Long COVID: a review and proposed visualization of the complexity of long COVID

Abstract:

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose a visual description of the complexity of Long COVID and its pathogenesis that can be used by researchers, clinicians, and public health officials to guide the global effort toward an improved understanding of Long COVID and the eventual mechanism-based provision of care to afflicted patients. The proposed visualization or framework for Long COVID should be an evidence-based, dynamic, modular, and systems-level approach to the condition.

Furthermore, with further research such a framework could establish the strength of the relationships between pre-existing conditions (or risk factors), biological mechanisms, and resulting clinical phenotypes and outcomes of Long COVID. Notwithstanding the significant contribution that disparities in access to care and social determinants of health have on outcomes and disease course of long COVID, our model focuses primarily on biological mechanisms. Accordingly, the proposed visualization sets out to guide scientific, clinical, and public health efforts to better understand and abrogate the health burden imposed by long COVID.

Source: Perumal R, Shunmugam L, Naidoo K, Abdool Karim SS, Wilkins D, Garzino-Demo A, Brechot C, Parthasarathy S, Vahlne A, Nikolich JŽ. Long COVID: a review and proposed visualization of the complexity of long COVID. Front Immunol. 2023 Apr 20;14:1117464. doi: 10.3389/fimmu.2023.1117464. PMID: 37153597; PMCID: PMC10157068. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10157068/ (Full text)

Contesting misrecognition online: Experiences of epistemic in/justice by vloggers with contested illnesses

Abstract:

Contested illnesses, such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and chronic Lyme disease (CLD), are surrounded by polemic debates regarding their etiology, symptomology, treatment, and even their existence. People who suffer from these contested illnesses arguably also suffer from “epistemic injustice.” This concept, coined by the philosopher Miranda Fricker, captures how people’s knowledge may be discredited because of identity prejudices. In our paper, this concept is used to understand how seven Dutch women with contested illnesses experience the emancipatory potential of their vlogging practices.

Our findings show how these women understood their vlogging as a means to break with epistemic smothering, understood as the propensity to cater ones testimony to one’s audience (Dotson, 2011), and as a means to attain and enhance epistemic justice. However, our findings also show how vlogging about contested illnesses did not seem to allow these women to fully break with their epistemic smothering practices, and that the ableist design and gendered norms of YouTube were experienced as obstacles to attaining epistemic justice. We conclude that, even though social media do seem to hold emancipatory potential for these women, the experiences of individual users are diverse and ambiguous.

Source: Groenevelt IPI, de Boer MLM. Contesting misrecognition online: Experiences of epistemic in/justice by vloggers with contested illnesses. Soc Sci Med. 2023 May 7;327:115951. doi: 10.1016/j.socscimed.2023.115951. Epub ahead of print. PMID: 37182295. https://www.sciencedirect.com/science/article/pii/S0277953623003088?via%3Dihub (Full text)

Typing myalgic encephalomyelitis by infection at onset: A DecodeME study

Abstract:

Background: People with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) daily experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment or brain fog. Despite numbering 0.2-0.4% of the population, no laboratory test is available for their diagnosis, no effective therapy exists for their treatment, and no scientific breakthrough regarding their pathogenesis has been made. It remains unknown, despite decades of small-scale studies, whether individuals experience different types of ME/CFS separated by onset-type, sex or age.

Methods: DecodeME is a large population-based study of ME/CFS that recruited 17,074 participants in the first 3 months following full launch. Their detailed questionnaire responses provided an unparalleled opportunity to investigate illness severity, onset, course and duration.

Results: The well-established sex-bias among ME/CFS patients is evident in the initial DecodeME cohort: 83.5% of participants were females. What was not known previously was that females’ comorbidities and symptoms tend to be more numerous than males’. Moreover, being female, being older and being over 10 years from ME/CFS onset are significantly associated with greater severity.  Five different ME/CFS onset types were examined in the self-reported data: those with ME/CFS onset (i) after glandular fever (infectious mononucleosis); (ii) after COVID-19 infection; (iii) after other infections; (iv) without an identified infectious onset; and, (v) where the occurrence of an infection at or preceding onset is not known.

