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6,501 | childhood onset autoimmunity thought to result from dysregulated cytokine signaling and interstitial lung disease AntiIL 6R monoclonal antibody (tocilizumab) Cytotoxic T lymphocyte antigen (CTLA4) haploinsufficiency with autoimmune infiltration CHAI Heterozygous loss of function pathogenic variants in CTLA4 Hypogammaglobulinemia and autoantibody mediated cytopenias, lymphadenopathy, splenomegaly, organ specific autoimmunity, and lymphocytic infiltration of nonlymphoid organs CHAI more commonly seen in older children or young adults, whereas disease onset in LATAIE is typically earlier CTLA4 Ig fusion drug (Abatacept) mTOR inhibitors Common variable immune deficiency caused by defect in lipopolysaccharide responsive and beigelike anchor protein LRBA deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration, and enteropathy LRBA deficiency LATAIE LRBA encodes the lipopolysaccharide responsive and beigelike anchor protein, thought to regulate CTLA4 Antibody deficiency, infection, autoimmunity, and lymphoproliferation, often linked with enteropathy or inflammatory bowel disease Lymphocyte infiltration also seen in lungs and brain CTLA4 Ig fusion drugs Hydroxy chloroquine or chloroquine mTOR inhibitors Note: The majority of these syndromes have been defined based on the genomic defect with associated symptoms. From Bride K, Teachey D. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Res. 2017;6:1928. Table 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1334 Part XII u Immunology Treatment Rapamycin (sirolimus) will often control the adenopathy and autoim mune cytopenias. Malignancies can be treated with the usual proto cols used in patients unaffected by ALPS. Stem cell transplantation is another possible option in treating the autoimmune manifestations of ALPS. 174.8 Nuclear Factor B Pathway Defects Danielle E. Arnold and Jennifer W. Leiding The NF B pathways consist of canonical (NF B1) and noncanon ical (NF B2) pathways. On cellular activation, both pathways lead to activation and translocation of NF B proteins into the nucleus, where they initiate downstream inflammatory responses. Defects in many proteins in both pathways have been described. Table 174.7 describes immune defects of the NF B pathways that cause symp toms of immune dysregulation or autoimmunity. Treatment of NF B defects includes prevention of infections and replacement of immunoglobulin and has included HSCT. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 174.7 Defects of Nuclear Factor B Pathways Associated with Immune Dysregulation PROTEIN INHERITANCE AUTOIMMUNE OR INFLAMMATORY COMPLICATIONS OTHER MANIFESTATIONS IMMUNOLOGIC PHENOTYPE IKBKG (NEMO) XL Colitis Ectodermal dysplasia Osteopetrosis Lymphedema Bacterial infections Opportunistic infections DNA viral infections Hypogammaglobulinemia Hyper IgM Hyper IgA Hyper IgD Poor antibody responses Decreased NK cell function Decreased TLR responses NF B1 AD Pyoderma gangrenosum Lymphoproliferation Cytopenia Hypothyroidism Alopecia areata Enteritis LIP NRH Atrophic gastritis Squamous cell carcinoma Respiratory tract infections Superficial skin infections Lung adenocarcinoma Respiratory insufficiency Aortic stenosis Non Hodgkin lymphoma Hypogammaglobulinemia IgA deficiency NF B2 AD Alopecia totalis Trachyonychia Vitiligo Autoantibodies: thyroid peroxidase, glutamate decarboxylase, thyroglobulin Central adrenal insufficiency Viral respiratory infections Pneumonias Sinusitis Otitis media Recurrent herpes Asthma Type 1 Chiari malformation Interstitial lung disease Early onset hypogamma globulinemia Low vaccine responses |
6,502 | Variable B cell counts Low switched memory B cells (CD19CD27IgD) Low marginal zone B cells (CD19CD27IgD) XL, X linked; AD, autosomal dominant; LIP, lymphocytic interstitial pneumonitis; NRH, nonregenerative hyperplasia; TLR, toll like receptor. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 175 u Defects of Innate Immunity 1335 The innate immune system is the bodys first defense against patho gens, and includes barriers such as the skin as well as neutrophils, natural killer (NK) cells, the toll like receptors (TLRs) for microbial pathogen recognition, cytokines, and the complement system. Break down of different parts of this system can predispose primarily to dif ferent pathogens, such as viruses, fungi, bacteria, and mycobacteria. The innate immune system also plays an important role in engaging the adaptive immune response. 175.1 Predisposition to Fungal Infections Jenna R.E. Bergerson and Alexandra F. Freeman Despite constant exposure to environmental fungi at sites like the respiratory and gastrointestinal tracts and the skin, immunocompe tent individuals do not develop invasive fungal disease because highly sophisticated host defenses have evolved with time. The genetic basis for inborn errors of immunity (IEIs) presenting with mucocutaneous andor invasive fungal disease have provided valuable insight into the immunologic mediators necessary for antifungal host defense. Cer tain IEIs whose phenotype includes fungal disease, such as chronic granulomatous disease (CGD), APECED, GATA2 deficiency, and dominant negative STAT3 pathogenic variants (Job syndrome), are examples. Candida and Aspergillus are the two most commonly encountered opportunistic fungi in clinical practice; both of these fungi are recog nized in host tissues by pattern recognition receptors (PRRs) on the cell surface. When triggered by a relevant ligand, activation of these recep tors results in pathogen uptake and killing. Most relevant to antifungal immunity is the C type lectin receptor (CLR) family, which recognizes specific fungal cell wall components called pathogen associated molec ular patterns, like glucans or mannans. When CLRs like Dectin 1 bind ligand, the CARD9BCL10MALT1 complex (BCM complex) is formed. Signaling via downstream pathways ultimately results in pro duction of proinflammatory cytokines and promotes fungal uptake and killing by myeloid phagocytes. The molecular mechanisms that protect against host mucosal infec tions with Candida spp. are vastly different than those that confer protection against systemic infection. Neutrophils, monocytes, and macrophages are seemingly dispensable for immunity to mucosal Candida infection; chronic mucocutaneous candidiasis (CMC) is not seen in neutropenic patients or those with CGD. Instead, mucocutane ous candidiasis seems to correlate with impairments in T lymphocyte number or function. Interleukin (IL) 17 signaling is also a critical pathway for protection against CMC. On receptor activation, the adap tor molecule ACT1 is recruited to the IL 17 receptor and mediates the induction of signaling pathways that upregulate the transcription of cytokines and antimicrobial peptides (AMPs) that help clear Candida from the mucosal surfaces. Control of endemic fungi, such as Histo plasma, is dependent |
6,503 | on the IL 12IFNgSTAT1 pathway. Chronic mucocutaneous candidiasis is characterized by severe, persistent, or recurrent symptomatic infection of the nails, skin, oral, or genital mucosa by the Candida genus. CMC has been associated with a number of IEIs, in which it is one of many disease features along with other infections andor autoimmune manifestations. However, CMC can also be a main feature of a primary immunodeficiency dis ease (PIDD) (Table 175.1). Antifungal therapy is the hallmark of treatment in these diseases. Episodes of CMC typically respond to either topical or oral therapy. Recurrences are common without secondary prophylaxis. Prophylaxis should be initiated in those patients with frequent and early recurrences after discontinuation of antifungal therapy. Prophylaxis is important not only to reduce the morbidity associated with recurrent episodes of CMC, but also to prevent mucosal inflammation, which can increase the risk of squamous cell carcinoma. Repeated courses of antifungal therapy increase the risk of developing resistance to antifungal therapy. All cases of CMC should be confirmed with culture, and susceptibility testing should guide the choice of antifungal if a therapeutic response is not observed. Systemic fungal disease should be guided by culture and suscepti bility data with consideration of antifungal penetration in the affected tissue. Additional factors to consider include concomitant medications (triazoles are metabolized by P450 and prolong the QT interval with the exception of isavuconazole, which shortens it), liver function, and kidney function (amphotericin use). It is important to also consider that voriconazole is associated with additional toxicities including an increased risk of squamous cell carcinoma of the skin, fluorosis, periph eral neuropathy, and visual disturbances. Survival of life threatening fungal infection should also mandate secondary antifungal prophylaxis unless the underlying immunodeficiency is cured by hematopoietic stem cell transplantation (HSCT). CARD9 DEFICIENCY CARD9 deficiency is caused by biallelic loss of function (LOF) patho genic variants in CARD9. CARD9 contributes to antifungal host defense in a pathogen and organ specific manner with a striking predilection for Candida albicans central nervous system (CNS) infec tions. CARD9 deficiency is the only known IEI in which patients are predisposed to both mucocutaneous and systemic candidiasis, with C. albicans typically isolated. The CNS is the most common site of sys temic involvement, with CNS candidiasis often presenting as either meningoencephalitis or an intracranial abscess obstructive hydro cephalus. The next most common site of systemic involvement is bone. Neutrophils are absent in all involved exudates and tissues. Deep dermatophytosis and subcutaneous phaeohyphomycosis infections can also be seen in CARD9 deficiency. Trichophyton rubrum and Trichophyton violaceum were the most common dermatophyte species. Severe complications like lymphadenitis, extension into adja cent organs with fistula formation, and dissemination to the CNS have been seen. Dermal biopsies show necrotizing granulomatous inflam mation, subcutaneous nodules, and severe ulceration of the superfi cial tissues. Subcutaneous phaeohyphomycosis with a predilection for facial involvement has also been reported. Granulomatous inflamma tion with scattered lymphocytes and eosinophils are seen on biopsy. Extrapulmonary aspergillosis and a variety of dematiaceous fungi have also been reported |
6,504 | including Phialophora verrucosa, Exophiala spi nifera, Ochroconis musae, and Corynespora cassiicola. Clinical manifestations of CARD9 deficiency are fully penetrant by the fourth or fifth decade of life with about 40 of patients present ing in adulthood. Sequencing of CARD9 is required to establish the diagnosis, and determination of functional consequences of CARD9 variants is difficult. Lymphocyte phenotyping is usually normal, as are absolute neutrophil and monocyte counts despite a lack of neu trophils in infected CSF. Nearly 60 of affected patients have findings of elevated serum IgE andor hypereosinophilia. Treatment of fungal infection follows the tenets outlined earlier, frequently with infec tious diseases consultation followed by lifelong antifungal prophylaxis unless HSCT is successfully performed. Two patients with CARD9 deficiency have been successfully treated with HSCT leading to clinical remission. There is a potential role for treatment of fungal disease with granulocyte macrophage colony stimulating factor (GM CSF) therapy in CARD9 deficiency, but there is variability in response that may relate to the underlying pathogenic variant(s) responsible for disease; thus seeking expert advice is recommended. Chapter 175 Defects of Innate Immunity Jenna R.E. Bergerson and Alexandra F. Freeman Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1336 Part XII u Immunology STAT1 GOF STAT1 gain of function (GOF) pathogenic variants present with CMC, autoimmunity, intracranial aneurysms, andor squamous cell carcinoma. This condition likely accounts for more than 50 of CMC cases; CMC affects most patients with this diagnosis and typically pres ents in the first year of life. Candida involvement of the oropharynx is most common, but esophagitis, genital, and skin and nail disease are also common. C. albicans is the most common cause of CMC, but other Candida species have also been isolated. Azole resistance is a major challenge over time making treatment difficult. Invasive fungal infections are less common in this disease but can be quite severe. Disseminated Histoplasmosis, Cryptococcus, Coccidi oides, and Paracoccidioides can be difficult to treat and, in some cases, have been fatal. Pulmonary and disseminated mold infections have been reported infrequently and include organisms such as Aspergillus, Nan nizziopsis, and Mucorales. Pneumocystis jiroveci pneumonia has been reported rarely. A wide range of other types of pathogens cause infections in this patient population as well including recurrent bacterial sinopulmonary infections, typically due to Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. Bronchiectasis, when present, may further produce susceptibility to pathogens such as Pseudomonas. Less commonly skin infections such as folliculitis or cellulitis are also observed. Mycobacterial infections are typically due to BCG in those from countries that routinely immunize against tuberculosis (TB), and nontuberculous mycobacteria (NTM) adenitis or TB, or NTM lung infections. NTM infections do not usually disseminate widely in STAT1 GOF as they do in autosomal recessive or dominant STAT1 LOF. Severe or recurrent viral infections, most commonly due to her pesviruses (herpes simplex virus HSV, varicella zoster virus |
6,505 | VZV, Epstein Barr virus (EBV), cytomegalovirus CMV, BK, and JC), are also troublesome in over 30 of patients. Recurrent oral mucocuta neous disease due to HSV or recurrent VZV infection are the most frequent viral disease manifestations. EBV and CMV viremias are commonly detected, but CMV disease is infrequent as is symptomatic EBV disease. Human papillomavirus (HPV) driven warts and mol luscum are seen in a small number of these patients and are difficult to treat. Although rare, progressive multifocal leukoencephalopathy (PML) from JC virus is of particular concern due to its high mortality. PML has been seen with and without additional immune modulation; therapies that are sometimes indicated for the autoimmunity seen in STAT1 GOF, such as rituximab, need to be used with caution. Additional disease manifestations include autoimmunity, vascu lopathy, and malignancy. Autoimmune thyroid disease is most com mon, but type 1 diabetes mellitus, vitiligo, alopecia, pernicious anemia, autoimmune cytopenias, inflammatory bowel disease, and lupus like disease have all been observed and, in many cases, the autoimmune manifestations can be quite refractory and difficult to control. Aph thous ulcers are also especially common and can be very painful. Cerebral aneurysms are the most common vasculopathy seen, but extracerebral vascular abnormalities occur as well. These aneurysms may be the result of vasculitis, perhaps from pathogens like VZV; serial Table 175.1 Medelian Susceptibility to Mycobacterial Disease Defects GENEINHERITANCE CLINICAL PHENOTYPE TREATMENT Complete IFNgR1R2 deficiency IFNgR1 or IFNgR2AR Early onset disseminated NTM or BCG Antimycobacterials; HSCT Autosomal dominant IFNgR1 deficiency IFNgR1AD NTM or BCG osteomyelitis, disseminated Salmonella, disseminated endemic mycoses Antimycobacterials; adjuvant IFN IL 12RB1 deficiency IL12RB1AR Disseminated NTM, BCG, Salmonella Mucocutaneous candidiasis Variable penetration Antimycobacterials; consider IFN with careful monitoring IL 12p40 deficiency IL12BAR Disseminated NTM, BCG, Salmonella Variable penetration Antimycobacterials; consider IFN with careful monitoring IL 12Rb2 deficiency IL12RB2AR NTM, BCG, and tuberculosis Antimycobacterials IL 23R deficiency IL23RAR NTM, BCG, and tuberculosis Antimycobacterials STAT1 LOF STAT1AD Disseminated BCGNTM, often osteomyelitis Antimycobacterials; consider IFN SPPL2a deficiency SPPL2AAR Disseminated BCG Antimycobacterials TYK2 deficiency TYK2AR Disseminated BCG, tuberculosis, viral infections Antimycobacterials Macrophage gp91 phox deficiency CYBBXL; distinct variants than those causing CGD Disseminated BCG Antimycobacterials IRF8 deficiency (dominant) IRF8AD Disseminated BCG, NTM Antimycobacterials IRF8 deficiency (recessive) IRF8AR Viral, mycobacterial, mucocutaneous candidiasis Antimicrobials, consider HSCT ISG15 deficiency ISG15AR Disseminated BCG Antimycobacterials RORt deficiency RORCAR Disseminated BCG and mucocutaneous candidiasis Antimicrobials JAK1 LOF JAK1AR Bacterial, viral, and disseminated NTM Antimicrobials AD, Autosomal dominant; AR, autosomal recessive; BCG, bacilli Calmette Gurin; CGD, chronic granulomatous disease; HSCT, hematopoietic stem cell transplantation; IFN, inter feron; LOF, loss of function; NTM, nontuberculous mycobacteria. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 175 u Defects of Innate Immunity 1337 prospective imaging should be a part of routine screening. The most common malignancy observed is squamous cell carcinoma, mainly of the skin, oropharynx, and esophagus. Chronic inflammation caused by mucosal Candida infections may |
6,506 | play an important role, as well as inflammation driven by increased STAT1 activity. Management has been largely targeted against the infections and treatment of autoimmunity when present. Many of the patients need antifungal prophylaxis, and azole resistance may emerge and limit therapeutic choices to topical nystatin or amphotericin washes, or IV echinocandins. It is worth highlighting that voriconazole is not recom mended in this patient population due to its photosensitivity and long term skin cancer risk. In those patients with recurrent sinopulmonary infections andor bronchiectasis, antibiotic prophylaxis is likely to be beneficial. Azithromycin prophylaxis, if pulmonary NTM is not pres ent, may be beneficial not only for prevention of recurrent airway infections, but also will yield some antiinflammatory benefits. Recur rent HSV or VZV infections suggest the need for prophylaxis with acyclovir or valacyclovir. The autoimmunity is typically treated with immune suppression, and many have received long courses of cortico steroids. However, there are positive reports of success controlling this inflammation and autoimmunity with JAK inhibition. Ruxolitinib has been used in STAT1 GOF to treat alopecia, enteropathy, autoimmune cytopenias, and hepatitis. There is one report of JAK inhibition being used early in the course of associated insulin dependent diabetes, with resolution of the need for insulin and remission of the diabetes. JAK inhibition also can be highly effective in the treatment of CMC because there is growing evidence that the CMC observed in this disease is due to exuberant inflammation rather than infection susceptibility. Severe or disseminated infections have progressed while on JAK inhibition, thus, it is best to start this treatment only when invasive infections are adequately controlled. Some patients develop hypogammaglobulinemia over time; immune globulin replacement may be indicated. HSCT is not yet the preferred option for treatment of STAT1 GOF. HSCT in this population of patients has been difficult with high morbidity and mortality, although it is important to note that many of these trans plants were done before the genetic diagnosis was known and a variety of conditioning regimens were used. IL 17F DEFICIENCY A dominant negative missense pathogenic variant in IL17F was reported in multiple patients from one kindred with CMC. About 65 of these patients had CMC manifesting as persistent thrush, vulvo vaginal candidiasis, and interdigital intertrigo. Lymphocyte phenotyp ing and quantitative immunoglobulin levels were normal in the one patient who had such testing. Diagnosis relies on sequencing of IL 17F, but can also be suspected if flow cytometry shows absent intracellular IL 17F producing CD3 cells in patients with detectable IL 17A and IL 22 producing CD3 cells. Although there is insufficient clinical information to suggest ideal management of patients with IL 17F defi ciency, we recommend a similar approach as outlined for management of CMC. IL 17RA DEFICIENCY IL 17RA deficiency also presents with CMC, but usually with onset within the first year of life. Candidiasis involved the oropharynx in 95 of patients, the genitals in 38 (60 females), the skin or scalp in 67, and the nails in 19. Episodes of |
6,507 | CMC seemed to respond to topical or oral therapy. Staphylococcal skin infections were seen in 65 of the cohort, with such lesions also manifesting in the first year of life. Bacte rial recurrent sinopulmonary infections occur in just over one third of these patients, and all responded to antibiotic therapy. Lymphocyte phenotyping is normal, and diagnosis should be made by sequencing of the IL17RA gene, particularly when early onset CMC and concurrent S. aureus skin infections are present. As CMC is a presenting feature of all reported patients with IL 17RA deficiency, oral antifungal prophylaxis should be initiated. Strong con sideration should be given to also initiating antibiotic prophylaxis in those who have culture proven bacterial infections that are recurrent or severe. In those with recurrent sinopulmonary infections, although the spectrum of organisms is not known, covering for common bacte rial etiologies like S. pneumoniae, H. influenzae, and Moraxella catarrh alis should be sufficient to prevent disease. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 175.2 Innate Immunity Defects with Predominant Susceptibility to Viral Infections Jenna R.E. Bergerson and Alexandra F. Freeman Defects in innate immunity that predispose to viral infections are divided into three main groups: those primarily predisposing to HPV, those predisposing primarily to HSV encephalitis, and those predis posing to other viruses, many of which interfere with interferon (IFN) signaling. Some of these defects are described in the following sections along with other rare defects highlighted in Table 175.2. PREDOMINANT HPV SUSCEPTIBILITY Epidermodysplasia verruciformis (EV) is the main clinical presenta tion for diseases with autosomal recessive pathogenic variants in the transmembrane channel like 6 and 8 (TMC6 and TMC8) genes and more recently described in the calcium and integrin binding protein 1 (CIB1) gene, encoding for the proteins EVER1, EVER2, and CIB1, respectively. EVER1, EVER2, and CIB1 complex together for kera tinocyte intrinsic immunity, and disruption of this complex leads to HPV susceptibility. The typical warts affecting healthy individuals are from HPV types; however, in EV, HPV causes symptomatic dis ease, which is usually asymptomatic in healthy individuals but associ ated with cancer in some immune compromised individuals. The warts are frequently not the typical verrucous appearance seen in healthy children, but are usually flat warts, and can look like tinea versicolor with pigment changes. The warts appear in sun exposed areas and have a high incidence of cancer transformation. Individuals with EV do not usually have increased risk of other infections; they have nor mal immune evaluations including normal lymphocyte number and function. Diagnosis is with genetic testing after suspicion with atypi cal widespread HPV disease. There is no specific treatment, although warts are treated with standard therapies (see Chapter 708). Patients needed to be counseled to avoid UV and radiation exposure, and these individuals need frequent screening for skin cancer. WHIM (wart, hypogammaglobulinemia, infections, myeloka thexis) syndrome is an autosomal dominant (AD) disease caused by GOF pathogenic variants in CXCR4. Increased responsiveness of the CXCR4 receptor to its ligand CXCL12 (also known as SDF 1) results |
6,508 | in increased retention of the neutrophils in the bone marrow and thus the finding of myelokathexis (neutropenia related to the inability of neutrophils to leave the marrow). Patients also have lymphopenia with decreased B , T and NK lymphocytes, along with hypogammaglobu linemia. Although recurrent infections are common, they tend not to be as severe as expected from the neutropenia because the neutrophils often are released from the bone marrow with infection; dental issues likely related to the neutropenia are common. Recurrent sinopulmo nary infections likely relate more to the hypogammaglobulinemia, and some patients develop bronchiectasis. Warts typically start in childhood or adolescence and are often particularly severe with poor response to therapy. Evolution into squamous cell carcinomas can occur; patients require monitoring. Treatment traditionally has been supportive in treating infections and preventive with immune globulin therapy and G CSF, which usually needs to be dosed at lower concentrations due to frequently experienced debilitating bone pain. Plerixafor, an antagonist of CXCR4, may provide a specific therapy. There are several other PIDDs that primarily affect lymphocytes that have HPV susceptibility as a major component and are discussed in Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1338 Part XII u Immunology other chapters. Many of these diseases, such as DOCK8 deficiency and GATA2 deficiency, have broader susceptibility than just HPV. CD28 deficiency has susceptibility specific for HPV resulting in warts and cutaneous horns. Compared to EV, those with CD28 deficiency have predisposition to the more common and HPV types. Predisposition to Severe Viral Infections Host control of viral infections is predominately dependent on nor mal type 1 IFN signaling (Fig. 175.1; see Table 175.2). Type 1 IFNs, including the IFN subtypes and IFN , bind to their heteroreceptor comprising IFNAR1 and IFNAR2 leading to phosphorylation of TYK2 and JAK1. Activation of TYK2 and JAK1 leads to phosphorylation of STAT1 and STAT2, which then cause upregulation of interferon stimulated genes (ISGs). There are multiple potential defects along this pathway that can lead to viral susceptibility. The role of this path way has been highlighted with the COVID 19 pandemic, with not only genetic defects but also autoantibodies against type I IFNs leading to more severe disease. Autosomal recessive pathogenic variants in IFNAR1 and IFNAR2 lead to a lack of TYK2 phosphorylation for IFNAR1 defects, and both TYK2 and JAK1 phosphorylation for IFNAR2 with subsequent downstream deficiency of ISG upregulation. Despite the severe in vitro findings, the viral infection susceptibility appears more limited. Both are rare dis eases, with most patients developing severe or fatal illness after live viral vaccination with the measles mumps rubella (MMR) vaccine (largely measles component) or yellow fever vaccine. Herpes viral control is vari able, with a fatal case of herpes encephalitis reported in IFNAR1 defi ciency, and poor control of human herpesvirus 6 (HHV6) in IFNAR2. Variants have been described with |
6,509 | severe SARS CoV2 infection. These diseases appear to have incomplete penetrance, with some affected indi viduals having better control of viral infections or vaccination. Naturally acquired viral infections have been controlled much more than live viral vaccinations. These diseases are rare and therapy remains unclear, but avoiding live viral vaccines, considering antiviral prophylaxis for HSV VZV infections, and vaccination of affected individuals and close con tacts for influenza and COVID 19 appears prudent. Genetic defects in STAT1 can be activating (STAT1 GOF) or can be heterozygous or recessive with LOF. Autosomal recessive complete STAT1 deficiency is the most severe defect with most cases being fatal early in life. As IFN , IFN , and IFN all signal through STAT1, completely impaired signaling predisposes individuals to both severe early onset viral disease in addition to disseminated mycobacterial disease. Herpes family infections are common as well as live viral dis seminated infection. The disease is fatal without HSCT early in life, but HSCT outcomes have been poor with several children having herpes family inflammatory complications after HSCT, such as with hemo phagocytic lymphohistiocytosis (HLH) or severe CMV disease. There are also patients with autosomal recessive hypomorphic STAT1 patho genic variants who have some residual STAT1 disease that appears to have a less severe phenotype. Treatment is with aggressive antimicro bials to treat presenting infections and prevent new infections until HSCT is performed. Autosomal recessive complete STAT2 deficiency presenting early in life with severe viral infections is not as severe as STAT1 deficiency due to maintenance of IFN signaling. Compared to IFNAR1 and IFNAR2 deficiency, there is more severe disease with naturally acquired viral infections such as respiratory syncytial virus (RSV) and enteroviruses, but similarly severe disease has been seen with MMR vaccine. Some children have been described to have a Kawasaki like inflammatory presentation. The phenotype has been variable with some deaths early in life and some surviving to adulthood. Treatment remains uncertain with few patients reported, but live viral vaccines should be avoided, antiviral prophylaxis provided, and influenza vaccination given to those affected and close contacts. Autosomal recessive IRF9 deficiency appears to present similarly to STAT2 deficiency. After IFN or IFN stimulation leads to STAT1 and STAT2 phosphorylation, these STAT proteins can heterodimer ize with IRF9 to lead to ISG upregulation. This is a very rare defect presenting with naturally occurring or vaccine strain viruses. Life threatening influenza and severe enterovirus infections have been described in addition to vaccine strain varicella and MMR dissemina tion. Treatment remains uncertain with few patients reported, but live viral vaccines should be avoided, antiviral prophylaxis considered, and influenza and COVID 19 vaccination given to those affected and close contacts. Defects have been described in cytosolic sensors of viral DNA or RNA replication by products that lead to fairly specific viral sus ceptibility. Melanoma differentiation associated protein 5 (MDA5), encoded by the IFIH1 gene, is a cytosolic sensor of double stranded RNA by products of RNA viral replication. Several patients have been described with LOF variants, |
6,510 | either autosomal recessive or dominant, with presumed dominant negative effect, resulting in severe suscepti bility to respiratory viruses including rhinovirus and influenza. Reti noic acid inducible gene I (RIG I), encoded by the DDX58 gene, plays a similar role, and a patient has been described with LOF variants hav ing severe influenza infection. RNA polymerase III deficiency (POL III) is a cytosolic DNA sensor detecting replication by products of DNA viruses. AD pathogenic variants have been reported in POL III in children and adults with severe varicella zoster disease causing pneu monitis, encephalitis, and CNS vasculitis. Treatment is not defined, but avoiding live viral vaccines, providing antiviral prophylaxis, and providing non live annual influenza and COVID 19 vaccination to affected individuals and family members appear prudent. NK functional and quantitative defects can occur on their own or as part of combined immune deficiencies and are associated with viral infections (see Chapter 167). Pathogenic variants in the FCGR3A gene, encoding CD16, which is a Fc receptor on NK cells, impair NK cyto toxicity. A few patients have been described who have susceptibility to herpes family viruses with EBV related disease such as Castleman disease or HSV and VZV infections. Patients also develop significant warts from HPV infection. Antiviral prophylaxis should be given to prevent HSVVZV infections, in addition to HPV vaccination. Predominant HSV Encephalitis Defects that affect TLR3 signaling predispose quite specifically to HSV encephalitis due to their role in the activation of type 1 IFNs in the CNS (Fig. 175.2; see Table 175.2). Double stranded RNA is detected by TLR3, which then recruits the adaptor TRIF to activate TRAF3 to induce IFN , IFN , and inflammatory cytokines through TBK1 and IRF3 and other proteins. UNC93B1 acts as a transporter protein to JA K STAT1 STAT1 IRGs TNK Lymphocyte IL12 R1R2IFNgR IFNg X X X X AFB, Salmonella, fungi IL12R Beta 1 Beta 2 Fig. 175.1 Host control of mycobacteria. Macrophages ingest mycobacteria leading to secretion of cytokine IL 12, which then binds to its heterodimer receptor on the T lymphocytes and NK cells leading to the secretion of IFN . IFN binds to its heterodimer receptor, IFN R1 and IFN R2, leading to JAK1 and JAK2 phosphorylation, and then STAT1 phosphorylation. Where defects lead to MSMD are marked by an X. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 175 u Defects of Innate Immunity 1339 Table 175.2 Defects with Predominant Susceptibility to Viral Infections GENEINHERITANCE CLINICAL PHENOTYPE SPECIFIC TREATMENT GENEINHERITANCE Epidermodysplasia verruciformis EVER1, EVER2, CIB1AR Diffuse flat warts, with increased skin cancers Avoid UVradiation exposure, skin cancer screening. WHIM syndrome CXCR4AD Warts, squamous cell cancer, sinopulmonary infections, neutropenia, hypogammaglobulinemia G CSF, IgRT, plerixafor IFNAR1 deficiency IFNAR1AR Severe disease after live viral vaccination (MMR, yellow fever), herpesviruses Avoid live viral vaccination, consider HSVVZV prophylaxis IFNAR2 deficiency IFNAR2AR Severe disease after live viral |
6,511 | vaccination (MMR, yellow fever), herpesviruses Avoid live viral vaccination, consider HSVVZV prophylaxis Complete STAT1 deficiency STAT1AR Early onset severe viral and disseminated Mycobacteria Early HSCT STAT2 deficiency STAT2AR Severe respiratory viruses, enterovirus; some live viral vaccine disease Avoid live viral vaccines IRF9 deficiency IRF9AR Severe respiratory viruses, enterovirus; some live viral vaccine disease Avoid live viral vaccines IRF7 deficiency IRF7AR Severe influenza Influenza vaccination MDA5 deficiency IFIH1AR or AD Severe respiratory tract infections Influenza vaccination RNA polymerase III deficiency POL3A,POL3C, POL3FAD Severe varicella zoster Antiviral prophylaxis CD16 deficiency FCGR31AR Herpes family infections, HPV Antiviral prophylaxis IL 18BP deficiency IL18BPAR Fulminant hepatitis A Hepatitis A vaccination TLR3 deficiency TLR3AD and AR HSV encephalitis, severe influenza, zoster Antiviral prophylaxis TRAF3 deficiency TRAF3AD HSV encephalitis Antiviral prophylaxis TRIF deficiency TRIFAD and AR HSV encephalitis Antiviral prophylaxis UNC93B1 deficiency UNC93B1AR HSV encephalitis Antiviral prophylaxis TBNK1 deficiency TBNK1AD HSV encephalitis Antiviral prophylaxis IRF3 deficiency IRF3AD HSV encephalitis Antiviral prophylaxis DRB1 deficiency DRB1AR Brainstem encephalitis Antiviral prophylaxis Although influenza vaccination is highlighted for certain inborn errors of immunity (IEIs), influenza vaccination should be given to all those with IEIs and their close contacts unless there is a contraindication. In addition, HPV vaccination should be given per the recommended schedule. Vaccination at an earlier age can be considered for certain defects with HPV predisposition. AD, Autosomal dominant; AR, autosomal recessive; G CSF, granulocyte colony stimulating factor; HPV, human papillomavirus; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus IFN, interferon; MMR, measles mumps rubella; UV, ultraviolet; VZV, varicella zoster virus; WHIM, (wart, hypogammaglobulinemia, infections, myelokathexis) syndrome. transport TLR3 and other TLRs from the endoplasmic reticulum to the endosome to allow RNA binding. The TLR3 pathway is redundant for leukocyte immunity, but it is essential for CNS host viral immu nity; thus the infection susceptibility of these defects is primarily CNS HSV disease. The defects in signaling are not found in leukocytes but required fibroblasts and inducible pluripotent stem cell generation of CNS cells to demonstrate abnormal IFN responses with HSV infection. Pathogenic variants in multiple genes along this pathway have simi lar presentations with HSV encephalitis including autosomal recessive and dominant LOF variants in TLR3, dominant pathogenic variants in TRAF3, dominant and recessive pathogenic variants in TRIF, recessive pathogenic variants in UNC93B1, and dominant pathogenic variants in TBK1 and IRF3. The HSV encephalitis tends to present in infancy and early childhood on HSV exposure, with frontal and temporal lobes pre dominantly affected. Dominant pathogenic variants in TLR3 have also been associated with severe influenza and varicella zoster encephalitis in a few adults. Genetic diagnosis is essential as routine immunologic studies are normal. Treatment is supportive with acyclovir or similar prophylaxis. Rarely children can have brainstem CNS infections, including HSV; defects in the TLR3 pathway have not been found in these cases. Autosomal recessive hypomorphic pathogenic variants in DBR1 (deb ranching enzyme 1) have been identified in children with brainstem encephalitis caused by HSV, norovirus, and influenza virus. DBR1 is an RNA lariat debranching enzyme that degrades spliced |
6,512 | RNA introns, which is ubiquitously expressed in humans but with highest amounts in the brainstem and peripheral nervous system. With decreased func tion, there is increased accumulation of lariat introns that presumably interfere with viral recognition and control. Genetic diagnosis can allow prophylaxis with antivirals such as acyclovir and influenza vac cination of the affected individual and close contacts. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1340 Part XII u Immunology 175.3 Susceptibility to Invasive Bacterial Infections Jenna R.E. Bergerson and Alexandra F. Freeman Inborn errors of immunity (IEIs) with predominant susceptibility to invasive bacterial infections such as meningitis, sepsis, arthritis, osteomyelitis, and deep seated abscesses are rare, and are mostly due to neutrophil defects or defects in innate immunity. Inherited disor ders of the Toll and IL 1 receptor (TIR) pathway are innate immunity defects with a very distinct phenotype with invasive pyogenic bacterial infections and usually the absence of fever and inflammatory mark ers. TLRs on white blood cell surfaces sense bacterial peptides leading to activation of the NF B and MAPK pathway leading to inflamma tory mediators (Fig. 175.3). IEIs associated with impaired TLR signal ing include pathogenic variants in NEMO, IKBA, MyD88, and IRAK4 (Table 175.3). IRAK4 DEFICIENCY IRAK4 deficiency presents in infancy and early childhood with severe, recurrent bacterial infections, specifically due to S. pneumoniae, S. aureus, and Pseudomonas aeruginosa. Unique to this disorder, clostridial infections have also been reported. An impairment in mounting a fever at the beginning of infection with a corresponding rise in CRP are also hallmark features of this disease. Most patients with IRAK4 deficiency present with their first bacterial infection before 2 years of age; there is a high mortality rate in the early years. However, the frequency and sever ity of infections in IRAK4 deficiency improves with age, with none of the reported patients having invasive bacterial infections after the onset of adolescence, even those not on prophylactic antibiotics. Approximately 50 of IRAK4 deficient patients continue to have noninvasive skin and upper respiratory infections after adolescence. Delayed separation of the umbilical cord has been reported in IRAK4 deficient patients due to an unclear mechanism. Diagnosis relies on clinical suspicion and genetic testing because other immunologic studies are variable or require research laboratory testing. All T and B cell and NK cell subsets are unremarkable, but there may be a deficiency of unswitched memory B cells with normal levels of switched memory B cells. Specific antibody levels to pneu mococcal and allohemagglutinins of the ABO system are impaired in up to 30 of patients. Serum IgE and IgG4 concentrations are ele vated in up to 65 and 30, respectively. Defective IL 6 production leads to the inability to increase plasma CRP or mount fevers. With out the clinical findings of fever and inflammatory markers, there may |
