Cardiac Complications of Infections Due to Respiratory Syncytial Virus and Human Metapneumovirus: A Systematic Review and Pooled Analysis of Clinical Features

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This systematic review addresses an interesting and clinically relevant topic by summarizing the reported cardiac complications associated with RSV and hMPV infections. The manuscript is generally comprehensive, well structured, and appropriately cautious regarding the limitations of evidence derived primarily from case reports and case series. The figures and tables are informative, and the age-stratified sensitivity analysis strengthens the interpretation. I have a few comments that may help improve the manuscript.

1. The objective and eligibility criteria should consistently refer to both RSV and hMPV. For example, Section 2.1.1 states that the objective was to summarize cardiac outcomes after RSV infection, while Section 2.4 similarly refers only to confirmed RSV infection. These statements should be revised to include hMPV.

2. The manuscript occasionally describes the study as a “meta-analysis.” However, the analysis appears to involve pooling individual cases from case reports and case series without a conventional meta-analytic model. The authors should clarify this terminology and consistently describe the work as a systematic review with pooled individual-case analysis, unless a formal meta-analysis was performed.

3. The multivariable regression models include a relatively large number of explanatory variables despite the limited sample, particularly the 31 hMPV cases. The very wide confidence intervals—for example, for dyspnea and ICU admission—suggest sparse-data effects and considerable instability. The authors should consider simplifying the models or provide a clearer justification for the number of included variables. At minimum, these findings should be explicitly described as exploratory and interpreted cautiously in the Abstract and Discussion.

4. The cases span a long period, from 1973 to 2026, during which diagnostic methods, cardiac imaging, clinical awareness, and reporting practices changed substantially. In addition, the COVID-19 pandemic affected RSV and hMPV circulation, healthcare-seeking behavior, and respiratory-virus testing. The authors should briefly discuss whether the pandemic period and other temporal changes may have influenced case ascertainment. A formal pre-/post-COVID comparison may not be reliable because of the small and unevenly distributed sample, although descriptive numbers by period could be provided if feasible.

5. Because age has a highly heterogeneous and likely skewed distribution, reporting the median and interquartile range in addition to, or instead of, the mean and 95% confidence interval may be more appropriate and would align better with the Mann–Whitney U test used for group comparisons.

6. The description of most reports as having “high or very high methodological quality” may be somewhat strong given that the evidence consists mainly of case reports and case series. It may be more accurate to state that most reports achieved high appraisal or reporting-quality scores while acknowledging the inherent limitations of these study designs.

Overall, this is a useful and carefully conducted review. The conclusions are generally supported by the available evidence, provided that the exploratory nature and statistical limitations of the comparative analyses are made sufficiently clear.

Author Response

Reviewer 1: Point-to-point reply

Estimated Reviewer,

we warmly thank you for the time you spent into the present review and for the suggestions you shared with us, that radically improved the overall quality of our study. Please refer to the following point-to-point reply for details.

Comment:  The objective and eligibility criteria should consistently refer to both RSV and hMPV. For example, Section 2.1.1 states that the objective was to summarize cardiac outcomes after RSV infection, while Section 2.4 similarly refers only to confirmed RSV infection. These statements should be revised to include hMPV.

Reply: thank you for your comment. In fact, a very early stage of the present study was originally designed for only including RSV cases. Some “relics” of this stage of developed escaped our quality check. This issue has been fixed across the main text.

Comment: The manuscript occasionally describes the study as a “meta-analysis.” However, the analysis appears to involve pooling individual cases from case reports and case series without a conventional meta-analytic model. The authors should clarify this terminology and consistently describe the work as a systematic review with pooled individual-case analysis, unless a formal meta-analysis was performed.

Reply: thank you for this comment. It was a mistake resulting from early proofs of the paper which, similarly to the previous point, survived the final proofreading. Therefore, we removed all the instances.

