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Pediatric Severe Combined Immunodeficiency Clinical Presentation

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
 
Updated: Feb 24, 2016
 

History

Patients with severe combined immunodeficiency (SCID) may present with multiple severe or recurrent illnesses during the first months of life. Initially, growth appears normal, but failure to thrive with severe emaciation ensues secondary to diarrhea and chronic infections. In the past, SCID was often diagnosed after children acquired serious infections, such as pneumonia due to P jiroveci (carinii). Today, most infants should be recognized before the development of failure to thrive or Pneumocystis infection.

Within the first 3 months of life, infants with SCID present with persistent and recurrent diarrhea, otitis media, thrush, and respiratory infections (see the image below). In this setting, a thorough medical and family history, with particular attention to recurrent infections, should be obtained. The history should include questions about the following:

  • Family history of consanguinity
  • Sibling death in infancy (eg, multiple deaths during infancy due to infection or unexplained deaths in male infants) or previous miscarriages in the mother
  • Family history of SCID or other primary immunodeficiency
  • Poor feeding and poor weight gain
  • Chronic diarrhea
  • Previous infections, especially pneumonia

See the image below.

This patient presented with fever and paralysis of This patient presented with fever and paralysis of his left arm 3 months after receiving his third oral poliovirus vaccine. Past history included chronic thrush presenting in the absence of antibiotic therapy or breastfeeding at 2 months, chronic diarrhea from 4 months, and recurrent otitis media. He was at the 90th percentile for height and weight, similar to his parents. Major histocompatibility complex (MHC) class II deficiency was diagnosed by immunologic tests.

Diarrhea may be caused by rotavirus, adenovirus, and enterovirus. Cryptosporidiosis is also reported frequently. Diarrhea resembling Crohn disease complicates some types of SCID, such as major histocompatibility complex (MHC) class II deficiency.

Patients with SCID have repeated infections, which are typically more severe than comparable infections occurring in children with normal immunity. The frequency may be greater than 8 per year. Patients may require antibiotics for longer than 2 months; at times, intravenous (IV) antibiotics may be necessary. Patients with SCID may have recurrent deep skin or organ abscesses.

Mucocutaneous candidiasis is often more severe than expected and is resistant to treatment. Bacterial otitis media and pneumonia are common. Viral infections caused by varicella zoster virus (VZV), herpes simplex virus (HSV), respiratory syncytial virus (RSV), rotavirus, adenovirus, enterovirus, parainfluenza virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are seen. Asking the mother about risk factors for HIV infection is important; infants with transplacental HIV infection may present in much the same fashion as SCID.

Dismissing an infant’s death caused by an overwhelming common bacterial or viral infection without further investigation is a mistake. Whenever an infant with a history of unusually frequent and severe common infections dies of infection, an autopsy should be performed to assess lymphoid and thymic tissue. Peripheral blood lymphocytes can survive for several days; thus, blood should be saved for assessment of T-cell and B-cell markers by flow cytometry and for responses to mitogens.

Defects in the cell-mediated immune system become more apparent because breastfeeding may mask the humoral immune defects during the early neonatal period. T-cell defects, such as candidiasis affecting the esophagus, may occur. For example, cytomegalovirus (CMV) infection, measles, and varicella, which are usually self-limited, infect the lungs and the brain, resulting in life-threatening pneumonia, meningitis, and sepsis. Pulmonary involvement with P jiroveci (carinii) pneumonia (PCP) can also be severe.

Autoimmune phenomena, especially hemolytic anemia and neutropenia, are more common in CD3 deficiency and MHC class II mutations. The absolute lymphocyte count is less than 3000/μL, and the proliferative response of the lymphocytes to mitogens activation is less than 10% of control values.

