How COVID-19 causes neurological damage

Authors: Date:nnNovember 14, 2022 University of Basel

Summary:It’s not uncommon for people to lose their sense of taste and smell due to a COVID-19 infection. In others, the disease has had an even stronger impact on the nervous system, with effects ranging from lasting concentration problems to strokes. Now, researchers have reported new insights into the development of ‘neuro-COVID’.

It’s not uncommon for people to lose their sense of taste and smell due to a Covid-19 infection. In others, the disease has had an even stronger impact on the nervous system, with effects ranging from lasting concentration problems to strokes. Now, researchers led by Professor Gregor Hutter from the Department of Biomedicine at the University of Basel and University Hospital of Basel have reported new insights into the development of “neuro-Covid” in the journal Nature Communications.

Specifically, the team investigated how different severities of neuro-COVID can be detected and predicted by analyzing the cerebrospinal fluid and blood plasma of affected individuals. Their findings also offer some indications of how to prevent neurological damage due to Covid-19.

The study included 40 Covid-19 patients with differing degrees of neurological symptoms. In order to identify typical changes associated with neuro-Covid, the team of researchers compared these individuals’ cerebrospinal fluid and blood plasma with samples from a control group. They also measured the brain structures of test subjects and surveyed participants 13 months after their illness in order to identify any lasting symptoms.

Holes in the blood-brain barrier

Particularly in the group with the most serious neurological symptoms, the researchers identified a link with an excessive immune response. On the one hand, affected individuals showed indications of impairment of the blood-brain barrier, which the study’s authors speculate was probably triggered by a “cytokine storm” — a massive release of pro-inflammatory factors in response to the virus.

On the other hand, the researchers also found antibodies that targeted parts of the body’s own cells — in other words, signs of an autoimmune reaction — as a result of the excessive immune response. “We suspect that these antibodies cross the porous blood-brain barrier into the brain, where they cause damage,” explains Hutter. They also identified excessive activation of the immune cells specifically responsible for the brain — the microglia.

Blood test as a long-term objective

In a further step, Hutter and his team investigated whether the severity of neurological symptoms is also perceptible in brain structures. Indeed, they found that people with serious neuro-Covid symptoms had a lower brain volume than healthy participants at specific locations in the brain and particularly at the olfactory cortex — that is, the area of the brain responsible for smell.

“We were able to link the signature of certain molecules in the blood and cerebrospinal fluid to an overwhelming immune response in the brain and reduced brain volume in certain areas, as well as neurological symptoms,” says Hutter, adding that it is now important to examine these biomarkers in a greater number of participants. The aim would be to develop a blood test that can already predict serious cases, including neuro-Covid and long Covid, at the start of an infection.

Targets for preventing consequential damage

These same biomarkers point to potential targets for drugs aimed at preventing consequential damage due to a Covid-19 infection. One of the biomarkers identified in blood, the factor MCP-3, plays a key role in the excessive immune response, and Hutter believes there is the potential to inhibit this factor medicinally.

“In our study, we show how coronavirus can affect the brain,” he says. “The virus triggers such a strong inflammatory response in the body that it spills over to the central nervous system. This can disrupt the cellular integrity of the brain.” Accordingly, Hutter says that the primary objective must be to identify and halt the excessive immune response at an early stage.

Journal Reference:

  1. Manina M. Etter, Tomás A. Martins, Laila Kulsvehagen, Elisabeth Pössnecker, Wandrille Duchemin, Sabrina Hogan, Gretel Sanabria-Diaz, Jannis Müller, Alessio Chiappini, Jonathan Rychen, Noëmi Eberhard, Raphael Guzman, Luigi Mariani, Lester Melie-Garcia, Emanuela Keller, Ilijas Jelcic, Hans Pargger, Martin Siegemund, Jens Kuhle, Johanna Oechtering, Caroline Eich, Alexandar Tzankov, Matthias S. Matter, Sarp Uzun, Özgür Yaldizli, Johanna M. Lieb, Marios-Nikos Psychogios, Karoline Leuzinger, Hans H. Hirsch, Cristina Granziera, Anne-Katrin Pröbstel, Gregor Hutter. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional studyNature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-34068-0

Optic nerve sheath diameter is associated with outcome in severe Covid-19

Authors: Jakob PansellPeter C. RudbergMax BellOla Friman & Charith Cooray Scientific Reports volume 12, Article number: 17255 (2022) Cite this article1500 Accesses 4 AltmetricMetrics

Abstract

Neurological symptoms are common in Covid-19 and cerebral edema has been shown post-mortem. The mechanism behind this is unclear. Elevated intracranial pressure (ICP) has not been extensively studied in Covid-19. ICP can be estimated noninvasively with measurements of the optic nerve sheath diameter (ONSD). We performed a cohort study with ONSD ultrasound measurements in severe cases of Covid-19 at an intensive care unit (ICU). We measured ONSD with ultrasound in adults with severe Covid-19 in the ICU at Karolinska University Hospital in Sweden. Patients were classified as either having normal or elevated ONSD. We compared ICU length of stay (ICU-LOS) and 90 day mortality between the groups. 54 patients were included. 11 of these (20.4%) had elevated ONSD. Patients with elevated ONSD had 12 days longer ICU-LOS (95% CI 2 to 23 p = 0.03) and a risk ratio of 2.3 for ICU-LOS ≥ 30 days. There were no significant differences in baseline data or 90 day mortality between the groups. Elevated ONSD is common in severe Covid-19 and is associated with adverse outcome. This may be caused by elevated ICP. This is a clinically important finding that needs to be considered when deciding upon various treatment strategies.

Introduction

Neurological symptoms and complications are common in Covid-19. High levels of biomarkers of neuronal damage have been recorded1,2. In an early post-mortem series of patients that had died with Covid-19 there was evidence of neuroinflammation in many patients and mild to moderate cerebral edema in nearly half of all cases3. The pathophysiologic mechanisms are not clear but one known factor is the increased risk of thromboembolism and micro thrombotic events in Covid-19. Other suggested mechanisms include hyperinflammation resulting in neural or vascular complications, autoimmune disorders and encephalopathy. Persistent hypoxemia and multiple organ failure also occur in severe Covid-19 and may result in hypoxic neuronal injuries1,2. Elevated intracranial pressure (ICP) is a known cause of secondary brain injury in other pathologies4 but has not been extensively studied in severe Covid-19. A few studies of invasively measured ICP in Covid-19 have been performed in less severe cases. In one such study elevated ICP was diagnosed upon lumbar puncture in a number of patients with Covid-related headache5. Three studies using noninvasive estimation of ICP in severe Covid-19 have been published6,7,8. One of these studies suggest that elevated estimated ICP could be associated with a longer Intensive Care Unit Length of Stay (ICU-LOS) but not with short-term mortality in severe Covid-196.

Studies of the possible mechanism of neurological symptoms and complications in Covid-19 are few and small and no long-term follow-up has to our knowledge been done. It is well-known that ICP can be estimated by measuring the Optic Nerve Sheath Diameter (ONSD) with sonography9,10. The optic nerve sheath contains a subarachnoid space with circulating cerebrospinal fluid (CSF). When ICP increases, a volume shift occurs, leading to more CSF circulating in the subarachnoid space surrounding the optic nerve. This dilates the optic nerve sheath and increases ONSD. Limitations to ONSD as an ICP estimate are e.g. individual baseline variations of ONSD and inter-rater reliability10. ONSD correlates with eye diameter (ED)11. Adjusting for ED can lead to better precision when estimating ICP with ONSD, by partly mitigating for individual baseline variations. ONSD divided by ED increased precision in ICP estimation in two previously published studies12,13 and in one study from our research group, currently undergoing peer review. We therefore used this approach, with a method that has been described in previous publications14. In the two previously published studies the optimal cut-off to identify elevated ICP was 0.2613 and 0.2512 respectively. The study from our research group, currently undergoing review, was larger than both of these studies and used the same protocol as we used in this study. The optimal cut-off in that study was 0.295. We therefore set this as the threshold for elevated ONSD/ED. A recent study from our group showed that ONSD measurements could be performed with excellent inter-rater reliability using a standardized protocol14.

The aim of this study was to explore ONSD in patients with severe covid-19 and examine it for possible associations with ICU-LOS and 90 day mortality.

Methods

Ethical considerations

The study was conducted in accordance with the Helsinki declaration and was approved by the Swedish Ethical Review Authority, record number 2020-03004. The requirement for informed consent from the study subjects was waived by the Swedish Ethical Review Authority due to the nature of the cohort that makes informed consent unfeasible. ONSD ultrasound is a safe, noninvasive, and painless procedure that can be performed without interfering with patient care. The cut-off for elevated estimated ICP was unknown to ONSD operators during the data collection. ICP estimation therefore could not influence clinical decisions or treatment strategies. We informed the patients’ next of kin and gave them right to opt out on behalf of the patient.

Patient cohort

Inclusion criteria

All patients ≥ 18 years old treated for Covid-19 in the ICU at Karolinska University Hospital in Stockholm during the time-period November 2020 to April 2021, sedated or unconscious and on invasive ventilation, were eligible for inclusion. Exclusion criteria were ocular disease or ocular trauma. We used a convenience sample since our two ONSD operators had a heavy clinical workload in the ICU during this period. Eligible patients were included if available for ONSD examination when an ONSD operator was available. We were therefore not able to measure all patients at the same time during their ICU stay.

Clinical data collection

Measurements were performed by two experienced ultrasound operators. Both had theoretical and practical training in ONSD ultrasound with at least 30 exams prior to this study. We used a protocol we developed based on the CLOSED protocol15. Our operators have shown excellent inter-rater reliability when using this protocol14. We performed ONSD ultrasound with a General Electrics GE Vivid S70 machine using a linear 11L-probe. Power was reduced to achieve a Mechanical Index < 0.23 and frequency was kept at 10 MHz as outlined in the CLOSED protocol for ONSD sonography15. ONSD and ED were both averaged from measurements in the transversal and the sagittal plane for each eye. Color Doppler was utilized to visualize the central retinal artery and/or vein to properly identify the optic nerve and its direction. ONSD was measured perpendicular to the optic nerve, three millimeters behind the retina.

We recorded baseline data including age, sex, comorbidities, the ICU day for ONSD/ED measurement, ratio of pO2/FiO2 (PFI), pCO2, the occurrence of acute kidney injury (AKI) and the need for vasopressor and/or inotropic support. We retrospectively added data on PEEP, pressure support/pressure control setting, ventilator mode, accumulated hours of prone positioning before ONSD exam, as well as ICU-LOS, 90 day mortality and number of days alive during the first 90 days from admission to the ICU, from electronical patient charts.

