Cited by 207Dental Research and COVID-19Oral microbiology and periodontitis researchCOVID-19 Clinical Research Studies

Oral Microbiome and SARS-CoV-2: Beware of Lung Co-infection

Open access
Bao, Lirong, Zhang, Cheng, Dong, Jiajia, Zhao, Lei, Li, Yan, Sun, Jianxun·2020·Frontiers in Microbiology

Abstract

The new coronavirus SARS-CoV-2, the cause of COVID-19, has become a public health emergency of global concern. Like the SARS and influenza pandemics, there have been a large number of cases coinfected with other viruses, fungi, and bacteria, some of which originate from the oral cavity. Capnocytophaga, Veillonella, and other oral opportunistic pathogens were found in the BALF of the COVID-19 patients by mNGS. Risk factors such as poor oral hygiene, cough, increased inhalation under normal or abnormal conditions, and mechanical ventilation provide a pathway for oral microorganisms to enter the lower respiratory tract and thus cause respiratory disease. Lung hypoxia, typical symptoms of COVID-19, would favor the growth of anaerobes and facultative anaerobes originating from the oral microbiota. SARS-CoV-2 may aggravate lung disease by interacting with the lung or oral microbiota via mechanisms involving changes in cytokines, T cell responses, and the effects of host conditions such as aging and the oral microbiome changes due to systemic diseases. Because the oral microbiome is closely associated with SARS-CoV-2 co-infections in the lungs, effective oral health care measures are necessary to reduce these infections, especially in severe COVID-19 patients. We hope this review will draw attention from both the scientific and clinical communities on the role of the oral microbiome in the current global pandemic.

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Written from the paper’s full text.

TL;DR

This review argues that the oral microbiome can serve as a reservoir for lung co-infections in COVID-19, with aspiration, mechanical ventilation, poor oral hygiene, and lung hypoxia as key pathways. It recommends oral hygiene measures for COVID-19 patients and outlines research approaches including better diagnostics, lung organoids, and co-infection animal models.

Key findings

  • Oral opportunistic pathogens such as *Capnocytophaga*, *Veillonella*, *Leptotrichia buccalis*, *Veillonella parvula*, *Capnocytophaga gingivalis*, and *Prevotella melaninogenica* were found in COVID-19 patient BALF by mNGS; in an Eastern China multicenter study, 11 of 20 co-infections were identified in laboratory-confirmed COVID-19 cases, with common pathogens including *Acinetobacter baumannii*, *Klebsiella pneumoniae*, *Aspergillus flavus*, *Candida glabrata*, and *Candida albicans*, and 5 cases coinfected with a virus.
  • Risk factors including poor oral hygiene, cough, increased inhalation, and mechanical ventilation provide a route for oral microorganisms to enter the lower respiratory tract; lung hypoxia favors growth of anaerobes and facultative anaerobes from the oral microbiota, and ventilator-associated pneumonia incidence is reported as 5% to 67%.
  • SARS-CoV-2 receptor ACE2 is expressed in 0.52% of oral cells, with 95.86% expressed in tongue epithelial cells; SARS-CoV-2 was detected in initial saliva of 91.7% (11/12) of patients, and viral load in throat swabs and sputum peaked at 5–6 days after onset at 10^4 to 10^7 copies/ml.
  • Oral care agents including povidone iodine (0.23–1%), cetylpyridinium chloride (0.05–0.10%), and hydrogen peroxide (0.5–1.5%) reduce oral microbiota; 0.02% chlorhexidine is ineffective against coronaviruses while 0.05% is SARS-CoV-2 sensitive, and improved oral hygiene care can reduce aspiration pneumonia risk and mortality risk by as much as 60%.

Methods

  • Narrative review; no primary experiments or systematic search strategy are reported. The authors synthesize published literature on SARS-CoV-2/COVID-19, SARS, influenza, oral microbiome, co-infections, host immunity, oral care, diagnostics, lung organoids, and animal models.
  • Evidence cited includes clinical studies, mNGS/metagenomic sequencing, BALF and saliva sample studies, prior reviews, and preclinical models; the paper includes a table of mouth rinse components and a schematic figure of the oral-lung axis.
  • Formal inclusion criteria, search terms, and risk-of-bias assessment are not stated in the paper.

