Post-acute coronavirus disease 2019 syndrome (PACS), following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19), is typically characterized by long-term debilitating symptoms affecting multiple organs and systems. Unfortunately, there is currently a lack of effective treatment strategies. Altered gut microbiome has been proposed as one of the plausible mechanisms involved in the pathogenesis of PACS; extensive studies have emerged to bridge the gap between the persistent symptoms and the dysbiosis of gut microbiome. Recent clinical trials have indicated that gut microbiome modulation using probiotics, prebiotics, and fecal microbiota transplantation (FMT) led to improvements in multiple symptoms related to PACS, including fatigue, memory loss, difficulty in concentration, gastrointestinal upset, and disturbances in sleep and mood. In this review, we highlight the latest evidence on the key microbial alterations observed in PACS, as well as the use of microbiome-based therapeutics in managing PACS symptoms. These novel findings altogether shed light on the treatment of PACS and other chronic conditions.

Individuals with long COVID lack evidence-based treatments and have difficulty participating in traditional site-based trials. Our digital, decentralized trial investigates the efficacy and safety of nirmatrelvir/ritonavir, targeting viral persistence as a potential cause of long COVID.

The PAX LC trial (NCT05668091) is a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial in 100 community-dwelling, highly symptomatic adult participants with long COVID residing in the 48 contiguous US states to determine the efficacy, safety, and tolerability of 15 days of nirmatrelvir/ritonavir compared with placebo/ritonavir. Participants are recruited via patient groups, cultural ambassadors, and social media platforms. Medical records are reviewed through a platform facilitating participant-mediated data acquisition from electronic health records nationwide. During the drug treatment, participants complete daily digital diaries using a web-based application. Blood draws for eligibility and safety assessments are conducted at or near participants' homes. The study drug is shipped directly to participants' homes. The primary endpoint is the PROMIS-29 Physical Health Summary Score difference between baseline and Day 28, evaluated by a mixed model repeated measure analysis. Secondary endpoints include PROMIS-29 (Mental Health Summary Score and all items), Modified GSQ-30 with supplemental symptoms questionnaire, COVID Core Outcome Measures for Recovery, EQ-5D-5L (Utility Score and all items), PGIS 1 and 2, PGIC 1 and 2, and healthcare utilization. The trial incorporates immunophenotyping to identify long COVID biomarkers and treatment responders.

The PAX LC trial uses a novel decentralized design and a participant-centric approach to test a 15-day regimen of nirmatrelvir/ritonavir for long COVID.

SARS-CoV-2 causes an acute respiratory tract infection that resolves in most people in less than a month. Yet some people with severely weakened immune systems fail to clear the virus, leading to persistent infections with high viral titres in the respiratory tract. In a subset of cases, persistent SARS-CoV-2 replication results in an accelerated accumulation of adaptive mutations that confer escape from neutralizing antibodies and enhance cellular infection. This may lead to the evolution of extensively mutated SARS-CoV-2 variants and introduce an element of chance into the timing of variant evolution, as variant formation may depend on evolution in a single person. Whether long COVID is also caused by persistence of replicating SARS-CoV-2 is controversial. One line of evidence is detection of SARS-CoV-2 RNA and proteins in different body compartments long after SARS-CoV-2 infection has cleared from the upper respiratory tract. However, thus far, no replication competent virus has been cultured from individuals with long COVID who are immunocompetent. In this Review, we consider mechanisms of viral persistence, intra-host evolution in persistent infections, the connection of persistent infections with SARS-CoV-2 variants and the possible role of SARS-CoV-2 persistence in long COVID. Understanding persistent infections may therefore resolve much of what is still unclear in COVID-19 pathophysiology, with possible implications for other emerging viruses.

Currently, there is no effective way to identify older patients with community-acquired pneumonia (CAP) at high risk of long-term death. We aimed to develop and validate a pneumonia scoring system to predict 180-day mortality, and compare its performance with the commonly used CURB-65 score.

The prospective cohort study enrolled patients aged 65 years and older with CAP from 10 medical centers in China between April 2021 and December 2023. The primary outcome was 180-day mortality. A Cox proportional hazards model was used to develop a new pneumonia scoring system, and the area under the time-dependent curve (AUC) was used to assess its discriminatory power. Internal validation was performed using both bootstrap resampling and 10-fold cross-validation. The model was visualized by a nomogram and a questionnaire. The optimal cutoff value of the nomogram was determined based on the maximum Youden index for the 180-day mortality prediction, dividing patients into high- and low-risk groups. The performance of model in predicting both short- and long-term mortality was compared with CURB-65 using AUC, sensitivity, specificity, negative predictive value and positive predictive value.

A total of 619 patients, with a median age of 78 years (IQR: 70.5-85.0), were included in the analysis. The 180-day mortality was 6.9%. The model was developed using six variables, including age, the ratio of pulse oximetry saturation (SpO2) to the fraction of inspired oxygen (FiO2), loneliness, Barthel index, Clinical Frailty Scale and malnutrition. The AUC of the model for predicting 180-day, 90-day and 30-day mortality were 0.829, 0.832 and 0.904, respectively. The cut-off value for the model was 142, while it was 2 for CURB-65. Using the cut-off values, the AUC of the model for predicting 180-day mortality was 0.768 (95% confidence interval [CI]: 0.695-0.842), significantly higher than that of CURB-65(AUC: 0.573, 95%CI: 0.488-0.659). A similar trend was observed for predictions of 90-day, 30-day and in-hospital mortality.

This study developed and validated a prediction model for long-term mortality in older patients with CAP, showing better discriminatory power and accuracy over CURB-65.

