Cytomegalovirus Reactivation in Critically Ill Immunocompetent Patients

Limaye, Ajit P.; Kirby, Katharine A.; Rubenfeld, Gordon D.; Leisenring, Wendy M.; Bulger, Eileen M.; Neff, Margaret J.; Gibran, Nicole S.; Huang, Meei Li; Hayes, Tracy K. Santo; Corey, Lawrence; Boeckh, Michael

doi:10.1001/jama.300.4.413

Cited by 374 publications

(208 citation statements)

References 33 publications

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“…We also found that reactivation of HHVs other than HSV-1 mostly occurred in classically high-risk immunocompromised patients. Although recent studies have shown that CMV reactivation is common in nonimmunosuppressed, critically ill patients [8,9], our results showed that CMV reactivation of the lung was rare in this patient population. Overall, clinically significant pulmonary reactivation of HHVs was almost exclusively observed in patients with endotracheal intubation or known immunocompromised status, indicating that patients with this clinical picture merit careful investigation for HHVs in the lung.…”

Section: Discussioncontrasting

confidence: 69%

“…HSV-1 [3,17], VZV [18], EBV [19], and HHV-6 [20,21]) have also been implicated as etiologic agents. Moreover, recent studies have documented frequent pulmonary reactivation and/or infection of HSV-1 [6,7] and CMV [8,9] in critically ill patients with no known immunocompromise. Therefore, ALI/ARDS patients with unknown etiology should be examined for possible viral pneumonia caused by HHVs, which often presents with bilateral ground-glass opacification and/or consolidation [17,21,22].…”

Section: Discussionmentioning

confidence: 99%

“…Human herpes viruses (HHVs) have been recognized as clinically important pathogens of pulmonary infections that can result in ALI/ARDS in immunocompromised patients [2,3,4], and they have also been recognized as potential pathogens in nonimmunocompromised critically ill patients [5,6,7,8,9]. However, there have been few comprehensive studies to date on the prevalence and pathogenic role of HHVs in ALI/ARDS patients, partly due to the limited diagnostic tools available for identifying different HHVs in a clinical sample.…”

Section: Introductionmentioning

confidence: 99%

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Detection of Herpes Viruses by Multiplex and Real-Time Polymerase Chain Reaction in Bronchoalveolar Lavage Fluid of Patients with Acute Lung Injury or Acute Respiratory Distress Syndrome

et al. 2013

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Background: Human herpes viruses (HHVs) are important pathogens in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Rapid and efficient diagnostic tools are needed to detect HHVs in the lung in ALI/ARDS patients. Objectives: This study aimed to evaluate the usefulness of multiplex and real-time polymerase chain reaction (PCR) analysis of bronchoalveolar lavage fluid (BALF) for detecting HHV reactivation in ALI/ARDS patients. Methods: Between August 2008 and July 2012, eighty-seven BALF samples were obtained from ALI/ARDS patients with unknown etiology and analyzed for HHVs. The types of HHVs in the BALF samples were determined using qualitative multiplex PCR followed by quantitative real-time PCR. Results: Multiplex PCR identified herpes simplex virus type 1 (HSV-1) (n = 11), Epstein-Barr virus (EBV) (n = 16), cytomegalovirus (CMV) (n = 21), HHV type 6 (HHV-6) (n = 2), and HHV-7 (n = 1) genomic DNA in 35 (40%) of the BALF samples, including 14 (16%) samples containing 2 or 3 HHV types. CMV and EBV reactivation was rare in immunocompetent patients, whereas reactivation of HSV-1 was predominantly observed in intubated patients regardless of their immune status. Overall, HHVs were almost exclusively found in patients with immunosuppression or endotracheal intubation. Real-time PCR detected 0.95-1.59 × 10⁶ copies of viral DNA/μg human genome DNA, and HSV-1 (n = 4), CMV (n = 9), and HHV-6 (n = 1) were identified as potentially pathogenic agents. Conclusions: The implementation of multiplex and real-time PCR of BALF was feasible in ALI/ARDS patients, which allowed efficient detection and quantification of HHV DNA.

