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Risk Factors Associated with the Mortality of COVID-19 Patients Aged ≥60 Years Neither Intubated nor Treated with Mechanical Ventilation: A Multicentre Retrospective Cohort Study during the First Wave in Spain

BioMed 2022, 2(3), 341-358; https://doi.org/10.3390/biomed2030027

by Dante R. Culqui^1,2,*, Josep Ortega Segura², Elisabeth Da Costa-Venancio³, Anna Renom-Guiteras^3,4, Esther Roquer⁵, Sherly Melissa Muñoz Tejada⁶, Patricia Rodriguez², Adilis L. Alba Travieso², Isis Medrano²

, Lizzeth Canchucaja-Gutarra³, Marta Herrero-Torrus³, Paula Jurado-Marín³, Mónica Marín-Casino³, Rosa Ana Sabaté-Garcia³, Cristina Roqueta³, María del Carmen Martinez⁵, Gabriel De Febrer⁷, José Antonio López-Bueno¹, MÁ Navas-Martín^1,*

, Working Group about Survival in Old COVID-19 Patients², César Garriga^8,†

and Joan A. Cayla^9,†

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Reviewer 1: Anonymous

Reviewer 2: Anonymous

Reviewer 3:

Carlos A. M. Carvalho

BioMed 2022, 2(3), 341-358; https://doi.org/10.3390/biomed2030027

Submission received: 27 June 2022 / Revised: 24 July 2022 / Accepted: 3 August 2022 / Published: 11 August 2022

Round 1

Reviewer 1 Report

1. The conclusions and output of this study need to be more detailed or interpreted. What are the clinical outcomes of this study that will be helpful for old-age individuals? Please discuss and explain.

2. This study includes all patients, above 60 years of age when usually many or different types of complications may be associated with a person. Did the authors confirm the whole medical history of these patients?

3. What about the vaccination status of these patients? Please provide the relevant details.

4. Line 29-31. How do coughing and diarrhea have protective effects? Please justify and discuss.

5. Authors analyzed fever, malaise, dyspnoea, and atrial fibrillation as major death-associated symptoms while showing antithrombotic treatment has protective effects. Are these patients not given any fever reducer or steroids? Please justify and discuss.

6. Malaise is usually defined as a general discomfort feeling with other associated diseases for which exact reason is known. In old age peoples, this may be because of many other reasons. Please describe or justify, how malaise is a relevant symptom in the case of COVID-19 old age patients?

7. Are these patients provided with any cough suppressants?

8. Line 34-35. fever, malaise, dyspnoea, and atrial fibrillation help to identify patients at higher risk of mortality. These symptoms are very general in COVID-19, especially when we talk about old-age patients. Please justify and discuss.

9. What of the statistics in this study? Please include a section in material and methods about statistical analysis and also provide the details in figures or figure legends.

10. There are many limitations to this study? Please include a separate section about the limitation of this study.

Author Response

The authors appreciate the subjection provided by review.

Reviewer 1:

Comments and Suggestions for Authors

The conclusions and output of this study need to be more detailed or interpreted. What are the clinical outcomes of this study that will be helpful for old-age individuals? Please discuss and explain.

Response to reviewer:

Thank you for this comment. We have now reworded the conclusions in order to make them more carefully interpreted.

Information to be included:

Line 324:

This study is one of the few studies describing the main characteristics and analysing factors potentially related to mortality in a sample of unvaccinated older persons admitted to intermediate care hospitals (social-health centers (HAI)) with COVID-19 who were offered non-invasive treatment.

Mortality due to COVID-19 in this population was relevant. Clinical conditions such as initial fever, malaise, dyspnoea and atrial fibrillation were associated with an increased risk of death. These findings may help identifying those older patients with COVID-19 who may specially benefit from a closer surveillance by health care professionals, especially in countries that do not yet have a good vaccination coverage and health infrastructure.

The use of antithrombotic agents (including both oral anticoagulants and low-molecular-weight heparins) was associated with a lower risk of mortality in this population, suggesting that treatment protocols for the management of COVID-19 in this population should consider their use.

This study includes all patients, above 60 years of age when usually many or different types of complications may be associated with a person. Did the authors confirm the whole medical history of these patients?

Answer: The authors confirmed that all information about the whole medical history of these patients to the time of admission to care was confirmed with the patients' medical records.

We have included this information in the Materials and Methods part.

What about the vaccination status of these patients? Please provide the relevant details.

