A consequence of this viral spread is an increase in critically ill patients, most often throughout flu season, which lasts from October to April in the United States. Critically ill influenza patients may suffer from direct viral invasion or a secondary bacterial infection that arises as a result of infection by the flu virus. Outbreaks of viral respiratory infection , such as influenza, can lead to a high death toll, often over a short period of time.
The is due in part to the mode of viral transmission. Through tiny respiratory droplets in the air, respiratory virus particles can easily travel from one person to another. Globally, upper and lower respiratory infections are the fourth highest cause of mortality. In the U. Serious influenza can lead to pneumonia, which is severe lung inflammation that occurs in response to an infection, and in which the air sacs fill with pus, making it difficult to breathe.
The link between influenza, pneumonia, and sepsis is complex. But, in patients with severe influenza, pneumonia—and therefore sepsis—is often caused by a secondary bacterial infection. The association between influenza and bacterial pneumonia became well established following the flu pandemic.
By the midth century , influenza A and B viruses were both known to predispose patients to bacterial infections. Three additional studies were performed in the US, one among adult patients who because of symptoms, presented to different types of facilities throughout the US for testing, of whom some tested SARS-CoVpositive and others tested SARS-CoVnegative [ 64 ]; another in the frail elderly in nursing homes and assisted living facilities [ 65 ]; and a third in hospitalised adults [ 66 ].
Wolfe and colleagues noted essentially similar findings in their study, and the common bacterial co-pathogens were S. In addition, ICU admission Using Cox proportional hazards regression and following adjustment for age, ICU admission, mechanical ventilation, corticosteroid administration, and pre-existing comorbidities, patients with bacterial co-infections had an increased risk of in-hospital mortality adjusted HR 3.
Relatively few studies have been undertaken describing co-infections in children with COVID infection [ 67 , 68 , 69 , 70 ]. Nevertheless, what has been undertaken suggests that paediatric patients with COVID infection present with epidemiological, clinical, and radiological characteristics that are distinct from adults.
Lastly, elevated procalcitonin, and a consolidation with a surrounding halo sign, may be more common than in adults, possibly representing a typical sign in paediatric patients [ 67 , 68 , 69 , 70 ].
There have also been reports of co-infection in patients with COVID involving other respiratory pathogens, which may be more common in some regions than in others.
The first of these is tuberculosis TB. Chen and colleagues described both active and latent TB as being a risk factor for COVID infection, in an observational case-control study from Shenyang, China [ 71 ]. TB diagnosis was based on an interferon-gamma release assay on peripheral blood. Not only were patients with active or latent TB more susceptible, but the symptom progression of the COVID infection was more rapid and more severe. While suggesting that these findings needed to be confirmed in much larger studies, these authors suggested that all patients with COVID infection should be tested for TB.
Thereafter a case-control study of 49 cases, which was a global cohort of current or former TB patients with post-TB sequelae , was published, including patients from eight countries and three continents [ 73 ]. There was some discussion in the literature about the interpretation of the findings, particularly regarding the timing, with the suggestion that since TB has a chronic course, while COVID was an acute illness, this co-infection may be purely incidental; however, there was concern about the high mortality of that study of There was also a concern though, aside from these comments, that these co-infections, even if co-incidental, may nevertheless be an issue in countries with high TB and post-TB sequelae burdens and that both infections could have a significant, synergistic social and economic impact worldwide [ 74 ].
A further concern with regard to TB is the potential impact that the COVID pandemic may have on national programs for eradication of diseases such as TB, with recognition of the important need to continue and even strengthen these national programs and encourage people to continue to access healthcare for timely diagnosis and treatment of TB, as required [ 76 , 77 ].
Oliva and co-workers [ 79 ] reported a case series of SARS-CoV-2 with Chlamydia or Mycoplasma infections and Nicolson and colleagues [ 80 ] reviewed the evidence for whether these infections are linked to progression of the COVID disease and its lethal outcome.
Also, reports have emerged, documenting cases with coronavirus disease associated with Pneumocystis jirovecii pneumonia, either simultaneously, or within a few days of each diagnosis, which represents a particular diagnostic dilemma, especially in people living with HIV unless routinely tested for [ 81 , 82 ], and with other fungal infections [ 83 ].