Persistent symptoms after an acute infection is an emerging public health concern, but the pathobiology of such conditions is not well understood. One possible scenario involves the persistence of lingering antigen. We have previously reported that patients with postinfectious Lyme arthritis often harbor the peptidoglycan (PG) cell wall of Borrelia burgdorferi, the Lyme disease agent, in the synovial fluid of their inflamed joints after treatment. However, it is not yet known how B. burgdorferi PG persists, in what form, or if it may play a role in other postinfectious complications after Lyme disease. Using a murine model, we developed a real-time in vivo system to track B. burgdorferi PG as a function of cell wall chemistry and validated our findings using both molecular and cellular approaches. Unlike typical bacterial PG, the unique chemical properties of polymeric B. burgdorferi PG drive murine liver accumulation, where the cell wall material persists for weeks. Kupffer cells and hepatocytes phagocytose and retain B. burgdorferi PG and, although liver occupancy coincides with minimal pathology, both organ-specific and secreted protein profiles produced under these conditions bear some similarities to reported proteins enriched in patients with chronic illness after acute infection. Moreover, transcriptomic profiling indicated that B. burgdorferi PG affects energy metabolism in peripheral blood mononuclear cells. Our findings provide mechanistic insights into how a pathogenic molecule can persist after agent clearance, potentially contributing to illness after infection.

Autoimmune encephalitides (AEs) are neurological disorders caused by autoantibodies against neuronal and glial surface proteins. Nearly 20 years after their discovery, AE have evolved from being frequently misdiagnosed and untreated to a growing group of increasingly well-characterized conditions where patients benefit from targeted therapeutic strategies. This narrative review provides an immunological perspective on AE, focusing on NMDAR, CASPR2 and LGI1 encephalitis as the three most common forms of AE associated with anti-neuronal surface autoantibodies. We examine the autoreactive B cell subsets, the tolerance checkpoints that may fail, and the known triggers and predispositions contributing to disease. In addition, we discuss the roles of other immune cells, including T cells and microglia, in the pathogenesis of AE. By analyzing therapeutic strategies and treatment responses we draw insights into AE pathophysiology. Written at a time of transformative therapeutic advancements through cell therapies this work underscores the synergy between detailed immunological research and the development of innovative therapies.

Persistent and troublesome physical symptoms are common and can, regardless of their cause, greatly impair patients' quality of life. Reflecting complex brain-body interactions, they are observed across all healthcare specialties, commonly overlap across them, and receive inconsistent diagnoses. In response, the international research network EURONET-SOMA has proposed a diagnostic classification for persistent and troublesome symptoms entitled "functional somatic disorder (FSD)". Focusing on symptom patterns across organ systems, the FSD approach aims to enhance diagnosis, treatment, and healthcare access for patients. However, further research is needed to validate its effectiveness and clinical utility. This study assessed the frequency and applicability of the FSD proposal within a population-based sample.

FSD diagnostic criteria were cross-sectionally operationalised within the multi-disciplinary prospective cohort study Lifelines, conducted in the Dutch population. Kruskal-Wallis and chi-square tests with effect size estimates were used to investigate differences in the diagnostic subgroups regarding chronic diseases, functional comorbidities and psycho-behavioural features. Binary logistic regression with elastic net penalisation was used to investigate sociodemographic, psycho-behavioural and clinical factors associated with FSD.

Of the study population (N = 88,925), 58% met the diagnostic criteria for FSD. Of those meeting FSD, 31% reported a single distressing symptom, 18% had several symptoms attributable to one organ system and 52% reported multiple symptoms from various organ systems. Moderate differences between these subgroups were found for health status, neuroticism, long-term life difficulties and healthcare utilisation. Elastic net regression showed comorbid chronic musculoskeletal (OR 1.8), gastrointestinal disease (OR 1.4), neurological disease (OR 1.2), and female sex (OR 1.2) predicted FSD. Concurrent anxiety (OR 1.6), healthcare visits (OR 1.3) and long-term difficulties (OR 1.2) were associated with the presence of FSD.

This study supports refining the FSD criteria to avoid over-inclusiveness. Current symptom severity and frequency thresholds need adjustment to better identify those needing treatment. The distinction between single and multiple symptom categories is important, and optional specifiers like comorbid chronic diagnoses and psychological factors seem valuable for predicting FSD. Despite warranting further research, the FSD classification is promising for diagnosing persistent and troublesome symptoms across medical specialties.

Various factors associated with long COVID have been evidenced, but the heterogeneity of definitions and epidemiological investigations has often hidden risk pathways relevant for understanding and preventing this condition.

This nationwide random sampling survey conducted in France after the Omicron waves in autumn 2022 assessed eight sets of factors potentially associated with long COVID in a structured epidemiological investigation based on a conceptual model accounting for the relationships between these sets of factors. A representative sample of 1813 adults of whom 55% were infected with SARS-CoV-2 was assessed for infection dates and context, post-COVID symptoms and these factors. Four definitions of long COVID, including the World Health Organisation's, were used.

Female sex, household size (≥2), low financial security, negative impact of COVID-19 pandemic on occupation and work conditions, number of comorbidities (≥2), presence of respiratory disease, mental and sensory disorders, number of SARS-CoV-2 infections (≥2) and initial symptoms (≥6), perceived high severity of COVID-19 are positively and consistently associated with long COVID. Age ≥ 75 years, retirement, SARS-CoV-2 vaccination (≥2 doses) and good perceived information regarding long Covid are negatively associated with the condition.

The broad spectrum of factors confirmed here strongly suggests that long COVID should be regarded not only as a direct complication of SARS-CoV-2 infection but also as driven by a broader network of contextual, medical, psychological and social factors. These factors should be better considered in strategies aimed at limiting the long COVID burden in the general population.

Shared symptoms and biological abnormalities between post-acute sequelae of SARS-CoV-2 infection (PASC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could suggest common pathophysiological bases and would support coordinated treatment efforts. Empirical studies comparing these syndromes are needed to better understand their commonalities and differences.