Answer: We do not have information on vaccination because the study was conducted during the first wave of COVID-19, when no vaccine was yet available. Since it cannot be deduced from the article that it was done during the first wave, we include in the title the phrase: First wave of COVID-19 in Spain).

Title Says: Risk factors associated with the mortality of COVID-19 pa-tients aged ≥60 years neither intubated nor treated with me-chanical ventilation: A multicentre retrospective cohort study.

Title should said: Risk factors associated with the mortality of COVID-19 pa-tients aged ≥60 years neither intubated nor treated with me-chanical ventilation: A multicentre retrospective cohort study during first wave in Spain.

Line 29-31. How do coughing and diarrhea have protective effects? Please justify and discuss.
Response to reviewer:

As explained in lines 261-266, cough as a PF, could be related to the patients’ frailty. In patients with immobility Syndrome, cough reflex is usually reduced or goes away. Therefore, in patients with a better overall status cough may be associated with higher survival, evidencing a better respiratory functional capacity.

With regard to diarrhea, we didn’t find any other studies that identified this symptom as a PF. Gaos et al (ref. 16 in our study ) in a systemic review found that digestive symptoms to be associated with severity of the covid19, but not with a higher mortality risk. A study done in our country (Rubio-Rivas M, et al Predicting Clinical Outcome with Phenotypic Clusters in COVID-19 Pneumonia: An Analysis of 12,066 Hospitalized Patients from the Spanish Registry SEMI-COVID-19. Journal of Clinical Medicine. 2020; 9(11):3488. https://doi.org/10.3390/jcm9113488) identified clusters of symptoms. Those authors identified clusters of symptoms that were associated with a higher mortality risk and digestive symptoms were not among these symptoms. Therefore, we hypothesize that patients with GI symptoms may have a milder degree of the covid-19 disease. However, more studies are necessary to investigate this issue.

We have now included a sentence in the discussion explaining this latest issue.

Information to be included:

Line 261: A systematic review [16] mentions that digestive symptoms have been associated with the severity of the disease, but are not associated with increased mortality. Furthermore, digestive symptoms were not among the clusters of symptoms mostly associated with mortality risk among patients with covid-19 as studied by Rubio-Rivas (add reference).

Authors analyzed fever, malaise, dyspnoea, and atrial fibrillation as major death associated symptoms while showing antithrombotic treatment has protective effects. Are these patients not given any fever reducer or steroids? Please justify and discuss.

Response to reviewer:

The patients that were included in this study could have been given fever reducers. However, fever was chosen as an initial symptom. Thus, even if fever was reduced by fever reducers, this was taken into consideration as initial symptom for that patient. In order to guarantee that there is no misunderstanding in the manuscript, we have introduced a modification.

Fever reducers were not included by the research team among the medical treatments considered to be potential risk factors for mortality among the study population.

Instead, methylprednisolone, hydrocortisone and dexamethasone were steroids included among the medical treatments potentially associated with a higher risk of mortality.

We hope we have answered to the reviewer question.

Information to be included:

Line 110: Instead of “Symptoms: fever, cough, …” we have now written “Initial symptoms: fever, cough, …”.

Malaise is usually defined as a general discomfort feeling with other associated diseases for which exact reason is known. In old age peoples, this may be because of many other reasons. Please describe or justify, how malaise is a relevant symptom in the case of COVID-19 old age patients?

Response to reviewer:

Thank you for this comment. We agree that the discussion should include a paragraph on malaise and its rellevance within the covid-19 context for older age patients as a mortality risk factor. We have now added it.

Information to be included:

Line 267: Malaise was a RF of mortality in the present study. This symptom seams to be related to the response of the body's immune system to infection. Indeed, covid-19 disease results in a massive cytokine storm which results in a variety of symptoms including malaise ( Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med. 2020 Jun 25;58(7):1131-1134. doi: 10.1515/cclm-2020-0198. PMID: 32119647. Dittadi R, Afshar H, Carraro P. The early antibody response to SARS-Cov-2 infection. Clin Chem Lab Med. 2020 Sep 25;58(10):e201-e203. doi: 10.1515/cclm-2020-0617. PMID: 32639941.). Thus, the presence of malaise may be associated with a more massive cytokine reaction, resulting in a more severe disease with a higher mortality risk (Rabaan AA, et al. Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm. Vaccines (Basel). 2021 Apr 29;9(5):436 doi:10.3390/vaccines9050436. PMID: 33946736; PMCID: PMC8145892.)

