Pediatrics_Nelson

Pediatrics_Nelson. Selective IgA deficiency is defined as serum IgA levels less nadir at 6 months of age is accentuated, with immunoglobuthan 10 mg/dL with normal levels of other immunoglobulins. lin levels less than 200 mg/dL. Immunoglobulin levels remain The diagnosis cannot be confirmed until the patient is at least 4 diminished throughout the first year of life and usually increase years of age when IgA levels should reach adult levels. Selective to normal, age-appropriate levels, generally by 2 to 4 years of IgA deficiency occurs in approximately 1 in 500 individuals. age. The incidence of sinopulmonary infection is increased in Most patients with selective IgA deficiency are asymptomatic. some patients. The diagnosis is supported by normal levels of In others it is associated with recurrent sinopulmonary infec-both B and T cells and by normal antibody responses to protions, IgG2 subclass deficiency, specific antibody deficiency, tein antigens such as diphtheria and tetanus toxoids. The tranfood


Pediatrics_Nelson

Pediatrics_Nelson. infec-both B and T cells and by normal antibody responses to protions, IgG2 subclass deficiency, specific antibody deficiency, tein antigens such as diphtheria and tetanus toxoids. The tranfood allergy, autoimmune disease, or celiac disease. IgA defi-sient nature of this disorder cannot be confirmed, however, ciency occurs in families, suggesting autosomal inheritance. until immunoglobulin levels return to normal ranges.


Pediatrics_Nelson

Pediatrics_Nelson. IgG subclass deficiency occurs when the level of antibod-Specific antibody deficiency syndrome is characterized by ies in one or more of the four IgG subclasses is selectively recurrent infections with normal immunoglobulin levels and Agammaglobulinemia X-linked, AR Infancy (6–9 Recurrent infections, Arrest in B-cell Lymphoid hypoplasia mo) sinusitis, pneumonia, differentiation (pre-B level); meningitis (encapsulated mutations in: Btk gene bacteria, enteroviruses) (X-linked); μ chain, BLNK, Igα, Igβ, Vpre-B, and λ5 (AR) Hyper-IgM syndrome AR Variable Sinopulmonary infections Defect in AID, UNG Autoimmunity AD, Autosomal dominant; AID, activation-induced cytidine deaminase; AR, autosomal recessive; ITP, idiopathic thrombocytopenic purpura; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; UNG, uracil-DNA glycosylase.


Pediatrics_Nelson

Pediatrics_Nelson. SLE, systemic lupus erythematosus; UNG, uracil-DNA glycosylase. normal lymphocyte numbers and subsets, but the disorder has an inability to synthesize specific antibody to polysaccharideantigens, such as to the 23-valent pneumococcal vaccine. Thepathogenesis of this disorder is unknown. Lack of specific antibody titers explains the recurrent infections and justifies therapy. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Disorders that affect T-cell development or function usuallyresult in combined immunodeficiency because T cells providenecessary signals for B-cell differentiation. X-linked hyper-IgM syndrome, the most common form of hyper-IgM syndrome, is a combined immunodeficiency with deficient T-cellfunction due to defects in CD40 ligand. Defects in CD40 causeautosomal recessive hyper-IgM syndrome and present similarly to X-linked hyper-IgM syndrome (Fig. 73-2 and Table 73-2). Hyper-IgM syndrome is characterized by a failure ofimmunoglobulin isotype switching from IgM and IgD to IgG,IgA, or IgE, and a lack of memory responses. Affected patientshave normal or elevated serum levels of IgM with low or absentlevels of IgG, IgA, and IgE. Immunoglobulin isotype switching allows a B cell to maintain antigen specificity while alteringimmunoglobulin function, and is directed by cytokines and interaction between CD40 ligand on CD4 T cells and CD40 onB cells (see Fig. 73-2). Signal transduction via CD40


Pediatrics_Nelson

Pediatrics_Nelson. specificity while alteringimmunoglobulin function, and is directed by cytokines and interaction between CD40 ligand on CD4 T cells and CD40 onB cells (see Fig. 73-2). Signal transduction via CD40 activatesseveral signaling molecules and transcription factors, including nuclear factor κB (NF-κB) and two enzymes, activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase(UNG), which are required for class switching. Deficiency ofAID or UNG presents with a failure of immunoglobulin isotype switching without any abnormality in T-cell function.These forms of hyper-IgM are antibody deficiency diseases andnot combined immunodeficiencies (see Table 73-1).


Pediatrics_Nelson

Pediatrics_Nelson. All patients with hyper-IgM syndrome have increased susceptibility to sinopulmonary infections, whereas patients with defects in CD40 ligand or CD40 are susceptible to opportunistic infections, such as P. jiroveci (carinii) and Cryptosporidium parvum. Signaling via CD40 on B cells and other antigen-presenting cells leads to upregulation of co-stimulatory molecules important for promoting T-cell differentiation and for activating cell-mediated immune responses. The hyper-IgM phenotype is also found in an X-linked disorder associated with ectodermal dysplasia, resulting from defects in the gene encoding the NF-κB essential modulator (NEMO). Patients with defects in NEMO are susceptible to a wider spectrum of infectious organisms, especially meningitis and infection with atypical mycobacteria, because NF-κB signaling is important for the function of both innate and adaptive immune systems.


Pediatrics_Nelson

Pediatrics_Nelson. Severe combined immunodeficiency (SCID) is characterized by a profound lack of T-cell numbers or function, andB-cell dysfunction resulting from the absence of B cells fromthe gene defect itself, or secondary to lack of T-cell function(see Table 73-2). T cells develop from bone marrow−derived


Pediatrics_Nelson

Pediatrics_Nelson. Figure 73-2 Schematic representation of the interaction between a CD4 T cell and a B cell. T-cell activation follows T-cell receptor (TCR) recognition of peptide antigen presented via MHC class II molecules resulting in CD40 ligand (CD40L) expression and cytokine synthesis. CD40L stimulates the B cell via CD40, resulting in expression of co-stimulatory molecules (B7) that are important in T-cell priming and cytokine synthesis that drives T-cell differentiation. CD40 and cytokine signaling in B cells activate activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG) to promote immunoglobulin isotype switching and somatic hypermutation. Defects in CD40L cause X-linked hyper-IgM (X-HIM), and defects in CD40, AID, or UNG cause autosomal recessive hyper-IgM (AR-HIM). Defects in either CD40L or CD40 affect T-cell co-stimulation and priming, leading to T-cell defects, whereas defects in AID and UNG maintain normal T-cell co-stimulation and function.


Pediatrics_Nelson

Pediatrics_Nelson. Table 73-2 Combined Immunodeficiency Diseases DISORDER GENETICS ONSET MANIFESTATIONS PATHOGENESIS ASSOCIATED FEATURES Hyper-IgM syndrome (see Table 73-1) X-linked, AR First year Sinopulmonary infections, opportunistic infections, Pneumocystis jiroveci Defect in CD40 ligand (X-linked) or CD40 (AR) Neutropenia, liver disease, cancer AD, Autosomal dominant; ADA, adenosine deaminase; AR, autosomal recessive; dATP, deoxyadenosine triphosphate; dGTP, deoxyguanosine triphosphate; GVHD, graft-versus-host disease; IL, interleukin; IL-2Rγ, interleukin-2 receptor gamma chain; MHC, major histocompatibility complex; PNP, purine nucleoside phosphorylase; SCID, severe combined immunodeficiency; T− B−, T− cells absent and B cells present; T− B−, T cells absent and B cells absent.


Pediatrics_Nelson

Pediatrics_Nelson. precursors in the thymus (see Fig. 73-2), where they undergoseveral stages of development characterized by DNA recombination of the variable region of T-cell antigen receptor genes togenerate a diverse T-cell receptor repertoire. A process of positive selection occurs in the thymus to select thymocytes withantigen receptors that can interact with major histocompatibility complex (MHC) molecules to ensure their survival (see Fig. 73-2). Thymocytes differentiate into CD4 or CD8 T cells if theyinteract with MHC class II or class I molecules, respectively.Some of the positively selected thymocytes, however, haveantigen receptors that recognize self-antigens presented byMHC molecules in the thymus. These cells are deleted in the thymus by a process of negative selection. Positive selectionand negative selection in the thymus ensure that the mature Tcells that leave the thymus can function with the individual’sMHC molecules and recognize a multitude of foreign antigenswithout mounting


Pediatrics_Nelson

Pediatrics_Nelson. negative selection in the thymus ensure that the mature Tcells that leave the thymus can function with the individual’sMHC molecules and recognize a multitude of foreign antigenswithout mounting autoimmune responses. SCID can resultfrom any specific genetic mutation that interferes with T-celldevelopment in the thymus or T-cell function in the periphery.


Pediatrics_Nelson

Pediatrics_Nelson. Clinical manifestations of SCID include failure to thrive, severe bacterial infections, chronic candidiasis and other fungal infections, chronic viral infections, infection with P. jiroveci (carinii) and other opportunistic organisms, and intractable diarrhea. Patients often have skin disease similar to eczema, possibly related to graft-versus-host disease (GVHD) from engraftment of maternal lymphocytes, which usually is not fatal. Patients with SCID are extremely susceptible to fatal GVHD from lymphocytes in blood transfusions and can be infected by cytomegalovirus-positive blood products. Patients with T-cell disorders always should receive irradiated blood products.


Pediatrics_Nelson

Pediatrics_Nelson. X-linked SCID, the most common form, is caused by mutations in the gene on chromosome Xq13.1 coding for the common gamma chain of the interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. Affected patients have no T cells or NK cells in the peripheral blood but have normal numbers of B cells. Immunoglobulin levels are low or undetectable because there are no CD4 T cells to stimulate B cells. The defect in T-cell development results from a failure of signaling via the IL-7 receptor, and IL-15 is required for NK-cell development. There are many causes of autosomal recessive SCID. Defects in Janus kinase 3 (Jak3), which binds to the common gamma chain, results in a similar phenotype as X-linked SCID. Defects in the IL-7 receptor, ZAP-70, and subunits of the CD3 molecule result in a deficiency of T cells with normal Band NK-cell numbers. In addition there is a variety of defects that affect DNA recombination in T and B cells, including two genes called recombinase activating


Pediatrics_Nelson

Pediatrics_Nelson. a deficiency of T cells with normal Band NK-cell numbers. In addition there is a variety of defects that affect DNA recombination in T and B cells, including two genes called recombinase activating gene (RAG) 1 and 2 as well as other genes important in DNA excision and repair such as Artemis. Defects in any of the genes that abolish DNA recombination or DNA repair result in autosomal recessive SCID with no T cells or B cells present. Mutations in RAG1, RAG2, or Artemis that preserve limited function result in Omenn syndrome, a variant form of SCID that is characterized by exfoliative erythroderma, lymphadenopathy, hepatosplenomegaly, marked eosinophilia, elevated serum IgE, and impaired T-cell function. Patients with Omenn syndrome have T cells in the periphery, but these T cells have a limited repertoire.