6,513 | be a low threshold for diagnostic imaging and initiating empiric parenteral antibiotic treatment against S. pneumoniae, S. aureus, and P. aeruginosa. Antibiotic prophylaxis should be implemented with agents like clotrimazole plus penicillin, and immunizations against pneumococcus serotypes, H. influenzae, and Neisseria meningitidis given. If patients have a poor response to vaccination, immunoglobu lin replacement should be considered. There is a paucity of data to support the duration of antibiotic prophylaxis, but given that invasive pyogenic infections seem to resolve by adolescence a trial discontin uation could be considered at this time. Nonetheless these patients continue to have skin and upper respiratory infections and may ben efit from lifelong antibiotic prophylaxis targeting pyogenic bacteria. MYD88 DEFICIENCY MyD88 deficiency resembles the clinical and laboratory findings in IRAK4 deficiency (Fig. 175.4; see Table 175.1). These patients have a susceptibility to serious bacterial infections due primarily to S. pneu moniae, S. aureus, and P. aeruginosa, including an inability to mount fever at the beginning of infection. CRP does not rise early during infec tion, likely due to impaired IL 6 production. Invasive bacterial infec tions begin before age 2 years and seem to improve with age, although noninvasive bacterial infections similarly persist after adolescence. Diagnosis is similar to IRAK4 deficiency relying on genetics, as routine immunologic testing is nondiagnostic. MyD88 deficient patients may have elevated serum IgE and IgG4 concentrations in up to 50 and JAK1 TYK2 STAT1 STAT2 Type I Interferons (e.g. IFNalpha, Beta) Interferon Stimulated Genes (ISGs) X X X XX X X IRF9 I F N A R 2 I F N A R 1 Fig. 175.2 Defects along type 1 interferon (IFN) signaling lead to viral susceptibility. Type 1 IFNs bind to their heteroreceptor comprising IFNAR1 and IFNAR2 leading to TYK2 and JAK1 phosphorylation followed by phos phorylation of STAT1 and STAT2, which then cause upregulation of IFN stimulated genes (ISGs). IRF9 can also heterodimerize with STAT2 leading to ISG upregulation. Multiple genetic defects along this pathway (marked with X) can lead to viral susceptibility. Viral R NA Endosome YTLR3 TRIF TRAF3 TBK1 IRF3 IFN alpha Y Y TLR3 X X X X X X UNC93B1 Endoplasmic Reticulum Fig. 175.3 Defects that affect toll like receptor (TLR) 3 signaling pre dispose to HSV encephalitis by impairing type I interferon (IFN) activa tion. Double stranded RNA is detected by TLR3, which then recruits the adaptor TRIF to activate TRAF3 and then through TBK1 and IRF3 to induce IFN and other inflammatory cytokines. UNC93B1 transports TLR3 from the endoplasmic reticulum to the endosome. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 175 u Defects of Innate Immunity 1341 33 of patients tested (respectively), as well as a specific deficiency of unswitched memory B cells. Treatment of MyD88 deficiency should follow the same principles as outlined previously for IRAK4 deficiency. Other inherited disorders of the TIR |
6,514 | pathway like IRAK1 deficiency and TIRAP deficiency will be addressed in Table 175.3. ISOLATED CONGENITAL ASPLENIA Asplenia refers to the complete lack of splenic tissue and includes a heterogenous group of conditions ranging from surgical asplenia to congenital asplenia. Congenital asplenia can be part of a syndrome of multiple congenital anomalies (see Chapter 480.11) or, less often, it can be isolated (see Table 175.3). A diagnosis of isolated congenital asplenia (ICA) is made on the basis of the presence of Howell Jolly bodies (HJBs) on blood smear and the lack of a detectable spleen at ultrasound in the absence of cardiovascular malformations. Some cases are due to an AD inheri tance; relatives of those with ICA should be evaluated because the outcome is typically poor without initiation of antibiotic prophylaxis and pneumococcal vaccination. Half of all isolated cases are due to pathogenic variants in RPSA, a protein component of the small ribo somal subunit. Involvement of related key spleen patterning genes involved during embryogenesis can also result in splenic agenesis. Presentation is typically with overwhelming, refractory infections due to encapsulated bacteria, particularly S. pneumoniae, but also other encapsulated bacteria like H. influenzae and N. meningitidis. Diseases like malaria and babesiosis also affect asplenic patients more severely due to defective removal of intra erythrocytic parasites. In all cases of pneumococcal sepsis, a blood smear should be evaluated for HJBs in addition to an abdominal ultrasound to identify patients with ICA. Immunization against pneumococcal serotypes and meningococcal serotypes is essential. Conjugated vaccines are preferred to unconjugated vaccines. Influenza vaccination should also occur yearly due to the risk of pneumococcal superinfection. Long term oral penicillin prophylaxis (amoxicillin 10 mgkg twice daily to max 250 mg OR 3 years: penicillin V 125 mg twice daily, 3 years: penicillin 250 mg twice daily) is recom mended, as is early initiation of IV antibiotics in the setting of febrile illnesses. Patient education is a critical part in management. Patients should recognize and react to fever as a life threatening emergency with initiation of antibiotic therapy at home (pediatric dosage of amoxicillin clavulanate 45 mgkg twice daily or levofloxacin 10 mgkg for penicillin allergic patients) even before seeking medical care. Animal bites (risk of Capnocytophaga) also should be recognized as a medical emergency requiring local wound care and debridement, and a short course of anti biotic therapy (amoxicillin clavulanate for 3 5 days). Lastly, when travel ing patients should know what to do in case of fever, and if in a tropical area recognize the increased risk for malaria. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 175.4 Mendelian Susceptibility to Mycobacterial Diseases Jenna R.E. Bergerson and Alexandra F. Freeman The group of diseases referred to as mendelian susceptibility to mycobacterial diseases (MSMDs) centers around the synthesis and signaling of IFN required for the ability of macrophages to con trol intracellular infections including mycobacteria as well as some other intracellular bacteria, fungi and viruses (see Table 175.1). Control of mycobacterial infections relies on the IL 12IFN STAT1 pathway |
6,515 | (see Fig. 175.4). When the macrophages ingest mycobacteria or other intracellular organisms, they secrete the cyto kine IL 12, which binds to its receptor, a heterodimer comprising IL 12RB1 plus IL 21RB2, on the T lymphocytes and NK cells. This then leads to the secretion by the TNK lymphocytes of IFN . IFN binds to its heterodimer receptor, IFN R1 and IFN R2, leading to JAK1 and JAK2 phosphorylation, and then STAT1 phosphoryla tion. STAT1 is a transcription factor that leads to the upregulation of IFN regulated genes (IRGs), which leads to the clearance of these infections. Control of mycobacteria relies on this pathway, but also other intracellular microorganisms such as endemic fungi (e.g., His toplasma and Coccidioides), Salmonella, leishmaniasis, and, in part, some viruses, such as those in the herpes virus family. The MSMD defects typically present with disseminated BCG or with extrapulmonary nontuberculous and environmental mycobacteria (NTM); individuals with disseminated mycobacterial disease with either bone or visceral involvement should be evaluated. Depending on the type of defect, the infection may be more localized, such as the osteomy elitis seen frequently with dominant LOF defects in IFN R1 or STAT1, Table 175.3 Innate Defects with Bacterial Susceptibility DISEASE GENEINHERITANCE CLINICAL PHENOTYPE LABORATORY PARAMETERS IRAK4 deficiency IRAK4, AR Early onset invasive pyogenic bacterial infections resolving in adolescence Persistence of noninvasive skin and URT infections IL 6, undetectable CRP in setting of infection CSM B cells Poor specific antibody levels to pneumococcus MyD88 deficiency MYD88, AR Early onset invasive pyogenic bacterial infections resolving in adolescence Persistence of noninvasive skin and URT infections IL 6, undetectable CRP in setting of infection CSM B cells IRAK1 deficiency IRAK1, XL Undefined as reported in only one patient with Rett syndrome Unknown TIRAP deficiency TIRAP, AR Undefined Identified in nine members of one family with only one affected (pneumonia and sepsis from PVL associated Staphylococcus aureus Selectively CSM B cells Isolated congenital asplenia RPSA, AD Sepsis with encapsulated bacteria, absent spleen HJB on blood smear PBX1, NKX2 5, BAPX1, POD1, AR Sepsis with encapsulated bacteria, absent spleen HJB on blood smear AD, Autosomal dominant; AR, autosomal recessive; CSM; class switched memory; HJB; Howell Jolly bodies; IL, interleukin; PVL, Panton Valentine leukocidin; URT, upper respiratory tract; XL, X linked. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1342 Part XII u Immunology or with more disseminated disease often with lymph node, bowel, and hepatosplenic involvement. Extrapulmonary TB should also raise suspi cion of MSMD in young BCG vaccinated children. Mycobacterial disease restricted to the lungs is much less frequently associated with MSMD, but more often with diseases predisposing to bronchiectasis. In addition, young children with isolated cervical adenitis from NTM do not usually have MSMD; the evaluation can be limited to those with recurrent or dif ficult to treat disease. Therapy relies on targeted antimicrobials, but cytokine adjuvants, such as |
6,516 | IFN , and consideration of HSCT varies based on the defect. Related defects that predispose to CMC are noted in Table 175.4. IFN R Defects The IFN receptor is a heterodimer comprised of IFN R1 and IFN R2, and defects in both components lead to abnormal signaling. There are biallelic and heterozygous pathogenic variants that lead to differing presentations. Autosomal Recessive Complete IFN R1IFN R2 Deficiency The most severe defect of the IFN R defects are homozygous or compound heterozygous pathogenic variants that block all IFN signaling. The variants are in the extracellular domains of the pro tein and lead to no surface receptor expression. In countries where BCG is given, these patients typically present in infancy with dis seminated BCG; in other countries affected patients present usually in early childhood with disseminated NTM, such as Mycobacterium avium complex (MAC). Salmonella and Listeria can also cause severe infection; there may be more severe disease with common respira tory viruses and herpes family viruses. Diagnosis is with genetic testing, but some laboratories can also suggest the diagnosis by per forming flow cytometry showing no surface expression of the IFNg on monocytes or lack of intracellular STAT1 phosphorylation after stimulation with IFN . Treatment of complete IFN R1 deficiency is aggressive antimi crobial therapy until HSCT. Adjuvant IFN is not helpful because signaling is blocked; addition of IFN has been used successfully in some cases of disseminated MAC. These patients usually have disseminated NTM or BCG and require combination antibiotics through HSCT, with breakthrough infections being seen often if antibiotics are withdrawn. High serum IFN levels in the blood are typical when infection is present and has been correlated with a poor HSCT outcome; these levels can be followed and HSCT optimally performed when they decline. Autosomal Dominant IFN R1 Deficiency Compared with complete 2 deficiency, AD IFN R1 deficiency allows partial IFNg signaling, and thus a typically less severe clinical course. Most pathogenic variants are small frameshift deletions in the intracellu lar domain of the IFNGR1 gene, thus blocking both the JAK binding site as well as the receptor recycling domain, eliminating the removal of the nonfunctional receptor from the cell surface. Clinical presentation is usu ally later in childhood or adolescence with more focal NTM infections, which is usually osteomyelitis. BCG can present with osteomyelitis as well, at a younger age than is usually seen for the environmental NTM. Dis seminated endemic fungi infections with Histoplasma and Coccidioides are seen, in addition to disseminated Salmonella infections. Diagnosis relies on genetic testing, but in laboratories able to perform flow cytometry for IFN R expression, diagnosis is suspected by increased IFN R expression due to the inability to recycle the receptor. Intracellular STAT1 phosphory lation is reduced after IFN stimulation, although not absent such as with the complete defects. Treatment involves antimicrobials guided by the specific infection, with combination antibiotics needed for NTMBCG. The addition of IFN is MyD88 MyD88 TRAF6 MAPK AP1 IRAK3 IRAK1 NEMO IRAK4 IRAK2 NFKB NFKBs TLR7 TLR8 |
6,517 | TLR9 TLR1 TLR5 TLR6 TLR10IL1RTLR2TLR4 X X XT I R A P IL6, IL1, TNF IL6, IL1, TNF Fig. 175.4 TLRIL 1R pathways. MyD88 is a cytosolic adaptor protein that bridges TLRs and IL 1Rs to the IRAK complex and subsequently allows for the downstream production of cytokines and interferons (IFNs) through the NF B and MAPK pathways. All TLRs, except TLR3, as well as multiple IL 1Rs use MyD88 and IRAK4. Where defects lead to predominant susceptibility to invasive bacterial infections are marked by an X. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 175 u Defects of Innate Immunity 1343 often helpful to clear the infection because some IFN signaling remains. After clearance of the infection, lifelong prophylaxis is suggested such as with azithromycin therapy, and consideration of fluconazole for Coccidioi des endemic regions. IFN is not usually long term for prophylaxis. HSCT has been performed in rare cases but is typically not considered necessary. Autosomal Recessive IL 12 Receptor Beta 1 (IL 12RB1) Deficiency Biallelic typically missense or nonsense pathogenic variants in IL 12RB1 result in complete loss of IL 12 signaling leading to disseminated NTM or other intracellular infections. Compared with complete IFN R deficiency, the penetration and expressivity of IL 12RB1 deficiency is much more variable. Some patients are asymptomatic, even if BCG is given, whereas others develop severe disease early in life with early mortality; even within families the disease can have very different pre sentations. This defect is also more common than IFN R deficiency. Disseminated BCG is common in countries in which the vaccine is given and disseminated environmental NTM presents at much more variable ages in other countries. Although there is increased childhood mortality from this defect, patients who clear disseminated BCG infec tion have lower rates of subsequent NTM infection than those who did not have a BCG infection. Disseminated Salmonella is seen frequently. IL 12RB1 forms a heterodimer with IL 23R, so perturbation of this signaling cascade also results in an increased rate of mucocutaneous candidiasis. Diagnosis is confirmed with genetic testing, but some lab oratories can test the lymphocyte response to IL 12 signaling, noting absence of STAT4 phosphorylation or IFN secretion. Treatment is aimed at antimicrobials for the diagnosed infection. Secondary prophylaxis is suggested after clearance of mycobacterial infections, such as with azithromycin. Adjuvant IFN therapy has been used in cases where antimicrobials do not adequately clear the infection. Increased doses than are used in CGD may be needed, with prudence being to titrate up the dose slowly as hyperinflammatory pre sentations can complicate the therapy. There is very little experience with HSCT in IL 12RB1 deficiency. AD STAT1 Loss of Function Although GOF and complete LOF STAT1 defects can be associated with NTM infections, NTM infections occur with the highest fre quency in AD STAT1 LOF, which is to |
6,518 | be expected because STAT1 is downstream of the IL 12IFN pathway. Presentation is typically with more focal NTM or BCG infections, often with osteomyelitis, similar to that seen with AD IFN R1 deficiency. Diagnosis requires genetic testing. Patients typically respond well to combination antimicrobials and can then be placed on long term prophylaxis. Infants with com plete STAT1 deficiency have had disseminated BCG; this defect also has severe viral infections. TYK2 Deficiency JAK proteins and TYK2 are part of the JAKSTAT signal transduction pathway. TYK2 is downstream of IFN and , as well as IL 12IL 23, with its activation leading to STAT1 phosphorylation. Patients have had disseminated BCG, TB, and viral infections. DIFFERENTIAL DIAGNOSIS FOR MSMD MSMD centers around the control of intracellular organisms including Mycobacteria by the lymphocytemacrophage interactions involving the IL 12IFN STAT1 pathway. However, other primary and second ary immune deficiencies should be included in the differential diagno sis of those presenting with disseminated NTM. Disseminated NTM is a common infection for those with GATA2 deficiency, which typi cally presents in adolescence or adulthood, and is often associated with monocytopenia and myelodysplasia, susceptibility to HPV, and pulmo nary alveolar proteinosis. Nuclear factor B (NEMO) deficiency and other genetic defects involved in NF B activation, such as defects in IkB, are combined immune deficiencies that present with recurrent bacterial, viral, and disseminated mycobacterial disease; NEMO and IKB may both have ectodermal dysplasia as part of the phenotype. Disseminated NTM is a less frequent complication for other myeloid and lymphocyte IEIs such as CGD, NFKB1 deficiency, and severe com bined immune deficiency (SCID). Disseminated NTM is also associ ated with autoantibodies against IFN ; these should be considered for adult onset disease. In the United States, antiIFN autoantibody disease with disseminated NTM is much more common in Asian females but is seen in males and females in East Asian countries. HIV AIDS should always be ruled out for those with disseminated NTM. Disseminated NTM can also be seen secondary to immune suppres sive medications, with TNF blockade being the most common cause. Hairy cell leukemia has an increased incidence of disseminated NTM. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 175.4 Chronic Mucocutaneous Candidiasis Associated Inborn Errors of Immunity SYNDROME GENE INHERITANCE FUNGAL SPECIES OTHER MANIFESTATIONS CARD9 deficiency (30 CMC) CARD9 AR Candida spp. (often CNS involvement), CMC Aspergillus spp. (extrapulmonary), dermatophytes, phaeohyphomycosis Some with increased IgE and eosinophilia IL 17F deficiency (67 CMC) IL17F AD CMC Asthma, folliculitis IL 17RA deficiency (100 CMC) IL17RA AR CMC Folliculitis, susceptibility to Staphylococcus aureus (skin) bacterial infections IL 17RC (100 CMC) IL17RC AR CMC None ACT1 (100) TRAF3IP2 AR CMC Seborrheic dermatitis STAT1 GOF (95 CMC) STAT1 AD CMC, Histoplasma capsulatum, Coccidioides spp. Talaromyces marneffei, Trichophyton, Cryptococcus, Aspergillus, Mucorales Herpes viral infections, bacterial sinopulmonary and skin infections, mycobacterial pulmonary and disseminated infections, CNS aneurysms, autoimmunity AD, Autosomal dominant; AR, autosomal recessive; CMC, chronic mucocutaneous candidiasis; CNS, central nervous system; GOF, gain of function; IL, interleukin. Downloaded for mohamed ahmed (dr.mms2020gmail.com) |
6,519 | at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1344 Part XII u Immunology GENERAL INFECTION PREVENTION AND MANAGEMENT STRATEGIES Whenever possible, precautionary measures to reduce or minimize exposure to infection should be implemented. Whereas patients with severe immunologic defects (e.g., severe combined immunodeficiency SCID) would benefit from strict isolation, patients with other, less severe types of primary immunodeficiency disease (PID) usually do not require such restrictive measures. It is imperative to maximize the patients quality of life while implementing appropriate infection miti gation strategies. Using shared decision making, the clinician, patient, and caregivers should regularly discuss the risks, benefits, and alterna tives of infection mitigation strategies, as the patients clinical situation and risk change over time. Universal precautions, including but not limited to proper and thorough hand hygiene, should be frequently practiced by patients as well as their close contacts. The use of masks that cover the nose and mouth should be considered to avoid infection, especially when highly transmissible infections (e.g., SARS CoV 2) are prevalent in the community. This is especially important in those PID patients before hematopoietic stem cell transplant (HSCT) while on immunosuppressive medications and afterward while awaiting immune reconstitution. There is a low threshold to do further diagnostic testing to identify acute infections early and to start antimicrobial ther apy or admit the patient to hospital for aggressive treatment if needed. It is also important to practice standard routine oral hygiene. Guide lines for antibiotic prophylaxis prior to dental procedures in PID patients has not been well established. Antibiotic prophylaxis is recom mended for patients with PIDs requiring invasive dental procedures such as root canals and tooth extraction. In particular, those patients with PID with ongoing odontogenic infections require antibiotics before and during dental treatment. There is not enough evidence for antibiotic prophylaxis for noninvasive dental procedures such as oral examinations. IMMUNIZATIONS Some PID patients will not mount an adequate immune response to vaccinations because of their underlying immunologic defect. None theless, immunizations should be given to prevent infections to PID patients who are able to respond to vaccination. Specific immunization practices are covered in Chapter 215. Immunization with live viral or bacterial vaccines (BCG) is contraindicated in many PIDs due to the risk of acquiring the live vaccinerelated disease. Specific recommen dations for vaccines in PID are shown in Table 176.1. Patients who are on immunoglobulin G (IgG) replacement therapy (IgRT) do not require routine vaccinations because they receive passive immunization. Protective levels of antibodies against tetanus toxoid, diphtheria toxoid, measles, varicella, pertussis, pneumococci, and three meningococcal serotypes are documented in patients receiving IgRT. GUIDANCE FOR CLOSE CONTACTS Household members and other close contacts should not receive live oral polio virus or live influenza vaccine because they may shed the virus and transmit infection. Household members should generally be vaccinated to all recommended vaccines, including MMR and varicella, to facilitate herd immunity. Transmission |
6,520 | of MMR vaccine viruses has not been reported. The risk of transmission of varicella vac cine virus from a healthy person to an immunocompromised person is rare. If a close contact develops varicella rash after immunization with the varicella or zoster vaccines, isolation of the patient and administra tion of varicella zoster immune globulin is recommended. COVID 19 VACCINE The impact and severity of SARS CoV 2 infection likely varies depending on the underlying immune defect. Small case series have suggested that B cell lymphopenia (such as in X linked agammaglobu linemia XLA) may actually be a protective factor and correlates with milder COVID 19 course. Meanwhile, patients with biallelic loss of function variants in AIRE, who have autoimmune polyendocrine syn drome type 1 (APS 1), appear to have higher risk for life threatening COVID 19 pneumonia due to the presence of autoantibodies to type I interferons (IFNs). Although all PID patients will benefit from infec tion prevention and mitigation practices, it is becoming apparent that morbidity and mortality is variable among PID patients. The most effective COVID prevention practices include the stan dard infection prevention strategies for all diseases including frequent handwashing, minimizing exposure to sick contacts, self isolation quarantining while ill, and mask wearing when in crowded public areas or areas with suboptimal ventilation. The most effective prevention strategy against COVID 19 is vaccination. Although this is a rapidly changing situation, a variety of organizations have created recom mendations for immunodeficiency patients. The consensus is that PID patients should be vaccinated with non live vaccines based on what has been approved for the age group in their country. Patients with humoral deficiencies who do not respond with measurable antibody titers should still be considered for vaccination as vaccines can induce cellular immunity as well. In the United States, the Centers for Disease Control and Preven tion (CDC) recommends administration of a third or fourth dose in high risk patients, such as immunocompromised patients, including PID patients with moderate to severe immunodeficiency and patients on chronic immunosuppressive therapy. PROPHYLAXIS Antimicrobial Prophylaxis Prophylactic antibiotics are one of the mainstays for infection preven tion in patients with PID. The specific antimicrobial prophylaxis rec ommended differs depending on the type of PID because patients with different PIDs are susceptible to different pathogens. IMMUNODEFICIENCIES AFFECTING CELLULAR AND HUMORAL IMMUNITY Severe Combined Immunodeficiency Patients with SCID will require definitive treatment with allogeneic HSCT to correct the immune defect. It is crucial that patients remain infection free to maximize chances of long term survival. With the implementation of newborn screening for SCID, infants with SCID are being detected before they develop infections. When SCID is suspected, the number of people in contact with the infant should be limited. Due to risk of transmission of cytomegalovirus (CMV) through breast milk, many PID transplant centers recommend cessation of breastfeeding until the CMV status of both the mother and infant is established. Antimicrobial prophylaxis should be directed toward pneumonia caused by Pneumocystis jiroveci with a combination of sulfamethoxa |
6,521 | zole and trimethoprim. However, in infants under 2 months of age, there is a concern for bilirubin displacement from albumin and sub sequent risk of kernicterus. In these young infants, close monitoring of bilirubin levels is recommended or alternatives such as atovaquone, dapsone, and pentamidine can be considered. Fluconazole to prevent mucocutaneous candidiasis and acyclovir for viral prophylaxis can be considered as well. In countries where BCG vaccine is commonly administered in early infancy, daily chemoprophylaxis until definitive treatment with HSCT and immune reconstitution is needed with iso niazid and rifampin due to the risk of disseminated BCG infection. Chapter 176 Approaches to Treatment of Primary Immune Deficiency Diseases Alissa McInerney, Stefani Su, and Artemio M. Jongco III Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 176 u Approaches to Treatment of Primary Immune Deficiency Diseases 1345 Palivizumab, a humanized monoclonal antibody against respiratory syncytial virus (RSV), can be considered for children under 2 years of age with SCID during the RSV season to prevent serious disease. The specific RSV seasonal patterns differ between countries. HYPER IgMCD40LG DEFICIENCY Patients with hyper IgM or CD40LG deficiency are especially suscepti ble to P. jiroveci pneumonia (PJP) and require prophylaxis with a com bination of sulfamethoxazole and trimethoprim. These patients are also at special risk for developing sclerosing cholangitis, which can be associated with Cryptosporidium parvum infection. To prevent the risk of cryptosporidium infection, steps need to be taken to avoid drinking contaminated water and places where risk of infection is higher, such as at recreational water parks. COMBINED IMMUNODEFICIENCIES WITH ASSOCIATED OR SYNDROME FEATURES DiGeorge Syndrome22q11 Deletion Syndrome Most patients with DiGeorge syndrome do not require antimicrobial prophylaxis as most patients do not have severe immunodeficiency (i.e., partial DiGeorge syndrome). Less than 1 of patients have sig nificant thymic aplasia and profound T and B cell lymphopenia (i.e., complete DiGeorge syndrome), putting them at risk of PJP and CMV; PJP prophylaxis is recommended. Wiskott Aldrich Syndrome Patients with Wiskott Aldrich syndrome (WAS) are susceptible to a variety of viral and bacterial infections. Prophylactic antimicrobials against infection by PJP and herpes simplex virus are often recommended. If splenectomy is necessary for severe refractory thrombocytopenia, those patients would then require penicillin prophylaxis to protect against infection by encapsulated organisms. Ataxia Telangiectasia Opportunistic infections in patients with ataxia telangiectasia are infrequent; however, sinopulmonary infections are common. Prophy lactic azithromycin is commonly used empirically, however, efficacy data are sparse. STAT3 HYPER IgE SYNDROME (JOB SYNDROME) These patients are susceptible to skin infections predominantly with Staphylococcus aureus causing cold abscesses with diminished inflam matory response. Chronic mucocutaneous candidiasis occurs in over 70 of patients. Pneumonia is a frequent infection with risk of lead ing to bronchiectasis and pneumatoceles. Common causative pathogens include Staphylococcus, Streptococcus pneumoniae, Haemophilus influen zae, and fungal organisms such as Aspergillus and P. jiroveci. Antimicrobial prophylaxis with |
6,522 | a combination of sulfamethoxazole and trimethoprim and antifungal medications such as itraconazole is recommended. NF B ESSENTIAL MODULATOR (NEMO) DEFICIENCY Patients with NF B essential modulator (NEMO) deficiency are sus ceptible to nontuberculous mycobacteria (NTM), similar to patients with IFN and interleukin (IL) 12 defects. Prophylaxis with azithro mycin should be considered. However, these patients are also at risk for many bacterial infections, viral infections such as herpesviruses, and opportunistic infections such as PJP. Acyclovir for viral prophylaxis and a combination of sulfamethoxazole and trimethoprim for PJP prophy laxis should be considered as well. PREDOMINANTLY ANTIBODY DEFICIENCIES Hypogammaglobinemias Lifelong IgRT is the mainstay of infection prevention for patients with major antibody deficiencies such as agammaglobulinemia and com mon variable immunodeficiency (CVID). Prophylactic antibiotics can be used in conjunction with IgRT for patients who develop recurrent respiratory tract infections, which can lead to severe complications of bronchiectasis. Macrolide antibiotics such as azithromycin are com monly used for prophylaxis due to their anti inflammatory properties in chronic lung disease. Low dose oral azithromycin reduces the num ber of exacerbation episodes per patient year, with a consequent reduc tion in additional courses of antibiotics and risk of hospitalization. Other Antibody Deficiencies Patients with minor antibody deficiencies such as transient hypo gammaglobulinemia of infancy (THI), selective IgA deficiency, IgG Table 176.1 Immunizations in Patients with Primary Immunodeficiency Diseases PRIMARY DEFECT EXAMPLE OF SPECIFIC IMMUNODEFICIENCY NOT RECOMMENDED RECOMMENDED Predominantly antibody deficiencies Hypogammaglobulinemias (X linked agammaglobulinemia, common variable immunodeficiency) Other antibody deficiencies (selective IgA deficiency, IgG subclass deficiencies, specific antibody deficiency with normal immunoglobulins) Live attenuated vaccines excluding BCG Live attenuated influenza, OPV, adenovirus, typhoid, yellow fever Inactivated vaccines All vaccines likely effective Pneumococcal and Hib Combined immuno deficiencies Complete defects (SCID, complete DiGeorge syndrome) Partial defects (partial DiGeorge syndrome, Wiskott Aldrich syndrome, ataxia telangiectasia) All live vaccines Live attenuated influenza, OPV, rotavirus, adenovirus, smallpox, typhoid, yellow fever, BCG All vaccines likely ineffective Inactivated vaccines, live attenuated MMR, varicella, and herpes zoster if documentation of adequate T cell number Complement None All routine vaccines, especially pneumococcal and meningococcal vaccines Phagocytic function Chronic granulomatous disease, leukocyte adhesion defects Live attenuated influenza, adenovirus, typhoid, BCG All inactivated vaccines, other live attenuated viral vaccines IFN IL 12 pathway defects BCG Age related levels of immunocompetence proposed by the CDC: 1 yr, 1500; 1 5 yr, 1,000; and 6 yr, 500 CD4 T cellsmm3 for HIV may also be used. BCG, Bacille Calmette Gurin; OPV, oral poliovirus vaccine; SCID, severe combined immune deficiency; MMR, measles, mumps, rubella; IFN , interferon gamma; IL 12, interleukin 12. Data from Medical Advisory Committee of the Immune Deficiency Foundation, Shearer WT, Fleisher TA, et al. Recommendations for live viral and bacterial vaccines in immunodefi cient patients and their close contacts. J Allergy Clin Immunol. 2014;133(4):961966. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1346 Part XII u Immunology |
6,523 | subclass deficiency, or specific antibody deficiency with normal immu noglobulins can usually be managed without need for IgRT. Patients who experience chronic or recurrent infections may benefit from prophylactic antibiotics. Prophylactic antibiotics and IgRT are equally effective as first line treatment in preventing infections in specific anti body deficiency patients. CONGENITAL PHAGOCYTE DEFECTS Chronic Granulomatous Disease Patients with chronic granulomatous disease (CGD) are susceptible to severe bacterial and fungal infections. The most common bacterial organisms include S. aureus, Serratia marcescens, Burkholderia cepa cia, and Nocardia species. The majority of fungal infections in CGD are attributed to Aspergillus species causing invasive aspergillosis. Pro phylaxis with a combination of sulfamethoxazole and trimethoprim and itraconazole is recommended. Leukocyte Adhesion Deficiency Antibiotic prophylaxis to protect against infections with S. aureus or gram negative bacilli is recommended. DEFECTS IN INTRINSIC AND INNATE IMMUNITY Interferon IL 12 Pathway Defects Patients with IFN IL 12 pathway defects are at special risk for infec tions with intracellular pathogens such as nontuberculosis Mycobacte rium species as well as Salmonella. Prophylaxis with daily azithromycin or clarithromycin is recommended. COMPLEMENT DEFICIENCIES Deficiency of terminal pathway components can lead to recurrent neis serial infections. Antibiotic prophylaxis with penicillin can be consid ered. Immunization against S. pneumoniae, H. influenzae, and Neisseria meningitidis is strongly recommended. IMMUNOGLOBULIN G REPLACEMENT THERAPY Human immunoglobulin preparations, derived from the plasma of paid donors, can be administered intravenously (IVIG), subcutane ously (SCIG), or intramuscularly (IMIG) to treat a variety of disorders, including inborn errors of immunity, acquired immunodeficiency, and autoimmune and inflammatory disorders. IgRT provides passive immu nity through preformed antibodies against a wide range of pathogens that are encountered by the general population, leading to immediate but transient protection; IgRT has an integral role in the treatment of patients with defects in the humoral immune system. IgRT is also used for a variety of medical conditions because of its anti inflammatory and immunomodulating effects. Products Although most products are approved for a specific administration route, several 10 IVIG solutions can be administered subcutaneously with good patient tolerability. More concentrated 20 SCIG and 16 IMIG products should not be used intravenously. Available products and their key properties are summarized in Table 176.2. IMIG is rarely used because of its inferior safety and tolerability profile. Injections are painful, the injectable volume is limited, and the risk of local injury and adverse reactions is higher. Both IVIG and SCIG products are effective in treating humoral immunodeficiencies, without significant differences in the infection rates between the two routes. Incidence of infection is inversely correlated with dose regardless of route. INDICATIONS FOR IgRT IgRT is indicated for the treatment of primary immunodeficien cies characterized by absent or deficient antibody production, which comprises the majority of PIDs. The utility of IgRT in decreasing the frequency and severity of infection is well accepted for agammaglobu linemia (e.g., XLA) and hypogammaglobulinemia (e.g., CVID). There are six distinct phenotypes of primary immunodeficiency for which IgRT is or may be indicated: (1) agammaglobulinemia due to absence of |
6,524 | B cells, (2) hypogammaglobulinemia with poor antibody function, (3) normal immunoglobulin levels with impaired specific antibody production, (4) hypogammaglobulinemia with normal antibody func tion, (5) isolated IgG subclass deficiency with normal immunoglobulin levels and normal quality antibody responses, and (6) recurrent infec tions related to an unknown immune mechanism. Agammaglobulinemia Due to Absence of B cells IgRT reduces both acute and chronic infections in this patient popula tion; the number and severity of infectious complications are inversely correlated with IgRT dose. When IgG trough levels are maintained above 800 mgdL, serious bacterial illness and enteroviral meningo encephalitis are prevented; increasing trough levels up to 1,000 mg dL are associated with decreased risk for pneumonia. In the setting of SCID, IgRT is warranted at diagnosis because maternally derived IgG wanes after birth, during the posttransplant period, or gene therapy or enzyme replacement (for adenosine deaminase ADA deficiency) until B cell function reconstitution, or indefinitely if B cell function is not restored. Hypogammaglobulinemia with Poor Antibody Function Patients with recurrent infections who demonstrate decreased immu noglobulin concentrations andor impaired response to protein andor polysaccharide vaccines benefit from IgRT. CVID falls in this category. Initiation of IgRT is associated with decreased infection rate compared with pretreatment. Adequate IgRT dosing is associated with decreased frequency of sinopulmonary infections, which can mitigate the devel opment of lung inflammation, bronchiectasis, and chronic lung dis ease. Growing evidence and expert consensus support individualizing IgRT dosing to keep the patient relatively infection free, achieving a biologic trough or biologic steady state level, and following clinical outcomes rather than using a standardized dose in all patients by dis ease. In addition to CVID, patients with class switching defects, such as autosomal recessive and X linked hyper IgM syndromes, also dem onstrate decreased infection rates from a variety of pathogens. NORMAL IMMUNOGLOBULIN LEVELS WITH IMPAIRED SPECIFIC ANTIBODY PRODUCTION Determining whether and when IgRT is indicated for these patients can be challenging. Available evidence and expert consensus suggest that IgRT should be given when there is well documented nonrespon siveness to polysaccharide vaccines and recurrent infections that are inadequately managed by antibiotic prophylaxis. Protective concentra tion of antibody to polysaccharide antigens is considered 1.3 gmL and conversion from nonprotective to protective titers. In children 2 5 years, 50 of concentrations tested are considered protective, with an observed increase of at least twofold postvaccination, while the thresh old is 70 in patients aged 6 65 years. Selective antibody deficiency has been categorized into four phenotypesmild, moderate, severe, and memory (where the patient can mount an adequate initial response that wanes within 6 months). If an IgRT trial is started, it should be discontinued after a period of time so that antibody responses can be reevaluated a minimum of 3 months after discontinuation. Some chil dren can demonstrate clinical improvement and improved response after pneumococcal polysaccharide vaccine challenge after a short trial of IgRT, whereas others continue to have recurrent infections and restart IgRT. Hypogammaglobulinemia with Normal Antibody Function Age specific normal ranges |
