key: cord-0827177-h1kr5v50
authors: Rodriguez-Gonzalez, Carmen; Chamorro-de-Vega, Esther; Valerio, Maricela; Amor-Garcia, Miguel Angel; Tejerina, Francisco; Sancho-Gonzalez, Milagros; Narrillos-Moraza, Alvaro; Gimenez-Manzorro, Alvaro; Manrique-Rodriguez, Silvia; Machado, Marina; Olmedo, Maria; Escudero-Vilaplana, Vicente; Villanueva-Bueno, Cristina; Torroba-Sanz, Beatriz; Melgarejo-Ortuño, Alejandra; Vicente-Valor, Juan; Herranz, Ana; Bouza, Emilio; Muñoz, Patricia; Sanjurjo, Maria
title: COVID-19 in hospitalized patients in Spain: a cohort study in Madrid
date: 2020-11-28
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106249
sha: 2460aab777766e1c7945c126cdf15ca63f329257
doc_id: 827177
cord_uid: h1kr5v50

Few large series describe the clinical characteristics, outcomes and costs of COVID-19 in western countries. This cohort reports the first 1,255 adult cases who received anti-COVID-19 treatment at a Spanish hospital from March 1 to 24, 2020. The cost of treatment was calculated. Logistic regression model was used to explore the risk factors present on admission associated with ARDS. Bivariate Cox proportional hazard ratio model was employed to determine the hazard ratio (HR) between individual factors and death. We included 1,255 patients (median age 65 years; 57.8% male), of which 92.3% required hospitalization. Prevalence of hypertension, cardiovascular diseases and diabetes mellitus was 45.1%, 31.4%, and 19.9%, respectively. Lymphocytopenia (54.8%), elevated alanine aminotransferase (33.0%) and elevated lactate dehydrogenase (58.5%) were frequent. Overall, 36.7% of patients developed ARDS, 10.0% were admitted to an intensive care unit and 21.3% died. Most frequent antiviral combinations used were lopinavir/ritonavir plus hydroxychloroquine (44.2%), followed by triple therapy with β-interferon 1b (32.5%). Corticosteroids and tocilizumab were used in 25.2% and 12.9% of patients, respectively. The total cost of anti-COVID-19 agents was €511,825 (€408 per patient). In the multivariate analysis, risk factors associated with ARDS included older age, obesity, diabetes mellitus, severe hypoxemia, lymphocytopenia, increased creatine kinase and increased C-reactive protein. In the multivariate Cox model, older age (HR 1.07 -95%CI 1.06-1.09), cardiovascular disease (HR 1.34 -95%CI 1.01-1.79), diabetes mellitus (HR 1.45 -95%CI 1.09-1.92), severe hypoxemia (HR 2.01 -95%CI 1.49-2.72), lymphocytopenia (HR 1.62 -95%CI 1.20-2.20) and increased C-reactive protein (HR 1.04 -95%CI 1.02-1.06) were risk factors for mortality.

Spain is one of the western countries with the highest incidence of COVID-19 patients and many hospitals have suffered from an enormous healthcare overload during the present pandemic. The first case with COVID-19 was admitted in our center on March 1, 2020. Until June 1, more than 2,700 patients were admitted.

There are few medical series that describe the clinical characteristics and outcome of hospitalized patients with SARS-CoV-2 infection in western countries. Three previous cohort studies from Italy, the United Kingdom and the New York City area have reported a mortality rate of up to 26% [1] [2] [3] . In addition, the treatments for COVID-19 vary significantly among countries, partly because of the lack of evidence of their effectiveness and shortage problems for some of the experimental drugs.

In this study, we report the clinical characteristics, treatment patterns, and outcomes of the first 1,255 patients that received antiviral or immunosuppressive treatment for COVID-19 at the Gregorio Marañón University General Hospital. Risk factors present on admission associated with developing acute respiratory distress syndrome (ARDS) and mortality were explored.

The study was conducted at Gregorio Marañón University General Hospital, a tertiary care institution with 1,200 beds, serving a population of 350,000 inhabitants. At the peak of the pandemic on March 29, this hospital had 1,064 COVID beds, of which 135 were ICU beds.

The study sample included all consecutive acute cases in adults confirmed by PCR from March 1 to 24, 2020, who consequently received specific anti-COVID-19 treatment, either antiviral or immunosuppressive. We excluded patients with mild disease that did not require specific treatment and were referred to Primary Care for follow-up.