Pediatrics_Nelson

Pediatrics_Nelson. Deficiencies in adenosine deaminase (ADA) and purine nucleoside phosphorylase, two enzymes involved in the purine salvage pathway, also result in SCID. Accumulation of nucleoside substrates or their metabolic products in the plasma and urine is toxic to lymphocytes, including T, B, and NK cells. Most patients exhibit severe infection early in life, although the diagnosis in patients with partial enzyme function may not be established until after 5 years of age or, occasionally, in adulthood. Patients with late-onset diagnosis are generally lymphopenic; they may have B cells and normal total immunoglobulin levels but little functional antibody (Nezelof syndrome). All patients with ADA or purine nucleoside phosphorylase deficiency SCID have lymphopenia and loss of immune function over time.


Pediatrics_Nelson

Pediatrics_Nelson. Bare lymphocyte syndrome results from defects in transcription factors that regulate expression of class II molecules or genes that affect transport of antigen peptides, which leads to the absence of either MHC class I or MHC class II molecules. Lymphoid tissue and B cells may be present in normal amounts, but CD4 T cells are decreased or absent in class II deficiency, whereas CD8 cells are decreased or absent in class I deficiency. Some patients may have normal numbers of CD4 or CD8 T cells, but none of the T cells are functional because peptide antigens cannot be presented to T cells.


Pediatrics_Nelson

Pediatrics_Nelson. DiGeorge syndrome, also known as velocardiofacial syndrome or CATCH 22 syndrome (cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia), is the result of dysmorphogenesis of the third and fourth pharyngeal pouches, resulting in hypoplasia of the thymus required for T-cell maturation. Most, but not all, patients with DiGeorge syndrome have a defect on chromosome 22q11.2.DiGeorge syndrome is classically characterized by hypocalcemic tetany, conotruncal and aortic arch anomalies, and increased infections. The diagnosis is established by fluorescent in situ hybridization or a polymerase chain reaction with a DNA probe to detect deletions in chromosome 22q11.2.Most patients have partial immune defects with low T-cell numbers and function that generally improve with age. Severe T-cell deficiency is rare, but it results in SCID due to a complete lack of T cells. Most important, DiGeorge syndrome and bare lymphocyte syndrome do not respond well to bone marrow


Pediatrics_Nelson

Pediatrics_Nelson. with age. Severe T-cell deficiency is rare, but it results in SCID due to a complete lack of T cells. Most important, DiGeorge syndrome and bare lymphocyte syndrome do not respond well to bone marrow transplantation as do other forms of SCID because the defects are in the thymus, although transfer of mature T cells during transplant may confer some immune function.


Pediatrics_Nelson

Pediatrics_Nelson. Wiskott-Aldrich syndrome is an X-linked disorder characterized by thrombocytopenia, eczema, defects in cell-mediated and humoral immunity, and a predisposition to lymphoproliferative disease (Table 73-3). It is caused by mutations of the gene on chromosome Xp11.22 coding for the Wiskott-Aldrich syndrome protein (WASP), expressed in lymphocytes, platelets, and monocytes. Deficiency of this protein results in elevated levels of IgE and IgA, decreased IgM, poor responses to polysaccharide antigens, waning T-cell function, and profound thrombocytopenia. Opportunistic infections and autoimmune cytopenias become problematic in older children. Isolated X-linked thrombocytopenia also results from mutations of the identical gene. One third of patients with Wis-kott-Aldrich syndrome die as a result of hemorrhage, and two thirds die as a result of recurrent infection caused by bacteria, cytomegalovirus, P. jiroveci (carinii), or herpes simplex virus. Stem cell transplantation has corrected the


Pediatrics_Nelson

Pediatrics_Nelson. of hemorrhage, and two thirds die as a result of recurrent infection caused by bacteria, cytomegalovirus, P. jiroveci (carinii), or herpes simplex virus. Stem cell transplantation has corrected the immunologic and hematologic problems in some patients.


Pediatrics_Nelson

Pediatrics_Nelson. Ataxia-telangiectasia is a syndrome caused by the ATM (ataxia-telangiectasia, mutated) gene on chromosome 11q22.3(see Table 73-3). Patients have cutaneous and conjunctival Wiskott-Aldrich X-linked, Early infancy Thrombocytopenia, atopic 53-kD protein (WASP) Polysaccharide antibody syndrome (Xp11.22) dermatitis, recurrent defect deficiency, small infections platelets, decreased cell-mediated immunity, lymphoproliferation AD, Autosomal dominant; AR, autosomal recessive; NK, natural killer.


Pediatrics_Nelson

Pediatrics_Nelson. AD, Autosomal dominant; AR, autosomal recessive; NK, natural killer. telangiectasias and progressive cerebellar ataxia with degeneration of Purkinje cells. IgA deficiency, IgG2 subclass deficiencyof variable severity, low IgE levels, and variably depressedT-cell function may be seen. The normal function of the ATM gene is not clear but appears to be involved in detecting DNAdamage, blocking cell growth division until the damage isrepaired, or both. Ataxia-telangiectasia cells are exquisitelysensitive to irradiation. Leukemias, lymphomas, and diabetesalso may be present. Sexual maturation is delayed. There isno uniformly effective therapy, but antimicrobial therapy andintravenous immunoglobulin (IVIG) replacement therapymay be helpful. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Chronic mucocutaneous candidiasis (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED])is characterized by chronic or recurrent candidal infections of the mucous membranes, skin, and nails (see Table 73-3). There is normal antibody production but significantly decreased or absent lymphocyte proliferation and delayed skin reactivity to Candida. Patients usually do not respond to topical antifungal therapy and must be treated with oral antifungal agents. In most patients, an autoimmune endocrine disorder, such as hypoparathyroidism and Addison disease, develops by early adulthood. Other autoimmune disorders have been reported. The insidious onset requires the need for frequent evaluation for autoimmune endocrine disorders. This disease results from a defect in the gene for the transcription factor autoimmune regulator (AIRE), which is necessary for expression of peripheral tissue antigens in the thymus, resulting in a negative selection in the thymus and in tolerance


Pediatrics_Nelson

Pediatrics_Nelson. the transcription factor autoimmune regulator (AIRE), which is necessary for expression of peripheral tissue antigens in the thymus, resulting in a negative selection in the thymus and in tolerance to these tissues in normal individuals.


Pediatrics_Nelson

Pediatrics_Nelson. Patients with X-linked lymphoproliferative disease (see Table 73-3) have a defect in immune responsiveness to Epstein-Barr virus (EBV). Boys with this disease are normal until infected with EBV, which is acutely fatal in 80% of patients. The disease is caused by a mutation in the gene called SH2D1A at chromosome Xq25, which codes for an adapter protein involved in signal transduction of lymphocytes. With EBV infection, the mutation results in an extensive expansion of CD8 T cells, hepatic necrosis, and death. Boys who survive initial EBV infection have significant hypogammaglobulinemia and are at high risk for developing aplastic anemia and lymphoma. A similar disorder is seen in boys with mutations in XIAP, which results in X-linked lymphoproliferative disorder type 2. Avoid transfusions with blood products unless they are irradiated and cytomegalovirus-negative.


Pediatrics_Nelson

Pediatrics_Nelson. Avoid transfusions with blood products unless they are irradiated and cytomegalovirus-negative. Avoid live virus vaccines, especially in patients with severe T-cell deficiencies or agammaglobulinemia, and in household members. Use prophylaxis to Pneumocystis jiroveci (carinii) in T-cell immunodeficiency, and in X-linked hyper-IgM, consider antifungal prophylaxis in T-cell immunodeficiency. Follow pulmonary function in patients with recurrent pneumonia. Use chest physiotherapy and postural drainage in patients with recurrent pneumonia. Consider using prophylactic antibiotics because minor infections can quickly disseminate. Examine diarrheal stools for Giardia lamblia and Clostridium difficile. Avoid unnecessary exposure to individuals with infection. Boil water for T-cell defects and hyper-IgM syndrome (Cryptosporidium risk). Use immunoglobulin for severe antibody deficiency states (400–600 mg/kg q3–4 wk IV).


Pediatrics_Nelson

Pediatrics_Nelson. Hyper-IgE syndrome is characterized by markedly elevated serum IgE levels, a rash that resembles atopic dermatitis, eosinophilia, and staphylococcal abscesses of the skin, lungs, joints, and viscera (see Table 73-3). Infections with H. influenzae type b, Candida, and Aspergillus also may occur. These patients have coarse facial features, develop osteopenia, and may have giant pneumatoceles in the lungs after staphylococcal pneumonias. Although serum IgG, IgA, and IgM levels are normal, humoral immune responses to specific antigens are reduced, as is cell-mediated immunity. Long-term treatment with antistaphylococcal medications is indicated, and immunoglobulin replacement therapy may be helpful. Most patients have an autosomal dominant form of inheritance, whereas some patients appear to have an autosomal recessive inheritance. Defects in the TYK2 and DOCK8 genes have been found in a patient with an autosomal recessive hyper-IgE syndrome, and defects in the STAT3 (signal transducer


Pediatrics_Nelson

Pediatrics_Nelson. have an autosomal recessive inheritance. Defects in the TYK2 and DOCK8 genes have been found in a patient with an autosomal recessive hyper-IgE syndrome, and defects in the STAT3 (signal transducer and activator of transcription 3) gene were identified in autosomal dominant hyper-IgE syndrome.


Pediatrics_Nelson

Pediatrics_Nelson. The approach to therapy of lymphocyte disorders depends on the diagnosis, clinical findings, and laboratory findings (Table 73-4). When immunodeficiency is suspected and while the evaluation is in process, all blood products need to be irradiated and negative for cytomegalovirus. Lymphocytes present in blood products can cause fatal GVHD in patients with SCID. Cytomegalovirus infection can be fatal in an immunodeficiency patient undergoing stem cell transplantation. Live virus vaccines should be withheld from patients and household members until a diagnosis is established.


Pediatrics_Nelson

Pediatrics_Nelson. Infections should be treated with appropriate antibiotics;prophylactic antibiotics can be used to prevent recurrent infections, provide a better quality of life, and decrease possible consequences. Antibiotic prophylaxis can be provided withonce-daily administration of trimethoprim-sulfamethoxazole or amoxicillin at one half of the total daily therapeutic dose.Patients with severe T-cell deficiencies should receive prophylaxis against Pneumocystis and fungi until treated withstem cell transplantation. Patients with milder forms of antibody deficiency diseases may benefit from vaccination with protein-conjugate vaccines to H. influenzae type b and S. pneumoniae, assaying post vaccination titers at least 1 monthlater. These vaccines are administered routinely to youngchildren; older children and adults with antibody deficiencysyndrome should also receive them to generate protectiveantibody levels.


