Infection with SARS-CoV-2 Variants Is Associated with Different Long COVID Phenotypes

Abstract:

COVID-19 has been associated with a broad range of long-term sequelae, commonly referred to as “long-COVID” or “post-COVID-19” syndrome. Despite an increasing body of literature, long COVID remains poorly characterized. We retrospectively analysed data from electronic medical records of patients admitted to the post-COVID-19 outpatient service of the Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy, between June 2020 and June 2021, 4-12 weeks after hospital discharge.

A total of 428 patients, 41% women, median age 64 years, underwent a follow-up visit a median 53 days after hospital discharge. Overall, 76% patients reported at least one persistent symptom, including dyspnoea (37%), chronic fatigue (36%), insomnia (16%), visual disorders (13%) and brain fog (13%). Increasing oxygen support (OR 1.4, 95% CI 1.1-1.8), use of immunosuppressants (OR 6.4, 95% CI 1.5-28) and female sex (OR 1.8, 95% CI 1.1-2.9) were associated with a higher risk of long COVID symptoms.

Comparison between symptomatic patients infected in the period March-December 2020 (prevalent circulation of wild-type SARS-CoV-2) with those infected in the period January-April 2021 (prevalent circulation of B.1.1.7 Alpha variant) showed a significant modification in the pattern of symptoms belonging to the neurological and cognitive/emotional categories.

Our findings confirmed shortness of breath and chronic fatigue as the most frequent long COVID manifestations, while female sex and severe COVID-19 course were the main risk factors for developing lingering symptoms. SARS-CoV-2 variants may induce different long COVID phenotypes, possibly due to changes in cell tropism and differences in viral-host interaction.

Source: Spinicci M, Graziani L, Tilli M, Nkurunziza J, Vellere I, Borchi B, Mencarini J, Campolmi I, Gori L, Giovannoni L, Amato C, Livi L, Rasero L, Fattirolli F, Marcucci R, Giusti B, Olivotto I, Tomassetti S, Lavorini F, Maggi L, Annunziato F, Marchionni N, Zammarchi L, Bartoloni A. Infection with SARS-CoV-2 Variants Is Associated with Different Long COVID Phenotypes. Viruses. 2022 Oct 27;14(11):2367. doi: 10.3390/v14112367. PMID: 36366465; PMCID: PMC9698829. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9698829/ (Full text)

Differences in Symptoms among Black and White Patients with ME/CFS

Abstract:

Study samples of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have primarily involved White subjects, so the literature on ethnic differences is sparse. The current study identified a sample of 19 Black patients diagnosed with ME/CFS and compared them with White patients with ME/CFS, as well as with healthy controls. The studies used a similar psychometrically sound assessment tool to assess symptoms in all subjects.

Findings indicated there were significant differences between patients with ME/CFS versus controls, but few differences between patients who identified as Black or White. The results suggest there might be few symptom differences between patients with ME/CFS in these two ethnic groups. The implications of these findings are discussed.

Source: Jason LA, Torres C. Differences in Symptoms among Black and White Patients with ME/CFS. J Clin Med. 2022 Nov 12;11(22):6708. doi: 10.3390/jcm11226708. PMID: 36431185. https://www.mdpi.com/2077-0383/11/22/6708 (Full text)

The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome

Background: Fatigue is common after viral infections, including SARS-CoV-2.1 Our purpose was to report the prevalence and impact of persistent fatigue 6 months after SARS-CoV-2 infection, considering post-exertional malaise2 and criteria for chronic fatigue syndrome.3

Methods: Since March 2020, individuals tested for SARS-CoV-2 at the Geneva University Hospitals outpatient testing center benefit from remote ambulatory follow-up (COVICARE). This study included all individuals tested between March 2020 and December 2020 and whose follow-up was at 6 months or more after their test date.

Follow-up included questions about the prevalence of symptoms (yes/no) and their severity using a Likert scale (mild, moderate, or severe). Fatigue was assessed using the Eastern Cooperative Oncology Group (ECOG) scale and the Chalder fatigue scale. The Chalder fatigue scale was scored using the 4-item Likert and the bimodal scoring schemes. A score of ≥ 4 on bimodal scoring indicated severe fatigue.

