Characterizing Long COVID in Children and Adolescents

Key Points:

Question  What prolonged symptoms experienced by youth are most associated with SARS-CoV-2 infection?

Findings  Among 5367 participants in the RECOVER-Pediatrics cohort study, 14 symptoms in both school-age children (6-11 years) and adolescents (12-17 years) were more common in those with vs without SARS-CoV-2 infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. Empirically derived indices for PASC research and associated clustering patterns were developed.

Meaning  This study developed research indices for characterizing pediatric PASC. Symptom patterns were similar but distinguishable between school-age children and adolescents, highlighting the importance of characterizing PASC separately in different age groups.

Abstract

Importance  Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.

Objective  To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.

Design, Setting, and Participants  Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.

Exposure  SARS-CoV-2 infection.

Main Outcomes and Measures  PASC and 89 prolonged symptoms across 9 symptom domains.

Results  A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise–related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.

Conclusions and Relevance This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Source: Rachel S. Gross, MD, MS; Tanayott Thaweethai, PhD; Lawrence C. Kleinman, MD, MPH; et al. JAMA. Published online August 21, 2024. doi:10.1001/jama.2024.12747 https://jamanetwork.com/journals/jama/article-abstract/2822770

Dysregulation of tetrahydrobiopterin metabolism in myalgic encephalomyelitis/chronic fatigue syndrome by pentose phosphate pathway

Abstract:

Background: Tetrahydrobiopterin (BH4) and its oxidized derivative dihydrobiopterin (BH2) were found to be strongly elevated in ME/CFS patients with orthostatic intolerance (ME + OI).

Objective: However, the molecular mechanism of biopterin biogenesis is poorly understood in ME + OI subjects. Here, we report that the activation of the non-oxidative pentose phosphate pathway (PPP) plays a critical role in the biogenesis of biopterins (BH4 and BH2) in ME + OI subjects.

Research design and results: Microarray-based gene screening followed by real-time PCR-based validation, ELISA assay, and finally enzyme kinetic studies of glucose-6-phosphate dehydrogenase (G6PDH), transaldolase (TALDO1), and transketolase (TK) enzymes revealed that the augmentation of anaerobic PPP is critical in the regulations of biopterins. To further investigate, we devised a novel cell culture strategy to induce non-oxidative PPP by treating human microglial cells with ribose-5-phosphate (R5P) under a hypoxic condition of 85%N2/10%CO2/5%O2 followed by the analysis of biopterin metabolism via ELISA, immunoblot, and dual immunocytochemical analyses. Moreover, the siRNA knocking down of the taldo1 gene strongly inhibited the bioavailability of phosphoribosyl pyrophosphate (PRPP), reduced the expressions of purine biosynthetic enzymes, attenuated GTP cyclohydrolase 1 (GTPCH1), and suppressed subsequent production of BH4 and its metabolic conversion to BH2 in R5P-treated and hypoxia-induced C20 human microglia cells. These results confirmed that the activation of non-oxidative PPP is indeed required for the upregulation of both BH4 and BH2 via the purine biosynthetic pathway. To test the functional role of ME + OI plasma-derived biopterins, exogenously added plasma samples of ME + OI plasma with high BH4 upregulated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in human microglial cells indicating that the non-oxidative PPP-induced-biopterins could stimulate inflammatory response in ME + OI patients.

Conclusion: Taken together, our current research highlights that the induction of non-oxidative PPP regulates the biogenesis of biopterins contributing to ME/CFS pathogenesis.

Source: Bulbule S, Gottschalk CG, Drosen ME, Peterson D, Arnold LA, Roy A. Dysregulation of tetrahydrobiopterin metabolism in myalgic encephalomyelitis/chronic fatigue syndrome by pentose phosphate pathway. J Cent Nerv Syst Dis. 2024 Aug 19;16:11795735241271675. doi: 10.1177/11795735241271675. PMID: 39161795; PMCID: PMC11331476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331476/ (Full text)

Designing and optimizing clinical trials for long COVID

Abstract:

Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence.

