Comparison of post-COVID symptoms in patients with different severity profiles of the acute disease visited at a rehabilitation unit.

BACKGROUND AND AIM: Studies in the literature suggest the severity of COVID-19 may impact on post-COVID sequelae. We retrospectively compared the different patterns of symptoms in relation to the severity of acute COVID-19 in patients visited at our post-COVID rehabilitation unit.
METHODS: We compared respiratory, muscular, cognitive, emotional, and health-related-quality-of-life (HRQoL) measures in three groups of post-COVID patients: those who had not required hospitalization for the acute disease, those who had been admitted to a general hospital ward, and those who had been admitted to the ICU. The main inclusion criteria were persistent dyspnoea (mMRC ≥2) and/or clinical frailty (scale value ≥3).
RESULTS: We analyzed data from 178 post-COVID patients (91 admitted to the ICU, 60 to the ward, and 27 who had not required admission) at first visit to our post-COVID rehabilitation unit. Most patients (85.4%) had at least one comorbidity. There were more males in all groups (58.1%). ICU patients were older (p<0.001). The most frequent symptoms in all groups were fatigue (78.2%) and dyspnea (75.4%). Muscle strength and effort capacity were lower in the ICU group (p<0.001). The SF36 mental component and level of anxiety were worse in patients not admitted to the ICU (p<0.001). No differences were found between groups regarding respiratory pressure but 30 of 57 patients with a decrease in maximum inspiratory pressure had not required mechanical ventilation.
CONCLUSION: Clinical profiles of post-COVID syndrome differed between groups. Muscle parameters were lower in the ICU group but patients who had not needed ICU admission had worse anxiety and HRQoL scores. Many patients who had not required mechanical ventilation had respiratory muscle weakness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04852718.

Introduction

The persistence of symptoms after COVID infection is commonly referred to as post-acute COVID syndrome (PACS). Although there is no consensus, PACS is generally considered to include two subgroups, patients with prolonged or persistent PACS and patients with sequelae. Prolonged PACS syndromes are defined as the persistence of symptoms 4 weeks after the acute COVID infection, with an on-going, relapsing/remitting, or progressively improving course. The sequelae subgroup is defined as the presence of irreversible tissue damage 12 weeks after the acute disease. Such injuries can trigger varying degrees of permanent dysfunction and the corresponding symptomatology [1]. Mumoli et al. [2] suggest that these symptoms could be due to an aberrant immune response. The prevalence and clinical presentation of PACS is heterogeneous. The most frequent symptoms are fatigue, (52%), cardiorespiratory symptoms (mainly dyspnoea on exertion) (30–42%), and neurological symptoms (40%) [1].

According to various authors, following acute COVID-19 infection, approximately 45% of patients require healthcare support after discharge and around 5–10% have low functional capacity at 3, 6 and 12 months [3-6]. In a cohort of adult patients hospitalized for mild to severe COVID-19, Betschart et al. [3] found functional limitations persisted one year after hospitalization, and suggested that specific individualized support should be continued until full recovery. Along similar lines, another recent study [7] analyzed the need for health resources due to the persistence of symptoms in three profiles of post-COVID patients who presented sequelae at 6 months after COVID-19 infection (non-hospitalized, hospitalized, and ICU patients). The results showed that although the three groups of patients presented a high health burden, the more severe the acute illness, the greater the needs. The authors suggested that long-term multidisciplinary care is warranted for patients with sequelae of COVID-19.

Several guidelines have proposed specific and multidimensional rehabilitation programs to address this clinical situation [8, 9]. At our hospital, a post-COVID rehabilitation facility (MPCR) was established with the collaboration of a multidisciplinary team of rehabilitation physicians, pneumologists, physiotherapists, occupational therapists and speech therapists.

With the hypothesis that symptoms and limitations of post-COVID syndrome could differ according to the severity of the acute disease, our objective was to compare the patterns of symptoms in patients seen at our post-COVID rehabilitation unit in relation to the severity of acute COVID-19.

Material and method

Design

We performed a retrospective observational study based on medical records from the first consultation at the MPCR.

Inclusion criteria were: 1) patients who had had COVID-19 infection confirmed by a serological or molecular test (PCR); 2) living at home; 3) a negative PCR or IgM at initial evaluation in the MPCR or at least 28 days after diagnosis; 4) symptoms (mMRC ≥2 and/or clinical frailty scale value ≥3). Exclusion criteria were: 1) active COVID infection; 2) previous cognitive impairment; and 3) residence outside the hospital’s health care service area.

The study was approved by the local clinical research ethics committee (IIBSP-COV-2020-155). Data collected were recorded expressly for the purpose of the study. Informed consent from patients was waived in view of the retrospective nature of the study. The trial was registered in ClinicalTrials.gov (NCT04852718).

Evaluation measures

Our post-COVID rehabilitation consultation was started in June 2020. The patients were referred to our rehabilitation unit from primary care (GP), from the pneumology outpatient department, or at discharge from hospital.