Patients were treated at their attending physician´s discretion, according to local protocol (Appendix) and clinical judgment. Routine blood examinations included: complete blood cell count, serum biochemical tests (renal and liver function profile, lactate dehydrogenase -LDH-and creatine kinase -CK-), C-reactive protein (CRP) and coagulation profile. If ARDS, coinfection or cardiac complications were suspected, procalcitonin, serum ferritin, interleukin-6 -IL-6-and myocardial enzymes (N-terminal pro-brain natriuretic peptide -NT-proBNP-and troponin) were performed, accordingly. Chest radiographs or computerized tomography scan (CT) were also done when necessary.

The criteria for discharge were absence of fever for at least 3 days, a chest radiograph that demonstrated pneumonia stabilization and remission of respiratory failure (respiratory rate <22/min and arterial oxygen saturation -O2Sat-of >94% by pulse-oximetry).

Patients were followed up until May 10, 2020. Data collected included patient demographic information, comorbidities, laboratory tests and treatments for COVID-19, including type and duration of antiviral and immunosuppressive combinations, oxygen therapy and mechanical ventilation. The outcomes were also analyzed, including the development of acute respiratory distress syndrome -ARDS-, length of stay, discharge, readmission and mortality. World Health Organization interim guidelines were used to define ARDS [4] .

We calculated the cost (€) of antiviral and immunosuppressive therapies for COVID-19, based on the drug acquisition cost and the actual dose administered. In the case of Spain, the costs of drugs are based on the laboratory sale price (LSP) plus 4% value added tax (VAT) minus the 7.5% reduction required by the Spanish government as one of the extraordinary measures to reduce public deficit [5] .

The study protocol was approved by the research ethics committee of the hospital (FARM-COVID-19 v.1) and by the Spanish Agency of Medicines and Medical Devices (CGR-REM-2020-06).

Continuous variables were described as medians with their interquartile ranges (IQRs) and categorical variables as frequencies with their percentages. The association between categorical variables was studied using the Pearson's chi2 test. For the numerical variables, the Student's T test or the Mann-Whitney U test were used depending on the normality of the variable.

Survival rate was calculated by the Kaplan-Meier method. Time to death was defined as the time from hospital admission to death. The follow-up date was May 10, 2020. To explore the risk factors associated with the development of ARDS, the univariable and multivariable logistic regression model was used.

Bivariate Cox proportional hazard ratio (HR) model was used to determine HRs and 95% confidence intervals (CI) between individual factors and the progression to death. Considering the total number of ARDS (n=461) and deaths (n=268) in our study and to avoid overfitting the models, 14 variables were chosen for multivariable analysis. The variables were selected on the following basis: (i) if there was a significant difference (P<0.10) between groups in the univariate analysis, (ii) if there was a previous evidence that the variable could be a risk factor associated to mortality in patients with COVID-19 [1, 6] , and (iii) if they were considered as clinically relevant. Variables from the univariable analysis were excluded if the number of events was too small to calculate odds or hazard ratios (<2%). We chose age, sex, the presence of obesity, and five comorbidities: hypertension, cardiovascular disease, diabetes, chronic obstructive pulmonary disease and renal impairment. In addition, the presence of O2Sat of <90% by pulse-oximetry, lymphocyte count, C-reactive protein, D-dimer, LDH and CK at admission were also included as potential risk factors for ARDS and mortality.

All analyses were based on existing data. In multivariate analyses, missing values in qualitative variables were considered a separate category. All tests were 2-sided, and a P value less than .05 was considered statistically significant. IBM SPSS Statistics for Windows, version 25.0. Armonk, NY: IBM Corp. was used for all calculations.

A total of 1,255 patients were included in the study. Of these, 1,158 (92.3%) required hospitalization whereas 97 (7.7%) were sent home with empirical antiviral treatment after being evaluated and observed in the Emergency Room for more than 24 hours. We collected and analyzed data from these 1,255 patients. Laboratory findings on hospital admission are also shown in Table 1 . The most remarkable laboratory abnormalities (according to the local reference ranges) included the following: lymphocytopenia (54.8%), elevated alanine aminotransferase (33.0%), elevated LDH (58.5%), CK (11.4%) and D-dimer (>1,000 ng/mL) (9.0%). Most patients presented an elevated C-reactive protein (95.0%), whereas only 9.2% of patients presented elevated procalcitonin.

