Long COVID: major findings, mechanisms and recommendations

Abstract:

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field.

In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

Source: Davis, H.E., McCorkell, L., Vogel, J.M. et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol (2023). https://doi.org/10.1038/s41579-022-00846-2 https://www.nature.com/articles/s41579-022-00846-2

Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review

Abstract:

Objective: The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders.

Methods: This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords “COVID 19” or “vaccine” and “headache” to assess the appropriateness of all published articles for their inclusion in the review.

Results: Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced.

Conclusions: The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care.

Source: Caronna E, van den Hoek TC, Bolay H, Garcia-Azorin D, Gago-Veiga AB, Valeriani M, Takizawa T, Messlinger K, Shapiro RE, Goadsby PJ, Ashina M, Tassorelli C, Diener HC, Terwindt GM, Pozo-Rosich P. Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review. Cephalalgia. 2023 Jan;43(1):3331024221131337. doi: 10.1177/03331024221131337. PMID: 36606562. https://journals.sagepub.com/doi/full/10.1177/03331024221131337 (Full text)

Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature

Abstract:

The present study aims to provide a critical overview of the literature on the relationships between post-acute COVID-19 infection and cognitive impairment, highlighting the limitations and confounding factors. A systematic search of articles published from 1 January 2020 to 1 July 2022 was performed in PubMed/Medline. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies using validated instruments for the assessment of cognitive impairment were included. Out of 5515 screened records, 72 studies met the inclusion criteria.

The available evidence revealed the presence of impairment in executive functions, speed of processing, attention and memory in subjects recovered from COVID-19. However, several limitations of the literature reviewed should be highlighted: most studies were performed on small samples, not stratified by severity of disease and age, used as a cross-sectional or a short-term longitudinal design and provided a limited assessment of the different cognitive domains. Few studies investigated the neurobiological correlates of cognitive deficits in individuals recovered from COVID-19. Further studies with an adequate methodological design are needed for an in-depth characterization of cognitive impairment in individuals recovered from COVID-19.

Source: Perrottelli A, Sansone N, Giordano GM, Caporusso E, Giuliani L, Melillo A, Pezzella P, Bucci P, Mucci A, Galderisi S. Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature. J Pers Med. 2022 Dec 15;12(12):2070. doi: 10.3390/jpm12122070. PMID: 36556290; PMCID: PMC9781311. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781311/ (Full text)

Long COVID: The latest manifestations, mechanisms, and potential therapeutic interventions

Abstract:

COVID-19 caused by SARS-CoV-2 infection affects humans not only during the acute phase of the infection, but also several weeks to 2 years after the recovery. SARS-CoV-2 infects a variety of cells in the human body, including lung cells, intestinal cells, vascular endothelial cells, olfactory epithelial cells, etc. The damages caused by the infections of these cells and enduring immune response are the basis of long COVID. Notably, the changes in gene expression caused by viral infection can also indirectly contribute to long COVID.

We summarized the occurrences of both common and uncommon long COVID, including damages to lung and respiratory system, olfactory and taste deficiency, damages to myocardial, renal, muscle, and enduring inflammation. Moreover, we provided potential treatments for long COVID symptoms manifested in different organs and systems, which were based on the pathogenesis and the associations between symptoms in different organs.

Importantly, we compared the differences in symptoms and frequency of long COVID caused by breakthrough infection after vaccination and infection with different variants of concern, in order to provide a comprehensive understanding of the characteristics of long COVID and propose improvement for tackling COVID-19.

Source: He ST, Wu K, Cheng Z, He M, Hu R, Fan N, Shen L, Li Q, Fan H, Tong Y. Long COVID: The latest manifestations, mechanisms, and potential therapeutic interventions. MedComm (2020). 2022 Dec 8;3(4):e196. doi: 10.1002/mco2.196. PMID: 36514781; PMCID: PMC9732402. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9732402/ (Full text)

Musculoskeletal complications in long COVID-19: A systematic review

Abstract:

Background: Coronavirus disease 2019 (COVID-19) has crippled humanity since early 2020. Various sequelae of COVID-19 have been reported in different body systems. Musculoskeletal symptoms are widely reported during COVID-19 infection, but musculoskeletal complications in long COVID-19 are underreported. However, post-COVID-19 survivors have reported complaints of persisting or new-onset fatigue, myalgia, arthralgia, arthritis, muscle weakness, etc in clinical practice. The well-known detrimental effects of steroids on the musculoskeletal system coupled with their over-the-counter availability can also be anticipated since they were the cornerstone of life-saving management in this pandemic.

Aim: To determine the musculoskeletal complications in long COVID.

Methods: We performed a systematic review of ‘systematic reviews and meta-analyses’.