6,525 | differ among laboratories and having IgG levels below the lower limit of normal for age without accompanying infections may not be clinically significant. The IgG levels of children experiencing THI normalize with time. THI may be exacerbated by pre term birth. In the absence of significant infections, IgRT is not routinely recommended for these children. Acquired hypogammaglobulinemia arising from medication (e.g., seizure medications, B cell depletion therapy) can also fall in this category. Severe hypogammaglobulinemia, conventionally defined as IgG levels 150 mgday, is considered a risk Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. C hap ter 1 7 6 u A p p ro aches to Treatm ent o f Prim ary Im m une D eficiency D iseases 1 3 4 7 Table 176.2 Available Immunoglobulin Replacement Therapy Products ROUTE PRODUCT DOSAGE FORM DILUENT REFRIG ERATION REQUIRED? FILTRATION REQUIRED? OSMOLALITY (mOsmkg) SODIUM PH IgA (mcgmL) STABILIZER OR REGULATOR PATHOGEN INACTIVATION REMOVAL IV Asceniv 10 liquid NA Yes No Not available 0.100 0.140 molL 4.0 4.6 200 Glycine and polysorbate 80 FP, SD, VF Bivigam 10 liquid NA Yes No 510 100 140 mM 4.0 4.6 200 Glycine FP, SD, NF Flebogamma DIF 5 5 liquid NA No Optional 240 370 Trace 5.0 6.0 50 D sorbitol Past, SD, dsNF, FP, PEG, pH 4 Flebogamma DIF 10 10 liquid NA No No 240 370 Trace 5.0 6.0 100 D sorbitol Past, SD, dsNF, FP, PEG, pH 4 Gammagard 5 SD Lyophilized Sterile water No Yes 636 8.5 mgmL 6.8 1 2 glucose and glycine CEF, CHROM, SD Gammaplex 5 liquid NA No 15 20 m filter preferred 420 500 30 to 50 mmolL 4.8 5.0 4 Sorbitol and glycine and polysorbate 80 SD, VF, low pH Gammaplex 10 liquid NA No No 280 30 mML 4.9 5.2 20 Glycine and polysorbate 80 SD, VF, low pH Octagam 5 liquid NA No Optional 310 380 0.03 mEqmL 5.1 6.0 200 Maltose CEF, UF, CHROM, SD, pH 4 Octagam 10 liquid NA No Optional 310 380 30 mmolL 4.5 5.0 106 Maltose CEF, SD, pH 4, UF, CHROM Panzyga 10 liquid NA No Optional 240 310 Trace 4.5 5.0 100 Glycine SD, CEF, NF, CHROM Privigen 10 liquid NA No No 240 440 Trace 4.6 5.0 25 L proline CEF, CHROM, pH 4, DF, NF, OAF IV or SC Gammagard liquid 10 liquid NA No Optional 240 300 None added 4.6 5.1 37 Glycine CEF, CHROM, SD, pH 4, NF Gammaked 10 liquid NA, incompatible with saline No No 258 None added 4.0 4.5 46 Glycine CEF, pH 4.2, DF, CAP, CHROM, NF Gamunex C 10 liquid NA, incompatible with saline No No 258 None added 4.0 4.5 46 Glycine CEF, pH 4.2, DF, CAP, CHROM, NF Continued D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U |
6,526 | niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. 1 3 4 8 P art X II u Im m unolog y ROUTE PRODUCT DOSAGE FORM DILUENT REFRIG ERATION REQUIRED? FILTRATION REQUIRED? OSMOLALITY (mOsmkg) SODIUM PH IgA (mcgmL) STABILIZER OR REGULATOR PATHOGEN INACTIVATION REMOVAL SC Cutaquig 16.5 liquid NA Yes No 310 380 30 mmolL 5.0 5.5 600 Maltose CEF, UF, CHROM, SD, pH 4 Cuvitru 20 liquid NA No No 208 290 None 4.6 5.1 80 Glycine CEF, CHROM, NF, SD Hizentra 20 liquid NA No No 380 Trace, 10 mmolL 4.6 5.2 50 Proline CEF, CHROM, pH 4.2, DF, NF, VF, OAF HyQvia 10 liquid recombinant human hyaluronidase NA No No 240 300 None added 4.6 5.1 37 Glycine CEF, CHROM, SD, pH 4, NF Xembify 20 liquid NA 2 8C No 280 404 None 4.1 4.8 70 Glycine CEF, CHROM, CAP, NF, DF, low pH IM GamaSTAN 16.5 liquid NA 2 8C No Not available Not measured 4.1 4.8 Not measured Glycine CEF, CAP, CHROM, NF, low pH, DF GamaSTAN SD 1518 liquid NA 2 8C No Not available 0.4 0.5 6.4 7.2 Not measured Glycine CEF, SD, UF Precautions and laboratory abnormalities associated with specific stabilizers include the following: Glucose: May alter glycemic control in patients with diabetes mellitus. L proline: Cannot be used in patients with hyperprolinemia. Maltose: Falsely elevates glucose readings in certain blood glucose monitoring systems, may contain trace corn protein (potential allergen), and may increase plasma osmolality (usually not clinically important). Polysorbate 80: Some patients may be hypersensitive (also known as Tween 80); reactions can be delayed type. Sorbitol, D sorbitol: Cannot be used in patients with hereditary fructose intolerance. Sucrose: Avoid in patients with renal impairment or increased risk of acute kidney injury. Pathogen inactivationremoval using CEF, DF, UF, CAP, CHROM, Nano, dsNF, VF, SD, Past, FP, or OAF. Not required (2 to 25C). Storage is 2 8C for 24 months or 25C for 9 months. Storage is 2 8C for 36 months or 25C for 6 months. Storage is 2 8C for 24 months or 25C for 6 months. Storage is 2 8C for 36 months or 25C for 12 months. Storage is 2 8C for 36 months or 25C for 3 months. GamaSTAN SD has been discontinued in the United States. Note: Brand names and descriptions refer to products available in the United States and some other countries; product availability, specific composition, and other details regarding individual products vary in other countries. IgA, Immunoglobulin A; IV, intravenous; NA, not applicable; FP, fraction precipitation; SD, solvent detergent; VF, virus filtration; Nano, NF, nanofiltration; DIF, dual inactivation and filtration; Past, pasteurization; dsNF, double sequential nanofiltration; PEG, polyethylene glycol precipitation; CEF, cold ethanol fractionation; DF, depth filtration; UF, ultrafiltration; CHROM, chromatography; SC, subcutaneous; CAP, caprylate; OAF, octanoic acid fractionation; IM, intramuscular. Adapted from Perez |
6,527 | EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1S46; with data from Immune Deficiency Foundation. Characteristics of Immunoglobulin Products Used to Treat Primary Immunodeficiencies. Accessed 81021. https:primaryimmune.orgsitesdefaultfilespublicationsIDFIG20Booklet202020.pdf Table 176.2 Available Immunoglobulin Replacement Therapy Productscontd D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. Chapter 176 u Approaches to Treatment of Primary Immune Deficiency Diseases 1349 factor for infection, and empiric trial of IgRT is reasonable. However, patients with levels between 150 and 250 mgdL deserve further con sideration of antibody function and individual clinical history. Isolated IgG Subclass Deficiency with Normal Immunoglobulin Levels and Normal Quality Antibody Responses Most patients with subclass deficiency are asymptomatic, but a few may have recurrent infections and poor antibody responses to specific anti gens. First line management includes prophylactic antibiotics and treat ment of other comorbidities, such as allergic rhinitis, that can contribute to the development of sinopulmonary infections. IgRT is not routinely recommended for these patients; some case studies have demonstrated reduced infection rate, decreased antibiotic use, and improved quality of life among patients on therapy. Recurrent Infections Related to an Unknown Immune Mechanism There are defined immunodeficiencies, such as ataxia telangiectasia, WAS, and STAT3 deficiency, as well as syndromic immunodeficiencies, such as Jacobsen syndrome, which can present with variable humoral immune defects. IgRT can prevent infections in select patients, and the decision to start IgRT and dosing considerations should be tailored to individual needs. INDIVIDUALIZING IgRT Clinicians, patients, and caregivers need to consider each patients spe cific clinical situation and comorbidities, incorporate patient and care giver preferences, and consider flexibility in dosing route and frequency. Children and adolescents may object to the multiple and more frequent needlesticks associated with SCIG. Once the decision is made to start IgRT, the clinician, patient, and caregivers need to periodically reassess and adjust as needed. Available IgRT products differ from one another and are not interchangeable; the product used should be matched care fully to the patient characteristics to maximize patient safety. There are eight guiding principles on the safe, effective, and appropriate use of IgRT in patients with primary immunodeficiency (Table 176.3). CONSIDERATIONS FOR PRODUCT SELECTIONS IVIG IgA Content The amount of IgA in various products varies. Rarely, severe allergic reactions, including anaphylaxis, have been reported in patients with IgE anti IgA or IgG anti IgA. In these cases, use of low IgA containing IVIG products or SCIG, which appears to be tolerated by these patients despite having higher IgA content, is recommended. Anaphylaxis due to IgA in SCIG has not been reported. Adverse Reactions All IgRT products are associated with a potential risk for adverse reac tions, but historically IVIG is associated with |
6,528 | higher risk. Most IVIG adverse reactions are rate related, mild, and occur in 515 of infu sions. Slowing or stopping the infusion for 15 30 minutes usually leads to complete resolution. Premedication regimens can also help. Ensur ing adequate hydration or switching to SCIG has been used successfully to mitigate this risk. Risk factors for experiencing adverse reactions include (1) having IVIG for the first time, (2) having or recently hav ing a bacterial infection, (3) having underlying chronic inflammation, (4) using higher concentration products, (5) using lyophilized prod uct, and (6) fast infusion rates. Future reactions become less likely after subsequent infusions with the same product. However, patients can develop adverse reactions at any point even to products they have tol erated previously; clinicians and patients need to remain vigilant. For enhanced safety, patients who have experienced prior adverse reactions may benefit from getting infusions at a medical facility, instead of at home with an infusion nurse. Serious adverse events, including acute renal failure, neurodegen eration, and thromboembolic events, can occur during or soon after infusion. Thromboembolic events such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism are rare, but they need to be watched for and require timely intervention when they occur. Risk factors include preexisting cardiovascular dis ease, diabetes mellitus, dehydration, sepsis, increased blood viscos ity, hypercholesterolemia, and hypertension. The use of indwelling venous catheters solely for IVIG administration is not recommended due to the increased risk for thromboembolism and infection with these devices. SCIG Products Available products range from 1020 concentration and offer much dosing flexibility for patients. Facilitated SCIG (fSCIG) involves recom binant human hyaluronidase to facilitate the SC administration of large volumes of IgG among multiple sites and a variety of dosing schedules. Many studies demonstrate equivalence and noninferiority of SCIG and IVIG for management of PIDs. Table 176.3 Guiding Principles for Effective Use of IgRT for Patients with Primary Immunodeficiency GUIDING PRINCIPLE RATIONALE Indication for IgRT IgG is indicated as replacement therapy for patients with PI characterized by absent or deficient antibody production; PI is an FDA approved indication for IgRT Diagnoses A large number of PI diagnoses exist for which IgRT is indicated and recommended; many diagnoses have low total IgG levels, but some have a normal level with documented specific antibody deficiency Frequency of IgRT Treatment is indicated as ongoing replacement therapy for PI; treatment should not be interrupted once a definitive diagnosis has been established Dose IVIG is indicated for PI patients at a starting dose of 400 600 mgkg every 3 4 wk; SCIG is generally used at a starting dose of 100 200 mgkgwk; SCIG dosing frequency is flexible IgG trough levels IgG trough levels can be useful in some diagnoses to guide care but should not be a consideration in access to IgRT Site of care The decision to infuse IgRT in a hospital, outpatient infusion center, community office, or home based setting must be based on patient clinical characteristics Route Administration route must be |
6,529 | based on patient characteristics; throughout life, certain patients may be more appropriate for IV or SC therapy depending on many factors, and patients should have access to either route as needed Product IVIGSCIG are not generic drugs and products are not interchangeable; a specific product needs to be matched to patient characteristics to ensure patient safety; product change should only occur with active participation of the prescribing physician IgRT, Immunoglobulin replacement therapy; IgG, immunoglobulin G; PI, primary immunodeficiency; FDA, US Food and Drug Administration; SCIG, subcutaneous immunoglobulin; IV, intravenous; SC, subcutaneous; IVIG, intravenous immunoglobulin. Data from Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1S46; with data from Yong PL, Boyle J, Ballow M, et al. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology. Clin Immunol. 2010;135(2):255263. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1350 Part XII u Immunology Adverse Reactions SCIG is well tolerated by many patients, including children and IgA deficient patients, and its safety profile is well documented. The most common adverse reaction is local infusion site reactions that can range from mild to severe, but severe local reactions are rare. The prevalence of these local site reactions appears to diminish when infusions are continued. Carefully cleaning the skin of the infusion site with alcohol and using appropriately sized infusion needles or catheters can further decrease risk of local reactions. IV administration of 10 products that are approved for both IV and SC administration is unlikely to be prob lematic, but 20 products should not be used intravenously. Premedi cation is usually not needed for SCIG, but pretreatment of the infusion site with local anesthetic creams may improve tolerability in children. In the United States, patients are routinely provided epinephrine autoinjectors as part of an anaphylaxis kit for home infusions, regard less of prior history of allergic reactions to IgRT. DOSING CONSIDERATIONS The IgRT dose that keeps a patient relatively infection free var ies between patients and can vary in the same patient over time, so the goal of IgRT should be to maximize clinical outcomes and not to achieve a specific IgG level. Conversion from IVIG to SCIG The bioavailability of SCIG is approximately 67 lower compared to IVIG. Thus the monthly dose of SCIG required to achieve an equivalent monthly area under the curve (AUC) is 1.37 times the IVIG dose for 16 products and 1.53 for 20 products. No significant differences in infec tion incidence or outcome have been shown between studies that do not utilize this dose adjustment compared to studies with this dose adjust ment. In clinical practice, AUC dose adjustment is |
6,530 | rarely used. IVIG Dosing For IVIG, many clinical immunologists use 400 600 mgkg every 3 4 weeks as an acceptable starting point for maintenance therapy, while continuing to check annual trough levels. Infusion rates start slowly (e.g., 0.01 mLkgmin) to minimize adverse reactions, and the rate can be increased as tolerated. Clinicians should monitor weight changes and adjust dosing accordingly. Also, IgG levels may need to be checked more frequently if the patient experiences breakthrough infections, devel ops new medical conditions (e.g., protein losing conditions), or is not responding to treatment as expected. Because pharmacokinetics also dif fers among patients, a specific IVIG dose can result in different trough levels in patients with similar body mass. There is insufficient evidence to routinely recommend higher loading IVIG doses in patients with low IgG levels at presentation; this practice has been associated with higher risk for adverse reactions at IgRT start. There is limited data on optimal dosing intervals for IVIG, and current practices vary widely. SCIG Dosing For traditional SCIG, a starting dose of 100 200 mgkg of body weight per week is commonly used. For hyaluronidase fSCIG, a starting dose of 400 600 mgkg via one or two sites every 3 4 weeks is common. When fSCIG is given every 3 4 weeks, the initial peak will still be lower than that of IVIG given at the same intervals, but the trough serum levels will be similar. Patients have more dosing frequency flexibility because there are products approved for daily, weekly, biweekly, or monthly dos ing. Infusion rates generally range from 10 35 mLhr per site by pump with volumes of 15 40 mL per site. The number of sites depends on the total volume for the target dose, and typical infusion sites include abdomen, outer thigh, upper arm, and buttocks. Manual rapid push protocols that do not require infusion pumps have been reported to be safe and tolerable by patients in small nonrandomized trials. Steady state serum IgG levels should be monitored periodically after approxi mately 3 months and can be used to assess patient adherence. Facilitated SCIG The dosing of hyaluronidase fSCIG is similar to IVIG. In the United States, fSCIG is approved for use in patients 2 years or older. Unlike traditional SCIG, a four dose7 week ramp up period is recom mended when starting fSCIG, even in patients who have used other IgRT products successfully. Once established on therapy, fSCIG infu sion rates can be increased as tolerated by the patient from 50 mLhr up to 300 mLhr. The IgG is infused via peristaltic pump or large volume battery operated pump, similar to IVIG, which has been programmed to account for the higher pressure of fSCIG compared with IV. ADMINISTRATION DETAILS Premedication Many patients tolerate IVIG infusions without premedication. Pediat ric pretreatment regimens include oral acetaminophen or ibuprofen, oral or IV or IM diphenhydramine, or alternatively a nonsedating antihistamine andor a glucocorticoid such as oral prednisolone or IV hydrocortisone. Maintaining adequate hydration before infusion orally or |
6,531 | via IV fluids with normal saline may be beneficial, especially for patients with preexisting renal disease or other risk factors (e.g., concomitant use of nephrotoxic agents). Premedication is usually not required for SCIG. VACCINATION WHILE ON IgRT Administration of IgRT may interfere with vaccination efficacy because the antibodies in the product might bind to the antigens in the vaccine and inhibit the immune response. The IgG in the IgRT product may hinder the viral replication that is needed to induce the desired immune response in live virus vaccines such MMR or varicella (varicella zoster virus VZV). Antibody containing blood products from the United States do not interfere with the immune response to yellow fever vac cine and are not believed to interfere with the response to live typhoid, live attenuated influenza, rotavirus, or zoster vaccines. The duration of inhibition ranges from 3 11 months and is related to the amount of antigen specific antibody contained in the immune globulin or blood product. For patients on IgRT, 8 months since last IVIG infusion is the suggested waiting time before administering live vaccines. Although no specific recommended waiting time has been suggested for SCIG, many clinicians will also wait for 8 months since last infusion. If the antibody containing product is administered before the vac cine is scheduled, the vaccine should be delayed for the suggested interval. If a dose of MMR or VZV vaccine is administered after an antibody containing product but at an interval shorter than the sug gested interval, the vaccine dose should be repeated at the suggested interval unless an antibody response to the vaccine is documented. If the antibody containing product is necessary within 14 days after administration of MMR or VZV vaccine, the vaccine dose should be repeated after the suggested interval, unless an antibody response to the vaccine is documented. Caution is advised when checking and interpreting IgG based serolo gies while on IgRT. Stopping IgRT to assess vaccine efficacy in immuno deficient patients is generally not recommended. Neoantigen vaccines such as Salmonella typhi Vi can be used to assess a patients ability to make specific antibodies while on IgRT, but this is not widely available. Annual inactivated influenza vaccine is generally recommended for immunodeficient patients, including those on IgRT, presumably to stimulate Tcell immunity, although data are lacking that demonstrate induction of protective antibodies. The influenza vaccine may be given simultaneously or at any time interval before or after IgRT infusion. Clinical trials using gene therapy with retroviral vectors have been conducted for several inborn errors of immunity including ADA SCID, X linked SCID, X linked CGD, and WAS in which immunity was restored but with leukoproliferative complications due to insertion of the vector into oncogenes, in all except for ADA SCID. The use of lentiviral vectors represented a breakthrough in the field with clinical recovery and immune reconstitution while minimizing vector related complications. For further details on HSCT and gene therapyediting, see Chapters 177 and 178. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. |
6,532 | Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 177 u Principles and Clinical Indications of Hematopoietic Stem Cell Transplantation 1351 Allogeneic (from a donor) or autologous (from the same individual) hematopoietic stem cells have been used to cure both malignant and non malignant disorders. Autologous transplantation is employed as a rescue strategy after delivering otherwise lethal doses of chemotherapy with or without radiotherapy in children with hematologic malignancies such as relapsed lymphoma or selected solid tumors (e.g., neuroblastoma, brain tumors). Allogeneic transplantation is used to treat children with genetic diseases of blood cells, such as hemoglobinopathies, primary immunode ficiency diseases, various inherited metabolic diseases, and bone marrow failure. Allogeneic transplant is also used as treatment for hematologic malignancies, such as leukemia and myelodysplastic syndromes. Bone marrow had originally represented the only source of hematopoietic progenitor cells. Growth factor (granulocyte colony stimulating factor) mobilized peripheral blood hematopoietic stem cells and umbilical cord blood hematopoietic progenitors have also been regularly used in clinical practice to perform hematopoietic stem cell transplantation (HSCT). A human leukocyte antigen (HLA) matched sibling was tradition ally the only type of donor employed. Matched unrelated volunteers, full haplotype mismatched family members, and unrelated cord blood donors have been largely utilized to transplant patients lacking an HLA identical relative. Protocols for allogeneic HSCT consist of two parts: the preparative regimen and transplantation itself. During the preparative condition ing regimen, chemotherapy, at times in conjunction with irradiation, is administered to eliminate the patients hematopoietic system and to sup press the immune system, especially T cells, so that graft rejection is pre vented. In patients with malignancies, the preparative regimen also serves to significantly reduce the tumor burden. The patient then receives an intravenous infusion of hematopoietic cells from the donor. Less aggres sive conditioning regimens, known as reduced intensity conditioning regimens, are also used in pediatric patients. These regimens are mainly immunosuppressive and aim at inducing a state of reduced immune com petence of the recipient to avoid the rejection of donor cells. The immunology of HSCT is distinct from that of other types of transplant because, in addition to stem cells, the graft contains mature blood cells of donor origin, including T cells, B cells, natural killer cells, and dendritic cells. These cells repopulate the recipients lymphohema topoietic system and give rise to a new immune system, which helps eliminate residual leukemia cells that survive the conditioning regi men. This effect is known as the graft versus leukemia (GVL) effect. The donor immune system exerts its T cellmediated GVL effect through alloreactions directed against histocompatibility anti gens displayed on recipient leukemia cells. However, because some of these histocompatibility antigens are also displayed on tissues, unwanted T cellmediated alloreactions may ensue. Specifically, donor alloreactive immune cells may attack recipient tissues, particularly the skin, gastrointestinal (GI) tract, and liver, causing acute or chronic graft |
6,533 | versus host disease (GVHD), a condition of varying severity that in some cases can be life threatening or even fatal (see Chapter 179). The success of allogeneic HSCT is undermined by diversity between donors and recipients in major and minor histocompatibility antigens. HLA, including HLA A, HLA B, and HLA C major histocompatibility complex (MHC) class I molecules, present peptides to CD8 T cells, whereas the HLA DR, HLA DQ, and HLA DP MHC class II molecules present peptides to CD4 T cells. There are hundreds of variant forms of each class I and class II molecule, and even small differences can elicit alloreactive T cell responses that mediate graft rejection andor GVHD. Disparities for HLA A, HLA B, HLA C, or HLA DRB1 alleles in the donor recipient pair are independent risk factors for both acute and chronic GVHD. There is also increasing evidence that HLA DQ and HLA DP may play a role, prompting some transplant centers to also explore matching at these alleles. Minor histocompatibility antigens derive from differences between the HLA matched recipient and donor in peptides that are presented by the same HLA allotype. These antigens result from polymorphisms of non HLA proteins, differences in the level of expression of proteins, or genetic differences between males and females. An example of the latter is repre sented by the H Y antigens encoded by the Y chromosome, which can stimulate GVHD when a female donor is employed to transplant an HLA identical male recipient. Thus, from this evidence, GVHD may occur even when the donor and recipient are HLA identical. The preferred donor for any patient undergoing HSCT has tradition ally been an HLA identical sibling. Because polymorphic HLA genes are closely linked and usually constitute a single genetic locus, any pair of siblings has a 25 chance of being HLA identical. Thus, also in view of the limited family size in the developed countries, 2530 of patients in need of an allograft can receive their transplant from an HLA identical sibling. This percentage is even lower in patients with inherited disorders because affected siblings will not be considered donor candidates. HSCT FROM AN HLAIDENTICAL SIBLING DONOR Allogeneic HSCT from an HLA compatible sibling is the treatment of choice for children with hematologic malignancies and various con genital or acquired diseases (Table 177.1). Best results are achieved in patients with congenital or acquired nonmalignant disorders because the risk of disease recurrence is low and the cumulative transplantation related mortality is lower than in children receiving transplants for hematologic malignancies. ACUTE LYMPHOBLASTIC LEUKEMIA Allogeneic HSCT is used for pediatric patients with acute lymphoblastic leukemia (ALL), either in the first complete remission when a child is con sidered at high risk of leukemia recurrence (e.g., those carrying poor risk cytogenetic characteristics or with high levels of minimal residual disease), or in second or further complete remission after previous marrow relapse. ALL is the most common indication for HSCT in childhood. Several patient , donor , disease , and |
6,534 | transplant related variables may influence the outcome of patients with ALL given an allogeneic HSCT. The prob abilities of 3 year overall survival (OS) for US patients 18 years of age with ALL transplanted in the first or second complete remission is 7080 and 6070, respectively. Inferior results are obtained in patients receiving transplants in more advanced disease phases (5060; Fig. 177.1). The use of total body irradiation (TBI) during the preparative regimen offers an advantage in terms of better event free survival (EFS) compared to a regi men consisting of cytotoxic drugs alone, but it can induce more long term side effects. This has prompted more investigation into TBI sparing alter natives. Less intensive GVHD prophylaxis is also associated with a better outcome. Bone marrow is generally the preferred source of stem cells to be employed for transplantation, although this differs among transplant centers. Although the main benefit for allogeneic HSCT recipients with leukemia derives from the GVL effect displayed by immunocompe tent cells, disease recurrence remains the main cause of treatment Chapter 177 Principles and Clinical Indications of Hematopoietic Stem Cell Transplantation Rachel A. Phelan and David Margolis Section 6 Hematopoietic Stem Cell Transplantation Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1352 Part XII u Immunology failure. The risk of failing to eradicate leukemia is influenced by many variables, including disease phase, molecular lesions of tumor cells, and disparity for major or minor histocompatibility antigens in the donorrecipient pairs. To overcome the hurdle of tumor elu sion caused by HLA loss on malignant cells, the use of nonHLA restricted chimeric antigen receptors (CARs) has also been used. This therapeutic strategy is based on genetic reprogramming of T cells through artificial immune receptors that reproducibly and effi ciently redirect the antigen specificity of polyclonal T lymphocytes toward target antigens expressed by leukemic cells. When expressed by T cells, CARs mediate antigen recognition and tumor cytolysis in an MHC unrestricted fashion and can target any molecule (protein, carbohydrate, or glycolipid) expressed on the surface of tumor cells, thus bypassing one of the major tumor escape mechanisms based on the downregulation of MHC molecules. CARs are composed of an extracellular specific antigen binding moiety, obtained from the variable regions of a monoclonal antibody, linked together to form a single chain antibody (scFv), and of an intracellular signaling com ponent derived from the chain of the T cell receptor (TCR) CD3 complex. The addition to the CAR gene construct of co stimulation signals and cytokines promoting T cell expansion and survival improves the antitumor efficiency of the engineered T cells and their survival in the tumor milieu. Gamma retrovirus and lentiviruses are usually used to transduce CARs into T lymphocytes to be employed in the clinical setting. These vectors have been shown to efficiently infect T lymphocytes, integrate into the host genome, and produce robust |
6,535 | expression of the gene in human T cells and their progeny. ACUTE MYELOID LEUKEMIA Allogeneic HSCT is largely employed as postremission treatment of pediatric patients with acute myeloid leukemia (AML) who meet cer tain high risk disease criteria. This subset of children with AML in first complete remission who are given allogeneic HSCT as consolidation therapy have a better probability of EFS than those treated with either chemotherapy alone or autologous transplantation. Results obtained in patients given HSCT after either a TBI containing or a chemotherapy based preparative regimen are similar. Therefore, for AML, condi tioning regimens generally omit the use of TBI because of associated long term side effects. Children with acute promyelocytic leukemia in IMMUNOLOGIC DISORDERS Variants of severe combined immunodeficiency Hyper IgM syndrome Leukocyte adhesion deficiency Omenn syndrome Zap 70 kinase deficiency Cartilage hair hypoplasia PNP deficiency CD40 ligand deficiency MHC class II deficiency Wiskott Aldrich syndrome Chdiak Higashi syndrome Kostmann syndrome (infantile malignant agranulocytosis) Chronic granulomatous disease Autoimmune lymphoproliferative syndrome X linked lymphoproliferative disease (Duncan syndrome) IPEX syndrome Interleukin 10 receptor deficiency Hemophagocytic lymphohistiocytosis Interferon receptor deficiency Griscelli disease Granule deficiency OTHER DISORDERS Selected severe variants of platelet function disorders (e.g., Glanzmann thrombasthenia, congenital amegakaryocytic thrombocytopenia) Selected types of mucopolysaccharidosis (e.g., Hurler disease) or other liposomalperoxisomal disorders (e.g., Krabbe disease, adrenoleukodystrophy) Infantile malignant osteopetrosis Life threatening cytopenia unresponsive to conventional treatments Table 177.1 Indications for Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Diseases MALIGNANCY ALL First complete remission for patients at very high risk of relapse T cell immunophenotype and poor response to corticosteroid therapy Not in remission at the end of the induction phase Marked hypodiploidy (43 chromosomes) Minimal residual disease at the end of consolidation therapy High risk infant ALL Second complete remission Third or later complete remission Acute myeloid leukemia in first complete remission or in advanced disease phase Philadelphia chromosomepositive chronic myeloid leukemia Myelodysplastic syndromes Hodgkin and non Hodgkin lymphomas Selected solid tumors Metastatic neuroblastoma Rhabdomyosarcoma refractory to conventional treatment Very high risk Ewing sarcoma High risk CNS tumors ANEMIAS Severe acquired aplastic anemia Fanconi anemia Paroxysmal nocturnal hemoglobinemia Congenital dyskeratosis Diamond Blackfan anemia Thalassemia major Sickle cell disease Shwachman Diamond syndrome ALL, Acute lymphoblastic leukemia; CNS, central nervous system; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X linked; MHC, major histocompatibility complex; PNP, purine nucleoside phosphorylase. 0 20 40 60 80 100 P ro ba bi lit y, 0 1 2 3 Years p0.001CR1 (n332) CR2 (n472) Relapsenever in CR (n42) 4 5 Fig. 177.1 Survival after matched related donor hematopoietic stem cell transplantation for acute lymphoblastic leukemia (ALL), age 18 years, 2008 2018. CR1, first complete remission; CR2, second or greater remission. (From Phelan R, Arora M, Chen M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US sum mary slides 2020. http:www.cibmtr.org.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 177 u |
6,536 | Principles and Clinical Indications of Hematopoietic Stem Cell Transplantation 1353 molecular remission at the end of treatment with chemotherapy and all trans retinoic acid, or with AML and translocation t(8;21) inver sion of chromosome 16 (inv16), translocation t(16;16), or normal cyto genetics and presence of NPM1 or CEPB pathogenic variants are no longer considered eligible for allogeneic HSCT in first complete remis sion in view of their improved prognosis with alternative treatments. Studies suggest restricting the use of HSCT to those patients with poor molecular lesions, such as FLT3 internal tandem duplication or mixed lineage leukemia abnormalities, or with high levels of minimal residual disease at the end of induction therapy. Approximately 4060 of pedi atric patients with AML in the second complete remission can be res cued by HSCT. The probabilities of 3 year OS for US patients 18 years of age with AML transplanted in the first or second complete remis sion is 6070. Similar to ALL, inferior results are obtained in patients receiving transplants in more advanced disease phases (3040). CHRONIC MYELOGENOUS LEUKEMIA For many years, allogeneic HSCT has been considered the only proven curative treatment for children with Philadelphia positive (Ph) chronic myelogenous leukemia. Leukemia free survival of chronic myelogenous leukemia patients after an allograft is 4580. The phase of disease (chronic phase, accelerated phase, blast crisis), recipient age, type of donor employed (related or unrelated), and time between diag nosis and HSCT are the main factors influencing the outcome. The best results are obtained in children transplanted during the chronic phase from an HLA identical sibling within 1 year from diagnosis. Unlike other forms of pediatric leukemia, infusion of donor leukocytes can reinduce a state of complete remission in a large proportion of patients experiencing leukemia relapse. Treatment with the specific BCR ABL tyrosine protein kinase inhibitors (imatinib mesylate, dasatinib, nilotinib), targeting the enzy matic activity of the BCR ABL fusion protein, has modified the natu ral history of the disease and thus the indications for transplantation. The indication for HSCT in this population is generally reserved for patients with a poor response to tyrosine kinase inhibitors or those who do not tolerate their side effects. JUVENILE MYELOMONOCYTIC LEUKEMIA Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy of early childhood, representing 23 of all pediatric leukemias. JMML is characterized by hepatosplenomegaly and organ infiltration, with excessive proliferation of cells of monocytic and granulocytic lineages. Hypersensitivity to granulocyte macrophage colony stimulating factor (GM CSF) and pathologic activation of the RAS RAF MAP (mitogen activated protein) kinase signaling pathway play an important role in the pathophysiology. JMML usually runs an aggressive clinical course, with a median duration of survival for untreated children of 12 months from diagnosis. Rare patients with CBL1 or N RAS mutations can survive for years without an allograft. HSCT can cure approximately 5060 of patients with JMML. Patients who receive a transplant from an unrelated donor have com parable outcome to those given HSCT from an HLA compatible related donor. Cord blood |
6,537 | transplantation represents a suitable alterna tive option. Leukemia recurrence is the main cause of treatment failure in children with JMML after HSCT, with the relapse rate as high as 4050. Because children with JMML frequently have massive spleen enlargement, splenectomy has been performed before transplantation. Spleen size at the time of HSCT and splenectomy before HSCT do not appear to affect the posttransplantation outcome. Donor leukocyte infusion is not useful to rescue patients experiencing disease recur rence; a second allograft can induce sustained remission in approxi mately 30 of children with JMML relapsing after a first HSCT. MYELODYSPLASTIC SYNDROMES OTHER THAN JUVENILE MYELOMONOCYTIC LEUKEMIA Myelodysplastic syndromes are a heterogeneous group of clonal disor ders characterized by ineffective hematopoiesis leading to peripheral blood cytopenia and a propensity to evolve toward AML. HSCT is the treatment of choice for children with refractory anemia with excess of blasts (RAEB) and for those with RAEB in transformation (RAEB t). The probability of survival without evidence of disease for these children is 6570. It is still unclear whether patients with myelo dysplastic syndromes and a blast percentage 20 benefit from pre transplantation chemotherapy. HSCT from an HLA identical sibling is also the preferred treatment for all children with refractory cytopenia. Transplantation is also considered in children with refractory cytope nia associated with monosomy 7, GATA 2 deficiency, complex karyo type, life threatening infections, profound neutropenia, or transfusion dependency. For children with refractory cytopenia, the probability of EFS after HSCT may be as high as 80, and disease recurrence is rarely observed. This observation has provided the rationale for testing reduced intensity regimens in these patients. NON HODGKIN LYMPHOMA AND HODGKIN DISEASE Childhood non Hodgkin lymphoma (NHL) and Hodgkin disease (HD) are very responsive to conventional chemoradiotherapy; some patients have refractory disease or are at high risk for relapse. HSCT can cure a proportion of patients with relapsed NHL and HD and should be offered early after relapse, while the disease is still sensitive to therapy. If an HLA matched donor is available, allogeneic transplantation can be offered to patients with NHL to take advantage of the GVL effect. Patients with sensitive disease and limited tumor burden have favorable outcomes, with EFS rates of 5060. Patients with relapsed or refractory HD do well after autologous HSCT, with EFS of 5060. HD patients may also benefit from a GVL effect when given an allograft. ACQUIRED APLASTIC ANEMIA Because the probability of long term survival for a matched sibling bone marrow transplant (BMT) is reproducibly 80 for children and young adults, BMT is the treatment of choice for children and young adults with acquired severe aplastic anemia. Historically, the treatment of choice for children and young adults without an HLA matched sib ling has been intensive immunosuppression. Because the outcomes of matched unrelated donor transplant for children with acquired aplastic anemia have improved substantially over the years, the use of unre lated donor HSCT upfront without prior immunosuppressive therapy is being considered more frequently. For patients who do |