Exposure and outcomes

We corrected for individual variations of ONSD baseline by dividing ONSD with ED, as previously suggested12,13. We set a cut off for exposure of elevated ONSD/ED at ≥ 0.295 mm. Outcome measures, comparing patients with and without high ONSD/ED, were ICU-LOS and mortality within 90 days from ICU admission.

Statistical analysis

Patients were divided into two groups: elevated ONSD/ED (≥ 0.295 mm) and normal ONSD/ED (< 0.295 mm). ICU-LOS in both groups was tested for normality with the Shapiro–Wilk’s test and subsequently compared with 95% CI, using a two-sample t-test with unequal variances and significance level set at 0.05. The outcomes 90 day mortality and ICU-LOS dichotomized at ≥ 30 days were compared between groups using Fisher’s exact test. A Kaplan–Meier survival graph with 95% CI was produced for survival during the first 90 days since ICU admission. Continuous baseline data in both groups was tested for normality using the Shapiro Wilk’s test and subsequently compared with 95% CI, using a two-sample t-test with unequal variances and significance level set at 0.05. We used Fisher’s exact test to compare binary baseline data between groups. Median day of ICP estimation was compared between the two groups using Fisher’s exact non-parametric equality of medians test. We performed a linear regression analysis on day of ICP estimation and ONSD/ED.

Sensitivity analyses for the potential effects of extreme values in this relatively small data set were performed by sequentially excluding patients from both groups with high ICU-LOS (> 50 days), low ICU-LOS (< 5 days) and patients with high or low ICU-LOS. We also performed a sensitivity analysis by removing patients who died in the ICU to avoid confounding of ICU-LOS by ICU mortality.

All calculations and graphs were performed and created in Stata, v 14.2.

Ethics approval and consent to participate

This study adheres to The Helsinki declaration and was approved by the Swedish Ethical Review Authority, record number 2020-03004. The requirement for informed consent from the study subjects was waived by the Swedish Ethical Review Authority due to the nature of the cohort that makes informed consent unfeasible. Next of kin were informed and given the right to opt out on behalf of the patient.

Results

We performed measurements in 55 patients from November 2020 to April 2021. One patient was excluded upon request from next of kin and 54 patients were included in the final analysis. There were no attempted measurements of ONSD that did not succeed. Measurements were performed once per patient. All patients were sedated at time of measurement. Median day for ONSD measurement after ICU admission was day six with an interquartile range of 4 to 13 (see Table 1 for baseline data of the cohort).Table 1 Baseline data.

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Loss to follow up on ICU-LOS occurred in one patient due to transfer to a hospital with a different system for electronic patient charts. In one patient there was no available data for pCO2 within a reasonable temporal proximity to the ICP estimation. None of these two patients had an elevated ONSD/ED.

11 out of 54 patients (20.4%) had an elevated ONSD/ED (≥ 0.295 mm). Patients with an elevated ONSD/ED had a mean ICU-LOS of 38 days (95% CI 26 to 50). Patients with a normal ONSD/ED had a mean ICU-LOS of 26 days (95% CI 21 to 30). The difference between the two groups of 12 days in ICU-LOS was significant (95% CI 2 to 23, p = 0.03). The risk ratio for long ICU-LOS (≥ 30 days) in ICU survivors with elevated ONSD/ED was 2.3 compared to normal ONSD/ED, with an absolute risk difference of 43% (p = 0.04). Elevated ONSD/ED predicted long ICU-LOS with sensitivity 33%, specificity 93%, positive predictive value 75% and negative predictive value 68%. There was no significant difference in 90 day mortality. The 95% CIs were widely overlapping in the Kaplan Meier survival graph over 90 days (Table 2, Fig. 1). The difference in ICU-LOS remained significant through sensitivity analyses with exclusion of extreme values in ICU-LOS and cases of ICU-mortality (Table 3).Table 2 Outcome measures reported and compared by normal or elevated ONSD/ED.

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figure 1
Figure 1

Table 3 Sensitivity analyses.

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There were no significant differences in age, sex, comorbidities or day of ONSD/ED measurement between patients with elevated ONSD/ED and normal ONSD/ED, respectively. Pregnancy, prior stroke, TBI or hydrocephalus/chronic intracranial hypertension were however too rare in this material to perform analyses of differences between the groups. There was one pregnant patient, three patients with previous stroke and one patient with previous TBI. ONSD/ED was normal in these five patients. There was no significant difference in the need for vasopressor or inotrope support, the occurrence of acute kidney injury, ventilator mode, ventilator settings, accumulated prone position time, PFI or pCO2 between the two groups (Table 4). There was no significant correlation between day of ONSD/ED measurement and measured ONSD/ED with a coefficient of 0.00 (95% CI − 0.00 to 0.00, p = 0.80).Table 4 Comparison of baseline data by normal or elevated ONSD/ED.

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Discussion

This study shows that elevated ONSD/ED is common in severe Covid-19 and is associated with a significantly longer ICU-LOS in these patients. The association between ONSD/ED and ICU-LOS was not explained by baseline factors such as age, gender or co-morbidities, nor by timing of ONSD measurement during the ICU stay. It was also unrelated to ventilator modes or settings, accumulated prone positioning time, and the degree of hemodynamic, respiratory or renal failure at the time of ONSD/ED measurement.

Our findings closely match those of the only previous study estimating ICP noninvasively in patients with severe Covid-19 using ONSD sonography. In that study ONSD was measured in 49 patients and 10 of them (18.9%) were estimated to have an elevated ICP. These patients had a significantly longer ICU-LOS than the patients with an estimated normal ICP (45 days vs 36 days) but showed no significant differences in ICU- or hospital mortality6. We analyzed longer term outcome by comparing 90 day mortality between the groups. Another difference between that study and our study is that we corrected ONSD for ED.

Elevated ICP is not the only possible explanation to an elevated ONSD. Optic neuritis also leads to an increase in ONSD and has been reported in Covid-199,16. It is however a rare complication to Covid-19 and therefore we deem it unlikely to cause the 20% occurrence of elevated ONSD that we see in this study. Prone positioning is a common treatment strategy in severe Covid-19. Prone positioning often leads to facial edema and in some cases elevated intra-ocular pressure17. It is unclear whether repeated prone positioning and accumulated prone positioning time affects ONSD. Prone positioning is daily performed in many patients with severe Covid-19 in our ICU setting and tends to increase with increasing severity of disease. If accumulated prone positioning time affects ONSD this would confound our findings. However, we detected no significant difference in accumulated prone positioning time between patients with normal and elevated ONSD/ED. Accumulated prone positioning time therefore cannot explain the association between ICU-LOS and ONSD/ED in our data.

ONSD has a well-established association with ICP9,10 and was not related to baseline factors or any of the potential confounders that were measured in our cohort. We therefore believe that the most likely interpretation of our results is that elevated ICP may be common and associated with adverse outcomes in Covid-19. There are several possible explanations to why elevated ICP would occur in severe Covid-19. High ventilator pressures and right ventricular failure are common in respiratory failure in general and specifically in severe Covid-1918,19,20,21. Both affect central venous pressure and thereby ICP22,23,24. Hypothetically, there could be a cumulative effect where sustained high ventilator pressures and sustained right ventricular failure over time would cause and exacerbate cerebral edema. High ventilator pressures are likely associated with longer ICU-LOS due to lung damage and is therefore a potential confounder in our study. There were however no significant differences in ventilator modes or ventilator pressures between patients with normal and elevated ONSD/ED at the time of ONSD/ED measurement in our data. Hypercapnia also may cause elevated ICP25. It is a common occurrence in late stage, severe Covid-1920 and is often permitted in respiratory failure to facilitate lung protective ventilation19. Again, no significant difference in pCO2 between patients with normal and elevated ONSD/ED was found in our data. We do not believe that either ventilator pressures or hypercapnia are driving factors behind the association between ONSD/ED and ICU-LOS. Systemic inflammation and neuroinflammation are other possible mechanisms of cerebral edema and therefore elevated ICP, alongside hypoxic lesions caused by hypoxemia, vascular complications and thromboembolic events. All of these can occur in severe Covid-191,2,3 and are plausible explanations to our findings.

The suggestion that elevated ICP may be common in severe Covid-19, and is associated with adverse outcome, is clinically important. Firstly, because it provides a new perspective on the strategy of permissive hypercapnia mentioned above. Hypercapnia does not seem to be the driving factor behind our findings and pCO2 levels were overall moderate in our cohort. Higher levels of pCO2 will however further elevate ICP in patients with ICP instability25. Secondly, a practice has arisen, based on experiences from several ICUs, to sometimes position severe cases of Covid-19 flat or even in Trendelenburg position as a rescue maneuver. This is due to the paradoxical improvement in lung compliance sometimes witnessed in severe cases of Covid-19 in these positions, a phenomenon that recently was reviewed26. These positions as well as permissive hypercapnia will inevitably increase ICP25,27. No patients were in the Trendelenburg position when ONSD/ED was measured. If elevated ICP is a contributing factor to outcomes in severe Covid-19 this must be taken into consideration when discussing these mentioned treatment strategies. Likewise, treatment strategies regarding blood pressure targets, serum osmolality and dialysis doses in patients with acute kidney injury may need to be revised if elevated ICP truly is a factor in severe Covid-19. Further, the possibility to prognosticate ICU-LOS based on ONSD/ED may be clinically relevant. A reliable tool to predict length of ICU-LOS may inform such decisions as timing of tracheostomy and patient transfer. Prediction of ICU-LOS could provide valuable information for management decisions regarding allocation of resources.

There are limitations to this study, the most obvious being the small sample size. There may be a difference in 90 day mortality and associations between ICU-LOS and other parameters that this study was underpowered to detect. There were no statistically significant differences in comorbidities between the groups, however our small sample size may be underpowered to detect potentially true differences. Moreover, the small sample size may make results sensitive to outliers. Important to note though, our results were robust throughout sensitivity analyses, as previously described. The convenience sample strategy that was necessary to perform this study during an ongoing pandemic made it vulnerable to selection bias. Also, this strategy led to ICP estimation being performed at different times during the patients’ ICU stay. This might have affected the results if ONSD changed through the course of the disease. But since the day of ONSD/ED measurement was not correlated to ONSD/ED, we do not believe this to interfere with results. Outcome measures pose another set of limitations in this study. ICU-LOS is prone to confounding by ICU-mortality but our findings were robust throughout sensitivity analysis excluding cases of ICU mortality. Neither ICU-LOS nor survival yield information regarding long term quality of life or neurological function. This may be one of the greatest limitations of this study. Finally, it should be stressed that ONSD sonography does not yield precise values of ICP. It is an ICP surrogate and false positives are to be expected. Also, there is no consensus regarding ONSD/ED cut-off to identify elevated ICP. Our cut-off at 0.295 mm is based on unpublished data currently undergoing peer review.

