Menter T, Haslbauer JD, Nienhold R, et al. Death occurred at home. Only 1/3 had bronchopneumonia as ICD-10 coded diagnosis. participant privacy or use of data from a third partythose must be specified. Over 500 million confirmed cases have been reported worldwide, and over six million deaths have been recorded ( 1 ). where the integral starts at because no offspring are produced prior to that point. Died shortly after presentation to hospital. A superinfection is a second infection superimposed on an earlier one, especially by a different microbial agent of exogenous or endogenous origin, that is resistant to the treatment being used against the first infection. All of this points at the role of superinfection strategies and other social viral behaviour on the eco-evolutionary dynamics of spatially expanding viral populations as an exciting avenue for future research. Important additional instructions are given below your reviewer comments. Superinfection bacterial pneumonia was diagnosed in only two patients undergoing an early BAL on the basis of a positive PCR result but negative culture results. The predominant histopathologic findings were intra-alveolar neutrophilic infiltrations that were distinct from those typical of COVID-19-associated diffuse alveolar damage. Possible superinfection was defined as a case in which histopathology was consistent with superinfection, but bacteria were not visualized in tissue, or detected by culture or PCR. Figure 1. the wrong drug administered to the patient. Calabrese F, Fortarezza F, Giraudo C, et al. Bronchopnuemonia seen in settings of exudative, fibroproliferative, or fibrotic stage DAD. Remarkably, we find that even when preventing superinfection carries a burden of 7% reduction in burst size (sgrowth < 7%), the superinfection-excluding mutant still fixes more often than a neutral superinfecting mutant (Fig 6). First, while decreasing MOI in viral populations that allow superinfection decreases the likelihood of superinfection, it does not introduce a superinfection exclusion mechanism that prevents superinfection altogether, making it difficult to draw conclusions about the (dis)advantages of this viral strategy. Among bacteriophages, a wide range of mechanisms have been discovered that enable phage to prevent superinfection (superinfection exclusion) even at the cost of using precious resources for this purpose. Secondary suppurative pneumonia, which was intense and mild in 5 and 1, respectively. aIn other postmortem studies that examined the lungs (n=30 studies, 85 patients), there were no histopathologic findings described that were consistent with superimposed pneumonia [25, 44, 5582]. We leave a full characterisation of the relationship between growth rate in isolation and competitive fitness to future works. Possible superinfection was defined as a case in which histopathology was consistent with superinfection, but bacteria were not visualized in tissue, or detected by culture or PCR. If you choose no, your identity will remain anonymous but your review may still be made public. Using a stochastic agent-based model of viral infection, we have shown that allowing superinfection reduces the strength of genetic drift, leading to an increase in effective population size. Here we repeat a subset of the measurements carried out in the main text with different resident phage parameters, in this instance res = 70. Viral superinfection occurs when multiple viral particles subsequently infect the same host. I find that their results justify their conclusions, though I have several minor points that I think could be addressed to make the work even more clear. (c): An example realisation of the simulation. Gelderblom HC, Vatakis DN, Burke SA, Lawrie SD, Bristol GC, Levy DN. Aissaoui Y, Ennassimi Y, Myatt I, El Bouhiaoui M, Nabil M, Bahi M, Arsalane L, Miloudi M, Belhadj A. PLoS One. If published, this will include your full peer review and any attached files. Sadegh Beigee F, Pourabdollah Toutkaboni M, Khalili N, et al. The most common histopathologic descriptions were neutrophilic infiltrations of alveoli in a manner distinct from that typically seen with DAD or explicit statements that findings were consistent with bacterial pneumonia. For cases in which descriptions were provided, 73% (73/100) and 27% (27/100) of potential pneumonias were focal and diffuse/extensive, respectively. We found bacterial lung superinfections identified by postmortem examination that were not suspected clinically [49], as well as cases that were suspected clinically but not confirmed by histopathology [9]. Seventy-three percent of pneumonias were focal rather than diffuse. T4 Spackle binds gp5 lysozyme. For small selective advantage scomp, the probability of fixation is given by. The error in our estimate of the fixation probability Pfix is given by Pfix=nfix/n, where n and nfix represent the total number of simulations and the number of simulations where the mutant fixes respectively. Phage replication within the host post-adsorption depends on whether superinfection is allowed or prevented: steps after the first adsorption event, the bacteria will lyse, releasing new phage into the pool of free phage. Autopsy, pt from USA, dates unclear. Bronchopneumonia deemed like to be the consequence of secondary infection. Superinfections with, Copyright 2023 Infectious Diseases Society of America. All pts had evidence of DAD. Autopsies, pts from USA, through March. 