Long Covid Syndrome/Symptoms

Clinical signs and symptoms of long COVID can be grouped in the following clusters:

1. Respiratory: shortness of breath, congestion, persistent cough, pulmonary embolism, etc.
2. Neurological/psychiatric: brain fog, malaise, tiredness, headaches, migraines, depression, inability to focus/concentrate, altered cognition, insomnia, vertigo, panic attacks, tinnitus, anosmia, phantom smells, parosmia, etc.
3. Musculoskeletal: myalgias, fatigue, weakness, joint pains, inability to exercise, post-exertional malaise, inability to perform normal activities of daily life (ADL’s), muscle mass loss, etc.
4. Cardiovascular: blood clots, heart problems (including hear attack), palpitations, arrhythmias, Raynaud like syndrome, hypotension, tachycardia on exertion.
5. Autonomic: Postural tachycardia syndrome (POTs), abnormal sweating.
6. GIT disturbance: Anorexia, diarrhea, bloating, vomiting, nausea, etc.
7. Dermatologic: Itching, rashes, dermatographia, hair loss.
8. Mucus membranes: Running nose, sneezing, Burning and itchy eyes.
9. Auditory: tinnitus, hearing loss and vertigo.
10. Endocrine dysfunction: adrenal gland dysfunction, thyroid dysfunction, estrogen and progesterone dysfunction, testosterone dysfunction.

 

The global prevalence of post-COVID syndrome four months after the infection is now estimated at 49% of all patients. About 54% of hospitalized patients had long-hauler symptoms; about 34% of non-hospitalized patients had symptoms. Among those who were hospitalized, only 26% fully recovered after five months, and nearly half still had symptoms one year later. Those who needed mechanical ventilation were 58% less likely to heal fully; obese people were half as likely to recover fully. At the two-year mark, 55% of hospitalized patients had at least one COVID-19 symptom, compared to 68% six months after infection. Patients generally had poorer health two years later and still experienced pain, fatigue, problems with sleeping and mental health issues. They went to a doctor more often, had ongoing difficulty exercising, and experienced poor quality of life.

 

It may be, therefore, that the spike protein portion of the SAR-CoV-2 virus or its fragments, such as the S1 portion, are responsible for much of the pathological findings in long-haul COVID. The spike protein or its fragments can circulate in the body after infection and cause inflammation and blood clotting in any part of the body where it accumulates.

 

Long Covid has been linked to more than 200 symptoms, according to the following scientific papers. Shortness of breath, fatigue, and sleep disorders or insomnia are the most common symptoms. Others include anxiety, depression, body aches, headache, heart palpitations and “brain fog” — which describes challenges associated with cognition, like thinking, concentration, communication, comprehension, memory and motor function. Some sufferers have organ damage, to the heart, lungs, kidneys, skin and brain.

 

Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum, and meningeal cytotoxic T lymphocyte infiltration was seen in 79% patients. SARS-CoV-2 could be detected in the brains of 53% of examined patients, with SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem, according to Jakob Matschke et al., “Neuropathology of patients with COVID-19 in Germany: a post-mortem case series,” Lancet Neurology 2020; 19:919–29 October 5, 2020, https://doi.org/10.1016/S1474-4422(20)30308-2, JIF 59.935 (top 0.5% journals in Clinical Neurology).

 

SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis, according to Clemens A. Schmitt et al., “COVID-19 and cellular senescence,” Nature Reviews Immunology, 05 October 2022, https://doi.org/10.1038/s41577-022-00785-2, JIF 108.555 (top 0.6% journals in Immunology).

 

In the UK, for example, an estimated 945 000 people (1.5% of the population) had self-reported long COVID on July 4, 2021, according to the UK Office for National Statistics, as disclosed in the Editorial, “Understanding long COVID: a modern medical challenge,” Lancet, Volume 398, Issue 10302, P725, August 28, 2021, https://doi.org/10.1016/S0140-6736(21)01900-0, JIF 202.731 (top 0.6% journals in Medicine, General & Internal).