Given that ONSD/ED showed no association with baseline factors or any of the potential confounders we measured, we still believe that elevated ICP is the most likely explanation for elevated ONSD/ED in this cohort.

Conclusions

We conclude that elevated ONSD/ED is common in severe Covid-19, is associated with adverse outcome and can predict ICU-LOS ≥ 30 days. These results are in line with results from the only similar previous study. Having analyzed several important potential confounders, we believe that the remaining and most likely explanation for this is that elevated ICP occurs and correlates with, or contributes to, morbidity in severe Covid-19. This would have clinical implications and should therefore prompt further studies into possible mechanisms and treatment strategies. We recommend that ongoing or future studies of ICP in severe Covid-19 should be performed with larger cohorts, recording exact data on patient positioning and including more patient-centered outcome measures.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to constraints in the ethical permission granted by the Swedish Ethical Review Authority but are available from the corresponding author on reasonable request. The ethical approval for this study allows publication of aggregated data only.

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Impact of Systemic Diseases on Olfactory Function in COVID-19 Infected Patients

Authors: Ayat A Awwad,1 Osama MM Abd Elhay,2 Moustafa M Rabie,3 Eman A Awad,4 Fatma M Kotb,4 Hend M Maghraby,4 Rmadan H Eldamarawy,4 Yahia MA Dawood,1 Mostafa IEI Balat,1 Ahmed IM Hasan,5 Ahmed H Elsheshiny,6 Said SMM El Sayed,2 Albayoumi AB Fouda,2 Ahmad MF Alkot2 DovPress November 7, 2022

1Otorhinolaryngology department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 2Medical Physiology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 3Public Health and Community Medicine Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 4Internal medicine department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 5Pediatric Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; 6Neurology department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Correspondence: Ayat A Awwad, Otorhinolaryngology department, Faculty of Medicine, Al-Azhar University, Al Zhraa University Hhospital, Alabasia, Cairo, 11517, Egypt, Email ayatnasr7419@yahoo.com; dr.ayat@azhar.edu.eg Osama MM Abd Elhay, Medical Physiology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt, Email osama.m.m.abdelhay@gmail.com; osamaabdelhay@domazhermedicine.edu.eg

Background: COVID-19 (SARS-CoV-2/2019-nCoV) is now a major public health threat to the world. Olfactory dysfunctions (ODs) are considered potential indicating symptoms and early case identification triaging for coronavirus disease 2019 (COVID-19). The most common reported comorbidities are diabetes mellitus, chronic lung disease, and cardiovascular disease. The objective of this study was to evaluate prevalence of different types of smell disorders in patients with laboratory-confirmed COVID-19 infection and impact of involved systemic diseases.
Methodology: A cross-sectional retrospective study has been done for patients with laboratory-confirmed COVID-19 infection (mild-to-moderate). The data collected from patient’s files and developed online electronic questionnaire (WhatsApp) based on the patients most common and recurrent reported data including: a) symptoms of olfactory dysfunction and associated covid19 symptoms fever and headache, cough, sore throat, pneumonia, nausea, vomiting and diarrhea, arthralgia and myalgia and taste dysfunction. b) Associated systemic diseases including: diabetes, hypertension, asthma, chronic renal disease, chorionic liver disease and hypothyroidism.
Results: Of 308 patients confirmed with Covid-19 infection, (72.4%) developed OD distributed as follows; complete anosmia (57.8%), troposmia (8.4%), hyposmia (2.9%), partial anosmia (2.6%) and euosmia (0.6%). Significantly increased prevalence of diabetes, hypertension asthma in the group with olfactory dysfunction (p < 0.001), chronic liver disease (p = 0.005), and hypothyroidism (p = 0.03).
Conclusion: The development of ODs after Covid-19 infection was associated with mild disease form and lower hospitalization. In addition, it showed significant relationship with preexisting systemic diseases. Anosmia is the common modality of ODs.

Keywords: COVID-19, anosmia, olfactory dysfunction

Introduction

World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) to be pandemic after it quickly spread all over the world.1 The involved cause is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2 Human-to-human transmission is extremely rapid.3 Coronavirus is contagious with an incubation period ranging from 2 to 14 days. Through this period, patients can transmit infection even if asymptomatic.4

Asia reported that the most prevalent symptoms as: fever, myalgia, arthralgia cough, dyspnea, headache, diarrhea, rhinorrhea, and sore throat.5 Also, respiratory complications as pneumonia, lung fibrosis, and even death have been reported.6 Later, atypical presentation of the disease is widely observed including olfactory and gustatory malfunction but without rhinorrhea or nasal obstruction which are usually associated to other respiratory viral infections.7

WHO considers smell disorders as key symptoms of COVID-19.8 The American Academy of Otolaryngology–Head and Neck Surgery Foundation, 20209 together with Ear, Nose, and Throat Society of the United Kingdom (ENTUK) recommended self-isolation for patients presenting with these clinical features. Many countries reported the association smell disorder and taste with COVID-1910–12, but evidence remains controversial. In addition, none of them was concerned the incidence of different types of dysfunction.

COVID-19 virus appears to be more severe in severe older people and people with systemic conditions (such as diabetes, hypertension and asthma).13

The previous studies confirmed on olfactory dysfunction alone, neither its types nor impact of chronic diseases on OD so the aim of this study is to evaluate prevalence of different types of smell disorders in patients with laboratory-confirmed COVID-19 infection and impact of involved systemic diseases on ODs.

Methodology

The study was approved from Ethical Committee of the Faculty of medicine of Al-Azhar University (IRP) which complies with the Declaration of Helsinki. A cross-sectional retrospective study to patients with laboratory-confirmed COVID-19 infection (mild-to-moderate) who admitted in Al – Azhar University hospitals, fever hospitals, in addition to some of our patient’s clinics in Cairo, Egypt between the period from June 2020 to December 2020. The patients were divided into asymptomatic and symptomatic. The severity of the symptomatic diseases was classified into mild, moderate and severe.14

Informed consent was obtained from all patients (or a parent or legal guardian of patients under 18 years of age). The data collected from patient’s files and developed online electronic questionnaire (WhatsApp). Electronic questionnaire was designed by Professional otorhinolaryngologist, so that each participant could complete the survey. Questionnaire was based the patients most common and recurrent reported data including:

  • 4 items for assessment of ODs including: presence of smell dysfunction (yes or no), types of smell dysfunction (anosmia, hyposmia, partial anosmia, euosmia and troposmia).
  • 8 items for symptoms associated with covid-19 including: fever, headache, cough, sore throat, pneumonia, nausea, vomiting, diarrhea, arthralgia, myalgia and taste dysfunction (yes/no)
  • 6 items for associated systemic diseases including: diabetes, hypertension, asthma, chronic renal disease, chorionic liver disease and hypothyroidism (yes or no)

Inclusion criteria were: (> 12 years old of both genders); laboratory-confirmed COVID-19 infection (reverse transcription polymerase chain reaction, RT-PCR); native speaker patients, and patients clinically able to fulfill the questionnaire.

Patients with history of smell disorders, and not confirmed COVID-19, were unable to fulfill the questionnaire in addition to patients admitted to intensive care were also excluded from the study.

The data were collected, tabulated, and analyzed by Statistical Package for Social Sciences (version 21; SPSS Inc., Chicago, IL, USA). Two types of statistics were done:

  • Descriptive statistics [eg percentage (%), mean (x) and standard deviation (SD)],
  • Analytic statistics: which include the following:
    1. Chi-square test (χ2): was used to indicate presence or absence of a statistically significant difference between two qualitative variables.
    2. P-value of <0.05 was considered statistically significant.

Results

Demographic characteristics, comorbidities, and symptoms at the onset were reported in all patients confirmed with COVID-19 as shown in Table 1.

Table 1 Characteristics of Study Participants (N = 308)

The prevalence of ODs were 72% (223) with anosmia being the most common presented type (57.8%) while euosmia was the least presented type being only in (0.6%) as shown in Table 2 and Figure 1.

Table 2 Prevalence of Different Types of Olfactory Dysfunction Among COVID-19 Infected Patients (N = 308)

Figure 1 Prevalence of olfactory dysfunction types among cases who suffers from this dysfunction.

The frequency of ODs were significantly high with increasing in age (P value =0.000). But there was no significant difference between genders (P value =0.167) as reported in Table 3. Significant increases in different types of ODs with increasing in age (P value =0.000) while, there was no significant difference regarding gender (P value = 0.564) as shown in Table 4. Anosmia was the commonest presenting type of smell dysfunction in both genders (Figure 2).

Table 3 Frequency Distribution of Olfactory Dysfunction Occurrence According to Age and Sex

Table 4 Frequency Distribution of Olfactory Dysfunction Types in Relation to Age and Sex

Figure 2 Percent distribution of olfactory dysfunction types according to sex.

Regarding to other symptoms, the frequency of ODs were significantly associated to fever and headache, arthralgia, myalgia, taste dysfunction (P value =0.000), cough (P value =0.001), sore throat (P value =0.037), diarrhea, nausea and vomiting (P value =0.002). But it was not significantly associated with Pneumonia (P value =0.077) as shown in Table 5. ODs were the only presenting symptoms in 59.7% of patients Figure 3.

Table 5 Frequency Distribution of Olfactory Dysfunction Occurrence According to the Other Symptoms Experienced

Figure 3 Percent distribution of olfactory dysfunction as the only presenting symptom.

The frequency of ODs were significantly associated with diabetes, hypertension, asthma (P value=0.000), chronic liver disease, hypothyroidism (P value =0.003) and chronic renal disease (P value =0.005) as reported in Table 6. The different types of smell dysfunction showed significant association with asthma, chronic renal disease (P value =0.000), diabetes (P value =0.003), and hypertension (P value =0.002) while, there was no significant association with chronic liver disease and hypothyroidism (P value =0.158 and 0.524 respectively). Anosmia was the most common type of OD in association with diabetes, hypertension, asthma and chronic liver disease while, troposmia was the most common type of OD associated with chronic renal disease. The only case presented with euosmia was reported in chronic liver disease Table 7.