Pediatrics_Nelson

Pediatrics_Nelson. Immunoglobulin replacement therapy, intravenously orsubcutaneously, is a lifesaving therapy for patients with severeantibody deficiency diseases and SCIDs. It provides passiveimmunity against common microorganisms and reduces thefrequency and severity of infection in most patients. Immunoglobulin replacement therapy is usually administered ata total monthly dose of 400 to 600 mg/kg of body weightadministered intravenously every 3 to 4 weeks, or subcutaneously by infusion pump every 1 to 2 weeks. IVIG therapyshould be monitored by regularly measuring trough immunoglobulin levels and, more important, the patient’s clinical course. Patients who continue to have recurrent infections, especially in the last week before the administration of IVIG,may require higher doses or more frequent administration.A combination of prophylactic antibiotics and immunoglobulin replacement therapy may be indicated in patientswho continue to have recurrent infections. Complications of IVIG therapy include


Pediatrics_Nelson

Pediatrics_Nelson. combination of prophylactic antibiotics and immunoglobulin replacement therapy may be indicated in patientswho continue to have recurrent infections. Complications of IVIG therapy include transfusion reactions with chills,fever, and myalgias. They usually can be prevented in subsequent infusions by pretreatment with an antihistamine, anantipyretic, and by a slower rate of infusion. Headache fromaseptic meningitis can develop after IVIG therapy, usually inthe first 24 hours. It most often responds to treatment with ibuprofen. Allergic reactions to IVIG can occur in patientswith absent IgA. Allergic reactions are rare and should not occur in patients who have detectable serum IgA levels or patients who cannot synthesize any antibodies. Subcutaneous administration of immunoglobulin has fewer adverseeffects but may be complicated by local reactions at the site(s)of infusion. The risk of transmission of infectious agents,despite preparation from large numbers of selected donors,is


Pediatrics_Nelson

Pediatrics_Nelson. fewer adverseeffects but may be complicated by local reactions at the site(s)of infusion. The risk of transmission of infectious agents,despite preparation from large numbers of selected donors,is extremely low.


Pediatrics_Nelson

Pediatrics_Nelson. Therapy for severe T-cell disorders is stem cell transplantation, preferably from a human leukocyte antigen–matchedsibling (see Chapter 76). Immunoglobulin replacement provides passive antibody-mediated immunity. Some patientscontinue to have poor B-cell function after stem cell transplantation and require lifelong immunoglobulin replacementtherapy. GVHD, in which the transplanted cells initiate animmune response against the host tissues, is the main complication of stem cell transplantation. Patients with the ADAdeficiency form of SCID who lack matched sibling donors canreceive repeated intramuscular replacement doses of ADA,stabilized by coupling to polyethylene glycol. Gene therapyhas been performed in several patients with common gammachain deficiency and ADA deficiency by transfer of a normalgene into bone marrow stem cells, which are infused into thepatient. Gene therapy for common gamma chain deficiencywas successful in most of the treated patients; however, itwas complicated


Pediatrics_Nelson

Pediatrics_Nelson. a normalgene into bone marrow stem cells, which are infused into thepatient. Gene therapy for common gamma chain deficiencywas successful in most of the treated patients; however, itwas complicated by the development of leukemia in somepatients.


Pediatrics_Nelson

Pediatrics_Nelson. Population-based screening programs for SCID is underwaybecause early identification of SCID prior to infectious complications improves outcomes. Polymerase chain reaction amplification of T-cell receptor excision circles (TRECs) formed duringT-cell receptor recombination can be performed on newbornscreening blood spots to detect severe T-cell lymphopenia. Newborn screening for TRECs has been shown to detect SCID at birth,and this test has been recommended for universal screening.


Pediatrics_Nelson

Pediatrics_Nelson. Neutrophils play important roles in immunity and wound healing; their primary function is ingesting and killing pathogens.Neutrophil disorders can result from deficient cell numbersor defective function (Table 74-1). Patients with neutrophildisorders are susceptible to a variety of bacterial infectionsand certain fungi. Suggestive signs include mucous membrane infections (gingivitis), abscesses in the skin and viscera,lymphadenitis, poor wound healing, delayed umbilical cordseparation, or absence of pus. Neutrophils develop in the bonemarrow from hematopoietic stem cells by the action of severalcolony-stimulating factors, including stem cell factor, granulocyte-monocyte colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), and interleukin-3. On leavingthe bone marrow, mature neutrophils are found in the circulation or reside in the marginating pool. Adhesion molecules arenecessary for neutrophils to roll and adhere to vascular endothelium and extravasate from the


Pediatrics_Nelson

Pediatrics_Nelson. mature neutrophils are found in the circulation or reside in the marginating pool. Adhesion molecules arenecessary for neutrophils to roll and adhere to vascular endothelium and extravasate from the blood into sites of infection, where they phagocytose and kill pathogens, especially thosecoated by complement or antibodies. Chemotactic factors, including the complement fragment C5a, interleukin-8, andbacterial formulated peptides, mobilize neutrophils to enter tissues and sites of infections. Neutrophils kill ingested pathogensusing granular enzymes or by activation of oxygen radicals.


Pediatrics_Nelson

Pediatrics_Nelson. Disorders of Neutrophil Numbers Available @ StudentConsult.com Diarrhea Neutropenia Failure to Thrive


Pediatrics_Nelson

Pediatrics_Nelson. The normal neutrophil count varies with age. Neutropenia is defined as an absolute neutrophil count (ANC) less than 1500/mm3 for white children 1 year of age or older. African American children normally have lower total white blood cell and neutrophil counts. The effect of neutropenia depends on its severity. The susceptibility to infection is minimally increased until the ANC is less than 1000/mm3. Most patients do well with an ANC greater than 500/mm3. At these levels, localized infections are more common than generalized bacteremia. Serious bacterial infections are more common with an ANC less than 200/mm3. The major types of infections associated with neutropenia are cellulitis, pharyngitis, gingivitis, lymphadenitis, abscesses (cutaneous or perianal), enteritis (typhlitis), and pneumonia. The sites of the infection usually are colonized heavily with normal bacterial flora that becomes invasive in the presence of neutropenia. Neutropenia may be congenital or acquired (Table 74-2)


Pediatrics_Nelson

Pediatrics_Nelson. The sites of the infection usually are colonized heavily with normal bacterial flora that becomes invasive in the presence of neutropenia. Neutropenia may be congenital or acquired (Table 74-2) and may be associated with specific diseases, especially infections (Table 74-3), or result from drug reactions (Table 74-4).


Pediatrics_Nelson

Pediatrics_Nelson. There are several forms of congenital neutropenia. Severe congenital neutropenia (Kostmann syndrome) is an autosomal recessive disorder in which myeloid cells fail to mature beyond the early stages of the promyelocyte due to mutations in the HAX-1 gene. The peripheral blood may show an impressive monocytosis. Although endogenous G-CSF levels are increased, exogenous G-CSF produces a rise in the neutrophil count, improving the care of these children. Acute myeloid leukemia has developed in a few patients who have survived into adolescence. Stem cell transplantation may be curative. Defects in G6PC3 and GFI1 have also been shown to cause severe congenital neutropenia. Cyclic neutropenia is a stem cell disorder in which all marrow elements cycle. It may be transmitted as an autosomal dominant, recessive, or sporadic disorder. Because of the short half-life of neutrophils in the blood (6 to 7 hours) compared to platelets (10 days) and red blood cells (120 days), neutropenia is the only


Pediatrics_Nelson

Pediatrics_Nelson. recessive, or sporadic disorder. Because of the short half-life of neutrophils in the blood (6 to 7 hours) compared to platelets (10 days) and red blood cells (120 days), neutropenia is the only clinically significant abnormality. The usual cycle is 21 days, with neutropenia lasting 4 to 6 days, accompanied by monocytosis and often by eosinophilia. Severe, debilitating bone pain is common when the neutrophil count is low. G-CSF results in increasing neutrophil numbers and a shorter duration of neutropenia. Defects in ELA2, the gene encoding for neutrophil elastase, has been found in patients with cyclic neutropenia. Further analysis has demonstrated ELA2 mutations in some cases of severe congenital neutropenia.


Pediatrics_Nelson

Pediatrics_Nelson. Severe congenital neutropenia that may be either persistent or cyclic also is a component of Shwachman-Diamond syndrome, an autosomal recessive syndrome of pancreatic insufficiency accompanying bone marrow dysfunction. This is a panmyeloid disorder in which neutropenia is the most prominent manifestation. Metaphyseal dysostosis and dwarfism may occur. Patients usually respond to G-CSF. Other congenital neutropenia caused by deficient neutrophil production vary in severity and are poorly characterized. A gain of function mutation in the Wiskott-Aldrich syndrome protein has also been associated with an X-linked form of severe congenital neutropenia. Benign congenital neutropenia is a functional diagnosis for patients with significant neutropenia in whom major infectious complications do not develop. Many patients whose ANC ranges from 100 to 500/mm3 have an increased frequency of infections, particularly respiratory infections, but the major problem is the slow resolution of infections


Pediatrics_Nelson

Pediatrics_Nelson. develop. Many patients whose ANC ranges from 100 to 500/mm3 have an increased frequency of infections, particularly respiratory infections, but the major problem is the slow resolution of infections that develop. These disorders may be sporadic or familial and, in some instances, are transmitted as an autosomal dominant disorder. Severe congenital neutropenia may be associated with severe combined immunodeficiency in reticular dysgenesis, a


Pediatrics_Nelson

Pediatrics_Nelson. Table 74-1 Phagocytic Disorders NAME DEFECT COMMENT Chronic granulomatous disease Bactericidal X-linked recessive (66%), autosomal recessive (33%); eczema, osteomyelitis, granulomas, abscesses caused by Staphylococcus aureus, Burkholderia cepacia, Aspergillus fumigatus Chédiak-Higashi syndrome Bactericidal plus chemotaxis; Autosomal recessive; oculocutaneous albinism, neuropathy, giant (1q42I-44) poor natural killer function neutrophilic cytoplasmic inclusions; malignancy, neutropenia Myeloperoxidase deficiency Bactericidal, fungicidal Reduced chemiluminescence; autosomal recessive (1:4000); persistent candidiasis in diabetic patients Glucose-6-phosphate Bactericidal Phenotypically similar to chronic granulomatous disease dehydrogenase deficiency Burns, malnutrition Bactericidal plus chemotaxis Reversible defects Shwachman-Diamond Chemotaxis, neutropenia Pancreatic insufficiency, metaphyseal chondrodysplasia; autosomal syndrome


Pediatrics_Nelson

Pediatrics_Nelson. Burns, malnutrition Bactericidal plus chemotaxis Reversible defects Shwachman-Diamond Chemotaxis, neutropenia Pancreatic insufficiency, metaphyseal chondrodysplasia; autosomal syndrome CR3, Complement receptor 3; LFA-1, leukocyte function-associated antigen type 1; Mac-1, macrophage 1 antigen. disorder of hematopoietic stem cells affecting all bone marrow lineages due to mutations in the AK2 gene.


Pediatrics_Nelson

Pediatrics_Nelson. disorder of hematopoietic stem cells affecting all bone marrow lineages due to mutations in the AK2 gene. Isoimmune neutropenia occurs in neonates as the result of transplacental transfer of maternal antibodies to fetal neutrophil antigens. The mother is sensitized to specific neutrophil antigens on fetal leukocytes that are inherited from the father and are not present on maternal cells. Isoimmune neonatal neutropenia, similar to isoimmune anemia and thrombocytopenia, is a transient process (see Chapters 62 and 151). Cutaneous infections are common, and sepsis is rare. Early treatment of infection while the infant is neutropenic is the major goal of therapy. Intravenous immune globulin may decrease the duration of neutropenia.


