Persistent Dyspnea after Recovery from COVID-19: Two Case Reports from Bangladesh

Globally, millions of documented SARS-CoV-2 infections with hundreds of thousands of deaths already reported. The majority of the fatal events have been reported in adults older than 70 years and those who have multiple co-morbidities. Despite the misery fatality of the virus, a significant number of peoples recovered from critical conditions also. Mild cases improved significantly with symptomatic management with strict maintenance of isolation. Therefore, many people believed that COVID-19 is a short-term illness, mild cases recovered completely within 2 weeks and severe or critical illness may require 3-6 weeks for complete recovery. However, the latest issue coming forward is delayed recovery in the surviving patients from severe or moderate COVID presenting with multisystem complications. We reported two cases of post COVID complications, newly named as "long COVID syndrome”. We described the common symptoms two patients experienced following recovery from acute phase of COVID-19 and how they were managed. We also discussed on the pathogenesis and management plan of common symptoms persisting after recovery of COVID-19.

Long COVID syndrome after SARS-CoV-2 survival in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients have a more severe COVID-19 course than the general population. Many patients report different persistent symptoms after SARS-CoV-2 infection. The aim of our study is to analyze the prevalence of long COVID-19 symptoms and assess if COVID-19 affects pulmonary hypertension (PH) prognosis. PAH/CTEPH patients who survived COVID-19 for at least 3 months before visiting the PH centers were included in the study. The patients were assessed for symptoms in acute phase of SARS-CoV-2 infection and persisting in follow-up visit, WHO functional class, 6-min walk distance, NT-proBNP concentration. The COMPERA 2.0 model was used to calculate 1-year risk of death due to PH at baseline and at follow-up. Sixty-nine patients-54 (77.3%) with PAH and 15 (21.7%) with CTEPH, 68% women, with a median age of 47.5 years (IQR 37-68)-were enrolled in the study. About 17.1% of patients were hospitalized due to COVID-19 but none in an ICU. At follow-up (median: 155 days after onset of SARS-CoV-2 symptoms), 62% of patients reported at least 1 COVID-19-related symptom and 20% at least 5 symptoms. The most frequently reported symptoms were: fatigue (30%), joint pain (23%), muscle pain (17%), nasal congestion (17%), anosmia (13%), insomnia (13%), and dyspnea (12%). Seventy-two percent of PH patients had a low or intermediate-low risk of 1-year death due to PH at baseline, and 68% after COVID-19 at follow-up. Over 60% of PAH/CTEPH patients who survived COVID-19 suffered from long COVID-19 syndrome, but the calculated 1-year risk of death due to PH did not change significantly after surviving mild or moderate COVID-19.

Ventilation dynamics using a portable device coupled to the six-minute walk test in people with long-COVID syndrome: a preliminary study.

OBJECTIVE: To investigated the dynamic ventilatory responses and their influence on functional exercise capacity in patients with long-COVID-19 syndrome (LCS). RESULTS: Sixteen LCS patients were subjected to resting lung function (spirometry and respiratory oscillometry-RO) and cardiopulmonary performance to exercise (Spiropalm®-equipped six-minute walk test-6MWT and cardiopulmonary exercise test-CPX). At rest, spirometry showed a normal, restrictive and obstructive pattern in 87.5%, 6.25% and 6.25% of participants, respectively. At rest, RO showed increased resonance frequency, increased integrated low-frequency reactance and increased difference between resistance at 4-20 Hz (R4-R20) in 43.7%, 50%, and 31.2% of participants, respectively. The median of six-minute walking distance (DTC6) was 434 (386-478) m, which corresponds to a value of 83% (78-97%) of predicted. Dynamic hyperinflation (DH) and reduced breathing reserve (BR) were detected in 62.5% and 12.5% of participants, respectively. At CPX, the median peak oxygen uptake (VO2peak) was 19 (14-37) ml/kg/min. There was a significant correlation of 6MWD with both R4-R20 (rs=-0.499, P = 0.039) and VO2peak (rs=0.628, P = 0.009). Our results indicate that DH and low BR are contributors to poor exercise performance, which is associated with peripheral airway disease. These are promising results considering that they were achieved with simple, portable ventilatory and metabolic systems.

