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. 2021 Oct 5;16(10):e0258095. doi: 10.1371/journal.pone.0258095

Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study

Abdallah S Attia 1, Mohammad Hussein 1, Mohamed A Aboueisha 1,2, Mahmoud Omar 1, Mohanad R Youssef 1, Nicholas Mankowski 1, Michael Miller 1, Ruhul Munshi 1, Aubrey Swinford 1, Adam Kline 1, Therese Nguyen 1, Eman Toraih 1,3, Juan Duchesne 1, Emad Kandil 1,*
Editor: Tai-Heng Chen4
PMCID: PMC8491909  PMID: 34610034

Abstract

Introduction

Several studies have described typical clinical manifestations, including fever, cough, diarrhea, and fatigue with COVID-19 infection. However, there are limited data on the association between the presence of neurological manifestations on hospital admission, disease severity, and outcomes. We sought to investigate this correlation to help understand the disease burden.

Methods

We delivered a multi-center retrospective study of positive laboratory-confirmed COVID-19 patients. Clinical presentation, laboratory values, complications, and outcomes data were reported. Our findings of interest were Intensive Care Unit (ICU) admission, intubation, mechanical ventilation, and in-hospital mortality.

Results

A total of 502 patients with a mean age of 60.83 ± 15.5 years, of them 71 patients (14.14%) presented with altered mental status, these patients showed higher odds of ICU admission (OR = 2.06, 95%CI = 1.18 to 3.59, p = 0.01), mechanical ventilation (OR = 3.28, 95%CI = 1.86 to 5.78, p < 0.001), prolonged (>4 days) mechanical ventilation (OR = 4.35, 95%CI = 1.89 to 10, p = 0.001), acute kidney injury (OR = 2.18, 95%CI = 1.28 to 3.74, p = 0.004), and mortality (HR = 2.82, 95%CI = 1.49 to 5.29, p = 0.01).

Conclusion

This cohort study found that neurological presentations are associated with higher odds of adverse events. When examining patients with neurological manifestations, clinicians should suspect COVID-19 to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.

Introduction

Since the Spanish flu pandemic in 1918, humankind hasn’t encountered such an overwhelming health crisis created by the novel 2019 coronavirus disease (COVID-19) pandemic [1]. As of August 2, 2020, the World Health Organization (WHO) reports that 680,894 people have died around the world, spanning different countries, ethnicities, religions, and socioeconomic class. Furthermore, the Emergency Committee on COVID-19 unanimously admitted that the outbreak still poses a public health emergency of international concern [2].

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was initially thought to primarily infect the respiratory system with dyspnea, cough, expectoration, and chest pain being common presenting symptoms [3]. However, as the pandemic continues, it is has been shown that the virus affects a wide range of organ systems, including the gastrointestinal, hepatic, renal, and cardiovascular systems. Well-documented extrapulmonary findings in COVID-19 patients include diarrhea, nausea, vomiting, elevated liver enzymes, kidney dysfunction, elevated troponin and CK-MB, systolic dysfunction, and heart failure, especially those who developed a severe and critical illness [3–9].

Some articles have illustrated symptoms suggestive of potential nervous system involvement with many studies demonstrating anosmia, ageusia, dizziness, seizure, altered mental status (AMS), myalgia, headache, syncope, somnolence, and coma in COVID-19 patients [7–9, 10]. Neuropsychiatric manifestations, such as anxiety, depression, insomnia, and psychosis, are reported as well [7, 10]. Case reports and case series have reported para-infectious conditions including Guillain-Barre syndrome and ataxia [11]. However, there is limited data available describing neurological symptoms as presenting manifestations among COVID-19 patients. The purpose of this multi-center retrospective cohort study was to investigate whether presenting with neurological symptoms is a predictor of poor health outcomes and adverse events in COVID-19 positive patients.

Methods

Study design and population

This is a multi-center retrospective cohort study that was performed after acquiring Tulane University Institutional Review Board (IRB) approval. The patient data were collected on COVID-19 confirmed positive patients, who were admitted from March 20, 2020, to May 10, 2020, to Tulane Medical Center (TMC) and University Medical Center (UMC) in New Orleans, LA. The patient data was collected using Research Electronic Data Capture (REDCap) hosted at Tulane University Medical School. REDCap is a secure, web-based software platform designed to support data capture for research studies, providing an intuitive interface for validated data capture and audit trails for tracking data manipulation and export procedures [12]. Patients were divided into two groups: with and without altered mental status (AMS) which encompasses confusion, amnesia, loss of alertness, disorientation, defects in judgment or thought, unusual or strange behavior, poor regulation of emotions, and disruptions in perception, psychomotor skills, and behavior. Patients were diagnosed with AMS on admission by the attending physician and patients were not on any sedative agents at the time of diagnosis.

Variables

Demographics, presenting symptoms, comorbidities, clinical notes, laboratory values, and health outcomes were extracted from the electronic medical records using a standardized data collection. Patient orientation and mental state were determined using Glasgow Coma Scale (GCS), patients with decreased GCS were considered to have Altered mental status. The severity of the disease was determined by two scoring systems: CURB-65 and Quick Sequential Organ Failure Assessment (qSOFA). The CURB-65 score is based on the presence of confusion, blood urea nitrogen level >19 mg/dL (>7 mmol/L), respiratory rate ≥30, blood pressure (systolic <90 mmHg or diastolic ≤60 mmHg), and age ≥65 years [13]. (2) The qSOFA score is based on a GCS <15, respiratory rate ≥22, and systolic blood pressure ≤100 [14].

Outcomes

A comparison between patients with and without AMS was performed. Outcome measures investigated included disease course, Intensive Care Unit (ICU) admission, intubation, unplanned reintubation, mechanical ventilation, duration of mechanical ventilation, prolonged mechanical ventilation, ARDS, bacteremia, sepsis, acute kidney injury, length of hospital stay, and mortality.

Statistical analysis

Data management was performed using SAS v9.4, while SPSS v26.0 was used for statistical analysis. Chi-square and Fisher’s Exact tests were applied for categorical variables. Student’s t and Mann-Whitney U tests were used for continuous variables. The two-sided p-value was set to be significant at <0.05. Multiple regression analysis was iterated using binary logistic regression models for all outcomes and cox hazard proportionate regression model for survival, adjusted by age, sex, obesity, and neuropsychiatric comorbidity.

