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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 4  |  Page : 211-216

Prognosis and sequelae of severe COVID-19 patients after 6 months of hospital discharge: A retrospective cohort study


Emergency and Critical Care Center, Kishiwada Tokusyukai Hospital, Osaka, Japan

Date of Submission08-May-2022
Date of Acceptance11-Jul-2022
Date of Web Publication26-Dec-2022

Correspondence Address:
Dr. Daiki Shirasu
15-12-401 Harukiwakamatsu-cho, Kishiwada-City, Osaka
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijciis.ijciis_38_22

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   Abstract 


Background: We investigated the prognosis, sequelae, and related factors of severe coronavirus disease (COVID-19) patients who required invasive mechanical ventilation 6 months after discharge from the hospital.
Methods: COVID-19 patients admitted to Kishiwada Tokusyukai Hospital between April 1, 2020, and May 31, 2021, and treated with an invasive mechanical ventilator were included in this study. We conducted a telephone visit 6 months after discharge to confirm survival and asked questions about sequelae.
Results: The mortality rate 6 months after discharge was 7.4%. Tracheostomy (odds ratio [OR], 0.03; 95% confidence interval [CI], 0.003–0.26), high Acute Physiology and Chronic Health Evaluation II score (16.0 [interquartile range [IQR], 11.5–17.2] vs. 11.0 [IQR, 8.0–14.0]), prolonged hospital stay (17.0 [IQR, 12.7–24.5] vs. 10.0 [IQR, 8.0–13.0]), and prolonged ventilation duration (12.5 [IQR, 10.7–20.0] vs. 8.0 [IQR, 6.0–11.0]) were associated with the risk of death. Moreover, 49% of the patients had residual disability. The most common sequelae were hoarseness, respiratory distress on exertion (31% of symptomatic patients), and muscle weakness (22%). The prone positioning therapy (OR, 5.55; 95% CI, 1.35–32.97) was associated with hoarseness, and the use of muscle relaxants (OR, infinity; 95% CI, 1.14–infinity) was a risk factor for muscle weakness.
Conclusion: Although the mortality rate after the acute phase of COVID-19 was not high, many patients experienced sequelae. Careful treatment should be continued after the end of acute treatment for patients with prolonged respiratory failure due to COVID-19. Muscle relaxants and prone positioning therapy may cause sequelae and should be performed carefully.

Keywords: Complications, COVID-19, life expectancy, risk factors, severe acute respiratory syndrome coronavirus-2


How to cite this article:
Shirasu D, Shinozaki M, Iino T, Kaji A. Prognosis and sequelae of severe COVID-19 patients after 6 months of hospital discharge: A retrospective cohort study. Int J Crit Illn Inj Sci 2022;12:211-6

How to cite this URL:
Shirasu D, Shinozaki M, Iino T, Kaji A. Prognosis and sequelae of severe COVID-19 patients after 6 months of hospital discharge: A retrospective cohort study. Int J Crit Illn Inj Sci [serial online] 2022 [cited 2023 Jan 29];12:211-6. Available from: https://www.ijciis.org/text.asp?2022/12/4/211/364742




   Introduction Top


Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread rapidly from China to the rest of the world in 2019 and is still not under control 2 years later. COVID-19 causes severe respiratory failure in more patients than influenza virus infection and other viral infections.[1] COVID-19 patients have been reported to have various symptoms that persist even after surviving the acute phase.[2] However, there have been no reports examining risk factors for long-term prognosis and sequelae in severe COVID-19 patients requiring invasive mechanical ventilation (IMV). We aimed to examine the prognosis and sequelae of severe COVID-19 patients 6 months after discharge from the hospital and the factors associated with these prognoses and sequelae.


   Methods Top


Study design and setting

We performed a retrospective observational study using data from electronic medical records. Informed consent was obtained from each patient during the telephone visit.

Selection of participants

We included patients who were admitted to Kishiwada Tokushukai Hospital (Osaka, Japan) between April 1, 2020 and May 31, 2021. All the patients were admitted with COVID-19, which was confirmed by a loop-mediated isothermal amplification assay or real-time reverse transcription–polymerase chain reaction assays from nasal swab samples. All the patients were treated in a ward in the Emergency and Critical Care Center, which has the same function as the intensive care unit.

