Inflammation in COVID-19: A Risk for Superinfections
Round 1
Reviewer 1 Report
NA
Author Response
thank you!
Reviewer 2 Report
Overall, a nice review on superinfections. However, when reading the title, I expected to read a more on whether the acute and chronic inflammation caused by the SARS-CoV-2 infection render the infected more prone to other infections? This is considered a bit with regard to IL-6 therapy but limited. I am here not thinking of ICU pt, with many reasons to get superinfected but more general, does the inflammation caused by the SARS-CoV-2 infection make the host more prone to super infection and if so, what would the immunological mechanism be? In the treatment of COVID-19, only one inflammation-based biomarker guided treatment has been improved by EMA, the suPAR-guided anakinra treatment (IL-1 receptor antagonist). And suPAR is perhaps the best measure of chronic inflammation and strongest biomarker of COVID-19 outcome and the authors should consider to include this (see eg. SAVE MORE trial). The following sentence should include a direction (positive or negative correlation) "As a consequence, in addition to the wide-range of side effects (e.g., gastrointestinal bleeding, metabolic complications, hormonal imbalance, fluid retention, weight gain, anxiety, and disturbed sleep pattern) (81), secondary infections were also found to be correlated with dexamethasone use" as this also address whther inhibiting the inflammation makes the host more or less prone to superinfections.
Author Response
Reviewer 2: thank you for you comments. Here are the changes made :
Comment #1 inflammation and it’s effect of secondary infection. New section#8 "inflammation; a friendly fire?" was added due to the new data found regarding anti inflammatory state in the first day of incubation period and the hypo-inflammatory state following; causing dysfunction of the immune system making the host more prone to secondary infection.
Comment#2: regarding suPAR – under section 8, a paragraph regarding supar and save trial was added.
" Soluble urokinase plasminogen receptor (suPAR) levels are a biomarker of chronic inflammation (78). In SAVE MORE trial, an increase of the soluble urokinase plasminogen receptor levels (suPAR) in covid-19 patients was indicative of increased risk of disease progression and respiratory failure. Treatment with anakinra (IL-1 inhibitor) has significantly reduced worse clinical outcome and was associated with lower incidence of secondary infections (79).
"
Comment #3 : positive correlation was added to last sentence of section#9
In addition to the wide-range of side effects (e.g., gastrointestinal bleeding, metabolic complications, hormonal imbalance, fluid retention, weight gain, anxiety, and disturbed sleep pattern) (81), secondary infections were also found to be positively correlated with dexamethasone use (82).
Reviewer 3 Report
Article is very interested, well written, giving the overall information of this huge problem in COVID pandemia.
I have several suggestions and remarks:
In intoduction:
-section 3: please explain the abbreviations of cytokines, some of them are not routinely used
-section 4: ..."viral infections was mostly seen in adult males with median ages of 34-59?". In Europe and America, elderly people were much more affected (age over 60-75). Please use additional references for that.
-you have section 4 twice?; correct it please
-section 9 Tocilizumab: "...After the emergent approval of the use of tocilizumab in the treatment of Covid19 patients, higher rates of secondary bacterial infections were seen in some studies after the use of IL-6 inhibitors versus non-users (115-118)- it should be explained what is a potential mechanism (if any?) for that according to this references. Tocilizumab was usually used together with dexamethasone in this trials, so it is hardly possible to difference immunosupressive effect ...
-It should be also emphasized the importance of overbooking in ICU wards, problem of proper isolation of patients with suspected or diagnosed secondary bacterial infections. In first few waves of pandemia protective suits and gloves were changed less frequently due to fear of virus infection. Due to the large influx of patients, the staff was overworked. The level of prevention of the spread of infection was certainly questionable, which are all important parameters that also contributed to the high incidence of secondary bacterial infections.This should also be emphasized in a separate section.
-Authors should additionaly correct manuscript due to spelling and grammar mistakes
Author Response
Thank you for your comments :
Comment # 1 : cytokine abbreviation added on section 3 : on 3rd paragraph.
IP10- Interferon gamma-induced protein 10
MCP-1 Monocyte chemoattractant protein-1
MIP-1α - Macrophage inflammatory protein-1 alpha
Comment #2 : reference changed. The new refenrence ia a meta-analysis with 43 studies with over 3600 patients mean age was reported from 39-72 ( median of 41 years old) – the new refenence (Fu L, Wang B, Yuan T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect. 2020;80(6):656-665. doi:10.1016/j.jinf.2020.03.041) replaced the old one on the refenerece section.
Comment #3 – number of sections were corrected on manuscript.
Comment #4 – Section 10 (after section number correction) regarding tocilizumab – the following explanations were added –
After the emergent approval of the use of tocilizumab in the treatment of Covid19 patients, higher rates of secondary bacterial infections were seen in some studies after the use of IL-6 inhibitors versus non-users (115-117), while other reported lower risk of superinfection following the use of tocilizumab, attributing the lower risk for superinfection, in one hand, to il-6 inhibitor ability to suppress sepsis related immune exhaustion and on another hand to the lower risk of clinical deterioration and need of mechanical ventilation on the tocilizumab group (118). In addition, other papers indicated no statistical significance in the emergence of secondary infection after the use of tocilizumab (119-122). Difference of outcomes might be attributed to the lack of standard definition of superinfection and unadjusted analysis in some studies.
Comment #5 : full section( number 11)
Infection control practices can control and prevent hospital acquired infections. In covid-19 pandemic due to the lack of prior forcasting, hospitals faced a severe shortage on disinfectants leading to inadequate infection control strategies especially in ICUs. Heavy workload, higher nurse to patient ratio (due to the large influx of patients with high infection rate in health worker staff) shorter rest period between shifts, as well as improper design of physical hospital spaces (covid19 ICU located in departments without proper facilities), lack or poor-quality equipment were all addressed as causes of higher incidence of secondary infections (121). In addition, fear was significant in healthcare workers during the SARS pandemic. (122) It results in increasing risk of transmission of sars-cov-2 and other events including secondary bacterial infection due to the disregarding evidence-based practices or in the other hand escalation of unnecessary prevention practices or personal protective equipment worsening the personal equipment shortages(123). All above are important parameters contributing to the high incidence of secondary infections.
Round 2
Reviewer 2 Report
The manuscript has improved with the changes added
