The impact of the SARS-COV2 infection on the disorder of consciousness rehabilitation unit.

BACKGROUND AND
OBJECTIVE: Disorders of consciousness include coma (cannot be aroused, eye remain closed), vegetative state-VS (can appear to be awake, but unable to purposefully interact) and minimally conscious state-MCS (minimal but definite awareness). The objective of this study is to assess the impact of the SARS-CoV-2 infection on the Disorder of Consciousness (DOC) Rehabilitation Unit.
METHODS: This is a retrospective, longitudinal, descriptive, observational, pilot study. We consecutively enrolled 18 patients (age range: 40-72 years, 9 females and 9 males), from three to five months after a brain injury. They were grouped into VS (n = 8) and MCS (n = 10). A confirmed case of COVID-19 was defined as a positive result on high-throughput sequencing or real-time reverse-transcription polymerase chain reaction analysis of throat swab specimens. We collected data of lung Computed Tomography (CT) and laboratory exams. DOC patients who were positive for SARS-CoV-2 were classified into severe and no severe infected group, according to the American Thoracic Society guidelines.
RESULTS: A total of 18 hospitalized patients with (16) and without confirmed (2) SARS-CoV-2 infection were included in the analysis. After one month, a follow-up clinical evaluation reported that one patient died, one patient was transferred from Covid Unit to Emergency Unit and 3 patients were resulted negative to double swab and they returned to Rehabilitative Unit. Significant differences were reported about hypertension, cardiac disease and respiratory problems between the patients with severe infection and patients without severe infection (P< 0.001). The laboratory findings, such as blood cell counts (P < 0.001), C-reactive protein, D-dimer, potassium and vitamin D levels, seemed to be considered as useful prognostic predictors.
CONCLUSIONS: To our knowledge, this is the first longitudinal study on a sample of chronic DOC patients affected by SARS-CoV-2. This study may offer important new clinical information on COVID-19 for management of DOC patients. Our findings showed that for the subjects with severe infection due to COVID-19, rapid clinical deterioration or worsening could be associated with clinical and laboratory findings, which could contribute to high mortality rate. During the COVID-19 epidemic period, the clinicians should consider all the reported risk factors to avoid delayed diagnosis or misdiagnosis and to prevent the infection transmission in DOC Rehabilitation Unit.

Introduction

On March 11, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak a pandemic due to the dramatic increasing number of cases outside China [1, 2].

In Italy, on February 2020 the emergence of the COVID-19 epidemic first in Lombardy, and then in other regions, determined the need to implement containment measures for a phenomenon that stressed national healthcare system [3].

It is known that the coronaviruses can adapt very quickly and cross the species barrier, such as with SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). In humans, coronavirus infection may often lead to severe clinical symptoms and high mortality. As for COVID-19, several studies have described typical clinical manifestations including fever, cough, anosmia, ageusia, diarrhea, fatigue and other symptoms. COVID-19 also presented characteristic laboratory findings and lung computed tomography (CT) abnormalities.

In a retrospective, observational study [4], the authors reported neurologic manifestations in a COVID-19 Chinese population.

Patients with severe disability caused by a neurological disease often have different comorbidities and many risk factors for poor outcome in SARS-COV2 infection.

Disorders of Consciousness (DOC) include patients in coma, vegetative/unresponsive wakefulness syndrome (VS/UWS) and minimally consciousness state (MCS) [5, 6].

DOC patients are considered as a particular and delicate population that presents important pre-existing impairment in central nervous, cardiac and respiratory systems.

This particular clinical population often needs long-term treatments and devices, such as tracheostomy tube, central venous catheters, nasogastric or gastrostomy tube and indwelling catheters, which highly increase the comorbidity burden.

In addition, a significant high rate of poor outcomes and mortality should be expected in DOC patients who become infected with SARS-CoV-2.

To date, no data are available on the impact of the SARS-CoV-2 infection on survival of chronic DOC patients in Rehabilitation DOC Unit. In fact, to our knowledge, this is the first longitudinal study on a sample of DOC patients affected by SARS-CoV-2.

