key: cord-0841317-jtvtonkm
authors: Duarte‐Millán, Miguel A.; Mesa‐Plaza, Nieves; Guerrero‐Santillán, Marta; Morales‐Ortega, Alejandro; Bernal‐Bello, David; Farfán‐Sedano, Ana I.; García de Viedma‐García, Vanessa; Velázquez‐Ríos, Laura; Frutos‐Pérez, Begoña; De Ancos‐Aracil, Cristina L.; Soria Fernández‐Llamazares, Guillermo; Toledano‐Macías, María; Cristóbal‐Bilbao, Rafael; Luquín‐Ciuro, Nuria; Marrero‐Francés, Jorge; Piedrabuena‐García, Sara I.; Satué‐Bartolomé, José A.; Gonzalo‐Pascua, Sonia; Rivilla‐Jiménez, Marta; Carpintero‐García, Lorena; Ayala‐Larrañaga, Ibone; García‐Bermúdez, Virginia; Lara‐Montes, Celia; Llerena‐Riofrío, Álvaro R.; RIvas‐Prado, Luis; Walter, Stefan; Escriba‐Barcena, Almudena; San Martín López, Juan V.; Ruíz‐Giardín, José M.
title: Prognostic factors and combined use of tocilizumab and corticosteroids in a Spanish cohort of elderly COVID‐19 patients
date: 2021-12-07
journal: J Med Virol
DOI: 10.1002/jmv.27488
sha: fb9bd1dbf52dd05f6c6dfed51e0690ea8783d522
doc_id: 841317
cord_uid: jtvtonkm

Coronavirus disease 2019 (COVID‐19) infection in elderly patients is more aggressive and treatments have shown limited efficacy. Our objective is to describe the clinical course and to analyze the prognostic factors associated with a higher risk of mortality of a cohort of patients older than 80 years. In addition, we assess the efficacy of immunosuppressive treatments in this population. We analyzed the data from 163 patients older than 80 years admitted to our institution for COVID‐19, during March and April 2020. A Lasso regression model and subsequent multivariate Cox regression were performed to select variables predictive of death. We evaluated the efficacy of immunomodulatory therapy in three cohorts using adjusted survival analysis. The mortality rate was 43%. The mean age was 85.2 years. The disease was considered severe in 76.1% of the cases. Lasso regression and multivariate Cox regression indicated that factors correlated with hospital mortality were: age (hazard ratio [HR] 1.12, 95% confidence interval [CI]: 1.03–1.22), alcohol consumption (HR 3.15, 95% CI: 1.27–7.84), CRP > 10 mg/dL (HR 2.67, 95% CI: 1.36–5.24), and oxygen support with Venturi Mask (HR 6.37, 95% CI: 2.18–18.62) or reservoir (HR 7.87, 95% CI: 3.37–18.38). Previous treatment with antiplatelets was the only protective factor (HR 0.47, 95% CI: 0.23–0.96). In the adjusted treatment efficacy analysis, we found benefit in the combined use of tocilizumab (TCZ) and corticosteroids (CS) (HR 0.09, 95% CI: 0.01–0.74) compared to standard treatment, with no benefit of CS alone (HR 0.95, 95% CI: 0.53–1.71). Hospitalized elderly patients suffer from a severe and often fatal form of COVID‐19 disease. In this regard, several parameters might identify high‐risk patients upon admission. Combined use of TCZ and CS could improve survival.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a major cause of acute respiratory syndrome and mortality. 1 Initially data from China showed a total case-fatality rate of 2.3%, but in patients, over 80 years this rate may be as high as 14.8%. 2 Spain has been one of the most severely affected European countries reaching up to three times the usual capacity of intensive care units (ICUs). 3 Elderly patients and nursing homes were especially hit by the pandemic.

According to the Spanish National Surveillance Net, the 80-years and older population showed the highest hospitalization −44.7%and mortality −21.8%rates. 4 COVID-19 in elderly patients is a matter of great importance for its morbi-mortality. Until now, several reports have tried to establish risk factors for poor outcomes, but few studies have focused on the elderly population 5, 6 Furthermore, these patients are underrepresented in clinical trials and the specific use of some treatments should be confirmed in this group of patients. More evidence is needed about SARS-CoV-2 infection in this group of patients.

In this study, we aim to: (a) describe clinical characteristics as well as outcomes of patients over 80 years admitted for COVID-19;

(b) identify prognostic factors for risk of death; and (c) assess the efficacy of immunosuppressive treatmentstocilizumab (TCZ) and corticosteroids (CS)applied to this population.

We design a single-center, retrospective observational study that included all patients older than 80 years, admitted into our institution between March 1 and April 30, 2020, with a diagnosis of COVID-19 and followed up until hospital discharge. Due to the difficulties to provide adequate follow-up in that pandemic scenario, patients referred to other hospitals from our Emergency Department were ultimately excluded. The Fuenlabrada University Hospital's local Ethics Committee approved this study (APR 20/26).