The time elapsed between recovery from the acute disease and visit to the MPCR varied from 3 to 9 months.

From the medical records gathered at first visit to the MPCR we assessed the following variables: 1) the Barthel index (BI) [10]; 2) cognitive status according to the Pfeiffer scale [11]; 3) dyspnoea in daily activities according to the Medical Research Council (mMRC) scale [12]; 4) anxiety and depression with the HADS scale [13]; 5) health-related-quality-of-life (HRQoL) with the generic SF-36 questionnaire [14]; 6) muscle strength scale (mMRC) [15]; 7) the short physical performance battery (SPPB) for frailty [16]; 8) manual dynamometry using the Jamar Hydraulic Hand Dynamometer [17]; 9) effort capacity with the 6-minute walk test-6MWT [18];10) oxygen saturation (SpO2) during the 6MWT; 11) respiratory muscle strength measured by maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax) [19]; with the Pocket Spiro MPM-100 device; and 12) the EAT-10 Dysphagia questionnaire [20].

Based on the results from this assessment, the team decided whether or not the patient’s required rehabilitation.

Statistical analysis

Analysis of variance (ANOVA) was used for quantitative variables, providing the mean and its corresponding standard deviation for each group. If significant, the post-hoc Scheffe test was also used. In the case of categorical variables, the Chi square was used, providing the absolute value (frequency) and its percentage. The Pearson correlation coefficient was used for quantitative variables, and the non-parametric Spearman test was used to validate the results.

The probability of a type I error was set to the value of 5% (alpha = 0.05). All analyses were performed using the statistical package IBM-SPSS statistics (V26.0).

Results

Sample description

From June 2020 to June 2021, we recorded data from 178 patients. There was a predominance of men (58.9% vs 41.1%), and mean age was 59.6±11.6 years. One hundred and fifty-two patients had required hospital admission, 91 of whom were admitted to the intensive care unit (ICU). The mean hospital stay for the total group of patients was 34.8±32.8 days (range from 1 to 227). Most of the patients attended had COVID-19 in the first wave of the disease. Regarding the patients admitted to the ICU or the conventional ward, the mean time from hospital discharge and the first visit to the MPCR was 109.7±79.6 days (range 12 to 432 days), this period was longest in patients admitted during the first wave than the third wave (Table 1).

Table 1

General characteristics of patients according to the three pandemic waves analysed.

PATIENTS	TOTAL	P	1st Wave	P1	2nd Wave	P2	3rd Wave	P3
N (%)	178		115 (64,6%)		19 (10.7%)		44 (24.7%)
Male n (%)	105 (58.9%)	0.023	57 (49,7.4)	0.055	14 (73.7%)	0.794	31 (70.5%)	0.021
Age (years)	59.6±11.6	0.034	58.9±11.9	0.494	55.3±13.6	0.046	63.0±8.8	0.139
ICU Admission (n/%)	91 (51.1%)	< 0.001	43 (37.4%)	0.117	10 (52.6%)	0.014	38 (86.4%)	< 0.001
Ward (n/%)	60(34%)		51 (44.3%)		4 (21.1%)		4 (9.1%)
No Admission (n/%)	27 (15.3%)		20(17.4%)		5 (26.3%)		2 (4.5%)
Hospital discharge / Visit (days)	109.7±79.6	< 0.001	136.7 ±87.5	0.221	100.3±55.4	0.141	56.4±20.5	< 0.001

1 Wave from March to May 2020; 2 Wave from July to October 2020; 3 Wave: from December 2020 to February 2021; p = comparison between the three waves; p1 = comparison between 1st wave and 2nd wave; p2 = comparison between 2nd and 3rd wave; p3 = comparison between 1st and 3rd wave.

Patients admitted to the ICU were older than patients in the other two groups and there were more males (p<0.001) (Table 1). ICU patients had a mean stay of 26.8±19.4 days (range 3 to 107). They all required invasive mechanical ventilation (IMV). Tracheotomy was needed in 34 (37.4%) patients, pronation techniques in 41 (45.1%) and ECMO in 10 (9.1%).

One hundred and fifty-two of the 178 patients (85.4%) had at least one comorbidity before COVID-19 infection without differences between groups (Table 2). These comorbidities were obesity (43.6%), arterial hypertension (AHT) (36.3%), respiratory disease (33%), and heart disease (13.4%). ICU Patients had a higher number of cardiovascular comorbidities such as heart disease (p = 0.02) and AHT (p = 0.01) than the other two groups.

Table 2

Characteristics of the patients and results of the evaluation measures according to the severity profile.

