Neurological manifestations of long-COVID syndrome: a narrative review

Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for ‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data.

The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae.

In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.

Source: Stefanou M-I, Palaiodimou L, Bakola E, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Therapeutic Advances in Chronic Disease. January 2022. doi:10.1177/20406223221076890 https://journals.sagepub.com/doi/full/10.1177/20406223221076890 (Full text)

Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation

In a previous post, we demonstrated that the symptoms and physiology of postexertional symptom exacerbation (PESE) are inconsistent with deconditioning. PESE worsens in response to exercise and demonstrates a variable clinical presentation. We will build a clinical rationale for energy system first aid as a place to start helping people with PESE.

Graded Exercise May Be Harmful to People With PESE

It is not surprising that patients with PESE frequently report worsening symptoms and function with exercise prescribed based on time and activity quotas,1 based on the physiological evidence. The United Kingdom’s Pacing, graded Activity, and Cognitive behaviour therapy, a randomized Evaluation (UK PACE) compared the clinical outcomes of specialist medical care, adaptive pacing, and graded exercise therapy (GET) in 641 people with idiopathic, disabling fatigue.9 In this study, GET was a quota-based progressive exercise program, where subjects incrementally increased exercise regardless of symptoms. PESE was not a specific recruitment criterion for this trial.8,9 The trial did not adhere to the published protocol, without appropriate justification. The raw data was independently reanalyzed according to the original protocol,10 Upon reanalysis, most symptomatic and functional outcome findings from the UK PACE trial did not reach thresholds for clinical relevance. Many ME/CFS experts contend the results of GET are marginal, probably not clinically relevant or beneficial.10

Despite the important concerns of the UK PACE trial, the trial continues to exert outsized influence on clinical guidelines.3 Some countries’ systems developed formal treatment pathways based on flawed results. Treatment pathways involving GET may have exposed an untold number of patients with ME/CFS worldwide to a GET program that, at best, is marginally effective, and at worst, may be harmful. Recent clinical guidelines for people with PESE, such as long COVID, no longer involve GET.6,7 These omissions reflect the ongoing re-evaluation of how clinical care should proceed for people with PESE, including people with long COVID. Implicit to this re-evaluation is a further reflection on the generally accepted idea that “movement is medicine” in a way that universally benefits clinical populations.

Read the full article HERE.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 3: “Energy System First Aid” for People With Postexertional Symptom Exacerbation. JOSPT blog, Published online on February 16, 2022. https://doi.org/10.2519/jospt.blog.20220216 (Full text)

Long COVID-19 symptoms: clinical characteristics

Abstract:

Background: To describe persistent symptoms in long COVID-19 non-severe outpatients and report the 6-month clinical recovery (CR) rate.

Methods: Observational study enrolling outpatients (≥18 years) with confirmed non-severe COVID-19 (positive nasopharyngeal RT-PCR or presence of SARS-CoV-2 antibodies) who consulted for persistent symptoms after the first pandemic wave (March-May 2020). CR was assessed at the 6-month visit and defined as complete (no symptom), partial (persistent symptoms of lower intensity) or lack of recovery (no improvement).

Results: Sixty-three patients (79% women, mean age: 48 years) enrolled; main symptoms (mean 81 days after acute infection): asthenia/myalgia (77%), dyspnea (51%), headaches (35%), cough (33%). At 6 months (n=56), 30% had complete, 57% partial, and 13% lack of recovery. The proportion of patients with >2 persistent symptoms was 27% at 6 months (main symptoms: dyspnea [54%] and asthenia/myalgia [46%]).

Conclusion: We observed a slow but high recovery rate at 6 months among these outpatients.