Diagnosis of confirmed cases was performed by real-time reverse transcription-polymerase chain reaction (PCR) from nasopharyngeal swab samples (platform Roche Cobas Z 480). During the period of greatest healthcare overload, there was no availability of PCR tests for all patients. According to hospital protocols, patients with high clinical suspicion (bilateral pneumonia, lymphopenia, and close contact with positive cases) were defined and managed as probable cases. Probable cases were included in statistical analysis.

The following variables were recorded from electronic medical records.

• Baseline characteristics and comorbidities at the time of initial contact: age, sex, former or current smoker, previous alcohol consumption, hypertension, diabetes mellitus (DM), dyslipidemia, obesity (defined as body mass index (BMI) > 3 kg/m 2 ), chronic kidney disease (CKD) (glomerular filtration rate <60 ml/min), heart disease (including arrhythmias, ischemic disease, heart failure, and valvular disease), respiratory pathology (chronic obstructive pulmonary disease, asthma, chronic respiratory insufficiency, and use of previous mechanical noninvasive ventilation devices), venous thromboembolic disease (VTE), cirrhosis, neurological conditions (dementia and neurodegenerative disorders, previous stroke, or epilepsy), anemia, history of malignancy (including hematological and solid cancer), autoimmune disease, and autonomy for activities of daily living.

• Previous treatments: antiplatelets, anticoagulants, angiotensinconverting enzyme inhibitors (ACEIs), angiotensin receptors antagonists type II (ARA-II), nonsteroidal anti-inflammatory drugs (NSAIDs), inhaled corticosteroids, and immunosuppressive therapies.

• Symptoms and clinical signs on admission: fever (temperature over 37.8°C), cough, dyspnea, chest pain, digestive symptoms, confusion, blood pressure, heart rate, tachypnea, and mental status.

• Laboratory parameters: lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin, D-dimer (DD), creatinine, glomerular filtration rate (GFR), urea, sodium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), albumin, white cell blood count, neutrophils, lymphocytes, hemoglobin, platelets. Severity of disease on admission:

Classified as mild, moderate, or severe according to recommendations from WHO guidelines. Critical cases were re-classified into the severe group. 7 We recorded additional information about oxygen supplementation on entry, and radiological findings on entry.

• Treatments received during the course of the hospital stay: Antibiotics, chloroquine/hydroxychloroquine, ritonavir/lopinavir, interferon beta 1b, CS, TCZ, and heparin (prophylactic or intermediate-high

| 1541 doses). Due to its retrospective observational design, the dose of CS administered was not predefined in advance. Our institutional protocol contemplated the possibility of CS use in case of rapidly progressive respiratory failure or elevation of inflammatory parameters (such as CRP > 10 mg/dL), despite antiviral or antimalarial treatment.

Although the institutional protocol recommended doses of 20 mg dexamethasone for 5-10 days or 250/500 mg methylprednisolone pulses for 3-5 days, the final dose was individually decided by the treating physician. Data were collected on daily and total doses received, in mg equivalent to prednisone. The use of TCZ (in 2 doses of 600 mg on consecutive days) was restricted during part of the study due to stock-outs. When available, it was used with the same criteria as CS, generally in the absence of response to them.

• Length of stay, complications during hospitalization (bacterial infection, kidney and liver worsening, heart failure, thrombosis, bleeding, confusional syndrome, and blood transfusion), and final outcomes (survival or death).

The main outcome was mortality for both analyses: prognostic risk factors and efficacy of treatments. Patients were followed up until discharge or death.

The descriptive variables were analyzed using means and standard deviations (Student's t-test) as well as counts and percentage 

During the first wave of the COVID-19 pandemic, a total of 1700 patients were admitted to our center. Of them, 163 (9.5%) were over 80 years old and were included in the study.

Baseline characteristics, comorbidities, and previous treatments are presented in Table 1 , comparing survivors (93 cases) and deceased (70 cases, 43% of total). Seventy-five (46%) of patients were female. The median age was 85.2 years. None of these patients were admitted to the ICU.

The most frequent comorbidity was hypertension in 82.2% of cases, followed by heart disease 50.9%, CKD 44.1%, neurological conditions 38%, former and current smoker 36.9%-, DM 35.6%, obesity 35.4%, and respiratory diseases 30.7%. CKD was more frequent among patients that died (56.2% vs. 35.2%, p = 0.02) while the rest of the variables did not show relevant differences. ACEIs and ARAII were frequently used among patients (91 cases, 55.8%) without differences between both groups.

Regarding the remaining drugs, they had similar rates of use, except for immunosuppressive agents, which were more frequently used among patients who eventually died (18.8% vs. 6.5%, p = 0.03).

Data about symptoms, clinical signs, laboratory, and radiological findings, and severity of disease upon admission are shown in Table 2 .

Cough and dyspnea were the most frequent symptoms (69.4% and 63.4%), while fever was present in 40.1% of all cases. Notably, digestive symptoms were more frequent in the survival group (25.8% vs. 10%). Tachypnea and tachycardia were more frequent in dead patients (66.7% vs. 27.9% and 95 bpm vs. 86.5 bpm, respectively). In addition, these patients presented more frequently altered mental status (confusion in 24.2% vs. 11.1% and coma in 10.6% vs. 0%).