Results

Demographics, comorbidities, and symptoms

We included a total of 502 COVID-19 confirmed positive patients with a mean age of 60.83 ± 15.5 years, and 238 patients (47.4%) were males. Their mean body mass index (BMI) was 33.32 ± 8.54 Kg/m2, with 57.2% being obese having BMI >30 Kg/m2 and 24.7% being overweight with a BMI >25 kg/m2. Most participants were African Americans (74.7%). On admission, 37 (7.37%) participants were classified as asymptomatic, 71 patients (14.14%) presented with AMS including 25 patients without any other manifestations, and 394 (78.48%) presented with other non-specific, respiratory, and gastrointestinal symptoms without neuropsychiatric symptoms, Fig 1. Patients with AMS were significantly older (68.61 ± 16.36 years versus 59.56 ± 15.01 years, p <0.001) and had lower BMI (30.91 ± 8.36 Kg/m2 versus 33.83 ± 8.50 Kg/m2, p = 0.021). Patients with AMS were less likely to be African American (66.2% versus 76.1%, p = 0.023), obese (45.1% versus 59.2%, p = 0.028), and have shortness of breath on admission (33.8% versus 58.2%, p < 0.001), Table 1.

Fig 1. Hierarchical classification of patients according to neuropsychiatric symptoms and comorbidities.

Fig 1

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Table 1. Characteristics of COVID-19 patients at admission.

Characteristics Non-AMS (n = 431) AMS (n = 71) P value
Demographic data
Age Mean ± SD 59.56 ± 15.01 68.61 ± 16.36 <0.001
18–49 years 97 (22.7) 12 (17.1) <0.001
50–64 years 172 (40.2) 12 (17.1)
≥ 65 years 159 (37.1) 46 (65.7)
Sex Female 228 (53.1) 33 (47.1) 0.36
Male 201 (46.9) 37 (52.9)
Race African American 328 (76.1) 47 (66.2) 0.023
White 72 (16.7) 12 (16.9)
Not Reported 31 (7.2) 12 (16.9)
BMI, kg/m2 Mean ± SD 33.83 ± 8.50 30.91 ± 8.36 0.021
Smoking None 302 (70.1) 44 (62) 0.26
Past smoker 90 (20.9) 21 (29.6)
Current smoker 39 (9) 6 (8.5)
Chief complaints
Asymptomatic Asymptomatic 37 (8.6%) NA NA
Non-specific Fever 97 (22.5) 11 (15.5) 0.21
Fatigue/weakness 31 (7.2) 1 (1.4) 0.06
Myalgia/FLS 28 (6.5) 5 (7) 0.79
Headache 6 (1.4) 1 (1.4) 0.99
Respiratory symptoms Shortness of breath 251 (58.2) 24 (33.8) <0.001
Cough 104 (24.1) 11 (15.5) 0.12
Chest pain 13 (3) 0 (0) 0.23
GIT symptoms Nausea, vomiting, diarrhea 28 (6.5) 3 (4.2) 0.60
Comorbidities
Neuropsychiatric Overall 99 (23) 23 (32.4) 0.10
Cerebrovascular disease 29 (6.7) 9 (12.7) 0.09
Seizures 6 (1.4) 1 (1.4) 0.99
Mood disorders 43 (10) 7 (9.9) 0.97
Anxiety disorder 24 (5.6) 6 (8.5) 0.41
Schizophrenia 10 (2.3) 3 (4.2) 0.40
Other comorbidities Overall 378 (87.7) 64 (90.1) 0.69
Obesity 255 (59.2) 32 (45.1) 0.028
Hypertension 303 (70.3) 54 (76.1) 0.39
Diabetes 185 (42.9) 26 (36.6) 0.36
Chronic heart failure 39 (9) 11 (15.5) 0.13
Arrhythmia 40 (9.3) 8 (11.3) 0.66
Coronary artery disease 39 (9) 10 (14.1) 0.20
Asthma 66 (15.3) 6 (8.5) 0.15
COPD 30 (7) 6 (8.5) 0.62
Chronic kidney disease 63 (14.6) 13 (18.3) 0.47
Cancer 46 (10.7) 9 (12.7) 0.68
Clinical assessment
Severity qSOFA score 0.58 ± 0.61 1.40 ± 0.76 <0.001
CURB65 score 1.22 ± 1.00 2.63 ± 1.07 <0.001
Orientation Glasgow coma score 15.00 ± 0.00 9.41 ± 4.08 <0.001
Vital signs Temperature (F) 99.65 ± 1.72 98.75 ± 1.67 <0.001
Pulse rate 91.21 ± 19.06 83.18 ± 21.20 0.002
Systolic blood pressure 126.34 ± 20.18 122.84 ± 24.56 0.21
Diastolic blood pressure 74.33 ± 14.82 70.07 ± 15.77 0.033
Mean arterial pressure 101.10 ± 18.08 100.54 ± 21.13 0.82
Respiratory rate 22.25 ± 7.39 21.39 ± 6.16 0.37
ABG findings SaO2 92.87 ± 7.88 94.26 ± 7.37 0.18
pH respiratory 7.26 ± 1.02 7.40 ± 0.07 0.45
PaCO2 39.27 ± 13.99 38.17 ± 9.62 0.67
PaO2 86.44 ± 60.70 99.33 ± 99.46 0.34
Anion gap 11.73 ± 10.53 12.90 ± 3.55 0.56
Lactic acid 54.82 ± 108.90 33.87 ± 85.16 0.66
HCO3 24.96 ± 3.19 22.91 ± 4.94 0.017
FiO2 (%) 33.59 ± 24.87 58.57 ± 33.08 <0.001
PaO2/FiO2 ratio 265.26 ± 103.25 192.89 ± 114.26 0.003
Laboratory findings
Complete blood picture White blood cells (x109/L) 7.85 ± 5.26 9.69 ± 6.03 0.013
Hemoglobin (g/dl) 12.11 ± 2.08 11.98 ± 2.07 0.66
Hematocrit (%) 36.32 ± 5.91 35.95 ± 5.95 0.69
Platelet count (x109/L) 237.75 ± 100.14 239.22 ± 126.82 0.92
Neutrophil count (x109/L) 6.58 ± 8.78 8.85 ± 11.16 0.07
Lymphocyte count (x109/L) 1.34 ± 1.94 1.08 ± 0.77 0.29
Neutrophil lymphocyte ratio 7.18 ± 9.76 10.78 ± 9.38 0.007
Electrolytes Serum sodium (mmol/L) 209.29 ± 937.39 138.85 ± 5.20 0.59
Serum potassium (mmol/L) 4.09 ± 1.14 4.06 ± 0.65 0.84
Serum chloride (mmol/L) 101.46 ± 5.24 101.75 ± 14.86 0.82
Calcium corrected (mmol/L) 9.02 ± 0.67 8.90 ± 0.80 0.18
Glycemic profile Random blood sugar (mg/dl) 144.47 ± 84.51 158.75 ± 97.36 0.22
HbA1c (%) 7.94 ± 3.05 5.70 ± 0.00 0.49
Renal function test Blood urea nitrogen (mg/dl) 25.01 ± 20.39 31.15 ± 19.23 0.025
Serum creatinine (mg/dl) 1.74 ± 2.00 2.03 ± 2.19 0.28
Liver function test Total protein (g/dl) 6.98 ± 0.74 6.88 ± 0.55 0.48
Albumin (g/dl) 3.29 ± 0.55 3.06 ± 0.67 0.017
Bilirubin (mg/dl) 0.61 ± 0.45 0.69 ± 0.49 0.35
Alkaline phosphatase (U/L) 75.41 ± 44.18 74.27 ± 33.48 0.90
AST (U/L) 48.16 ± 33.70 54.27 ± 43.07 0.41
ALT (U/L) 35.52 ± 29.73 33.43 ± 26.72 0.73
Cardiac marker Troponin (ng/ml) 3.63 ± 16.61 0.78 ± 1.55 0.62
Inflammatory markers C-reactive protein (mg/dl) 32.36 ± 47.69 93.61 ± 81.27 0.001
Procalcitonin (ng/ml) 11.64 ± 66.58 0.30 ± 0.30 0.50
Ferritin (ng/ml) 989.76 ± 1,922.35 1,428.71 ± 2,825.35 0.38
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AMS: altered mental status, FLS: Flu-like symptoms, GIT: gastrointestinal tract, NA: not applicable.