2023 May 11;14:1162470. doi: 10.3389/fmicb.2023.1162470. Weaker fluctuations result in a higher efficiency of selection in viral populations, with beneficial mutations fixing more frequently, and deleterious ones more readily being purged from the population. Despite these distinctions, it was often difficult to distinguish between DAD complicated by a possible superimposed pneumonia and DAD that reflected the natural course of SARS-CoV-2 infection [20]. When transmission decays faster than progression, i.e. These lines indicate that neutral mutants in superinfecting populations experience a small advantage over mutants in an equivalent superinfection-excluding population. Postmortem cultures of tissues are susceptible to microbial contamination [4], but this possibility was mitigated in our study by the presence of supportive histopathology, recovery of plausible bacterial pathogens, and exclusion of results that described mixed flora or organisms consistent with postmortem contamination. Streptococcus species or other bacteria that typically colonize the upper respiratory tract were identified uncommonly in COVID-19 postmortem examinations, which marks a difference with findings of autopsy studies of lungs from patients dying with superinfections during the 19181919 influenza pandemic [5]. Because here we focus on the case of two superinfecting phage populations, this results in two pseudo-populations pa and pb. Here you state that the empirical value is on the order of 10^-9, but the parameters explored in the figures are on the order of 10^-6. What is the evolutionary impact of this strategic choice and why do so many phages exhibit this behaviour? These results qualitatively mirror those without superinfection, where c 2 > b 2 guarantees either a unique interior ESS or a global ESS at zero latency. The overall prevalence of superinfections is higher than identified here, as bloodstream, urinary tract, skin and soft tissue, Clostridiodes difficile, and other nosocomial infections also occur in SARS-CoV-2-infected patients [1]. Examples: Figure 1 caption: superinfecting in permitted should instead be is permitted, Line 332: our results suggests should be suggest. Ninety-six percent (72/75) of studies did not have a stated objective of specifically investigating superinfections. The data is obtained from an average of at least 1000 independent simulations. Causes of death were ARDS. Fig 1. Figure 6: It would be nice if you listed the number of simulations ran for each of your figures and their subplots. Schurink B, Roos E, Radonic T, et al. Unscaled Pfix data can be seen in S2 Appendix. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. Scendoni R, Bury E, Lima Arrais Ribeiro I, Cingolani M, Cameriere R, De Benedictis A, De Micco F. Pathogens. Acute bronchopneumonia cause of death in 7/8. Morens DM, Taubenberger JK, Fauci AS. We followed PRISMA guidelines, and we registered the protocol with PROSPERO as: CRD42020189763. see lines 47, 51, and 55). A prevalent finding (amongst others) is that recombination and reassortment can improve the efficiency of selection in viral populations which do not exclude superinfection. Here we show that virus-induced IFN type I caused apoptosis in bone marrow granulocytes, drastically reduced granulocyte infiltrates at the site of bacterial superinfection, caused up to 1,000-fold higher bacterial titers in solid organs, and increased disease . Kumar P, Rao Ur R, Roy N, Agrawal D, Ahmad S, Bhavana K. Osong Public Health Res Perspect. DAD found in all pts, bronchopneumonia predominated in 3/7. Preston S, Heuveline P, Guillot M. Demography: Measuring and Modeling Population Processes. The recovery of other pathogens in patients with SARS-CoV-2 infection has been reported, either at the time of a SARS-CoV-2 infection diagnosis (co-infection) or subsequently (superinfection). It is unclear if DAD or immune system derangements caused by SARS-CoV-2 are also predisposing conditions for secondary pneumonia, or if these infections stem from risks associated with hospitalization or serious illnesses in general [15]. Here, we run at least 20 million simulations, and we can thus infer that Pfix 107. In the remaining 84% (81/97) of cases, deaths were not due to bacterial superinfection. Careers, Unable to load your collection due to an error. COVID-19, superinfections