Limitations

  • The authors state that little work has been done on coronaviruses and oral microbiomes, that the mechanism of interaction between oral bacteria and respiratory viruses to promote lung infection has not been studied in depth, and that more mechanism studies are needed.
  • The authors note limited data available to date, that one cited saliva study had a small sample size, and that the frequency of asymptomatic or RT-PCR-negative patients with CT pneumonia-like lesions is unknown.
  • Evident from the text: this is a narrative review relying partly on preprints and indirect evidence from influenza and SARS; it does not directly test whether oral care improves COVID-19 outcomes or establish causality between oral microbiota and SARS-CoV-2 lung co-infection.

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Integrity signals

Registry

Crossref · 10.3389/fmicb.2020.01840

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    Microbiota that have migrated from the oral cavity, rather than those from the nasal flora, is likely to be an important source of microbiota in the lungs under normal conditions.

    “Microbiota that have migrated from the oral cavity, rather than those from the nasal flora, is likely to be an important source of microbiota in the lungs under normal conditions (Bassis et al., 2015).”
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    The oral microbiome could be a driving force for bacteriome shifts by regulating mucosal immunity, which directly or indirectly affects pathogenicity.

    “The oral microbiome could be a driving force for bacteriome shifts by regulating mucosal immunity, which directly or indirectly affects pathogenicity (Li et al., 2019).”
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    Metatranscriptome sequencing of bronchoalveolar lavage fluid from 8 COVID-19 patients revealed elevated levels of oral and upper respiratory commensal bacteria.

    “Metatranscriptome sequencing for the bronchoalveolar lavage fluid (BALF) of 8 COVID-19 patients revealed the presence of elevated levels of oral and upper respiratory commensal bacteria (Shen et al., 2020).”
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    Lung microbiota are more similar to those in the oropharynx than those in the air, nasopharynx or lower digestive tract.

    “Multiple studies have shown that lung microbiota are more similar to those in the oropharynx, than those in the air, nasopharynx or lower digestive tract (Segal et al., 2013; Venkataraman et al., 2015).”
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    Acellular bronchoalveolar lavage samples from half of healthy individuals are enriched with oral taxa.

    “It was demonstrated that acellular bronchoalveolar lavage samples from half of healthy individuals are enriched with oral taxa (Segal et al., 2016)”
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    An oral-lung aspiration axis is a key factor leading to many infectious diseases.

    “It is well-known that an oral-lung aspiration axis is a key factor leading to many infectious diseases (Mammen et al., 2020).”
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    SARS-CoV-2 is a single-stranded RNA β-coronavirus and a member of the subgenus Sarbecovirus (beta-CoV lineage B).

    “SARS-CoV-2 is a single-stranded RNA β-coronavirus and a member of the subgenus Sarbecovirus (beta-CoV lineage B).”
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    SARS-CoV-2 is the cause of COVID-19.

    “Corona Virus Disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have spread worldwide (Zhu N. et al., 2020).”
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    The oral cavity houses the second largest microbiota in the human body and can include bacteria, fungi, viruses, and archaea.

    “The oral cavity houses the second largest microbiota in the human body and can include bacteria, fungi, viruses, and archaea (Dewhirst et al., 2010).”
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    The dominant genera of healthy lungs include Streptococcus, Fusobacterium, Pseudomonas, Veillonella, Prevotella, and Capnocytophaga, which also colonize the oral cavity.

    “The dominant genera of healthy lungs include Streptococcus, Fusobacterium, Pseudomonas, Veillonella, Prevotella, and Capnocytophaga (Beck et al., 2015; Dickson and Huffnagle, 2015; Wypych et al., 2019; Shen et al., 2020), colonizing the oral cavity as well.”
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    The main bacterial genera by abundance in the normal oral cavity include Neisseria, Corynebacterium, Leptotrichia, Streptococcus, Prevotella, Veillonella, Fusobacterium, and Capnocytophaga.

    “The main bacterial genera, by abundance, present within the normal oral cavity include Neisseria, Corynebacterium, Leptotrichia, Streptococcus, Prevotella, Veillonella, Fusobacterium, and Capnocytophaga (Li et al., 2014).”
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    Many human bacterial pathogens can colonize the respiratory tract of healthy individuals asymptomatically.

    “Additionally, many human bacterial pathogens can also colonize the respiratory tract of healthy individuals asymptomatically (Arora et al., 2015).”
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    The oral cavity is an ecological reservoir for potential pathogens and is involved in local and systemic diseases.

    “it is supposed that the oral cavity, an ecological reservoir for potential pathogens, is involved in local and systemic diseases (Warinner et al., 2014).”
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    The frequency of influenza and bacterial co-infection ranged from 2% to 65%.

    “The frequency of influenza and bacterial co-infection ranged from 2% to 65%.”
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    1450/2010 (72%) of COVID-19 patients received antimicrobial therapy.