6,538 | not have a matched sibling donor or well matched unrelated donor, historically the transplant options were very disappoint ing. Fortunately, there is hope in using haploidentical transplant for this disease. The use of a reduced intensity conditioning regimen combined with GVHD prophylaxis, including posttransplant cyclophosphamide, have shown significant improvement over prior experiences with survival approaching transplants using well matched unrelated donors. INHERITED BONE MARROW FAILURE SYNDROMES Fanconi anemia (FA) and dyskeratosis congenita are genetic disorders associated with a high risk of developing pancytopenia. FA is an auto somal recessive disease characterized by spontaneous chromosomal fragility, which is increased after exposure of peripheral blood lympho cytes to DNA crosslinking agents, including clastogenic compounds such as diepoxybutane, mitomycin C, and melphalan. Patients with FA, along with being at risk for pancytopenia, show a high propensity to develop clonal disorders of hematopoiesis, such as myelodysplas tic syndromes and AML. HSCT can rescue aplastic anemia and pre vent the occurrence of clonal hematopoietic disorders. In view of their defects in DNA repair mechanisms, which are responsible for the chro mosomal fragility, FA patients have an exquisite sensitivity to alkylat ing agents and radiation therapy. Thus they must be prepared for the allograft with reduced doses of cyclophosphamide and only judicious use of radiation. Many FA patients were once successfully transplanted after receiving low dose cyclophosphamide and thoracoabdominal irradiation. However, the use of this regimen is associated with an increased incidence of posttransplantation head and neck cancers. Low dose cyclophosphamide combined with fludarabine has been very well tolerated in patients with FA who have a matched related donor. The addition of low dose TBI and antithymocyte globulin (ATG) for those with an unrelated donor has shown similar success. Currently, the 5 year OS is 90 in patients with FA who receive HSCT before the transformation to hematologic malignancy. Because of their underly ing disorder, however, patients with FA must be monitored closely in Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1354 Part XII u Immunology the years after transplant to assess for late effects, including secondary malignancies and endocrinopathies. Allogeneic HSCT remains the only potentially curative approach for severe bone marrow failure associated with dyskeratosis congenita, a rare congenital syndrome characterized also by atrophy and reticular pigmentation of the skin, nail dystrophy, and leukoplakia of mucous membranes. Results of allograft in these patients have been relatively poor, with a 10 year survival of 2030, because of both early and late complications, reflecting increased sensitivity of endothelial cells to radiotherapy and alkylating agents. THALASSEMIA Conventional treatment (i.e., regular blood transfusion and iron chelation therapy) has dramatically improved both the survival and the quality of life of patients with thalassemia, changing a previously fatal disease with early death to a chronic, slowly progressive disease compatible with prolonged survival. However, HSCT remains the only curative treatment for patients with thalassemia. In |
6,539 | these patients the risk of dying from transplant related complications depends primarily on patient age, iron overload, and concomitant hepatic viral infections. Adults, especially with chronic active hepatitis, have a poorer outcome than children. Among children, three classes of risk have been identi fied on the basis of three parameters: regularity of previous iron che lation, liver enlargement, and presence of portal fibrosis. In pediatric patients without liver disease who have received regular iron chelation (class 1 patients), the probability of survival with transfusion indepen dence is 90, whereas for patients with low compliance with iron chelation and signs of severe liver damage (class 3 patients), the prob ability of survival has been 60. With improvements in supportive care and conditioning regimens, even patients with more advanced liver disease have had excellent out comes (Fig. 177.2). The most effective pharmacologic combinations (e.g., including cyclosporine and methotrexate) should be employed to prevent GVHD. The outcome of patients transplanted from an unre lated donor has been reported similar to that of HLA identical sibling recipients. The increased use of umbilical cord blood and haploidenti cal donors in this population is being explored to expand the num ber of patients eligible for HSCT. Also, advancements in gene therapy are being made in thalassemia in clinical trials, which may eventually change the approach to this disease. SICKLE CELL DISEASE Disease severity varies greatly among patients with sickle cell disease, with 520 of the overall population suffering significant morbidity from vasoocclusive crises and pulmonary, renal, or neurologic dam age. Hydroxyurea, an agent favoring the synthesis of fetal hemoglobin, reduces the frequency and severity of vasoocclusive crises and improves the quality of life for patients with sickle cell disease; however, allogeneic HSCT is the only curative treatment for this disease currently. Although HSCT can cure homozygous hemoglobin S, hemoglobin S0, or hemo globin sickle cell disease, selecting appropriate candidates for transplanta tion is difficult. Patients with sickle cell disease may survive for decades, but some patients have a poor quality of life, with repeated hospitaliza tions for painful vasoocclusive crises and central nervous system (CNS) infarcts. The main indications for performing HSCT in patients with sickle cell disease are history of strokes or abnormal transcranial Doppler ultrasound, recurrent acute chest syndrome, andor recurrent vasoocclu sive crises. The results of HSCT are best when performed in children with an HLA identical sibling, with a probability of cure of 8090. However, the use of alternative donor transplants in this population, including matched unrelated donors and haploidentical donors, is being investi gated through a number of clinical trials and may increase the number of patients eligible to undergo potentially curative HSCT. Reduced intensity and reduced toxicity regimens are also being explored to further decrease transplant related morbidity and mortality, although graft failure remains an important issue in this patient population. Gene therapy for sickle cell disease is currently being investigated in clinical trials. IMMUNODEFICIENCY DISORDERS HSCT is the treatment of choice for children affected by severe combined immunodeficiency (SCID), |
6,540 | as well as for other inherited immunodeficiencies, including Wiskott Aldrich syndrome, leukocyte adhesion deficiency (LAD), and chronic granulomatous disease (see Table 177.1). With an HLA identical sibling, the probability of survival approaches 100, with less favorable results for patients transplanted from an HLApartially matched relative. Some children with SCID, mainly those without residual natural killer activity or maternal T cell engraftment, may be transplanted without receiving any preparative regimen; the donor lymphoid cells are usually the only elements that engraft. Sustained donor engraftment is more difficult to achieve in children with Omenn syndrome, hemophagocytic lymphohistiocy tosis (HLD), or LAD. Life threatening opportunistic fungal and viral infections occurring before the allograft adversely affect the patients outcome after HSCT. Because of this, patients with the most severe immunodeficiencies must be transplanted as early as possible to pre vent infectious complications. INHERITED METABOLIC DISEASES Inherited metabolic diseases are a broad group of diseases that result from the accumulation of substrate within tissues caused by dys function of the lysosome or peroxisome. The use of HSCT has been established for a variety of inherited metabolic diseases, including mucopolysaccharidosis type 1 (Hurler syndrome) and adrenoleuko dystrophy (ALD). Although some of these diseases are treatable with exogenous enzyme replacement therapy, the clinical manifestations of disease tend to progress over time, especially disease in the CNS, where enzyme is unable to be reliably delivered. It is thought that undergoing HSCT results in the engraftment of microglial cells that are able to provide new enzyme to the areas where enzyme replace ment therapy, if available, cannot have a substantial impact. Multiple studies have shown significantly improved outcomes for patients who are diagnosed with their underlying conditions relatively early and are able to undergo HSCT expeditiously, before significant damage from accumulated substrate that may be irreversible. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 0 0.0 0.2 5.0 10.0 15.0 20.0 25.0 0.4 0.6 0.8 1.0 Survival Functions OS EFS Years C u m u la ti ve S u rv iv al Fig. 177.2 Overall survival (OS) and event free (graft failure) sur vival (EFS) after hematopoietic stem cell transplantation in children 1 year from transplant for thalassemia major. (From Chaudhury S, Ayas M, Rosen C, et al. A Multicenter Retrospective Analysis Stress ing the Importance of Long Term Follow Up after Hematopoietic Cell Transplantation for Thalassemia. Biol Blood Marrow Transplant. 2017;23(10):16951700.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 178 u Hematopoietic Stem Cell Transplantation from Alternative Sources and Donors 1355 Two thirds of patients who need allogeneic hematopoietic stem cell trans plantation (HSCT) do not have an available HLA identical sibling. Alter native sources of hematopoietic stem cells (HSCs) are being increasingly used and include matched unrelated donors, unrelated umbilical cord blood, and HLA haploidentical relatives. Each of these three options has advantages and limitations, but rather than being considered |
6,541 | com peting alternatives, they should be regarded as complementary strategies to be chosen after a careful evaluation of the relative risks and benefits in the patients best interest. The choice of the donor will depend on vari ous factors related to urgency of transplantation; patient , disease , and transplant related factors; center experience; and physician preference. UNRELATED DONOR TRANSPLANTS One of the most widely used strategies for children who need an allograft and do not have an available HLA identical sibling is to identify an unrelated HLA matched donor in a registry. Worldwide international registries include almost 27 million HLA typed volun teer donors. HLA A, HLA B, HLA C class I loci, and the DRB1 class II locus are the HLA loci that most influence outcome after HSCT from an unrelated volunteer. Other class II loci (namely, DQB1 and DP1 loci), as well as killer cell immunoglobulin like receptor (KIR) haplotypes, are also increasingly considered when choosing a donor, although their impact on outcome is less well elucidated. Although in the past serologic (low resolution) typing was used for HLA A and HLA B loci, currently the unrelated donors are selected using high resolution (allelic) molecular typing of loci HLA A, HLA B, HLA C, and DRB1. The chance of finding an HLA matched unrelated donor depends on the frequency of the HLA phenotype, which is closely linked to the ethnic origin of the registry donors. Data from the National Mar row Donor Program (NMDP) donor registry and banked cord blood units estimated that essentially every patient in need of a transplant would be able to find a donor in a timely fashion, despite the recipients raceethnic group, donor availability, and cell dose. However, many of those patients may not have access to an ideal graft, defined as HLA matching of a minimum of 88 for bone marrow and 66 for cord blood. Initially, HLA polymorphism and the intrinsic limitations of con ventional (i.e., serologic) HLA typing techniques unfavorably affected the accuracy of matching, thus increasing rejection rates and the inci dence of acute and chronic graft versus host disease (GVHD). The advent of both high resolution molecular HLA classes I and II loci typ ing coupled with progress in the prophylaxis and treatment of GVHD has resulted in a reduction of transplantation related mortality and improvement in outcome. Indeed, outcomes from a fully matched unrelated volunteer donor are now similar to those of HSCT from an HLA identical sibling. The outcomes of haploidentical transplanta tion are similarly reaching that of matched unrelated donors as well as matched sibling donors. Although a single locus disparity in patients with leukemia may be seen as beneficial by a reduction in the relapse rate caused by the graft versus leukemia (GVL) effect, in patients with nonmalignant disorders in whom GVL is not beneficial, optimal results are obtained only when a donor matched at the allelic level with the recipient is selected. In general, a single HLA disparity in the donor recipient |
6,542 | pair, irrespective of whether antigenic or allelic in nature, predicts a greater risk of non leukemia mortality; multiple allelic disparities at different HLA loci have an additive detrimental effect and are associated with an even worse outcome. To reduce the risk of acute GVHD, ex vivo T cell deple tion of the graft has been employed, with variable efficacy. Studies are looking at selectively depleting donor T cells, which are the T cells that drive GVHD, while preserving the T cells and natural killer (NK) cells, which may be responsible for GVL and protection from infection. Although the majority of patients who have required a matched unre lated donor transplant have received a bone marrow or peripheral stem cell graft, for patients who urgently need a transplant, the time required to identify a suitable donor from a potential panel, establish eligibility, and harvest the cells may lead to relapse and failure to transplant. For this sub set of patients who urgently need a transplant, attention has focused on unrelated cord blood and HLA haploidentical, mismatched family donors. UMBILICAL CORD BLOOD TRANSPLANTS Umbilical cord blood transplantation (UCBT) is a viable option for children who need allogeneic HSCT. UCBT offers the advantages of absence of risks to donors, reduced risk of transmitting infec tions, and for transplants from unrelated donors, immediate avail ability of cryopreserved cells, with the median time from start of search to transplantation of only 3 4 weeks. Compared with bone marrow transplantation (BMT), the advantages of UCBT are also represented by lower incidence of chronic GVHD and the possi bility of using donors showing HLA disparities with the recipient. Despite these advantages, the large experience gained over the last 2 decades has demonstrated that UCBT patients may be exposed to an increased risk of early fatal complications, mainly because of a lower engraftment rate of donor hematopoiesis, delayed kinetics of neutrophil recovery (risk of infection), and lack of adoptive trans fer of pathogen specific memory T cells. Transfer of donor derived, memory T cells significantly contributes to early immunologic recon stitution of children after unmanipulated allogeneic bone marrow or peripheral blood stem cell transplantation. Concerning the issues of engraftment and hematopoietic recovery, it has been demonstrated that an inverse correlation exists between the number of nucleated cord blood cells infused per kilogram recipient body weight and the risk of dying for transplantation related causes. In particular, engraftment is a major concern when the nucleated cells are 2.5 107kg of recipient body weight. Because a cord blood unit usually contains between 1 109 and 1.8 109 cells, it is not surprising that UCBT has been less frequently employed for adolescents or adults with body weight 40 kg. Indeed, it can be estimated that only 30 of the UCB units available in the bank inventory could suffice for a 75 kg patient, according to the recommended threshold cell dose. Efforts have focused on approaches capable of increasing the number of UCB cells to be transplanted. Selection of the richest cord |
6,543 | blood units or infusion of 2 units in the same recipient (i.e., double UCBT) have been explored to improve the results of UCBT. The results of these stud ies have been mixed, with one large study demonstrating no survival advantage for children and adolescents that receive double UCBT. Pre liminary studies of ex vivo expansion of a single umbilical cord sample with UM171, an HSC self renewal agonist, have suggested improved engraftment, reduced infection, and low rates of severe acute GVHD. The long term results of UCB transplants are similar to those after transplantation from other sources of HSCs for pediatric hematologic malignancies. In patients with hematologic malignancies, recipients of UCBT may be transplanted from donors with greater HLA disparities, receive 1 log fewer nucleated cells, have delayed neutrophil and platelet recovery, and show reduced incidence of GVHD compared with children given BMT from unrelated donors. In one study, there were similar rates of acute GVHD, but significantly less chronic GVHD in patients who received UCBT. Nevertheless, both the relapse rate and the overall survival probability did not differ in unrelated UCBT or BMT pediatric recipients. Thus, in the absence of an HLA identical family donor, unrelated UCBT can be considered a suitable option for children with malignant and non malignant disorders. Results of UCBT have been of particular interest in children with certain nonmalignant disorders to proceed to transplant quickly and prevent further progression of disease. Chapter 178 Hematopoietic Stem Cell Transplantation from Alternative Sources and Donors Rachel A. Phelan and David Margolis Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1356 Part XII u Immunology HAPLOIDENTICAL TRANSPLANTS HSCT from an HLA haploidentical (haplo HSCT) donor offers an immediate source of HSCs to almost all patients who fail to find a matched donor, whether related or unrelated, or a suitable cord blood unit. Indeed, almost all children have at least one haploidentical3 loci mismatched family member who is promptly available as donor. The few patients who reject the haploidentical transplant also have the advantage of another immediately available donor within the family. Moreover, this may represent an approach that would be attractive in the global health setting, where more sophisticated donor registries and cell processing techniques are less unavailable. Efficient T cell depletion of the graft has been demonstrated to prevent acute and chronic GVHD even when using haploidentical parental grafts. This can be done ex vivo or in vivo with the use of che motherapeutic agents before and after cell infusion. The use of post transplant cyclophosphamide is one such in vivo technique now being widely incorporated into haploidentical transplant regimens. The ben efits of T cell depletion were first demonstrated in transplantation of children with severe combined immunodeficiency (SCID). More than 300 transplants in SCID patients using haploidentical donors have been performed worldwide, with a high rate of long term partial |
6,544 | or complete immune reconstitution. The elimination of mature T cells from the graft, necessary for prevent ing GVHD in a context of great immune genetic disparity, results in recipi ents being unable to benefit from the adoptive transfer of donor memory T lymphocytes, through their peripheral expansion, are the main factor responsible for protection from infections in the first few months after transplantation. A state of profound immunodeficiency lasts for at least 4 6 months after transplantation in haplo HSCT recipients. Sophisticated strategies of adoptive infusions of T cell lines or clones specific for the most common and life threatening pathogens (Epstein Barr virus EBV, human cytomegalovirus, Aspergillus, adenovirus) have been successfully tested in trials to protect the recipients in the early posttransplant period. For many years the absence of the T cellmediated GVL effect has been considered as rendering the recipients of a T celldepleted allograft more susceptible to leukemia relapse. However, it has been demonstrated that a GVL effect displayed by donor NK cells can com pensate for this lack of T specific alloreactivity when an HLA disparate NK alloreactive relative is employed as a donor. Selective approaches of graft manipulation in haploidentical and unre lated donor transplant have also been developed. In particular, promising results have been obtained through a negative depletion of T lymphocytes carrying the chains of the T cell receptor, which are believed to be the mediators of GVHD. B lymphocytes are also depleted to prevent EBV related lymphoproliferative disease. Through this approach the patient can benefit from the adoptive transfer of committed hematopoietic pro genitors, mature NK cells and T cells, which can confer a protection against life threatening infections as well as provide a GVL effect. The outcomes of haplo HSCT have been more extensively reported in adults than in children. The reported probability of survival at 3 4 yr after a haplo HSCT in children with acute leukemia ranged from 1848. Survival was influenced by many factors, most importantly the state of remission at transplantation, with poorer outcomes in chil dren with myeloid leukemias than in those with lymphoid leukemia. In haplotype mismatched parent to child HSCT, patients with acute leu kemia grafted from the mother had reduced relapse rates compared with recipients of paternal grafts, translating into better event free survival. DONOR VERSUS RECIPIENT NK CELL ALLOREACTIVITY NK cells are the first lymphocytes derived from the donor to recover after allogeneic HCT. Donor versus recipient NK cell alloreactivity derives from a mismatch between donor NK clones, carrying specific inhibitory receptors for selfmajor histocompatibility complex (MHC) class I molecules, and MHC class I ligands on recipient cells. NK cells are primed to kill by several activating receptors, which play an important role in the NK cellmediated GVL effect. Human NK cells discriminate allelic forms of MHC molecules via KIRs, which are clonally distrib uted with each cell in the repertoire bearing at least one receptor that is specific for self MHC class I molecules. Because NK cells co express inhibitory receptors |
6,545 | for selfMHC class I molecules, autologous cells are not killed. When faced with mismatched allogeneic targets, NK cells sense the missing expression of selfclass I alleles and mediate alloreac tions. In mismatched transplants, there are many donor recipient pairs in which the donor NK inhibitory cells do not recognize the recipients class I alleles as self. Consequently, the donor NK cells are not blocked and are activated to lyse the recipients lymphohematopoietic cells. Haplo HSCT trials demonstrate that MHC class I mismatches, which generate an alloreactive NK cell response in the graft versus host direction, eradicate leukemia cells, improve engraftment, and protect from T cellmediated GVHD. The potential for donor versus recipient NK cell alloreactivity, which can be predicted by standard HLA typing, is increasingly being examined when selecting the donor of choice. The importance of KIR haplotype in transplants other than haploidentical transplantation in preventing GVHD as well as relapse has been shown to be increasingly beneficial. AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION Autologous transplantation, using the patients own stored marrow, is associated with a low risk of life threatening transplant related compli cations, although the main cause of failure is disease recurrence. Bone marrow was once the only source of stem cells employed in patients given an autograft. The majority of patients treated with autologous HSCT receive hematopoietic progenitors mobilized in peripheral blood by either cytokines alone (mainly granulocyte colony stimulating fac tor) or by cytokines plus cytotoxic agents. A CXCR4 antagonist can be extremely effective in mobilizing hematopoietic progenitors in the periphery. Compared with bone marrow, the use of peripheral blood progenitors is associated with a faster hematopoietic recovery and a comparable outcome. Autologous HSCT is employed primarily for selected children with relapsed lymphomas and select solid tumors (Table 178.1). Patients with sensitive lymphomas and minimal tumor burden have favorable outcomes after autologous HSCT, with disease free survival rates of 5060, whereas high risk patients with bulky tumor or poorly responsive disease have a poor outcome, with survival rates of 1020. Autologous HSCT in patients with high risk neuroblastoma is asso ciated with a better outcome than conventional chemotherapy. A Chil drens Oncology Group (COG) study demonstrated further survival advantage by performing two sequential, or tandem, transplants that use different chemotherapeutic agents. Because of these improved out comes, tandem autologous transplants are now considered the stan dard recommended treatment. In these patients, posttransplantation infusion of a monoclonal antibody directed against a molecule (GD2) expressed on the surface of neuroblastoma cells confers a protection against the risk of tumor recurrence. For children with brain tumors at high risk of relapse, or resistant to conventional chemotherapy and irradiation, the dose limiting tox icity for intensifying therapy is myelosuppression, thus providing a role for stem cell rescue. Several studies provide encouraging results for patients with different histologic types of brain tumors treated with autologous HSCT. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography Table 178.1 Indications for Autologous Hematopoietic Stem Cell Transplantation for Pediatric Diseases Relapsed Hodgkin or non Hodgkin lymphoma Stage |
6,546 | IV or relapsed neuroblastoma High risk, relapsed, or resistant brain tumors Stage IV Ewing sarcoma Life threatening autoimmune diseases resistant to conventional treatments Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 179 u Graft Versus Host Disease, Rejection, and Venoocclusive Disease 1357 A major cause of mortality and morbidity after allogeneic hema topoietic stem cell transplantation (HSCT) is graft versus host disease (GVHD), which is caused by engraftment of immunocom petent donor T lymphocytes in an immunologically compromised host who shows histocompatibility differences with the donor. These differences between the donor and the host may result in donor T cell activation against either recipient major histocompatibility complex (MHC) antigens or minor histocompatibility antigens. GVHD is usually subdivided in two forms: acute GVHD, which occurs within 3 months after transplantation, and chronic GVHD, which, although related, is a different disease, occurring later and displaying some clinical and pathologic features that resemble those observed in selected autoimmune disorders (e.g., systemic sclerosis, Sjgren syndrome). ACUTE GRAFT VERSUS HOST DISEASE Acute GVHD is caused by the alloreactive, donor derived T cells contained in the graft, which attack nonshared recipients antigens on target tissues. A 3 step process generates the clinical syndrome. First, conditioning induced tissue damage activates recipient antigen presenting cells, which present recipient alloantigens to the donor T cells transferred with the graft and secrete cytokines, such as interleukin (IL) 12, favoring the polarization of T cell response in the type 1 direction. Second, in response to recipient antigens, donor T cells become activated, proliferate, expand, and generate cytokines such as tumor necrosis factor (TNF) , IL 2, and inter feron (IFN) . In the third step of the process, these cytokines cause tissue damage and promote differentiation of cytotoxic CD8 T cells, which, together with macrophages, kill recipient cells and fur ther disrupt tissues. Acute GVHD usually develops 2 8 weeks after transplantation. The primary manifestations depend on the sites of involvement and may include an erythematous maculopapular rash (Figs. 179.1 and 179.2), persistent anorexia, vomiting andor diarrhea, and liver dis ease with increased serum levels of bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Diagnosis may benefit from skin, liver, or gastrointestinal (GI) biopsy for confirmation. Endothelial damage and lymphocytic infiltrates are seen in all affected organs. The epidermis and hair follicles of the skin are damaged, the hepatic small bile ducts show segmental disruption, and there is destruction of the crypts and mucosal ulceration of the GI tract. Grade I acute GVHD (skin rash alone) has a favorable prognosis and often requires no treatment, or topical treatment alone. Grade II GVHD is a moderately severe multiorgan disease requiring immunosuppressive therapy. Grade III GVHD is a severe multiorgan disease, and grade IV GVHD is a life threatening, often fatal condition (Table 179.1). The standard pharmacologic prophylaxis of GVHD after an unmanipulated |
6,547 | allograft relies mainly on posttransplant admin istration of immunosuppressive drugs, such as cyclosporine or tacrolimus or combinations of either with methotrexate or pred nisone, antiT cell antibodies, mycophenolate mofetil (MMF), and other immunosuppressive agents. Infusion of cyclophosphamide on days 3 and 4 after transplantation has been used as a strategy to deplete alloreactive donor T lymphocytes that become activated after exposure to recipient antigens. This approach has been suc cessful in patients undergoing haploidentical transplantation. Pre transplantation infusion of either antithymocyte globulin (ATG) or monoclonal antibodies (mAbs) such as alemtuzumab is largely used to modulate alloreactivity of donor T cells, in particular in patients given the allograft from either an unrelated donor or a partially matched relative. An alternative approach is the removal of T lym phocytes from the graft (T cell depletion). Other approaches are being used to selectively remove the T cells, which are thought to be responsible for the development of GVHD, while preserving the T cells in order to sustain graftversusleukemia (GVL) and the ability to fight infection. Any form of GVHD prophylaxis may impair posttransplantation immunologic reconstitution, increasing the risk of infection related deaths. Traditional T cell depletion of the graft is also associated with an increased risk of leukemia recur rence in patients transplanted from an HLA identical sibling or an unrelated volunteer. Despite prophylaxis, significant acute GVHD develops in approx imately 30 of recipients of HSCT from matched siblings and in as many as 60 of HSCT recipients from unrelated donors. These numbers are estimates, and the actual risk of acute GVHD is highly variable depending on several factors. Risk for development of GVHD is increased by diagnosis of malignant disease, older donor and recipient age, and in patients given an unmanipulated allograft. The most important risk factor for acute GVHD is the presence of disparities for HLA molecules in the donor recipient pair. Acute GVHD is usually initially treated with glucocorticoids; approximately 4050 of patients show a complete response to Chapter 179 Graft Versus Host Disease, Rejection, and Venoocclusive Disease Rachel A. Phelan and David Margolis Fig. 179.1 Acute graft versus host disease. Involvement of the scalp, ears, palms, and soles is common. (From Paller AS, Mancini AJ, eds. Hurwitz Clinical Pediatric Dermatology. 5th ed. Philadelphia: Elsevier, 2016. p 577.) Fig. 179.2 Acute graft versus host disease. Almost confluent erup tion of erythematous macules and papules in an immunodeficient neo nate treated with extracorporeal membrane oxygenation (ECMO) and transfusion of nonirradiated blood. (From Paller AS, Mancini AJ, eds. Hurwitz Clinical Pediatric Dermatology. 5th ed. Philadelphia: Elsevier; 2016. p 577.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1358 Part XII u Immunology corticosteroids. The risk of transplantation related mortality is much higher in patients who do not respond to corticosteroids than in those showing a complete response. Ruxolitinib, target ing the JAK signaling pathway, or other |
6,548 | drugs targeting molecules expressed on T cells or cytokines released during the inflammatory cascade (including infliximab and etanercept targeting TNF, vedol izumab targeting integrin, and tocilizumab targeting IL 6), which underlies the pathophysiology of GVHD, have been used in patients with steroid resistant acute GVHD. Extracorporeal photo pheresis is another second line treatment for GVHD and is most efficacious for skin GVHD. A patients peripheral blood is exposed to a photosensitive compound and then exposed to ultraviolet light. The cells are then reinfused into the patient. It is thought that this process results in an increase in apoptosis of lymphocytes respon sible for GVHD as well as the upregulation of anti inflammatory cytokines and regulatory T cells. Promising results in children with steroid resistant acute GVHD have also been obtained using mes enchymal stromal cells, which are able to blunt the inflammatory response associated with acute GVHD. CHRONIC GRAFT VERSUS HOST DISEASE Chronic GVHD develops or persists 3 months after transplantation and is the most frequent late complication of allogeneic HSCT with an incidence of approximately 25 in pediatric patients. Chronic GVHD is the major cause of nonrelapse mortality and morbidity in long term HSCT survivors. Acute GVHD is recognized as the most important factor predicting the development of the chronic form of the disease. The use of matched unrelated volunteers as donors and use of unmanipulated peripheral blood as the stem cell source have increased the incidence and severity of chronic GVHD. Other factors that predict occurrence of chronic GVHD include older donor and recipient ages, female donor for male recipient, diagnosis of malig nancy, and use of total body irradiation (TBI) as part of the prepara tive regimen. Chronic GVHD is a disorder of immune regulation character ized by autoantibody production, increased collagen deposition and fibrosis, and clinical symptoms similar to those seen in patients with autoimmune diseases (Table 179.2). The predominant cyto kines involved in the pathophysiology of chronic GVHD are usually Table 179.1 Clinical Staging and Grading of Acute Graft Versus Host Disease STAGE SKIN (ACTIVE ERYTHEMA ONLY) LIVER (BILIRUBIN) UPPER GI LOWER GI (STOOL OUTPUTDAY) 0 No active (erythematous) GVHD rash 2 mgdL No or intermittent nausea, vomiting, or anorexia Adult: 500 mLday or 3 episodesday Child: 10 mLkgday or 4 episodesday 1 Maculopapular rash 25 BSA 2 3 mgdL Persistent nausea, vomiting or anorexia Adult: 500 999 mLday or 3 4 episodesday Child: 10 19.9 mLkgday or 4 6 episodesday 2 Maculopapular rash 2550 BSA 3.1 6 mgdL Adult: 1,000 1,500 mLday or 5 7 episodesday Child: 20 30 mLkgday or 7 10 episodesday 3 Maculopapular rash 50 BSA 6.1 15 mgdL Adult: 1,500 mLday or 7 episodesday Child: 30 mLkgday or 10 episodesday 4 Generalized erythroderma (50 BSA) plus bullous formation and desquamation 5 BSA 15 mgdL Severe abdominal pain with or without ileus or grossly bloody stool (regardless of stool volume) Overall clinical grade (based on most severe target organ involvement): Grade 0: no stage 1 4 of any organ. Grade I: |
6,549 | stage 1 2 skin without liver, upper GI, or lower GI involvement. Grade II: stage 3 rash andor stage 1 liver andor stage 1 upper GI andor stage 1 lower GI. Grade III: stage 2 3 liver andor stage 2 3 lower GI, with stage 0 3 skin andor stage 0 1 upper GI. Grade IV: stage 4 skin, liver, or lower GI involvement, with stage 0 1 upper GI. GI, Gastrointestinal; GVH, graft versus host; BSA, body surface area. From Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft versus Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016;22(1):410. Table 179.2 Clinical Findings in Chronic Graft Versus Host Disease ORGAN SYSTEM SYMPTOMS AND SIGNS Systemic Immunodeficiency and recurrent infections Skin Lichen planus, scleroderma, hyperpigmentation or hypopigmentation, erythema, freckling, ichthyosis, ulcerations Flexion contractures Vaginal scars Onycholysis Nail loss Hair Alopecia; scarring or nonscarring Mouth Sicca syndrome, lichen planus, depapillation of tongue with variegations, scalloping of lateral margins, xerostomia, mucocele Joints Diffuse myositistendonitis, arthritis, contractures Eyes Decreased tearing, injected sclerae, scarring conjunctivitis, keratopathy Liver Increased enzymes, cholestasis, hepatomegaly, cirrhosis Gastrointestinal Failure to thrive, malabsorption, chronic diarrhea Esophageal strictures Lung Cough, dyspnea, wheezing Bronchiolitis obliterans, chronic rales, pneumothorax, fibrosis Hematology Thrombocytopenia, eosinophilia, Howell Jolly bodies (splenic dysfunction) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 179 u Graft Versus Host Disease, Rejection, and Venoocclusive Disease 1359 type II cytokines such as IL 4, IL 5, and IL 13. IL 4 and IL 5 con tribute to eosinophilia and B cell hyperactivity with elevated IgM, IgG, and IgE titers. Associated monoclonal gammopathies indicate clonal dysregulation. Chronic GVHD is dependent on the develop ment and persistence of donor T cells that are not tolerant to the recipient. Maturation of transplanted stem cells within a damaged thymus could lead to errors in negative selection and production of cells that have not been tolerized to recipient antigens and are therefore autoreactive or, more accurately, recipient reactive. This ongoing immune reactivity results in clinical features resembling a systemic autoimmune disease with lichenoid and scleroderma tous skin lesions, malar rash, sicca syndrome, arthritis, joint con tractures, bronchiolitis obliterans, and bile duct degeneration with cholestasis. Patients with chronic GVHD involving only the skin and liver have a favorable course (Figs. 179.3 and 179.4). Extensive multi organ disease may be associated with a very poor quality of life, recurrent infections associated with prolonged immunosuppressive regimens to control GVHD, and a high mortality rate. Morbidity and mortality are highest in patients with a progressive onset of chronic GVHD that directly follows acute GVHD, intermediate in those with a quiescent onset after resolution of acute GVHD, and lowest in patients with de novo onset in the absence of acute GVHD. Chronic GVHD can be classified as mild, moderate, or |
6,550 | severe depending on extent of involvement. Single agent prednisone is the standard treatment, although other agents have been employed with variable success. Ruxolitinib, a Janus kinase inhibitor, has been a beneficial treatment for steroid dependent or refractory chronic GVHD. In addition, ibrutinib, a Bruton tyrosine kinase inhibitor, has been approved by the FDA for the treatment of chronic GVHD. Treatment with imatinib mesylate, which inhibits the synthesis of collagen, has been effective in some patients with chronic GVHD and sclerotic features. As a consequence of prolonged immunosup pression, patients with chronic GVHD are particularly susceptible to infections and should receive appropriate antibiotic prophylaxis, including trimethoprimsulfamethoxazole (TMPSMX). Chronic GVHD resolves in most pediatric patients but may require 1 3 years of immunosuppressive therapy before the drugs can be withdrawn without the disease recurring. Chronic GVHD promotes the devel opment of secondary neoplasms, in particular in patients with Fan coni anemia, and has a significant impact on quality of life. GRAFT FAILURE Graft failure is a serious complication exposing patients to a high risk of fatal infection. Primary graft failure is defined as failure to achieve a neutrophil count of 0.5 109L after transplantation. Secondary graft failure is loss of peripheral blood counts following initial transient engraftment of donor cells. Causes of graft failure after autologous and allogeneic transplantation include transplan tation of an inadequate stem cell dose (more frequently observed in children given cord blood transplantation) and viral infections such as with cytomegalovirus or human herpesvirus type 6, which are often associated with activation of recipient macrophages. Graft failure after allogeneic transplantation, however, is mainly caused by immunologically mediated rejection of the graft by residual recipient type T cells that survive the conditioning regimen. Diagnosis of graft failure resulting from immunologic mecha nisms is based on examination of peripheral blood and marrow aspirate and biopsy, along with molecular analysis of chimerism status. Persistence of lymphocytes of host origin in allogeneic transplant recipients with graft failure indicates immunologic rejection. The risk of immune mediated graft rejection is higher in patients given HLA disparate, T celldepleted grafts, reduced intensity conditioning regimens, and transplantation of low num bers of stem cells, and in recipients who are sensitized toward major HLA antigens or, less frequently, minor histocompatibility antigens. Allosensitization develops as a consequence of preceding blood product transfusions and is observed particularly in recipi ents with aplastic anemia, sickle cell disease, and thalassemia. In HSCT for nonmalignant diseases, such as mucopolysaccharidoses, graft failure is also facilitated by the absence of previous treatment with cytotoxic and immunosuppressive drugs. In thalassemia, graft failure is promoted by expansion of recipient hematopoietic cells. GVHD prophylaxis with methotrexate, an antimetabolite, and anti infective prophylaxis with TMPSMX or ganciclovir may also delay engraftment. Treatment of graft failure usually requires removing all poten tially myelotoxic agents from the treatment regimen and attempting a short trial of hematopoietic growth factors, such as granulocyte colony stimulating factor. A second transplant, usually preceded Fig. 179.3 Chronic graft versus host disease (GVHD), lichenoid. After bone marrow |