Pediatrics_Nelson

Pediatrics_Nelson. Autoimmune neutropenia usually develops in children 5 to 24 months of age and often persists for prolonged periods. Neutrophil autoantibodies may be IgG, IgM, IgA, or a combination of these. Usually the condition resolves in 6 months to 4 years. Although intravenous immune globulin and corticosteroids have been used, most patients respond to G-CSF. Autoimmune neutropenia rarely may be an early manifestation of systemic lupus erythematosus, rheumatoid arthritis, or autoimmune lymphoproliferative disease. Disorders of Neutrophil Migration


Pediatrics_Nelson

Pediatrics_Nelson. Neutrophils normally adhere to endothelium and migrate to areas of inflammation by the interaction of membrane proteins, called integrins and selectins, with endothelial cell adhesion molecules. A hallmark of defects in neutrophil migration is the absence of pus at sites of infection. In leukocyte adhesion deficiency type I (LAD-I), infants lacking the β2 integrin CD18 exhibit the condition early in infancy with failure of separation of the umbilical cord (often 2 months after birth) with attendant omphalitis and sepsis (see Table 74-1). The neutrophil count usually is greater than 20,000/mm3 because of failure of the neutrophils to adhere normally to vascular endothelium and to migrate out of blood to the tissues (Fig. 74-1). Cutaneous, respiratory, and mucosal infections occur. Children with this condition often have severe gingivitis. Sepsis usually leads to death in early childhood. This disorder is transmitted as an autosomal recessive trait. Stem cell transplantation can be


Pediatrics_Nelson

Pediatrics_Nelson. with this condition often have severe gingivitis. Sepsis usually leads to death in early childhood. This disorder is transmitted as an autosomal recessive trait. Stem cell transplantation can be lifesaving.


Pediatrics_Nelson

Pediatrics_Nelson. LAD-II results from impairment of neutrophil rolling along the vascular wall, which is the first step in neutrophil migration into tissues and sites of infection. Rolling is mediated by sialylated and fucosylated tetrasaccharides related to the sialylated Lewis X (S-LeX) blood group found on the surface of neutrophils, monocytes, and activated lymphocytes binding to selectin molecules on vascular endothelium (see Fig. 74-1).LAD-II results from a general defect in fucose metabolism leading to the absence of S-LeX blood group on the surface of neutrophils and other leukocytes. LAD-III is a rare disorder caused by defects in the KINDLIN-3 protein resulting in defective neutrophil adhesion as well as platelet defects. Defective migration of neutrophils has also been described in Hyper-IgE syndrome and with mutations in the RAC2 gene (see Chapter 73 and Table 74-1). Disorders of Neutrophil Function Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Disorders of Neutrophil Function Available @ StudentConsult.com Defects in neutrophil function are relatively rare inherited disorders and tend to be associated with a marked susceptibility to bacterial and fungal infection. Chronic granulomatous disease (CGD) is a disorder of white blood cells that results Drugs: idiosyncratic, cytotoxic (myelosuppressive) Radiation Chemicals: DDT, benzene Immune-mediated: T and B cell and immunoglobulin Infections (viruses, rickettsia) Infiltrative processes: tumor, storage disease Myelodysplasia Aplastic anemia Kostmann syndrome (HAX-1, G6PC3, ELA-2, G-CSF, GFI-1) Cyclic neutropenia (ELA-2) Cartilage hair hypoplasia Shwachman-Diamond syndrome Diamond-Blackfan syndrome Griscelli syndrome Chédiak-Higashi syndrome WHIM syndrome (warts, hypogammaglobulinemia, infections, Pseudoneutropenia: Shift to Bone Marrow


Pediatrics_Nelson

Pediatrics_Nelson. Pseudoneutropenia: Shift to Bone Marrow Destruction: neonatal isoimmune, autoimmune, hypersplenism Autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome) Leukoagglutination: lung, after cardiac bypass surgery ELA-2, Elastase 2; G6PC3, glucose-6-phosphatase catalytic subunit 3; G-CSF, granulocyte colony-stimulating factor; GFI-1, growth factor independent 1; HAX-1, HS1-associated protein X-1.


Pediatrics_Nelson

Pediatrics_Nelson. HAX-1, HS1-associated protein X-1. from defective intracellular killing of bacteria and intracellular pathogens by neutrophils and macrophages because of an inability to activate the “respiratory burst,” the catalytic conversion of molecular oxygen to superoxide (O2–). Reduced nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that catalyzes the respiratory burst, consists of four subunits; gp91phox, p22phox, p47phox, and p67phox. Defects in any of these enzymes lead to an inability to kill catalase-positive pathogens such as S. aureus and enteric gram-negative bacteria (Burkholderia) and fungi (Aspergillus fumigatus, Candida albicans). The gp91phox gene is located on chromosome Xp21.1 and is responsible for the most common form of the disease. The other gene defects are inherited in an autosomal recessive manner. The chromosome locations for HIV, human immunodeficiency virus.


Pediatrics_Nelson

Pediatrics_Nelson. HIV, human immunodeficiency virus. Table 74-4 Drug-Associated Neutropenia CYTOTOXIC Myelosuppressive, chemotherapeutic agents Immunosuppressive agents IDIOSYNCRATIC Indomethacin Para-aminophenol derivatives Pyrazolone derivatives (aminopyrine, dipyrone, oxyphenbutazone) Chloramphenicol Sulfonamides Antithyroid drugs (propylthiouracil, methimazole, carbimazole) Phenothiazines (chlorpromazine, phenothiazines) Penicillins and semisynthetic penicillins Adapted from Dale DC: Neutropenia. In Lichtman MA, Kipps TJ, Seligsohn U, et al, editors: Williams Hematology, ed 8, New York, 2010, McGraw-Hill.


Pediatrics_Nelson

Pediatrics_Nelson. Adapted from Dale DC: Neutropenia. In Lichtman MA, Kipps TJ, Seligsohn U, et al, editors: Williams Hematology, ed 8, New York, 2010, McGraw-Hill. these genes are 16q24 for p22phox, 7q11.23 for p47phox, and 1q25 for p67phox. Glucose-6-phosphate dehydrogenase also is involved in the production of superoxide, and severe forms of glucose-6-phosphate dehydrogenase deficiency also result in CGD. Patients characteristically have lymphadenopathy, hypergammaglobulinemia, hepatosplenomegaly, dermatitis, failure to thrive, anemia, chronic diarrhea, and abscesses. Infections occur in the lungs, the middle ear, gastrointestinal tract, skin, urinary tract, lymph nodes, liver, and bones.


Pediatrics_Nelson

Pediatrics_Nelson. Figure 74-1 Schematic representation of neutrophil migration from the vascular space across the vascular endothelium into tissues. Neutrophils bind to selectin (Eor P-selectin) molecules on the surface of vascular endothelium via sialylated and fucosylated tetrasaccharides related to the S-LeX blood group found on the surface of neutrophils. The bound neutrophils roll along the endothelium and become tightly bound by the interaction of the adhesion molecule leukocyte function-associated antigen type 1 (LFA-1) on the neutrophil and intercellular adhesion molecule type 1 on vascular endothelium, allowing neutrophils to move through the endothelium and into the tissue spaces. (Adapted from Janeway CA, Travers P, Walport M, et al: Immunobiology: the Immune System in Health and Disease, ed 4, New York, 1999, Elsevier.) Granulomas are prominent and may obstruct the pylorus or ureters.


Pediatrics_Nelson

Pediatrics_Nelson. Chédiak-Higashi syndrome, an abnormality of secondary granules, is an autosomal recessive disorder caused by a mutation in a cytoplasmic protein (CHS1) thought to be involved in organellar protein trafficking, resulting in a fusion of the primary and secondary granules in neutrophils. Giant granules are present in many cells, including lymphocytes, platelets, and melanocytes. Patients usually have partial oculocutaneous albinism. The defect in Chédiak-Higashi syndrome results in defective neutrophil and natural killer cell function, leading to recurrent and sometimes fatal infections with streptococci and staphylococci. Most patients progress to an accelerated phase associated with Epstein-Barr virus infection and characterized by a lymphoproliferative syndrome with generalized lymphohistiocytic infiltrates, fever, jaundice, hepatomegaly, lymphadenopathy, and pancytopenia. The condition resembles hemophagocytic lymphohistiocytosis.


Pediatrics_Nelson

Pediatrics_Nelson. The evaluation of a neutropenic child depends on clinical signs of infection, family and medication history, age of the patient, cyclic or persistent nature of the condition, signs of bone marrow infiltration (malignancy or storage disease), and evidence of involvement of other cell lines. Neutropenia is confirmed by a complete blood count and differential. A bone marrow aspirate and biopsy may be necessary to determine whether the neutropenia is due to a failure of production in the bone marrow, infiltration of the bone marrow, or loss of neutrophils in the periphery. Antineutrophil antibodies help diagnose autoimmune neutropenia.


Pediatrics_Nelson

Pediatrics_Nelson. Neutrophil chemotactic defects can be excluded by the presence of neutrophils at the site of infection. The Rebuck skin window is a 4-hour in vivo test for neutrophil chemotaxis thatis not performed routinely by most laboratories. In vitro studies of neutrophil migration are available in specialized laboratories.Flow cytometry for the presence of adhesion molecules, such as CD18 or CD15, can help diagnose leukocyte adhesion defects.Point mutations that affect the function of the adhesion molecule but do not alter antibody binding are missed using flow cytometry. CGD can be diagnosed by the flow cytometry-based test usingdihydrorhodamine 123 or the nitroblue tetrazolium test (seeChapter 72). Light microscopy of neutrophils for the presence ofgiant granules can help diagnose Chédiak-Higashi syndrome.


Pediatrics_Nelson

Pediatrics_Nelson. Therapy for neutropenia depends on the underlying cause. Patients with severe bacterial infections require broad-spectrum antibiotics; the resolution of neutropenia is the most important prognostic factor. Most patients with severe congenital neutropenia or autoimmune neutropenia respond to therapy with G-CSF. Granulocyte transfusion should be reserved for life-threatening infection. Chronic mild neutropenia not associated with immunosuppression can be managed expectantly with prompt antimicrobial treatment of softtissue infections, which usually are caused by S. aureus or group A streptococcus.


Pediatrics_Nelson

Pediatrics_Nelson. Frequent courses of antibiotics, including trimethoprim-sulfamethoxazole prophylaxis, and surgical débridement of infections are required in CGD. Because A. fumigatus can cause serious infection in patients with CGD, moldy hay, decomposing compost, and other nests of fungi must be avoided, and prophylactic antifungals can be helpful. The frequency of infection in CGD is lessened by treatment with recombinant interferon-γ administered subcutaneously three times a week. Stem cell transplantation (see Chapter 76) may be lifesaving in CGD, LAD-1, and Chédiak-Higashi syndrome.


