Human Metapneumovirus (HMPV): Advances in Diagnosis, Molecular Epidemiology, and Clinical Impact of an Underrecognized Respiratory Virus
, Rehab Ahmed 1, Abdul Haseeb 2, Salwa Qasim Bukhari 3, Zinab Alatawi 4, Ahmad J. Mahrous 5, Mahmoud E. Elrggal 6, Ali M. Atoom 7, Yasmin N. Ramadan 8 and Ahmed A. Kotb 8
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Authors,
Thank you for submitting your manuscript and for your valuable contribution to this important topic. Your work provides a timely overview of the hMPV and highlights several key aspects of its impact.
To further strengthen the manuscript, I kindly encourage you to revise it by addressing the comments provided in the attachment. In particular, improving the depth of analysis, enhancing the clarity and flow of the writing, and updating the reference list with more recent literature will significantly improve the overall quality and impact of the paper.
I appreciate your efforts and look forward to seeing a revised version of your manuscript.
Comments for author File: 
Comments.pdf
The quality of the English language requires improvement throughout the manuscript. The authors are encouraged to revise the text carefully to correct grammatical errors, improve sentence structure, and ensure clarity. Attention should also be given to maintaining a logical flow and coherence of ideas across all sections to enhance overall readability.
Author Response
Review Report 1
This review gives an important and up-to-date overview of the public health problem caused by hMPV, especially in vulnerable groups. The manuscript clearly explains the virus’s molecular features, its clinical effects, and the pressure it puts on health systems. Overall, it serves as an important reminder to take action against the growing impact of hMPV.
However, the review has some important limitations. In some sections, it mainly describes previous studies without enough critical analysis, so gaps and disagreements in the research are not clearly discussed. The writing also needs improvement, as there are repeated ideas, unclear sentences, and overall length issues that affect readability. In addition, the reference list is somewhat unbalanced. Although some recent studies from 2024–2025 are included, many citations are older, which makes the review seem partly outdated compared to current research in microbiome and virology.
Response: Thank you for your comprehensive and constructive evaluation of our manuscript. We appreciate your insightful comments regarding the need for greater critical analysis, improved clarity, and updated references.
Add reference for the statement of “Human metapneumovirus (HMPV) is the second most common cause of severe 65 pneumonia in children under five, behind respiratory syncytial virus (RSV), according to 66 the 2024 Pneumonia Etiology Research for Child Health (PERCH) project.” In the line of 65-67.
Response: Thank you for this valuable comment. Done.
Add reference for the information of “four-year prospective investigation that included About 1,400 hospitalized 82 patients and revealed that HMPV caused 8% of acute respiratory illnesses and their hos-83 pitalization, which is higher than other respiratory viruses such as influenza A and com-84 parable to RSV, the other member in its family.” In the line of 82-85.
Response: Thank you for this valuable comment. Done.
The gap of recent information and justification of this review article is not clear in the introduction. Please justify and mention the gap of recent knowledge.
Response: Thank you for this valuable comment. We agree that the initial version of the Introduction did not sufficiently highlight the gap in current knowledge and the justification for this review. To address this, we have revised the Introduction by adding a dedicated paragraph that clearly outlines the existing gaps in the literature, including limited integration of recent epidemiological, molecular, and clinical findings, as well as ongoing uncertainties regarding transmissibility, genotype–severity relationships, and vaccine development. We have also clarified the rationale and novelty of the present review in light of recent advances in the field.
Authors did not mention that how they select the study to include in their review article. Please mention the search strategies and inclusion criteria for the selected articles.
Response: Thank you for this important comment. Accordingly, we have added a new section titled “Literature Search Strategy” to the manuscript. This section outlines the databases searched, keywords used, inclusion and exclusion criteria, and the general approach to selecting relevant studies. This addition improves the transparency and methodological rigor of the review.
In the older taxonomy the virus was under the Paramyxoviridae family. Correct the statement “The virus can disrupt the innate immune response comparable to other members of 136 the Paramyxoviridae family but with special particular methods.” In the line of the 136-137
Response: Thank you for this important observation. We have corrected the statement to reflect the updated taxonomy, recognizing that human metapneumovirus is currently classified under the Pneumoviridae family rather than Paramyxoviridae. The sentence has been revised accordingly, and we have also clarified the historical classification for accuracy.