    “It’s reported that 1450/2010 (72%) of COVID-19 patients received antimicrobial therapy (Rawson et al., 2020).”
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    Viral load is higher in the nose than in the throat, and the viral nucleic acid change model in SARS-CoV-2 patients is similar to influenza but different from SARS-CoV.

    “Other research has indicated a higher viral load in the nose than in the throat, viral nucleic acid change model in the patients infected with SARS-CoV-2 were similar to those in the patients with influenza viruses but different from that of SARS-CoV (Wang et al., 2020).”
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    During the 2009 influenza pandemic, almost one in four patients presented bacterial complications.

    “During the 2009 influenza pandemic, almost one in four patients presented bacterial complications (MacIntyre et al., 2018).”
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    Streptococcus pneumoniae and Staphylococcus aureus accounted for 35% and 28% of influenza bacterial infections.

    “Among them, Streptococcus pneumoniae and Staphylococcus aureus, which accounted for 35% and 28% of infections (Klein et al., 2016).”
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    SARS-CoV-2 shares 79.5% sequence identity with SARS-CoV.

    “Genome sequencing demonstrated that SARS-CoV-2 shares 79.5% sequence identity with SARS-CoV (Zhou et al., 2020)”
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    SARS-CoV-2 is the seventh member of the Coronaviridae known to infect humans, two of which, SARS-CoV and MERS-CoV, caused global health threats previously.

    “It is the seventh member of the Coronaviridae known to infect humans so far, two of which, SARS-CoV and MERS-CoV, caused global health threats previously (Guarner, 2020; Letko et al., 2020).”
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    Bacterial co-infection occurred in 7% of hospitalized COVID-19 patients.

    “In addition, bacterial co-infection occurred in 7% of hospitalized COVID-19 patients.”
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    Risk factors such as increased inhalation, poor oral hygiene, and viral infection are related to the occurrence of respiratory infection.

    “These studies suggested that keen vigilance should be maintained against infections derived from the oral microbiome during infection by respiratory viruses and have uncovered risk factors such as increased inhalation, poor oral hygiene, and viral infection are related to the occurrence of respiratory infection (Pace and McCullough, 2010; Krone et al., 2014; Iki et al., 2016).”
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    95% of the mortality in the 1918 Spanish flu was due to bacterial infection.

    “The “Spanish flu” of 1918 was the most severe influenza pandemic on record, 95% of the mortality due to bacterial infection (Morens et al., 2008).”
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    Bacterial complications increased morbidity and mortality of influenza infection.

    “Epidemiological data indicated that bacterial complications further increased morbidity and mortality of influenza infection.”
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    The mechanisms by which the oral microbiome can influence respiratory disease is complicated and multifactorial, simultaneously affected by environmental, host, and microbial factors.

    “The mechanisms by which the oral microbiome can influence respiratory disease is complicated and multifactorial, simultaneously affected by environmental, host, and microbial factors (Xu et al., 2018).”
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    The majority of COVID-19 patients present a mild course with common symptoms including low fever, fatigue, and dry cough, while severe cases present dyspnea within a week and rapid deterioration into ARDS, multiple organ failure.

    “The majority of COVID-19 patients present a mild course, common symptoms including low fever, fatigue, and dry cough, while severe cases always present dyspnea within a week from the onset of symptoms, with rapid deterioration into serious complications, such as acute respiratory distress syndrome (ARDS), multiple organ failure, etc (Sharma et al., 2020).”
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    Although bacteria are typically secondary invaders during influenza infections, they express virulence factors that promote viral pathogenesis, resulting in increased viral load and declined clearance rates.

    “Although bacteria are typically secondary invaders during influenza infections, they express virulence factors that promote viral pathogenesis. As a result, viral load increases and clearance rates decline (McCullers, 2014).”
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    5 co-infection cases were found coinfected with a virus, including rhinovirus/enterovirus, H3N2, influenza B and respiratory syncytial virus, suggesting that virus co-infection were not uncommon in winter pneumonia patients.

    “In addition, 5 co-infection cases were found coinfected with a virus, including rhinovirus/enterovirus, H3N2, influenza B and respiratory syncytial virus, suggesting that virus co-infection were not uncommon in winter pneumonia patients.”
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    The receptor for SARS-CoV-2, human angiotensin-converting enzyme 2 (ACE2), is expressed in 0.52% of oral cells, of which 95.86% is expressed in tongue epithelial cells.