Comment: The multivariable regression models include a relatively large number of explanatory variables despite the limited sample, particularly the 31 hMPV cases. The very wide confidence intervals—for example, for dyspnea and ICU admission—suggest sparse-data effects and considerable instability. The authors should consider simplifying the models or provide a clearer justification for the number of included variables. At minimum, these findings should be explicitly described as exploratory and interpreted cautiously in the Abstract and Discussion.

Reply: we agree with this comment but we respectfully think that the multivariable analysis may add significand added value to our study. In any way, as we totally agreed that the previous version could share some inappropriate message about the reliability of the analyses, we implemented the following amendment: (1) age-stratified univariable analysis was shifted from appendix material to Table 7, while the Table 7 which in the original version reported data of multivariable analysis was moved to the appendix material (Appendix Table A5) in order to stress the second intervention (2), i.e. the role of exploratory analysis we associated with regression analysis, which was stressed in both abstract, methods and discussion (e.g. abstract: In exploratory multivariable analyses, … These estimates were characterized by wide confidence intervals and should be interpreted cautiously … methods: Given the limited number of available cases, particularly in the hMPV group, these multivariable models were intended as exploratory analyses rather than confirmatory analyses. Accordingly, adjusted estimates were interpreted primarily in terms of their direction and uncertainty, with particular caution applied to associations characterized by wide confidence intervals …). Thank you again for this point!

Comment: The cases span a long period, from 1973 to 2026, during which diagnostic methods, cardiac imaging, clinical awareness, and reporting practices changed substantially. In addition, the COVID-19 pandemic affected RSV and hMPV circulation, healthcare-seeking behavior, and respiratory-virus testing. The authors should briefly discuss whether the pandemic period and other temporal changes may have influenced case ascertainment. A formal pre-/post-COVID comparison may not be reliable because of the small and unevenly distributed sample, although descriptive numbers by period could be provided if feasible.

Reply: As for the previous point, we totally agreed with this point. In order to cope with this suggestion, we implemented a simple univariable comparison on the occurrence of RSV vs. hMPV before and after COVID-19 pandemic (i.e. results section: “More than half of all cases (53.9%) were reported after the onset of the COVID-19 pandemic in 2020, and the proportion of hMPV cases reported during this period (83.9%) was significantly higher than that of RSV cases (40.8%; chi-squared test, p < 0.001). As shown in Figure 2, the chronological distribution of reported cases differed substantially between the two viruses. While cases of RSV with documented cardiac involvement have been reported since the early 1970s, hMPV-associated cases appeared only several decades later, reflecting the more recent identification of hMPV as a human pathogen”). Also Figure 2 received a simple editing in order to highlighten the cases occurring after the onset of SARS-CoV-2 pandemic. Eventually, discussion was amended by including a new subsection within “limits”: “Moreover, not only the long timespan covered by the included reports encompasses major changes in diagnostic methods, cardiac imaging, clinical awareness, and respiratory-virus testing practices. These changes have been dramatically accelerated during and after the COVID-19 pandemic, and we can rule out that it eventually resulted in the increased detection and reporting of hMPV cases. Improvements in diagnostic availability may therefore have influenced case ascertainment and reporting and should be considered when interpreting chronological differences in the available evidence”).

Comment: Because age has a highly heterogeneous and likely skewed distribution, reporting the median and interquartile range in addition to, or instead of, the mean and 95% confidence interval may be more appropriate and would align better with the Mann–Whitney U test used for group comparisons.

Reply: we totally agreed, and we added median values with IQR within the tables, replacing the averages with their 95%CI across the main text. It was particularly useful as – otherwise shown by Figure 2, the median of RSV cases collapsed to 1.5 years, stressing the very different populations we implemented in our analysis. Thank you.

Comment: The description of most reports as having “high or very high methodological quality” may be somewhat strong given that the evidence consists mainly of case reports and case series. It may be more accurate to state that most reports achieved high appraisal or reporting-quality scores while acknowledging the inherent limitations of these study designs.

