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PEER REVIEW HISTORY
BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to
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ARTICLE DETAILS
TITLE (PROVISIONAL)
AUTHORS
Risk of Sepsis in Patients with Amyotrophic Lateral Sclerosis: A
Population-Based Retrospective Cohort Study in Taiwan
Lee, Cynthia Wei-Sheng; Chen, Hsuan-Ju; Liang, Ji-An; Kao, ChiaHung
VERSION 1 - REVIEW
REVIEWER
REVIEW RETURNED
Paul Mehta, MD
National ALS Registry, CDC/ATSDR, Atlanta, GA, USA
27-Sep-2016
GENERAL COMMENTS
A well written paper on sepsis and ALS.
Minor edit: p4, line 39, insert "(CCI)".
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Jerry Fagliano, PhD, MPH
Drexel University
Dornsife School of Public Health
Philadelphia, Pennsylvania
United States of America
30-Sep-2016
re: checklist #14. The wording of much of the first paragraph is too
similar to sentences cited by the authors and should be re-written.
Overall the study is well-designed and addresses a question of
importance and interest. Results have implications that could benefit
ALS patients.
See below for detailed comments and suggestions.
Review
Title:
Risk of sepsis in patients with amyotrophic lateral sclerosis: a
population-based retrospective cohort study
Summary of manuscript:
This manuscript reports on a study of the risk of developing sepsis
among a cohort of people diagnosed with ALS in Taiwan in the
period January 1, 2000 through December 31, 2010. Risk among
this population is contrasted to the risk of sepsis among a random
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sample of participants in the national health insurance program
(essentially the general population), frequency matched on age, sex,
and diagnosis year of cases. The ALS population was followed for
occurrence of sepsis from the day of application for a catastrophic
illness certificate (used as a surrogate for diagnosis date) through
the date of first sepsis diagnosis, withdrawal from the insurance
program, or the end of 2011 (whichever came first). The comparison
population subjects were assigned a random index date during the
calendar year on which they were matched to the ALS case.
Potential confounding factors considered in the analysis were the
matching variables, a comorbidity score, use of b2-adrenoceptor
agonists, and life support treatment. (Since person-time ends at the
dx of sepsis, this means that medication use or life support
treatment had to occur prior to sepsis dx.)
Incidence density rates for development of sepsis were calculated
for the ALS and non-ALS populations from incidence counts and
person-time of follow-up, stratified by sex, age, and comorbidity
score. Rate ratios for sepsis contrasting ALS to non-ALS cases were
also calculated, adjusting for these factors. Cumulative incidence
curves were plotted for ALS and non-ALS populations; cumulative
incidence was modeled using Cox proportional hazards regression,
adjusted for age, sex and comorbidity score, b2-adrenoceptor
agonist use, and life support treatment.
Comments:
Introduction:
The opening paragraph (pg. 6) needs to clarify that the discussion of
sepsis refers to hospitalizations of all patients, not just ALS patients.
The juxtaposition of the sentences implies otherwise. Also, the
introduction should discuss the reason why b2-adrenoceptor
agonists are examined specifically in this study, since this one class
of drugs was singled out for consideration in the study design.
Much of paragraph 1 should be re-written in the authors‟ words,
since there is too much similarity to the wording from the cited
articles.
Methods:
(pg 8, line 53) “diagnosed” should be “diagnosis”
The definition of sepsis includes ICD-9-CM codes 038 (“Septicemia”)
and 995.91 (“Sepsis”). Is there a reason why code 995.92 (“Severe
sepsis”) was not included in the case definition? (pg 9 line 10)
The methods section should more clearly note that life support
treatments (ICU or ventilator use) necessarily had to occur before
the diagnosis of sepsis, according to the follow-up period definition.