    “the receptor for SARS-CoV-2, human angiotensin-converting enzyme 2 (ACE2), is also expressed in 0.52% of oral cells, of which 95.86% is expressed in tongue epithelial cells (Xu H. et al., 2020).”
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    In some patients with no symptoms or negative RT-PCR results, chest CT scans revealed viral pneumonia-like lesions in the lungs, such as bilateral patchy shadows or ground glass opacity, and even lung consolidation, but the frequency is unknown.

    “It is also notable that in some patients with no symptoms or negative RT-PCR results that chest computed tomographic (CT) scans revealed viral pneumonia-like lesions in the lungs, such as bilateral patchy shadows or ground glass opacity, and even lung consolidation, but the frequency is unknown (Wang et al., 2020; Yan et al., 2020).”
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    Bacteria are known to participate in interactions between host cells and viruses.

    “In fact, bacteria are known to participate in interactions between host cells and viruses.”
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    A recent study revealed coinfection with Moraxella catarrhalis in laboratory-proven cases of SARS-CoV-2, and quantified increased bacterial burden in some patients over others.

    “A recent study revealed coinfection with Moraxella catarrhalis in laboratory-proven cases of SARS-CoV-2, and quantified increased bacterial burden in some patients over others (Peddu et al., 2020).”
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    The tongue dorsum is one habitat niche of oral microbes, where the dominant microflora are Prevotella and Veillonella, which are associated with an increased risk of death due to pneumonia in older, frail patients.

    “The tongue dorsum is one habitat niche of oral microbes, there the dominant microflora are Prevotella and Veillonella, which are associated with an increased risk of death due to pneumonia in older, frail patients (Asakawa et al., 2018; Kageyama et al., 2018).”
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    Premisecitation

    P. gingivalis is the most important periodontitis pathogen, while Streptococcus sp., in general, constitute the main component of oral flora.

    “P. gingivalis is the most important periodontitis pathogen, while Streptococcus sp., in general, constitute the main component of oral flora (Kuroda et al., 2010).”
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    Dental plaques contain pathogens which could aggravate the state of pneumonia, including P. gingivalis, which can synergistically enhance pathogenicity.

    “Dental plaques contain pathogens which could aggravate the state of pneumonia (Olsen, 2015), including P. gingivalis, which can synergistically enhance pathogenicity (Miller et al., 2018).”
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    Interpretationnone given

    Lung hypoxia would stimulate the growth of anaerobes and facultative anaerobes derived from oral microbiota.

    “Additionally, lung hypoxia would stimulate the growth of anaerobes and facultative anaerobes derived from oral microbiota.”
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    • Rests on an assumption: Lung hypoxia favors the growth of anaerobes and facultative anaerobes originating from the oral microbiota.
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    Influenza is the most common type of acute respiratory infection.

    “Influenza is the most common type of acute respiratory infection (Hanada et al., 2018)”
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    Interpretationreasoning

    Together, these factors result in respiratory dysbiosis, and thus cause respiratory disease.

    “Together, these factors result in respiratory dysbiosis, and thus cause respiratory disease.”
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    Some conditional pathogens such as Enterococcus faecalis, Klebsiella pneumonia, Acinetobacter baumannii, Stenotrophomonas maltophilia, and Candida albicans could come from hospital environment, nosocomial infection, but the majority inhabit the oral cavity.

    “Some conditional pathogens such as Enterococcus faecalis, Klebsiella pneumonia, Acinetobacter baumannii, Stenotrophomonas maltophilia, and Candida albicans could come from hospital environment, nosocomial infection, but the majority inhabit the oral cavity (Zheng et al., 2003; Li et al., 2005).”
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    Interpretationnone given

    Risk factors such as poor oral hygiene, cough, increased inhalation under normal or abnormal condition, and mechanical ventilation are the main routes by which oral microbiota enter the airways.

    “Risk factors such as poor oral hygiene, cough, increased inhalation under normal or abnormal condition, and mechanical ventilation are the main routes by oral microbiota enter the airways.”
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    Premisecitation

    Long-term bed rest people cannot cough as easily or as well, which allows pooled mucus to stagnate and reduces the clearance of potentially pathogenic material and irritants.

    “Long-term bed rest people cannot cough as easily or as well, which allows pooled mucus to stagnate and reduces the clearance of potentially pathogenic material and irritants (Knight et al., 2009).”
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    Bacterial complications were an important complication of the 2009 influenza pandemic.

    “bacterial complications were an important complication of the 2009 influenza pandemic (MacIntyre et al., 2018).”
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    Long-term bed rest, mechanical ventilation, and glucocorticoid therapy are all risk factors for opportunistic infection.