6,551 | transplantation, this patient had acute GVHD and subse quently developed cutaneous scaling papules and plaques typical of li chen planus. (From Paller AS, Mancini AJ, eds. Hurwitz Clinical Pediatric Dermatology. 5th ed. Philadelphia: Elsevier; 2016. p 577.) Fig. 179.4 Chronic graft versus host disease. Note the extensive alopecia of the scalp with dyschromia and numerous sclerodermatous plaques of the scalp and back. (From Paller AS, Mancini AJ, eds. Hur witz Clinical Pediatric Dermatology. 5th ed. Philadelphia: Elsevier; 2016. p 579.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1360 Part XII u Immunology by a highly immunosuppressive regimen, is frequently employed to rescue patients experiencing graft failure. High intensity regimens are generally tolerated poorly if administered within 100 days from a first transplant because of cumulative toxicities, but this risk must be balanced with the risk of infection from prolonged neutropenia and lymphocytopenia. VENOOCCLUSIVE DISEASE Hepatic venoocclusive disease (VOD), also known as sinusoidal obstruction syndrome, presents with hepatomegaly, right upper quadrant tenderness, jaundice, coagulopathy, thrombocytopenia, and weight gain from fluid retention and ascites (Table 179.3). It results from endothelial damage within the liver, which can then progress to multiorgan dysfunction. Onset is usually within 30 days of transplantation, with an incidence of approximately 15, depending on the intensity of the conditioning protocol. Risk fac tors include young age, prior hepatic disease (fibrosis, cirrhosis), abdominal radiation, repeated transplantations, neuroblastoma, osteopetrosis, and familial hemophagocytic lymphohistiocytosis. The severe form of VOD has a high mortality rate (80) without treatment. Prophylaxis has traditionally used ursodeoxycholic acid and occa sionally heparin; only defibrotide has demonstrated efficacy in treat ing VOD. A phase 3 study demonstrated improvement in survival and response rate to VOD in patients treated with defibrotide. Defibrotide is a combination of porcine oligodeoxyribonucleotides that reduces procoagulant activity and enhances fibrinolytic properties of endothe lial cells. Defibrotide is FDA approved for the treatment of VOD in adult and pediatric patients with renal or pulmonary dysfunction after HSCT. Defibrotide is often used as prophylaxis in Europe, with data showing efficacy, but this use is not yet approved in the United States. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 179.3 Severity Grading Thresholds of Sinusoidal Obstructive Syndrome Among Children, Adolescents, and Young Adults MILD MODERATE SEVERE VERY SEVERE ALT, AST, GLDH (mgdL) 2 normal 2 5 normal 2 5 normal 5 normal Bilirubin (mgdL) 2 2 2 Bilirubin doubles in 48 hr Coagulopathy (not responsive to vitamin K administration; INR) 1.5 1.5 1.9 2 Need for replacement of coagulation factors Ascites Mild (minimal fluid by liver, spleen or pelvis) Moderate (1 cm fluid) Severe (fluid in all 3 regions with 1 cm fluid in at least 2 regions) Requires paracentesis Weight gain (from baseline) 2.5 510 despite diuretic use 10 Persistent rise Renal function score KDIGO 1: serum creatinine 1.5 1.9 baseline or 0.3 mgdL (26.5 mmolL) increase or |
6,552 | urine output 0.5 mLkghr for 6 12 hr KDIGO 2: serum creatinine 2.0 2.9 baseline or urine output 0.5 mLkghr for 12 hr KDIGO 3: serum creatinine 3.0 baseline or increase in serum creatinine 4.0 mgdL (353.6 mmolL) or initiation of renal replacement therapy or decrease in eGFR to 35 mLmin per 1.73 m2 (patients 18 years) or urine output 0.3 mLkghr for 24 hr or anuria for 12 hr (patients 18 years) Persistent need for renal replacement therapy Encephalopathy CAPD 9 CAPD 9 CAPD 9 CAPD 9 Persistent RT 3 days 3 7 days 7 days Pulmonary function 2 L 2 L NIVIMV IMV ALT, Alanine aminotransferase; AST, aspartate aminotransferase; GLDH, glutamate dehydrogenase; INR, international normalized ratio; KDIGO, Kidney Disease: Improving Global Outcomes score; eGFR, estimated glomerular infiltration rate; CAPD, Cornell Assessment of Pediatric Delirium; RT, refractory thrombocytopenia; NIV, noninvasive ventilation; IMV, invasive mechanical ventilation. From Mahadeo KM, Bajwa R, Abdel Azim H, et al. Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syn drome: An international expert position statement. Lancet Haematol. 2020;7(1):e61e72. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 180 u Infectious Complications of Hematopoietic Stem Cell Transplantation 1361 Hematopoietic stem cell transplantation (HSCT) recipients experience a transient but profound state of immune deficiency. The risk of infec tion depends on the stage after transplantation (pre vs postengraft ment), ongoing immunosuppression, disruption in barrier functions (indwelling catheters, graft versus host disease GVHD, mucositis, and preexisting infections (Fig. 180.1). Management approaches may include the use of prophylactic antimicrobials, preemptive antimicro bials for infection prior to symptomatic disease, or antimicrobial treat ment of documented or suspected infection. Immediately after transplantation, the absence or paucity of neu trophils (neutropenia) renders patients susceptible to bacterial and fungal infections. Consequently, consideration is given to the use of antipseudomonal and antifungal prophylaxis during the conditioning regimen. Evidence is moderate quality against systemic antibacterial prophylaxis and for systemic antifungal prophylaxis, which is reflected in published society guidelines. Even with the use of prophylactic mea sures, the majority of patients will develop fever and signs of infec tion in the early posttransplantation period. The common pathogens include enteric gram negative bacteria and fungi. An indwelling cen tral venous line, routinely employed in all children given HSCT, is a significant risk factor for infection. Staphylococcal species and Candida species are the most frequent pathogens in catheter related infections (see Chapter 224). Multidrug resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae can cause infection, with prevalence highly variable among centers. Severe lower respiratory tract disease caused by seasonal respiratory viruses, such as influenza, respiratory syncytial virus (RSV), parainfluenza virus, and human metapneumovirus, can occur during the pre or postengraftment phase. Emerging infections, such as SARS CoV 2, can also cause severe or persistent infection in immuno compromised individuals. Published guidelines from the International Pediatric |
6,553 | Fever and Neutropenia Guideline Panel address the manage ment of fever and neutropenia after HSCT (Table 180.1). Chapter 180 Infectious Complications of Hematopoietic Stem Cell Transplantation Anna R. Huppler Phase I, Preengraftment, 30 days Neutropenia, mucositis and acute graftversus host disease Central line Respiratory and enteric viruses Facultative gramnegative bacilli Cytomegalovirus EpsteinBarr virus lymphoproliferative disease Gastrointestinal tract Streptococcus species Days after transplant Without standard prophylaxis Primarily among persons who are seropositive before transplant 063001030 High incidence (10 ) Low incidence (10 ) Episodic and endemic Continuous risk Staphylococcus epidermidis Encapsulated bacteria (e.g., pneumococcus) Varicellazoster virus All Candida species Aspergillus species Aspergillus species Pneumocystis jiroveci Toxoplasma gondii Strongyloides stercoralis Impaired cellular immunity and acute and chronic graft versushost disease Impaired cellular and humoral immunity and chronic graftversus host disease Host immune system defect Allogeneic patients Device risk Phase II, Postengraftment, 30100 days Phase III, Late phase, 100 days Herpes simplex virus Fig. 180.1 Phases of opportunistic infections among allogeneic HSCT recipients. (From Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among he matopoietic stem cell transplant recipients published correction appears in MMWR Recomm Rep. 2004 May 14;53(19):396. MMWR Recomm Rep. 2000;49(RR 10):1CE7.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1362 Part XII u Immunology Table 180.1 Overall Summary of Recommendations for Management of Fever and Neutropenia INITIAL MANAGEMENT Risk Stratification A1. Adopt a validated risk stratification strategy and incorporate it into routine clinical management (strong recommendation, low quality evidence). Evaluation A2. Obtain blood cultures at the onset of FN from all lumens of central venous catheters (strong recommendation, low quality evidence). A3. Consider obtaining peripheral blood cultures concurrent with central venous catheter cultures (weak recommendation, moderate quality evidence). A4. Consider urinalysis and urine culture in patients in whom a clean catch, midstream specimen is readily available (weak recommendation, low quality evidence). A5. Obtain chest radiography only in patients with respiratory signs or symptoms (strong recommendation, moderate quality evidence). Treatment A6. In high risk FN: A6a. Use monotherapy with an antipseudomonal lactam, a fourth generation cephalosporin, or a carbapenem as empirical therapy in pediatric high risk FN (strong recommendation, high quality evidence). A6b. Reserve addition of a second gram negative agent or a glycopeptide for patients who are clinically unstable, when a resistant infection is suspected, or for centers with a high rate of resistant pathogens (strong recommendation, moderate quality evidence). A7. In low risk FN: A7a. Consider initial or step down outpatient management if the infrastructure is in place to ensure careful monitoring and follow up (weak recommendation, moderate quality evidence). A7b. Consider oral antibiotic administration if the child is able to tolerate this route of administration reliably (weak recommendation, moderate quality evidence). ONGOING MANAGEMENT Modification of Treatment B1. In patients who are responding to initial empirical antibiotic therapy, |
6,554 | discontinue double coverage for gram negative infection or empirical glycopeptide (if initiated) after 24 to 72 hours if there is no specific microbiologic indication to continue combination therapy (strong recommendation, moderate quality evidence). B2. Do not modify the initial empirical antibacterial regimen based solely on persistent fever in children who are clinically stable (strong recommendation, low quality evidence). B3. In children with persistent fever who become clinically unstable, escalate the initial empirical antibacterial regimen to include coverage for resistant gram negative, gram positive, and anaerobic bacteria (strong recommendation, very low quality evidence). Cessation of Treatment B4. In all patients, discontinue empirical antibiotics in patients who have negative blood cultures at 48 hours, who have been afebrile for at least 24 hours, and who have evidence of marrow recovery (strong recommendation, low quality evidence). B5. In patients with low risk FN, consider discontinuation of empirical antibiotics at 72 hours in patients who have negative blood cultures and who have been afebrile for at least 24 hours, irrespective of marrow recovery status, as long as careful follow up is ensured (weak recommendation, moderate quality evidence). EMPIRICAL ANTIFUNGAL THERAPY Risk Stratification C1. Patients at high risk of IFD are those with AML, high risk ALL, or relapsed acute leukemia, and children undergoing allogeneic HSCT. Children with prolonged neutropenia and children receiving high dose corticosteroids are also at high risk of IFD. All others should be categorized as IFD low risk (strong recommendation, low quality evidence). Evaluation C2. In terms of biomarkers to guide empirical antifungal management for prolonged (96 hours) FN in IFD high risk patients: C2a. Consider not using serum GM (weak recommendation, moderate quality evidence). C2b. Do not use d glucan (strong recommendation, low quality evidence). C2c. Do not use fungal PCR testing in blood (strong recommendation, moderate quality evidence). C3. In terms of imaging for the evaluation of prolonged (96 hours) FN in IFD high risk patients: C3a. Perform CT of the lungs (strong recommendation, low quality evidence). C3b. Consider imaging of abdomen in patients without localizing signs or symptoms (weak recommendation, low quality evidence). C3c. Consider not routinely performing CT of sinuses in patients without localizing signs or symptoms (weak recommendation, low quality evidence). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 180 u Infectious Complications of Hematopoietic Stem Cell Transplantation 1363 HSCT recipients remain at increased risk of developing severe infec tions even after the neutrophil count has normalized because of pro longed depression in T cell number and function. The manifestations of GVHD, as well as the associated immunosuppressive therapy, are additional risk factors for fungal and viral opportunistic infections. After umbilical cord blood transplant (UCBT), infections are the consequence of both slow neutrophil engraftment and donor T cell navet. In haploidentical transplantation, T cell depletion results in an increased risk of infection in the first 4 6 months. Recipients |
6,555 | of this type of transplantation, as well as those receiving UCBT, do not have the benefit of adoptive transfer of donor derived, antigen experienced T cells. For HSCT recipients after engraftment, invasive fungal dis ease (IFD), herpesviruses, and adenovirus infections represent life threatening complications that significantly affect outcomes. Addi tional pathogens to consider include nontuberculous mycobacteria, BK virus, Clostridium difficile, and norovirus. IFD remains a significant cause of infectious morbidity and mor tality in allogeneic HSCT recipients. Empirical treatment for IFD is considered for HSCT patients with persistent fever despite 96 hours of broad spectrum antibiotic treatment. The most common organisms are Aspergillus and Candida species. Infections also occur with non Aspergillus molds, including Mucor and Rhizopus species (among other agents of mucormycosis), Fusarium, and Scedosporium species. Pneu mocystis jiroveci is a unique, noncultivatable cause of fungal pneumo nia in immunocompromised patients. Despite prompt and aggressive administration of potent antifungal agents, proven cases of IFD carry case fatality rates of 2070. IFD can present early after transplant, although there is a shift toward presentation of infection in the posten graftment period in the presence of GVHD. The risk of developing IFD is mainly influenced by history of previous fungal infection, duration of neutropenia, use of corticosteroid therapy, mucosal tissue damage (GVHD, posttransplant cytomegalovirus CMV infection, viral respi ratory tract infections), and for candidiasis, presence of central venous catheters. Disseminated candidiasis presents frequently as a central venous cath eterassociated infection. However, up to 50 of patients with dissemi nated candidiasis do not present with positive blood cultures. Patients with and without candidemia can have infection of normally sterile organs, including liver, spleen, kidney, brain, heart, and eye. Mortality rates in pediatric series range from 1025. Echinocandins (micafungin, caspofungin) are the initial drugs of choice for candidiasis in immuno compromised patients with pediatric data supporting reduced 14 day failure rates compared to initial triazole or amphotericin B therapy. Pulmonary disease is the common presentation of invasive aspergil losis. The upper airway mucosa (nose and sinuses) can also be a site of initial infection. Infection progresses from lung or sinus sites by direct extension across tissue or angioinvasion resulting in hematogenous dissemination to brain and other organs. The earliest imaging finding is classically one or more small pulmonary nodules (Figs. 180.2 and 180.3). As a nodule enlarges, the dense central core of infarcted tis sue may become surrounded by edema or hemorrhage, forming a hazy rim known as the halo sign. When bone marrow function recovers, the infarcted central core may cavitate, creating the crescent sign. Unfortu nately, radiographic signs, including the halo sign, crescent sign, and cavitation, have low sensitivity in pediatric patients. Clinical criteria are used to diagnose proven or probable IFD, requiring direct or indirect microbiologic data. Direct, culture based diagnosis requires invasive Fig. 180.2 Angioinvasive aspergillosis. A, Pos teroanterior radiograph shows multiple nodules in the lungs (arrows). B, CT section at the level of the intermediary bronchus shows a nodule sur rounded by a halo of ground glass attenuation |
6,556 | (arrows). (From Franquet T. Nonneoplastic paren chymal lung disease. In Haaga JR, Boll DT, eds. CT and MRI of the Whole Body, 6th ed. Philadel phia: Elsevier; 2017. Fig 36.13.) A B Fig. 180.3 Angioinvasive aspergillosis. CT section at the level of the lower trachea shows a consolidation with an eccentric cavitation and air crescent sign (arrows). This finding in this neutropenic patient is highly diagnostic of angioinvasive aspergillosis. (From Franquet T. Nonneo plastic parenchymal lung disease. In Haaga JR, Boll DT, eds. CT and MRI of the Whole Body, 6th ed. Philadelphia: Elsevier; 2017. Fig 36.14.) Table 180.1 Overall Summary of Recommendations for Management of Fever and Neutropeniacontd Treatment C4. In IFD high risk patients with prolonged (96 hours) FN unresponsive to broad spectrum antibacterial agents, initiate caspofungin or liposomal amphotericin B for empirical antifungal therapy (strong recommendation, high quality evidence). C5. In IFD low risk patients with prolonged (96 hours) FN, consider withholding empirical antifungal therapy (weak recommendation, low quality evidence). ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia; FN, fever and neutropenia; GM, galactomannan; HSCT, hematopoietic stem cell transplantation; IFD, invasive fungal disease; PCR, polymerase chain reaction. Modified from Lehrnbecher T, Robinson P, Fisher B, et al. Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem cell transplantation recipients: 2017 Update. J Clin Oncol. 2017;35(18):20822094. Table 1, p. 20842086. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1364 Part XII u Immunology procedures, such as sinus endoscopy or lung biopsy. Indirect measures, including fungal biomarkers, are used in HSCT patients to screen for or diagnose probable aspergillosis. Galactomannan from serum or bronchoalveolar lavage fluid is an adjunct to diagnostic strategies because of a high negative predictive value for aspergillosis; however, lack of detection of mucormycosis limits its utility as a single diagnos tic test. Other limitations include poor positive predictive values due to false positive test results and lack of validation in patients without neutropenia. Another widely available biomarker, (13) d glucan, is insufficiently studied for routine use in pediatric patients. Fungal infection prevention includes isolation of the patient in a laminar airflow or positive pressure room. Universal prophylaxis to prevent Pneumocystis pneumonia is advocated until the return of T cell function in HSCT patients; the primary agent for prophylaxis is trimethoprimsulfamethoxazole. Alternative agents are pentamidine, dapsone, and atovaquone. For prevention and treatment of other IFDs, liposomal amphotericin B, azole compounds (itraconazole, voricon azole, posaconazole, isavuconazole), and echinocandins (caspofungin, micafungin) are used. Voriconazole represents the treatment of choice for adult patients with invasive aspergillosis, but achieving adequate trough levels can be challenging in young children. The agents of mucormycosis are resistant to most azole and echinocandin medica tions, which makes liposomal amphotericin B the initial drug of choice. IFD often does not respond satisfactorily to antifungal agents alone, and infection may persist until adequate source |
6,557 | control is achieved with surgical debridement and immune function recovers. Herpesviruses, including CMV, Epstein Barr virus (EBV), human herpesvirus 6 (HHV 6), herpes simplex virus (HSV 1 and HSV 2), and varicella zoster virus (VZV) are pathogens that can cause significant disease after HSCT. Because herpesviruses can establish latency in the human host, symptomatic infection can occur from viral reactivation as well as acquisition from the donor or de novo infection. Baseline sus ceptibility to disease and viremia before symptom development can be established with laboratory monitoring (pretransplant donor recipient serology, posttransplant viral load monitoring) and can inform deci sions on prophylactic and preemptive antiviral treatment. CMV infection remains the most common and potentially severe viral complication in patients receiving allogeneic HSCT. Risk factors for CMV viremia include recipient seropositivity, UCBT, and acute GVHD. The period of maximal risk for CMV disease is 1 4 months after transplantation. Late presentation of CMV disease is associated with GVHD. Until CMV specific T cell responses develop months after transplant, CMV infection may result in a variety of syndromes, including fever, leukopenia, thrombocytopenia, hepatitis, pneumoni tis, retinitis, esophagitis, gastritis, and colitis. CMV pneumonia has been reported to occur in up to 1520 of bone marrow transplant recipients, with a case fatality rate of 85 in the absence of early treat ment. Tachypnea, hypoxia, and nonproductive cough signal respira tory involvement. Chest radiography often reveals bilateral interstitial or reticulonodular infiltrates, which begin in the periphery of the lower lobes and spread centrally and superiorly. Gastrointestinal CMV involvement may lead to ulcers of the esophagus, stomach, small intes tine, and colon with complications of bleeding or perforation. Fatal CMV infections are often associated with persistent viremia and mul tiorgan involvement. CMV disease has largely been prevented through prophylaxis or preemptive approaches. Prophylaxis is based on administration of anti viral drugs to at risk transplanted patients for a median duration of 3 months after transplantation. The major drawbacks of this approach are drug toxicity, late CMV disease after withdrawal of prophylaxis, potential unnecessary treatment of patients who would not have reac tivated CMV infection, and low cost effectiveness. Preemptive therapy aims at treating only patients who experience CMV reactivation and thus are at risk of developing overt disease; it starts on detection of CMV in blood but before symptom development. The major drawback of this strategy is the need of serial monitoring of CMV by polymerase chain reaction (PCR) in blood. First line therapy is usually ganciclo vir, with foscarnet as an alternative for resistant strains or ganciclovir intolerance. EBV related posttransplant lymphoproliferative disease (PTLD) is a major complication in HSCT and solid organ transplantation. In patients receiving HSCT, selective procedures of T cell depletion sparing B lymphocytes and use of HLApartially matched family and unrelated donors are risk factors for the development of PTLD. PTLD usually presents in the first 4 6 months after transplantation as high grade, diffuse, large cell B cell lymphomas that are oligoclonal or monoclonal. High EBV viral loads in blood |
6,558 | by PCR predict devel opment of PTLD. Standard treatment of PTLD includes the reduc tion of immunosuppression, monoclonal antibodies directed against CD20 on B cells (rituximab), or cytotoxic chemotherapy. Prophy lactic strategies with rituximab for EBV positive recipients during conditioning for HSCT have also been employed. Histologic diag nosis of PTLD is required to assess for the emergence of neoplasms in which cells are CD19 but CD20, thus eliminating susceptibility to rituximab. Disseminated adenovirus infection is a life threatening complica tion of HSCT recipients. Clinical manifestations include fever, hepati tis, enteritis, meningoencephalitis, and pneumonia. Young children or recipients of donor cells nave to adenovirus (T celldepleted grafts or UCBT) are at particular risk of developing this complication. Diagno sis is based on the demonstration of high viral loads by PCR in blood or recovery of virus in tissue biopsies. Pharmacologic treatment of adenovirus infections is with the antiviral cidofovir, which has signifi cant renal toxicity and limited potency at controlling viral replication. The enterally available prodrug brincidofovir showed initial promise in allogeneic pediatric HSCT recipients with refractory adenovirus infection but is not available clinically for this indication. Recovery of immune system function is associated with improved survival with dis seminated adenovirus infection. In immunocompromised hosts, severe viral infections, including PTLD and adenovirus infection, originate from a deficiency of virus specific cytotoxic T lymphocytes (CTLs). This finding provides the rationale for developing strategies of adoptive cell therapy to restore virus specific immune competence. Multiple protocols are in clinical trials and available at some centers for the rapid generation of specific CTL lines of donor or third party origin. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 181 u Late Effects of Hematopoietic Stem Cell Transplantation 1365 Pediatric hematopoietic stem cell transplantation (HSCT) is considered standard of care treatment for several malignant and nonmalignant conditions. Treatment generally involves exposure to chemotherapy and occasionally radiation to encourage engraftment of donor stem cells and prevent donor and recipient rejection. The period immediately after transplant is associated with the risk for a number of serious acute complications, including profound immunosuppression and subse quent risk for infection, graft versus host disease (GVHD), and organ toxicities (see Chapters 179 and 180). Fortunately, significant progress has been made in supportive care strategies to reduce the risk of acute complications and treat them more effectively if they do arise. This has resulted in a growing number of pediatric patients who are now long term survivors following HSCT. The estimated total number of HSCT survivors in 2009 was 108,900, and this is expected to increase 5 times by 2030 to over 500,000. Of these survivors, approximately 14 (64,000) in 2030 will have received a transplant in childhood (18 years of age). Exposure to chemotherapy, radiation, or a combination of both, places patients at similar long term |
6,559 | risks as the pediatric cancer population; the high doses and types of chemotherapy and radiation often amplify the risk for issues such as ovarian failureinfertility and neurocognitive dif ficulties. Total body irradiation (TBI) has been shown to increase dra matically the risk for late complications after transplant. In addition, late effects may be additive if the patient received therapy before HSCT for their underlying malignancy. Moreover, the indication for transplant in pediatric patients is not always related to malignancy, but rather an underlying immunodeficiency, bone marrow failure syndrome, or meta bolic disorder. These patients are potentially at risk for late effects related to this underlying disease and require different types of monitoring. Essentially, every organ system can be impacted by the long term effects of therapy, and each must be considered when undergoing late effects surveillance (Table 181.1). As a result of growing evidence of the importance of lifelong care for HSCT survivors, multiple groups have published consensus guidelines to help in caring for this patient popula tion. As the field of survivorship continues to expand, we recommend the following reference for real time evidence based recommendations from the Childrens Oncology Group (see http:survivorshipguidelines.org). ENDOCRINE EFFECTS Children given HSCT before puberty may develop growth impair ment, precluding achievement of the genetic target for adult height. The decrease in growth velocity is similar for boys and girls and is more frequently observed in patients given TBI as part of the preparative regimen. Chronic GVHD and its treatment with corticosteroids may also contribute to growth impairment. Growth impairment of patients given TBI is mainly a result of direct damage of cartilage plates and to the effect of TBI on the hypothalamic pituitary axis, which leads to an inappropriately low production of growth hormone (GH). GH deficiency is susceptible to at least partial correction through administration of hormonal replacement therapy. Annual growth evaluation should be performed in all children after HSCT. Children showing a decreased growth velocity should be fur ther investigated through evaluation of bone age and secretion of GH in response to pharmacologic stimulus. The use of TBI during the preparative regimen involves the thy roid gland in the irradiation field and may result in hypothyroidism. Younger children are at greater risk of developing hypothyroidism. Chemotherapy only preparative regimens have far fewer adverse effects on normal thyroid function. The site of injury by irradiation is at the level of the thyroid gland rather than at the pituitary or hypo thalamus. Therapy with thyroxine is very effective for overt hypothy roidism. The cumulative incidence of hypothyroidism increases over time, underscoring the importance of annual thyroid function studies. Gonadal hormones are essential for normal pubertal growth, as well as for development of secondary sexual characteristics. A significant proportion of patients receiving TBI containing preparative regimens as well as high doses of alkylating agents show delayed development of secondary sexual characteristics, resulting from primary ovarian or testicular failure. Laboratory evaluation of these patients reveals ele vated follicle stimulating hormone and luteinizing hormone levels with |
6,560 | depressed estradiol and testosterone serum levels. These patients benefit from careful follow up with evaluation of annual sexual maturity rating (Tanner) scores and endocrine function. Supplementation of gonadal hormones is useful for primary gonadal failure and is administered with GH to promote pubertal growth. Infertility during adulthood remains a significant risk for these patients, especially those undergoing traditional myeloablative conditioning for HSCT. The use of reduced intensity regimens may result in sparing fertility in a large proportion of patients, although conditioning regimens vary and studies are limited. Bone health of HSCT survivors can also be impacted by hormonal changes as well as lifestyle practices, such as inadequate exercise andor dietary intake of vitamin D. Prior exposures, including corticosteroid use, can result in changes to bone density as well as predispose to the development of avascular necrosis. Dual energy x ray absorptiometry (DXA) scans are routinely incorporated into the care of those patients at risk for low bone mineral density. CARDIOVASCULAR EFFECTS Survivors of childhood HSCT are at risk for the future development of cardiovascular complications. This population can be prone to develop ing metabolic syndrome (dyslipidemia, hypertension, diabetes mellitus, obesity), especially those with a history of TBI exposure and subsequent hormonal derangements. Prior exposures such as anthracycline che motherapy and chest radiation further increase the risk for cardiomy opathy as well as atherosclerosis. As a result, routine anthropometric, imaging, and laboratory screening should be performed in survivors of childhood HSCT to assess and monitor their cardiovascular health. SECONDARY MALIGNANCY The overall risk of developing a secondary form of cancer is signifi cantly higher after HSCT than in the general population. Although few studies have specifically analyzed pediatric patients, available evidence indicates that the cumulative incidence of second malignancies shows a slight, but continuous, tendency to increase over time. The develop ment of myelodysplastic syndrome as well as secondary leukemias must be considered in survivors of HSCT. Several other types of sec ondary tumors have been identified in patients given HSCT. The most frequently diagnosed neoplasms are thyroid carcinoma, brain tumors, and epithelial cancers. Young age, male gender, use of TBI during the preparative regimen, chronic GVHD, and an intrinsic genetic predis position to develop cancer (Fanconi anemia) have been reported to be risk factors for development of secondary malignancies after HSCT. Routine physical exams, including yearly skin in exams, in those that received TBI are important in the care of these patients. GRAFT VERSUS HOST DISEASE In the posttransplant period, multiple studies have shown that quality of life is severely impacted by the presence of GVHD, which is an issue that is also unique to HSCT (see Chapter 179). OTHER EFFECTS HSCT patients can also experience complications related to their pul monary function, renal function, dental health, and gastrointestinal system, often related to prior exposures as well as their conditioning regimen. It is also important to note that long term survivors must be monitored for psychologic issues because of their prior and cur rent underlying health conditions. They may need |
6,561 | extra assistance Chapter 181 Late Effects of Hematopoietic Stem Cell Transplantation Rachel A. Phelan and David Margolis Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1366 Part XII u Immunology with school and vocational attainment. These patients are also often at higher risk for depression and anxiety; yearly psychosocial assess ments can identify survivors who need additional therapy or psycho tropic medication. Parents may also have posttraumatic stress from the experience. SPECIAL CONSIDERATIONS Certain patient populations who undergo HSCT are at increased risk for late effects. Young children appear to be at a heightened risk for late complications related to TBI, especially those related to growth, thyroid function, and neurocognition. Patients with an underlying genetic condition must also be monitored more closely for specific consequences of therapy, such as specific secondary malignancies in the Fanconi anemia population caused by an underlying DNA repair defect and patients with sickle cell anemia and thalassemia who are predisposed to iron overload. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 181.1 Summary of Late Effects After Hematopoietic Stem Cell Transplantation in Childhood EXPOSURE LATE EFFECT HSCT experience in general Dental abnormalities Renal toxicity Hepatic toxicity Low BMD Avascular necrosis Increased risk of second cancers Adverse psychosocialquality of life effects Mental health disorders, risk behaviors Psychosocial disability caused by pain or fatigue TRANSPLANTATION CONDITIONING Alkylating agent Cataract (busulfan) Pulmonary fibrosis (busulfan) Renal toxicity Urinary tract toxicity Gonadal dysfunction Therapy related AMLMDS Bladder cancer Epipodophyllotoxin DNA intersecting and cross linking agents (i.e., platinum, heavy metal) Therapy related AMLMDS Ototoxicity Renal toxicity Gonadal toxicity TBI Neurocognitive deficits Leukoencephalopathy Cataract Dental abnormalities GH deficiency Hypothyroidism, thyroid nodule Pulmonary toxicity Breast tissue hypoplasia Cardiac toxicity Renal toxicity Gonadal dysfunction Uterine vascular insufficiency Diabetes Dyslipidemia Musculoskeletal growth problems Second cancers PRETRANSPLANTATION EXPOSURES (NOT LISTED ABOVE) Anthracyclineanthraquinone Cardiac toxicity Therapy related AMLMDS EXPOSURE LATE EFFECT Bleomycin Pulmonary toxicity Cytarabine Neurocognitive deficits Leukoencephalopathy Methotrexate Neurocognitive deficits Leukoencephalopathy Renal toxicity Low BMD Corticosteroid Cataract Low BMD Avascular necrosis Cranial radiation Neurocognitive deficits Leukoencephalopathy Cerebrovascular disease Cataract Craniofacial abnormalities Dental abnormalities, xerostomia GH deficiency Hypothyroidism thyroid nodule Increased obesity Precocious puberty Brain tumor Spinal radiation (in addition to cranial dose) Cardiac toxicity Scoliosiskyphosis, musculoskeletal problems AFTER TRANSPLANTATION (NOT LISTED ABOVE) Chronic GVHD Xerophthalmia Xerostomia, dental abnormalities Pulmonary toxicity Gastrointestinal strictures Genitourinary strictures Skin and joint changes Immunodeficiency Second cancers, especially skin, oral, cervical, lymphoma Tyrosine kinase inhibitor Acute cardiac toxicity reported, but not known to cause late cardiotoxicity OTHER EXPOSURES Blood transfusions Hepatitis C, HIV Focused on those late effects that can develop or persist even after cessation of therapy. Includes etoposide, teniposide. At given total dose, risks greater for single fraction vs fractionated total body irradiation (TBI); single fraction myeloablative TBI (500 cGy) now rarely used. Effects listed are those more likely to be associated with doses used in HSCT survivors (e.g., those given for leukemia treatment, |
6,562 | 25 Gy); late effects are more likely if TBI also given. AMLMDS, Acute myeloid leukemiamyelodysplastic syndrome; BMD, bone mineral density; GH, growth hormone; GVHD, graftversushost disease; HSCT, hematopoietic stem cell transplantation. From Chow EJ, Anderson L, Baker KS, et al. Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Childrens Oncology Group Report. Biol Blood Marrow Transplant. 2016;22(5):782795. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. PART XIIIAllergic Disorders 1367 Allergic or atopic patients have an altered state of reactivity to common environmental and food antigens that do not cause clinical reactions in unaffected people. Patients with clinical allergy usually produce immu noglobulin E (IgE) antibodies to the antigens that trigger their illness. The term allergy represents the clinical expression of IgE mediated allergic diseases that have a familial predisposition and that manifest as hyperresponsiveness in target organs such as the lung, skin, gastroin testinal (GI) tract, and nose. The significant increase in the prevalence of allergic diseases in the last few decades is attributed to changes in environmental factors such as exposure to tobacco smoke, air pollu tion, indoor and outdoor allergens, respiratory viruses, obesity, and perhaps a decline in certain infectious diseases (hygiene hypothesis). The incidence of allergic asthma and atopic dermatitis started to grow to epidemic proportions after the 1960s. Since 2000, the preva lence of food allergy, eosinophilic esophagitis, and drug induced ana phylaxis has also risen to epidemic proportions. Currently more than 1 billion patients worldwide are expected to have at least one kind of allergic disease. The hygiene hypothesis, biodiversity hypothesis and epithelial barrier hypothesis are the three main hypotheses that pro pose mechanisms for the development of allergic diseases. HYGIENE HYPOTHESIS The relatively recent onset of the epidemics of allergic, autoimmune, and metabolic conditions leads to the question of what might underlie their development. A prominent hypothesis is the hygiene hypothesis, which proposes that certain microorganisms or infections protect against inflammatory diseases, and that their loss, due to hygiene measures, results in an increase in allergy, asthma, and autoimmunity. Growing up on a traditional farm has a protective effect from asthma and allergies, which provides a prominent example of the hygiene hypothesis. Chil dren in Amish communities in the United States, where traditional dairy farming is practiced, are highly protected from asthma and allergies. In contrast, Hutterite communities have a significantly higher prevalence of asthma and allergies in children. Interestingly, they practice industrial ized farming with extensive cleaning measures. Early development of a T helper type 1 (Th1) response together with T regulatory cell (Treg) response were proposed to play a role in prevention of allergic diseases. BIODIVERSITY HYPOTHESIS Allergic diseases are associated with a microbiome with increased coloni zation of opportunistic pathogens. The biodiversity hypothesis states that the observed increase in allergies is due to a loss of symbiotic relationships with bacteria and |
