Microorganisms Affect Severe Combined Immunodeficiency Patients: Comparison
Please note this is a comparison between Version 2 by Alfred Zheng and Version 1 by Darren Avinash Gopaul.

Severe combined immunodeficiency (SCID) is a primary inherited immunodeficiency disease that presents before the age of three months and can be fatal. It is usually due to opportunistic infections caused by bacteria, viruses, fungi, and protozoa resulting in a decrease in number and impairment in the function of T and B cells. Microorganisms can affect SCID Patients' condition.

  • severe combined immunodeficiency
  • microorganisms

1. Introduction

There are rare situations in which the immune system fails to mature at birth, and this can result in a primary immunodeficiency disease (PID) [1]. The immune system comprises the innate and adaptive immune responses. The innate response is the first line of defense against microorganisms. The adaptive immune response includes T-cell-mediated immunity, which destroys viruses and other intracellular microorganisms, and B-cell-mediated immunity, which eliminates bacteria and other extracellular microorganisms [2,3,4][2][3][4]. Of all the many PIDs described, severe combined immunodeficiency disease (SCID) is the best studied. It is considered a pediatric emergency in children [5]. The affected infants have a severely weakened immune system, leading to their inability to effectively protect against infection, even by the least pathogenic microorganisms [2,6][2][6].
SCID, or “the bubble boy disease”, is a rare disorder in which multiple genes involved in the development and function of various immune cells undergo mutation [7]. This condition affects both the adaptive and innate immune systems, often resulting in fatal complications within the first two years of life unless treated with hematopoietic stem cell therapy (HSCT), or gene therapy [8,9][8][9]. In the United States, SCID was added to the Recommended Uniform Screening Panel (RUSP) in 2010, and newborns are now screened for this highly fatal disease [10].
SCID can be defined as typical, atypical/leaky, Variant, or Omenn Syndrome [11,12,13][11][12][13]. “According to the European Society for Immunodeficiencies (ESID). Typical SCID is defined as a patient with: (a) mutation(s) in a gene associated with a typical SCID phenotype; or, (b) presentation with severe or opportunistic infections, persistent diarrhea and failure to thrive, in the presence of low (300/μL) or absent CD3+ or CD4+ or CD8+ T cells, reduced naive CD4+ (CD3+CD4+CD45RA+) and/or CD8+ (CD3+CD8+CD45RA+) T cells, elevated γδ T cells, absence of proliferative responses to mitogens, defined as proliferative response to phytohemagglutinin (PHA) lower than 10% of the control subject; or (c) T cells of maternal origin present. The most common types typical SCID often include X-linked SCID, adenosine deaminase deficiency SCID, RAG-1/RAG-2 deficiency, and IL7R SCID” [14].
More than a dozen genes are involved in the pathogenesis of SCID [15]. SCID is most commonly inherited in an X-linked recessive or autosomal recessive manner [2,9,16][2][9][16]. Although the diagnosis of SCID is usually made by flow cytometry, genetic testing is often needed for genetic counseling and prognostication [15]. However, early diagnosis and treatment could be missed or even delayed, because although SCID is often caused by many genetic factors, over 80% of cases of SCID are sporadic, with no known family history of congenital immunodeficiencies [17,18][17][18].
Atypical SCID is characterized by CD3+ > 300 cells/μL and reduced, but detectable, proliferative response to PHA (>10 < 30% of the control) [14]. It is also sometimes referred to as “leaky SCID” [19]. Variant SCID is diagnosed in cases with no known gene defect and a persistence of 300–1500 T cells/L with impaired function [20].

