key: cord-0686717-xb891utv authors: Mostaza, Jose M.; García-Iglesias, Francisca; González-Alegre, Teresa; Blanco, Francisco; Varas, Marta; Hernández-Blanco, Clara; Hontañón, Victor; Jaras-Hernández, María J.; Martínez-Prieto, Mónica; Menéndez-Saldaña, Araceli; Cachán, María L.; Estirado, Eva; Lahoz, Carlos title: Clinical course and prognostic factors of COVID-19 infection in an elderly hospitalized population date: 2020-07-27 journal: Arch Gerontol Geriatr DOI: 10.1016/j.archger.2020.104204 sha: 2ff5ededdbc5cee27e7131873851eda1bcf475d2 doc_id: 686717 cord_uid: xb891utv INTRODUCTION: Older subjects have a higher risk of COVID-19 infection and a greater mortality. However, there is a lack of studies evaluating the characteristics of this infection at advanced age. PATIENTS AND METHODS: We studied 404 patients ≥ 75 years (mean age 85.2 ± 5.3 years, 55% males), with PCR-confirmed COVID-19 infection, attended in two hospitals in Madrid (Spain). Patients were followed-up until they were discharged from the hospital or until death. RESULTS: Symptoms started 2 to 7 days before admission, and consisted of fever (64%), cough (59%), and dyspnea (57%). A total of 145 patients (35.9%) died a median of 9 days after hospitalization. In logistic regression analysis, predictive factors of death were age (OR 1.086; 1.015-1.161 per year, p = 0.016), heart rate (1.040; 1.018-1.061 per beat, p < 0.0001), a decline in renal function during hospitalization (OR 7.270; 2.586-20.441, p < 0.0001) and worsening dyspnea during hospitalization (OR 73.616; 30.642-176.857, p < 0.0001). Factors predicting survival were a female sex (OR 0.271; 0.128-0.575, p = 0.001), previous treatment with RAAS inhibitors (OR 0.459; 0.222-0.949, p = 0.036), a higher oxygen saturation at admission (OR 0.901; 0.842-0.963 per percentage point increase, p = 0.002), and a greater platelet count (OR 0.995; 0.991-0.999 per 10(6)/L, p = 0.025). CONCLUSION: Elderly patients with COVID-19 infection have a similar clinical course to younger individuals. Previous treatment with RAAS inhibitors, and demographic, clinical and laboratory data influence prognosis. During the last few months, a pandemic of COVID-19 infection has spread worldwide. Spain has been one of the most affected countries, with more than 200,000 infected subjects and 27,000 deaths registered until the middle of May 2020. Madrid is one of the Spanish regions with the highest population density, and the one with the greatest number of confirmed cases. A few studies have defined the characteristics of those subjects most prone to COVID-19 infection (Guan W et al: Richardson et al) , and the natural course of this disease (Zhou F et al) . However, although older patients are the most vulnerable segment of the population in this pandemic (Guan W, Richardson S et al) , there is a lack of detailed descriptions of the natural progression of this disease in the elderly (Niu S et al) . Moreover, although COVID-19 infection affects all age groups, the majority of deaths have been among elderly people, and it is not known whether risk factors associated with a worse prognosis in younger persons, (Zhou F et al) are also present in the older ones. The objective of the present study was to investigate the clinical course of infection in subjects 75 years or older admitted in two hospitals in Madrid (Spain), and to analyse factors that may contribute to mortality. Retrospective cohort study in patients aged 75 or older, with a PCR confirmed diagnosis of COVID-19 infection, admitted to either Carlos III or Cantoblanco Hospitals (Madrid, J o u r n a l P r e -p r o o f Spain), between March 1 st , 2020 to April 21 st , 2020 and discharged by May 10 th . During these dates, only COVID-19 infected subjects were hospitalized in these Centers. Both are tributaries of La Paz Hospital, and they only attended subjects with no indication for ICU admission. Demographic, clinical, laboratory, treatments, and outcome data were obtained through manual revision of the Hospital's clinical charts and were anonymized before their inclusion in the database. We selected those treatments that have previously reported to influence the clinical course of COVID-19 infection (statins, ACE inhibitors, Angiotensin II receptor blockers, anticoagulants, and antiplatelet drugs), or those that could theoretically influence its prognosis (steroids and/or immunosuppressive treatment). Blood analysis and a chest x-ray were routinely obtained at admission. Fever was defined as a temperature >37.5ºC. Worsening dyspnea was considered if, during hospital admission, there was a respiratory failure that required an increased in the administered FiO2. We calculated the ratio of pulse oximetric saturation/ fraction of inspired oxygen (SpO2/FiO2) in all patients (Rice TW et al) . Diagnosis of acute respiratory distress syndrome (ARDS) and their stages were considered according to the Berlin definition, after excluding