COVID-19 patient experiences in pre-hospital pathways: a processual qualitative approach using the life-events calendar method highlights diagnostic delays and healthcare renunciation. (preprint)

Background During the height of the COVID-19 pandemic in 2020, 11% of patients who were hospitalized in France were immediately admitted to intensive care. We aimed to identify and characterize the different types of primary care pathways of patients hospitalized for COVID-19 using patients’ self-reported experiences. Method We conducted a qualitative study using biographic interviews of patients who were hospitalized for COVID-19 between September 2020 and December 2021 in the infectious disease departments in Marseille and Nice. The biographical interviews used a life-events calendar approach to understand the sequences of clinical and care events prior to hospitalization. Results 31 pathways were described. Short care pathways (i.e., admission to hospital ≤ 3 days after symptom onset) were more likely to be reported by older patients and those with comorbidities. These pathways were characterized by closer GP surveillance and by sudden symptom onset and rapid progression of the disease. Long care pathways (i.e., >10 days after system onset) were reported more by younger patients with no comorbidities. Multiple tests and medical consultations returning false-negatives had led this population to doubt they had COVID-19. They were more likely to present severe symptoms requiring intensive care. The study revealed key importance of patients’ loved ones in the process of their hospitalization. Conclusion This study highlights that primary care management of COVID-19 patients needing hospitalization in France was particularly slow and detrimental to their health. It also underlines the need to improve the identification and monitoring of patients at risk of complications.

Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients treated for lymphoid malignancies (preprint)

BACKGROUND Immunocompromised patients such as patients with hematological malignancies have impaired immune response to two doses of BNT162b2 (Pfizer / BioNtech) vaccine against SARS-CoV-2. Evaluation of a repeated immune stimulation with a third vaccine dose is needed. METHODS a vaccine monitoring observatory was conducted in outpatients who were treated for lymphoid malignancies (LM) to monitor both immune and cellular response measured the day of administration of the dose 3 of the mRNA vaccine BNT162b2 and again three to four weeks. Elecsys ® Anti-SARS-CoV-2 immunoassay was used to asses to the level of SARS-CoV-2 anti-Spike (S) antibodies (Abs) titer and SARS-CoV-2-specific T-cell responses were assessed by a whole blood Interferon-Gamma Release Immuno Assay (IGRA) (QuantiFERON Human IFN-gamma SARS-CoV-2, Qiagen®). RESULTS Among the 43 assessable patients (suffering from chronic lymphocytic leukemia (CLL) (n=15), indolent and aggressive B cell non-Hodgkin lymphoma (NHL) (n=14), and multiple myeloma (MM) (n=16)), 18 (41,8%) had no anti-S Abs before the dose 3 of BNT162b2 vaccine (n=9 CLL, n=8 NHL, n=1 MM), and they all 18 remained negative after the dose 3. Amongst the 25 patients with positive anti-S titers before dose 3, all patients remained positive and 23 patients increased their anti-S titer after dose 3. Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients, dose 3 of BNT162b2 vaccine significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3. CONCLUSIONS Dose 3 of BNT162b2 vaccine stimulated humoral immune response among patients with LM, in particular patients with MM (who had higher anti-S baseline titer after dose 2) and those with no anti-CD20 treatment history within a year. T-cell response was increased among patients in particular with no active chemotherapy regimen. Our data support the use of an early third vaccine dose among immunocompromised patients followed for LM though some of them will still have vaccine failure.

Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients with lymphoid malignancies (preprint)

BACKGROUND: Immunocompromised patients such as patients with hematological malignancies have impaired immune response to two doses of BNT162b2 (Pfizer / BioNtech) vaccine against SARS-CoV-2. Evaluation of a repeated immune stimulation with a third vaccine dose is needed. METHODS: a vaccine monitoring observatory was conducted in outpatients who were treated for lymphoid malignancies (LM) to monitor both immune and cellular response measured the day of administration of the dose 3 of the mRNA vaccine BNT162b2 and again three to four weeks. Elecsys ® Anti-SARS-CoV-2 immunoassay was used to asses to the level of SARS-CoV-2 anti-Spike (S) antibodies (Abs) titer and SARS-CoV-2-specific T-cell responses were assessed by a whole blood Interferon-Gamma Release Immuno Assay (IGRA) (QuantiFERON Human IFN-gamma SARS-CoV-2, Qiagen®). RESULTS: Among the 43 assessable patients (suffering from chronic lymphocytic leukemia (CLL) (n=15), indolent and aggressive B cell non-Hodgkin lymphoma (NHL) (n=14), and multiple myeloma (MM) (n=16)), 18 (41,8%) had no anti-S Abs before the dose 3 of BNT162b2 vaccine (n=9 CLL, n=8 NHL, n=1 MM), and they all 18 remained negative after the dose 3. Amongst the 25 patients with positive anti-S titers before dose 3, all patients remained positive and 23 patients increased their anti-S titer after dose 3. Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients, dose 3 of BNT162b2 vaccine significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3. CONCLUSIONS Dose 3 of BNT162b2 vaccine stimulated humoral immune response among patients with LM, in particular patients with MM (who had higher anti-S baseline titer after dose 2) and those with no anti-CD20 treatment history within a year. T-cell response was increased among patients in particular with no active chemotherapy regimen. Our data support the use of an early third vaccine dose among immunocompromised patients followed for LM though some of them will still have vaccine failure.

Spread of the SARS-CoV-2 UK-variant in the South East of France: impact on COVID-19 patients age, comorbidity profiles and clinical presentation, week 50 2020 to week 8 2021 (preprint)

Abstract Objectives: The variant 20I/501Y.V1, associated to a higher risk of transmissibility, emerged in Nice city (South East of France, French Riviera) during January 2021. The pandemic has resumed late December 2020 in this aera. A high incidence rate together with a fast turn-over of the main circulating variants, provided us the opportunity to analyze modifications in clinical profile and outcome traits. Methods: Observational study in the University hospital of Nice from December 2020 to February 2021. We analyzed data of sequencing of SARS-CoV-2 from the sewage collector and PCR screening from all positive samples at the hospital. Then, we described the characteristics of all COVID-19 patients admitted in the emergency department (ED) (n=1247) and those hospitalized in the infectious diseases ward or ICU (n=232). Demographic data, clinical signs and severity were documented by the NEWS-2, SAPS-2 and SOFA scores were recorded and analyzed. Results: the UK-variant was absent in the area in December, then increasingly spread in January representing 59% of the PCR screening performed mid-February. The rate of patients over 65 years admitted to the ED decreased from 63% to 50% (p=0.001). The mean age of hospitalized patients in the infectious diseases ward decreased from 70.7 to 59.2 (p<0.001) while the proportion of patients without comorbidity increased from 16% to 42% (p=0.007). Neither the NEWS-2 score nor the main signs of clinical severity have changed over time. Conclusion: Spread of the UK-variant in the South East of France affects younger and healthier patients.

Spread of the SARS-CoV-2 UK-variant in the South East of France: impact on COVID-19 patients age, comorbidity profiles and clinical presentation (preprint)

Objectives: The variant 20I/501Y.V1, associated to a higher risk of transmissibility, emerged in Nice city (South East of France, French Riviera) during January 2021. The pandemic has resumed late December 2020 in this aera. A high incidence rate together with a fast turn-over of the main circulating variants, provided us the opportunity to analyze modifications in clinical profile and outcome traits. Methods: : Observational study in the University hospital of Nice from December 2020 to February 2021. We analyzed data of sequencing of SARS-CoV-2 from the sewage collector and PCR screening from all positive samples at the hospital. Then, we described the characteristics of all COVID-19 patients admitted in the emergency department (ED) (n=1247) and those hospitalized in the infectious diseases ward or ICU (n=232). Results: : the UK-variant was absent in this area in December, then increasingly spread in January representing 59% of the PCR screening performed mid-February. The rate of patients over 65 years admitted to the ED decreased from 63% to 50% (p=0.001). The mean age of hospitalized patients in the infectious diseases ward decreased from 70.7 to 59.2 (p<0.001) while the proportion of patients without comorbidity increased from 16% to 42% (p=0.007). Conclusion: Spread of the UK-variant in the South East of France affects younger and healthier patients.

