Pulmonary Dysfunction after Pediatric COVID-19

Abstract:

Background: Long COVID occurs in lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field MRI may identify persistent pulmonary manifestations after SARS-CoV-2 infection.

Purpose: To characterize both morphologic and functional changes of lung parenchyma on low-field MRI in children and adolescents with post COVID-19 compared with healthy controls.

Materials and Methods: Between August and December 2021, a cross-sectional, prospective clinical trial using low-field MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes on MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive RT-PCR test and serological parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants and with long COVID.

Results: A total of 54 participants post COVID-19 infection (mean age, 11 years ±3 [SD], 56 males) and 9 healthy controls (mean age, 10 years ±3 [SD], 70 males) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (V/Q match) was reduced from 81±6.1% in healthy controls to 62±19% (P =.006) in the recovered group and 60±20% (P=.003) in the long COVID group. V/Q match was lower in post COVID patients with infection less than 180 days (63±20%, P=.03), 180 to 360 days (63±18%, P=0.03) and 360 days ago (41±12%, P<.001) as compared with the never-infected healthy controls (81±6.1%).

Conclusion: Low-field MRI showed persistent pulmonary dysfunction in both children and adolescents recovered from COVID-19 and with long COVID.

ClinicalTrials.gov: NCT04990531

Source: Heiss R, Tan L, Schmidt S, Regensburger AP, Ewert F, Mammadova D, Buehler A, Vogel-Claussen J, Voskrebenzev A, Rauh M, Rompel O, Nagel AM, Lévy S, Bickelhaupt S, May MS, Uder M, Metzler M, Trollmann R, Woelfle J, Wagner AL, Knieling F. Pulmonary Dysfunction after Pediatric COVID-19. Radiology. 2022 Sep 20:221250. doi: 10.1148/radiol.221250. Epub ahead of print. PMID: 36125379.

Long-term neurologic outcomes of COVID-19

Abstract:

The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection.

Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy.

We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.

Source: Xu, E., Xie, Y. & Al-Aly, Z. Long-term neurologic outcomes of COVID-19. Nat Med (2022). https://doi.org/10.1038/s41591-022-02001-z https://www.nature.com/articles/s41591-022-02001-z (Full text)

How “long covid” is shedding light on postviral syndromes

Long covid really shouldn’t have been a surprise, says Vett Lloyd, a biologist at Mount Allison University in Sackville, Canada. “When the pandemic started, the general assumption was that there were two possible outcomes to an infection—you’d either get better or die,” she says.

But there’s a possible third outcome. It’s long been known that a number of disease causing pathogens—some viral and some bacterial—are associated with ongoing post-infection symptoms in a significant minority of patients.

“There was no real reason to think SARS-CoV-2 should be any different than the original SARS, which also caused post-infection syndromes,” says Lloyd. She is one of many researchers who hope that the attention and funding directed towards long covid will help to shed light on how and why other infections can lead to persistent and sometimes debilitating symptoms.

Read the rest of this article HERE.

Source: Owens B. How “long covid” is shedding light on postviral syndromes BMJ 2022; 378 :o2188 doi:10.1136/bmj.o2188  https://www.bmj.com/content/378/bmj.o2188 (Full text)

Higher rates of long covid symptoms in patients with mild covid-19

Abstract:

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has affected over 61 million U.S. citizens, and up to 30-80% of COVID-19 survivors may go on to develop post-acute sequelae of SARS-CoV-2 (PASC). These sequelae can be debilitating and often impair quality of life and daily function. Although it has been suggested that severity of acute COVID-19 infection is directly related to PASC development, this association remains unclear.

METHODS: This prospective cohort study was conducted through consecutive recruitment of confirmed and probable COVID-19 patients with persistent symptoms lasting ≥3 weeks from disease onset or positive SARS-CoV-2 test from academic PASC clinics at Emory University and Grady Memorial Hospital in Atlanta, GA during January-December 2021. Sociodemographic, comorbidity, and acute COVID-19 data were collected. Severe acute COVID- 19 was defined as requiring hospitalization, and critical acute COVID-19 required intensive care. New or worsening symptoms persisting ≥3 weeks from COVID-19 onset were collected using a standardized review of systems, and confirmed by clinician interview. Differences in PASC symptom type were assessed by calculating risk ratios (RR) and 95% confidence intervals (CI) using the Taylor series, and difference in PASC duration was assessed using student’s t-test. Two-tailed p-values ≤0.05 were considered significant.