The DePaul brief questionnaire was used to identify post-exertional malaise and criteria for chronic fatigue syndrome.

The Sheehan Disability Scale was used to assess functional impairment. Reduced work capacity was defined as missing days off work or having a reduced productivity on the Sheehan disability scale.

Comorbidities were considered present if pre-existing prior to SARS-CoV-2 infection. Statistical analysis included descriptive comparisons of percentages using chi-square tests and Student’s t test.

Results: Overall, 5515 individuals participated in this study (response rate 70.7%), with 5406 participants at 6 months or more after their test date. A total of 1497 (27.7%) participants had a documented positive SARS-CoV-2 test and were ultimately included in the study. The median time for follow-up was 225 days (interquartile range 207–398). Respectively, fatigue was reported by 17.2%, post-exertional malaise by 8.2%, and the presence of criteria for chronic fatigue syndrome by 1.1% of SARS-CoV-2-positive individuals, compared to 8.9%, 3.5%, and 0.5% of SARS-CoV-2-negative individuals. Characteristics are presented in Table 1.

Out of SARS-CoV-2-positive participants with fatigue (n = 258), 35.3% had moderate to severe limitations on the ECOG scale, and 83.0% had a score ≥ 4 on the Chalder fatigue scale. The Chalder fatigue scale revealed a mean score of 19 out of 33, SD 5.4, and a mean score of 6.7 out of 11, SD 3.3 using bimodal scoring. After adjusting for age and sex, 47.7% of SARS-CoV-2-positive individuals with fatigue at 6 months or more had the frequency and severity criteria for post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome.

Individuals had a higher prevalence of insomnia, cognitive impairment, headaches, generalized pain, functional impairment, reduced work capacity, and decreased physical activity, after SARS-CoV-2 infection. The prevalence of these sequelae was adjusted for age and sex and was increasingly higher with severe fatigue, with post-exertional malaise, or when criteria for chronic fatigue syndrome were present (Fig. 1).

Discussion: Fatigue is the most common and persistent post-COVID symptom. The spectrum of fatigue severity in post-COVID individuals ranges from feeling tired to having severe fatigue, post-exertional malaise, or criteria for chronic fatigue syndrome with an increasing impact on health, functional capacity, and physical activity.

Almost half of individuals experiencing fatigue at 6 months after the infection had post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome, prompting physicians to consider pacing as a management option, in the absence of other treatment options at this stage. SARS-CoV-2 infection was positively associated with fatigue and post-exertional malaise.

Results showed that individuals with fatigue were more likely to be vaccinated. This was partially explained by the baseline distribution as older individuals and those with more comorbidities were more likely to get vaccinated.

Results compare to recent reviews showing an overlap between post-COVID condition and chronic fatigue syndrome. Our study graded post-COVID fatigue by severity in correlation with functional capacity, and showed the high prevalence of post-exertional malaise.

Limitations include the self-reported nature of this follow-up with individuals infected in 2020 and follow-up in 2021, lacking comparisons to individuals infected with other variants. Additionally, this study considered having received at least 2 doses as full vaccination, a concept that continues to evolve with time.

Physicians, employers, and insurance companies should address fatigue on a spectrum, accounting for the correlated functional impairment, decreased activity levels, and potentially poorer quality of life.

Source: Nehme M, Chappuis F, Kaiser L, Assal F, Guessous I. The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome. J Gen Intern Med. 2022 Nov 10:1–5. doi: 10.1007/s11606-022-07882-x. Epub ahead of print. PMID: 36357723; PMCID: PMC9648889. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648889/ (Full text)

 

Is SARS-CoV-2 the only cause of long-COVID?

Abstract:

Around 10% of adults infected with SARS-CoV-2 that survive a first episode of COVID-19 appear to experience long-term clinical manifestations. The signs and symptoms of this post-acute COVID-19 syndrome (PACS) include fatigue, dyspnea, joint pain, myalgia, chest pain, cough, anosmia, dysgeusia, headache, depression, anxiety, memory loss, concentration difficulties, and insomnia. These sequelae remind the constellation of clinical manifestations previously recognized as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS).