    “Long-term bed rest, mechanical ventilation, and glucocorticoid therapy are all risk factors for opportunistic infection.”
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    Some pathogens, such as anaerobes, cannot be easily cultured, making accurate diagnosis and treatment of infections challenging.

    “Some pathogens, such as anaerobes, cannot be easily cultured, making accurate diagnosis and treatment of infections challenging.”
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    Premisecitation

    Ventilator-associated pneumonia (VAP) frequently occurs in patients requiring mechanical ventilation, leading to high mortality, with an incidence from 5% to 67% depending on the population studied and the diagnostic criteria used.

    “Ventilator-associated pneumonia (VAP) frequently occurs in patients requiring mechanical ventilation, leading to high mortality, with an incidence from 5% to 67% depending on the population studied and the diagnostic criteria used (Barbier et al., 2013; Torres et al., 2017).”
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    Premisecitation

    Aspiration pneumonia is closely related to oral microorganisms due to the aspiration of oropharyngeal secretions.

    “It is speculated that aspiration pneumonia is also closely related to oral microorganisms due to the aspiration of oropharyngeal secretions (Hajishengallis, 2015).”
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    Sputum appeared to be a good clinical sample with a high positive rate (74.4∼88.9%), followed by nasal swabs (53.6∼73.3%) and throat swabs (50∼61.3%).

    “Sputum appeared to be a good clinical sample with a high positive rate (74.4∼88.9%), followed by nasal swabs (53.6∼73.3%) and throat swabs (50∼ 61.3%).”
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    In a study on 213 confirmed COVID-19 patients, viral RNA could be detected in all BALF samples of severe cases, but not from mild cases.

    “According to a study on 213 confirmed COVID-19 patients, viral RNA could be detected in all BALF samples of severe cases, but not from mild cases.”
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    SARS-CoV-2 can be detected from different body fluids and the rate of positive test results vary depending on the sample size, days after illness onset, and severity of illness.

    “SARS-CoV-2 can be detected from different body fluids and the rate of positive test results vary depending on the sample size, days after illness onset, and severity of illness.”
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    Interpretationnone given

    The frequency of microaspiration will rise in chronic inflammatory respiratory diseases.

    “The frequency of microaspiration will rise in chronic inflammatory respiratory diseases, therefore it is necessary to pay attention to co-infections caused by oral microorganisms.”
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  • May combine two claims.

    Premisecitation

    Poor oral hygiene habits can lead to the accumulation of many periodontal microorganisms in the oral cavity, and oral dysbiosis can accelerate lung function decline, which in turn can increase the incidence of pneumonia.

    “Poor oral hygiene habits can lead to the accumulation of many periodontal microorganisms in the oral cavity, and oral dysbiosis can accelerate lung function decline (Takeuchi et al., 2018; Winning et al., 2019), which in turn can increase the incidence of pneumonia (Kumar, 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Takeuchi et al., 2018 source

      Not checked in the free run.

    • cites Winning et al., 2019 source

      Not checked in the free run.

    • cites Kumar, 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Saliva appeared to be a good clinical specimen in the early stage of the disease, with SARS-CoV-2 detected in the initial saliva of 91.7% (11/12) of patients, however the sample size was small in that study.

    “What’s more, saliva appeared to be a good clinical specimen in the early stage of the disease, with SARS-CoV-2 detected in the initial saliva of 91.7% (11/12) of patients (To et al., 2020b), however the sample size was small in that study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites To et al., 2020b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When the onset time was greater than 14 days, the positive rate of BALF, sputum, and nasal swabs showed similar results, and were still much higher than throat swabs.

    “When the onset time was greater than 14 days, the positive rate of BALF, sputum, and nasal swabs showed similar results, and were still much higher than throat swabs (Yang et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leung et al. (2013) found that the number of Pseudomonas and Bacillus in the oropharynx increased significantly after influenza virus infection, whereas the number of Prevotella, Veillonella, and Neisseria decreased significantly.

    “Leung et al. (2013) conducted an unbiased high-throughput sequencing method to analyze the oropharyngeal microorganisms of pneumonia patients with or without influenza virus infection, and found that the number of Pseudomonas and Bacillus in the oropharynx increased significantly after influenza virus infection, whereas the number of Prevotella, Veillonella, and Neisseria decreased significantly.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Leung et al., 2013 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Influenza viruses rely on neuraminidase (NA) activity to release progeny viruses from infected cells and spread the infection.