Table 6 Frequency Distribution of Olfactory Dysfunction Occurrence According to the Different Comorbidities

Table 7 Frequency Distribution of Olfactory Dysfunction Types in Relation to the Comorbidities

Discussion

The CDC (Center for Disease Control and Prevention) has highlighted the loss of smell as a significant symptom of COVID-19. In addition, recent research has indicated that OD may serve as an early clinical manifestation of this contagious.15–17

The current study was conducted to study the prevalence of different types of olfactory disorders in patients with laboratory-confirmed COVID-19 infection and its relationship with preexisting systemic comorbidities. Handling the effects of systemic comorbidities on olfactory manifestations in Covid-19 patients is poorly discussed in the literature. This poses a strong point in favor of our study.

We included a total of 308 patients confirmed with Covid-19 infection, 223 patients from them developed olfactory dysfunction (72.4%). When analyzing OD encountered in our research, it was distributed as follows; complete anosmia (57.8%), troposmia (8.4%), hyposmia (2.9%), partial anosmia (2.6%) and euosmia (0.6%). This is in line with multiple previous studies which reported that smell alternations are frequent manifestations of Covid-19 infection, with a prevalence ranging from 19.4% to 88%.3,12,13

This prevalence appears to be widely different between different studies. Mao et al reported lower prevalence (5%) in China18 and Marzano et al (18%) in Italy.19 Others reported much higher prevalence, reaching up to 98% in the study of Moein et al20 and 100% in the study of Heidari et al21 in Iran. This great heterogenicity could be explained by different sample sizes, patient characteristics, and methods of evaluating OD. In addition, Meng et al22 reported the difference of incidence in different countries as COVID-19 has three central variants A, B and C. Variants A and C which affect the nasal cavity causing OD were prevalent in Europe and America. Beside, human species affects significantly the susceptibility for infection.

Brann et al23 suggested that OD associated with Covid-19 infection is due to viral invasion of olfactory epithelial cells and vascular pericytes, which will negatively impact olfactory neuronal function. Additionally, nasal inflammation, congestion, and swelling may prevent olfactory molecules from reaching the olfactory cleft. Therefore, this conductive malfunction may play a role in developing OD.24

Lechien et al25 study handling the same perspective, the encountered OD was distributed as follows; anosmia (79.6%), while the remaining cases had hyposmia (20.4%). In another study, Vaira et al26 reported that among the Covid patients diagnosed with olfactory dysfunction, mild, moderate, and severe hyposmia was detected in 76, 59, and 45 patients, respectively. In addition, the remaining 61 cases had anosmia. It is expected to find some differences between different studies regarding the type of olfactory function diagnosed, according to the sample population included and criteria used to define each type.

In the current study, a significant difference was noted between patients with and without OD regarding patient age (p < 0.001), which tended to be significantly younger in the OD group. On the contrary a previous meta-analysis by Desiato et al17 has against this relationship. Several mechanisms could explain this association between advancing age and declining olfactory function including, nasal epithelial atrophy, olfactory bulb shrinkage, cribriform plate changes, in addition to age-associated cortical degeneration.27–29,30

However, another study by Mercante et al31 reported that the severity of OD was significantly increased in younger individuals, while older ones expressed mild or no symptoms. This confirms our findings.

Our findings showed no significant impact of gender on the development of this complication (p = 0.167). Thakur et al25 confirmed the previous findings regarding the insignificant association between gender and OD (p = 0.59). On the other hand, a recent meta-analysis by Saniasiaya et al32 had shown that the female gender is a risk factor for this manifestation, as it showed higher predominance compared to men. Researchers attributed that finding to the sex-related difference in the inflammatory process.33 Additionally, female patients were more sensitive than males to detect small alternations.32

Our findings showed a significant association between OD and fever, which is more prevalent in patients with this complication. In accordance with the previous results, Lechien et al25 reported a significant positive association between OD and fever (p < 0.001).

In the current study, the headache was significantly more prevalent in patients with OD (p < 0.001). This coincides with multiple previous studies which confirmed the association between headache and olfactory disturbances.34,35 This association was explained by either CNS involvement by the virus itself or hypoxic headache, which results from nasal congestion, which is associated with a decrease in olfactory function.36,37

In our study, taste dysfunction was significantly more encountered in patients with olfactory disturbances. This was confirmed before; as Lechien et al26 reported a significant positive association between both olfactory and gustatory functions (p < 0.001). Also Speth et al38 confirmed the previous findings.

In the current study, one could notice the significantly higher prevalence of other clinical findings (including sore throat, cough, diarrhea, nausea, vomiting, arthralgia, and myalgia) in association with OD.

Likewise, Talavera et al39 also reported the significant relationship between anosmia, myalgia, and cough in patients with Covid disease (p = 0.006). Nevertheless, other manifestations did not express a significant association with olfactory disturbances (p > 0.05).

Conversely, Yan et al12 reported that olfactory dysfunction was associated with a mild disease form. Moreover, another study Izquierdo-Domínguez et al40 reported that the same dysfunction was associated with lower C-reactive protein levels and a lower need for hospitalization.

Our findings showed significantly increased diabetes prevalence in the group with OD (p < 0.001). Although there is a paucity of studies handling the link between diabetes and OD in Covid-19 patients, the association between diabetes and the development of such dysfunction is well documented in a recent meta-analysis by Kim et al.41

Multiple mechanisms could induce this, including olfactory neurodegeneration and diabetes-associated microvascular disease.22,42,43 Of course, with the presence of these diabetes-associated factors, catching Covid-19 infection will increase the chance of having that dysfunction, especially in diabetic personnel. It was previously reported that the diabetic population is at high risk of having OD compared to healthy controls (OR = 1.58).41 In contrast to the previous findings, Talavera et al39 noted no significant impact of diabetes on the development of anosmia (p = 0.448). It was present in 17.1% and 20.5% of patients with and without anosmia, respectively.

Our findings showed that olfactory disturbances were significantly associated with hypertension (p < 0.001). Hypertension was present in 23.3% and 3.5% of patients with and without this dysfunction. We are the first researchers to report that finding in Covid-19 patients to the best of our knowledge. Our finding is supported by the accumulating evidence supporting the association between OD and cardiovascular disease.44,45 Several theories could explain this association; cardiovascular disease is common in the elderly, which is associated with degenerative neuronal changes, as discussed before. Also, the proinflammatory cytokines present with atherosclerosis could decrease olfactory function. Furthermore, some cardiovascular medications have a negative impact on hearing.46,47,48

In a recent study conducted in 2021, hypertensive patients expressed a lower prevalence of OD (p < 0.001), which was present in 74.9% and 88% of patients without and with hypertension, respectively.3 This is in contrast with our findings. In fact, the role of hypertension and the potential intake of angiotensin-converting enzyme inhibitors in the development of OD need to be well discussed in the upcoming studies.

In the current study, the prevalence of asthma showed a significant increase in patients with OD (p < 0.001). Asthma and olfactory impairment have never been linked, according to a recent report published in 2021 by Rhyou et al.48 However, the presence of allergic rhinitis or sinusitis in association with asthma surely decreases the olfactory sensation.29,49

Another study negated any significant difference between the anosmia and non-anosmia groups regarding the prevalence of respiratory diseases, which was present in 19.9% and 27% of patients in the same groups, respectively (p = 0.109).39

Our findings showed a higher prevalence of chronic liver disease in association with anosmia (p = 0.003). Previously, Heiser et al50 reported that olfactory deficits are frequently encountered in patients with cirrhosis. This functional decline is the result of calorie, protein, and micronutrient deficiency in such patients.51 This evidence was supported by the improvement of this function after liver transplantation, as reported by Bloomfield et al.52

In the current study, the prevalence of chronic kidney disease was significantly higher in association with OD (p = 0.005). In fact, patients with such comorbidities often complain of olfactory impairment, which could be the consequence of malnutrition and decreased fluid intake.53,54 Uremia itself could induce neuropathy and decreased smell sensation.54

Our findings showed that hypothyroidism was significantly more common in the OD group (p = 0.03). In line with the previous findings, Tsivgoulis et al55 have reported that hypothyroidism is associated with more prolonged Covid-19 induced anosmia. Sorrily, there is no clear data about whether hypothyroidism can induce OD in adult humans.56

Our study has some limitations; we should have evaluated the impact of OD on patient outcome and long-term nasal function. In addition to this retrospective study may together have some bias to mention. This study did not perform an objective olfactory test on the patients but was based on an electronic questionnaire, which may affect the accuracy of the survey.

All in all, based on our findings, complete anosmia was the most presented modality of OD. Fever, headache, taste dysfunction, sore throat, cough, diarrhea, nausea, vomiting, arthralgia, and myalgia were common symptoms associated with OD. Mild disease form, low C-reactive protein and lower need for hospitalization were common association with OD. Significant increases in incidence of OD in diabetes mellitus, hypertension, bronchial asthma, chronic liver disease, chronic kidney disease and hypothyroidism. Lower incidence of respiratory symptoms in anosmia compared to non-anosmia group.

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How Covid-19 damages lungs explained

Authors: mINT oCTOBER 31, 2022

sYNOPSIS

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012.

Covid-19: The virus attacks mitochondria, continuing an ancient battle that began in the primordial soup

Kingston (Canada), (The Conversation): Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those bacteria eventually became mitochondria, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes).

Ultimately, mitochondria became the powerhouses within all human cells.

Fast-forward to the rise of novel coronaviruses like SARS-CoV-2, and the global spread of COVID-19. Approximately five per cent of people infected with SARS-CoV-2 suffer respiratory failure (low blood oxygen) requiring hospitalization. In Canada about 1.1 per cent of infected patients (almost 46,000 people) have died.

This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria — more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.

How COVID-19 affects lungs

People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:

First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up).

Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.

Together, these abnormalities lower blood oxygen. However, the cause of these abnormalities was unknown. In 2020, our team of 20 researchers at three Canadian universities set about to unravel this mystery. We proposed that SARS-CoV-2 worsened COVID-19 pneumonia by targeting mitochondria in airway epithelial cells (the cells that line the airways) and pulmonary artery smooth muscle cells.

We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and sensors of oxygen. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction.

This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels.

It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage — an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction — were making lung injury and hypoxemia (low blood oxygen) worse.

Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels.

We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels.

Attacking mitochondria

Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these viral proteins also target host proteins, causing them to malfunction. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.

Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization).

In our experiments, we didn’t need to use a replicating virus to damage the mitochondria — simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied.

We are now developing drugs that may one day counteract COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify a promising mitochondrial fission inhibitor, called Drpitor1a.

Our team’s infectious diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition — fatigue and neurologic dysfunction — could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.

The ongoing evolutionary battle

This research also has an interesting evolutionary angle. Considering that mitochondria were once bacteria, before being adopted by cells back in the primordial soup, our findings reveal an Alien versus Predator scenario in which viruses are attacking “bacteria.”

Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.

The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.

Pandemic pivot

The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field — virology — in an effort to make a small contribution to the COVID-19 puzzle.