Pediatrics_Nelson

Pediatrics_Nelson. The prognosis depends on the particular defect. Milder and transient defects in neutrophil numbers have a better prognosis. Prolonged absence of neutrophils or their function has a poor prognosis, especially with the risk of bacterial and fungal sepsis. Treatment with prophylactic antibiotics and interferon-γ has improved the prognosis of patients with CGD. Stem cell transplantation is the only currently available mode of therapy that can reverse the poor prognosis of severe neutrophil defects. As in other genetic defects, prenatal diagnosis and genetic counseling are possible for all known gene mutations. The complement system consists of plasma and membrane proteins that function in the innate immune response as well as facilitate adaptive immunity. Complement proteins can kill pathogens with or without antibodies, opsonize pathogens LECTIN PATHWAY CLASSIC PATHWAY ALTERNATIVE PATHWAY (Antibody independent) (Antibody dependent) (Antibody independent) C4 C1 (C1q, C1r, C1s) C3


Pediatrics_Nelson

Pediatrics_Nelson. LECTIN PATHWAY CLASSIC PATHWAY ALTERNATIVE PATHWAY (Antibody independent) (Antibody dependent) (Antibody independent) C4 C1 (C1q, C1r, C1s) C3 B, D, P C2b Figure 75-1 Complement component cascade involving the classic, alternative, and lectin pathways. The initiating events for the pathways differ, but they result in the production of C3 cleaving enzyme activity, which is the pivotal step as the three pathways converge to the terminal activation sequences. Ag-Ab, Antigen-antibody complex; B, factor B; D, factor D (factor B clearing enzyme); P, properdin. to facilitate their uptake by phagocytes, or mediate inflammation. The complement system can be activated through three pathways—classic, alternative, or lectin—that involve a cascade-like, sequential activation of complement factors resulting in an amplified response (Fig. 75-1). Disorders of the complement system predispose to recurrent infection, autoimmunity, and angioedema (Table 75-1).


Pediatrics_Nelson

Pediatrics_Nelson. The three pathways for complement activation are initiated by different mechanisms. The classic pathway is activated by antigen-antibody complexes or by C-reactive protein. The alternative pathway may be activated by C3b generated through classic complement activation or by spontaneous hydrolysis of C3 on microbial surfaces. The lectin pathwayis initiated by the interaction of mannose-binding lectin with microbial carbohydrate. Activation of the classic pathway by an antigen-antibody complex is initiated by the binding of C1q to the Fc portion of an antibody molecule in the immune complex. C1r auto-activates and cleaves C1s, which cleaves C4 and then C2, forming the C3 convertase, C4b2a. C4b2a is activated by the lectin pathway when mannose-binding protein binds to sugar residues on the surface of pathogens, and mannose-binding protein–associated proteases (MASP) cleave C4 and C2. The alternative pathway is always active at a low level and is amplified when active C3 binds to a


Pediatrics_Nelson

Pediatrics_Nelson. the surface of pathogens, and mannose-binding protein–associated proteases (MASP) cleave C4 and C2. The alternative pathway is always active at a low level and is amplified when active C3 binds to a surface that lacks regulatory proteins. C3b generated from C3 binds to factor B, which is cleaved by factor D to form the alternative pathway C3 convertase, C3bBb. Properdin binds to and stabilizes the C3 convertase (see Fig. 75-1). The C3 convertase can cleave C3 resulting in further C3b deposition and activation of the alternative pathway that acts as an amplification loop by generating more C3b, or it can form the C5 convertase which initiates the formation of a membrane attack complex (MAC). The MAC is a complex of C5b, C6, C7, C8, and several C9 molecules that is common to all three pathways (see Fig. 75-1). The MAC generates pores in the cell membrane, leading to lysis of the cells. C3a and C5a, produced by cleavage of C3 and C5 respectively, can release histamine from mast cells and


Pediatrics_Nelson

Pediatrics_Nelson. (see Fig. 75-1). The MAC generates pores in the cell membrane, leading to lysis of the cells. C3a and C5a, produced by cleavage of C3 and C5 respectively, can release histamine from mast cells and basophils, leading to increased vascular permeability and smooth muscle contraction. In addition, C5a has chemotactic


Pediatrics_Nelson

Pediatrics_Nelson. C1q, C1r SLE, glomerulonephritis; encapsulated C2 SLE, glomerulonephritis; encapsulated bacterial infections C3 Recurrent bacterial infections, rare glomerulonephritis, or SLE C4 SLE, glomerulonephritis; encapsulated bacterial infections Properdin Recurrent infections, severe meningococcal infection MBL Increased susceptibility to infections Factor H Glomerulonephritis, atypical HUS Factor I Recurrent infections, glomerulonephritis MCP Glomerulonephritis, atypical HUS HUS, hemolytic uremic syndrome; MBL, mannose binding lectin; MCP, membrane cofactor protein; SLE, systemic lupus erythematosus.


Pediatrics_Nelson

Pediatrics_Nelson. MCP Glomerulonephritis, atypical HUS HUS, hemolytic uremic syndrome; MBL, mannose binding lectin; MCP, membrane cofactor protein; SLE, systemic lupus erythematosus. activity, attracting phagocytes to the site of complement activation, and it can cause degranulation of phagocytic cells. C3b acts as an opsonin when attached to the surface of a pathogen by binding to phagocytes via complement receptor 1 (CR1). Its degradation product, iC3b, can bind to CR3 on the surface of phagocytes leading to the ingestion of the C3b-coated or iC3b-coated pathogen. iC3b and its breakdown product C3dg can bind complement receptor 2 (CR2) on B cells leading to activation and differentiation.


Pediatrics_Nelson

Pediatrics_Nelson. The complement system is under tight regulation because it has potent inflammatory activity and the potential to cause significant damage to host cells. The complement cascade is inherently regulated by the short half-life C4b and C3b and byinstability of the C3 convertases, C4b2a, and C3bBb. C1-inhibitorregulates the cascade by blocking active sites on C1r, C1s, and the MASP. Factor I destabilizes C3 convertase complexes and degrades the active fragments. Other inhibitors include membrane proteins, such as decay accelerating factor, CR1, membrane cofactor protein (MCP), and plasma proteins such as C4b-binding protein and factor H. Formation of the MAC can be blocked by cell surface CD59, protein S, and other plasma proteins. Deficiency of any of these regulatory proteins can result in an inflammatory response, tissue damage, or excessive complement consumption.


Pediatrics_Nelson

Pediatrics_Nelson. Disorders of complement proteins can result from inherited deficiency or can be secondary to increased consumption. The consequences of decreased complement depend on the affected factor (see Table 75-1). Deficiencies of early components of the classic pathway (C1, C2, or C4) are not usually associated with severe infections, although patients with C2 deficiency may present with milder recurrent infections. Patients with C1, C2, or C4 deficiency are susceptible to autoimmune diseases, especially systemic lupus erythematosus. The exact mechanism of this susceptibility is not known but is thought to arise from the role of these early components in clearing immune complexes.


Pediatrics_Nelson

Pediatrics_Nelson. Deficiency of properdin, C3, or the terminal componentspredisposes patients to severe recurrent infections. Deficiency of C3, the major opsonin, due to a genetic defect or secondary to excessive consumption, predisposes patients to infections, especially with encapsulated organisms. Deficiency of one of the terminal components that compose the MAC predisposes patients to infection with Neisseria meningitidis. Complement deficiency may be found in 40% of patients presenting with recurrent neisserial infections. Deficiency of mannose-binding lectin also is associated with an increased frequency of bacterial infections, including sepsis.


Pediatrics_Nelson

Pediatrics_Nelson. Congenital deficiency of C1-inhibitor results in hereditary angioedema, characterized by recurrent episodes of nonpruritic angioedema lasting 48 to 72 hours, which occur spontaneously or after minor trauma, stress, or anxiety. Abdominaledema can cause acute abdominal pain; edema of the upperairway can be life threatening and may necessitate emergencytracheostomy. The disorder is inherited as an autosomal dominant disease and results from a heterozygous deficiency of C1-inhibitor leading to serum levels less than 30% of normal values. Some mutations (type II hereditary angioedema) resultin normal levels of C1-inhibitor with defective function. An acquired form of angioedema results from autoantibodies toC1-inhibitor in lymphoid malignancies or autoimmune disorders but is uncommon in childhood. C1-inhibitor is a regulatorof Hageman factor (clotting factor XIIa), clotting factor XIa,plasma kallikrein, and plasmin in addition to C1r and C1s. Lackof inhibition of the contact system,


Pediatrics_Nelson

Pediatrics_Nelson. childhood. C1-inhibitor is a regulatorof Hageman factor (clotting factor XIIa), clotting factor XIa,plasma kallikrein, and plasmin in addition to C1r and C1s. Lackof inhibition of the contact system, Hageman factor and plasmakallikrein, is responsible for the development of angioedema.Deficiencies in the complement regulatory proteins factor H,factor I, and MCP result in atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and have been linked to age-related macular degeneration.


Pediatrics_Nelson

Pediatrics_Nelson. The CH50 test is a widely available test of classic complement pathway function, based on an antibody-dependent hemolytic assay, which measures the serum dilution that results in lysis of 50% of sheep red blood cells. The CH50 test depends on the function of all nine complement proteins, C1 through C9. The AH50 test, which measures complement activation using red blood cells from different species (e.g., rabbit) that can activate the alternative pathway without antibody, is less widely available than the CH50 test and requires the alternative pathway components and C5 to C9. Abnormal results of both tests indicate a deficiency in a terminal component common to both pathways, whereas an abnormal result of one or the other test indicates a deficiency of an early component of the respective pathway. If the CH50 or AH50 levels are abnormal, individual components can be analyzed in specialized laboratories.


Pediatrics_Nelson

Pediatrics_Nelson. Determination of C1-inhibitor levels and function is needed to diagnose hereditary angioedema. Some functional tests miss rare mutations that allow C1-inhibitor to bind C1s, but not one or more of the other enzymes with which it interacts. Low C1-inhibitor levels or function results in chronically decreased C4 levels and decreased C2 levels during acute attacks. Low C1q levels are found in acquired C1-inhibitor deficiency, which distinguishes it from hereditary angioedema. Tests for autoantibodies to C1-inhibitor and C1q can be performed by enzyme-linked immunosorbent assay.


Pediatrics_Nelson

Pediatrics_Nelson. Specific treatment of complement deficiencies with component replacement is not available. Long, frequent courses of antibiotics constitute the primary therapy. Immunization of patients and close contacts with pneumococcal and meningococcal vaccines may be useful, but infections may still occur in immunized complement-deficient patients. Replacement of complement proteins by plasma transfusion has been used in some patients with C2 deficiency, factor H deficiency, or factor I deficiency. MCP deficiency is treated with renal transplantation because it is a membrane protein.


Pediatrics_Nelson

Pediatrics_Nelson. Patients with C1-inhibitor deficiency and frequent episodes of angioedema respond to prophylactic use of an oral attenuated androgen (stanozolol or danazol), which increases serum concentrations of C1-inhibitor. Adverse effects, including masculinization in females, growth arrest, and hepatitis, limit their use. Prophylactic administration of fresh frozen plasma before surgery can prevent angioedema, but administration during an acute episode may exacerbate the episode. Angioedema of the airway can present as an acute emergency, necessitating a tracheostomy because administration of epinephrine, antihistamines, or corticosteroids is ineffective in reversing this type of angioedema. Purified C1-inhibitor is available and can be used prophylactically (before surgery) and during acute episodes of angioedema. Angiotensin-converting enzyme inhibitors, such as captopril, should be avoided in patients with C1-inhibitor deficiency because these drugs can precipitate episodes of angioedema by


Pediatrics_Nelson

Pediatrics_Nelson. of angioedema. Angiotensin-converting enzyme inhibitors, such as captopril, should be avoided in patients with C1-inhibitor deficiency because these drugs can precipitate episodes of angioedema by inhibiting degradation of kinins that mediate edema formation. Novel therapeutic agents, including a kallikrein inhibitor and a bradykinin receptor 2 antagonist, are being investigated as potential therapy for hereditary angioedema.