We analyzed electronic health record data from 6.5 million adult patients from the National COVID Cohort Collaborative. PASC and ME/CFS diagnostic groups were defined based on recorded diagnoses, and other recorded conditions within the two groups were used to train separate machine learning-driven computable phenotypes (CPs). The most predictive conditions for each CP were examined and compared, and the overlap of patients labeled by each CP was examined. Condition records from the diagnostic groups were also used to statistically derive condition clusters. Rates of subphenotypes based on these clusters were compared between PASC and ME/CFS groups.

Approximately half of patients labeled by one CP are also labeled by the other. Dyspnea, fatigue, and cognitive impairment are the most-predictive conditions shared by both CPs, whereas other most-predictive conditions are specific to one CP. Recorded conditions separate into cardiopulmonary, neurological, and comorbidity clusters, with the cardiopulmonary cluster showing partial specificity for the PASC groups.

Data-driven approaches indicate substantial overlap in the condition records associated with PASC and ME/CFS diagnoses. Nevertheless, cardiopulmonary conditions are somewhat more commonly associated with PASC diagnosis, whereas other conditions, such as pain and sleep disturbances, are more associated with ME/CFS diagnosis. These findings suggest that symptom management approaches to these illnesses could overlap.

Background/Objectives: Long COVID specialized outpatient clinics (sOCs), which are part of the recommended long COVID care, usually face high demand. Few studies focused on the experience of care in such facilities in Germany. This study investigated how patients experience care in a sOC at a German university hospital. Methods: Semi-structured interviews were conducted with patients attending this clinic between October 2022 and January 2023. Data analysis was based on thematic analysis. Results: The themes from interviews with 14 patients (F = 11, M = 3) could be broadly categorized into statements on the pathway to the sOC, and statements on care provided in the sOC. Findings show that patients' high expectations at the sOC appointment were shaped by previous experiences with care, which were mainly perceived as inadequate. Care in the sOC was predominantly perceived as competent, empathetic and relevant for further care and coping with the disease. A deterioration in health directly related to the consultation (classifiable as post-exertional malaise) was frequently described, as was a high need for ongoing consultation. Conclusions: Overall, the findings point to a need for adaptations in the sOC, such as identifying optimized models of care and tailoring them to the patients' limited resources. This includes measures to improve care outside the sOC.

Long COVID (also termed postacute sequelae of SARS-CoV-2, or PASC) affects up to 10% of people recovering from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnosis is hampered by diffuse symptomatology, lack of biomarkers, incomplete understanding of pathogenesis, and lack of validated treatments. In terms of pathogenesis, hypothesized causes include virus persistence, the legacy of endotheliitis and thrombosis, low-grade tissue-based inflammation and/or scarring, perturbation of the host virome/microbiome, or triggering of autoimmunity. Several studies show preexisting and/or de novo production of autoantibodies after infection with SARS-CoV-2, but the persistence of these antibodies and their role in causing long COVID is debated. Here, we review the mechanisms through which autoimmune responses can arise during and after viral infection, focusing on the evidence for B-cell dysregulation and autoantibody production in acute and long COVID.

Serious respiratory infections can occur in both in-hospital and out-of-hospital settings. These infections are known as community-acquired pneumonias (CAPs). Streptococcus pneumoniae and other microorganisms commonly cause atypical pneumonia. This study examined the clinical features, medication therapy, and prognosis of 85 cases of community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae (MPP) and Chlamydia psittaci(C. psittaci)neumoniae (CPP).

A retrospective analysis was conducted at Shaoxing People's Hospital from July 2021 to August 2024, using targeted next-generation sequencing (tNGS) of bronchoalveolar lavage fluid (BALF). Patients were classified into the MPP group (54 patients) and the CPP group (31 patients). Compared with the control group, the CPP group had a significantly lower proportion of patients with a contact history of poultry and birds, a shorter length of hospital stay, and a lower percentage of severe pneumonia cases.

The MPP group demonstrated higher incidences of cough and sputum production; conversely, the occurrences of fever, fatigue, diminished appetite, and generalised myalgia were comparatively lower. The MPP group exhibited markedly diminished levels of neutrophils, C-reactive protein, procalcitonin, erythrocyte sedimentation rate, heparin-binding protein, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, direct bilirubin, pH, lactic acid, and D-dimer compared with the CPP group. In contrast, the MPP group had a markedly higher lymphocyte count, platelet count, albumin levels, as well as higher concentrations of blood sodium and blood chloride. The drug treatment regimens differed between the two groups, resulting in one unfavourable outcome within the MPP group.

In summary, fatigue, fever, and reduced appetite are more prominent symptoms in patients with CPP, whereas cough and sputum production are the primary manifestations of MPP. Pleural effusion is more prevalent in patients with CPP, Additionally, these patients also have increased inflammatory responses and decreased immune function.

