Clinical and Epidemiological Features of Hospitalized and Ambulatory Patients with Human Monkeypox Infection: A Retrospective Observational Study in Portugal

Round 1

Reviewer 1 Report

General comments

The introduction is too long.  This is a clinical paper, describing clinical features, so the epidemiological features (which by now are well described) may be safely omitted.

I like the level of clinical detail – it is really helpful for clinicians like myself.  

The paper should be reviewed by a native English speaker once – there are many sentences that don’t sound quite right.  There is also unconventional use of certain words – these are pointed out below.

The following section deals with the Introduction. I suggest cutting it drastically. The introduction should say that the authors want to focus on clinical aspects of MPX and propose theories for their presence (I like the hypotheses related to the presence of anogenital lesions, oral/facial lesions, for example.)

Line 35                                 Ungrammatical clause:  “… all of which under antiretroviral therapy …”   This should be “ … all of whom were under …”

Line 51                                 “… neither too closely related to Orthopoxvirus”.  I think the sentence makes more sense if this is written like that:  “… nor to closely related Orthoxviruses…”

Line 52                                 The authors should explain why there is concern for the re-appearance of smallpox wen it has been eradicated.  (And there is no animal reservoir.)   They suggest many possible factors they may contribute to its spread should it re-emerge but how would it emerge in the first place?  Perhaps it is necessary to mention that there are stocks of smallpox virus in the world, and their falling into the wrong hands is the worry? 

Lines 55 – 58                     The language is wrong. The way it is written, we are supposed to believe that there are some unknown factors that account for changes in human epidemiology, climate change, etc.  I suspect the authors want to say that apart from waning immunity against orthopox viruses, factors like climate change, deforestation etc are hypothesized to contribute to the possible re-emergence of smallpox.    Note that this is a sentence that can be challenged because smallpox has no animal reservoir.

                                               My suggestion is to remove lines 52 to 62, for avoidance of controversy. It is not relevant to the manuscript anyway, as this is a clinical article.

Lines 87, 88                       I am not sure that encephalitis, myocarditis are “common” complications.

 

Comments on sections after introduction

Line 154                                It is important to have a small section on the method used.  At least reference it.

Line 193                In line 249, the authors say THREE of the patients had been previously vaccinated against smallpox. Please clarify. 

Line 225                The word “observed” is used unconventionally here. I suspect the authors want to say the patients presented and were tested one week after symptom onset?

Line 266                The usual way of saying it is “supportive” treatment.

Table 4                  Patient C.  In line 269, the authors suggest this was an MPX pneumonia with their phrase “without additional infectious agents being identified”.  But in the Table it appears that only “hemocultures” had been done.  Was there a sputum or throat swab sample for some sort of pneumonia multiplex assay (currently in widespread use)? What about conventional sputum gram stain and culture? Or (if their hospital does not use a pneumonia multiplex assay), what about tests like urinary Legionella or pneumococcal antigen?  

Line 308                Example of incorrect grammar:  “ … supports the idea that the sexual route has probably been the major mode of transmission in this outbreak …”  Perhaps “supports the sexual route as the major mode of transmission …” sounds better? The use of the word “outbreak” in this sentence also does not sit well with me. In this “series” might be better?  The authors might then want to add another sentence saying that that would accord with the general understanding that very close contact, including sexual contact, has fuelled the current outbreak.

Lines 318 – 321  I do not understand the intent of this long sentence. I am unable to see the link between viremia as a cause of fever and inoculation of the virus through abraded skin. 

Line 340                (and the entire paragraph)  I get the authors’ drift but the whole paragraph is quite  clumsy said. “Not only” should have a “but” later in the sentence. Is 6.6 days a “minor delay” in the authors’ opinion? Yet the authors say that the pain could led the patient to be “prompt” in seeking medical attention. I suggest that this paragraph be re-worked. The last sentence of the paragraph is the important one. 

 

 

Author Response

Comment: The introduction is too long. This is a clinical paper, describing clinical features, so the epidemiological features (which by now are well described) may be safely omitted.

Response:

The authors thank the reviewer for the comment. The Introduction was revised and shortened as suggested.

 

Comment: I like the level of clinical detail – it is really helpful for clinicians like myself.

Response:

We appreciate the positive feedback from the reviewer regarding the utility of the manuscript.

 

Comment: The paper should be reviewed by a native English speaker once – there are many sentences that don’t sound quite right. There is also unconventional use of certain words – these are pointed out below.

Response:

The manuscript was entirely revised and the English improved.

