Disseminated adenovirus infection after allogeneic stem cell transplant and the potential role of brincidofovir – Case series and 10 year experience of management in an adult transplant cohort

Ramsay, Isobel; Attwood, C.; Irish, Dianne; Griffiths, Paul; Kyriakou, Charalampia; Lowe, David M.

doi:10.1016/j.jcv.2017.09.013

Cited by 45 publications

(37 citation statements)

References 34 publications

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“…The observation that patients can succumb to disseminated HAdV disease within a few days after presenting with symptoms of systemic infection highlights the need for careful diagnostic monitoring and early implementation of therapeutic measures [23]. Although lethal HAdV infections have been described both in adult and pediatric allogeneic SCT recipients, the reported frequency of invasive infections with severe clinical courses is considerably higher in children [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] (Table 2). Different groups have tried to define thresholds of HAdV levels in plasma as a trigger for the initiation of antiviral treatment [44][45][46], Table 1.…”

Section: Abstract: Antiviral Therapy; Hadv; Molecular Virus Detectionmentioning

confidence: 99%

Adenovirus persistence, reactivation, and clinical management

2019

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Adenoviral infections continue posing a major threat in severely immunocompromised patients including particularly allogeneic stem cell transplant recipients. Although exogenous infections occur in some instances, the majority of invasive events appear to arise from viral reactivation. In the pediatric setting, adenoviruses were demonstrated to persist in the gastrointestinal tract, and the intestinal epithelium serves as the main site of viral replication preceding invasive infection. Regular monitoring of serial stool samples for the presence and load of adenoviruses has therefore become a routine diagnostic tool for post‐transplant patient surveillance, and can serve as a trigger for early initiation of treatment. In the adult setting, the source of infection or reactivation is less clear, and monitoring of peripheral blood specimens is the predominant approach for patient surveillance. Timely initiation of antiviral treatment is reportedly required for prevention or successful control of disseminated disease mediated by adenoviruses, and appropriate diagnostic monitoring is therefore of paramount importance. Currently available antiviral agents and immune therapeutic approaches have not been able to entirely overcome the life‐threatening courses of invasive adenoviral infections in the immunocompromised clinical setting.

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Section: Abstract: Antiviral Therapy; Hadv; Molecular Virus Detectionmentioning

confidence: 99%

Adenovirus persistence, reactivation, and clinical management

2019

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“…47,122,123 Disseminated disease occurs in up to 10% to 20% of patients and is associated with allogeneic HCT, receipt of a T-cell-depleted graft, infection in the early post-transplant period, presence of GVHD, use of systemic steroids, and lymphopenia. 23,24,121,124 The presence of viremia as well as the height of the viral load is a meaningful predictor of risk for invasive and disseminated disease as well as mortality. 40,47,122,125 Overall mortality for all syndromes can be high, especially so for patients with pneumonia or disseminated disease, particularly in recipients of T cell-depleted grafts.…”

Section: Adenovirusmentioning

confidence: 99%

Respiratory Virus Infections of the Stem Cell Transplant Recipient and the Hematologic Malignancy Patient

Fontana

Strasfeld

2019

Infectious Disease Clinics of North America

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Respiratory virus infections (RVIs) are increasingly recognized as a cause of significant morbidity and mortality in recipients of hematologic stem cell transplant (HCT) and patients with hematologic malignancy (HM). 1,2 With now widespread use of molecular diagnostics, the epidemiology and spectrum of clinical disease of these infections can be better characterized. Apart from influenza, the currently available antivirals are limited in efficacy and/or associated with potential for toxicity, thus emphasizing the importance of prevention strategies. This article provides a review of the epidemiology, clinical characteristics, management, and prevention of RVIs in HCT recipients and HM patients.No disclosures. KEYWORDS Respiratory virus infection Hematopoietic stem cell transplant RSV Influenza Parainfluenza Human metapneumovirus Rhinovirus Coronavirus KEY POINTSThe morbidity and associated complications of respiratory virus infections are greater in hematopoietic stem cell transplant recipients and patients with hematologic malignancy than in immunocompetent individuals, with severity of illness related to the degree of immunosuppression. Molecular microbiologic testing is the gold standard for diagnosis, allowing differentiation of what are largely overlapping clinical syndromes. Most of the respiratory viruses, apart from influenza and in some circumstances respiratory syncytial virus and adenovirus, are managed supportively. Prevention is key and should focus on vaccination for influenza, avoidance of ill contacts, and compliance with principles of infection control.Infect Dis Clin N Am 33 (2019) 523-544 a Studies are a combination of PCR and traditional laboratory methods (eg, culture, direct fluorescent antibody, and enzyme immunoassay). b PCR-based studies. c Includes all-cause and attributable mortality with variable timeframe to death. d One mortality in a coinfected patient attributed to enterovirus/rhinovirus infection.

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“…Although DNA synthesis inhibitors such as cidofovir and ganciclovir are considered to be standard treatments, these drugs are often associated with serious adverse effects (11) and have limited efficacy in systemic HAdV infections (9). Brincidofovir, a phospholipid conjugate of cidofovir, is currently in clinical trials for the treatment of HAdV-induced diseases (12,13). This drug has several advantages over cidofovir (e.g., oral delivery and increased cellular uptake), but it is still associated with gastrointestinal toxicity in some patients.…”

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confidence: 99%

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

Saha

Parks

2019

J Virol

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Human adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease. IMPORTANCE Although human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.

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Disseminated adenovirus infection after allogeneic stem cell transplant and the potential role of brincidofovir – Case series and 10 year experience of management in an adult transplant cohort

Cited by 45 publications

References 34 publications

Adenovirus persistence, reactivation, and clinical management

Adenovirus persistence, reactivation, and clinical management

Respiratory Virus Infections of the Stem Cell Transplant Recipient and the Hematologic Malignancy Patient

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

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