Interest of proton pump inhibitors in reducing the occurrence of COVID-19 : a 1 case-control study 2

8 Background: COVID-19 is a disease of the elderly as 95% of deaths related to COVID-19 occur in 9 people over 60 years of age. Despite the urgent need for a preventive treatment there are currently 10 no serious leads, other than the vaccination. 11 Objective: To find a preventive treatment of COVID-19 in elderly patients. 12 Design: Retrospective case-control study. 13 Setting: Robertsau Geriatric Hospital of the University Hospitals of Strasbourg, France. 14 Patients: 179 elderly patients who had been in contact with the SARS-CoV-2, of whom 89 had tested 15 RT-PCR-positive (COVID-pos) for the virus and 90 had tested RT-PCR-negative (COVID-neg). 16 Measurements: Treatments within 15 days prior to RT-PCR (including antihypertensive drugs, 17 antipsychotics, antibiotics, nonsteroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), 18 paracetamol, anticoagulant, oral antidiabetics (OADs), corticosteroids, immunosuppressants), 19 comorbidities, symptoms, laboratory values, and clinical outcome were all collected using the 20 electronic patient record. 21 Results: COVID-pos patients more frequently had a history of diabetes (P=.016) and alcoholism 22 (P=.023), a lower leukocyte count (P=.014) and a higher mortality rate– 29.2% versus 14.4% – 23 (P=.014) when compared to COVID-neg patients. Patients on PPIs were 2.3 times less likely (odds 24 ratio [OR] = 0.4381, 95% confidence interval [CI] [0.2331, 0.8175], P=.0053) to develop COVID-19 25 infection, compared to those not on PPIs. No other treatment decreased or increased this risk. 26 COVID-19 patients on antipsychotics (P=.0013) and OADs (P=.0166) were less likely to die. 27 Limitations: retrospective study. 28 Conclusion: PPIs treatment lowered the risk of development of COVID-19 infection, and 29 antipsychotics and OADs decreased the risk of mortality in geriatric patients. If further studies 30 confirm this finding, PPIs could be used preventatively in the elderly in this pandemic context. 31 Moreover, OADS and antipsychotics should be tested in clinical trials. 32


38
In November 2019, Wuhan city in China became the centre of an outbreak of pneumonia due to a 39 novel coronavirus (SARS-CoV-2). This disease was named coronavirus disease 2019 (COVID-19) in 40 February 2020 by the World Health Organization (WHO). 1 COVID-19 is far more dangerous for people 41 aged over 60, with a death rate of 3.6% between 60 and 69 years, 8.0% between 70 and 79 years and 42 14.8% after 80 years -and, according to Italian statistics, over 20% after 90 years -, compared to 43 2.3% in the general population. 2,3 According to WHO, in Europe, 95% of deaths related to  have occurred in people over 60 years of age; 4 the median age of death for 18176 Europeans was 80 45 years (range: 24-105). 4 Furthermore, 91% of deaths occurred in patients with at least one underlying 46 condition: cardiovascular disease (42%), diabetes (20%), renal disease (17%), malignancy (17%), 47 neurological disease including dementia (14%), and lung disease (11%). 4 Chinese data have 48 confirmed that most of the elderly patients who died had multiple comorbidities, and in particular 49 cardiovascular disease (10.5% mortality), diabetes (7.3%), chronic respiratory disease (6.3%) and 50 hypertension (6%). 2 In the United States, obesity appears to be an additional risk factor to other co-51 morbidities. 5 COVID-19 is therefore an eminently geriatric disease, i.e., it most strongly affects the 52 elderly with multiple comorbidities. 53 To date, there are no data on treatments that can prevent the development of particularly 54 in the elderly, who are the group most at risk. Therapeutic vaccine trials have begun but even if they 55 are effective, with a favourable risk-benefit balance it is unlikely that we will have access to these 56 vaccines for at least a year. 6 By then, COVID-19 will have caused major morbidity and mortality. 57 Passive antibody administration through transfusion of convalescent plasma could be a strategy of 58 great interest, but with many challenges. 7 These limitations are regulatory, logistical and scientific, 59 covering donor eligibility, donor recruitment, collection and transfusion, but also the demonstration 60 of its effectiveness in the elderly population. Thus, a curative rather than a preventive use appears to 61 be more feasible. 7 62 Treatments commonly used in the elderly may have a protective effect against COVID-19. Thus, 63 angiotensin 2 AT1 receptor antagonist (angiotensin II receptor blockers [ARBs]) could be of interest 64 to treat or prevent COVID-19. 8 COVID-19 uses ACE2 as a receptor, a modulator of the activity of 65 different angiotensins (I, II and A). The COVID-19-ACE2 interaction increases the activity of 66 angiotensin and thus increases the activity of the AT1 receptor, which results in increased pulmonary 67 vascular permeability and therefore contributes to lung injury. Thus, ARBs could be a protector 68 against lung injury due to SARS-CoV-2, by inhibiting AT1 receptor. 9 Another avenue of potentially 69 preventive or curative drugs is lysosome-targeted drugs, such as antibiotics, nonsteroidal anti-70 inflammatories (NSAIDs), and proton pump inhibitors (PPIs). 10,11 71 In order to look for a treatment that could prevent the development of COVID-19 in elderly patients, 72 we studied the treatments that elderly hospitalized patients were taking before they were tested for 73  We investigated which treatments taken regularly in the 15 days prior to the first swab could have a 87 preventive effect on the disease by analysing the risk associated with each drug. We also looked at 88 the effect of these treatments taken beforehand on survival. If a treatment with an effect on survival 89 was found, we checked whether this treatment was also taken after the first RT-PCR. norepinephrine reuptake inhibitors, tetracyclic, tricyclic), antipsychotics (risperidone, olanzapine, 110 quetiapine, clozapine, haloperidol), anxiolytics (benzodiazepine, zopiclone, zolpidem), anti-epileptics, 111 antibiotics, L-thyroxin, NSAIDs, PPIs, paracetamol, antiplatelet therapies, anticoagulants, oral 112 antidiabetics (OADs), insulin, corticosteroids (oral or inhaled), immunosuppressants, and potassium, 113 were compared between SARS-CoV-2 RT-PCR-positive (COVID-pos) and RT-PCR-negative patients 114 (COVID-neg transcript was used for relative quantification. The RT-PCR is specific for SARS-CoV2 and assay 127 sensitivity is around 10 copies/reaction. 128

Statistical analysis 129
The Statistical Package for Social Sciences software (SPSS ver. 22.0.0.0) was used for demographic 130 and clinical data. Differences in these data were assessed using parametric t-tests and for categorical 131 measures χ 2 tests were applied. For each test statistic, a probability value of <0.05 was regarded as 132 significant. 133 For exhibiting treatment effect on the probability to have positive RT-PCR, Logistic regression models 134 were used, estimated with Bayesian techniques (McMC, Markov chains and Monte Carlo integration 135 in R statistical software) with the prior assumption that the probabilities of positive RT-PCR in the 136 absence of treatment and in the presence of treatment were of the order of 0.50. The same kind of 137 model was used with aim to study the treatment impact on mortality adjusting on RT-PCR status. 138 For posterior summaries, median and symmetric 95% credible intervals were retrieved, and the 139 posterior probability for a parameter to be negative (or positive) was use as a similar quantity than 140 the frequentist p-value. 141

Role of funding source 142
There was no funding source. COVID-neg). COVID-pos patients more frequently had a history of diabetes (P=.016) and alcoholism 152 (P=.023), a higher frequency of viral compatible symptoms -particularly cough and asthenia -153 (P<.0001), a lower leukocyte count (P=.014) and a higher mortality rate (29.2%) when compared to 154 COVID-neg patients (14.4%) (P=.014). The median length of stay at the hospital site was 8 weeks (SD 155 82 weeks; minimum=2 weeks, maximum=658 weeks). The median time from hospital entry to SARS-156 CoV-2 testing was 27 days (SD 567 days; min=0 day, max=576 days). One hundred and twenty-seven 157 patients (70.9%) had already been hospitalized for more than 8 days by the time they were tested. 158 The median length of follow-up after first SARS- of patients' families, were prohibited. This nosocomial contamination is likely also related to the low 218 use of masks upstream of the contagion, at the beginning of the pandemic in France as there were 219 insufficient stocks, 21 as well as to the lack of mass testing capability in France, 22 and more generally 220 to the inexperience and denial of the French population in the face of such a pandemic in its early 221 stages. 222 The two co-morbidities that were significantly more common than the others in our COVID-pos 223 patients were diabetes and chronic alcoholism. Both diseases decrease immune capacity and 224 promote infections, 23,24 which is entirely consistent given the context. The mortality rate in our study 225 was particularly high: in our geriatric hospital, COVD-19 has doubled the patient mortality rate. First, 226 the mortality rate for COVID-neg patients, which was 14.4% (over the month and a half of the study), 227 was close to the mortality rate in the follow-up and rehabilitation units of the HUS geriatric hospital 228 in 2017, which was 10% (unpublished data). COVID-pos patients had a mortality rate of 29.2%, which 229 was equivalent to the data in residential institutions for dependent elderly people (EHPAD or 230 retirement homes) in France where the mortality rate described is 25 to 33% (unpublished data). In 231 the same way in Italy and in China, the mortality rate is reported to have reached 34.5% in elderly 232 people. 25 233 We have demonstrated also that OADs seem to diminish the mortality of elderly patients with 234 COVID-19. Recent research analysed the interaction between SARS-CoV-2 proteins and human 235 proteins. 26 It appears that SARS-CoV-2 proteins probably interact with the mTORC1 (mammalian 236 target of rapamycin complex 1) pathway. 26 Metformin, which was the main OAD used in our diabetic 237 COVID-pos patients (83.3%), is an indirect inhibitor of mTORC1, and thus could explain the potential 238 interest of metformin against  Antipsychotics also decreased COVID-pos patient 239 mortality: none of the 12 COVID-pos patients on antipsychotics died. As early as 1975, the first 240 findings of the antiviral properties of antipsychotics were reported, first clinically, with the massive 241 decrease of recurrences of genital herpes infections under chlorpromazine, and then biologically. 