Source: Seang S, Itani O, Monsel G, Abdi B, Marcelin AG, Valantin MA, Palich R, Fayçal A, Pourcher V, Katlama C, Tubiana R. Long COVID-19 symptoms: clinical characteristics and recovery rate among non-severe outpatients over a six-month follow-up. Infect Dis Now. 2022 Feb 11:S2666-9919(22)00038-0. doi: 10.1016/j.idnow.2022.02.005. Epub ahead of print. PMID: 35158095; PMCID: PMC8832844. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8832844/ (Full text)

Assessment and Management of Long COVID

Abstract:

Almost two years into the pandemic, the scientific and healthcare communities continue to learn a great deal regarding COVID-19, the disease produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Broad variability during acute COVID-19 infection is seen, ranging from asymptomatic presentation to death. The vast majority of individuals who develop COVID-19 return to their pre-COVID-19 baseline within several weeks.

However, a portion of patients will develop a post-COVID-19 syndrome of persistent cognitive, somatic, and behavioral symptoms. This syndrome, designated as post-acute sequelae of SARS-CoV-2 infection, is more commonly known as long COVID. The objectives of this paper are to inform psychologists regarding our current understanding of the underlying pathophysiology of COVID-19, review criteria for range of severity during acute illness, present clinical manifestations of long haul phenomena, and discuss the emerging literature base of evidence-based treatment and management approaches.

Source: Rivas-Vazquez, R.A., Rey, G., Quintana, A. et al. Assessment and Management of Long COVID. J Health Serv Psychol 4821–30 (2022). https://doi.org/10.1007/s42843-022-00055-8  (Full study)

Determinants of Persistence of Symptoms and Impact on Physical and Mental Wellbeing in Long COVID: A Prospective Cohort Study

Abstract:

Background: Residual symptoms can be detected for several months after COVID-19. To better understand the predictors and impact of symptom persistence we analysed a prospective cohort of COVID-19 patients.

Methods: Patients were followed for 9 months after COVID-19 onset. Duration and predictors of persistence of symptoms, physical health and psychological distress were assessed.

Results: 465 patients (54% males, 51% hospitalised) were included; 37% presented with at least 4 symptoms and 42% complained of symptom lasting more than 28 days. At month 9, 20% of patients were still symptomatic, showing mainly fatigue (11%) and breathlessness (8%). Hospitalisation and ICU stay vs. non-hospitalised status increased the median duration of fatigue of 8 weeks. Age > 50 years (OR 2.50), ICU stay (OR 2.35), and presentation with 4 or more symptoms (OR 2.04) were independent predictors of persistence of symptoms at month 9. A total of 18% of patients did not return to optimal pre-COVID physical health, while 19% showed psychological distress at month 9. Hospital admission (OR 2.28) and persistence of symptoms at day 28 (OR 2.21) and month 9 (OR 5.16) were independent predictors of suboptimal physical health, while female gender (OR 5.27) and persistence of symptoms at day 28 (OR 2.42) and month 9 (OR 2.48) were risk factors for psychological distress.

Conclusions: Patients with advanced age, ICU stay and multiple symptoms at onset were more likely to suffer from long-term symptoms, which had a negative impact on both physical and mental wellbeing. This study contributes to identify the target populations and Long COVID consequences for planning long-term recovery interventions.

Source: Righi E, Mirandola M, Mazzaferri F, Dossi G, Razzaboni E, Zaffagnini A, Ivaldi F, Visentin A, Lambertenghi L, Arena C, Micheletto C, Gibellini D, Tacconelli E. Determinants of Persistence of Symptoms and Impact on Physical and Mental Wellbeing in Long COVID: A Prospective Cohort Study. J Infect. 2022 Feb 9:S0163-4453(22)00065-2. doi: 10.1016/j.jinf.2022.02.003. Epub ahead of print. PMID: 35150765; PMCID: PMC8828388. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828388/ (Full text)

Exploring the Trajectory Recovery Curve of the number of Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study

Abstract:

Objective: This multicenter study investigated the recovery curve of the number of post-COVID symptoms in previously hospitalized survivors by using an exponential decay model and mosaic plots.

Methods: Patients hospitalized during the first wave of the pandemic (from March 10 to May 31, 2020) due to COVID-19 from five hospitals in Madrid (Spain) were scheduled for two telephone interviews at two follow-ups with a five-month period in between and were asked about the presence of post-COVID symptoms. The total number of post-COVID symptoms was monitored. Clinical features, symptoms at hospital admission, and hospitalization data were collected from medical records.