The diverse team we put together also brought expertise in mitochondrial biology, cardiopulmonary physiology, SARS-CoV-2, transcriptomics, synthetic chemistry, molecular imaging and infectious diseases.

Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.

Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at Vaccine and Infectious Disease Organization (VIDO) in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus.

Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.

“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.

Our discovery will hopefully be translated into new medicines to counter future pandemics.

Auditory Disturbances and SARS-CoV-2 Infection: Brain Inflammation or Cochlear Affection? Systematic Review and Discussion of Potential Pathogenesis

Pietro De Luca1Alfonso Scarpa1Massimo Ralli2Domenico Tassone3Matteo Simone3Luca De Campora3Claudia Cassandro4† and Arianna Di Stadio Frontiers in Medicine

Patients affected by COVID-19 present a series of different symptoms; despite some of these are common, other less likely appear. Auditory symptoms seem to be less frequent, maybe because rarer or, alternatively, because they are underestimated during the clinical investigation. The hearing impairment might be related to the central or peripheral involvement of the auditory pathways; in particular, the likelihood of thrombosis might be one of the causes. To date, the prevalence of auditory symptoms such as sudden or progressive sensorineural hearing loss and tinnitus is unclear in COVID-19 patients. However, their presence might be an early sign of thrombosis or spread of the infection into the brain. In this systematic review of the literature we investigated the presence of auditory symptoms in COVID-19 patients and discussed their potential origin and causal relationship with SARS-CoV-2. Results showed that, despite rarely, auditory impairment can appear in patients with COVID-19 and should always be investigated for an early treatment and potential indicator of involvement of the central nervous system.

Introduction

Coronavirus Disease 19 (COVID-19) has spread worldwide, negatively impacting the healthcare systems and institutions (1). COVID-19 presents several symptoms, that generally arise 2-14 days after the start of the infection. Common symptoms include fever, cough, shortness of breath, respiratory distress; furthermore, olfactory and gustatory alterations have been widely reported (23). The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is responsible of different neurological manifestations and systemic complication (4).

Despite rarely, several viral infections that determine inflammation of the cochlea can cause auditory deficits (5); the pathogenetic mechanisms of these symptoms have been widely explained and confirmed by the literature (67). Researchers have attributed their onset to the peripheral damage affecting the cochlea (6) or to the involvement of the central auditory pathways (8).

Several studies have described the presence of brain lesions as responsible of auditory impairment (911), supporting the hypothesis that SARS-CoV-2, which has neuro-invasive characteristics, might determine a central hearing loss in COVID-19 patients both in the active phase and during recovery (12). It has been shown that the virus can spread from neuroepithelium to the olfactory bulb to the brain (1315), causing loss of smell (16), persistent cough after pneumonia resolution (17), memory deficit (18), and neurocognitive problems (19).

Although the central hypothesis seems to be the most plausible, the peripheral involvement of the cochlea cannot be totally excluded.

The presence of auditory symptoms in COVID-19 might be underestimated because they are not a primary symptom of the disease, while they might be a sign of the spread of the virus in the superior auditory pathways, or of a thrombosis.

The aim of this paper is to assess the incidence of sudden sensorineural hearing loss (SSNHL) and hearing deterioration in COVID-19 patients and discuss their possible causes.

Methods

This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist and statement recommendations (Figure 1). The nature of this review did not require Institutional Review Board approval.

Figure 1

FIGURE 1. Prisma diagram to illustrate the method used to select the articles.

Search Strategy

A comprehensive search strategy, developed in partnership with a medical librarian, was performed on PubMed, Scopus and Google Scholar without time restrictions. The keywords used were: “hearing loss,” “hearing impairment” “tinnitus” “audio and vestibular symptom” “sudden hearing loss,” “SARS-CoV-2” and “COVID-19”. Only articles in the English language were considered for the analysis.

Two independent investigators reviewed the articles extracted from the literature review. Duplicates were removed, then each reviewer singularly filled in an Excel data sheet (Microsoft Corporation, USA) including information extracted from the articles. Files were then compared and disagreements on the inclusion/exclusion papers were debated until complete agreement of both researchers. Only papers that received full consensus were considered.

PRISMA guidelines were followed to conduct the systematic review and the full list of references was screened for potentially relevant articles.

Study Selection Criteria

We included articles with the following characteristics: patients (0-99 years) affected by sudden sensorineural hearing loss or hearing deterioration after SARS-CoV-2 infection, written in English language, with full-text available. There were no restrictions in terms of diagnostic tools used to detect SARS-CoV-2. Suspected/unconfirmed COVID-19 patients were excluded. Selected articles were read in full to assess the study objectives and the level of evidence.

Data Extraction

A spreadsheet was filled using the data extracted from the articles read in full by the researchers. The following information were included: name of the author, year of publication, type of study, country where the study was conducted, number of subjects analyzed, patients’ characteristics, auditory results, treatment, outcome, presence or absence of the comparison group, characteristics of control groups.

Risk of Bias Assessment

The National Institutes of Health’s (NIH) quality assessment tools were used to assess the risk-of-bias checklists due to the different study designs (20). The rating of each study was categorized as: poor, fair or good (i.e., unbiased and fully described). The two authors independently gave a score to each article and any disagreement was resolved by direct comparison among the researchers.

Results

Study Selection

One-hundred seventeen records were identified (Figure 1 and Table 1). After removal of duplicates and abstract evaluation, 93 articles were excluded. Twenty-four full-text articles matched the inclusion/exclusion criteria. Five full-text articles were excluded because at high-risk of bias and the remaining 19 were included in the systematic review. The articles identified an association between SARS-CoV-2 and hearing impairment/sudden sensorineural hearing loss. All studies were published over a period of 2 years, between 2019 and 2021.

Table 1

TABLE 1. Summary of studies included in the systematic review.

Study Characteristics

Sudden Sensorineural Hearing Loss in Patients With SARS-CoV-2 Infection

Twelve full-text articles were identified (72131) (Table 2); we identified 11 case reports and 1 case series. Two studies were conducted in Turkey, two in France, two in the United Kingdom, and one in each of the following countries: Thailand, Germany, Brazil, Australia, Egypt, and United States of America. Sixteen patients (10 men and 6 women; age range 18-84 years) evaluated in these studies tested positive for COVID-19. All patients suffered from SSNHL; tinnitus was reported by four patients. Two patients suffered from vertigo, two had nausea or vomiting, and one was affected by ear fullness. Four subjects had bilateral impairment. Five patients had right SSNHL and five left SSNHL; in two studies the side of the affection was not specified. The hearing function was always (100%) assessed by pure tone audiometry (PTA); tympanometry was performed in three studies, speech audiometry and otoacoustic emissions in one, respectively. Two studies did not report the audiological assessment.

Table 2

TABLE 2. Characteristics of studies exploring sudden sensorineural hearing loss (SSNHL) in patients with COVID-19 and included in the systematic review.

Nine patients were exclusively treated by oral steroids, one subject with intratympanic steroid only; three patients were treated by combining oral steroid and intratympanic corticosteroids. In one case the treatment was not described. One patient, who did not recover, needed cochlear implant and only one patient recovered spontaneously.

Three patients completely recovered the auditory function (only one spontaneously) and five had a partial improvement; two studies did not mention the hearing outcome.

Hearing Loss in Patients With SARS-CoV-2 Infection

Seven full-text articles were identified (27323638) (Table 3). They included four prospective studies, one retrospective study, one case series, and one case report. The studies were conducted in Italy, Portugal, Iran, United Kingdom, Turkey, Egypt, and Qatar. A total of one 188 patients were evaluated. Ninety-three patients were males, 95 were females; age ranged from 0 to 82 years. Only one study did not report details about age and gender of the patients. Hearing ability was assessed by PTA by four authors, speech audiometry in one study, otoacoustic emissions in three and tympanometry in two articles. Only one author reported hearing capacity as “self-reported hearing loss” without objective assessment.

Table 3

TABLE 3. Characteristics of studies exploring hearing loss (HL) in patients with COVID-19 included in the systematic review.

Discussion

The results of our systematic review showed that, despite uncommon, the hearing function might be affected by SARS-CoV-2 infection. Because of wide differences among the studies and the lack of clinical trials, we were not able to perform a meta-analysis to clarify the real prevalence of this symptom.

Gallus et al. (32) performed a retrospective study investigating the audiological and vestibular characteristics of 48 non-hospitalized patients affected by COVID-19; after two consecutive negative RT-PCR on nasopharyngeal swabs, the doctors analyzed patients’ auditory and vestibular functions. All subjects were investigated by pure-tone audiometry, tympanometry, and cochleo-stapedius reflex. Four (8.3%) of them reported self-perception of hearing loss, in presence of normal hearing threshold at the time of testing.

Alves de Sousa et al. (33) in a prospective study showed that patients with light forms of COVID-19 had worse auditory thresholds at 1,000, 2,000, 4,000, and 8,000 Hz compared to healthy subjects, and the severity of hearing loss worsened in patients with moderate-severe forms of the disease. The results observed by Karimi-Galougahi et al. (34) and the report from Chirakkal et al. (38) confirmed the association between hearing deterioration and SARS-CoV-2 infection in a sample of five patients.

Celik et al. tested the auditory function on newborns from mothers who suffered from COVID-19 during pregnancy; 37 infants were studied by transient evoked otoacoustic emission (TEOAEs), distortion product otoacoustic emission (DPOAE), and contralateral suppression of otoacoustic emission (CLS OAE). The results were compared to healthy controls. The authors found statistically significant differences between TEOAEs (3,000 and 4,000 Hz) of infants exposed to COVID-19 infection during pregnancy compared to the ones of non-exposed newborns. Analyzing the results of CLS OAE, the authors observed similar significant statistical differences in all auditory frequencies (more significant at high frequencies) (35). Mustafa et al. used TEOAE to evaluate the hearing function in a cohort of asymptomatic COVID-19 patients; their results were compared to those of non-infected subjects. The authors identified that TEOAE amplitude was significant worse in SARS-CoV-2 positive subjects compared to the control (36). Munro et al. investigated the hearing functions of 138 adult patients with confirmed SARS-CoV-2 infection using a questionnaire; 16 (13.2%) patients referred changes in their hearing status after COVID-19 diagnosis; unfortunately, no audiological evaluation was performed to objectively assess the hearing in this cohort (37).