Pediatrics_Nelson

Pediatrics_Nelson. Hematopoietic stem cell transplantation (HSCT) can cure some patients with primary immunodeficiency disease (Table 76-1). Use of HSCT is limited to immunodeficiency diseases with T-cell defects, some metabolic storage diseases (see Chapters 55 and 56), malignancies (see Chapter 154), aplastic anemia (see Chapter 150), hemoglobinopathies (Chapter 150), and a few other disorders. Wiskott-Aldrich syndrome X-linked hyper-IgM X-linked lymphoproliferative syndromes Cartilage hair hypoplasia Autoimmune lymphoproliferative syndrome (Fas defect) Severe congenital neutropenia Shwachman-Diamond syndrome Immune dysregulation, polyendocrinopathy, enteropathy, X-linked


Pediatrics_Nelson

Pediatrics_Nelson. The principle of HSCT is to replace a patient’s defective bone marrow stem cells with normal stem cells. Hematopoietic stem cells reside in the bone marrow but can also be obtained from peripheral blood or cord blood. Peripheral blood does not contain a significant proportion of stem cells unless the donor’s bone marrow is actively stimulated to generate stem cells. Cord blood is a good source of stem cells and is used for sibling and unrelated HSCT.


Pediatrics_Nelson

Pediatrics_Nelson. Major histocompatibility complex (MHC) compatibilityis crucial in the choice of a stem cell donor to avoid rejection of the donor cells by the host immune system and to prevent graft-versus-host disease (GVHD) caused by contaminating mature T cells. The donor stem cells give rise to T cells that develop in the host thymus and need to interact with donor and host antigen-presenting cells. In cases with MHC mismatched donors, mature T cells need to be removed from the donor to reduce the risk of GVHD; this complication outweighs the disadvantage of a prolonged time of 90 to 120 days before T-cell development. Patients are at risk for developing B-cell lymphoproliferative disease, usually associated with Epstein-Barr virus, when T-cell–depletion techniques are used, likely due to the delay in T-cell engraftment.


Pediatrics_Nelson

Pediatrics_Nelson. The most important factor affecting outcomes in HSCT is the similarity of the donor MHC. The best outcomes are obtained using MHC-identical siblings (25% chance of a matched sibling) as donors, followed by matched unrelated donors. Unlike transplantation for other disorders, MHC haploidentical bone marrow from a parent (preferred) or a sibling can be used to treat severe combined immunodeficiency (SCID), likely the result of these patients lacking functioning T cells. Stem cells from a partially mismatched donor, such as a parent, can give rise to a functioning immune system because the patient shares at least half of the MHC molecules with the donor stem cells.


Pediatrics_Nelson

Pediatrics_Nelson. MHC molecules are highly polymorphic, and typing is currently performed on DNA rather than by serology. Bone marrow and cord blood registries are available worldwide. Searching and identifying a donor can be a lengthy process, especially for some underrepresented ethnic backgrounds. Finding a suitable cord blood donor is faster because the cord blood already has been obtained and stored, whereas bone marrow donors have to be identified, located, and tested. A matched sibling, if available, is the preferred source of hematopoietic stem cells.


Pediatrics_Nelson

Pediatrics_Nelson. Patients with SCID are ideal candidates for HSCT, which is the only option for treatment of SCID at this time. Patients are unlikely to survive beyond 1 to 2 years of age without transplantation, and they have no T-cell function to reject donor cells. Thus they may not need to undergo conditioning with chemotherapy or irradiation before transplantation. The development of transplantation using T-cell–depleted, haploidentical bone marrow from a parent for SCID has provided almost every patient with SCID a potential donor. The mother is the preferred source for haploidentical bone marrow, if she is able to donate, because some transfer of maternal T cells can occur during pregnancy, and these maternal T cells can reject cells obtained from the father. The survival rate after HSCT for SCID is approximately 90% with MHC-identical and 60% with haploidentical bone marrow transplantation. Early transplant before the acquisition of infection improves outcomes. Because newborn screening for


Pediatrics_Nelson

Pediatrics_Nelson. is approximately 90% with MHC-identical and 60% with haploidentical bone marrow transplantation. Early transplant before the acquisition of infection improves outcomes. Because newborn screening for SCID is now possible, stem cell transplantation can occur as early as possible when the infants are healthy, providing the best opportunity for a cure.


Pediatrics_Nelson

Pediatrics_Nelson. The decision to treat other primary immunodeficiency diseases with HSCT is more difficult because it is difficult to predict the prognosis of a particular patient because of the variability in clinical course of most primary immunodeficiency diseases. This must be weighed with the risks of transplantation. In addition, HSCT for other primary immunodeficiencies is less successful than for SCID because patients typically have some T-cell function and require conditioning with the risks that it entails. The availability of a matched related sibling favors the decision to perform HSCT. Disorders of B cells have not been treated with HSCT because, in many cases, donor B cells do not engraft, and patients usually do well with intravenous immunoglobulin. Regardless a variety of primary immunodeficiencies have been treated with HSCT (see Table 76-1)


Pediatrics_Nelson

Pediatrics_Nelson. Rejection of the grafted cells is the first potential complication of HSCT and depends on the immunocompetence of thepatient, the degree of MHC incompatibility, and the number of cells administered. Preconditioning with myeloablativedrugs, such as busulfan and cyclophosphamide, can preventgraft rejection but may be complicated by pulmonary toxicity and by venoocclusive disease of the liver, which resultsfrom damage to the hepatic vascular endothelium and canbe fatal. Myeloablation results in anemia, leukopenia, andthrombocytopenia, making patients susceptible to infectionand bleeding disorders. Neutropenic precautions should bemaintained and patients supported with red blood cell andplatelet transfusions until the red blood cell, platelet, and neutrophil lineages engraft. Reduced intensity preconditioninghas been used recently to prevent graft rejection and decreasethe adverse effects of myeloablation. B-cell lymphoproliferative disorder can develop after T-cell depleted bone


Pediatrics_Nelson

Pediatrics_Nelson. intensity preconditioninghas been used recently to prevent graft rejection and decreasethe adverse effects of myeloablation. B-cell lymphoproliferative disorder can develop after T-cell depleted bone marrowtransplantation. GVHD can arise from an MHC-mismatched transplantation or from mismatch in minor histocompatibility antigens that are not tested for before transplantation.T-cell depletion of haploidentical bone marrow reduces the risk of GVHD. Patients with SCID transplanted withT-cell–depleted haploidentical bone marrow do not usuallydevelop severe GVHD. Acute GVHD begins 6 or more daysafter transplantation and can result from transfusion of non-irradiated blood products in patients with no T-cell function.Acute GVHD presents with fever, skin rash, and severe diarrhea. Patients develop a high, unrelenting fever; a morbilliform maculopapular erythematous rash that is painful andpruritic; hepatosplenomegaly and abnormal liver functiontests; and nausea, vomiting, abdominal pain, and


Pediatrics_Nelson

Pediatrics_Nelson. a high, unrelenting fever; a morbilliform maculopapular erythematous rash that is painful andpruritic; hepatosplenomegaly and abnormal liver functiontests; and nausea, vomiting, abdominal pain, and waterydiarrhea. Acute GVHD is staged from grades 1 to 4, depending on the degree of skin, fever, gastrointestinal, and liverinvolvement. Chronic GVHD results from acute GVHD lasting longer than 100 days and can develop without acuteGVHD or after acute GVHD has resolved. Chronic GVHD is characterized by skin lesions (hyperkeratosis, reticularhyperpigmentation, fibrosis, and atrophy with ulceration),limitation of joint movement, interstitial pneumonitis, andimmune dysregulation with autoantibody and immune complex formation.


Pediatrics_Nelson

Pediatrics_Nelson. Klein C: Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes, Annu Rev Immunol 29:399–413, 2011 Ricklin D, Hajishengallis G, Yang K, et al: Complement: a key system for immune surveillance and homeostasis, Nat Immunol 11:785–797, 2010 Szabolcs P, Cavazzana-Calvo M, Fischer A, et al: Bone marrow trans plantation for primary immunodeficiency diseases, Pediatr Clin N Am 57:207–237, 2010 Waleed A, Bousfiha A, Casanova JL, et al: Primary immunodeficiency diseases: an update on the classification from the International Union of ciency, Front Immunol 2:1–26, 2011 Asriani M. Chiu 14 Atopy is a result of a complex interaction between multiple genes and environmental factors. It implies specific IgE-mediated diseases, including allergic rhinitis, asthma, and atopic dermatitis. An allergen is an antigen that triggers an IgE response in genetically predisposed individuals.


Pediatrics_Nelson

Pediatrics_Nelson. Hypersensitivity disorders of the immune system are classified into four groups, based on the mechanism that leadsto tissue inflammation (Table 77-1). Type I reactions are triggered by the binding of antigen to high-affinity IgE receptors on the surface of tissue mast cells, circulating basophils,or both, causing the release of preformed chemical mediators, such as histamine and tryptase, and newly generatedmediators, such as leukotrienes, prostaglandins, and platelet-activating factor. These mediators contribute to the development of allergic symptoms, with anaphylaxis as the mostprofound symptom. Several hours after the initial response, a late-phase reaction may develop with an influx of other inflammatory cells such as basophils, eosinophils, monocytes, lymphocytes, and neutrophils, and their inflammatorymediators. Recruitment of these cells leads to more persistentand chronic symptoms.


Pediatrics_Nelson

Pediatrics_Nelson. Type II (antibody cytotoxicity) reactions involve IgM, IgG, or IgA antibodies binding to the cell surface and activating the entire complement pathway resulting in lysis of the cell or release of anaphylatoxins, such as C3a, C4a, and C5a (see Chapter 75). These anaphylatoxins trigger mast cell degranulation, resulting in inflammatory mediator release. The target can be cell surface membrane antigens, such as red blood cells (hemolytic anemia); platelet cell surface molecules (thrombocytopenia); basement membrane molecules in the kidney (Goodpasture syndrome); the alpha chain of the acetylcholine receptor at the neuromuscular junction (myasthenia gravis); and thyroid-stimulating hormone receptor on thyroid cells (Graves disease).


Pediatrics_Nelson

Pediatrics_Nelson. Type III (immune complex) reactions involve the formation of antigen-antibody or immune complexes that enter into the circulation and are deposited in tissues such as blood vessels and filtering organs (i.e., liver, spleen, and kidney). These complexes initiate tissue injury by activating the complement cascade and recruiting neutrophils that release their toxic mediators. Local reactions caused by the injection of antigen I—Anaphylactic <30 min IgE Pollens, food, Histamine, tryptase, Anaphylaxis, immediate late 2–12 h venom, drugs leukotrienes, urticaria, allergic phase prostaglandins, platelet-rhinitis, allergic activating factor asthma CSF, Cerebrospinal fluid; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon-γ; TB, tuberculosis; TNF-α, tumor necrosis factor-α.


Pediatrics_Nelson

Pediatrics_Nelson. CSF, Cerebrospinal fluid; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon-γ; TB, tuberculosis; TNF-α, tumor necrosis factor-α. into tissue are called Arthus reactions. The administration of large amounts of antigen leads to serum sickness, a classic example of a type III reaction. Other type III–mediated reactions include hypersensitivity pneumonitis and some vasculitic syndromes.