 

Most COVID-19 survivors had a good physical and functional recovery during 1-year follow-up, and had returned to their original work and life. The health status in our cohort of COVID-19 survivors at 12 months was still lower than that in the control population, according to Lixue Huang et al., “1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study,” Lancet 2021; 398:747-58, August 28, 2021, https://doi.org/10.1016/S0140-6736(21)01755-4, JIF 202.731 (top 0.6% journals in Medicine, General & Internal).

 

There is growing evidence suggesting that beyond the acute phase of SARS-CoV-2 infection, people with COVID-19 could experience a wide range of post-acute sequelae, including diabetes, according to Yan Xie et al., “Risks and burdens of incident diabetes in long COVID: a cohort study,” Lancet Diabetes & Endocrinology 2022;10:311-321, March 21, 2022, https://doi.org/10.1016/S2213-8587(22)00044-4, JIF 44.867 (top 1.4% journals in Endocrinology & Metabolism).

 

Regardless of initial disease severity, COVID-19 survivors had longitudinal improvements in physical and mental health, with most returning to their original work within 2 years; however, the burden of symptomatic sequelae remained fairly high. COVID-19 survivors had a remarkably lower health status than the general population at 2 years. The study findings indicate that there is an urgent need to explore the pathogenesis of long COVID and develop effective interventions to reduce the risk of long COVID, according to Lixue Huang et al., “Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study,” Lancet Respiratory Medicine, 10:863-76, September 2022, https://doi.org/10.1016/S2213-2600(22)00126-6, JIF 102.642 (top 1.5% journals in Respiratory System and top 3% journals in Critical Care Medicine).

 

The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials, according to The PHOSP-COVID Collaborative Group, “Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study,” Lancet Respiratory Medicine 2022;10:761-75, August 01, 2022, https://doi.org/10.1016/S2213-2600(22)00127-8, JIF 102.642 (top 1.5% journals in Respiratory System and top 3% journals in Critical Care Medicine).

 

Extensive viral protein expression and infectious viral particles were detected in neurospheres and brain organoids infected with SARS-CoV-2, which suggest SARS-CoV-2 can productively infect the human brain. These results provided insight on the pathognomonic symptoms of anosmia (loss of smell) and ageusia (loss of taste) as well as other neurological manifestations of COVID-19 including seizure, encephalopathy, encephalitis, Guillain-Barre syndrome, and Miller Fisher syndrome, according to Bao-Zhong Zhang et al., “SARS-CoV-2 infects human neural progenitor cells and brain organoids,” Cell Research (2020) 30:928–931; 4 August 2020, https://doi.org/10.1038/s41422-020-0390-x, JIF 46.351 (top 2.1% journals in Cell Biology).

 

Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic β cells can be infected by SARS-CoV-2 and cause β cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in β cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic β cells in patients who succumbed to COVID-19 and selectively infects human islet β cells in vitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces β cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic β cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce β cell killing, according to Chien-Ting Wu et al., “SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment,” Cell Metabolism, 2021 Aug 3;33(8):1565-1576.e5, https://doi.org/10.1016/j.cmet.2021.05.013, JIF 31.373 (top 2% journals in Endocrinology & Metabolism and 4% journals in Cell Biology).

 

The spike protein itself, in the absence of the rest of the virus, can cause inflammation and damage to the endothelium or the cell lining of the lungs and the vascular system. This damage leads to promotion of lung injury by decreasing the level of ACE2, as well as the development of blood clots, which can cause heart attack and stroke. However, N-acetyl-L-cysteine (NAC) treatment can be used as a rescue, according to Yuyang Lei, “SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2,” Circulation Research, 2021; 128:1323-1326, https://doi.org/10.1161/CIRCRESAHA.121.318902, JIF 23.218 (top 3% journals in Peripheral Vascular Disease, top 4% journals in Cardiac & Cardiovascular Systems and top 4% journals in Hematology).