Lastly, Abdoli [ 86 ] expressed concerns that helminthic co-infection may increase morbidity and mortality in COVID due to their suppressive effect on the immune response. Lastly, several reviews, some with meta-analyses, have been published describing the occurrence of co-infections and secondary infections in patients with COVID infections [ 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. Both studies appear to have been conducted in all patients, including both adults and children, and it appears that both true co-infections and secondary infections were included.
Langford and colleagues performed a living rapid review and meta-analysis of bacterial co-infection and secondary infection, using the CDC definition of such cases [ 90 ]. Bacterial co-infections were reported in 3. The authors attribute the possible reasons for differences in the reported bacterial co-infections and superinfections as being due to regional variations in patient populations, their access to care, and infection prevention and control measures implemented.
Most of the studies reported high rates of antibiotic use, being This may also have had impacted on the documentation of additional bacterial infections. Lai and colleagues did an extensive literature review of both co-infections and secondary infections with viruses, bacteria and fungi in patients with COVID [ 91 ].
They noted that the studies were all observational, cross sectional studies and that there was considerable variation in the reporting of co-infections in the different studies. There was a range of viral and bacterial pathogens noted, many of which appear to be the common, community-acquired pathogens, but some studies reported pathogens that more clearly appear to be nosocomial pathogens.
Furthermore, the authors noted that clinical, radiological, and routine laboratory data could not distinguish between co-infecting pathogens and COVID The authors correctly concluded that future large-scale well-designed, prospective studies needed to be conducted to answer the questions regarding the true prevalence of COVID co-infection, the risks of such infections, the microbiological causes of such infections, and their impact on patient outcomes.
Only, thereafter, can informed decisions be made regarding empirical antibiotic use in suspected cases of COVID infection. Anthony and coworkers also recognised, particularly because of the similarity of the presentation of COVID and influenza, that coinfection rates may not be low, but rather underreported [ 92 ].
Lastly, while it would have been ideal in the current review to grade the evidence for the occurrence of co-infections and superinfections according to the quality and frequency of the additional testing, this would not have been possible. Many of the studies are small, often they are retrospective, clear indication of when the additional testing was undertaken was usually not evident and several of the studies were not primarily set out to document these infections.
All these issues, as well as the issue regarding differentiating carriage from true infections, with the additional testing, need to be appropriately and comprehensively addressed in future studies.
The next section of this review will describe the mechanism s most likely associated with the occurrence of microbial co-infections and superinfections, starting initially with the apparent synergistic effects of viral-bacterial interactions.
A significant amount of information in the literature regarding these effects relates to the interaction between the influenza virus and bacterial pathogens, in particular, S. This is followed by a review of what is known about the mechanisms of these interactions, as well as mechanisms that are suggested, regarding the interactions of SARS-Cov-2 with other pathogens.
The latter will include an overview of the potential role of activated platelets, and their immunosuppressive effects, in enhancing the risk of SARS-CoV-2 co-infections and superinfections. When reviewing the data presented below, the reader will recognize that much of what is described in the literature, relates to the occurrence of viral infections, followed some time later by, most commonly, bacterial infections, and, therefore, that these mechanisms described relate predominantly to superinfections rather than true co-infections, as we have defined in the current review.
Secondary bacterial pneumonia, particularly due to the pneumococcus, following influenza epidemics and pandemics, as an important cause of excess mortality, initially suggested in studies from the influenza pandemic, was subsequently confirmed during the , H1N1, influenza pandemic [ 94 ]. Studies have reported that the mechanisms may include; i destruction of the respiratory epithelium and exposure of the basement membrane [ 95 ], and, ii upregulation of molecules that bacteria use as receptors especially due to the viral neuraminidase activity [ 95 ], both of which increase bacterial adherence to the respiratory epithelium, as well as, iii impaired function of immune cells, including neutrophils and macrophages, the latter affected by the release of interferon-gamma produced during T-cell responses to influenza, that impairs clearance of pneumococci for the lung by alveolar macrophages [ 96 ].