6,563 | dysbiosis caused by changes in the microbiome of the gut, skin, and respiratory system. Healthy microbiota on the surface of the mucosal barrier regulates many aspects of epithelial barrier homeostasis, such as the modulation of barrier permeability and expression of epithe lial barrier molecules, angiogenesis, vascular permeability, local microin flammation, and mucosal tolerance. Young children at risk of developing allergies have been shown to suffer from gut microbiome dysbiosis with an overall reduced microbiome diversity. The dysbiotic microbiota has been characterized by an underrepresentation of certain bacterial taxa that may produce immune regulatory and epithelial barrier healing or protective factors, such as short chain fatty acids, retinoic acid, and vitamin D. Several shortcomings of the hygiene and biodiversity hypotheses include the fact that water sanitation was established in many western cities in the 1920s, but allergy and asthma epidemics only started in the 1960s. The protective role of parasitic infections that increase biodiversity has been questioned for the same reason. Many parasitic infections started to decrease in 1910 in New York, whereas allergies started to increase after the 1960s. Allergic asthma is still on the rise in some cities in Asia and Africa, which have low standards of hygiene. Another limitation of the hygiene hypothesis and biodiversity hypothesis is that probiotics are not viable alternatives for the prevention or treatment of allergies. More over, studies of migrants who move from developing countries to affluent regions demonstrate a rapid increase in asthma and allergic diseases. It appears that domestic living conditions, increased birth by cesarean sec tion, antibiotic usage, dietary practices, urbanization, and indoor air pol lution are more prominent factors compared with general public hygiene. EPITHELIAL BARRIER HYPOTHESIS The epithelial barrier hypothesis is a broader hypothesis that covers hygiene and biodiversity hypotheses and adds further insights in the pathogenesis and recent development of allergic diseases. The defective epithelial barrier concept also applies to many autoimmune and meta bolic diseases showing increased prevalence during the last few decades, such as diabetes, rheumatoid arthritis, multiple sclerosis, liver steatosis, and obesity. There is epidemiologic evidence from humans and disease models in laboratory animals that demonstrate that even trace amounts of certain toxic substances can damage epithelial barriers, initiate inflam mation of the epithelium, and increase microbial dysbiosis and bacterial translocation toward the inside and beneath the epithelium. The epithe lial barrier consists of four main components: the epithelial microbiota; the epithelial cell; structural proteins, such as filaggrin, loricrin, and involucrin and tight junctions and adherence junctions; and secreted epithelial products, such as mucus, antimicrobial peptides and fatty acids. Humans are exposed daily to a variety of toxins and chemicals, and substantial data demonstrate disruption of the epithelial barrier by allergens, certain bacteria and their toxins, fungi, viruses, laundry and dishwasher detergents, household cleaners, surfactants, enzymes and emulsifiers used in the food industry, cigarette smoke, particulate matter, diesel exhaust, ozone, nanoparticles, and microplastics. Epithelial cell activation and release of epithelial cell cytokines, such as interleukin (IL) 25, IL 33, and thymic stromal lymphopoietin (TSLP) |
6,564 | play a major role in the development and exacerbation of allergic dis eases. Local tissue inflammation opens epithelial barriers. Open epi thelial barriers in the mucosa allow the entrance of foreign substances, including allergens, into deeper tissues. Both Th1 and T helper type 2 (Th2) inflammation affect the skin and mucosal epithelial barriers. Th2 cells and group 2 innate lymphoid cells (ILCs 2) play major roles utiliz ing IL 13 as major cytokines in the opening of the tight junction barrier. Microbial dysbiosis caused by transepithelial translocation of com mensal microbes, colonization by opportunistic pathogens, and decreased biodiversity are hallmarks of barrier damaged tissues. Colonization by opportunistic pathogens in the microbiota takes place in tissues with a defective epithelial barrier. A dysregulated subepithelial immune response, local inflammation, and incorrect regeneration and remodeling take place as the continuum and chronicity of the local inflammation. Migration of inflamed cells to other affected tissues and systemic low level immune acti vation and microinflammation are additional players in the development and exacerbation of many chronic inflammatory diseases (Fig. 182.1). Chapter 182 Allergy and the Immunologic Basis of Atopic Disease Cezmi A. Akdis and Scott H. Sicherer Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1368 Part XIII u Allergic Disorders KEY ELEMENTS OF ALLERGIC DISEASES Allergens Allergens are almost always proteins, but not all proteins are allergens. For a protein antigen to display allergenic activity, it must induce IgE production, which must lead to a type 1 hypersensitivity response on subsequent exposure to the same protein. Biochemical properties of the allergen; stimulating factors of the innate immune response around the allergen substances at the time of exposure; stability of the allergen in the tissues, digestive system, skin, or mucosa; and the dose and time of stay in lymphatic organs during the interaction with the immune system are factors that may cause an antigen to become an allergen. This is distinguished from general antigen responses, which induce a state of immune responsiveness without associated IgE production. Most allergens are proteins with a molecular weight of 10 70 kDa. Molecules 10 kDa do not bridge adjacent IgE antibody molecules on the surfaces of mast cells or basophils. Most molecules 70 kDa do not pass through mucosal surfaces, a feature needed to reach antigen presenting cells (APCs) for stimulation of the immune system. Allergens frequently contain proteases, which promote skin and mucosal epithelial bar rier dysfunction and increase allergen penetration into host tissues. A relatively high dose of exposure and stability of the allergenic protein in body fluids to reach the immune cells are important determinants of an allergen. Low molecular weight moieties, such as drugs, can become allergens by reacting with serum proteins or cell membrane proteins to be recognized by the immune system. Carbohydrate structures can also be allergens and are most relevant with the increasing use of biologics |
6,565 | in clinical practice; patients with cetuximab induced anaphylaxis have IgE antibodies specific for galactose 1,3 galactose. T Cells Everyone is exposed to potential allergens. Atopic individuals respond to allergen exposure with rapid expansion of Th2 cells that secrete cyto kines, such as IL 4, IL 5, and IL 13, favoring IgE synthesis and eosino philia. Allergen specific IgE antibodies associated with atopic response are detectable by serum testing or positive immediate reactions to aller gen extracts on skin prick testing. The Th2 cytokines IL 4 and IL 13 play a key role in immunoglobulin isotype switching to IgE (Fig. 182.2). IL 5 and IL 9 are important in the differentiation and development of eosinophils. The combination of IL 3, IL 4, and IL 9 contributes to mast cell activation. T cell and eosinophil migration to allergic inflamma tion areas are controlled by IL 4 and IL 13 upregulating their adhesion to endothelial cell walls. IL 9 is responsible for mucus production. Th2 cytokines are important effector molecules in the pathogenesis of asthma and allergic diseases; acute allergic reactions are characterized by infiltra tion of Th2 cells into affected tissues. In addition, IL 25, IL 33, and TSLP secreted from epithelial cells on exposure to allergens and respiratory viruses contribute to Th2 response and eosinophilia. A fraction of the immune response to allergens results in activation and proliferation of Th1 cells. Th1 cells are typically involved in the eradication of intracellular organisms, such as mycobacteria, because Defective epithelial barrier healing capacity due to inflammation Exposure to epithelial barrierdamaging agents and opening of the skin and mucosal barriers Colonization of opportunistic pathogens S. aureus, Moraxella, Haemophilus, pneumococcus Microbial dysbiosis characterized with decreased biodiversity and change in commensals Microbial translocation to interand subepithelial areas Systemic immune response to commensals and opportunistic pathogens Chronic skin and mucosal inflammation T cell ILC2 B cell MC DC M Fig. 182.1 The physiopathology of the epithelial barrier hypothesis. Genetic defects in barrier related molecules or exposure to epithelial barrier damaging agents cause an opening of the skin and mucosal tight junction barriers. This is followed by translocation of microbiota to inter and subepi thelial areas and colonization of opportunistic pathogens, such as Staphylococcus aureus, Moraxella, Haemophilus and pneumococcus. An immune response develops toward commensals and opportunistic pathogens in the gut and respiratory system and systemic inflammation takes place. In most cases of allergic diseases, a systemic type 2 inflammation predominates, and is directed against allergens, but also commensals and opportunistic pathogens. AntiS. aureus antibodies show a very high prevalence in asthma, chronic sinusitis, and atopic dermatitis. This is associated with microbial dysbiosis and decreased biodiversity of commensals. Chronic inflammation in the subepithelial area develops as the main pathogenetic feature of these diseases. Defective epithelial barrier healing capacity due to inflammation and epigenetic changes take place, developing a vicious circle of leaky barriers, microbial dysbiosis, and chronic inflammation. DC, Dendritic cell; IL, interleukin; ILC, innate lymphoid cells; MC, mast cell; M, macrophage. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at |
6,566 | University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 182 u Allergy and the Immunologic Basis of Atopic Disease 1369 of the ability of Th1 cytokines to activate phagocytes and promote the production of opsonizing and complement fixing antibodies. The Th1 component of allergen specific immune response contributes to chro nicity and the effector phase in allergic disease. Activation and apopto sis of epithelial cells induced by Th1 cellsecreted interferon (IFN ), tumor necrosis factor (TNF) , and Fas ligand constitute an essential pathogenetic event for the formation of eczematous lesions in atopic dermatitis and bronchial epithelial cell shedding in asthma. Chronic lesions of allergic reactions are characterized by infiltration of Th1 and Th17 cells. This is important because Th1 cytokines such as IFN can potentiate the function of allergic inflammatory effector cells such as eosinophils, thereby contributing to disease severity. Th17 and Th22 cells link the immune response to tissue inflammation; IL 17A and IL 17F and IL 22 are their respective prototype cytokines. Although both T helper cell subsets play roles in immune defense to extracellular bacteria, IL 17 aug ments inflammation, whereas IL 22 plays a tissue protective role. Cyto kines in the IL 17 family act on multiple cell types, including epithelial cells and APCs, to cause the release of chemokines, antimicrobial peptides, and proinflammatory cytokines to enhance inflammation and antimicrobial responses. In addition, Th9 cells produce IL 9, but not other typical Th1, Th2, and Th17 cytokines, and constitute a distinct population of effector T cells that promotes tissue inflammation. Figure 182.3 depicts the complex cytokine cascades involving Th1, Th2, Th9, Th17, and Th22 cells. Tregs are a subset of T cells thought to play a critical role in expres sion of allergic and autoimmune diseases. These cells have the ability to suppress effector T cells of Th1, Th2, Th9, Th17, and Th22 phenotypes (Fig. 182.4). Tregs express CD4CD25 surface molecules and immu nosuppressive cytokines such as IL 10, IL 35, and transforming growth factor (TGF 1). The forkhead boxwinged helix transcription factor gene FOXP3 is expressed specifically by CD4CD25 Tregs and pro grams their development and function. Adoptive transfer of Tregs inhib its the development of airway eosinophilia and protects against airway hyperreactivity in animal models of asthma. T cell response to allergens in healthy individuals shows a wide range, from no detectable response to involvement of active peripheral tolerance mechanisms mediated by different subsets of Tregs. Individuals who are not allergic even though they are exposed to high doses of allergens, such as beekeepers and cat Th2 Stem cell factor Mast cell B cell Allergen IgE GMCSF EOS IL4 IL4, IL9 IL13 IgE DC CD40LMHCTCR CD40 IL5 IL9 IL9 IL4 IL3 Fig. 182.2 Role of Th2 cytokines in allergic cascade. DC, Dendritic cell; EOS, eosinophil; GM CSF, granulocyte macrophage colony stimulating factor; IL, interleukin. Innate immune response stimulating substances IL21, IL18, IL27 Differentiation |
6,567 | cytokines: Functions: Effector cytokines: IL4 IL21IL4 TGF? TGF?, IL6, IL1? IL21, IL23 TGF? IL6 IFN? IL4, IL5, IL9, IL13, IL25, IL31, IL33 IL21IL9, IL10 IL6, IL8, IL17A, IL17F, IL22, IL26 IL22 Intracellular pathogens, apoptosis of tissue cells Helminths, allergic inflammation, IgE, chronic eosinophilic inflammation Antibody synthesis Mucus production, tissue inflammation Extracellular pathogens, chronic neutrophilic inflammation Tissue inflammation Polarization signals Micromilieu: vitamins, cytokines, histamine, adenosine, aryl hydrocarbons Antigen DC Th1 Th2 Th9 Th17 Th22 TFH naive T cell Fig. 182.3 Effector T cell subsets. Following antigen presentation by dendritic cells (DCs), nave T cells differentiate into Th1, Th2, Th9, Th17, Th22, and follicular helper (TFH) effector subsets. Their differentiation requires cytokines and other cofactors that are released from DCs and also expressed in the micromilieu. T cell activation in the presence of interleukin 4 (IL 4) enhances differentiation and clonal expansion of Th2 cells, per petuating the allergic response. IFN , Interferon ; TGF , transforming growth factor . (From Akdis M, Palomares O, van de Veen W, et al. TH17 and TH22 cells: A confusion of antimicrobial response with tissue inflammation versus protection. J Allergy Clin Immunol. 2012;129:14381449.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1370 Part XIII u Allergic Disorders owners, show a detectable allergen specific IgG4 response accompanied by IL 10producing Tregs. It is thought that CD4CD25 Tregs play an important role in mitigating the allergic immune response, and that the lack of such cells may predispose to the development of allergic dis eases. Patients with pathogenic variants in the human FOXP3 gene lack CD4CD25 Tregs and develop severe immune dysregulation, with poly endocrinopathy, food allergy, and high serum IgE levels (XLAADIPEX disease) (see Chapter 165.4). In addition to Treg cells, IL 10secreting and allergen specific Breg cells increase during allergen specific immu notherapy and may play a role in allergen tolerance. Innate Lymphoid Cells Immune responses in populations of lymphoid cells that lack rearranged T and B cell antigen receptors and surface markers for myeloid and lymphoid lineages, such as T, B, and natural killer (NK) cells, show simi larities to Th1, Th2, and Th17Th22 types of immune responses. These latter cells are defined as ILC1s, ILC2s, and ILC3s, respectively, based on their transcription factors and cytokine production patterns. ILC1s mainly produce IFN ; ILC2s produce IL 5, IL 9, and IL 13; and ILC3s produce IL 17 and IL 22 without any need of antigenallergen exposure. Strong evidence indicates that ILCs play substantial roles in protection against infection and the pathogenesis of inflammatory diseases, such as asthma, allergic diseases, and autoimmune diseases. ILCs control the mucosal environment through close interaction with epithelial cells and other tissue cells, cytokine production, and induction of chemokines that recruit suitable cell populations to initiate and promote distinct types of immune response development and tissue inflammation. ILC2s are likely involved in the induction of |
6,568 | asthma, allergic rhinitis, eosinophilic esophagitis, and atopic dermatitis through activation by epithelium derived cytokines (e.g., IL 33, IL 25, TSLP) and interaction with other immune cells. IL 10secreting ILCs with an immune regulatory func tion have been reported. These cells develop from ILC2s and play sup pressive roles in allergic inflammation, particularly through IL 10. Antigen Presenting Cells Dendritic cells (DCs), Langerhans cells, monocytes, and macrophages have the ability to present allergens to T cells, thereby modulating aller gic inflammation by controlling the type of T cell development. APCs are a heterogeneous group of cells that share the property of antigen presentation in the context of the major histocompatibility complex (MHC) and are found primarily in lymphoid organs and the skin. DCs and Langerhans cells are unique in their ability to prime nave T cells and are responsible for the primary immune response, or the sensiti zation phase of allergy. Monocytes and macrophages are thought to contribute to activating memory T cell responses on reexposure to allergen, which characterizes the elicitation phase of allergy. Peripheral DCs residing in sites such as the skin, intestinal lamina propria, and lung are relatively immature. These immature DCs take up antigens in tissues and then migrate to the T cell areas in locally drain ing lymph nodes. The DCs undergo phenotypic and functional changes during migration, characterized by increased expression of MHC class I, MHC class II, and co stimulatory molecules that react with CD28 expressed on T cells. In the lymph nodes, they directly present processed antigens to resting T cells to induce their proliferation and differentiation. Mature DCs have been designated as myeloid or plasmacytoid on the basis of their ability to favor Th1 or Th2 differentiation, respectively. The critical factor for polarization to Th1 cells is the level of IL 12 pro duced by myeloid DC. In contrast, plasmacytoid DCs have low levels of IL 12. Plasmacytoid DCs particularly play a role in antiviral immu nity by rapid production of high amounts of IFN and help B cells for antibody production. There is considerable interest in the role of TSLP, which is overexpressed in the mucosal surfaces and skin of atopic indi viduals. TSLP enhances Th2 differentiation by inducing expression of OX40L on immature myeloid DCs in the absence of IL 12 production. Tissue macrophages are also acting as APCs. They show two main effec tor subsets in tissues, namely the M1 and M2 macrophages. M1 macro phages are classically activated, typically by IFN or lipopolysaccharide (LPS) like innate immune response stimulating substances, and pro duce proinflammatory cytokines, phagocytize microbes, and initiate an immune response. M1 macrophages produce nitric oxide (NO) or reactive oxygen intermediates (ROIs) to protect against bacteria and viruses. M2 macrophages are alternatively activated by allergen exposure and certain cytokines such as IL 4, IL 10, or IL 13. M2 macrophages will produce either polyamines to induce proliferation or proline to induce collagen production. These macrophages are associated with wound healing and tissue repair remodeling and activation of |
6,569 | Th2 cells and ILC2s. Presence of allergen specific IgE on the cell surfaces of APCs is a unique feature of atopy. Importantly, the formation of high affinity IgE receptor I (FcRI)IgEallergen complexes on APC surfaces greatly facil itates allergen uptake and presentation. The clinical importance of this phenomenon is supported by the observation that FcRI positive Lang erhans cells bearing IgE molecules are a prerequisite for skin applied, aeroallergen provocation of eczematous lesions in patients with atopic dermatitis. The role of the low affinity IgE receptor II (FcRII, CD23) Fig. 182.4 Control of allergen specific immune responses. FoxP3, CD4, CD25, and Tr1 cells contribute to the control of allergen specific im mune responses in several major ways: suppression of dendritic cells (DCs) that support the generation of effector T cells; suppression of Th1, Th2, and Th17 cells; suppression of allergen specific IgE, and induction of IgG4 andor IgA; suppression of mast cells, basophils, and eosinophils; interaction with resident tissue cells and remodeling; and sup pression of effector T cell migration to tissues. IL, Interleukin. (From Akdis CA, Akdis M. Mechanisms and treatment of allergic disease in the big pic ture of regulatory T cells. J Allergy Clin Immunol. 2009;123:735746.) Suppression of Th17 effector cells Remodeling in the tissues Basophil Mast cells Eosinophil T reg DC Th2 Th1 Th17 B cell Direct and indirect suppressive effects on mast cells, basophils, and eosinophils Suppression of Th2 effector cells Suppression of Th1 effector cells Suppression of effector T cell migration to tissues Endothelial cells Induction of IgG4 Suppression of IgE Suppression of inflammatory dendritic cells. Induction of IL10producing dendritic cells Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 182 u Allergy and the Immunologic Basis of Atopic Disease 1371 on monocytesmacrophages is less clear, although under certain condi tions it apparently can also facilitate antigen capture. Cross linking of FcRII, as well as FcRI, on monocytesmacrophages leads to the release of inflammatory mediators. There is a critical role for DCs in induction of oral tolerance; tolerogenic DCs are compartmentalized within the mucosa and present antigen through a mechanism designed to produce a Th1Treg suppressive response that ablates allergen specific T cells. Immunoglobulin E and Its Receptors The acute allergic response depends on IgE and its ability to bind selec tively to the chain of the high affinity FcRI or the low affinity FcRII (CD23). Cross linking of receptor bound IgE molecules by allergen ini tiates a complex intracellular signaling cascade, followed by the release of various mediators of allergic inflammation from mast cells and basophils. The FcRI molecule is also found on the surface of antigen presenting DCs (e.g., Langerhans cells), but differs from the structure found on mast cellsbasophils in that the FcRI molecule found on DCs lacks the chain. CD23 is found on B cells, eosinophils, platelets, and DCs. Cross linking and FcRI aggregation |
6,570 | on mast cells and basophils can also lead to anaphylaxis (see Chapter 174). Differential expression of tyrosine kinases responsible for positive and negative regulation of mast cellbasophil degranulation are thought to be responsible for this aberrant allergic response. The induction of IgE synthesis requires two major signals. The first sig nal (signal 1) initiates IL 4 or IL 13 activation of germline transcription at the Ig locus, which dictates isotype specificity. The second signal (signal 2) involves the engagement of CD40 on B cells by CD40 ligand expressed on T cells. This engagement results in activation of the recombination machinery, resulting in DNA switch recombination. Interactions between several co stimulatory molecule pairs (CD28 and B7; lymphocyte func tionassociated antigen 1 and intercellular adhesion molecule 1; CD2 and CD58) can further amplify signal 1 and signal 2 to enhance IgE synthesis. Factors that inhibit IgE synthesis include Th1 type cytokines (IL 12, IFN , IFN ), IL 10 from Tregs, Breg cells, and regulatory DCs and microbial DNA containing CpG (cytosine phosphate guanine) repeats. Eosinophils Allergic diseases are characterized by peripheral blood and tissue eosin ophilia. Eosinophils participate in both innate and adaptive immune responses and, like mast cells, contain dense intracellular granules that are sources of inflammatory proteins (see Fig. 169.1). These granule proteins include major basic protein, eosinophil derived neurotoxin, peroxidase, and cationic protein. Eosinophil granule proteins damage epithelial cells, induce airway hyperresponsiveness, and cause degran ulation of basophils and mast cells. Major basic protein released from eosinophils can bind to an acidic moiety on the M2 muscarinic receptor and block its function, thereby leading to increased acetylcholine levels and the development of increased airway hyperreactivity. Eosinophils are also a rich source of prostaglandins and leukotrienes (LTs); in par ticular, cysteinyl LT C4 contracts airway smooth muscle and increases vascular permeability. Other secretory products of eosinophils include cytokines (IL 4, IL 5, TNF ), proteolytic enzymes, and ROIs, all of which significantly enhance allergic tissue inflammation. Several cytokines regulate the function of eosinophils in allergic dis ease. Eosinophils develop and mature in the bone marrow from myeloid precursor cells activated by IL 3, IL 5, and granulocyte macrophage colony stimulating factor (GM CSF). Allergen exposure of allergic patients causes resident hematopoietic CD34 cells to express the IL 5 receptor. The IL 5 receptor activation induces eosinophil maturation, causing eosinophils to synthesize granule proteins, prolonging their survival, potentiating degranulation of eosinophils, and stimulating release of eosinophils from the bone marrow. GM CSF also enhances proliferation, cell survival, cytokine production, and degranulation of eosinophils. Certain chemokines, such as RANTES (regulated on activa tion, normal T cell expressed and secreted), macrophage inflammatory protein 1 (MIP 1), and eotaxins are important for recruiting eosino phils into local allergic tissue inflammatory reactions. Eotaxins mobilize IL 5dependent eosinophil colonyforming progenitor cells from the bone marrow. These progenitors are rapidly cleared from the blood and either return to the bone marrow or are recruited to inflamed tissue sites. Mast Cells Mast cells are derived from CD34 |
6,571 | hematopoietic progenitor cells that arise in bone marrow. On entering the circulation, they travel to peripheral tis sue, where they undergo tissue specific maturation. Mast cell development and survival relies on interactions between the tyrosine kinase receptor c kit expressed on the surface of mast cells and the fibroblast derived c kit ligand, the stem cell factor. Unlike mature basophils, mature mast cells do not typically circulate in the blood. They are instead widely distributed throughout connective tissues, where they often lie adjacent to blood ves sels and beneath epithelial surfaces that are exposed to the external envi ronment, such as the respiratory tract, GI tract, and skin. So placed, mast cells are positioned anatomically to participate in allergic reactions. At least two subpopulations of human mast cells are recognized: mast cells with tryptase and mast cells with both tryptase and chymase. Mast cells with tryptase are the predominant type found in the lung and small intestinal mucosa, whereas mast cells with both tryptase and chymase are the pre dominant type found in skin, the GI submucosa, and blood vessels. Mast cells contain, or produce on appropriate stimulation, a diverse array of mediators that have different effects on allergic inflammation and organ function. They include preformed granule associated media tors (histamine, serine proteases, proteoglycans) and membrane derived lipid, cytokine, and chemokine mediators arising from de novo synthesis and release. The most important mast cellderived lipid mediators are the cyclooxygenase and lipoxygenase metabolites of arachidonic acid, which have potent inflammatory activities. The major cyclooxygenase product of mast cells is prostaglandin D2, and the major lipoxygenase products are the sulfidopeptide LTs: LTC4 and its peptidolytic derivatives LTD4 and LTE4. Mast cells also can produce cytokines that promote Th2 type responses (IL 4, IL 13, GM CSF) and inflammation (TNF , IL 6) and regulate tissue remodeling (TGF, vascular endothelial cell growth factor). Immunologic activation of mast cells and basophils typically begins with cross linkage of IgE bound to the FcRI with multivalent allergen. Mast cell surface FcRI is increased by IL 4 and IgE. Surface levels of FcRI decrease in patients receiving treatment with anti IgE antibody that lowers serum IgE, which is of potential therapeutic interest. MECHANISMS OF ALLERGIC TISSUE INFLAMMATION IgE mediated immune responses can be classified chronologically according to three reaction patterns. The early phase response is the immediate response after allergen is introduced into target organs. This response is characterized by mast cell degranulation and release of preformed mediators, occurring within an immediate time frame of 1 30 minutes after allergen exposure and resolving within 1 3 hours. Acute reactions are associated with increased local vascular perme ability, which leads to leakage of plasma proteins, tissue swelling, and increased blood flow, as well as itching, sneezing, wheezing, and acute abdominal cramps in the skin, nose, lung, and GI tract, respectively, depending on the targeted organ. A second, late phase response can occur within hours of allergen exposure, reaching a maximum at 6 12 hours and resolving by 24 |
6,572 | hours. Late phase responses are characterized in the skin by edema, redness, and induration; in the nose by sustained nasal blockage; and in the lung by airway obstruction and persistent wheezing. In general, late phase responses are associated with early infiltration of neutro phils and eosinophils, followed by basophils, monocytes, macrophages, and Th2 type cells. Recruitment of inflammatory cells from the circu lation requires increased expression of adhesion molecules on their cell surfaces and expression of their ligand on endothelial cells, which are under the control of cytokines. Several hours after allergen exposure, TNF released by activated mast cells induces the vascular endothelial expression of cell adhesion molecules, and this change leads to transen dothelial migration of various inflammatory cells. Preferential accu mulation of eosinophils occurs through interactions between selective adhesion molecules on the eosinophil cell surface (e.g., 41 integrin or very late antigen 4); vascular cell adhesion molecule 1 surface expres sion can be enhanced by IL 4 and IL 13 on endothelial cells. ILC2s receive signals from the epithelial cells, such as IL 33, TSLP, and IL 25, and are activated and start to release their cytokines IL 5 and IL 13 to initiate a type 2 immune response. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1372 Part XIII u Allergic Disorders Chemokines are chemotactic cytokines that play a central role in tissue directed migration of inflammatory cells. RANTES, MIP 1, monocyte chemotactic protein (MCP) 3, and MCP 4 are chemoat tractants for eosinophils and mononuclear cells, whereas eotaxins are relatively selective for eosinophils. These chemoattractants have been detected in epithelium, macrophages, lymphocytes, and eosinophils at sites of late phase responses and allergic tissue inflammation. Blockade of these chemokines leads to significant reduction in tissue directed migration of allergic effector cells. In the third reaction pattern, chronic allergic disease, tissue inflam mation can persist for days to years. Several factors contribute to per sistent tissue inflammation, including recurrent exposure to allergens and microbial agents. The repeated stimulation of allergic effector cells such as mast cells, basophils, eosinophils, and Th2 cells contributes to unresolved inflammatory conditions. Additionally, Th2 type cytokines (IL 3, IL 5, GM CSF) secreted during allergic reactions can prolong survival of allergic effector cells by delaying apoptosis. Local differ entiation of tissue infiltrating eosinophil precursors induced by IL 5 results in self generation of eosinophils, further sustaining damage of local tissue. Tissue remodeling leading to irreversible changes in target organs is also a feature of chronic allergic disease. In asthma, remodel ing involves thickening of the airway walls and submucosal tissue, as well as smooth muscle hypertrophy and hyperplasia, which are associ ated with a decline in lung function. This is an unexpected role for eosinophils in airway remodeling as well as chronic inflammation. In atopic dermatitis, lichenification is an obvious manifestation of skin remodeling. Generally, it is considered |
6,573 | that a type 2 immune response underlines a majority of asthma cases, atopic dermatitis, chronic rhinosinusitis, and allergic rhinitis as a general characteristic of an immuneinflam matory response. Type 2 immune response involves Th2 cells, type 2 B cells, ILC2, IL 4secreting NK T cells, basophils, eosinophils, and mast cells and their major cytokines. From a complex network of cytokines, IL 4, IL 5, IL 9, and IL 13 are mainly secreted from the immune sys tem cells, and IL 25, IL 31, IL 33, and TSLP from tissue cells, particu larly epithelial cells. Many asthma related antigens, such as protease allergens, fungal extracts, and viral infection, trigger IL 33, TSLP, and IL 25 production from epithelial cells and various immune cells and induce eosinophilic asthmalike airway inflammation through activa tion of lung ILC2s. IL 31 plays a role in pruritus in atopic dermatitis. Th2 cytokines do not only maintain allergic inflammation but also influence tissue remodeling by activating resident cells in target organs; IL 4, IL 9, and IL 13 induce mucus hypersecretion and metaplasia of mucus cells; IL 4 and IL 13 stimulate fibroblast growth and synthesis of extracel lular matrix proteins; and IL 5 and IL 9 increase subepithelial fibrosis. TGF produced by eosinophils and fibroblasts can also enhance sub epithelial fibrosis. IL 11 expressed by eosinophils and epithelial cells contributes to subepithelial fibrosis, in addition to enhancing depo sition of collagen and the accumulation of fibroblasts. The resulting tissue injury amplifies further epithelial injury through proinflamma tory cytokine release, extracellular matrix deposition in target organs, and angiogenesis. Genetic predisposition to aberrant injury repair responses may contribute to chronicity of illness. Once the allergic immune response is established, it can be self perpetuating due to a general type 2 immune response and can lead to chronic disease in genetically predisposed individuals. The subsequent infiltration of Th1 cells and Th17 cells enhances the inflammatory potential of allergic effector cells and contributes to chronic tissue inflammatory responses through the release of proinflammatory cytokines and chemokines. In addition, an autoimmune response might be playing a causative role in allergic inflammation resulting from possible mechanisms through IgE autoantibodies, IgG autoantibodies, and Th1 cell and Th17 cell autoreactivity. GENETIC BASIS OF ATOPY Allergic diseases are complex genetic conditions susceptible to envi ronmental triggers. Several major groups of genes are associated with allergic diseases: genes that regulate systemic expression of atopy (increased IgE synthesis, eosinophilia, mast cell responses) and that are usually expressed among various allergic diseases, genes that control barrier function in specific target organs (e.g., skin in atopic dermatitis, lung in asthma, GI tract in food allergy), and genes encoding pattern recognition receptors of the innate immune system that engage micro bial pathogens and influence adaptive immune responses (Fig. 182.5). Once allergic responses have been initiated, a genetic predisposition to chronic allergic inflammation and aberrant injury repair responses contribute to tissue remodeling and persistent disease. Atopic diseases have a strong familial predisposition, with approx imately 60 heritability found in twin studies |
6,574 | of asthma and atopic dermatitis. The 5q23 35 region comprises several genes implicated in allergic disease pathogenesis, including genes coding for Th2 cytokines (IL 3, IL 4, IL 5, IL 9, IL 13, GM CSF). Among these, IL4 is a well studied potential candidate gene. A nucleotide change at position 589 of the IL4 promoter region is associated with the formation of a unique binding site for nuclear factor for activated T cells (NF AT) transcrip tion factor, increased IL 4 gene transcription, higher NF AT binding affinity, and increased IgE production. Similarly, IL13 coding region variants have been associated with asthma and atopic dermatitis. An association has been found between atopy and a gain of function poly morphism on chromosome 16, which codes for the subunit of the IL 4R. This finding is consistent with the important role of IL 4, IL 13, and their receptors in the immunopathogenesis of allergic diseases. Genome wide searches have also linked atopy to chromosome region 11q13. The gene encoding the subunit of FcRI has been proposed to be the candidate gene in this region. The subunit gene modifies the FcRI activity on mast cells, and several variants of FcRI are associ ated with asthma and atopic dermatitis. Chromosome 6 contains genes coding for human leukocyte antigen class I and class II molecules, which regulate the specificity and intensity of the immune responses to specific allergens. IgE responses to specific allergens, such as ragweed antigen Amb a V and mite allergen Der p I, have been linked to specific MHC class II loci. TNF , a key cytokine that contributes to the influx of inflammatory cells, is also located on chromosome 6. TNF poly morphisms are associated with asthma. A recent genome wide associa tion study showed that genetic polymorphisms in the gene encoding IL 33, which is a major activator of ILC2s, and its receptor IL 1RL1 (ST2) are strongly linked to asthma development. Barrier dysfunction has a key role in the pathogenesis of allergic dis eases. Genetic linkage studies of atopic dermatitis have demonstrated the importance of chromosome 1q21, which contains a cluster of genes involved in epidermal differentiation. Filaggrin is a protein that is essential in the formation of the stratum corneum. Null pathogenic variants of the filaggrin gene are strongly associated with early onset and severe atopic dermatitis. Pathogenic variants in the gene encoding the serine protease inhibitor SPINK5 has been shown to cause Neth erton disease, a single gene disorder associated with erythroderma, food allergy, and high serum IgE levels. A common polymorphism in SPINK5 (in particular, Glu420Lys) increases the risk of develop ing atopic dermatitis and asthma. SPINK5 is expressed in the outer epidermis and is thought to be critical to neutralizing the proteolytic activity of Staphylococcus aureus and common allergens such as Der p I, which use these proteases to penetrate the skin to induce allergic responses. Barrier dysfunction is involved in other allergic diseases, such as asthma and rhinosinusitis, but likely involves other barrier genes, |
6,575 | such as those encoding tight junctions. Epithelial tight junctions form a strong barrier on the apical side of mucosal epithelial cells and stratum granulosum of the skin. Epithelial tight junction defects shown in asthma and atopic dermatitis have been linked to two mechanisms, such as polymorphisms in certain claudin molecules or epigenetic reg ulation of the tight junction molecules. Epithelial cells obtained from asthmatic tissues cannot form a strong barrier in cultures. Chemical inhibition of histone deacetylases strengthens the barrier development capacity of these epithelial cells. Candidate genes associated with asthma susceptibility have been identified by positional cloning: GPRA (G proteincoupled recep tor for asthma susceptibility on chromosome 7p14), ADAM 33 (a disintegrin and metalloproteinase 33 on chromosome 20p), and Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 182 u Allergy and the Immunologic Basis of Atopic Disease 1373 DPP10 (dipeptidyl peptidase 10 on chromosome 2q14). The func tions of these genes do not fit into classical pathways of atopy and therefore provide new insights into asthma pathogenesis. GPRA encodes a G proteincoupled receptor, with isoforms expressed in bronchial epithelial cells and smooth muscle in asthmatic persons, suggesting an important role for these tissues in asthma. ADAM 33 is expressed in bronchial smooth muscle and has been linked to bronchial hyperresponsiveness. DPP10 encodes a dipeptidyl dipeptidase that can remove the terminal 2 peptides from certain proinflammatory chemokines, a change that may modulate allergic inflammation. Pattern recognition receptors of the innate immune system, which are expressed by epithelial cells and DCs, are associated with disease susceptibility. These receptors recognize specific microbial compo nents. Polymorphisms in CD14 (engages endotoxin), Toll like receptor 2 (which engages S. aureus), and T cell immunoglobulin domain and mucin domain (which engage hepatitis A virus) correlate with asthma andor atopic dermatitis susceptibility. Dysregulation of these frontline immune defense systems would permit abnormal response to common environmental allergens. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Asthma AB13BP, ACO1, ATG3, BTNL2, C11orf71, C1orf100, C5orf56, CDHR3,CDK2,CHCHD9, COL22A1, CRB1, CRCT1, CTNNA3, DENND1B, EDIL3, FAM19A2 GAB1, GSDMA, HPSE2, IGSF3, IKZF4, IL15RA, IL2RA, IL2RB, IL5RA, IL6R, KIAA1271, KLF6, KLHL5, LOC338591, LOC729675, MKLN1, NDFIP1, NOTCH4, ORMDL3, PBX2, PCDH20, PDE4D, PRKCQ, PRKG1, PSAP, PTHLH, PYHIN1, RBM17, RORA, SCG3, SIM2, SLC22A5, SLC30A8, SPATS2L, T, TLE4, TNS1, VAV3, XKR6, XPR1, ZNF432, ZNF614, ZNF665, ZNF841 ACTL9, ADO, BAT1, CARD11, CCDC80, CREBL1, CYP24A1, EGR2, FLG, GLB1, GPSM3, KIF3A, LOC100505634, LOC100630917, MIR1208, NCF4, NLRP10, OR10A3, OVOL1, PFDN4, TNXB, ZNF365 CROCC, DAB2, DHRS7, ENTPD6, ETS1, FOXA1, GATA3, GLI3, IL1RL2, IL21R, NFATC2, PEX14, PLCL1, PPM1A, PTGER4, SEMA6A, TPD52, TTC6 ABL2, CDH13, CRIM1, DARC, DNAH5, DOCK10, EPS15, FCER1A, HCG27, HLAA, HLAG, LOC730217, NAB2, OPRK1, OR10J3, OR6X1, SUCLG2, SYNPO2, TLN1, TMEM108, WWP2, ZNF71 IL2, STAT6 IL13, RAD50 HLA region, SLC25A46 LPP LRRC32 IL18R1 IL1RL1 C6orf10 TLR1, TSLP, WDR36 GSDMB, IKZF3, IL33, RANBP6, SMAD3 CLEC16A, ZBTB10 TMEM232, ID2, IL4R Rhinitis Serum lgEAtopy Atopic dermatitis EMSY, HLAC IL18RAP ADAD1, |