Patients who did not receive IMV, who died during hospitalization, who could not be weaned from the ventilator at discharge, and who could not be followed up after 6 months of discharge were excluded from the life expectancy study (Group 1). Furthermore, patients who were deceased at follow-up and those who were unable to report their own sequelae by telephone due to their tracheostomy status were excluded from Group 1 and included in the study of sequelae (Group 2). All eligible patients were at least 18 years old. No patient was excluded due to age or previous illness.

Patient and public involvement

No patient was involved in the design of this study.

Interventions

Six months after discharge from our hospital, we called the patients to confirm whether they were still alive and asked them whether they had any sequelae. If any symptoms remained, they were asked to describe them using an open-ended question.

Measurements

The blood test values used in this study were obtained on the 1st day of admission to our hospital. If the measured value exceeded the upper limit, the upper limit was used as a substitute. We used the first partial pressure of oxygen in arterial blood value after intubation for patients who were intubated at our hospital and the first value measured at our hospital for patients who were transferred to our hospital after intubation. The Sequential Organ Failure Assessment score and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were also determined using the results of blood tests and blood gas analysis, which were measured for the first time in our hospital. The items extracted from the electronic medical record were those considered to be critical factors for COVID-19 and those associated with lung damage. Because some of these tests were only performed at the time of admission, blood test values were taken from the time of admission, not immediately before discharge. We used the last chest radiograph obtained during the hospital stay for scoring. The percentage of infiltrated shadows in 0% of the lung field was scored as 0, 1%–25% as 1, 26%–50% as 2, 51%–75% as 3, and 76%–100% as 4, similar to the Murray score.[3]

Outcomes

We examined mortality and sequelae 6 months after discharge from our hospital. In a subanalysis, we examined the factors influencing mortality and residual disability. When studying factors affecting sequelae, we examined the symptoms that most patients complained of and whether the items that seemed to be associated with each symptom were risk factors for each symptom.

Analysis

All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed with additional statistical functions frequently used in biostatistics.[4] A two-sided P < 0.05 was considered statistically significant. Fisher's exact test was used to evaluate univariate associations of categorical variables. Quantitative variables were compared using the Mann–Whitney U-test according to data distributions and variances. We noted results using numbers, medians, proportions, interquartile ranges (IQRs), odds ratios (ORs), and 95% confidence intervals (95% CIs). All of them were quantified using EZR. Given that the missing values had no substitutes, they were added into the analysis as such.

This study was not funded by any of the authors. The corresponding author has full access to all the data in the study and had the final responsibility for the decision to submit for publication.


   Results Top


Characteristics of study subjects

During the study period, 168 patients were admitted to our hospital for COVID-19. We excluded 9 nonintubated patients, 38 patients who died during hospitalization, 12 patients who could not be weaned from the ventilator at the time of discharge from our hospital, and one patient who could not be followed up. A total of 108 patients (Group 1) were included in the life expectancy study. For the study of sequelae, we excluded eight patients who died 6 months after discharge from our hospital and one patient who did not voluntarily report sequelae by telephone due to tracheostomy, and 99 patients (Group 2) were included [Figure 1]. We followed up the patients till 6 months after discharge from our hospital, but the specific number of days until follow-up is unknown.
Figure 1: The relationship between prognosis and related factors was assessed in Group 1. The relationship between sequelae and related factors was assessed in Group 2

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Main results

Six months after discharge from our hospital, 8 (7.4%) patients died. [Table 1] shows the baseline for the survival and death groups. Results of the analysis showed that tracheostomy (OR, 0.03; 95% CI, 0.003–0.26), high APACHE II score (16.0 [IQR 11.5–17.2] vs. 11.0 [IQR 8.0–14.0]), prolonged hospitalization days (17.0 [IQR 12.7–24.5] vs. 10.0 [IQR 8.0–13.0]), and prolonged ventilation days (12.5 [IQR 10.7–20.0] vs. 8.0 [IQR 6.0–11.0]) were associated with death at 6 months [Table 2]. Next, the study results on sequelae showed that 49 patients (49% of Group 2 participants) complained of symptoms 6 months after discharge. [Table 3] shows the symptoms and percentages of the patients with sequelae. The most common symptoms were hoarseness and respiratory distress on exertion (31% of symptomatic patients), followed by muscle weakness (22%) and hair loss (16%). Of the 15 patients who complained of respiratory distress on exertion, only one required oxygen therapy.
Table 1: Baseline data of the survival and death groups