Throughout the entire follow-up period, a total of 911 (72.6%) patients had findings of bilateral infiltrates on radiographic imaging, while 219 (17.4%) patients had unilateral infiltrates.

Out of 1,255 patients included in the study, 1,158 (92.3%) required hospitalization with a median hospital stay of 11 days (IQR, 7-19). A total of 461 (36.7%) patients developed ARDS, and 126 (10.0%) were admitted to an ICU. The length of ICU stay was 17 days (IQR 9-31). Overall mortality at day 28 after admission was 18.6% (IC95%: 16.6% -20.9%). At the end of follow-up, on May 10, 268 patients had died (21.3%) ( Figure 1 ). The mortality rate in hospitalized patients was 22.9%, 20.6% in non-ICU units and 41.3% in ICU. All clinical outcomes are presented in Table 2 .

Overall, 1,025 (81.7%) required oxygen support in the hospital, with a median duration of 9 days (IQR 5-15). Of these, 345 (27.4%) required non-invasive ventilation (non-invasive positive pressure ventilation -NIPPV-or high-flow supplemental oxygen) and 113 (9.0%) invasive mechanical ventilation (IMV . Time from the onset of symptoms reported by the patients to the start of antivirals was a median of 6 (3-7) days. The median duration of antiviral treatment was 9 (7-12) days. The most frequent antiviral combination was lopinavir/ritonavir (LPV/r) plus hydroxychloroquine (HCQ), which was used in 44.2% of patients (Table 3) . Triple therapy with β-interferon 1b was prescribed in 32.7% of patients, more frequently in patients with ARDS (47.5%). The combination of HCQ plus azithromycin was used only in 7.7% of patients. Overall, 31 (2.5%) patients (all admitted in one of the ICUs) received the experimental antiviral remdesivir (RDV), which was only available within a compassionate-use basis. In all of these cases, patients were treated with an alternative antiviral therapy until RDV was available, with a median delay for its initiation of 16 (13-18) days from the onset of symptoms. Among these patients, 11

patients died (35.5%) and 8 (25.8%) were still hospitalized at the study end point.

A total of 317 (25.2%) patients received systemic corticosteroids (Table 3) , with a median elapsed of 11 (9) (10) (11) (12) (13) (14) days from the onset of the symptoms. The mortality rate in this subpopulation was 35.6%.

Corticosteroids was used in 53.4% of patients that developed ARDS. In this subpopulation, the mortality rate was 42.7%, compared to 62.3% in those who did not receive corticosteroids (p<0.001).

Tocilizumab (TCZ) was used in 162 patients (12.9%), of which 63.0% received 2 or 3 dosages. More than half of the patients (56.8%) were on the ICU at the moment of its first administration. An improvement in oxygen-support status was achieved in 17.9% and 54.9% of patients at day 7 and day 28 post TCZ administration. This benefit was clearly higher in patients without IMV (68% vs 41% at day 28). At the study end point, mortality was 33.3%, compared to 60.8% in those patients with ARDS who did not receive TCZ (p<0.001).

Anticoagulation therapy with low molecular weight heparin was prescribed at prophylactic or intermediate dosages in 86.7% of hospitalized patients. Only 36 patients (3.1%) received full therapeutic-intensity anticoagulation, in all cases due to high clinical suspicion of thrombosis.

The total acquisition cost of antiviral and immunosuppressive agents for the treatment of the 1,255 COVID-19 patients was €511,825. The mean treatment cost per patient was €408, and the median €80 (IQR 51-207). The total cost of antivirals was €137,861 (€110 per patient, median €74 -IQR 47-157-). The highest expense in antivirals was due to the consumption of LPV/r (€66,890), followed by β-interferon 1b (€64,970), HCQ (€5,806) and azithromycin (€195). RDV was purchased at no cost through the Compassionate Use Access Program, which was enabled through the collaboration of the provider (Gilead Sciences, Inc.) and the Spanish Agency of Medicines and Medical Devices (AEMPS).

The total cost of tocilizumab was €371,784 (€2,295 per treated patient, median €2,096 -IQR 1,048-3,143-), and the cost of corticosteroids was €2,180 (€6.9 per treated patient, median €5.4 -IQR 2.7-8.1-).