Methods

Study design

This is a retrospective, longitudinal, descriptive, observational pilot study. All patients were consecutively assessed from 15 February to 26 March 2020 in post-acute rehabilitation DOC Unit of IRCCS Centro Neurolesi "Bonino-Pulejo" of Messina (Italy).

Participants

We studied 18 patients (age range: 40–72 years, 9 females and 9 males) from three to five months after a brain injury (see Table 1 for clinical and demographic details). By using validated behavioral scales such as Revised Coma Recovery Scale (CRS-R), the patients were grouped into VS (n = 8) and MCS (n = 10). CRS-R is unique in establishing a diagnosis and outcome directly from the examination findings. The basic structure of the CRS-R is similar to the Glasgow Coma Scale (GCS), but its subscales (auditory, visual, motor, oromotor/verbal, communication, and arousal) are much more detailed, targeting more subtle signs of recovery of consciousness [7]. A confirmed case of COVID-19 was defined as a positive result on high-throughput sequencing or real-time reverse-transcription polymerase chain reaction analysis of throat swab specimens.

Table 1

Clinical and demographic details of DOC patients.

Patient	clinical diagnosis	gender/age	etiology	Lesions (CT or MRI)	Month since injury	CRS-R sub-scores	CRS-R total scores
01	MCS	F/42	Trauma	Bilateral frontal, right parietal, lobe lesions	4.1	2 1 3 1 0 2	8
02	MCS	M/67	Hemorrhage	Bilateral temporal lobe lesions	3.0	1 1 3 0 0 2	7
03	MCS	F/72	Hemorrhage	Right frontal, temporal lobe and brain stem lesions	4.9	1 2 3 0 0 2	8
04	MCS	M/41	Trauma	Bilateral frontal lobe lesions	3.2	1 1 4 0 0 2	8
05	MCS	F/47	Anoxia	Diffuse demyelination	3.1	2 3 2 1 0 1	9
06	MCS	M/52	Hemorrhage	Brain stem and cerebellum lesions	4.8	1 1 3 0 0 3	8
07	MCS	M/71	Hemorrhage	Brain stem lesions	4.0	1 3 4 0 1 1	10
08	MCS	F/42	Hemorrhage	Left parietal lobe lesions	4.8	2 1 3 0 0 1	7
09	MCS	M/65	Trauma	Bilateral frontal lobe and left parietal lobe lesions	4.2	2 1 3 1 0 1	8
10	VS	M/62	Anoxia	Diffuse demyelination	5.0	1 0 1 0 0 1	3
11	VS	M/38	Anoxia	Diffuse demyelination	5.0	1 0 1 1 0 1	4
12	VS	M/67	Trauma	Right frontal and parietal lobe lesions	3.4	1 1 1 0 0 1	4
13	VS	F/72	Hemorrhage	Right temporal, and occipital lobe lesions	3.7	1 0 1 0 0 2	4
14	VS	F/68	Trauma	Bilateral parietal and temporal lesions	4.8	1 1 1 0 0 2	5
15	VS	F/63	Anoxia	Diffuse demyelination	4.1	0 0 1 0 0 2	3
16	VS	M/55	Hemorrhage	Left frontal and temporal lobe lesions	3.7	1 1 1 0 0 1	4
17	VS	F/64	Trauma	Right parietal and temporal lobe lesions	3.4	1 0 1 0 0 2	4
18	VS	F/40	Anoxia	Diffuse demyelination	3.3	1 1 0 0 0 1	3

CRS-R = Coma Recovery Scale-Revised; Six subscales score of CRS-R indicating the assessment of auditory, visual, motor, verbal, communication functions and arousal. DOC = Disorder of Consciousness; MCS = minimally consciousness state; VS = vegetative syndrome.

