Disseminated Adenovirus Infection in Cancer Patients Presenting with Focal Pulmonary Consolidation

Lee, Yeon Joo; Palomino-Guilen, Paola; Babady, N. Esther; Lamson, Daryl M.; George, Kirsten St.; Tang, Yi‐Wei; Papanicolaou, Genovefa A.

doi:10.1128/jcm.01893-13

Cited by 19 publications

(10 citation statements)

References 16 publications

(13 reference statements)

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“…Telomere shortening is a hallmark of aging that could sequester MRN and render ‘old’ cells more permissive for viral replication (Suram and Herbig, 2014). The prevalence of virus infections, including adenovirus, is a serious and often fatal complication in cancer patients treated with chemotherapy, especially in the case of children (Hough et al, 2005; Lee et al, 2014; Steiner et al, 2008). DNA damage is one of the earliest hallmarks of cancer (Halazonetis et al, 2008) and could explain the permissiveness of many tumor cell-lines for ΔE1B-55K/ΔE4-ORF3 viral genome replication (G.S.…”

Section: Discussionmentioning

confidence: 99%

Viral and Cellular Genomes Activate Distinct DNA Damage Responses

Shah

O’Shea

2015

Cell

101

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Summary In response to cellular genome breaks, MRE11/RAD50/NBS1 (MRN) activates a global ATM DNA damage response (DDR) that prevents cellular replication. Here we show that MRN-ATM also has critical functions in defending the cell against DNA viruses. We reveal temporally distinct responses to adenovirus genomes: a critical MRN-ATM DDR that must be inactivated by E1B-55K/E4-ORF3 viral oncoproteins and a global MRN independent ATM DDR to viral nuclear domains that does not impact viral replication. We show that MRN binds to adenovirus genomes and activates a localized ATM response that specifically prevents viral DNA replication. In contrast to chromosomal breaks, ATM activation is not amplified by H2AX across megabases of chromatin to induce global signaling and replicative arrest. Thus, γH2AX foci discriminate ‘self’ and ‘non-self’ genomes and determine if a localized anti-viral or global ATM response is appropriate. This provides an elegant mechanism to neutralize viral genomes without jeopardizing cellular viability.

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Section: Discussionmentioning

confidence: 99%

Viral and Cellular Genomes Activate Distinct DNA Damage Responses

Shah

O’Shea

2015

Cell

101

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“…Moreover, 2 patients who died from severe pneumonitis and ARDS with a positive adenovirus PCR test did not have another apparent cause of respiratory illness. It was described that disseminated adenovirus infection can cause pulmonary consolidation, such as bacterial pneumonia [17,18]. Because of similar clinical and radiographic findings, adenovirus infection may be under-recognized as a cause of fatal pneumonia in immunocompromised patients with severe lymphopenia or lymphocyte dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Significant Transplantation-Related Mortality from Respiratory Virus Infections within the First One Hundred Days in Children after Hematopoietic Stem Cell Transplantation

Hutspardol

Essa

Richardson

et al. 2015

Biology of Blood and Marrow Transplantation

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Respiratory viral infections (RVI) are important in hematopoietic stem cell transplantations (HSCT) and knowledge regarding incidence, morbidity, mortality, and long-term pulmonary complications is limited. We report a study to evaluate incidence and outcomes, both short and long-term, of RVI in children receiving HSCT. Between January 2000 and December 2012, 844 patients underwent hematopoietic stem cell transplantation (HSCT) at the Hospital for Sick Children: 491 were allogeneic and 353 were autologous. When screening for causes of death in the first year after HSCT in the 844 patients, we found that RVI as a cause of death was only evident in the first 100 days after HSCT. Fifty-four (6.5%) patients were found to have an RVI within the first 100 days after HSCT (allogeneic = 32, autologous = 22). Upper and lower respiratory tract infections were documented in 31 (57%) and 23 (43%) patients, respectively. Viruses were parainfluenza (35%), respiratory syncytial virus (28%), influenza (22%), adenovirus (7%), human metapneumovirus (4%), coronavirus (2%), and rhinovirus (2%). Three patients relapsed with their primary disease before day 100 and were excluded. The overall mortality for the remaining 51 patients was 10% (allogeneic = 4, autologous = 1). All 5 deaths were directly attributable to RVI and all 5 deaths occurred in patients with a lower respiratory tract infection. The remaining patients were followed for a median of 4.3 years (range, 1.4 to 11.8) and no chronic pulmonary complications were observed. A clear seasonal pattern for contracting RVI was evident with 65% of total RVI occurring between October and March (35 of 427 versus 19 of 417, P = .03). Given the significant mortality from RVI and the challenges in preventing them, choosing the time to start HSCT, whenever possible, may help prevent RVI and improve outcomes.

