disorders, such as anemia and low platelet count
• Autoimmunity may occur

Physical findings include the following[1][4]][2][10][11]:  

• Meningitis symptoms    
• Septicemia   
• Arthritis      
• Bacteremia      
• Fever      
• Frequent cough     
• Malaise    
• Intestinal malabsorption   
• Bronchiectasis   
• Graft versus host reaction    
• Recurrent tonsillitis    
• Acute suffocation     
• Extensive cutaneous viral and bacterial (Staphylococcal) infections   
• Multiple gross defects    
• Absence of tonsil   
• Sore throat    
• Purulent conjunctivitis   
• Granuloma   
• Skin abnormalities, e.g., pyodermatitis    
• Multiple cancers, e.g., brain tumor   
• Eczema    
• Failure to thrive    
• Chronic diarrhea   
• Tuberculosis   
• Short Stature    
• Lymphoproliferative disorders  
• The absence of lymph nodes  
• Bleeding   
• Thymic aplasia or hypoplasia  
• Recurrent abscess  
• Tetany  
• Cachexia 
• Candidiasis (oral and elsewhere)
• Lupus-like syndrome
• Angioedema
• Malnutrition
• Cardiac abnormalities, e.g., cardiac murmur and conotruncal malformation  
• Hypothermia   
• Asthenia
• Anorexia
• Loss of weight
• Headache  
• Convulsions 
• Hypoparathyroidism 
• Aphthous stomatitis   
• Urinary sepsis  
• Fetal demise  
• Hydrops fetalis   
• Denture abnormalities   
• Pruritus   
• Vasculitis   
• Hearing impairment and deafness  
• Erythroderma    
• Myopathy   
• Intrauterine growth retardation 
• Dwarfism 
• Lymphocytic interstitial pneumonitis  
• Albinism   
• Microcephaly  
• Glomerulonephritis   
• Hemolytic-uremic syndrome  
• Macroglossia   
• Cafe-au-lait spots   
• Exocrine pancreatic insufficiency   
• Serositis   
• Osteoporosis and fractures    
• Scoliosis  
• Poor wound healing
• Mental retardation  
• Nail dystrophy  
• Late-onset primary encephalopathy   
• Thyroiditis
• Urogenital abnormalities   
• Venous telangiectasias of trunk and limbs  
• Chondrodysplasia
• Amyloidosis  
• Delayed cord separation  
• Periodontitis

Evaluation

The immunological investigation of a patient with SCID includes the assessment of immunoglobulins, including isohemagglutinins and antibody activity, B and T-lymphocyte counts, lymphocyte stimulation assays, NK cell function, quantification of components of the complement system and phagocytic activity.[9][12][13]

Blood lymphocyte subpopulations

• Total lymphocyte count
• T lymphocytes (CD3, CD4, and CD8)
• B lymphocytes (CD19 and CD20)
• CD4/CD8 ratio
• NK cell count

Lymphocyte stimulation assays

• Phorbol ester and ionophore
• Phytohemagglutinin
• Antiserum to CD3

Quantitative Serum Immunoglobulins

• IgG
• IgM
• IgA
• IgE

IgG Sub-Classes

• IgG1
• IgG2
• IgG3
• IgG4

Antibody Activity 

IgG antibodies (post-immunization)

• Tetanus toxoid
• Diphtheria toxoid
• Pneumococcal polysaccharide
• Polio

IgG antibodies (post-exposure)

• Rubella
• Measles
• Varicella zoster

Detection of isohemagglutinins (IgM)

• Anti-type A blood
• Anti-type B blood

Other assays

• Test for heterophile antibody
• Anti-streptolysin O titer
• Immunodiagnosis of infectious diseases (HIV, hepatitis B, and C, HTLV and dengue)
• Serum protein electrophoresis

Phagocytic function  

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

• Unstimulated
• Stimulated

Neutrophil mobility

• In medium alone
• In the presence of chemoattractant

Complement System Evaluation[14]

Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting

• C3 serum levels
• C4 serum levels
• Factor B serum levels 
• C1 inhibitor serum levels

Hemolytic assays

• CH50
• CH100
• AH50

Microbiological studies

• Blood (bacterial culture, HIV by PCR, HTLV testing)
• Urine (testing for cytomegalovirus, sepsis, and proteinuria)
• Nasopharyngeal swab (testing for Rhinovirus)
• Stool (testing for viral, bacterial or parasitic infection)
• Sputum (bacterial culture and pneumocystis PCR)
• Cerebrospinal fluid (culture, chemistry, and histopathology)