An exhausted antiviral immune response is observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-SARS-CoV-2 syndrome, also termed long COVID. In this study, potential mechanisms behind this exhaustion were investigated. First, the viral load of Epstein-Barr virus (EBV), human adenovirus (HAdV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was determined in sputum samples (n = 29) derived from ME/CFS patients (n = 13), healthy controls (n = 10), elderly healthy controls (n = 4), and immunosuppressed controls (n = 2). Secondly, autoantibodies (autoAbs) to type I interferon (IFN-I) in sputum were analyzed to possibly explain impaired viral immunity. We found that ME/CFS patients released EBV at a significantly higher level compared to controls (p = 0.0256). HHV6 was present in ~50% of all participants at the same level. HAdV was detected in two cases with immunosuppression and severe ME/CFS, respectively. HCMV and SARS-CoV-2 were found only in immunosuppressed controls. Notably, anti-IFN-I autoAbs in ME/CFS and controls did not differ, except in a severe ME/CFS case showing an increased level. We conclude that ME/CFS patients, compared to controls, have a significantly higher load of EBV. IFN-I autoAbs cannot explain IFN-I dysfunction, with the possible exception of severe cases, also reported in severe SARS-CoV-2. We forward that additional mechanisms, such as the viral evasion of IFN-I effect via the degradation of IFN-receptors, may be present in ME/CFS, which demands further studies.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post COVID-19 Condition (PCC) are debilitating, chronic multi-systemic illnesses that require multidisciplinary care. However, people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) are often precluded from accessing necessary disability and social support services. These unmet care needs exacerbate the existing illness burdens experienced by pwME/CFS and pwPCC. To deliver appropriate care and optimise health outcomes for pwME/CFS and pwPCC, the development of evidence-based healthcare policies that recognise the disabling impacts of these illnesses must be prioritised. This systematic review summarises the health-related quality of life (HRQoL) of pwME/CFS and pwPCC when compared with healthy controls (HCs) to elucidate the impacts of these illnesses and guide healthcare policy reform.

CINAHL, Embase, MEDLINE, PubMed, PsycINFO and the Web of Science Core Collection were systematically searched from 1st January 2003 to 23rd July 2024. Eligible publications included observational studies capturing quantitative HRQoL data among pwME/CFS or pwPCC when compared with HCs. The use of validated patient-reported outcome measures (PROMs) was mandatory. Eligible studies were also required to employ the most stringent diagnostic criteria currently available, including the Canadian Consensus Criteria or International Consensus Criteria for ME/CFS and the World Health Organization case definition for PCC (PROSPERO ID: CRD42024501309).

This review captured 16 studies, including eight studies among pwME/CFS, seven studies among pwPCC and one study among both illness cohorts. Most participants were female and middle-aged. All pwPCC had experienced prolonged COVID-19 symptoms for at least three months. When compared with HCs, all HRQoL domains were significantly impaired among pwME/CFS and pwPCC. Both illnesses had a salient impact on physical health, including pain and ability to perform daily and work activities. While direct comparisons between pwME/CFS and pwPCC were limited by inconsistencies in the PROMs employed, comparable impact trends across HRQoL domain scores were observed.

ME/CFS and PCC have similar, profound impacts on HRQoL that warrant access to multidisciplinary disability and social support services. Future research must harmonise HRQoL data collection and prioritise longitudinal investigations among pwME/CFS and pwPCC to characterise PCC subgroups (including those fulfilling ME/CFS criteria) and predictors of prognosis.

The COVID-19 (C-19) pandemic has highlighted the significance of understanding the long-term effects of this disease on the quality of life of those infected. Long COVID-19 (L-C19) presents as persistent symptoms that continue beyond the main illness period, usually lasting weeks to years. One of the lesser-known but significant aspects of L-C19 is its impact on neuropsychiatric manifestations, which can have a profound effect on an individual's quality of life. Research shows that L-C19 creates neuropsychiatric issues such as mental fog, emotional problems, and brain disease symptoms, along with sleep changes, extreme fatigue, severe head pain, tremors with seizures, and pain in nerves. People with cognitive problems plus fatigue and mood disorders experience great difficulty handling everyday activities, personal hygiene, and social interactions. Neuropsychiatric symptoms make people withdraw from social activity and hurt relationships, thus causing feelings of loneliness. The unpredictable state of L-C19 generates heavy psychological pressure through emotional suffering, including depression and anxiety. Neuropsychiatric changes such as cognitive impairment, fatigue, and mood swings make it hard for people to work or study effectively, which decreases their output at school or work and lowers their job contentment. The purpose of this narrative review is to summarize the clinical data present in the literature regarding the neuropsychiatric manifestations of L-C19, to identify current methods of diagnosis and treatment that lead to correct management of the condition, and to highlight the impact of these manifestations on patients' quality of life.

Childhood maltreatment (CM), i.e. physical, psychological, or sexual abuse and neglect, affects approximately one third of the general population and is an important risk factor for all major psychiatric disorders. Exposure to CM also has a profound impact on immune function, with both factors independently implicated in the development and prognosis of different mental disorders. This study aims to 1) assess differences in immune markers among adults diagnosed with psychiatric disorders with and without a history of CM and 2) explore the role of CM as a mediating factor in immune abnormalities among psychiatric patients compared to non-psychiatric controls.

A PRISMA-compliant systematic search of PubMed, Web of Science and Embase databases was performed until October 24th, 2024 for original studies that assessed immune markers in trauma-stratified adult psychiatric patients (PROSPERO ID CRD42021273059). We modelled random-effects meta-analyses to compare levels of pro-inflammatory (PIM), anti-inflammatory (AIM) and cellular immune markers (CIM) between traumatized (CM + ) and non-traumatized (CM-) individuals, and investigated exposure to CM as a mediating factor in the immune abnormalities among adult psychiatric patients compared to non-psychiatric controls. Secondary analyses were performed for diagnostic subgroups and individual immune markers. Study quality was assessed with the Newcastle Ottawa Scale.

We included data from 53 studies on n = 12,141 patients with mood disorders (MD), schizophrenia spectrum disorders (SSD), substance use disorders (SUD), eating disorders (ED) and anxiety disorders (AD). We uncovered a consistent transdiagnostic impact of CM on blood-based pro-inflammatory molecules (OR = 1.186; 95 % CI 1.030-1.365, p = 0.018) among patients with psychiatric disorders. This effect was not observed in the non-psychiatric controls included in the same studies. We did not find evidence of specific trauma-induced abnormalities in immune composite scores for separate diagnostic subgroups, except for PIM in SUD patients (OR = 2.324, 95 % CI 1.043-5.182, p = 0.039). Interleukin 6 (IL-6) was identified as a significant mediator between CM exposure and a psychiatric diagnosis in adulthood (OR = 1.609; 95 % CI 1.100-2.353, p = 0.014), while increases in C-reactive protein (CRP) and Interleukin 10 (IL-10) did not appear to be trauma-specific.

