key: cord-0825849-b2z3umwd
authors: Wu, Nannan; Chen, Li-Kuang; Zhu, Tongyu
title: Phage therapy for secondary bacterial infections with COVID-19
date: 2021-11-09
journal: Curr Opin Virol
DOI: 10.1016/j.coviro.2021.11.001
sha: 58e238eedcf70943c1593b510834934141b1067a
doc_id: 825849
cord_uid: b2z3umwd

With more than 200 million people affected and 4.5 million deaths so far, the coronavirus disease 2019 (COVID-19) pandemic has become one of the greatest disasters in human history. Secondary bacterial infections (SBIs) are a known complication of viral respiratory infections, and are significantly associated with poorer outcomes in COVID-19 patients despite antibiotic treatments. The increasing antimicrobial resistance (AMR) in bacteria and the decreasing options available in our antimicrobial armory worsen this crisis and call for alternative treatment options. As natural killers of bacteria, phages are recognized as promising alternatives to antibiotics in treating pulmonary bacterial infections, however, little is known about their use for treating SBIs during virus pandemics such as COVID-19. This review highlights the situation of SBIs in COVID-19 patients, and the distinct strengths and limitations of phage therapy for their containment.

Despite of the relatively low incidence of initial bacterial co-infections (≤2 days after admission) and of secondary infections (>2 days after admission) among patients hospitalized with coronavirus disease 2019 (COVID-19) [1] •, in severely ill patients secondary bacterial infections (SBIs) are over-represented and raise ongoing challenges. Growing evidence shows that many COVID-19 patients die of secondary infections, although most of them receive intensive antibiotic treatments [1] [2] [3] •. In comparison to pneumonia attributable to other respiratory pathogens, severe COVID-19, due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) characteristically causes a longer duration of illness 2 agents are urgently needed.

Phage therapy has gained a worldwide renewal of interest following the promising results from recent case studies with customized phages. Since the outbreak of the COVID-19 pandemic, scientists have proposed the potential of phages in different aspects of pandemic containment, such as phage therapy for SBIs [7, 8] , and phage display for antiviral antibody screening [9] ••. However, in contrast to the explosion of studies on anti-SARS-CoV-2 antibodies using phage display techniques [10] , little is known about the real-world potential of phages in COVID-19 patients with SBIs.

The application of phage therapy has not been reported during previous virus pandemics.

Up to now, our group has published the only paper reporting phage therapy of COVID-19 patients with secondary carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia

[11] ••. Adaptive Phage Therapeutics (APT), a clinical-stage biotechnology company, has also announced a study treating bacterial co-infected COVID-19 patients with phages [12] ••. This opinion review attempts to highlight the situation of SBIs in COVID-19, as well as the strengths and limitations of using natural phages for its control. We also introduce a workflow of phage therapy adapted to COVID-19 patients.

Secondary infections, mostly bacterial infections, are well-known complications of viral respiratory infections. COVID-19 patients with SBIs were shown to be significantly associated with longer hospitalizations, higher rates of intensive care unit admission, and poorer outcomes compared to those without SBIs [13, 14] •. A nationwide study in the United Kingdom found that despite the overall rarity of laboratory-confirmed bacterial infections, recorded positivity rates of cultures from patients admitted to critical care were high-602 (42·1%) of 1429 cultures from sputum, 207 (51·5%) of 402 cultures from deep respiratory samples, and 500 (8·1%) of 6157 cultures from blood [1] •. Of note, this study found no association between bacterial infections and mortality of intensive care unit (ICU) patients, and that contrasts with most studies. In New York City, USA, Kubin and colleagues identified 350 (12%) patients with laboratory-confirmed secondary infections among 3028 hospitalized COVID-19 patients and found that hospital mortality of patients with secondary-/coinfections was significantly higher than the mortality of those without (33% versus 19%) [15] .

In Wuhan, China, Zhou and colleagues reported observation in 191 hospitalized COVID-19 patients and found that even though 95% of patients received antibiotics, 27/28 patients with SBIs died [3] . This can be compared with the studies reporting that most deaths in recent influenza pandemics likely resulted directly from secondary bacterial pneumonia [16, 17] .

J o u r n a l P r e -p r o o f

Several studies revealed that SARS-CoV-2 pneumonia is associated with a longer duration of illness than pneumonia attributed to other pathogens [4] •. Critically ill COVID-19 patients with prolonged hospital stays were at increased risk of SBIs. Combination [7, 19, 20] .

At the beginning of March, 2020, our group applied phage therapy to successfully control an outbreak of secondary CRAB infections in an ICU dedicated to COVID-19 patients in 

The rarity of the practice of phage therapy in COVID-19 could be partially explained by the remaining challenges in this area. Phage therapy still faces several hurdles, including safety, efficacy, accessibility, acceptability and regulatory issues, which were detailed in recently Second, how significant are phage induction of, and influence on, host inflammatory responses, and are the effects phage-or patient-specific? Third, does SARS-CoV-2 hitch a ride with bacteria to facilitate its distribution? If this is substantiated, manipulation of secondary bacteria from COVID-19 patients will certainly require high biosafety levels.

Declaration of interest: none.

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Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

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Increased antimicrobial resistance during the COVID-19 pandemic

How covid-19 is accelerating the threat of antimicrobial resistance

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Secondary bacterial infection in COVID-19 patients is a stronger predictor for death compared to influenza patients

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