	TOTAL	p	ICU	P1	WARD	P2	No Admission	P3
N	178		91 (51.1%)		60 (33.7%)		27 (15.2%)
Male (n / %)	105 (58.9%)	<0.001	65 (71.4%)	0.008	30 (50%)	0.145	9 (33.3%)	<0.001
Age	59.6±11.6	<0.001	63.3 ± 9.9	0.025	58.5 ± 11.7	0.010	50.9±12.5	< 0.001
Comorbidities	152 (85,4%)	0.609	80 (87.9%)	0.430	50 (83.3%)	0.833	22 (81.5%)	0.406
Barthel Index	96.5±7.7	0.002	94.5±9.6	0.012	98.2±4.5	0.896	99.3±3.8	0.014
Cognitive impairment (Pfeiffer) n/%	11 (6,2%)	0.121	7 (7.8%)	0.078	1 (1.7%)	0.064	3 (11.1%)	0.597
mMRC dyspnoea (n /%)	134 (75.3%)	0.682	66 (72.5%)	0.418	47 (78.3%)	0.954	21(77.8%)	0.581
HAD anxiety n/%	56 (31.5%)	0.001	17 (18.7%)	<0.001	28 (46.7%)	0.606	11(40.7%)	0.023
HAD depression n/%	42 (23.6%)	0.096	16 (17.6%)	0.185	16 (26.7%)	0.333	10 (37%)	0.04
SF36 PCS	36.4±9.4	0.254	36.9±9.5	0.99	37±9.1	0.3	33.4±9.6	0.308
SF 36 MCS	44.6±11.8	0.007	47.7±10.9	0.008	41±11.1	0.658	43.6±13.8	0.397
mMRC strength	57.6±3.9	<0.001	56.3±4.5	<0.001	58.8±2.5	0.891	59.3±1.1	0.002
SPPB	9.6±2.6	0.155	9.3±2.8	0.269	10±2.3	0.954	10.2±2.1	0.335
Dynamometry impairment n/%	146 (82.5%)	0.001	83 (92.2%)	<0.001	41 (68%)	0.193	22 (81.5%)	0.129
P6MM (meters)	435.9±138	0.001	403.8±140.8	0.120	450.1±138.9	0.145	512.1±85.2	0.002
Desaturation (SpO 2 ) (n)	26 (14.6%)	0.006	18 (69.2%)	0.298	8 (30.8%)	0.012	0	0.001
PImax (cmH 2 O)	79.1±26.6	0.279	82.1±28.2	0.51	76.9±27.1	0.89	73.9±18.1	0.38
PEmax (cm H 2 O)	101.8±27.3	0.881	102.5±24.3	0.9	100.3±34.9	0.93	102.7±16.1	0.99

ICU: patients admitted to the intensive care unit, general ward, and not admitted. mMRC: Modified Medical Research Council scale; HAD: hospital anxiety and depression questionnaire SF36: quality of life questionnaire; 6MWT: 6-minute walk test; SpO2: oxyhemoglobin saturation; PImax: maximum inspiratory pressure; PEmax: maximum expiratory pressure. p = comparison between the three groups; p1 = comparison between ICU-ward; p2 = comparison between ward—no admission; p3 = comparison between ICU-no admission.

The most frequent complications in patients admitted to the hospital (ICU or conventional ward) were muscular weakness (42.4%), neurological (19.2%), respiratory (18.1%), or cardiologic (9.6%) complications and pulmonary thromboembolism (8.5%). Thirteen patients of the 41 ICU (31.7%) patients who required pronation techniques had peripheral neurological complications (neuropathy of the tibial, axillary or ulnar nerves). There was a positive correlation (p<0.01) between these complications and pronation.

The symptoms reported at the first visit of the MPCR were fatigue (78.2%), dyspnoea (75.4%), effort intolerance (27%), neurological alterations (distal paraesthesia or motor deficit) (26%), and anxious-depressive syndrome 14.5%.

Outcomes

The mean BI for all groups was 96.5±7.7 (range 64–100), with moderate dependence (BI<60) in 2% and mild dependence (BI<90) in 14.5% of patients. The BI was lower in ICU patients (p = 0.002).

Eleven patients (6.2%) showed cognitive impairment according to the Pfeiffer scale. These patients were all referred to the neuropsychology clinic and mild-moderate impairment was confirmed in 8. There were no differences between groups. In 25 patients (14%) who reported memory loss or difficulty concentrating, the Pfeiffer score was normal. In 14 of these 25 patients, a neuropsychological evaluation was done and 12 patients showed mild-moderate cognitive impairment. The total number of patients with cognitive impairment was therefore 20 (11.2%).

The mMRC scale revealed dyspnoea in 134 patients (75.3%), with a score of 1 in 56 and scores of 2 to 3 in the remaining group. There were no significant differences between groups.

According to the HADs scale, anxiety was detected in 56 patients, with a mean value of 6.27±4.2 (range 1 to 21). Anxiety was more common in patients admitted to a general ward and in those not admitted to hospital than in patients admitted to the ICU (p<0.001). Depression was diagnosed in 42 patients, with a mean value of 5.27±3.8 (range 1 to 15). It was more common in patients who were not admitted to hospital (p = 0.04).

