Congenital Immunodeficiencies
Congenital Immunodeficiencies: Excerpt from Pediatric Infectious Disease
Basic Considerations
Pediatricians who manage serious pediatric infections must often address a basic
question:
Primary Immunodeficiencies
Epidemiology
The identification of primary immunodeficiencies in children is critical. A
child with an unrecognized immunodeficiency may expire from an overwhelming
opportunistic infection. Even when not fatal, multiple pneumonias in such
patients can progress to chronic, debilitating pulmonary disease. Children with
underlying immunodeficiency are also susceptible to adverse reactions if
administered live vaccinations. It is important that the pediatrician consider
the possibility of underlying immunodeficiency when managing serious infections
in the first year of life.
The average child can have between six and eight respiratory infections per
year. This number can increase if there are additional risk factors, such as
attendance at day care, sibling exposures, or atopic disease. Although parents
may complain that their child is
“always sick,” these infections are usually self-limited upper respiratory infections.
Age-related Clinical Patterns for Primary Immunodeficiencies
The immunodeficiencies involving T cells, such as severe combined
immunodeficiency (SCID) or DiGeorge
’s syndrome, appear at an earlier age. These defects often present in the first 6
months of life with failure to thrive, diarrhea, pneumonia, and thrush.
Significant lymphopenia is often seen. Antibody deficiency disease, such as
X-linked agammaglobulinemia (Bruton
’s disease) often clinically manifest as maternal immunoglobulin levels wane
after 6 months of age. Immunoglobulin deficiencies typically present with
severe recurrent bacterial respiratory infections.
Presentation
It can be a considerable challenge for the primary care physician to distinguish
the immunologically normal child having recurrent viral infections from the
child who may have a primary immunodeficiency that requires specific diagnosis
and therapy.
There has been an attempt to devise criteria for the evaluation of primary
immunodeficiencies, often referred to as
“red flags.”
Diagnosis
Once a decision to screen for primary immunodeficiency is made, the following
can be helpful laboratory screen:
• Measurement of serum immunoglobulin levels, including immunoglobulin E (IgE)
• Quantification of specific antibody responses to vaccination
• Absolute lymphocyte count
• T-cell numbers: (CD3, CD4, CD8) and B-cell numbers (CD19, CD20)
• In vitro lymphocyte proliferation tests (T cell function)
• Total complement levels (CH50)
• Nitroblue tetrazolium test (NBT)
Screening labs which come back abnormal, particularly in the correct clinical
context, warrant referral to a pediatric immunologist or infectious disease
specialist.
Specific Primary Immunodeficiencies
X-linked Agammaglobulinemia
Epidemiology and Etiology
Bruton’s agammaglobulinemia is a pure B-cell immunodeficiency with a prevalence of 1 in
100,000 male children. Fifty percent of cases lack a family history and are
thought to be the result of a spontaneous mutation. The cause of Bruton
’s agammaglobulinemia is a series of heterogenous mutations in the Bruton’s tyrosine kinase (BTK) gene, which is on the long arm of the X chromosome at locus q21.3. The result
of these heterogenous mutations is an arrest of B-cell maturation by the
defective production of a tyrosine kinase protein. Affected individuals are
unable to generate immunoglobulins.
Presentation
X-linked agammaglobulinemia is characterized by recurrent sinopulmonary
infections with pyogenic organisms, notably
Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae. Infections typically occur after the age of 6 months when maternal antibody
levels fall.
Pseudomonas species or staphylococcal sepsis associated with neutropenia has also been
described as a presenting symptom. Chronic
Giardia species infection and chronic enteroviral meningitis and meningoencephalitis
are also well documented in this condition.
Ureaplasma urealyticum has been reported as a cause of septic arthritis and chronic osteomyelitis in
patients with Bruton
’s agammaglobulinemia.
Diagnosis
Diagnosis of Bruton’s agammaglobulinemia is made by measurement of quantitative immunoglobulins as
well as quantitation of circulating CD19 cells (B cells). Typically, patients
have IgG levels of less than 200 mg/dL and no circulating B cells. Bruton
’s patients also typically do not make appropriate antibodies after routine
immunizations. Assays for mutations in the
BTK genes are done at research facilities and are not widely available.
