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Severe Combined Immunodeficiency

SCID

Severe combined immunodeficiency encompasses various disorders, characterized by the impairment of the immune system. Both humoral and cell-mediated immunity are affected and the genetic background of each separate disorder varies.


Presentation

Children born with SCID have a significant imbalance in their immune cell count: Absent T cells and further impairment in the functionality of B and NK cells, although the degree of severity varies depending on the particular type. Despite the type and phenotype, every individual affected by SCID possesses a dysfunctional immune system and is susceptible to various opportunistic infections.

During the first months after birth, maternal antibodies that have been passed down to the child manage to compensate for the innate ability of the person to produce their own antibodies. Maternal antibodies, however, have a brief life cycle. Once they cease to exist, low levels of T and/or B and NK cells render the patient unable to protect themselves against pathogens and produce functional immunoglobulins. Other vital components, which would normally contribute to immunity are dysfunctional or lacking: the thymus gland is hypoplastic, granulocytes are defective, tonsils and other lymphoid structures do not exist or are severely underdeveloped and lymphocytes are scarce in lymph nodes. 

As a result, infections occur and persist. Symptoms compatible with pneumonia, otitis media and sepsis become evident, alongside rashes, diarrhea, hindered growth and fragility [5]. Individuals exhibit the following infections as a result of the organisms inability to protect itself against all kinds of pathogens:

Additionally, affected individuals may develop generalized vaccinia due to a smallpox vaccine. Pneumonia due to P. jiroveci is frequently diagnosed in children suffering from SCID and poses a real challenge in terms of treatment [6].