We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued.

Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes.

Third, studies should have multiple illness comparator cohorts for IACCIs such as myalgic encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses.

Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity.

Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel.

Source: Vogel JM, Pollack B, Spier E, McCorkell L, Jaudon TW, Fitzgerald M, Davis H, Cohen AK. Designing and optimizing clinical trials for long COVID. Life Sci. 2024 Aug 13;355:122970. doi: 10.1016/j.lfs.2024.122970. Epub ahead of print. PMID: 39142505. https://www.sciencedirect.com/science/article/pii/S0024320524005605 (Full text)

ANZMES Releases Essential Resource for Healthcare Professionals to Manage Hospital Stays of Severe ME/CFS and long COVID Patients

Press Release:

 by 

ANZMES (the National Advisory on ME/CFS and a RNZCGP registered provider of continuing education) has released a short reference guide for secondary care. The resource acts as a guide for healthcare professionals in managing hospital stays for patients suffering from severe-very severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID (lC). It aims to improve patient care by addressing the unique needs and symptoms of patients with severe ME/CFS and lC during their hospital admissions.

“ME/CFS is a complex condition and its severity is often misunderstood by healthcare professionals. Severe patients are housebound. Very severe patients are bedbound, with very high needs requiring 24/7 care. Hospitalisation often occurs due to undernutrition, infections, and dysautonomic issues. Therefore, it is crucial that healthcare professionals have the knowledge to effectively manage patients during hospital admissions so as not to exacerbate their severe and debilitating symptoms,” says ANZMES president, Fiona Charlton.

“Our aim with this new resource is to provide a clear and concise reference guide for healthcare professionals to enhance patient care. While the assessment and evaluation of long COVID may differ from ME/CFS, the management of long COVID closely mirrors it, so we have leveraged our medical team’s expertise to develop a guide to support the effective care of these patients in a hospital setting.” She says.

The resource outlines essential strategies for managing severe symptoms, including intense muscle and joint pain, extreme sensitivity to light, sound, touch, and chemicals, impaired mobility often necessitating a wheelchair, severe gastrointestinal issues, and increased susceptibility to infections due to immune dysfunction.

“For very severe patients, a light touch of the arm can be interpreted by the body as pain. Bright light can cause post-exertional malaise. People with very severe ME/CFS and long COVID spend the majority of their lives in darkened rooms, wearing noise cancelling headphones and eye masks. They are unable to eat properly, or bathe and toilet themselves without full time carers, and it is often a family member who assumes this role.” The impact of this on everyone cannot be underestimated.

An overview of key recommendations include:

  • Sensory Adjustments: Dim lighting, minimise noise, and provide private rooms to reduce sensory stress.
  • Medication and Nutrition: Avoid histamine-releasing anaesthetics and muscle relaxants. Use medications like propofol, midazolam, and fentanyl with caution. Monitor hydration and consider IV saline for orthostatic intolerance.[1]
  • Activity and Rest: Recognise that even minimal interactions, such as being spoken to or exposure to light, can trigger PEM. Prioritise rest and avoid any unnecessary activity.
  • Communication and Cognitive Support: Involve family and caregivers as representatives, especially when the patient cannot communicate; or simplify communication by providing written instructions and allowing extra time for patients to process information.
  • Care and Support: Recognise the psychological impact, validate the severity of conditions, and provide access to counselling and mental health support. Include family members or caregivers in discussions and allow them to stay with the patient if requested.

ANZMES emphasises the importance of personalised care plans, the involvement of patient’s family members and their regular health team to understand the severity of their condition. The guide also encourages connections with local support groups and resources for additional advocacy and support for not only patients, but also their carers to avoid burnout. Remote consultations and home visits are recommended to avoid unnecessary hospital admissions.

ANZMES president, Fiona Charlton concludes “We believe that education is key to improving outcomes for patients with severe-very severe ME/CFS and long COVID. By providing this resource, we aim to enhance the knowledge and confidence of healthcare professionals so they are equipped when these patients are admitted under their care.”

