Inpatient post-COVID-19 rehabilitation program featuring virtual reality-Preliminary results of randomized controlled trial.

Background: Numerous recommendations from pulmonary scientific societies indicate the need to implement rehabilitation programs for patients after COVID-19. The aim of this study was to propose an innovative comprehensive intervention based on a hospital-based pulmonary rehabilitation program for individuals with post-acute sequelae of COVID-19. Methods: It was decided to evaluate two forms of hospital rehabilitation: traditional and one provided through virtual reality. Preliminary results are based on a group of 32 patients (20 female and 12 male), of average age 57.8 (4.92) years in the period of 3-6 months after the initial infection. Primary outcomes included analysis of lung function, exercise performance and stress level. A 3-week, high-intensity, five-times per week pulmonary rehabilitation program was designed to compare the effectiveness of a traditional form with a VR-led, novel form of therapy. Results: The analysis of the results showed a statistically significant improvement in both groups with regard to exercise performance expressed as 6MWT distance. Moreover, a statistically significant decrease in dyspnoea levels following the 6MWT was also noted in intergroup comparison, but the between-group comparison revealed non-statistically significant changes with low effect size. Regarding lung function, the analysis showed essentially normal lung function at baseline and a non-statistically significant improvement after the completion of the rehabilitation program. The analysis of the stress level showed a statistically significant improvement in both groups within the inter-group comparison, yet the between-group comparison of deltas values showed a non-significant difference with low effect size. Conclusion: A 3-weeks inpatients pulmonary rehabilitation program led to improvement of the exercise performance of people with post-acute sequelae of COVID-19, but not lung function. Furthermore, the program was shown to reduce patients' stress levels. A comparison of the traditional form of rehabilitation to the novel form using VR, shows similar effectiveness in terms of exercise performance and stress levels.

Encephalic nocardiosis after mild COVID-19: A case report.

The COVID-19 pandemic and the associated post-acute sequelae of COVID-19 (PASC) have led to the identification of a complex disease phenotype that is associated with important changes in the immune system. Herein, we describe a unique case of Nocardia farcinica cerebral abscess in an individual with sudden immunodeficiency several months after mild COVID-19. Intravenous Bactrim and Imipenem were prescribed for 6 weeks. After this, a 12-month course of Bactrim and Clavulin was prescribed to be taken orally, given the N. farcinica infection at the level of the central nervous system. This case report highlights the need for future research into the pathophysiology of COVID-19 and PASC immune dysregulation in convalescent individuals. It also draws attention to the need for timely consideration of opportunistic infections in patients with a history of COVID-19.

COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis.

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae.

The diagnosis of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. To identify biomarkers associated with PASC we analyzed plasma samples collected from PASC and COVID-19 patients to quantify viral antigens and inflammatory markers. We detect SARS-CoV-2 spike predominantly in PASC patients up to 12 months post-diagnosis.

The Greek Collaborative Long COVID Study: Non-Hospitalized and Hospitalized Patients Share Similar Symptom Patterns.

Long COVID-19 syndrome refers to persisting symptoms (>12 weeks) after the initial coronavirus infection and is estimated to affect 3% to 12% of people diagnosed with the disease globally. AIM: We conducted a collaborative study with the Long COVID patient organization in Greece, in order to estimate the characteristics, symptoms, and challenges these patients confront. METHODS: Data were collected from 208 patients using unstructured qualitative free-text entries in an anonymized online questionnaire. RESULTS: The majority of respondents (68.8%) were not hospitalized and reported lingering symptoms (66.8%) for more than six months. Eighteen different symptoms (fatigue, palpitations, shortness of breath, parosmia, etc.) were mentioned in both hospitalized and community patients. Awareness of Long COVID sequelae seems to be low even among medical doctors. Treatment options incorporating targeted rehabilitation programs are either not available or still not included inthe management plan of Long COVID patients. CONCLUSIONS: Patients infected with coronavirus with initial mild symptoms suffer from the same persistent symptoms as those who were hospitalized. Long COVID syndrome appears to be a multi-systemic entity and a multidisciplinary medical approach should be adopted in order to correctly diagnose and successfully manage these patients.

Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis.

Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C-such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)-overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR ß variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection.

Multiparameter analysis of vascular remodeling in post-Acute sequelae of COVID-19

