{'fraction_non_alphanumeric': 0.034463794683776354, 'fraction_numerical': 0.010999083409715857, 'mean_word_length': 4.798087141339001, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Tailored combined cytomegalovirus management in lung transplantation: a retrospective analysis

Background: There is no univocal prophylactic regimen to prevent cytomegalovirus (CMV) infection/disease in lung transplantation (LT) recipients. The aim of this study is to evaluate short-term clinical outcomes of a tailored combined CMV management approach. Methods: After 1-year follow up, 43 LT patients receiving combined CMV prophylaxis with antiviral agents and CMV-specific IgG were evaluated in a retrospective observational study. Systemic and lung viral infections were investigated by molecular methods on a total of 1134 whole blood and 167 bronchoalveolar lavage (BAL) and biopsy specimens. CMV immunity was assessed by ELISPOT assay. Clinical and therapeutic data were also evaluated. Results: We found 2/167 cases of CMV pneumonia (1.2%), both in the donor-positive/recipient-positive (D+/R+) population, and 51/167 cases of CMV pulmonary infection (BAL positivity 30.5%). However, only 32/167 patients (19.1%) were treated due to their weak immunological response at CMV ELISPOT assay. Viremia ⩾100,000 copies/mL occurred in 33/1134 specimens (2.9%). Regarding CMV-serological matching (D/R), the D+/R– population had more CMV viremia episodes (p < 0.05) and fewer viremia-free days (p < 0.001). Conclusions: Compared to previous findings, our study shows a lower incidence of CMV pneumonia and viremia despite the presence of a substantial CMV load. In addition, our findings further confirm the D+/R– group to be a high-risk population for CMV viremia. Overall, a good immunological response seems to protect patients from CMV viremia and pneumonia but not from CMV alveolar replication. The reviews of this paper are available via the supplemental material section.


Did authors emphasize the efficacy of ELISPOT to investigate the CMVinfections?
R. Thank you for your comments. In CMV ELISPOT assay paragraph we included a description of CMV response status, discussing its changes and then we described it during all types of infections.

Discussion is too long. Authors must discuss concisely.
R. Thanks for the comment. We reduced the length of the discussion. Some points have been shortened and referred to the references. Discussion has been managed by topics mirroring the results 3. Non-standard division data must be expressed as median with interquartile range.
R. Thank you for the suggestion, we provided median and IQRs and we corrected tables.

Authors should show the results of ELISPOT in figure or table.
R. Thanks, we provided a new table

Why was CMV pneumonia higher incidence in D+/R+ group than that in D+/R-?
R. Thank you for your question; in our cohort we reported an incidence of pneumonia of 1% with only 2 cases and both were in D+/R+ population. This is an intresting and new result and it was worthy to be referred. These events occurred only in the first month after LTx. We think that the strong immunosuppressive regimen exposed patients to an higher risk regardless to their serostatus, with an higher incidence in the most represented population. Anyway, due to the low numbers, the low incidence in D+/R+ population and the lack of pneumonia in the D+/R-or D-/R+ population no definitive conclusion could be taken and this is one of the limits of our study. We discussed this results in discussion section of the paper. R. Thank you for your observation. In our center we administer a universal combined prophylaxis scheme with a sequential administration of antiviral drugs and CMVIG; this scheme is used regardless D/R serostatus thus D+/R-received same LTx prophylaxis scheme of others groups of patients. As regards post-LTx management of infections, we based our treatment decisions on ELISPOT evalutuation. Even in this case we considered the immune response to CMV measured with ELISPOT a better indicator then serostatus. This is partially confirmed by our results: we demonstrated that ELISPOT protected patients against CMV viremia but we hadn't same results for pulmonary infections. As regards duration of therapies we didn't find any differences among different D/R groups when we considered pulmonary infections. In case of CMV viremia, D+/Rpatients were more treated than other groups but number of days of treatment wasn't significantly higher if compared to other groups. These data are represented in Table 2 and 3.

CMV infection has indirect bad consequences to the graft and patients survival, so data referred to functional evolution and survival should be necessarily included.
R. Thank you for your comment. We agree on the importance of mortality ad functional data, both potentially influenced by CMV infections, but the one year follow-up study was not planned to evidence differences in functional data or in mortality. Indeed the different immunosuppressive therapies, acute rejections, infections different from CMV ones, ICU stay, surgical complications, comorbilities etc could jeopardize too much the results in our limited number of patients and could give wrong interpretations and conclusions. In particular with a low number of CMV pneumonia (the most important risk factor for graft damage). So, when we designed the study, we decided to avoid functional data and to focus just on infections' data. Anyway, following the reviewer's suggestion, we add data about survival of patients and mean days of survival for the 4 different groups in the text and in Table 2.