 

Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism. Anne Louise Oaklander et al., “Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID,” Neurology Neuroimmunology & Neuroinflammation 2022;9:e1146, https://doi.org/10.1212/NXI.0000000000001146, JIF 11.360 (top 6% journals in Clinical Neurology and top 7% journals in Neurosciences).

 

Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden, such as brain fog and cognitive dysfunction, including poor attention, executive functioning, problem solving, and decision making (85%), memory impairments, including both short-term and long-term memory loss (73%), according to Hannah E. Davis et al., “Characterizing long COVID in an international cohort: 7 months of symptoms and their impact,” eClinicalMedicine, 38 (July 15, 2021) 101019, https://doi.org/10.1016/j.eclinm.2021.101019, JIF 17.033 (top 7% journals in Medicine, General & Internal).

 

COVID-19 survivors were less accurate and slower in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores. The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age, according to Adam Hampshire et al., “Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort,” eClinicalMedicine 2022;47:101417, 28 April 2022, https://doi.org/10.1016/j.eclinm.2022.101417, JIF 17.033 (top 7% journals in Medicine, General & Internal).

 

COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30% of cases and can persist even after the infection is over (long COVID). Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARSCoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19, according to Mirren Charnley et al., “Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19,” Nature Communications, (2022) 13:3387, https://doi.org/10.1038/s41467-022-30932-1, JIF 17.694 (top 8% journals in Multidisciplinary Sciences).

 

Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury, according to Ibolya Rutkai et al., “Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates,” Nature Communications, (2022) 13:1745, https://doi.org/10.1038/s41467-022-29440-z, JIF 17.694 (top 8% journals in Multidisciplinary Sciences).

 

Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise, according to Inderjit Singh et al., “Persistent exertional intolerance after COVID-19 Insights from invasive cardiopulmonary exercise testing,” Chest, 161#1, 54-63, January 01, 2022, https://doi.org/10.1016/j.chest.2021.08.010, JIF 11.393 (top 9% journals in Respiratory System and top 15% journals in Critical Care Medicine).

 

Emerging clinical data from the current COVID-19 pandemic suggests that ~ 40% of COVID-19 patients develop neurological symptoms attributed to viral encephalitis while in COVID long haulers chronic neuro-inflammation and neuronal damage result in a syndrome described as Neuro-COVID. We hypothesize that SAR-COV2 induces mitochondrial dysfunction and activation of the mitochondrial-dependent intrinsic apoptotic pathway, resulting in microglial and neuronal apoptosis. The goal of our study was to determine the effect of SARS-COV2 on mitochondrial biogenesis and to monitor cell apoptosis in human microglia non-invasively in real time using Raman spectroscopy, providing a unique spatio-temporal information on mitochondrial function in live cells. We treated human microglia with SARS-COV2 spike protein and examined the levels of cytokines and reactive oxygen species (ROS) production, determined the effect of SARS-COV2 on mitochondrial biogenesis and examined the changes in molecular composition of phospholipids. Our results show that SARS- COV2 spike protein increases the levels of pro-inflammatory cytokines and ROS production, increases apoptosis and increases the oxygen consumption rate (OCR) in microglial cells. Increases in OCR are indicative of increased ROS production and oxidative stress suggesting that SARS-COV2 induced cell death. Raman spectroscopy yielded significant differences in phospholipids such as Phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC), which account for ~ 80% of mitochondrial membrane lipids between SARS-COV2 treated and untreated microglial cells. These data provide important mechanistic insights into SARS-COV2 induced mitochondrial dysfunction which underlies neuropathology associated with Neuro-COVID, according to Erin Clough et al., “Mitochondrial Dynamics in SARS‑COV2 Spike Protein Treated Human Microglia: Implications for Neuro‑COVID,” Journal of Neuroimmune Pharmacology (2021) 16:770–784, https://doi.org/10.1007/s11481-021-10015-6, JIF 7.285 (top 10% journals in Pharmacology & Pharmacy and top 14% journals in Neurosciences).