Stating this explicitly will head off any confusion about the timing and
causal relationship between sepsis and use of the life-saving
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measures. (pg 10, line 12)
It is not stated how the death of a study subject was handled. While
this may have been a reason that a study subject had “withdrawn
from the insurance program” (pg 9, line 15), it would be helpful to
clarify whether death is marked in this way, or if some other
resource was accessed for this information. This is important
because mortality of ALS patients after diagnosis is so high, and the
accuracy of this determination impacts the calculation of personyears.
Since the ALS and non-ALS groups were frequency matched on
age, sex, and comorbidity score, it seems unnecessary to discuss
statistical tests of differences between the ALS and non-ALS groups.
(pg 10, line 32)
(p 10, line 50) delete “curves of the”
Results:
As said above, it might be sufficient to just state that because the
groups were frequency matched on age, sex and comorbidity score,
distributions of these factors in the ALS and non-ALS groups were
similar or nearly identical. Reporting on statistical tests contrasting
the groups on these factors in the results section and in Table 1 isn‟t
informative, though the distributions themselves are of interest to
show in the table. (pg 11, line 44)
The first sentence of the paragraph on pg 12 should be moved to the
top of next paragraph where the cumulative incidence analysis is
reported.
Table 2 is confusing. The left half shows sepsis event counts,
person-years and incident density rates for the non-ALS and ALS
populations, while the right side appears to be the result of
univariate and multivariate Cox proportional hazard regression
analyses. One can calculate the crude incidence density rate ratios
from the left side, and these are not the same as the crude hazard
ratios shown (though close). It seems that these should be separate
tables.
In the current Table 2, adjusted HRs for sepsis are closer to 1.0 than
the crude HRs, overall and in most strata. Given the frequency
matching, it seems that the confounding effect is due to the b2adrenoceptor and/or the life support variables in the model. It would
be useful to know which variable (one or both) is actually
responsible for the changes in HR after adjustment.
Table 3 (and the discussion of it in the text on page 13) ought to
come before what is now the right side of Table 2 and its associated
text.
(pg 13, line 34) “additional” should be “addition”, and delete “with”
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Discussion:
The first sentence is worded poorly given the study question and
analysis. It should say something like, “The results indicated that a
history of ALS is associated with an increased risk of sepsis.” (pg 14,
line 18)
Suggest re-writing second sentence: “Compared to non-ALS
patients, ALS patients were at a higher risk of developing sepsis.
This was true for both women and men and all age groups; the
relative risk was greatest among patients aged younger than 45
years.” (pg 14, line 21)
“Severe sepsis” is mentioned in relation to a cited study, raising the
question again as to why or whether this was excluded from the
case definition. (pg 15, line 7)
(pg 15, line 24) “sepsis” should not be included as a muscle wasting
disorder
(pg 16, line 44) replace “undergo in” with “occur in”
(pg 17, line 12) insert “relative” before “risk”
VERSION 1 – AUTHOR RESPONSE
Reviewer: 1
Reviewer Name
Paul Mehta, MD
Institution and Country
National ALS Registry, CDC/ATSDR, Atlanta, GA, USA
Please state any competing interests or state „None declared‟:
None declared.
Please leave your comments for the authors below
A well written paper on sepsis and ALS.
Minor edit: p4, line 39, insert "(CCI)".
Re: We really appreciate Dr. Mehta‟s positive comments. The abbreviation (CCI) has been inserted
into the Abstract.
Reviewer: 2
Reviewer Name
Jerry Fagliano, PhD, MPH
Institution and Country
Drexel University
Dornsife School of Public Health
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Philadelphia, Pennsylvania
United States of America
Please state any competing interests or state „None declared‟:
None declared
Please leave your comments for the authors below
re: checklist #14. The wording of much of the first paragraph is too similar to sentences cited by the
authors and should be re-written.
Overall the study is well-designed and addresses a question of importance and interest. Results have
implications that could benefit ALS patients.
Re: We are grateful for the positive comments and constructive suggestions. The first paragraph of
the Introduction has been re-written.
