As previously discussed, many immunologically normal children experience frequent, transient, nonsevere respiratory tract infections, occasionally in tandem with AOM. Although there are no scientific data to buttress this claim, our practice experience suggests that many of these children are fair-skinned, blue-eyed, and blond. If the child has had no invasive infections, is well between episodes, has a history suggestive of frequent exposure to infectious agents, is exposed to tobacco smoke in the home, has normal growth and development, has a normal physical examination, and/or has never been hospitalized for infection, the parents may be reassured that the child does not have an immune deficiency. Frequency of infections may be decreased by common sense behaviors such as frequent handwashing, decreasing exposure to environmental tobacco smoke, and removal from day care or placement in a day care with fewer children. As these children grow, their immune system strengthens and the frequency of infection naturally decreases. In general, infection and illness are less frequent in the summer months.

In addition to the modifiable factors listed above, bad luck is frequently the stated explanation for why some children experience “more than their share” of respiratory infections. However, it is likely that certain genetic polymorphisms play a role in the risk for infection. For example, mannose binding lectin (MBL) is an acute phase protein that is secreted by hepatocytes. Part of the innate immune system, it is able to activate complement via the classic pathway. Several mutant alleles in the MBL gene have been described, and about 5% of the population is homozygous for these mutant alleles; thus, they have very low levels of MBL in serum.⁵ A population-based, prospective cohort study from Greenland showed that among children aged 6–17 months, MBL-insufficient children experienced 2.9 times more acute respiratory infections (95% CI, 1.8–4.8) than MBL-sufficient children.⁶ There was no effect among children aged 18–23 months, suggesting that once the adaptive immune system matures, the presence of MBL is less important.

Polymorphisms in other genes that encode proteins involved in immune function are also relatively common. Examples include the 4th component of complement (C4) and the Fcγ receptor on phagocytic cells (a receptor necessary for bacteria opsonized with Ig [immunoglobulin] G to be ingested by phagocytes). Patients with either of these defects (partial C4 deficiency or the presence of an Fcγ receptor with decreased affinity for IgG-coated bacteria) appear to be at increased risk for various infections.⁷

Children with CF often present in the first few years of life with a history of frequent respiratory
infections and poor growth. They may have a history of slow passage of meconium in the newborn period. Parents may also state that kissing the child leaves a salty taste in the mouth. Because CF is common (prevalence ∼1 in 2,500), easily diagnosed, and requires complex medical care, a sweat test for this condition should be ordered whenever the diagnosis is considered (Chapter 22).

This is the preferred term for a group of disorders characterized by abnormal ciliary structure or function. About 50% of patients with PCD have situs inversus, in which case the term Kartagener syndrome is used. Like CF, PCD is usually transmitted in an autosomal recessive fashion. It is much less common than CF; the estimated prevalence is 1 in 20,000. However, symptoms are milder than in patients with CF, and it is probably underdiagnosed.⁸ In one series of 55 children with PCD, 37 (67%) had a history of neonatal respiratory distress, 38 (69%) had situs inversus, and 42 (76%) had a history of early-onset persistent rhinorrhea. The mean age at diagnosis was 4.4 years, which is considerably younger than in most series.⁹ Bronchiectasis and nasal polyps are common but do not usually manifest until the second decade of life. One group has proposed the following criteria for investigating the possibility of PCD: (a) patients with chronic otitis, rhinosinusitis, and bronchitis in whom other entities have been excluded (CF, allergy, immunologic disorders, and α₁-antitrypsin deficiency); (b) term infants with neonatal respiratory distress syndrome of unknown cause; and (c) patients with situs inversus and recurrent airway infections.¹⁰

The diagnosis is usually made by epithelial cell brushing from the nasal turbinates or bronchi. Ciliary beat frequency is evaluated by phase-contrast microscopy and ultrastructural changes are detected by electron microscopy. Concurrent bacterial infection can cause secondary ciliary dyskinesia, so ciliary brushings should be obtained at least 4–6 weeks after resolution of a respiratory infection.

A child who has recurrent pneumonia, especially if all episodes occur in the same lobe, may have a structural abnormality that predisposes to the development of infection, such as congenital cystic adenomatoid malformation or pulmonary sequestration (Chapter 8). These conditions are best diagnosed by fine cut computed tomography.