Are these patients provided with any cough suppressants?

Answer: The use of antitussives was not recorded in the patients studied. We have included this information in the discussion section (Line 274).

Line 34-35. fever, malaise, dyspnoea, and atrial fibrillation help to identify patients at higher risk of mortality. These symptoms are very general in COVID-19, especially when we talk about old-age patients. Please justify and discuss.

Answer: as authors we agree with the reviewer's observation, however in the context of the first wave, it could be considered important to know the initial characteristics of the disease without vaccination, so we have included within the abstract the following comment: "Although some symptoms are very general in COVID-19, in the context of the first wave without vaccination, when not much was known about the disease, such symptoms could be useful.”

What of the statistics in this study? Please include a section in material and methods about statistical analysis and also provide the details in figures or figure legends.

We have included the following information in the material and methods section:

The survival function of the patients in the groups studied, the risk of occurrence of the Covid-19 death event, as well as the mean survival time were determined.

The probability distribution of survival times in Covid-19 patients was performed using the non-parametric Kaplan-Meier method, followed by Cox regression analysis by specific age groups and the final multivariate analysis in which the variables that were significant (Hazard Ratio (HR) were entered and both protective and risk factors were identified in the total population and in the age groups studied.

There are many limitations to this study? Please include a separate section about the limitation of this study.

We have included a limitations section in the manuscript.

Reviewer 2 Report

Congratulation for your work and your efforts to support with your data advanced therapeutic options for Covid-19 patients. We always encourage investigators who orchestrate efforts and ideas to provide the scientific community with new and significant information. I personally acknowledge that you have contributed laboriously to define your objectives but I have some comments about the methodology followed and the interpretation of your results. Noteworthy the extensive analysis of your data provided valuable information but however there are some points that I would like to comment and your response will be definitely appreciated.

Comment1: As for the selection of the study variables I would like to stress that some of the parameters are considered as generalized condition which are hiding distinct disorder. General discomfort for example cannot be defined objectively, while many condition can lead to this. Even more the feeling of dyspnoea is a very subjective response, while oxygen saturation or the PaO₂ and even more the ratio to the fraction of inspired oxygen (GiO₂) are considered valuable and objective factors.

Comment2: Please define the term dyslipidemia while triglycerides and LDL or HDL differ in terms of pathophysiology pathways.

Comment3: Please define and interpret the term Polypharmacy to the morbidity status of the patients receiving many pills. I am wondering if you mean increase pills arithmetically which can create confusion and les adherence to the patient or many underlying diseases.

Author Response

The authors appreciate the subjection provided by review.

Reviewer 2:

Comments and Suggestions for Authors

Comment1:

As for the selection of the study variables I would like to stress that some of the parameters are considered as generalized condition which are hiding distinct disorder. General discomfort for example cannot be defined objectively, while many condition can lead to this. Even more the feeling of dyspnoea is a very subjective response, while oxygen saturation or the PaO2 and even more the ratio to the fraction of inspired oxygen (GiO 2) are considered valuable and objective factors.

Response to reviewer:

As authors we agree with reviewer 2. However, we believe that in the context of the first wave and in the face of multiple doubts, a fairly broad exploration is warranted, which in some cases as the reviewer rightly says may not be very specific. We have therefore decided to include the following comment in limitations:

"Regarding the selection of the study variables, some of the parameters studied are considered as generalised conditions that could hide a different disorder. General malaise, for example, cannot be objectively defined, while many conditions can lead to this situation, on the other hand the sensation of dyspnoea is a very subjective response, while oxygen saturation or PaO 2 and even more the ratio to inspired oxygen fraction (GiO 2 ) are considered as valuable and objective factors, so results related to symptoms should be taken with caution".

Comment2:

Please define the term dyslipidemia while triglycerides and LDL or HDL differ in terms of pathophysiology pathways.

We have included the definition of dyslipidemia in the methodology section:

The term dyslipidemia indicates an elevated concentration of lipids in the blood. There are several categories of this disorder, depending on which lipids are altered. The two most important forms are hypercholesterolaemia and hypertriglyceridaemia, although other disorders can be common, such as hyperchylomicronemia or decreased HDL-cholesterol. (insert reference) (https://www.elsevier.es/es-revista-offarm-4-articulo-dislipidemias-13079594)

Comment3:

Please define and interpret the term Polypharmacy to the morbidity status of the patients receiving many pills. I am wondering if you mean increase pills arithmetically which can create confusion and les adherence to the patient or many underlying diseases.

