Predictors of fatal neurological complications among admitted COVID-19 patients with their implication in outcome: A Case Control study.

BACKGROUND: COVID-19 is known to be associated to potentially fatal neurological complications; therefore, it is essential to understand the risk factors for its development and the impact they have on the outcome of COVID-19 patients. AIMS: To determine the risk factors for developing fatal neurological complications and their outcome in hospitalized COVID-19 patients.
MATERIAL AND METHODS: Case control study based on hospitalized patients was conducted from July 15th 2021 to December 15th 2021. Cases and controls were COVID-19 confirmed patients with and without severe neurological manifestations. Age, comorbid conditions, vaccination status, Blood Sugar Random (BSR), D-dimers levels, anticoagulation type and dosage were taken as predictors (exposure variables) for developing neurological complications. In the case-only (subgroup) analysis, 28-day mortality were analyzed using the same predictors including admission hypoxemia. Chi square test and regression model were built to calculate OR with 95%CI.
RESULTS: Among 383 patients (median age, 56 years [IQR, 24-110]; 49.9% men); 95 had neurological complications (cases) and 288 did not (controls). Development of neurological complications among COVID-19 related hospitalizations was significantly associated with old age >71 yrs. (cases, 23.2%; controls, 13.5%; OR, 3.31; 95% CI, 1.28-8.55), presence of diabetes mellitus (37.9% vs. 24%; OR, 1.9; 95% CI, 1.2-3.1), admission hyperglycemia (BSR 351-600 mg/dl), (29.5% vs. 7.6%; OR, 3.11; 95%CI, 1.54-6.33), raised D-dimer levels 5000-10,000 ng/ml (41% vs. 11.8%; OR, 5.2; 95% CI, 3.02-8.9), prophylactic dose anticoagulation (43.2% vs. 28.1%; OR, 1.9; 95%CI, 1.2-3.1), and unvaccinated status of COVID-19 patients (90.5% vs. 75.6%; OR, 3.01; 95% CI, 1.44-6.25). Neurological complications with COVID-19 were associated with increased likelihood of death or invasive mechanical ventilation by day 28 (86.3% vs. 45.1%; OR, 7.66; 95% CI, 4.08-14.4). In case-only analysis (median age, 56 years [IQR, 27,110]; 50.5% women), 67 (70.5%) had CVE, 21 (22.1%) had Encephalitis, and 7 (7.4%) had GBS as neurological manifestations. 28-day mortality among these patients was strongly associated with a lower likelihood of vaccination. (6.1% cases vs. 30.8% controls; OR, .146; 95%CI, .033- .64), being younger 17-45 yrs. (12.2% vs. 46.2%; OR, .162; 95%CI, .045-.58), having no comorbid condition (19.5% vs. 61.5%; OR, .151; 95%CI, .044- .525), having cerebrovascular events and GBS as type of neurological manifestation (76.8% vs.30.8%; OR, 7.46; 95%CI, 2.06-26.96), (2.4% vs. 38.4%; OR, .04; 95%CI, .007- 0.24) respectively, and presence of hypoxemia at admission (91.5% vs. 15.4%; OR, 58.92; 95%CI, 10.83-320.67).
CONCLUSION: Old age, presence of Diabetes Mellitus, unvaccinated status of patients, high BSR at admission, high D-dimers, and prophylactic dose anticoagulation were identifies as increased risk factors for developing serious neurological complications among COVID-19 patients. Neurological problems in COVID-19 patients raised death risk 7.6-fold. The most common neurological complication was cerebrovascular events, followed by encephalitis and GBS. Unvaccinated status, cerebrovascular events, and admission hypoxemia are associated with an increased likelihood of 28-day mortality among these patients.

Introduction

Although COVID-19 is typified by respiratory symptoms and complications, neurological presentations of disease must not be underestimated. At least one subjective neurological symptom has been reported in nearly 36 to 85% of COVID-19 patients, highlighting the importance of the disease’s neurological repercussions [1, 2]. Initially, headache, gustatory and olfactory dysfunctions and confusion were the most common general non-specific neurological symptoms reported by COVID-19 patients while major neurological problems such as ischemic and hemorrhagic stroke, cerebral (sinus) venous thrombosis, Encephalitis, Guillain–Barré syndrome and posterior reversible encephalopathy syndrome (PRES) had also been observed with severe cases [3, 4]. With the introduction of variants of concern (VOC), such as the delta variant (B.1.167.2) of SARS-COV-2, the disease’s severity and complications had been escalated [5]. Patients with severe COVID-19 infection had a higher rate of neurological complications than those with moderate infection. Moreover, neurological complications may have poor impact on outcome of COVID-19 patients [6, 7].