    “Influenza viruses rely on neuraminidase (NA) activity to release progeny viruses from infected cells and spread the infection.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Premisecitation

    Cytotoxic products of P. gingivalis (e.g., lipopolysaccharide) can induce host cells release of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which in turn increase NO production leading to lung epithelial cell damage.

    “Cytotoxic products of P. gingivalis (e.g., lipopolysaccharide) can induce host cells release of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Ke et al., 2016), which in turn increase NO production leading to lung epithelial cell damage (Alayan et al., 2006; Wu et al., 2016; Ahamed et al., 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ke et al., 2016

      Not checked in the free run.

    • cites Alayan et al., 2006 source

      Not checked in the free run.

    • cites Wu et al., 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The viral load of SARS-CoV-2 in posterior oropharyngeal saliva samples was highest during the first week of symptom onset.

    “Another study (To et al., 2020a) reported that the viral load of SARS-CoV-2 in posterior oropharyngeal saliva samples was highest during the first week of symptom onset.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites To et al., 2020a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prevotella proteins, rather than viral proteins, are involved in increasing clinical severity of COVID-2019, i.e., Prevotella plays role in COVID-2019 outbreak.

    “As per the results, Prevotella proteins, rather than viral proteins, are involved in increasing clinical severity of COVID-2019, i.e., Prevotella plays role in COVID- 2019 outbreak and attention should be paid to understanding disease mechanisms and improving treatment outcomes (Khan and Khan, 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Khan and Khan, 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The viral load in throat swabs and sputum samples peaked at 5-6 days after onset and ranged from 10^4 to 10^7 copies/ml.

    “The viral load in throat swabs and sputum samples peaked at 5–6 days after onset and ranged from 104 to 107 copies/ml (Pan et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pan et al., 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    NA is an important target of anti-influenza drugs.

    “NA is, therefore, an important target of anti-influenza drugs.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Premisecitation

    Culture supernatants of NA-producing oral bacteria, like Streptococcus oralis and Streptococcus mitis, can promote the release of influenza virus and cell-to-cell spread of the infection, and also help to increase viral M1 protein expression levels and activation of cellular ERK.

    “It was known that the culture supernatants of NA-producing oral bacteria, like Streptococcus oralis and Streptococcus mitis, can promote the release of influenza virus and cell-to-cell spread of the infection, and also help to increase viral M1 protein expression levels and activation of cellular ERK.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kamio et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients infected by SARS-CoV-2, Fusobacterium periodonticum significantly decreased in the nasopharynx, while in the gut, the proportion of probiotics (like Bifidobacterium, Lactobacillus, and Eubacterium) was significantly reduced, and the proportion of conditioned pathogenic bacteria was significantly increased, such as Corynebacterium and Ruthenibacterium, which could lead to microbial tran

    “What’s more, the imbalance of microbiota was also found in patients infected by SARS-CoV-2, Fusobacterium periodonticum significantly decreased in the nasopharynx (Moore et al., 2020),while in the gut, the proportion of probiotics (like Bifidobacterium, Lactobacillus, and Eubacterium) was significantly reduced, and the proportion of conditioned pathogenic bacteria was significantly increased, such”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Moore et al., 2020 source

      Not checked in the free run.

    • cites Yu et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SspA is a key factor in regulating the host innate immunity, is an immunostimulatory component of S. gordonii that promotes bacterial adhesion, and purified SspA can induce IL-6 and monocyte chemotatic protein-1 production from human lung epithelial cells.

    “The cell-wall-anchored protein Staphylococcal surface protein A (SspA), a key factor in regulating the host innate immunity, is an immunostimulatory component of S. gordonii that promotes bacterial adhesion, and purified SspA can induce IL-6 and monocyte chemotatic protein-1 production from human lung epithelial cells (Andrian et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Andrian et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prevotella primarily activates toll-like receptor 2 and enhances the expression of inflammatory cytokines, including IL-23 and IL-1.

    “Lung inflammation has been associated with enrichment of the lung microbiome with Prevotella, this organisms primarily activates toll-like receptor 2 and enhance the expression of inflammatory cytokines, including IL-23 and IL-1 (Segal et al., 2013, 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Segal et al., 2013, 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Like SARS-CoV and MERS-CoV, SARS-CoV-2 can also induce excessive and aberrant non-effective host immune responses that are associated with severe lung pathology, and lead to death.

    “Like SARS-CoV and MERS-CoV, SARS-CoV-2 can also induce excessive and aberrant non-effective host immune responses that are associated with severe lung pathology, and lead to death (Hui and Zumla, 2019; Huang et al., 2020).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hui and Zumla, 2019

      Not checked in the free run.