Management
Treatment is the replacement of antibodies with intravenous immunoglobulin using
400 mg/kg per dose every 4 weeks. The goal is to maintain an IgG level of
greater than 500 mg/dL.
Hyper-IgM Syndrome
Epidemiology and Etiology
This syndrome usually has X-linked inheritance, but autosomal forms are
occasionally seen. Patients with hyper-IgM syndrome have low levels of IgG and
elevated levels of IgM. The cause of the condition is a defective or deficient
CD40 ligand, a type 2 transmembrane glycoprotein. This protein is involved in
the activation of B cells as well as in T-cell activation on monocytes and
macrophages.
Presentation
Children with this condition present with chronic pyogenic infections similar to
hypogammaglobulinemia patients. They are also susceptible to a variety of
infections usually characteristic of T-cell immunodeficiency.
Diagnosis
The high rate of P. jiroveci is a distinct feature of X-linked hyper-IgM syndrome and should be strongly
considered in an HIV-negative child with PCP and hypogammaglobulinemia. Chronic
diarrhea and failure to thrive are also frequently encountered in these
patients.
Management
Survival for this condition is poor and has been reported to be as low as 20% at
25 years of age. The mainstay of therapy is monthly intravenous immune globulin
(IVIG) and PCP prophylaxis. There is increasing enthusiasm for bone marrow
transplantation as a curative therapy.
DiGeorge’s Syndrome
Epidemiology and Etiology
DiGeorge’s syndrome is a congenital condition that results from alterations occurring
during development of the third and fourth pharyngeal pouches. DiGeorge
’s syndrome is characterized by unusual facial features, congenital heart
disease, and hypocalcemia.
Presentation
Most children with DiGeorge’s syndrome who have heart defects show a chromosomal 22Q11 deletion. It is
becoming apparent that the 22Q11 deletion syndrome includes not only DiGeorge
’s syndrome but also velocardiofacial syndrome. This deletion syndrome also has a
large variability in expression; defects can include cardiac abnormalities,
characteristic facial features, hypoparathyroidism, and cleft palate
abnormalities.
Diagnosis
The test for DiGeorge’s syndrome is a Fluorescence in situ hybridization (FISH) test on chromosome 22.
This test should be considered in a patient with congenital heart disease
(particularly abnormalities of the aortic arch) that is accompanied by unusual
facial features and hypocalcemia.
DiGeorge’s anomaly can also be associated with significant immunodeficiency. The initial
description focused on severe T-cell immunodeficiency, although this is now
considered rare, with an incidence of less than 2%. Despite the rarity of pure
T-cell immunodeficiency, there is a considerable spectrum of immunodeficiency
in patients with DiGeorge
’s syndrome.
It is believed that patients with “complete” DiGeorge’s syndrome (severe T-cell immunodeficiency) do not improve spontaneously and are
clinically similar to patients with severe combined immune deficiency. It has
been recommended that the test of choice for determining the degree of T-cell
immunodeficiency in DiGeorge
’s syndrome is the mitogen response; only patients with no mitogen response are
considered to have the complete form.
Although T-cell immunodeficiency in DiGeorge’s syndrome remains rare, it is increasingly appreciated that humoral
immunodeficiency is relatively common. In some series, more than three fourths
of patients with the 22Q11.2 deletion have a history of severe or recurrent
infection. In these patients, the humoral abnormalities can range from
decreased immunoglobulin measurements to abnormal responses to polysaccharide
vaccinations. It is recommended that the patients found with 22Q11 deletion
should undergo a thorough evaluation of both T-cell function and humoral
immunity.
Management
Treatment of patients with complete DiGeorge’s syndrome has typically been bone marrow or thymic transplantation.
Hyper-IgE Syndrome (Job’s Syndrome)
Epidemiology and Etiology
Hyper-IgE syndrome is a multisystem disorder characterized by recurrent skin
abscesses, pneumonia with pneumatocele formation, and elevated levels of serum
IgE. A genetic linkage to chromosome 4Q has been reported.