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“…Although fatal adenovirus infection has been reported in non-transplant paediatric and adult patients on chemotherapy [5][6][7][8], there is still no consensus on how to deal with an isolated adenovirus positive result in a peripheral (non-blood) sample type on a routine basismany such patients also have asymptomatic adenovirus infections. From a virological viewpoint, since all systemic antiviral drugs are only virostatic and not virucidal, earlier adenovirus PCR blood testing allowing earlier treatment to prevent further increases in viral load, may improve clinical outcomes [1].…”

Section: Discussionmentioning

confidence: 99%

“…No post-mortem investigations were performed. Thus, the disseminated adenovirus infection was deemed to be the cause of the patient's multi-organ failure and death on the basis of the high levels of viremia, which coincided with the patient's rapid deterioration, as described in other cases [5][6][7][8].…”

Section: Case Reportmentioning

confidence: 97%

“…Human adenoviruses are non-enveloped, doublestranded DNA viruses. They exist as seven species (A-G) with greater than 50 types identified so far that can affect different organs and cause a wide spectrum of disease in both immunocompetent [1][2][3][4] and immunocompromised [1,[5][6][7][8] individuals, including pneumonitis, hepatitis, gastroenteritis and conjunctivitis [1]. Although adenoviruses are important respiratory pathogens in haematology patients, adenovirus surveillance in blood is not normally performed in non-transplant adult patients.…”

Section: Introductionmentioning

confidence: 99%

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Case report: a fatal case of disseminated adenovirus infection in a non-transplant adult haematology patient

2018

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BackgroundWe report a fatal case of disseminated adenovirus infection in a non-transplant haematology adult patient with chronic lymphocytic leukaemia who had completed combination chemoimmunotherapy a few months before developing respiratory symptoms. In such non-transplant patients, monitoring for adenovirus in the blood is not routine. However, with adenoviruses, when there is a more peripheral (i.e. non-blood) site of infection such as the chest, serial adenovirus monitoring in blood for the duration of that illness may be warranted.Case presentationThis case started with an initial bacterial chest infection that responded to treatment, followed by an adenovirus pneumonitis that disseminated to his blood a week later with levels of up to 92 million adenovirus DNA copies/ml. Despite prompt treatment with cidofovir, his respiratory function continued to deteriorate over the next two weeks and he was moved to intensive care. Intravenous immunoglobulin and ribavirin were subsequently added to his treatment. However, he died soon after this with a final adenovirus load of 20 million copies/ml in his blood.ConclusionsWe recommend that even in non-transplant haematology patients, where such patients present with an acute respiratory adenovirus infection, teams should consider checking the blood for adenovirus to check for signs of disseminated infection. The earlier this can be tested, the earlier treatment can be initiated (if adenovirus positive), which may produce more successful clinical outcomes.

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Disseminated Adenovirus Infection in Cancer Patients Presenting with Focal Pulmonary Consolidation

Cited by 19 publications

References 16 publications

Viral and Cellular Genomes Activate Distinct DNA Damage Responses

Viral and Cellular Genomes Activate Distinct DNA Damage Responses

Significant Transplantation-Related Mortality from Respiratory Virus Infections within the First One Hundred Days in Children after Hematopoietic Stem Cell Transplantation

Case report: a fatal case of disseminated adenovirus infection in a non-transplant adult haematology patient

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