Data are presented as mean and standard deviation or frequency and percentage. BMI: body mass index. SaO2: oxygen saturation, PaO2: partial pressure of oxygen, PaCO2: partial pressure of carbon dioxide, HCO3: bicarbonate, FiO2: Fraction of inspired oxygen, AST: Aspartate transaminase, ALT: alanine transaminase, HbA1c: glycosylated hemoglobin. Chi-square, Fisher’s Exact, Student’s t, or Mann-Whitney U tests were used. P-value at <0.05 was considered significant.

Clinical assessment

Patients with AMS had a higher qSOFA score (1.40 ± 0.76 versus 0.58 ± 0.61, p <0.001), CURB-65 score (2.63 ± 1.07 versus 1.22 ± 1.00, p <0.001) and lower GCS (9.41 ± 4.0815.00 ± 0.00, p<0.001) compared to non-AMS cohorts, Table 1.

Laboratory findings

Patients presented with AMS had a lower PaO2/FiO2 (192.89 ± 114.26 versus 265.26 ± 103.25, p = 0.003) and higher white blood cell count (9.69 ± 6.03 versus 7.85 ± 5.26, p = 0.013), neutrophil-to-lymphocyte ratio (10.78 ± 9.38 versus 7.18 ± 9.76, p = 0.007), blood urea nitrogen (31.15 ± 19.23 versus 25.01 ± 20.39, p = 0.02), and C-reactive protein (CRP) (93.61 ± 81.27 versus 32.36 ± 47.69, p = 0.001) compared to patients without AMS, Table 1.

Adverse events

Patients presented with AMS showed worse outcomes compared to patients without AMS. Presenting with AMS was associated with higher rates of ICU admission (42.3% versus 27.7%, p = 0.017), intubation (45.1% versus 27%, p = 0.003), mechanical ventilation (47.9% versus 24.6%, p < 0.001), unplanned reintubation (35.3% versus 9.5%, p = 0.012), sepsis (23.9% versus 13.5%, p = 0.03), and acute kidney injury (N = 26, 36.6% versus N = 90, 20.9%, p = 0.006), Table 2.

Table 2. Outcomes of COVID-19 patients with and without altered mental status.

Characteristics Non-AMS (n = 431) AMS (n = 71) P-value
N (%) or M±SD N (%) or M±SD
Hospital admission Floor 312(72.3) 41 (57.7) 0.017
ICU 119 (27.7) 30 (42.3)
Procedures Mechanical ventilation 106 (24.6) 34 (47.9) <0.001
Require intubation 115 (27) 32 (45.1) 0.003
Extubation* 84 (73) 17 (53.1) 0.032
Develop complications Negative 215 (49.9) 31 (43.7) 0.37
Positive 216 (50.1) 40 (56.3)
Type of complications ARDS 139 (32.3) 21 (29.6) 0.68
Unplanned reintubation** 8 (9.5) 6 (35.3) 0.012
Sepsis 58 (13.5) 17 (23.9) 0.030
Bacteremia 32 (7.4) 2 (2.8) 0.20
Acute kidney injury 90 (20.9) 26 (36.6) 0.006
Mortality Alive 381 (88.4) 50 (70.4) <0.001
Dead 50 (11.6) 21 (29.6)
Death location*** Floor 3 (7) 3 (14.3) 0.38
ICU 40 (93) 18 (85.7)
Days to event Renal failure 2.44 ± 3.19 2.67 ± 4.62 2.44
ARDS 1.97 ± 2.10 0.60 ± 1.34 1.97
Sepsis 1.19 ± 2.14 0.75 ± 1.50 1.19
Extubation 8.93 ± 5.47 8.67 ± 7.30 0.90
Death 15.07 ± 9.27 9.05 ± 5.08 0.007
Ventilation days Overall 1.43 ± 3.51 4.63 ± 6.08 <0.001
Discharged 0.90 ± 2.78 2.82 ± 6.88 0.017
Deceased 6.33 ± 5.38 6.83 ± 4.12 0.76
Total LOS Overall 12.24 ± 11.11 10.89 ± 9.79 0.40
Discharged 11.89 ± 11.29 12.09 ± 11.84 0.92
Deceased 14.81 ± 9.45 9.05 ± 5.08 0.011
ICU LOS Overall 9.38 ± 7.60 8.46 ± 5.97 0.56
Discharged 7.96 ± 6.52 10.29 ± 9.01 0.39
Deceased 12.27 ± 8.84 7.86 ± 4.70 0.040
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Data are presented as mean and standard deviation (M±SD) or frequency and percentage between parentheses.