Autoimmune Studies[15][16]

• Anti-nuclear antibodies (ANA)
• Detection of specific auto-immune antibodies for systemic disorders (anti-ds DNA, rheumatoid factor, anti-histones, anti-Smith, anti-(SS-A) and anti-(SS-B)
• Detection of anti-RBC, antiplatelet, and anti-neutrophil
• Testing for organ-specific auto-immune antibodies

Coagulation tests 

• Factor V assay
• Fibrinogen level
• Prothrombin time
• Thrombin time
• Bleeding time

Other investigations of immunodeficiency disorders 

• Bone marrow biopsy
• Levels of cytokines
• Chest x-ray
• Diagnostic ultrasound
• CT scan
• Histopathological studies
• Liver function test
• Blood chemistry
• Tumoral markers
• Complete blood cell count    
• Tuberculin test
• Fluorescent in situ hybridization (FISH)
• DNA testing (for most congenital disorders)

Treatment / Management

A bone marrow transplant may be beneficial in the following sub-groups[17]:

• RAG1/2 SCID
• ADA-SCID  
• Artemis SCID
• Wiskott-Aldrich syndrome

Use of gammaglobulin may show benefit in the following sub-groups:

• ADA-SCID
• RAG1/2 SCID
• Jak 3 kinase deficiency
• Artemis SCID
• Bare lymphocyte syndrome
• MHC class II deficiency
• X-linked SCID
• CD3 SCID

Other treatment options include the following:

• Transfer factor
• Antibiotics
• Antifungals
• Antiparasitic drugs
• Anti-virals
• Irradiated blood transfusions
• Vitamins
• Gene therapy (experimental) 
• Anti-inflammatory drugs
• Use of cytokines (e.g., IL-2 and gamma interferon) 

Differential Diagnosis

At the top of the differential for SCID are other forms of combined immunodeficiency.  These patients have several characteristics that overlap in their clinical presentation.  Patients with agenesis of the thymus or T cell deficiency (such as in DiGeorge syndrome or CHARGE syndrome) may present with opportunistic infections similar to SCID.

 Additional immunodeficiencies that merit consideration in the differential include the following:

• Calcium channel deficiencies
• Wiskott-Aldrich syndrome
• NF-kappa-B essential modifier (NEMO) deficiency
• Zeta-chain-associated protein 70 deficiency
• HIV/AIDS

 Malabsorption syndromes that cause extreme malnutrition may also have similar presentations to SCID.[18]

Prognosis

SCID has the poorest prognosis among combined immunodeficiencies unless bone marrow transplantation or gene therapy (experimental) is successfully performed. In general, for improving the quality of life of patients with primary immunodeficiencies, long-term management with antimicrobials is needed. Most primary immunodeficiencies require personalized management, e.g., genetic testing for various enzyme impairments.[9] 

Complications

• Life-threatening overwhelming infections caused by bacteria, viruses, fungi, and parasites[1][11]
• Multiorgan failure
• Endocrinopathy
• Opportunistic malignancy[19]
• Septic shock
• Congenital disabilities
• Respiratory insufficiency
• Anaphylactic shock
• Bleeding disorders 
• Cardiac failure  
• Acute and chronic renal failure  
• Premature death
• Metabolic disturbances (e.g., acidosis and alkalosis)
• Neurological complications including seizures and coma

Pearls and Other Issues

• SCID is the most severe expression of all combined immunodeficiencies
• NK cells may or may not be present, and establishing the presence or absence of these cells can be helpful in prognostication
• Treatment is limited, and the disease is invariably fatal within the first year of life

Enhancing Healthcare Team Outcomes

SCID should be managed by an interprofessional team that likely includes a pediatrician, geneticist, clinical immunologist, pediatrician, nurse practitioner, and an infectious disease specialist. The treatment team may also provide counseling to the parents, given the poor prognosis associated with the disease. Because of the high morbidity of the disorder, a palliative team consisting of a nurse, a social worker, and a pain specialist should also have involvement in the care. Pediatric hematology nurses assist in the care of these patients and report changes to the team. Pharmacists review medications, check for interactions and educate patient's families about side effects and compliance. [Level 5]