Neuropathology is caused by a combination of immunological and hypoxia-induced damage superimposed by coagulation abnormalities [8]. ACE 2 receptors being the principal binding sites for SARS-COV-2, are found in neurons, oligodendrocytes, astrocytes, substantia nigra, posterior cortex, brainstem and olfactory bulb. As a result, SARS-CoV-2 has the ability to infect neurons and glial cells throughout the brain [8, 9]. Blood-brain barrier(BBB) is broken by elevated cytokine levels, chemokine, and free radicals linked to activation of the immune system. Triggered inflammatory cascade can cause reactive astrogliosis [10]. Once the virus has crossed the BBB and entered the CNS, it will be difficult to eliminate it since the nervous system lacks substantial histocompatibility antigens and the immune response will be confined to cytotoxic T cells. The patient finally develops acute encephalitis, viral toxic encephalopathy, or acute cerebrovascular accidents (CVAs) [8, 10]. Infectious toxic encephalopathy (ITE) is a reversible brain dysfunction syndrome marked by cerebral edema caused by systemic toxemia and hypoxia, which can result in delirium and coma. In COVID-19 patients, virus-induced cytokine storm and coagulation abnormalities increase the likelihood of acute CVA [11].

There are several clinical, laboratory and radiological investigations that can predict the severity of disease and outcome in COVID-19 patients assigned to respiratory complications [12]. The vast majority of studies on neurological complications, including meta-analyses, focus on the kind of neurological complication and the outcome, while predictors of neurological sequelae are underexplored [13, 14], but there are hardly any relevant predictors for neurological sequelae. So, we designed an observational study at COVID-19 High Dependency Unit of tertiary care hospital to investigate possible predicting factors that may put COVID-19 patients at risk of developing serious neurological complications, as well as to observe any impact of complications and predictors on patients’ outcome.

Material and methods

A Case Control study approved by Institutional Review Board, Department of medical education, Qauid e Azam Medical College Bahawalpur, vide letter no.1283, and was carried out between July 15th, 2021 and December 15th 2021, delta period of SARS-COV-2 in Pakistan, to find out risk factors for fatal neurological complications in admitted COVID-19 patients and their impact on outcome. Study comprised adults aged 18 years and above for potential eligibility through daily review of hospital admissions and electronic record of COVID-19 High Dependency Unit and Intensive Care Units, at Sir, Sadiq Abbasi Hospital, Bahawalpur, a tertiary care hospital that received referrals of COVID-19 confirmed patients from all primary, secondary, and tertiary care hospitals of division, Bahawalpur, Punjab, Pakistan. An informed written consent was taken from patients or their escorts. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline was followed in this study.

The cases were patients with a clinical syndrome consistent with acute COVID-19 and a positive PCR for SARS-CoV-2 (done by extraction and amplification method on Quant Studio 5 applied biosystem machine) or suggested HRCT who were hospitalized within 10 days of symptom onset and developed an acute onset severe neurological complication at admission or within 28 days of hospital stay. Neurological manifestations were defined as recent onset focal neurological deficit or altered sensorium gained after having symptoms of COVID-19 or laboratory confirmation of it. In addition to a full neurological evaluation by a neurologist, neuroimaging such as computed tomography, MRI brain, CSF analysis, and Nerve Conduction Studies were performed where indicated. The study excluded participants having a history of previous neurological illnesses that left them with residual weakness and those with partial or unknown vaccination status. Considering the study’s focus on serious neurological manifestations (focal neurological deficit, arterial or venous stroke, encephalitis leading to decrease in consciousness, or acute demyelinating disorders), as a complication of COVID-19, mild neurological symptoms e.g. loss of taste and smell, headache and facial nerve palsy were excluded. Controls were recruited from a pool of eligible COVID-19 confirmed participants who had been hospitalized within two weeks of the case’s enrollment and matched in gender and duration by a 3:1 ratio. Matching for admission dates minimized the risk of lead time bias.