*Percentage among intubated patients

**Percentage among extubated patients

*** data for the death location for 7 patients were missing.

Mortality and length of stay

Patients presented with AMS had a higher rate of mortality (29.6% versus 11.6%, p < 0.001), earlier death (9.05 ± 5.08 days versus 15.07 ± 9.27, p = 0.007), and longer duration on ventilators (4.63 ± 6.08 days versus 1.43 ± 3.51 days, p < 0.001), Table 2.

Predictors risk factor for poor outcomes in patients with AMS

The multiple regression analysis was adjusted for age, sex, obesity, and neuropsychiatric comorbidities. This analysis revealed that patients presented with AMS had higher odds of ICU admission (OR = 2.06, 95% CI = 1.18 to 3.59, p = 0.010), intubation (OR = 2.53, 95% CI = 1.44 to 4.43, p = 0.001), mechanical ventilation (OR = 3.28, 95% CI = 1.86 to 5.78, p < 0.001), prolonged (>4 days) ventilation (OR = 4.35, 95% CI = 1.86 to 10, p = 0.001), sepsis (OR = 2.02, 95% CI = 1.10 to 3.73, p = 0.024), acute kidney injury (OR = 2.18, 95% CI = 1.28 to 3.74, p = 0.004), and mortality (HR = 2.81, 95% CI = 1.49 to 5.29, p = 0.001), Fig 2.

Fig 2. Impact of altered mental status as a predictor risk factor for poor outcomes.

Fig 2

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Multiple regression analysis was iterated using binary logistic regression models for all outcomes and cox hazard proportionate regression model for survival, adjusted by age, sex, obesity, and neuropsychiatric comorbidity. Results are reported as odds ratio (OR) for all outcomes or hazard ratio (HR*) for survival.

Discussion

The COVID-19 pandemic has been a serious health emergency and has caused an unprecedented international disaster while creating damaging social, economic, and political consequences that will likely have devastating long-term effects. Following disease-control guidelines, identifying risk factors, and recognizing different manifestations of COVID-19 infection is critical to deterring the spread and progression to severe disease. In response to this crisis, we conducted a retrospective cohort study on 502 hospitalized laboratory-confirmed COVID-19 patients to identify the outcomes associated with neurological symptoms, specifically AMS.

Angiotensin-converting enzyme 2 (ACE2) is the host functional receptor recognized by viral protein (spike) and allows the SARS-CoV-2 to enter the cell [15]. It is documented that SARS-CoV-2 has a higher affinity for ACE2 compared to its predecessor, SARS-CoV, explaining the higher rates of transmission. Due to the high presence of ACE2 on type II alveolar epithelial cells, the lung is the primary target and most vulnerable organ. However, the expression of ACE2 is ubiquitous, presenting in other multiple human tissues, including adipose tissue and nervous system [7, 16–18]. Due to increased expression in ACE2 in adipose tissue, obese individuals, could develop an explosive systemic inflammatory response, possibly contributing to the development of a more severe form of the disease [19]. Expression of ACE2 on glial cells, neurons, and capillary endothelial cells suggests that SARS-CoV-2 may invade the central nervous system (CNS) via direct invasion or cerebrovascular endothelium [7, 20–22].

Paniz-Mondolfi et al. reported the presence of SARS-CoV-2 in brain tissue from the post-mortem examination of a COVID-19 patient by implementing a transmission electron microscope. The viral particles were detected in the frontal lobe and matched the structural characteristics of SARS-CoV-2. Notably, these viral particles were found in the small vesicles of endothelial cells, which supports CNS invasion via hematogenous pathways may be a cause of the rapid progression of neurological symptoms [23]. Additionally, SARS-CoV-2 was identified in the cerebrospinal fluid (CSF) via polymerase chain reaction (PCR) in a male patient suffering from impaired consciousness and transient generalized seizures, with typical meningitis and encephalitis characteristics shown on the magnetic resonance imaging (MRI). Interestingly, this case presented with negative PCR results in the nasopharyngeal swab, which indicated that CNS invasion might have occurred in the early phase of COVID-19 infection [24]. It is also suggested that direct invasion into the neuronal cells and retrograde transport from the olfactory bulb may be the pathophysiology of anosmia experienced by some COVID-19 patients [22, 25].

To our knowledge, this is the first cohort study comparing outcomes between COVID-19 patients with and without neurologic symptoms, specifically AMS, while utilizing validated scoring systems (GCS, CURB-65, and qSOFA). Our initial univariate analysis showed that 14.14% of the COVID-19 patients presented to the hospital with AMS. These patients had higher rates of developing adverse events such as ICU admission, intubation, mechanical ventilation, prolonged ventilation, extended hospital stay, and mortality. But they had a lower rate of shortness of breath which could be explained due to the decreased reporting of symptoms with patients with AMS [26]. Out of the patients presenting with AMS in our cohort, 25 (35.2%) presented with no other symptoms. Mao et al. also reported that neurological symptoms, including impaired consciousness, occurred early in the disease course, sometimes preceding typical respiratory symptoms [7]. This suggests that neurological symptoms, such as AMS, may be signs of impending clinical decline in the early stages of COVID-19.