Immunological Facet and Inception after Post-COVID-19 Vaccination.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced coronavirus disease 2019 (COVID-19) pandemic has produced an unparalleled setback for the world's economy and health. One of the best therapies to significantly lower severe illness and mortality from SARS-CoV-2 infection is vaccination. Worldwide vaccination campaigns are being implemented. New-onset autoimmune problems, such as immune thrombotic thrombocytopenia, autoimmune liver disorders, IgA nephropathy, Guillain-Barré syndrome, systemic lupus erythematosus, and rheumatoid arthritis, have recently been described more frequently after receiving COVID-19 vaccine. The creation of specific autoantibodies, molecular mimicry, and the function of specific vaccine adjuvants all emerge to play a significant role in autoimmunity. The post-acute sequelae of SARS-CoV-2, usually known as Long Covid Syndrome, are beginning to be better understood in terms of the disparities in immune responses seen in individuals with and without the condition. We anticipate that the knowledge gleaned from several COVID-19 investigations will be put to use in research on the inflammatory mechanisms implicated in serious and protracted illnesses, which is still a key unmet need.

Neuroimmune dysfunction

Many investigators have suggested that long COVID is an autoimmune disease. Classic autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (MS), are characterized by a misdirected and overzealous immune reactivity. Cytokines are small proteins secreted mostly by immune blood cells. Neuroimmunology is dedicated to understanding the interaction between the immune and nervous systems, demonstrated clearly in neurologic diseases such as MS and myasthenia gravis. Cytokines are important in patients that experience neuropsychiatric symptoms during, and long after chemotherapy, known as chemo brain. Important evidence for auto immunity in patients with long-COVID relates to the presence of antibodies in the blood or chronic fatigue syndrome that are directed against normal brain tissue. Immune responses themselves can mimic viral illnesses and some of the symptoms of the long-COVID syndrome, albeit transiently. © 2023 John Wiley & Sons Ltd. All rights reserved.

Brain homeostasis run amok

This chapter elucidates how normal homeostatic brain mechanisms may run amok and how this process explains the presently unexplained symptoms of long-COVID syndrome. It describes how reorganizations in brain connectivity, referred to as neuroplasticity, provide us with a framework for the brain independently perpetuating symptoms such as fatigue, pain, cognitive problems, sleep disturbances, and headaches in the absence of peripheral organ damage, and reviews supporting studies done in chronic fatigue syndrome/Myalgic encephalomyelitis and fibromyalgia. The chapter provides evidence from recent reports that such neuroplasticity is associated with the persistent symptoms of long-COVID syndrome. The brain's automatic responses, those not engaged in consciousness, work via the autonomic nervous system, which controls breathing, heart rate, blood pressure, hormone secretions, and bowel functions, among other things. The human nervous system consists of many, highly interconnected circuits or networks that control everything the body does, from simple reflexes to higher order thinking, and everything in between. © 2023 John Wiley & Sons Ltd. All rights reserved.

Historical perspectives, including chronic fatigue syndrome/Myalgic Encephalomyelitis and Fibromyalgia

The illnesses that most resemble long-COVID syndrome are Chronic Fatigue Syndrome (CFS)/Myalgic Encephalomyelitis (ME) and fibromyalgia. This chapter describes the similar symptoms of these conditions to long-COVID syndrome. It discusses what is termed chronic Lyme disease, or post-treatment Lyme disease syndrome, as an example of an analogous, unexplained syndrome following an infection. CFS/ME are diagnostic labels used to describe a syndrome characterized by chronic fatigue, post-exertional malaise, muscle pain, and cognitive disturbances often attributed to a possible infection but without a defined cause or pathology. Fibromyalgia, like CFS/ME, has been around for centuries in various guises. Abnormalities of the central and autonomic nervous system are prominent in fibromyalgia and CFS/ME. CFS/ME and fibromyalgia are sometimes referred to as functional, somatic syndromes. Patients with CFS/ME and fibromyalgia often express frustration with medical professionals' approach to their illness. © 2023 John Wiley & Sons Ltd. All rights reserved.

IL-6 Serum Levels in COVID-19 Patients With Vertigo.