Through the mechanisms described above, influenza A virus infection has been shown to facilitate pneumococcal colonization, transmission, and active disease [ 97 ], although, as shown by others, this appears to be independent of the upregulation of the platelet-activating receptor PAF-R [ 98 ].
Additional studies have highlighted the important role that S. A number of investigators recently reviewed the proposed mechanisms by which viral infections, and particularly SARS-Co-V-2, may predispose to concomitant and subsequent bacterial infections [ 15 , ].
They emphasised that the damage that viruses cause to the respiratory epithelium, as well as their effects on innate and adaptive immunity, antagonising IFN responses that enhance bacterial adherence, colonisation, growth, and invasion into healthy sites in the respiratory tract, are important mechanisms [ 15 , ]. They then translate many of these mechanisms into what is known with regard to the SARS-CoV-2 virus, or indicate putative mechanisms. Mirzaei and colleagues [ 87 ] provide a very valuable overview of bacterial coinfections with viruses, in general, and SARS-CoV-2, in particular, reviewing in detail possible putative mechanisms by which viruses may predispose to bacterial coinfection but also postulating the mechanisms by which bacterial coinfection with SARS-CoV-2 occurs, and providing functional suggestions for both the management and control of them.
Downregulation and differential regulation of immune genes are mechanisms that may create a positive environment for establishment of secondary bacterial infections [ ], favouring bacterial attachment to host structural cells and pro-inflammatory environment conducive to suppression of anti-bacterial host defences.
Since the importance of the gut-lung axis in controlling bacterial pneumonia is well established, disturbance of the gut microbiota may well be a mechanism that may potentially affect the disease outcomes in patients with severe COVID infection, including predisposing to secondary lung infections [ 15 ]. Lastly, Golda and colleagues documented that the human coronavirus NL63 enhanced adherence of S.
Interestingly, this enhanced binding correlated with an increased expression of the platelet-activating factor receptor, but much as Diavotopoulos et al. The preceding clinical overview has highlighted the complexity of distinguishing between co-infection and super-infection following hospital admission of patients with severe COVID infection.
Given the identities of several of the common causative pathogens together with poor responsiveness to antimicrobial chemotherapy and unfavourable clinical outcomes, super-infection secondary to severe SARS-CoVassociated immunosuppression [ , ] exacerbated in many cases by immunosenescence, seems prominent. This contention is supported by the additional risks posed by the contribution of inappropriate use of antibiotics administered to patients with less severe disease to the emergence of multidrug-resistant microbial pathogens in the hospital environment together with the fact that those with severe COVID and associated immunosuppression must also endure prolonged hospital stays, often necessitating mechanical ventilation in the ICU setting, posing the potential hazard of nosocomial infection.
In addition, intense immunosuppression associated with SARS-CoV-2 infection may also trigger the activation of quiescent, biofilm-encased airway pathogens such as the pneumococcus, H. The human platelet has been increasingly recognized as being a key player in orchestrating the excessive COVIDrelated systemic inflammation that drives not only generalized immunosuppression, but also the development of acute respiratory distress syndrome ARDS and cardiac dysfunction that severely complicates this acute viral disease [ , , , ].
In this context, platelets have been reported to express angiotensin-converting enzyme 2 ACE2 , presumably derived from megakaryocytes, that interacts with the spike protein of SARS-CoV-2, resulting in platelet activation [ ]. These most likely involve the recognition of viral single-stranded RNA by platelet Toll-like receptor 7 TLR7 during the viraemic phase of the disease, which may precede the onset of symptoms [ ].
Although potentially protective in early-stage disease [ , , ], uncontrolled systemic hyperactivation of platelets results in inflammation-triggered immunosuppression and microvascular occlusion.
Prominent mechanisms of platelet-driven systemic immunosuppression in this setting include the following:. These and other mechanisms, such as those driven by platelet-activated neutrophils are likely to underpin the intense immunosuppression associated with severe COVOD [ ].