The patients with AMS presented with comparatively more severe disease, shown by the significantly higher CURB-65 and qSOFA scores at the time of admission. Additionally, patients with AMS presented with significantly higher neutrophil-to-lymphocyte ratio and CRP, which are risk factors of poor health outcomes and possible predictors of severe disease [27–30]. However, it cannot be definitively determined if AMS is a result of a more severe disease or that neurological involvement, manifesting as AMS, is causing more severe features of COVID-19.

Older age, obesity, and being African American are all associated with poor health outcomes in COVID-19 patients [19, 31–34]. The prevalence of obese patients in our study was 57% which is higher than Louisiana’s average (35%) [35]. It should be acknowledged that the AMS cohort has a significantly older average age. However, when adjusted for age, AMS remained more associated with poor health outcomes, Fig 2. Notably, patients with AMS were less likely to be African American or have obesity, which strengthens the argument that AMS may be an independent risk factor for poor health outcomes in COVID-19 patients. But we were unable to explain the reason why.

There are many established etiologies of AMS, including neurologic, toxicologic, trauma, psychiatric, and infectious [34]. Neuropsychiatric comorbidities could predispose patients to develop AMS. In our cohort, there was no significant difference in the prevalence of neuropsychiatric comorbidities between patients with and without AMS. Additionally, AMS was remained associated with poor health outcomes when the analysis was adjusted for neuropsychiatric comorbidities, Fig 2. Dehydration is also associated with developing AMS, especially in elderly patients [36]. Diarrhea and vomiting are possible causes of dehydration, and there was no significant difference in the prevalence of these symptoms between the study groups. Additionally, AMS secondary to hospital-induced delirium can be ruled out, since all these patients presented with AMS at admission.

Further studies are needed to determine if presenting with only AMS is also associated with poor health outcomes, and why they are presented less in obese and African American patients, which may further strengthen the argument that it should be considered an independent risk factor for poor health outcomes. Limiting data analysis to data upon admission is a potential limitation, which makes it prone to missing data such as CT-scans, MRI, and CSF analysis, which are vital in identifying brain injury and signs of neurological invasion of SAR-CoV-2.

Data Availability

All relevant data are within the manuscript.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Tai-Heng Chen

10 Mar 2021

PONE-D-21-02993

Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study

PLOS ONE

Dear Dr. Aboueisha,

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.

Please submit your revised manuscript by Apr 24 2021 11:59PM. 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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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.

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We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

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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: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

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: No

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: In this study, authors investigated the association between altered mental status and outcomes in COVID- 19 patients. They found that patients with altered mental status had poor outcomes compared to those patients without altered mental status. Despite the results, I think that there are some concerns.

1. The altered mental status is a vague term and definition. Please clarify the definition of altered mental status.

2. Depth of sedation could be related to altered mental status. Please provide the information of sedative agents.

3. Please provide the causes of altered mental status such as seizure, sepsis associated encephalopathy, metabolic encephalopathy and stroke.

4. When did evaluate the altered mental status during hospitalization? Please provide this information.

Reviewer #2: My comments are below:

Comment 1: In the line 81 and 82, 'Patients were divided into two groups: with and without altered mental status (AMS).' The definition of AMS was not clear. In order to get a more objective results, an operational definition for AMS is essential.

Comment 2:In the line 109 and 110, '...(BMI) was 33.32...with 57.2% being obese and 24.7 being overweight.' It's better to more clearly define 'obese' and 'overweight' . In addition, obesity is a critical issue for COVID-19 patients, it's also suitable to provide the BMI of normal population in New Orleans for comparison if possible.

Comment 3: The data of table 2 needs to be carefully corrected. For example, the meaning of the data in every parentheses made me confusing (e.g. in the first row of ED disposition : 134 (77) , 31 (72.1); however in the first row of Hospital admission: 310 (72.3), 41(57.7) ; the calculation method of each parentheses was inconsistent ! the inconsistency also noted in the sub-table of Procedures . Besides, the case numbers of hospital admission in Non-AMS group was 310+119=429 , but in the first row : Non-AMS (n=431), the authors should explain the discrepancy).

Comment 4:　In line 211-212 '... patients with AMS were less likely to be African American or have obesity...', but the authors didn't provide possible reasons for the differences. Besides, I wonder the body surface area might also differed between non-AMS and AMS groups.

Comment 5: According to fig 2, the AMS group was more likely to be intubated and needs mechanical ventilation, but in table 1, the respiratory symptoms of AMS group seemed to be less, especially ' Shortness of breath', this contradiction needs to be discussed.

**********

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.

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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: No

Reviewer #2: Yes: Chi-Hsiang Chou

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Attachment

Submitted filename: COVID-19-AMS.docx

Click here for additional data file. (12.5KB, docx)
PLoS One. 2021 Oct 5;16(10):e0258095. doi: 10.1371/journal.pone.0258095.r002

Author response to Decision Letter 0

14 Apr 2021

Comment 1: In the line 81 and 82, 'Patients were divided into two groups: with and without altered mental status (AMS).' The definition of AMS was not clear. In order to get a more objective results, an operational definition for AMS is essential.

Author Response Thank you for the comment. The Definition has been clarified in the manuscript and it is as following: altered mental status (AMS) which encompasses confusion, amnesia, loss of alertness, disorientation, defects in judgment or thought, unusual or strange behavior, poor regulation of emotions, and disruptions in perception, psychomotor skills, and behavior. Line (82-85)

Comment 2: In the line 109 and 110, '...(BMI) was 33.32...with 57.2% being obese and 24.7 being overweight.' It's better to more clearly define 'obese' and 'overweight' . In addition, obesity is a critical issue for COVID-19 patients, it's also suitable to provide the BMI of normal population in New Orleans for comparison if possible.

Author Response Thank you for pointing this out. We agree with this comment. Therefore, we have added the definition of the Obesity and overweight in the results. (line114,115)

The % of Obese population in Louisiana has been added to the discussion where our cohort had higher percentage of obese patient than the average of Louisiana population. Changes has been marked in the manuscript. (215-217)

Comment 3(A): The data of table 2 needs to be carefully corrected. For example, the meaning of the data in every parentheses made me confusing (e.g. in the first row of ED disposition: 134 (77) , 31 (72.1); however in the first row of Hospital admission: 310 (72.3), 41(57.7) ; the calculation method of each parentheses was inconsistent ! the inconsistency also noted in the sub-table of Procedures .