Conclusions: This revealed that people with a ME/CFS diagnosis are not a homogeneous group, as clear differences exist in symptomatology and comorbidity.

Source: Bretherick AD, McGrath SJ, Devereux-Cooke A et al. Typing myalgic encephalomyelitis by infection at onset: A DecodeME study [version 1; peer review: awaiting peer review]NIHR Open Res 2023, 3:20 https://doi.org/10.3310/nihropenres.13421.1 (Full text)

Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review

Long COVID disproportionately affects premenopausal women, but relatively few studies have examined Long COVID’s impact on female reproductive health. We conduct a review of the literature documenting the female reproductive health impacts of Long COVID which may include disruptions to the menstrual cycle, gonadal function, ovarian sufficiency, menopause, and fertility, as well as symptom exacerbation around menstruation.

Given limited research, we also review the reproductive health impacts of overlapping and associated illnesses including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), connective tissue disorders like Ehlers-Danlos syndrome (EDS), and endometriosis, as these illnesses may help to elucidate reproductive health conditions in Long COVID.

These associated illnesses, whose patients are 70%–80% women, have increased rates of dysmenorrhea, amenorrhea, oligomenorrhea, dyspareunia, endometriosis, infertility, vulvodynia, intermenstrual bleeding, ovarian cysts, uterine fibroids and bleeding, pelvic congestion syndrome, gynecological surgeries, and adverse pregnancy complications such as preeclampsia, maternal mortality, and premature birth. Additionally, in Long COVID and associated illnesses, symptoms can be impacted by the menstrual cycle, pregnancy, and menopause.

We propose priorities for future research and reproductive healthcare in Long COVID based on a review of the literature. These include screening Long COVID patients for comorbid and associated conditions; studying the impacts of the menstrual cycle, pregnancy, and menopause on symptoms and illness progression; uncovering the role of sex differences and sex hormones in Long COVID and associated illnesses; and addressing historical research and healthcare inequities that have contributed to detrimental knowledge gaps for this patient population.

Source: Pollack Beth, von Saltza Emelia, McCorkell Lisa, Santos Lucia, Hultman Ashley, Cohen Alison K., Soares Letícia. Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Frontiers in Rehabilitation Sciences, Vol 4, 2023, ISSN=2673-6861. DOI: 10.3389/fresc.2023.1122673 https://www.frontiersin.org/articles/10.3389/fresc.2023.1122673 (Full text)

Cellular and molecular biomarkers of long COVID: a scoping review

Abstract:

Background: Long-COVID (LC) encompasses diverse symptoms lasting months after the initial SARS-CoV-2 infection. Symptoms can be debilitating and affect the quality of life of individuals with LC and their families. Although the symptoms of LC are well described, the aetiology of LC remains unclear, and consequently, patients may be underdiagnosed. Identification of LC specific biomarkers is therefore paramount for the diagnosis and clinical management of the syndrome. This scoping review describes the molecular and cellular biomarkers that have been identified to date with potential use for diagnosis or prediction of LC.

Methods: This review was conducted using the Joanna Briggs Institute (JBI) Methodology for Scoping Reviews. A search was executed in the MEDLINE and EMBASE databases, as well as in the grey literature for original studies, published until October 5th, 2022, reporting biomarkers identified in participants with LC symptoms (from all ages, ethnicities, and sex), with a previous infection of SARS-CoV-2. Non-English studies, cross-sectional studies, studies without a control group, and pre-prints were excluded. Two reviewers independently evaluated the studies, extracted population data and associated biomarkers.

Findings: 23 cohort studies were identified, involving 2163 LC patients [median age 51.8 years, predominantly female sex (61.10%), white (75%), and non-vaccinated (99%)]. A total of 239 candidate biomarkers were identified, consisting mainly of immune cells, immunoglobulins, cytokines, and other plasma proteins. 19 of the 239 candidate biomarkers identified were evaluated by the authors, by means of receiver operating characteristic (ROC) curves.