Introduction Dizziness and vertigo represent well-established symptoms of COVID-19. An overexpression of cytokines, a condition often described with the term "cytokine storm" or "hypercytokinemia", is a key characteristic of SARS-Cov-2 infection and plays a pivotal role in disease progression and prognosis. Among them, IL-6 is of major importance.  Purpose The purpose of this study is to investigate any probable IL-6 serum titer difference in COVID-19 patients with vertigo (V+) or without vertigo (V-) admitted to the COVID-19 internal medicine departments of Attikon University Hospital, Athens, Greece, within 12 months. Methods The sample consisted of 52 COVID-19 patients who were diagnosed between January 1, 2020, and December 31, 2020. Of those, 31 reported vertigos during their admission (V+), while the remaining 21 COVID-19 patients did not complain of such symptoms (V-). Results Higher IL-6 serum levels post-COVID-19 infections lead to higher incidence rates of vertigo symptoms (p<.005), regardless of gender and age (p.005).

COVID-Associated Cast-Forming Cholangiopathy: A Commentary on Disease Mechanism, Treatment, and Prognosis.

The complete impact of COVID-19 infection continues to develop since the onset of the COVID-19 pandemic. COVID-19 cholangiopathy has been recently described in a subset of patients who recovered from severe COVID-19 infection. The most common phenotype of patients suffering from COVID-19 cholangiopathy had severe infection requiring a stay in the intensive care unit, mechanical ventilation and vasopressor medications. Patients with COVID-cholangiopathy present with severe and prolonged cholestatic liver injury. In cases where biliary cast formation is identified, we defined the entity as "COVID-19 cast-forming cholangiopathy". This subset of COVID-19 cholangiopathy is not well understood and there are no standardized diagnosis or management to this date. The reported clinical outcomes are variable, from resolution of symptoms and liver test abnormalities to liver transplant and death. In this commentary, we discuss the proposed pathophysiology, diagnosis, management, and prognosis of this disease.

Cystatin-c May Indicate Subclinical Renal Involvement, While Orosomucoid Is Associated with Fatigue in Patients with Long-COVID Syndrome.

Long-COVID syndrome is associated with high healthcare costs, but its pathophysiology is not yet fully understood. Inflammation, renal impairment or disturbance of the NO system emerge as potential pathogenetic factors. We aimed to investigate the relationship between symptoms of long-COVID syndrome and serum levels of cystatin-c (CYSC), orosomucoid (ORM), l-arginine, symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). A total of 114 patients suffering from long-COVID syndrome were included in this observational cohort study. We found that serum CYSC was independently associated with the anti-spike immunoglobulin (S-Ig) serum level (OR: 5.377, 95% CI: 1.822-12.361; p = 0.02), while serum ORM (OR: 9.670 (95% CI: 1.34-9.93; p = 0.025) independently predicted fatigue in patients with long-COVID syndrome, both measured at baseline visit. Additionally, the serum CYSC concentrations measured at the baseline visit showed a positive correlation with the serum SDMA levels. The severity of abdominal and muscle pain indicated by patients at the baseline visit showed a negative correlation with the serum level of L-arginine. In summary, serum CYSC may indicate subclinical renal impairment, while serum ORM is associated with fatigue in long-COVID syndrome. The potential role of l-arginine in alleviating pain requires further studies.

Lingering SARS-CoV-2 in Gastric and Gallbladder Tissues of Patients with Previous COVID-19 Infection Undergoing Bariatric Surgery.

BACKGROUND: Lingering severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gut tissue might be a source of infection during bariatric surgery. This study aimed to confirm the presence of SARS-CoV-2 nucleocapsid in gastric and gallbladder tissues removed during bariatric surgery in individuals previously infected with coronavirus disease 2019 (COVID-19) who had negative polymerase chain reaction results prior to the surgery. METHODS: Gastric and gallbladder specimens from 80 patients who underwent bariatric surgery between November 2021 and May 2022 and had a history of COVID-19 infection with gastrointestinal symptoms were examined for the presence of lingering SARS-CoV-2 nucleocapsid proteins using immunohistochemistry. RESULTS: Gastric specimens from 26 (32.5%) patients and 4 (100%) cholecystectomy specimens showed positive cytoplasmic staining for the anti-SARS-CoV-2 nucleocapsid protein in surface mucosal epithelial cells. The mean age was 37.8 ± 10.3 years. The average body mass index was 44.2 ± 7.0 kg/m2; most of the patients were females (71.3%). The positive staining group was significantly younger than the negative staining group (p = 0.007). The full-dose vaccination rate was 58.8%, with a median of 91 days after the last vaccine dose. A positive serological anti-spike IgG response was observed in 99% of the patients. The median time between initial COVID-19 infection and surgery was 274 and 380 days in the positive and negative staining groups, respectively (p = 0.371). CONCLUSION: Gastric and gallbladder tissues can retain SARS-CoV-2 particles for a long time after COVID-19 infection, handling stomach specimens from patients during an operation must be done with care, as we usually do, but now with the knowledge that in 1/3 of patients they can be present. Performing LSG on post-COVID patients did not seem to increase perioperative morbidity.