Results: Of the 63 articles screened, 24 articles were included. Two articles specifically discussed children and adolescents. One article discussed rehabilitation intervention. No article addressed rehabilitation of musculoskeletal issues in long COVID-19 in particular. Fatigue was the most common musculoskeletal complication.

Conclusion: Fatigue is found to be very common along with myalgia and arthralgia. There were no studies on rehabilitation intervention in musculoskeletal complications specifically. Considering the lacuna in literature and the needs of the current situation, further studies are warranted to standardize effective rehabilitation interventions in musculoskeletal complications. More homogenous studies are needed. Studies on functional impairment due to musculoskeletal involvement are essential.

Source: Swarnakar R, Jenifa S, Wadhwa S. Musculoskeletal complications in long COVID-19: A systematic review. World J Virol. 2022 Nov 25;11(6):485-495. doi: 10.5501/wjv.v11.i6.485. PMID: 36483107; PMCID: PMC9724204. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9724204/ (Full text)

The bidirectional association between diabetes and long-COVID-19 – A systematic review

Abstract:

Some evidence suggests that diabetes may be a risk factor for the development of post-acute sequelae of COVID-19 (PASC). Recent data also indicate that new-onset diabetes may be a complication of COVID-19. Here, we review the existing evidence.

Following PRISMA guidelines, we conducted a systematic review through August 8, 2022. We included longitudinal studies reporting on the risk of PASC (i.e., sequelae that extend beyond four weeks after initial infection) in people with and without diabetes, and studies reporting on the risk of new-onset diabetes in people with vs without COVID-19 with a minimum of 4-weeks of follow-up. All studies were published in English. Among 5,532 studies screened, 39 were included in the final review.

Among 25 studies reporting on diabetes and PASC, 44 % (n = 11) identified diabetes as a significant risk factor for PASC (increased relative risk ranging from 7 % to 342 %) while 56 % (n = 14) did not. Among 14 studies reporting on new-onset diabetes, 12 (86 %) reported that COVID-19 (vs no COVID) was significantly associated with new-onset diabetes with increased risks ranging from 11 % to 276 %. COVID-19 survivors may be at increased risk for new-onset diabetes, but whether pre-existing diabetes is also a risk factor for PASC remains unclear.

Source: Harding JL, Oviedo SA, Ali MK, Ofotokun I, Gander JC, Patel SA, Magliano DJ, Patzer RE. The bidirectional association between diabetes and long-COVID-19 – A systematic review. Diabetes Res Clin Pract. 2022 Dec 7;195:110202. doi: 10.1016/j.diabres.2022.110202. Epub ahead of print. PMID: 36496030; PMCID: PMC9727969. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727969/ (Full text)

Effect of Vaccination against SARS-CoV-2 on Long COVID-19: A Narrative Review

Abstract:

Vaccines against SARS-CoV-2 have saved millions of lives and played an important role in containing the COVID-19 pandemic. Vaccination against SARS-CoV-2 is also associated with reduced disease severity and, perhaps, with COVID-19 symptom burden.

In this narrative review, we present, in a clinically relevant question-and-answer manner, the evidence regarding the association between vaccination against SARS-CoV-2 and long COVID-19. We discuss how the mechanism of action of vaccines could interplay with the pathophysiology of post-COVID-19 condition.

Furthermore, we describe how specific factors, such as the number of vaccine doses and the type of SARS-CoV-2 variants, may affect post-COVID-19 condition. We also discuss the role of timing for vaccination in relation to the onset of long COVID-19 symptoms, as it seems to affect the frequency and severity of the condition.

Additionally, we describe the potential modifying effect of age, as well as the association of type and level of immune response with long COVID-19. We also describe how system-specific long COVID-19 sequelae, namely neurocognitive-psychologic symptoms and cardiovascular pathology, could be altered by vaccination.

Last, we address the question of whether seasonal influenza vaccination has a meaningful impact on the frequency of long COVID-19.

Source: Tofarides AG, Christaki E, Milionis H, Nikolopoulos GK. Effect of Vaccination against SARS-CoV-2 on Long COVID-19: A Narrative Review. Life (Basel). 2022 Dec 8;12(12):2057. doi: 10.3390/life12122057. PMID: 36556422. https://www.mdpi.com/2075-1729/12/12/2057 (Full text)

The effectiveness of coronavirus disease 2019 (COVID-19) vaccine in the prevention of post-COVID-19 conditions: A systematic literature review and meta-analysis

Abstract:

Background: Although multiple studies have revealed that coronavirus disease 2019 (COVID-19) vaccines can reduce COVID-19-related outcomes, little is known about their impact on post-COVID-19 conditions. We performed a systematic literature review and meta-analysis on the effectiveness of COVID-19 vaccination against post-COVID-19 conditions (ie, long COVID).