Age, co morbid illnesses, blood sugar level in mg/dl, D-Dimer level in ng/ml, type and dose of anticoagulation, and prior vaccination status were exposure predictor variables. Participants were categorized into three major groups based on their age. Co morbid conditions and their number in each participant were also noted, with a particular emphasis on uncontrolled comorbid factors for severe COVID-19. Random Blood Sugar in mg/dl was also noted at the time of admission; however, it changed as a result of hospital and disease-related stress, as well as intravenous steroid. On the basis of their blood sugar levels, the participants were divided into three categories: less than 200 mg/dl, 201–350 mg/dl, and 351 to 600 mg/dl. D-dimers were checked within 24 hours of hospitalization, prior to the initiation of anticoagulation, based on the results participants were divided into four categories: less than 500ng/ml, 501-5000ng/ml, 5001 to 10000 ng/ml and more than 10,000 ng/ml. The D-dimers were expressed in ng/ml FEU (Fibrinogen equivalent unit). Oral anticoagulants, Low Molecular Weight Heparin (LMWH), and unfractionated heparin were identified as anticoagulation types given during hospitalization or prior to it. On the basis of dosage, anticoagulation was categorized as either therapeutic or prophylaxis. Enoxaparin 40 mg daily for a body weight of < 100 kg, 60 mg daily for a body weight of more than or equal to 100 kg, and Rivaroxaban 10 mg daily were considered thromboprophylactic doses of anticoagulation. Enoxaparin 1 mg/kg body weight twice daily and Rivaroxaban 15 or 20 mg daily were considered therapeutic anticoagulation doses. Patients’ vaccination status was determined by entering their National Identity numbers, which were obtained from their hospital electronic records, into a national database of vaccination program, along with the dates of their first and second doses of vaccination, and categorizing them as fully vaccinated or unvaccinated while excluding the partially vaccinated participants.

In the main analysis, the primary outcome measure was the development of neurological complications at admission or within 28 days of hospital stay. We also gathered data on the severity of COVID-19. These outcome measures were recorded until hospital discharge or 28 days following hospitalization, whichever came first. The major classification of illness severity was based on a dichotomous measure that divided between individuals who died or required invasive mechanical ventilation and those who did not. To determine severity, the patient’s highest ordinal level within the first 28 days of hospitalization was employed. To categorize COVID-19 severity, we used a customized version of the World Health Organization COVID-19 Clinical Progression Scale, which goes from infection naïve (level 0) to infected albeit asymptomatic (level1) to death (level 9). To determine severity, the patient’s highest ordinal level within the first 28 days of hospitalization was employed. The highest severity level observed could range from level 4 to level9, including hospitalized with no oxygen support (level4), with standard oxygen therapy (level5), with high-flow nasal cannula or noninvasive ventilator support (level6), with mechanical ventilation (level7), or with mechanical ventilation and additional organ assistance (hemodynamic support, extracorporeal membrane oxygenation, or new Renal Replacement Therapy (level 9)). According to scale level 4 were categorized as moderate disease, level 5 as severe disease and level 6,7 and 8 as critical illness. Patients with severity levels 6, 7, 8 and 9 required ICU care.

In case-only (subgroup) analysis, patients with neurological complications were analyzed. The frequency and percentage of each type of neurological complication were noted. Cases and controls were categorized as those who died and those who did not, using the same exposure variables (predictors) as in the primary analysis, with the addition of type of neurological manifestation and hypoxemia at the time of admission. The primary outcome measures were illness progression to death within 28-days of hospital admission, survival leading to discharge from the hospital with residual weakness, or complete remission of neurological symptoms, whichever occurred first. The secondary outcome measures were also same as in primary analysis. Furthermore, the correlation between each type of neurological manifestation and predictor variables was evaluated independently.

In statistical analysis, median with inter quartile range (IQR) were taken for continuous variables and frequencies and percentages for categorical variables in both primary and subgroup analysis. The association between outcome and predictor variables was calculated in term of odds ratios (ORs) with their 95% CI. Odds Ratio for whom a 95% Confidence Interval crossing the null is considered insignificant. Chi Square test of independence and multinomial logistic regression model were created to calculate OR and significance values for dichotomous and multilevel dependent variables wherever applicable, keeping p value < .05 to be statistically significant. The following equation was used to determine the exposure effect for the prevention or occurrence of outcome: exposure predictability of outcome = (1- OR) 100%. R2 value is used to determine the correlation between each type of neurological problem and the predictor variable in subgroup analysis. Data was analyzed using version 26 of IBM SPSS statistics.

Results

During study period, total 105 cases were enrolled, however, 10 patients were excluded, and the major cause of exclusion was previous history of neurological illness with residual weakness and undiagnosed neurological manifestation. A total of 383 analyzed populations [median age 56 yrs; IQR (24, 110), 49.9% males, median no. of comorbid conditions 1 IQR (0, 4)], comprised 95 cases and 288 gender and duration matched controls. Of the total studied population, 62.4% of participants were from the age group 46–70 yrs., and 33.7% of patients had at least one comorbid condition for severe OVID-19. Frequency and percentages for categorical variables and median with IQR for continuous variables among cases and controls are given in Table 1.

