Neurological manifestations during SARS-CoV-2 infection at the Douala General Hospital, Cameroon

¹Faculty of Health Sciences University of Buea, Douala General Hospital, P.O. Box 4856, Douala, Cameroon, ²Douala General Hospital, P.O. Box 4856, Douala, Cameroon, ³Faculty of Medicine and Pharmaceutical Sciences, University of Dschang, Douala General Hospital, P.O. Box 4856, Douala, Cameroon, ⁴Faculty of Heath Science, Mountain University, P.O. Box 208, Bangangté, Cameroon, ⁵Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala General Hospital, P.O. Box 4856, Douala, Cameroon, ⁶Centre Hospitalier Universitaire Mohammed VI de Marrakech, P.O. Box 2360 Principal, Morocco, ⁷Douala General Hospital, Douala, Cameroun, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala Laquintinie Hospital, Douala, Cameroon, ⁸Douala General Hospital, Douala, Cameroon, ⁹Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala General Hospital, P.O. Box 4856, Douala, Cameroon, ¹⁰Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala Laquintinie Hospital, P.O. Box 4856, Douala, Cameroon

^&Corresponding author
Daniel Gams Massi, Faculty of Health Sciences University of Buea, Douala General Hospital, P.O. Box 4856, Douala, Cameroon

Introduction    

Coronavirus disease 2019 (COVID-19) is caused by a coronavirus called SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) first described in Wuhan (China) [1]. COVID-19 was declared a global pandemic by the World Health Organization (WHO) in March 2020 [1]. The new coronavirus belongs to a family of viruses that generally cause mild illnesses or serious respiratory illnesses such as Middle East respiratory syndrome (MERS-COV), and severe acute respiratory syndrome (SARS-CoV-2) [2]. Despite containment and social distancing measures, the virus quickly spread across the world, causing significant morbidity and mortality [3]. As of August 2021, there were 221 million confirmed cases of COVID-19 and nearly 4.4 million deaths worldwide. Cameroon recorded 82,454 cases of COVID-19 and 1,338 deaths in August 2021 [4].

If COVID-19 mainly affects the respiratory tract, several studies indicate a significant tropism for the nervous system [5]. Neurological complications have been reported affecting both the central nervous system (CNS) and the peripheral nervous system (PNS) [6]. The neurological manifestations observed during COVID-19 could result from direct neurotropism, immune-mediated mechanisms, and/or metabolic effects during severe SARS-CoV-2 infection [7]. The frequency of neurological manifestations varies from 7.1% to 82% depending on the study [8,9]. Several studies have demonstrated a high incidence of neurological manifestations in hospitalized patients, which ranged from nonspecific neurological symptoms to more serious complications, such as encephalopathy and cerebrovascular diseases [10].

In Northern Africa, an observational hospital-based study found a frequency of 50.8% of neurological manifestations [11]. In Cameroon, Fogang et al. reported a frequency of 63.8% of neurological manifestations, mostly headaches, altered consciousness, and anosmia [12]. Despite the reduction in reported cases, COVID-19 still needs particular attention from health organizations. This study aimed to describe the neurological manifestations and to determine the outcome in patients with COVID-19 hospitalized at the Douala General Hospital in Cameroon during the outbreak of the pandemic.

Methods     

Study design and setting: we carried out a retrospective cohort study at the Douala General Hospital. It is a university hospital and the main referral health center in Douala (the economic capital of Cameroon). During the outbreak, patients suspected of COVID-19 were received and screened in the emergency department. Those with moderate to severe infection were sent to the COVID-19 unit for quarantine and treatment. Patients with mild symptoms/signs were treated and confined to home. The COVID-19 Unit was run by physicians who assessed patients on a rotating basis including two neurologists, two cardiologists, two pulmonologists, a nephrologist, an internist, a rheumatologist, two intensive-care physicians, five general practitioners, and three teams of two nurses, one nursing assistant and one hospital care worker. This unit comprised seventeen beds with a wall-mounted oxygen supply capacity for eight patients, and several devices including seven concentrators, one respirator, and one non-invasive ventilation device. Patients who have been hospitalized for COVID-19 with neurological manifestations were regularly followed up in the neurology outpatient unit after being discharged.

Study population: we carefully reviewed the medical records of patients with COVID-19 admitted to the study site from March 2020 to May 2021 (15 months). Our study population consisted of medical records of patients hospitalized for moderate to severe COVID-19: (1) patients confirmed positive for SARS-CoV-2 using the real-time polymerase chain reaction (PCR) or COVID-19 antigen tests after nasopharyngeal sample and/or (2) patients presenting thoracic CT scan abnormalities suggestive of COVID-19. Incomplete medical records (incomplete identification, lack of diagnostic evidence for SARS-CoV-2, no neurological assessment) were excluded. We systematically included all the medical records of patients meeting the inclusion criteria. Data contained in these records were transcribed into an anonymized data collection sheet.