Pediatrics_Nelson

Pediatrics_Nelson. Type IV (cellular immune–mediated or delayed-hypersensitivity) reactions involve recognition of antigen by sensitized T cells. Antigen-presenting cells form peptides that are expressed on the cell surface in association with major histocompatibility complex class II molecules. Memory T cells recognize the antigen peptide/major histocompatibility complex class II complexes. Cytokines, such as interferon-γ, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor, are secreted from this interaction, which activates and attracts tissue macrophages. Contact allergies (nickel, poison ivy, topical medications) and immunity to tuberculosis are type IV reactions. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com A family history of allergic disease is often present in affected patients. Multiple genes predispose to atopy. If one parent has allergies, the risk that a child will develop an allergic disease is 25%. If both parents have allergies, the risk increases to 50% to 70%. Similar atopic diseases tend to occur in families. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com Children with allergic rhinitis exhibit frequent nasal itching and rubbing of the nose with the palm of the hand, the allergic salute, which can lead to a transverse nasal crease found across the lower bridge of the nose. Allergic shiners, blue-gray to purple discoloration below the lower eyelids that is attributed to venous congestion, along with swollen eyelids or conjunctival injection are often present in children. Dermatologic findings of atopy include hyperlinearity of the palms and soles, white dermatographism, pityriasis alba, prominent creases under the lower eyelids (Dennie−Morgan folds or Dennie lines), and keratosis pilaris (asymptomatic horny follicular papules on the extensor surfaces of the arms).


Pediatrics_Nelson

Pediatrics_Nelson. Cutaneous manifestations are most common and range from generalized xerosis (dry skin) to urticaria to the pruritic, erythematous papules, and vesicles of atopic dermatitis. There may be involvement of the upper respiratory tract with allergic rhinitis and the lower respiratory tract with asthma. Allergic disease may involve only the skin or the nose, eyes, lungs, and gastrointestinal tract alone or in combination. It is distinguished by environmental exposure to an inciting trigger and usually a history of previous similar disease or development of symptoms after a suspected trigger. Many patients have more than one allergic symptom. Atopy is characterized by elevated levels of IgE (Table 77-2)


Pediatrics_Nelson

Pediatrics_Nelson. Atopy is characterized by elevated levels of IgE (Table 77-2) Available @ StudentConsult.com and eosinophilia (3% to 10% of white blood cells or an absolute eosinophil count of >250 eosinophils/mm3) with a predominance of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13. Extreme eosinophilia suggests a nonallergic disorder such as infections with tissue-invasive parasites, drug reactions, or malignancies (Table 77-3). A classic example of a type IV reaction is the tuberculin skin test. A small amount of purified protein derivative from Mycobacterium tuberculosis is injected intradermally (see Chapter 124). In a previously sensitized individual, a type IV inflammatory reaction (induration) develops over the next 24 to 72 hours.


Pediatrics_Nelson

Pediatrics_Nelson. There are two methods for identifying allergen-specific IgE: in vivo skin testing and in vitro serum testing (Table 77-4).In vivo skin testing introduces allergen into the skin via a prick/puncture or intradermal injection. The allergen diffuses through the skin to interact with IgE that is bound to mast cells. Cross-linking of IgE causes mast cell degranulation, which results in a histamine release; this prompts the development of a central wheal and erythematous flare. The wheal and flare are measured 15 to 20 minutes after the allergen has been placed. Properly performed skin tests are the best available method for detecting the presence of allergen-specific IgE.


Pediatrics_Nelson

Pediatrics_Nelson. In vitro serum testing, such as immunoassays like the radioallergosorbent test (also known as RAST) and enzyme-linked immunosorbent assay (also known as ELISA), measures levels of antigen-specific IgE. Many allergists and laboratories regard the ImmunoCAP System as the method of choice. This method uses a solid phase and shows higher sensitivity, Results available immediately Preferable to skin testing for dermatographism Widespread dermatitis Uncooperative children From Skoner DP: Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis, J Allergy Clin Immunol 108:S2−S8, 2001.


Pediatrics_Nelson

Pediatrics_Nelson. From Skoner DP: Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis, J Allergy Clin Immunol 108:S2−S8, 2001. specificity, and reproducibility. The assay uses a quantitative fluorescent immunoassay (FEIA); FEIA is more sensitive than other assays. These tests are indicated for patients who have dermatographism or extensive dermatitis; who cannot discontinue medications, such as antihistamines, that interfere with skin test results; who are very allergic by history, where anaphylaxis is a possible risk; or who are noncompliant for skin testing. The presence of specific IgE antibodies alone is not sufficient for the diagnosis of allergic diseases. Diagnosis must be based on the physician’s assessment of the entire clinical picture, including the history and physical examination, the presence of specific IgE antibodies, and the correlation of symptoms to IgE-mediated inflammation.


Pediatrics_Nelson

Pediatrics_Nelson. Diagnostic imaging has a limited role in the evaluation of allergic disease. Chest radiography is helpful with the differential diagnosis of asthma. Sinus radiography and computed tomography may be useful, but when these images are abnormal, they do not distinguish allergic disease from nonallergic disease.


Pediatrics_Nelson

Pediatrics_Nelson. Inflammatory cells (mast cells, eosinophils, T lymphocytes, neutrophils), chemical mediators (histamine, leukotrienes, platelet-activating factor, bradykinin), and chemotactic factors (cytokines, eotaxin) mediate the underlying inflammation found in asthmatic airways. Inflammation contributes to airway hyperresponsiveness (airways constricting in response to allergens, irritants, viral infections, and exercise). It also results in edema, increased mucus production in the lungs, influx of inflammatory cells into the airway, and epithelial cell denudation. Chronic inflammation can lead to airway remodeling, which results from a proliferation of extracellular matrix proteins and vascular hyperplasia and may lead to irreversible structural changes and a progressive loss of pulmonary function.


Pediatrics_Nelson

Pediatrics_Nelson. Asthma is the most common chronic disease of childhood in industrialized countries, affecting nearly 7 million children younger than 18 years of age in the United States. The number of people with asthma continues to grow. One in 11 children (7 million) had asthma, and 1 in 12 (18.7 million) adults (totaling over 25 million or 8% of U.S. population) had asthma in 2010 compared to 1 in 14 people (about 20 million, or 7%) in 2001. One in 5 children went to the emergency department for an asthma-related visit in 2009. Women are more likely than men to have asthma, and boys are more likely than girls to have asthma. Available @ StudentConsult.com Children with asthma have symptoms of coughing, wheezing, shortness of breath or rapid breathing, and chest tightness. The history should elicit the frequency, severity, and factors that worsen the child’s symptoms as well as a family history of Tracheal stenosis Toxic inhalation, including smoke


Pediatrics_Nelson

Pediatrics_Nelson. Tracheal stenosis Toxic inhalation, including smoke From Lemanske RF Jr, Green CG: Asthma in infancy and childhood. In Middleton E Jr, Reed CE, Ellis EF, et al, editors: Allergy: Principles and Practice, ed 5, St Louis, 1998, Mosby–Year Book, p 878. asthma and allergy. Exacerbating factors include viral infections, exposure to allergens and irritants (e.g., smoke, strong odors, fumes), exercise, emotions, and change in weather/humidity. Nighttime symptoms are common. Rhinosinusitis, gastroesophageal reflux, and nonsteroidal anti-inflammatory drugs (especially aspirin) can aggravate asthma. Treatment of these conditions may lessen the frequency and severity of the asthma.


Pediatrics_Nelson

Pediatrics_Nelson. During acute episodes, tachypnea, tachycardia, cough, wheezing, and a prolonged expiratory phase may be present. Physical findings may be subtle. Classic wheezing may not be prominent if there is poor air movement from airway obstruction. As the attack progresses, cyanosis, diminished air movement, retractions, agitation, inability to speak, tripod sitting position, diaphoresis, and pulsus paradoxus (decrease in blood pressure of >15 mm Hg with inspiration) may be observed. Physical examination may show evidence of other atopic diseases such as eczema or allergic rhinitis.


Pediatrics_Nelson

Pediatrics_Nelson. Objective measurements of pulmonary function (spirometry) help establish the diagnosis and direct the treatment of asthma. Spirometry is used to monitor response to treatment, assess degree of reversibility with therapeutic intervention, and measure the severity of an asthma exacerbation. Children older than 5 years of age can perform spirometry maneuvers. Variability in predicted peak flow reference values make spirometry preferred to peak flow measures in the diagnosis of asthma. For younger children who cannot perform spirometry maneuvers or peak flow, a therapeutic trial of controller medications helps in the diagnosis of asthma.


Pediatrics_Nelson

Pediatrics_Nelson. Allergy skin testing should be included in the evaluation of all children with persistent asthma but not during an exacerbation of wheezing. Positive skin tests results, identifying immediate hypersensitivity to aeroallergens (e.g., as tree and grass pollens, and dust), correlate strongly with bronchial allergen provocative challenges. In vitro serum tests, such as radioallergosorbent test (also known as RAST), fluorescent enzyme immunoassay (also known as FEIA), or enzyme-linked immunosorbent assay, are generally less sensitive in defining clinically pertinent allergens, are more expensive, and require several days for results compared to several minutes for skin testing (see Table 77-4).


Pediatrics_Nelson

Pediatrics_Nelson. A chest radiograph should be performed with the first episode of asthma or with recurrent episodes of undiagnosed cough or wheeze to exclude anatomic abnormalities. Repeat chest radiographs are not needed with new episodes unless there is fever (suggesting pneumonia) or localized findings on physical examination. Two novel forms of monitoring asthma and airway inflammation directly include exhaled nitric oxide analysis and quantitative analysis of expectorated sputum for eosinophilia. Many childhood conditions can cause wheezing and coughingof asthma (Table 78-1) but not all cough and wheeze is asthma. Misdiagnosis delays correcting the underlying cause andexposes children to inappropriate asthma therapy (Table 78-2). Allergic bronchopulmonary aspergillosis is a hypersensitivity type of reaction to antigens of the mold Aspergillus fumigatus. It occurs primarily in patients with steroid-dependent asthma and in patients with cystic fibrosis.


Pediatrics_Nelson

Pediatrics_Nelson. Optimal medical treatment of asthma includes several key components: environmental control, pharmacologic therapy, and patient education, including attainment of C—Cystic fibrosis R—Respiratory tract infections A—Aspiration (swallowing dysfunction, gastroesophageal reflux, tracheoesophageal fistula, foreign body) D—Dyskinetic cilia L—Lung and airway malformations (laryngeal webs, laryngotracheomalacia, tracheal stenosis, vascular rings and slings) E—Edema (heart failure, congenital heart disease) From Schidlow DV: Cough. In Schidlow DV, Smith DS, editors: A Practical Guide to Pediatric Disease, Philadelphia, 1994, Hanley & Belfus.


Pediatrics_Nelson

Pediatrics_Nelson. From Schidlow DV: Cough. In Schidlow DV, Smith DS, editors: A Practical Guide to Pediatric Disease, Philadelphia, 1994, Hanley & Belfus. self-management skills. Because many children with asthma have coexisting allergies, steps to minimize allergen exposure should be taken (Table 78-3). For all children with asthma, exposures to tobacco and wood smoke and to persons with viral infections should be minimized. Influenza immunizations are indicated. Asthma medications can be divided into long-term control medications and quick-relief medications.