Results: A total of 1,593 COVID-19 survivors were assessed 8.4 (T1) and 13.2 (T2) months after hospitalization. The mean number of post-COVID symptoms was 2.6 (SD 2.0) at T1 and 1.5 (SD 1.4) at T2. The trajectory curve showed a decrease prevalence trend. The analysis also revealed that 985 (61.8%) subjects reported a greater number (T1>T2), 549 (34.5%) equal number (T1 =T2) and 59 (3.7%) lower number (T1<T2) of post-COVID symptoms in the first (T1: 8.4 months) in comparison with the second (T2: 13.2 months) assessment.

Conclusion: Current trajectory analysis revealed an overall decrease in the tendency in the number of post-COVID symptoms throughout the two years after the infection.

Source: Fernández-de-Las-Peñas C, Martín-Guerrero JD, Cancela-Cilleruelo I, Moro-López-Menchero P, Rodríguez-Jiménez J, Pellicer-Valero OJ. Exploring the Trajectory Recovery Curve of the number of Post-COVID Symptoms: The LONG-COVID-EXP-CM Multicenter Study. Int J Infect Dis. 2022 Feb 9:S1201-9712(22)00083-2. doi: 10.1016/j.ijid.2022.02.010. Epub ahead of print. PMID: 35150911; PMCID: PMC8826603. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826603/ (Full text)

Antihistamines for Postacute Sequelae of SARS-CoV-2 Infection

Abstract:

Postacute sequelae of SARS-CoV2 (PASC) infection is an emerging global health crisis, variably affecting millions worldwide. PASC has no established treatment. We describe 2 cases of PASC in response to opportune administration of over-the-counter antihistamines, with significant improvement in symptoms and ability to perform activities of daily living. Future studies are warranted to understand the potential role of histamine in the pathogenesis of PASC and explore the clinical benefits of antihistamines in the treatment of PASC.

Source: Melissa D. Pinto, Natalie Lambert, Charles A. Downs, Heather Abrahim, Thomas D. Hughes, Amir M. Rahmani, Candace W. Burton, Rana Chakraborty. Antihistamines for Postacute Sequelae of SARS-CoV-2 Infection. The Journal for Nurse Practitioners, 2022, ISSN 1555-4155, https://doi.org/10.1016/j.nurpra.2021.12.016.
https://www.sciencedirect.com/science/article/pii/S155541552100547X  (Full text)

Clinical patterns of somatic symptoms in patients suffering from post-acute long COVID: a systematic review

Abstract:

Background: Long COVID-19 may affect patients after hospital discharge.

Aims: This study aims to describe the burden of the long-term persistence of clinical symptoms in COVID-19 patients.

Methods: We conducted a systematic review by using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline. The PubMed and Google Scholar databases were searched for studies that included information on the prevalence of somatic clinical symptoms lasting at least 4 weeks after the onset of a PCR- or serology-confirmed diagnosis of COVID-19. The prevalence of persisting clinical symptoms was assessed and risk factors were described when investigated. Psychological symptoms and cognitive disorders were not evaluated in this study.

Results: Thirty-seven articles met the inclusion criteria. Eighteen studies involved in-patients only with a duration of follow-up of either less than 12 weeks, 12 weeks to 6 months, or more. In these studies, fatigue (16-64%), dyspnea (15-61%), cough (2-59%), arthralgia (8-55%), and thoracic pain (5-62%) were the most frequent persisting symptoms. In nineteen studies conducted in a majority of out-patients, the persistence of these symptoms was lower and 3% to 74% of patients reported prolonged smell and taste disorders. The main risk factors for persisting symptoms were being female, older, having comorbidities and severity at the acute phase of the disease.

Conclusion: COVID-19 patients should have access to dedicated multidisciplinary healthcare allowing a holistic approach. Effective outpatient care for patients with long-COVID-19 requires coordination across multiple sub-specialties, which can be proposed in specialized post-COVID units.