2. Microorganisms Affecting SCID Patients

2.1. Viruses

Opportunistic viral infections, e.g., with cytomegalovirus, Epstein–Barr virus, adenovirus, enterovirus, herpes simplex virus, respiratory syncytial virus, rotavirus, and parainfluenza virus, can cause severe disseminated infections in SCID patients and can be fatal if left undiagnosed or untreated [51,52,53][21][22][23]. Cytomegalovirus (CMV) has been found to be excreted in breastmilk, and breastfeeding should not be advised for SCID patients unless the mother is found to be CMV-antibody-negative [15].
Infection with Adenovirus can manifest as ocular, respiratory, gastrointestinal, or hepatic diseases in immunocompetent patients and is often mild and self-limiting [54][24]. However, in patients with SCID, adenovirus may produce severe and prolonged viral pneumonia, bronchiolitis, hepatitis, or gastroenteritis, with a potentially fatal outcome [55][25].
Rotavirus is the leading cause of severe gastroenteritis in children, and vaccination is the mainstay of prevention [56][26]. However, the live rotavirus vaccine has been found to cause severe diarrhea in children with SCID and should therefore be avoided [57][27]. Epstein–Barr virus infections affect over 95% of the human population at some point in their lives, but are usually asymptomatic [58][28]. Symptomatic infections in adolescents may result in infectious mononucleosis characterized by fever, sore throat, splenomegaly, and lymphadenopathy. The virus typically attacks B cells; therefore, SCID patients with impaired or absent B cells are at an increased risk of EBV-associated lymphomas as a result of persistent viremia and lymphoproliferation [59][29].
Parvovirus B-19 is a common infection in rapidly dividing erythroid progenitor cells, with children being the main source of infection [60][30]. Immunocompetent host infections can be asymptomatic or symptomatic, and include erythema infectiosum, arthropathy, anemia, thrombocytopenia, hepatitis, and myocarditis. In immunocompromised hosts, infection with Parvovirus B-19, chronic red cell aplasia, acute lymphoblastic leukemia (ALL), and virus-associated hemophagocytic syndrome (VAHS) [61][31].
Varicella-zoster virus (VZV) infection occurs primarily via respiratory inoculation and establishes lifetime latency in the sensory ganglia of immunocompetent patients [62][32]. Immunocompromised patients are at an increased risk of complications, such as reactivation, herpes zoster, retinal necrosis, and even death [62][32]. Worldwide vaccination via live VZV vaccines has prevented many of the complications of VZV infection [63][33]; however, vaccination in SCID patients has been associated with disseminated infection [64][34] including vaccine-associated pneumonia [65][35], and should therefore be avoided.

2.2. Bacteria

Recurrent sinopulmonary infections are characteristic of primary immunodeficiencies such as SCID, and can result in severe complications including lung abscess, empyema, and pneumatocele. The bacterial causes of pneumonia include Staphylococcus aureus, Pseudomonas spp., Mycobacterium bovis, and other atypical mycobacteria [66][36]. Clinical imaging provides an important diagnostic clue in acute pulmonary infections in children with primary immunodeficiencies, as they often lack a thymic shadow [67][37].
Clinical manifestations of SCID include gastrointestinal infections, chronic diarrhea, and failure to thrive. Gram-positive bacteria, such as Staphylococcus aureus, and Gram-negative bacteria such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Burkholderia, and Chryseobacterium, are also commonly implicated [21][38]. SCID patients who lack immunoglobulins are at constant risk of recurrent infections with encapsulated bacteria [68][39].
Omenn syndrome is an autosomal recessive form of SCID that is usually T-B-NK+ and is highly fatal owing to recurrent opportunistic infections [36,69][40][41]. Skin sepsis is observed in patients with Omenn syndrome. Skin sepsis in Omenn syndrome can occur due to colonization by bacteria such as Staphylococcus aureus, Streptococcus pyogenes, enterococcus, and Gram-negative bacteria such as Pseudomonas species [36,70,71][40][42][43]. Cutaneous manifestations of bacterial infections include recurrent and life-threatening skin abscesses, folliculitis, impetigo, and furunculosis [72][44]. Survival rarely exceeds several months after birth in the absence of curative treatment.