Sriwijtalaia and Wiwanitkit were the first to describe a correlation between COVID-19 and hearing loss (21); unfortunately, detailed data about patients’ characteristic were missing. Similarly, Degen et al. (22) described a 60-year-old man with profound SSNHL and COVID-19, but they did not report the outcome after treatment. Lang et al. (23) described a 30-year-old woman with severe unilateral SSNHL treated with oral steroids without significative improvement of the symptom. Furthermore, Lamounier et al. (24) and Koumpa et al. (25) showed that patients (one case for each author) could obtain partial recovery of their hearing function combining oral and intratympanic steroids. Guigou et al. described a 29-year-old man with bilateral SSNHL and positive to SARS-CoV-2, who obtained complete recovery of the hearing after treatment with oral corticosteroids (26). Notably, in this patient the SSNHL was the presenting symptom of COVID-19.

Chern et al. showed a case of bilateral intralabyrinthine hemorrhage in an adult woman affected by COVID-19; the patient suffered from bilateral SSNHL, aural fullness and vertigo. The magnetic resonance imaging (MRI) showed bilateral intralabyrinthine hemorrhage, which was identified as the cause of the hearing symptoms. The patient partially recovered hearing function after treatment with high-dose oral prednisone and left intratympanic dexamethasone injection (31).

Perret et al. described a case of acute labyrinthitis and SSNHL (29); the patient was treated with oral prednisone and showed progressive recovery. The oral steroid treatment was effective also for treating the hearing impairment in a patient on peritoneal dialysis program who showed SSNHL as presenting symptom of SARS-CoV-2 infection (29). An improvement of the hearing capacity was also reported by Abdel Rhman and Abdel Wahid (30); in this case the patient was treated with intratympanic steroids.

Kilic et al., speculating that hearing loss could be a presenting symptom of COVID-19, performed a real-time polymerase chain reaction (RT-PCR) in five consecutive male patients presenting with unilateral SSNHL. Only one of these subjects was positive for SARS-CoV-2, and SSNHL positively responded to COVID-19-specific treatment in the SARS-CoV-2 (739).

Finally, Jacob et al. observed a complete and spontaneous recovery of hearing in a 61-year-old woman with SSNHL and SARS-CoV-2 infection (27).

Etiopathology of Hearing Impairment in COVID-19

In patients affected by COVID-19, hearing loss and hearing disturbances might be related to a central and/or peripheral involvement of the auditory pathways. The cause can be indirectly (e.g., thrombosis) or directly (e.g., viral spread) related to SARS-CoV2.

SARS-CoV-2 infection increases the risk of systemic thrombosis (40), a condition that may determine neurological symptoms (41). Thrombosis is more common in the mild/moderate forms of the disease (42) rather than in severe ones, probably because in the latter anti-coagulant therapy is promptly administered (4243). An alteration of coagulation rate (44) could cause a macro and/or micro thrombosis, with consequent transitory ischemia and hypoxia in the auditory pathways determining the onset of hearing alterations. The thrombus, which can occlude the cochlear-vestibular artery or one of its afferent vessels (Figure 2), could determine transitory SSNHL or, in case of extremely rapid resolution, a slight hearing impairment or tinnitus. However, despite rapid resolution, transitory hypoxia into the cochlea could stress the inner ear cells and increase the concentration of reactive oxygen species (ROS), that could be responsible of additional damage of the hair cells. On the other hand, a thrombus in one of the vessels of the superior auditory pathways (Figure 2) can determine central hearing loss (45).

Figure 2

FIGURE 2. Direct Virus Effect. The image clearly shows the contiguity between the olfactory and the auditory areas. The virus can easy spread from the olfactory bulb to the olfactory area, reach the auditory area and once there inducing neuroinflammation responsible of the onset of the auditory symptoms.

Another hypothesis is that central auditory pathways—especially the auditory cortex (Figure 3)—might undergo the same inflammatory process observed in the olfactory area (16), directly caused by SARS-CoV-2. Recently, it has been confirmed that SARS-CoV2 spreads up to the olfactory bulb passing through the olfactory epithelium and lamina cribrosa (13); we speculate that the virus might, for contingency among the olfactory and auditory areas (Figure 3), determine transitory neuro-inflammation and consequent hearing symptoms. This hypothesis, although only speculative, could be supported by the clinical evidence of symptoms’ resolution using steroids.

Figure 3

FIGURE 3. Indirect Virus Effect. The images illustrates the different position of a potential trombosis, which can determine the onset of the audio-vestibular disorders because it stops the blood flow in the audiovestibular artery.

Moreover, the presence of vertigo/dizziness (4647) in patients with COVID-19 could have the same etiopathogenesis; in fact, a thrombosis in the audio-vestibular artery may alter the blood flow both in the cochlea and the vestibule explaining the presence of these symptoms (47). However, because of vestibular compensative mechanism, equilibrium disorders may be less perceived by the patients than hearing disturbances.

Vestibular disorders arising from central origin have been already confirmed in other diseases (4849); it is reasonable that SARS-CoV-2 spreading in the vestibular pathways may be responsible of equilibrium disorders observed in COVID-19 patients.

Limits of the Study

This study presents several limitations. First, the sample size (204 patients) is small. Second, the quality rating of the studies is not always satisfactory; in fact, there are several case reports and the cross-sectional studies have uncontrolled designs or provide insufficient details on the control groups. Third, in some studies the hearing deterioration could be already present before SARS-CoV-2 infection. Lastly, some of these studies described “self-reported symptoms” without an objective assessment of the hearing.

Conclusions

Hearing loss, despite rarely, might be present in COVID-19 patients. Auditory evaluation, although with all preventive measures to prevent contagion for healthcare providers, should be performed, especially if hearing disturbance are self-reported. The early recognition of these non-specific symptoms, which might be an early sign of brain inflammation, could help in preventing the spread of the infection to other areas of the brain.

Coronavirus and the Nervous System

Authors: NIH What is SARS-CoV-2 and COVID-19?

What is SARS-CoV-2 and COVID-19?

Coronaviruses are common causes of usually mild to moderate upper respiratory tract illnesses like the common cold, with symptoms that may include runny nose, fever, sore throat, cough, or a general feeling of being ill. However, a new coronavirus called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged and spread to cause the COVID-19 pandemic.

COVID-19, which means Coronavirus disease 2019, is an infectious disease that can affect people of all ages in many ways. It is most dangerous when the virus spreads from the upper respiratory tract into the lungs to cause viral pneumonia and lung damage leading to Acute Respiratory Distress Syndrome (ARDS). When severe, this impairs the body’s ability to maintain critical levels of oxygen in the blood stream—which can cause multiple body systems to fail and can be fatal.

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What do we know about the effects of SARS-CoV-2 and COVID-19 on the nervous system?

Much of the research to date has focused on the acute infection and saving lives. These strategies have included preventing infection with vaccines, treating COVID-19 symptoms with medicines or antibodies, and reducing complications in infected individuals.

Research shows the many neurological symptoms of COVID-19 are likely a result of the body’s widespread immune response to infection rather than the virus directly infecting the brain or nervous system. In some people, the SARS-CoV-2 infection causes an overreactive response of the immune system which can also damage body systems. Changes in the immune system have been seen in studies of the cerebrospinal fluid, which bathes the brain, in people who have been infected by SARS-CoV-2. This includes the presence of antibodies—proteins made by the immune system to fight the virus—that may also react with the nervous system. Although still under intense investigation, there is no evidence of widespread viral infection in the brain. Scientists are still learning how the virus affects the brain and other organs in the long-term. Research is just beginning to focus on the role of autoimmune reactions and other changes that cause the set of symptoms that some people experience after their initial recovery. It is unknown if injury to the nervous system or other body organs cause lingering effects that will resolve over time, or whether COVID-19 infection sets up a more persistent or even chronic disorder.

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What are the immediate (acute) effects of SARS-CoV-2 and COVID-19 on the brain?

Most people infected with SARS-CoV-2 virus will have no or mild to moderate symptoms associated with the brain or nervous system. However, most individuals hospitalized due to the virus do have symptoms related to the brain or nervous system, most commonly including muscle aches, headaches, dizziness, and altered taste and smell. Some people with COVID-19 either initially have, or develop in the hospital, a dramatic state of confusion called delirium. Although rare, COVID-19 can cause seizures or major strokes. Muscular weakness, nerve injury, and pain syndromes are common in people who require intensive care during infections. There are also very rare reports of conditions that develop after SARS-CoV-2 infection, as they sometimes do with other types of infections. These disorders of inflammation in the nervous system include Guillain-Barré syndrome (which affects nerves), transverse myelitis (which affects the spinal cord), and acute necrotizing leukoencephalopathy (which affects the brain).

Bleeding in the brain, weakened blood vessels, and blood clots in acute infection

The SARS-CoV-2 virus attaches to a specific molecule (called a receptor) on the surface of cells in the body. This molecule is concentrated in the lung cells but is also present on certain cells that line blood vessels in the body. The infection causes some arteries and veins—including those in the brain—to  become thin, weaken, and leak. Breaks in small blood vessels have caused bleeding in the brain (so-called microbleeds) in some people with COVID-19 infection. Studies in people who have died due to COVID-19 infection show leaky blood vessels in different areas of the brain that allow water and a host of other molecules as well as blood cells that are normally excluded from the brain to move from the blood stream into the brain. This leak, as well as the resulting inflammation around blood vessels, can cause multiple small areas of damage. COVID-19 also causes blood cells to clump and form clots in arteries and veins throughout the body. These blockages reduce or block the flow of blood, oxygen, and nutrients that cells need to function and can lead to a stroke or heart attack.

stroke is a sudden interruption of continuous blood flow to the brain. A stroke occurs either when a blood vessel in the brain becomes blocked or narrowed or when a blood vessel bursts and spills blood into the brain. Strokes can damage brain cells and cause permanent disability. The blood clots and vascular (relating to the veins, capillaries, and arteries in the body) damage from COVID-19 can cause strokes even in young healthy adults who do not have the common risk factors for stroke.

COVID-19 can cause blood clots in other parts of the body, too. A blood clot in or near the heart can cause a heart attack. A heart attack or Inflammation in the heart, called myocarditis, can cause heart failure, and reduce the flow of blood to other parts of the body. A blood clot in the lungs can impair breathing and cause pain. Blood clots also can damage the kidneys and other organs.

Low levels of oxygen in the body (called hypoxia) can permanently damage the brain and other vital organs in the body. Some hospitalized individuals require artificial ventilation on respirators. To avoid chest movements that oppose use of the ventilator it may be necessary to temporarily “paralyze” the person and use anesthetic drugs to put the individual to sleep. Some individuals with severe hypoxia require artificial means of bringing oxygen into their blood stream, a technique called extra corporeal membrane oxygenation (ECMO). Hypoxia combined with these intensive care unit measure generally cause cognitive disorders that show slow recovery.