Epidemiological and clinical perspectives of long COVID syndrome.

Long COVID, or post-acute COVID-19 syndrome, is characterized by multi-organ symptoms lasting 2+ months after initial COVID-19 virus infection. This review presents the current state of evidence for long COVID syndrome, including the global public health context, incidence, prevalence, cardiopulmonary sequelae, physical and mental symptoms, recovery time, prognosis, risk factors, rehospitalization rates, and the impact of vaccination on long COVID outcomes. Results are presented by clinically relevant subgroups. Overall, 10-35% of COVID survivors develop long COVID, with common symptoms including fatigue, dyspnea, chest pain, cough, depression, anxiety, post-traumatic stress disorder, memory loss, and difficulty concentrating. Delineating these issues will be crucial to inform appropriate post-pandemic health policy and protect the health of COVID-19 survivors, including potentially vulnerable or underrepresented groups. Directed to policymakers, health practitioners, and the general public, we provide recommendations and suggest avenues for future research with the larger goal of reducing harms associated with long COVID syndrome.

Negative correlation between ACE2 gene expression levels and loss of taste in a cohort of COVID-19 hospitalized patients: New clues to long-term cognitive disorders.

In early 2020, one of the most prevalent symptoms of SARS-CoV-2 infection was the loss of smell (anosmia), found in 60-70% of all cases. Anosmia used to occur early, concomitantly with other symptoms, and often persisted after recovery for an extended period, sometimes for months. In addition to smell disturbance, COVID-19 has also been associated with loss of taste (ageusia). The latest research suggests that SARS-CoV-2 could spread from the respiratory system to the brain through receptors in sustentacular cells localized to the olfactory epithelium. The virus invades human cells via the obligatory receptor, angiotensin-converting enzyme II (ACE2), and a priming protease, TMPRSS2, facilitating viral penetration. There is an abundant expression of both ACE2 and TMPRSS2 in sustentacular cells. In this study, we evaluated 102 COVID-19 hospitalized patients, of which 17.60% presented anosmia and 9.80% ageusia. ACE1, ACE2, and TMPRSS2 gene expression levels in nasopharyngeal tissue were obtained by RT-qPCR and measured using ΔCT analysis. ACE1 Alu287bp association was also evaluated. Logistic regression models were generated to estimate the effects of variables on ageusia and anosmia Association of ACE2 expression levels with ageusia. was observed (OR: 1.35; 95% CI: 1.098-1.775); however, no association was observed between TMPRSS2 and ACE1 expression levels and ageusia. No association was observed among the three genes and anosmia, and the Alu287bp polymorphism was not associated with any of the outcomes. Lastly, we discuss whetherthere is a bridge linking these initial symptoms, including molecular factors, to long-term COVID-19 health consequences such as cognitive dysfunctions.

The relationship between chronic immune response and neurodegenerative damage in long COVID-19.

In the past two years, the world has faced the pandemic caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), which by August of 2022 has infected around 619 million people and caused the death of 6.55 million individuals globally. Although SARS-CoV-2 mainly affects the respiratory tract level, there are several reports, indicating that other organs such as the heart, kidney, pancreas, and brain can also be damaged. A characteristic observed in blood serum samples of patients suffering COVID-19 disease in moderate and severe stages, is a significant increase in proinflammatory cytokines such as interferon-α (IFN-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interleukin-6 (IL-6) and interleukin-18 (IL-18), as well as the presence of autoantibodies against interferon-α (IFN-α), interferon-λ (IFN-λ), C-C motif chemokine ligand 26 (CCL26), CXC motif chemokine ligand 12 (CXCL12), family with sequence similarity 19 (chemokine (C-C motif)-like) member A4 (FAM19A4), and C-C motif chemokine ligand 1 (CCL1). Interestingly, it has been described that the chronic cytokinemia is related to alterations of blood-brain barrier (BBB) permeability and induction of neurotoxicity. Furthermore, the generation of autoantibodies affects processes such as neurogenesis, neuronal repair, chemotaxis and the optimal microglia function. These observations support the notion that COVID-19 patients who survived the disease present neurological sequelae and neuropsychiatric disorders. The goal of this review is to explore the relationship between inflammatory and humoral immune markers and the major neurological damage manifested in post-COVID-19 patients.