Perhaps the most common of the usually symptomatic humoral immune deficiency syndromes, transient hypogammaglobulinemia of infancy may be just an exaggeration and prolongation of the physiologic gamma globulin nadir that all infants experience.¹² These children are typically well during the first 3–6 months of life, when passive antibody from their mothers provides protection against most common pathogens. As this pool of passive antibody disappears, however, these patients begin to experience recurrent respiratory tract infections. Common cold syndrome and AOM are the most common syndromes, but sinusitis, bronchiolitis, and pneumonia may also occur. Recurrent gastroenteritis or “formula intolerance” has also been described.¹² Generally, babies with this syndrome do not become infected with atypical pathogens, nor do they experience severe or life-threatening infections. In contrast to patients with X-linked agammaglobulinemia (discussed in the following text), patients with transient hypogammaglobulinemia of infancy have normal levels of circulating B cells and mount normal responses to diphtheria and tetanus immunizations.¹³ Although IgG is the principal antibody isotype affected, levels of other antibodies may also be decreased. In one series of 40 patients, IgG levels were low in 30 (75%), IgA levels were low in 17 (43%), and IgM levels were low in 10 (25%). Physical examination should reveal the presence of lymphoid tissue, without lymphadenopathy. Immunoglobulin levels eventually normalize; occasionally, patients will require IVIG therapy for a few months to a year.^12,14 In most patients, immunoglobulin levels are normal by age 3 years, but in some they may be subnormal until 5 years.¹⁴ In a few, transient hypogammaglobulinemia of infancy is a precursor of a persistent immunoglobulin problem, usually IgA deficiency.¹¹

XLA is due to a B-cell maturational defect.¹⁵ It is caused by a mutation in the gene encoding Bruton tyrosine kinase (BTK), a cytoplasmic protein required
for the growth and development of B-cell precursors. Without it, B-cells never become antibody-secreting cells; therefore, antibody is scant to absent. Circulating B cells in the blood are similarly missing. This disorder presents similarly to transient hypogammaglobulinemia of infancy, previously described, in that the first few months of life are uneventful, attributable to passive maternal antibody. Thereafter, the child develops frequent sinopulmonary infections, mostly due to encapsulated gram-positive organisms, especially S. pneumoniae. Most of these bacterial infections can be readily treated with antibiotics; their frequency, however, can lead to destructive processes in the lungs and sinuses. Patients with agammaglobulinemia are also subject to severe or prolonged infections with nonenveloped viruses, especially the enteroviruses. Chronic enteroviral meningitis is an especially interesting syndrome seen almost exclusively in patients with XLA.¹⁶ Progressive viremia and paralytic poliomyelitis secondary to live attenuated oral polio vaccine (no longer available in the United States) has also been described in these patients. T-cell function is normal or nearly so. Therefore, patients with this disorder do not suffer from fungal infections or prolonged infection with enveloped viruses, such as respiratory syncytial virus (RSV) or influenza virus. The gene defect for XLA has been located to the X chromosome at position Xq21.2-22. Carrier females are immunologically normal. Physical examination of these children is generally unremarkable except that lymphoid tissue is scant. If a patient with a compatible clinical history has no visible tonsils and no palpable lymph node enlargement, the diagnosis of XLA should be strongly considered.

CVID is a complex and heterogeneous immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and a variety of immunological abnormalities. In addition to recurrent infections (primarily upper and lower respiratory infections), patients with this syndrome are also at increased risk for autoimmune disease and malignancy.¹⁷ The incidence is approximately 1 in 100,000. The exact genetic defect is unknown, and it is likely that several different defects can result in the CVID phenotype. CVID can occur at any age; in most patients the disease does not become clinically apparent until the second or third decade of life. Its presentation can mimic that of cystic fibrosis. Most cases are sporadic but sometimes there is a family history of CVID (or of selective IgA deficiency). Unlike patients with XLA, circulating numbers of B cells are usually normal. However, IgG, IgM, and IgA levels are all usually decreased. In at least some cases of CVID, the fundamental immunologic abnormality is probably due to a defect in T cell help.¹⁸

Like patients with XLA, patients with CVID experience recurrent infections (especially sinusitis, otitis media, and pneumonia) with encapsulated organisms. Diarrhea, particularly due to Giardia, is common. Persistent enteroviral meningitis has also been described but is less common than in patients with XLA.¹⁹ Some patients with CVID also develop infections typical of patients with T-cell defects, such as Pneumocystis pneumonia.