Understanding ME/CFS and long COVID:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a long-term, multi-systemic illness affecting the nervous, endocrine, autonomic, and immune systems. Patients experience severe fatigue, post-exertional malaise (PEM), unrefreshing sleep, cognitive impairment, and orthostatic intolerance. With over 100-200+ potential symptoms, the condition’s impact can vary greatly, making diagnosis and management highly individualised. Roughly 25% of all ME/CFS cases are categorised as mild, 50% as moderate-severe and 25% as very severe.[2] [3]

Long COVID is characterised by persistent, unexplained symptoms following infection with COVID-19 (SARS-CoV-2) lasting more than 12 weeks and not explained by an alternative diagnosis. Both conditions share symptoms such as extreme fatigue, cognitive dysfunction, and post-exertional symptom exacerbation (PESE), with up to 50% of long COVID cases fitting the diagnostic criteria for ME/CFS.

Post-Exertional Malaise (PEM)

Post-Exertional Malaise (PEM), also referred to as post-exertional symptom exacerbation (PESE) in the context of long COVID, is a debilitating response to normal, every-day activities in people with ME/CFS. For individuals with severe-very severe ME/CFS or lC, this can be triggered by sensory overload, such as exposure to light or even simple conversations. Repeated episodes of PEM can exacerbate these already severe symptoms, and even minimal exertion can lead to significant setbacks for the patient’s health and wellbeing.

About ANZMES

ANZMES, the Associated New Zealand ME Society, is the National Advisory on ME/CFS. Established in 1980, ANZMES has been at the forefront of research, representation, and education for ME/CFS in Aotearoa/New Zealand. The organisation is a registered provider of continuing medical education with the Royal New Zealand College of General Practitioners (RNZCGP) and is dedicated to improving the lives of those affected by ME/CFS and long COVID. ANZMES is a founding member of the World ME Alliance.

 

Fast Targeted Metabolomics for Analyzing Metabolic Diversity of Bacterial Indole Derivatives in ME/CFS Gut Microbiome

Abstract:

Disruptions in microbial metabolite interactions due to gut microbiome dysbiosis and metabolomic shifts may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and other immune-related conditions. The aryl hydrocarbon receptor (AhR), activated upon binding various tryptophan metabolites, modulates host immune responses. This study investigates whether the metabolic diversity-the concentration distribution-of bacterial indole pathway metabolites can differentiate bacterial strains and classify ME/CFS samples.

A fast targeted liquid chromatography-parallel reaction monitoring method at a rate of 4 minutes per sample was developed for large-scale analysis. This method revealed significant metabolic differences in indole derivatives among B. uniformis strains cultured from human isolates. Principal component analysis identified two major components (PC1, 68.9%; PC2, 18.7%), accounting for 87.6% of the variance and distinguishing two distinct B. uniformis clusters. The metabolic difference between clusters was particularly evident in the relative contributions of indole-3-acrylate and indole-3-aldehyde.

We further measured concentration distributions of indole derivatives in ME/CFS by analyzing fecal samples from 10 patients and 10 healthy controls using the fast targeted metabolomics method. An AdaBoost-LOOCV model achieved moderate classification success with a mean LOOCV accuracy of 0.65 (Control: precision of 0.67, recall of 0.60, F1-score of 0.63; ME/CFS: precision of 0.64, recall of 0.7000, F1-score of 0.67).

These results suggest that the metabolic diversity of indole derivatives from tryptophan degradation, facilitated by the fast targeted metabolomics and machine learning, is a potential biomarker for differentiating bacterial strains and classifying ME/CFS samples.

Mass spectrometry datasets are accessible at the National Metabolomics Data Repository (ST002308, DOI: 10.21228/M8G13Q; ST003344, DOI: 10.21228/M8RJ9N; ST003346, DOI: 10.21228/M8RJ9N).

