Key Points
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Chronic/recurrent respiratory tract infections are common problems for children with allergy but may also be the presenting symptoms of an underlying defect in host defense such as primary and secondary immunodeficiency, cystic fibrosis, ciliary dyskinesia and dysfunctional swallowing.
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Diagnosis of an underlying disorder is essential for optimal clinical management.
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Presenting features of immunodeficiency include increased susceptibility to infection (chronic or recurrent infections, infections of unusual severity, infections caused by opportunistic pathogens), autoimmune/inflammatory disorders and syndrome complexes.
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The types of infections and other symptoms should guide the choice of screening laboratory tests.
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Mutation analysis can confirm the diagnosis and facilitate genetic counseling and screening of other family members who may be asymptomatic.
Many children who present for allergy evaluation have chronic/recurrent respiratory tract infections. Allergy may predispose the patient to such symptoms because swelling of the nasal mucosa causes obstruction of the sinus ostia and eustachian tubes. However, one must be alert to the possibility of other underlying problems, including primary immunodeficiency diseases, secondary immunodeficiency caused by other illnesses or medications, cystic fibrosis, ciliary disorders and pulmonary aspiration. Environmental factors such as exposure to cigarette smoke, day care and the number of household members must also be considered. This chapter provides an approach to evaluating children for these disorders.
Definition of Recurrent Infections
It is difficult to define increased susceptibility to infection with precision ( Box 7-1 ). For example, chronic/recurrent otitis media is very common in the first two years of life but thereafter decreases in frequency. Rather than defining an arbitrary number of ear infections that is ‘too many’, the nature and pattern of those infections provide a more reliable guide to identify the child who deserves further evaluation. Ear infections that increase in frequency after the age of 2 years, are associated with infections at other sites or occur in the context of failure to thrive should raise the suspicion of an underlying disorder. Similarly, it is unusual for a child to have more than one episode of pneumonia per decade of life, chronic or recurrent sinusitis or bronchitis.
Frequency
More than one episode of pneumonia per decade of life
Increasing frequency of otitis media in children older than 2 years
Persistent otitis media and drainage despite patent tympanostomy tubes
Persistent sinusitis despite medical and, when appropriate, surgical treatment
Severity
Pneumonia with empyema
Bacterial meningitis, arthritis or osteomyelitis
Sepsis
Mastoiditis
Infection with opportunistic pathogens
Pneumocystis jirovecii pneumonia
Mucocutaneous candidiasis
Invasive fungal infection
Vaccine-acquired poliomyelitis
Bacille Calmette-Guérin infection after vaccination
Infections at multiple anatomic locations
Lack of other epidemiologic explanations (e.g. daycare center, exposure to cigarette smoke, environmental allergies)
Anatomic or physiologic features suggestive of a syndrome complex
Failure to thrive
Other clues to an abnormal susceptibility to infection include a history of infections at multiple anatomic locations or relatively unusual infections such as sepsis, septic arthritis, osteomyelitis and meningitis. In some instances, patients may present with one or more infections that are unusually severe, lead to an unexpected complication (e.g. pneumonia with empyema or otitis media with mastoiditis) or are caused by an organism of relatively low virulence (e.g. Aspergillus or Pneumocystis jirovecii).
Sometimes, the most challenging aspect of evaluating the past medical history is assessing the reliability of the data. It may be difficult to distinguish pneumonia from atelectasis with fever in children with reactive airway disease. Sinusitis is easily mistaken for purulent rhinitis, unless a computed tomography scan documents sinus involvement. Diarrhea may be the result of infection or an adverse effect of antibiotic therapy. Finally, the infections in a patient with an immunodeficiency may not be severe or progressive because of rapid institution of antibiotic therapy. Indeed, many patients ultimately diagnosed with a primary immunodeficiency present with an infection history that is not distinguishable from normal children.
It is also important to account for environmental exposure. There is an obvious explanation for frequent infections in an infant attending a large daycare center during the winter months, whereas the same number of infections might raise concern in an only child cared for in the home. Similarly, exposure to cigarette smoke and drinking from a bottle in a supine position are known risk factors for a variety of respiratory tract symptoms including infections. A sometimes useful clue is whether the child has had distinctly more infections than his/her siblings by a comparable age.
Early diagnosis of an underlying disorder is critical because it may lead to more effective approaches to therapy and appropriate anticipatory guidance. Furthermore, because some underlying disorders are inherited in Mendelian fashion, early diagnosis is essential for making genetic information available to the families of affected individuals.