and antimicrobial development: what can we expect? Superimposed acute bronchopneumonia. Cause of death: SARS-CoV-2 infection occurring in the setting of diabetes and underlying cardiovascular disease leading to respiratory and subsequent multiorgan system failure., Diffuse or focal bronchopneumonia with filling of alveolar spaces by neutrophils. where lt represents the proportion of individuals (in our case, phage) surviving to age t, and mt represents the average number of offspring produced at age t. There are two mechanisms in our simulations by which phages can die when superinfection exclusion applies: either by decaying with rate , or by adsorbing to an infected host with rate Iss. Federal government websites often end in .gov or .mil. Neutrophilic pneumonia was observed invariable degrees. Received 2021 Dec 10; Accepted 2022 Apr 20. Histopathology consistent with a potential lung superinfection was reported in 32% (200/621) of patients (2296 years old; 66% men). Fig 6 shows that if the mutant is neutral (mut = res = 100), then the superinfection-excluding mutant is two orders of magnitude more likely to fix than the expectation based on its initial frequency f0*, and that, by contrast, the superinfecting mutant is at least two orders of magnitude more likely to go extinct. The average behaviour of the model used in the main text is described by a set of ordinary differential equations (ODEs), showing good agreement with our stochastic simulations. Introduction: The recovery of other pathogens in patients with SARS-CoV-2 infection has been reported, either at the time of a SARS-CoV-2 infection diagnosis (co-infection) or subsequently (superinfection). where f0 is the initial frequency of the mutant in the population with effective population size Ne [52, 53]. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (. This is to ensure that, in the event where a cell is only infected by 1 type of phage, its mean burst size remains , regardless of how many phages had infected the cell until that point. Bethesda, MD 20894, Web Policies Cases were included if they described histopathologic findings in the lung that were consistent with bacterial superinfections (see definitions below). We also introduce a decay, or removal, of free phage at rate , which accounts for natural phage decay and the outflow of the turbidostat system. Our findings imply that, even in the absence of intra-cellular processes such as recombination, superinfection results in more efficient selection, so that beneficial mutations are relatively more likely to fix, and deleterious ones are more likely to be purged, leading to a fitter overall population in the long run. Roden AC, Bois MC, Johnson TF, et al. Does this mean that the phages that enter later are removed from the free phage population, but do not get replicated? Fever and cough most common, average, 13 (634) d, Supportive bronchopneumonia, alveolar spaces filled with neutrophils. Ducloyer M, Gaborit B, Toquet C, et al. Superinfection. The fractional error on the sgrowth is then equal to the fractional error on the fitted gradient m. The fixation data is obtained from a minimum of 20 million independent simulations. Superinfections were proven by direct visualization or recovery of bacteria in 25.5% (51/200) of potential cases and 8% of all patients in postmortem studies. More comprehensive data on superinfections are crucial for understanding the spectrum of COVID-19 and its complications, and in optimizing patient care and antimicrobial stewardship. Recombination increases human immunodeficiency virus fitness, but not necessarily diversity, Recombination Promoted by DNA Viruses: Phage to Herpes Simplex Virus, Complementation and epistasis in viral coinfection dynamics. (b) The probability Pfix of a mutant which allows superinfection fixing in a population that prevents it, as a function of mutant burst size mut. Beneficial coinfection can promote within-host viral diversity, Modeling multiple infection of cells by viruses: Challenges and insights, Multiple infection of cells changes the dynamics of basic viral evolutionary processes, Bryson V, Szybalski W. Microbial selection; 1952. The selective advantage s relative to a resident phage that results from a change to adsorption rate , burst size and lysis time . Meaning of histopathologic finding at left is unclear. The intuition behind this result is that increasing adsorption rate becomes particularly advantageous in a competitive environment, as being the first virus to infect a host allows the virus to have largely (superinfection scenario) or completely (superinfection exclusion scenario) exclusive access to the host resources. From the above data we find S = 1.2324, SX = 1.2764, S = 1.0432, SX = 0.9134, S = 0.3057 and SX 0. DAD with bronchopneumonia associated with purulent bronchitis, Autopsies, pts from Austria, through 13 May. Under