Author Response Thank you for pointing this out. The ED depositions data account for patients how came through the Emergency Room a total of 166 in non AMS and 43 for AMS and between the parentheses represent the (%) of the ER cases but these data don’t show any significance, so it was removed to avoid any confusion. (table 2)

Comment 3(B) the calculation method of each parentheses was inconsistent! the inconsistency also noted in the sub-table of Procedures

Author Response Thank you for pointing this out. The data has been clarified in the table caption. The data for the Extubation were calculated based on intubated patients and the no. of patients requiring reintubation were based on the no. of extubated patients. (Table 2)

Comment 3(C) Besides, the case numbers of hospital admission in Non-AMS group was 310+119=429, but in the first row: Non-AMS (n=431), the authors should explain the discrepancy).

Author response: Thank you for pointing this out. Revising our data showed it was a Clerical error. The correct no. is 431 in the Non-AMS group divided into Floor admission (312) and ICU (119) (table 2)

Comment 4:　 In line 211-212 '... patients with AMS were less likely to be African American or have obesity...', but the authors didn't provide possible reasons for the differences.

B-Besides, I wonder the body surface area might also differed between non-AMS and AMS groups.

Author response:

A- Thank You for raising such an important point, however. Our Data could not explain why the AMS patients were less likely to be African or have obesity, but this strengthens the argument that AMS may be an independent risk factor for poor health outcomes in COVID-19 patients. This point was added as one of the limitations in the study to be addressed by future research. Line (235)

B- We did not have access to the data for body surface area of the patients. So, we cannot address this point.

Comment 5: According to fig 2, the AMS group was more likely to be intubated and needs mechanical ventilation, but in table 1, the respiratory symptoms of AMS group seemed to be less, especially ' Shortness of breath', this contradiction needs to be discussed.

Author Response:

We agree with this suggestion the contraindication could be explained due to the decreased reporting of presenting complain with AMS Patients according to

Han JH, Bryce SN, Ely EW, et al. The effect of cognitive impairment on the accuracy of the presenting complaint and discharge instruction comprehension in older emergency department patients. Annals of emergency medicine 2011;57(6):662-71.e2. doi: 10.1016/j.annemergmed.2010.12.002 [published Online First: 2011/01/29].

Amended in the discussion (199-201)

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (21KB, docx)

Decision Letter 1

Tai-Heng Chen

6 May 2021

PONE-D-21-02993R1

Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study

PLOS ONE

Dear Dr. Aboueisha,

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.

Please submit your revised manuscript by Jun 20 2021 11:59PM. 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,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

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: (No Response)

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: (No Response)

Reviewer #2: Partly

**********

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

Reviewer #1: (No Response)

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: (No Response)

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 Response)

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 did not find "Author's response to reviewer recommendation".

My comments were as follows

In this study, authors investigated the association between altered mental status and outcomes in COVID- 19 patients. They found that patients with altered mental status had poor outcomes compared to those patients without altered mental status. Despite the results, I think that there are some concerns.

1. The altered mental status is a vague term and definition. Please clarify the definition of altered mental status.

2. Depth of sedation could be related to altered mental status. Please provide the information of sedative agents.

3. Please provide the causes of altered mental status such as seizure, sepsis associated encephalopathy, metabolic encephalopathy and stroke.

4. When did evaluate the altered mental status during hospitalization? Please provide this information.

Reviewer #2: Comment 1:In the line 81 and 82, 'Patients were divided into two groups: with and

without altered mental status (AMS).' The definition of AMS was not clear. In order to

get a more objective results, an operational definition for AMS is essential.

Author Response Thank you for the comment. The Definition has been clarified in the

manuscript and it is as following: altered mental status (AMS) which encompasses

confusion, amnesia, loss of alertness, disorientation, defects in judgment or thought,

unusual or strange behavior, poor regulation of emotions, and disruptions in

perception, psychomotor skills, and behavior. Line (82-85)

Responses 1: Although the authors described ‘altered mental status (AMS)’ in detail, it’s still difficult to practice in real world. The contents in Line (82-85) were only ‘descriptions’ of AMS, not ‘definitions’. In my opinion, it might be better to use the scores of Glasgow Coma Scale (GCS). In this way, we will be able to quantify AMS. It would also be easier for the audience to realize.

Comment 2:In the line 109 and 110, '...(BMI) was 33.32...with 57.2% being obese and

24.7 being overweight.' It's better to more clearly define 'obese' and 'overweight' . In

addition, obesity is a critical issue for COVID-19 patients, it's also suitable to provide

the BMI of normal population in New Orleans for comparison if possible.

Author Response Thank you for pointing this out. We agree with this comment.

Therefore, we have added the definition of the Obesity and overweight in the results.

(line114,115)

The % of Obese population in Louisiana has been added to the discussion where our

cohort had higher percentage of obese patient than the average of Louisiana

population. Changes has been marked in the manuscript. (215-217)

Responses 2: Agree.

Comment 3(A):The dat of table 2 needs to be carefully corrected. For example, the

meaning of the data in every parentheses made me confusing (e.g. in the first row of

ED disposition: 134 (77) , 31 (72.1); however in the first row of Hospital admission:

310 (72.3), 41(57.7) ; the calculation method of each parentheses was inconsistent !

the inconsistency also noted in the sub-table of Procedures .

Author Response Thank you for pointing this out. The ED depositions data account for patients how came through the Emergency Room a total of 166 in non AMS and 43 for AMS and between the parentheses represent the (%) of the ER cases but these datadon’t show any significance, so it was removed to avoid any confusion. (table 2)

Response 3(A): Agree.

Comment 3(B)the calculation method of each parentheses was inconsistent! the

inconsistency also noted in the sub-table of Procedures

Author Response Thank you for pointing this out. The data has been clarified in the

table caption. The data for the Extubation were calculated based on intubated patients and the no. of patients requiring reintubation were based on the no. of extubated patients. (Table 2)

Response 3(B): Agree.

Comment 3(C)Besides, the case numbers of hospital admission in Non-AMS group

was 310+119=429, but in the first row: Non-AMS (n=431), the authors should explain

the discrepancy).