HRQoL showed a clear deterioration with a mean value of 36.4±9.4 in the physical component and 44.6±11.8 in the mental component of the SF36 questionnaire. ICU patients had a better score in the mental component than those in the ward (p = 0.008).

The peripheral muscle strength study showed a mean value of the mMRC scale of 57.6 ±3.9 (38–60), being significantly lower in ICU patients (p<0.001).

The mean value of manual dynamometry was 16.6±7.2. We found values lower than reference values in 146 patients; 92.2% in the ICU, 68% in patients admitted to the ward, and 81.5% in not admitted patients (p<0.001).

The mean SPPB value was 9.6±2.6, without differences between groups. The value was below 9 in 61 patients (34.1%). Six of 61 patients (9.8%) were classified as disabled, 19 (31.1%) as frail and 36 (59%) as pre-frail.

The mean distance on the 6MWT was 435.9±138 (range 75 to 750) meters. Only eight patients had scores below the reference value. Patients admitted to the ICU walked less distance than those who were not admitted (p = 0.002), but there were no differences with those admitted to the ward.

Twenty-six patients presented desaturation (mean SpO2 < 90%) during the 6MWT, 18 in ICU patients, 8 in patients admitted to the ward, and none in the not admitted group. CO diffusion capacity (DLco) was only available for 15 of the 26 patients. Of these, 8 presented a decrease and 7 were normal.

The mean value of PImax was 79.1±26.6 cmH2O (range 23 to 157). In 57 patients (31.8%) the value was below the reference value. Twenty-seven of the 57 were admitted to the ICU and required IMV. The mean PEmax value, was 101.8±27.3 cmH2O, within the reference range in the three groups.

Swallowing disorders were detected in 16 patients: 8 ICU patients who required IMV, 7 general ward patients who did not require IMV, and 1 patient who did not need hospital admission.

The time elapsed between hospital discharge and first visit to the MPCR showed a positive correlation with BI, mMRC force and 6MWT score (p<0.001). We also found a positive correlation between the value of manual dynamometry, mMRC force, 6MWT and the physical component of the SF36 questionnaire (p = 0.001).

See all results in Table 2.

Discussion

In this comparison of post-COVID syndrome according to the severity of the acute disease, ICU patients had more severe muscular weakness, less anxiety and better HRQoL scores than patients in the conventional ward and patients not admitted to hospital.

In reference to BI, our patients showed a mild level of dependence. This contrasts with findings from other studies. Curci et al. [21] and Belli et al. [22] found a high level of dependence (BI<60) in patients admitted to their rehabilitation department, without differences between those who needed IMV and those who did not. The difference between our results and those of Belli and Curci may be because they evaluated patients immediately after hospital discharge while we evaluated patients at least 3 months after discharge. We found a positive correlation between the time from discharge and degree of functional capacity.

The Pfeiffer questionnaire showed low ability to detect cognitive impairment in our patients. This could explain the differences with the results from Johnsen et al. [23]. At the three-month follow up, these authors observed cognitive impairment in over 50% of their patients, predominantly in those who were hospitalized. In contrast, in our series we only found cognitive impairment in 11,2% of patients in the same clinical conditions as in Johnsen et al. study.

Dyspnoea appears to be a prevalent symptom in all studies [4–6, 24] and our findings coincide with these previous observations. The mMRC scale showed a good ability to detect dyspnoea in all three groups.

Also, in accordance with previous studies, we found anxiety and depression were high in patients with post-COVID syndrome. Several authors [4–6, 24–26] has attributed this to impaired functional capacity. Wang et al. [26] suggest male gender, older age, and less use of social media as predisposing factors. It is of note in our sample that patients admitted to the UCI had lower anxiety. We hypothesize that this may be due to the intensive monitoring since admission, the prompt rehabilitation, and patients’ relief at having overcome a critical situation.

Similarly, to other authors who measured HRQoL in post COVID patients we observed low values in all patients despite the different questionnaires used [27-30]. HRQoL is considered to be influenced by factors such as age, the need or not for IMV, length of hospital stay, male gender, comorbidities, and persistence of symptoms of the infection itself [28, 29]. In our sample the best scores in the SF-36 mental component were observed in ICU patients. Again, we hypothesize that the close supervision and earlier rehabilitation play an important role.

Muscular weakness is a predominate clinical sign in all series published to date [5, 6, 21, 22, 24] but few specify which tests were performed. Using SPPB, as in our study, Belli et al. [22], found functional capacity was worse than in our study, likely because they did perform this evaluation immediately after hospital discharge. However, like these authors, we not find differences between patients who needed IMV and those who did not. Therefore, coinciding with findings by Tanriverdi et al. [31], we found that ICU patients showed lower strength values than the other two groups according to measurements observed for mMRC force and manual dynamometry.