6,576 | BCL6, CAMK4, MICA, TLR6, TLR10 ANAPC1, COL21A1, FAM114A1, HLAB, IL21, KIAA1109, MICB, MIR574, MYC, PVT1, SGK493 Fig. 182.5 Overlapping sets of genes have been reported in genome wide association studies (GWASs) for asthma, rhinitis, serum immunoglobu lin E (IgE) levels, atopy, and atopic dermatitis, supporting a common genetic element within the mechanisms predisposing individuals toward differ ent allergic disease phenotypes. GWASs have also identified many genes in association with only one allergic disease phenotype; these most likely represent the tissue specific component of each allergic disease (e.g., FLG in the epidermal barrier in atopic dermatitis). More GWASs have been conducted analyzing genetic variants associated with asthma than with other allergic diseases. In the future it is likely that more risk variants for other allergic diseases will be identified. Genes reported in more than one GWAS are shown in bold font. The genes reported for SNPs detected to be significantly associated (P 1 105) with each allergic disease phenotype were obtained by searching the National Human Genome Research Insti tute GWAS catalog. (From Holloway JW. The genetics of allergic disease and asthma. In: Leung DYM, Akdis CA, Bacharier LB, et al., eds. Pediatric Allergy Principles and Practice. 4th ed. Philadelphia: Elsevier; 2021. Fig. 3.3, p 22.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 182 u Allergy and the Immunologic Basis of Atopic Disease 1373.e1 Bibliography Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, auto immunity and other chronic conditions? Nat Rev Immunol. 2021;32(22):749751. Akdis CA, Arkwright PD, Brggen MC, et al. Type 2 immunity in the skin and lungs. Allergy. 2020;75(7):15821605. Bachert C, Akdis CA. Phenotypes and emerging endotypes of chronic rhinosinusitis. J Allergy Clin Immunol Pract. 2016;4(4):621628. Celebi Szener Z, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol. 2020;145(6):15171528. Cevhertas L, Ogulur I, Maurer DJ, et al. Advances and recent developments in asth ma in 2020. Allergy. 2020;75(12):31243146. Kortekaas Krohn I, Shikhagaie MM, Golebski K, et al. Emerging roles of in nate lymphoid cells in inflammatory diseases: Clinical implications. Allergy. 2018;73(4):837850. Kuo IH, Yoshida T, De Benedetto A, et al. The cutaneous innate immune response in patients with atopic dermatitis. J Allergy Clin Immunol. 2013;131:266278. Liu AH, Anderson 3rd WC, Dutmer CM, et al. Advances in asthma 2015: across the lifespan. J Allergy Clin Immunol. 2016;138(2):397404. Mjsberg J, Spits H. Human innate lymphoid cells. J Allergy Clin Immunol. 2016;138(5):12651276. Morita H, Kubo T, Rckert B, Ravindran A, et al. Induction of human regulatory in nate lymphoid cells from group 2 innate lymphoid cells by retinoic acid. J Allergy Clin Immunol. 2019;143(6). 21902201.e9. Palomares O, Akdis M, Martn Fontecha M, Akdis CA. Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells. Immunol Rev. 2017;278(1):219236. Tang TS, Bieber T, Williams HC. Does autoreactivity play |
6,577 | a role in atopic dermati tis? J Allergy Clin Immunol. 2012;129:12091215. Van de Veen W, Stanic B, Yaman G, et al. IgG4 production is confined to human IL 10 producing regulatory B cells that suppress antigen specific immune responses. J Allergy Clin Immunol. 2013;131:12041212. Vercelli D. Remembrance of things past: HLA genes come back on the allergy stage. J Allergy Clin Immunol 129:846847 Wang M, Tan G, Eljaszewicz A, et al. Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithe lial cells. J Allergy Clin Immunol. 2019;143(5):18921903. Zabielinski M, McLeod MP, Aber C, et al. Trends and antibiotic susceptibility patterns of methicillin resistant and methicillin sensitive Staphylococcus aureus in an outpatient dermatology facility. JAMA Dermatol. 2013;149(4):427 432. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1374 Part XIII u Allergic Disorders ALLERGY HISTORY Obtaining a complete history from the allergic patient involves elicit ing a description of all symptoms along with their timing and duration, exposure to common allergens, and responses to previous therapies. Because patients often suffer from more than one allergic disease, the presence or absence of other allergic diseases, including allergic rhi noconjunctivitis, asthma, food allergy, eosinophilic esophagitis, atopic dermatitis, and drug allergy, should be determined. A family history of allergic disease is common and is one of the most important factors predisposing a child to the development of allergies. The risk of allergic disease in a child approaches 50 when one parent is allergic and 66 when both parents are allergic, with maternal history of atopy having a greater effect than paternal history. Several characteristic behaviors are often seen in allergic children. Because of nasal pruritus and rhinorrhea, children with allergic rhi nitis often perform the allergic salute by rubbing their nose upward with the palm of their hand. This repeated maneuver may give rise to the nasal crease, a horizontal wrinkle over the bridge of the nose. Characteristic vigorous rubbing of the eyes with the thumb and side of the fist is frequently observed in children with allergic conjunctivitis. The allergic cluck is produced when the tongue is placed against the roof of the mouth to form a seal and withdrawn rapidly in an effort to scratch the palate. The presence of other symptoms, such as fever, uni lateral nasal obstruction, and purulent nasal discharge, suggests other diagnoses. The timing of onset and the progression of symptoms are relevant. The onset of recurrent or persistent nasal symptoms coinciding with placement in a daycare center might suggest recurrent infection rather than allergy. When patients present with a history of episodic acute symptoms, it is important to review the setting in which symptoms occur as well as the activities and exposures that immediately precede their onset. Symptoms associated with lawn mowing suggest allergy to grass pollen or fungi, whereas if symptoms occur in |
6,578 | homes with pets, animal dander sensitivity is an obvious consideration. Reproduc ible reactions after ingestion of a specific food raise the possibility of food allergy. When symptoms wax and wane but evolve gradually and are more chronic in duration, a closer look at whether the timing and progression of symptoms correlate with exposure to a seasonal aeroal lergen is warranted. Aeroallergens, such as pollens and fungal spores, are prominent causes of allergic disease. The concentrations of these allergens in out door air fluctuate seasonally. Correlating symptoms with seasonal pol lination patterns of geographically relevant plants and trees along with information provided by local pollen counts can aid in identifying the allergen. Throughout most of the United States, trees pollinate in the early spring, grasses pollinate in the late spring and early summer, and weeds pollinate in late summer through the fall. The presence of fun gal spores in the atmosphere follows a seasonal pattern in the north ern United States, with spore counts rising with the onset of warmer weather and peaking in late summer months, only to recede again with the first frost through the winter. In warmer regions of the southern United States, fungal spores and grass pollens may cause symptoms on a perennial basis. Rather than experiencing seasonal symptoms, some patients suf fer allergic symptoms year round. In these patients, sensitization to perennial allergens usually found indoors, such as dust mites, animal dander, cockroaches, and fungi, warrants consideration. Species of certain fungi, such as Aspergillus and Penicillium, are found indoors, whereas Alternaria is found in both indoor and outdoor environments. Cockroach and rodent allergens are often problematic in urban envi ronments. Patients sensitive to perennial allergens often also become sensitized to seasonal allergens and experience baseline symptoms year round with worsening during the pollen seasons. The age of the patient is an important consideration in identifying potential allergens. Infants and young children are often first sensitized to allergens that are in their environment on a continuous basis, such as dust mites, animal dander, and fungi. Sensitization to seasonal aller gens usually takes several seasons of exposure to develop and is thus unlikely to be a significant trigger of symptoms in infants and toddlers. Food allergies are more common in infants and young children, resulting primarily in cutaneous, gastrointestinal, and, less frequently, respiratory and cardiovascular symptoms. Symptoms of immediate or IgE mediated hypersensitivity food reactions typically develop within minutes to 2 hours after ingestion of the offending food. Symptoms of nonIgE mediated food allergies are often delayed or chronic (see Chapter 192). Complete information from previous evaluations and prior treat ments for allergic disease should be reviewed, including impact of changes in local environment (e.g., home vs school), response to medi cations, elimination diets, and duration and impact of allergen immu notherapy (if applicable). Improvement in symptoms with medications or avoidance strategies used to treat allergic disease provides additional evidence for an allergic process. A thorough environmental survey should be performed, focusing on potential sources of allergen andor |
6,579 | irritant exposure, particularly when respiratory symptoms (upperlower) are reported. The age and type of the dwelling, how it is heated and cooled, the use of humidifiers or air filtration units, and any history of water damage should be noted. Forced air heating may stir up dust mite, fungi, and animal allergens. The irritant effects of wood burning stoves, fireplaces, and kerosene heaters may provoke respiratory symptoms. Increased humidity or water damage in the home is often associated with greater exposure to dust mites and fungi. Carpeting serves as a reservoir for dust mites, fungi, and animal dander. The number of domestic pets and their movements about the house should be ascertained. Special attention should be focused on the bedroom, where a child spends a significant proportion of time. The age and type of bedding, the use of dust mite covers on pillows and mattresses, the number of stuffed animals, type of window treatments, and the accessibility of pets to the room should be reviewed. The number of smokers living in the home, and what and where they smoke is useful information. Activities that might result in exposure to allergens or respiratory irritants such as paint fumes, cleansers, sawdust, or glues should be identified. Similar information should be obtained in other environments where the child spends long periods, such as a relatives home or school setting. PHYSICAL EXAMINATION In patients with asthma, spirometry should be performed. If respira tory distress is observed, pulse oximetry should be performed. The child presenting with a chief complaint of rhinitis or rhino conjunctivitis should be observed for mouth breathing, paroxysms of sneezing, sniffingsnorting, throat clearing, and rubbing of the nose and eyes (representing pruritus; see Chapter 184). Infants should be observed during feeding for nasal obstruction severe enough to inter fere with feeding or for more obvious signs of aspiration or gastro esophageal reflux. The frequency and nature of coughing that occurs during the interview and any positional change in coughing or wheez ing should be noted. Children with asthma should be observed for congested or wet cough, tachypnea at rest, retractions, and audible wheezes, which may worsen with crying. Patients with atopic dermati tis should be monitored for repetitive scratching and the extent of skin involvement. Because children with severe asthma as well as those receiving chronic or frequent oral corticosteroids may experience growth sup pression, an accurate height should be plotted at regular intervals. The Chapter 183 Diagnosis of Allergic Disease Supinda Bunyavanich, Jacob Kattan, and Scott H. Sicherer Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 183 u Diagnosis of Allergic Disease 1375 use of inhaled glucocorticoids in prepubertal children is associated with a small initial decrease in attained height (1 cm) that may per sist as a reduction in adult height. Poor weight gain in a child with chronic chest symptoms should prompt consideration |
6,580 | of cystic fibro sis. Anthropometric measures are also important to monitor in those on restricted diets because of multiple food allergies or eosinophilic esophagitis. Blood pressure should be measured to evaluate for steroid induced hypertension. The patient with acute asthma may present with pulsus paradoxus, defined as a drop in systolic blood pressure during inspiration 10 mm Hg. Moderate to severe airway obstruction is indi cated by a decrease of 20 mm Hg. An increased heart rate may be the result of an asthma flare or the use of a agonist or decongestant. Fever is not caused by allergy alone and should prompt consideration of an infectious process, which may exacerbate asthma. Parents are often concerned about blue gray to purple discolorations beneath their childs lower eyelids, which can be attributed to venous stasis and are referred to as allergic shiners (Fig. 183.1). They are found in up to 60 of allergic patients and almost 40 of patients without allergic disease. Thus shiners may suggest, but are not diagnostic of, allergic disease. In contrast, the Dennie Morgan folds (Dennie lines) are a feature of atopy (see Fig. 183.1). These are prominent infraorbital skin folds that extend in an arc from the inner canthus beneath and parallel to the lower lid margin. In patients with allergic conjunctivitis, involvement of the eyes is typically bilateral (see Chapter 188). Examination of the conjunctiva reveals varying degrees of lacrimation, conjunctival injection, and edema. In severe cases, periorbital edema involving primarily the lower eyelids or chemosis (conjunctival edema that is gelatinous in appear ance) may be observed. The classic discharge associated with allergic conjunctivitis is usually described as stringy or ropy. In children with vernal conjunctivitis, a more severe, chronic phenotype, examina tion of the tarsal conjunctiva may reveal cobblestoning. Keratoconus, or protrusion of the cornea, may occur in patients with vernal conjunc tivitis or periorbital atopic dermatitis as a result of repeated trauma produced by persistent rubbing of the eyes. Children treated with high dose or chronic corticosteroids are at risk for development of posterior subcapsular cataracts. The external ear should be examined for eczematous changes in patients with atopic dermatitis, including the postauricular area and base of the earlobe. Because otitis media with effusion is common in children with allergic rhinitis, pneumatic otoscopy should be per formed to evaluate for the presence of fluid in the middle ear and to exclude infection. Examination of the nose in allergic patients may reveal the pres ence of a nasal crease. Nasal patency should be assessed, and the nose examined for structural abnormalities affecting nasal airflow, such as septal deviation, turbinate hypertrophy, and nasal polyps. Decrease or absence of the sense of smell should raise concern about chronic sinusitis or nasal polyps. Nasal polyps in children should raise con cerns of cystic fibrosis. The nasal mucosa in allergic rhinitis is classi cally described as pale to purple compared with the beefy red mucosa of patients with nonallergic rhinitis. Allergic nasal secretions are typi cally thin and |
6,581 | clear. Purulent secretions suggest another cause of rhi nitis. The frontal and maxillary sinuses should be palpated to identify tenderness to pressure that might be associated with acute sinusitis. Examination of the lips may reveal cheilitis caused by drying of the lips from continuous mouth breathing or repeated licking of the lips in an attempt to replenish moisture and relieve discomfort (lip lickers dermatitis). Tonsillar and adenoidal hypertrophy along with a history of impressive snoring raises the possibility of obstructive sleep apnea. The posterior pharynx should be examined for the pres ence of postnasal drip and posterior pharyngeal lymphoid hyperplasia (cobblestoning). Chest findings in asthmatic children vary significantly and may depend on disease duration, severity, and activity. In a child with well controlled asthma, the chest should appear entirely normal on exami nation between asthma exacerbations. Examination of the same child during an acute episode of asthma may reveal hyperinflation, tachy pnea, use of accessory muscles (retractions), wheezing, and decreased air exchange with a prolonged expiratory time. Tachycardia may be caused by the asthma exacerbation or accompanied by jitteriness after treatment with agonists. Decreased airflow or rhonchi and wheezes over the right chest may be noted in children with mucus plugging and right middle lobe atelectasis. The presence of cyanosis indicates severe respiratory compromise. Unilateral wheezing after an episode of coughing and choking in a small child without a history of previous respiratory illness suggests foreign body aspiration. Wheezing limited to the larynx in association with inspiratory stridor may be seen in older children and adolescents with vocal cord dysfunction. Digital clubbing is rarely seen in patients with uncomplicated asthma and should prompt further evaluation to rule out other potential chronic diagnoses, such as cystic fibrosis. The skin of the allergic patient should be examined for evidence of urticariaangioedema or atopic dermatitis (see Chapters 189 and 186). Xerosis, or dry skin, is the most common skin abnormality of allergic children. Keratosis pilaris, often found on facial cheeks and extensor surfaces of the upper arms and thighs, is a benign condition character ized by skin colored or slightly pink papules caused by keratin plugs lodged in the openings of hair follicles. Examination of the skin of the palms and soles may reveal thickened skin and exaggerated palmar and plantar creases (hyperlinearity) in children with moderate to severe atopic dermatitis. DIAGNOSTIC TESTING In Vitro Tests Allergic diseases are often associated with increased numbers of eosino phils circulating in the peripheral blood and invading the tissues and secretions of target organs. Eosinophilia, defined as the presence of 500 eosinophilsL in peripheral blood, is the most common hematologic abnormality of allergic patients. Seasonal increases in the number of circu lating eosinophils may be observed in sensitized patients after exposure to allergens such as tree, grass, and weed pollens. The number of circulating eosinophils can be suppressed by certain infections and systemic cortico steroids. In certain pathologic conditions, such as drug reactions, eosino philic pneumonias, and eosinophilic esophagitis, significantly increased numbers of eosinophils may be |
6,582 | present in the target organ in the absence Fig. 183.1 Bilateral Dennie Morgan folds. Several linear wrinkles beneath the lower eyelashes (arrow) associated with bilateral allergic shiners: dark circles beneath the lower eyelid (arrowheads). (From Blanc S, Bourrier T, Albertini M, et al. Dennie Morgan fold plus dark circles: suspect atopy at first sight. J Pediatr. 2015;166:1541.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1376 Part XIII u Allergic Disorders of peripheral blood eosinophilia. Increased numbers of eosinophils are observed in a wide variety of disorders in addition to allergy; eosinophil counts 1,500 without an identifiable etiology should suggest one of the two hypereosinophilic syndromes (Table 183.1; see Chapter 169). Nasal and bronchial secretions may be examined for the presence of eosinophils and neutrophils. The presence of eosinophils in the sputum of patients with atopic asthma is frequently seen. An increased number of eosinophils in a smear of nasal mucus with Hansel stain is a more sen sitive indicator of nasal allergies than peripheral blood eosinophilia and can aid in distinguishing allergic rhinitis from other causes of rhinitis. An elevated IgE value is often found in the serum of allergic patients, because IgE is the primary antibody associated with immediate hyper sensitivity reactions. IgE values are measured in international units (IU), with 1 IU equal to 2.4 ng of IgE. Serum IgE levels gradually rise over the first years of life to peak in the teen years and decrease steadily thereafter. Additional factors, such as genetic influences, gender, cer tain diseases, and exposure to cigarette smoke and allergens, also affect serum IgE levels. Total serum IgE levels may increase 2 to 4 fold dur ing and immediately after the pollen season and then gradually decline until the next pollen season. Comparison of total IgE levels among patients with allergic diseases reveals that those with atopic dermatitis tend to have the highest levels, whereas patients with allergic asthma generally have higher levels than those with allergic rhinitis. Although average total IgE levels are higher in populations of allergic patients than in comparable populations without allergic disease, the overlap in levels is such that the diagnostic value of a total IgE level is poor. Approximately half of patients with allergic disease have total IgE levels in the normal range. However, measurement of total IgE is indicated when the diagnosis of allergic bronchopulmonary aspergillosis is suspected because total serum IgE concentration 1,000 ngmL is a criterion for diagnosis of this disorder (see Chapter 283.1). Total serum IgE may also be elevated in several nonallergic diseases (Table 183.2). The presence of IgE specific for a particular allergen can be docu mented in vivo by skin testing or in vitro by the measurement of allergen specific IgE (sIgE) levels in the serum (Table 183.3). The first test for documenting the presence of sIgE was called the radio allergosorbent |
6,583 | test (RAST) because it used a radiolabeled anti IgE antibody. RAST has been replaced by an improved generation of auto mated enzymatic sIgE immunoassays. These immunoassays typically use solid phase supports to which allergens of an individual allergen extract are bound. A small amount of the patients serum is incubated with the allergen coated support. The allergen coated support bound to the patients sIgE is then incubated with enzyme conjugated antihu man IgE. Incubation of this sIgEantihuman IgE complex with a fluo rescent substrate of the conjugated enzyme results in the generation of fluorescence that is proportional to the amount of sIgE in the serum sample. The amount of sIgE is calculated by interpolation from a stan dard calibration curve and reported in arbitrary mass units (kilo IU of allergen specific antibody per unit volume of sample, kUAL). Labora tory reports may specify classes, counts, or units, but quantification of results in kUAL is most useful. sIgE immunoassays are available for foods, environmental allergens, insect venoms, natural rubber latex, and a small number of lactam drugs. The sensitivity and specific ity of immunoassays for particular allergens vary widely from 3095. These immunoassays are not diagnostic for allergy and should not be used for allergy screening. Only targeted sIgE levels for specific anti gens should be measured when there is a clinical indication to suspect a specific allergy. Table 183.1 Differential Diagnosis of Childhood Eosinophilia HEMATOLOGICONCOLOGIC Neoplasm (lung, gastrointestinal, uterine) Leukemialymphoma Myelofibrosis Myeloproliferative (FIP1L1 PDGFRA positive) hypereosinophilic syndrome Lymphatic hypereosinophilic syndrome Systemic mastocytosis IMMUNOLOGIC T cell immunodeficiencies Hyper IgE (Job) syndromes Wiskott Aldrich syndrome Autoimmune lymphoproliferative syndrome (ALPS) Sarcoidosis Graft versus host disease Drug hypersensitivity including drug reaction with eosinophilia and systemic symptoms (DRESS) Postirradiation Postsplenectomy ENDOCRINE Addison disease Hypopituitarism CARDIOVASCULAR Loeffler disease (fibroplastic endocarditis) Congenital heart disease Hypersensitivity vasculitis Eosinophilic myocarditis GASTROINTESTINAL Benign proctocolitis Inflammatory bowel disease Eosinophilic gastrointestinal diseases (EGID) PHYSIOLOGIC Prematurity Infants receiving hyperalimentation Hereditary INFECTIOUS Parasitic (with tissue invasive helminths, e.g., trichinosis, strongyloidiasis, pneumocystosis, filariasis, cysticercosis, cutaneous and visceral larva migrans, echinococcosis) Bacterial (brucellosis, tularemia, cat scratch disease, Chlamydia) Fungal (histoplasmosis, blastomycosis, coccidioidomycosis, allergic bronchopulmonary aspergillosis) Mycobacterial (tuberculosis, leprosy) Viral (HIV 1, HTLV 1, hepatitis A, hepatitis B, hepatitis C, Epstein Barr virus) PULMONARY Allergic (rhinitis, asthma) Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome) Loeffler syndrome Hypersensitivity pneumonitis Eosinophilic pneumonia (chronic, acute) Pulmonary interstitial eosinophilia DERMATOLOGIC Atopic dermatitis Pemphigus Dermatitis herpetiformis Infantile eosinophilic pustular folliculitis Eosinophilic fasciitis (Schulman syndrome) Eosinophilic cellulitis (Wells syndrome) Kimura disease (angiolymphoid hyperplasia with eosinophilia) FIP1L1 PDGFRA, FIP1 like 1platelet derived growth factor receptor ; HTLV, human T lymphotropic virus 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 183 u Diagnosis of Allergic Disease 1377 Table 183.3 Determination of Allergen Specific IgE by Skin Testing vs In Vitro Testing VARIABLE SKIN TEST sIgE ASSAY Risk of allergic reaction Yes (especially ID) No Relative sensitivity High |
6,584 | High Affected by antihistamines Yes No Affected by corticosteroids Usually not No Affected by extensive dermatitis or dermatographism Yes No Broad selection of antigens Fewer Yes Immediate results Yes No Expensive No Yes Lability of allergens Yes No Results evident to patient Yes No Skin testing may be the prick test or intradermal (ID) injection. NEOPLASTIC DISEASES Hodgkin disease IgE myeloma Bronchial carcinoma OTHER DISEASES AND DISORDERS Alopecia areata Bone marrow transplantation Burns Cystic fibrosis Dermatitis, chronic acral Erythema nodosum, streptococcal infection Guillain Barr syndrome Kawasaki disease Liver disease Medication related Nephritis, drug induced interstitial Nephrotic syndrome Pemphigus, bullous Polyarteritis nodosa, infantile Primary pulmonary hemosiderosis Juvenile idiopathic arthritis Table 183.2 Nonallergic Diseases Associated with Increased Serum IgE Concentrations PARASITIC INFESTATIONS Ascariasis Capillariasis Echinococcosis Fascioliasis Filariasis Hookworm Onchocerciasis Malaria Paragonimiasis Schistosomiasis Strongyloidiasis Trichinosis Visceral larva migrans INFECTIONS Allergic bronchopulmonary aspergillosis Candidiasis, systemic Coccidioidomycosis Cytomegalovirus mononucleosis HIV type 1 infections Infectious mononucleosis (Epstein Barr virus) Leprosy Pertussis Viral respiratory infections IMMUNODEFICIENCY Autosomal dominant hyper IgE syndrome (STAT3 variants) Autosomal recessive hyper IgE syndrome (DOCK8, TYK2 variants) IgA deficiency, selective Nezelof syndrome (cellular immunodeficiency with immunoglobulins) Thymic hypoplasia (DiGeorge anomaly) Wiskott Aldrich syndrome Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1378 Part XIII u Allergic Disorders Component testing refers to diagnostic tests where sIgE is measured to specific proteins that comprise allergens (e.g., Ara h 2 from peanut, Bet v 1 from birch pollen), rather than to a mixture of the allergens extracted from the source. Testing sIgE to component allergens may add additional diagnostic value by differentiating immune responses that are directed toward clinically relevant allergenic proteins. In Vivo Tests Allergen skin testing is the primary in vivo procedure for the diagno sis of allergic disease. Mast cells with sIgE antibodies attached to high affinity receptors on their surface reside in the skin of allergic patients. The introduction of minute amounts of an allergen into the skin of the sensitized patient results in cross linking of IgE antibodies on the mast cell surface, thereby triggering local mast cell activation. Once activated, these mast cells release a variety of preformed and newly generated mediators that act on surrounding tissues. Histamine is the mediator most responsible for the immediate wheal and flare reac tions observed in skin testing. Examination of the site of a positive skin test result reveals a pruritic wheal surrounded by erythema. The time course of these reactions is rapid in onset, reaching a peak within 10 20 minutes and usually resolving over the next 30 minutes. Skin testing is performed using the prickpuncture technique. With this technique, a small drop of allergen is applied to the skin surface, and a tiny amount is introduced into the epidermis by lightly pricking or puncturing the outer layer of skin through the drop of extract with a small needle or other device. When the skin prick |
6,585 | test (SPT) result is negative but the history suggestive, selective skin testing (for vaccines, venom, drugs, and aeroallergens) using the intradermal technique may be performed. This technique involves using a 26 gauge needle to inject 0.01 0.02 mL of an allergen extract diluted 1,000 to 10 fold into the dermis of the arm. Intradermal skin tests are not recommended for use with food allergens because of the risk of triggering anaphylaxis. Irritant rather than allergic reactions can occur with intradermal skin testing if higher concentrations of extracts are used. Although skin prick testing is less sensitive than intradermal skin testing, positive SPT results tend to correlate better with clinical symptoms. The number of skin tests performed should be individualized, with the allergens suggested by the history. A positive and negative control SPT, using histamine and saline, respectively, is performed with each set of skin tests. A negative control is necessary to assess for derma tographism, in which reactions are caused merely by applying pres sure to overly sensitive skin. A positive control is necessary to establish the presence of a cutaneous response to histamine. Medications with antihistaminic properties, in addition to adrenergic agents such as ephedrine and epinephrine, suppress skin test responses and should be avoided for appropriate intervals (approximately five half lives) before skin testing. Prolonged courses of systemic corticosteroids may sup press cutaneous reactivity by decreasing the number of tissue mast cells as well as their ability to release mediators. Whether identified via serologic or skin testing, detection of sIgE denotes a sensitized state (i.e., atopy or a tendency toward develop ment of allergic disease) but is not equivalent to a clinically relevant allergic diagnosis. Many children with positive tests have no clini cal symptoms on exposure to the allergen. Increasingly strong test results (higher serum sIgE results or larger SPT wheal sizes) gener ally correlate with increasing likelihood of clinical reactivity (but not severity). Neither serologic testing nor skin testing for allergy is pre dictive of reaction severity or threshold of reactivity, and these tests will be negative when the allergy is not IgE mediated, such as in food proteininduced enterocolitis syndrome. The limitations of these test modalities underscore the need for a detailed medical history that can guide the selection and interpretation of test results. Large panels of indiscriminately performed screening tests may provide misleading information and are not recommended. Both serum sIgE tests and SPT are sensitive and have similar diag nostic properties. The benefits of the serologic immunoassays are that performance is not limited by the presence of skin disease (i.e., active atopic dermatitis) or medication use (i.e., antihistamines). Advan tages of skin testing are that they provide rapid results to the patient family during the clinic visit, do not require venipuncture, and are less costly. Under certain circumstances, provocation testing is performed to examine the association between allergen exposure and the develop ment of symptoms. The bronchial provocation test most frequently performed clinically is the methacholine challenge, which causes potent bronchoconstriction of asthmatic |
6,586 | but not of normal airways; it is performed to document the presence and degree of bronchial hyper reactivity in a patient with suspected asthma. After baseline spirometry values are obtained, increasing concentrations of nebulized methacho line are inhaled until a drop occurs in lung function, specifically a 20 decrease in FEV1 (forced expiratory volume in the first second of expi ration), or the patient is able to tolerate the inhalation of a set concen tration of methacholine, typically 25 mgmL. Oral food challenges are performed to determine whether a specific food causes symptoms or whether a suspected food can be added to the diet. Food challenges are performed when the history and results of skin tests and immunoassays for sIgE are insufficient to clarify the diagnosis of an allergy. These challenges may be performed in an open single blind, double blind, or double blind placebo controlled man ner and involve the ingestion of gradually increasing amounts of the suspected food at set intervals until the patient either experiences a reaction or tolerates a normal portion (i.e., one serving size) of the food openly. Although the double blind placebo controlled food chal lenge is currently the gold standard test for diagnosing food allergy, it is typically only performed in research studies due to the time and labor intensive nature of this method. Because of the potential for significant allergic reactions, oral food challenges should be performed only in an appropriately equipped facility with personnel experienced in the per formance of food challenges and the treatment of anaphylaxis, includ ing cardiopulmonary resuscitation. Upper gastrointestinal endoscopy is required to confirm the diag nosis of eosinophilic esophagitis. One or more biopsy specimens from the proximal and distal esophagus must show eosinophil predominant inflammation. With few exceptions, 15 eosinophils per high power field (peak value) is considered a minimum threshold for the diagnosis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 183 u Diagnosis of Allergic Disease 1378.e1 Bibliography Adkinson Jr NF, Bochner BS, Burks AW, et al., eds. Middletons allergy: principles practice. 9th ed. Philadelphia: ElsevierSaunders; 2019. Cevhertas L, Ogulur I, Maurer DJ, et al. Advances and recent developments in asth ma in 2020. Allergy. 2020;75(12):31243146. Dykewicz MS, Wallace DV, Amrol DJ, et al. Rhinitis 2020. A practice parameter up date. J Allergy Clin Immunol. 2020;146(4):721767. Gonsalves NP, Aceves SS. Diagnosis and treatment of eosinophilic esophagitis. J Al lergy Clin Immunol. 2020;145(1):17. Hew M, Menzies Gow A, Hull JH, et al. Systematic Assessment of Difficult to Treat Asthma: Principles and Perspectives. J Allergy Clin Immunol Pract. 2020;8(7):22222233. Khan DA, Banerji A, Blumenthal K et al. Drug allergy: A 2022 practice parameter Update. J Allergy Clin Immunol 2022;150(6)13331393. Nowak Wegrzyn A, Berin MC, Mehr S. Food Protein Induced Enterocolitis Syn drome. J Allergy Clin Immunol Pract. 2020;8(1):2435. Rodrigues J, Kuruvilla ME, |
6,587 | Vanijcharoenkarn K, Patel N, Hom MM, Wallace DV. The spectrum of allergic ocular diseases. Ann Allergy Asthma Immunol. 2021;126(3):240254. Sicherer SH, Warren CM, Dant C, Gupta RS, Nadeau KC. Food Allergy from Infancy Through Adulthood. J Allergy Clin Immunol Pract. 2020;8(6):1854 1864. Worm M, Vieths S, Mahler V. An update on anaphylaxis and urticaria. J Allergy Clin Immunol. 2022;150(6):12651278. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 184 u Allergic Rhinitis 1379 Allergic rhinitis (AR) is a common chronic disease affecting 2030 of children. AR is an inflammatory disorder of the nasal mucosa marked by nasal congestion, rhinorrhea, and itching, often accompanied by sneezing and conjunctival inflammation. Its recognition as a major chronic respiratory disease of children derives from its high preva lence, detrimental effects on quality of life and school performance, and comorbidities. Children with AR often have related conjunctivitis, sinusitis, otitis media, serous otitis, hypertrophic tonsils and adenoids, and eczema. Childhood AR is associated with a threefold increase in risk for asthma at an older age. Over the past 50 years an upsurge in AR has been observed throughout the world, with some symptom surveys reporting incidence rates approaching 40. Heritability of allergic con ditions attests to genetic factors, but the increase stems from changes in the environment, diet, and the microbiome. The symptoms may appear in infancy, with the diagnosis generally established by the time the child reaches age 6 years. The prevalence peaks late in childhood. Risk factors include family history of atopy and serum IgE higher than 100 IUmL before age 6 years. Early life exposures andor their absence have a profound influence on the development of the allergic phenotype. The risk increases in children who are exposed to tobacco smoke prenatally, and above all before the infants reach 1 year, and those with heavy exposure to indoor allergens. A critical period exists early in infancy when the genetically susceptible child is at greatest risk of sensitization. Delivery by cesarean section is associated with AR and atopy in children with a parental history of asthma or allergies. This association may be explained by the lack of exposure to the maternal microbiota through fecalvaginal flora during delivery. Children between 2 and 3 years old who have elevated anticockroach and antimouse IgE are at increased risk of wheezing, AR, and atopic der matitis. The occurrence of three or more episodes of rhinorrhea in the first year of life is associated with AR at age 7 years. Favorably, the expo sure to dogs, cats, and endotoxin early in childhood protects against the development of atopy. Prolonged breastfeeding, not necessarily exclu sive, is beneficial. There is also a decreased risk of asthma, AR, and atopic sensitization with early introduction to wheat, rye, oats, barley, fish, and eggs. However, reduced diversity of the intestinal microbiota during infancy is associated with increased risk of |