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Physical Examination

Physical findings are multisystemic. The abnormal findings are primarily related to the various superimposed infections or to graft-versus-host disease (GVHD) rather than to SCID itself. The patient may present with the following:

  • Failure to thrive, manifesting as decreased weight, height, and head circumference
  • Dehydration from chronic diarrhea
  • Recurrent, painful otitis media, which may be more severe than typical, is common
  • Eczematous rash from GVHD, which may be mistaken for atopic dermatitis, especially in Omenn syndrome
  • Increased respiratory rate and effort and crepitations secondary to pneumonia (especially PCP)
  • Fever from sepsis, systemic fungal infections, or generalized herpes
  • Absent lymphatic tissue, including tonsils; lack of recognizable peripheral lymphoid organs should raise suspicion of SCID in children with multiple aggressive infections
  • Lymphadenopathy and hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome
  • Neurologic sequelae and developmental regression (loss of developmental milestones), especially in purine nucleotide phosphorylase (PNP) deficiency (the cause of which is genetic, not infectious); neurologic perturbation also occurs secondary to central nervous system (CNS) infection
  • Abdominal findings, including tenderness secondary to gastrointestinal (GI) infections and hepatomegaly from viral hepatitis
  • Candidiasis

Infants with SCID have an extensive and diverse group of cutaneous disorders. Recurrent skin abscesses are present. Extensive candidiasis in the mouth and diaper area may persist beyond the neonatal period and may involve the rest of the skin. Severe seborrheic dermatitis is observed over the scalp, ears, and nasolabial folds. Intractable eczemalike dermatitis is noted. Impetigo and severe skin infections with deep ulcers in the perineum, tongue, and buccal mucosa are observed. Recurrent furunculosis may develop.

A generalized herpetic dermatitis may also be noted. Cutaneous manifestations of GVHD may also be present from maternally derived T cells that are reacting host cells in the absence of opposing host T cells. Such manifestations include the following:

  • In the acute setting, a maculopapular or morbilliform rash can occur and progress to erythroderma and exfoliative dermatitis
  • In chronic GVHD, lichenoid or sclerodermoid lesions are described

The dermatologic disorders of incontinentia pigmenti and hypohidrotic ectodermal dysplasia are associated with severe pneumococcal infections and progressive bronchiectasis, even with immunoglobulin (Ig) replacement.

Dermatophytosis is uncommon in SCID patients, although a case has been described with widespread tinea corporis due to Trichophyton mentagrophytes.[30] Children with Artemis-deficient SCID additionally suffer from numerous oral and genital ulcers. Some patients with a mild form of JAK3-deficient SCID may present with extensive cutaneous transitory warts.

Adenosine deaminase (ADA) deficiency is accompanied by abnormalities to ribs and vertebrae caused by defects in cartilaginous structures.

Sparse hair, abnormal dentition, and osteopetrosis are other manifestations in SCID patients. Hypomorphic heterozygous mutations in IKBA causes autosomal dominant ectodermal dysplasia with immunodeficiency (AD-EDA-ID) with impaired nuclear factor kappa B (NFκB) signaling pathways; however, this defect also causes severely impaired T-cell receptor (TCR) signaling with the resultant clinical phenotype of SCID.

Unique features of Omenn syndrome and the Omennlike syndrome caused by GVHD include erythroderma, lymphoid hyperplasia, hypereosinophilia, and hepatosplenomegaly. Growing numbers of leaky SCID mutations have been shown to manifest Omenn syndrome; accordingly, this syndrome is now considered to consist of dysregulated inflammatory processes revealed in leaky SCID.

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Complications

Patients are at risk for infections from inadequate immune reconstitution from bone marrow transplantation (BMT) or enzyme replacement. Opportunistic infections usually follow more common infections. P jiroveci and fungal pneumonias cause death in classic cases. CMV, VZV, and HSV infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other enteroviruses precludes stem cell reconstitution.

Ensure that the child does not receive any live virus vaccines until after BMT engraftment, especially polio or bacille Calmette-Guérin (BCG) vaccine. Vaccinating children with SCID is not only futile, because they cannot make antibody, but also dangerous, because they can develop disease (eg, poliomyelitis) from attenuated viruses and may even die after exposure to these vaccines.

