Ebook Transplant infections (3rd edition): Part 2
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Ebook Transplant infections (3rd edition): Part 2
SECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2STRUCTURE AND REPLICATIONHuman cytomegalovirus (HCMV) IS a member of the betasubfamily of the herpesviridae, along with human herpesvirus (HHV)-
6 and HHV-7. The CMV virion is composed of a double-stranded DNA genome encased in an i Cl wa hedral capsid. Surrounding the capsid is a region known Ebook Transplant infections (3rd edition): Part 2as the tegument (or matrix) and an outermost lipid membrane containing viral glycoproteins, which mediate viral binding to and entry into the host celEbook Transplant infections (3rd edition): Part 2
l.The genome contains approximately 23(1 thousand base pairs of DNA that encode approximately 200 proteins, and is organized into long and short uniquSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2 is the 97th open reading frame (ORF) in the unique long segment. Some genes also have names based on historical usage or homologies to genes of other herpesvi ruses; ƯL55, for example, is also known as glycoprotein B.CMV grows in a limited number of cell lines in the laboratory, such as diploid hum Ebook Transplant infections (3rd edition): Part 2an fibroblasts, endothelial cells, and macrophages. During human infection, however, CMV has been found in a wide range of cells, including endotheliaEbook Transplant infections (3rd edition): Part 2
l cells, epithelial cells, blood cells including neutrophils, and smooth muscle cells (3). The presence of CMV in these cells may lx- due to active reSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2n.The ability to persist in a latent state in which evidence of viral replication is undetectable but replication -Competent virus is present is a hallmark of herpesviruses. In the case of CMV, little is known about the site or mechanisms of latency. Since CMV can be transmitted from seropositive bl Ebook Transplant infections (3rd edition): Part 2oixl donors, a blixxl component is likely to be one site of latency. Several studies suppoit the idea that cells of the granulocyte-monocyte lineage hEbook Transplant infections (3rd edition): Part 2
arbor latent CMV (4-6). Transplantation of solid organs clearly can transmit CMV, so it is possible that cells other than those mentioned above can haSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2lls is not yet clear.INTERACTION OF CMV WITH THE HOST IMMUNE SYSTEMAdaptive ImmunityThe importance of a competent immune system in controlling C.MV replication is manifested by the clear association of immunosuppression with CMV disease. The role of humoral immunity in controlling CM V replication i Ebook Transplant infections (3rd edition): Part 2s not clear. Antibodies to multiple different CMV proteins, primarily glycoproteins 1' (gB) and H (gH), develop during infection (7-9). Although antibEbook Transplant infections (3rd edition): Part 2
odies to gB and gH can neutralize the virus in cell culture, they do not appear to prevent primary infection in adults, but rather may function to limSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2hocyte (CTL) response, anil the proportion of circulating CD8+ T-cells in healthy individuals that arc specific for CMV antigens ranges from 10% to 40%. depending on the age of the person (12-17). Numerous CMV proteins arc targeted by the CD8+ T-cell response, the most immunodominant ones being the Ebook Transplant infections (3rd edition): Part 2gene products of ƯLI23 (IE-1), UL122 (IE-2), and UL83 (pp65) (14,17-23). l_ick of CMV-spccific C.D8+ CTL responses predispose to CMV infection, whereaEbook Transplant infections (3rd edition): Part 2
s reconstitution of CMV-spccific CD84- CTL responses after hematopoietic cell transplantation (HCT) correlates with protection from CMV and improved oSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2f CMV-specific CD44- cells IS associated with late CMV disease and death in patients who have undergone HCT (32). CMV-specific CD4+ cells likely function at least in part by helping to maintain robust CMV-spccific CD84- cell responses (28,33).Innate ImmunityInnate immunity also functions to control Ebook Transplant infections (3rd edition): Part 2CMV replication. CMV triggers cellular inflammatory cytokine production upon binding to the target cell, mediated in part by the interaction of gB andEbook Transplant infections (3rd edition): Part 2
