This study investigated the clinical outcomes of patients with a neurological condition who were infected with SARS-CoV-2 up to three and a half years post infection in a large, low-income, racially, and ethnically diverse population in the Bronx and its environs. The major findings are: i) COVID-19 hospitalized patients were more likely to die and experience MACE, and ii) both hospitalized and non-hospitalized COVID-19 patients showed higher cumulative incidence of altered mental status, fatigue, sleep disturbance, dyspnea compared to non-COVID controls.
While some studies have reported that patients with pre-existing neurological conditions are at higher risk of experiencing more severe acute manifestations of SARS-CoV-2 infection 1–6, there are fewer studies that investigated longer term outcomes in these vulnerable populations with respect to COVID-19 hospitalization status. Lindamann et al. 42 analyzed 709 COVID-19 patients from a regional German secondary hospital who were hospitalized between May 1, 2020 to January 31, 2021 up to 9 months post-infection. 250 patients had chronic neurological disorders and 457 patients did not have chronic neurological disorders. They found that acute COVID-19 mortality was 2.0 times higher (95%CI: 1.37–2.92), and unfavorable functional outcome during acute COVID-19 (modified Rankin Scale > 3 at discharge) was 1.67 times higher (95% CI: 1.07–2.59) in the neurologically impaired group. Patients with existing chronic neurological disorders had 1.73 times higher odds for developing new-onset neurological disorders (95% CI: 0.97–3.08).
Conway et al. 4 studied post-COVID-19 outcomes of 109 adult patients with MS and COVID-19 infection at the Brigham MS Center in England between March 9, 2020 and April 1, 2021 up to 12 months post-infection. Neurologic worsening post-COVID-19 was defined as having a relapse, pseudorelapse, new brain MRI activity, worsening of preexisting MS and related disorders symptoms, or development of other long-term neurologic symptoms. They found that 41 patients (36.9%) had neurologic worsening post-COVID-19. Of those, 19 (46.3%) had pseudorelapses, 2 (4.8%) had relapses, and 24 (58.5%) patients reported worsening of preexisting MS and related disorders symptoms, or other new long-term neurologic symptoms. Neurologic worsening was associated with hospitalized (moderate or severe) COVID-19 (p = 0.001), and incomplete COVID-19 recovery (p = 0.02) but not with age, sex, MS type, race, disease duration, EDSS, vitamin D use, or disease modifying therapy use.
Bsteh et al. 7 studied the long-term outcomes up to a year of 211 adult patients with MS and COVID-19 infection in Austria between Jan 1, 2020 and Jun 30, 2021, and compared them to 211 adult patients with MS without COVID-19. Most (90.5%) patients in their cohort had a mild COVID-19 course. At follow-up, 70% had recovered completely 3 months after COVID-19, 83% after 6 months and 94% after 12 months. Compared to matched controls, fatigue, hyposmia and dyspnea were significantly more frequent at 3 months and still slightly at 6 months, while there was no difference at 12 months. Patients with MS and COVID-19 had neither a significantly increased risk for relapses (OR 1.1; p = 0.70) nor disability worsening (OR 0.96; p = 0.60) compared to patients with only MS.
In a study of MS patients with (n = 56) and without COVID-19 (n = 69), Etemadifar et al. 21 investigated the incidence rate of relapses up to six months post-infection. They found COVID-19 patients had a lower risk of MS relapse (incidence rate ratio = 0.275; p = 0.026). There was no difference in relapse risk between hospitalized and non-hospitalized COVID-19 patients. The frequency of relapses in the COVID-19 group did not differ when comparing the six-month period before COVID-19 infection and the six-month period following COVID-19 infection. This follow-up time is relatively short.
In another study of 150 MS patients with COVID-19 and 150 non-COVID MS matched controls from Italy 8, Vercellino et al. investigated the long-term outcomes at six to nine month follow up. Following SARS-CoV-2 infection, COVID-19 patients did not have a greater risk of relapses, MRI changes, or confirmed disability worsening.
We have previously shown that at our institution 10, patients with pre-existing MS who tested positive for SARS-CoV-2 and survived the acute infection experienced elevated long-term risk of mortality and optic neuritis compared to those without a documented history of COVID-19.
Our study is novel and built on prior studies. Our sample size consisted of 15,159 patients with a pre-existing major neurological condition, where 3,222 patients had COVID-19 and 11,937 patients had no COVID-19 that spanned a longer pandemic duration (Mar 1, 2020 to Jul 1, 2023) and longer follow time (up to 3.5 years). The longer pandemic duration likely consisted of patients with less severe COVID-19 overall. Differences in findings could be due to differences in patient cohorts, duration of pandemic included in the study, follow-up time, study design, sample sizes, and neurological conditions included, and outcomes assessed, among others.
Hospitalization status
When examining hospitalization status, we found that patients with neurological conditions who were hospitalized due to COVID-19, but not those not hospitalized, exhibited a higher likelihood of mortality compared to controls. However, both hospitalized and non-hospitalized COVID-19 patients showed increased cumulative incidences of altered mental status, fatigue, sleep disturbances, and dyspnea when contrasted with non-COVID patients. These findings suggest that a substantial number of individuals with mild COVID-19 disease could also face some heightened risks of developing certain adverse post-infection outcomes.