Reply: again, we totally agreed with this comment, and the section was revised as follows: “Briefly, most reports achieved high appraisal scores according to the tool from Murad et al. [54], with 73.2% of RSV case reports and 80.6% of hMPV case reports achieving a quality score of five or six out of six. Although the body of evidence also included conference abstracts, no report receved a score below three, whereas 26.7% of RSV case reports and 19.3% of hMPV case reports achieved scores of three to four (see Appendix Table A3 for individual scores)”.

Eventually, we would thank you for the accurate and very collaborative approach of your comments, which radically improved the quality of our paper.

On the behalf of all Authors, thank you.

MR

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

General comment
The manuscript addresses an important and clinically relevant topic, particularly for clinicians working in emergency medicine, pediatrics, infectious diseases, and intensive care. The authors have made a valuable effort to compile published cases of cardiac complications associated with respiratory syncytial virus (RSV) and human metapneumovirus (hMPV). Given the clinical importance of these potentially severe complications, this review may provide a useful contribution to the literature. However, several aspects should be reconsidered to strengthen the manuscript and ensure that the conclusions are supported by the available evidence.
1. Population heterogeneity and statistical analysis
My main concern is the substantial heterogeneity of the study population, which includes neonates, children, adults, and older patients, with considerable differences in underlying conditions, clinical presentations, and diagnostic approaches. In addition, the relatively small sample size, particularly in the hMPV group, limits the reliability of the multivariable analyses. The wide confidence intervals reported for several associations further illustrate the uncertainty of these estimates.
I would encourage the authors to simplify the statistical approach and focus primarily on a descriptive synthesis of the available cases. Presenting demographic characteristics, cardiac manifestations, diagnostic findings, clinical management, and reported outcomes separately for RSV and hMPV would provide clinically meaningful information without suggesting differences between the viruses that cannot be reliably established from the available evidence. Age-stratified descriptive analyses, where sufficient data are available, may be particularly informative.

An additional concern relates to the use of the Charlson Comorbidity Index (CCI) in a population that includes both pediatric and adult patients. The CCI was originally developed and validated for adult populations, and its applicability to neonates and children is limited. The authors should clarify how this score was applied across the different age groups and discuss the implications of using an adult-oriented comorbidity measure in the pediatric population.
Given the substantial differences in age distribution between the RSV and hMPV groups, I would suggest considering an age-stratified descriptive analysis, at least separating pediatric and adult patients, if the available data permit. This could provide clinically useful information regarding the distribution of cardiac manifestations, diagnostic investigations, and reported outcomes in different age groups. Further pediatric age stratification may be informative where sufficient cases are available.
However, I would not recommend additional complex multivariable analyses within these smaller subgroups. The purpose of age stratification should primarily be to improve the clinical interpretation of the findings and to acknowledge the heterogeneity of the included population.
2. Definition of cardiovascular abnormalities
The criteria used to define tachycardia and bradycardia should be clarified. Given the broad age range of the study population, age-specific reference values are essential, particularly in pediatric patients. The authors should specify whether heart rate abnormalities were independently classified using age-appropriate thresholds or whether the definitions reported in the original publications were accepted.
It would also be important to distinguish sinus tachycardia, which may occur as a physiological response to fever, hypoxemia, or respiratory distress, from documented cardiac tachyarrhythmias. If sufficient information is unavailable in the original reports, this limitation should be explicitly acknowledged.
3. Diagnostic classification and clinical interpretation
The diagnostic criteria used to classify myocarditis and other cardiac manifestations should be described more clearly. In particular, the authors should distinguish confirmed myocarditis from clinically suspected myocarditis and nonspecific myocardial injury whenever the available data permit.
The identification of RSV or hMPV in respiratory samples does not necessarily establish a causal relationship with cardiac involvement. Alternative explanations, including systemic inflammation, hypoxemia, pre-existing cardiac disease, and coinfections, should be considered when interpreting the reported findings.
4. Consistency of tables, figures, and text
Several inconsistencies were identified between the numerical results reported in the text and the corresponding tables, including discrepancies in percentages, patient counts, and statistical results. The authors should carefully review the entire manuscript to ensure consistency across all reported data, paying particular attention to absolute numbers, percentages, denominators, and statistical comparisons.
Cross-references to tables and figures should also be checked. For example, in Section 3.1, the reference to Table 1 should be clarified, as Figure 1 is more appropriate when referring to the study selection process illustrated by the PRISMA flow diagram.
5. Discussion and conclusions
The Discussion and Conclusions should more clearly reflect the limitations associated with a heterogeneous population derived primarily from published case reports and case series. In particular, the observed differences should not be interpreted as evidence of distinct clinical patterns or differences in the risk of cardiac complications between RSV and hMPV.
The main contribution of this study may lie in describing the spectrum of reported cardiac manifestations and highlighting the importance of considering cardiac involvement in patients with severe respiratory viral infections.
Overall comment
Overall, I consider this manuscript clinically relevant and potentially suitable for publication following substantial revision. A predominantly descriptive approach, clearer clinical definitions, careful verification of the reported data, and a more cautious interpretation of the findings would strengthen the manuscript and improve its usefulness to clinicians.