Author response:Thank you for pointing this out. Revising our data showed it was a

Clerical error. The correct no. is 431 in the Non-AMS group divided into Floor admission (312) and ICU (119) (table 2)

Response 3(C): Floor admission was still 310 in table 2. This should be corrected.

Comment 4: In line 211-212 '... patients with AMS were less likely to be African

American or have obesity...', but the authors didn't provide possible reasons for the

differences.

B-Besides, I wonder the body surface area might also differed between non-AMS and

AMS groups.

Author response:

A-Thank You for raising such an important point, however. Our Data could not explain

why the AMS patients were less likely to be African or have obesity, but this

strengthens the argument that AMS may be an independent risk factor for poor health outcomes in COVID-19 patients. This point was added as one of the limitations in the study to be addressed by future research. Line (235)

Response 4(A): Agree.

B-We did not have access to the data for body surface area of the patients. So, we

cannot address this point.

Responses 4(B): Agree.

Comment 5:According to fig 2, the AMS group was more likely to be intubated and

needs mechanical ventilation, but in table 1, the respiratory symptoms of AMS group

seemed to be less, especially ' Shortness of breath', this contradiction needs to be

discussed.

Author Response:

We agree with this suggestion the contraindication could be explained due to the

decreased reporting of presenting complain with AMS Patients according to

Han JH, Bryce SN, Ely EW, et al. The effect of cognitive impairment on the accuracy of

the presenting complaint and discharge instruction comprehension in older emergency department patients. Annals of emergency medicine 2011;57(6):662-71.e2. doi:10.1016/j.annemergmed.2010.12.002 [published Online First: 2011/01/29].Amended in the discussion (199-201)

Responses 5: Agree.

**********

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: No

Reviewer #2: Yes: Chi-Hsiang Chou

[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.]

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Attachment

Submitted filename: PLOS-COV-19-Revised.docx

Click here for additional data file. (14.9KB, docx)
PLoS One. 2021 Oct 5;16(10):e0258095. doi: 10.1371/journal.pone.0258095.r004

Author response to Decision Letter 1

20 Jun 2021

Response to reviewers' comments

(PONE-D-21-02993)

“Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study.”

Dear Prof. Emily Chenette,

Editor-in-Chief

PLOS ONE Journal

First, we apologize for delayed response and we are extremely grateful for both reviewers comments and feedback. We would like to thank the editors and reviewer the for giving us the opportunity to submit a revised draft of Our manuscript titled “Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study” to PLOS ONE Journal.

We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments on our paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. We have highlighted the changes within the manuscript. We hope that our responses address the reviewers concerns and wish it meets PLOS journal standards.

Here is a point-by-point response to the reviewers’ comments and concerns.

Reviewer 1 Comments

Comment 1: The altered mental status is a vague term and definition. Please clarify the definition of altered mental status.

Author Response Thank you for the great input we have tried to the best of our knowledge identify the AMS term as highlighted in the methodology section (Line 83-85). Also, we provided the Mean and SD of both cohort where the AMS group had a GCS of 9.41 ± 4.08 as seen in table 1.

Comment 2: Depth of sedation could be related to altered mental status. Please provide the information of sedative agents.

Author Response Thank you for the valuable feedback. Sedation will alter the patient level of consciousness, but all our patients had Altered mental status on admission as diagnosed by the attending physician, so they were not on any sedation at the time of diagnosis. This is explained in methodology section in lines (85-86)

Comment 3: Please provide the causes of altered mental status such as seizure, sepsis associated encephalopathy, metabolic encephalopathy and stroke.

Author Response Your feedback is precious. The underlying cause of the AMS is essential to the management plan. In our cohort, we adjusted for neuropsychiatric comorbidities in AMS and non-AMS group, as shown in Figure 2, accounting for the vital role Neuropsychiatric comorbidities could play in developing AMS by performing multivariate analysis patients with COVID-19 who present with AMS have a worse outcome.

The Neuropsychiatric comorbidity could be found in figure 1.

Comment 4: When did evaluate the altered mental status during hospitalization? Please provide this information.

Author Response Evaluation was performed on Admission. We are grateful for your feedback it has been added to the methodology section in line (85)

Reviewer 2 comments

Comment 1 Although the authors described ‘altered mental status (AMS)’ in detail, it’s still difficult to practice in real world. The contents in Line (82-85) were only ‘descriptions’ of AMS, not ‘definitions. In my opinion, it might be better to use the scores of Glasgow Coma Scale (GCS). In this way, we will be able to quantify AMS. It would also be easier for the audience to realize.

Author response Thank you for your valuable feedback. Adding GCS would be a great addition to the paper; patients enrolled in the study were further assessed using the GCS; the mean and SD of GCS for both groups with and without AMS are present in table 1. we showed that the AMS group had a mean and SD of 9.41 ± 4.08.

Response 3(C): Floor admission was still 310 in table 2. This should be corrected.

Author response It has been corrected

We are glad that our response answered reviewer 2 previous comments.

you will find them below

Comment 1:In the line 81 and 82, 'Patients were divided into two groups: with and without altered mental status (AMS).' The definition of AMS was not clear. In order to get a more objective results, an operational definition for AMS is essential. Author Response Thank you for the comment. The Definition has been clarified in the manuscript and it is as following: altered mental status (AMS) which encompasses confusion, amnesia, loss of alertness, disorientation, defects in judgment or thought, unusual or strange behavior, poor regulation of emotions, and disruptions in perception, psychomotor skills, and behavior. Line (82-85)

Responses 1: Although the authors described ‘altered mental status (AMS)’ in detail, it’s still difficult to practice in real world. The contents in Line (82-85) were only ‘descriptions’ of AMS, not ‘definitions’. In my opinion, it might be better to use the scores of Glasgow Coma Scale (GCS). In this way, we will be able to quantify AMS. It would also be easier for the audience to realize.

Answered Above

Comment 2: In the line 109 and 110, '...(BMI) was 33.32...with 57.2% being obese and24.7 being overweight.' It's better to more clearly define 'obese' and 'overweight' . In addition, obesity is a critical issue for COVID-19 patients, it's also suitable to provide the BMI of normal population in New Orleans for comparison if possible.

Author Response Thank you for pointing this out. We agree with this comment.