Our findings confirm a transdiagnostic impact of exposure to CM on increased pro-inflammatory molecular and cellular immune levels in psychiatric patients. IL-6 emerged as a crucial mediator, suggesting that CM leads to specific immune alterations predisposing individuals to psychiatric conditions. This meta-analysis highlights the role of trauma-induced immune abnormalities as a potentially crucial mechanism contributing to increased vulnerability towards mental illness later in life.

Many common symptoms in post-acute sequelae following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) overlap with those of multiple sclerosis (MS). We examined symptoms and performance of the PASC score, developed in the general population, in MS based on infection history.

We surveyed North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants regarding infections and categorized participants based on infection history. Symptoms experienced before, during, and after infection were used to identify persistent new symptoms. PASC was defined as a score ⩾ 12 based on the National Institutes of Health (NIH) study RECOVER.

Of 4787 participants surveyed, 2927 were included: 294 (10%) having recent COVID-19; 853 (29.1%) recent non-COVID-19 infection; 246 (8.4%) recent COVID-19 and non-COVID-19 infection; 1534 (52.4%) uninfected, defined as never having COVID-19 nor any infection within the past 6 months. Compared to those uninfected, infection groups reported at least a two-fold increase in fever, cough, loss of smell/taste, and shortness of breath. Based on persistent new symptoms, PASC was identified in only 1.5% of participants with COVID-19.

Our study suggests lower than expected prevalence of PASC in MS and a complex association between infections and development of new persistent symptoms following infections. The similar proportions classified with PASC across infection groups shows that symptoms of PASC are common and complicate assessment of PASC in MS.

The emergence of post-COVID-19 condition (PCC) after SARS-CoV-2 infection underscores the critical need for preparedness in addressing future post-acute infection syndromes (PAIS), particularly those linked to epidemic outbreaks. The lack of standardized clinical and epidemiological data during the COVID-19 pandemic has significantly hindered timely diagnosis and effective treatment of PCC, highlighting the necessity of pre-emptively standardizing data collection in clinical studies to better define and manage future PAIS. In response, the Cohort Coordination Board, a consortium of European-funded COVID-19 research projects, has reviewed data from PCC studies conducted by its members. This paper leverages the Cohort Coordination Board's expertise to propose a standardized catalogue of variables, informed by the lessons learned during the pandemic, intended for immediate use in the design of future observational studies and clinical trials for emerging infections of epidemic potential.

The early implementation of standardized data collection, facilitated by the PAIS data catalogue, is essential for accelerating the identification and management of PAIS in future epidemics. This approach will enable more precise syndrome definitions, expedite diagnostic processes, and optimize treatment strategies, while also supporting long-term follow-up of affected individuals. The availability of harmonized data collection protocols will enhance preparedness across European and international cohort studies, and trials enabling a prompt and coordinated response, as well as more efficient resource allocation, in the event of emerging infections and associated PAIS.

Understanding the evolution of virulence, that is, the harm pathogens cause their hosts, has major and wide-spread repercussions. A central concept of virulence evolution is the so-called 'trade-off hypothesis', a seemingly straightforward relationship between virulence and transmission. However, substantial ambiguity in terminology related to this hypothesis threatens progress in the field. To address this, we apply a Hierarchy-of-Hypotheses approach to provide structured, visual representations of ideas linked to this hypothesis. We illustrate that the trade-off hypothesis is a complex set of many different hypotheses and trade-offs, and we clarify ambiguities and biases in commonly used terminology in the literature. Thereby, we hope to facilitate a more precise understanding of what the trade-off hypothesis means, enabling more targeted and precise hypothesis testing.

The prevalence and risk factors for ongoing symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [SCV2]) or influenza infection are not well characterized. We conducted a prospective cohort study of households wherein ≥1 individual was infected with SCV2 or influenza to evaluate prevalence of and factors associated with ongoing symptoms at 90 days.

Index cases and their household contacts provided baseline health and sociodemographic information and collected daily respiratory specimens for 10 days following enrollment. Participants completed a follow-up survey 90 days after enrollment to characterize ongoing symptoms.

We analyzed 1967 participants enrolled between December 2021 and May 2023. The risk of ongoing symptoms did not differ by infection status in SCV2 (SCV2-positive: 15.6%; SCV2-negative: 13.9%; odds ratio [OR]: 1.14; 95% CI: .7-1.69) or influenza (influenza-positive: 8.8%; influenza-negative: 10.0%; OR: .87; 95% CI: .45-1.72) households. However, among study participants with a documented infection, SCV2-positive participants had nearly twice the odds of ongoing symptoms as influenza-positive participants (OR: 1.92; 95% CI: 1.27-2.97).

These results suggest that SCV2 households have a significantly higher prevalence of ongoing symptoms compared with influenza households (OR: 1.78; 95% CI: 1.28-2.47). Among participants with SCV2 infection, underlying conditions (adjusted OR [aOR]: 2.65; 95% CI: 1.80-3.90) and coronavirus disease 2019 (COVID-19)-like symptoms (aOR: 2.92; 95% CI: 1.15-7.43) during acute infection increased odds of ongoing symptoms at 90 days, whereas hybrid immunity reduced the odds of ongoing symptoms (aOR: 0.44; 95% CI: .22-.90).

Classification of persons with long COVID (LC) or post-COVID-19 condition must encompass the complexity and heterogeneity of the condition. Iterative refinement of the classification index for research is needed to incorporate newly available data as the field rapidly evolves.

To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities.

Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024.

SARS-CoV-2 infection.

Presence of LC and participant-reported symptoms.

A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures.