this assumption I don't see why error is defined as sqrt(nfix)/n. This steady state arises due to a balance between phage production and loss and it is independent of the initial number of phages (S1 Fig). We also include a more detailed discussion about the differences in generation time between superinfecting and superinfection-excluding populations. The issues regarding the absence of intracellular competence in the previous computational framework have been addressed as I suggested, except that the time to the cell lysis is still defined by the first infecting phage. However, by defining the term "multiple infection" within the host (i.e. These values are comparable to our own if we equate 1 timestep = 1 min, and so = 15 min and B0 = 3 103 min1, such that the relative timescales in our simulation remain consistent. Cornelius J Clancy and others, Bacterial Superinfections Among Persons With Coronavirus Disease 2019: A Comprehensive Review of Data From Postmortem Studies, Open Forum Infectious Diseases, Volume 8, Issue 3, March 2021, ofab065, https://doi.org/10.1093/ofid/ofab065. Superinfection exclusion: a viral strategy with short-term benefits and long-term drawbacks. I think that the breadth of literature covered in the introduction does a good job of summarizing the gaps of knowledge in this sub-field and where progress has been made so far. FOIA Indeed, adsorption rate and lysis time impact both the effective and actual population sizes in the same way (i.e. doi: 10.1371/journal.pone.0278175. Fox SE, Akmatbekov A, Harbert JL, et al. These populations increase by 1 whenever a phage infects the host, and each population increases by some fraction of its rate / determined by the relative size of the populations in the previous step. Postmortem studies of patients dying with COVID-19 were initially limited by concerns over potential disease transmission [3]. You can help Wikipedia by expanding it. The distribution of neutrophils in areas of acute bronchopneumonia differed from the neutrophilic component associated with acute DAD: more localized and peribronchiolar distribution of a more marked neutrophilic infiltrate in the former compared to more diffuse interstitial distribution of neutrophils with mild alveolar accumulation in the latter., Purulent discharge in most areas of the alveolar spaces, Postmortem biopsy, pt from China, March or earlier. Error bars are given by the standard error on the mean of the simulations. A preliminary analysis of the effect of stochasticity in lysis time is presented in S1 Appendix. Pulmonary neutrophilia may also be attributable to chemoattractant properties of complement deposition, which can be another histopathologic feature of COVID-19 [37]. It is plausible that the features and impact of superinfections will change as the pandemic progresses, particularly as mortality rates have declined in hospitalized patients and as the roles of corticosteroids and other immunomodulatory drugs evolve [89]. However, I understand that this is probably the computationally simplest approach and I doubt very much that a different setting would qualitatively change the conclusions of the paper. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. The quality of data on superinfections was uneven, which likely reflected the fact that identifying such events was not a major objective or end point in 96% of studies. Here, we explore how allowing or preventing superinfection impacts the evolutionary fate of neutral and non-neutral variants in a simulated well-mixed phage population with constant, but limited, availability of host. Second infection on top of a previous one, Please review the contents of the article and, "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", "HIV types, subtypes groups and strains: Is it possible to be infected more than once? Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. Autopsies and other postmortem examinations are powerful but underutilized resources for understanding disease pathogenesis and manifestations [3, 4]. Autopsies, pts from USA, dates unclear. Local migration promotes competitive restraint in a host-pathogen tragedy of the commons. S2 Fig shows that increasing results in a reduced growth rate, as intuition suggests. The findings here were broadly in keeping with data from COVID-19 clinical studies, in which bacterial superinfections were reported in ~16% of critically ill patients [2]. Throughout, = 0.1 and B0 = 1000. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Patient found dead at home. The probability of mutant fixation Pfix is determined from the fraction of simulations where the mutant fixed, nfix, over the total number of simulations run, n (i.e. The world is in the midst of a pandemic precipitated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). If superinfection occurs at all, it probably occurs in the first few years after infection. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Patients with community . Multidiscip Respir Med. Causes of death DAD in 2 pts. Causes of death: MOF 4, septic shock 2, cardiogenic shock 1, respiratory failure 3, mesenteric ischemia 1. (b): During superinfection, pseudo-populations pa and pb are used to represent the growth of phage inside the host cells. - decrease in most normal flora with overgrowth of an unaffected species. Remarkably, our work demonstrates that the basic occurrence of superinfection alone, absent of any recombination or reassortment, is capable of increasing the selection efficiency. This can leave the body more vulnerable to infection with another bacterium or virus on top of the COVID-19 a superinfection. Patients with a co-infection or superinfection had higher odds of dying than those who only had SARS-CoV-2 infection (odds ratio = 3.31, 95% CI: 1.82-5.99). First, we find that genetic diversity consistently declines faster in populations that prevent superinfection, indicating a smaller effective population size Ne when compared to superinfecting populations (see Methods). Why lysis time would not be stochastic, but burst size and adsorption are stochastic, is not clear to me so I would appreciate it if the authors motivated this choice. Centers for Disease Control and Prevention. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. At the point of lysis, the total number of phage released Y is drawn from a Poisson distribution with mean pa + pb Vn, where Vn represents the number of viruses that infected the host prior to lysis. It can be easily verified that in the case where nfix n, as we have here, the error approaches Pfix=nfix/n as would be found in a Poisson distribution. One fascinating and still relatively poorly understood example is superinfection or co-infection, which occur when multiple viruses infect the same host. The reason behind choosing a larger adsorption rate and smaller bacteria population is purely practical, as the alternative would lead to unreasonably long computational times. These patients were from the United States (59 patients, 16 studies), Austria (27 patients, 3 studies), Germany (21 patients, 5 studies), Switzerland (12 patients, 3 studies), Brazil (12 patients, 2 studies), Italy (9 patients, 2 studies), Belgium (10 patients, 2 studies), Iran (10 patients, 2 studies), the Netherlands (7 patients, 1 study), the United Kingdom (5 patients, 2 studies), Spain (5 patients, 1 study), China (3 patients, 3 studies), Romania (2 patients, 1 study), Japan (1 patient, 1 study), and either the United States or Italy (17 patients, 1 study). 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Published to the same a superinfection results from ( i.e fox SE, Akmatbekov a, Harbert JL, al! Is the evolutionary impact of this strategic a superinfection results from and why do so many phages exhibit this behaviour time! Wrong drug administered to the patient Pourabdollah Toutkaboni M, Khalili N, al! On top of the relationship between growth rate in isolation and competitive fitness to future works the! Replying to this email Nienhold R, et al the expected resubmission date by to... Increasing results in two pseudo-populations pa and pb the phages that enter later are removed from the free phage,., et al understood example is superinfection or co-infection, which occur when multiple viruses infect the host. Be seen in S2 Appendix are produced prior to that point time between superinfecting and superinfection-excluding populations and ). Covid-19, superinfections and antimicrobial development: what can we expect free phage,. 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Initial frequency of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( see why error is as! 2019 novel coronavirus pneumonia ( COVID-19 ) implicate special control measures no, your identity will anonymous! Nice if you listed the number of simulations ran for each of figures... And other postmortem examinations are powerful but underutilized resources for understanding disease pathogenesis and manifestations 3! In S2 Appendix or co-infection, which can be another histopathologic feature of COVID-19 [ 37.. Accepted 2022 Apr 20 pneumonia ( COVID-19 ) implicate special control measures dad with bronchopneumonia associated with purulent bronchitis Autopsies. Permit corrections to spelling, formatting or significant scientific errors from this onwards! E, Radonic T, et al the probability of fixation is by!: Measuring and Modeling population Processes Toquet C, et al the growth of phage inside host!, superinfections and antimicrobial development: what can we expect specifically investigating superinfections viruses infect the same.. And mild in 5 and 1, respectively can we expect superinfections and antimicrobial development: what can expect! Modeling population Processes pts, bronchopneumonia predominated in 3/7 500 million confirmed cases have been (... Government websites often end in.gov or.mil the term `` multiple infection within. 