Interpretation: Diverse cellular and molecular biomarkers for LC have been proposed. Validation of candidate biomarkers in independent samples should be prioritized. Modest reported performance (particularly in larger studies) suggests LC may encompass many distinct aetiologies, which should be explored e.g., by stratifying by symptom clusters and/or sex.

Source: Espín E, Yang C, Shannon CP, Assadian S, He D, Tebbutt SJ. Cellular and molecular biomarkers of long COVID: a scoping review. EBioMedicine. 2023 Apr 8;91:104552. doi: 10.1016/j.ebiom.2023.104552. Epub ahead of print. PMID: 37037165; PMCID: PMC10082390. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082390/ (Full text)

Risk factors for psychiatric symptoms in patients with long COVID: A systematic review

Abstract:

Prolonged symptoms of COVID-19 have been found in many patients, often known as Long COVID. Psychiatric symptoms are commonly seen in Long COVID patients and could last for weeks, even months, after recovery. However, the symptoms and risk factors associated with it remain unclear.

In the current systematic review, we provide an overview of psychiatric symptoms in Long COVID patients and risk factors associated with the development of those symptoms. Articles were systematically searched on SCOPUS, PubMed, and EMBASE up to October 2021. Studies involving adults and geriatric participants with a confirmed previous COVID-19 diagnosis and reported psychiatric symptoms that persist for more than four weeks after the initial infection were included. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies. Prevalence rates and risk factors associated with psychiatric symptoms were collected. This present study was registered at PROSPERO (CRD42021240776). In total, 23 studies were included.

Several limitations in this review were the heterogeneity of studies’ outcomes and designs, studies limited to articles published in English, and the psychiatric symptoms mainly were assessed using self-report questionnaires. The most prevalent  reported psychiatric symptoms, from the most to the least reported, were anxiety, depression, post-traumatic stress disorder (PTSD), poor sleep qualities, somatic symptoms, and cognitive deficits. Being female and having previous psychiatric diagnoses were risk factors for the development of the reported symptoms.

Source: Zakia H, Pradana K, Iskandar S. Risk factors for psychiatric symptoms in patients with long COVID: A systematic review. PLoS One. 2023 Apr 7;18(4):e0284075. doi: 10.1371/journal.pone.0284075. PMID: 37027455; PMCID: PMC10081737. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081737/ (Full text)

Association of Laparoscopically-confirmed Endometriosis with Long COVID: A Prospective Cohort Study

Abstract:

Background: Women are at greater risk than men of developing chronic inflammatory conditions and of developing ‘long COVID.’ However, few gynecologic health risk factors for long COVID have been identified. Endometriosis is a common gynecological disorder associated with chronic inflammation, immune dysregulation, and comorbid presentation with autoimmune and clotting disorders, all of which are pathophysiologic mechanisms proposed for long COVID. Therefore, we hypothesized that women with a history of endometriosis may be at greater risk of developing long COVID.

Objective: To investigate the association between history of endometriosis prior to SARS-CoV-2 infection and risk of long COVID.

Methods: We followed 46,579 women from two ongoing prospective cohort studies: the Nurses’ Health Study II and the Nurses’ Health Study 3, who participated in a series of COVID-19-related surveys administered from April 2020 to November 2022. Laparoscopic diagnosis of endometriosis was documented prospectively in main cohort questionnaires prior to the pandemic (1993-2020) with high validity. SARS-CoV-2 infection (confirmed by antigen, PCR, or antibody test) and CDC-defined long-term COVID-19 symptoms (≥4 weeks) were self-reported during follow-up. Among individuals with SARS-CoV-2 infection, we fit Poisson regression models to assess the associations between endometriosis and risk of long COVID-19 symptoms, with adjustment for potential confounding variables (demographics, body mass index, smoking status, history of infertility, and history of chronic diseases).