    • cites Huang et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular immunity and cytokines status are closely related to the state of illness, with high levels of IL-6 and IL-10 levels in severe patients.

    “It has been confirmed that the cellular immunity and cytokines status are closely related to the state of illness, with high levels of IL-6 and IL-10 levels in severe patients (Wan et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wan et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under certain conditions, Streptococcus gordonii can attack host fibronectin, and subsequent cytokine production can induce inflammatory responses.

    “Under certain conditions, Streptococcus gordonii can attack host fibronectin, and subsequent cytokine production can induce inflammatory responses (Erb-Downward et al., 2011; Liu et al., 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Erb-Downward et al., 2011 source

      Not checked in the free run.

    • cites Liu et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The levels of serum IL-6 and IL-8 were significantly increased in patients with lung dysfunction, and local inflammatory factors spread into systemic circulation.

    “The levels of serum IL-6 and IL-8 were significantly increased in patients with lung dysfunction, and local inflammatory factors spread into systemic circulation (Yang et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P. gingivalis can produce Gingipain, which affects the innate immune response and promotes chronic inflammation.

    “Animal experiments (Benedyk et al., 2016) suggested that P. gingivalis can produce Gingipain, which then affect the innate immune response and promote chronic inflammation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Benedyk et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The presence of oral microbes such as Streptococcus, Prevotella and Porphyromonas can not only change the microbial composition of the respiratory system, but also promote a series of cytokine responses and affect the immune homeostasis of the lungs.

    “The presence of oral microbes such as Streptococcus, Prevotella and Porphyromonas can not only change the microbial composition of the respiratory system, but also promote a series of cytokine responses and affect the immune homeostasis of the lungs.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Premisecitation

    In the elderly, apart from increased risk of severe disease, recovery could also be slower and poor, increasing the possibility of recrudescence or aggravation as time passes.

    “Apart from the increased risk of severe disease, recovery could also be slower and poor, thus increasing the possibility of recrudescence or aggravation as time passes (Boe et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Boe et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    About 1/4 to 1/2 of patients infected by SARS-CoV-2 had chronic comorbidities.

    “About 1/4∼1/2 patients infected by SARS-CoV-2 had chronic comorbidities, and the prognosis was strongly associated with the presence and number of comorbidities (Chen N. et al., 2020; Guan et al., 2020a).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chen N. et al., 2020

      Not checked in the free run.

    • cites Guan et al., 2020a

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The chronic inflammatory process contributes to changes in microbiota composition, potentially making it harder to intervene.

    “This not only suggest that these anaerobic commensals play an important role in the level of resilience against pathogen overgrowth and disease, but also emphasizes that the chronic inflammatory process contributes to the changes in microbiota composition, potentially making it harder to intervene.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Premisecitation

    In COVID-19 patients, both peripheral CD4+ T and CD8+ T counts were significantly reduced but hyperactivated.

    “Based on anatomic reports (Xu Z. et al., 2020), found that both the peripheral CD4+ T and CD8+ T counts of the COVID-19 patients were significantly reduced, but hyperactivated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xu Z. et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In COVID-19 patients, there was an increase in highly pro-inflammatory CCR6+ Th17 in CD4+ T cells and a high concentration of cytotoxic granules in CD8+ T cells.

    “Additionally, there was an increase in highly pro-inflammatory CCR6+ Th17 in CD4+ T cells and a high concentration of cytotoxic granules in CD8+ T cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xu Z. et al., 2020

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Co-infection is critical to prognosis in COVID-19.

    “Drawing on the experiences of SARS in 2003 and influenza outbreaks, we recommend that oral hygiene in COVID 19 patients be a concern as co-infection is critical to prognosis.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    During the SARS-CoV-2 global outbreak, numerous cases are coinfected with other pathogens, some of which originate from the oral cavity.

    “During the SARS-CoV-2 global outbreak, numerous cases are coinfected with other pathogens, some of which originate from the oral cavity.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Immune disorders caused by viral infection can promote additional bacterial/fungal infections, hence increase the risk of secondary pneumonia.

    “As discussed above, poor oral hygiene can lead to a large accumulation of pathogens in the oral cavity and immune disorders caused by viral infection can promote additional bacterial/fungal infections, hence increase the risk of secondary pneumonia.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Premisecitation

    Povidone iodine (0.23-1%), cetylpyridinium chloride (0.05-0.10%), and hydrogen peroxide (0.5-1.5%) all effectively reduce the number of oral microbiota.