The COVID-19 infection, a current worldwide health concern, manifests as an alveolar-interstitial pneumonia with unknown long-Term evolution. It is also associated with vascular dysfunction and shows a vascular remodeling with a changed balance between small-and large-caliber vessels. In this study, we question the existence of residual vascular alteration in post-Acute sequelae of COVID-19 (PASC) by investigating possible associations between vascular remodeling biomarkers extracted from CT and functional, radiological and morphological parameters. The used vascular biomarkers concern the blood volume ratio of vessels with cross-section area inferior to 5 mm2 versus vessels of crosssection area inferior to 50 mm2 (BV5/BV50), an index of local peripheral vascular density and a peripheral composite vascular remodeling index, both measured in the antero-postero-lateral lung periphery (excluding mediastinal region). As a functional parameter, diffusing capacity of the lung for carbon monoxide (DLCO) is a measure depending on the vascular perfusion and the amount of interstitial thickening, a decreased DLCO value suggesting altered vascular perfusion. Imaging biomarkers can be extracted from the analysis of perfusion lung scintigraphy or CT scan. Some of them are included in our study. Radiological features include CT attenuation as a measure of persistence of ground glass opacity and development of changes suggestive to look for fibrosis, such as reticulations. As additional morphological parameter, lung deformation observed between inspiration/expiration maneuvers may be suggestive of the presence of reticulations inducing lung stiffness and breathing deficiency. The investigation of associations between vascular remodeling biomarkers obtained from CT and the above functional, radiological and morphological parameters revealed moderate to strong correlations highlighting the ability to capture the persistence of vascular alterations in PASC in relation with the development of fibrotic patterns, which is a promising direction for future research. © 2022 SPIE.

Marginal BH4 deficiencies, iNOS, and self-perpetuating oxidative stress in post-acute sequelae of Covid-19.

The treatment of post-acute sequelae of Covid-19 (PASC) has been informed primarily by symptomatic parallels with other chronic inflammatory syndromes. This manuscript takes a more systemic approach by examining how a marginal deficiency of tetrahydrobiopterin (BH4) resulting from mutations of the GCH1 (GTP cyclohydrolase 1) gene may result in the uncoupling of inducible Nitric Oxide Synthase (iNOS) early in the initial response of the innate immune system to SARS-CoV-2. The resulting production of superoxide instead of nitric oxide leads to a self-perpetuating cycle of oxidative stress with the potential to impair numerous metabolic processes and damage multiple organ systems. This marginal deficiency of BH4 may be exhibited by 30% or more of the patient population that have heterozygous or homozygous mutations of GCH1. As the cycle of oxidative stress continues, there is less BH4 available for other metabolic needs such as 1) resisting increased ferroptosis with its damage to organs, and 2) regulating the deactivation of the hyperinflammatory state. Finally, possible steps are proposed for clinical treatment of the hypothesized oxidative stress involved with PASC.

Quality of Life (QoL) Is Reduced in Those with Severe COVID-19 Disease, Post-Acute Sequelae of COVID-19, and Hospitalization in United States Adults from Northern Colorado.

The longitudinal quality of life (QoL) of COVID-19 survivors, especially those with post-acute sequelae (PASC) is not well described. We evaluated QoL in our COVID-19 survivor cohort over 6 months using the RAND SF-36 survey. From July 2020-March 2021 we enrolled 110 adults from the United States with a positive SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) into the Northern Colorado Coronavirus Biobank (NoCo-COBIO). Demographic data and symptom surveillance were collected from 62 adults. In total, 42% were hospitalized, and 58% were non-hospitalized. The Rand SF-36 consists of 36 questions and 8 scales, and questions are scored 0-100. A lower-scale score indicates a lower QoL. In conclusion, hospitalization, PASC, and disease severity were associated with significantly lower scores on the RAND SF-36 in Physical Functioning, Role Limitation due to Physical Health, Energy/Fatigue, Social Functioning, and General Health. Long-term monitoring of COVID-19 survivors is needed to fully understand the impact of the disease on QoL and could have implications for interventions to alleviate suffering during recovery.

SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long COVID.

Over 10% of COVID-19 convalescents report post-COVID-19 complications, namely, 'long COVID' or 'post-COVID syndrome,' including a number of neuro-psychiatric symptoms. The pathophysiology of COVID-19 in the central nervous system is poorly understood but may represent post-COVID injury, ongoing sterile maladaptive inflammation, or SARS-CoV-2 persistence. We describe a long COVID patient with SARS-CoV-2 RNA in the cerebrospinal fluid, which seems important, specifically due to recent reports of gray matter volume loss in COVID-19 patients. Further studies of SARS-CoV2 RNA, markers of inflammation, and neuronal damage in the CSF of patients with long COVID would be useful and should address whether the CNS can serve as a reservoir of SARS-CoV-2, clarify the pathway by which COVID-19 contributes to CNS dysfunction, and how best to therapeutically address it.

Recommendations for the recognition, diagnosis, and management of long COVID: a Delphi study.