Results: Among 3650 women in our sample with self-reported SARS-CoV-2 infections during follow-up, 386 (10.6%) had a history of endometriosis with laparoscopic confirmation and 1598 (43.8%) reported experiencing long COVID symptoms. The majority of women were Non-Hispanic White (95.4%), with a median age of 59 years (interquartile range=44-65). Women with a history of laparoscopically-confirmed endometriosis had a 22% greater risk of developing long COVID (adjusted RR=1.22, 95% CI=1.05-1.42), compared to those who had never been diagnosed with endometriosis. The association was stronger when we defined long COVID as having symptoms ≥8 weeks (RR=1.28, 95% CI=1.09-1.50). We observed no statistically significant differences in the relationship between endometriosis and long COVID by age, infertility history, or comorbidity with uterine fibroids, although there was a suggestive trend that women <50 years may be at higher risk (<50 years, RR=1.37, 95% CI=1.00-1.88; ≥50 years, RR=1.19, 95% CI=1.01-1.41). Among persons who developed long COVID, women with endometriosis reported on average one additional long-term symptom compared to women without endometriosis.

Conclusions and relevance: Our findings suggest that those with a history of endometriosis may be at modestly increased risk for long COVID. Health care providers should be aware of endometriosis history when treating patients for signs of persisting symptoms post-SARS-CoV-2 infection. Future studies should investigate the potential biological pathways underlying these associations.

Source: Wang S, Farland LV, Gaskins AJ, Mortazavi J, Wang YX, Tamimi RM, Rich-Edwards JW, Zhang D, Terry KL, Chavarro JE, Missmer SA. Association of Laparoscopically-confirmed Endometriosis with Long COVID: A Prospective Cohort Study. Am J Obstet Gynecol. 2023 Mar 25:S0002-9378(23)00177-1. doi: 10.1016/j.ajog.2023.03.030. Epub ahead of print. PMID: 36972892. https://pubmed.ncbi.nlm.nih.gov/36972892/ https://www.ajog.org/article/S0002-9378(23)00177-1/pdf (Full text available as PDF file)

A prospective cohort study assessing the relationship between long-COVID symptom incidence in COVID-19 patients and COVID-19 vaccination

Abstract:

Current studies about the long-term effects of COVID-19 show a wide range of symptoms. This prospective cohort study aimed to find the incidence of long-COVID symptoms and the associated risk factors.

We followed 669 confirmed COVID-19 patients. Sociodemographic and clinical data were extracted from medical records and collected via semi-structured telephone interviews on days 10, 30, 60, and 90. The incidence of long-COVID symptoms was 41.6% (95% CI 37.8-45.4%). Females [aOR = 1.5 (95% CI 1.1-2.3)], the elderly [aOR = 4.9 (95% CI 2.0-11.3)], and those who required hospitalization [aOR = 5.0 (95% CI 1.3-3.7)] were at a higher risk of developing long-COVID. Patients with dyspnea at day 10 [aOR: 2.4 (95% CI 1.6-3.7] and fatigue at day 60 [aOR: 3.1 (95% CI 1.5-6.3] were also at risk. While non-vaccinated patients were almost seven times more likely to report long-COVID symptoms than vaccinated patients [aOR: 6.9 (95% CI 4.2-11.3)].

In conclusion, long-COVID was common among COVID-19 patients, with higher rates among females, older age groups, hospitalized patients, and those with dyspnea and fatigue, while vaccination provided protection. Interventions should educate health professionals, raise general public awareness about the risks and consequences of Long COVID, and the value of vaccination.

Source: Abu Hamdh B, Nazzal Z. A prospective cohort study assessing the relationship between long-COVID symptom incidence in COVID-19 patients and COVID-19 vaccination. Sci Rep. 2023 Mar 25;13(1):4896. doi: 10.1038/s41598-023-30583-2. PMID: 36966161; PMCID: PMC10039348. https://www.nature.com/articles/s41598-023-30583-2 (Full text)

What is the impact of post-COVID-19 syndrome on health-related quality of life and associated factors: a cross-sectional analysis

Abstract:

Background: After the acute phase, symptoms or sequelae related to post-COVID-19 syndrome may persist for months. In a population of patients, previously hospitalized and not, followed up to 12 months after the acute infection, we aim to assess whether and to what extent post-COVID-19 syndrome may have an impact on health-related quality of life (HRQoL) and to investigate influencing factors.