Comments on the Quality of English Language

Although the manuscript is generally understandable, some sentences could benefit from language editing to improve clarity and readability. However, as I do not have specific expertise in English-language editing, I would recommend that the journal consider a professional linguistic review.

Author Response

Reviewer 1: Point-to-point reply

Estimated Reviewer,

we warmly thank you for the time you spent into the present review and for the suggestions you shared with us, that radically improved the overall quality of our study. Please refer to the following point-to-point reply for details.

Concern 1. Population heterogeneity and statistical analysis. My main concern is the substantial heterogeneity of the study population, which includes neonates, children, adults, and older patients, with considerable differences in underlying conditions, clinical presentations, and diagnostic approaches. In addition, the relatively small sample size, particularly in the hMPV group, limits the reliability of the multivariable analyses. The wide confidence intervals reported for several associations further illustrate the uncertainty of these estimates. I would encourage the authors to simplify the statistical approach and focus primarily on a descriptive synthesis of the available cases. Presenting demographic characteristics, cardiac manifestations, diagnostic findings, clinical management, and reported outcomes separately for RSV and hMPV would provide clinically meaningful information without suggesting differences between the viruses that cannot be reliably established from the available evidence. Age-stratified descriptive analyses, where sufficient data are available, may be particularly informative.

Reply: We thank the Reviewer for this important comment. We agree that the marked heterogeneity of the available cases, particularly with respect to age, comorbidity burden, diagnostic work-up, and historical period, represents a major limitation of the present study and substantially constrains any direct comparison between RSV- and hMPV-associated cases.

Accordingly, we revised the manuscript to place substantially greater emphasis on the descriptive characterization of the available evidence. Demographic characteristics, clinical presentation, cardiac manifestations, diagnostic findings, clinical management, and outcomes are now presented separately for RSV and hMPV cases, and their interpretation has been revised to avoid suggesting pathogen-specific differences that cannot be reliably established from the available case-based evidence.

Following the Reviewer’s suggestion, we also performed age-stratified descriptive analyses (<1 year, 1–17 years, and ≥18 years) (current Table 5). These analyses showed that most of the differences observed in the overall sample were attenuated after stratification by age, further supporting the interpretation that part of the apparent differences between RSV and hMPV cases may reflect the markedly different age distribution of the reported cases rather than pathogen-specific clinical phenotypes.

We also agree that the relatively small sample size, particularly for hMPV, and the wide confidence intervals substantially limit the reliability of multivariable estimates. We therefore considered removing the multivariable analyses altogether. However, we ultimately retained them solely as exploratory analyses, because they may provide complementary information on the structure of the pooled case-based dataset after simultaneous consideration of selected covariates. We have now explicitly stated in the Methods, Results, and Discussion that these models are exploratory rather than confirmatory and that their estimates should be interpreted with considerable caution because of sparse-data effects, statistical imprecision, and potential model instability. Accordingly, no causal or pathogen-specific inference is drawn from these analyses (e.g. abstract: In exploratory multivariable analyses, … These estimates were characterized by wide confidence intervals and should be interpreted cautiously … methods: Given the limited number of available cases, particularly in the hMPV group, these multivariable models were intended as exploratory analyses rather than confirmatory analyses. Accordingly, adjusted estimates were interpreted primarily in terms of their direction and uncertainty, with particular caution applied to associations characterized by wide confidence intervals …).

