History

The clinician must determine (1) the frequency, location, severity, and complications of the infections; (2) the accuracy of how infections were documented; (3) the presence or absence of a symptom-free interval; (4) the microbiologic features of any isolate; and (5) the response to antibiotic therapy. A single chronic infection may wax and wane with intermittent, inadequate treatment and may manifest as a series of infections. Furthermore, a detailed history can elucidate other risk factors for recurrent infections. Many nonimmune disorders are characterized by an increased susceptibility to infection that must also be considered (see Table 41.3 ). A detailed history can provide clues as to the likelihood and nature of a primary immune deficiency ( Table 41.4 ).

Perinatal History

The clinician should determine if there was exposure to maternal viral infection during gestation (human immunodeficiency virus [HIV], cytomegalovirus (CMV), herpes simplex virus, rubella), or a history of prematurity, blood transfusions, respiratory distress syndrome (with bronchopulmonary dysplasia), or other pertinent neonatal illnesses. Infants previously placed on ventilators may develop chronic obstructive lung disease (bronchopulmonary dysplasia), predisposing them to recurrent pulmonary infections. Most perinatal HIV infections are seen in children whose mother or mother’s partner has engaged in high-risk behavior (i.e., multiple sex partners or use of cocaine or intravenous drugs). Attention should be paid to the time of umbilical cord separation since infants with a history of delayed umbilical cord separation and recurrent episodes of sepsis or pneumonia should be evaluated for leukocyte adhesion deficiency .

Medical History

A variety of nonimmune medical issues can result in recurrent infections (see Table 41.3 ). Approximately 30% of children with recurrent sinopulmonary symptoms can be categorized as atopic (allergic on a hereditary basis). These subjects have normal growth and development, and episodes of recurrent illness may be afebrile, respond poorly to antibiotics, and be accompanied by upper respiratory symptoms such as coughing, sneezing, or wheezing. There may be a family history of atopic disease, and the patient’s past medical history may include episodic wheezing, protracted cough after upper respiratory tract infection (URI) hay fever, allergies to foods, or eczema. The physical examination of allergic school-aged children may reveal typical characteristics including the following: dark circles under the eyes; open mouth with dry lips; coated tongue; evidence of nasal obstruction; transverse nasal crease; boggy, pale nasal mucosa; mucus in the pharynx; posterior pharyngeal “cobblestoning”; and postnasal drip.

Malnutrition and specific vitamin deficiencies may alter immune cell function. Protein-losing states due to gastrointestinal (e.g., inflammatory bowel disease, protein-losing enteropathy) or renal disease (e.g., nephrotic syndrome) may lead to hypocomplementemia, hypogammaglobulinemia, and recurrent infections. Chronic treatment with corticosteroids and other immunosuppressants can result in acquired immunodeficiency and recurrent infections.

Anatomic Abnormalities

Recurrent infections in primary immune deficiencies typically affect different anatomic locations. Structural or anatomic defects often result in recurrent infections that are generally localized to the affected organ system. Approximately 10% of children with recurrent infections have an underlying chronic disease or a structural defect that predisposes them to recurrent infections (see Table 41.3 ).

Eustachian tube abnormalities or cleft palate result in recurrent or chronic otitis media; congenital heart disease results in an increased risk of endocarditis; and posterior urethral valves, vesicoureteral reflux, or ureteral pelvic junction obstruction results in recurrent urinary tract infections. Recurrent pneumonia may result from congenital malformations (trachea-esophageal fistulas, cystic adenomatoid malformation, or sequestration), from aspiration of a foreign body (peanut, small toys) or chronic aspiration (gastroesophageal reflux or swallowing disorders), and from bronchopulmonary dysplasia. Repeated pneumonias in dependent lobes warrant evaluation for recurrent aspiration. Chronic illnesses that result in recurrent pulmonary infections include cystic fibrosis, primary ciliary dyskinesia, or α ₁ -antitrypsin deficiency. Recurrent sinus infections can occur due to anatomic defects of the sinuses (polyps, stenotic os). Endotracheal intubation predisposes the patient to recurrent pulmonary infections with nosocomial organisms. Right middle lobe syndrome and sequestered lung can appear as recurrent pneumonia in the same anatomic location.