Concerning the 6MWT, although ICU patients covered a shorter distance, almost all our participants had a score within the reference value. These results support those of Eksombatchai et al. [32] who found no significant differences between patients with severe or mild disease at 2 months after COVID. However, our findings contrast with those of other authors who reported patients did not manage to finish the test or to walk less than 200 meters a several weeks [21] or even at 3 months after hospital discharge [27]. The high proportion of effort desaturation in our series contrast with that found by other authors [27, 32]. The reason for this difference could be because they did not measure this parameter during the 6MWT.

Respiratory muscles weakness is a frequent finding in COVID-19 patients receiving IMV. Using ultrasound, Farr et al. [33] showed those patients with COVID-19 and IMV treatment had a greater reduction in the contractile capacity of the diaphragm than patients with the same characteristics but without COVID. Moreover, Abodonya et al. [34] suggested that PImax could be altered in patients with post-Covid syndrome. Although they did not measure PImax, they showed that respiratory muscle training improves symptoms, lung function, HRQoL, and exercise capacity. In our study, we observed a high percentage of patients had a decrease in Pimax and more than half of them did not require IMV. We hypothesize that inspiratory muscle weakness maybe is due to factors other than IMV, such as the lack of early physiotherapy in non-ICU patient’s or the infection itself.

Strengths and limitations of the study

The main limitations of this study are its retrospective design and the different time lapses between recovery from the acute disease and performance of the MPCR. Moreover, the convenience sampling applied caused an imbalance in the distribution of the three groups.

Finally, fatigue was assessed only from the symptoms reported by the patients.

The main strength of our study is the comparison of post-COVID symptoms in three severity profiles of acute infection. This has been previously studied by Ziyed et al. [7] but our study included two further important aspects, HRQoL and respiratory muscle strength.

Conclusions

On comparing the clinical characteristics of post-COVID-19 in three severity profiles, we found muscle parameters were lower in the ICU group, anxiety and HRQoL scores were worse in patients who had not needed ICU admission, and respiratory muscle weakness was worse in patients who had not required mechanical ventilation.

We consider these findings emphasize the relevance of early rehabilitation and assessment of respiratory muscle strength in patients with post-COVID syndrome.

(XLSX)

Click here for additional data file.

31 May 2022

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Peter Schwenkreis

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please provide additional details regarding participant consent. In the Methods section, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors describe symptoms of patients who attended a Post-COVID Rehabilitation Consultation after acute COVID-19. Patients are categorized in no hospital treatment, hospital treatment, ICU and ventilation treatment. However, the baseline or reference groups for these categories are not known. I think the paper is interesting, however some weaknesses should be discussed. I hope my comment will be helpful

Comments

1. Abstract: First sentence

Little is known about the impact of the severity of COVID-19 on post-COVID sequelae.

I think this is not a fair statement. I would think, it is appropriate to write: Following literature, severity of COVID-19 seems to impact on post-COVID sequelae.

2. Introduction: Is the following sentence correct? The sequelae subgroup is defined as the presence of irreversible tissue damage 12 weeks …… Is it tissue damage or is it the persistence or emergence of symptoms?

3. I think you will have to elaborate on your study question. Now you write: “With the hypothesis that symptoms and limitations of post-COVID syndrome could differ according the severity of the acute disease, our objective was to compare these data in three severity profiles of COVID-19 infection.” However, all patients enrolled in your study took part in the Post-COVID Rehabilitation Consultation. Therefore, it is not possible to study the influence of severity of acute COVID-19 on Post-COVID symptoms. What you can study is the different patterns of symptoms in patients admitted to a rehabilitation program depending on severity of acute COVID-19. I think this is a relevant study questions as the patients might have different needs depending on symptoms.

4. The previous point considered, I suggest to think about the title of your paper. Isn’t it more a descriptive study of symptoms shown by patients coming for Post-COVID consultation to a clinic?

5. The introduction is very short. I think at least a few studies on risk factors for Post-COVID should be mentioned. Stick to the larger ones or the more recent ones for not getting overwhelmed.

6. Did you calculate a response rate?

7. Discussion: you write: “The Pfeiffer questionnaire showed low sensitivity to detect cognitive impairment in our patients.” Is it really sensitivity? Do you know the real proportion of patients with cognitive impairment?

8. Limitations and strength: your write: The main strength is that, to our knowledge, it is the first study to compare post-COVID symptoms in three severity profiles of acute infection. I am afraid, this is not correct. For an example please see Ziyad Al-Aly, Yan Xie, Benjamin Bowe Nature | Vol 594 | 10 June 2021.

8. Limitations: It should be mentioned that the non-hospital group is very small.

Good luck with the revision

Reviewer #2: My major comment concerns the different group seizes. I am no statistic expert, the very different group seizes complicate to rate the value of the results.

I have a view other comments:

Introduction: The sequelae subgroup is defined as the presence of irreversible tissue damage 12 weeks after the acute disease.