Graft failure with BMT and posttransplant GVHD are well recognized, although both have decreased with improved BMT preparatory techniques. GVHD) may ensue if the blood products given before BMT are not depleted of white blood cells by filtration or irradiation. Ensure that all blood products are also negative for CMV to avoid systemic CMV disease.

Gene therapy has been associated with virus-induced malignancies. Cancer, usually non-Hodgkin lymphoma, is seen in patients with cartilage-hair hypoplasia who survive beyond early childhood.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Smeeta Sinha, MD Resident Physician, Department of Dermatology, Rutgers New Jersey Medical School

Smeeta Sinha, MD is a member of the following medical societies: Alpha Omega Alpha, Phi Beta Kappa, Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Acknowledgements

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Consulting fee Consulting; Celgene Honoraria Safety Monitoring Committee; GSK - Glaxo Smith Kline Consulting fee Consulting; TenXBioPharma Consulting fee Safety Monitoring Committee

Stephen C Dreskin, MD, PhD Director of Allergy, Asthma, and Immunology Practice, Professor of Medicine, Departments of Internal Medicine and Immunology, University of Colorado Health Sciences Center

Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American Association of Immunologists, American Association of Neuropathologists, American Association of Ophthalmic Pathologists, American Association of Oral and Maxillofacial Surgeons, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology

Disclosure: Genentech Consulting fee Consulting

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

James Fulton Jr, MD, PhD Center for Cosmetic Dermatology; Consultant, Vivant Pharmaceuticals, LLC

James Fulton Jr, MD, PhD is a member of the following medical societies: American Academy of Cosmetic Surgery, American Academy of Dermatology, American Society for Laser Medicine and Surgery, Dermatology Foundation, International Society of Cosmetic and Laser Surgeons, and Skin Cancer Foundation

Disclosure: Vivant Pharmaceuticals Grant/research funds Consulting

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians

Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva Consulting; Meda Honoraria Speaking and teaching

Charles H Kirkpatrick, MD Professor of Medicine and Immunology, University of Colorado School of Medicine; Director of Adult Immune Deficiency Program, Department of Medicine, University of Colorado Health Sciences Center; Consulting Staff, Department of Medicine, National Jewish Medical and Research Center

Charles H Kirkpatrick, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Physicians, American Federation for Clinical Research, American Society for Clinical Investigation, and Clinical Immunology Society

Disclosure: Lev Pharmaceuticals Consulting fee Consulting

James M Oleske MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary Allergy Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School; Professor, Department of Quantitative Methods, University of Medicine and Dentistry of New Jersey

James M Oleske is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of HIV Medicine, American Academy of Hospice and Palliative Medicine, American Academy of Pain Management, American Academy of Pediatrics, American Association of Pediatrics, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, American Public Health Association, American Society for Microbiology,American Thoracic Society, Arab Board of Family Medicine, Association of Clinical Researchers and Educators (ACRE), Infectious Diseases Society of America, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, National Association of Pediatric Nurse Practitioners, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Eyal Oren, MD Consulting Staff, Institute for Asthma and Allergy

Eyal Oren, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology and American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

Elizabeth A Secord, MD Clinical Associate Professor, Department of Pediatrics, Division of Pediatric Immunology, Wayne State University

Elizabeth A Secord, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and American Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

David J Valacer, MD Consulting Staff, Hoffman La Roche Pharmaceuticals

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Henry K Wong, MD, PhD Associate Professor of Dermatology, Ohio State University College of Medicine

Henry K Wong, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, International Society for Cutaneous Lymphomas, and Society for Investigative Dermatology

Disclosure: Amgen Consulting fee Speaking and teaching; Centocor Honoraria Speaking and teaching; Celgene Grant/research funds None; Abbott Labs Grant/research funds Independent contractor

