February 12, 2016
Editors, BMC Pediatrics
Re:
High Burden of Rotavirus Gastroenteritis in Very Young Infants
Dear Colleagues:
We sincerely appreciate the generally favorable review of our work and the detailed critiques from both
expert consultants. Our responses to the reviewers' many helpful suggestions are enumerated below and
identified in a marked copy of the revised paper. A clean version of our manuscript is also provided, but
the page numbers noted in this letter refer to the marked version.
Referee #1
1.
Table 2 provides a detailed breakdown of the rotavirus serotypes responsible for gastroenteritis in
specific age categories for the 7 seasons since 1999-2000 when PCR-genotyping was initiated. As
the reviewer astutely recognized, the age distribution of G2 rotavirus cases was misrepresented in
the Results section. We have corrected the inaccurate text and added more specific information to
the presentation on page 5, lines 17-24, per the reviewer's request.
2.
We agree with the suggestion to more clearly label the y-axis of Figure 1A to preempt causal
misinterpretation of the units as percentages. Accordingly, the potentially misleading "Frequency"
has been changed to the more precise "Number of Cases".
3.
Figure 1C has been deleted as recommended because the plot adds relatively little new
information to the data presented elsewhere in the paper.
4.
The reviewer rightly points out that the age distribution for community-acquired cases presenting
to the hospital may be skewed toward younger age groups than the overall distribution in the
community because infants may be more compromised by gastroenteritis than older children. We
have added this caveat to the discussion of the limitations of our study on page 7, lines 20-23. The
potential impact of vaccine-induced herd immunity on maternal antibody levels and infants before
vaccination is addressed on page 8, lines 10-13, of the Discussion section.
Referee #2
General comments
1.
The kind and instructive feedback from the reviewer is gratifying. His point about humbly
acknowledging the limitations of our own methodology is appropriate. We have consequently
addressed the methodological shortcomings of our own work more explicitly (confer the
paragraph opening with the statement "The methodological limitations of our analysis should be
acknowledged." on page 7, line 15), and subsequently softened our conclusions on this basis
throughout the Discussion section.
Specific comments
1.
The reviewer rightly raises the question of denominator data which are unfortunately not
retrievable in a reliable and consistent manner over the many years of surveillance covered by our
report. We can assert with a fair degree of confidence that referral patterns have remained
generally stable over this time period and the number of cases of respiratory infection both in the
pre- and post-rotavirus vaccine era has been essentially constant through early 2009.
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2.
Since we highlight the number of cases diagnosed during the first few month of life in the Results
section of the Abstract, we have better defined "very young infants" by rephrasing as "infants <3
months old" on page 2, lines 20-21, in the Conclusions of the Abstract.
3.
Although we concur with the reviewer about the value of these additional data, the information is
not obtainable from the available records, as noted in our first response immediately above in this
section. Although not even semi-quantitative, our impression is that the number of children
presenting with winter gastroenteritis (and respiratory infections) had not dramatically changed
during the period of surveillance prior to introduction of the rotavirus vaccines.
4.
The "non-white" category potentially includes children of African, Asian, Hispanic, Eskimo, and
Native American heritage. This explanation has been added to Table 1 (which reports the
demographic characteristics of the patients included in our analysis) on page 17 as a footnote. The
neighborhoods surrounding CHOP in West Philadelphia are ethnically diverse but predominantly
African-American.
5.
Any patient presenting to CHOP with gastroenteritis was eligible for inclusion, as now noted on
page 3, line 24, of the Methods section. The actual age breakdown for patients included in the
analysis (including the full range of ages) is summarized on page 5, lines 9-16, where the prevaccine and post-vaccine eras are compared. This information is reiterated in more detail in the
legend for Figure 1B on page 19. The maximum age of an outlier patient in the analysis was 20
years ("240 months"), whereas the median age [IQR] was 11 [5-21] months. So more than 75% of
the patients were under 2 years of age. The intended purpose of the old Figure 1C (now deleted at
the behest of Referee 1) was to display the entire age distribution; we would gladly reinsert this
figure at your discretion.
6.
We agree with the reviewer's emphasis on children <3 months of age who would receive little
direct benefit from a vaccination schedule commencing at 8-12 weeks of life, although they might
be protected to some degree by herd immunity. These points have been incorporated in the
Discussion section on page 8, lines 10-15 and 17-19.
7.
The problematic wording has been modified to read "the proportion of patients with reovirus
identified in their stool samples" instead of "the relative risk of identifying reovirus in stool" on
page 7, lines 2-3, to satisfy the concern voiced by the reviewer.
8.
As advised, we now indicate that the first dose of rotavirus vaccine usually administered at ~2
months of age may afford significant protection within a few weeks of receipt as a bridge to
subsequent doses on page 8, lines 13-15.
9.
The cost:benefit ratio for neonatal vaccination against rotavirus will depend on several unknown
factors, including (but not limited to) the degree of herd immunity and its effects on maternal
antibodies. These important issues are now acknowledged and addressed on page 8, lines 10-19.
10. The possible implications of vaccine-induced herd immunity are considered on page 8, lines 1013.
11. The durability of vaccine-elicited immunity has not yet been precisely established, but preliminary
data suggest substantial protection will endure for >3 years after completion of the full series of
the monovalent (RV1) or pentavalent (RV5) vaccines. Recommendations about booster doses in
older children seem premature at this point given the current state of our knowledge and persistent
concerns about vaccine-associated intussusception in children beyond 8 months of age, and are
tangential to the main thrust of this report.
12. Our conclusion has been qualified as proposed by the reviewer in both lines 1 and 19 on page 8.
We trust that attention to the consultant's insightful and informative criticisms as translated into
our revised manuscript have strengthened our presentation.
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Editorial matters
1.
The Disclosures page has been replaced by a 'Competing Interests' section on page 9.
2.
A new section describing Authors' Contributions has been added as page 10.
3.
The Abstract on page 2 has been modestly reformatted to exactly meet BMC specifications for
medical articles. The word count is presently 296.
All authors have made substantive contributions to the report, and have subsequently reviewed and
approved an essentially final version of the revised manuscript. Merck and Co., Inc., which markets the
pentavalent rotavirus vaccine (RotaTeq), supported this study in part. Disclosures regarding potential
conflicts of interest are detailed in the paper itself.
Thank you for your time and consideration. Your response is eagerly anticipated.
Respectfully submitted,
Mark J. DiNubile, M.D.
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