 

Comment: The following section deals with the Introduction. I suggest cutting it drastically. The introduction should say that the authors want to focus on clinical aspects of MPX and propose theories for their presence (I like the hypotheses related to the presence of anogenital lesions, oral/facial lesions, for example.)

Response:

The Introduction was thoroughly revised, as suggested.

 

Comment: Line 35 Ungrammatical clause: “…all of which under antiretroviral therapy …” This should be “ … all of whom were under …”

Response:

Corrected.

 

Comment: Line 51 “… neither too closely related to Orthopoxvirus”. I think the sentence makes more sense if this is written like that: “… nor to closely related Orthoxviruses…”

Response:

Corrected.

 

Comment: Line 52 The authors should explain why there is concern for the re-appearance of smallpox when it has been eradicated. (And there is no animal reservoir.) They suggest many possible factors they may contribute to its spread should it re-emerge but how would it emerge in the first place? Perhaps it is necessary to mention that there are stocks of smallpox virus in the world, and their falling into the wrong hands is the worry?

Response:

The reference to smallpox was a mistake, it should be read “Monkeypox” on line 53. Anyway, the whole paragraph was removed as the authors believe that it was not adding relevant information to a clinical article.

 

Comment: Lines 55 – 58 The language is wrong. The way it is written, we are supposed to believe that there are some unknown factors that account for changes in human epidemiology, climate change, etc. I suspect the authors want to say that apart from waning immunity against orthopox viruses, factors like climate change, deforestation, etc. are hypothesized to contribute to the possible re-emergence of smallpox. Note that this is a sentence that can be challenged because smallpox has no animal reservoir.

My suggestion is to remove lines 52 to 62, for avoidance of controversy. It is not relevant to the manuscript anyway, as this is a clinical article.

Response:

The paragraph was removed as suggested. The authors believe that it was not adding relevant information to a clinical article

 

Comment: Lines 87, 88 I am not sure that encephalitis, myocarditis are “common” complications.

Response:

Corrected.

 

Comment: Comments on sections after introduction

Line 154 It is important to have a small section on the method used. At least reference it.

Response:

The authors considered that this comment referred to a lack of detail in data privacy. Therefore the following explanation of the process was included: “Only relevant epidemiological and clinical data were collected, limiting the description of personal details. Data were de-identified by assigning a code to each subject and creating a separated identification database that was destroyed after data collection.”

 

Comment: Line 193 In line 249, the authors say THREE of the patients had been previously vaccinated against smallpox. Please clarify.

Response:

There were three vaccinated patients as explained in lines 234-246. The information “only one vaccinated patient”(line 193) was a mistake and the information in the table was corrected.

 

Comment: Line 225 The word “observed” is used unconventionally here. I suspect the authors want to say the patients presented and were tested one week after symptom onset?

Response:

Observed was changed to medical consult and testing.

 

Comment: Line 266 The usual way of saying it is “supportive” treatment.

Response:

Corrected

 

Comment: Table 4 Patient C. In line 269, the authors suggest this was an MPX pneumonia with their phrase “without additional infectious agents being identified”. But in the Table it appears that only “hemocultures” had been done. Was there a sputum or throat swab sample for some sort of pneumonia multiplex assay (currently in widespread use)? What about conventional sputum gram stain and culture? Or (if their hospital does not use a pneumonia multiplex assay), what about tests like urinary Legionella or pneumococcal antigen?

Response:

Hemocultures, viral multiplex and S. pneumonia, and Legionella spp. urinary antigen tests were negative – the information is now in the table. Sputum was not collected due to the absence of a productive cough.

 

Comment: Line 308 Example of incorrect grammar: “ …supports the idea that the sexual route has probably been the major mode of transmission in this outbreak …” Perhaps “supports the sexual route as the major mode of transmission …” sounds better? The use of the word “outbreak” in this sentence also does not sit well with me. In this “series” might be better? The authors might then want to add another sentence saying that that would accord with the general understanding that very close contact, including sexual contact, has fuelled the current outbreak.

Response:

Corrected following the reviewer’s suggestions.

 

Comment: Lines 318 – 321 I do not understand the intent of this long sentence. I am unable to see the link between viremia as a cause of fever and inoculation of the virus through abraded skin. 

Response:

The reference to viremia was removed. The sentence was shortened and simplified to “The preferential anogenital location of the lesions is particularly interesting because it may suggest that a direct inoculation mechanism occurs through the contact of infected semen or anal secretions with abrased skin or mucosa during sex”.