Pediatrics_Nelson

Pediatrics_Nelson. Inhaled corticosteroids are the most effective anti-inflammatory medications for the treatment of chronic, persistent asthma and are the preferred therapy when initiating longterm control therapy. Early intervention with inhaled corticosteroids reduces morbidity but does not alter the natural history of asthma. Regular use reduces airway hyperreactivity, the need for rescue bronchodilator therapy, risk of hospitalization, and risk of death from asthma. Inhaled corticosteroids are available as an inhalation aerosol, dry powder inhaler, and nebulizer solution.


Pediatrics_Nelson

Pediatrics_Nelson. The potential risks of inhaled corticosteroids are favorably balanced with their benefits. A reduction in growth velocity may occur with poorly controlled asthma or inhaled corticosteroids use. Low-to-medium dose inhaled corticosteroids may decrease growth velocity, although these effects are small (approximately 1 cm in the first year of treatment), generally not progressive, and may be reversible. Regularly scheduled height measurements should be monitored. Inhaled corticosteroids do not have clinically significant adverse effects on hypothalamic-pituitary-adrenal axis function, glucose metabolism, or subcapsular cataracts or glaucoma when used at low-to-medium doses in children. Rinsing the mouth after inhalation and using spacers help lessen the local adverse effects of dysphonia and candidiasis and decrease systemic absorption from the gastrointestinal tract. Inhaled corticosteroids should be titrated to the lowest dose needed to maintain control of a child’s asthma. For children


Pediatrics_Nelson

Pediatrics_Nelson. and decrease systemic absorption from the gastrointestinal tract. Inhaled corticosteroids should be titrated to the lowest dose needed to maintain control of a child’s asthma. For children with severe asthma, higher dose inhaled corticosteroids may be needed to minimize the oral corticosteroid dose, but other “add-on” therapy should be considered (see the following sections).


Pediatrics_Nelson

Pediatrics_Nelson. Leukotrienes, synthesized via the arachidonic acid metabolism cascade, are potent mediators of inflammation and smooth Viral upper Limit exposure to viral infections (day care respiratory tract with fewer children) (RSV, influenza virus) with persistent asthma Tobacco smoke, No smoking around the child or in child’s wood smoke home Help parents and caregivers quit smoking Eliminate use of wood stoves and fireplaces Dust mites Essential actions Encase pillow, mattress, and box spring in allergen-impermeable encasement Wash bedding in hot water weekly Avoid sleeping or lying on upholstered furniture Minimize number of stuffed toys in child’s bedroom Reduce indoor humidity to <50% If possible, remove carpets from bedroom and play areas; if not possible, vacuum frequently Animal dander Remove the pet from the home or keep outdoors (if removal is not acceptable) Keep pet out of bedroom


Pediatrics_Nelson

Pediatrics_Nelson. Use a filter on air ducts in child’s room Wash pet weekly (the evidence to support this has not been firmly established) Cockroach allergens Do not leave food or garbage exposed Use boric acid traps Reduce indoor humidity to <50% Fix leaky faucets, pipes Indoor mold Avoid vaporizers Reduce indoor humidity to <50% Fix leaky faucets, pipes From American Academy of Allergy Asthma & Immunology: Pediatric Asthma: Promoting Best Practice, Milwaukee, Wisconsin, 1999, American Academy of Allergy Asthma & Immunology, p 50. RSV, Respiratory syncytial virus.


Pediatrics_Nelson

Pediatrics_Nelson. Allergy Asthma & Immunology, p 50. RSV, Respiratory syncytial virus. muscle bronchoconstriction. Leukotriene modifiers are oral, daily-use medications that inhibit these biologic effects in the airway. Two classes of leukotriene modifiers include cysteinyl leukotriene receptor antagonists (zafirlukast and montelukast) and leukotriene synthesis inhibitors (zileuton). The leukotriene receptor antagonists have much wider appeal than zileuton. Zafirlukast is approved for children older than 5 years of age and is given twice daily. Montelukast is dosed once daily, at night, as 4-mg granules or chewable tablets (for children 6 months to 5 years), 5-mg chewable tablets (6 to 14 years), and 10-mg tablets (15 years of age or older). Pediatric studies show the usefulness of leukotriene modifiers in mild asthma and the attenuation of exercise-induced bronchoconstriction. These agents may be helpful as steroid-sparing agents in patients with asthma that is more difficult to control.


Pediatrics_Nelson

Pediatrics_Nelson. Long-Acting β2-Agonists Long-acting β2-agonists, formoterol and salmeterol, have twice-daily dosing and relax airway smooth muscle for 12 hours but do not have any significant anti-inflammatory effects. Adding a long-acting bronchodilator to inhaled corticosteroid therapy is more beneficial than doubling the dose of inhaled corticosteroids. Multiple formulations are available. Formoterol is approved for use in children older than 5 years of age for maintenance asthma therapy and for prevention of exercise-induced asthma. It has a rapid onset of action similar to albuterol (15 minutes). Salmeterol is approved for children 4 years of age or older and has an onset of 30 minutes. Because combination agents administer two medications simultaneously, compliance is generally improved.


Pediatrics_Nelson

Pediatrics_Nelson. Theophylline was more widely used previously, but, because current management is aimed at inflammatory control, its popularity has declined. It is mildly to moderately effective as a bronchodilator and is considered an alternative, add-on treatment to lowand medium-dose inhaled corticosteroids. Omalizumab (Xolair) is a humanized anti-IgE monoclonal antibody that prevents binding of IgE to high-affinity receptors on basophils and mast cells. It is approved for moderate to severe allergic asthma in children 12 years of age and older. Xolair is delivered by subcutaneous injection every 2 to 4 weeks, depending on body weight and pretreatment serum IgE level.


Pediatrics_Nelson

Pediatrics_Nelson. Short-Acting β2-Agonists Short-acting β2-agonists, such as albuterol, levalbuterol, and pirbuterol, are effective bronchodilators that exert their effect by relaxing bronchial smooth muscle within 5 to 10 minutes of administration. They last for 4 to 6 hours. Generally a short-acting β2-agonist is prescribed for acute symptoms and as prophylaxis before allergen exposure and exercise. The inhaled route is preferred because adverse effects—tremor, prolonged tachycardia, and irritability—are less. Overuse of β2-agonists implies inadequate control; a change in medications may be warranted. The definition of overuse depends on the severity of the child’s asthma; use of more than one metered dose inhaler canister per month or more than eight puffs per day suggests poor control.


Pediatrics_Nelson

Pediatrics_Nelson. Ipratropium bromide is an anticholinergic bronchodilator that relieves bronchoconstriction, decreases mucus hyper-secretion, and counteracts cough-receptor irritability by binding acetylcholine at the muscarinic receptors found in bronchial smooth muscle. It seems to have an additive effect with β2-agonists when used for acute asthma exacerbations. Long-term use of anticholinergic medications in asthma is not supported by the literature.


Pediatrics_Nelson

Pediatrics_Nelson. Short bursts of oral corticosteroids (3 to 10 days) are administered to children with acute exacerbations. The initial startingdose is 1 to 2 mg/kg/day of prednisone followed by 1 mg/kg/dayover the next 2 to 5 days. Oral corticosteroids are available inliquid or tablet formulations. Prolonged use of oral corticosteroids can result in systemic adverse effects such as hypothalamic-pituitary-adrenal suppression, cushingoid features, weightgain, hypertension, diabetes, cataracts, glaucoma, osteoporosis, and growth suppression. Children with severe asthma mayrequire oral corticosteroids over extended periods. The doseshould be tapered as soon as possible to the minimum effectivedose, preferably administered on alternate days. Approach to Therapy


Pediatrics_Nelson

Pediatrics_Nelson. Therapy is based on the concept that chronic inflammation is a fundamental feature of asthma and that the processes underlying asthma can vary in intensity over time, requiring treatment to be adjusted accordingly. Classification of asthma severity is emphasized for initiation of therapy in patients not currently receiving controller medications. Assessing control is emphasized for monitoring and adjusting therapy. A stepwise approach is used for management of infants and young children 0 to 4 years, children 5 to 11 years (Fig. 78-1), youths 12 years or older, and adults (Fig. 78-2). Medication type, amount, and scheduling are determined by the level of asthma severity or asthma control. Therapy is then increased (stepped up) as necessary and decreased (stepped down) when possible. A short-acting bronchodilator should be available for all children with asthma. A child with intermittent asthma has asthma symptoms less than two times per week. To determine whether a child is having


Pediatrics_Nelson

Pediatrics_Nelson. short-acting bronchodilator should be available for all children with asthma. A child with intermittent asthma has asthma symptoms less than two times per week. To determine whether a child is having more persistent asthma, using the Rules of Two is helpful: daytime symptoms occurring two or more times per week or nighttime awakening two or more times per month implies a need for daily anti-inflammatory medication.


Pediatrics_Nelson

Pediatrics_Nelson. Inhaled corticosteroids are the preferred initial long-term control therapy for children of all ages (Fig. 78-3). Daily longterm control therapy is recommended for infants and young children 0 to 4 years of age who had four or more episodes of wheezing in the previous year that lasted more than 1 day, affected sleep, and who have a positive asthma predictive index. For children over 5 years of age with moderate persistent asthma, combining long-acting bronchodilators with low-tomedium doses of inhaled corticosteroids improves lung function and reduces rescue medication use. For children with severe persistent asthma, a high-dose inhaled corticosteroid and a long-acting bronchodilator are the preferred therapy. The guidelines also recommend that treatment be reevaluated within 2 to 6 weeks of initiating therapy. Once asthma is under control, control should be assessed on an ongoing basis every 1 to 6 months. The asthma should be well controlled for at least 3 months before stepping


Pediatrics_Nelson

Pediatrics_Nelson. of initiating therapy. Once asthma is under control, control should be assessed on an ongoing basis every 1 to 6 months. The asthma should be well controlled for at least 3 months before stepping down therapy. Note that asthma management guidelines are based on review of the published evidence, not solely on age recommendations and dosages approved by the U.S. Food and Drug Administration.


Pediatrics_Nelson

Pediatrics_Nelson. Step up if needed (first check inhaler technique, adherence, environmental control, and comorbid conditions) Step down if possible (and asthma is well controlled at least 3 months)


Pediatrics_Nelson

Pediatrics_Nelson. Preferred Intermittent asthma Persistent asthma: Daily medication Consult with asthma specialist if Step 3 care or higher is required. The stepwise approach is meant to assist, not Consider consultation at Step 2.Intermittent Asthma Persistent Asthma: Daily Medication Consult with asthma specialist if Step 4 care or higher is required. Consider consultation at Step 3. Alternative Alternative Quick-Relief Medication Quick-Relief Medication SABA PRN Low-dose ICS Cromolyn or Montelukast Cromolyn LTRA Nedocromil, or Theophylline Medium-dose ICS Medium-dose ICS + LABA or Montelukast High-dose ICS + LABA or Montelukast High-dose ICS LABA orMontelukast+ +Oral corticosteroids ICS Preferred SABA PRN Low-dose ICS Low-dose ICS Medium-dose ICS + + + LABALABA, LTRA, or Theophylline High-dose ICS + LABA High-dose ICS LABA + + Oral corticosteroids Oral corticosteroids Children 0–4 years of ageChildren 5–11 Years of Age Each Step: Patient Education and Environmental Control Each Step: Patient