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]
Some causes and examples of SCID[4][5]:
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]
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.
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.
Major immunological features of severe combined immune deficiency include the following[9]:
Physical findings include the following[1][4]][2][10][11]:
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
Lymphocyte stimulation assays
Quantitative Serum Immunoglobulins
IgG Sub-Classes
Antibody Activity
IgG antibodies (post-immunization)
IgG antibodies (post-exposure)
Detection of isohemagglutinins (IgM)
Other assays
Phagocytic function
Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)
Neutrophil mobility
Complement System Evaluation[14]
Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting
Hemolytic assays
Microbiological studies
Coagulation tests
Other investigations of immunodeficiency disorders
A bone marrow transplant may be beneficial in the following sub-groups[17]:
Use of gammaglobulin may show benefit in the following sub-groups:
Other treatment options include the following:
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:
Malabsorption syndromes that cause extreme malnutrition may also have similar presentations to SCID.[18]
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]
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]
[1] | Aluri J,Desai M,Gupta M,Dalvi A,Terance A,Rosenzweig SD,Stoddard JL,Niemela JE,Tamankar V,Mhatre S,Bargir U,Kulkarni M,Shah N,Aggarwal A,Lashkari HP,Krishna V,Govindaraj G,Kalra M,Madkaikar M, Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India. Frontiers in immunology. 2019; [PubMed PMID: 30778343] |
[2] | Wekell P,Hertting O,Holmgren D,Fasth A, Fifteen-minute consultation: Recognising primary immune deficiencies in children. Archives of disease in childhood. Education and practice edition. 2019 Feb 7; [PubMed PMID: 30733240] |
[3] | Notarangelo LD,Fischer A,Geha RS,Casanova JL,Chapel H,Conley ME,Cunningham-Rundles C,Etzioni A,Hammartröm L,Nonoyama S,Ochs HD,Puck J,Roifman C,Seger R,Wedgwood J, Primary immunodeficiencies: 2009 update. The Journal of allergy and clinical immunology. 2009 Dec; [PubMed PMID: 20004777] |
[4] | Gennery A, Recent advances in understanding RAG deficiencies. F1000Research. 2019; [PubMed PMID: 30800289] |
[5] | Adenosine deaminase deficiency: a review., Flinn AM,Gennery AR,, Orphanet journal of rare diseases, 2018 Apr 24 [PubMed PMID: 29690908] |
[6] | Modell V,Quinn J,Orange J,Notarangelo LD,Modell F, Primary immunodeficiencies worldwide: an updated overview from the Jeffrey Modell Centers Global Network. Immunologic research. 2016 Jun; [PubMed PMID: 26802037] |
[7] | Kwan A,Abraham RS,Currier R,Brower A,Andruszewski K,Abbott JK,Baker M,Ballow M,Bartoshesky LE,Bonilla FA,Brokopp C,Brooks E,Caggana M,Celestin J,Church JA,Comeau AM,Connelly JA,Cowan MJ,Cunningham-Rundles C,Dasu T,Dave N,De La Morena MT,Duffner U,Fong CT,Forbes L,Freedenberg D,Gelfand EW,Hale JE,Hanson IC,Hay BN,Hu D,Infante A,Johnson D,Kapoor N,Kay DM,Kohn DB,Lee R,Lehman H,Lin Z,Lorey F,Abdel-Mageed A,Manning A,McGhee S,Moore TB,Naides SJ,Notarangelo LD,Orange JS,Pai SY,Porteus M,Rodriguez R,Romberg N,Routes J,Ruehle M,Rubenstein A,Saavedra-Matiz CA,Scott G,Scott PM,Secord E,Seroogy C,Shearer WT,Siegel S,Silvers SK,Stiehm ER,Sugerman RW,Sullivan JL,Tanksley S,Tierce ML 4th,Verbsky J,Vogel B,Walker R,Walkovich K,Walter JE,Wasserman RL,Watson MS,Weinberg GA,Weiner LB,Wood H,Yates AB,Puck JM,Bonagura VR, Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014 Aug 20 [PubMed PMID: 25138334] |
[8] | Al-Herz W,Al-Mousa H, Combined immunodeficiency: the Middle East experience. The Journal of allergy and clinical immunology. 2013 Mar [PubMed PMID: 23321211] |
[9] | Chinn IK,Shearer WT, Severe Combined Immunodeficiency Disorders. Immunology and allergy clinics of North America. 2015 Nov; [PubMed PMID: 26454313] |
[10] | Staines Boone AT,Chinn IK,Alaez-Versón C,Yamazaki-Nakashimada MA,Carrillo-Sánchez K,García-Cruz MLH,Poli MC,González Serrano ME,Medina Torres EA,Muzquiz Zermeño D,Forbes LR,Espinosa-Rosales FJ,Espinosa-Padilla SE,Orange JS,Lugo Reyes SO, Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature. Frontiers in pediatrics. 2018; [PubMed PMID: 30719430] |
[11] | Amatuni GS,Currier RJ,Church JA,Bishop T,Grimbacher E,Nguyen AA,Agarwal-Hashmi R,Aznar CP,Butte MJ,Cowan MJ,Dorsey MJ,Dvorak CC,Kapoor N,Kohn DB,Markert ML,Moore TB,Naides SJ,Sciortino S,Feuchtbaum L,Koupaei RA,Puck JM, Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010-2017. Pediatrics. 2019 Jan 25; [PubMed PMID: 30683812] |
[12] | Murata C,Ramírez AB,Ramírez G,Cruz A,Morales JL,Lugo-Reyes SO, [Discriminant analysis to predict the clinical diagnosis of primary immunodeficiencies: a preliminary report]. Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993). 2015 Apr-Jun; [PubMed PMID: 25958376] |
[13] | Routes J,Abinun M,Al-Herz W,Bustamante J,Condino-Neto A,De La Morena MT,Etzioni A,Gambineri E,Haddad E,Kobrynski L,Le Deist F,Nonoyama S,Oliveira JB,Perez E,Picard C,Rezaei N,Sleasman J,Sullivan KE,Torgerson T, ICON: the early diagnosis of congenital immunodeficiencies. Journal of clinical immunology. 2014 May; [PubMed PMID: 24619621] |
[14] | Kirschfink M,Mollnes TE, Modern complement analysis. Clinical and diagnostic laboratory immunology. 2003 Nov; [PubMed PMID: 14607856] |
[15] | Dosanjh A, Autoimmunity and Immunodeficiency. Pediatrics in review. 2015 Nov; [PubMed PMID: 26527628] |
[16] | De Rose DU,Giliani S,Notarangelo LD,Lougaris V,Lanfranchi A,Moratto D,Martire B,Specchia F,Tommasini A,Plebani A,Badolato R, Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications. Clinical immunology (Orlando, Fla.). 2018 Jun; [PubMed PMID: 29548898] |
[17] | Shamriz O,Chandrakasan S, Update on Advances in Hematopoietic Cell Transplantation for Primary Immunodeficiency Disorders. Immunology and allergy clinics of North America. 2019 Feb; [PubMed PMID: 30466768] |
[18] | Borzutzky A,Crompton B,Bergmann AK,Giliani S,Baxi S,Martin M,Neufeld EJ,Notarangelo LD, Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. Clinical immunology (Orlando, Fla.). 2009 Dec [PubMed PMID: 19740703] |
[19] | Tanaka R,Tachibana K,Suda K,Kondo H,Noguchi M, A severe combined immunodeficiency disease mouse model of human adenocarcinoma with lepidic-predominant growth. Pathology, research and practice. 2018 Dec; [PubMed PMID: 30287185] |