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This patient presented with fever and paralysis of his left arm 3 months after receiving his third oral poliovirus vaccine. Past history included chronic thrush presenting in the absence of antibiotic therapy or breastfeeding at 2 months, chronic diarrhea from 4 months, and recurrent otitis media. He was at the 90th percentile for height and weight, similar to his parents. Major histocompatibility complex (MHC) class II deficiency was diagnosed by immunologic tests.
This patient with an autosomal recessive type of severe combined immunodeficiency died of cytomegalovirus pneumonia when aged 22 months after prior infections that included recurrent otitis, pneumonia, and oral thrush. A CMV inclusion body is pictured in the upper left of the photo.
Histologically, the thymus in severe combined immunodeficiency usually lacks Hassall corpuscles and is depleted of lymphocytes. In this photo, a Hassall corpuscle is identified to the right of center.
Table 1. Common Causes of SCID, Cellular Defects, and Inheritance Pattern
Genetic Disease Causing SCID T-Cell Defect B-Cell Defect NK-Cell Defect Inheritance Pattern
Reticular dysgenesis Yes Yes Yes Autosomal recessive
ADA deficiency Yes Yes Yes Autosomal recessive
RAG1 and RAG2 deficiency Yes Yes No Autosomal recessive
TCR and BCR recombination gene deficiency Yes Yes No Autosomal recessive
Common γ chain deficiency Yes No Yes X-linked
JAK3 deficiency Yes No No Autosomal recessive
IL-7Ra deficiency Yes No No Autosomal recessive
Omenn syndrome Yes No No Autosomal recessive
ZAP-70 kinase CD4+ present No No Autosomal recessive
CD4+ lymphopenia CD8+ present No No Autosomal recessive
MHC II deficiency CD8+ present No No Autosomal recessive
p56lck deficiency CD8+ present No No Autosomal recessive
ADA = adenosine deaminase; BCR = B-cell receptor; JAK = Janus-associated kinase; MHC = major histocompatibility complex; RAG = recombination-activating gene; SCID = severe combined immunodeficiency; TCR = T-cell receptor, ZAP = ζ chain-associated protein.
Table 2. Intravenous Immunoglobulin Preparations
Brand (Manufacturer) Manufacturing Process pH Additives Parenteral Form and Final Concentrations IgA Content, µg/mL
Carimune NF (CSL Behring) Kistler-Nitschmann fractionation; pH 4, nanofiltration 6.4-6.8 6% solution: 10% sucrose, < 20 mg NaCl/g protein Lyophilized powder 3%, 6%, 9%, 12% Trace
Flebogamma (Grifols USA) Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization 5.1-6 Sucrose free, contains 5% D-sorbitol Liquid 5% < 50
Gammagard Liquid 10% (Baxter Bioscience) Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation 4.6-5.1 0.25 M glycine Ready-for-use liquid 10% 37
Gamunex (Talecris Biotherapeutics) Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation 4-4.5 Contains no sugar, contains glycine Liquid 10% 46
Gammaplex (Bio Products) Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation 4.8-5.1 Contains sorbitol (40 mg/mL); do not administer if fructose intolerant Ready-for-use solution 5% < 10
Iveegam EN (Baxter Bioscience) Cohn-Oncley fraction II/III; ultrafiltration; pasteurization 6.4-7.2 5% solution: 5% glucose, 0.3% NaCl Lyophilized powder 5% < 10
Polygam S/D, Gammagard S/D (Baxter Bioscience for the American Red Cross) Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated 6.4-7.2 5% solution: 0.3% albumin, 2.25% glycine, 2% glucose Lyophilized powder 5%, 10% < 1.6 (5% solution)
Octagam† (Octapharma USA) Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization 5.1-6 10% maltose Liquid 5% 200
Panglobulin (Swiss Red Cross for the American Red Cross) Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration 6.6 Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl Lyophilized powder 3%, 6%, 9%, 12% 720
Privigen Liquid 10% (CSL Behring) Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH4 incubation and depth filtration 4.6-5 L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) Ready-for-use liquid 10% < 25
*IVIg products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs).



†Withdrawn from US market on September 24, 2010, because of unexplained reports of thromboembolic events.



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