This is a very strict and clinically not helpful definition. How can a clinician know that the presenting symptoms are due to irreversible tissue damage? In particular the symptom fatigue eludes the problems of this definition.

It maybe helpful to make in the abstract transparent, that only patients with persistent dyspnoea or fraility were included in the study.

The assessment battery is differentiated. How were fatigue and fatigability measured?

How did the patients find the rehabilitation department? Was there a kind of admission by their GP? Could patients present themselves?

In the discussion section the authors stated, that dyspnoea appears to be a prevalent symptom, but this was one of their inclusion criteria.

History is a good predictor of anxiety and depression. How many patients had a history of anxiety and depression?

Quality of life is influenced by the presence of anxiety and depression. Not surprisingly the group with the lowest incidence of anxiety and depression has the best quality of life.

Concerning myopathy, is ICU acquired weakness, critical illness polyneuropathy and critical illness myopathy in the focus of the authors? How was the diagnosis myopathy made? Were there clinical neurophysiologic examinations? Was the diagnosis based on clinical examination? How likely were the acquired weaknesses after ICU stay due to a COVID specific pathophysiologic reason?

Concerning the conclusion, the effects of early rehabilitation were not the topic of the paper.

Why is the assessment of respiratory muscle strength important?

Why are anxiety and HRQol worse in non ICU patients? This two items may have a correlation. It could make sense to treat anxiety and depression.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Albert Nienhaus

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

29 Jun 2022

REVIEW COMMENTS TO THE AUTHOR

Peter Schwenkreis, Academic Editor

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

The manuscript meets the requirements of PlosOne journal, in our opinion.

2. Please provide additional details regarding participant consent.

The patients did not complete the informed consent, since it is a retrospective study, based on the data obtained in the medical records collected in our rehabilitation clinic.

We have added the following sentence in Material and methods:

“Informed consent from patients was waived in view of the retrospective nature of the study”.

3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016.

The corresponding author has the ORCID ID

Reviewer #1:

The authors describe symptoms of patients who attended a Post-COVID Rehabilitation Consultation after acute COVID-19. Patients are categorized in no hospital treatment, hospital treatment, ICU and ventilation treatment. However, the baseline or reference groups for these categories are not known. I think the paper is interesting, however some weaknesses should be discussed. I hope my comment will be helpful

Comments

1. Abstract: First sentence

Little is known about the impact of the severity of COVID-19 on post-COVID sequelae.

I think this is not a fair statement. I would think it is appropriate to write: Following literature, severity of COVID-19 seems to impact on post-COVID sequelae.

We have now reworded this sentence in the revised manuscript to read…

“Studies in the literature suggest the severity of COVID-19 may impact on post-COVID sequelae”

2. Introduction: Is the following sentence, correct? The sequelae subgroup is defined as the presence of irreversible tissue damage at 12 weeks.

Yes, this is correct. We defined the sequelae in accordance with the definition from a consensus in Catalonia (reference nº 1)

Is it tissue damage or is it the persistence or emergence of symptoms?

Regarding tissue damage or persistence of symptoms, this is not yet known. This point was discussed in the editorial of Munoli (reference 2) and in our consensus (reference 1). Because it is a very new clinical entity, we probably need more time to understand this.

3. I think you will have to elaborate on your study question. Now you write: “With the hypothesis that symptoms and limitations of post-COVID syndrome could differ according the severity of the acute disease, our objective was to compare these data in three severity profiles of COVID-19 infection.” However, all patients enrolled in your study took part in the Post-COVID Rehabilitation Consultation. Therefore, it is not possible to study the influence of severity of acute COVID-19 on Post-COVID symptoms. What you can study is the different patterns of symptoms in patients admitted to a rehabilitation program depending on severity of acute COVID-19. I think this is a relevant study questions as the patients might have different needs depending on symptoms.

Thank you for this suggestion.

We have now rewritten the objective (in the Abstract and in the Introduction), adding that the study is about patients visited at our rehabilitation unit.

In the abstract:

“We retrospectively compared the different patterns of symptoms in relation to the severity of acute COVID-19in patients visited at our post-COVID rehabilitation unit.”

In the introduction: “Our objective was to compare the patterns of symptoms in patients seen at our post-COVID rehabilitation unit in relation to the severity of acute COVID-19. “

4. The previous point considered; I suggest to think about the title of your paper. Isn’t it more a descriptive study of symptoms shown by patients coming for Post-COVID consultation to a clinic?

Yes, thank you. We have now added “visited at a rehabilitation unit”

“Comparison of post-COVID symptoms in patients with different severity profiles of the acute disease visited at a rehabilitation unit”

5. The introduction is very short. I think at least a few studies on risk factors for Post-COVID should be mentioned. Stick to the larger ones or the more recent ones for not getting overwhelmed.

