Category: Overlapping Illnesses

Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes

Abstract:

Background: Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested.

Methods: We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning.

Findings: We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems.

Interpretation: Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC.

Source: Reese JT, Blau H, Casiraghi E, Bergquist T, Loomba JJ, Callahan TJ, Laraway B, Antonescu C, Coleman B, Gargano M, Wilkins KJ, Cappelletti L, Fontana T, Ammar N, Antony B, Murali TM, Caufield JH, Karlebach G, McMurry JA, Williams A, Moffitt R, Banerjee J, Solomonides AE, Davis H, Kostka K, Valentini G, Sahner D, Chute CG, Madlock-Brown C, Haendel MA, Robinson PN; N3C Consortium; RECOVER Consortium. Generalisable long COVID subtypes: Findings from the NIH N3C and RECOVER programmes. EBioMedicine. 2022 Dec 21;87:104413. doi: 10.1016/j.ebiom.2022.104413. Epub ahead of print. PMID: 36563487; PMCID: PMC9769411. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9769411/ (Full text)

Characteristics and predictors of Long COVID among diagnosed cases of COVID-19

Abstract:

Background: Long COVID or long-term symptoms after COVID-19 has the ability to affect health and quality of life. Knowledge about the burden and predictors could aid in their prevention and management. Most of the studies are from high-income countries and focus on severe acute COVID-19 cases. We did this study to estimate the incidence and identify the characteristics and predictors of Long COVID among our patients.

Methodology: We recruited adult (≥18 years) patients who were diagnosed as Reverse Transcription Polymerase Chain Reaction (RTPCR) confirmed SARS-COV-2 infection and were either hospitalized or tested on outpatient basis. Eligible participants were followed up telephonically after four weeks and six months of diagnosis of SARS-COV-2 infection to collect data on sociodemographic, clinical history, vaccination history, Cycle threshold (Ct) values during diagnosis and other variables. Characteristics of Long COVID were elicited, and multivariable logistic regression was done to find the predictors of Long COVID.

Results: We have analyzed 487 and 371 individual data with a median follow-up of 44 days (Inter quartile range (IQR): 39,47) and 223 days (IQR:195,251), respectively. Overall, Long COVID was reported by 29.2% (95% Confidence interval (CI): 25.3%,33.4%) and 9.4% (95% CI: 6.7%,12.9%) of participants at four weeks and six months of follow-up, respectively. Incidence of Long COVID among patients with mild/moderate disease (n = 415) was 23.4% (95% CI: 19.5%,27.7%) as compared to 62.5% (95% CI: 50.7%,73%) in severe/critical cases(n = 72) at four weeks of follow-up. At six months, the incidence among mild/moderate (n = 319) was 7.2% (95% CI:4.6%,10.6%) as compared to 23.1% (95% CI:12.5%,36.8%) in severe/critical (n = 52). The most common Long COVID symptom was fatigue. Statistically significant predictors of Long COVID at four weeks of follow-up were-Pre-existing medical conditions (Adjusted Odds ratio (aOR) = 2.00, 95% CI: 1.16,3.44), having a higher number of symptoms during acute phase of COVID-19 disease (aOR = 11.24, 95% CI: 4.00,31.51), two doses of COVID-19 vaccination (aOR = 2.32, 95% CI: 1.17,4.58), the severity of illness (aOR = 5.71, 95% CI: 3.00,10.89) and being admitted to hospital (Odds ratio (OR) = 3.89, 95% CI: 2.49,6.08).

Conclusion: A considerable proportion of COVID-19 cases reported Long COVID symptoms. More research is needed in Long COVID to objectively assess the symptoms and find the biological and radiological markers.

Source: Arjun MC, Singh AK, Pal D, Das K, G A, Venkateshan M, Mishra B, Patro BK, Mohapatra PR, Subba SH. Characteristics and predictors of Long COVID among diagnosed cases of COVID-19. PLoS One. 2022 Dec 20;17(12):e0278825. doi: 10.1371/journal.pone.0278825. PMID: 36538532; PMCID: PMC9767341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767341/ (Full text)

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)

Computable Clinical Phenotyping of Postacute Sequelae of COVID-19 in Pediatrics Using Real-World Data

INTRODUCTION:

Since the SARS-CoV-2 pandemic began in late 2019, over 13 million children in the United States have been infected with the virus [1]. Although many of these acute infections have not resulted in severe morbidity or mortality, a subset of children and adolescents have experienced recurrent or persistent symptoms beyond the typical recovery period [2]. The constellation of findings that occur postinfection is known as postacute sequelae of SARS-CoV-2 (PASC), or colloquially as “long-Covid.” The U.S. Centers for Disease Control and Prevention (CDC) defines PASC as a wide range of health problems that linger for more than 4 weeks following an acute COVID-19 infection [3]. Although this is an area of active research, relatively little is currently known about its clinical epidemiology in the pediatric population.

Considering the large number of children who have been affected by COVID-19, it is critical that we monitor the rates, trends, and outcomes of PASC in this population. An important first step toward these efforts is the development of a tool that can quickly and easily identify cases in large clinical populations. With the widespread adoption of electronic health records (EHR), it is now possible to develop computable phenotypes using data that are collected for clinical care, which can be used for population-level analysis to inform the public health response [4, 5]. In this report, we describe a novel phenotyping algorithm to define the burden, clinical spectrum, and outcomes of pediatric PASC using real-world data.

Source: Tomini A Fashina, Christine M Miller, Elijah Paintsil, Linda M Niccolai, Cynthia Brandt, Carlos R Oliveira, Computable Clinical Phenotyping of Postacute Sequelae of COVID-19 in Pediatrics Using Real-World Data, Journal of the Pediatric Infectious Diseases Society, 2022;, piac132, https://doi.org/10.1093/jpids/piac132 https://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piac132/6957369 (Full text)

Pediatric Post-Acute Sequelae of SARS-CoV-2 infection

Abstract:

Aim: Youth who have not recovered from COVID-19 have been referred to as having Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The goal of this study was to better understand which symptoms persisted since onset of infection and how these symptoms compare to symptoms experienced by those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Method: A sample of 19 parents who had a child with PASC were recruited using social media to fill out a questionnaire detailing symptoms at two time points. The first time point included their child’s current symptoms and the second captured symptoms at initial infection. These participants were compared to a sample of 19 youth with ME/CFS.

Results: Findings indicated significant decreases among several immune, neuroendocrine, pain, post-exertional malaise (PEM), and COVID-19 Centers for Disease Control and Prevention (CDC) domain symptoms from time of acute infection to time of current reporting. Fatigue remained at a high level as did several symptoms within the sleep and PEM domains. Participants with ME/CFS had overall worse symptomatology when compared to participants with PASC, especially in the neurocognitive domain.

Conclusion: Most symptoms of those with PASC decline over time, but several remain at high levels, including fatigue. These findings are helpful in better understanding common symptom presentation profiles for youth with PASC and can be used to more adequately tailor diagnostic criteria and treatment strategies for youth.

Source: Leonard A. Jason, Madeline Johnson & Chelsea Torres (2023) Pediatric Post-Acute Sequelae of SARS-CoV-2 infection, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2022.2162764 https://www.tandfonline.com/doi/abs/10.1080/21641846.2022.2162764

Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?

Abstract:

Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI). These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS).
OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection. The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID.
We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels. We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability ), also affects the vasa vasorum to impair the function of the capacitance vessels.
In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.
Source: Wirth KJ, Löhn M. Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect? Medicina. 2022; 58(12):1807. https://doi.org/10.3390/medicina58121807 https://www.mdpi.com/1648-9144/58/12/1807 (Full text)

Mid- and Long-Term Atrio-Ventricular Functional Changes in Children after Recovery from COVID-19

Abstract:

Background: Although most children may experience mild to moderate symptoms and do not require hospitalization, there are little data on cardiac involvement in COVID-19. However, cardiac involvement is accurately demonstrated in children with MISC. The objective of this study was to evaluate cardiac mechanics in previously healthy children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a long-term follow-up by means of two-dimensional speckle-tracking echocardiography (STE).
Methods: We analyzed a cohort of 157 paediatric patients, mean age 7.7 ± 4.5 years (age range 0.3–18 years), who had a laboratory-confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or mildly symptomatic for COVID-19. Patients underwent a standard transthoracic echocardiogram and STE at an average time of 148 ± 68 days after diagnosis and were divided in three follow-up groups (<180 days, 180–240 days, >240 days). Patients were compared with 107 (41 females—38%) age- and BSA-comparable healthy controls (CTRL).
Results: Left ventricular (LV) global longitudinal strain (post-COVID-19: −20.5 ± 2.9%; CTRL: −21.8 ± 1.7%; p < 0.001) was significantly reduced in cases compared with CTRLs. No significant differences were seen among the three follow-up groups (p = NS). Moreover, regional longitudinal strain was significantly reduced in LV apical-wall segments of children with disease onset during the second wave of the COVID-19 pandemic compared to the first wave (second wave: −20.2 ± 2.6%; first wave: −21.2 ± 3.4%; p = 0.048). Finally, peak left atrial systolic strain was within the normal range in the post-COVID-19 group with no significant differences compared to CTRLs.
Conclusions: Our study demonstrated for the first time the persistence of LV myocardial deformation abnormalities in previously healthy children with an asymptomatic or mildly symptomatic (WHO stages 0 or 1) COVID-19 course after an average follow-up of 148 ± 68 days. A more significant involvement was found in children affected during the second wave. These findings imply that subclinical LV dysfunction may also be a typical characteristic of COVID-19 infection in children and are concerning given the predictive value of LV longitudinal strain in the general population.
Source: Sabatino J, Di Chiara C, Di Candia A, Sirico D, Donà D, Fumanelli J, Basso A, Pogacnik P, Cuppini E, Romano LR, Castaldi B, Reffo E, Cerutti A, Biffanti R, Cozzani S, Giaquinto C, Di Salvo G. Mid- and Long-Term Atrio-Ventricular Functional Changes in Children after Recovery from COVID-19. Journal of Clinical Medicine. 2023; 12(1):186. https://doi.org/10.3390/jcm12010186 https://www.mdpi.com/2077-0383/12/1/186 (Full text)

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Abstract:

Background Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid.

Methods This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14.

Result The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385).

Conclusions There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial.

Trial registration NCT04510194.

Source: Bramante CT, Buse JB, Liebovitz D, Nicklas J, Puskarich MA, Cohen K, Belani H, Anderson B, Huling JD, Tignanelli C, Thompson J, Pullen M, Siegel L, Proper J, Odde DJ, Klatt N, Sherwood N, Lindberg S, Wirtz EL, Karger A, Beckman K, Erickson S, Fenno S, Hartman K, Rose M, Patel B, Griffiths G, Bhat N, Murray TA, Boulware DR. Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up. medRxiv [Preprint]. 2022 Dec 23:2022.12.21.22283753. doi: 10.1101/2022.12.21.22283753. PMID: 36597543; PMCID: PMC9810227.  https://www.medrxiv.org/content/10.1101/2022.12.21.22283753v1.full (Full text)

COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients

Abstract:
Background: Better understanding of long-term health effects after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become one of the healthcare priorities in the current pandemic. We analyzed large and diverse patient cohort to study health effects related to SARS-CoV-2 infection occurring more than one month post-infection.
Methods: We analyzed 17,487 patients who received diagnoses for SARS-CoV-2 infection in a total of 122 healthcare facilities in the United States prior to April, 14,2022. Patients were propensity score matched with patients diagnosed with the common cold, influenza, or viral pneumonia from March 1, 2020, to April 1, 2021. For each outcome, SARS-CoV-2 was compared to a generic Viral Respiratory Infection (VRI) by predicting diagnoses in the period between 30 and 365 days post-infection. Both COVID-19 and VRI patients were propensity score matched with patients with no record of COVID-19 or VRI and the same methodology was applied. Diagnoses where COVID-19 infection was a significant positive predictor in both COVID-19 vs VRI and COVID-19 vs Control comparisons were considered COVID-19-specific effects.
Results: Compared to common VRIs, SARS-CoV-2 was associated with diagnoses palpitations, hair loss, fatigue, chest pain, dyspnea, joint pain, and obesity in the post-infectious period.
Conclusions: We identify that some diagnoses commonly described as “long COVID” do not appear significantly more frequent post-COVID-19 infection compared to other common VRIs. We also identify sequelae which are specifically associated with a prior SARS-CoV-2 infection.
Source: William I Baskett, MS, Adnan I Qureshi, MD, Daniel Shyu, MD, Jane M Armer, PhD, RN, Chi-Ren Shyu, PhD, COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients, Open Forum Infectious Diseases, 2022;, ofac683, https://doi.org/10.1093/ofid/ofac683 (Full text)