In addition, the MCA was retained as an exploratory descriptive approach and showed substantial overlap between RSV and hMPV cases, without clear separation of their overall clinical presentations. We have clarified that this finding should not be interpreted as evidence of phenotypic equivalence.

Finally, the Discussion and Conclusions have been extensively revised to emphasize that the principal contribution of the present systematic review is the characterization of the spectrum of reported cardiac involvement associated with RSV and hMPV, rather than estimation of incidence, comparative risk, or pathogen-specific causality. We believe that these revisions substantially address the Reviewer’s concern while preserving the exploratory analyses as secondary and hypothesis-generating components of the study.

Concern 2: An additional concern relates to the use of the Charlson Comorbidity Index (CCI) in a population that includes both pediatric and adult patients. The CCI was originally developed and validated for adult populations, and its applicability to neonates and children is limited. The authors should clarify how this score was applied across the different age groups and discuss the implications of using an adult-oriented comorbidity measure in the pediatric population.:

Reply: We respectfully agree with this comment and have revised the manuscript to better explain both the rationale for including the CCI in our analyses and, importantly, the limitations associated with its use in a population including pediatric patients. More specifically, the Methods section was expanded by adding the following explanatory text:

“The Charlson Comorbidity Index (CCI) was retrospectively derived from the clinical information available in the original reports to provide a standardized summary measure of the burden of reported underlying conditions across a highly heterogeneous population [52]. The CCI was used primarily as a pragmatic tool to facilitate comparison across cases rather than as a validated prognostic instrument [52,53]. As the CCI was originally developed for adult populations and has limited validation in children, values obtained in pediatric cases should be interpreted cautiously.”

In addition, as part of the extensive revision of the Discussion undertaken in response to this and related comments from Reviewer 1, we have explicitly acknowledged the use of the CCI in a population encompassing both pediatric and adult patients as a study limitation (i.e. Seventh, the use of the CCI in a population encompassing both pediatric and adult patients represents an additional limitation. Although the index provided a pragmatic, standardized framework for summarizing heterogeneous comorbidity profiles, it was not specifically developed or validated for pediatric populations. Therefore, CCI-based comparisons, particularly those involving children and infants, should be interpreted as descriptive measures of reported comorbidity burden rather than validated estimates of prognosis or clinical complexity.). We have clarified that CCI-based comparisons, particularly those involving infants and children, should be regarded as descriptive measures of reported comorbidity burden rather than as validated estimates of prognosis or clinical complexity. We believe that these amendments clarify the rationale for retaining the CCI while minimizing the risk of overinterpretation of CCI-based findings.Given the substantial differences in age distribution between the RSV and hMPV groups, I would suggest considering an age-stratified descriptive analysis, at least separating pediatric and adult patients, if the available data permit. This could provide clinically useful information regarding the distribution of cardiac manifestations, diagnostic investigations, and reported outcomes in different age groups. Further pediatric age stratification may be informative where sufficient cases are available.

However, I would not recommend additional complex multivariable analyses within these smaller subgroups. The purpose of age stratification should primarily be to improve the clinical interpretation of the findings and to acknowledge the heterogeneity of the included population.

Concern 3. Definition of cardiovascular abnormalities:  The criteria used to define tachycardia and bradycardia should be clarified. Given the broad age range of the study population, age-specific reference values are essential, particularly in pediatric patients. The authors should specify whether heart rate abnormalities were independently classified using age-appropriate thresholds or whether the definitions reported in the original publications were accepted. It would also be important to distinguish sinus tachycardia, which may occur as a physiological response to fever, hypoxemia, or respiratory distress, from documented cardiac tachyarrhythmias. If sufficient information is unavailable in the original reports, this limitation should be explicitly acknowledged.