 

Comment: Line 340 (and the entire paragraph) I get the authors’ drift but the whole paragraph is quite clumsy said. “Not only” should have a “but” later in the sentence. Is 6.6 days a “minor delay” in the authors’ opinion? Yet the authors say that the pain could led the patient to be “prompt” in seeking medical attention. I suggest that this paragraph be re-worked. The last sentence of the paragraph is the important one.

Response:

The paragraph is now divided in two: the first contains our thoughts on presentation with single ulcers; the second is about the delay to seek medical attention (“The last sentence of the paragraph is the important one.”)

Reviewer 2 Report

I have read with interest this manuscript

It is really well documented and easily to read and understand.

I just have some comments to the article.

1. In line 149, I can read that 3 people have recieved the smallpox vaccine but in table 1 there is only one registered. Which is the real number of vaccinated patients?

2. I recommend homogenizing all abbreviations from monkeypox to MPXV (as referred to at the beginning of the text). Sometimes I have encountered MPV, MPX, MPVX...

3. The WHO has recommended a new numenclature for the clades: clade I and clade II (a and b), instead of the traditional Congo and  West Africa.

4. The paper implies that no semen samples have been taken to analyze the presence of monkeypox in them. Why were no samples taken?

Likewise, in cases of proctitis, was PCR for Monkeypox ever requested?

5. In lines 322- 325, Also, the high number of patients with oral, lip, and face lesions equally suggests that the same inoculation mechanism through oral sex may occur, similarly to what has been described in other STIs, such as syphilis and HPV. Although our  findings suggest this mechanism to be plausible, it has not been described in previous Monkeypox outbreaks. Sexual transmissión haven´t been proved yet. Although MKXV PCR had been positive in some seminal samples, no repicable virus had been found. Direct contact of the lesion with the skin may be sufficient for transmission and anal sex may also facilitate this route, but not through seminal fluid.

The same could be thought of the patient who presented lesions in the venipuncture area, would they be due to contact with the contaminated needle or blood? Perhaps at the present time it is more plausible to think that it is caused by contact.

6. Have you registered if during the period of time of the study the time elapsed between symptoms onset and the medical consultation has diferences. Maybe at the begining or the outbreak (in May) patients were worried than the patients of July and they consulted earlier. 

7. Review the text from line 355 to line 357, the information is not very clear.

Author Response

Comment: I have read with interest this manuscript

It is really well documented and easily to read and understand.

Response:

The authors thank the reviewer for the positive feedback regarding the manuscript as well as the valuable inputs which we think have improved the text.

 

Comment: I just have some comments to the article.

Response:

The entire manuscript was revised according to the suggestions.

 

Comment: 1. In line 149, I can read that 3 people have recieved the smallpox vaccine but in table 1 there is only one registered. Which is the real number of vaccinated patients?

Response:

There was a mistake in the table which was amended. There were three vaccinated patients.

 

Comment: 2. I recommend homogenizing all abbreviations from monkeypox to MPXV (as referred to at the beginning of the text). Sometimes I have encountered MPV, MPX, MPVX...

Response:

The manuscript was revised concerning the abbreviations, which were corrected.

 

Comment: 3. The WHO has recommended a new numenclature for the clades: clade I and clade II (a and b), instead of the traditional Congo and West Africa.

Response:

The WHO reference is now on the manuscript, after the corrected nomenclature.

 

Comment: 4. The paper implies that no semen samples have been taken to analyze the presence of monkeypox in them. Why were no samples taken?

Response:

Semen samples were not processed in the National Reference Lab – only exudate lesion fluid, oropharyngeal exudate, urine, and blood were collected. This procedure was determined by the National Lab. In our institution, MPXV PCR is not yet performed so we have to comply with the National ab norms.

 

Comment: Likewise, in cases of proctitis, was PCR for Monkeypox ever requested?

Response:

In cases of proctitis lesions, fluid was collected from lesions in the anal or perianal areas.

 

Comment: 5. In lines 322- 325, Also, “the high number of patients with oral, lip, and face lesions equally suggests that the same inoculation mechanism through oral sex may occur, similarly to what has been described in other STIs, such as syphilis and HPV. Although our  findings suggest this mechanism to be plausible, it has not been described in previous Monkeypox outbreaks”. Sexual transmissión haven´t been proved yet. Although MKXV PCR had been positive in some seminal samples, no repicable virus had been found. Direct contact of the lesion with the skin may be sufficient for transmission and anal sex may also facilitate this route, but not through seminal fluid.

Response:

The sentences were rewritten removing the reference to transmission through seminal fluid: “The preferential anogenital location of the lesions is particularly interesting because it may suggest that direct contact of the lesion with the skin may be sufficient for transmission and anal sex may also facilitate this route. Also, the high number of patients with oral, lip, and face lesions equally suggests that the same mechanism through oral sex may occur. Although our findings suggest this mechanism to be plausible, it has not been described in previous Monkeypox outbreaks.”