Data collection: we collected data from sociodemographic features such as age, sex, profession, marital status, place of residence; medical, surgical, toxicological, and family history; vital parameters: blood pressure, heart rate, oxygen saturation, temperature, Glasgow coma scale (GCS). Clinical features comprised extra-neurological signs (asthenia, anorexia, cough, sputum, dyspnea, arthralgia, odynophagia, rhinorrhea, vomiting, diarrhea, abdominal pain, fever), CNS-related signs (headache, dizziness, altered consciousness, meningeal syndrome, delirium, raised intracranial pressure, cerebellar syndrome, …), and PNS-related signs (myalgia, anosmia, ageusia, blurred vision, cramps, tingling). We also looked for neurological diseases and extra-neurological disorders associated with COVID-19. Outcomes included the onset of neurological manifestations and in-hospital mortality.

Definitions: acute kidney injury: serum creatinine level ≥1.3 mg/dl in men and ≥1.1 mg/dl in women or documented acute kidney injury; acute respiratory distress syndrome: pulse oximeter oxygen saturation less than 95% or documented oxygen therapy; alcohol: medical history of alcohol intake; altered consciousness: GCS less than 15; cancer: a medical history of cancer, treated or not; chronic kidney disease: medical history of chronic kidney disease; chronic obstructive pulmonary disease: medical history of chronic obstructive disease (COPD) treated or not; diabetes: medical history of diabetes, treated or not; hepatitis B: positive hepatitis B serology or medical history of hepatitis B, treated or not; HIV: positive HIV serology or medical history of HIV, treated or not; hypertension: medical history of hypertension, treated or not; in-hospital mortality: documented death occurred during hospitalization; neurological manifestations: the presence of neurological symptoms, signs, and diseases; obesity: a medical history of obesity, body mass index ≥30, or abdominal circumference > 102 cm in men and > 88 cm in females; previous stroke: a medical history of documented stroke based on CT scan or MRI; smoking: a medical history of cigarette smoking.

Statistical analysis: data collected were analyzed using IBM® SPSS® Statistics 20.0 software. Categorical variables were expressed as frequency (percentage). Continuous variables were presented as mean (standard deviation) or median when appropriate. Chi-square or Fischer tests were used to compare categorical and continuous variables, respectively. Sociodemographic data, vital parameters, and extra neurological signs and disorders were included in the univariable analysis using cross-table and calculating the odd ratio (OR) with 95% Confidence Interval (CI). Neurological manifestations and in-hospital mortality were the dependent variables. We introduced the variables significantly associated to neurological manifestations and in-hospital mortality into the binary logistic regression to identify predictive factors. The survival curve of patients with and without neurological manifestations was analyzed using the Kaplan-Meier method. The significance threshold was set at p-value <0.05.

Ethical considerations: this study has been approved by the institutional ethical committee of the Mountain University, Bangante, Cameroon (N° 2021/037/UdM/PR/CEI). Written informed consent was not required from individual patients.

Results     

Characteristics of the study population: out of the 400 patients in the registry, 385 medical records were available. After excluding 6 incomplete files, 379 patients´ medical records were included in the study. The mean age was 56.5 (15.6) years. Patients > 60 years old represented 44.6% of cases, and male patients accounted for 56.2% of cases (Table 1). The most common comorbidities were hypertension, diabetes, and chronic kidney disease (Table 1). Hospital duration was greater than 7 days in 46.9% of patients (n=177).

Clinical manifestations: neurological manifestations were reported in 48.8% of patients (n=185). Headache and altered consciousness were the most common CNS-related signs (Figure 1). We also found encephalopathy (3.7%), ischemic stroke (3.4%), and intracerebral hemorrhage (1.6%). The most frequent extra-neurological symptoms/signs were asthenia (87.3%) and fever (67.5%) (Figure 2). Pneumonia (87.1%), acute kidney injury (2.9%), pulmonary edema (2.4%), septic shock (0.5%), pulmonary embolism (0.3%), heart failure (0.3%) and rhabdomyolysis (0.8%) were the extra-neurological disease found in patients with COVID-19.

