The most frequent symptoms of clinical presentation were fever, dyspnoea, and cough; hospital mortality was quite high; male sex and serum LDH level were associated with severe disease; and serum sodium concentration was associated with mortality.
Although the most frequent symptoms were the same as in the hospitalized adult population [12,18–20], they were less frequent than has been reported in this population (especially cough and fever), even though the diagnosis of respiratory infection was an inclusion criterion in our study. In general population, cohorts of Covid 19 hospitalized patients [18–20] have reported prevalence of fever and cough between 72-88% and 65-73%, respectively. On the other hand, confusion stands out as a symptom present in 11% of our sample. Gutiérrez-Rodríguez et al. and Annweiler et al. [11,21] reported frequencies similar to ours in the subgroup of patients 80 years or older. These findings are in line with those observed in the majority of diseases of this population (including infections), in which less symptomatic or atypical presentations are more frequently observed [3–5]. This reinforces the need for a lower suspicion threshold in this population, especially when evaluated in an emergency department.
A low frequency of non-respiratory symptoms was observed. However, given the absence of a systematic search for these symptoms, we cannot exclude an information bias whereby patients who reported respiratory symptoms at the beginning of the evaluation were not also asked about non-respiratory symptoms, resulting in undetected symptoms.
Prognostic factors of severe disease and mortality
Age, unlike in the younger population [2,6,22,23], did not bring an added risk in any of the models built here, and male sex was associated with severe disease but not mortality. The trials by Gutiérrez-Rodríguez et al. and Covino et al. did not find that age or sex were associated with mortality either. However, Ramos-Rincon et al. reported age and male sex as variables associated with mortality from a multicentre cohort of 2772 very old hospitalized patients so we cannot rule out a lack of statistical power of our sample in these results. Institutionalization was not included in our analysis due to the fact that the registration of this variable was not as reliable as the other included variables. Furthermore, we consider that institutionalization, in contrast to variables like chronic diseases or previous pharmacological treatments, is an external indicator instead of being an intrinsic factor of a patient. For this reason, the evaluation of institutionalization as prognostic factor (in difference to its evaluation as predictor factor) might not be recommended.
Unlike laboratory parameters and those related to emergency assessment (some of which were associated with worse prognosis), no chronic disease or previous pharmacological treatment was associated with worse or better outcomes. Previous treatments have not been evaluated as prognostic factors in the before mentioned trials[9–11] so we cannot compare our results with them. In a younger cohort, Mostaza et al., in people older than 75 years, did find a better prognosis in patients who previously took renin-angiotensin-aldosterone system antagonists. Regarding previous chronic diseases, it is remarkable that, in contrast to studies in younger populations, no chronic disease was associated with mortality. Although we cannot exclude a lack of statistical power for this result, it is similar to the study by Ramos-Rincon et al. which also did not find an association between chronic diseases and mortality (except for obesity which was significantly associated with mortality in the bivariant analysis, although it was not included in the multivariant models). In another study with a very old population, Covino et al. reported severe dementia as an independent risk factor for death, although age, since it was not apparently included in their multivariate analysis, cannot be rule out as a confounding factor.
Only the serum LDH level was associated with severe disease among laboratory parameters. We have not found studies that evaluated the factors associated with this result in the older or oldest-old population. In adult population studies, LDH is one of the most powerful factors associated with severe disease among laboratory parameters [26–29]. Thus, in the meta-analysis of Zhang et al. , LDH was the only laboratory parameter associated with both adult respiratory distress syndrome and indication for Intensive Care Unit (ICU) admission. LDH is present in body tissues and is released from damaged cells [30,31], increases lactate production , and is a good predictor of lung injury .
Serum sodium was associated with mortality in our sample. Of the aforementioned studies, Gutiérrez-Rodríguez et al.  did not find a significant association in their bivariate analysis, and Ramos-Rincon et al. and Covino et al. did not include this parameter in their reports. Below, we propose a hypothesis for this result.
Among the laboratory parameters, it stands out that the parameters associated with worse prognosis were different for severe disease and mortality, although both outcome variables are closely related. We highlight the fact that 1.1 out of every four people who died did not previously present any criteria of severe disease. Given the definition of this in our study based on strict respiratory criteria, we hypothesize that some of the patients could have died from complications in other body systems (cardiovascular, thrombotic, metabolic, and renal complications have been described ) and not so much from severe respiratory involvement. In this sense, serum sodium (a marker of metabolic alteration or renal function) would predominate as a prognostic factor for mortality and not as much for severe respiratory disease. That the association of this parameter with mortality was maintained despite adjusting the model for oxygen saturation reinforces our hypothesis.
With respect to our analyses of severe disease, we have to comment the possibility of competing risk factors when the patients died without severe disease criteria (in these patients, dead competes with the severe disease outcome). This would be significant if the proportion of patients who died without severe disease criteria would have been similar or larger than the proportion of patients with severe disease, or if the follow-up time would have been very long (more than 5 years). In our study, the proportion of patients who died without severe disease criteria (15,5%) was significantly lower than the patients with severe disease (57,3%) and the follow-up time of our cohort was very short. Thus, we consider the impact of a situation of competing risk factors insignificant or improbable in our trial.
Although the highest lethality of COVID-19 is seen in the older population, especially among the hospitalized population, the hospital mortality found in our sample was higher than that of other hospital series of oldest-old populations in Spain (35-47%). We highlight the high proportion of institutionalized patients in our sample (61%), reflecting a population with greater clinical fragility and therefore with less ability to respond to an organic stressor. Thus, the series reported by Gutiérrez-Rodríguez et al.  had a mortality (41%) and a proportion of institutionalized patients (70%) more similar to those of our sample than those reported by Mostaza et al. (mortality 35% and proportion of institutionalized 23%) . In neighbouring countries, Zerah et al. (France)  reported a lower lethality (31%) in a cohort of 821 hospitalized patients aged 70 or older, although with a proportion of institutionalized patients much lower than our sample (29%). Finally, we have to mention, in relation to the high mortality in our sample, the high pressure to which the Spanish Sanitary System was exposed during this time which might have influenced or limited the access for this population group to certain health care resources including admission to Intensive Care Units.
Regarding the extrapolation or comparison of our results with the results in other samples, it is important to consider, in addition to the high mortality and high proportion of institutionalized patients, that our patients were managed in secondary referral centres, so our results cannot be extrapolated to populations treated on an outpatient basis or in centres of maximum complexity (tertiary), such as patients undergoing organ transplants. Furthermore, in our sample only 4 patients had less than 2 chronical diseases which means that our results cannot be extrapolated to patients without significant comorbidity.
The sample size of our study does not allow us to take the results as conclusive. Some laboratory parameters (AST, ALT, ferritin, and creatinine), despite having significant associations with some of the outcome variables in the bivariate analysis, could not be included in the multivariate models due to significant data loss.
Most likely, some COVID-19 patients were already admitted with severe disease criteria. In these cases, the validity of our results regarding the variables of clinical presentation and laboratory parameters (including serum LDH level) may be affected. The sample size prevented us to perform any sensitivity analysis whereby we recognize this limitation. However, the variables of chronic diseases and previous treatments would continue to be valid in these patients because the temporal relationship remains accurate. Finally, we were unable to evaluate variables of previous functional status, a variable of known prognostic association in most diseases in this population, including COVID-19 [35,37].
In conclusion, the symptoms of clinical presentation typical of respiratory infection by SARS-CoV-2 (fever, dyspnoea, and cough) are less frequent in the oldest-old population, male sex and LDH level are associated with severe disease, and serum sodium is associated with mortality.