 

Comment: The same could be thought of the patient who presented lesions in the venipuncture area, would they be due to contact with the contaminated needle or blood? Perhaps at the present time it is more plausible to think that it is caused by contact.

Response:

The text was rewritten: “papules and pustules in venopunction sites. This fact is of utter importance because it once more suggests the development of local lesions by direct inoculation of a potentially infectious fluid. Nevertheless, in this particular case, there is no way to confirm whether the inoculated fluid was blood or lesion exudate contaminating the needle.”

Comment: 6. Have you registered if during the period of time of the study the time elapsed between symptoms onset and the medical consultation has diferences. Maybe at the begining or the outbreak (in May) patients were worried than the patients of July and they consulted earlier.

Response:

The authors compared the time elapsed in the months considered in the study. There were no significant differences. But as the distribution in each month’s sample was very heterogenous (ranging from 0 to 28 days) and due to the low numbers in each month (July only had 7 patients) we believed this data had low statistical value and we preferred not to include it in the manuscript.

 

Comment: 7. Review the text from line 355 to line 357, the information is not very clear.

Response:

The text was revised and the author expect that now the information is more clear.

Reviewer 3 Report

In this manuscript, the authors have presented a detailed retrospective observational cross-sectional study of adult patients presenting to the Infectious Disease Department of Hospital de Curry Cabral in Lisbon, Portugal between 5 May 2022 and 26 July 2022 and who had laboratory-confirmed Monkeypox virus (MPXV) infection. The study includes both inpatients and outpatients and describes demographics, presenting symptoms, clinical features, route of transmission, HIV status, sexual orientation and sexual practices, infection with other STIs, small pox vaccination and treatment.

This study provides important empirical data to support the understanding of the epidemiology of the recent MPXV outbreak in Europe and other developed countries, including Portugal, in order to inform prevention strategies. The study results support the findings of similar studies, which showed that the majority of infected individuals identified as men who have sex with men (MSM) and that transmission was most likely sexual, however the authors found that contact with MPXV infected blood was also a potential route of transmission.

I would recommend the following minor amendments, which I feel would improve the overall quality of the manuscript:

i) As there are already a considerable number of published articles describing the origins and features of MPXV, as well as a recently published review article in Infectious Diseases Reports (by Antunes et al), I would recommend citing this article and shortening the background paragraphs on MPXV in the Introduction in order to better highlight the paragraphs describing the recent outbreak of MPXV and the aims of the study.

ii) In the Results, the paragraph before Table 3 (lines 249-260) is repeated after Table 4 (lines 278-289), so would recommend deleting the latter paragraph.

Author Response

Comment: In this manuscript, the authors have presented a detailed retrospective observational cross-sectional study of adult patients presenting to the Infectious Disease Department of Hospital de Curry Cabral in Lisbon, Portugal between 5 May 2022 and 26 July 2022 and who had laboratory-confirmed Monkeypox virus (MPXV) infection. The study includes both inpatients and outpatients and describes demographics, presenting symptoms, clinical features, route of transmission, HIV status, sexual orientation and sexual practices, infection with other STIs, small pox vaccination and treatment.

This study provides important empirical data to support the understanding of the epidemiology of the recent MPXV outbreak in Europe and other developed countries, including Portugal, in order to inform prevention strategies. The study results support the findings of similar studies, which showed that the majority of infected individuals identified as men who have sex with men (MSM) and that transmission was most likely sexual, however the authors found that contact with MPXV infected blood was also a potential route of transmission.

Response:

The authors thank the reviewer’s encouraging comments. The manuscript was thoroughly revised following the suggestions and we believe that it has improved after that.

 

Comment: I would recommend the following minor amendments, which I feel would improve the overall quality of the manuscript:

1. i) As there are already a considerable number of published articles describing the origins and features of MPXV, as well as a recently published review article in Infectious Diseases Reports (by Antunes et al), I would recommend citing this article and shortening the background paragraphs on MPXV in the Introduction in order to better highlight the paragraphs describing the recent outbreak of MPXV and the aims of the study.

Response:

The manuscript was shortened, as recommended, and the paper by Antunes et al. included as a reference in the Introduction.

 

Comment: ii) In the Results, the paragraph before Table 3 (lines 249-260) is repeated after Table 4 (lines 278-289), so would recommend deleting the latter paragraph.

Response:

Thank you for the comment. The repeated paragraph was deleted.