Examining the Efficacy of Antimicrobial Therapy in Preventing the Development of Postinfectious Glomerulonephritis: A Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

1. Metaanalysis should be “meta-analysis” for consistent writing throughout the manuscript.
2. Figure 1 and Table 1 are hard to read and understand due to the pixelated resolution.
3. Introduction Page 42-42, “Newer theories also suggest an antibody and T cell-mediated response to self-antigens due to molecular mimicry”- The statement should be supported by more than one appropriate reference.
4. In statistical analysis section, please use the full form“inverse variance index (I²)” for a better understanding.
5. In results sections. 2 studies evaluated the efficacy of Penicillin V; why didn’t the author mention antimicrobial used in the rest of the 9 studies? A description of antimicrobials used in all 9 studies could be benefitted from additional information.

 

 

Author Response

1. Metaanalysis should be “meta-analysis” for consistent writing throughout the manuscript.

-We could not find an instance of “metaanalysis” in the formatted documents we received.

2. Figure 1 and Table 1 are hard to read and understand due to the pixelated resolution.

-They have now been replaced. Thank you.

3. Introduction Page 42-42, “Newer theories also suggest an antibody and T cell-mediated response to self-antigens due to molecular mimicry”- The statement should be supported by more than one appropriate reference.

Thank you for bringing this up. We have added two additional citations to support this theory:

Rodríguez-Iturbe B, Batsford S. Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet. Kidney Int. 2007;71(11):1094-1104. doi:10.1038/sj.ki.5002169

Luo YH, Chuang WJ, Wu JJ, et al. Molecular mimicry between streptococcal pyrogenic exotoxin B and endothelial cells. Lab Invest. 2010;90(10):1492-1506. doi:10.1038/labinvest.2010.93

4. In statistical analysis section, please use the full form“inverse variance index (I²)” for a better understanding.

This has been now corrected. Thank you.

5. In results sections. 2 studies evaluated the efficacy of Penicillin V; why didn’t the author mention antimicrobial used in the rest of the 9 studies? A description of antimicrobials used in all 9 studies could be benefitted from additional information.

Addressed in results section; also added a column to Table 1 to display which antimicrobials were used in each included study. Thank you for your comment.

Reviewer 2 Report

Review report:

Article: Examining the efficacy of antimicrobial therapy in preventing the development of post-infectious glomerulonephritis. A systematic review and meta-analysis

Emily Bateman1, Sara Mansour1, Euchariachristy Okafor1, Kedzie Arrington1, Bo Young Hong2, and Jorge Cervan-tes1*

Journal: MDPI-Infectious Diseases Report

Manuscript id- 1601501

 

Objective: The study objective is to determine if antimicrobial therapy utilized to treat an initial infection has an effect in reducing the development of PIGN in humans.

The study authors reviewed the efficacy of antimicrobial therapy in preventing the development of post-infectious glomerulonephritis and found that antimicrobial treatment for the initial bacterial infection may help diminish the development of PIGN by using a very limited number of clinical study reports.

The study authors state that the majority of recent PIGN cases affect children and occur in low socioeconomic countries. In industrialized countries, the incidence of PIGN has become increasingly rare. Is this just because the availability of early treatment options for bacterial infections or due to differential immune responses, as noted by the study authors?

The study authors reviewed a very small pool of studies to analyze and review their objective to reach this conclusion. It would be better to increase the number of studies to reach this conclusion. Therefore, the study authors conclusion may not be promising at this point.

Also, the data presented in figure 1 and table 1 are not readable, please upload a legible document.

Author Response

The study authors reviewed the efficacy of antimicrobial therapy in preventing the development of post-infectious glomerulonephritis and found that antimicrobial treatment for the initial bacterial infection may help diminish the development of PIGN by using a very limited number of clinical study reports.

The study authors state that the majority of recent PIGN cases affect children and occur in low socioeconomic countries. In industrialized countries, the incidence of PIGN has become increasingly rare. Is this just because the availability of early treatment options for bacterial infections or due to differential immune responses, as noted by the study authors?

Thank you for your comment. Two more references suggesting the potential causes for declining incidence rates of PIGN have been added:

Ilyas M, Tolaymat A. Changing epidemiology of acute post-streptococcal glomerulonephritis in Northeast Florida: a comparative study. Pediatr Nephrol. 2008;23(7):1101-1106. doi:10.1007/s00467-008-0778-1

Schwartz B, Facklam RR, Breiman RF. Changing epidemiology of group A streptococcal infection in the USA. Lancet. 1990;336(8724):1167-1171.

The study authors reviewed a very small pool of studies to analyze and review their objective to reach this conclusion. It would be better to increase the number of studies to reach this conclusion. Therefore, the study authors conclusion may not be promising at this point.

Thank you for your comment. We performed a comprehensive systematic review in order to analyze and compare the effect of antibiotics (as per our objective). The resulting number of studies is beyond our control.

We have added a sentence in the conclusion, to reflect the limitation of the small number of studies analyzed.

Also, the data presented in figure 1 and table 1 are not readable, please upload a legible document.

Corrected. Thank you.

Reviewer 3 Report

The Authors did a meta-analysis about the efficacy of antimicrobial therapy in preventing the development of post-infectious glomerulonephritis.

The paper is interesting, well written, and the search of literature is wide.