Interventions

We collected data of lung Computed Tomography (CT), laboratory exams (blood cell count, blood chemical analysis, coagulation testing, liver and renal function testing, C-reactive protein, vitamin D serum level, glycemic state control, electrolytes) and other factors, such as Body Mass Index (BMI) and steroid regime use.

Comparison

We compared all collected data between patients with severe and non severe infection, according to the American Thoracic Society guidelines.

Ethics

No ethical committee approval was necessary according to national regulations because this was a retrospective analysis of routinely collected anonymized clinical data. However, the written informed consent was obtained from the legal guardian of all patients.

Statistical analysis

Mean and standard deviations (SD) were used for normally distributed data and median and range for data that were not normally distributed. Continuous variables were compared by using Wilcoxon rank sum test. Proportions for categorical variables were compared using χ2 test. Because of the small sample size, ordinal, interval and ratio measures are presented as median and range.

All statistical analyses were performed using R (version 3.3). The level of significance was set at a P less than 0.05.

Results

A total of 18 hospitalized patients with (16) and without confirmed (2) SARS-CoV-2 infection were included in the analysis. Of these patients, 15 presented at least one of the following disorders: hypertension (11 patients), diabetes (8 patients), cardiac disease (5 patients). The most common symptoms at onset of COVID-19 disease were fever (15 patients) and respiratory problems (7 patients).

According to the American Thoracic Society guidelines [8], among the 16 patients having confirmed SARS-CoV-2 infection, 10 patients had severe infection and 6 patients had non severe infection. The patients with severe infection were significantly older (mean age, 61.1 years vs 48.4 years; P <0 .001) and presented other disorders, such as hypertension (10 vs 5), and other typical COVID-19 symptoms such as fever (10 vs 5) and respiratory problems (7 vs 5), if compared with no severe infection subjects. Sixteen patients were diagnosed as having COVID-19 by a positive SARS-CoV-2 nucleic acid detection, and then they were transferred to a specific Covid Unit. Lung CT showed a typical interstitial pneumonia picture, associated to ground-glass opacity. Patients with severe infection had more increased inflammatory response, including higher white blood cell counts, lower lymphocyte and neutrophil counts, and increased C-reactive protein levels compared with the patients without severe infection (P < 0.001). In addition lower potassium levels in patients with severe infection were found (P<0.001).

The patients with severe infection presented also higher D-dimer levels than patients without severe infection (P < 0.001), probably due to a consumptive coagulation system. In addition, patients with severe infection presented multiple organ involvement, such as kidney (increased creatinine levels—P <0.01) and liver (increased alanine aminotransferase—P <0.03 and aspartate aminotransferase levels—P <0.01). All SARS-CoV-2 patients with infection had a low vitamin D serum level (see Table 2).

Table 2

Laboratory findings of DOC COVID-19 and not COVID-19.

Laboratory findings	Total Covid + (n.16)	Covid + severe (n.10)	Median (range)	Covid—(n.2)	P
			Covid + no severe (n.6)
Count, x 109/L
White blood cell	5.4 (0.9–19.2)	6.3 (0.9–19.2)	4.9 (2.3–15.4)	4.0 (2.9–5.1)	<0.005
Neutrophil	3.1 (0.3–17.2)	2.9 (0.3–17.2)	3.4 (2.9–15.4)	8.3 (4.2–12.5)	<0.001
Lymphocyte	1.0 (0.4–2.3)	0.8 (0.4–2.3)	1.5 (0.9–2.1)	1.9 (1.5–2.3)	<0.001
C-reactive proteine, mg/L	36.2 (1.2–180.3)	55.2 (2.2–180.3)	10.1 (1.2–46.3)	28.2 (1.5–55.0)	<0.001
D-dimer, mg/L	0.9 (0.5–18.3)	1.1 (0.5–18.3)	0.8 (1.1–9.7)	0.8 (0.8–0.9)	<0.001
Aminotransferase, U/L
Alanine	33.2 (12.0–877.2)	44.5 (12.0–877.2)	21.3 (15.3–289.2)	45.5 (33.0–58.0)	<0.03
Aspartate	29.3 (9.0–933.1)	44.3 (9.0-.933–1)	25.1 (12.3–198.5)	28.0 (12.0–44.0)	<0.01
Creatinine, μmol/L	55.3 (31.2–833.2)	66.2 (31.2-833-2)	52.5 (22.1–125.4)	29.0 (25.0–33.0)	<0.01
Vitamin D ng/ml	7.1 (6.5–28.3)	6.8 (6.5–28.3)	11.2 (10.1–55.3)	39.5 (35.0-44-0)	<0.001
Potassium mmol/L	1.85 (1,2–3,9)	1.6 (1.2–1.9)	2,9 (2.3–3.9)	3.3 (3.1–3.5)	<0.001
Sodium mmol/L	139 (135–143)	137 (135–139)	142 (140–143)	141.5 (141–142)	<0.007
Calcium mmol/L	7.9 (6.9–8.9)	7.3 (6.9–7.9)	8,3 (8.1–8.9)	8.1 (7.9–8.3)	<0.007
Glycemia mg/dl	178 (113–267)	233 (211–267)	189 (123–234)	133 (123–143)	<0.007

