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Research Digest | Issue 106

Welcome to the 106th edition of Emerge Australia’s Digest. In this month’s issue, we explore literature that delves deeper into the connections between metabolic and immune alterations in Long COVID and ME/CFS. We also highlight reports on the long-term effects of SARS-CoV-2 in children and a detailed analysis of the clinical phenotypes identified in a cohort of young individuals with ME/CFS following EBV-IM.

And don’t forget about our newly implemented ‘text-to-speech’ feature that reads aloud this month’s Research Digest summaries. Simply click the button associated with the summary below, and the research summaries will be read to you. 

Contributing Digesters: Jyothsna, Shan, Solène and Sarah.

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Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome

Authors: Saito S, Shahbaz S, Luo X, Osman M, Redmond D, Cohen Tervaert JW, Li L, & Elah S (University of Alberta, Canada) 
Publication: Frontiers in Immunology 
Link: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1341843/full

While many acute infections may cause persistent symptoms due to organ damage, persistent symptoms may also arise without organ damage or following mild, acute disease. This study aimed to compare individuals with Long COVID (LC) 12 months post-SARS-CoV-2 infection to those who had SARS-CoV-2 infection but did not develop LC, as well as those who had been hospitalised with severe COVID-19.  

Participants in the study included: 30 LC patients, 15 individuals who have had a SARS-CoV-2 infection but have since recovered (R), 15 acute hospitalised COVID-19 patients (A), and 15 healthy controls (HCs). The participants were predominantly female, and all who have had COVID-19 had contracted the Wuhan strain of SARS-CoV-2. Both LC and R groups were recruited 12 months post-infection. All LC patients who did not meet diagnostic criteria for ME/CFS (Fukuda criteria) were excluded from the study. Blood samples were taken from all participants, and metabolic analysis conducted on the samples.  

Metabolic analysis revealed that LC patients had a different metabolic profile to the other three groups. While the R group was different to the LC group, it also differed from the HC group.  

LC patients showed elevated pro-inflammatory cytokines and autoantibodies, such as interleukin-1 alpha (IL-1α), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), interferon gamma-induced protein 10 (IP-10), C-reactive protein (CRP), and serum amyloid A (SAA). This indicated ongoing immune dysregulation and inflammation post-infection, potentially contributing to persistent symptoms. Reduced ATP levels in LC patients could contribute to enduring fatigue and multi-organ symptoms, highlighting metabolic dysregulation complexity. 

The authors acknowledge the study limitations, emphasising the need for larger cohort studies, multiple blood sampling sessions, and research on subsequent SARS-CoV-2 variants. They note that the underrepresentation of males and imbalanced group sizes had impacted statistical data. They also acknowledge that the absence of lipid analysis inhibited comprehensive understanding, and suggest future studies include lipid analysis in larger LC cohorts and animal models.

Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study

Authors: Ozonoff A, Jayavelu ND, Liu S, Melamed E, Milliren CE, Qi J, … Rouphael N (Emory University, USA)
Publication: Nature Communications
Link: https://www.nature.com/articles/s41467-023-44090-5

The IMMuno Phenotyping Assessment in a COVID-19 Cohort (IMPACC) study aimed to explore the immune responses of people who have been hospitalised with COVID-19 across 15 sites in the US.  

1164 adults who presented to hospital with COVID-19 between May 2020 and March 2021 were enrolled as participants in this longitudinal study. None of the participants had received a COVID-19 vaccination before admission. Blood and nasal swabs were collected on days 4, 7, 14, 21, and 28 post-hospital admissions, and for those who survived hospitalisation (702), surveys of participant-reported outcomes (PROs) were conducted every three months for a year after leaving hospital. 

Upon admission, 75% of participants had chest imaging that displayed lung infiltrate, 52% had elevated C-reactive protein levels, and 50% had elevated D-dimer. Whilst they were inpatients, 83% experienced one or more complications, and 27% received ICU care. Three months after discharge, 52% still experienced at least one symptom, such as dyspnea (29%), myalgia (21%), or malaise (18%). 

Statistical analysis of the PROs found four main cluster patterns amongst the physical deficits of those experiencing post-acute sequelae of SARS-CoV-2 (PASC): those experiencing minimal effects (MIN, 60.7%), those experiencing mostly physical symptoms (PHY, 15.6%), those with mostly mental or cognitive deficits (COG, 13.9%), and those whose deficits were multidomain (MLT, 9.8%). Whilst acute COVID-19 disease severity was not found to be linked with specific PASC presentations, distinct demographics, comorbidities, and pathology results were found to be associated with these deficit clusters. 

In comparison with those in the MIN cluster, PHY participants were more likely to be female and non-white. Whilst in hospital, they were more likely to have higher levels of virus, lower IgG, and, after their hospital stay, experience comorbidities such as cardiopulmonary disease or a chronic neurologic disorder. Participants with COG deficits tended to be females older than 65. During their hospital stay, they were more likely to have lower levels of circulating B leukocytes and elevated levels of fibroblast growth factor 21 (FGF21), and later had an increased risk of chronic cardiac disease. Those in the MLT cluster were more likely to have higher viral levels, higher FGF21, lower IgG, lower levels of circulating B leukocytes, and fewer naïve B cells whilst in hospital, and subsequently more likely to have chronic neurologic disorder or chronic pulmonary disease. Interferon autoantibodies were detected in 4.3% of participants across all four deficit clusters, and the PHY, COG, and MLT clusters all displayed altered molecular metabolism. 