Older age, male sex, the presence of obesity, all mentioned comorbidities (with the exception of asthma and cancer), and the presence of fever and an O2Sat below 94% at admission were more common in patients that developed ARDS (Table 1) . Regarding blood examinations, the prevalence of lymphocytopenia and elevated values of creatinine, LDH, CK, D-dimer, and myocardial enzymes were also significantly higher in this population. Table 4 describes the results of the univariable and multivariable logistic regression model for the risk factors associated with ARDS. In the univariate analysis, all factors included in the model was associated with an increased risk of ARDS. In the multivariable model, however, only older age, the presence of obesity, diabetes mellitus, lymphocytopenia, O2Sat <90%, elevated CK and C-reactive protein were independently associated with increased odds of ARDS.

Univariate Cox models showed that all factors related to the development of ARDS, except obesity, were also associated with increased risk of death ( 

We reported the clinical characteristics and outcomes of a cohort of over 1,200 patients with COVID-19 who were admitted to a public hospital in the Community of Madrid during the rising phase of the SARS-CoV-2 pandemic. The region was one of the most severely affected during the pandemic, with 14,597 COVID-19 cases and 11,153 (76.4%) hospitalizations by the end of this study [7] . To our knowledge, this is the first large cohort that describes the use and costs of anti-COVID-19 agents, as well as the risk factors present on admission associated with ARDS and mortality in the Spanish population.

One of our main findings is the high proportion (37%) of hospitalized COVID-19 patients that developed ARDS, an issue that has not been thoroughly examined in previous studies. Our mortality rate was high (21%), although similar to those observed in other western countries. In particular, a mortality rate of 21% was also found in the Italian region of Lombardy and in the New York City area, and up to 26% in the United Kingdom [1] [2] [3] .

The proportion of patients admitted to our ICUs (11%) was slightly lower to the 14%-17% reported in those countries [1] [2] [3] , even though the number of ICU beds had been multiplied by 6 (up to 135). Nevertheless, it should be noted our figures do not include the proportion of patients that received non-invasive mechanical ventilation outside the ICU wards.

As expected, compared to non-ICU units, the mortality rate in ICU was higher (41% vs 21%). A lower mortality rate (26%) was reported in the ICU units of Lombardia region [8] , though in this cohort the followup period was short, with 58% of patients still in the ICU at the time of analysis. Mortality as high as 58% was observed among patients requiring ICU care and mechanical ventilation in the New York City area and the Wuhan region in China [2, 9] . A recent metanalysis described a combined ICU mortality of 41.6% (95% CI 34.0-49.7%) in patients with completed ICU admissions [10] . Interestingly, this metanalysis also found that as the pandemic progresses, the mortality rates have fallen from above 50% to 40%; possibly due to improvements in treatments and less care burden.

Our high rate of hospitalizations and mortality reflect the elevated prevalence of comorbid conditions in our COVID-19 population. Our patients were predominantly elderly, with hypertension, cardiovascular disease and diabetes mellitus as the main comorbidities. Multivariate analysis performed using Cox regression modeling confirmed that older age and the presence of diabetes and cardiovascular disease remain independently associated with mortality. Conversely, we were not able to demonstrate the relationship between obesity and mortality, although this was clearly associated with increased odds of ARDS (OR 2.29). This is probably explained by the high prevalence of elderly population admitted and also a possible under-reporting by clinical staff.

Another interesting find was the relatively short time interval between onset of symptoms and hospital admission (6 days), although 9% of patients were admitted 10 days after the onset of symptoms. These findings are quite similar to those of the UK [3] , where the median time to admission was 4 days (IQR 1-8).

Despite this, our patients´ respiratory status at admission was generally poor, with half of the patients presenting a SatO2 <94%. In addition, the laboratory values were indicative of an impaired immuneinflammatory profile, characterized by lymphocytopenia and elevated C-reactive protein and LDH in more than half of the patients. We were able to demonstrate that, at admission, the presence of SatO2 <94%, lymphocytopenia and increased C-reactive protein are independently associated with ARDS and mortality.