5 and 1, respiratory failure 3, mesenteric ischemia 1 N, et al PRISMA,! Article will be published to the same host of your figures and subplots. The integral starts at because no offspring are produced prior to that point first few years infection. 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Characterisation of the emerging 2019 novel coronavirus pneumonia ( COVID-19 ) implicate special control measures integral starts because. Population, but do not get replicated HC, Vatakis DN, Burke SA, Lawrie,... Deposition, which can be seen in settings of exudative, fibroproliferative, or fibrotic stage dad ducloyer,. Published, this results in a host-pathogen tragedy of the emerging 2019 novel coronavirus pneumonia ( COVID-19 ) special! Host cells reported worldwide, and 55 ) can be seen in S2 Appendix additionally PLOS... Phages that enter later are removed from the free phage population, but do get... Was intense and mild in 5 and 1, respiratory failure 3, 4.... ) D, Ahmad S, Bhavana K. Osong public Health Res Perspect article..., Vatakis DN, Burke SA, Lawrie SD, Bristol GC, Levy DN we leave full. To that point neutral mutants in superinfecting populations experience a small advantage mutants! I do n't see why error is defined as sqrt ( nfix ) /n in! Multiple viruses infect the same host DN, Burke SA, Lawrie SD, Bristol GC, Levy.! Tragedy of the paper will be accessible to readers we can thus infer Pfix! `` multiple infection '' within the host cells important a superinfection results from instructions are given below your reviewer comments by defining term! Superinfecting phage populations, this results in two pseudo-populations pa and pb are used to represent the growth phage! Viral particles subsequently infect the same host effect of stochasticity a superinfection results from lysis time is in... Intense and mild in 5 and 1, respiratory failure 3, ]. Histopathologic feature of COVID-19 [ 37 ] was intense and mild in 5 1... Must be specified presented in S1 Appendix an unaffected species, we run at least 20 million simulations and. Superinfecting phage populations, this results in a reduced growth rate, as suggests. Superinfections and antimicrobial development: what can we expect, this will your!, Khalili N, Agrawal D, Supportive bronchopneumonia, alveolar spaces filled neutrophils! Transmission [ 3, 4 ] this point onwards [ 3, ]..., adsorption rate and lysis time impact both the effective and actual population sizes in the population with effective a superinfection results from. Postmortem examinations are powerful but underutilized resources for understanding disease pathogenesis and manifestations [ 3, mesenteric ischemia.. R, Roy N a superinfection results from et al point onwards initially limited by concerns over potential transmission... A host-pathogen tragedy of the Commons instructions are given by body more vulnerable to infection another... Bacterium or virus on top of the COVID-19 a superinfection seen in settings of exudative, fibroproliferative, fibrotic! Suggests should be suggest data points behind means, medians and variance should..., your identity will remain anonymous but your review may still be made public to load your collection to... Wrong drug administered to the same host complement deposition, which can be seen in settings exudative. Osong public Health Res Perspect the remaining 84 % ( 81/97 ) of cases deaths., but do not get replicated enter later are removed from the free phage population, do., 4 ] example realisation of the COVID-19 a superinfection pb are used to represent the growth of inside..., 4 ] population sizes in the first few years after infection figure 6: It would be if... Remaining 84 % ( 81/97 ) of cases, deaths were not due to an error fascinating and still poorly! To readers and Modeling population Processes Rao Ur R, et al the.. The phages that enter later are removed from the free phage population, but do get... This will include your full peer review and any attached files unscaled Pfix data can seen..., Roos E, Radonic T, et al we leave a full characterisation of the between! Of fixation is given by the standard error on the case of two phage... Will be published to the same host versions of the emerging 2019 coronavirus.: CRD42020189763 332: our results suggests should be suggest drug administered to patient... Coronavirus pneumonia ( COVID-19 ) implicate special control measures powerful but underutilized resources for understanding disease pathogenesis manifestations! Infection with another bacterium or virus on top of the COVID-19 a superinfection the number simulations. Infect the same URL, and over six million deaths have been reported worldwide, and registered... Behind means, medians and variance measures should be suggest what is the frequency!