Table 1

Characteristics of case patients (with neurological complications) and control patients (without neurological complications).

Characteristics	No. (%)
	Cases (n = 95)	Controls (n = 288)
Age Median, IQR	56(27,110)	56(25,99)
Age groups
25–45 yrs.	16(16.8)	67(23.3)
46–70 yrs.	57(60)	182(63.2)
≥71 yrs.	22(23.2)	39(13.5)
No. of comorbid conditions Median, IQR	1(0,4)	1(0,4)
Comorbid conditions
No risk factor	24(25.3)	87(30.2)
DM	36(37.9)	69(24)
Cardiovascular diseases	27(28.4)	108(37.5)
Pulmonary disease	1(1.1)	11(3.8)
Obesity	0	1(0.3)
Old Age	7(7.4)	12(4.2)
Vaccination status
Vaccinated	9(9.5)	70(18.3)
Unvaccinated	86(90.5)	218(75.7)
BSR(mg/dl) Median, IQR	218(80,578)	174(98,340)
<200	37(38.9)	206(71.5)
201–350	30(31.6)	82(28.5)
351–600	19(20)	0
D-dimers(ng/ml)	5900(280,13,000)	2100(320,7900)
≤500	9(9.5)	12(4.2)
501–5000	28(29.5)	225(78.1)
5000–10,000	39(41)	34(11.8)
>10,000	19(20)	17(5.9)

Development of neurological complication among COVID-19 patients was significantly associated with old age ≥71 yrs. [22 (23.2%) cases Vs. 39(13.5%) controls; OR, 3.31; 95%CI, 1.28–8.55; p < .05], having Diabetes Mellitus as a comorbid condition [36(37.9%) vs. 69(24%); OR, 1.9; 95%CI, 1.2–3.1; p < .05], high D-dimer level 5000–10000 ng/ml [39(41%) vs. 34(11.8%); OR, 5.20; 95%CI, 3.02–8.9; p < .01], prophylactic dose of anticoagulation [41(43.2%) vs. 81(28.1%); OR, 1.9; 95%CI, 1.2–3.1; p < .05] and unvaccinated status of COVID-19 patients [86(90.5%) vs. 218(75.7%); OR, 3.01; 95%CI, 1.44–6.25; p < .01]. With increased likelihood of vaccination, there was decreased chance of neurological complications, [9(9.5%) vs. 70(18.3%); OR, .332; 95%CI, .16-.69, p < .001]. Estimated vaccine effectiveness against development of neurological complications was (1–0.33) ×100 = 66.9%. Association between exposure variables and development of neurological complications are given in Fig 1.

Fig 1

Association between predictor variables and development of neurological complications among COVID-19 patients.

DM (Diabetese Mellitus), CVD (cardiovascular Diseases), BSR (blood sugar random), LMWH (Low molecular weight heparin). Association is measured in term of OR 95% CI shown in forest plot. In this model, an odds ratio <1 indicated decreased likelihood of neurological complication, and vice versa.

With increased likelihood of neurological complications there was decreased chances of having admission hypoxemia [18(18.9%) cases vs. 11(3.8%) controls; OR, .17 95% CI; .07-.37, p < .001]. When keeping the critical illness as reference category in multinomial regression analysis, 19(20%) vs. 11(3.8%) had moderate disease, (OR, 6.008; 95% CI, 2.668–13.529; p < .001), 30(31.6%) Vs. 117(40.6%) had severe disease (OR, .892; 95%CI, .531–1.497; p = .665). This means that patients with neurological complications are more likely to have moderate disease than those who do not.

Eighty three (86.3%) cases Vs. 130(45.1%) had disease progression to death or shifting to invasive ventilator support, OR 7.66, 95%CI (4.08, 14.4), RR 5.1 95%CI (2.93, 8.81) and p < .001. So, patients who had neurological complications had 660% more chances of dying than those without them.

In a case-only (subgroup) analysis, [median age 56 yrs., IQR (27,110), 48 (50.5%) were females, 67 (70.5%) patients developed Cerebral Vascular Events (CVE), seven (7.4%) had GBS (Guillain Barre Syndrome) confirmed by Nerve Conduction Study, and 21 (22.1%) had Encephalitis]. Among patients with CVE, 55 (82%) had ischemic infarct of arterial territory on Computed Tomography, six (9%) had hemorrhagic infarct, and six (9%) patients had cerebral venous thrombotic events, including three cases with cavernous venous sinus thrombosis. Association between the death outcome and the predictor variables is depicted in Table 2.

Table 2

Association between predictor variables and death outcome among patients with neurological complications.