Any direct communication to the cerebrospinal fluid that bypasses the blood–brain barrier predisposes patients to a central nervous system infection. Basilar skull fractures and dermal sinus tracts or fistulas may communicate with the subarachnoid space or neural tissue. Other conditions predisposing patients to opportunistic infections of the central nervous system include penetrating foreign body, cerebrospinal fluid shunts, myelomeningocele, and encephalocele. Local infections of the sinuses or of the middle ear may spread to contiguous structures to form cerebral abscesses or subdural-epidural empyema. Intravenous drug abuse, bacterial endocarditis, and heart disease with right-to-left shunt are associated with an increased risk of central nervous system infections.

Family History

Specific patterns of inheritance have been determined for a variety of immunologic defects. Genetic defects of immunity can be inherited as X-linked, autosomal recessive, or autosomal dominant disorders. Monogenic primary immunodeficiencies may exhibit reduced penetrance (some people with the genetic abnormality do not exhibit a clinical phenotype) and variable expressivity (different signs and symptoms with same genetic defect). A family history of unexplained infant deaths or serious infection should be sought, particularly in male infants since a number of important immune deficiencies are X-linked. Evidence of consanguinity should be sought as many serious primary immune deficiencies are autosomal recessive. Since allergic diseases can appear as recurrent infections, a family history of atopy is important. A child who has 1 allergic parent or 2 allergic parents is predisposed to allergic reactions by 25% and 50%, respectively.

Physical Examination

The physical examination may provide important clues to the diagnosis of a primary immune deficiency (see Table 41.4 ). Longitudinal evaluation of height and weight are crucial in identifying infants with failure to thrive or acute weight loss. Chronic upper respiratory infections are suggested by scarred tympanic membranes, postnasal drip, and cervical adenopathy. Transverse nasal creases, circles under the eyes, and posterior pharyngeal “cobblestoning” suggest respiratory allergy. Recurrent cough, wheezing, digital clubbing, and chest deformity are suggestive of pulmonary disease. Mouth ulceration or stomatitis can be a sign of immune deficiency or autoinflammatory disorder. Auscultation of the apex of the heart in the right side of the thorax (dextrocardia) may be accompanied by ciliary motility abnormalities or asplenia. Lymphadenopathy, hepatosplenomegaly, pallor, wasting, and recent weight loss are suggestive of systemic disease. Absence of lymph tissue (tonsils and lymph nodes) is suggestive of a B cell deficiency, while absence of thymic tissue on chest radiograph in an infant is suggestive of T cell deficiency. Parotid enlargement with lymphadenopathy and hepatosplenomegaly is suggestive of HIV infection. Skin abnormalities including alopecia, eczema, pyoderma, and telangiectasia can be important clues. Evidence of hematologic disease, such as pallor, petechiae, and jaundice can be associated with immunodeficiencies. Generalized lymphadenopathy and splenomegaly may be suggestive of HIV disease, a phagocyte disorder with recurrent infections, or a lymphoproliferative disorder.

Diagnostic Categories

The information obtained from the history and physical examination is usually sufficient to make a tentative classification:

• 1.
  

  The patient who is probably healthy.

  
  
• 2.
  

  The atopic or allergic patient.

  
  
• 3.
  

  The patient with a nonimmunologic defect in host defense (see Table 41.3 ).

  
  
• 4.
  

  The patient with hereditary inflammatory disorders ( Table 41.5 ).