Predictive factors and in-hospital mortality: in the univariable analysis, anorexia, arthralgia, and odynophagia were significantly associated with neurological manifestations. Predictive factors of neurological manifestations were arthralgia (aOR: 2.39, 95% CI 1.39 - 4.12; p= 0.002) and odynophagia (aOR: 4.84, 95% CI 1.02 - 23; p=0.04) (Table 2). There was no significant difference in the in-hospital mortality among patients with (29.7%) and without (20.1%) neurological manifestations. Type 2 diabetes, altered consciousness, hemorrhagic stroke, encephalopathy, acute respiratory distress syndrome (ARDS), pneumonia, acute kidney injury were significantly associated with in-hospital mortality. Predictive factors of in-hospital mortality in patients with COVID-19 and neurological manifestations were type 2 diabetes (aOR: 2.3, 95%CI 1.04 - 5.1; p=0.04), altered consciousness (aOR: 2.3, 95%CI 1.04 - 5.1; p < 0.001), hemorrhagic stroke (aOR: 11.26, 95%CI 3.77 - 33.62; p= 0.018), and ARDS (aOR: 39.7, 95%CI 16.52 - 95.4; p< 0.001) (Table 3). The Kaplan-Meier curve did not show any significant difference between the two groups of patients (Figure 3).

Discussion     

The aim of this study was to study the features and outcomes of patients hospitalized for COVID-19 with neurological manifestations in a tertiary health care center in Cameroon. Patients with COVID-19 were mainly males of more than 60 years old. Neurological manifestations were reported in 48.8% of cases. Arthralgia and odynophagia were the predictive factors of neurological manifestations. No significant difference in in-hospital mortality was found among patients with and without neurological manifestations. However, type 2 diabetes, altered consciousness, hemorrhagic stroke, and ARDS were predictive factors of in-hospital mortality in patients with COVID-19 and neurological manifestations.

Patients aged over 60 were the main age group. In the same country, Mbarga et al. found 21.2% of patients aged over 60 [13]. This difference could be explained by the methodology. Mbarga et al. included patients with mild, moderate, and severe forms, while we collected data from moderate to severe COVID-19 cases [13]. The mean age of our patients was close to the mean ages (52.7 to 59.9 years) reported by other authors [8,12,14]. Male patients represented the majority of cases. Similar results have been reported by other authors [12,15]. The predominance of SARS-CoV-2 infection in male patients could be explained by the greater frequency of cardiovascular diseases in men, and the possible protective role of female hormones. However, Mao and colleagues reported a female predominance [14]. COVID-19 affected people of all ages and both sexes. The most vulnerable people, especially the elderly, were particularly affected by this infection. Several studies have demonstrated the higher prevalence of elderly people among patients admitted to hospitalization [2,5-7]. More frequent cardiovascular diseases and declining immunity contribute to the high prevalence of COVID-19 in old people [16]. The risk of being hospitalized or dying from this infection increased considerably with age [17]. In this study, hypertension and diabetes represented the most frequent comorbidities. This is consistent with several studies [14,18,19]. SARS-CoV-2 enters the human cell by binding to angiotensin-converting enzyme-2 (ACE2) receptors, which are highly expressed in hypertensive and diabetic patients treated with ACE inhibitors and angiotensin receptor blockers [20].

Close to half of our patients presented neurological manifestations. Two studies found neurological manifestations in 42.2% and 50.5% of cases [11,21]. Eighty two percent of patients with COVID-19 presented neurological manifestations in China [8]. The frequency of neurological manifestations varies from 36.4% to 60.8% according to several authors [14,20,22]. The greater frequency in some studies could be explained by the inclusion of patients with mild COVID-19 [8,22]. The most common neurological signs were headaches, altered consciousness, ageusia, and anosmia. Kim and colleagues reported headaches (33.3%), myalgias (31.4%), anosmia (17.6%), and ageusia (17.6%) [22] as the main neurological signs [22]. Altered consciousness and headaches were the most frequent neurological signs in hospitalized patients in several studies [14,20,23]. Anosmia and ageusia were reported with great disparity in 5% to 86% of cases [24,25]. For Meppiel et al. the most frequent non-specific neurological symptoms were headache, dizziness, and myalgia in hospitalized patients [26]. In a small percentage of patients, we found neurological diseases such as encephalopathy, ischemic stroke, and intracerebral hemorrhage (1.6%). In the French COVID-19 registry, the frequency of neurological diseases varied from 8% to 13% of cases [9]. According to a systematic review, stroke, seizures, meningoencephalitis, and immune-related neurological diseases were the main neurological disorders associated with COVID-19 [27].

In this study, arthralgia and odynophagia were the predictive factors of neurological manifestations. In other studies, cardiovascular risk factors were found as predictive factors of neurological manifestations [27-30]. However, in Spain, a significant association was found between odynophagia and the occurrence of neurological manifestations such as headaches, anosmia, and ageusia [24,31]. The contiguity of the oropharynx and nasopharynx may explain the high frequency of anosmia, ageusia, and odynophagia [24]. Two studies reported arthralgia almost always associated with myalgia (arthromyalgia) in 16.6% to 48% of cases [32,33]. A systematic review demonstrated a link between arthromyalgia, autoimmune encephalitis, and Guillain Barré syndrome [34]. The cytokine storm could have a direct impact on the skeletal muscle and the joints, leading to arthralgia and myalgia [35].