This condition has been described following distinct infectious events, mostly acute viral illnesses. In this way, the pathophysiology of PACS might overlap with mechanisms involved in other post-infectious fatigue syndromes. The risk of PACS is more frequent in women than men. Additional host genetic factors could be involved.

There is a dysregulation of multiple body organs and systems, involving the immune system, the coagulation cascade, endocrine organs, autonomic nervous system, microbiota-gut-brain axis, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, etc. Hypothetically, an abnormal response to certain infectious agents could trigger the development of postinfectious fatigue syndromes.

Source: Pintos-Pascual I, Moreno-Torres V, Ibánez-Estéllez F, Corrales-Rodriguez P, Treviño A, Corpas M, Corral O, Soriano V, de Mendoza C. Is SARS-CoV-2 the only cause of long-COVID? AIDS Rev. 2022 Nov 25. doi: 10.24875/AIDSRev.22000025. Epub ahead of print. PMID: 36427058.  https://pubmed.ncbi.nlm.nih.gov/36427058/

Transcutaneous Vagus Nerve Stimulation in the Treatment of Long Covid-Chronic Fatigue Syndrome

Abstract:

Many patients do not recover following Covid infection. The resulting illness is called Long Covid. Because there is no agreed upon treatment for this ailment, we decided to do an open label pilot study using non-invasive, transcutaneous stimulation of the auricular branch of the vagus nerve. Inclusion criteria required the patient to fulfill criteria for having chronic fatigue syndrome. Fourteen patients provided evaluable data. Eight of these fulfilled our requirements for treatment success. Since our criterion for a successful study was that at least a third of patients had to show a positive response to treatment, this was a successful pilot that warrants a follow up study that is appropriately sham controlled.

Source: Benjamin H Natelson, Michelle Blate, Tiffany Soto. Transcutaneous Vagus Nerve Stimulation in the Treatment of Long Covid-Chronic Fatigue Syndrome. medRxiv 2022.11.08.22281807; doi: https://doi.org/10.1101/2022.11.08.22281807 https://www.medrxiv.org/content/10.1101/2022.11.08.22281807v1.full-text (Full text)

Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients

Abstract:

Importance  Identification of long-term post–COVID-19 symptoms among hospitalized and nonhospitalized patients is needed.

Objective  To compare the presence of post–COVID-19 symptoms 2 years after acute SARS-CoV-2 infection between hospitalized and nonhospitalized patients.

Design, Setting, and Participants  A cross-sectional cohort study was conducted at 2 urban hospitals and general practitioner centers from March 20 to April 30, 2020, among 360 hospitalized patients and 308 nonhospitalized patients with acute SARS-CoV-2 infection during the first wave of the pandemic. Follow-up was conducted 2 years later.

Main Outcomes and Measures  Participants were scheduled for a telephone interview 2 years after acute infection. The presence of post–COVID-19 symptoms was systematically assessed, with particular attention to symptoms starting after infection. Hospitalization and clinical data were collected from medical records. Between-group comparisons and multivariate logistic regressions were conducted.

Results  A total of 360 hospitalized patients (162 women [45.0%]; mean [SD] age, 60.7 [16.1] years) and 308 nonhospitalized patients (183 women [59.4%]; mean [SD] age, 56.7 [14.7] years) were included. Dyspnea was more prevalent at the onset of illness among hospitalized than among nonhospitalized patients (112 [31.1%] vs 36 [11.7%]; P < .001), whereas anosmia was more prevalent among nonhospitalized than among hospitalized patients (66 [21.4%] vs 36 [10.0%]; P = .003). Hospitalized patients were assessed at a mean (SD) of 23.8 (0.6) months after hospital discharge, and nonhospitalized patients were assessed at a mean (SD) of 23.4 (0.7) months after the onset of symptoms. The number of patients who exhibited at least 1 post–COVID-19 symptom 2 years after infection was 215 (59.7%) among hospitalized patients and 208 (67.5%) among nonhospitalized patients (P = .01). Among hospitalized and nonhospitalized patients, fatigue (161 [44.7%] vs 147 [47.7%]), pain (129 [35.8%] vs 92 [29.9%]), and memory loss (72 [20.0%] vs 49 [15.9%]) were the most prevalent post–COVID-19 symptoms 2 years after SARS-CoV-2 infection. No significant differences in post–COVID-19 symptoms were observed between hospitalized and nonhospitalized patients. The number of preexisting medical comorbidities was associated with post–COVID-19 fatigue (odds ratio [OR], 1.93; 95% CI, 1.09-3.42; P = .02) and dyspnea (OR, 1.91; 95% CI, 1.04-3.48; P = .03) among hospitalized patients. The number of preexisting medical comorbidities (OR, 3.75; 95% CI, 1.67-8.42; P = .001) and the number of symptoms at the onset of illness (OR, 3.84; 95% CI, 1.33-11.05; P = .01) were associated with post–COVID-19 fatigue among nonhospitalized patients.