  
  
  
  

  TABLE 41.5

  
  

  Autoinflammatory Disorders

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Disease	Genetic Defect/Presumed Pathogenesis	Inheritance	Affected Cells	Functional Defects	Associated Features
  Familial Mediterranean fever	Mutations of MEFV (lead to gain of pyrin function, resulting in inappropriate IL-1β release)	AR	Mature granulocytes, cytokine-activated monocytes	Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased	Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease
  Mevalonate kinase deficiency (hyper 0 IgD syndrome)	Mutations of MVK (lead to a block in the mevalonate pathway). Interleukin-1β mediates the inflammatory phenotype	AR		Affecting cholesterol synthesis; pathogenesis of disease is unclear	Periodic fever and leukocytosis with high IgD levels
  Muckle–Wells syndrome	Mutations of NLRP3 (also called PYPAF1 or NALP3) lead to constitutive activation of the NLRP3 inflammasome	AD	PMNs, monocytes	Defect in cryopyrin, involved in leukocyte apoptosis and NF-κB signaling and IL-1 processing	Urticaria, SNHL, amyloidosis
  Familial cold autoinflammatory syndrome	Mutations of NLRP3 (see above) Mutations of NLRP12	AD	PMNs, monocytes	Same as above	Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure
  Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)	Mutations of NLRP3 (see above)		PMNs, chondrocytes	Same as above	Neonatal-onset rash, chronic meningitis, and arthropathy with fever and inflammation
  TNF receptor–associated periodic syndrome (TRAPS)	Mutations of TNFRSF1A (resulting in increased TNF inflammatory signaling)	AD	PMNs, monocytes	Mutations of 55-kDa TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF	Recurrent fever, serositis, rash, and ocular or joint inflammation
  Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome	Mutations of PSTPIP1 (also called C2BP1) (affects both pyrin and protein tyrosine phosphatase to regulate innate and adaptive immune responses)	AD	Hematopoietic tissues, upregulated in activated T cells	Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response	Destructive arthritis, inflammatory skin rash, myositis
  Blau syndrome	Mutations of NOD2 (also called CARD15) (involved in various inflammatory processes)	AD	Monocytes	Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling	Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies, 30% develop Crohn disease
  Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)	Mutations of LPIN2 (increased expression of the proinflammatory genes)	AR	Neutrophils, bone marrow cells	Undefined	Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders
  Early-onset inflammatory bowel disease	Mutations in IL-10 (results in increase of many proinflammatory cytokines)	AR	Monocyte/macrophage, activated T cells	IL-10 deficiency leads to increase of TNFγ and other proinflammatory cytokines	Enterocolitis, enteric fistulas, perianal abscesses, chronic folliculitis
  Early-onset inflammatory bowel disease	Mutations in IL-10RA (see above)	AR	Monocyte/macrophage, activated T cells	Mutation in IL-10 receptor alpha leads to increase of TNFγ and other proinflammatory cytokines	Enterocolitis, enteric fistulas, perianal abscesses, chronic folliculitis
  Early-onset inflammatory bowel disease	Mutations in IL-10RB (see above)	AR	Monocyte/macrophage, activated T cells	Mutation in IL-10 receptor beta leads to increase of TNFγ and other proinflammatory cytokines	Enterocolitis, enteric fistulas, perianal abscesses, chronic folliculitis

   
  

  AD, autosomal dominant; AR, autosomal recessive; Ig, immunoglobulin; IL, interleukin; NF-κB, nuclear factor-κB; PMN, polymorhonuclear neutrophil; SNHL, sensorineural hearing loss; TNF, tumor necrosis factor.
  
  
  
  
• 5.
  

  The immunodeficient patient.

Patient Who Is Probably Healthy

Many healthy children have repeated minor infections, or have a relatively brief history of repeated infections, or a single prolonged illness from which recovery has been delayed. Most upper respiratory tract infections last less than 7 days, and duration of longer than 14 days is unusual. Most children younger than 1 year who have a large family or who attend daycare develop respiratory or gastrointestinal infections about 6 times during the 1st year of life. The onset of the recurrent infection may coincide with entry into day care, preschool, or kindergarten. The healthy child has normal growth and development before the illness and usually a normal physical examination finding. When a discrepancy exists between the severity of an illness as reported by the parent and the child’s physical appearance, it is often prudent to delay a detailed evaluation until more objective findings are documented by repeat examinations during acute episodes. Laboratory testing might include a complete blood cell count, inflammatory markers (i.e., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) to exclude rheumatic disorders or occult infections, and measurement of immunoglobulin levels and vaccine specific titers as a screen. Cultures and imaging of the affected area may provide additional data. With reassurance of the parents, these children recover spontaneously. Simple measures, rather than a complex set of laboratory studies, are often the only treatment required.

Patient with Hereditary Inflammatory Disorders

Autoinflammatory syndromes , formerly known as periodic fever syndromes , are a heterogeneous and ever increasing group of rare inflammatory disorders that manifest with recurrent fevers and/or inflammatory episodes (see Table 41.5 ). Recurrent fevers or inflammation can often be mistaken for recurrent infections. Patients exhibit characteristic physical findings during these episodes, such as fever, various rashes, lymphadenopathy, aphthous stomatitis, arthritis, and serositis with abdominal, chest, or testicular pain. These episodes can be periodic or sporadic, but the characteristic features occur with each episode. Laboratory evaluation may show elevated white blood cell (WBC) counts and elevated inflammatory markers during the episode that typically resolve between episodes. Importantly, infectious work-ups are often repeatedly negative, and the patient is typically well between febrile episodes.

There are also an increasing number of disorders of immune dysregulation that have been described ( Table 41.6 ). Unlike autoinflammatory disorders, these disorders result in a failure to control T and B cell responses, resulting in autoimmunity . These disorders are not typically episodic, and once autoimmunity develops it continues until treated. Many of these disorders are also associated with immune deficiency and recurrent infection, thus patients experience recurrent infections simultaneously with autoimmune manifestations.

Immunodeficient Patient

Approximately 5-10% of children with recurrent infections have an underlying immunodeficiency. Frequently, the onset of infections occurs between the ages of 6 and 12 months, but delays in diagnosis are not uncommon. In addition, certain immune deficiencies such as common variable immunodeficiency disease (CVID) can present in adolescence or young adulthood; thus it is critical to consider immune defects in children of any age. Infections in patients with primary immune deficiencies often vary in type, location, and severity, although sinopulmonary infections are common. Failure to thrive may occur and can be a sign of a serious immune defect. Patients with primary immune defects often require repeated courses of antibiotics or intravenous antibiotics, or may have infections with unusual organisms or exhibit unexpected complications. Such children may respond to antibiotics but become ill when the medications are discontinued.

Diagnostic Approach to the Patient with Recurrent Infections

Patients with recurrent, severe, or unusual infections involving multiple sites or organ systems should be investigated for an immunodeficiency ( Fig. 41.1 ). Initial tests are recommended for patients suspected of a primary immune deficiency, although a variety of immune defects can occur despite normal screening tests. Thus it is recommended that advanced testing be performed in consultation with a clinical immunologist.

Initial work-up and follow-up studies of patients with suspected immune deficiency. Consultation with a clinical immunologist is recommended to guide advanced testing and interpret results. CBC, complete blood count; CGD, chronic granulomatous disease; LAD, leukocyte adhesion defect; NK, natural killer cell; IL, interleukin; IFN, interferon.

A complete blood count with manual differential should always be obtained in the evaluation of any child suspected of immunodeficiency. A neutrophil count below 500/mm ³ might indicate severe congenital neutropenia, cyclic neutropenia, idiopathic neutropenia, marrow failure, or replacement of marrow by leukemia or a tumor if other hematopoietic cell lines are affected. Analysis of the peripheral blood smear is important as this can detect neutrophil abnormalities (e.g., abnormal granules in Chédiak-Higashi) or evidence of asplenia (i.e., Howell-Jolly bodies).

Serum immunoglobulin levels (IgG, IgA, IgM, IgE) are essential to the work-up of suspected primary immunodeficiency. Antibody levels vary with age, with normal adult values of IgG at birth from transplacental transfer of maternal IgG, a physiologic nadir occurring between 3 and 6 months of age, and a gradual increase to adult values over several years. IgA and IgM are low at birth and levels increase gradually over several years, with IgA taking the longest to reach normal adult values. When IgG levels are low, albumin levels should be measured because increased loss of proteins, as in protein-losing enteropathy or nephrotic syndrome, can result in hypogammaglobulinemia. High immunoglobulin levels suggest intact B cell immunity and can be found in diseases with recurrent infections, such as chronic granulomatous disease (CGD), immotile cilia syndrome, cystic fibrosis, HIV infection, autoimmune diseases (lupus), and other disorders leading to chronic inflammation. Elevated IgE levels can be found in a number of immune deficiencies such as hyper-IgE syndrome, but more likely represent atopic diseases (atopic dermatitis).