Characteristics	Deaths n(%)	Survivals n(%)	OR 95%CI	p value
Total no.	82	13
Age yrs, Median IQR	59(30,110)	46(27,67)
Age group
25–45 yrs.	10(12.2)	6(46.2)	.162(.045 to .58)	< .01
46–70 yrs.	50(61)	7(53.8)	1.34(.412 to 4.35)	>.05
≥71 yrs.	22(26.8)	0	10.04(.57, 176.02)	>.05
No. of comorbid, IQR	1(0,4)	0(0,3)
No risk factor	16(19.5)	8(61.5)	.151(.044, .525)	.003
DM	34(41.5)	2(15.4)	3.895(.811, 18.72)	.09
CVD	24(29.3)	3(23.1)	1.379(.349, 5.46)	.65
Pulmonary disease	1(1.2)	0	.496(.019,12.84)	.7
Old Age	7(8.5)	0	2.68(.144, 49.77)	.51
Vaccination Status
Vaccinated	5(6.1)	4(30.8)	.146(.033, .64)	< .05
Unvaccinated	77(93.9)	9(69.2)	6.84(1.55, 30.22)	< .05
Neurological manifestation
Cerebrovascular Accidents	63(76.8)	4(30.8)	7.46(2.06, 26.96)	< .01
GBS	2(2.4)	5(38.4)	.04(.007, 0.24)	< .001
Encephalitis	17(20.7)	4(30.8)	.588(.16, 2.14)	.422
D-dimers, median(IQR)	6500 (280,13000)	1500(350,7800)
≤500	5(6.1)	4(30.8)	.144(.033, .63)	.016
501–5000	21(25.6)	7(53.8)	.29(.09,.97)	.04
5000–10,000	37(45.1)	2(15.4)	4.52(.94, 21.69)	.05
>10,000	19(23.2)	0	8.29(.47, 145.94)	.14
BSR, IQR	232(80,578)	167(120,429)
<200	30(36.6)	7(53.8)	.16(.02, .137)	.095
201–350	25(30.5)	5(38.5)	.185(.02, 1.69)	.136
351–600	27(32.9)	1(7.7)	5.40(.590, 49.46)	.136
Anticoagulation dose
No anticoagulant	6(7.3)	0(0)
Prophylactic	34(41.5)	7(53.8)	.620(.186, 2.06)	>.05
Therapeutic	42(51.2)	6(46.2)	1.612(.484,5.37)	>.05
Hypoxemia at Admission	75(91.5)	2(15.4)	58.92(10.83, 320.67)	< .001

The frequency and percentage of categorical variables were determined independently for each type of neurological condition, as given in Table 3.

Table 3

Type of neurological complications and categorical variables.

characteristics	Cerebrovascular events n(%)	Encephalitis n(%)	Guillain Barre Syndrome n(%)
Age groups
17–45 yrs.	9/67(13.4)	3/21(14.3)	4/7(57.1)
46–70 yrs.	43/67(64.2)	11/21(52.4)	3/7(42.9)
≥71 yrs.	15/67(22.4)	7/21(33.3)	0/7(0)
No risk factor	15/67(22.4)	3/21(14.3)	6/7(85.7)
DM	25/67(37.3)	10/21(47.6)	1/7(14.3)
CVD	20/67(29.9)	7/21(33.3)	0/7(0)
Vaccinated	3/67(4.5)	4/21(19)	2/7(28.6)
Unvaccinated	64/67(95.5)	17/21(81)	5/7(71.4)
BSR mg/dl
≤200	21/67(31.3)	11/21(52.4)	5/7(71.4)
201–350	26/67(38.8)	3/21(14.3)	1/7(14.3)
351–600	20/67(29.9)	7/21(33.3)	1/7(14.3)
D-dimers (ng/ml)
≤500	0/67(0)	5/21(23.8)	4/7(57.1)
501–5000	10/67(14.9)	15/21(71.4)	3/7(42.9)
5001–10,000	39/67(58.2)	0/21(0)	0/7(0)
>10,000	18/67(26.9)	1/21(4.8)	0/7(0)
Anticoagulation
Prophylactic dose	36/67(53.7)	11/21(52.4)	1/7(14.3)
Therapeutic dose	26/67(38.8)	10/21(47.6)	6/7(85.7)

COVID-19 patients with complete vaccination status had a lower risk of developing cerebrovascular events, (OR, 146; 95%CI, .044-.479; p.01); however, no significant association was found for GBS and encephalitis, p>.05, in the multinomial regression model where the absence of neurological complications was kept as a reference category Fig 2. Depicts the relationship between various types of neurological complications, age groups, and D-dimer levels in terms of R2.