RESULTS: Of 269 enrollees, median age was 52 years (range 18-93) and there were more women (74%) than men (26%). There were 152 (57%) African American, 76 (28%) White, and 21 (8%) Hispanic. Among PASC patients, the most common symptoms were dyspnea (68%), fatigue (63%), brain fog (48%), dizziness (27%), chest pain (25%), cough (23%) and headache (23%) with a median PASC duration of 132 days (range 21-523). Acute COVID-19 severity was asymptomatic in one participant, mild in 149 (55%), severe in 95 (35%), and critical in 23 (9%). Asymptomatic- mild acute COVID-19 patients had more persistent dyspnea (RR 1.33, 95%, CI 1.09- 1.61), fatigue (RR 1.53, 95%CI 1.22-1.91), brain fog (RR 2.00, 95%CI 1.44-2.67), dizziness (RR 2.03, 95%CI 1.27-3.25), and headache (RR 2.07, 95%CI 1.22-3.48) compared with severe-critical acute disease, who had a non-significant trend towards more cough and chest pain. Asymptomatic-mild participants were further from incident infection (153 days) compared to severe-critical participants (110 days) (p=0.04).

CONCLUSIONS: Contrary to previous observations, COVID-19 survivors who experienced asymptomatic-mild infections may develop higher rates of prevalent PASC symptoms compared to those with severe- critical antecedent infections. These findings are not attributable to PASC duration, as longer PASC duration has been previously associated with fewer symptoms. To ensure early identification and linkage to specialized care, clinicians should be aware of PASC in patients with antecedent asymptomatic-mild acute COVID-19 infections.

Source: Walker, T.; Truong, A.; Summers, A.; Dixit, A.; Goldstein, F.; Hajjar, I.; Echols, M.; Cook, S.; Lee, E.; Tekwani, S.; Carroll, K.; Sanz, I.; Lee, E. H.; Han, J. Higher rates of long covid symptoms in patients with mild covid-19. Journal of General Internal Medicine ; 37:S280, 2022. Article in English | EMBASE | ID: covidwho-1995854 https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1995854?lang=en

Long COVID in children and adolescents

Abstract:

Purpose of review: Although acute COVID-19 has been milder in children and young people compared with adults, there is a concern that they may suffer persistent symptoms. There is a need to define the clinical phenotype, determine those most at risk, the natural course of the condition and evaluate preventive and therapeutic strategies for both mental health and physical symptoms.

Recent findings: More recent studies with control groups reported a lower prevalence of persistent symptoms in children and young people exposed to SARS-CoV-2. A systematic review and meta-analysis found that the frequency of the majority of reported persistent symptoms is similar in SARS-CoV-2 positive cases and controls. Children and young people infected with SARS-COV-2 had small but significant increases in persisting cognitive difficulties, headache and loss of smell. Factors associated with persisting, impairing symptoms include increased number of symptoms at the time of testing, female sex, older age, worse self-rated physical and mental health, and feelings of loneliness preinfection.

Summary: This review highlights the importance of a control group in studies following SARS-CoV-2 infection, the need for case definitions and research to understand the outcomes of long COVID in children and young people.

Source: Stephenson T, Shafran R, Ladhani SN. Long COVID in children and adolescents. Curr Opin Infect Dis. 2022 Sep 12. doi: 10.1097/QCO.0000000000000854. Epub ahead of print. PMID: 36094094.  https://journals.lww.com/co-infectiousdiseases/Fulltext/2022/10000/Long_COVID_in_children_and_adolescents.14.aspx (Full text)

After the virus has cleared-Can preclinical models be employed for Long COVID research?

Abstract:

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics.

After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics.

Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.

Source: Jansen EB, Orvold SN, Swan CL, Yourkowski A, Thivierge BM, Francis ME, Ge A, Rioux M, Darbellay J, Howland JG, Kelvin AA. After the virus has cleared-Can preclinical models be employed for Long COVID research? PLoS Pathog. 2022 Sep 7;18(9):e1010741. doi: 10.1371/journal.ppat.1010741. PMID: 36070309; PMCID: PMC9451097. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451097/ (Full text)

Long Covid: where we stand and challenges ahead

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches.

Source: Mantovani, A., Morrone, M.C., Patrono, C. et al. Long Covid: where we stand and challenges ahead. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01052-6 https://www.nature.com/articles/s41418-022-01052-6 (Full text)

Differences in Long-COVID Symptoms between Vaccinated and Non-Vaccinated (BNT162b2 Vaccine) Hospitalized COVID-19 Survivors Infected with the Delta Variant