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Table 2: Demographic and clinical characteristics of the patients

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Table 3: Description and percentage of sequelae in patients discharged from our hospital (n 49)

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For the three most common sequelae, hoarseness, respiratory distress on exertion, and muscle weakness, we investigated whether the items that may be associated with each symptom were risk factors. As a result, no factor was associated with respiratory distress during exertion [Table 4]. However, prone positioning therapy was associated with hoarseness (OR, 5.55; 95% CI, 1.35–32.97), and the use of muscle relaxants was a risk factor for muscle weakness (OR, infinity; 95% CI 1.14–infinity) [Table 5] and [Table 6].
Table 4: Risk factors for respiratory distress

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Table 5: Risk factors for hoarseness

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Table 6: Risk factors for weakness

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   Discussion Top


Our hospital is an acute care hospital located in the southern part of Osaka Prefecture, Japan. Regarding the treatment of COVID-19 patients, only severe cases requiring IMV are handled. In Osaka, the coordinating department of the prefecture selects hospitals for the hospitalization of COVID-19 patients according to the severity of the disease. Our hospital provides treatment for patients requested by the department. The patients are transported to our hospital either as a transfer from a mild to moderate care hospital or as a direct transfer from an ambulance. Patients who have completed treatment with a ventilator at our hospital and are extubated or require a tracheostomy but can be weaned from the ventilator are transferred to a hospital for moderate illness selected by the coordinating organization again and then discharged home after rehabilitation. As we accept patients based on this system, our patients have a consistent background in terms of the severity of illness.

Previous studies have identified men, the elderly, obesity, and coagulation disorders as risk factors for poor life expectancy.[5],[6] We showed that tracheostomy, high APACHE2 scores, prolonged hospitalization days, and prolonged ventilation days were associated with death 6 months after discharge.

In our hospital, tracheostomy was performed when the patient had prolonged respiratory failure and was not expected to be weaned from the ventilator for a long time. Furthermore, because the above system determines the admission and discharge of patients, prolonged hospitalization indicates prolonged ventilation periods. Therefore, both the practice of tracheostomy and prolonged hospital stay indicates that respiratory failure is prolonged. Patients who could not be weaned from the ventilator were excluded from the study, but even if they were finally weaned from the ventilator at discharge, the prolonged respiratory failure might have affected their long-term prognosis.

Regarding sequelae, previous studies with a population of more than 100 patients have reported on patients with mild to moderate disease, but there have been no reports on severe cases requiring artificial IMV 6 months after hospital discharge.[7]

In the literature on 2649 patients with mild to moderate disease, Munblit et al. found that 57.9% of patients had residual symptoms 7 months after discharge, including 21.2% with fatigue, 14.5% with respiratory distress on exertion, and 7.1% with hair loss.[7] None of the patients complained of hoarseness.[8] Taboada et al. reported that among 92 severe patients with residual symptoms 6 months after discharge, 57.1% had respiratory distress on exertion. There was no mention of muscle weakness, hair loss, or hoarseness.[9]

Compared to our results, the number of patients complaining of dyspnea on exertion was higher than that reported by Munblit et al.[7] and lower than that reported by Taboada et al.[8] The number of patients complaining of muscle weakness was similar to that reported by Munblit et al.[7] We found cases of patients who complained of hoarseness in our study. This did not correlate with IMV duration but was thought to be due to the tracheal intubation procedure itself and performing prone positioning therapy, which causes the intubation tube to compress around the vocal cords. Both the use of muscle relaxants and prone positioning therapy correlated with muscle weakness. In our hospital, muscle relaxants are often administered continuously when prone positioning therapy is performed, and muscle relaxants may be the most relevant cause of muscle weakness.

