PONE-D-19-35060

The effect of HIV status on the frequency and severity of acute respiratory illness

PLOS ONE

Dear Dr Brown,

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'Funding: This study was supported by grants from the National Institute for Health Research (DRF-

2015-08-210) and British HIV association. The funders had no role in the collection, analysis, or

interpretation of data, in the writing of the report or in the decision to submit the paper for

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This prospective study by Brown Colleagues exams the incidence and severity of acute respiratory illnesses in an HIV-infected population on ART and compares it to non HIV-infected subjects. They report that the incidence of acute infections is similar in the two groups, but that the severity is worse in the HIV-infected subjects leading to greater seeking of care from the health care system by this group.

In general this is an easy to read, well written manuscript. The size of the two populations is reasonable. Follow up of the subjects over a year is very good for these types of studies. The main concerns relate to how the data was analyzed as described below.

Major Comments:

1. It appears there were two attempts at objective assessment of upper respiratory tract severity. The first was a “web-based symptom questionnaire” graded on a “0-6 scale, including questions on daily activities and treatment.” The second was a subject “diary”, which also appears to have been scored somehow given the data in the results section was also given as “points”. It is unclear how these two measurement tools are different. It would be nice to show these grading systems in supplemental materials to better assess the quality of the data. Furthermore, it needs to be clear in the methods that the first tool is actually web-based. In the methods section it read like the investigators were doing the question asking, which obviously introduces bias if the interviewer knows the subject status. It was not apparent that the first tool was web-based till the first sentence under the “Severity and Duration of Illness” section in the results.

2. There are a lot of differences between the two groups (Table 1). This is important because their adjustment for potential confounding effects was based on “a priori” factors known to be associated with acute respiratory illnesses rather than actual differences between the two groups. Thus, while baseline smoking, baseline respiratory symptoms, and baseline PFTs were appropriately considered, it is not clear that all the significant differences between the groups were taken into account in their univariate and multivariate analysis. Differences that were adjusted for that might be significant include:

a. UK born versus other – relates to different potential prior exposures and cultural responses to illness which might impact assessment of disease severity.

b. Immunizations – much higher in the HIV positive group, which may have lessened the incidence in the HIV positive group.

c. Significantly higher incidence of inhaler use, especially corticosteroids, in the HIV group. These by themselves can affect the incidence and severity of respiratory illnesses.

3. One of the author’s conclusions is that it is “possible to identify individuals at greater risk of more frequent or severe acute respiratory illness (using the degree of airflow obstruction, history of smoking or recreational drug use, and the presence of chronic respiratory symptoms). Does this hold for both HIV-infected subjects and uninfected subjects, or just the HIV population alone? From the tables, it looks like these risk factors were lumped together regardless of HIV status.

Minor Comments:

1. At the end of the Statistical analysis it states that further details are provided in supplemental information. I do not see any supplemental information. Based on major comment 2 above, this is important.

2. While this is in general very well written, for some reason there are multiple grammatical errors in the 4th paragraph of the discussion.

3. Which of the two severity measures is being used in Figure 1?

Reviewer #2: This is a very robust epidemiologic study looking at respiratory symptoms in a cohort of people living with HIV (PLwHIV) and relatively matched controls over a several year period of fairly robust regular communication. Respiratory illness was intentionally loosely defined to capture events that may result in communication with a healthcare professional or treatment. St. Georges Respiratory Questionaire (SGRQ) and the MRC dyspnea scale data was collected at baseline and during any acute illness. In addition an unweighted symptom score was collected daily during acute illness recovery. The PLwHIV were well controlled with all on ART and the majority with suppressed viral load. An attempt was made to identify the common viruses that were representative of the acute illnesses but this may be biased as more severe illness may result in less willingness to return for a swab. The control group is mostly age and gender matched with Ethnicity, sexuality, immunizations and respiratory medication use being different. The subjects had pre-bronchodilator spirometry and both restrictive and obstructive defects were more common in the PLwHIV. Associated with this both the SGRQ and MRC favored more symptoms in PLwHIV. The main outcome of the study, rate of acute illness was the same in both groups with most of the significant findings being related to the subjective measures of respiratory symptom severity. Consistent with would be predicted obstruction, prior smoking, and baseline dyspnea were all associated with greater illness frequency. Although the symptoms scores were higher and PLwHIV contacted medical providers more frequently use of non-prescription medications was equivalent. Overall 158 np swabs were evaluated and there was no difference in the rate of positive swabs between groups or in type of virus recovered. Overall the data is robust and discussed with appropriate notation of the limitations.

1. The incidence of “restrictive” lung disease seems quite large in comparison to prior studies. This would be more appropriately called this PRISm (preserved ratio impaired spirometry) given the individuals only had pre-bronchodilator spirometry. This likely would also be consistent with a predilection for increased symptoms and likely an increased risk of future incident COPD. I do not think this has previously been described. This may be worth adding to the discussion given the findings of the Rotterdam Study would be consistent. From this standpoint it may be important to note who (trained respiratory therapist, research coordinator, nurse) performed the spirometry as an important caveat would be poor effort can give this sort of finding as well but would not explain the association only with PLwHIV.

2. Likey discussion should include the fact that the spirometry was all prebronchodilator and likely over represents the population as having COPD.

3. Inclusion of more information on the symptom score that was utilized at illness initiation and daily diaries would be beneficial. The presumption is that this symptom score was de novo invented and likely has not been confirmed to be of value as an unscaled entity in this disease process. Although this does not lessen the value of this information, knowing that the subscales of the SGRQ were all significantly more in PLwHIV suggests knowing more information about what makes up the Figure 1 results would help.

4. Figure 2 is not particularly well presented. The coloring is based on the percentage of each virus but likely would be improved if both “pie” graphs utilized the same color for same viruses. It is not clear to me if there is any difference in any measured virus as I suspect as the only notation in the text is that Rhinovirus is the most common in both groups and many viral swabs were negative. For instance it seems that influenza vaccination is more common in PLwHIV but yet isolating influenza (probably not significant) was more common in PLwHIV. Given this is probably the most novel piece of data in this study it would be nice if it were slightly better presented.

5. oropharyngeal swabs. Page 4 and 10 states oropharyngeal swabs were utilized all other references suggest these were nasopharyngeal swabs. Likely this is a typo to correct. Suspect they all should be nasopharyngeal given it was a PCR assay.

6. A comment is made that tabulation of “febrile” illness rate is possible and likely it would be worthy to comment how this related to the subsets of acute illnesses and viral recovery from nasopharyngeal swabs.

7. The one factor that may be overlooked is the comfort with which PLwHIV may feel in interacting with health care professionals that may differ from the control population. It is possible that there is a bias towards reporting symptoms in this population given ongoing drug side effects and discussion of them not only establish rapport with health care professionals but may also have resulted in beneficial interactions. There seems to be proof of this in that the use of over the counter medications was equivalent despite the fact that more contact with providers and actual prescribed medications was higher in PLwHIV. Whether this is conditioned by health care providers or as stated a manifestation of mild COPD and PRISm would be nearly impossible to separate as finding a control population with a similar degree of health care exposure would be impossible.

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Reviewer #1: No

Reviewer #2: No

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The effect of HIV status on the frequency and severity of acute respiratory illness

PONE-D-19-35060R1

Dear Dr. Brown,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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Eduard J Beck, PhD, FAFPHM, FFPH, FRCP

Academic Editor

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Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: All issues have been addressed. No further changes are recommended. Figures are significantly improved

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No