Source: Tian H, Wang L, Aiken E, Ortega RJV, Hardy R, Placek L, Kozhaya L, Unutmaz D, Oh J, Yao X. Fast Targeted Metabolomics for Analyzing Metabolic Diversity of Bacterial Indole Derivatives in ME/CFS Gut Microbiome. bioRxiv [Preprint]. 2024 Jul 29:2024.07.29.605643. doi: 10.1101/2024.07.29.605643. PMID: 39131327; PMCID: PMC11312560. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11312560/ (Full text)

Nonpelvic comorbid symptoms of 45 patients with pain of pelvic venous origin, before and after treatment

Abstract:

Objective: To report the prevalence and severity of nonpelvic symptoms for patients with venous-origin chronic pelvic pain (VO-CPP) and to describe outcomes after pelvic vein stenting and embolization.

Methods: We retrospectively reviewed outcomes of 45 women with VO-CPP who underwent treatment with iliac vein stenting and/or embolization. Patients completed symptom-severity questionnaires before and after treatment that assessed for pelvic pain, and multiple other symptoms, including brain fog, anxiety, depression, musculoskeletal pain, fatigue, migraines and more.

Results: Patient age ranged from 18 to 65 years. The prevalence of common symptoms was as follows: migraines, 69%; brain fog, 76%; anxiety attacks, 58%; excess sweating, 64%; hip pain, 73%; diarrhea, 62%; constipation, 76%; and abdominal bloating, 82%. After treatment, most symptom scores improved by more than 50%; exceptions were excessive sweating (41% improvement) and bloating (47% improvement). Prevalence of individual symptoms that bundle into POTS ranged from 29% to 76%, where symptom improvement ranged from 23% to 59% after treatment. Overlapping individual symptoms characteristic of fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) were present in 64% to 82% of patients and all improved by 49% to 63% after treatment.

Conclusions: Pelvic venous flow abnormality is linked causally to a spectrum of interrelated symptoms, of which many can be bundled into named syndromes of unknown cause. With catheter- based treatment of pelvic venous pooling, nonpelvic symptom and syndrome scores improved.

Source: Smith SJ, Smith BH, Sichlau MJ, Chen B, Knight D, Rowe PC. Nonpelvic comorbid symptoms of 45 patients with pain of pelvic venous origin, before and after treatment. Phlebology. 2024 Aug 10:2683555241273109. doi: 10.1177/02683555241273109. Epub ahead of print. PMID: 39126670.  https://pubmed.ncbi.nlm.nih.gov/39126670/

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI

Abstract:

Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS.

This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated.

In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.

Source: Schönberg L, Mohamed AZ, Yu Q, Kwiatek RA, Del Fante P, Calhoun VD, Shan ZY. Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI. J Cereb Blood Flow Metab. 2024 Aug 7:271678X241270528. doi: 10.1177/0271678X241270528. Epub ahead of print. PMID: 39113421. https://journals.sagepub.com/doi/10.1177/0271678X241270528 (Full text)

Post-Exertional Malaise in Veterans with Gulf War Illness

Abstract:

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO).

Sixty-seven Veterans (n=39 GWI; n=28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hours post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA).

Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α=0.05). Data were analyzed for the full sample of Veterans with GWI (n=39) compared to CO (n=28) and a subsample of Veterans (n=18) who endorsed “feeling unwell after physical exercise or exertion” (“PEM endorsers”) during screening.

Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to “PEM endorsers” resulted in significant interactions for Pain- and GWI-related PEM models.

These results indicate that not all GVs with GWI experience PEM 24 hr after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.