In the figure 1 and its narration throughout the manuscript, the authors superficially discussed only the antigenomic (negative sense RNA) but avoid the mRNA translation process. This is partially correct. I will recommend the authors to revise the figure and also the narration.
Response: We thank the reviewer for this insightful comment. We agree that the original version of Figure 1 and its accompanying description did not sufficiently distinguish between viral transcription, translation, and genome replication processes. In response, we have revised both the figure and the corresponding text
The authors mention the immune evasion process of hMPV in the line of 136-142. But this information is insufficient for the molecular epidemiology study. Please completely describe the immune evasion of hMPV with example in real life evidence, e.g., hospital case due to immune evasion of hMPV.
Response: We thank the reviewer for this observation. We clarify that the immune evasion mechanisms of HMPV are comprehensively discussed in Section 6 (Immunopathogenesis and Immune Evasion). To improve clarity and avoid redundancy, we have revised the Molecular Characteristics section (lines 136–142) to remove superficial discussion of immune evasion and instead direct readers to Section 6, where this topic is covered in detail at both molecular and clinical levels.
In the epidemiology section, the authors sometimes avoid the session or time or year to mention the outbreak. It is very important and critical for epidemiological data. Moreover, the authors discussed only few limited countries data. I will recommend to add a table include with more countries data.
Response: Thank you for this valuable and constructive comment. We have added a summary table that compiles epidemiological data from multiple countries, including study periods and key findings, to provide a clearer and more comprehensive overview.
In the clinical signs, the figure 3 does not indicate that all the clinical sign, e.g., dizziness or lightheadedness. Moreover, in this figure the anatomical location of the heart is not correct. So, revise the figure and present in different way to explain the clinical symptoms. 2
Response: Thank you for this valuable and constructive comment. Done.
In the figure 4 the authors mention that the RIG I and MDA5 acts on MAV. But actually, the viral M2 protein acts on the MAV which is the mitochondrial protein and then disrupt the signaling of RIG-I and suppress the TRAF3, TRAF5, TRAF6 and ultimately the IRF3 and NF-kB activation will be blocked. Moreover, the hMPV also causes the adaptive immune evasion as well as innate immune evasion. The figure 4 is incomplete to express the immune evasion process of hMPV. I will recommend to revise the narration and figure 4 related to immune evasion.
Response: Thank you for this valuable and constructive comment. We have expanded the figure and discussion to include adaptive immune evasion mechanisms.
In the figure 5, the elements used for different instruments e.g., ELISA reader is not correct. Please replace with resemble elements
Response: Thank you for this valuable and constructive comment. Done
Please add sufficient references for describing the management of hMPV. This is common the disruption of gut lungs microbiota during hMPV. The authors did not mention any strategies to minimize the secondary bacterial infection. Moreover, fecal microbiota transplantation is more advance methods to minimize the gut microbiota disruption during viral infection.
Response: Thank you for this insightful and constructive comment. Done.
In all the figure’s note, add the elaboration of every abbreviation used in the figure.
Response: Thank you for this insightful comment. Done.
Please improve the Language and Grammer with the flow and coherent information throughout the manuscript.
Response: Thank you for this valuable suggestion. We have carefully revised the manuscript to improve the overall language, grammar, and readability.
Reviewer 2 Report
Comments and Suggestions for AuthorsTo be honest, I too had mistakenly assumed that HMPV was not a particularly problematic virus. This review has made me realise once again that this was a mistaken view. I would like to thank the authors. I believe this review is well worth reading for many clinicians, as it provides an excellent summary of the nature of this virus and the current state of research. I hope that, in the future, chimeric vaccines—particularly those that can be co-administered with influenza vaccines—will be brought into practical use. This is because vaccines based on attenuated strains, unlike those based on multiple components such as mRNA, have multiple valences, making it difficult for resistant strains to emerge.
I have a few concerns regarding the R0 or Re of this virus. I wondered whether these had been measured accurately.
295 F gene of 295 HMPV shows a relatively stable evolutionary rate
Firstly, this is a very interesting phenomenon. This is because, in the influenza virus, all ORFs evolve at roughly the same rate. https://www.nature.com/articles/s41598-019-55254-z Similarly, the fact that multiple strains circulate simultaneously is quite different from influenza or COVID-19, which is also interesting. I believe this phenomenon suggests that this virus infects only a very small proportion of the population. For example, with influenza or COVID-19, an outbreak is almost always caused by a single strain.
