Review for 10.1186/s12876-023-03052-3 (2023)

Title: Endoscopic and histopathological hints on infections in patients of common variable
immunodeficiency disorder with gastrointestinal symptoms
Version: 3 Date: 31 Aug 2023
Reviewer's report:
Xiaoqin Li et al present their  clinical, endoscopic and biopsy findings in  those 21 of in total
87 CVID patients visiting Peking Union Medical College Hospital during 20 years (2000-2020)
and with available endoscopic findings.
Their findings differ strongly from published, larger, similar cohorts (usually from Europe or
North America, referenced  in the article). The percentage of patients with villous atrophy is very
high indeed, while inflammatory bowel diseases and liver or biliary diseases seem surprisingly
rare. Associations of NLH and infections have been sought previously yet not found. However,
the finding here might well not only be coincidental but relevant to "Chinese CVID patients"
and thus worthy of a report and such a report will in future help to design further studies and
better treatment protocols in Far East.
Due to the phenotypic diagnostic criteria used, differences in end organ manifestations are
common in series from other countries outside Europe and North America (between these
continents, patients seem to present variably, but still in total surprisingly uniformly when
different regions are compared between each other). For example, cohorts from Middle East
and neighbouring countries often contain more patients with clear , overt and much earlier onset
clinical T cell deficiency than the  additinal LOCID phenotype seen in Europe and NA..
Outside appr. 15% of CVIDs with known monogenic diseases after NGS testing, the remaining
85% seem often rather sporadic (though with higher frequencies of dysgammaglobulinemia
in close relatives than in general population), this intrinsically reflects the variable patient
cohort elsewhere in the world, which end up getting the CVID label. In some Middle East
countries, patients may often even have undergone systematic and extensive NGS, yet without
a better available diagnosis than CVID even after that. Either idiopathic/sporadic  CVID
manifests differently against different polygenic backgrounds, or patients represent unknown
other monogenic defects or acquired disease states in such countries (where often CVID seems
to be much more rare in prevalence than in Europe and NA). Thus, if PAGID/ESID criteria are
used, this in not the shortcoming of authors but intrinsic to study population and used criteria.
It should be noted that the newer criteria do not seem to perform any better, i.e. these are
also phenotypic and geographic differences in what we call CVID remain. Of course, endemic
enteropathogens to the region also may play a role.
However, the authors should tell, whether they performed panels/whole exome/genome in their
clinic, whether thus known monogenic causes were excluded, and whether patients' potential
WES/WGS results were analyzed as a cohort . Since the GI manifestations they describe are
surprisingly similar between patients (unlike in most published studies, even from Middle East,
South America, Australasia and so forth), one unavoidably wonders if the CVID patients in their
cohort may actually have one or few monogenic diseases, either known or completely novel?
Studying these patients´results in NGS may help to uncover this. And reporting whether studies
were performed should be told.
Outside such intrinsic caveats one needs to understand when interpreting authors' results, the
quality of scientific English used in the manuscript is sadly below needed. Thus, native speaker
versed in medical writing should correct its language. Manuscript now  uses non-idiomatic words
(hypoalbumin >hypoalbuminemia) and incomplete/strange sentence structures, colloquialisms,
unconventional use of tenses and so forth. This will impair the impact of their manuscriptand
ability to convey their findings to scientific community.
The discussion should be shortened by at least 30%, the main limitation currently is the lack of
genetic testing or its reporting, not so the variability of criteria published. I am afraid that until
we solve the  genetic/transcriptional/epigenetic/? causes behind those 85% of sporadic CVIDs,
we are stuck with less than satisfactory CVID criteria and yet still we need to treat these patients
the best we can, irrespective of their background genetics and geographic origin.