    “Povidone iodine (PV-I, 0.23∼1%), cetylpyridinium chloride (CPC, 0.05∼0.10%), and hydrogen peroxide (0.5∼1.5%) all effectively reduce the number of oral microbiota (Ardizzoni et al., 2018; Eggers et al., 2018; Li and Meng, 2020).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ardizzoni et al., 2018 source

      Not checked in the free run.

    • cites Eggers et al., 2018 source

      Not checked in the free run.

    • cites Li and Meng, 2020

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Improving oral hygiene care by either mechanical or chemical control of dental plaque biofilm formation would reduce the number of potential respiratory pathogens and inhibit droplet-borne virus route through the oral cavity, and hence reduce the risk and mortality risk of aspiration pneumonia.

    “Improving oral hygiene care by either mechanical or chemical control of dental plaque biofilm formation would reduce the number of potential respiratory pathogens and inhibit droplet-borne virus route through oral cavity, and hence consequently reduce the risk and mortality risk of aspiration pneumonia.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Premisecitation

    Mouthwash containing chlorhexidine (0.02%) or CPC can impair both the biofilm formation of viridans streptococci and the adhesion, proinflammatory effects, and immune escape abilities of Candida albicans.

    “Mouthwash containing chlorhexidine (CHX, 0.02%) or CPC have the ability to impair both the biofilm formation of viridans streptococci and the adhesion, proinflammatory effects, and immune escape abilities of Candida albicans (Ardizzoni et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ardizzoni et al., 2018 source

      Not checked in the free run.

76 of 76
  • The paper relies on this without support.

    Lung hypoxia favors the growth of anaerobes and facultative anaerobes originating from the oral microbiota.

    “Additionally, lung hypoxia would stimulate the growth of anaerobes and facultative anaerobes derived from oral microbiota.”
  • The paper relies on this without support.

    Compared with healthy individuals, those with chronic diseases have a certain degree of microecological disorder.

    “Compared with healthy individuals, those with chronic diseases have a certain degree of microecological disorder.”
  • The paper relies on this without support.

    Oral microbiota is prone to entering the lower respiratory tract due to increased aspiration and the presence of mechanical ventilation.

    “Given the fact that oral microbiota is prone to entering the lower respiratory tract due to increased aspiration and the presence of mechanical ventilation, the prevalence of fatal VAP may increase.”
  • The paper relies on this without support.

    Current guidelines for the management of COVID-19 scarcely emphasize oral care.

    “However, current guidelines for the management of COVID-19 scarcely emphasize oral care.”
  • The paper relies on this without support.

    SARS-CoV-2 is vulnerable to oxidation.

    “Since SARS-CoV-2 is vulnerable to oxidation, antiseptic mouthwash or gel containing broad spectrum oxidative agents, such as hydrogen peroxide or PV-I, is recommended to reduce the oral microbiota and potentially SARS-CoV-2 as well.”
  • The paper relies on this without support.

    Little work has been done on the coronaviruses and oral microbiomes.

    “Until now, little work had been done on the coronaviruses and oral microbiomes, and much remains for future study.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. 2020, Guideline for the Diagnosis and Treatment of Novel Coronavirus Pneumonia
  2. 2020, Coronavirus Disease (COVID-2019) Situation Report – 151.
  3. Zheng, 2003, The clinical characteristics of secondary infections of lower respiratory tract in severe acute respiratory syndrome., Chin. J. Respir. Crit. Care Med., 2, 270

Cited by

Sorted by citations

Authors
Bao, L., Zhang, C., Dong, J., Zhao, L., Li, Y., & Sun, J.
Affiliations
Sichuan University (CN)
Corresponding author
  • Li, Yan
  • Sun, Jianxun
Venue
Frontiers in Microbiology
Published
2020-07-31
Volume
11
Pages
1840-1840
ISSN
1664-302X (ISSN-L)
OpenAlex
W3046848575
Cited by
207
References
158
Citations by year
2026: 7 · 2025: 11 · 2024: 26 · 2023: 47 · 2022: 57 · 2021: 53 · 2020: 6
FWCI
1.95
Type
journal article
Language
en
Open access
Locations
  • Frontiers in Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81771085, 81700036, 81991502, 81970944)
Topics
  • Health Sciences › Dentistry › General Dentistry › Dental Research and COVID-19
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
SARS-CoV-2, COVID-19 pandemic, oral microbiota, Capnocytophaga, Veillonella, lower respiratory tract infection, mechanical ventilation, poor oral hygiene, anaerobic bacteria, cytokines, T cell response, aging, oral care

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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