DOC = Disorder of Consciousness; COVID-19 = Coronavirus Disease 2019.

In addition, all patients presented a low BMI (median 17 for COVID+ and median 19.5 for COVID-).

After one month, a follow-up clinical evaluation reported that one patient had died, one patient was transferred from Covid Unit to Emergency Unit and 3 patients tested negative to double swab and returned to Rehabilitative Unit.

The first patient died for cardiac arrest. He was a 60 years old post-anoxic heart disease VS patient without severe infection.

The second patient was transferred from Covid Unit to Emergency Unit for respiratory insufficiency. He was a young post-anoxic VS patient, affected by Brugada syndrome, with severe infection and serious multiple organ involvement.

The three patients who returned to Rehabilitative DOC Unit, after a double negative swab, were MCS patients, without severe infection (one 40 years old post-traumatic patient, one post-hemorrhagic middle age patient and one 40 years old post-hemorrhagic patient). In addition, they presented lower-than-normal vitamin D serum and potassium levels, but higher than those of patients with severe infections (P < 0.01).

After one month, a follow-up clinical evaluation reported that the remaining 11 patients (9 with severe and 2 without severe infection), were clinically stable and hospitalized at the Covid Unit, as they were still positive to control swabs.

Finally, 2/18 VS patients (one post-hemorrhagic middle age patient and one 40 years old post-anoxic patient) were negative to a double swab. The female showed: 1) fever; 2) typical higher white blood cell and neutrophil counts; 3) lower lymphocyte counts; 4) increased C-reactive protein levels. These findings were similar to SARS-CoV-2 positive patients with severe infection, even if she showed a no typical COVID-19 lung CT. The male patient presented: 1) no fever; 2) normal white blood cell counts; 3) no typical COVID-19 lung CT. Finally, both patients had normal D-dimer and vitamin D serum levels (see Table 2). Glycemic state control was abnormal in all patients (see Table 2), but no significant correlation with level of infection severity was found (P< 0.007).

In addition, all patient with confirmed SARS-CoV-2 infection were treated with dexamethasone 6 mg IV once daily plus standard of care for up to 10 days or until hospital discharge.

Discussion

To our knowledge, this is the first longitudinal report of DOC patients with SARS-CoV-2 hospitalized in a Rehabilitation Unit.

Our sample is to be considered as very particular population, because DOC patients very often present several neurological, cardiological and pulmonary problems. Indeed, they are more likely to contract infections than other neurological patients.

The main results of the study showed that DOC patients are unfortunately a population susceptible to SARS-CoV-2 infection, especially if there is an outbreak of infection. In fact, seriously compromised systems, tracheostomy tube and particular radiological and laboratory settings could be responsible for a high susceptibility to contract the infection.