Comments:
Introduction:
The opening paragraph (pg. 6) needs to clarify that the discussion of sepsis refers to hospitalizations
of all patients, not just ALS patients. The juxtaposition of the sentences implies otherwise. Also, the
introduction should discuss the reason why b2-adrenoceptor agonists are examined specifically in this
study, since this one class of drugs was singled out for consideration in the study design.
Much of paragraph 1 should be re-written in the authors‟ words, since there is too much similarity to
the wording from the cited articles.
Re: We separated the discussion of sepsis from ALS by moving it to the second paragraph. The
reason why β2-adrenoceptor agonists are examined specifically in this study has been added to the
first paragraph: “Currently, no cure exists for ALS cases. It is hypothesized that β2-adrenoceptor
agonists may have beneficial effects in treating ALS via restraining protein degradation, promoting
protein synthesis, stimulating synthesis and release of neurotrophic factors, regulating microglial and
systemic immune function, preserving the structural and functional integrity of motor endplates, and
enhancing energy metabolism.”
The paragraph 1 has been re-written in our words.
Methods:
(pg 8, line 53) “diagnosed” should be “diagnosis”
Re: Thank you very much for your comments and we have followed your suggestion to make
changes. The sentence has been revised as follows:
Both groups with missing information (sex and age) and/or with a previous diagnosis of sepsis (ICD-9CM 038) before index date were excluded from this study.
The definition of sepsis includes ICD-9-CM codes 038 (“Septicemia”) and 995.91 (“Sepsis”). Is there
areason why code 995.92 (“Severe sepsis”) was not included in the case definition? (pg 9 line 10).
Re: Thank you very much for your comments. Diseases were diagnosed according to the codes in the
International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) version of
the 2001 in Taiwan National Health Insurance, so the ICD-9-CM code for “Severe sepsis” (995.92)
and “Sepsis” (995.91) was not used in the National Health Insurance Research Database. We had
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modified it in the revised manuscript.
The methods section should more clearly note that life support treatments (ICU or ventilator use)
necessarily had to occur before the diagnosis of sepsis, according to the follow-up period definition.
Stating this explicitly will head off any confusion about the timing and causal relationship between
sepsis and use of the life-saving measures. (pg 10, line 12)
Re: Thank you very much for your comments. We have modified the sentence as your suggestion.
The sentence has been revised as follows:
“We also considered users of life-support treatments, including intensive care unit and ventilator use,
during the period from the index date through the date of endpoint.”
It is not stated how the death of a study subject was handled. While this may have been a reason that
a study subject had “withdrawn from the insurance program” (pg 9, line 15), it would be helpful to
clarify whether death is marked in this way, or if some other resource was accessed for this
information. This is important because mortality of ALS patients after diagnosis is so high, and the
accuracy of this determination impacts the calculation of person-years.
Re: Thank you very much for your comments. The database of Taiwan National Health Insurance we
used lacked these data. The “survival data” cannot be analyzed accurately. Although we can retrieve
the data of patients who were withdrawn from the insurance program, the reasons for withdrawal from
the insurance program included not only death but also emigration, prison sentence, etc. We believed
these factors could bias the study results. We have emphasized these limitations in our revised
manuscript.
Since the ALS and non-ALS groups were frequency matched on age, sex, and comorbidity score, it
seems unnecessary to discuss statistical tests of differences between the ALS and non-ALS groups.
(pg 10, line 32)
Re: Thank you very much for your suggestion. We have modified the sentence as your suggestion.
The sentence has been revised as follows:
“The chi-square test was used to determine the differences between the 2 groups in the distribution of
the medications therapy and life-support measures (including ICU and ventilator use).”
(p 10, line 50) delete “curves of the”
Re: Thank you very much for your comments. We have deleted “curves of the” as your suggestion.