Source: Nguyen NN, Hoang VT, Dao TL, Dudouet P, Eldin C, Gautret P. Clinical patterns of somatic symptoms in patients suffering from post-acute long COVID: a systematic review. Eur J Clin Microbiol Infect Dis. 2022 Feb 10:1–31. doi: 10.1007/s10096-022-04417-4. Epub ahead of print. PMID: 35142947; PMCID: PMC8830952. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8830952/ (Full text)

Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study

Abstract:

Background: We describe post-COVID symptomatology in a non-hospitalised, national sample of adolescents aged 11-17 years with PCR-confirmed SARS-CoV-2 infection compared with matched adolescents with negative PCR status.

Methods: In this national cohort study, adolescents aged 11-17 years from the Public Health England database who tested positive for SARS-CoV-2 between January and March, 2021, were matched by month of test, age, sex, and geographical region to adolescents who tested negative. 3 months after testing, a subsample of adolescents were contacted to complete a detailed questionnaire, which collected data on demographics and their physical and mental health at the time of PCR testing (retrospectively) and at the time of completing the questionnaire (prospectively). We compared symptoms between the test-postive and test-negative groups, and used latent class analysis to assess whether and how physical symptoms at baseline and at 3 months clustered among participants. This study is registered with the ISRCTN registry (ISRCTN 34804192).

Findings: 23 048 adolescents who tested positive and 27 798 adolescents who tested negative between Jan 1, 2021, and March 31, 2021, were contacted, and 6804 adolescents (3065 who tested positive and 3739 who tested negative) completed the questionnaire (response rate 13·4%). At PCR testing, 1084 (35·4%) who tested positive and 309 (8·3%) who tested negative were symptomatic and 936 (30·5%) from the test-positive group and 231 (6·2%) from the test-negative group had three or more symptoms. 3 months after testing, 2038 (66·5%) who tested positive and 1993 (53·3%) who tested negative had any symptoms, and 928 (30·3%) from the test-positive group and 603 (16·2%) from the test-negative group had three or more symptoms. At 3 months after testing, the most common symptoms among the test-positive group were tiredness (1196 [39·0%]), headache (710 [23·2%]), and shortness of breath (717 [23·4%]), and among the test-negative group were tiredness (911 [24·4%]), headache (530 [14·2%]), and other (unspecified; 590 [15·8%]). Latent class analysis identified two classes, characterised by few or multiple symptoms. The estimated probability of being in the multiple symptom class was 29·6% (95% CI 27·4-31·7) for the test-positive group and 19·3% (17·7-21·0) for the test-negative group (risk ratio 1·53; 95% CI 1·35-1·70). The multiple symptoms class was more frequent among those with positive PCR results than negative results, in girls than boys, in adolescents aged 15-17 years than those aged 11-14 years, and in those with lower pretest physical and mental health.

Interpretation: Adolescents who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but had a higher prevalence of single and, particularly, multiple symptoms at the time of PCR testing and 3 months later. Clinicians should consider multiple symptoms that affect functioning and recognise different clusters of symptoms. The multiple and varied symptoms show that a multicomponent intervention will be required, and that mental and physical health symptoms occur concurrently, reflecting their close relationship.

Funding: UK Department of Health and Social Care, in their capacity as the National Institute for Health Research, and UK Research and Innovation.

Source: Stephenson T, Pinto Pereira SM, Shafran R, de Stavola BL, Rojas N, McOwat K, Simmons R, Zavala M, O’Mahoney L, Chalder T, Crawley E, Ford TJ, Harnden A, Heyman I, Swann O, Whittaker E; CLoCk Consortium, Ladhani SN. Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study. Lancet Child Adolesc Health. 2022 Feb 7:S2352-4642(22)00022-0. doi: 10.1016/S2352-4642(22)00022-0. Epub ahead of print. PMID: 35143770; PMCID: PMC8820961. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820961/  (Full text)

Long COVID symptoms in SARS-CoV-2-positive adolescents and matched controls (LongCOVIDKidsDK): a national, cross-sectional study

Abstract:

Background: Many adolescents have been affected by the COVID-19 pandemic either directly by being infected with the virus or indirectly by lockdowns and restrictions influencing normal living. We aimed to investigate health, including symptoms of long COVID, in adolescents (aged 15-18 years) who tested positive for SARS-CoV-2 compared with a control group.