6,588 | allergic disease at school age. ETIOLOGY AND CLASSIFICATION Two factors necessary for expression of AR are sensitivity to an aller gen and the presence of the allergen in the environment. AR classi fication as seasonal or perennial is giving way to the designations intermittent and persistent. The two sets of terms are based on dif ferent suppositions, but inhalant allergens are the main cause of all forms of AR irrespective of terminology. AR may also be categorized as mild intermittent, moderate severe intermittent, mild persistent, and moderate severe persistent (Fig. 184.1). The symptoms of inter mittent AR occur on 4 days per week or for 4 consecutive weeks. In persistent AR, symptoms occur on 4 days per week andor for 4 consecutive weeks. The symptoms are considered mild when they are not troublesome, the sleep is normal, there is no impairment in daily activities, and there is no incapacity at work or school. Severe symp toms result in sleep disturbance and impairment in daily activities and school performance. In temperate climates, airborne pollen responsible for exacerba tion of intermittent AR appear in distinct phases: trees pollinate in the spring, grasses in the early summer, and weeds in the late summer. In temperate climates, mold spores persist outdoors only in the summer, but in warm climates they persist throughout the year. Symptoms of intermittent AR typically cease with the appearance of frost. Knowl edge of the time of symptom occurrence, the regional patterns of pol lination and mold sporulation, and the patients allergen specific IgE (sIgE) is necessary to recognize the cause of intermittent AR. Persis tent AR is most often associated with the indoor allergens: house dust mites, animal danders, mice, and cockroaches. Cat and dog allergies are of major importance in the United States. The allergens from saliva and sebaceous secretions may remain airborne for a prolonged time. The ubiquitous major cat allergen, Fel d 1, may be carried on cat own ers clothing into such cat free settings as schools and hospitals. PATHOGENESIS The exposure of an atopic host to an allergen leads to the production of sIgE, which is strongly associated with eczema throughout child hood and with asthma and rhinitis after age 4 years. The clinical reac tions on reexposure to the allergen have been designated as early phase and late phase allergic responses. Bridging of the IgE molecules on the surface of mast cells by allergen initiates the early phase allergic response, characterized by degranulation of mast cells and release of preformed and newly generated inflammatory mediators, including histamine, prostaglandin 2, and the cysteinyl leukotrienes. The late phase allergic response appears 4 8 hour following allergen exposure. Inflammatory cells, including basophils, eosinophils, neutrophils, mast cells, and mononuclear cells, infiltrate the nasal mucosa. Eosinophils release proinflammatory mediators, including cysteinyl leukotrienes, cationic proteins, eosinophil peroxidase, and major basic protein, and serve as a source of interleukin (IL) 3, IL 5, granulocyte macrophage colony stimulating factor, and IL 13. Repeated intranasal introduction of allergens causes priming, which is |
6,589 | a more brisk response even with a lesser provocation. Over the course of an allergy season, a multifold increase in submucosal mast cells takes place. These cells, once thought to have a role exclusively in the early phase allergic response, have an important function in sustaining chronic allergic disease. CLINICAL MANIFESTATIONS Symptoms of AR may be ignored or mistakenly attributed to a respira tory infection. Older children blow their noses, but younger children tend to sniff and snort. Nasal itching brings on grimacing, twitching, and picking of the nose that may result in epistaxis. Children with AR often perform the allergic salute, an upward rubbing of the nose with an open palm or extended index finger. This maneuver relieves itching and briefly unblocks the nasal airway. It also gives rise to the nasal crease, a horizontal skin fold over the bridge of the nose. The diagnosis of AR is based on symptoms in the absence of an upper respiratory tract infection and structural abnormalities. Typical complaints include Chapter 184 Allergic Rhinitis Tamara T. Perry and Scott H. Sicherer Intermittent symptoms ?4 daysweek or ?4 weeks at a time Mild Normal sleep Normal daily activities Normal work and school No troublesome symptoms Moderatetosevere One or more items Abnormal sleep Impairment of daily activities, sport and leisure Difficulties caused at school or work Troublesome symptoms Persistent symptoms ?4 days a week andor ? 4 weeks at a time Fig. 184.1 Global Allergic Rhinitis and Its Impact on Asthma (ARIA) classification of allergic rhinitis. Every box can be subclassified further into seasonal or perennial on the basis of timing of symptoms or when causative and allergen therapeutic factors are considered. For example, a UK patient with grass pollen allergy might have moderate severe per sistent seasonal rhinitis in June and July and may be suitable for specific allergen immunotherapy. (From Scadding GK, Durham SR, Mirakian R, et al. BASCI guidelines for the management of allergic and non allergic rhinitis. Clin Exp Allergy. 2008;38:1942.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1380 Part XIII u Allergic Disorders intermittent nasal congestion, itching, sneezing, clear rhinorrhea, and conjunctival irritation. Symptoms increase with greater exposure to the responsible allergen. The patients may lose their sense of smell and taste, though this has also been noted as a symptom of mild COVID 19 or other viral upper respiratory infections. Some experience headaches, wheezing, and coughing. Preschoolers with chronic wheezing and rhi nitis experience more severe wheezing than children without rhinitis. Nasal congestion is often more severe at night, inducing mouth breath ing and snoring, interfering with sleep, and rousing irritability. Signs on physical examination include abnormalities of facial devel opment, dental malocclusion, the allergic gape (continuous open mouth breathing), chapped lips, allergic shiners (dark circles under the eyes; see Fig. 183.1), and the transverse nasal crease. Conjunctival edema, itching, tearing, and |
6,590 | hyperemia are frequent findings. A nasal exam performed with a source of light and a speculum may reveal clear nasal secretions; edematous, boggy, and bluish mucus membranes with little or no erythema; and swollen turbinates that may block the nasal airway. It may be necessary to use a topical decongestant to perform an adequate examination. Thick, purulent nasal secretions indicate the presence of infection. DIFFERENTIAL DIAGNOSIS Evaluation of AR entails a thorough history, including details of the patients environment and diet and a family history of allergic con ditions (e.g., eczema, asthma, AR), physical examination, and labo ratory evaluation. The history and laboratory findings provide clues to the provoking factors. Symptoms such as sneezing, rhinorrhea, nasal itching, and congestion and lab findings of elevated IgE, sIgE antibodies, and positive allergy skin test results typify AR. Intermit tent AR differs from persistent AR by history and skin test results. Nonallergic rhinitides give rise to sporadic symptoms; their causes are often unknown. Nonallergic inflammatory rhinitis with eosino phils imitates AR in presentation and response to treatment, but without elevated IgE antibodies. Vasomotor rhinitis is characterized by excessive responsiveness of the nasal mucosa to physical stimuli. Other nonallergic conditions, such as infectious rhinitis, structural problems (e.g., nasal polyps, septal deviation), rhinitis medica mentosa (caused by overuse of topical vasoconstrictors), hormonal rhinitis associated with pregnancy or hypothyroidism, neoplasms, vasculitides, and granulomatous disorders may mimic AR (Table 184.1 and Fig. 184.2). Occupational risks for rhinitis include expo sure to allergens (grain dust, insects, latex, enzymes) and irritants (wood dust, paint, solvents, smoke, cold air). COMPLICATIONS AR is associated with complications and comorbid conditions. Under treated AR detracts from the quality of life, aggravates asthma, and enhances its progression. Children with AR experience frustration over their appearance. Allergic conjunctivitis, characterized by itch ing, redness, and swelling of the conjunctivae, has been reported in at least 20 of the population and 70 of patients with AR, most frequently in older children and young adults. The two conditions share pathophysiologic mechanisms and epidemiologic characteris tics (see Chapter 188). Chronic sinusitis is a common complication of AR, sometimes associated with purulent infection, but most patients have negative bacterial cultures despite marked mucosal thickening, and sinus opacification. The inflammatory process is characterized by marked eosinophilia. Aspirin exacerbated respiratory disease (AERD) is character ized by the presence of chronic rhinosinusitis with nasal polyposis, asthma, and aspirin sensitivity. The pathophysiology of AERD is not fully understood and symptoms often respond poorly to therapy such as leukotriene modifiers, intranasal or systemic steroids, and aspirin desensitization. Surgical removal of nasal polyps is also a common intervention; however, the rate of recurrence is high with frequent regrowth of polyps. New biologic therapies are available for patients with chronic rhinosinusitis with nasal polyposis and patients with AERD may benefit from the addition of these new therapies. Rhinitis that coexists with asthma may be taken too lightly or com pletely overlooked. Up to 78 of patients with asthma have AR, and 38 of patients with AR have |
6,591 | asthma. Aggravation of AR coincides with exacerbation of asthma, and treatment of nasal inflammation reduces bronchospasm, asthma related emergency department visits, and hospitalizations. Postnasal drip associated with AR commonly causes persistent or recurrent cough. Eustachian tube obstruction Table 184.1 Causes of Rhinitis ALLERGIC RHINITIS Seasonal Perennial Perennial with seasonal exacerbations NONALLERGIC RHINITIS StructuralMechanical Factors Deviated septumseptal wall anomalies Hypertrophic turbinates Adenoidal hypertrophy Foreign bodies Nasal tumors Benign Malignant Choanal atresia CSF leakage Infectious Acute infections Chronic infections Congenital syphilis InflammatoryImmunologic Granulomatosis with polyangiitis Sarcoidosis Midline granuloma Systemic lupus erythematosus Sjgren syndrome Nasal polyposis Physiologic Primary ciliary dyskinesia Atrophic rhinitis Hormonally induced Hypothyroidism Pregnancy Oral contraceptives Menstrual cycle Exercise Atrophic Drug induced Rhinitis medicamentosa Oral contraceptives Antihypertensive therapy Aspirin Nonsteroidal antiinflammatory drugs Cocaine Reflex induced Gustatory rhinitis Chemical or irritant induced Posture reflexes Nasal cycle Environmental factors Odors Temperature (cold air) Weatherbarometric pressure Occupational (irritants) OTHER Nonallergic rhinitis with eosinophilia syndrome Perennial nonallergic rhinitis (vasomotor rhinitis) Emotional factors From Skoner DP. Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol. 2001;108(1 Suppl);108:S2S8. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 184 u Allergic Rhinitis 1381 and middle ear effusion are frequent complications. Chronic allergic inflammation causes hypertrophy of adenoids and tonsils that may be associated with eustachian tube obstruction, serous effusion, otitis media, and obstructive sleep apnea. AR is linked to snoring in children. The association between rhinitis and sleep abnormalities and subse quent daytime fatigue is well documented and may require multidisci plinary intervention. The Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) is suitable for children 6 12 years old, and the Adolescent Rhinoconjunctivitis Quality of Life Questionnaire (ARQLQ) is appro priate for patients 12 17 years old. Children with rhinitis have anxiety and physical, social, and emotional issues that affect learning and the ability to integrate with peers. The disorder contributes to headaches and fatigue, limits daily activities, and interferes with sleep. There is evidence of impaired cognitive functioning and learning that may be exacerbated by the adverse effects of sedating medications. AR causes an estimated 824,000 missed school days and 4,230,000 days of decline in quality of life activities. Patients with AR report an impairment in the activities of daily living similar to patients with moderate to severe asthma. Some (but not many) patients improve during their teenage years, only to develop symptoms again as young adults. Symptoms often abate in the fifth decade of life. LABORATORY FINDINGS Epicutaneous skin tests provide the best method for detection of sIgE, with a positive predictive value (PPV) of 48.7 for epidemiologic diag nosis of AR. Skin tests are inexpensive and sensitive, and the risks and discomfort are minimal. Responses to seasonal respiratory allergens are rare before two seasons of exposure, and children 1 year old sel dom display positive skin test responses to these allergens. To avoid false negative results, |
6,592 | montelukast should be withheld for 1 day, most sedating antihistamine preparations for 3 4 days, and nonsedating antihistamines for 5 7 days. Serum immunoassays for sIgE provide a suitable alternative (PPV of 43.5) for patients with dermatographism or extensive dermatitis, those taking medications that interfere with mast cell degranulation, others at high risk for anaphylaxis, and some who cannot cooperate with the procedure. Presence of eosinophils in the nasal smear supports the diagnosis of AR, and neutrophils suggest infectious rhinitis. Eosinophilia and measurements of total serum IgE concentrations have relatively low sensitivity. TREATMENT Guideline directed management has been shown to improve disease control. Global Allergic Rhinitis and its Impact on Asthma (ARIA) provides an evidence based approach to treatment and includes quality of life measures useful for the evaluation of symptoms and the assessment of the response to therapy. Safe effective prevention and relief of symptoms are the current goals of treatment. Specific measures to limit indoor allergen exposure may reduce the risk of sensitization and symptoms of allergic respiratory disease. Sealing the patients mattress, pillow, and covers in allergen proof encasings reduces the exposure to mite allergen. Bed linen and blankets should be washed every week in hot water (54.4C 130F). The only effective measure for avoiding animal allergens in the home is the removal of the pet. Avoidance of pollen and outdoor molds can be accomplished by staying in a controlled environment. Air conditioning allows for keep ing windows and doors closed, reducing the pollen exposure. High efficiency particulate air (HEPA) filters lower the counts of airborne mold spores. Oral antihistamines help reduce sneezing, rhinorrhea, and ocular symptoms. Administered as needed, antihistamines provide accept able treatment for mild intermittent disease. Antihistamines have been Negative skinprick test and nasal allergen challenge Positive skinprick test andor nasal allergen challenge Occupational (allergic and nonallergic) Acute rhinosinusitis Chronic rhinosinusitis cigrellanoNcigrellA Infective Exclude predisposing causes Cystic fibrosis Primary ciliary dyskinesia Immunodeficiency Immunopathology Polyps Nonallergic rhinitis with eosinophilia Consider aspirin, entopy (local nasal IgE) Immunopathologic findings Eosinophilic granulomatosis with polyangiitis Granulomatosis with polyangiitis Sarcoidosis Relapsing polychondritis Systemic lupus erythematosus Structural abnormalities Deviated septum Nasal valve dysfunction Nasal polyps Foreign body Adenoidal hypertrophy Choanal atresia Cerebrospinal fluid leak Nasal or CNS tumors Druginduced Oral contraceptive Rhinitis medicamentosa Antihypertensives Cocaine use Aspirin or NSAID Others Noninfective, nonallergic rhinitis Neurogenic (gustatory, emotional, coldair induced) Atrophic Gastroesophageal reflux Idiopathic Hormonal Pregnancy Menstrual cycle Puberty Hormone replacement therapy Acromegaly Hypothyroidism Noninfective Rhinitis Fig. 184.2 Diagnostic algorithm for rhinitis. Nasal allergen challenge is a research procedure and is not undertaken routinely. CNS, Central nervous system; NSAID, nonsteroidal antiinflammatory drug. (From Greiner AN, Hellings PW, Rotiroti G, Scadding GK. Allergic rhinitis. Lancet. 2011;378:21122120.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1382 Part XIII u Allergic Disorders classified as first generation (relatively sedating) or second generation (relatively nonsedating). Antihistamines usually are administered by mouth but |
6,593 | are also available for topical ophthalmic and intranasal use. Both first and second generation antihistamines are available as non prescription drugs. Second generation antihistamines are preferred because they cause less sedation. Preparations containing pseudo ephedrine, typically in combination with other agents, are used for relief of nasal and sinus congestion and pressure and other symptoms such as rhinorrhea, sneezing, lacrimation, itching eyes, oronasopha ryngeal itching, and cough. These are not considered first line agents and should be used with caution. Pseudoephedrine is available with out prescription generally in fixed combination with other agents such as first generation antihistamines (brompheniramine, chlorphenira mine, triprolidine), second generation antihistamines (desloratadine, fexofenadine, loratadine), antipyretics (acetaminophen, ibuprofen), antitussives (guaifenesin, dextromethorphan), and an anticholinergic (methscopolamine). Pseudoephedrine is an oral vasoconstrictor dis trusted for causing irritability and insomnia and for its association with infant mortality. Because younger children (2 3 years) are at increased risk of overdosage and toxicity, some manufacturers of oral nonpre scription cough and cold preparations have voluntarily revised their product labeling to warn against the use of preparations containing pseudoephedrine for children 4 years old. Pseudoephedrine is mis used as a starting material for the synthesis of methamphetamine and methcathinone. Tables 184.2, 184.3, and 184.4 provide examples of pre scription, nonprescription, and combined oral agents, respectively, for treatment of AR. Oral leukotriene receptor antagonists are not recom mended for initial treatment of AR because of reduced efficacy com pared to other agents and serious neuropsychiatric events that have been reported with montelukast. The anticholinergic nasal spray ipratropium bromide is effec tive for the treatment of serous rhinorrhea (Table 184.5). Intranasal decongestants (oxymetazoline and phenylephrine) should be used for 5 days and should not to be repeated more than once a month to avoid rebound nasal congestion. Sodium cromoglycate (available as nonprescription drug) is effective but requires frequent adminis tration, every 4 hours. Leukotriene modifying agents have a modest effect on rhinorrhea and nasal blockage (see Chapter 185 for addi tional indications and side effects). Nasal saline irrigation is a good adjunctive option with all other treatments of AR. Patients with more persistent, severe symptoms require intranasal corticosteroids, the most effective therapy for AR, which may also be beneficial for con comitant allergic conjunctivitis (Table 184.6). These agents reduce the symptoms of AR with eosinophilic inflammation, but not those of rhinitis associated with neutrophils or free of inflammation. Beclo methasone, triamcinolone, and flunisolide are absorbed from the gas trointestinal tract, as well as from the respiratory tract; budesonide, fluticasone, mometasone, and ciclesonide offer greater topical activ ity with lower systemic exposure. More severely affected patients may benefit from simultaneous treatment with oral antihistamines and intranasal corticosteroids. Allergen specific immunotherapy is a well defined treatment for IgE mediated allergic disease. It may be administered by subcutane ous or sublingual routes. Sublingual immunotherapy (SLIT) has been used successfully in Europe and South America and is now approved by the U.S. Food and Drug Administration. Allergy immunotherapy (AIT) is an effective treatment for AR and allergic conjunctivitis. In |
6,594 | addition to reducing symptoms, it may change the course of allergic disease and induce allergen specific immune tolerance. Immunother apy should be considered for children in whom IgE mediated allergic symptoms cannot be adequately controlled by avoidance and medi cation, especially in the presence of comorbid conditions. Immuno therapy for AR prevents the onset of asthma. Moreover, progress in molecular characterization of allergens raises the possibility of defined vaccines for allergen immunotherapy. Omalizumab (anti IgE anti body) is effective for difficult to control asthma and is likely to have a beneficial effect on coexisting AR. Dupilumab (IL 4 antagonist) is approved in adults for the treatment of chronic rhinosinusitis with nasal polyposis and has shown improvement in nasal symptoms scores as well as improvements in lung function among patients with AERD. Typically, treatment of AR with oral antihistamines and nasal cor ticosteroids provides sufficient relief for most patients with coexisting allergic conjunctivitis. If it fails, additional therapies directed primar ily at allergic conjunctivitis may be added (see Chapter 188). Intranasal corticosteroids are of some value for the treatment of ocular symptoms, but ophthalmic corticosteroids remain the most potent pharmacologic agents for ocular allergy, although they carry the risk of adverse effects such as delayed wound healing, secondary infection, elevated intraoc ular pressure, and formation of cataracts. Ophthalmic corticosteroids are only suited for the treatment of allergic conjunctivitis that does not respond to the medications previously discussed. Sound practice calls for the assistance of an ophthalmologist. Table 184.2 Oral Allergic Rhinitis Treatments (Prescription, Examples) GENERICBRAND STRENGTH FORMULATIONS DOSING SECOND GENERATION ANTIHISTAMINES Desloratadine Clarinex Reditabs 2.5 mg, 5 mg Orally disintegrating tablet Children 6 11 mo of age: 1 mg once daily Clarinex Tablets 5 mg Tabs Children 12 mo to 5 yr: 1.25 mg once daily Clarinex Syrup 0.5 mgmL Syrup Children 6 11 yr: 2.5 mg once daily Adults and adolescents 12 yr: 5 mg once daily LEUKOTRIENE ANTAGONIST Montelukast Singulair 10 mg Tablets 6 mo to 5 yr: 4 mg daily Singulair Chewables 4 mg, 5 mg Chewable tablets 6 14 yr: 5 mg daily Singulair Oral Granules 4 mgpacket Oral granules 14 yr: 10 mg daily Contains phenylalanine As advised by the FDA, montelukast should be used to treat allergic rhinitis only in patients who are not treated effectively with or cannot tolerate other alternative therapies. Dosing recommendations taken in part from Kleinman K, McDaniel L, Molloy M for the Johns Hopkins Hospital. The Harriet Lane Handbook. 22nd ed. Philadelphia: Elsevier; 2021. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 184 u Allergic Rhinitis 1383 Table 184.3 Oral Allergic Rhinitis Treatments (Nonprescription, Examples) GENERICBRAND STRENGTH FORMULATIONS DOSING FIRST GENERATION H1 ANTAGONISTS Chlorpheniramine maleate Chlor Trimeton OTC 4 mg Tablets 2 5 yr: 1 mg every 4 6 hr (max 6 mgday) 6 11 yr: 2 mg every 4 6 hr (max |
6,595 | 12 mgday) Chlor Trimeton Syrup OTC 2 mg5 mL Syrup 12 yr: 4 mg every 4 6 hr (max 24 mgday) SECOND GENERATION H1 ANTAGONISTS Cetirizine Childrens Zyrtec Allergy Syrup OTC 1 mgmL Syrup 611 mo: 2.5 mg daily Childrens Zyrtec Chewable OTC 5 mg, 10 mg Chewable tablets 12 23 mo: initial 2.5 mg once daily; dosage may be increased to 2.5 mg twice daily Zyrtec Tablets OTC 5 mg, 10 mg Tablets 2 5 yr: 2.5 mgday; may be increased to max of 5 mgday given either as a single dose or divided into two doses Zyrtec Liquid Gels OTC 10 mg Liquid filled gels 6 yr: 5 10 mgday as a single dose or divided into two doses Levocetirizine Xyzal 5 mg 0.5 mgmL Tablet Oral solution 6 mo 5 yr: 1.25 mg daily in the evening 6 11 yr: 2.5 mg daily in the evening 12 yr: 5 mg daily in the evening Desloratadine Clarinex 0.5 mgmL Oral solution 6 11 mo: 1 mg daily 1 5 yr: 1.25 mg daily 6 11 yr: 2.5 mg daily Clarinex 5 mg Tablet 12 yr 5 mg daily Fexofenadine HCl OTC 30 mg, 60 mg, 180 mg Tablet 6 11 yr: 30 mg twice daily 12 adult: 60 mg twice daily; 180 mg daily Childrens Allegra OTC ODT 30 mg ODTs 6 11 yr: 30 mg twice daily Childrens Allegra Oral Suspension OTC 30 mg5 mL Suspension 2 11 yr: 30 mg every 12 hr Allegra OTC Tabs 30, 60, 180 mg Tablet 12 yr adult: 60 mg every 12 hr; 180 mg daily Loratadine Childrens Claritin OTC Alavert OTC ODT 5 mg5 mL 10 mg 10 mg 10 mg 5 mg 1 mgmL Syrup ODTs Tablets Liquid filled caps Chewable tablets Syrup 2 5 yr: 5 mg daily 6 adult: 10 mg daily 2 5 yr: 5 mg daily 6 yr: 10 mg once daily or 5 mg twice daily Contains phenylalanine. ODT, Orally disintegrating tablet; OTC, over the counter. Dosing recommendations taken in part from Kleinman K, McDaniel L, Molloy M for the Johns Hopkins Hospital. The Harriet Lane Handbook. 22nd ed. Philadelphia: Elsevier; 2021. Table 184.4 Combined Antihistamine Sympathomimetic (Examples) GENERIC STRENGTH FORMULATIONS DOSING Chlorpheniramine maleate Phenylephrine HCl Sudafed Sinus Allergy 4 mg 10 mg Tablets 12 yr: 1 tablet every 4 hr, not to exceed 6 tablets per day Cetirizine pseudoephedrine Zyrtec D 12 hour 5 mg cetirizine 120 mg pseudoephedrine Extended release tablet 12 yr: 1 tablet every 12 hr Dosing recommendations taken in part from Kleinman K, McDaniel L, Molloy M for the Johns Hopkins Hospital. The Harriet Lane Handbook. 22nd ed. Philadelphia: Elsevier; 2021. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1384 Part XIII u Allergic Disorders Table 184.5 Miscellaneous Intranasal Sprays DRUG INDICATIONS (I), MECHANISM(S) OF ACTION (M), AND DOSING COMMENTS, CAUTIONS, ADVERSE |
6,596 | EVENTS, AND MONITORING Ipratropium bromide I: Symptomatic relief of rhinorrhea M: Anticholinergic Atrovent inhalation aerosol is contraindicated in patients with hypersensitivity to soy lecithin Safety and efficacy of use beyond 4 days in patients with the common cold have not been established Adverse effects: Epistaxis, nasal dryness, nausea Atrovent nasal spray (0.06) Colds (symptomatic relief of rhinorrhea): 5 12 yr: 2 sprays in each nostril tid 12 yr and adults: 2 sprays in each nostril tid qid Azelastine I: Treatment of rhinorrhea, sneezing, and nasal pruritus M: Antagonism of histamine H1 receptor May cause drowsiness Adverse effects: Headache, somnolence, bitter taste Astelin 6 12 yr: 1 spray bid 12 yr: 1 2 sprays bid Cromolyn sodium I: AR M: Inhibition of mast cell degranulation Not effective immediately; requires frequent administration NasalCrom 2 yr: 1 spray tid qid; max 6 times daily Oxymetazoline Afrin Nostrilla I: Symptomatic relief of nasal mucosal congestion M: Adrenergic agonist, vasoconstricting agent 0.05 solution: instill 2 3 sprays into each nostril bid; therapy should not exceed 3 days Excessive dosage may cause profound CNS depression Use in excess of 3 days may result in severe rebound nasal congestion Do not repeat more than once a month Use with caution in patients with hyperthyroidism, heart disease, hypertension, or diabetes Adverse effects: Hypertension, palpitations, reflex bradycardia, nervousness, dizziness, insomnia, headache, CNS depression, convulsions, hallucinations, nausea, vomiting, mydriasis, elevated intraocular pressure, blurred vision Phenylephrine I: Symptomatic relief of nasal mucosal congestion M: Adrenergic, vasoconstricting agent Use in excess of 3 days may result in severe rebound nasal congestion Do not repeat more than once a month 0.16 and 0.125 solutions are not commercially available Adverse effects: Reflex bradycardia, excitability, headache, anxiety, dizziness Neo Synephrine 2 6 yr: 1 drop every 2 4 hr of 0.125 solution as needed Note: Therapy should not exceed 3 continuous days 6 12 yr: 1 2 sprays or 1 2 drops every 4 hr of 0.25 solution as needed Note: Therapy should not exceed 3 continuous days 12 yr: 1 2 sprays or 1 2 drops every 4 hr of 0.25 to 0.5 solution as needed; 1 solution may be used in adults with extreme nasal congestion Note: Therapy should not exceed 3 continuous days bid, 2 times daily; CNS, central nervous system; tid, 3 times daily; qid, 4 times daily. Table 184.6 Intranasal Inhaled Corticosteroids DRUG INDICATIONS (I), MECHANISM(S) OF ACTION (M), AND DOSING COMMENTS, CAUTIONS, ADVERSE EVENTS, AND MONITORING Beclomethasone OTC I: AR M: Antiinflammatory, immune modulator Shake container before use; blow nose; occlude one nostril, administer dose to the other nostril Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth Beconase AQ (42 gspray) Qnasl (80 gspray) OTC 6 12 yr: 1 spray in each nostril bid; may increase if needed to 2 sprays in each nostril bid 12 yr: 1 or 2 sprays in each nostril bid Flunisolide OTC 6 14 yr: 1 spray in each nostril tid or 2 sprays in each nostril bid; not to exceed |
6,597 | 4 spraysday in each nostril 15 yr: 2 sprays in each nostril bid (morning and evening); may increase to 2 sprays tid; maximum dose: 8 spraysday in each nostril (400 gday) Shake container before use; blow nose; occlude one nostril, administer dose to the other nostril Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 184 u Allergic Rhinitis 1385 Table 184.6 Intranasal Inhaled Corticosteroidscontd DRUG INDICATIONS (I), MECHANISM(S) OF ACTION (M), AND DOSING COMMENTS, CAUTIONS, ADVERSE EVENTS, AND MONITORING Triamcinolone Nasacort AQ (55 gspray) OTC Fluticasone propionate (available as generic preparation) OTC I: AR M: Antiinflammatory, immune modulator Shake container before use; blow nose; occlude one nostril, administer dose to the other nostril Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth 2 6 yr: 1 spray in each nostril qd 6 12 yr: 1 2 sprays in each nostril qd 12 yr: 2 sprays in each nostril qd I: AR M: Antiinflammatory, immune modulator Shake container before use; blow nose; occlude one nostril, administer dose to the other nostril Ritonavir significantly increases fluticasone serum concentrations and may result in systemic corticosteroid effects Use fluticasone with caution in patients receiving ketoconazole or other potent cytochrome P450 3A4 isoenzyme inhibitor Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth Flonase (50 gspray) OTC 4 yr: 1 2 sprays in each nostril qd Fluticasone furoate Veramyst (27.5 gspray) 2 12 yr: Initial dose: 1 spray (27.5 gspray) per nostril qd (55 gday) Patients who do not show adequate response may use 2 sprays per nostril qd (110 gday) Once symptoms are controlled, dosage may be reduced to 55 g qd Total daily dosage should not exceed 2 sprays in each nostril (110 g)day 12 yr and adolescents: Initial dose: 2 sprays (27.5 gspray) per nostril qd (110 gday) Once symptoms are controlled, dosage may be reduced to 1 spray per nostril qd (55 gday) Total daily dosage should not exceed 2 sprays in each nostril (110 g)day Mometasone I: AR M: Antiinflammatory, immune modulator Mometasone and its major metabolites are undetectable in plasma after nasal administration of recommended doses Preventive treatment of seasonal AR should begin 2 4 wk before pollen season Shake container before use; blow nose; occlude one nostril, administer dose to the other nostril Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth Nasonex (50 gspray) 2 12 yr: 1 spray in each nostril qd 12 yr: 2 sprays in each nostril qd Budesonide OTC I: AR M: Antiinflammatory, immune modulator Shake container before use; blow nose; occlude one nostril, administer dose to the other nostril Adverse effects: Burning and irritation of nasal mucosa, epistaxis Monitor growth Rhinocort Aqua (32 gspray) OTC 6 12 yr: 2 sprays in each nostril qd 12 yr: up to |
6,598 | 4 sprays in each nostril qd (max dose) Ciclesonide I: AR M: Antiinflammatory, immune modulator Before initial use, gently shake, then prime the pump by actuating 8 times If the product is not used for 4 consecutive days, gently shake and reprime with 1 spray or until a fine mist appearsOmnaris Zetonna (50 gspray) 2 12 yr: 1 2 sprays in each nostril qd 12 yr: 2 sprays in each nostril qd Azelastinefluticasone (137 g azelastine50 g fluticasone) Dymista 6 yr: 1 spray in each nostril bid Shake bottle gently before using Blow nose to clear nostrils Keep head tilted downward when spraying Insert applicator tip 14 to 12 inch into nostril, keeping bottle upright, and close off the other nostril Breathe in through nose While inhaling, press pump to release spray OTC, Over the counter; AR, allergic rhinitis; qd, once daily; bid, 2 times daily; tid, 3 times daily. PROGNOSIS Therapy with nonsedating antihistamines and topical corticosteroids, when taken appropriately, improves health related quality of life mea sures in patients with AR. The reported rates of remission among chil dren are 1023. Pharmacotherapy that will target cells and cytokines involved in inflammation and treat allergy as a systemic process is on the horizon, and more selective targeting of drugs based on the development of specific biomarkers and genetic profiling may soon be realized. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 184 u Allergic Rhinitis 1385.e1 Bibliography Burks AW, Calderon MA, Casale T, et al. Update on allergy immunotherapy: Ameri can Academy of Allergy, Asthma ImmunologyEuropean Academy of Allergy and Clinical ImmunologyPRACTALL consensus report. J Allergy Clin Immunol. 2013;131:12881296. Codispoti CD, Bernstein DI, Levin L, et al. Early life mold and tree sensitivity is as sociated with allergic eosinophilic rhinitis at 4 yr of age. Ann Allergy Asthma Im munol. 2015;114:193198.e4. Cox LS. Sublingual immunotherapy for allergic rhinitisis 2 year treatment suffi cient for long term benefit? JAMA. 2017;317(6):591593. Dykewicz MS, Wallace DV, Amrol DJ, et al. Rhinitis 2020: A practice parameter up date. J Allergy Clin Immunol. 2020;146(4):721767. Federal Drug Administration. Singulair (montelukast) and all montelukast generics: strengthened boxed warning due to restricting use for allergic rhinitis. https:w ww.fda.govsafetymedical product safety informationsingulair montelukast and all montelukast generics strengthened boxed warning due restricting use. Garcia Aymerich J, Benet M, Saeys Y, et al. Phenotyping asthma, rhinitis and eczema in MeDALL population based birth cohorts: an allergic comorbidity cluster. Al lergy. 2015;70:973984. Kim JM, Lin SY, Suarez Cuervo C, et al. Allergen specific immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review. Pediatrics. 2013;131(6):11551167. Laidlaw TM, Mullol J, Fan C, et al. Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD. J Allergy Clin Immunol Pract. 2019;7:2462. Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treat ment |
6,599 | of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA. 2013;309:12781288. Patil VK, Kurukulaaratchy RJ, Venter C, et al. Changing prevalence of wheeze, rhini tis and allergic sensitisation in late childhood: Findings from 2 Isle of Wight birth cohorts 12 yr apart. Clin Exp Allergy. 2015;45:14301438. Roberts G, Xatzipsalti M, Borrego LM, et al. Paediatric rhinitis: position paper of the European Academy of Allergy and Clinical Immunology. Allergy. 2013;68:1102 1116. Scadding GK. Optimal management of allergic rhinitis. Arch Dis Child. 2015;100:576 582. Schmitt J, Schwarz K, Stadler E, et al. Allergy immunotherapy for allergic rhinitis ef fectively prevents asthma: results from a large retrospective cohort study. J Allergy Clin Immunol. 2015;136:15111516. The Medical Letter. Allergic rhinitis. Med Lett Drugs Ther. 2017;59:7180. Valenta R, Campana R, Focke Tejkl M, et al. Vaccine development for allergen specific immunotherapy based on recombinant allergens and synthetic allergen peptides: lessons from the past and novel mechanisms of action for the future. J Allergy Clin Immunol. 2016;137:351357. Wallace DV, Dykewicz MS, Oppenheimer J, et al. Pharmacologic treatment of sea sonal allergic rhinitis: synopsis of guidance from the 2017 joint task force on prac tice parameter. Ann Intern Med. 2017;167:876881. Westman M, Lupinek C, Bousquet J, et al. Early childhood IgE reactivity to pathogenesis related class 10 proteins predicts allergic rhinitis in adolescence. J Allergy Clin Immunol. 2015;135. 1199 1206.e11199 1206.e11. Wheatly LM, Togias A. Allergic rhinitis. N Engl J Med. 2015;372(15):456462. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 185 u Childhood Asthma 1387 bronchiolitis in the first year of life is a significant predisposing factor for asthma at age 5 years. This association implies that host features affecting immunologic host defense, inflammation, and the extent of airways injury from ubiquitous viral pathogens underlie susceptibil ity to recurrent wheezing in early childhood. Other airways exposures can also exacerbate ongoing airways inflammation, increase disease severity, and drive asthma persistence. Home allergen exposures in sensitized individuals can initiate airways inflammation and hypersen sitivity to other irritant exposures and are causally linked to disease severity, exacerbations, and persistence. Consequently, eliminating the offending allergen(s) can lead to resolution of asthma symptoms. Environmental tobacco smoke and common air pollutants can aggra vate airways inflammation and increase asthma severity. Cold, dry air; hyperventilation from physical play or exercise; and strong odors can trigger bronchoconstriction. Although many exposures that trigger and aggravate asthma are well recognized, the causal environmental features underlying the development of host susceptibilities to the vari ous common airway exposures are not as well defined. Living in rural or farming communities may be a protective environmental factor. EPIDEMIOLOGY Asthma is a common chronic disease, causing considerable morbidity. In 2020 7 million children (11 of U.S. children) had been diag nosed with asthma, with 70 of this group reporting current asthma. Male gender and living in poverty are demographic risk factors for having childhood asthma |
6,600 | in the United States. About 13 of males vs 9 of females have had asthma, and 15 of all children living in poor families (family income less than poverty threshold) have asthma. Childhood asthma is among the most common causes of childhood emergency department (ED) visits, hospitalizations, and missed school days. In the United States in 2019, childhood asthma accounted for 750,000 ED visits, nearly 75,000 hospitalizations, and 178 deaths. However, there are ethnic disparities in asthma outcomes, with nearly three times more deaths as a result of asthma in Black non Hispanic vs White non Hispanic children. Worldwide, childhood asthma appears to be increasing in preva lence, despite considerable improvements in our management and pharmacopeia to treat asthma. Although childhood asthma may have plateaued in the United States after 2008, numerous studies conducted in other countries have reported an increase in asthma prevalence of approximately 50 per decade. Globally, childhood asthma preva lence varies widely in different locales. A study of childhood asthma prevalence in 233 centers in 97 countries (International Study of Asthma and Allergies in Childhood, Phase 3) found a wide range in the prevalence of current wheeze in 67 year old children (2.437.6) and 1314 year old children (0.832.6). Asthma prevalence corre lated well with reported allergic rhinoconjunctivitis and atopic eczema prevalence. Childhood asthma seems more prevalent in modern met ropolitan locales and more affluent nations, and is strongly linked with other allergic conditions. In contrast, children living in rural areas of developing countries and farming communities with domestic animals are less likely to experience asthma and allergy. Approximately 80 of all asthmatic patients report disease onset before 6 years of age. However, of all young children who experience recurrent wheezing, only a minority go on to have persistent asthma in later childhood. Early childhood risk factors for persistent asthma have been identified (Table 185.1) and have been described as major (parent asthma, eczema, inhalant allergen sensitization) and minor (allergic rhinitis, wheezing apart from colds, 4 peripheral blood eosinophils, food allergen sensitization) risk factors. Allergen sensitization (allergy) in young children with recurrent cough andor wheeze is the strongest identifiable factor for the persistence of childhood asthma. Types of Childhood Asthma There are two common types of childhood asthma based on different natural courses: (1) recurrent wheezing in early childhood, primarily triggered by common respiratory viral infections, that usually resolves during the preschoollower school years and (2) chronic asthma associ ated with allergy that persists into later childhood and often adulthood (Table 185.2). School age children with mild to moderate persistent asthma generally improve as teenagers. About 40 of these children, most of whom have milder disease, will develop intermittent disease. Inhaled corticosteroid (ICS) controller therapy for children with persis tent asthma does not alter the likelihood of outgrowing asthma in later childhood; however, reduced lung growth and progressive decline in lung function can be features of persistent, problematic disease. Asthma is also classified by disease severity (e.g., intermittent or persistent mild, moderate, or severe) or control |
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