Sex differences
Prior studies have reported that males are more susceptible to more acute severe COVID-19 outcomes, including mortality, disease severity 43, and acute kidney injury 29, 35. Here we suggest that male sex of patients with pre-existing neurological conditions had higher risk of long-term outcomes, including post-infection mortality and MACE. The increased susceptibility of males to severe COVID-19 outcomes is multifaceted and involves a complex interplay of biological, immunological, hormonal, and behavioral factors. Biological variances, including differences in immune responses between males and females, might be influenced by hormonal disparities-such as estrogen potentially offering protective effects while testosterone could have suppressive impacts on the immune system 44. Genetic variations on the X chromosome and hormonal influences may contribute to females mounting stronger immune responses 44, 45. Additionally, behavioral aspects like higher rates of smoking, alcohol consumption, and delayed healthcare-seeking behavior among males, along with a higher prevalence of certain underlying health conditions, such as cardiovascular diseases, hypertension, and diabetes, may collectively contribute to the increased vulnerability of males to severe outcomes from COVID-19 43, 46. Understanding these multifaceted influences can guide tailored interventions and treatments for at-risk populations.
Race and ethnicity differences
Our data suggest that Blacks and Hispanics with neurological conditions are at higher risks of post-infection MACE. The disparities in COVID-19 outcomes across racial and ethnic groups are multifaceted, stemming from a convergence of socioeconomic, structural, and health-related factors. Marginalized communities face disproportionate challenges including limited access to quality healthcare, higher exposure in essential jobs, and crowded living conditions 47. Systemic disparities in healthcare access and quality, coupled with historical injustices and discrimination, erode trust and hinder healthcare-seeking behaviors among certain groups 48, 49. Pre-existing health conditions, more prevalent in some racial and ethnic populations due to underlying systemic inequalities, contribute to worsened COVID-19 outcomes 50, 51. Additionally, genetic, developmental, and environmental variations among different ethnicities might influence immune responses and disease susceptibility. Addressing these disparities necessitates approaches involving equitable resource allocation, improved healthcare access, culturally sensitive interventions, and efforts to alleviate social determinants of health, aiming to mitigate the disproportionate impact of COVID-19 on marginalized communities. However, our data needed to be interpreted with caution because of the small sample size of White patients.
Together, our findings corroborate a growing body of literature that COVID-19 could have significant long-term negative impact on health in more vulnerable patient populations, and emphasize the need for vigilant monitoring of at-risk individuals, irrespective of hospitalization status 52, 53.
Mechanisms
The causes underlying how COVID-19 worsens long-term outcomes in patients with pre-existing neurological conditions are unknown. The acute direct viral effects, hyperinflammation, cytokine storm, dysregulated immune response, hypercoagulation, metabolic and cardiovascular distress, and multi-organ dysfunction during acute COVID-19 could worsen health conditions broadly, resulting in post-infection outcomes in survivors with pre-existing neurological conditions 54. The initial SARS-CoV-2 infection could make these group of patients more susceptible to secondary health problems, including infection such as pneumonia and sepsis 16, 55. It is thus not surprising that COVID-19, especially severe COVID-19, could have long lasting negative effects and increased risk of worse outcomes in at-risk individuals, including those with pre-existing neurological conditions. Other factors surrounding the pandemic, such as the effects of isolation, psychosocial stress, reduced physical activity, unhealthy diet, and reduced access to care during the pandemic could also contribute worse post-infection outcomes 13.
Limitations
There are several limitations in our analysis. Our findings were limited to patients who returned to our health system. It is possible that patients who returned were more likely to have more severe COVID-19. However, patient records included those who returned for any medical reason, including but not limited to routine office visits. SARS-CoV-2 vaccination status was not reliably recorded if patients received vaccines outside of the Montefiore Health System, and thus it was difficult to analyze with respect to our outcomes. Outcomes may be affected by other factors including strain of SARS-CoV-2, various treatments for COVID-19, and severity of pre-existing neurological condition. The cohort was composed of patients who had at least one of several pre-existing neurological disorders, each with unique etiologies and leading to distinct deficits. Future studies should correlate long-term outcomes with COVID-19 related hyperinflammatory markers. A high percentage of patients in our COVID-19-exposed cohort were hospitalized (79%). There are many contributing factors to this high percentage. Patients who were transferred from nursing homes to our institution (a disproportionate number of which have neurodegenerative disorders) were classified as hospitalized in our EMR. As a precautionary measure, clinicians in our institution decided to admit a large proportion of these patients, many of whom were older and had several pre-existing comorbidities. It is also possible that some of the non-COVID patients had asymptomatic COVID-19 or were never tested, being erroneously labeled as non-COVID. To mitigate this effect, we excluded patients who had positive at home or antibody COIVD-19 tests from the non-COVID group. As with any retrospective study, there could be other unintended patient selection biases and latent confounding.