We have now included findings from other studies as suggested by the reviewer: The text now reads:

“According to various authors, following acute COVID-19 infection, approximately 45% of patients require healthcare support after discharge and around 5-10% have low functional capacity at 3, 6 and 12 months3-6. In a cohort of adult patients hospitalized for mild to severe COVID-19, Betschart et al3 found functional limitations persisted one year after hospitalization, and suggested that specific individualized support should be continued until full recovery. Along similar lines, another recent study7 analyzed the need for health resources due to the persistence of symptoms in three profiles of post-COVID patients who presented sequelae at 6 months after COVID-19 infection (non-hospitalized, hospitalized, and ICU patients). The results showed that although the three groups of patients presented a high health burden, the more severe the acute illness, the greater the needs. The authors suggested that long-term multidisciplinary care is warranted for patients with sequelae of COVID-19.”

6. Did you calculate a response rate?

We could not calculate a sample rate because we analyzed the results retrospectively. All the patients were included.

7. Discussion: you write: “The Pfeiffer questionnaire showed low sensitivity to detect cognitive impairment in our patients.” Is it really sensitivity? Do you know the real proportion of patients with cognitive impairment?

In our opinion, the Pfeiffer questionnaire was not sensitive in our patients. As this is a descriptive study only, we cannot determine the exact proportion of patients with this impairment.

8. Limitations and strength: your write: The main strength is that, to our knowledge, it is the first study to compare post-COVID symptoms in three severity profiles of acute infection. I am afraid, this is not correct. For an example please see Ziyad Al-Aly, Yan Xie, Benjamin Bowe Nature | Vol 594 | 10 June 2021.

We thank the reviewer for the bibliographic citation of Ziyed et al. We were unaware of this study. It is indeed important to consider it because it compares the same patient profiles as in our study. We have now added a paragraph in the introduction (see point 5) and added a comment in the section of limitations and strengths. It reads as follows:

“The main strength of our study is the comparison of post-COVID symptoms in three severity profiles of acute infection. This has been previously studied by Ziyed et al7 but our study included two further important aspects, HRQoL and respiratory muscle strength.”

.

9. Limitations: It should be mentioned that the non-hospital group is very small.

We think we have made this clear now too.

“The main limitations of this study are its retrospective design and the different time lapses between recovery from the acute disease and performance of the MPCR. Moreover, the convenience sampling applied caused an imbalance in the distribution of the three groups”

Good luck with the revision. Thank you very much for the helpful suggestions.

Reviewer #2:

My major comment concerns the different group seizes. I am no statistic expert; the very different group seizes complicate to rate the value of the results.

As our study is descriptive and with a convenience sampling, there is an imbalance in the distribution of the three groups of patients, as expected, according to the severity of the disease.

We have now added this limitation in the manuscript…”

Moreover, the convenience sampling applied caused an imbalance in the distribution of the three groups.”

1.- Introduction: The sequelae subgroup is defined as the presence of irreversible tissue damage 12 weeks after the acute disease.

This is a very strict and clinically not helpful definition. How can a clinician know that the presenting symptoms are due to irreversible tissue damage? In particular, the symptom fatigue eludes the problems of this definition.

1a). The sequelae subgroup is defined as the presence of irreversible tissue damage 12 weeks after the acute disease. This is a very strict and clinically not helpful definition.

This is correct. We cannot know if the symptoms are due to irreversible tissue damage. However, our comment is based on the clinical definition from the consensus in our country (reference nº 1) :

1. Long-COVID: persistence of symptoms (present or not at the onset of the infection) after 4 weeks of infection, with a permanent, relapsing / remitting or progressive improvement course.

2. Sequelae: irreversible tissue damage after 12 weeks that could trigger different degrees of permanent dysfunction and associated symptomatology.

How can a clinician know that the presenting symptoms are due to irreversible tissue damage?

Regarding tissue damage or persistence of symptoms, this is not yet known. This point was discussed in the editorial of Munoli (reference 2) and also in our consensus (reference 1). Because it is a very new clinical entity, we probably need more time to understand this.

2. - It maybe helpful to make in the abstract transparent, that only patients with persistent dyspnoea or fraility were included in the study.

Thank you. We have now added these two selection criteria in the abstract:

“The main inclusion criteria were persistent dyspnoea (mMRC ≥2) and/or clinical frailty (scale value ≥3).”

3.- The assessment battery is differentiated. How were fatigue and fatigability measured?

Fatigue is a symptom, so, we based this on what the patients told us. We did not use any specific scale. However, it was related to the other outcomes, such as the Borg scale during the 6MWT, muscle strength measures (SPPB, mMRC muscle strength scale) and even the frailty scale. We did not analyse fatigability in our study.

4- How did the patients find the rehabilitation department? Was there a kind of admission by their GP? Could patients present themselves?

We have now clarified this in the Material and Methods:

“The patients were referred to our rehabilitation unit from primary care (GP), from the pneumology outpatient department, or at discharge from hospital”.