Fig 2

Correlation between age in yrs. and D-dimer levels with different types of neurological manifestations.

CVA (Cerebrovascular Events), GBS (Guillen Barre Syndrome). (a) Shows patients with GBS were from young age group, there was decline in cases with increase in age, and Cerebrovascular Events were more from old age group and same with encephalitis. (b) Shows relationship between D-dimers and neurological manifestation, patients with GBS had negative correlation with D-dimers whereas patients with CVA had positive correlation elaborated as R2 value.

Discussions

In this analysis of adults hospitalized for COVID-19 between mid-July 2021 and mid-December 2021 (delta period in Pakistan), old age, diabetes mellitus as a comorbid factor, unvaccinated status, admission hyperglycemia 351–600 mg/dl, raised D-dimer level 5000–10000 ng/ml, and prophylactic dose anticoagulation were associated with an increased risk of neurological complications among COVID-19 admitted patients. Young age, complete vaccination, BSR less than 350 mg/dl, and D-dimers less than 5000ng/ml, as well as therapeutic dosage anticoagulation, were associated with a lower risk of neurological problems among CVOID-19 admitted patients. COVID-19 patients with neurological problems are less likely to have hypoxemia at admission and more likely to have moderate lung disease compared to COVID-19 patients without neurological problems, yet they had a 660% increased risk of death compared to the other group. In the case-only (subgroup) analysis, being young (25–45 yrs.), not having a co-morbid condition, being fully vaccinated, and having a D-dimers level below 5000 ng/mL were significantly associated with a lower risk of death, whereas being unvaccinated, having admission hypoxemia, and cerebrovascular event as a type of neurological complication were higher risk factors. Cerebrovascular events were the most prevalent form of neurological complication among cases, and full vaccination provides nearly 85% protection against their development in COVID-19 breakthrough cases who require hospitalization. The majority of patients who acquired GBS, were younger than those who had cerebrovascular events and encephalitis. D-dimer levels were found to be higher among patients with cerebrovascular events and lower in patients with GBS, but had no significant correlation with encephalitis.

OR in this analysis corresponds to increased risk of neurological complications in older age group of COVID-19 patients [1, 15]; Whereas in a previous study young age group is found to be risk factor for neurological complications. But the majority neurological manifestations were nonspecific in the study [16]. Those with Diabetes Mellitus as a comorbid factor with severe covid-19 were more likely to develop neurological sequelae, whereas patients with cardiovascular illness had no such risk [11].

Vaccination was less likely among participants with neurological complication. Estimated vaccine effectiveness against serious neurological sequelae among COVID-19 breakthrough infections is 66.9%, which is comparable to vaccine effectiveness against prevention of hospitalizations and disease progression to death among COVID-19 admitted patients for respiratory complications [17].

Patients with severe hyperglycemia (>350 mg/dl) were 3.1 times more likely to suffer neurological complications, while patients with markedly raised D-dimers (> 5,000ng/μl) were 5.2 times more probable. Patients on prophylactic dose anticoagulation were 1.9 times more likely to develop neurological complications, while those on therapeutic dose anticoagulation had 59% lower chances of developing the sequelae [18, 19]. There was no significant effect of therapeutic anticoagulation on death outcome among patients who already developed neurological complications [20]. In comparison to oral anticoagulation those participants who were on LMWH (enoxaparin) had 47% lesser chances of getting the neurological complication.

In COVID-19 patients who have neurological complications, the risk of disease progression to death is 7.6 times higher than in those who do not [11]. Almost 80% patients had severe respiratory disease at time of hospitalization. So, patients with severe COVID-19 are more likely to get neurological complications [21].

Among patients who developed neurological complications Cerebrovascular events (76.8%) were the most common presentation, followed by encephalitis and GBS [9, 22]. In this group, 18.9% of patients did not have any hypoxemia at the time of admission to the hospital, while 20% of patients had moderate respiratory complications, highlighting that neurological complications can occur as distinct and substantial consequence of COVID-19. When analyzing the risk factors for mortality and survival among patients with neurological complications, research indicates that young patients with no risk factors, who are fully vaccinated, have a low D-dimer, and do not have hypoxemia at the time of hospitalization are more likely to survive and have a better outcome. There was no significant association between the rest of the risk factors evaluated and death or survival outcomes in these patients. Mostly, 71.4% patients with GBS had good prognosis [23]. Whereas, there was great mortality among other type of complications i.e. Stroke and Encephalitis [6, 16].

