Review – Kaplan Pediatrics: Immune-Mediated Disease

 

EVALUATION OF SUSPECTED IMMUNE DEFICIENCY

Initial screening for recurrent infections

•  CBC, manual differential, platelet count, smear

• What normal values tell you:
  • Normal absolute lymphocyte count—unlikely T-cell defect
  • Normal absolute neutrophil count—eliminates congenital or acquired neutro- penia and both forms of leukocyte adhesion deficiency
  • Normal platelet count—excludes Wiskott-Aldrich syndrome
  • Howell-Jolly bodies present—suggests asplenia
  • Normal ESR (erythrocyte sedimentation rate)—excludes chronic bacterial or fungal infection

Table 10-1. Evaluation of Immune-mediated Disease

Suspected Deficiency	Clinical Presentation	Initial Labs	Definitive
B Cell	Recurrent infections with encapsulated bacterial, enteroviral and hepatitis viruses	•  Quantitative immunoglobulins •  Normal IgA excludes most	•  Flow cytometry using monoclonal antibodies to B cell-specific CD antigen •  Then, molecular Dx if no previous FH
T Cell	Recurrent opportunistic infections with chronic diarrhea and failure- to-thrive	•  Absolute lymphocyte count •  Normal precludes Dx •  If low → Candida intradermal skin test •  Normal precludes all	•  Mitogen stimulation for function •  Then flow cytometry as above •  Then molecular Dx if no previous FH
Phagocytic	Recurrent staph and gram negative infections	•  Respiratory burst assay using rhodamine dye (replaced NBT) •  Flow cytometry for CD antigens specific for leukocyte adhesion deficiencies	•  Molecular DX
Complement	•  Pyogenic infections •  Life-threatening septicemia •             Neisseria infections	•  CH50	•  Specific complement assays •  Molecular DX

 

 

87

 

 

 

 

 

Note

Phagocyte deficiency often leads to multiple infections with catalase positive organisms, such as staph. Complement deficiency results in susceptibility to infection with Neisseria.

Definitive Tests to Make the Specific Diagnosis

Agammaglobulinemia

• Enumerate blood B cells—flow cytometry using dye-conjugated monoclonal anti- bodies to B-cell–specific CD antigens (CD19, CD20)

 

T-cell deficiency

• Enumerate T cells (as above for CD2, CD3, CD4, CD8)

•  Needs to be performed on any infant who is lymphopenic because of possibility of SCID

• T-cell function

– Mitogen stimulation (PHA concanavalin A, pokeweed mitogen); measurement of cytokine production

 

Phagocytic cell defects

•  Neutrophil respiratory burst; best way is rhodamine dye (has replaced the NBT test [nitroblue tetrazolium test])

 

Natural killer (NK) cells

• Flow cytometry—NK-specific CD antigens (CD16, CD56)

 

SPECIFIC DEFECTS

 

Defects of Antibody Production (B-cell Defects)

Bruton agammaglobulinemia

A 15-month-old child presents to the physician with fever of 39°C (102ºF). On physical examination, the patient is noted to have a right tympanic membrane that is erythematous and bulging and that has obscure landmarks and no mobility. On review of the medical record you note that since 9 months of age this patient has had multiple infections with otitis media, sinusitis, and pneumonia.

 

• Xq22 (Bruton tyrosine kinase); X-linked → boys
• Fine until age 6–9 months
• Extracellular pyogenic infections ( pneumoniae, H. influenza, M. pneumoniae); hepatitis viruses, enteroviruses (CNS infections)
• Examination—lymphoid hypoplasia (tonsils and adenoids; no splenomegaly or lymphadenopathy)
• Significant decrease in all immunoglobins
• Flow cytometry—absence of circulating B cells

•  Treatment—monthly IVIg (intravenous immune globulin) and antibiotics for infections

 

 

 

 

 

Common variable immune deficiency

• Hypogammaglobulinemia with phenotypically normal B cells (acquired, later age of onset)

– Do not differentiate normally into Ig-providing cells

• Equal sex distribution
• Infections like Bruton, but rare enteroviral meningitis

•  Normal or even increased lymphoid tissue

• Significant autoantibody production (to IgA)
• Significant increase in lymphomas (especially women in fifth to sixth decade)

 

Selective IgA deficiency

A 3-year-old child is brought to your office because of recurrent upper respiratory infections and recurrent urinary tract infections, as well as chronic diarrhea.