Methods: LongCOVIDKidsDK was a national, cross-sectional study carried out in Denmark, which included SARS-CoV-2-positive adolescents and matched controls. All Danish adolescents aged 15-18 years with a positive SARS-CoV-2 test during the period Jan 1, 2020, to July 12, 2021, and a control group matched (1:4) by age and sex were sent a survey from July 20, 2021. Participants had until Sept 15, 2021, to respond. Symptoms associated with COVID-19, school attendance, and health-related quality of life were investigated using ancillary questions and validated questionnaires (Paediatric Quality of Life Inventory [PedsQL] and Children’s Somatic Symptoms Inventory-24 [CSSI-24]). Statistical analyses included descriptive statistics and logistic regression. This study is registered at ClinicalTrials.gov, NCT04786353.

Findings: 24 315 adolescents with a positive SARS-CoV-2 test (case group) and 97 257 matched controls were invited to participate. 3013 matched controls were excluded because of suspected SARS-CoV-2 infection. 6630 (27·3%) responded in the case group and 21 640 (22·3%) responded and were eligible to participate in the control group. Across both groups, median age was 17·6 years (IQR 16·4-18·5), 16 277 (57·6%) of 28 270 responders were female, and 11 993 (42·4%) were male. Participants in the case group had greater odds of having at least one long COVID symptom lasting at least 2 months compared with the control group (3159 [61·9%] vs 12 340 [57·0%], odds ratio 1·22 [95% CI 1·15-1·30]; p<0·0001). Participants in the case group reported significantly lower symptom scores (ie, less somatic distress) on the CSSI-24 than in the control group: mean 10·7 (SD 11·4, median 7·0 [IQR 2·0-15·0]) versus 11·9 (10·6, 9·0 [4·0-17·0]; p<0·0001). Participants in the case group had better quality of life scores on the PedsQL than in the control group: physical functioning mean score 88·7 (SD 13·9, median 93·8 [IQR 84·4-100·0]) versus 86·5 (14·3, 90·6 [81·3-96·9]; p<0·0001); emotional functioning 77·1 (20·3, 80·0 [65·0-95·0]) versus 71·7 (21·4, 75·0 [60·0-90·0]; p<0·0001); social functioning 93·1 (12·5, 100·0 [90·0-100·0]) versus 88·4 (16·2, 95·0 [80·0-100·0]; p<0·0001); and school functioning 66·9 (22·5, 65·0 [60·0-85·0]) versus 62·9 (22·1, 65·0 [50·0-80·0]; p<0·0001). More participants in the case group than in the control group reported 16 or more sick days (1205 [18·2%] vs 2518 [11·6%]; p<0·0001) and 16 or more days of school absence (695 [10·5%] vs 1777 [8·2%]; p<0·0001).

Interpretation: Participants with SARS-CoV-2-positive tests had more long-lasting symptoms and sick leave, whereas participants in the control group had more short-lasting symptoms and worse quality of life. Knowledge of long COVID in adolescents is important to guide clinical recognition and management of this condition.

Funding: AP Møller and Chastine McKinney Møller Foundation.

Source: Kikkenborg Berg S, Dam Nielsen S, Nygaard U, Bundgaard H, Palm P, Rotvig C, Vinggaard Christensen A. Long COVID symptoms in SARS-CoV-2-positive adolescents and matched controls (LongCOVIDKidsDK): a national, cross-sectional study. Lancet Child Adolesc Health. 2022 Feb 7:S2352-4642(22)00004-9. doi: 10.1016/S2352-4642(22)00004-9. Epub ahead of print. PMID: 35143771; PMCID: PMC8820960.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820960/  (Full text)