 

Fatigue predominance was the most common presentation and was associated with elevated IL-6 levels and female sex. Dyspnea predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were more likely than erythrocyte sedimentation rate and C-reactive protein to be elevated in patients with post-acute sequelae of SARS-CoV-2 infection, according to Ravindra Ganesh et al., “The female predominant persistent immune dysregulation of the post COVID syndrome: A cohort study,” Mayo Clinic Proceedings 2022 Mar, 97(3), 454-464, https://doi.org/10.1016/j.mayocp.2021.11.033, JIF 12.213 (top 11% journals in Medicine, General & Internal).

 

The preliminary evidence on the pulmonary, cardiovascular, neurological, hematological, multisystem inflammatory, renal, endocrine, gastrointestinal, and integumentary sequelae show that COVID-19 continues after acute infection. Interdisciplinary monitoring with holistic management that considers nutrition, physical therapy, psychological management, meditation, and mindfulness in addition to medication will allow for the early detection of post-acute COVID-19 sequelae symptoms and prevent long-term systemic damage, according to Shreeya Joshee et al., “Long-term effects of COVID-19,” Mayo Clinic Proceedings, March 01, 2022, 97(3), 579-599, https://doi.org/10.1016/j.mayocp.2021.12.017, JIF 12.213 (top 11% journals in Medicine, General & Internal).

 

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19, according to Jungang Chen et al., “SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus,” Communications Biology (2021) 4:682, https://doi.org/10.1038/s42003-021-02220-z, JIF 6.548 (top 16% journals in Biology).

 

A recent meta-analysis estimated 80% of those infected with SARS-CoV-2 develop at least 1 long-term symptom. In addition, time since infection, acute phase severity, geographic region, and select sociodemographic characteristics, such as age and sex, are among the factors likely to influence post-COVID-19 condition prevalence estimates, according to Chen Chen et al., “Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: A meta-analysis and systematic review,” The Journal of Infectious Diseases, 16 April 2022, jiac136, https://doi.org/10.1093/infdis/jiac136, JIF 7.759 (top 17% journals in Microbiology, top 20% journals in Infectious Diseases and top 24% journals in Immunology).

 

Persistent symptoms associated with post-acute COVID-19 syndrome seem to impact physical and cognitive function, health-related quality of life, and participation in society. The most common persistent symptoms reported a year after infection were fatigue (82%), brain fog (67%), and headache (60%), as disclosed in Laura Tabacof et al. “Post-acute COVID-19 syndrome negatively impacts physical function, cognitive function, health-related quality of life, and participation,” American Journal of Physical Medicine & Rehabilitation, January 2022, Volume 101, Issue 1, pp. 48-52, https://doi.org/10.1097/PHM.0000000000001910, JIF 3.412 (top 18% journals in Rehabilitation and top 40% journals in Sport Sciences).

 

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS), according to Theoharis C. Theoharides et al. “Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue,” Biofactors 2021;47:232–241, https://doi.org/10.1002/biof.1726, JIF 6.438 (top 20% journals in Endocrinology & Metabolism and top 22% journals in Biochemistry & Molecular Biology).

 

Chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The SARS-CoV-2 S1 protein (a portion of the spike protein) persisted in the immune cells called nonclassical monocytes of patients with long-haul COVID for up to 15 months after initial infections. The S1 protein found in these patients appeared to be debris left over from initial infection with the virus and was not the result of ongoing, persistent viral growth and replication. Therefore, it is unlikely that long-haul COVID patients are infectious to others. Rather, the scientific evidence indicates that these patients’ immune systems are stuck on overdrive, pouring out inflammatory molecules in response to the persistence of the S1 spike protein fragment. These monocytes are capable of causing inflammation throughout the entire body, according to Bruce K. Patterson et al., “Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection,” Frontiers in Immunology, 10 January 2022, https://doi.org/10.3389/fimmu.2021.746021, JIF 8.787 (top 22% journals in Immunology).