With respect to treatment, the majority of our patients received the combination of LPV/r plus HCQ +/interferon β-1b, according to the protocol of the hospital. The use of HCQ + azithromycin was limited to patients with contraindication to LPV/r, generally because of drug interactions or intolerance in elderly patients with multiple comorbidities. At the time of this study, there was no evidence about which antivirals were more effective, as they were still being tested in clinical trials. On May 7, a small clinical trial reported that LPV/r was not associated with a reduction on the time to clinical improvement or with mortality rate in patients with severe COVID-19 [11] . However, these patients started LPV/r with a median delay of 13 days from the onset of symptoms, so a benefit in the case of early onset could not be ruled out. Pending the results from other clinical trials, the Pharmacy and Therapeutic Committee of the hospital decided to maintain LPV/r as a feasible alternative, if it could be administered early in the course of the disease.

Regarding HCQ, until June 5 no results from any clinical trial have been reported. However, recent preliminary results from the RECOVERY trial [12] have pointed that HCQ has no benefit on 28-day mortality (26% vs 23% usual care -HR 1.11 [95% CI 0.98-1.26]-). While waiting for the publication of these preliminary results, its off-label use was no longer recommended in our hospital. Finally, RDV was used in only 2.5% of patients, due to the logistic difficulties of obtaining it in Spain. This prevents drawing solid conclusions about its effectiveness, beyond a mortality rate in this small ICU subpopulation which was above 30%.

On the other hand, our study seems to point towards a favorable effect with the use of corticosteroids and TCZ in patients with ARDS. Corticosteroids were used predominantly in this subpopulation because on the earlier weeks of the pandemic their benefit in less critical patients was still to be proven. Analyzing only the 461 patients with ARDS, the mortality rate in those treated with corticosteroids was 43% compared to 62%

if not treated. Similarity, mortality was lower in those patients with ARDS who received TCZ than in those who did not receive it (33% vs 61%). However, we cannot draw solid conclusions due to the retrospective non-randomized design of the study, in which up to 35% of the patients received corticosteroids and TCZ simultaneously. In addition, the use of TCZ was limited to patients with a very severe COVID-19 infection because of the lack of evidence of its effectiveness and shortage problems in Spain. An earlier use of TCZ may perhaps demonstrate greater benefits. In any case, its actual impact on mortality should be elucidated through the placebo-controlled clinical trials that are currently recruiting patients.

Finally, our study also highlights the elevated cost of COVID-19 treatment, with approximately €0.44 million per 1,000 hospitalized patients. Higher expenses were attributable to the treatment of ARDS with TCZ, which accounted for €0.37 million. This study has some limitations. First, the study population only included patients from Gregorio Marañón University General Hospital, although it should be mentioned that this hospital served up to 13% of the total COVID-19 patients in the Community of Madrid. Second, its observational design, which among other limitations, did not permit us to establish a strong relationship between treatment patterns and outcomes.

Third, our registry, though extensive, does not provide data about complications during hospitalization or drug adverse events. Lastly, because this is a real-life study, not all laboratory tests were available for the majority of patients (ie. serum ferritin, IL-6), therefore their role might be underestimated in predicting inhospital death.

This is one of the largest cohort studies among hospitalized patients with COVID-19 in western countries, which describes the clinical characteristics, the use and costs of treatments, and the risk factors for ARDS and mortality. We found that older age, the presence of diabetes mellitus, cardiovascular disease, an oxygen saturation <90% at admission, lymphocytopenia and elevated PCR were factors independently associated with acute respiratory distress syndrome and mortality. Our study also suggests that corticosteroids and tocilizumab may be beneficial for patients with severe disease. However, doubleblinded placebo control randomized clinical trials are still required to determine the most effective treatments for COVID-19.

The authors thank Athento ® for their assistance in data mining. The authors thank JM Bellón for his assistance with the statistical analyses. The authors thank Angelica Minero for editing the article. .001 Data are presented as n (%). 1 Combinations that were prescribed in < 20 patients are not presented. 2 69% of patients received this combination of antivirals simultaneously. 3 61% of patients received this combination of antivirals simultaneously. 4 All patients were treated with an alternative antiviral therapy until remdesivir was available. 5 Corticosteroid treatment was classified as pulse dose if ≥ 125 mg of methylprednisolone or equivalent was administered every 24h, or as low-intermediate dosage otherwise. Abbreviations: ARDS, acute respiratory distress syndrome; AZT, azithromycin; HCQ, hydroxychloroquine; LPV/r, lopinavir/ritonavir; RDV, remdesivir. 

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