Presentation
Patients present with papular, pustular eruptions of the scalp and face in the
first year of life; these patients often have persistent eosinophilia. Skin
biopsy of the pustules reveals a perivascular dermatitis or folliculitis with a
predominance of eosinophils.
Diagnosis
The development of a high IgE level (usually greater than 2,000 µm/mL) and subsequent skin abscesses and/or pneumatoceles, suggest the diagnosis.
IgE levels may fluctuate unrelated to the severity of skin disease and
infection, and it may be necessary to obtain multiple levels to diagnose the
illness. Osteopenia and bone fractures have also been suggested as strongly
supportive of the disease. Coarse facial features, as well as delayed loss of
primary teeth, is well described in Job
’s syndrome.
Management
Treatment is supportive, consisting of often long-term treatment with an
antistaphylococcal antibiotic. Surgery may be necessary for persistent
pneumatocele formation.
Chronic Granulomatous Disease
Epidemiology and Etiology
In chronic granulomatous disease (CGD), usually X-linked recessive, patients
lack the ability for neutrophil oxidative metabolism. Neutrophils in patients
with chronic granulomatous disease cannot produce hydrogen peroxide, which
leads to an inability to kill ingested organisms.
Presentation
The most common organism causing infection in patients with CGD is S. aureus. Chronic pneumonia progressing to pneumatocele formation is a common presenting
sign. CGD may also present with fever of unknown origin and
S. aureus liver abscesses. Serratia marcescens adenitis and sepsis is another typical infection in patients with this
condition.
Pseudomonas cepacia, a common pathogen in end-stage cystic fibrosis, is also seen as a cause of
acute and chronic pneumonia in patients with this disorder. Granuloma formation
can cause obstruction of the urinary tract; patients present with abdominal
pain and hydronephrosis.
Diagnosis
The diagnosis is made by the nitroblue tetrazolium (NBT) test. This test
measures oxidative activity in white cells. A normal person will have a test
result of 95% to 100%; patients with CGD have a 0% NBT test. In addition to NBT
tests, reference laboratories can do genetic analysis to determine the exact
genetic mutation and thus the mode of inheritance.
Management
Treatment of patients with CGD includes lifelong prophylaxis against infection.
Oral trimethoprim-sulfamethoxazole, as well as itraconazole, is given. These
medications decrease the incidence of
S. aureus and Aspergillus species infections, respectively. In addition, subcutaneous gamma interferon
(Actimmune), given three
times per week, is used as a prophylactic agent. Corticosteroids can be useful
in treat
ment of granulomas causing obstructive symptoms.
Wiskott-Aldrich Syndrome
Epidemiology and Etiology
Wiskott-Aldrich syndrome is an X-linked disorder that usually becomes
symptomatic in early infancy. The responsible gene (
WASP) has been localized to the X chromosome. Mutations of the gene are thought to
affect T-cell functioning. The classic clinical triad of Wiskott-Aldrich is
thrombocytopenia, recurrent infections, and eczema.
Presentation
A common presenting sign in patients with this disorder is bleeding following
circumcision. Recurrent otitis media and respiratory infections are often seen.
Patients can also have abnormalities of both B-cell and T-cell immunity as well
as decreased responses to polysaccharide antigens. Children with this condition
have elevated IgA and IgE levels accompanied by low levels of IgM.
Diagnosis
The diagnosis is confirmed by the finding of small platelets. Patients with
Wiskott-Aldrich syndrome also have an increased incidence of autoimmune disease
and malignancies, particularly lymphomas. Prophylactic immunoglobulin and
aggressive management of breakthrough bacterial infections is often needed.
Management
Bone marrow transplantation can be curative.
Common Variable Immunodeficiency
Epidemiology and Etiology
Common variable immunodeficiency (CVI) is similar to Bruton’s hypogammaglobulinemia except that it appears to be acquired later in life
rather than being present at birth. Patients with CVI do not have the defects
in the CD40 ligand or the
BTK gene mutations that define hyper-IgM and Bruton’s agammaglobulinemia syndromes.
Presentation
The clinical manifestations of CVI are similar to those of primary
hypogammaglobulinemia. Patients have recurrent sinopulmonary disease, often
with
H. influenzae and S. pneumoniae. Involvement of the gastrointestinal tract can be seen in patients with CVI;
patients may have chronic malabsorption or chronic infection with
Giardia lamblia. Autoimmune disorders are more frequent in these patients and may include
rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis. The
risk for gastric carcinoma and lymphoma is also greatly increased in this
population.