 

•  Most common B-cell defect

• Near absence of serum and secretory IgA
• Males and females
• Respiratory, gastrointestinal, urogenital, and skin infections (same organisms as others)
• High incidence of autoimmune disease and increased malignancies

•  Serum antibodies to IgA → fatal anaphylactic reactions if given blood with IgA

 

IgG subclass deficiency

An 8-year-old girl complains of acute sore throat of 2 day’s duration, accompanied by fever and mild abdominal pain. Physical examination reveals enlarged, erythematous tonsils with exudate and enlarged, slightly tender cervical lymph nodes.

 

• One or more of the 4 subclasses are decreased despite a normal or even increased total IgG
• Most are IgG2—also have IgA deficiency
• May be an early marker for more general immune dysfunction
• No IVIg unless there are deficiencies of antibodies to broad array of antigens

 

Defects of Cellular Immunity (T cell Defects)

• More severe; no survival beyond infancy or early childhood (without definitive treatment)

 

 

 

 

DiGeorge syndrome

A 3-week-old infant presents with a generalized seizure. The patient was born to a 22-year-old white woman, G1P1, full term, via spontaneous vaginal delivery. The mother had good prenatal care and denies tobacco, drugs, and alcohol. There were no complications at delivery. The patient weighed 7 lb 6 oz at birth and has gained weight. The infant has been feeding and sleeping well. On physical examination the patient has hypertelorism, low-set ears, micrognathia, and a fish mouth.

 

 

 

 

 

Note

Other chromosome 22 microdeletion syndromes are the velocardial-facial

syndrome and the conotruncal anomaly face syndrome. They are known as the CATCH-22 syndromes: Cardiac, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia.

• Dysmorphogenesis of the third and fourth pharyngeal pouches; microdeletion 22q11.2

–             Thymic hypoplasia

• Parathyroid hypoplasia causes neonatal hypocalcemic seizures; tetany
• Anomalies of great vessels (e.g., right aortic arch)
• Other CHD (conotruncal lesions, ASD, VSD)
• Esophageal atresia
• Bifid uvula

–             Dysmorphic features

• Short philtrum
• Hypertelorism (widely spaced eyes)

°          Mandibular hypoplasia

• Fish mouth
• Low-set, large, notched ears (posteriorly rotated)

• Decreased IgA and increased IgE; low absolute lymphocyte count; Decreased CD3 T cells
• Absent respiratory burst to mitogens
• Decreased or absent thymic tissue with normal lymphoid tissue—partial to complete
• Opportunistic infections—fungi, viruses, carinii
• Graft-versus-host disease (GVHD); special care with blood transfusions

•  Treatment—transplantation of thymic tissue of MHC-compatible sibling or half- matched parenteral bone marrow

 

Combined Antibody and Cellular Defects

Severe combined immunodeficiency (SCID)

• Absence of all adaptive immune function and perhaps natural killer function
• Classic presentation—first few months of life
• Opportunistic and viral infections ( albicans, P. carinii, varicella, measles, parainfluenza 3, CMV [cytomegalovirus], EBV [Epstein-Barr virus])
• Diarrhea, extreme wasting

–             Pneumonia, otitis media, sepsis, cutaneous infections

• GVHD from maternal immunocompetent T cells crossing placenta
• Severe lymphopenia from birth
• No mitogen response

 

 

 

 

 

 

–             Small or no thymus, absent lymphoid tissue

• No immunoglobulins
• No antibody responses

• Types

–             X-linked—most common

• Autosomal recessive—less common in United States than in Europe adenine deaminase (ADA) deficiency—lowest antibodies and lymphocyte counts

•  Treatment—This is a true pediatric emergency → bone marrow transplant or death by 1 year of age

• If diagnosed in first 3 months of life, >95% treated successfully (more recent— gene therapy)

 

Combined Immunodeficiencies

Wiskott-Aldrich syndrome

A 1-year-old infant presents to his physician with severe eczema. On physical examination, the patient is noted to have draining ears as well as a petechial rash. Review of the medical record reveals that the patient has recurrent infections, including otitis media and pneumonia.

 

• X-linked recessive (WASP = Wiskott-Aldrich syndrome protein)
• Findings
  • Atopic dermatitis (eczema)
  • Thrombocytopenia with normal megakaryocytes but small defective platelets (petechiae)
  • Susceptibility to infection (recurrent)
  • Palpable adenopathy; splenomegaly and lympahdenopathies

•  First—often prolonged bleeding from circumcision

• First year—atopic dermatitis and recurrent infection; primarily polysaccharide encapsulated bacteria → pneumonia, meningitis, sepsis; later, carinii and herpes
• Impaired humoral response—highly variable [Ig]
  • Most with decreased IgM, increased IgA and IgE, and normal or slightly low IgG
• T cells moderately decreased and variable decreased mitogen response
• Rare survival beyond teens without bone marrow transplant
• Complications—malignancy, infections, bleeding

 

Note

Combined immunodeficiency’s major difference from SCID is the presence of low but not absent T-cell function.