Conclusion

Old age, diabetes mellitus, unvaccinated status, admission hyperglycemia, raised D-dimer levels, and prophylactic dose anticoagulation were all risk factors for neurological problems in COVID-19 admitted patients. Neurological problems in COVID-19 patients raised death risk 7.6-fold. Young age, being fully vaccinated, having no comorbidity, and a low D-dimer level were substantially related to a lower chance of death, whereas being unvaccinated, having admission hypoxemia, and having a cerebrovascular event were greater risk factors. The most common fatal neurological complications among COVID-19 patients were cerebrovascular events, followed by encephalitis. Because neurological complications had an unexpectedly high mortality rate, this COVID-19-related complication should not be overlooked in hospitalized patients, and each patient should be thoroughly examined and checked for the presence of risk factors for neurological manifestations to prioritize them and consider any preventable consequences.

Limitations of study

Retrospective nature of study and different types of neurological complications among cases are limitations of study. We need longitudinal prospective studies among COVID-19 patients in order to establish strength to observations. Moreover, study duration was short and only included delta period so the result cannot be generalized to all variants of SARS-COV-2.

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14 Jul 2022

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a) Did participants provide their written or verbal informed consent to participate in this study?

b) If consent was verbal, please explain i) why written consent was not obtained, ii) how you documented participant consent, and iii) whether the ethics committees/IRB approved this consent procedure.

3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

4. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

5. Please remove your figures from within your manuscript file, leaving only the individual TIFF/EPS image files, uploaded separately.  These will be automatically included in the reviewers’ PDF.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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

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

Reviewer #1: Yes

Reviewer #2: No

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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: Keywords should include important terms like Cerebrovascular events, and COVID 19. The keywords used are general, non-specific, and should be edited.

When mentioning reference numbers in the parenthesis, a full stop should be following the references at end of the sentence, not preceding the references.

Line 78-82: Is the author trying to suggest an increased risk of neurological disease with Delta variant as compared to COVID 19 in general? Please clarify for the readers.

Please abstain from a colloquial style of wiring that will also remove redundancy from the text.

Instead of mentioning molecular testing for COVID, please mention the detail with the type of PCR and instrumentation used for testing.

Line 150 - Were partially vaccinated patients included or excluded from the study? It should be clarified.

Line 192 - 18 patients among the cases had no hypoxemia at the time of admission, please state what was the reason for admission. Neurological symptoms or any other criteria used for admission should be mentioned.

Line 197-198 It will be interesting to mention respiratory illness severity and type of respiratory support in relation to neurological complications as increased risk of dying from covid 19.

Reviewer #2: This article requires an overhaul to address major concerns with formatting, stylistic approaches, grammar, methodology, and the presentation of your findings. While significant as a study from this corner of the world, it requires a more scientific approach towards your statistical inclusion of predictors, case-matching strategy, and extrapolation of findings. I believe with improvements and revisiting your data, this study can become a significant and worthy publication.

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

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

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

Reviewer #1: Yes: Bushra Tehreem

Reviewer #2: No

Submitted filename: PONE-D-22-05696_reviewer.pdf

Click here for additional data file.

2 Aug 2022

Response to Academic editor:

We much appreciate your consideration of this paper for publication. We have meticulously rectified the shortcomings identified by the academic editor.

1. The manuscript has been modified to adhere to the journal's specifications.

2. The revised manuscript includes a clear statement that written consent was obtained from study participants.

3. Dataset has been given in supporting information in xlsx file.

4. Full ethic statement is included in the methodology section of revised manuscript.

5. Figures are withdrawn from the manuscript file and converted to TIFF format in separate files.

Response to Reviewer #1:

Thank you very much for your valuable insight into our work. We have addressed your comments carefully

1. In the revised manuscript, Key words have been edited and important terms such as cerebrovascular events, COVID-19, encephalitis, predictors, and outcome have been added.

2. Full stops are correctly placed following the reference number at the end of sentences.

3. The study was conducted during the delta period of SARS-CoV-2 in Pakistan, which was the worst in terms of disease spread, severity, and fatality. Moreover, more neurological problems were reported compared to earlier waves. Therefore, it was important to highlight its fatality in the introduction, despite the fact that it was not compared to the other waves and, as stated in the study's limitations, its results cannot be generalized.

4. Informal writing style has been avoided as much as possible in the revised version.

5. Type and specifications of SARS-COV-2 PCR testing have been described in detail in the revised manuscript's methodology section.

6. Only fully vaccinated or unvaccinated participants were included in the study, excluding partially vaccinated patients from both cases and controls. A clear statement on vaccination status is included in both the methodology and results sections of revised manuscript.

