XI. Disorders of Granulocytes (Figure 15-3)

A.Chronic granulomatous disease (CGD)

1.Definition. CGD is a group of disorders characterized by defective neutrophil oxidative metabolism as a result of defects in the multicomponent-reduced nicotinamide–adenine dinucleotide phosphate (NADPH) oxidase system. Defective oxidative metabolism results in severely impaired intracellular killing of catalase-positive bacteria and some fungal pathogens.

2.Etiology. The inheritance of CGD is predominantly X-linked (70%).

3.Clinical features

a.Increased susceptibility to infections involving the lungs, lymph nodes, liver, spleen, bones, and skin. Abscess formation is characteristic.

b.Major pathogens include S. aureus, Pseudomonas aeruginosa, Salmonella species, Klebsiella pneumoniae, Serratia marcescens, Escherichia coli, C. albicans, and Aspergillus species.

4.Diagnosis. Tests demonstrate defective neutrophil oxidative burst. The nitroblue tetrazolium (NBT) test was the classic test and has been replaced by the dihydrorhodamine (DHR) flow cytometry test.

5.Management

a.Abscesses often require surgical drainage and antibiotics.

b.Prophylactic trimethoprim–sulfamethoxazole reduces the incidence of serious infections.

c.Prophylactic itraconazole reduces the incidence of Aspergillus infections.

d.Interferon-γ is given prophylactically.

e.Bone marrow transplantation is curative.

f.Gene therapy is a potential future cure.

B.Disorders of adherence and motility

1.Shwachman–Diamond syndrome. This syndrome is an autosomal recessive condition characterized by decreased neutrophil chemotaxis, neutropenia, and pancreatic exocrine insufficiency. Patients present with recurrent soft tissue infection, chronic diarrhea, short stature and failure to thrive. (See also , section V.B.6.)

2.Chédiak–Higashi syndrome. This syndrome is characterized by variable neutropenia and thrombocytopenia and giant lysosomal granules in neutrophils. Neutrophils and monocytes have functional defects, and natural killer cell function is impaired. S. aureus causes the majority of infections. Patients also have partial oculocutaneous albinism (see also , section V.B.5.a).

3.Lymphocyte adhesion defects (LAD). This is a clinical syndrome characterized by delayed umbilical cord separation and skin healing, leukocytosis, (with elevated neutrophil counts of 20,000–100,000/dL), gingival inflammation, as well as recurrent necrotic infections of skin, mucous membranes, and GI tract. Despite the leukocytosis, few leukocytes are found in the large ulcerative lesions because of defect in neutrophil migration due to the absence of an adhesion molecule (lymphocyte function-associated antigen 1 [LFA-1]).

C.Neutropenia is discussed in , section V.

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FIGURE 15-3 Disorders of granulocytes.

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XII. Disorders of the Complement System

The complement system is composed of plasma proteins and cellular receptors functioning in an integrated series of reactions to prevent infections.

A.Definition. These disorders involve absence or dysfunction of individual complement components or regulatory proteins.

B.Etiology. Complement deficiencies are genetically determined. Most are autosomal recessive.

C.Clinical features are variable and depend on the biologic function of the components that are deficient.

1.Deficiencies of the early components of the classic pathway (C1q, C2, and C4) are associated with autoimmune diseases, such as systemic lupus erythematosus.

2.Deficiencies of the late components of the classic pathway (C5, C6, and C8) are associated with increased susceptibility to disseminated meningococcal and gonococcal infections.

3.Deficiency or dysfunction of C1 esterase inhibitor causes hereditary angioedema.

Patients may experience episodic swelling of various body parts, especially the hands and feet. The bowel wall may also swell, leading to severe abdominal pain. Angioedema affecting the airway can be fatal.

D.Diagnosis

1.Quantitative. Specific assays measure levels of specific components.

2.Qualitative. A normal total serum hemolytic complement (CH50) indicates that all components of the classic complement pathway are present and functional.

E.Management

1.Prompt diagnosis and treatment of bacterial infections

2.Management of autoimmune disease

3.Therapy with fibrinolysis inhibitors and attenuated androgens (such as danazol) for hereditary angioedema

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Review Test

1.An 8-year-old boy presents to the emergency department in acute severe respiratory distress after being stung by a bee. Vital signs are notable for a respiratory rate of 60 breaths/minute, heart rate of 120 beats/minute, and a blood pressure of 70/50 mm Hg. Physical examination shows severe respiratory distress, wheezing, and a diffuse urticarial eruption on the trunk and extremities. Which of the following is the best initial treatment for this patient?

