Tag: long covid symptoms

Severe Fatigue and Persistent Symptoms at Three Months Following SARS-CoV-2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study

Abstract:

Background: Most research on SARS-CoV-2 variants focuses on initial symptomatology with limited data on longer-term sequelae. We sought to characterize the prevalence and differences in prolonged symptoms at three months post SARS-CoV-2-infection across the three major variant time-periods (pre-Delta, Delta, and Omicron).

Methods: This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, individual and organ system-based symptoms, and presence of ≥3 total symptoms across variants among COVID-positive and COVID-negative participants 3 months after their initial SARS-CoV-2 diagnosis. Variant periods were defined by dates with ≥50% dominant strain. We performed a sensitivity analysis using ≥90% dominance threshold and multivariable logistic regression modeling to estimate the independent effects of each variant adjusting for socio-demographic characteristics, baseline health, and vaccine status.

Results: The study included 3,223 participants (2,402 COVID-positive and 821 COVID-negative). Among the COVID-positive cohort, 463 (19.3%) were pre-Delta, 1,198 (49.9%) during Delta, and 741 (30.8%) during Omicron. Prolonged severe fatigue was highest in the pre-Delta COVID-positive cohort compared with Delta and Omicron cohorts (16.7% vs 11.5% vs 12.3%, respectively; p = 0.017), as was presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; p < 0.001). No difference was seen in the COVID-negative cohort between variant time-periods. In multivariable models, there was no difference in severe fatigue between variants. There was decreased odds of having ≥3 symptoms in Omicron compared with other variants; this was not significant after adjusting for vaccination status.

Conclusions: Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during the pre-Delta period compared with Delta and Omicron periods; however, these differences were no longer significant after adjusting for vaccination status. This suggests a potential beneficial effect of vaccination on the risk of developing long-term symptoms.

Source: Gottlieb M, Wang R, Yu H, Spatz ES, Montoy JC, Rodriguez R, Chang AM, Elmore JG, Hannikainen PA, Hill M, Huebinger RM, Idris AH, Lin Z, Koo K, McDonald S, O’Laughlin KN, Plumb ID, Santangelo M, Saydah S, Willis M, Wisk LE, Venkatesh A, Stephens KA, Weinstein RA; INSPIRE Group. Severe Fatigue and Persistent Symptoms at Three Months Following SARS-CoV-2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study. Clin Infect Dis. 2023 Jan 27:ciad045. doi: 10.1093/cid/ciad045. Epub ahead of print. PMID: 36705268.  https://pubmed.ncbi.nlm.nih.gov/36705268/ (Full study available as PDF file)

Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms

Abstract:

Introduction: Long COVID is the overarching name for a wide variety of disorders that may follow the diagnosis of acute SARS-COVID-19 infection and persist for weeks to many months. Nearly every organ system may be affected.

Methods: We report nine patients suffering with Long COVID for 101 to 547 days. All exhibited significant perturbations of their immune systems, but only one was known to be immunodeficient prior to the studies directed at evaluating them for possible treatment. Neurological and cardiac symptoms were most common. Based on this data and other evidence suggesting autoimmune reactivity, we planned to treat them for 3 months with long-term high-dose immunoglobulin therapy. If there was evidence of benefit at 3 months, the regimen was continued.

Results: The patients’ ages ranged from 34 to 79 years—with five male and four female patients, respectively. All nine patients exhibited significant immune perturbations prior to treatment. One patient declined this treatment, and insurance support was not approved for two others. The other six have been treated, and all have had a significant to remarkable clinical benefit.

Conclusion: Long-term high-dose immunoglobulin therapy is an effective therapeutic option for treating patients with Long COVID.

Source: Thompson JS, Thornton AC, Ainger T and Garvy BA (2023) Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms. Front. Immunol. 13:1033651. doi: 10.3389/fimmu.2022.1033651 https://www.frontiersin.org/articles/10.3389/fimmu.2022.1033651/full (Full text)

Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC)

Abstract:

With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved.
Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020–2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.
Source: Ong IZ, Kolson DL, Schindler MK. Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC). Biomedicines. 2023; 11(2):377. https://doi.org/10.3390/biomedicines11020377 https://www.mdpi.com/2227-9059/11/2/377

The emotional well-being of Long COVID patients in relation to their symptoms, social support and stigmatization in social and health services: a qualitative study

Abstract:

Background: Long COVID patients have experienced a decline in their quality of life due to, in part but not wholly, its negative emotional impact. Some of the most prevalent mental health symptoms presented by long COVID patients are anxiety, depression, and sleep disorders. As such, the need has arisen to analyze the personal experiences of these patients to understand how they are managing their daily lives while dealing with the condition. The objective of this study is to increase understanding about the emotional well-being of people diagnosed with long COVID.

Methods: A qualitative design was created and carried out using 35 patients, with 17 participants being interviewed individually and 18 of them taking part in two focus groups. The participating patients were recruited in November and December 2021 from Primary Health Care (PHC) centers in the city of Zaragoza (Northern Spain) and from the Association of Long COVID Patients in Aragon. The study topics were emotional well-being, social support networks, and experience of discrimination. All an inductive thematic content analyses were performed iteratively using NVivo software.

Results: The Long COVID patients identified low levels of self-perceived well-being due to their persistent symptoms, as well as limitations in their daily lives that had been persistent for many months. Suicidal thoughts were also mentioned by several patients. They referred to anguish and anxiety about the future as well as a fear of reinfection or relapse and returning to work. Many of the participants reported that they have sought the help of a mental health professional. Most participants identified discriminatory situations in health care.

Conclusions: It is necessary to continue researching the impact that Long COVID has had on mental health, as well as to provide Primary Health Care professionals with evidence that can guide the emotional treatment of these patients.

Source: Samper-Pardo M, Oliván-Blázquez B, Magallón-Botaya R, Méndez-López F, Bartolomé-Moreno C, León-Herrera S. The emotional well-being of Long COVID patients in relation to their symptoms, social support and stigmatization in social and health services: a qualitative study. BMC Psychiatry. 2023 Jan 25;23(1):68. doi: 10.1186/s12888-022-04497-8. PMID: 36698111; PMCID: PMC9875186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875186/ (Full text)

Chronic viral coinfections differentially affect the likelihood of developing long COVID

Abstract:

BACKGROUND. The presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.

METHODS. In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.

RESULTS. We observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen–diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).

CONCLUSION. Overall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.

Source: Peluso MJ, Deveau TM, Munter SE, Ryder D, Buck A, Beck-Engeser G, Chan F, Lu S, Goldberg SA, Hoh R, Tai V, Torres L, Iyer NS, Deswal M, Ngo LH, Buitrago M, Rodriguez A, Chen JY, Yee BC, Chenna A, Winslow JW, Petropoulos CJ, Deitchman AN, Hellmuth J, Spinelli MA, Durstenfeld MS, Hsue PY, Kelly JD, Martin JN, Deeks SG, Hunt PW, Henrich TJ. Chronic viral coinfections differentially affect the likelihood of developing long COVID. J Clin Invest. 2023 Feb 1;133(3):e163669. doi: 10.1172/JCI163669. PMID: 36454631. https://www.jci.org/articles/view/163669 (Full text)

Cardiac Autonomic Function in Long COVID-19 Using Heart Rate Variability: An Observational Cross-Sectional Study

Abstract:

Background: Heart rate variability is a non-invasive, measurable, and established autonomic nervous system test. Long-term COVID-19 sequelae are unclear; however, acute symptoms have been studied.

Objectives: To determine autonomic cardiac differences between long COVID-19 patients and healthy controls and evaluate associations among symptoms, comorbidities, and laboratory findings.

Methods: This single-center study included long COVID-19 patients and healthy controls. The heart rate variability (HRV), a quantitative marker of autonomic activity, was monitored for 24 h using an ambulatory electrocardiogram system. HRV indices were compared between case and control groups. Symptom frequency and inflammatory markers were evaluated. A significant statistical level of 5% (p-value 0.05) was adopted.

Results: A total of 47 long COVID-19 patients were compared to 42 healthy controls. Patients averaged 43.8 (SD14.8) years old, and 60.3% were female. In total, 52.5% of patients had moderate illness. Post-exercise dyspnea was most common (71.6%), and 53.2% lacked comorbidities. CNP, D-dimer, and CRP levels were elevated (p-values of 0.0098, 0.0023, and 0.0015, respectively). The control group had greater SDNN24 and SDANNI (OR = 0.98 (0.97 to 0.99; p = 0.01)). Increased low-frequency (LF) indices in COVID-19 patients (OR = 1.002 (1.0001 to 1.004; p = 0.030)) and high-frequency (HF) indices in the control group (OR = 0.987 (0.98 to 0.995; p = 0.001)) were also associated.

Conclusions: Patients with long COVID-19 had lower HF values than healthy individuals. These variations are associated with increased parasympathetic activity, which may be related to long COVID-19 symptoms and inflammatory laboratory findings.

Source: Menezes Junior ADS, Schröder AA, Botelho SM, Resende AL. Cardiac Autonomic Function in Long COVID-19 Using Heart Rate Variability: An Observational Cross-Sectional Study. J Clin Med. 2022 Dec 22;12(1):100. doi: 10.3390/jcm12010100. PMID: 36614901; PMCID: PMC9821736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821736/ (Full text)

Improvement of Long COVID symptoms over one year

Abstract:

Importance: Early and accurate diagnosis and treatment of Long COVID, clinically known as post-acute sequelae of COVID-19 (PASC), may mitigate progression to chronic diseases such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our objective was to determine the utility of the DePaul Symptom Questionnaire (DSQ) to assess the frequency and severity of common symptoms of ME/CFS, to diagnose and monitor symptoms in patients with PASC.

Methods: This prospective, observational cohort study enrolled 185 people that included 34 patients with PASC that had positive COVID-19 test and persistent symptoms of >3 months and 151 patients diagnosed with ME/CFS. PASC patients were followed over 1 year and responded to the DSQ at baseline and 12 months. ME/CFS patients responded to the DSQ at baseline and 1 year later. Changes in symptoms over time were analyzed using a fixed-effects model to compute difference-in-differences estimates between baseline and 1-year follow-up assessments.

Participants: Patients were defined as having PASC if they had a previous positive COVID-19 test, were experiencing symptoms of fatigue, post-exertional malaise, or other unwellness for at least 3 months, were not hospitalized for COVID-19, had no documented major medical or psychiatric diseases prior to COVID-19, and had no other active and untreated disease processes that could explain their symptoms. PASC patients were recruited in 2021. ME/CFS patients were recruited in 2017.

Results: At baseline, patients with PASC had similar symptom severity and frequency as patients with ME/CFS and satisfied ME/CFS diagnostic criteria. ME/CFS patients experienced significantly more severe unrefreshing sleep and flu-like symptoms. Five symptoms improved significantly over the course of 1 year for PASC patients including fatigue, post-exertional malaise, brain fog, irritable bowel symptoms and feeling unsteady. In contrast, there were no significant symptom improvements for ME/CFS patients.

Conclusion and relevance: There were considerable similarities between patients with PASC and ME/CFS at baseline. However, symptoms improved for PASC patients over the course of a year but not for ME/CFS patients. PASC patients with significant symptom improvement no longer met ME/CFS clinical diagnostic criteria. These findings indicate that the DSQ can be used to reliably assess and monitor PASC symptoms.

Source: Oliveira CR, Jason LA, Unutmaz D, Bateman L, Vernon SD. Improvement of Long COVID symptoms over one year. Front Med (Lausanne). 2023 Jan 9;9:1065620. doi: 10.3389/fmed.2022.1065620. PMID: 36698810; PMCID: PMC9868805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868805/ (Full text)

Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial

Abstract:

Background: With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug.

Methods: The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test.

Results: Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60-40.90) vs 83.5 (23.9) p < 0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442 (180) (95% CI 358-525) vs 662 (18) meters p < 0.001. 31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort.

Conclusions: An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO2 to have a favourable safety profile. Our data may help other researchers in designing trials.

Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 . EudraCT: 2021-000764-30. Registered 21 May 2021, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000764-30/SE.

Source: Kjellberg A, Hassler A, Boström E, El Gharbi S, Al-Ezerjawi S, Kowalski J, Rodriguez-Wallberg KA, Bruchfeld J, Ståhlberg M, Nygren-Bonnier M, Runold M, Lindholm P. Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial. BMC Infect Dis. 2023 Jan 20;23(1):33. doi: 10.1186/s12879-023-08002-8. PMID: 36670365; PMCID: PMC9854077. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9854077/ (Full text)

Two-Years Follow-Up of Symptoms and Return to Work in Complex Post-COVID-19 Patients

Abstract:

Introduction: Many COVID-19 patients present with severe long-lasting symptoms. They might benefit from a coordination team to manage such complex situations, but late efficacy still needs to be determined.
Population and Methods: Out of 105 contacts, 45 patients had two phone consultations separated by personalized support 15 and 22 months, respectively, after COVID infection. Self-reported symptoms, feelings of improvement and ability to return to work allowed us to determine the efficacy of the therapeutic strategy proposed.
Results: Unlike what was expected, many post-COVID-19 patients directly contacted the coordination team and had significant pre-existing comorbidities. Despite exercise, respiratory, olfactory rehabilitations, cognition/speech therapy and/or psychological support, the more frequent self-reported symptoms (fatigue, neurocognitive disorders, muscles and joint pain) did not resolve. However, dyspnea, anxiety and chest pain were significantly reduced. Finally, 2/3 of the patients felt some degree of improvement and returned to work either partially or fully, but 1/3 remained complaining of symptoms and out of work as late as 22 months after COVID occurrence. All patients greatly appreciated the second phone consultation.
Conclusions: In such complex situations, besides early and adapted rehabilitations and psychological help allowing better symptom management, relatively simple actions such as a phone call might be very useful to reduce patients’ feelings of abandonment.
Source: Van Wambeke E, Bezler C, Kasprowicz A-M, Charles A-L, Andres E, Geny B. Two-Years Follow-Up of Symptoms and Return to Work in Complex Post-COVID-19 Patients. Journal of Clinical Medicine. 2023; 12(3):741. https://doi.org/10.3390/jcm12030741 https://www.mdpi.com/2077-0383/12/3/741 (Full text)

Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Potential neurophysiological biomarkers for these enigmatic entities

Since early in the pandemic, fatigue has been recognized as one of the most common persistent complaints in individuals infected with SARS-CoV-2, and constitutes one main symptom of the so-called long-COVID syndrome. The term fatigue refers to a sustained feeling of tiredness, which can be present at rest; it is not directly related to physical activity, but can be exacerbated disproportionally by exertion.

Survivors of other recent coronavirus outbreaks, such as severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012 also developed chronic fatigue. These ‘post-infectious’ fatigue syndromes, including long-COVID, resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic disorder of unknown physiopathology characterized by fatigue, post-exertional malaise, chronic muscle or skeletal pain, and cognitive impairment (‘brain fog’).

Despite it being an extremely disabling symptom, the results of routine examinations are often normal in patients complaining of lingering fatigue, a phenomenon that has also led the medical-scientific community to view this condition with skepticism.

In physiology, fatigue is defined as a decrease in the maximal force-generating capacity of a muscle during exercise. It may result from peripheral processes distal to the neuromuscular junction and from central processes controlling the discharge rate of motoneurons.

Physical fatigue related to both central and peripheral nervous system dysfunction can be assessed with neurophysiological techniques including transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of nerve trunks or intramuscular nerve fibers, and electromyography (EMG) recordings.

In August 2021, the first study showing myopathic changes in quantitative EMG (qEMG) in long-COVID patients with musculoskeletal symptoms was published (). The same authors demonstrated myopathic qEMG features and histopathological changes in skeletal muscle biopsies in 16 patients with complaints of fatigue, myalgia, and/or weakness persisting for up to 14 months after mild to moderate COVID-19 (). The wide variety of histological changes in this study, including muscle fiber atrophy, mitochondrial changes, subsarcolemmal accumulation, inflammation, capillaries alteration, suggests that skeletal muscle may be a major target of SARS-CoV-2.

On the opposite side of the neuroaxis, dysfunction in the activity of the primary motor cortex and reduced corticomotor output may underlie fatigue.

The first TMS study on motor cortex physiology was conducted on 12 patients with long-term fatigue and ‘brain fog’ after severe COVID-19 (). It showed disruption of the physiological mechanism of post-contraction depression, i.e., the transient decrease in the amplitude of motor evoked potentials and prolongation of the cortical silent period after a fatiguing motor task, which depends on cortical inhibitory mechanisms and has the protective purpose of preventing muscle overload. Impairment of intracortical GABAergic activity, as indicated by disrupted long-interval intracortical inhibition, together with reduced excitability of the primary motor cortex was subsequently demonstrated in 67 patients with fatigue and cognitive difficulties after mild COVID-19 (). These patients also presented selective deficits in executive functions. Based on these findings, the authors proposed that fatigue depends on altered excitability and neurotransmission within the motor cortex at rest, and on abnormal reactivity to muscular exercise. In addition, reduced executive control may contribute to exacerbating poor physical performance and fatigue tolerance ().

These objective neurophysiological and histopathological findings showed for the first time that fatigue may due both to pathological processes in the muscle (the effector of the motor command) and/or at the site of motor command processing. The mechanisms of chronic dysfunction of neural and muscle cells may be sustained by inflammation or dysimmunity, triggered by SARS-COV-2 in predisposed individuals.

Immune-inflammatory and neuroendocrine mechanisms have also been implicated in ME/CFS. In particular, increased production of autoantibodies against CNS and autonomic nervous system targets, such as the ß2 adrenergic receptor (ß2AdR), have been documented (). As ß2AdR are important vasodilators, their functional disturbance may result in vasoconstriction and hypoxemia with chronic muscular and cerebral hypoperfusion.

The COVID-19 pandemic is likely to greatly increase the incidence of ME/CFS, so that the intense research on the pathophysiological mechanisms of fatigue in long-COVID can help to shed light on a poorly understood and underestimated syndrome.

Source: Versace V, Tankisi H. Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Potential neurophysiological biomarkers for these enigmatic entities. Clin Neurophysiol. 2023 Jan 13;147:58-59. doi: 10.1016/j.clinph.2023.01.001. Epub ahead of print. PMID: 36657309; PMCID: PMC9838078. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9838078/ (Full text)