5.- In the discussion section the authors stated, that dyspnoea appears to be a prevalent symptom, but this was one of their inclusion criteria.

We stated that the main inclusion criteria were “persistent dyspnoea (mMRC ≥2) and/or clinical frailty (scale value ≥3)”. Over 75% of patients had dyspnoea.

6.- History is a good predictor of anxiety and depression. How many patients had a history of anxiety and depression?

We did not analyze this point. We reviewed the charts and we found scarce data about previous history of anxiety and depression.

The only comorbidities we found were arterial hypertension, respiratory disease, and heart disease.

7.- Quality of life is influenced by the presence of anxiety and depression. Not surprisingly the group with the lowest incidence of anxiety and depression has the best quality of life.

Indeed, yes, we agree they are closely correlated.

8.- Concerning myopathy, is ICU acquired weakness, critical illness polyneuropathy and critical illness myopathy in the focus of the authors?

No, ICU acquired weakness, critical illness polyneuropathy and critical illness myopathy was not our focus.

How was the diagnosis myopathy made?

The diagnosis of myopathy was make using: the muscle strength scale (mMRC); the short physical performance battery (SPPB), the manual dynamometry and the effort capacity with the 6-minute walk test-6MWT.

Were there clinical neurophysiologic examinations? No.

Was the diagnosis based on clinical examination? Yes

How was the diagnosis myopathy made? It was a clinical diagnosis

Was the diagnosis based on clinical examination? Yes, using different scales

How likely were the acquired weaknesses after ICU stay due to a COVID specific pathophysiologic reason?

As this was a clinical diagnosis we cannot demonstrate whether this myopathy was specific for COVID or for ICU stage.

9.- Concerning the conclusion, the effects of early rehabilitation were not the topic of the paper.

No, but this was written as a take-home message.

“We consider these findings emphasize the relevance of early rehabilitation and assessment of respiratory muscle strength in patients with post-COVID syndrome”.

10.- Why is the assessment of respiratory muscle strength important?

The assessment of respiratory muscle is important because it could be a factor for effort dyspnea, as we discuss in the Discussion section.

In the follow-up patients, with weakness of respiratory muscles (PImax decreased) we start specific respiratory muscle training, and we found improvement in PImax and dyspnea. However, this finding will be a part of a second paper.

Why are anxiety and HRQol worse in non-ICU patients?

We do not have a good explanation. We only can hypothesize, as we did in the discussion section.

These two items may have a correlation.

Yes, we found a clear correlation between these two symptoms and the HRQoL higher than -0.60 with a p<0.001.

It could make sense to treat anxiety and depression.

We agree. We discuss this with patients and offer referral to the mental health service.

We thank the reviewers for all these helpful suggestions.

Submitted filename: response to the reviewers.docx

Click here for additional data file.

10 Jul 2022

16 Aug 2022

RESPONSE TO THE ACADEMIC EDITOR, Peter Schwenkreis,

1.- The first issue is the use of the term "sensitivity" with respect to the Pfeiffer questionnaire. "Sensitivity" (true positive rate) refers to the probability of a positive test, conditioned on truly being positive. Since you do not know the real proportion of patients with cognitive impairment, you must not use the term "sensitivity" or "sensitive" in this context.

In agreement with the editor, we have changed the term "sensitivity" for the “ability”.

2.- The second issue is the use of the term "myopathy" in your study. Apparently you use this term synonymously to muscular weakness, based on the muscle strength scale (mMRC), the short physical performance battery (SPPB), the manual dynamometry and the effort capacity with the 6-minute walk test-6MWT. However, muscular weakness as assessed by these tests is only a symptom, whereas myopathy is defined as a disease of the muscles resulting e.g. from specific inflamatory or metabolic processes. Muscular weakness is not necessarily caused by myopathy, but may also occur in deconditioned patients due to immobilization. You should therefore avoid the use of the term "myopathy" in this context, when you cannot be sure that the patients are indeed suffering from a specific muscular disease.

Thank you for pointing this out. We agree and have now changed the term “myopathy” to “muscular weakness”.

3.- Besides, you should include in the limitations section that "fatigue" was only assessed by patients reportings, not by standardized and validated questionnaires.

In agreement with the editor, now we have added the following sentence in the limitations section:

Finally, fatigue was assessed only from the symptoms reported by the patients.

We thank the Editor for these helpful suggestions.

Submitted filename: response to the reviewers v2.docx

Click here for additional data file.

30 Aug 2022

“ Comparison of post-COVID symptoms in patients with different severity profiles of the acute disease visited at a rehabilitation unit ”

PONE-D-22-11582R2

Dear Dr. Rous,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Peter Schwenkreis

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

7 Sep 2022

PONE-D-22-11582R2

Comparison of post-COVID symptoms in patients with different severity profiles of the acute disease visited at a rehabilitation unit

Dear Dr. Güell-Rous:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Peter Schwenkreis

Academic Editor

PLOS ONE