Specifically, of 18 patients included in this study, 16 were positive for COVID-19 (10 had severe infection and 6 had no severe infection) and 2 were negative. The patients with severe infection were older than those without severe infection and presented hypertension and symptoms such as fever and respiratory problems. Our patients affected by severe infection had all tracheotomy: this aspect could be favoring the infection and the gravity of pulmonary findings. Post-acute neurological pneumonia is associated with old age, history of diseases, neurological impairment and disease severity [9], and it is known that lung infections in these patients often lead to poor prognoses. In addition, dysphagia was present in all patients with severe infection and it is known to be one of the most common complications in post-acute neurological patients and is also a significant risk factor for lung infections in DOC patients.

Cardiological problems could also be considered as a poor prognostic factor. In fact, all patients with severe infection presented one or more comorbidity such as hypertension and other cardiac problems.

In addition, the 2 VS subjects who had a worse prognosis showed a pre-existing serious cardiological disease. The first patient died for cardiac arrest. He was a post-anoxic heart disease VS patient without severe infection. The second patient was transferred from Covid Unit to Emergency Unit for respiratory insufficiency. He was a post-anoxic VS patient affected by Brugada syndrome, with severe infection and serious multiple organ serum involvement.

The three patients who returned to our Rehabilitative Unit, after a double negative swab, did not show cardiac problems.

Another important aspect is the lymphocyte count. COVID-19 is a systemic infection with a significant impact on the hematopoietic system and hemostasis. Lymphopenia may be considered as a cardinal laboratory finding, with an important prognostic role. Neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases. Biomarkers, such high serum procalcitonin and ferritin have also emerged as poor prognostic factors. Furthermore, blood hypercoagulability is common among the hospitalized COVID-19 patients. Elevated D-Dimer levels are consistently reported, whereas their gradual increase during disease course is particularly associated with disease worsening [10]. We found that lymphocyte count was lower in patients with severe infection. This phenomenon could be indicative of the immunosuppression in patients with severe COVID-19 disease, even if our sample including immunosuppressed subjects for pre-existing clinical conditions. Moreover, we found that patients with severe infection had higher D-dimer levels if compared with no severe infection group. The VS patient who died, had a very low lymphocyte count and a very high level of D-dimer if compared to survival VS patients with severe infection.

Also vitamin D could be an important potential protective factor for SARS-CoV-2 infection.

Vitamin D plays a key role in calcium metabolism, and its involvement in the immune response [11], its protective effect on respiratory tract infections [12] and its immunomodulatory effect in patients with pneumonia [13] have been described. However, studies of hypovitaminosis D as a risk factor for severe complications in patients with pneumonia are conflicting [14], and a meta-analysis showed that hypovitaminosis D appears to be associated with an increased risk of adverse events in patients with pneumonia, although the molecular mechanisms related to the role of vitamin D against infections need further investigation [15].

Evidence supporting the role of vitamin D in reducing the risk of COVID-19 indicate that: a) the outbreak occurs in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; b) the number of cases in the Southern Hemisphere near the end of summer are low; c) vitamin D deficiency contributes to acute respiratory distress syndrome; d) case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration [16].

In our sample, the 3 patients who returned in our Rehabilitation Unit presented a vitamin D serum levels higher than those of subjects with severe infection. In addition, the 2 VS patients who were double negative, had normal vitamin D serum level.

The small number of studies investigating the immunomodulatory effects of vitamin D metabolites in respiratory virus-infected epithelial cells showed that the effects of vitamin D metabolites on the expression and secretion of pro-inflammatory cytokines and chemokines varied among the pathogens and suggested that they might be more effective against some pathogens than others [17].

In addition glycemic state control was abnormal in all patients (see Table 2), but no significant correlation with level of infection severity was found (P< 0.007). This was probably related to the fact that patients were treated with prolonged steroid therapy.

Finally all patients showed a low BMI (median 17 for COVID+ and median 19.5 for COVD-), probably related to: a) prolonged bed rest; b) diffuse muscular hypotrophy; c) parenteral or enteral nutrition.

