Reviewer #2 (Public Review): Stratification of viral shedding patterns in saliva of COVID-19 patients
Hyeongki ParkRaiki YoshimuraShoya IwanamiKwang Su KimKeisuke EjimaNaotoshi NakamuraKazuyuki AiharaYoshitsugu MiyazakiTakashi UmeyamaKen MiyazawaTakeshi MoritaKoichi WatashiChristopher B. BrookeRuian KeShingo IwamiTaiga Miyazaki
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Abstract:
Living with COVID-19 requires continued vigilance against the spread and emergence of variants of concern (VOCs). Rapid and accurate saliva diagnostic testing, alongside basic public health responses, is a viable option contributing to effective transmission control. Nevertheless, our knowledge regarding the dynamics of SARS-CoV-2 infection in saliva is not as advanced as our understanding of the respiratory tract. Here we analyzed longitudinal viral load data of SARS-CoV-2 in saliva samples from 144 patients with mild COVID-19 (a combination of our collected data and published data). Using a mathematical model, we successfully stratified infection dynamics into three distinct groups with clear patterns of viral shedding: viral shedding durations in the three groups were 11.5 days (95% CI: 10.6 to 12.4), 17.4 days (16.6 to 18.2), and 30.0 days (28.1 to 31.8), respectively. Surprisingly, this stratified grouping remained unexplained despite our analysis of 47 types of clinical data, including basic demographic information, clinical symptoms, results of blood tests, and vital signs. Additionally, we quantified the expression levels of 92 micro-RNAs in a subset of saliva samples, but these also failed to explain the observed stratification, although the mir-1846 level may have been weakly correlated with peak viral load. Our study provides insights into SARS-CoV-2 infection dynamics in saliva, highlighting the challenges in predicting the duration of viral shedding without indicators that directly reflect an individual's immune response, such as antibody induction. Given the significant individual heterogeneity in the kinetics of saliva viral shedding, identifying biomarker(s) for viral shedding patterns will be crucial for improving public health interventions in the era of living with COVID-19.Keywords:
Viral Shedding
2019-20 coronavirus outbreak
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Combination Casirivimab and Imdevimab and Development of Symptomatic COVID-19 in SARS-CoV-2 Infection
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histological and immunostaining of skin biopsies of seven cases of 'epidemic chilblains' with negative SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) testing and repeated serology was similar to those of a historical series of 11 cases of chilblains lupus, notably for high expression of CD123 and MxA [a type-I interferon (IFN-I)-induced protein] in both groups. 3Thus, they hypothesized that chilblains observed during the COVID-19 outbreak are linked to a high IFN response to SARS-CoV-2, leading to both negative RT-PCR and serology due to this effective antiviral response and that development of chilblains is due to IFN production.Their hypothesis is notably based on recent publications showing that impaired IFN response is observed in patients who are critically ill with COVID-19. 4,5ven though we agree that it cannot be absolutely excluded, there is no evidence that their reported cases without RT-PCR or serological confirmation are really related to the infection.In our series, where most cases were negative for SARS-CoV-2 both by PCR and serology, it is highly unlikely that they are false-negatives as serology was performed an average of 3 weeks after the onset of manifestation.Secondly, their hypothesis warranted further exploration, notably to confirm the high IFN production in patients with chilblains and negative serology and PCR.Testing of IFN levels was performed in blood samples in two patients in our series and showed a low level of IFN production.In addition, to extrapolate that high IFN production would lead to negative PCR and serology, starting from the findings that profoundly impaired IFN-I response characterized by low interferon production is observed in critically ill patients, is a very speculative hypothesis.Indeed, such high IFN response could be expected to cause other clinical manifestations in addition to chilblains.Finally, it was previously shown that CD123 immunostaining is not different between chilblain lupus erythematosus and idiopathic chilblains. 6So, the fact of observing this expression in 'epidemic chilblain' is not an argument for attributing them to SARS-CoV-2.We also observed in five cases a high expression of CD123 in patients with negative serology and without any associated infectious signs.
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Several skin manifestations have been described in association with the COVID-19 pandemic since March 2020. Acral chilblain-like lesions (CBLL), usually referred to as 'COVID toes', are among the most common and characteristic ones, even though the direct causative role of SARS-CoV-2 has been debated. Indeed, although some authors have reported the detection of SARS-CoV-2 within the lesions with immunohistochemistry and electron-microscopy,1, 2 the majority of patients with CBLL have had negative tests for SARS-CoV-2 (including serological tests and nasopharyngeal and in situ-skin PCR).3 A more likely hypothesis for the causation of CBLL in the setting of the COVID-19 pandemic is the development of a high interferon response to the virus, leading to a very efficient antiviral response and the development of CBLL, similar to the scenario observed in type 1 interferonopathies.4, 5 The recent observations of CBLL following anti-SARS-CoV-2 vaccination in patients with no COVID-19 infection6, 7 support this hypothesis. We present a new case of CBLL that developed shortly after vaccination with the BNT162b2 mRNA COVID-19 vaccine and discuss the significance of this and similar observations from the literature. An 82-year-old non-smoker woman had a history of psoriasis and had been treated with methotrexate for more than 10 years. She had no history of chilblains or Raynaud's syndrome. She denied any symptoms suggestive of COVID-19 since the beginning of the pandemic and had not been in contact with patients suffering from COVID-19. She consulted urgently in our department for slightly painful lesions on both hands and feet that occurred 24 h after the first injection of the BNT162b2 mRNA vaccine. Physical examination revealed macular violaceous and erythematous lesions of the fingers and toes, suggestive of CBLL (Fig. 1). The patient reported neither general symptoms nor unusual exposure to cold. Laboratory workup yielded normal results, concerning namely markers of inflammation, renal and hepatic function and tests for autoimmunity (antinuclear antibodies, cryoglobulinaemia, complement levels, D-dimers). Histological examination of a skin biopsy taken from a lesion of the hand showed a characteristic aspect of CBLL,8 including namely a partly necrotic epidermis overlying a dense dermal lymphocytic infiltrate forming rather well-circumscribed aggregates around blood vessels, eccrine sweat glands and occasionally nerves (Fig. 2). The endothelial cells of the blood vessels of the mid dermis were occasionally prominent. Direct immunofluorescence performed on a frozen skin biopsy was negative. Serological test carried out early on day 19 after the 1st vaccination dose was negative, ruling out SARS-CoV-2 infection. A specific serological test for vaccinal anti-S antibodies was also realized and proved positive (6.38 U/mL, N < 1). The interferon signature in blood was positive (10.5, N < 2.3). Skin reactions following administration of mRNA-based anti-SARS-CoV-2 vaccines have been very recently reported. They include mainly delayed large local reactions,9 reactions at the injection site and urticarial and morbilliform rashes.5 No severe reactions were associated with these skin signs. Interestingly, some cases of CBLL have also been reported within days following mRNA vaccination.6, 7 In our patient, the clinical and histological features of the lesions were indistinguishable from the CBLL observed during the first pandemic wave in 2020. The absence of prior history of chilblains and exposure to cold argue against common chilblains. The development of CBLL after mRNA vaccination in our patient and some patients reported in the literature supports the hypothesis that these lesions are triggered by the immune response to the virus and not to a direct cytopathogenic viral effect. The presence of a positive interferon signature also supports this contention. The patient in this manuscript has given written informed consent to the publication of her case details. The authors declare that they have no conflicts of interest. None.
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