Reply: again, we agreed with this comment and amended the main text in order to better reflect the analyses we performed during the collection and systematization of our data. More precisely, we included the following section within methods section: “… Heart rate and blood pressure values were independently classified according to age-specific reference values derived from currently available reference ranges [50,51]. Tachycardia and bradycardia based on heart rate measurements were considered separately from documented rhythm abnormalities. Sinus tachycardia was therefore not interpreted per se as evidence of a pathological tachyarrhythmia, whereas specific arrhythmias (e.g., supraventricular tachycardia, atrial fibrillation/flutter, ventricular tachycardia, and conduction abnormalities) were classified only when explicitly documented in the original report and/or supported by the reported ECG findings. … Cardiac diagnoses were classified according to the diagnostic terminology and supporting clinical, instrumental, imaging, and/or histopathological findings reported in the original publications. A diagnosis of myocarditis based on clinical or imaging findings was distinguished from direct evidence of viral myocardial involvement, which required identification of RSV or hMPV in cardiac tissue. Detection of the virus in respiratory specimens alone was not considered evidence of direct myocardial infection”. Eventually, we are confident that these amendments may solve this very significant issue.

4. Diagnostic classification and clinical interpretation. The diagnostic criteria used to classify myocarditis and other cardiac manifestations should be described more clearly. In particular, the authors should distinguish confirmed myocarditis from clinically suspected myocarditis and nonspecific myocardial injury whenever the available data permit. The identification of RSV or hMPV in respiratory samples does not necessarily establish a causal relationship with cardiac involvement. Alternative explanations, including systemic inflammation, hypoxemia, pre-existing cardiac disease, and coinfections, should be considered when interpreting the reported findings.

Reply: we fully agree with the Reviewer that detection of RSV or hMPV in respiratory specimens should not be interpreted as evidence of direct viral involvement of cardiac tissue or, by itself, as establishing a causal relationship between infection and the reported cardiac manifestation. We have therefore revised both the Methods and Discussion to clarify the diagnostic classification and to adopt a more cautious interpretation of the available case-based evidence.

More specifically, the Methods section now explicitly states:

“Cardiac diagnoses were classified according to the diagnostic terminology and supporting clinical, instrumental, imaging, and/or histopathological findings reported in the original publications. A diagnosis of myocarditis based on clinical or imaging findings was distinguished from direct evidence of viral myocardial involvement, which required identification of RSV or hMPV in cardiac tissue. Detection of the virus in respiratory specimens alone was not considered evidence of direct myocardial infection.”

This distinction was, in fact, applied whenever the information reported in the original publication allowed such classification since the original design of the paper. However, because many of the included reports did not provide sufficiently detailed diagnostic information to retrospectively reclassify myocarditis according to uniform contemporary criteria, we retained the diagnoses reported by the original authors rather than imposing a post hoc diagnostic classification unsupported by the source data. Please note, in this regard, that where data on the identification of RSV/hMPV in cardiac tissue were available, their description was extensively implemented within the main results section with a summary of this finding.

In parallel, we substantially revised the Discussion to avoid implying pathogen-specific cardiac causality. We now explicitly acknowledge that the available case-based evidence cannot determine whether the reported cardiovascular complications were directly caused by RSV or hMPV or arose indirectly through systemic mechanisms. In particular, we emphasize that direct viral involvement of myocardial or pericardial tissue was documented only in a very limited number of cases and that systemic inflammation, hypoxemia, ischemic or hemodynamic mechanisms, pre-existing cardiac disease, and coinfections may provide alternative or contributing explanations for the observed cardiac manifestations.