 

The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%), acording to Sandra Lopez-Leon et al., “More than 50 long‑term effects of COVID‑19: a systematic review and meta‑analysis,” Scientific Reports (2021) 11:16144, https://doi.org/10.1038/s41598-021-95565-8, JIF 4.997 (top 26% journals in Multidisciplinary Sciences).

 

Retrospective cohort study of 196,992 adults after COVID-19 infection in Clalit Health Services members in Israel between March 2020 and January 2021. The control cohort of 590,976 adults with at least one negative PCR and no positive PCR were age- and sex-matched. We did not observe an increased incidence of neither pericarditis nor myocarditis in adult patients recovering from COVID-19 infection, according to Ortal Tuvali et al., “The Incidence of Myocarditis and Pericarditis in Post COVID-19 Unvaccinated Patients—A Large Population-Based Study,” Journal of Clinical Medicine, 2022, 11, 2219. https://doi.org/10.3390/jcm11082219, JIF 4.964 (top 32% journals in Medicine, General & Internal).

 

Long COVID or post-COVID-19 syndrome first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is poorly understood as it affects COVID-19 survivors at all levels of disease severity, even younger adults, children, and those not hospitalized. While the precise definition of long COVID may be lacking, the most common symptoms reported in many studies are fatigue and dyspnoea that last for months after acute COVID-19. Other persistent symptoms may include cognitive and mental impairments, chest and joint pains, palpitations, myalgia, smell and taste dysfunctions, cough, headache, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long COVID, which the current review aims to address. In brief, long COVID may be driven by long-term tissue damage (e.g. lung, brain, and heart) and pathological inflammation (e.g. from viral persistence, immune dysregulation, and autoimmunity). The associated risk factors may include female sex, more than five early symptoms, early dyspnoea, prior psychiatric disorders, and specific biomarkers (e.g. D-dimer, CRP, and lymphocyte count), as disclosed in Shin Jie Yong, “Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments,” Infectious Diseases, 2021, Vol. 0, No. 0, 1-18, https://doi.org/10.1080/23744235.2021.1924397, JIF 5.838 (top 33% journals in Infectious Diseases).

 

Myocardial inflammation in COVID-19 has been documented. Current evidence demonstrates myocardial inflammation with or without direct cardiomyocyte damage, suggesting different pathophysiology mechanisms responsible of COVID-mediated myocarditis, according to Teresa Castiello et al., “COVID‑19 and myocarditis: a systematic review and overview of current challenges,” Heart Failure Reviews (2022) 27:251–261, https://doi.org/10.1007/s10741-021-10087-9, JIF 4.654 (top 38% journals in Cardiac & Cardiovascular Systems).

 

There are multiple reports of hearing loss (e.g. sudden sensorineural), tinnitus and rotatory vertigo in adults having a wide range of COVID-19 symptom severity. The pooled estimate of prevalence based primarily on retrospective recall of symptoms, was 7.6%, 14.8% and 7.2%, for hearing loss, tinnitus and rotatory vertigo, respectively. However, these could be an over-estimate because it was not always clear that studies report a change in symptom, according to Ibrahim Almufarrij et al., “One year on: an updated systematic review of SARS-CoV-2, COVID-19 and audio-vestibular symptoms,” International Journal of Audiology, 60:12, 935-945, https://doi.org/10.1080/14992027.2021.1896793, JIF 2.437 (top 41% journals in Audiology & Speech-language Pathology and top 51% in Otorhinolaryngology).