Response to reviewer:

As written in line 107 of the manuscript, polypharmacy was defined as the use of more than 5 drugs by one patient. This is one of the several accepted definitions of polypharmacy (Sirois et al. 2019). Thus, we did not collect data on the number of pills, but on whether participants were using more than 5 medications at admission.

Polypharmacy has been found associated with a higher risk of mortality among older persons (Chang 2020), and the reasons for these could be various. On one hand, polypharmacy could behave as a surrogate for multi-morbidity, which has been found associated with a higher risk of mortality (Iaccarino et al 2020). On the other hand, the use of multiple concomitant medications may outweigh individual benefits due to potential ensuing side effects (Turgeon 2017).

We have now added a sentence on this issue in the manuscript.

References:

Sirois C, Domingues NS et al. Polypharmacy Definitions for Multimorbid Older Adults Need Stronger Foundations to Guide Research, Clinical Practice and Public Health. 2019. Pharmacy (Basel). 7(3):126. doi: 10.3390/pharmacy7030126.

Chang T I et al. Polypharmacy, hospitalization, and mortality risk: a nationwide cohort study. 2020. Sci Rep. 3;10(1):18964. Doi: 10.1038/s41598-020-75888-8.

Iaccarino G et al. Age and Multimorbidity Predict Death Among COVID-19 Patients: Results of the SARS-RAS Study of the Italian Society of Hypertension. 2020. Hypertension. 76(2):366-372.

Turgeon, J., Michaud, V. & Stefen, L. Te dangers of polypharmacy in elderly patients. JAMA Intern. Med. 177, 1544 (2017).

Information to be included:

Line 237: “… Although not in the general population, as reported in the literature (23, 26, 27). Nevertheless, polypharmacy has been found associated with a higher risk of mortality among older persons (Chang 2020), and the reasons for these could be various. On one hand, polypharmacy could behave as a surrogate for multi-morbidity, which has been found associated with a higher risk of mortality (Iaccarino et al 2020). On the other hand, the use of multiple concomitant medications may outweigh individual benefits due to potential ensuing side effects (Turgeon 2017).”

Reviewer 3 Report

The manuscript reports a retrospective multicenter study that aimed to determine risk factors of death in ≥60 year-old patients diagnosed with COVID-19 who could not benefit from intubation and mechanical ventilation. Although the topic is additive to the current pandemic moment, some points requires revision and are listed below in the order of appearance in the text:

Lines 25-26: The results section of the abstract states that "683 patients were included", but Figure 1 of the materials and methods section indicates that 207 of these patients were "discarded for analysis".

Lines 41-41: Update the number of cases and deaths related to COVID-19 in the sentence "by March 2020, SARS-CoV-2 had infected more than 87,137 people, with more than 2,977 deaths worldwide".

Line 162: Translate "Total de Pacientes" to English.

Line 167: In Table 2, correct "Frecuency" to "Frequency".

Line 174: In Table 3, total population in indicated as 476 patients, but the sum of the groups separated according to age (60-74, 75-90 and more than 90 years old) results in 475 patients. Furthermore, some column headings require translation to English (e.g., "Factores", "Population 91 a mas", "IC" and "p. Valor"), "REF" meaning as "referential indicator variable as comparative in the group of variables analyzed" is not clear and red-colored p-values are not explained (probably, this color indicates statistical significance, but this was not made explicit). Besides, if "NS" stands for "Result is not statistically significant in the observed group" as indicated in the table footer, why some p values greater than 0.05 (e.g., 0.101, 0.763 and 0.147 for variables in the age factor) are not expressed as "NS" too?

Lines 176-177: Clarify what "RF" stands for in the sentence "When analyzed by age group, in the 60-74 years age group, constipation, chronic obstructive pulmonary disease (COPD) and neoplasia were RF".

Line 178: Authors state that "Ceftriaxone treatment showed a protective effect" in the 60-74 year-old group, but Table 3 indicates that its hazard ratio (HR) for this group was 4.49.

Lines 180-181: The sentence "symptoms such as: general discomfort, dyspnoea, fever and methylprednisolone treatment and as PF cough and diarrhoea" makes no sense.

Lines 182: Clarify what "PF" stands for in the sentence "in the 91 years or older group, dislipidemia is confirmed as PF".