The Clinical Presentation of Underlying Disorders
Allergy
Patients with allergic disease, rhinitis and/or asthma often have symptoms of both acute and chronic sinusitis. There is little to distinguish the symptoms or mucopurulent discharge in patients with immunodeficiency compared with those with allergic disease. Similarly, radiographic studies do not discriminate between the two. History is important because flare-ups of sinusitis often accompany exacerbations of the underlying allergic symptoms, and patients may report more symptomatic improvement when treated with corticosteroids than when treated with antibiotics. In general, a history of atopy makes a diagnosis of immunodeficiency less likely because the ability to produce specific IgE antibodies usually indicates normal B and T cell function. However, there are several exceptions to this generality. These include Wiskott-Aldrich syndrome (thrombocytopenia, eczema, immunodeficiency), hyper-IgE syndromes (severe atopic dermatitis and a history of retained primary teeth, bone fractures, pneumonia sometimes with empyema, or chronic/recurrent cutaneous viral infections such as warts and molluscum contagiosum) and the syndrome of X-linked immunodeficiency/dysregulation with polyendocrinopathy and enteropathy or IPEX (males who present early in life with severe atopic dermatitis, food and environmental allergies in association with endocrinopathy, especially insulin-dependent diabetes, and chronic diarrhea).
Recurrent sinopulmonary infections are also the most frequent illnesses associated with selective IgA deficiency, and IgA deficiency and allergy may be associated with each other. Even in blood bank donors in whom IgA deficiency was accidentally discovered, allergy may be twice as common as in healthy donors. The most common allergic disorders in IgA-deficient individuals are rhinosinusitis, eczema, conjunctivitis and asthma.
Because of the association between allergy and sinusitis, a careful history may often be sufficient, obviating the need for extensive testing for immunodeficiency. Screening for IgA deficiency may be of some help in understanding the association between the two in IgA-deficient individuals. Management of sinusitis should be medical with avoidance of surgery, unless all else fails.
Immunodeficiency
The primary immunodeficiency diseases were originally viewed as rare disorders, characterized by severe clinical expression early in life. However, it has become clear that these diseases are not as uncommon as originally suspected, that their clinical expression can sometimes be relatively mild, and that they are seen nearly as often in adolescents and adults as they are in infants and children. In fact, the presentation of immunodeficiency may be so subtle that the diagnosis will be made only if the physician is alert to that possibility.
Patients with primary immunodeficiency diseases most often are recognized because of their increased susceptibility to infection, but they may also present with a variety of other clinical manifestations ( Box 7-2 ). In fact, noninfectious manifestations, such as autoimmune disease, may be the first or the predominant clinical symptom of underlying immunodeficiency. Other immunodeficiency diseases may be diagnosed because of their known association with syndrome complexes.
Increased susceptibility to infection
Chronic/recurrent infections without other explanations
Infection with organism of low virulence
Infection of unusual severity
Autoimmune or inflammatory disease
Target cells (e.g. hemolytic anemia, immune thrombocytopenia, thyroiditis)
Target tissues (e.g. rheumatoid arthritis, vasculitis, systemic lupus erythematosus)
Syndrome complexes
Infection
An increased susceptibility to infection is the hallmark of the primary immunodeficiency diseases. In most patients, the striking clinical feature is the chronic or recurring nature of the infections rather than the fact that individual infections are unusually severe. However, not all immunodeficient patients are diagnosed after recurrent infections. In some, the first infection may be sufficiently unusual to raise the question of immunodeficiency. For example, an infant who presents with infection caused by P. jirovecii or another opportunistic pathogen is likely to be immunodeficient even if it is his or her first recognized infection.
Autoimmune/Chronic Inflammatory Disease
Immunodeficient patients can present with autoimmune or chronic inflammatory diseases. It is thought that the basic abnormality leading to immunodeficiency may also lead to faulty discrimination between self and non-self and, thus, susceptibility to develop an autoimmune disease. The manifestations of these disorders may be limited to a single target cell or organ (e.g. autoimmune hemolytic anemia, immune thrombocytopenia, autoimmune thyroiditis, inflammatory bowel disease) or may involve a number of different target organs (e.g. vasculitis or systemic lupus erythematosus). The autoimmune and inflammatory diseases are more commonly seen in particular primary immunodeficiency diseases, most notably common variable immunodeficiency, selective IgA deficiency, chronic mucocutaneous candidiasis and deficiencies of early components (C1 through C4) of the classical complement pathway.
Occasionally, a disorder that appears to be autoimmune in nature may in fact be due to an infectious agent. For example, the dermatomyositis that sometimes occurs in patients with X-linked agammaglobulinemia (XLA) is actually a manifestation of chronic enterovirus infection and not an autoimmune disease.