gH with toll-like receptor (TLB) 2 (34-36). Polymorphisms in TLR2 have been associated with CMV311312 Section V • Vital infectionsinfection after livSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2).Natural killer (NK) cells represent another arm of the innate immune response and have been shown to limit MCMV replication in mice (25,40-44). In humans, NK cell responses increase during CMV infection after renal transplantation, and a deficiency in NK cells is associated with severe CMV infecti Ebook Transplant infections (3rd edition): Part 2on (among other herpcsviruses) (45.46). The genotype of the donor activating killer immunoglobulin like receptor (aKIR), which regulates NK cell functEbook Transplant infections (3rd edition): Part 2
ion, has recently been demonstrated to influence the development ofCMV infection after allogeneic HCT (47-49). The mechanisms behind these associationSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2rleukin (IL)-HJ have been associated with CMV disease, whereas polymorphisms in monocyte chemoattractant protein I (MCP-I) are associated with reactivation after allogeneic HCT (50). Much more work needs to be done to determine the role(s) of these components of innate immunity in regulating CMV rep Ebook Transplant infections (3rd edition): Part 2lication in humans.Immune EvasionAn array of CMV genes has been found to function in immune evasion. For example, CM V has genes that inhibit apoptosiEbook Transplant infections (3rd edition): Part 2
s (51), major histocompatibility complex (MHC)-I-restricted antigen presentation (52). and interfcron-mediatcd pathways (53-56). CMV also encodes seveSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2ost immune response (57-61).DIAGNOSTIC METHODSThe serologic determination of lg( > and IgM has an important role in determining a patient's risk for CMV infection after transplantation (see "Risk Factors” section) or during immunosuppressive therapy, but is not useful in the diagnosis of CM V infect Ebook Transplant infections (3rd edition): Part 2ion or disease.Growth of ('MV in tissue culture takes several weeks, limiting its clinical usefulness as a diagnostic tool. Culture-proven viremia isEbook Transplant infections (3rd edition): Part 2
highly predictive of CM V disease, but is of limited utility for screening since this finding frequently coincides with the onset of symptomatic diseaSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2ed within 18 to 24 h after inoculation. This assay is not sensitive enough to use for routine blood monitoring (63), but is highly useful on bronchoalveolar lavage (BAL) fluid in the diagnosis of CMV pneumonia (65).The detection of the CMV pp65 tegument phosphoprotein in peripheral blood leukocytes Ebook Transplant infections (3rd edition): Part 2offers a rapid, sensitive, and specific mcthrxl of diagnosing CMV viremia. In this assay, peripheral leukocytes are spread on a glass slide, stained wEbook Transplant infections (3rd edition): Part 2
ith a fluorescent antibody directed against pp65, ami the number of positive cells is reported per number of total leukocytes on the slide, thereby prSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2 the development of invasive disease (66,67). Since this assay relies on the detection of pp65 in circulating leukocytes, it may not be reliable in patients with profound leukopenia. The predictive value of this assay has not been validated when performed on other body fluids such as BAL fluid.Quant Ebook Transplant infections (3rd edition): Part 2itative polymerase chain reaction (qPCR) relies on the amplification and quantitative measurement of (’MV DNA. PGR is the most sensitive method for deEbook Transplant infections (3rd edition): Part 2
tecting (’MV (68), whereas at the same time maintaining high specificity. In addition, it is very rapid, with results usually available within 24 h. qSECTION V • Viral InfectionsCytomegalovirus Infection after Stem Cell TransplantationMORGAN HAKKI, MICHAEL J. BOECKH, PER LJUNGMANCHAPTER22r4i VIRUS S Ebook Transplant infections (3rd edition): Part 2 testing has become the standard method for detecting CMV in blood (either whole blood or plasma) ami spinal fluid at many, if not most, institutions. Although I’CR has been used on BAL fluid (73), viral-load cut-offs have not been defined, and even though the sensitivity and negative predictive val Ebook Transplant infections (3rd edition): Part 2ues arc very high, the specificity ami positive predictive values arc not known.The detection of (’MV mRNA by nucleic acid sequencebased amplificationEbook Transplant infections (3rd edition): Part 2
(NASBA) on blood samples has proven to be as useful as I3NA PGR or p65 antigenemia for guiding preemptive therapy after HCT (74,75). However, this meGọi ngay
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