Clinical performance of oral sponge sampling for detection by RT-PCR of SARS-CoV-2 (preprint)

BackgroundThe current standard for coronavirus 2019 disease (COVID-19) diagnosis is reverse transcriptase-polymerase chain reaction (RT-PCR) testing of naso-pharyngeal swabs (NPS), Sampling with NPS is invasive and requires specialized and trained personnel, which limits rapid and repeated screening for the disease. A less invasive and possibly self-administered sampling method may increase the capacity for testing and be more effective in identifying, isolating, and filtering out currently infected persons. MethodsOver a period of three months, we included volunteers presenting with recent symptoms suggestive of a SARS-CoV-2 infection at a free COVID-19 screening center in the city of Nice, France. NPS as well as nasal and oral sponges were collected in parallel and analyzed by RT-PCR for SARS-CoV-2. ResultsOne hundred and forty-seven subjects were included, of whom, 41.5% were diagnosed with COVID-19 using NPS RT-PCR. RT-PCR on nasal and oral sponges showed a sensitivity of 87 to 98% and 72 to 87%, respectively for diagnosis of COVID-19 in symptomatic subjects, depending on the type of RT-PCR technique used. The specificity was 100% whatever the RT-PCR test. The viral load determined with the oral samples was significantly lower than with NPS. ConclusionTaken together, these results demonstrated that the oral sponge sampling method can be standardized, is easy to use and cheap. The acceptability makes it a repeatable test, notably for elderly people or children. It may become a high-frequency - low analytical sensitive testing strategy. Summary of the "take home" messageOral sponge sampling for SARS-CoV2 RT-PCR, is easy to use, can be self-administered with a sensitivity of up to 87 % in symptomatic patients.

A Tale of a Two Waves Epidemic: Characteristics and Mortality Risk Factors for COVID-19 ICU Patients in the French West Indies (preprint)

Introduction Guadeloupe, a French West Indies island, has been fiercely affected by two large waves of COVID.Therapeutic approach was different between the two waves in the intensive care unit (ICU). We aimed to compare the two different periods in terms of characteristics and outcomes and to evaluate risk factors associated with 60-day mortality in our overall cohort. Methods All consecutive patients with laboratory confirmed COVID-19 pneumonia and requiring oxygen support admitted in our ICU unit of University Hospital of Guadeloupe were prospectively included. Patients were treated during the first wave with a combination of Hydroxychloroquine and Azithromycin and during the second wave with dexamethasone and reinforced anticoagulation. Results   In our cohort, 187 patients were included, 31 during the first one and 156 during the second. Patients were mostly male (69%) with a median age of 64years old. Patients tend to be younger during the second wave and body mass index was higher (respectively 31 vs 27kg/m2, p=0.01). Overall mortality at Day 60 was high (45%) and not different between the two waves. Among patients under mechanical ventilation risk factors associated with death in a multivariate analysis were a high number of comorbidities, a high level of SOFA score and the delay of invasive mechanical ventilation (IMV) onset after admission in ICU (OR=1.6 (95% CI 1.2 – 2.4). Conclusion  Although therapeutics approach evolve, COVID-19 severe pneumonia is still associated with a high mortality rate in ICU. 