Another important aspect is the role of the Neurorehabilitation Units, such as those in which our DOC patients were admitted. These Units should admit only patients with sub-acute neurological disorders negative for Covid-19 infection in order to facilitate prompt availability of intensive care unit.

Our sample of DOC patients demonstrated the vulnerability of this Unit and the clinical precariousness of patients themselves. The greatest difficulty in applying these indications in the field of rehabilitation is related to the need to find the right balance between the provision of services useful to the patient and the reduction of the risk of spreading the virus.

The implementation of rehabilitative activities in hospital stays, and in services in general, can only be continued in compliance with the needs of the patients and the protection of the health of all staff, as the healthcare activities require close contact with the patient, or with the production of aerosols and secretions (as for respiratory rehabilitative interventions especially in tracheostomised management patients).

This study has, however, some limitations. First, only 18 patients were studied, even if it is important to underline that all studies that include DOC subjects do not report a very high sample size, due to a difficulty to recruit this category of patients. However, it is a first longitudinal study on DOC population infected by SARS-CoV-2.

Second, during the outbreak period of COVID-19, neuroimaging evaluation, such as magnetic resonance imaging, was avoided to reduce the risk of cross infection. Thus, we have no neuroimaging data about neurological outcomes that might worsen under infection conditions. Indeed, increasing evidence showed that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system, through the olfactory system for example, inducing neurological outcomes [18]. Therefore, it is not excluded that SARS-CoV-2 behave in this respect like other coronaviruses. Third, this is a retrospective, longitudinal, descriptive, observational pilot study: not having a control group or not having randomized patients, is certainly another limitation. But the particular category of patients, so difficult to recruit, and the possibility of having DOC patients affected by SARS-CoV-2 make these results unique.

In fact, disorder of consciousness represents a unique clinical condition, which poses problems that are less common in other diseases. Because of their distinctive characteristics, we preferred not to mix DOC patients with other neurological patients, even if this decision provided in a small sample size.

In conclusion, this study may offer important new clinical information on COVID-19 for management of DOC patients in Rehabilitation Unit. Our findings showed that for subjects with severe infection due to COVID-19, rapid clinical deterioration or worsening could be associated with clinical and laboratory findings which could contribute to high mortality rate. Moreover, from our results, some comorbidities seem to have a predictive role. Finally, during the epidemic period of COVID-19, clinicians should consider all the reported risk factors to avoid delayed diagnosis or misdiagnosis and to prevent the infection transmission in DOC Rehabilitation Unit.

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25 Sep 2020

PONE-D-20-26757

The impact of the SARS-COV2 infection on the Disorder of Consciousness Rehabilitation Unit

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Reviewer #1: I thank the authors for their challenging work. However, the paper needs lexical review, for example the choice of the words “ cardiopathic “ in page 5, “ always “ in page 6 and “ typology “ in page 8 is less familiar as the usual scientific lexicon.

Reviewer #2: - Overall, the research question is interesting however, major comments should be addressed and clarified.

- The readability and syntax of the manuscript will be substantially improved if it is reviewed by a formal translation agency or by a colleague whose first language is English.

Abstract:

- Short background on the DOC.

- Define VS and MCS.

- The design of the study should be described in the methods.

- The criteria of the subjects should be demonstrated e.g. age, genders.

- Did the author make two classifications in this study? VS and MCS, then severe and non-severe. Please, clarify

- Methods need more information.

- The size is very small to provide a conclusion.

- Change 16/18 to 16 and 2/18 to 2.

- Important differential results with p-values should be demonstrated.

- The conclusion should more concise to be related to the objective of the study.

Introduction:

- The introduction needs to be analyzed and rewritten.

- More information should be clarified about the DOC and its relation to SARS-CoV-2.

- The objective of the study is very important however the importance of the study still need more clarification in the introduction section.

- What was the hypothesis of the study.

Methods:

- What is the design of the study?

- What were the inclusion and exclusion of the study to select the participants?

- Did the author calculate the sample size and power of the study?