The mean values of analytical parameters are also shown in Table 2 The first assessment of the severity of the disease was clearly different between the groups. 90% of all patients who died had a severe disease on admission (65.6% among survivors). Furthermore, important differences were found in the need for oxygen support upon admission. 

In relation to the length of stay, treatments and complications suffered during hospitalization are shown in Table 3 . The time from the onset of self-reported symptoms to emergency department admission was 5.73 days in general, slightly shorter among the patients who died (4.89 vs. 6.32 days). Among the complications, acute kidney failure was the most prevalent, in 22% of the cases; followed by confusional syndrome in 14.6%.

Bacterial infections were documented in 8.5%, similarly among groups.

We first performed a univariate Cox regression analysis to identify prognostic factors associated with death. In a first step, we included 55 variables relatives to comorbidities, previous treatments, symptoms on admission, laboratory data, and severity of the disease.

Results with correspondent hazard ratio (HR) and confidence intervals (CI) are presented in Table 4 . In the univariate analysis, the T A B L E 1 Differences in baseline characteristics between survivors and deceased groups 

We assessed the efficacy of treatments with survival analysis of three groups: no immunosuppressive therapy (76 patients), CS alone (76 patients), or in combination with TCZ (9 patients).

No statistically significant differences were noted between groups regarding age, sex, and comorbidities. The proportions of severity and oxygen support in the groups receiving CS alone or combined with TCZ were higher than in the group of patients who did 

In this study we present the characteristics and outcomes of 163 elderly patients admitted to our institution during the first wave of the pandemic in Spain. Population over 80 years represent the largest group by age (23.8% of the cases confirmed until the end of May 2020). 4 Advanced age is a well-known independent factor for mortality and the overall mortality rate in this group ranges between 15%-35%. 2

The selection of the variables by Lasso regression was controlled by lambda to select the most accurate model In the elderly population, COVID-19 infection evolves rapidly to death in many cases. Once hospitalized, the time to death in our study was half of the time to recovery. Our analysis tries to clarify which symptoms, vital signs, laboratory data, and radiological findings on admission may be useful to better identify patients of high risk. Our study has some limitations in evaluating the efficacy of treatments, mainly due to its retrospective observational design, dose variability in therapies, and the small number of patients treated with the combined treatment. At the time these patients were treated, no treatment had shown an improvement in survival. 17 Most received antimalarials and lopinavir/ritonavir, which were later shown to be ineffective and excluded for the analysis 18, 19 Remdesivir was not available so no patient received it.

According to the postulated theories about a cytokine storm causing the lung damage 20,21 CS and an interleukine-6 blocker (TCZ)

were prescribed in some cases. CS has subsequently been validated in later studies as a mortality-reducing treatment in clinical trials in patients requiring oxygen therapy, 22 while some controversies remain about TCZ. [23] [24] [25] Some studies propose an extra benefit for TCZ when using it in addition to CS, rather than separately. 26 We found of special interest the role of immunosuppressive treatments in this special population. Aging itself is a predisposing condition to cytokine dysregulation and hyperinflammatory states, which may explain the higher mortality rates in the elderly. 27, 28 Interleukine-6 is considered a hallmark of inflammatory changes related to aging. 29 Despite a small number of patients treated with the combination of TCZ and CS, the adjusted model showed statistically significant benefit in terms of survival. The results should be interpreted with caution due to a wide confidence interval.

The evolution of those who received only CS seems worse than those who did not receive any treatment, but after the adjustment for severity, the survival curves become similar. It should be noted that in our institutional protocol, CS and TCZ were started under certain severity criteria but TCZ availability was limited for some periods of time. This fact justifies a more widespread use of corticosteroids.

Very high doses were often prescribed in a setting of lack of evidence or availability of other treatments. Consequently, the proportion of seriously ill patients was higher in the corticosteroids-treated group.

Despite the adjustment of the model for severity, the bias caused may have been sufficient to explain this result. We must also consider a harmful influence of the dose used as the dose shown to be beneficial in the studies is significantly lower than that received by our patients.

In conclusion, in this study, we extensively describe the clinical evolution of a cohort of elderly patients over 80 years of age with COVID-19 and highlight the most relevant prognostic factors.

Bearing in mind the high mortality rate and the concerns about effective therapeutic interventions, it is necessary to know the prognostic tools that allow better adaptation of medical care. Combined treatment with TCZ and CS may have a potential role in reducing mortality even in the elderly population.

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Prognostic factors and combined use of tocilizumab and corticosteroids in a Spanish cohort of elderly COVID-19 patients

The authors would like to thank Dr. Stefan Walter for his work, and deeply regret his passing before the final publication of this manu- 

The authors declare that there are no conflict of interests. The main author corroborates on behalf of Dr. Stefan Walter that no conflicts of interest affected his work in this study.

All authors contributed to data collection, analysis, and writing of the final version of the manuscript.

The data that support the findings of this study are openly available