In addition to the aforementioned mechanisms of immunosuppression, platelets and their mediators of inflammation, specifically reactive oxygen species, HMGB1, IL-8, and CD62P are also important drivers of the formation of neutrophil extracellular traps NETs which are believed to be major contributors to the pathogenesis of SARS-CoVassociated ARDs and cardiac damage [ , , , , , , , ]. Notwithstanding key involvement in intravascular and intrapulmonary obstruction [ , ], the histone components of NETs, as well as various granule-derived proteinases, are also potent cytotoxins for epithelium and vascular endothelium [ , , ].
In addition, NET-derived histone- and proteinase-mediated cytotoxic effects on epithelial and endothelial cells following infection with the human coronavirus NL63, as well as SARS-CoV-2, the influenza virus, and other respiratory viruses are probable major contributors to the development of secondary and super-bacterial infections.
This results from several mechanisms, including: i exposure of receptors for bacterial adhesins following injury to epithelial and endothelial cells; ii release of dormant potentially pathogenic intracellular pathogens from these cells; and iii via facilitation of extrapulmonary dissemination of bacterial pathogens [ , , ]. This manuscript is a detailed description of co-infections and secondary infections in patients with COVID infection, which clearly do occur, and which are associated with severe disease and associated poor outcome.
In the most recent preprint of a systematic review and meta-analysis, the authors attempted to dissect out co-infections from superinfections [ ]. However, it is interesting to note that a recent multicentre, international study, indicated in all countries that were included, there has recently been a significant and sustained reduction in overall invasive diseases in the communities due to S.
Nevertheless, the question remains as to what should be done with antibiotic therapy in the time of COVID Nevertheless, the main authors of that CAP guideline did offer an interpretation of how the guideline would apply to the management of patients with COVID, particularly with the concern regarding bacterial co-infections [ ]. Several additional guidelines were subsequently published, such as those from the Netherlands an evidence-based guideline [ ] , the UK the NICE guideline [ ] , and South Africa from the National Institute for Communicable Diseases [ ], as well as expert recommendations [ ].
These either contained, among other issues, antibiotic recommendations for treatment of co-infections and secondary infections with COVID infection or concentrated purely on antibacterial therapy. Metlay and Waterer [ ] offered recommendations regarding CAP management in the COVID era, indicating the following; i Empiric antibiotic therapy is recommended in patients with CAP, without COVID, but not all confirmed COVID cases, ii The relevant bacterial pathogens in patients with CAP and COVID are likely to be the same as in patients with CAP alone and, therefore, if antibiotics are to be used they should be the same, iii , testing sputum and blood for bacterial pathogens is most useful when there is a concern for multidrug-resistant pathogens, and iv procalcitonin may help prevent overuse of antibiotics.
The NICE guideline indicated that while it may be difficult to differentiate between COVID pneumonia and either primary or secondary bacterial pneumonia, bacterial infections are more likely if patients become rapidly unwell after only a few days of symptoms, and if they do not have typical COVID symptoms, but have pleuritic chest pain and purulent sputum [ ]. Furthermore, they recommended that depending on the patient, a range of microbiological investigations may need to be undertaken, and depending on the clinical and laboratory findings, patients should be treated for the appropriate condition, based on guideline recommendations [ ].
The guideline from the Netherlands recommended that maximum efforts should be made in all COVID cases to obtain sputum and blood for bacterial cultures and also to do urinary antigen testing [ ]. Given the frequency of the occurrence of co-infections and superinfections described in the current review, this would seem to be the most logical approach to this issue.
There appears to be consensus among these documents that in the presence of suspected bacterial co-infections, particularly in more severe cases, local guideline-concordant antibiotics should be commenced in patients with COVID, but that if all the cultures are negative and some indicate additionally that if the procalcitonin levels are low , it may be reasonable to discontinue antibiotics [ , , ].
It is quite clear from the review that additional infections, with various other pathogens, do occur in patients with SARS-CoV-2 infection, representing either true co-infections, or superinfections, as we defined in this review. Furthermore, many experts have provided a number of recommendations, regarding additional therapy, particularly antibiotic therapy, to guide clinicians managing patients with SARS-CoV-2 infection.