Diagnostic imaging of some people who have had COVID-19 show changes in the brain’s white matter that contains the long nerve fibers, or “wires,” over which information flows from one brain region to another. These changes may be due to a lack of oxygen in the brain, the inflammatory immune system response to the virus, injury to blood vessels, or leaky blood vessels. This “diffuse white matter disease” might contribute to cognitive difficulties in people with COVID-19. Diffuse white matter disease is not uncommon in individuals requiring intensive hospital care but it not clear if it also occurs in those with mild to moderate severity of COVID-19 illness.

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What is the typical recovery from COVID-19?

Fortunately, people who have mild to moderate symptoms typically recover in a few days or weeks. However, some  people who have had only mild or moderate symptoms of COVID-19 continue to experience dysfunction of body systems—particularly in the lungs but also possibly affecting the liver, kidneys, heart, skin, and brain and nervous system—months after their infection. In rare cases, some individuals may develop new symptoms (called sequelae) that stem from but were not present at the time of initial infection. People who require intensive care for Acute Respiratory Distress Syndrome, regardless of the cause, usually have a long period of recovery. Individuals with long-term effects, whether following mild or more severe COVID-19, have in some cases self-identified as having “long COVID” or “long haul COVID.” These long-term symptoms are included in the scientific term, Post Acute Sequelae of SARS-CoV-2 Infection (PASC).

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What are possible long-term neurological complications of COVID-19?

Researchers are following some known acute effects of the virus to determine their relationship to the post-acute complications of COVID-19 infection. These post-acute effects usually include fatigue in combination with a series of other symptoms. These may include trouble with concentration and memory, sleep disorders, fluctuating heart rate and alternating sense of feeling hot or cold, cough, shortness of breath, problems with sleep, inability to exercise to previous normal levels, feeling sick for a day or two after exercising (post-exertional malaise), and pain in muscle, joints, and chest. It is not yet known how the infection leads to these persistent symptoms and why in some individuals and not others.

Expand accordion content

Nerve damage, including peripheral neuropathy

Fatigue and post-exertional malaise

Cognitive impairment/altered mental state

Muscle, joint, and chest pain

Prolonged/lingering loss of smell (anosmia) or taste

Persistent fevers and chills

Prolonged respiratory effects and lung damage

Headaches

Sleep disturbances

Anxiety, depression, and stress post-COVID

 How do the long-term effects of SARS-CoV-2 infection/COVID-19 relate to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

Some of the symptom clusters reported by people still suffering months after their COVID-19 infection overlap with symptoms described by individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). People with a diagnosis of ME/CFS have wide-ranging and debilitating effects including fatigue, PEM, unrefreshing sleep, cognitive difficulties, postural orthostatic tachycardia, and joint and muscle pain. Unfortunately, many people with ME/CFS do not return to pre-disease levels of activity. The cause of ME/CFS is unknown but many people report its onset after an infectious-like illness. Rest, conserving energy, and pacing activities are important to feeling better but don’t cure the disease. Although the long-term symptoms of COVID-19 may share features with it, ME/CFS is defined by symptom-based criteria and there are no tests that confirm an ME/CFS diagnosis.

ME/CFS is not diagnosed until the key features, especially severe fatigue, post-exertional malaise, and unrefreshing sleep, are present for greater than six months. It is now becoming more apparent that following infection with SARS-CoV-2/COVID-19, some individuals may continue to exhibit these symptoms beyond six months and qualify for an ME/CFS diagnosis. It is unknown how many people will develop ME/CFS after SARS-CoV-2 infection. It is possible that many individuals with ME/CFS, and other disorders impacting the nervous system, may benefit greatly if research on the long-term effects of COVID-19 uncovers the cause of debilitating symptoms including intense fatigue, problems with memory and concentration, and pain.

Am I at a higher risk if I currently have a neurological disorder?

Much is still unknown about the coronavirus but people having one of several underlying medical conditions may have an increased risk of illness. However, not everyone with an underlying condition will be at risk of developing severe illness. People who have a neurological disorder may want to discuss their concerns with their doctors.

Because COVID-19 is a new virus, there is little information on the risk of getting the infection in people who have a neurological disorder. People with any of these conditions might be at increased risk of severe illness from COVID-19:

  • Cerebrovascular disease
  • Stroke
  • Obesity
  • Dementia
  • Diabetes
  • High blood pressure

There is evidence that COVID-19 seems to disproportionately affect some racial and ethnic populations, perhaps because of higher rates of pre-existing conditions such as heart disease, diabetes, and lung disease. Social determinants of health (such as access to health care, poverty, education, ability to remain socially distant, and where people live and work) also contribute to increased health risk and outcomes.

Can COVID-19 cause other neurological disorders?

In some people, response to the coronavirus has been shown to increase the risk of stroke, dementia, muscle and nerve damage, encephalitis, and vascular disorders. Some researchers think the unbalanced immune system caused by reacting to the coronavirus may lead to autoimmune diseases, but it’s too early to tell.

Anecdotal reports of other diseases and conditions that may be triggered by the immune system response to COVID-19 include para-infectious conditions that occur within days to a few weeks after infection:

  • Multi-system infammatory syndrome – which causes inflammation in the body’s blood vessels
  • Transverse myelitis – an inflammation of the spinal cord
  • Guillain-Barré sydrome (sometimes known as acute polyradiculoneuritis) – a rare neurological disorder which can range from brief weakness to nearly devastating paralysis, leaving the person unable to breathe independently
  • Dysautonomia – dysfunction of the autonomic nerve system, which is involved with functions such a breathing, heart rate, and temperature control
  • Acute disseminating encephalomyelitis (ADEM) – an attack on the protective myelin covering of nerve fibers in the brain and spinal cord
  • Acute necrotizing hemorrhagic encephalopathy – a rare type of brain disease that causes lesions in certain parts of the brain and bleeding (hemorrhage) that can cause tissue death (necrosis)
  • Facial nerve palsies (lack of function of a facial nerve) such as Bell’s Palsy
  • Parkinson’s disease-like symptoms have been reported in a few individuals who had no family history or early signs of the disease

Does the COVID-19 vaccine cause neurological problems?

Almost everyone should get the COVID-19 vaccination. It will help protect you from getting COVID-19. The vaccines are safe and effective and cannot give you the disease. Most side effects of the vaccine may feel like flu and are temporary and go away within a day or two. The U.S. Food and Drug Administration (FDA) continues to investigate any report of adverse consequences of the vaccine. Consult your primary care doctor or specialist if you have concerns regarding any pre-existing known allergic or other severe reactions and vaccine safety.

A recent study from the United Kingdom demonstrated an increase in Guillain-Barré Syndrome related to the Astra Zeneca COVID-19 vaccine (virally delivered) but not the Moderna (messenger RNA vaccine). Guillain-Barré syndrome (a rare neurological disorder in which the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis) has also occurred in some people who have received the Janssen COVID-19 Vaccine (also virally delivered). In most of these people, symptoms began within weeks following receipt of the vaccine. The chance of having this occur after these  vaccines is very low, 5 per million vaccinated persons in the UK study. The chance of developing Guillain-Barré Syndrome was much higher if one develops COVID-19 infection (i.e., has a positive COVID test) than after receiving the Astra Zeneca vaccine. The general sense is that there are COVID-19 vaccines that are safe in individuals whose Guillain-Barré syndrome was not associated with a previous vaccination and that actual infection is the greater risk for developing Guillain-Barré Syndrome. 

The U.S. Centers for Disease Control and Prevention (CDC) site offers information on vaccine resources. The National Institutes of Health (NIH) has information on vaccines for the coronavirus. The CDC  has make public its report on the association of Guillain-Barré Syndrome with the Janssen COVID-19 Vaccine and no increased incidence occurred after vaccination with the Moderna or Pfizer vaccines.

More information about Guillain-Barré Syndrome here.

There have been reports of  neurological complications from other SARS-CoV-2 vaccinations. Visit the FDA COVID-19 Vaccines webpage for information about coronavirus vaccines and fact sheets for recipients and caregivers that outline possible neurological and other risks.

COVID fog demystified

Authors: Jennifer Kao 1Paul W Frankland 2PMID: 35768007PMCID: PMC9197953DOI: 10.1016/j.cell.2022.06.020

Abstract

Acute mild respiratory SARS-CoV-2 infection can lead to a more chronic cognitive syndrome known as “COVID fog.” New findings from Fernández-Castañeda et al. reveal how glial dysregulation and consequent neural circuit dysfunction may contribute to cognitive impairments in long COVID.

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Main text

More than 2 years since the first detected cases of COVID-19, the virus continues to evolve new variants, infect hundreds of millions of people, and pose both acute and chronic threats to global health. In most infections, a patient’s symptoms resolve within 2 weeks. However, recovery from initial infection is not always straightforward. In a significant fraction of patients, symptoms can persist for several months. This syndrome, which has become known as “long COVID,” may occur even following initially mild cases (that is, those not requiring hospitalization) and can include significant cognitive dysfunction.

Initial awareness of long COVID emerged from anecdotal accounts, shared by patients on social media platforms such as Twitter, Facebook, and Slack (Callard and Perego, 2021). Since then, a large number of studies have used more formal methods to catalog the nature and frequency of long COVID symptoms. Within the cognitive domain, as many as one in four patients experience a range of symptoms that have become known colloquially as “COVID fog,” which includes problems in attention, language fluency, processing speed, executive function, and memory (Becker et al., 2021).

Given the sheer scale of infections, there is a pressing need to understand how cognitive dysfunction emerges in long COVID. In this issue of Cell, a new paper by Fernández-Castañeda and colleagues (Fernández-Castañeda et al., 2022Geraghty et al., 2019) begins to address this need. Using mice as a model, they expressed human ACE2, the viral entry receptor required for successful COVID infection. Because ACE2 expression was restricted to the trachea and lungs, these mice developed only a mild form of the disease that was limited to the respiratory system and largely cleared within a week following intranasal inoculation with SARS-CoV-2 virus.

As a starting point, the researchers noted the striking similarities between COVID fog and another cognitive syndrome known as “chemobrain.” Chemobrain (or cancer-therapy-related cognitive impairment, CRCI), is a neuroinflammatory condition that patients often experience following radiation or chemotherapy. In CRCI, elevations in neurotoxic cytokines and reactive microglia (brain-resident macrophages) lead to cascades of multicellular events that impact forms of both gray and white matter plasticity that are important for healthy cognition (Gibson and Monje, 2021).