congestive heart failure (ARDS task force). J o u r n a l P r e -p r o o f A decline in renal function was considered if creatinine level increased 1.5 times from the one obtained at admission. Hypotension was considered if blood pressure dropped below 90/60 mmHg in two consecutive occasions at least 8-hours apart. The continuous variables with a normal distribution are presented as mean ± standard deviation. Non-normally distributed continuous variables are reported as median (IQR). Symptoms started 2 to 7 days before admission, and consist in fever, cough, and dyspnea, and less frequently, diarrhea (17.3%), nausea and vomits (10.1%), nasal congestion (4.7%), and odynophagia (3.2%). Mortality rate was greater in males, and in subjects with a shorter period of symptoms, presence of fever and dyspnea, and a lower oxygen saturation at admission. Laboratory findings predictive of a worse outcome were a higher concentration of neutrophils, ALT, AST, LDH and C reactive protein (CRP), and in those with a lower lymphocyte and platelet count. During hospitalization, 43% of the participants had aggravation of their dyspnea, 37.6% developed ARDS, 13.1% had a decline in their renal function, and 24% a drop in their blood pressure below 90/60 mmHg. Of those with severe exacerbation of dyspnea (StO2/FiO2 <100), 81.2% died. The percentage of deaths was 27.3% when the deterioration was moderate (StO2/FiO2 100-200), 12.1% when it was mild (StO2/FiO2 200-300), and only 4.1% when patients did not have dyspnea exacerbation (StO2/FiO2 >300). At hospital admission, the factors associated with an increased mortality in the multivariate analysis were (table 2) , an older age, a shorter duration of symptoms before hospitalization, a faster heart rate, and higher levels of CRP. Factors associated with survival were a female sex, previous treatment with RAAS inhibitors, a higher oxygen saturation in the emergency ward and a higher platelet count. In order to further explore the association between RAAS inhibitors treatment and mortality, we performed a full adjusted model multivariate analysis, including all previously reported comorbidities associated with COVID-19 mortality and with RAAS inhibitors treatment (hypertension, diabetes, ischemic cardiovascular disease, congestive heart failure and chronic renal failure). The OR of mortality associated with the use of RAAS inhibitors remained significant (OR 0.61;95%CI 0.37-0.98). During hospitalization, factors associated with an increased mortality were dyspnea aggravation, the development of ARDS, a decline in renal function and a drop in bloodpressure below 90/60 mmHg (table 1) . We performed a second stepwise logistic regression analysis to evaluate the effect of both, prehospitalization and hospitalization factors on mortality (table 2) . Overall, older age, male sex, a lower oxygen saturation at admission, a faster heart rate, a lower platelet count, and worsening dyspnea and declining renal function during hospitalization were associated with a worse outcome. Subjects taking RAAS inhibitors before admission had a lower mortality rate. (Zhou et al) . Symptoms start 2 to 7 days before admission, generally with fever and cough, and are followed by shortness of breath, which brings the patient to the Hospital. Three to seven days after admission (7 to 13 after the initiation of symptoms), many patients may develop respiratory failure, progressing to ARDS, and death. It must be considered that our population consists of hospitalized patients, and for that reason of subjects with a more severe infection. The proportion of deaths was 36%, much higher than the observed in China (Niu S et al; Guan W et al) and lower than the reported in United States (Richardson S et al) for the same age ranges. There are no clear explanations for these differences, except for race or the threshold severity required for hospitalization. As previously indicated, younger patients were not transferred to our Hospitals, and remained in La Paz Hospital. The mortality rate for these younger subjects were, 0.5% for those below 40 years, 1.5% for those 40 to 49 years, 3.8% for those 50 to 59 years, and 11% for those 60 to 69 years (Borobia AM et al). As previously reported, women also had a lower mortality than men in this elderly population. Although the reasons for this gender difference are unknown, it has been suggested that males and females differ in their immunological responses and in their susceptibility to infection (Klein SL et al) . finding that could be explained by a greater contact of these subjects with the health system, increasing their risk of exposure to the virus. They also suggest that patients with these comorbidities may have a greater risk of death (Mancia G et al) . Our data do not support that some previously reported comorbidities influence the outcome of elderly patients. COVID infection severity is related to age (Richardson S et al, Guan W et