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S Afr Med J. COVID and antimicrobial stewardship: what is the interplay? Infect Control Hosp Epidemiol. Clin Infect Dis. Clin Med Lond. Lancet Microbe. In this study, the most common bacterial infections in patients with either influenza or COVID were Pseudomonas aeruginosa and Staphylococcus aureus , generally in agreement with previous studies 8.
Staphylococcus aureus is a known pathogen associated with secondary pneumonia during influenza infection 9. Its dissemination to the lungs is attributed to a combination of environmental changes and immune responses that create suitable conditions for Staphylococcus aureus infection 9. Pseudomonas aeruginosa is also associated with chronic predisposing respiratory conditions, including upper respiratory tract infections such as influenza 10 , While Pseudomonas aeruginosa is a common respiratory opportunistic pathogen, it is also known as the most common gram-negative bacterial species associated with severe hospital-acquired infections in some hospitals Furthermore, late infections with gram-positive bacteria were more common in COVID compared to influenza patients.
Generally, the overall time from admission to bacterial growth was longer for COVID compared to influenza patients. This possibly reflects the disease's natural history, characterized by a late deterioration, typically 7—10 days after symptoms onset, that might be accompanied by a secondary bacterial infection.
Alternatively, COVID patients are admitted in isolated dedicated wards under strict isolation protocol, limiting free medical and nursing personnel access. This might affect the quality of medical treatment and increase the likelihood of complications such as nosocomial infections, including line, device-related, skin, and soft tissue infections associated with gram-positive bacteria This hypothesis is in line with the increased hospitalization length, the longer overall time from admission to bacterial growth, and the higher rates of late gram-positive bacterial infections observed in COVID than influenza patients.
In addition, the higher fraction of late gram-positive infections isolated from blood cultures in COVID compared to influenza, further supports this notion. Although several studies characterized the secondary bacterial infections in COVID patients, our study is the first to compare the infecting bacterial pathogens with those observed in influenza patients from the same center, and to correlate secondary bacterial infections in both groups with disease severity and outcome.
Our study, however, has several limitations. First, it is retrospective in nature and relies on proper documentation of cultures and clinical parameters in the medical records. The study might also suffer from selection bias since the decision to obtain bacterial cultures was done by the treating clinician and most probably was affected by the severity of the disease. Second, given the local screening policy of every admitted patient for COVID during the pandemic, we also cannot rule out that a fraction of patients especially among the COVID group was hospitalized due to other medical conditions implicated in bacteremia that were completely unrelated to their viral infection.
Furthermore, since there were no influenza cases in Israel during the COVID pandemic, the two groups of patients might reflect different time periods. Last, the study's data was from a single center, and thus the infecting bacteria might reflect a site-specific microbiological profile. Taken together, our results show that secondary bacterial infections, in particular late gram-positive infections, are a clinically important complication with a significant correlation to poor outcomes in hospitalized COVID patients.
This calls for increased awareness of the treating physicians to the possibility of secondary bacterial infection as an etiology to late deterioration, suggesting that antibiotic treatment may be an essential component of the therapeutic armamentarium in selected patients with severe COVID As gram-positive bacteria are increasingly becoming resistant to antibiotics 15 , our results highlight the importance of implementing infection control measures specific for COVID hospitalized patients in addition to modification of antibiotic treatment protocols.
The need for informed consent was waived due to the retrospective nature of the study. After excluding the patients for which no culture was taken, influenza and COVID patients were selected for further analysis. Blood or sputum cultures were taken routinely at admission or according to the discretion of the treating clinician. The samples were transferred to the microbiology laboratory and processed according to the current standard practice procedures Positive cultures were further analyzed according to the current standard practice procedures Identification of isolates was performed using matrix-assisted laser desorption ionization—time-of-flight mass spectrometry.
GeneXpert assay was performed directly on positive blood cultures suspected of containing staphylococci after the gram staining. Bacterial growth during the first 48 h from admission was regarded as early or coinfection, and bacterial growth up to 2 weeks from admission was defined as a late infection.
Normality tests were conducted for all variables. Due to the non-normal distribution of our variables, we used the non-parametric Wilcoxon and Kruskal Wallis tests when appropriate, and median and interquartile range IQR are presented.
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