I have no specific point. My major concern is about the retrieved data (see ref. 18-26). Analysis of the 8 studies (see Table 2) showed that they were written in 1950, 1955, 1964, 1983, 1995, 2000, 2002 and 2006. I'm not sure that these data will allow you to draw a conclusion, as the history of antibiotic development and use have been changing over time.  

Author Response

The Authors did a meta-analysis about the efficacy of antimicrobial therapy in preventing the development of post-infectious glomerulonephritis.

The paper is interesting, well written, and the search of literature is wide.

Thank you for your comments.

I have no specific point. My major concern is about the retrieved data (see ref. 18-26). Analysis of the 8 studies (see Table 2) showed that they were written in 1950, 1955, 1964, 1983, 1995, 2000, 2002 and 2006. I'm not sure that these data will allow you to draw a conclusion, as the history of antibiotic development and use have been changing over time.  

Thank you for your comment. You bring up a good point. Penicillin is still an antibiotic of choice for Strep pharyngitis. Each of these studies used Penicillin, either oral, parenteral, or intramuscular as their main treatment-of-choice for bacterial infection, which we have now included in the table and Results section.

Reviewer 4 Report

The authors are to be commended for addressing this gap in the literature. For a condition so thoroughly taught in medical education, it's rarity in modern times makes studying it rather difficult. A meta-analysis is therefore  an appropriate methodology. 

Although this is a worthwhile contribution to the literature, the limitations inherent to meta-analyses and this one in particular should be emphasized.

Methods. Include description, justification, and reference for random effects analysis (briefly mentioned in results section).

Results. It seems worth mentioning why the 1995 study by Streeton was such an outlier with regards to effect size. Per table 1, this study contributed a disproportionate number of cases compared to the other studies. This needs to be addressed directly.

Discussion. Sources of potential bias need to be addressed directly. In meta-analyses, the sources of bias include the methodology, which was appropriate, and the studies themselves, which can become additive. 

Date ranges of studies span large timeframe (1950-2006). This may introduce an era-effect that should be acknowledged. This would include market introduction of new antibiotics.

The authors mention a prior meta-analysis from 2010 (ref 28) and the shortcomings of that study. This paper would benefit from mentioning what steps were taken in this study to avoid those same mistakes.

Last sentence. How can a larger cohort possibly be attained? The authors have considered studies going as far back as 1950. Perhaps a more pointed suggestion about how this might be achieved may be more appropriate...a call for collaboration?

Author Response

The authors are to be commended for addressing this gap in the literature. For a condition so thoroughly taught in medical education, it's rarity in modern times makes studying it rather difficult. A meta-analysis is therefore  an appropriate methodology. 

Thank you for your comment.

Although this is a worthwhile contribution to the literature, the limitations inherent to meta-analyses and this one in particular should be emphasized.

Methods. Include description, justification, and reference for random effects analysis (briefly mentioned in results section).

Thank you for your comment. I have added “Random effect analysis was utilized based on the assumption that the studies included in this analysis represent a random sample of effect sizes, and the true effect size varies from one study to the next” to the methods, with reference to Borenstein et al, 2009.

Results. It seems worth mentioning why the 1995 study by Streeton was such an outlier with regards to effect size. Per table 1, this study contributed a disproportionate number of cases compared to the other studies. This needs to be addressed directly.

Thank you for your comment. I have added, “Additionally, as seen in Table 2, Streeton et al demonstrated a potential outlier with an effect size of 0.10. These authors note that screening can recognize clinically asymptomatic cases. This, in combination with mass treatment and availability of Penicillin treatments may have prevented the spread of nephritogenic strains of GAS, as they were studying outbreaks in three remote communities” to help address this potential outlier. Table 1 also demonstrates many cases coming from Adam et al, which has similarly been elaborated (see comment regarding prior systematic review from 2010).

Discussion. Sources of potential bias need to be addressed directly. In meta-analyses, the sources of bias include the methodology, which was appropriate, and the studies themselves, which can become additive. 

More details have been added to the discussion to address these potential biases. Thank you for your comment.

Date ranges of studies span large timeframe (1950-2006). This may introduce an era-effect that should be acknowledged. This would include market introduction of new antibiotics.

Thank you for your comment. You bring up a good point, which was similarly brought up by the other reviewers. I have now included in the table and Results section the antibiotics used in each study, as Penicillin remained the treatment-of-choice.

The authors mention a prior meta-analysis from 2010 (ref 28) and the shortcomings of that study. This paper would benefit from mentioning what steps were taken in this study to avoid those same mistakes.

Thank you for your comment. A sentence has been added to the Data Collection section: “Screening also allowed for de-duplication that did not initially occur electronically.”

Additionally, the shortcomings of the prior systematic review from 2010 have been elaborated on: “A previous systematic review published in 2010 evaluated antimicrobials in preventing PSGN ²⁸. Zaffanello et al reported that the role of antimicrobials in PIGN prevention is unproven. However, of the nine studies that were included in the review, four appear to be subsets of the same data reported by Adam et al.”

Last sentence. How can a larger cohort possibly be attained? The authors have considered studies going as far back as 1950. Perhaps a more pointed suggestion about how this might be achieved may be more appropriate...a call for collaboration?

Thank you for your comment. The last sentence has been changed to: “However, given the analysis of only nine studies, larger cohort studies, likely through global retrospective chart reviews, would be needed to confirm this effect.” 

 

Round 2

Reviewer 2 Report

Accept the revised manuscript!

Thanks,

Prof. Rajapandi

Reviewer 3 Report

I have no further comments