Recurrent Infection
  • A 15-month-old boy presented with failure to thrive, neutropenia and recurrent infections. He was diagnosed with T-B-NK SCID. He subsequently developed right partial seizures with ipsilateral hemiparesis and became comatose.[ncbi.nlm.nih.gov]
  • In most cases, affected individuals experience recurrent infections, but they may also suffer from autoimmune diseases and malignancies.[oxfordmedicine.com]
Candidiasis
  • Candidiasis is a frequent finding and colonisation of skin, oropharynx, and gut is common in SCID. Invasive candidiasis is less common but might be a presenting feature and tissue biopsy specimens should always be processed for fungi.[doi.org]
  • Chronic diarrhea, ear infections, and profuse oral candidiasis commonly occur. SCID infants can have chronic skin infections caused by Candida, as well as a rash mistakenly diagnosed as eczema.[clinicaladvisor.com]
  • Candidiasis is first observed as "diaper rash" but then progresses to an extensive infection involving the skin, oral and esophogeal mucosa and the vagina.[themedicalbiochemistrypage.org]
  • Ear infections, recurrent Pneumocystis jirovecii (previously carinii) pneumonia, and profuse oral candidiasis commonly occur.[en.wikipedia.org]
  • Infants with SCID usually present with infections that are secondary to the lack of T-cell function (eg, Pneumocystis jiroveci (carinii) pneumonia [PCP], systemic candidiasis, generalized herpetic infections, severe failure to thrive secondary to gut[emedicine.com]
Sepsis
  • In both cases, sepsis and septic shock developed, with progression to multiorgan failure. Unfortunately, the 2 patients died, despite prompt, appropriate sepsis treatment and immunomodulatory therapy.[ncbi.nlm.nih.gov]
  • […] numerous, serious, and/or life-threatening infections that are not easily treated and do not respond to medications (as they would in children without SCID), including the following: pneumonia - infection of the lungs. meningitis - infection of the brain. sepsis[chw.org]
Lymphadenopathy
  • This report emphasizes the importance of lymphadenopathy as a sentinel sign of immunological disorders.[ncbi.nlm.nih.gov]
  • On examination, he had stable vital parameters with mild pallor but no icterus or lymphadenopathy. Anthropometric parameters were suggestive of moderate wasting.[omicsonline.org]
  • Clinical examination of the lymphoid system is important, however, because Omenn's syndrome (a form of SCID characterised by erythroderma, alopecia, and hepatosplenomegaly 13 ) and SCID with maternofetal lymphoid engraftment (MFE) are characterised by lymphadenopathy[doi.org]
Fever
  • Both patients presented similar signs and symptoms (fever, skin rash, diarrhea, pancytopenia, and icterus). Skin biopsies demonstrated Grade II GVHD involvement.[ncbi.nlm.nih.gov]
  • Discussion Our patient had persistent fever, weight loss, anemia, hepatosplenomegaly, skin rash and multiple osteolytic lesions.[omicsonline.org]
  • Symptoms and Types Symptoms will vary according to the type of infection the foal succumbs to, including: Pneumonia: nasal discharge, coughing, trouble breathing ( dyspnea ) Diarrhea Fever Weight loss Stunted growth Persistently low lymphocytes on blood[petmd.com]
Cough
  • Symptoms and Types Symptoms will vary according to the type of infection the foal succumbs to, including: Pneumonia: nasal discharge, coughing, trouble breathing ( dyspnea ) Diarrhea Fever Weight loss Stunted growth Persistently low lymphocytes on blood[petmd.com]
  • Some children develop a sharp, persistent cough with Pneumocystis pneumonia, blood disorders, or chronic hepatitis. Meningitis and blood poisoning pose a constant threat.[medicinenet.com]
  • There was no history of chronic cough or infertility in the mother before conception and there was no antenatal history of fever with/ without rash or genital ulcers.[omicsonline.org]
  • Several symptoms may indicate a possibility of SCID in a child, such as a family history of infant death, chronic coughs, hyperinflated lungs, and persistent infections.[en.wikipedia.org]
  • […] the number and severity of infection 7 appear seriously flawed and have failed to diagnose SCID patients. 8 Table 1 Classification of severe combined immunodeficiency Infants with SCID often suffer an ongoing bronchiolitic type illness with a chronic cough[doi.org]
Chronic Cough
  • Several symptoms may indicate a possibility of SCID in a child, such as a family history of infant death, chronic coughs, hyperinflated lungs, and persistent infections.[en.wikipedia.org]
  • There was no history of chronic cough or infertility in the mother before conception and there was no antenatal history of fever with/ without rash or genital ulcers.[omicsonline.org]
  • cough and wheeze, which gradually worsens.[doi.org]
Diarrhea
  • Both patients presented similar signs and symptoms (fever, skin rash, diarrhea, pancytopenia, and icterus). Skin biopsies demonstrated Grade II GVHD involvement.[ncbi.nlm.nih.gov]
  • Symptoms compatible with pneumonia, otitis media and sepsis become evident, alongside rashes, diarrhea, hindered growth and fragility.[symptoma.com]
Failure to Thrive
  • Patients usually present in first 6 months of life with respiratory/gastrointestinal tract infections and failure to thrive. Among the various types of severe combined immunodeficiency, enzyme deficiencies are relatively less common.[ncbi.nlm.nih.gov]
  • Infants present with recurrent infections, failure to thrive, and chronic diarrhoea. Key findings on examination may include the absence of lymphoid tissue, poor weight gain, or diffuse erythematous rash.[bestpractice.bmj.com]
Recurrent Diarrhea
  • Herein, we present a five-month-old boy with SCID who was referred to our center with recurrent diarrhea, respiratory infection and lymphadenopathy.[ncbi.nlm.nih.gov]
Abdominal Mass
  • In this report, we describe a 4-month-old male infant who was admitted to our hospital with progressive breathlessness and abdominal mass.[ncbi.nlm.nih.gov]
Oral Ulcers
  • We report the case of a 4-month-old white girl with a 2-month history of an oral ulcer, intermittent fever, recurrent otitis, decreased appetite, weight loss, and a new respiratory illness with hypoxemia.[ncbi.nlm.nih.gov]
Cyanosis
  • We describe a 34-week female twin who had developed feeding intolerance, perioral cyanosis, abdominal distension and neutropenia at 1 month of age.[ncbi.nlm.nih.gov]
  • Respiratory signs may include tachypnoea, nasal flaring, subcostal and intercostal recession, with widespread crepitations and rales, and cyanosis. There may be evidence of oral or perineal candidiasis and other superficial infections.[doi.org]
Hepatosplenomegaly
  • His brother, patient 2, was born preterm with a severe neonatal erythroderma, hepatosplenomegaly and lymphadenopathy. Patient 3, cousin of the two siblings, was also born preterm and fulfilled all criteria for classical OS.[ncbi.nlm.nih.gov]
  • Fariba Shirvani, Zahra Chavoshzadeh, Reza Arjmand and Abdollah Karimi, Four-Month-Old Boy With Fever, Hepatosplenomegaly and Diffuse Pulmonary Infiltrations, Archives of Clinical Infectious Diseases, 7, 2, (2012).[doi.org]
  • Discussion Our patient had persistent fever, weight loss, anemia, hepatosplenomegaly, skin rash and multiple osteolytic lesions.[omicsonline.org]
  • Patients with Omenn syndrome develop erythroderma, hepatosplenomegaly, and lymphadenopathy in addition to immunodeficiency, and may have T-cells that function poorly.[invitae.com]
Hepatomegaly
  • Systemic examination was remarkable with spleno-hepatomegaly but other systems were essentially normal. Initial investigations were suggestive of microcytic, hypochromic anemia, while rest was noncontributory ( Table 1 ).[omicsonline.org]
  • There may be hepatomegaly, with or without splenomegaly, particularly when disseminated Bacille Calmette–Guerin (BCG) infection is present.[doi.org]
Liver Dysfunction
  • The patient was referred to our hospital with liver dysfunction, respiratory distress, anal abscess, poor feeding and wasting; the patient appeared to suffer from severe and persistent infections.[ncbi.nlm.nih.gov]
Ecthyma
  • Pseudomonas aeruginosa causes ecthyma gangrenosum. Other bacteria, such as S. pneumoniae, P. jiroveci, H. influenzae, Listeria spp. and Legionella spp can infect a vulnerable individual and lead to pneumonia or meningitis.[symptoma.com]
Opisthotonus
  • Furthermore, this is the first report that describes the patient with X-SCID accompanying opisthotonus.[ncbi.nlm.nih.gov]
Neurologic Manifestation
  • Ömer Faruk Aydin and Banu Anlar, Neurological Manifestations of Primary Immunodeficiency Diseases, Clinical Pediatrics, 10.1177/0009922817737083, (000992281773708), (2017). Catharina P. B. Van der Ploeg, Maartje Blom, Robbert G. M.[doi.org]