 

Common neurological and neuropsychiatric symptoms in individuals with PASC include fatigue, myalgia, headaches, sleep disturbance, anxiety, depression, dizziness, anosmia, dysgeusia, and cognitive symptoms, often called a “brain fog.” It is important for clinicians to recognize that disease severity may not be a predictor of PASC symptoms as many patients presenting to outpatient COVID recovery centers experienced only mild initial SARS-CoV-2 infection. Primary cognitive symptoms include deficits in reasoning, problem solving, spatial planning, working memory, difficulty with word retrieval and poor attention, according to Jeffrey S. Fine et al., “Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of cognitive symptoms in patients with post-acute sequelae of SARS-CoV-2 infection (PASC),” PM&R 2022;14:96–111, https://doi.org/10.1002/pmrj.12745, JIF 2.218 (top 44% journals in Rehabilitation and top 71% journals in Sport Science).

 

Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms, according to Doublas B. Kell et al., “A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications,” Biochemical Journal (2022) 479(4): 537-559, https://doi.org/10.1042/BCJ20220016, JIF 3.766 (top 59% journals in Biochemistry & Molecular Biology).

 

Amyloidogenesis is the inherent ability of proteins to change their conformation from native state to cross β-sheet rich fibrillar structures called amyloids which result in a wide range of diseases like Parkinson's disease, Alzheimer’s disease, Finnish familial amyloidosis, ATTR amyloidosis, British and Danish dementia, etc. COVID-19, on the other hand is seen to have many similarities in symptoms with other amyloidogenic diseases and the overlap of these morbidities and symptoms led to the proposition whether SARS-CoV-2 proteins are undergoing amyloidogenesis and whether it is resulting in or aggravating amyloidogenesis of any human host protein. Thus the SARS-CoV-2 proteins in infected cells, i.e., Spike (S) protein, Nucleocapsid (N) protein, and Envelope (E) protein were tested via different machinery and amyloidogenesis in them were proven. In this review, we will analyze the pathway of amyloid formation in S-protein, N-protein, E-protein along with the effect that SARS-CoV-2 is creating on various host proteins leading to the unexpected onset of many morbidities like COVID-induced Acute Respiratory Distress Syndrome (ARDS), Parkinsonism in young COVID patients, formation of fibrin microthrombi in heart, etc., and their future implications, according to Prakriti Seth et al., “A comprehensive mini‑review on amyloidogenesis of different SARS‑CoV‑2 proteins and its effect on amyloid formation in various host proteins,” 3 Biotech (2022) 12:322, https://doi.org/10.1007/s13205-022-03390-1, JIF 2.893 (top 65% journals in Biotechnology & Applied Microbiology).

 

Despite a possible etiologic role of SARS-CoV-2 and an expectable increased incidence of myocarditis and pericarditis, data of this preliminary study, with a geographically limited sample size, suggest a decrease in acute myocarditis and a stable incidence of pericarditis and of myopericarditis/perimyocarditis, according to Giovanni Donato Aquaro et al., “Incidence of acute myocarditis and pericarditis during the coronavirus disease 2019 pandemic: comparison with the prepandemic period,” Journal of Cardiovascular Medicine 2022, 23:447–453, July 2022, https://doi.org/10.2459/JCM.0000000000001330, JIF 2.430 (top 70% journals in Cardiac & Cardiovascular Systems).

 

Presentation of the disease often includes upper respiratory symptoms like dry cough, dyspnea, chest pain, and rhinorrhea that can develop to respiratory failure, needing intubation. Furthermore, the occurrence of acute and subacute neurological manifestations such as stroke, encephalitis, headache, and seizures are frequently stated in patients with COVID-19. One of the reported neurological complications of severe COVID-19 is the demolition of the myelin sheath. Indeed, the complex immunological dysfunction provides a substrate for the development of demyelination. Nevertheless, few published reports in the literature describe demyelination in subjects with COVID-19. The short narrative review discloses probable pathological mechanisms that may trigger demyelination in patients with SARS‐CoV‐2 infection and summarize the clinical evidence, confirming SARS-CoV-2 condition as a risk factor for the destruction of myelin, in Zahra Shabani, “Demyelination as a result of an immune response in patients with COVID‑19,” Acta Neurologica Belgica, 02 May 2021, https://doi.org/10.1007/s13760-021-01691-5, JIF 2.471 (top 74% journals in Clinical Neurology and top 82% journals in Neurosciences).