7. The research was conducted at a hospital that received COVID-19 confirmed cases from other tertiary care hospitals. In the setting of a pandemic, the hospital received all sick admissions with positive PCR or HRCT findings diagnostic of COVID pneumonia with acute onset symptoms. Eighteen patients did not have hypoxemia at the time of hospitalization, but had positive PCR for SARS-COV-2 and extra pulmonary symptoms such as neurological or HRCT findings suggestive of COVID pneumonia without hypoxemia.

8. All patients with neurological complications were evaluated for the severity of respiratory illness, termed "Disease severity," which was measured by the WHO COVID-19 clinical progression scale in the methodology section. According to the scale, patients with moderate disease had no hypoxemia and did not require any oxygen support, patients with severe disease had hypoxemia and required oxygen support via simple face mask or rebreathing mask, and patients with critical illness required noninvasive or invasive ventilator support and required ICU care in general.

Response to Reviewer #2:

Thank you very much for your valuable comments for our original work. We have carefully put an effort to revise all sections of the manuscript to satisfy the reviewer's major concerns. Errors in grammar and sentence structure have been addressed thoroughly. Red highlighting denotes alterations to the manuscript.

Abstract:

Background in the abstract section has been edited for grammatical errors and extended to make it more comprehensive. Result section of structured abstract has been revised, clearly explaining the OR in scientific way. Conclusion of abstract also revised to conclude the results in a meaningful and scientific way.

Introduction:

Highlighted sentence has been edited with required changes and two more refernces on # 13 and 14 are added.

Methadology:

The methodology section has been thoroughly revised while preserving the original methodology. In the first paragraph of the methodology, the duration, design, and location of the study, as well as the ethical statement and design principles, are outlined in detail. The following paragraph describes the participants who defined the cases and matched controls. In the following paragraphs, predictor variables and primary and secondary outcome measures are discussed in detail in primary and subgroup analysis. In the last statistical analysis is mentioned. In order to make the methodology section more comprehensible for the readers, the majority of the text is rearranged and modified with pertinent amendments.

1. Division name is mentioned as Bahawalpur, Punjab, Pakistan.

2. Mild and serious neurological complications are described with example in the section where cases, controls and, inclusion and exclusion criteria are described.

3. Hospital admission criteria was positive PCR or HRCT chest suggestive of COVID-19 pneumonia and its related complications e.g high grade persistent fever, hypoxemia needing respiratory assistance, serious neurological complications , cardiac complications like myocarditis or renal complications like acute kidney injury.

4. In order to avoid lead time bias, controls are recruited within two weeks after case enrollment. Since COVID-19 presentation is with a brief history of febrile illness and pulmonary and extra pulmonary complications, it has an abrupt onset. While defining the potential study participants, it was stated that they must be admitted within 10 days after symptom onset or a positive PCR result. Obtaining a patient's PCR testing history was a second method for excluding participants who had persistent positive test. Covid-19.pshealthpunjab.gov.pk, provides a record of each positive or negative test conducted on the individual based on national Identity number. Patients with long history of symptom onset or positive PCR test, for more than 10 days were excluded.

Results:

The results section has been revised by revisiting the data and rearranging the results. With the aid of text, table 1 and figure 1, the main analysis’ results are outlined in detail. Afterwards, a case-only (subgroup) analysis is presented using text and table 2. In the last section, different neurological manifestations were evaluated independently in relation to predictor variables and outcome variables. To display the results of this investigation in a scientific manner, fig. 2 and a new table 3. Were incorporated.

While revisiting and presenting the data in a more effective manner, its originality was kept intact and no changes were made to the original data or statistics.

The discussion section has been meticulously revised to eliminate all grammatical mistakes. The first paragraph is substantially modified by incorporating additional results' conclusions.

The conclusion section is rewritten to better summarize the study's findings and provide valuable suggestions.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

30 Aug 2022

Predictors of Fatal Neurological Complications among Admitted COVID-19 Patients with their Implication in Outcome: A Case Control Study

PONE-D-22-05696R1

Dear Dr.  Aslam

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,

Soham Bandyopadhyay

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

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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: This revision is impressive and merits publication, given the authors' commitment to rigorous science, statistical method, and presentation of their findings. No further changes are recommended at the present moment.

**********

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 #2: Yes: M. Hamza Bajwa

**********

15 Sep 2022

PONE-D-22-05696R1

Predictors of Fatal Neurological Complications among Admitted COVID-19 Patients with Their Implication in Outcome: A Case Control Study

Dear Dr. Aslam:

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. Soham Bandyopadhyay

Academic Editor

PLOS ONE