- Methods section is very poor and needs more information and description.

- Statistical analysis: What is the statistical method used to assess the normal distribution of the collected data. "The significance threshold" is inadequate expression. Please, change it to "the level of significance".

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- The main limitation of the study design was not demonstrated.

- Briefly, the discussion section need major revisions.

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Reviewer #2: Yes: Walid Kamal Abdelbasset

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4 Mar 2021

Reviewer #1:

We thank the reviewer for the kind and appreciative words. We revised the paper, as suggested.

Reviewer #2:

We thank the reviewer for the time spent to revise the manuscript. We revised the paper, as suggested.

1) We improved English language English.

2) Abstract:

- We performed a short background on the DOC.

- We defined VS and MCS.

- We described the design of the study in the methods.

- We demonstrated the criteria of the subjects.

- We clarified the two classifications: VS and MCS, then severe and non-severe.

-We improved “Methods section”.

- Unfortunately, the sample population cannot be expanded, but 18 DOC patients, affected by SARS-COV2, are a considerable number and never reported in the literature.

- We changed Change 16/18 to 16 and 2/18 to 2.

- We reported the most important differential results with p-values.

- We revised the conclusion, as suggested.

3) Introduction:

- We revised the introduction, as suggested.

- No data, to date, were reported about DOC and relation to SARS-CoV-2: this is the first study. In addition this is a retrospective, longitudinal, observational study, that showed the impact, in a descriptive way, of a sudden SARS-COV2 infection. No power analysis was performed, because all patients of DOC Unit, were consecutively enrolled.

- We revised the report of objective of the in the introduction section.

- We better explained the hypothesis of the study.

4) Methods:

- Design of the study: this is a retrospective, longitudinal, descriptive, observational study. It was reported.

- We included in the study all patients admitted to our DOC rehabilitative unit, at the time the SARS-COV2 outbreak broke out. For this reason, no particular inclusion and/or exclusion were applied.

- The response is very similar to the previous point: we included in the study all patients admitted to our DOC rehabilitative unit, at the time the SARS-COV2 outbreak broke out. For this reason, no sample size and power of the study were calculated.

- We better described “methods section”.

- We better described “statistical analysis section”.

5) Results:

- We better described “results section”.

6) Discussions:

- We revised the introductory paragraph, as suggested.

- To date, no data about SARS-COV2 and DOC, were reported.

- We explained implications of the study.

- We better explained limitation of the study design.

30 Mar 2021

PONE-D-20-26757R1

The impact of the SARS-COV2 infection on the Disorder of Consciousness Rehabilitation Unit

PLOS ONE

Dear Dr. Ciurleo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: I have received the comments of the reviewers on your manuscript. The specific comments of the reviewers are included below. Please provide point by point response in your revised manuscript.

==============================

Please submit your revised manuscript by April 30th, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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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: http://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,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. 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: Yes

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. 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: Yes

Reviewer #2: Yes

**********

5. 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

**********

6. 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: Thank you for this longitudinal small-scale study. I would like the inclusion of the following in the retrospective paper: the steroid regimen use and dose regimen in the 18 patients, the body mass index for the 18 patient as it has been proven that an increased BMI contributes to increased mortality related to COVI-19 chest infection, and finally the inclusion of the metabolic profile including glycemic state control, electrolytes and BP control as all these could contribute to the encephalopathy cycle state of the patients.

Reviewer #2: Appreciating the authors for address the required corrections. However, some minor corrections should be addressed:

- I suggest authors add "pilot" to the design of the study in accordance with the small sample size.

- The methods section should be re-framed and re-arranged as the following:

a. Study design, setting

b. Participants

c. Intervention/issue of interest (exposure)

d. Comparison

e. Ethics and endpoint

f. Statistical analysis

- Clarify what the statistical method used to assess the data normality.

- Cite the Statistical Software used in data analysis.

**********

7. 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.

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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: MM

Reviewer #2: Yes: Walid Kamal Abdelbasset

[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.