Diagnosis
The diagnosis is suggested in a patient who suddenly develops recurrent
sinopulmonary infections, often requiring hospitalization and prolonged
antibiotics. Immunoglobulin levels are often markedly decreased, with IgG
concentrations less than 300 mg/dL.
Management
Patients need monthly immunoglobulin, usually at a dose of 400 mg/kg. Pneumonia
should be aggressively treated, often with long-term broad-spectrum
antibiotics. The development of bronchiectasis and chronic lung disease can
occur without aggressive and prolonged treatment.
Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCIDS) is a term given to a group of heterogenous disorders characterized by marked
deficiency of both B-cell and
T-cell immunity.
Epidemiology and Etiology
A large number of genetic defects may result in the final clinical picture of
T-cell and B-cell immunodeficiency.
Presentation
Patients are usually ill in the first months of life with failure to thrive and
chronic thrush. Severe lymphopenia, interstitial pneumonitis, and PCP are
common. Graft-versus-host disease (GVHD) is often seen and represents the
“reverse” of the more common host-versus-graft syndrome, in which a recipient (host)
rejects a transplanted donor organ (graft). In GVHD, it is usually maternal T
cells (graft) present in the neonatal circulation that, in the setting of
severe immunodeficiency, attack the child (host).
Diagnosis
Chronic dermatitis represents a common manifestation of GVHD in SCID and should
be considered an important clue in the correct clinical setting. Serum levels
of all immunoglobulins are usually markedly reduced. Peripheral T-cell number
and function are also low. Numerous defined genetic mutations have been shown
to result in SCID. In some instances, the genetic basis for the syndrome is
unknown.
Management
Therapy is IVIG replacement, prophylactic antibiotics, and consideration for
bone marrow transplantation. Early consideration of SCID in the appropriate
clinical context is critical because bone marrow transplantation is most
successful if done in the first 3 months of life.
Patients with severe combined immunodeficiency must not receive live viral
vaccines and should only receive irradiated, white blood cell
–depleted blood products.
Transient Hypogammaglobulinemia of Infancy
Epidemiology and Etiology
Following birth, maternally derived immunoglobulin declines, with the lowest
level reached at about 4 months of age. It is believed that there is a group of
infants in whom this physiologic nadir extends beyond 6 months of age. This
condition has been termed transient hypogammaglobulinemia of infancy. These
children have normal B-cell numbers and normal antibody responses to
immunization.
Presentation
Children who have the diagnosis of transient hypogammaglobulinemia of infancy
typically have an increased incidence of sinopulmonary infections, such as
otitis media, bronchitis, and sinusitis. Infections that are severe or with
opportunistic organisms, such as
P. jiroveci, are unusual and if present should warrant further investigation for an
alternative diagnosis.
Diagnosis
It has been suggested that the diagnosis of transient hypogammaglobulinemia can
only be made retrospectively. Alternative designations have been proposed,
including
“hypogammaglobulinemia of early childhood,” in which the addition of “recovery” or the “development of dysgammaglobulinemia” can eventually be added. Prospective series of patients with the diagnosis of
transient hypogammaglobulinemia of infancy have shown that most children
recover with normal immunoglobulin levels by 3 years of age. A minority of
patients with transient hypogammaglobulinemia of infancy continue to have low
immunoglobulin levels after this time.
Management
Treatment for this condition is generally supportive with aggressive antibiotic
therapy for respiratory infections. Immunoglobulin replacement therapy is
usually not given. Patients usually outgrow this condition by 2 to 3 years of
age, even if measured immunoglobulin concentration has not achieved normal
levels.
IgA Deficiency
Epidemiology and Etiology
Selective IgA deficiency is the most common primary immunodeficiency disease. It
is estimated that this immunodeficiency occurs in about in 1 in 500 children in
the general population. Patients with this disorder have serum IgA levels of
less than 5 mg/dL.