Adopting this framework, the authors quantified changes in cytokines and microglial/macrophage reactivity following SARS-CoV-2 infection. Reminiscent of CRCI, they found that microglial/macrophage reactivity was elevated in subcortical and hippocampal white matter in mice following mild respiratory COVID. Remarkably, this elevation was persistent and still evident even 7 weeks post infection. Outside of the brain, they detected elevated cytokine levels in the cerebrospinal fluid and serum of mice. Although levels of many cytokines were altered, one in particular grabbed their attention. CCL11 remained persistently elevated in mouse cerebrospinal fluid 7 weeks post infection. Notably, elevated CCL11 levels have been causally linked to cognitive impairments observed in normal aging (Villeda et al., 2011).

Similar patterns were found in patients with COVID-19 (Figure 1 ). Reactive microglia were elevated in subcortical white matter in individuals with COVID-19 (these patients were symptomatic for COVID-19 but died from other causes). Moreover, CCL11 was elevated in plasma from patients with long COVID. Remarkably, elevated CCL11 plasma levels were only detected in those long COVID patients with cognitive symptoms. CCL11 plasma levels were unaltered in long COVID patients who did not have cognitive symptoms. These findings suggest that CCL11 plays a central role in the brain pathology contributing to COVID fog.

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Figure 1

The neuroinflammatory basis of COVID fog

Acute mild respiratory COVID-19 infection can lead to a more chronic cognitive syndrome known as brain fog. Suggested pathways for brain fog include cytokine-induced activation of regional microglia, causing decreased hippocampal neurogenesis and a loss of myelinated subcortical axons.

There are several ways in which such a neuroinflammatory state might impact cognition. Previous work has shown that persistently reactive microglia in hippocampal white matter suppress hippocampal neurogenesis by blocking neuronal progenitor-cell differentiation into new granule cells (Monje et al., 2003). These newly generated neurons are important for the formation and stability of hippocampus-dependent memories. The authors found the numbers of new neurons were reduced in infected mice, and this reduction correlated with numbers of reactive microglia in the hippocampus. Remarkably, systemic administration of CCL11 recapitulated this same pattern in uninfected mice. Increased numbers of reactive microglia and decreased numbers of new neurons in these mice suggest a causal role for CCL11 in COVID fog pathology. These CCL11-induced outcomes were restricted to the hippocampus, suggesting that particular cytokines can have circuit-specific effects.

Another way in which CCL11 and/or reactive microglia might impact cognition is via effects on white matter. In CRCI, reactive microglia impair the formation of myelin-forming oligodendrocytes and myelin plasticity (Geraghty et al., 2019Gibson et al., 2019). Similarly, the authors found reduced numbers of oligodendrocytes and their precursor cells, as well as decreased axon myelination in the subcortical white matter, several weeks following infection in mice. Although behavior was not assessed in this study, it is nonetheless reasonable to assume that such changes would alter cognitive function following mild respiratory COVID in mice, as it does in other disease contexts (Geraghty et al., 2019Gibson et al., 2019). Since myelination regulates the speed and timing of communication between neurons, dysregulation of oligodendoglial lineage cells following infection might slow neural processing, disrupt brain synchrony, and impair cognition (Steadman et al., 2020).

The principle that inflammatory challenges may induce glial dysregulation and consequent neural circuit dysfunction is not specific to COVID-19. Many systemic infections are associated with lasting cognitive impairments. For instance, similar to COVID-19, the Spanish flu of 1918 (caused by H1N1 influenza virus infection) was associated with brain fog. In the current study, the authors compared the effects of mild respiratory SARS-CoV-2 infection with a mouse model of mild respiratory H1N1 influenza. Similar to SARS-CoV-2 infection, they found persistently elevated CCL11 in the H1N1 influenza infection. Therefore, CCL11-driven neuroinflammatory changes and cellular deficits may represent a common pathway to cognitive deficits in both mild respiratory COVID-19 and H1N1 influenza disease (as well as perhaps in other contexts, including aging).

However, different systemic infections can also have non-overlapping outcomes. For instance, whereas risk for anxiety and depression appears to be elevated in COVID-19, Spanish flu was associated with increased prevalence of psychosis (Honigsbaum, 2013). What accounts for these differences? One clue emerges from the current study. While CCL11 was elevated following SARS-CoV-2 and H1N1 influenza infection, a subset of cytokines was differentially regulated in these two conditions. It is likely that these non-overlapping cytokines (and their potentially non-overlapping circuit effects) might differentiate these diseases in terms of elevated risks for particular neuropsychiatric outcomes.

If cytokines have circuit-specific effects, should we consider cytokine profiling as a way to inform our treatment strategies for viral-induced/non-viral induced cognitive syndromes? Future research will no doubt address this and other outstanding questions. For instance, how are these effects mitigated by vaccination, administered before or after infection? And, perhaps most significantly, might interventions that block inducers of these cytokines or reset reactive microglia prove useful in treating COVID fog?

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Declaration of interests

The authors declare no competing interests.

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References

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How COVID-19 causes neurological damage found

Particularly in the group with the most serious neurological symptoms, the researchers identified a link with an excessive immune response.

Authors: PTI 15th November 2022 The Indian Express

COVID-19 may cause damage to the nervous system, even though it does not affect nerve cells, according to a small study.

While it was not uncommon for some people to lose their sense of taste and smell due to a Covid-19 infection, in others, the disease had had an even stronger impact on the nervous system, with effects ranging from lasting concentration problems to strokes, the study said.

Researchers, from the University of Basel and University Hospital Basel, Switzerland, have studied the mechanisms responsible for and reported new insights into the development of “neuro-Covid”, including identifying starting points for its prevention, the study said.

The team investigated how different severities of neuro-COVID can be detected and predicted by analyzing the cerebrospinal fluid and blood plasma of affected individuals.

Their findings, published in the journal Nature Communications, also indicate how to prevent neurological damage due to Covid-19.

The study included 40 Covid-19 patients with differing degrees of neurological symptoms.

n order to identify typical changes associated with neuro-Covid, the team of researchers compared cerebrospinal fluid and blood plasma of these individuals with samples from a control group.

They also measured the brain structures of test subjects and surveyed participants 13 months after their illness in order to identify any lasting symptoms.

Particularly in the group with the most serious neurological symptoms, the researchers identified a link with an excessive immune response.

On the one hand, the study said, affected individuals showed indications of impairment of the blood-brain barrier, which the study’s authors speculate was probably triggered by a “cytokine storm” — a massive release of pro-inflammatory factors in response to the virus.

On the other hand, the researchers also found antibodies that targeted parts of the body’s own cells — in other words, signs of an autoimmune reaction — as a result of the excessive immune response, the study said.

ALSO READ | Study: Blood tests might help to detect long covid in patients

“We suspect that these antibodies cross the porous blood-brain barrier into the brain, where they cause damage,” explained lead researcher Gregor Hutter.

Researchers also identified excessive activation of the immune cells specifically responsible for the brain — the microglia.

In a further step, Hutter and his team investigated whether the severity of neurological symptoms is also perceptible in brain structures.

Indeed, they found that people with serious neuro-Covid symptoms had a lower brain volume than healthy participants at specific locations in the brain and particularly at the olfactory cortex — that is, the area of the brain responsible for smell.

“We were able to link the signature of certain molecules in the blood and cerebrospinal fluid to an overwhelming immune response in the brain and reduced brain volume in certain areas, as well as neurological symptoms,” says Hutter, adding that it is now important to examine these biomarkers in a greater number of participants.

ALSO READ | Covid virus ‘more likely than not, result of a research-related incident’: US report

The aim, the study said, would be to develop a blood test that can already predict serious cases, including neuro-Covid and long Covid, at the start of an infection.

These same biomarkers point to potential targets for drugs aimed at preventing consequential damage due to a Covid-19 infection.

One of the biomarkers identified in blood, the factor MCP-3, plays a key role in the excessive immune response, and Hutter believes there is the potential to inhibit this factor medicinally, the study said.

“In our study, we show how coronavirus can affect the brain,” he says.

“The virus triggers such a strong inflammatory response in the body that it spills over to the central nervous system. This can disrupt the cellular integrity of the brain.”

Accordingly, Hutter said that the primary objective must be to identify and halt the excessive immune response at an early stage, the study said.ors

COVID-19 infections increase risk of long-term brain problems

Authors: Washington University in St. Louis Medical Xpress

COVID-19 infections increase risk of long-term brain problems
A comprehensive analysis of federal data by researchers at Washington University School of Medicine in St. Louis shows people who have had COVID-19 are at an elevated risk of developing neurological conditions within the first year after infection. Movement disorders, memory problems, strokes and seizures are among the complications. Credit: Sara Moser/Washington University School of Medicine

If you’ve had COVID-19, it may still be messing with your brain. Those who have been infected with the virus are at increased risk of developing a range of neurological conditions in the first year after the infection, new research shows. Such complications include strokes, cognitive and memory problems, depression, anxiety and migraine headaches, according to a comprehensive analysis of federal health data by researchers at Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care system.

Additionally, the post-COVID brain is associated with movement disorders, from tremors and involuntary muscle contractions to epileptic seizures, hearing and vision abnormalities, and balance and coordination difficulties as well as other symptoms similar to what is experienced with Parkinson’s disease.

The findings are published Sept. 22 in Nature Medicine.

“Our study provides a comprehensive assessment of the long-term neurologic consequences of COVID-19,” said senior author Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University. “Past studies have examined a narrower set of neurological outcomes, mostly in hospitalized patients. We evaluated 44 brain and other neurologic disorders among both nonhospitalized and hospitalized patients, including those admitted to the intensive care unit. The results show the devastating long-term effects of COVID-19. These are part and parcel of long COVID. The virus is not always as benign as some people think it is.”

Overall, COVID-19 has contributed to more than 40 million new cases of neurological disorders worldwide, Al-Aly said.

Other than having a COVID infection, specific risk factors for long-term neurological problems are scarce. “We’re seeing brain problems in previously healthy individuals and those who have had mild infections,” Al-Aly said. “It doesn’t matter if you are young or old, female or male, or what your race is. It doesn’t matter if you smoked or not, or if you had other unhealthy habits or conditions.”

Few people in the study were vaccinated for COVID-19 because the vaccines were not yet widely available during the time span of the study, from March 2020 through early January 2021. The data also predates delta, omicron and other COVID variants.

A previous study in Nature Medicine led by Al-Aly found that vaccines slightly reduce—by about 20%—the risk of long-term brain problems. “It is definitely important to get vaccinated but also important to understand that they do not offer complete protection against these long-term neurologic disorders,” Al-Aly said.

The researchers analyzed about 14 million de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation’s largest integrated health-care system. Patients included all ages, races and sexes.

They created a controlled data set of 154,000 people who had tested positive for COVID-19 sometime from March 1, 2020, through Jan. 15, 2021, and who had survived the first 30 days after infection. