A Clinical guide to pediatric infectious disease

4

Congenital Immunodeficiencies

Basic Considerations

Pediatricians who manage serious pediatric infections must often address a basic question:

Is this infection the result of bad luck (i.e., when bad bacteria meet good children), or is it the result of an underlying immune problem?

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,

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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.”

Signs of Primary Immunodeficiency

·         A family history of primary immunodeficiency

·         Infections with unusual organisms, such as P. jiroveci (formally carinii), which are so rare in the normal host that their presence always warrants an immune evaluation

·         Recurrent deep-seated bacterial infections such as sepsis, osteomyelitis, or meningitis

·         Increased number or severity of routine infections. Although this can be difficult to quantitate, greater than eight episodes of otitis media or two serious infections in the course of a year have been suggested as cutoffs.

·         Failure to thrive in the first year of life

·         Persistent oral thrush or mucocutaneous fungal infections after the first year of life

·         Poor growth and development between infections

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 vitrolymphocyte proliferation tests (T cell function)
  • Total complement levels (CH50)
  • Nitroblue tetrazolium test (NBT)

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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.

A major clinical clue in patients with Bruton's agammaglobulinemia is the paucity of cervical lymph nodes and tonsillar tissues; patients with a history of recurrent otitis media or sinusitis should have a careful evaluation of lymphoid tissue.

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

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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.

X-linked (Burton's) Agammaglobulinemia

·         Recurrent sinopulmonary infections

·         Pseudomonas species sepsis

·         Chronic enteroviral encephalitis

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.

For patients younger than 1 year of age, the most common clinical presentation is Pneumocystis jiroveci (PCP) infection.

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.

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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.

Hyper-IgM Syndrome

·         Low immunoglobulin with elevated IgM levels

·         Pneumocystis pneumonia

·         Pyogenic infection

·         Chronic Giardia species infection

·         Defective or absent CD40 ligand

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.

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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.

A major issue in the evaluation of DiGeorge's syndrome is to identify those patients who will have persistence of profoundly depressed T-cell immune function.

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.

DiGeorge's Syndrome

·         Facial defects, heart defects, hypocalcemia

·         Partial DiGeorge's syndrome: low T-cell function

·         Complete DiGeorge's syndrome: absent T-cell function

·         No spontaneous resolution with complete DiGeorge's syndrome

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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.

Hyper IgE Syndrome (Job's Syndrome)

·         Recurrent skin abscesses

·         Papulopustular rashes

·         Eosinophilia

·         Osteopenia, bone fractures

·         Recurrent pneumonia, pneumotocele formation

·         IgE levels may fluctuate over time

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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 marcescensadenitis 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 treatment of granulomas causing obstructive symptoms.

Chronic Granulomatous Disease

·         Majority are X-linked recessive

·         NBT = 0%

·         Common infections:
   S. aureus, pneumonia, liver abscess
   Aspergillus species, pneumonia, osteomyelitis
   Pseudomonas cepacia, pneumonia
   Serratia marcescens, adenitis, sepsis

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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.

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Management

Bone marrow transplantation can be curative.

Wiskott-Aldrich Syndrome

·         Triad of thrombocytopenia, recurrent infection, and eczema

·         Elevated IgA, IgE; decreased IgM

·         Small platelets

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.

The reason certain children lose the ability to make immunoglobulin is not clear. It is possible that this is caused by a variety of conditions rather than a single genetic defect. Patients with CVI may have normal or mildly decreased number of B cells.

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.

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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.

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Patients with severe combined immunodeficiency must not receive live viral vaccines and should only receive irradiated, white blood cell–depleted blood products.

Severe Combined Immunodeficiency

·         Heterogenous causes that result in a deficiency of T-cell and B-cell immunity

·         Failure to thrive

·         Chronic diarrhea

·         GVHD (rashes)

·         Pneumocystis jiroveci pneumonia

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.

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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.

Transient Hypogammaglobulinemia of Infancy

·         Prolonged nadir of immunoglobulin levels following the disappearance of maternal IgG

·         Recurrent mild respiratory infections

·         Normal B-cell numbers, response to immunizations

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.

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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.

Epidemiology 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.

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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 Child2002;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 Med1993;118(9):720–730.