Source: Lindheimer JB, Stegner AJ, Wylie GR, Klein-Adams JC, Almassi NE, Ninneman JV, Van Riper SM, Dougherty RJ, Falvo MJ, Cook DB. Post-exertional malaise in veterans with gulf war illness. Int J Psychophysiol. 2020 Jan;147:202-212. doi: 10.1016/j.ijpsycho.2019.11.008. Epub 2019 Nov 28. PMID: 31786249; PMCID: PMC6957714. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957714/ (Full text)

Developing a clinical-pathological framework of long COVID-related fatigue applied to public safety workers

Abstract:

In the wake of the COVID-19 pandemic, millions worldwide are still struggling with persistent or recurring symptoms known as long COVID. Fatigue is one of the most prevalent symptoms associated with long COVID, and for many it can be debilitating. Understanding the potential pathological processes that link fatigue to long COVID is critical to better guide treatment. Challenges with diagnosis and treatment are reviewed, recognizing that post-COVID fatigue does not always present with corroborating clinical evidence, a situation that is frustrating for both patients and healthcare providers.

Firefighters are a group of public safety workers who are particularly impacted by long COVID-related fatigue. Firefighters must be able to engage in strenuous physical activity and deal with demanding psychological situations, both of which may be difficult for those suffering from fatigue. Disruption in public safety worker health can potentially impact community welfare. This review creates a framework to explain the clinical-pathological features of fatigue resulting from long COVID, addresses diagnosis and treatment challenges, and explores the unique impact fatigue may pose for public safety workers and their organizations.

Source: Lofrano-Porto A, D’Isabel S, Smith DL. Developing a clinical-pathological framework of long COVID-related fatigue applied to public safety workers. Front Med (Lausanne). 2024 Jul 17;11:1387499. doi: 10.3389/fmed.2024.1387499. PMID: 39086937; PMCID: PMC11288841. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288841/ (Full text)

Clinical and Diagnostic Features of Post-Acute COVID-19 Vaccination Syndrome (PACVS)

Abstract:

Post-acute COVID-19 vaccination syndrome (PACVS) is a chronic disease triggered by SARS-CoV-2 vaccination (estimated prevalence 0.02%). PACVS is discriminated from the normal post-vaccination state by altered receptor antibodies, most notably angiotensin II type 1 and alpha-2B adrenergic receptor antibodies. Here, we investigate the clinical phenotype using a study registry encompassing 191 PACVS-affected persons (159 females/32 males; median ages: 39/42 years).

Unbiased clustering (modified Jaccard index) of reported symptoms revealed a prevalent cross-cohort symptomatology of malaise and chronic fatigue (>80% of cases). Overlapping clusters of (i) peripheral nerve dysfunction, dysesthesia, motor weakness, pain, and vasomotor dysfunction; (ii) cardiovascular impairment; and (iii) cognitive impairment, headache, and visual and acoustic dysfunctions were also frequently represented.

Notable abnormalities of standard serum markers encompassing increased interleukins 6 and 8 (>80%), low free tri-iodine thyroxine (>80%), IgG subclass imbalances (>50%), impaired iron storage (>50%), and increased soluble neurofilament light chains (>30%) were not associated with specific symptoms.

Based on these data, 131/191 participants fit myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and simultaneously also several other established dysautonomia syndromes. Furthermore, 31/191 participants fit none of these syndromes. In conclusion, PACVS could either be an outlier of ME/CFS or a dysautonomia syndrome sui generis.

Source: Mundorf AK, Semmler A, Heidecke H, Schott M, Steffen F, Bittner S, Lackner KJ, Schulze-Bosse K, Pawlitzki M, Meuth SG, Klawonn F, Ruhrländer J, Boege F. Clinical and Diagnostic Features of Post-Acute COVID-19 Vaccination Syndrome (PACVS). Vaccines (Basel). 2024 Jul 18;12(7):790. doi: 10.3390/vaccines12070790. PMID: 39066428; PMCID: PMC11281408. Mundorf AK, Semmler A, Heidecke H, Schott M, Steffen F, Bittner S, Lackner KJ, Schulze-Bosse K, Pawlitzki M, Meuth SG, Klawonn F, Ruhrländer J, Boege F. Clinical and Diagnostic Features of Post-Acute COVID-19 Vaccination Syndrome (PACVS). Vaccines (Basel). 2024 Jul 18;12(7):790. doi: 10.3390/vaccines12070790. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281408/ (Full text)