Workup

A physician will suspect SCID if an infant frequently presents with infections of various kinds. Hospitals in the United States frequently apply the T-cell receptor excision circle method (TREC) in order to screen newborns for the immunodeficiency [7].

The diagnosis of SCID is established after a meticulous measuring of white blood cells (WBC) via a complete blood count (CBC). Immunoglobulin levels should also be quantified. An additional method involves  testing for the proliferating reaction of white blood cells to mitogens, which can draw significant conclusions concerning the cell's capacity of responding to physiologic stimuli. In order to achieve a definitive diagnosis of SCID, a patient needs to exhibit a complete lack of T cells or a diminished number thereof, low lymphocyte levels and no cellular response to potent stimulators, such as mitogens.

Flow cytometry can also be used to quantify T, B and NK cell counts [8]. Fibroblasts and adenosine deaminase levels are also determined and a test which inactivates the X chromosome will help to establish a potential X-linked type of SCID. Parents can also be tested for the most common genetic mutations and genetic counseling is mandatory only for future offspring.

Anergy
  • MHC class I deficiency has been described, but pathological manifestations do not usually appear until later in life. 30 Lymphocyte proliferation studies confirm that lymphocytes are anergic and if there is anergy to certain mitogens, but not others,[doi.org]
Anergy
  • MHC class I deficiency has been described, but pathological manifestations do not usually appear until later in life. 30 Lymphocyte proliferation studies confirm that lymphocytes are anergic and if there is anergy to certain mitogens, but not others,[doi.org]
Trichophyton Mentagrophytes
  • We reported a case of SCID which was associated with a widespread skin infection with Trichophyton mentagrophytes.[ncbi.nlm.nih.gov]

Treatment

Bone marrow transplantation is an option which could offer the patient an uncomplicated life. An identical donor is required, although partially matched bone marrow harvested from a parent can also be transplanted. Despite the theoretically excellent prognosis of patients who receive bone marrow transplantations, the procedure entails considerable risk, given that chemotherapy or radiation treatment is required to annihilate existing bone marrow before the transplant is performed.

Another option involves the administration of levamisole, thymosin or transfer factor, with an aim to boost the immune system. Enzyme replacement therapy has received approval for the treatment of SCID caused by an ADA deficiency. Such therapy cannot naturally cure the disorder but eliminate the risk of succumbing to one of the contracted infections.