22 Apr 2021

Dear Editor,

detailed responses to the reviewers’ questions appear below:

Reviewer #1:

We thank the reviewer for the kind and appreciative words. We revised the paper, as suggested.

- we included steroid regimen use;

- we included BMI;

- we included metabolic profile.

Reviewer #2:

We thank the reviewer for the time spent to revise the manuscript. We revised the paper, as suggested.

Statistical section, already reports what was requested by the reviewer:

- statistical method used: "Mean and standard deviations (SD) were used for normally distributed data and median and range for data that were not normally distributed. Continuous variables were compared by using Wilcoxon rank sum test. Proportions for categorical variables were compared using χ2 test. Because of the small sample size, ordinal, interval and ratio measures are presented as median and range";

- statistical software used: "All statistical analyses were performed using R (version 3.3)".

We thank you again for your consideration of our work and look forward to hearing from you in due course.

Sincerely,

Rosella Ciurleo PharmD, PhD

IRCCS Centro Neurolesi “Bonino-Pulejo”

S.S. 113, Via Palermo, C.da Casazza

98124 Messina, Italy

Phone: + 39-090-60128109

Fax: + 39-090-60128850

e-mail: rossella.ciurleo@irccsme.it

Submitted filename: Response to reviewers.doc

Click here for additional data file.

11 May 2021

PONE-D-20-26757R2

The impact of the SARS-COV2 infection on the Disorder of Consciousness Rehabilitation Unit

PLOS ONE

Dear Dr. Ciuerlo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Please review the edit suggested by the reviewer prior to acceptance.

==============================

Please submit your revised manuscript by June 10th, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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: http://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,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. 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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. 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: Yes

Reviewer #2: Yes

**********

5. 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: No

Reviewer #2: Yes

**********

6. 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: I thank the authors for considering the review feedback. Kindly revise the grammatical context for there are subtle subject-verb agreement errors such as “ The male patient did not presented fever, had normal white blood cell counts and he did not showed typical lung CT findings for COVID-19 infection “

Reviewer #2: (No Response)

**********

7. 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: MM

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.

23 May 2021

We regret there were problems with the English. The paper has been carefully revised to improve the grammar and readability.

We have highlighted the changes in yellow. The words or sentences deleted are in red.

1 Jun 2021

PONE-D-20-26757R3

The impact of the SARS-COV2 infection on the Disorder of Consciousness Rehabilitation Unit

PLOS ONE

Dear Dr. Ciurleo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Please provide necessary changes as suggested below

==============================

Please submit your revised manuscript by June 30th, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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: http://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,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

I thank the authors for considering the review feedback. Kindly revise the grammatical context for there are subtle subject-verb agreement errors such as “ The male patient did not presented fever, had normal white blood cell counts and he did not showed typical lung CT findings for COVID-19 infection “

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

Reviewers' comments:

I thank the authors for considering the review feedback. Kindly revise the grammatical context for there are subtle subject-verb agreement errors such as “ The male patient did not presented fever, had normal white blood cell counts and he did not showed typical lung CT findings for COVID-19 infection “

[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.

5 Jun 2021

Reviewer:

We thank the reviewer for the kind and appreciative words. We revised the paper, as suggested.

- we revised grammatical context as required.

17 Jun 2021

The impact of the SARS-COV2 infection on the Disorder of Consciousness Rehabilitation Unit

PONE-D-20-26757R4

Dear Dr. Ciurleo,

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,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All comments have been addressed.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. 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: Yes

**********

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

Reviewer #1: Yes

**********

4. 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: Yes

**********

5. 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

**********

6. 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: I thank the authors for their vigorous efforts both in manuscript preparation and abiding by the reviewers’ recommendations

**********

7. 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: MM

21 Jun 2021

PONE-D-20-26757R4

The impact of the SARS-COV2 infection on the Disorder of Consciousness Rehabilitation Unit

Dear Dr. Ciurleo:

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. Muhammad Adrish

Academic Editor

PLOS ONE