27 242 Thus, phenothiazine and thiothixene compounds inhibit the replication of HSV 1 and 2, tick-borne 243 encephalitis virus, Epstein-Barr virus, and measles virus. 28 Haloperidol increases cell survival in the 244 context of retroviral infection. 29 In the same way, it has been demonstrated that the metabolites of 245 clozapine, a so-called atypical antipsychotic, inhibit the replication of human immunodeficiency virus 246 type 1. The discovery of these two types of therapeutic classes (OADs and antipsychotics) should 247 encourage us to test some of these drugs in therapeutic trials. We have therefore started a trial 248 called COVID-Aging, dedicated solely to the elderly: this trial is adaptive, so that we will be able to 249 include such drugs if one of the first drugs (hydroxychloroquine, azithromycin, or telmisartan) is 250 inconclusive as to its potential to improve patient survival. 251 This study has methodological limitations. First, it was retrospective. Nevertheless, the fact that all 252 data were accessible on professional medical software made it possible to better guarantee the 253 completeness of the data. The second limitation concerns the use of RT-PCR: its sensitivity is most 254 likely excellent, but the timing and depth of swabbing are limitations of this technique. To overcome 255 this, the swabs were repeated in the COVID-neg group and when possible, a chest CT scan was 256 performed. In only one case among 20 in the COVID-neg group was the CT scan consistent with 257 COVID-19 infection. 258

259
Here we have shown for the first time that some specific treatments frequently used in the elderly in 260 a geriatric context could have a preventive or curative effect. On the preventive side, PPIs seem to 261 reduce the risk of infection with COVID-19 in a highly contagious context. Therefore, it seems 262 important to keep patients on PPIs, including those taking them for no obvious reason, awaiting 263 further studies in this area. On the curative side, OADs and antipsychotics seem to have beneficial 264 effects on patient survival. In the latter case, it is obviously necessary for therapeutic trials to be 265 carried out, and this must be done quickly in view of the major mortality rate in the elderly. Our 266 finding regarding PPIs needs to be confirmed by further studies. If this were the case, PPIs would be 267 very good candidates in view of their safety profile. 268 269

Declaration of interests 270
We declare no competing interests. 271

Data sharing 273
After publication, the data will be made available to others on reasonable requests to the 274 corresponding author. A proposal with detailed description of study objectives and statistical analysis 275 plan will be needed for evaluation of the reasonability of requests. Additional materials might also be 276 required during the process of evaluation. Deidentified participant data will be provided after 277 approval from the corresponding author. 278 279 280 Acknowledgements 281 We thank all patients and their families involved in the study, and all the staff of the Robertsau 282 Geriatric Hospital in contact with patients, including interns, medical students, nurses, 283 physiotherapists, psychologists, nurses' aides, housekeepers, as well as the hospital's support teams. 284 We also thank Nick B.    The columns indicate the frequency of treatment in the sample, the odds-ratio -OR-(multiplication of the risk of COVID-19 when the patient has the treatment, as an a posteriori median and its 95% credibility interval), the estimated frequency of COVID-19 without treatment (median and 95% CI), the estimated frequency of COVID-19 with treatment (median and 95% CI) and the probability that the difference between the two frequencies ("with" and "without") is positive.