Monitoring the post-containment COVID-19 crisis in Guadeloupe: Early-warning signals of destabilisation through bootstrapped probability density functions (preprint)

We propose a method to detect early-warning information in relation with subtle changes occurring in the trend of evolution in data time series of the COVID-19 epidemic spread (e.g. daily new cases). The method is simple and easy to implement on laptop computers. It is designed to be able to provide reliable results even with very small amounts of data (i.e. {approx} 10 - 20). The results are given as compact graphics easy to interpret. The data are separated into two subsets: the old data used as control points to statistically define a "trend" and the recent data that are tested to evaluate their conformity with this trend. The trend is characterised by bootstrapping in order to obtain probability density functions of the expected misfit of each data point. The probability densities are used to compute distance matrices where data clusters and outliers are easily visually recognised. In addition to be able to detect very subtle changes in trend, the method is also able to detect outliers. A simulated case is analysed where R0 is slowly augmented (i.e. from 1.5 to 2.0 in 20 days) to pass from a stable damped control of the epidemic spread to an exponentially diverging situation. The method is able to give an early warning signal as soon as the very beginning of the R0 variation. Application to the data of Guadeloupe shows that a small destabilising event occurred in the data near April 30, 2020. This may be due to an increase of R0 {approx} 0.7 around April 13-15, 2020.

Model of a Testing-and-Quarantine Strategy to Slow-Down the COVID-19 Outbreak in Guadeloupe (preprint)

Using a stochastic epidemic model explicitly considering the entire population of Guadeloupe (1), we explore the domain of solutions presenting an efficient slowing down of the COVID-19 epidemic spread during the post-containment period. The considered model parameters are the basic reproduction number R0 to simulate the effects of social distancing, the time delay {delta}TQ elapsed between the detection of a symptomatic person and her/his placement in quarantine to suppress her/his contagiousness, and the number Na of asymptomatic people tested positively and isolated. We show that acceptable solutions are obtained for a wide range of parameter values. Thanks to a good control of the initial epidemic spread resulting from an early containment and efficient communication by the sanitary and administrative authorities, the present situation corresponds to a pre-epidemic state. The most safe solutions are a combinations of social distancing, numerous testing to perform a systematic isolation of symptomatic patients and guided detection of asymptomatic people in the entourage of localised symptomatic patients.

Prediction of the time evolution of the COVID-19 disease in Guadeloupe with a stochastic evolutionary model (preprint)

Predictions on the time-evolution of the number of severe and critical cases of COVID-19 patients in Guadeloupe are presented. A stochastic model is purposely developed to explicitly account for the entire population ({approx} 400000 inhabitants) of Guadeloupe. The available data for Guadeloupe are analysed and combined with general characteristics of the COVID-19 to constrain the parameters of the model. The time-evolution of the number of cases follows the well-known exponential-like model observed at the very beginning of a pandemic outbreak. The exponential growth of the number of infected individuals is controlled by the so-called basic reproductive number, R0, defined as the likely number of additional cases generated by a single infectious case during its infectious period TI . Because of the rather long duration of infectious period (about 14 days) a high rate of contamination is sustained during several weeks after the beginning of the containment period. This may constitute a source of discouragement for people restrained to respect strict containment rules. It is then unlikely that, during the containment period, R0 falls to zero. Fortunately, our models shows that the containment effects are not much sensitive to the exact value of R0 provided we have R0 < 0.6. For such conditions, we show that the number of severe and critical cases is highly tempered about 4 to 6 weeks after the beginning of the containment. Also, the maximum number of critical cases (i.e. the cases that may exceed the hospital ' s intensive care capacity) remains near 30 when R0 < 0.6. For a larger R0 = 0.8 a slower decrease of the number of critical cases occurs, leading to a larger number of deceased patients. This last example illustrates the great importance to maintain an as low as possible R0 during and after the containment period. The rather long delay between the beginning of the containment and the appearance of the slowing-down of the rate of contamination puts a particular strength on the communication and sanitary education of people. To be mostly efficient, this communication must be done by a locally recognised medical staff. We believe that this point is a crucial matter of success. Appendix Posterior model assessment with data acquired after April 11, 2020 added in a second version of the paper compares the model predictions with the data acquired from April 12 to May 25 2020, after the construction of the model discussed in the present study. The remarkable agreement between the model predictions and the data may be explained by the good quality of first-hand data used to constrain the model, the ability of the stochastic approach to integrate new information and stability of the sanitary situation due to the respect of the recommendations emitted by medical and administrative authorities by the guadeloupean population.