This study compared differences in the presence of post-COVID symptoms among vaccinated and non-vaccinated COVID-19 survivors requiring hospitalization due to the Delta (B.1.617.2) variant. This cohort study included hospitalized subjects who had survived SARS-CoV-2 infection (Delta variant) from July to August 2021 in an urban hospital in Madrid, Spain. Individuals were classified as vaccinated if they received full administration (i.e., two doses) of BNT162b2 (“Pfizer-BioNTech”) vaccines. Other vaccines were excluded. Those with just one dose of the BNT162b2 vaccine were considered as non-vaccinated.
Patients were scheduled for a telephone interview at a follow-up around six months after infection for assessing the presence of post-COVID symptoms with particular attention to those symptoms starting after acute infection and hospitalization. Anxiety/depressive levels and sleep quality were likely assessed. Hospitalization and clinical data were collected from medical records. A total comprising 109 vaccinated and 92 non-vaccinated COVID-19 survivors was included.
Vaccinated patients were older and presented a higher number of medical comorbidities, particular cardiorespiratory conditions, than non-vaccinated patients. No differences in COVID-19 onset symptoms at hospitalization and post-COVID symptoms six months after hospital discharge were found between vaccinated and non-vaccinated groups. No specific risk factor for any post-COVID symptom was identified in either group.
This study observed that COVID-19 onset-associated symptoms and post-COVID symptoms six-months after hospitalization were similar between previously hospitalized COVID-19 survivors vaccinated and those non-vaccinated. Current data can be applied to the Delta variant and those vaccinated with BNT162b2 (Pfizer-BioNTech) vaccine.
Source: Fernández-de-las-Peñas C, Ortega-Santiago R, Fuensalida-Novo S, Martín-Guerrero JD, Pellicer-Valero OJ, Torres-Macho J. Differences in Long-COVID Symptoms between Vaccinated and Non-Vaccinated (BNT162b2 Vaccine) Hospitalized COVID-19 Survivors Infected with the Delta Variant. Vaccines. 2022; 10(9):1481. https://doi.org/10.3390/vaccines10091481 https://www.mdpi.com/2076-393X/10/9/1481/htm (Full text)

Larger gray matter volumes in neuropsychiatric long-COVID syndrome

Abstract:

Neuropsychiatric symptoms are the most common sequelae of long-COVID. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it is necessary to further investigate brain structural changes in relation to course and neuropsychiatric symptom burden in long-COVID. To this end, the present study investigated 3T-MRI scans from long-COVID patients suffering from neuropsychiatric symptoms (n = 30), and healthy controls (n = 20). Whole-brain comparison of gray matter volume (GMV) was conducted by voxel-based morphometry.

To determine whether changes in GMV are predicted by neuropsychiatric symptom burden and/or initial severity of symptoms of COVID-19 and time since onset of COVID-19 stepwise linear regression analysis was performed. Significantly enlarged GMV in long-COVID patients was present in several clusters (spanning fronto-temporal areas, insula, hippocampus, amygdala, basal ganglia, and thalamus in both hemispheres) when compared to controls. Time since onset of COVID-19 was a significant regressor in four of these clusters with an inverse relationship. No associations with clinical symptom burden were found.

GMV alterations in limbic and secondary olfactory areas are present in long-COVID patients and might be dynamic over time. Larger samples and longitudinal data in long-COVID patients are required to further clarify the mediating mechanisms between COVID-19, GMV and neuropsychiatric symptoms.

Source: Besteher B, Machnik M, Troll M, Toepffer A, Zerekidze A, Rocktäschel T, Heller C, Kikinis Z, Brodoehl S, Finke K, Reuken PA, Opel N, Stallmach A, Gaser C, Walter M. Larger gray matter volumes in neuropsychiatric long-COVID syndrome. Psychiatry Res. 2022 Sep 6;317:114836. doi: 10.1016/j.psychres.2022.114836. Epub ahead of print. PMID: 36087363; PMCID: PMC9444315. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9444315/ (Full text)

Fatigue in Covid-19 survivors: The potential impact of a nutritional supplement on muscle strength and function

Summary:

Background: Fatigue with reduced tolerance to exercise is a common persistent long-lasting feature amongst COVID-19 survivors. The assessment of muscle function in this category of patients is often neglected.

Aim: To evaluate the potential impact of a daily supplementation based on amino acids, minerals, vitamins, and plant extracts (Apportal®) on muscle function, body composition, laboratory parameters and self-rated health in a small group of COVID-19 survivors affected by fatigue.

Methods: Thirty participants were enrolled among patients affected by physical fatigue during or after acute COVID-19 and admitted to the post-COVID-19 outpatient service at Fondazione Policlinico Gemelli in Rome between 1st March 2021 and 30th April 2021. All participants were evaluated at first visit (t0) and at control visit (t1), after taking a daily sachet of Apportal® for 28 days. Muscle function was analyzed using hand grip strength test, exhaustion strength time and the number of repetitions at one-minute chair stand test. Body composition was assessed with bioelectrical impedance analysis (BIA). Laboratory parameters, including standard blood biochemistry and ferritin levels, were evaluated at the first visit and during the control visit. A quick evaluation of self-rated health, before COVID-19, at t0 and t1, was obtained through a visual analogue scale (VAS).