Specific antibody titers after childhood vaccination (tetanus, diphtheria, Haemophilus influenzae type b, or Streptococcus pneumoniae ) reflect the capacity of the immune system to synthesize specific antibodies and to develop memory B cells. If titers are low, immunization with a specific vaccine and obtaining titers 4-6 weeks later should be performed to confirm a response to the immunization. Poor response to bacterial polysaccharide antigens is often found before 24 months of age; even in older individuals the antibody response to polysaccharide vaccines is typically less robust and less long-lived than protein antigens. The development of protein-conjugate polysaccharide vaccines to Streptococcus pneumoniae and Haemophilus influenzae has dramatically reduced invasive infections with these organisms in early childhood by improving the response to vaccination. Antibody responses to the S. pneumoniae serotypes found in the 23-valent polysaccharide vaccine, but not in the conjugate vaccine, can be used to test antibody responses to polysaccharide antigens.

Complement assays include the CH50 test, which measures the presence of proteins in the classical pathway of complement (C1, C2, C3, C4), and the AH50 test, which tests the proteins of the alternative pathway of complement (C3, factor B, properdin). In patients with deficiencies in complement protein, the CH50 levels or AH50 levels are generally zero, whereas they are low but not absent in disorders leading to complement consumption (e.g., systemic lupus erythematosus). If both the CH50 and AH50 levels are abnormal, a defect in the common pathway is likely (C5-C9). Specialized laboratories can measure the presence or function of specific complement proteins.

If the above studies are normal but a primary immune deficiency is still suspected, advanced studies can be performed. One such advanced study is flow cytometry to enumerate the percentage and absolute numbers of T cells, B cells and markers of B cell maturation, and NK cell subsets. Flow cytometry can also test for the presence of surface proteins that are necessary for normal immunity, such as major histocompatibility complex molecules or adhesion molecules. Functional T cell tests include T cell proliferation assays in response to mitogens (phytohemagglutinin or concanavalin A) or antigens (tetanus toxoid or Candida ). These in vitro assays assess the capacity of T cells to proliferate in response to a nonspecific stimulus (mitogens) or antigen-specific memory T cells (antigens). T cell proliferation in response to specific antigens requires a prior exposure to that unique antigen. Delayed-type hypersensitivity skin tests to protein antigens such as tetanus, diphtheria, Candida, or mumps demonstrate the presence and function of both antigen-specific T cells and antigen-presenting cells. If delayed-type hypersensitivity skin test results are negative, one may consider a booster vaccination and retesting 4 weeks later.

Tests for neutrophil function include the nitroblue tetrazolium (NBT) or dihydrorhodamine 123 (DHR) test for CGD. In the NBT test, oxygen radicals generated by activated neutrophils oxidize NBT to an insoluble dark blue dye that can be detected in neutrophils by microscopic examination. In the DHR test, oxygen radicals generated by activated neutrophils oxidize DHR, which results in the emission of light that is detected by flow cytometry. Neutrophils that are activated in patients with CGD cannot generate oxygen radicals and therefore have an abnormal NBT test (no blue neutrophils) or DHR test (no increase in light emitted from activated neutrophils).

Genetic testing to confirm the diagnosis of a primary immunodeficiency disease can be performed in specialized laboratories and may be helpful for deciding on a course of treatment, determining the natural history and prognosis of the disease, and to allow for genetic counseling. Chromosomal deletion/duplication microarrays are increasingly used to diagnose specific syndromic disorders that may have immunodeficiency due to genomic copy number variants (CNV) such as DiGeorge Syndrome. Specific gene or multiple gene sequencing is available commercially. With the advent of next generation sequencing techniques, it is now possible to sequence nearly all the genes in a subject. Because there are hundreds of genes known to cause primary immune deficiencies, this technology is being used in the diagnosis of primary immune deficiencies.