This study has several limitations. First, it was a single-center study. Although we followed the Japanese treatment guidelines, the treatment methods differ across facilities. Moreover, the use of therapeutic drugs and the implementation of prone positioning therapy have also changed over time in our hospital. Moreover, as a single facility, the number of severely ill COVID-19 patients was limited. Therefore, only eight patients were in the survival group 6 months after discharge from the hospital, and a multivariate analysis could not be performed.

Second, this study did not consider the differences in symptoms and severity of illness among SARS-CoV-2 variants. During the period covered by this study, the prevalent strains in Japan were mainly B.1.1.7 strain (alpha strain) and B.1.617.2 strain (delta strain). However, not all patients were tested for mutant strains. The mutant strain of B1.1.529 (Omicron strain), which is currently prevalent, is said to be more infectious but less severe than previous strains.[9] However, this study did not take these differences into account.

Third, in this study, open-ended interviews were conducted regarding the nature of the sequelae. Open-ended interviews may result in a smaller number of answers than survey forms with multiple answers for participants to choose from. Therefore, the content and rate of sequelae may be underestimated compared with those in other studies.


   Conclusion Top


After 6 months of discharge, the mortality rate in patients with severe COVID-19 who required IMV was 7.4%. Tracheostomy, high APACHE II scores, prolonged hospital stays, and prolonged ventilation days were associated with the risk of death. Moreover, 49% of the patients had residual symptoms. The most common sequelae were hoarseness, respiratory distress on exertion (31%), and muscle weakness (22%). Factors leading to muscle weakness include the use of muscle relaxants and prone positioning therapy. Many patients recovered from COVID-19 and survived but were plagued by sequelae. People who have prolonged respiratory failure due to COVID-19 should continue treatment cautiously after completing acute therapy. In addition, muscle relaxants and prone positioning therapy may cause sequelae and should be performed carefully.

Research quality and ethics statement

This study was approved by the Institutional Review Board/Ethics Committee at Kishiwada Tokushukai Hospital (Approval # 21-13; Approval date January 31, 2022). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guideline, specifically the STROBE guideline, during the conduct of this research project.

Acknowledgement

We would like to thank Editage (www.editage.com) for English language editing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
da Costa VG, Saivish MV, Santos DE, de Lima Silva RF, Moreli ML. Comparative epidemiology between the 2009 H1N1 influenza and COVID-19 pandemics. J Infect Public Health 2020;13:1797-804.  Back to cited text no. 1
    
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Raveendran AV, Jayadevan R, Sashidharan S. Long COVID: An overview. Diabetes Metab Syndr 2021;15:869-75.  Back to cited text no. 2
    
3.
Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988;138:720-3.  Back to cited text no. 3
    
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Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013;48:452-8.  Back to cited text no. 4
    
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Shahbazi F, Karami M, Mirzaei M, Mohammadi Y. Survival rates and prognostic factors in patients with coronavirus disease 2019: A registry-based retrospective cohort study. J Res Health Sci 2021;21:e00515.  Back to cited text no. 5
    
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Günster C, Busse R, Spoden M, Rombey T, Schillinger G, Hoffmann W, et al. 6-month mortality and readmissions of hospitalized COVID-19 patients: A nationwide cohort study of 8,679 patients in Germany. PLoS One 2021;16:e0255427.  Back to cited text no. 6
    
7.
Munblit D, Bobkova P, Spiridonova E, Shikhaleva A, Gamirova A, Blyuss O, et al. Incidence and risk factors for persistent symptoms in adults previously hospitalized for COVID-19. Clin Exp Allergy 2021;51:1107-20.  Back to cited text no. 7
    
8.
Taboada M, Moreno E, Cariñena A, Rey T, Pita-Romero R, Leal S, et al. Quality of life, functional status, and persistent symptoms after intensive care of COVID-19 patients. Br J Anaesth 2021;126:e110-3.  Back to cited text no. 8
    
9.
Wolter N, Jassat W, Walaza S, Welch R, Moultrie H, Groome M, et al. Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: A data linkage study. Lancet 2022;399:437-46.  Back to cited text no. 9
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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