Presentation
Some affected individuals go through life without any difficulty, whereas others
have increased numbers of upper respiratory infections. Patients can present
with chronic otitis media, sinusitis, or pneumonia. It is thought that patients
who have IgA deficiency and chronic respiratory infections may also have
associated IgG subclass deficiency.
There are other associations with this disorder, including chronic Giardia species infection, autoimmune and rheumatic diseases including inflammatory
bowel disease, celiac disease, and systemic lupus erythematosus.
Diagnosis
There is no consensus on when a child with recurrent otitis or sinusitis should
have IgA and possibly IgG subclass levels evaluated. Many investigators
consider greater than six episodes of otitis media a year a reasonable cutoff
for evaluation.
Management
Commercial immunoglobulin preparations do not contain large amounts of IgA. In
addition, there is an increased incidence of anaphylactic reactions to
immunoglobulin and blood products in patients with IgA deficiency.
Treatment of selective IgA deficiency is not monthly IVIG but rather aggressive treatment with antibiotics for respiratory
infections.
Complement Deficiencies
The classic and alternative complement pathways are initiated by antigen–antibody complexes. Patients with congenital deficiencies of parts of their
complement system can be susceptible to infection with a variety of bacteria.
The most frequently discussed complement deficiency in pediatrics is terminal
portion complement deficiency of C5, C6, C7, C8 or C9.
Terminal Complement Deficiency C5 through C9
Terminal complement deficiency C5 through C9 is associated with increased susceptibility to Neisseria species infection.
Epidemiolo gy and Etiology
The terminal complement components C5 to C9 are considered vital in the
complement-dependent killing of
Neisseria meningitidis.
Presentation
There have been estimates that about one half of affected children will develop
meningococcal disease. Additional studies have suggested that about 15% of
children presenting with their first episode of meningococcal disease have
terminal complement deficiency. Some specialists point out that the actual
incidence of complement deficiency diagnosed after meningococcal sepsis is
highly variable and related to the nationality of the population being studied.
Diagnosis
Many clinicians perform a screening test for complement deficiency on all
patients with their first systemic meningococcal or gonococcal infection. An
appropriate screening test is a total hemolytic complement (CH50) screening
assay. Patients with underlying complement deficiency usually have a level of
less than 10 EIA units. In such patients, a complete evaluation for individual
complement levels should be done.
Management
Patients identified with complement deficiency should be given the quadrivalent
meningococcal vaccine because this may reduce the risk for disease. Some
patients are given continuous antimicrobial prophylaxis. Affected patients
should have careful counseling on the management of all febrile episodes.
Selected Readings
Bastian J, Law S, Vogler L, et al. Prediction of persistent immunodeficiency in
the DiGeorge anomaly.
J Pediatr 1989;115(3):391–396.
Gennery AR, Barge D, O’Sullivan JJ, et al. Antibody deficiency and autoimmunity in 22 q 11.2 deletion
syndrome.
Arch Dis Child 2002;86(6):422–425.
Leggiadro RJ. Systemic meningococcal infection and complement deficiency. Pediatr Infect Dis J 2003;22(8):760–761.
Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of x-linked hyper
IgM syndrome.
J Pediatr 1997;131:47–54.
Overturf GD. Indications for the immunological evaluation of patients with
meningitis.
Clin Infect Dis 2003;36(2):189–194.
Shearer WT, Buckley RH, Engler RJ, et al. Practice parameters for the diagnosis
and management of immunodeficiency. The Clinical and Laboratory Immunology
Committee of the American Academy of Allergy, Asthma and Immunology
(CLIC-AAAAI).
Ann Allergy Asthma Immunol 1996;76(3):
282–294.
Sneller, MC, Strober W, Eisenstein E, et al. NIH conference: new insights into
common variable immunodeficiency.
Ann Intern Med 1993;118(9):720–730.
Pictures
Book Source Details
- Book Title: Pediatric Infectious Disease
- Author(s): Donald Janner MD
- Year of Publication: 2004
- Copyright Details: Pediatric Infectious Disease, Copyright © 2004 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: Pediatric Infectious Disease
Authors: Donald Janner MD
Publisher: Lippincott Williams & Wilkins
Copyright: 2004
ISBN: 0-7817-5584-0
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