About 20% of patients with CVID develop an autoimmune disease. Hemolytic anemia and immune thrombocytopenic purpura are the two conditions most commonly seen. Lymphoproliferation occurs in about 30% of patients and is manifested by adenopathy and splenomegaly. Some patients develop malignant lymphoma.

Two boys with a clinical syndrome resembling that of X-linked agammaglobulinemia who had grossly elevated levels of IgM and low to absent IgG and IgA were the first case reports of the syndrome now called Hyper-IgM syndrome. Subsequently, female cases were also reported. The phenotype is similar to that of XLA, except that patients with Hyper-IgM syndrome are also prone to some opportunistic infections, especially Pneumocystis jiroveci pneumonia. Patients with this syndrome also have a high incidence of autoimmune hematologic problems, including hemolytic anemia, thrombocytopenic purpura, and, especially, neutropenia. The disorder is caused by the inability to “class switch.” Resting B cells express IgM; antigenic stimulation, therefore, produces IgM first. In order to produce IgG or IgA, class switching must take place. In the absence of the ability to class switch, IgM levels become elevated. Although most patients have very elevated total IgM levels (more than 1,000 mg/dL), some patients have levels in the normal range. IgG levels are usually less than 150 mg/dL and IgA is not detectable. Class switching requires two signals, one
of which is the interaction of CD40 (expressed on B cells) and CD154 (CD40 ligand, expressed on T cells). Patients with the X-linked form of Hyper-IgM syndrome are incapable of producing functional CD154. This defect can be detected in utero.²⁰ Patients with the less common autosomal recessive variant have a different genotype. In these patients, class switching does not take place, despite appropriate cross-linking of CD40, suggesting a downstream signaling defect.²¹

IgA is the most plentiful immunoglobulin in the body. Much of it is locally produced and secreted, and the presence of specific IgA on mucosal surfaces has been shown to be protective against a variety of infections that begin with replication at those sites. These two facts, taken together, would suggest that IgA deficiency would predispose to frequent and severe infections of the respiratory and gastrointestinal tracts. However, most people with IgA deficiency do not know they are IgA deficient, as they are entirely asymptomatic.²² It has been estimated that from 1 in 300 to 1 in 700 individuals lacks appreciable IgA, which makes IgA deficiency the most common immunoglobulin deficiency.

IgG can be divided into four different subclasses. Some people have a deficiency of one or more of these subclasses, sometimes even in the face of a normal total IgG. There is considerable controversy regarding the role of IgG subclass deficiency in patients with frequent sinopulmonary infections. Patients with frequent, nonsevere infections who have deficiencies of one or more of the IgG subclasses have certainly been described. However, subclass deficiencies can also be found in healthy control subjects, particularly children in the first 4 years of life.

The fundamental question is whether there is a difference in the function of the different IgG subclasses; if there is not, then as long as total IgG levels are normal, subclass deficiency would not be expected to cause any problems. When subclass deficiencies were first described, there were reports that IgG2 was more important in the response to polysaccharide antigens. A failure to respond well to polysaccharide antigens would certainly predispose one to the type of infections generally seen in antibody-deficient patients. However, this was an in vitro finding, and it was not supported by subsequent in vivo experiments. Many papers describing frequent and severe infections in patients who have a combination of IgA deficiency and IgG subclass deficiency have been published.^23,24 Despite this, it is not clear how much of the problem stems from the IgA deficiency, and how much, if any, is attributable to the associated IgG subclass deficiency. It is probably fair to say that IgG subclass deficiency by itself is rarely a cause of significant recurrent infectious problems. A small percentage of patients with IgG subclass deficiency later go on to develop common variable immunodeficiency. In addition, in some families, one individual will have selective IgA deficiency, another will have IgG subclass deficiency, and yet another will develop CVID. Thus, these conditions may represent a spectrum of abnormalities of B-cell maturation.