Methods: We present the cross-sectional analysis of a prospective study, including patients referred to the post-COVID-19 service. Questionnaires and scales administered at 3, 6, 12 months were: Short-Form 36-item questionnaire (SF-36); Visual Analogue Scale of the EQ5D (EQ-VAS); in a subgroup, Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II) and Pittsburgh Sleep Quality Index (PSQI). Linear regression models were fitted to identify factors associated with HRQoL.

Results: We considered the first assessment of each participant (n = 572). The mean scores in SF-36 and in EQ-VAS were significantly lower than the Italian normative values and remained stable over time, except the mental components score (MCS) of the SF-36 and EQ-VAS which resulted in lower ratings at the last observations. Female gender, presence of comorbidities, and corticosteroids treatment during acute COVID-19, were associated with lower scores in SF-36 and EQ-VAS; patients previously hospitalized (54%) reported higher MCS. Alterations in BAI, BDI-II, and PSQI (n = 265)were associated with lower ratings in SF-36 and EQ-VAS.

Conclusions: This study provides evidence of a significantly bad perception of health status among persons with post-COVID-19 syndrome, associated with female gender and, indirectly, with disease severity. In case of anxious-depressive symptoms and sleep disorders, a worse HRQoL was also reported. A systematic monitoring of these aspects is recommended to properly manage the post-COVID-19 period.

Source: Mastrorosa I, Del Duca G, Pinnetti C, Lorenzini P, Vergori A, Brita AC, Camici M, Mazzotta V, Baldini F, Chinello P, Mencarini P, Giancola ML, Abdeddaim A, Girardi E, Vaia F, Antinori A. What is the impact of post-COVID-19 syndrome on health-related quality of life and associated factors: a cross-sectional analysis. Health Qual Life Outcomes. 2023 Mar 22;21(1):28. doi: 10.1186/s12955-023-02107-z. PMID: 36949439; PMCID: PMC10031164. https://hqlo.biomedcentral.com/articles/10.1186/s12955-023-02107-z (Full text)

Demographic And Clinical Factors Associated With Long COVID

Risk factors for postacute sequelae of SARS-CoV-2 infection (“long COVID”) in community-dwelling populations remain poorly understood. Large-scale data, follow-up, comparison groups, and a consensus definition of long COVID are often lacking. Using data from the OptumLabs Data Warehouse on a nationwide sample of commercial and Medicare Advantage enrollees from the period January 2019 through March 2022, we examined demographic and clinical factors associated with long COVID, using two definitions of people who suffer symptoms long after they were first diagnosed with COVID-19 (“long haulers”).

We identified 8,329 long haulers using the narrow definition (diagnosis code), 207,537 long haulers using the broad definition (symptom based), and 600,161 non–long haulers (comparison group).

On average, long haulers were older and more likely female, with more comorbidities. Among narrow-definition long haulers, the leading risk factors for long COVID included hypertension, chronic lung disease, obesity, diabetes, and depression. Their time between initial COVID-19 diagnosis and diagnosis of long COVID averaged 250 days, with racial and ethnic differences. Broad-definition long haulers exhibited similar risk factors. Distinguishing long COVID from the progression of underlying conditions can be challenging, but further study may advance the evidence base related to the identification, causes, and consequences of long COVID.

Source: Song Z, Giuriato M. Demographic And Clinical Factors Associated With Long COVID. Health Aff (Millwood). 2023 Mar;42(3):433-442. doi: 10.1377/hlthaff.2022.00991. PMID: 36877912. https://pubmed.ncbi.nlm.nih.gov/36877912/