Results:
As said above, it might be sufficient to just state that because the groups were frequency matched on
age, sex and comorbidity score, distributions of these factors in the ALS and non-ALS groups were
similar or nearly identical. Reporting on statistical tests contrasting the groups on these factors in the
results section and in Table 1 isn‟t informative, though the distributions themselves are of interest to
show in the table. (pg 11, line 44)
Re: Thank you very much for your comments. We have changed the sentence in the results section
and Table 1 as your suggestion.
The first sentence of the paragraph on pg 12 should be moved to the top of next paragraph where the
cumulative incidence analysis is reported.
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Re: Thank you very much for your comments. We have moved the sentence as your suggestion.
Table 2 is confusing. The left half shows sepsis event counts, person-years and incident density rates
for the non-ALS and ALS populations, while the right side appears to be the result of univariate and
multivariate Cox proportional hazard regression analyses. One can calculate the crude incidence
density rate ratios from the left side, and these are not the same as the crude hazard ratios shown
(though close). It seems that these should be separate tables.
Re: Thank you very much for your comments, and we have changed Table 2 as your suggestion.
In the current Table 2, adjusted HRs for sepsis are closer to 1.0 than the crude HRs, overall and in
most strata. Given the frequency matching, it seems that the confounding effect is due to the b2adrenoceptor and/or the life support variables in the model. It would be useful to know which variable
(one or both) is actually responsible for the changes in HR after adjustment.
Re: Thank you very much for your comments. We have followed the suggestion to established 3
models multivariate Cox proportional hazards regression analysis to investigate the association
between ALS and sepsis. The results were presented in the new Table 4.
Table 3 (and the discussion of it in the text on page 13) ought to come before what is now the right
side of Table 2 and its associated text.
Re: Thank you very much for your comments. We have moved the right side of Table 2 to the new
Table 4 in the revised manuscript.
(pg 13, line 34) “additional” should be “addition”, and delete “with”
Re: Thank you very much for your comments. This part of the text was deleted because of the new
analyses and results.
Discussion:
The first sentence is worded poorly given the study question and analysis. It should say something
like,“The results indicated that a history of ALS is associated with an increased risk of sepsis.” (pg 14,
line 18)
Re: The sentence has been modified as suggested.
Suggest re-writing second sentence: “Compared to non-ALS patients, ALS patients were at a higher
risk of developing sepsis. This was true for both women and men and all age groups; the relative risk
was greatest among patients aged younger than 45 years.” (pg 14, line 21)
Re: The sentence has been modified as suggested.
“Severe sepsis” is mentioned in relation to a cited study, raising the question again as to why or
whether this was excluded from the case definition. (pg 15, line 7)
Re: The ICD-9-CM code for “Severe sepsis” (995.92) was not used in the coding of NHI during the
study period. Physicians used “Septicemia” (038) exclusively to code sepsis.
(pg 15, line 24) “sepsis” should not be included as a muscle wasting disorder
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Re: We have deleted “sepsis” from the sentence.
(pg 16, line 44) replace “undergo in” with “occur in”
Re: We have replaced “undergo” with “occur”.
(pg 17, line 12) insert “relative” before “risk”
Re: We have inserted “relative” before “risk”.
VERSION 2 – REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Jerry Fagliano, PhD, MPH
Drexel University
Dornsife School of Public Health
Philadelphia, Pennsylvania
United States of America
05-Dec-2016
The authors have been responsive to my initial reviewer comments
and have made appropriate edits and other changes to the
manuscript.
Minor edit, page 6, line 36: I suggest inserting the word "all" before
"hospitalized patients" to be clearer that this paragraph is not limited
to ALS patients.
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Risk of sepsis in patients with amyotrophic
lateral sclerosis: a population-based
retrospective cohort study in Taiwan
Cynthia Wei-Sheng Lee, Hsuan-Ju Chen, Ji-An Liang and Chia-Hung Kao
BMJ Open 2017 7:
doi: 10.1136/bmjopen-2016-013761
Updated information and services can be found at:
http://bmjopen.bmj.com/content/7/1/e013761
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