Case 1-2018: A 39-Year-Old Woman with Rapidly Progressive Respiratory Failure

Hibbert, Kathryn A.; Shepard, Jo-Anne O.; Lane, Rebekah J.; Azar, Marwan M.

doi:10.1056/nejmcpc1712222

N Engl J Med

2018

DOI: 10.1056/nejmcpc1712222

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Case 1-2018: A 39-Year-Old Woman with Rapidly Progressive Respiratory Failure

Kathryn A. Hibbert

Jo-Anne O. Shepard

Rebekah J. Lane

et al.

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Cited by 4 publications

(2 citation statements)

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“…Though large-scale trials are lacking for most viral pneumonias, there has been successful use of antivirals for different viruses described in the literature. In fact for adenovirus, cidofovir is recommended and there was a recent publication in NEJM 1 regarding the same of successful use.…”

mentioning

confidence: 99%

Antiviral Drugs for Viral Pneumonia

Bansal

2023

Indian Journal of Critical Care Medicine

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mentioning

confidence: 99%

Antiviral Drugs for Viral Pneumonia

Bansal

2023

Indian Journal of Critical Care Medicine

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“…control a disseminated adenovirus infection in an immune-suppressed patient but caused permanent renal disease requiring lifelong dialysis (11).…”

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confidence: 99%

Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via both Nonobligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus

Chamberlain

Sortino

Sethna

et al. 2019

Antimicrob Agents Chemother

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Human adenovirus (AdV) can cause fatal disease in immune-suppressed individuals, but treatment options are limited, in part because the antiviral cytidine analog cidofovir (CDV) is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, nonnephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. Therefore, we have examined the effect of CDVpp on DNA synthesis by a purified adenovirus 5 (AdV5) DNA polymerase (Pol). CDVpp was incorporated into nascent DNA strands and promoted a nonobligate form of chain termination (i.e., AdV5 Pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 Pol. At elevated concentrations, CDVpp inhibited AdV5 Pol in a manner consistent with both chain termination and direct inhibition of Pol activity. Finally, a recombinant AdV5 was constructed, containing Pol mutations (V303I and T87I) that were selected following an extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated 50% effective concentration (EC50) for BCV and a 1.9-fold increased EC50 for CDV; thus, these results confirmed that viral resistance to BCV and CDV can be attributed to mutations in the viral Pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA Pol and that their antiviral activity may occur via both (nonobligate) chain termination and (at high concentration) direct inhibition of AdV5 Pol activity.

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Cidofovir

2018

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Case 1-2018: A 39-Year-Old Woman with Rapidly Progressive Respiratory Failure

Cited by 4 publications

References 21 publications

Antiviral Drugs for Viral Pneumonia

Antiviral Drugs for Viral Pneumonia

Cidofovir Diphosphate Inhibits Adenovirus 5 DNA Polymerase via both Nonobligate Chain Termination and Direct Inhibition, and Polymerase Mutations Confer Cidofovir Resistance on Intact Virus

Cidofovir

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