The Importance of Secretor-Status in Norovirus Infection Following Allogeneic Hematopoietic Stem Cell Transplantation

Round 1

Reviewer 1 Report

The authors use data from a retrospective study to test whether subjects that were immunocompromised, after halogenic hematopoietic stem cell transplantation (HCT), were also susceptible to norovirus (GII.4 genotype) infection in a similar way as the general population, that is, infection is highly dependent on the secretor phenotype.

The work is merely confirmatory that the results obtained for GII.4 norovirus (dependency of norovirus infection on the secretor status) also apply to HCT patients. Although this is a minor result it has some interest, as it shows that the dependency for HBGAs of GII.4 is very high, even in a scenario where the immune system is compromised. The percentage of negative secretors in the analyzed cohort (89 patients; 8% non-secretors) was lower compared to the general population (around 20% or higher), which is already an indication about the dependency of norovirus on the secretor status. A limitation is that norovirus genotype could not be determined for all subjects, including negative secretors that were infected. The authors therefore suggest to interpret the results with caution. Although further investigations with a high number of subjects is obviously necessary to draw more solid conclusions, this is a first exploratory study that has some interest and deserves publication.

Specific points:

Four different PCR methods where used along the studied period (2006-2016) to detect and genotype norovirus. Please comment on the likely limitations of this.

Is it valid to compare Ct from samples that were analyzed during 10 years with different methods to infer the viral loads in feces?

It is said that six of the secretor-negative patients had norovirus GII infection, but genotyping was not performed. In the abstract, it is said that GII.4 was only detected in secretors. This is confusing, as not all samples (specially those of non-secretors) were genotyped.

Author Response

Dear Reviewer,

Thank you for valuable comments which has helped us to improve the manuscript. Changes in the manuscript are marked with yellow.

Our responses to your commments are presented in the attachment.

Best regards

Lisa Swartling

Author Response File: Author Response.docx

Reviewer 2 Report

Swartling etc. determined the importance of secretor-status and norovirus genotype for the susceptibility and/or the clinical course of norovirus infection in allogeneic hematopoietic stem cell transplant (HCT) patients. The authors claimed that a secretor-negative genotype protects against norovirus infection in severely immunocompromised individuals. However, the evidence in the paper is not enough to support this conclusion. For example, the mean days of norovirus symptom in the secretor-negative group was even longer than the secretor-positive group.

1. The authors stated that there are no reports of the clinical picture in relation to norovirus genotypes in immunocompromised patients. This study screened norovirus in suchpatients, but still no detailed or comprehensive information was provided in this study.
2. How many samples of the patients have been screened? Please clarify. In addition, Line 113 “89 HCT patients with norovirus infection were identified....”and line 67 “Sixty- three of the patients had been included..... ”. 89 or 63?
3. Line 83-86, What are the genes targeted by the primers？
4. Ct-value in non-secretor reach 37 (line 122). How to exclude false positives?
5. Line 158. What’s the norovirus genotype for the patient with chronic symptoms?
6. Line 183-184. These non-secretors were all norovirus positive, and they were with longer mean days of norovirus symptom. How can the authors infer this conclusion?

Author Response

Dear Reviewer,

Thank you for your valuable comments, helping us to improve the manuscript. The changes in the revised manuscript are marked with yellow.

Please see the attachment with the responses (in blue text) to you your comments.

Best regards

Lisa Swartling

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors addressed the issues raised. No more comments.