Accordingly, throughout the revised manuscript we have adopted the terminology “RSV- or hMPV-associated cardiac involvement/complications” rather than implying a direct causal relationship, except where direct viral involvement was specifically documented. We believe that these revisions provide a clearer distinction between the reported cardiac diagnosis, evidence of direct viral myocardial involvement, and the broader question of causality.

Concern 5. Consistency of tables, figures, and text. Several inconsistencies were identified between the numerical results reported in the text and the corresponding tables, including discrepancies in percentages, patient counts, and statistical results. The authors should carefully review the entire manuscript to ensure consistency across all reported data, paying particular attention to absolute numbers, percentages, denominators, and statistical comparisons. Cross-references to tables and figures should also be checked. For example, in Section 3.1, the reference to Table 1 should be clarified, as Figure 1 is more appropriate when referring to the study selection process illustrated by the PRISMA flow diagram.

Reply: we warmly thank the reviewer for this point. In fact, the present study reflect a very long “gestation” of the eventual paper and several instances of the previous versions still remained across the text as a relic of its original stages of development. We have accurately reviewed the flow of text and double checked data. Eventually, we are confident that this issues has been solved.

Concern 6. Discussion and conclusions. The Discussion and Conclusions should more clearly reflect the limitations associated with a heterogeneous population derived primarily from published case reports and case series. In particular, the observed differences should not be interpreted as evidence of distinct clinical patterns or differences in the risk of cardiac complications between RSV and hMPV. The main contribution of this study may lie in describing the spectrum of reported cardiac manifestations and highlighting the importance of considering cardiac involvement in patients with severe respiratory viral infections.

Reply: We fully agree with the Reviewer and have substantially revised both the Discussion and Conclusions accordingly. In particular, we have reframed the interpretation of our findings to emphasize that the present study describes the spectrum of reported cardiac manifestations associated with RSV and hMPV infections, rather than providing evidence of distinct pathogen-specific clinical patterns or differences in the risk of cardiac complications.

Throughout the revised Discussion, we now explicitly acknowledge that the available evidence is derived predominantly from case reports and case series and is therefore particularly susceptible to selection and reporting biases. We have also emphasized the substantial heterogeneity of the included cases in terms of age, comorbidity burden, diagnostic work-up, geographical origin, historical period, and clinical follow-up. Importantly, the age-stratified analyses showed that most of the differences observed in the overall sample were attenuated within individual age groups, further supporting a cautious interpretation of apparent between-virus differences.

We have consequently revised the interpretation of both the multivariable analyses and the MCA. The former are now explicitly presented as exploratory and hypothesis-generating, whereas the substantial overlap between RSV and hMPV cases in the MCA space is described as indicating no clear separation of their overall clinical presentations, without interpreting this finding as evidence of phenotypic equivalence.

The Conclusions have also been extensively revised and now state:

“The present systematic review highlights that both RSV and hMPV infections can be associated with a broad spectrum of potentially severe cardiac complications, with myocarditis representing the predominant reported manifestation. The apparent differences between viral groups were strongly influenced by age, comorbidity, diagnostic work-up, coinfection, and selective publication. These data characterize the spectrum of reported presentations but cannot provide estimates of incidence, comparative risk, or pathogen-specific causality. Prospective, systematically investigated cohorts with standardized definitions of cardiac involvement and longitudinal follow-up are needed.”

Finally, in accordance with the Reviewer’s suggestion, we have reframed the clinical implications of the study toward increased awareness of possible cardiac involvement in patients with severe RSV or hMPV infection, rather than suggesting virus-specific patterns or differential risks. We believe that the revised Discussion and Conclusions now more accurately reflect both the principal contribution of the study and the limitations inherent in the available case-based evidence.

Overall comment: Overall, I consider this manuscript clinically relevant and potentially suitable for publication following substantial revision. A predominantly descriptive approach, clearer clinical definitions, careful verification of the reported data, and a more cautious interpretation of the findings would strengthen the manuscript and improve its usefulness to clinicians.

Reply: thank you!