A.Antihistamines

B.Systemic corticosteroids

C.Epinephrine

D.β-Adrenergic agonists

E.Inhaled corticosteroids

2.A 10-year-old girl presents with a history of chronic rhinorrhea, nasal itchiness, and sneezing. Physical examination reveals dark circles under her eyes and pale boggy nasal mucosa. Which of the following categories of medications is the most effective for controlling this patient’s signs and symptoms?

A.First-generation antihistamines

B.Second-generation antihistamines

C.Intranasal steroids

D.Intranasal cromolyn sodium

E.Decongestants

3.During a routine health maintenance visit, the mother of a 1-year-old girl is particularly concerned about the family’s history of food allergies. Which of the following are most likely to cause food allergic reactions?

A.Soy

B.Citrus fruits

C.Chocolate

D.Tomatoes

E.Cruciferous vegetables such as broccoli, brussels sprouts, cabbage, and cauliflower

4.The parents of a 5-year-old boy are concerned that their son may have food allergies. On two separate occasions, he exhibited a transient erythematous papular itchy rash and a stuffy nose within several hours after eating fish. Which of the following is the most definitive method for diagnosis of food allergy?

A.Skin tests using extracts from the suspected offending food

B.Radioallergosorbent testing (RAST) to identify IgE-specific food antibodies

C.Double-blind, placebo-controlled provocative oral food challenge

D.Total serum IgE measurements

E.Parental reports of the suspected food allergy

5.A 12-year-old girl presents with a 9-month history of chronic diarrhea and an increased susceptibility to infections. During this period, she has had two episodes of pneumonia and multiple prolonged episodes of diarrhea. Physical examination is normal. You suspect an immunodeficiency disorder. Laboratory evaluation reveals normal numbers of B cells and platelets; decreased serum concentrations of IgG, IgA, and IgM; low antibody titers in response to immunizations; and poor T-cell function. The total serum hemolytic complement (CH50) is normal. Which of the following is the most likely diagnosis?

A.Severe combined immunodeficiency disease

B.Common variable immunodeficiency disease

C.Chronic granulomatous disease

D.Complement deficiency

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E.Wiskott–Aldrich syndrome

6.A 4-year-old boy presents with a one-day history of fever (temperature up to 103°F [39.4°C]), a stiff neck, and altered mental status. Gram stain of the cerebrospinal fluid shows Gramnegative bacteria. His parents are concerned because he was also hospitalized with meningococcal sepsis at 2 months of age. Which of the following immunodeficiency disorders is the most likely diagnosis?

A.Chédiak–Higashi syndrome

B.Chronic granulomatous disease

C.Selective IgA deficiency

D.Ataxia telangiectasia

E.Complement deficiency

7.A 1-year-old boy has a history of multiple episodes of otitis media, sinusitis, and pneumonia. He has not had any fungal, protozoan, or mycobacterial infections. You suspect a disorder of humoral immunity. Which of the following is the best initial screening test?

A.Dihydrorhodamine (DHR) flow cytometry test

B.Quantitative serum immunoglobulins

C.Examination of the peripheral blood smear

D.Total hemolytic complement (CH50)

E.Anergy panel

8.A 10-year-old boy presents with rhinorrhea, sneezing, and an early morning cough, which is present throughout the year. He sleeps with a collection of stuffed monkeys, and his bedroom is carpeted. There are no pets in the household. Physical examination reveals Dennie lines and an allergic salute. Nasal smear shows 90% eosinophils. Which of the following is the most likely cause of his allergies?

A.Dust mites

B.Tree pollens

C.Weed pollens

D.Molds

E.Grasses

9.A 1-year-old girl has erythema and dry patches on her trunk, face, scalp, and extensor surfaces. She scratches frequently and seems sensitive to wool. Her parents also note that at times her cheeks get red, cracked, and weepy. Which of the following is the most likely diagnosis?

A.Early childhood eczema

B.Infantile eczema

C.Idiopathic urticaria

D.Drug allergy

The response options for statements 10–13 are the same. You will be required to select one answer for each statement in the following set.

A.Ataxia telangiectasia

B.Deficiencies of the early components of the complement cascade

C.Deficiencies of the late components of the complement cascade

D.Adenosine deaminase deficiency

E.Shwachman–Diamond syndrome

F.DiGeorge syndrome

G.Chronic granulomatous disease

H.Wiskott–Aldrich syndrome

For each patient, select the most likely diagnosis.

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1.A 1-year-old boy with a history of recurrent pneumonia, chronic diarrhea, and failure to thrive has a white blood cell count of 1500 cells/mm3.

2.A 2-year-old boy with a history of recurrent cervical adenitis and pneumonia presents with a perianal abscess.

3.An 18-month-old boy has a history of recurrent pneumococcal pneumonia, severe eczema, and a petechial rash on her trunk and face.

4.A 3-month-old boy with a history of chronic diarrhea and failure to thrive presents with

Pneumocystis carinii pneumonia.

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