Lines 205-208: In the sentence "One study mentions that there are factors associated with sex, which could increase the higher mortality of the male sex [17], such as the X chromosome, sex hormones which could play a key role in the innate and adaptive immunity of female patients to the COVID-19 virus", it is confusing whether authors are referring to male or female patients.

Line 217: Figure 2 should be in the results section of the manuscript, not in its discussion section. Besides, the graph shown in Figure 2C has no title for the y axis and unit for the x axis as well as requires translation of its color legend to English.

Line 227: Correct "covid-19" to "COVID-19" in the sentence "immobility and higher mortality due to covid-19".

Lines 228-229: Authors state that "mortality in patients with immobility increases from 23% to 53% as age increases", but this is not consistent with the data shown in Table 1. Besides, "the" must start with a capital letter in the sentence "the lethality rate in relation to recurrent falls".

Lines 246-247: Correct "5-90 years" to "75-90 years" in the sentence "older persons with atrial fibrillation had a higher risk of mortality (total population and 5-90 years)".

Lines 250-251 and 264: Delete the comma in the sentences "Chronic obstructive pulmonary disease (COPD) (Table 3), was associated with a higher risk of mortality in the 60 to 74 year group" and "In patients, with associated immobility syndrome".

Lines 273-274 and 278-279: Insert a period at the end of the sentences "Another study, suggested that anticoagulation for 7 days or longer may improve outcomes in hospitalized patients" and "Interestingly, several studies have associated greater benefit with therapeutic anticoagulation compared with prophylactic anticoagulation".

Line 296: Delete "on" in the sentence "several studies have reported on different results".

Lines 332-334: Correct "COVID" to "COVID-19" and replace the second "and" with "as well as" in the sentence "This study may help to improve the prognosis of older COVID patients in countries that do not yet have good vaccination coverage and health infrastructure and good monitoring programmes".

Author Response

The authors appreciate the subjection provided by review.

Reviewers 3:

Comments and Suggestions for Authors

We have included this information in the sample section:

In the general registry, 683 patients were entered, within the registry there were cases of patients whose length of stay in the study was not considered, since these had negative or atypical PCR dates.

These patients were considered and evaluated in the general descriptive analysis but were not considered in the Kaplan Meier survival analysis and Cox regression analysis, because these would produce a bias or error in the final analysis.

Lines 41-41: Update the number of cases and deaths related to COVID-19 in the sentence "by March 2020, SARS-CoV-2 had infected more than 87,137 people, with more than 2,977 deaths worldwide".

Line 162: Translate "Total de Pacientes" to English.

We have made the requested change, please use table 1 in excell attachment.

Line 167: In Table 2, correct "Frecuency" to "Frequency".

We have made the requested change, please use table 2 in excell attachment.

Response to reviewer:

We have made the requested change, please use table 3 in excell attachment.

The addition of all patient groups is 475 patients, from 60 to 74 (55 patients), from 75 to 90 (296 patients) and from 91 to more (124 patients)

Translation into English of the words population, factors.

"REF" meaning as "referential indicator variable as comparative in the group of variables analyzed" is not clear and red-colored p-values are not explained (probably, this color indicates statistical significance, but this was not made explicit). Besides, if "NS" stands for "Result is not statistically significant in the observed group" as indicated in the table footer, why some p values greater than 0.05 (e.g., 0.101, 0.763 and 0.147 for variables in the age factor) are not expressed as "NS" too?

Response to reviewer:

We have made the requested change, please use table 3 in excell attachment.

When performing the analysis of the multivariate model in the statistical software SPSS. It takes as a reference group the group of 60-74 with the other groups studied from (75 to 90) and (91 or more). Resulting in the Hazard ratio and confidence intervals for the groups studied.

Correction in table 3 of the level of significance in black and results of the age groups with p-value not significant with the acronym NS.

We have made the requested change

Line 178: Authors state that "Ceftriaxone treatment showed a protective effect" in the 60-74 year-old group, but Table 3 indicates that its hazard ratio (HR) for this group was 4.49.

Response to reviewer:

Line 178 correction, the Hazard ratio (HR) for the age group 60-74 for patients receiving Ceftriaxone treatment has no protective effect since this group has a Hazard ratio of 4.49.

Lines 180-181: The sentence "symptoms such as: general discomfort, dyspnoea, fever and methylprednisolone treatment and as PF cough and diarrhoea" makes no sense.