A pioneering approach is gene therapy, which can be applied in cases of X-linked SCID or SCID that results from an ADA deficiency, when a compatible donor for bone marrow transplant cannot be found. Therapy has been attempted prior to the age of 4 months old, to eliminate the complications of leukemia or defective gene transduction; however, this type of treatment has to be further investigated before it can receive any type of approval [9] [10].

Patients with SCID should also be symptomatically treated for the various infections they contract. An accurate identification of the pathogen is required, since the organism cannot rid itself of the bacterial, viral, fungal or protozoan load and causative treatment should be promptly administered. The FDA has also issued suggestions regarding dietary habits of people who are affected by SCID: only pasteurized milk, fruit and vegetable juices should be consumed to avoid contracting opportunistic infections.

Prognosis

Individuals are diagnosed with SCID during the first months of their lives. If diagnosis is not achieved, the young patient is expected to succumb to complications and only reach the age of 18-24 months. Patients who are treated with enzyme replacement have normal lifespans but experience a degradation in their immunity and those who receive a bone marrow transplantation lead uncomplicated lives.

Etiology

SCID involves disorders which are inherited via multiple patterns: X-linked, autosomal recessive or spontaneous mutations in more than 20 loci that have been identified. The type of inheritance pattern and the location of the mutation can by no means be associated with valid prognosis of the disease's severity.

The most common inheritance pattern for diseases of the SCID group is the X-lined pathway. The gene that encodes for the common γ-chain is defective; the γ-chain is a cytokine receptor component, present in the receptor complexes of six different interleukin receptors: IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. This results in the dysfunction of T and B cells, as well as NK cells.

Epidemiology

Given the plethora of different disorders categorized under the term SCID, an accurate comprehensive incidence is difficult to estimate. However, a USA study found the incidence of the typical SCID type, the SCID type involving incomplete genetic mutations and Omenn syndrome to be averagely 1 in 60,000 births [3]. Patients with SCID inherited via an autosomal recessive pattern is more commonly observed in areas where consanguinity is practiced. 

Sex distribution
Age distribution

Pathophysiology

The SCID group of diseases is in most of the cases a result of genetic mutation. A plethora of genes has been identified, whose defective structure is incriminated for the manifestations of severe combined immunodeficiency

Almost 50% of the SCID disorders are attributed to a mutation in the gene that encodes for the common γ chain of interleukin-2 in chromosome X (X-linked pattern). The γ chain is a component of minimum 6 cytokine receptors and greatly impairs the system's immunity. This specific mutation in the IL-2RG gene leads to patients with low or no T cells and NK cells and normal or elevated B cells.

The next most frequently observed SCID type is induced by low levels of adenosine deaminase and, in this case, the patient has low levels of T, B and NK cells or a complete lack thereof. Another possible mechanism involves an impaired α -chain receptor of interleukin-7.

SCID sub-types that are inherited via an autosomal recessive pattern are results of mutations in the following genes, amongst others:

  • Recombination autosomal genes (RAG1 and RAG2)
  • Janus kinase 3 (JAK3)
  • receptor type c (PTPRC)

Consanguinity greatly increases the possibility of giving birth to offspring affected by one of the aforementioned SCID types [4].

Generally, irrespective of the genetic background, all SCID disorders lead to absent T cells, symbolized as T-. Some forms also feature low or absent B and NK cells (NK-, B-) or normal/high cells (NK+, B+). Regardless of whether B cells are normal in numbers, the lack of T cells renders their function impaired. They are unable to partake in the fight against pathogens or produce immunoglobulins. In cases where B cells are able to produce some immunoglobulins, the latter are dysfunctional as well.

Prevention

SCID is a result of an inherited genetic mutation and can therefore not be prevented. However, the detection of the syndrome immediately after birth and the prompt administration of treatment can prevent complications and major infections. Therefore, screening tests can be used to attain early diagnosis, which can also lead to better surgical outcomes when a patient undergoes bone marrow transplantation [11]. 

The screening process is carried out in several states of the USA via the polymerase chain reaction (PCR) in the blood.

Summary

Severe combined immunodeficiency (SCID) is an inherited and potentially life-threatening group of disorders. They do not share the same genetic background, but most types are inherited via the X-linked pattern. Other types are attributed to the lack of adenosine deaminase (ADA).