BACKGROUND: In the absence of research into therapies and care pathways for long COVID, guidance based on 'emerging experience' is needed. AIM: To provide a rapid expert guide for GPs and long COVID clinical services. DESIGN AND SETTING: A Delphi study was conducted with a panel of primary and secondary care doctors. METHOD: Recommendations were generated relating to the investigation and management of long COVID. These were distributed online to a panel of UK doctors (any specialty) with an interest in, lived experience of, and/or experience treating long COVID. Over two rounds of Delphi testing, panellists indicated their agreement with each recommendation (using a five-point Likert scale) and provided comments. Recommendations eliciting a response of 'strongly agree', 'agree', or 'neither agree nor disagree' from 90% or more of responders were taken as showing consensus. RESULTS: Thirty-three clinicians representing 14 specialties reached consensus on 35 recommendations. Chiefly, GPs should consider long COVID in the presence of a wide range of presenting features (not limited to fatigue and breathlessness) and exclude differential diagnoses where appropriate. Detailed history and examination with baseline investigations should be conducted in primary care. Indications for further investigation and specific therapies (for myocarditis, postural tachycardia syndrome, mast cell disorder) include hypoxia/desaturation, chest pain, palpitations, and histamine-related symptoms. Rehabilitation should be individualised, with careful activity pacing (to avoid relapse) and multidisciplinary support. CONCLUSION: Long COVID clinics should operate as part of an integrated care system, with GPs playing a key role in the multidisciplinary team. Holistic care pathways, investigation of specific complications, management of potential symptom clusters, and tailored rehabilitation are needed.

Post-acute sequelae of COVID-19: Evidence of mood & cognitive impairment.

Acute health consequences associated with coronavirus disease 2019 (COVID-19) infection have been thoroughly characterized; however, long-term impacts are not yet understood. Post-acute sequelae of COVID-19 (PASC), also known as Long COVID syndrome, is the persistence of COVID-19 symptoms long after viral infection. In addition to physical symptoms, those with PASC experience changes in mental health, but few studies have empirically examined these effects. The current study investigated mood and cognitive functioning in individuals who have recovered from COVID-19 infection. We recruited 100 male and female adults (M â€‹= â€‹30 years old) with no history of mood or cognitive impairment prior to the COVID-19 pandemic (Jan. 2020). Half of the subjects were healthy controls (i.e., no prior COVID-19 infection) and half had received a past COVID-19 diagnosis (ascertained by PCR or antibody test) but were no longer infectious. Participants completed self-reported measures of stress, depression, and anhedonia, as well as the Attention Network Test (ANT), a behavioural measure of attentional alerting, orienting and executive functioning. Relative to controls, depression and anhedonia were significantly higher in the past-COVID group. Selective impairment in attention was observed in the past-COVID group, marked by deficits in executive functioning while alerting and orienting abilities remained intact. Effects were most pronounced among individuals diagnosed 1-4 months prior to assessment. There were no group differences in pandemic-related experiences with respect to social interaction, social distancing, or isolation. The past-COVID group scored significantly higher on perceived stress; however, this did not moderate any effects observed on mood or cognition. These findings implicate a protracted reaction to the virus, possibly via prolonged inflammation, contributing to sustained mood dysregulation and cognitive impairment. Future research should examine the neural and physiological underpinnings of PASC, particularly mechanisms that promote psychiatric sequelae 1-4 months following diagnosis.

A longitudinal SARS-CoV-2 biorepository for COVID-19 survivors with and without post-acute sequelae.

BACKGROUND: SARS-CoV-2 has swept across the globe, causing millions of deaths worldwide. Though most survive, many experience symptoms of COVID-19 for months after acute infection. Successful prevention and treatment of acute COVID-19 infection and its associated sequelae is dependent on in-depth knowledge of viral pathology across the spectrum of patient phenotypes and physiologic responses. Longitudinal biobanking provides a valuable resource of clinically integrated, easily accessed, and quality-controlled samples for researchers to study differential multi-organ system responses to SARS-CoV-2 infection, post-acute sequelae of COVID-19 (PASC), and vaccination. METHODS: Adults with a history of a positive SARS-CoV-2 nasopharyngeal PCR are actively recruited from the community or hospital settings to enroll in the Northern Colorado SARS-CoV-2 Biorepository (NoCo-COBIO). Blood, saliva, stool, nasopharyngeal specimens, and extensive clinical and demographic data are collected at 4 time points over 6 months. Patients are assessed for PASC during longitudinal follow-up by physician led symptom questionnaires and physical exams. This clinical trial registration is NCT04603677 . RESULTS: We have enrolled and collected samples from 119 adults since July 2020, with 66% follow-up rate. Forty-nine percent of participants assessed with a symptom surveillance questionnaire (N = 37 of 75) had PASC at any time during follow-up (up to 8 months post infection). Ninety-three percent of hospitalized participants developed PASC, while 23% of those not requiring hospitalization developed PASC. At 90-174 days post SARS-CoV-2 diagnosis, 67% of all participants had persistent symptoms (N = 37 of 55), and 85% percent of participants who required hospitalization during initial infection (N = 20) still had symptoms. The most common symptoms reported after 15 days of infection were fatigue, loss of smell, loss of taste, exercise intolerance, and cognitive dysfunction. CONCLUSIONS: Patients who were hospitalized for COVID-19 were significantly more likely to have PASC than those not requiring hospitalization, however 23% of patients who were not hospitalized also developed PASC. This patient-matched, multi-matrix, longitudinal biorepository from COVID-19 survivors with and without PASC will allow for current and future research to better understand the pathophysiology of disease and to identify targeted interventions to reduce risk for PASC. Registered 27 October 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04603677 .