The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

The gut microbiota (GM) plays an essential role in human health, influencing not only digestive processes but also the immune system´s functionality. The COVID-19 pandemic has highlighted the complex interaction between viral infections and the GM. Emerging evidence has demonstrated that SARS-CoV-2 can disrupt microbial homeostasis, leading to dysbiosis and compromised immune responses. The severity of COVID-19 has been associated with a reduction in the abundance of several beneficial bacteria in the gut. It has been proposed that consuming probiotics may help to re-colonize the GM. Although probiotics are important, prebiotics are essential for their metabolism, growth, and re-colonization capabilities. This chapter delves into the critical role of prebiotics in restoring GM after COVID-19 disease. The mechanisms by which prebiotics enhance the metabolism of beneficial bacteria will be described, and how prebiotics mediate the re-colonization of the gut with beneficial bacteria, thereby restoring microbial diversity and promoting the resilience of the gut-associated immune system. The benefits of consuming prebiotics from natural sources are superior to those from chemically purified commercial products.

There are estimated tens of millions of individuals throughout the world suffering from a variety of postinfectious sequela following infection with severe acute respiratory syndrome coronavirus 2 also commonly referred to as long coronavirus disease (COVID). Long COVID is providing an opportunity for the field of rheumatology to explore the relationship between similar syndromes including fibromyalgia seen in patients with underlying inflammatory and noninflammatory rheumatic diseases, as well as other postacute infectious sequela and bring our field's traditional skill sets to bear on improving our understanding of these disorders and the care of such patients.

Fatigue during the acute phase of dengue infection can persist as post-infectious fatigue (PIF), potentially impacting quality of life. We aimed to determine the prevalence and risk factors of fatigue and PIF among dengue patients.

This systematic review and meta-analysis was registered in the PROSPERO (CRD42024543058). We searched PubMed, Ovid MEDLINE, Web of Science, Embase, and CINAHL from their inception to June 22, 2024. Observational studies reporting the prevalence of fatigue or PIF among dengue patients were included. We excluded case studies, review articles, conference abstracts, protocols, duplicate publications, and studies without full text. Quality assessment was performed using Hoy's risk of bias tool. Data were analyzed using R software version 4.3.3. A random-effects model pooled prevalence with 95% confidence intervals (CIs). Risk factors were identified using odd ratios (ORs) and 95% CIs or p values. Heterogeneity, moderator analysis, sensitivity analysis, and publication bias were also assessed.

From 715 identified studies, 40 were included for review. Of these, 37 studies were included in the meta-analysis for fatigue prevalence and nine studies for PIF prevalence, respectively involving 37,790 and 5045 dengue patients. The pooled prevalence of fatigue was 59.0% (95% CI 0.47-0.70), and that of PIF was 20.0% (95% CI 0.10-0.36), with significant heterogeneity but no significant moderators. Sensitivity analysis confirmed the robustness of this meta-analysis. Female sex (pooled OR = 1.65, 95% CI 1.27-2.14), dengue hemorrhagic fever (pooled OR = 1.80, 95% CI 1.02-3.16), and preexisting comorbidities (pooled OR = 2.14, 95% CI 1.36-3.38) were significant risk factors for PIF.

This meta-analysis highlights the high prevalence of fatigue and PIF among dengue patients, with several risk factors identified. Although the study has its limitations, these results can inform future studies to more standardized study designs, improved definitions, and systematic assessment methods for fatigue, PIF, and potential moderators. These are essential to better understand the mechanisms of fatigue in dengue patients and explore potential interventions.

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Long COVID (also known as post-acute sequelae of SARS-CoV-2 infection [PASC] or post-COVID syndrome) is characterized by persistent symptoms that extend beyond the acute phase of SARS-CoV-2 infection, affecting approximately 10% to over 30% of those infected. It presents a significant clinical challenge, notably due to pronounced neurocognitive symptoms such as brain fog. The mechanisms underlying these effects are multifactorial, with mounting evidence pointing to a central role of cerebromicrovascular dysfunction. This review investigates key pathophysiological mechanisms contributing to cerebrovascular dysfunction in long COVID and their impacts on brain health. We discuss how endothelial tropism of SARS-CoV-2 and direct vascular infection trigger endothelial dysfunction, impaired neurovascular coupling, and blood-brain barrier disruption, resulting in compromised cerebral perfusion. Furthermore, the infection appears to induce mitochondrial dysfunction, enhancing oxidative stress and inflammation within cerebral endothelial cells. Autoantibody formation following infection also potentially exacerbates neurovascular injury, contributing to chronic vascular inflammation and ongoing blood-brain barrier compromise. These factors collectively contribute to the emergence of white matter hyperintensities, promote amyloid pathology, and may accelerate neurodegenerative processes, including Alzheimer's disease. This review also emphasizes the critical role of advanced imaging techniques in assessing cerebromicrovascular health and the need for targeted interventions to address these cerebrovascular complications. A deeper understanding of the cerebrovascular mechanisms of long COVID is essential to advance targeted treatments and mitigate its long-term neurocognitive consequences.

A considerable number of patients who contracted SARS-CoV-2 are affected by persistent multi-systemic symptoms, referred to as Post-COVID Condition (PCC). Post-exertional malaise (PEM) has been recognized as one of the most frequent manifestations of PCC and is a diagnostic criterion of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Yet, its underlying pathomechanisms remain poorly elucidated.

In this review, we describe current evidence indicating that key pathophysiological features of PCC and ME/CFS are involved in physical activity-induced PEM.

Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.