Syndrome Complexes
Immunodeficiency can be seen as part of a constellation of signs and symptoms in a syndrome complex. In fact, the recognition that a patient has a syndrome in which immunodeficiency occurs may allow a diagnosis of immunodeficiency to be made before there are any clinical manifestations of that deficiency ( Table 7-1 ). For example, children with the DiGeorge syndrome are usually identified because of the neonatal presentation of congenital heart disease, hypocalcemia, or both. This should lead to T lymphocyte evaluation before the onset of infections. Similarly, a diagnosis of Wiskott-Aldrich syndrome can be made in young boys with eczema and thrombocytopenia even before the onset of infections.
| Syndrome | Clinical Presentation | Immunologic Abnormality | Other Contributing Factors | Genes |
|---|---|---|---|---|
| Ataxia telangiectasia | Ataxia, telangiectasia | Variable B and T lymphocyte dysfunction | Dysfunctional swallow with pulmonary aspiration | ATM |
| DiGeorge syndrome | Congenital heart disease, hypoparathyroidism, abnormal facies | Thymic hypoplasia or aplasia | Craniofacial anomalies including cleft palate; physiologic abnormalities including dysfunction of soft palate | 22q11 deletion, 10p14 deletion, and others |
| Dysmotile cilia syndromes | Situs inversus, male infertility, ectopic pregnancy, upper and lower respiratory tract infections | None | 30 different genes | |
| Hyper-IgE syndromes | Coarse facies, eczematoid rash, retained primary teeth, bone fractures, pneumonia, chronic or recurrent cutaneous viral infections | Elevated serum IgE, eosinophilia | STAT3 (autosomal dominant) DOCK8 (autosomal recessive) | |
| Wiskott-Aldrich syndrome | Thrombocytopenia, eczema | Variable B and T lymphocyte dysfunction | WAS |
Cystic Fibrosis
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders among white populations, occurring with an incidence of almost 1 in 3,000 live newborns. The classic presentation of CF with chronic/recurrent sinopulmonary infections caused by Pseudomonas and Staphylococcus, diarrhea with malabsorption and failure to thrive, is easy to recognize. Newborn screening and new methods for diagnosis have led to the recognition of a broader clinical phenotype, including patients whose first or only manifestation is chronic/recurrent sinusitis. The diagnosis of CF should be considered in any patient with chronic/recurrent sinopulmonary infections, especially if Pseudomonas, Staphylococcus or Burkholderia cepacia is identified as a pathogen.
Abnormalities of Airway Anatomy and Physiology
A variety of anatomic abnormalities may increase a child’s susceptibility to upper and lower respiratory tract infections. Some, such as craniofacial anomalies involving the palate and the nose, may be readily apparent on physical examination. Others, such as bronchogenic cysts and extralobar pulmonary sequestrations, may be suspected when recurrent infections occur at a single anatomic site. Unilateral otitis media and sinusitis in a young child should prompt an investigation for a nasal foreign body.
Abnormalities of airway muscle function may cause similar symptoms. Swallowing dysfunction with aspiration may be obvious in a child with cerebral palsy who coughs and gags when eating. More subtle clues are a history of drooling or dysarthria.
Disorders of Ciliary Structure and Function
Primary ciliary dyskinesia (PCD) is a rare problem, estimated to occur with an incidence of less than 1 in 10,000 in the general population. In most cases it is inherited as an autosomal recessive trait, but PCD is genetically and clinically heterogeneous. Affected individuals have chronic/recurrent rhinitis, otitis media, sinusitis, pneumonia and bronchiectasis that begin at an early age. In approximately half of the cases there are accompanying abnormalities of laterality such as situs inversus or heterotaxy, and complex congenital heart disease has been reported in approximately 10% of cases. Abnormal ciliary function of spermatozoa can cause infertility in males, and abnormal ciliary function in the fallopian tubes can cause ectopic pregnancy.
PCD can be caused by abnormalities of any of the ciliary structural proteins (inner or outer dynein arms, radial spokes or microtubules) or by disordered orientation of cilia on mucosal surfaces, preventing them from beating in a synchronized wave that clears mucus from the airways. Identification of genetic mutations may diagnose PCD despite normal ultrastructural findings by electron microscopy.
Secondary Immunodeficiency
Immunodeficiency may occur secondary to other illnesses or medications. A variety of infections (including HIV, measles and Epstein-Barr virus [EBV]) may cause either temporary or long-lived abnormalities of humoral and/or cell-mediated immunity. Malnutrition or malabsorption can cause hypogammaglobulinemia and impaired cell-mediated immunity. A number of medications, most notably corticosteroids and chemotherapeutic agents, are immunosuppressive; phenytoin and other anticonvulsants can cause IgA deficiency and rarely panhypogammaglobulinemia. Posttraumatic splenectomy, or the ‘autosplenectomy’ that occurs at an early age in sickle cell anemia, leads to an increased risk of sepsis. Susceptibility to specific infections is determined by the cause of the secondary immunodeficiency; that is, patients with acquired deficiency of humoral immunity are at highest risk for infections with encapsulated bacteria and enteroviruses, whereas patients with acquired deficiency of cell-mediated immunity are at risk for infection by a wide variety of bacterial, fungal and viral pathogens.
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