 

Muscle fatigue and cognitive disturbances persist in patients after recovery from acute COVID-19 disease are resolved by 14 days supplementation of ImmunoSEB (systemic enzyme complex) and ProbioSEB CSC3 (probiotic complex), according to Abhijit Rathi et al., “A randomized controlled trial of the efficacy of systemic enzymes and probiotics in the resolution of post-COVID fatigue,” Medicines 2021, 8(9), 47, https://doi.org/10.3390/medicines8090047, JIF N/A.

 

Fatigue, cough, chest tightness, breathlessness, palpitations, myalgia and difficulty to focus are symptoms reported in long COVID. It could be related to organ damage, post viral syndrome, post-critical care syndrome and others. Clinical evaluation should focus on identifying the pathophysiology, followed by appropriate remedial measures. In people with symptoms suggestive of long COVID but without known history of previous SARS-CoV-2 infection, serology may help confirm the diagnosis, presented in A.V. Raveendran et al., “Long COVID: An overview,” Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 15 (2021) 869e875, https://doi.org/10.1016/j.dsx.2021.04.007, JIF N/A.

 

There is growing awareness that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, even in its mild or moderate respiratory forms, can include long-term neuropsychological deficits (severe = intensive care unit hospitalization, moderate = conventional hospitalization, mild = no hospitalization). Deficits were found in all domains of cognition, and the prevalence of psychiatric symptoms was relatively high in the three groups. The severe infection group performed more poorly on long-term episodic memory tests and exhibited greater anosognosia than did the other two groups. Those with moderate infection had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. Individuals with mild infection were more stressed, anxious, and depressed. The data support the hypothesis that the virus targets the central nervous system (notably the limbic system) and the notion that there are different neuropsychological phenotypes, according to Philippe Voruz et al., “Long COVID neuropsychological deficits after severe, moderate, or mild infection,” Clinical and Translational Neuroscience 2022, 6(2), 9, 29 March 2022 https://doi.org/10.3390/ctn6020009, JIF N/A.

 

It was demonstrated that adult human inner ear tissue co-expresses the angiotensinconverting enzyme 2 (ACE2) receptor for SARS-CoV-2 virus, and the transmembrane protease serine 2 (TMPRSS2) and FURIN cofactors required for virus entry. Furthermore, hair cells and Schwann cells in explanted human vestibular tissue can be infected by SARS-CoV-2, as demonstrated by confocal microscopy. The detailed mechanistic explanations of audiovestibular dysfunction in COVID-19 patients are disclosed in Minjin Jeong et al. “Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction,” Communications Medicine (2021)1:44, https://doi.org/10.1038/s43856-021-00044-w, JIF N/A.

 

As with many other diseases, inflammation is a key feature of COVID-19. When inflammation is overwhelming, it may lead to unfavorable outcomes or even death. Scientists all over the world are working tirelessly in search of therapeutic strategies to suppress or modulate inflammation in COVID-19. This review gives an overview of the role of inflammation in COVID-19, according to Rebecca S. Y. Wong, “Inflammation in COVID-19: from pathogenesis to treatment,” International Journal of Clinical and Experimental Pathology 2021;14(7):831-844, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339720/, JIF N/A.

DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), according to Diane E. Griffin “Why does viral RNA sometimes persist after recovery from acute infections?” PLOS Biology, June 1, 2022, https://doi.org/10.1371/journal.pbio.3001687, JIF N/A.