Neurological disorders, some of which are associated with viral infections, are growing due to the aging and expanding population. Despite strong defenses of the central nervous system, some viruses have evolved ways to breach them, which often result in dire consequences. In this review, we recount the various ways by which different viruses can enter the CNS, and we describe the consequences of such invasions. Consequences may manifest as acute disease, such as encephalitis, meningitis, or result in long-term effects, such as neuromuscular dysfunction, as occurs in poliomyelitis. We discuss evidence for viral involvement in the causation of well-known chronic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, as well as vascular dementia in the elderly. We also describe the approaches currently available to control a few of the neural viral infections. These include antivirals that are effective against human immunodeficiency virus and herpes simplex virus, as well as vaccines valuable for controlling rabies virus, poliomyelitis virus, and some flavivirus infections. There is an urgent need to better understand, at a molecular level, how viruses contribute to acute and, especially, chronic neurological diseases and to develop more precise and effective vaccines and therapies.

Post/Long COVID (syndrome) is defined as a condition with symptoms persisting for more than 12 weeks after the onset of SARS-CoV-2 infection that cannot be explained otherwise. The prevalence of self-reported otorhinolaryngological Post/Long COVID symptoms is high. The aim of this review was to analyze the current literature regarding the actual prevalence, knowledge of the etiopathology, and evidence-based treatment recommendations of otorhinolaryngology-related Post/Long COVID symptoms. A systematic literature search of articles published since 2019 in PubMed and ScienceDirect was performed and resulted in 108 articles. These were the basis for this review and formed a comprehensive series of consented therapy statements on the most important of otorhinolaryngology-related Post/Long COVID symptoms. Otorhinolaryngological symptoms did not appear isolated but as part of a multi-organ syndrome. Self-reported otorhinolaryngology-related Post/Long COVID symptoms were often not confirmed by objective testing. The confirmed prevalence estimated for anosmia, dysgeusia, cough, facial palsy, hoarseness/dysphonia, acute hearing loss, tinnitus, and vertigo/dizziness was about 4%, 2%, 4-19%, 0%, 17-20%, 8%, 20%, and 5-26%, respectively. There are manifold theoretical concepts of the etiopathology of different symptoms, but there is no clear evidence-based proof. This certainly contributes to the fact that there is no effective specific treatment option for any of the symptoms mentioned. Healthcare pathways must be established so that otorhinolaryngological Post/Long COVID symptoms can be recognized and evaluated and otorhinolaryngologists can provide counseling. This would also help to establish and selectively include patients in clinical trials investigating specific therapeutic concepts.

Regardless of their cause, persistent physical symptoms are distressing somatic complaints that occur on most days for at least several months. They are common in patients with somatic diseases, functional somatic disorders, mental disorders, and undiagnosed medical conditions and are often associated with significant impairment and medical costs. Despite their prevalence and impact, persistent physical symptoms are often overlooked in medical care. This Personal View stresses the importance of recognising persistent physical symptoms as a European health issue. It advocates improvements in research, clinical management, public health, and policy. Efforts should prioritise integrating models of symptom perception and biopsychosocial perspectives into medical care and education, fostering interdisciplinary collaboration, and developing standardised guidelines to enhance patient care, reduce stigma, and improve clinical outcomes. Increased research funding can accelerate progress in understanding and effectively managing persistent physical symptoms. Addressing these priorities will support patients and healthcare professionals, ensuring adequate care and a higher quality of life for affected individuals.

Commonly reported symptoms of long COVID may have different patterns of prevalence and presentation across different countries. While some limited data have been reported for the United Kingdom, national specificity for Scotland is less clear. We present a cross-sectional survey to examine the symptom prevalence, frequency, and severity of long COVID for people living with the condition in Scotland.

An online survey was created in the English language and was available between April 21, 2022 and August 5, 2022. Participants were included if they were ≥18 years old, living in Scotland, and had self-diagnosed or confirmed long COVID; and excluded if they were hospitalized during their initial infection. Within this article we quantify symptom prevalence, frequency, severity, and duration.

Participants (n = 253) reported the most prevalent long-COVID symptoms to be post-exertional malaise (95%), fatigue/tiredness (85%), and cognitive impairment (68%). Fatigue/tiredness, problems with activities of daily living (ADL), and general pain were most frequently occurring, while sleep difficulties, problems with ADL, and nausea were the most severe. Scottish Index of Multiple Deprivation associated with symptom number, severity, and frequency, whereas vaccine status, age, sex, and smoking status had limited or no association.

These findings outline the challenges faced for those living with long COVID and highlight the need for longitudinal research to ascertain a better understanding of the condition and its longer-term societal impact.

The COVID-19 pandemic has taught myriad lessons and left several questions we are yet to comprehend. Initially, the scientific community was concerned with the management of acute disease and immunization. Once the peak of the pandemic receded, it became clear that a proportion of patients were far from fully recovered. Researchers started to recognize those persisting symptoms as a new entity termed 'Long COVID,' where neurological symptoms are evident and have a major impact on quality of life.

The main purpose of this narrative review is to analyze and synthesize the current literature regarding Long COVID, its relation to the nervous system, and to explore the evidence on treatments for persistent neurological symptoms. The most common reported and observed neurologic manifestations include fatigue, cognitive impairment, pain, polyneuropathy, and neuropsychiatric disorders. A variety of pharmacologic and non-pharmacologic therapies have been evaluated and yielded mixed results. Many of them focused on immunomodulation and none currently have U.S. FDA approval.

Challenges remain in terms of clinical characterization and prognosis of Long COVID, besides understanding its pathophysiology. Standardization of biomarkers and diagnostic criteria will allow the use of common nomenclature and data elements in the design of future clinical studies.

Influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are acute respiratory infections (ARIs) that can cause substantial morbidity and mortality among at-risk individuals, including older adults. In this narrative review, we summarize themes identified in the literature regarding the epidemiology, seasonality, immunity after infection, clinical presentation, and transmission for these ARIs, along with the impact of the COVID-19 pandemic on seasonal patterns of influenza and RSV infections, with consideration of data specific to older adults when available. As the older adult population increases globally, it is of paramount importance to fully characterize the true disease burden of ARIs in order to develop appropriate mitigation strategies to minimize their impact in vulnerable populations. Challenges associated with characterizing the burden of these diseases include the shared symptomology and clinical presentation of influenza virus, RSV, and SARS-CoV-2, which complicate accurate diagnosis and highlight the need for improved testing and surveillance practices. To this end, multiple regional, national, and global virologic and disease surveillance systems have been established to provide accurate knowledge of viral epidemiology, support appropriate preparedness and response to potential outbreaks, and help inform prevention strategies to reduce disease severity and transmission. Beyond the burden of acute illness, long-term health consequences can also result from influenza virus, RSV, and SARS-CoV-2 infection. These include cardiovascular and pulmonary complications, worsening of existing chronic conditions, increased frailty, and reduced life expectancy. ARIs among older adults can also place a substantial financial burden on society and healthcare systems. Collectively, the existing data indicate that influenza virus, RSV, and SARS-CoV-2 infections in older adults present a substantial global health challenge, underscoring the need for interventions to improve health outcomes and reduce the disease burden of respiratory illnesses.Graphical abstract and video abstract available for this article.

Acute encephalitis syndrome (AES) presents with the onset of fever, altered sensorium and/or seizures, known to be caused by various infectious and non-infectious aetiological agents, among which viruses are the commonest. The severity of AES prompts rapid diagnosis, which is not met by time-consuming conventional diagnostic techniques. In this study, archived cerebrospinal fluid samples of laboratory-confirmed viral AES, an acute infectious condition and Guillain-Barré Syndrome (GBS), a post-infectious, autoimmune condition was assessed for soluble membrane attack complex (sMAC) using ELISA. Statistical analysis was performed to understand the diagnostic potential of sMAC in AES versus GBS patients. sMAC levels were significantly increased in viral encephalitis compared with GBS samples (43.69 ng/mL vs. 29.33 ng/mL, P < 0.05). The diagnostic potential of sMAC was assessed using the receiver operating characteristic (ROC) curve, which demonstrated excellent diagnostic discrimination between viral AES and GBS (area under curve = 0.8125, 95% CI, P < 0.0001). Using Youden's index, the optimal sMAC cut-off was calculated as 33.6 ng/mL for distinguishing AES from GBS. The findings of our study revealed significant increase in sMAC levels in AES patients in comparison to those with GBS. This underscores the utility of sMAC as a valuable tool in distinguishing between AES and GBS, thereby facilitating more tailored patient management strategies, which varies for acute infectious and post-infectious conditions especially those mediated by autoimmunity.

Long COVID (LC), an often-debilitating infection-associated chronic condition (IACC), affects millions of people globally. Globally, LC patients struggle to access timely, appropriate care, often experiencing disbelief, misunderstandings or being diverted from healthcare. Few studies have examined health system factors influencing LC healthcare access, especially in the Global South. Drawing on the concept of candidacy, we examine health system factors influencing access to LC care in Brazil's public healthcare system (Sistema Único de Saúde, SUS) and theorise implications for equitable access to public healthcare for IACCs globally.

We conducted a patient-engaged, qualitative study in the city of Rio de Janeiro. 29 individual semi-structured interviews were conducted with SUS professionals from administrative leaders to multidisciplinary primary and specialist care staff (November 2022 to July 2023). Verbatim transcripts were analysed using a pragmatic thematic analysis.

LC patients' candidacy for care is invisibilised within SUS through multiple, interacting processes. Interplay of an over-burdened health system, prioritisation of resources in response to (flawed) evidence of demand, misalignment of LC patient capacities and demands of navigating fragmented services, complex referral processes, professionals' lack of LC knowledge and disregard of the severity and morbidity of a chronic condition amid acute demands, led to the under-recognition of LC by healthcare professionals. Professionals' under-recognition perpetuates administrators' de-prioritisiation of resources, policies and training necessary to ensure access to appropriate care, creating a cycle of invisibilisation.

Urgent action to disrupt a cycle of invisibilisation is essential to mitigate patients' suffering and intensification of inequalities. Disrupting this pernicious cycle requires more than narrow clinical education efforts. Improved surveillance, education, patient involvement, attention to moral injury and building on existing multidisciplinary strengths may enhance access to LC care. Doing so offers wider benefits beyond patients with LC. We call for a paradigm shift in clinical approaches to IACCs.

Brain health may be impaired years after hospitalization for critical illness, and similar impairments occur after hospitalization for COVID-19. However, it remains unclear which patients are most likely to experience long-term brain health consequences and whether these adverse events differ between non-COVID critical illness and COVID-19.

In a prospective observational study, we enrolled patients hospitalized for (1) non-COVID critical illness (pneumonia, myocardial infarction, or ICU-requiring conditions) or for (2) COVID-19, from March 2020 to June 2021. Brain health was assessed at 18-month follow-up with cognitive, psychiatric, and neurological tests. We used both logistic regression and prediction models to test for associations between different variables and brain health.

We included 245 patients: 125 hospitalized for non-COVID critical illness and 120 for COVID-19 [mean age 61.2 (± 13.6) years, 42% women]. Brain health was impaired in 76% of patients (72% critical illness, 81% COVID-19; p = 0.14) at 18-month follow-up. The strongest predictive factors associated with impaired brain health were education < 13 years, age ≥ 70 years, and neuroticism traits in the best performing model (AUC = 0.63). When analyzing non-COVID critical illness and COVID-19 patients separately, low education was one of the few factors associated with impaired brain health in both groups (AUCs for best models: 0.66 and 0.69).

Brain health is comparably impaired after hospitalization for critical illness and COVID-19. Factors like higher age, lower education and neuroticism may help identifying vulnerable individuals, who could benefit from close monitoring to improve brain health after critical illness, regardless of the underlying disease etiology.