Conclusions and Relevance  This cross-sectional study suggested the presence of at least 1 post–COVID-19 symptom in 59.7% of hospitalized patients and 67.5% of nonhospitalized patients 2 years after infection. Small differences in symptoms at onset of COVID-19 were identified between hospitalized and nonhospitalized patients. Post–COVID-19 symptoms were similar between hospitalized and nonhospitalized patients; however, lack of inclusion of uninfected controls limits the ability to assess the association of SARS-CoV-2 infection with overall and specific post–COVID-19 symptoms 2 years after acute infection. Future studies should include uninfected control populations.

Source: Fernández-de-las-Peñas, Martín-Guerrero, Hernández-Barrera. Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients. November 15, 2022. doi:10.1001/jamanetworkopen.2022.42106 (Full text)

Association between long COVID symptoms and employment status

Abstract:

Background: Symptoms of Coronavirus-19 (COVID-19) infection persist beyond 2 months in a subset of individuals, a phenomenon referred to as long COVID, but little is known about its functional correlates and in particular the relevance of neurocognitive symptoms.

Method: We analyzed a previously-reported cohort derived from 8 waves of a nonprobability-sample internet survey called the COVID States Project, conducted every 4-8 weeks between February 2021 and July 2022. Primary analyses examined associations between long COVID and lack of full employment or unemployment, adjusted for age, sex, race and ethnicity, education, urbanicity, and region, using multiple logistic regression with interlocking survey weights.

Results: The cohort included 15,307 survey respondents ages 18-69 with test-confirmed COVID-19 at least 2 months prior, of whom 2,236 (14.6%) reported long COVID symptoms, including 1,027/2,236 (45.9%) reporting either ‘brain fog’ or impaired memory. Overall, 1,418/15,307 (9.3%) reported being unemployed, including 276/2,236 (12.3%) of those with long COVID and 1,142/13,071 (8.7%) of those without; 8,228 (53.8%) worked full-time, including 1,017 (45.5%) of those with long COVID and 7,211 (55.2%) without. In survey-weighted regression models, presence of long COVID was associated with being unemployed (crude OR 1.44, 95% CI 1.20-1.72; adjusted OR 1.23, 95% CI 1.02-1.48), and with lower likelihood of working full-time (crude OR 0.73, 95% CI 0.64-0.82; adjusted OR 0.79, 95% CI 0.70 -0.90). Among individuals with long COVID, the presence of cognitive symptoms — either brain fog or impaired memory — was associated with lower likelihood of working full time (crude OR 0.71, 95% CI 0.57-0.89, adjusted OR 0.77, 95% CI 0.61-0.97).

Conclusion: Long COVID was associated with a greater likelihood of unemployment and lesser likelihood of working full time in adjusted models. Presence of cognitive symptoms was associated with diminished likelihood of working full time. These results underscore the importance of developing strategies to respond to long COVID, and particularly the associated neurocognitive symptoms.

Source: Kristin Lunz Trujillo, Roy H Perlis, Alauna Safarpour, Mauricio Santillana, Katherine Ognyanova, James Druckman, David Lazer. Association between long COVID symptoms and employment status. medRxiv 2022.11.17.22282452; doi: https://doi.org/10.1101/2022.11.17.22282452 (Full text available as PDF file)

HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms

Abstract:

Due to the wide scope and persistence of COVID-19´s pandemic, post-COVID-19 condition represents a post-viral syndrome of unprecedented dimensions. SARS-CoV-2, in line with other infectious agents, has the capacity to activate dormant human endogenous retroviral sequences ancestrally integrated in human genomes (HERVs). This activation was shown to relate to aggravated COVID-19 patient´s symptom severity.