Methods: We searched PubMed, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 1, 2019, to April 27, 2022, for studies evaluating COVID-19 vaccine effectiveness against post-COVID-19 conditions among individuals who received at least 1 dose of Pfizer/BioNTech, Moderna, AstraZeneca, or Janssen vaccine. A post-COVID-19 condition was defined as any symptom that was present 3 or more weeks after having COVID-19. Editorials, commentaries, reviews, study protocols, and studies in the pediatric population were excluded. We calculated the pooled diagnostic odds ratios (DORs) for post-COVID-19 conditions between vaccinated and unvaccinated individuals. Vaccine effectiveness was estimated as 100% × (1 – DOR).

Results: In total, 10 studies with 1,600,830 individuals evaluated the effect of vaccination on post-COVID-19 conditions, of which 6 studies were included in the meta-analysis. The pooled DOR for post-COVID-19 conditions among individuals vaccinated with at least 1 dose was 0.708 (95% confidence interval (CI), 0.692-0.725) with an estimated vaccine effectiveness of 29.2% (95% CI, 27.5%-30.8%). The vaccine effectiveness was 35.3% (95% CI, 32.3%-38.1%) among those who received the COVID-19 vaccine before having COVID-19, and 27.4% (95% CI, 25.4%-29.3%) among those who received it after having COVID-19.

Conclusions: COVID-19 vaccination both before and after having COVID-19 significantly decreased post-COVID-19 conditions for the circulating variants during the study period although vaccine effectiveness was low.

Source: Marra AR, Kobayashi T, Suzuki H, Alsuhaibani M, Hasegawa S, Tholany J, Perencevich E, Maezato AM, Ricardo VCV, Salinas JL, Edmond MB, Rizzo LV. The effectiveness of coronavirus disease 2019 (COVID-19) vaccine in the prevention of post-COVID-19 conditions: A systematic literature review and meta-analysis. Antimicrob Steward Healthc Epidemiol. 2022 Dec 6;2(1):e192. doi: 10.1017/ash.2022.336. PMID: 36505947; PMCID: PMC9726631. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9726631/ (Full text)

The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis

Abstract:

Background: The aim of this study was to systematically synthesise the global evidence on the prevalence of persistent symptoms in a general post COVID-19 population.

Methods: A systematic literature search was conducted using multiple electronic databases (MEDLINE and The Cochrane Library, Scopus, CINAHL, and medRxiv) until January 2022. Studies with at least 100 people with confirmed or self-reported COVID-19 symptoms at ≥28 days following infection onset were included. Patient-reported outcome measures and clinical investigations were both assessed. Results were analysed descriptively, and meta-analyses were conducted to derive prevalence estimates. This study was pre-registered (PROSPERO-ID: CRD42021238247).

Findings: 194 studies totalling 735,006 participants were included, with five studies conducted in those <18 years of age. Most studies were conducted in Europe (n = 106) or Asia (n = 49), and the time to follow-up ranged from ≥28 days to 387 days. 122 studies reported data on hospitalised patients, 18 on non-hospitalised, and 54 on hospitalised and non-hospitalised combined (mixed). On average, at least 45% of COVID-19 survivors, regardless of hospitalisation status, went on to experience at least one unresolved symptom (mean follow-up 126 days). Fatigue was frequently reported across hospitalised (28.4%; 95% CI 24.7%-32.5%), non-hospitalised (34.8%; 95% CI 17.6%-57.2%), and mixed (25.2%; 95% CI 17.7%-34.6%) cohorts. Amongst the hospitalised cohort, abnormal CT patterns/x-rays were frequently reported (45.3%; 95% CI 35.3%-55.7%), alongside ground glass opacification (41.1%; 95% CI 25.7%-58.5%), and impaired diffusion capacity for carbon monoxide (31.7%; 95% CI 25.8%-3.2%).

Interpretation: Our work shows that 45% of COVID-19 survivors, regardless of hospitalisation status, were experiencing a range of unresolved symptoms at ∼ 4 months. Current understanding is limited by heterogeneous study design, follow-up durations, and measurement methods. Definition of subtypes of Long Covid is unclear, subsequently hampering effective treatment/management strategies.

Source: O’Mahoney LL, Routen A, Gillies C, Ekezie W, Welford A, Zhang A, Karamchandani U, Simms-Williams N, Cassambai S, Ardavani A, Wilkinson TJ, Hawthorne G, Curtis F, Kingsnorth AP, Almaqhawi A, Ward T, Ayoubkhani D, Banerjee A, Calvert M, Shafran R, Stephenson T, Sterne J, Ward H, Evans RA, Zaccardi F, Wright S, Khunti K. The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. EClinicalMedicine. 2022 Dec 1;55:101762. doi: 10.1016/j.eclinm.2022.101762. PMID: 36474804; PMCID: PMC9714474. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714474/ (Full text)