2.3. Fungi

Invasive fungal infections (IFI) rarely occur in immunocompetent individuals and are more likely to occur in patients with primary immunodeficiencies. Opportunistic fungal infections seen in SCID are similar to those in patients with AIDS, and are usually caused by opportunistic fungi such as Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans [73][45]. Pneumocystis jirovecii pneumonia is the most common respiratory infection in SCID, and it is often co-infected with a respiratory virus [70][42]. Patients with SCID may be offered prophylactic treatment against Pneumocystis jirovecii to prevent fatal complications.
Patients with SCID are at increased risk of disseminated fungal infections, with invasive Candida albicans and Aspergillus being the most prominent microorganisms [74][46]. Other rare microorganisms implicated in SCID include Acremonium and Pichia [75,76][47][48]. Colonization of the skin, oropharynx, and gut by Candida albicans typically manifests as persistent oral thrush or diaper dermatitis progressing to diffuse skin involvement [75][47]. Hematopoietic stem cell transplantation is the definitive treatment for SCID, and fluconazole (3 mg/kg OD) is administered as prophylaxis against candidiasis and is generally well tolerated by the patients [77][49].
Invasive aspergillosis (IA) is a life-threatening condition in immunocompromised children. Infection is typically acquired in the community or via nosocomial infections caused by exposure to hospital construction, renovation, and air-conditioning systems [78][50]. Bronchopneumonia is the most common presentation of infection with Aspergillosis in SCID, and other primary immunodeficiencies [79][51]. Other clinical manifestations of invasive aspergillosis include pulmonary infarction, pulmonary thrombosis, and pleural effusion [80,81][52][53].
Cryptococcosis is a subacute or chronic systemic mycosis caused by Cryptococcus neoformans [82,83][54][55]. Cryptococcus neoformans is an opportunistic fungus that infects immunocompromised individuals. The respiratory tract is the primary portal of entry and has been found to be fatal because of overwhelming pneumonia in patients with SCID [82][54]. Cryptococcus neoformans was found in the skin lesions of a patient with SCID who presented with a maculopapular rash along with lobar consolidation. The treatment was refractory to medical management, but responsive to hematopoietic stem cell therapy [84][56].

2.4. Parasites

Parasitic infections are the dominant cause of gastrointestinal disease in patients with SCID. Protozoans, e.g., Giardia duodenalis or Giradia intestinalis (Giardia lamblia) and Cryptosporidium spp. are the most common protozoans affecting patients with SCID. Other implicated parasites include Schistosoma species, Blastocystis hominis, Fasciola species, and Trichostrongylus species [85][57]. The gastrointestinal (GI) tract is the largest lymphoid organ of the body [86][58]. The GI manifestations are the second most common manifestations of primary immunodeficiency disorders (PID) after pulmonary disease [87][59]. Gastrointestinal disorders, such as chronic diarrhea, malabsorption, and abdominal pain, are seen in as many as 50% of patients with primary immunodeficiencies [88][60]. Giardia intestinalis is a zoonotic protozoan parasite typically found in the small intestine of humans and various animals. Infections can be asymptomatic or cause mild diarrhea in immunocompetent patients but can cause severe and chronic diarrhea and malabsorption in immunocompromised patients [89,90,91][61][62][63].
Cryptosporidium species, especially C. parvum, can cause severe and chronic enteropathy by releasing proinflammatory cytokines such as interleukin-8 (IL-8) in intestinal epithelial cells in patients with primary immunodeficiencies [92,93][64][65]. Disseminated cryptosporidiosis can lead to biliary tract disease, pancreatitis, pulmonary disease, and stunted growth in patients with SCID [92][64]. Disseminated cryptosporidiosis leading to overwhelming sepsis and death has been observed in patients with SCID [94][66]. Although the International Agency for Research on Cancer (IARC) has not considered protozoans as carcinogens for humans [95][67], Cryptosporidium has been associated with colonic adenocarcinoma in SCID mice [96][68]; therefore, physicians should be aware of this possible complication and infection in SCID patients should be treated promptly.
Immunization with vaccinia virus and bacille Calmette–Guérin (BCG) vaccine is widely used in several countries and has been observed to exacerbate factors in patients with SCID. These vaccines can lead to disseminated, fatal infection, and must not be administered to patients with SCID [97][69].


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