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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Detection of Herpes Viruses by Multiplex and Real-Time Polymerase Chain Reaction in Bronchoalveolar Lavage Fluid of Patients with Acute Lung Injury or Acute Respiratory Distress Syndrome

et al. 2013

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“…Observation from clinical studies showed that about 80% septic patients had a persistence of infectious focus at the day they died [9]. Some other studies also found that the active cytomegalovirus normally existed in the septic patient without resolution [10, 11]. These results indicate that the host immunity exhibits a tolerance status, which makes the patients at an increased risk of subjection to secondary pathogen infection.…”

Section: Introductionmentioning

confidence: 99%

Alterations of Dendritic Cells in Sepsis: Featured Role in Immunoparalysis

Xia

Liu

et al. 2015

BioMed Research International

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Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies.

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“…Repression of these genes in undifferentiated myeloid cells appears to be achieved through histone suppression of the major IE promotor, but, when the cells differentiate, changes in the histone-modified chromatin structure associated with the IE genes initiate gene expression and the lytic transcription program, resulting in release of viral progeny. In compromised immunological or physiological conditions that impair immune surveillance, the differentiation of newly recruited HCMV-infected monocytes into tissue macrophages can activate viral gene expression, leading to the local production and release of viral progeny (21, 28–30). Thus, HCMV promotes monocyte dissemination into the tissues, where differentiation-dependent activation of macrophages leads to virus expression and the release of HCMV throughout the body.…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus Enhances Macrophage TLR Expression and MyD88-Mediated Signal Transduction To Potentiate Inducible Inflammatory Responses

Smith

Shimamura

Musgrove

et al. 2014

The Journal of Immunology

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Circulating monocytes carrying human cytomegalovirus (HCMV) migrate into tissues, where they differentiate into HCMV-infected resident macrophages that upon interaction with bacterial products may potentiate tissue inflammation. Here we investigated the mechanism by which HCMV promotes macrophage-orchestrated inflammation using a clinical isolate of HCMV (TR) and macrophages derived from primary human monocytes. HCMV infection of the macrophages, which was associated with viral DNA replication, significantly enhanced TNF-α, IL-6 and IL-8 gene expression and protein production in response to TLR4 ligand (lipopolysaccharide, LPS) stimulation compared with mock-infected LPS-stimulated macrophages during a 6-day in vitro infection. HCMV infection also potentiated TLR5 ligand-stimulated cytokine production. To elucidate the mechanism by which HCMV infection potentiated inducible macrophage responses, we show that infection by HCMV promoted the maintenance of surface CD14 and TLR4 and 5, which declined over time in mock-infected macrophages, and enhanced both the intracellular expression of adaptor protein MyD88 and the inducible phosphorylation of IκBα and NF-κB. These findings provide additional information toward elucidating the mechanism by which HCMV potentiates bacteria-induced NF-κB-mediated macrophage inflammatory responses, thereby enhancing organ inflammation in HCMV-infected tissues.

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Cytomegalovirus Reactivation in Critically Ill Immunocompetent Patients

Cited by 374 publications

References 33 publications

Detection of Herpes Viruses by Multiplex and Real-Time Polymerase Chain Reaction in Bronchoalveolar Lavage Fluid of Patients with Acute Lung Injury or Acute Respiratory Distress Syndrome

Detection of Herpes Viruses by Multiplex and Real-Time Polymerase Chain Reaction in Bronchoalveolar Lavage Fluid of Patients with Acute Lung Injury or Acute Respiratory Distress Syndrome

Alterations of Dendritic Cells in Sepsis: Featured Role in Immunoparalysis

Cytomegalovirus Enhances Macrophage TLR Expression and MyD88-Mediated Signal Transduction To Potentiate Inducible Inflammatory Responses

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