Therefore, we have added the definition of the Obesity and overweight in the results. (line114,115) The % of Obese population in Louisiana has been added to the discussion where our cohort had higher percentage of obese patient than the average of Louisiana population. Changes has been marked in the manuscript. (215-217)

Responses 2: Agree.

Comment 3(A): The data of table 2 needs to be carefully corrected. For example, the meaning of the data in every parentheses made me confusing (e.g. in the first row of ED disposition: 134 (77) , 31 (72.1); however in the first row of Hospital admission: 310 (72.3), 41(57.7) ; the calculation method of each parentheses was inconsistent ! the inconsistency also noted in the sub-table of Procedures .

Author Response Thank you for pointing this out. The ED depositions data account for patients how came through the Emergency Room a total of 166 in non AMS and 43 for AMS and between the parentheses represent the (%) of the ER cases but these data don’t show any significance, so it was removed to avoid any confusion. (table 2)

Response 3(A): Agree.

Comment 3(B)the calculation method of each parentheses was inconsistent! the

inconsistency also noted in the sub-table of Procedures

Author Response Thank you for pointing this out. The data has been clarified in the table caption. The data for the Extubation were calculated based on intubated patients and the no. of patients requiring reintubation were based on the no. of extubated patients. (Table 2)

Response 3(B): Agree.

Comment 3(C)Besides, the case numbers of hospital admission in Non-AMS group was 310+119=429, but in the first row: Non-AMS (n=431), the authors should explain the discrepancy).

Author response: Thank you for pointing this out. Revising our data showed it was a Clerical error. The correct no. is 431 in the Non-AMS group divided into Floor admission (312) and ICU (119) (table 2)

Response 3(C): Floor admission was still 310 in table 2. This should be corrected.

Answered above

Comment 4: In line 211-212 '... patients with AMS were less likely to be African

American or have obesity...', but the authors didn't provide possible reasons for the differences.

B-Besides, I wonder the body surface area might also differed between non-AMS and AMS groups.

Author response:

A-Thank You for raising such an important point, however. Our Data could not explain why the AMS patients were less likely to be African or have obesity, but this strengthens the argument that AMS may be an independent risk factor for poor health outcomes in COVID-19 patients. This point was added as one of the limitations in the study to be addressed by future research. Line (235)

Response 4(A): Agree.

B-We did not have access to the data for body surface area of the patients. So, we

cannot address this point.

Responses 4(B): Agree.

Comment 5:According to fig 2, the AMS group was more likely to be intubated and needs mechanical ventilation, but in table 1, the respiratory symptoms of AMS group seemed to be less, especially ' Shortness of breath', this contradiction needs to be discussed.

Author Response:

We agree with this suggestion the contraindication could be explained due to the

decreased reporting of presenting complain with AMS Patients according to

Han JH, Bryce SN, Ely EW, et al. The effect of cognitive impairment on the accuracy of the presenting complaint and discharge instruction comprehension in older emergency department patients. Annals of emergency medicine 2011;57(6):662-71.e2. doi:10.1016/j.annemergmed.2010.12.002 [published Online First: 2011/01/29].Amended in the discussion (199-201)

Responses 5: Agree.

Attachment

Submitted filename: Response to reviewers 2.docx

Click here for additional data file. (23.2KB, docx)

Decision Letter 2

Tai-Heng Chen

22 Jul 2021

PONE-D-21-02993R2

Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study

PLOS ONE

Dear Dr. Aboueisha,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

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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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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: 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 your revised manuscript.

Authors modified and updated the manuscript based on the reviewer's comments.

Reviewer #2: I suggested the authors to provide the Glasgow Coma Scale (GCS) score of the AMS patients previously. However, I still cannot get any GCS data by this revised article. I think this point needs to be well explained.

**********

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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Reviewer #1: No

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.

PLoS One. 2021 Oct 5;16(10):e0258095. doi: 10.1371/journal.pone.0258095.r006

Author response to Decision Letter 2

8 Sep 2021

Response to reviewers' comments

(PONE-D-21-02993)

“Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study.”

Dear Prof. Emily Chenette,

Editor-in-Chief

PLOS ONE Journal

First, we apologize for delayed response because of hurricane Ida and the power loss afterward. we are extremely grateful for both reviewers’ comments and feedback. We would like to thank the editors and reviewer for giving us the opportunity to submit a revised draft of Our manuscript titled “Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study” to PLOS ONE Journal.

We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments on our paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. We have highlighted the changes within the manuscript. We hope that our responses address the reviewers concerns and wish it meets PLOS journal standards.

Here is a point-by-point response to the reviewers’ comments and concerns.

Reviewer 2 Comments

Comment I suggested the authors to provide the Glasgow Coma Scale (GCS) score of the AMS patients previously. However, I still cannot get any GCS data by this revised article. I think this point needs to be well explained.

Answer Thank you for your comments and reviews, we have edited the methodology section to show how used GCS and edited the results to highlight this finding

Line 91-92

Line 129-130

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (18KB, docx)

Decision Letter 3

Tai-Heng Chen

20 Sep 2021

Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study

PONE-D-21-02993R3

Dear Dr. Aboueisha,

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,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

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 #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 #2: Yes

**********

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

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 #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 #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 #2: The description "(9.41 ± 4.0815.00 ± 0.00, p<0.001)" on line 129-130 should be corrected. (I think the correct description might be "(9.41 ± 4.08 versus 15.00 ± 0.00, p<0.001)".

**********

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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 #2: No

Acceptance letter

Tai-Heng Chen

27 Sep 2021

PONE-D-21-02993R3

Altered mental status is a predictor of poor outcomes in COVID-19 patients: A cohort study.

Dear Dr. Aboueisha:

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. Tai-Heng Chen

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: COVID-19-AMS.docx

    Click here for additional data file. (12.5KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

    Click here for additional data file. (21KB, docx)
    Attachment

    Submitted filename: PLOS-COV-19-Revised.docx

    Click here for additional data file. (14.9KB, docx)
    Attachment

    Submitted filename: Response to reviewers 2.docx

    Click here for additional data file. (23.2KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

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    Data Availability Statement

    All relevant data are within the manuscript.

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