More than half of the patients who died had neurological manifestations. However, there were no difference in the survival curve between patients with and without neurological manifestations. Host factors including age (>50 years), sex, and comorbidities were frequently reported as predictive factors of mortality [17,36,37]. Diabetes and hypertension have also been reported as predictors of mortality [30]. In our COVID-19 unit, altered consciousness, intracerebral hemorrhage, diabetes, and ARDS were the predictive factors of in-hospital mortality in patients with neurological manifestations. The expression of the ACE2 receptor in the lungs and other tissues is increased in type 2 diabetes [38]. This hyperexpression of ACE2 receptors is associated with an increase in inflammatory response, leading to dysfunction of the alveolar-capillary barrier [39]. Altered consciousness was more frequently reported at the critical stage of the SARS-CoV-2 infection [22]. For Kim et al. nearly 86% of patients who had an altered consciousness died, including patients with encephalopathy, hypoxia, sepsis, and metabolic disorders [22]. Kenerly et al. also found altered consciousness as a predictive factor of mortality in hospitalized patients [40]. Some authors demonstrated a higher risk of death in patients with ARDS [37,41]. In the United States, more than half of patients with ARDS died [42]. Acute respiratory distress syndrome (ARDS) is characterized by acute and diffuse inflammatory damage to the alveolar-capillary barrier associated with increased vascular permeability and reduced compliance, compromising gas exchange and causing hypoxemia [43].

This was the first hospital-based study in Cameroon to determine predictive factors of neurological manifestations and in-hospital mortality of patients with COVID-19. However, this was a retrospective study subject to bias related to the quality of the data collected. The gold standard for the diagnosis of COVID-19 is the PCR-SARS-CoV-2. Some patients were diagnosed based on COVID-19 antigen, which is known to be less sensitive and less specific than the PCR-SARS-CoV-2. Some patients may have been underdiagnosed or falsely diagnosed during that period. In addition, this study was carried out in one center and over a limited period of time. Therefore, the results cannot be generalized to the entire community.

Conclusion     

In this study, the majority of patients with COVID-19 were male and two out of five patients were older than 60. About half of cases presented neurological manifestations, mainly headaches and altered consciousness. Odynophagia and arthralgia were predictive factors of neurological manifestations. No significant difference was found for in-hospital mortality among patients with and without neurological manifestations. Type 2 diabetes, altered consciousness, hemorrhagic stroke, and ARDS were predictive factors of in-hospital mortality.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Conception and study design: Daniel Gams Massi, Jamiilah Nchare Neve, and Njankouo Yacouba Mapoure. Data collection: Daniel Gams Massi, Jamiilah Nchare Neve, Fernando Kemta Lekpa, Bertrand Hugo Mbatchou Ngahane and Njankouo Yacouba Mapoure. Data analysis and interpretation: Daniel Gams Massi, Jamiilah Nchare Neve, and Njankouo Yacouba Mapoure. Manuscript drafting: Félicité Flore Djuikwo Teukeng, Charles Lebon Mbele Onana, Joël Cédric Bayem, Caroline Kenmegne, Annick Mélanie Magnerou, Salomon Mbahe. Manuscript revision: Daniel Gams Massi, Jamiilah Nchare Neve, Fernando Kemta Lekpa, Bertrand Hugo Mbatchou Ngahane, Njankouo Yacouba Mapoure, Félicité Flore Djuikwo Teukeng, Charles Lebon Mbele Onana, Joël Cédric Bayem, Caroline Kenmegne, Annick Mélanie Magnerou and Salomon Mbahe. All authors approved final version of the manuscript.

Acknowledgments     

We are grateful to the team from the COVID-19 unit at the Douala general hospital who made all the information available to us.

Tables and figures     

Table 1: sociodemographic and clinical characteristics of patients with COVID-19

Table 2: associated and predictive factors of neurological manifestations following SARS-CoV-2 infection

Table 3: associated and predictive factors of in-hospital mortality of patients with COVID-19 and neurological manifestations

Figure 1: neurological signs and symptoms in patients with COVID-19

Figure 2: extra-neurological signs and diseases associated with SARS-CoV-2 infection (ARDS: acute respiratory distress syndrome)

Figure 3: survival curve of SARS-CoV-2 patients with neurological and without neurological manifestations. This curve indicates no significant difference in the survival of patients with and without neurological manifestations

References