Expert guidance on the management and challenges of long-COVID syndrome: a systematic review.

INTRODUCTION: Long-COVID is a condition characterized by the permanence of symptoms beyond 4 weeks after an initial infection. It affects 1 out of 5 people and is loosely related to the severity of acute infection and pathological mechanisms, which are yet to be understood. AREAS COVERED: This article looks at currently available and under-studied therapies for long-COVID syndrome. It particularly gives focus to ongoing trials and reviews the underlying mechanisms. A comprehensive literature search was performed on PubMed and clincaltrial.gov of clinical trials concerning the management of long-COVID syndrome. EXPERT OPINION: 'Long-COVID' syndrome is a new emergency characterized by several symptoms such as fatigue, dyspnea, cognitive and attention disorders, sleep disorders, post-traumatic stress disorder, muscle pain, and concentration problems. Despite the many guidelines available to date, there are no established treatments of long-COVID. Pharmacological research is studying known drugs that act on the reduction or modulation of systemic inflammation, or innovative drugs used in similar pathologies. Rehabilitation now seems to be the safest treatment to offer, whereas we will have to wait for the pharmacological research trials in progress as well as plan new trials based on a better understanding of the pathogenic mechanisms.

AMBULATORY BLOOD PRESSURE VARIABILITY IN YOUNG ADULTS WITH LONG-COVID SYNDROME.

OBJECTIVE: The aim: To perform an overall assessment of BP and BP variability using ambulatory measurements in young adults with long COVID syndrome. PATIENTS AND METHODS: Materials and methods: We enrolled young patients with diagnosed long-COVID syndrome (n = 58, mean age 23.07 ± 1.54 years), compared with an age-matched healthy subjects who had not suffered from COVID-19 (n = 57, mean age 22.9 ± 1.83 years). Patients with long-COVID syndrome had recovered from mild/moderate illness and none had required hospitalization. Ambulatory 24 hours blood pressure (AMBP) parameters (mean BP, daytime BP, nighttime BP, pulse pressure, nocturnal systolic BP dipping, dipper status) were measured in all participants. The variability of systolic BP (SBP) and diastolic BP (DBP) values was assessed by the following common metrics, including the average real variability (ARV), the coefficient of variation (CV), the standard deviation (SD), and the weighed SD of SBP and DBP. RESULTS: Results: The average values of 24-hour ambulatory blood pressure, mean BP, daytime and nighttime systolic BP, diastolic BP and pulse pressure were found to be significantly different among patients with long COVID syndrome and control group. Group analyses showed that this difference was in SBP mean values (127.1 ± 6.65 mmHg and 115.93 ± 6.24 mmHg respectively) and DBP mean values (73.31 ± 5.30 mmHg and 68.79 ± 5.5 mmHg respectively) mainly at night. PP values at daytime were almost similar among groups, but PP values at nighttime were higher in patients with long-COVID syndrome (53.8 (52.44- 55.14) mmHg and 47.14 (46.45 - 47.88) mmHg respectively). Nocturnal SBP dipping was better in control group than in patients with long-COVID syndrome ( 5.3 ± 5.68 and 3.1 ± 3.79 mmHg respectively). Only 13 (22.4%) patients with long-COVID syndrome had normal dip-per status while more than half - 38 (66.7%) in healthy subjects. The values of ARV of SBP and DBP over 24-hour, awake, and asleep time frames were found to be greater in patients with long COVID syndrome than healthy controls (p < 0.05). CONCLUSION: Conclusions: Patients with long- COVID syndrome have higher BP mean values of 24-hour ABPM particularly at nightime, significant blood pressure BP variability, which increases the risk of cardiovascular events in future. Nevertheless, the further prospective investigations is warranted to investigate the potential mechanisms and causality associations.