Despite our limited understanding of how HERVs are turned off upon infection clearance, or how HERVs mediate long-term effects when their transcription remains aberrantly on, the participation of these elements in neurologic disease, such as multiple sclerosis, is already settling the basis for effective therapeutic solutions. These observations support an urgent need to identify the mechanisms that lead to HERV expression with SARS-CoV-2 infection, on the one hand, and to answer whether persistent HERV expression exists in post-COVID-19 condition, on the other.

The present study shows, for the first time, that the HERV-W ENV protein can still be actively expressed long after SARS-CoV-2 infection is resolved in post-COVID-19 condition patients. Moreover, increased anti-SARS-CoV-2 immunoglobulins in post-COVID-19 condition, particularly high anti-SARS-CoV-2 immunoglobulin levels of the E isotype (IgE), seem to strongly correlate with deteriorated patient physical function (r=-0.8057, p<0.01).

These results indicate that HERV-W ENV antigenemia and anti-SARS-CoV-2 IgE serology should be further studied to better characterize post-COVID-19 condition pathogenic drivers potentially differing in subsets of patients with various symptoms. They also point out that such biomarkers may serve to design therapeutic options for precision medicine in post-COVID-19 condition.

Source: Giménez-Orenga K, Pierquin J, Brunel J, Charvet B, Martín-Martínez E, Perron H, Oltra E. HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms. Front Immunol. 2022 Oct 27;13:1020064. doi: 10.3389/fimmu.2022.1020064. PMID: 36389746; PMCID: PMC9647063.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647063/ (Full text)

Psychogenic Explanations of Physical Illness: Time to Examine the Evidence

Abstract:

In some patients with chronic physical complaints, detailed examination fails to reveal a well-recognized underlying disease process. In this situation, the physician may suspect a psychological cause. In this review, we critically evaluated the evidence for this causal claim, focusing on complaints presenting as neurological disorders.

There were four main conclusions. First, patients with these complaints frequently exhibit psychopathology but not consistently more often than patients with a comparable “organic” diagnosis, so a causal role cannot be inferred.

Second, these patients report a high incidence of adverse life experiences, but again, there is insufficient evidence to indicate a causal role for any particular type of experience.

Third, although psychogenic illnesses are believed to be more responsive to psychological interventions than comparable “organic” illnesses, there is currently no evidence to support this claim.

Finally, recent evidence suggests that biological and physical factors play a much greater causal role in these illnesses than previously believed. We conclude that there is currently little evidential support for psychogenic theories of illness in the neurological domain. In future research, researchers need to take a wider view concerning the etiology of these illnesses.

Source: Carolyn E. Wilshire and Tony Ward. Psychogenic Explanations of Physical Illness: Time to Examine the Evidence. Perspectives on Psychological Science 2016, Vol. 11(5) 606–631. https://www.researchgate.net/publication/283476227_Psychogenic_explanations_of_physical_illness_Time_to_examine_the_evidence (Full text)

Co-Ultramicronized Palmitoylethanolamide/Luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome

Abstract:

Objective: Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI).

Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI.

Methods: Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700mg + 70mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity.

Results: Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected.

Conclusions: Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients.

Significance: This study confirms altered physiology of the motor cortex in long Covid and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.

Source: Viviana Versace, Paola Ortelli, Sabrina Dezi, Davide Ferrazzoli, Alessia Alibardi, Ilenia Bonini, Michael Engl, Roberto Maestri, Martina Assogna, Valentina Ajello, Elke Pucks-Faes, Leopold Saltuari, Luca Sebastianelli, Markus Kofler, Giacomo Koch. Co-Ultramicronized Palmitoylethanolamide/Luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome. Clinical Neurophysiology, 2022, ISSN 1388-2457, https://doi.org/10.1016/j.clinph.2022.10.017. https://www.sciencedirect.com/science/article/pii/S1388245722009385 (Full text)