Results: Participants aged 60 years and older were 13 (43%). Females represented the 70% of the study sample. Participants hospitalized for COVID-19 with low-flow oxygen supplementation represented the 43.3% of the study sample while 3.3% received noninvasive ventilation (NIV) or invasive ventilation. Hand grip strength improved from 26.3 Kg to 28.9 Kg (p < 0.05) at t1 as compared to t0. The mean time of strength exhaustion increased from 31.7 s (sec) at t0 to 47.5 s at t1 (p < 0.05). Participants performed a higher number of repetitions (28.3 vs. 22.0; p < 0.05) during the one-minute chair stand test at t1 as compared to t0. A trend, although not significant, in reduction of ferritin levels was found after nutritional supplementation (94.4 vs. 84.3, respectively; p = 0.01). The self-rated health status increased by at least 13 points (t0, mean 57.6 ± 5.86; t1, mean 71.4 ± 6.73; p < 0.05).

Conclusion: After 28 days of nutritional supplementation with Apportal® in COVID-19 survivors affected by fatigue with reduced tolerance to exercise, we found a significant improvement in means of muscle strength and physical performance, associated with enhancement of self-rated health status between t0 and t1.

Source: Vincenzo Galluzzo, Maria Beatrice Zazzara, Francesca Ciciarello, Giulia Savera, Cristina Pais, Riccardo Calvani, Anna Picca, Emanuele Marzetti, Francesco Landi, Matteo Tosato, Steering Committee, Francesco Landi, Elisa Gremese, Coordination, Roberto Bernabei, Massimo Fantoni, Antonio Gasbarrini, Field investigators, Gastroenterology team, Serena Porcari, Carlo Romano Settanni, Geriatric team, Francesca Benvenuto, Giulia Bramato, Vincenzo Brandi, Angelo Carfì, Francesca Ciciarello, Sofia Fabrizi, Vincenzo Galluzzo, Maria Rita Lo Monaco, Anna Maria Martone, Emanuele Marzetti, Carmen Napolitano, Francesco Cosimo Pagano, Cristina Pais, Sara Rocchi, Elisabetta Rota, Andrea Salerno, Matteo Tosato, Marcello Tritto, Maria Beatrice Zazzara, Riccardo Calvani, Lucio Catalano, Anna Picca, Giulia Savera, Francesco Paolo Damiano, Alessandra Rocconi, Alessandro Galliani, Giovanni Spaziani, Salvatore Tupputi, Camilla Cocchi, Flavia Pirone, Federica D’Ignazio, Stefano Cacciatore, Infectious disease team, Roberto Cauda, Enrica Tamburrini, A. Borghetti, Simona Di Gianbenedetto, Rita Murri, Antonella Cingolani, Giulio Ventura, E. Taddei, D. Moschese, A. Ciccullo, A. Dusina, Internal Medicine team, Leonardo Stella, Giovanni Addolorato, Francesco Franceschi, Gertrude Mingrone, M.A. Zocco, Microbiology team, Maurizio Sanguinetti, Paola Cattani, Simona Marchetti, Brunella Posteraro, M. Sali, Neurology team, Alessandra Bizzarro, Alessandra Lauria, Ophthalmology team, Stanislao Rizzo, Maria Cristina Savastano, G. Gambini, G.M. Cozzupoli, C. Culiersi, Otolaryngology team, Giulio Cesare Passali, Gaetano Paludetti, Jacopo Galli, F. Crudo, G. Di Cintio, Y. Longobardi, L. Tricarico, M. Santantonio, Pediatric team, Danilo Buonsenso, P. Valentini, D. Pata, D. Sinatti, C. De Rose, Pneumology team, Luca Richeldi, Francesco Lombardi, A. Calabrese, Paolo Maria Leone, Maria Rosaria Calvello, Enrica Intini, Giuliano Montemurro, Psychiatric team, Gabriele Sani, Delfina Janiri, Alessio Simonetti, G. Giuseppin, M. Molinaro, M. odica, Radiology team, Luigi Natale, Anna Rita Larici, Riccardo Marano, Rheumatology team, Annamaria Paglionico, Luca Petricca, Luca Gigante, G. Natalello, A.L. Fedele, M.M. Lizzio, B. Tolusso, Clara Di Mario, S. Alivernini, Vascular team, Angelo Santoliquido, Luca Santoro, Angela Di Giorgio, Antonio Nesci, V. Popolla, Fatigue in Covid-19 survivors: The potential impact of a nutritional supplement on muscle strength and function, Clinical Nutrition ESPEN, 2022, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2022.08.029. (Full text)