One expert has suggested the following criteria for diagnosis of clinically significant IgG subclass deficiency: (a) a history of recurrent bacterial infections, primarily respiratory; (b) impaired response to immunization with protein and/or polysaccharide antigens; (c) significant reductions in serum concentrations of one or more IgG subclasses; and (d) age 4 years or older.²⁵

Antibodies to protein antigens and antibodies to polysaccharide antigens are made through different pathways. Antibodies to polysaccharides are made by thymus-independent (T-independent) pathways. These pathways are generally not well developed in children until about the age 2 years. This explains why babies do not make good responses to polysaccharide vaccines (like the 23-valent polysaccharide pneumococcal vaccine or the quadrivalent meningococcal vaccine). Some patients never really fully develop the ability to mount responses to polysaccharide antigens.²⁶ These patients may be plagued by recurrent infections with encapsulated bacteria, especially S. pneumoniae. Their immunoglobulin levels may be normal, and IgG subclasses may also be normal, although low levels of IgG2 are not uncommon.

Although recurrent respiratory tract infections is not the usual presentation of children with untreated
HIV infection, the mother’s HIV status should be ascertained in all children with frequent infections, and the child should be tested for HIV antibody if the mother’s status is unknown.

Complement deficiencies are considerably less common than immunoglobulin deficiencies. Deficiency of one of the early components (especially C1q), however, closely resembles immunoglobulin deficiency. These patients generally suffer recurrent sinopulmonary infections with encapsulated bacteria (S. pneumoniae is the most common pathogen).²⁷ As a secondary effect, serum IgG may be decreased; IgG2 and IgG4 are almost always low.²⁸

Patients with C3 deficiency are generally more severely affected and suffer more frequent recurrences of infection. They are also more likely to have systemic infections such as bacteremia or meningitis. About 80% of these children also develop autoimmune disorders.²⁷

Though nonspecific, much useful information can be obtained from the CBC, including the presence or absence of anemia, neutropenia, neutrophilia, eosinophilia, and lymphopenia.

The presence of Howell-Jolly bodies suggests functional or anatomic asplenia.

Most laboratories are able to provide total immunoglobulin levels in a reasonable amount of time. Generally, IgG, IgA, and IgM levels are reported unless others are specified. When hyper-IgE syndrome (discussed later) is suspected, it is advisable to ask for IgE levels as well. It is not necessary to ask for IgG subclass levels on a routine basis. Immunoglobulin levels do not provide information about the production of specific immunity, but this is still a reasonable first screening test.

It is often useful to know whether the patient is able to mount an antibody response to an antigen to which he or she is known to be exposed. Most patients have had some immunizations; therefore, antibody levels against one or more of these immunogens can be obtained. Antitetanus and antidiphtheria antibody titers are commercially available. These antibodies are of the T-dependent type. To test T-independent responses, one can administer the 23-valent polysaccharide pneumococcal vaccine and measure the type-specific antibody response 1 month later. Ideally, prevaccination and postvaccination titers are measured simultaneously. If the child has previously received the 7-valent conjugated pneumococcal vaccine, one cannot ascribe a response to those 7 serotypes (4, 6, 9, 14, 18, 19, and 23) as indicative of a functional response to polysaccharide antigens. Also, recall that children younger than about 2 years are expected to have a very poor immune response to polysaccharide antigens, no matter how they are tested.

If the child has a protective antibody titer to tetanus but a low titer to diphtheria, the child should be given a booster vaccine, and the level rechecked in 2–3 weeks. If it boosts into the normal range, the patient is able to mount appropriate T-dependent antibody responses.

Unless it can be specifically proven that the child could not possibly have HIV infection, HIV antibody titer should be obtained as part of the workup of any child with frequent, recurrent, or recalcitrant infections. Infection with an opportunistic pathogen is even more suggestive of the possibility of HIV infection.

A sweat chloride is a simple screening test for cystic fibrosis. The test results are reliable when it is performed at a site with considerable experience.
Patients with suspected CF should be referred to such a site to obtain the test.

If more common causes of recurrent respiratory infections have been ruled out, an ENT (ear, nose and throat) physician can be consulted to perform a ciliary biopsy.

A chest radiograph should be obtained to look for evidence of chronic lung disease or bronchiectasis. If the patient has a suspected anatomic abnormality or foreign body, a fine-cut chest CT (computed tomography) should be obtained.

A CH50 is a reasonable screening test for patients in whom early complement component deficiency is suspected.

If suspected based on history and physical examination, pulmonary function testing in children more than 6 years old or a trial of bronchodilator therapy (children younger than 6 years) should be considered. Referral to an allergist for skin testing may be indicated if the child has symptoms suggestive of allergies (such as sneezing, itching, or a prominent seasonal component).