The primary defects that occur as a result of SCID include the complete absence of T cells (cell-mediated immunity) and low levels of B or natural killer cells (NK); B cells are the basic constituent of humoral immunity. Even in cases when the B cell levels are normal, they fail to function properly and produce immunoglobulins in the complete absence of T cells.

The immune system of the patients is therefore rendered dysfunctional: individuals are increasingly susceptible to viral infections, lung infections and diarrheic phenomena as early as the first postnatal semester. Growth is hindered and failure to diagnose and treat these types of conditions result in death within 12 months.

The severity of primary immunodeficiency conditions and their genetic variety created the need for a World-Health-Organization-founded committee, with the primary aim of disorder classification according to the underlying pathophysiological alterations [1]. The impaired immune system in primary immunodeficiency is not a result of an underlying condition but a congenital defect and 8 such broad categories have been established so far. One of them is severe combined immunodeficiency, whose disorders have been genetically localized and pinpointed during the past years [2].

Patient Information

Severe combined immunodeficiency (SCID) is a group of inherited conditions that lead to a dysfunctional immune system. Mutations in various genes have been incriminated, and each condition that belongs to the SCID group causes a certain degree of immunodeficiency.

All conditions lead to absent T white blood cells in the blood; T cells are an extremely important component of immunity, as they also influence the function of other cells (B cells), amongst others. Mild disease types lead to absent T cells, but normal T cells and Natural Killer cells. Severer symptoms are caused by diseases that lead to absent T cells and also low levels of T and Natural Killer cells. In the latter case, immunity is significantly compromised.

Symptoms are exhibited within the first 6 months of life. Up to that point, antibodies coming from the mother protect the infant from infection, until the immune system is ready to take action. Individuals who are affected by SCID, however, fail to produce their own antibodies and start to frequently suffer from infections. Typical infections include pneumonia, diarrhea, viral infections and fungal infections, each caused by a plethora of different microbes.

The diseases are diagnosed by performing a blood test in order to measure the levels of T and B cells. genetic tests are also available and some hospitals use the T-cell receptor excision circles test for screening purposes. Diagnosis must be made in time, because SCID will lead to death if left undiagnosed.

SCID can be treated with immunoglobulin administration, adequate antimicrobial treatment in case of infection or enzyme replacement, if the cause is enzyme deficiency. Patients should also be as protected as they can against infections. A bone marrow transplantation is the only way to cure the disease; the procedure is risky, however, and a compatible donor is not easy to find. Transplantation that is performed before the age of 3 years old has a remarkable prognosis.

References

Article

  1. Geha RS, Notarangelo LD, Casanova JL, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007 Oct; 120(4):776-94.
  2. Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010 Feb; 125(2 Suppl 2):S182-94.
  3. Kwan A, Abraham RS, Currier R, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014; 312(7):729.
  4. Fischer A. Severe combined immunodeficiencies. Immunodefic Rev. 1992; 3(2):83-100.
  5. Bakare N, Menschik D, Tiernan R, et al. Severe combined immunodeficiency (SCID) and rotavirus vaccination: reports to the Vaccine Adverse Events Reporting System (VAERS). Vaccine. 2010; 28(40):6609-6612.
  6. Yount WJ, Utsinger PD, Whisnant J, et al. Lymphocyte subpopulations in X-linked severe combined immunodeficiency (SCID): evidence against a stem cell defect; transformation response to calcium ionophore A23187. Am J Med. 1978; 65: 847-854.
  7. Morinishi Y, Imai K, Nakagawa N, et al. Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal Guthrie cards. J Pediatr. 2009; 155(6):829-833.
  8. Ryser O, Morell A, Hitzig WH. Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children. J Clin Immunol. 1988; 8(6):479-485.
  9. Ariga T. Gene therapy for primary immunodeficiency diseases: recent progress and misgivings. Curr Pharm Des. 2006; 12(5):549-56.
  10. Fischer A, Hacein-Bey S, Le Deist F, et al. Gene therapy for human severe combined immunodeficiencies. Immunity. 2001 Jul; 15(1):1-4.
  11. Brown L, Xu-Bayford J, Allwood Z, et al. Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. Blood. 2011 Mar 17; 117(11):3243-6.

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Last updated: 2019-07-11 20:04