Concern 7: Although the manuscript is generally understandable, some sentences could benefit from language editing to improve clarity and readability. However, as I do not have specific expertise in English-language editing, I would recommend that the journal consider a professional linguistic review.

Reply: We agree that the manuscript would benefit from further language editing. Accordingly, the revised version has undergone extensive linguistic revision throughout the manuscript, as indicated by the changes highlighted in yellow across the various sections. We have carefully revised the text for grammar, syntax, clarity, and overall readability. We hope that the extent and quality of these revisions have adequately addressed the language issues raised by the Reviewer.

Eventually, we would thank you for the accurate and very collaborative approach of your comments, which radically improved the quality of our paper.

On the behalf of all Authors, thank you.

MR

Reviewer 3 Report

Comments and Suggestions for Authors

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two very closely related pneumoviruses that are responsible for lower respiratory tract infections (LRTIs), including bronchiolitis and pneumonia across all age groups.  Both viruses exhibit seasonal patterns with high transmissibility and recurring infections.  RSV accounts for 3.6 million hospitalizations in infants and children annually and is a major cause of morbidity and mortality in the elderly.  HMPV similarly accounts for up to 10% of hospitalizations in children due to LRTIs and is also a major burden in older populations.

Like other respiratory viruses, most notably influenza virus, it has become increasingly apparent that both RSV and hMPV can also have detrimental effects on the cardiovascular system, especially in the elderly, causing complications including arrhythmia, myocarditis, stroke and myocardial infarction.  In this review, the authors summarize the status of our understanding of the cardiac complications resulting from RSV and hMPV infection. 

The major points made in the review are: 1) the cardiac disease manifestations resulting from RSV and hMPV overlap to a significant extent,  making them difficult to distinguish; 2) RSV cases cluster in the early years of life , but are also prevalent in the elderly, while hMPV exhibits a similar, though not as pronounced pattern, i.e. a U-shaped age distribution; 3) diagnostic imaging and instrumental investigations were commonly employed for both viruses, though slightly more so for hMPV; 4) the data do not enable resolution of  the question whether the cardiovascular complications are due to direct vs. indirect effects of the viruses; 5) the effects of both viruses in the elderly are greatly complicated by co-morbidities common in the elderly population; 6) the distribution of retrieved hMPV cases is skewed to more recent years compared to RSV due to its more recent identification as a human pathogen; and, 7) perhaps surprisingly, where a direct comparison was possible, RSV-infected patients appeared to be more likely to develop cardiac complications than those infected with influenza virus.  It should be said that the high level of stringency with respect to the inclusion of samples is very impressive and indicative of the care and attention to detail demonstrated by the authors. 

This review is considered a major contribution to our understanding of the impact of RSV and hMPV on the cardiovascular system.  The manuscript is superbly well-written, extremely comprehensive, highly detailed and thought-provoking from beginning to end.  It dives more deeply into these relationships than any previous study, thereby raising our awareness of the complications from these viruses to a completely new level.  To their credit, the authors acknowledge the limitations of the study, most importantly the low number of samples included in the study, which they say may reflect “the tip of the iceberg”, as well as several others.

There are really no issues, even minor, with the approach or the interpretation of the findings.  This is an exceptionally strong and impactful study that constitutes a clarion call for more careful evaluation of RSV-hMPV patient population for the risk of cardiovascular complications.

Author Response

We sincerely thank the Reviewer for the careful assessment of our manuscript and for these very encouraging comments. We greatly appreciate the Reviewer’s recognition of the potential contribution of our work, as well as of the care taken in case selection, data extraction, and interpretation of the available evidence.

As no specific amendments were requested, no changes were made in direct response to this comment. Nevertheless, during revision we further strengthened the discussion of the limitations inherent in the case-based nature of the available evidence and adopted a more cautious interpretation of between-group differences, also in response to comments raised by the other Reviewers. We hope that these revisions have further improved the clarity and robustness of the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for their thorough responses and revisions. All comments have been satisfactorily addressed, and I am pleased with the revised manuscript. I have no further comments.