This study found that more than half of the patients who required hospitalisation for COVID-19 would go on to develop PASC, an illness with distinct subtypes as a consequence of specific viral clearance by the immune system. As such, the authors recommend that immune responses during the acute phase be measured, from which a tailored treatment approach can be developed for each patient.

Postacute sequelae of SARS-CoV-2 in children

Authors: Rao S, Gross RS, Mohandas S, Stein CR, Case A, Dreyer B, … Stockwell MS (Columbia University, USA
Publication: Pediatrics
Link: https://doi.org/10.1542/peds.2023-062570 

Although post-acute sequelae of SARS Cov-2 (PASC) is estimated to affect up to 5.8 million children in the US, PASC studies in children are only just emerging in the literature. 

In most studies, the reported incidence of PASC in children ranges from 10 to 20 % within the first 6 months after acute infection. The PASC trajectory is mostly unknown as only few studies have examined the full range of symptoms or have implemented follow-up periods exceeding 12 months. 

Current identified risk factors for PASC in children are pre-omicron variant infections, increasing child age, higher severity of illness and number of organ systems involved during acute infection, underlying chronic medical conditions, and increased weight status. 

The most common respiratory PASC symptoms include cough, chest tightness, and shortness of breath, and to a lesser extent, chest pain, dyspnea (exertional or at rest). In a study, most children had normal spirometry; however, 15 % demonstrated obstructive deficits, and 31% responded positively to bronchodilators. Children with PASC commonly report persistent nasal congestion and rhinorrhoea. 

PASC-related cardiac complications include myocarditis, multisystem inflammatory syndrome in children (MIS-C), arrhythmias and electrocardiographic or conduction abnormalities. After 6 months, unexplained exercise intolerance, fatigue, resting sinus tachycardia, orthostatic hypotension, and postural orthostatic tachycardia syndromes can persist with or without MIS-C. PASC-related tachycardias can occur with or without ME/CFS symptoms. 

Most common mental-health manifestations observed in children with PASC are anxiety, attention-deficit/hyperactivity disorder, and disorders related to trauma or stressors. While neurologic manifestations include cognitive impairment (with a prevalence between 2 and 44 % depending on study), neuropathy, tics, chronic migraines, and sensory issues. 

Gastrointestinal symptoms include diarrhoea, abdominal pain, vomiting, and anorexia, which typically decrease over time.  

Children with PASC may present skin rashes including maculopapular eruptions, erythema, vesicles, pustules, desquamation, and urticarial lesions. 

MIS-C is the most serious PASC-related complication that usually develops 2 to 6 weeks after infection. MIS-C frequently affects children between 6 and 12 years old, although recognition of cases in neonates is increasing. The most serious complications in MIS-C are hypotension, shock, cardiac dysfunction (mainly of the left ventricle), arrhythmia, and myocarditis/pericarditis (with a prevalence of 34.3 %). One-year follow-up of children after MIS-C showed resolution of cardiac abnormalities and absence of long-term sequelae. 

A possible link between SARS Cov-2 infection and subsequent diagnosis of diabetes (type 1 or 2) exists in children similar to that observed in adults. Increased stress, increased rates of obesity in children, stress hyperglycaemia secondary to the hyper-inflammatory state during infection are potential mechanisms to explain this association. 

Further studies are needed to characterise distinct subgroups based on pattern of symptoms, understand PASC development, and identify effective therapies in children. 

One-year follow up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus

Authors: Pricoco R, Meidel P, Hofberger T, Zietemann H, Mueller Y, Wiehler K, … Behrends U (Technical University of Munich, Germany)
Publication: Frontiers in Pediatrics
Link: https://www.frontiersin.org/articles/10.3389/fped.2023.1266738/full 

Previous research has linked the development of ME/CFS in children, adolescents and young adults to infection with Epstein-Barr virus, followed by infectious mononucleosis (EBV-IM). This study sought to identify clinical phenotypes from a cohort of young persons with ME/CFS following EBV-IM. 

All participants had been diagnosed with ME/CFS following a confirmed EBV infection. Twelve adolescents aged 14-18 (meeting Canadian Consensus Criteria (CCC) or the 2017 paediatric criteria) and 13 young adults aged 19-22 (meeting CCC) were included. All participants experienced post-exertional malaise as part of their ME/CFS. Laboratory testing, symptom tracking (frequency and severity), physical capacity, and health-related quality of life (HRQOL) were tested at 6 and 12 months after initial data gathering.  

The authors found that young adults reported greater symptom severity, with worsening results in fatigue, physical and mental functioning, and HRQOL over the study’s duration compared to adolescents. After 12 months, 54% of adolescents experienced partial recovery and no longer fulfilled ME/CFS diagnostic criteria however, 100% of young adults still met CCC. Adolescents also showed improvements in physical functioning, symptom frequency and severity, and HRQOL over the 12 months. EBV serology and DNA load were not seen to correlate with clinical features of ME/CFS. Inflammation was not demonstrated in laboratory testing. Across all participants, the median time from symptom onset to diagnosis with ME/CFS was 13.8 months.  

The authors conclude that ME/CFS following EBV-IM infection can be severely debilitating. It is also characterised by diagnostic delays of ME/CFS, and showed limited responsiveness to standard medical intervention, especially among adults. Adolescents demonstrated better prognoses, however, their condition was more likely to fluctuate and impact their HRQOL. The authors conclude that further research into diagnostic biomarkers and the development of therapeutic interventions is essential to improve the medical care received by these patients and increase the likelihood of partial or full recovery. 

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