al) , and older subjects have an increased prevalence of different comorbidities, i.e. COPD, hypertension, cardiovascular disease, congestive heart failure, arrhythmia, and/or diabetes. Some studies that have found a relationship between comorbidities and COVID mortality, did not controll by age (Richardson S et al, Guan W et al) or have found that this relationship disappears after age adjustment (Zhou F et al) . Aside from male sex, we found that previous treatment with RAAS inhibitors was associated with a better prognosis. SARS CoV-2 enters the cell through the angiotensinconverting enzyme 2 (ACE2). It has been postulated that the use of RAAS inhibitors may up-regulate its tissue expression, favoring the virus infectivity (Sommerstein R et al) . Despite this, there is no clinical data suggesting a causal relationship between the use of RAAS inhibitors and increased infectivity or a worse prognosis. Moreover, some authors have suggested that there are theoretical actions of RAAS inhibition that could lead to a better outcome (Kuster et al) . In fact, several epidemiological studies demonstrate that this relation looks spurious (Mancia et al, Reynolds HR et al) . We found that the use of RAAS inhibitors reduces mortality even after adjusting for age, sex, hypertension, and other comorbidities associated with a greater use of these drugs. No other treatments did modify the prognosis. The potential benefit of RAAS inhibitors J o u r n a l P r e -p r o o f on survival should be confirmed in clinical trials, as our study cannot assume a cause and effect relationship. We also observed that a sudden initiation of symptoms, a higher prevalence of fever and dyspnea, a lower oxygen saturation at admission, and an increased inflammatory reaction, with higher levels of inflammatory markers, and with a lower platelet count, were associated with a poorer outcome. Probably, all these factors identify a subgroup of the infected individuals with an abrupt and dysfunctional immune response to disease progression, that leads to organ failure and death (Qin et al) . The amplified inflammatory response against the viral infection, may allow researchers to explore potential therapeutic interventions that target immunoregulation (Tay MZ et al) , Our study has some limitations. Only patients with a more severe disease, requiring hospitalization, were included. Some important data were not collected due to their poor consistency, like smoking habit and weight. And some important variables, like LDH or D-dimer, were not included in the multivariate analysis because they were measured in a limited number of patients. However, the advantage of the present study is the homogeneous sample, with a complete manual collection of data and follow-up of the population. We conclude that elderly patients with COVID-19 infection have a similar clinical course to younger individuals. Factors associated with an increased mortality were older age, male sex, an abrupt onset of symptoms, a greater inflammatory reaction, and the development of ARDS, renal failure or a blood pressure fall during admission. Treatment with RAAS inhibitors before admission was associated with a better outcome. Results are for 370 patients with a complete set of variables. *Variables included in the model were age, gender, Charlson Comorbidity Index, previous treatment with RAAS inhibitors, duration of symptoms before admission, presence of fever, heart rate, oxygen saturation at admission, lymphocyte count, neutrophil count, platelet count, and blood concentration of ALT, CRP and creatinine. **Variables included in the model were the same as before plus worsening dyspnea, decline renal function and hypotension during hospitalization. Clinical Characteristics of Coronavirus Disease 2019 in China Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19 and the Northwell COVID-19 Research Consortium. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinica characteristics of older patients infected wit COVID-19: A descriptive study National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network. Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS Acute Respiratory Distress Syndrome: The Berlin Definition A cohort of patients with COVID-19 in a major teaching hospital in Europe Sex differences in immune responses. Women have stronger innate and adaptive immunity and greater resistance to viral infections than men Aldosterone System Blockers and the Risk of Covid-19 COVID-19): Do Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Have a Biphasic Effect? SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Dysregulation of immune response in patients with COVID-19 in Wuhan, China The trinity of COVID-19: immunity, inflammation and intervention DBP= Diastolic blood pressure. LDH=Lactate dehydrogenase. RAAS= renin angiotensin aldosterone system The authors thank all patients who participated in the study.J o u r n a l P r e -p r o o f