 

 

 

 

Ataxia-telangiectasia

A 3-year-old child presents with ataxia, mask-like facies, drooling, tics, and irregular eye movements. According to the mother, the ataxia began at approximately 1 year of age. On examination of the patient’s eyes, he is noted to have telangiectasias. In addition, he also has a history of recurrent respiratory infections.

 

• A-T mutation on chromosome 11; protein kinase
• Moderate decrease in response to B- and T-cell mitogens
• Decreased CD3 and CD4 cells; variable humoral and cellular deficiency—most with selective IgA deficiency

•  Hypoplastic thymus → helper T-cell defects

• Physical examination:

} Mask-like facies

} Tics

} Drooling

} Irregular eye movements

• Progressive cerebellar ataxia—from beginning of walking; wheelchair by 10–12 years old
• Oculocutaneous telangiectasias—begin at 3–6 years old
• Chronic sinopulmonary disease, common viral infections—usually do well
• Complications—High incidence of malignancies—lymphoreticular but also adenocarcinoma

 

 

Table 10-2. Combined Immunodeficiencies

Feature	Severe Combined Immunodeficiency	Wiskott-Aldrich Syndrome	Ataxia-Teleangioectasia
Problem	Absence of all immune function ± NK cells	•  Low but not absent T cell function •  Impaired but not absent antibody formation	•  Low but not absent T cell function •  Impaired but not absent antibody formation
Genetics	•  Most in United States are X-linked •  Less are autosomal recessive (ADA deficiency) •  Mutations in any 1 of 12 known genes	X-linked recessive	Mutated gene: 11q22-23

(Continued)

 

 

 

 

 

 

Table 10-2. Combined Immunodeficiencies (Cont’d)

Feature	Severe Combined Immunodeficiency	Wiskott-Aldrich Syndrome	Ataxia-Teleangioectasia
Infections	•  First few months of life •  Recurrent/persistent diarrhea •  Pneumonia •  OM •  Sepsis •  Cutaneous infections •  Opportunistic infections •  Extreme wasting	•  Pyogenic infections with encapsulated bacteria in first year •  Later, opportunistic infections	Chronic sinopulmonary infections
Physical Exam	•  Small/absent thymus •  No lymphoid tissue	•  Eczema •  Petechiae and purpura •  Facial dysmorphic features •  Small thymus	•  Dysmorphic facial features •  Oculocutaneous teleangiectasias (age 3-6) •  Thymic hypoplasia
Lab Findings	•  No T-cells → severe lymphopenia at birth •  No mitogen response •  Ig severely decreased or absent •  No antibodies after immunizations	•  Neutropenia •  Ig highly variable, but most with decreased IgM, elevated IgA and IgE and normal to slightly low IgG •  Decreased mitogen response	•  Moderate decreased response to T and B cell mitogens •  Moderate decreased CD3 and CD4 •  Variable Ig (most with selective IgA deficiency)
Associated Findings	•  GVHD from immunocompetent maternal lymphocytes crossing placenta •  Also from non- irradiated blood products	•  Atopic dermatitis (in first year) and thrombocytopenic purpura (small defective platelets) → prolonged bleeding time with circumcision or bloody diarrhea early in life •  EBV = associated malignancies	•  Progressive cerebellar ataxia with start of walking •  Confined to wheelchair by age 10-12 •  High incidence of lymphoreticular malignancies and adenocarcinomas
Treatment	•  T cell-depleted half- matched parental stem cell transplant in first 3.5 months of life → >95% survival (ADA deficiency and X-linked have been Rx with gene therapy)	•  Manage skin disease •  Aggressive treatment of infections •  Platelet transfusion and splenectomy •  IVIG monthly •  Bone marrow transplant	•  Physical therapy •  Manage infections aggressively •  IVIG (if not selective IgA)

 

 

 

 

OTHER IMMUNE DEFICIENCIES

 

Phagocytic Defects

Chronic granulomatous disease (CGD)

• X-linked and autosomal recessive
• Neutrophils and monocytes can ingest but not kill catalase-positive micro- organisms
• Findings:

°         Recurrent lymphadenitis, pneumonia, skin infections

• Hepatic abscesses
• Osteomyelitis at multiple sites
• Unusual infections with catalase-positive organisms:

} S. aureus (most)

} Nocardia sp.

} S. marcescens

} B. cepacia

} Aspergillus

}  C. albicans

• Diagnosis—NBT now replaced by more accurate flow cytometry test using dihy- drorhodamine 123 fluorescence (DHR test)
• Treatment—bone marrow transplant