This phenomenon contradicts Figure 2, which assumes that R0 is similarly high.
Incidentally, as R0 is a mathematically unstable value, it is considered difficult to determine with precision.
https://www.mdpi.com/2673-8112/4/2/12
Or perhaps the values in Figure 2 are inaccurate (the figures for influenza and COVID-19 seem somewhat low). Should we not also re-examine the transmissibility of HMPV? It is rather difficult to imagine a situation where multiple highly transmissible viruses circulate simultaneously.
I would appreciate it if you could discuss this point. That is all from me. As this is a paper that will be of benefit to many readers, I hope it will be published without undue delay.
Author Response
Review Report 2
To be honest, I too had mistakenly assumed that HMPV was not a particularly problematic virus. This review has made me realise once again that this was a mistaken view. I would like to thank the authors. I believe this review is well worth reading for many clinicians, as it provides an excellent summary of the nature of this virus and the current state of research. I hope that, in the future, chimeric vaccines—particularly those that can be co-administered with influenza vaccines—will be brought into practical use. This is because vaccines based on attenuated strains, unlike those based on multiple components such as mRNA, have multiple valences, making it difficult for resistant strains to emerge.
I have a few concerns regarding the R0 or Re of this virus. I wondered whether these had been measured accurately.
295 F gene of 295 HMPV shows a relatively stable evolutionary rate
Firstly, this is a very interesting phenomenon. This is because, in the influenza virus, all ORFs evolve at roughly the same rate. https://www.nature.com/articles/s41598-019-55254-z. Similarly, the fact that multiple strains circulate simultaneously is quite different from influenza or COVID-19, which is also interesting. I believe this phenomenon suggests that this virus infects only a very small proportion of the population. For example, with influenza or COVID-19, an outbreak is almost always caused by a single strain.
This phenomenon contradicts Figure 2, which assumes that R0 is similarly high.
Incidentally, as R0 is a mathematically unstable value, it is considered difficult to determine with precision.
https://www.mdpi.com/2673-8112/4/2/12
Or perhaps the values in Figure 2 are inaccurate (the figures for influenza and COVID-19 seem somewhat low). Should we not also re-examine the transmissibility of HMPV? It is rather difficult to imagine a situation where multiple highly transmissible viruses circulate simultaneously.
I would appreciate it if you could discuss this point. That is all from me. As this is a paper that will be of benefit to many readers, I hope it will be published without undue delay.
Response: Thank you for your insightful and thought-provoking comments. We greatly appreciate your careful evaluation of the epidemiological aspects of HMPV, particularly regarding transmissibility and the interpretation of Râ‚€.
The values presented in Figure 2 were derived from previously published studies, including epidemiological observations reported by Hacker et al. 2022 HMPV Nicaragua study and summarized in recent reviews such as Cureus 2025 HMPV review. However, we fully agree with the reviewer that precise estimation of Râ‚€ for HMPV remains challenging and that available data are limited and context-dependent.
We acknowledge that, unlike influenza or SARS-CoV-2, HMPV often exhibits co-circulation of multiple genotypes, which may reflect complex epidemiological dynamics including partial immunity, regional variability, and differing evolutionary pressures. As correctly pointed out, this pattern may not align with assumptions of uniformly high transmissibility and highlights the limitations of directly comparing Râ‚€ values across respiratory viruses.
To address this important point, we have revised the manuscript as follows:
- Clarified that the Râ‚€ values presented in Figure 2 are approximate and derived from limited epidemiological data rather than robust modeling studies.
- Added a discussion emphasizing the uncertainty and variability in Râ‚€ estimation for HMPV.
- Revised the figure legend to explicitly state that these values should be interpreted with caution and are intended for general comparison rather than precise quantification.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Author,
Thank you for revising the manuscript. If possible, please add more recent citations to support your statements throughout the manuscript.
Author Response
Comment: Thank you for revising the manuscript. If possible, please add more recent citations to support your statements throughout the manuscript.
Response: Thank you for your valuable suggestion. We appreciate the importance of supporting statements with the most up-to-date evidence. In response, we have carefully reviewed the manuscript and incorporated several recent references throughout the text to strengthen and update the scientific support for our statements. The revised sections are now supported with current literature where appropriate. We believe these additions improve the accuracy and relevance of the review, and we are grateful for your constructive feedback, which helped enhance the quality of the manuscript.
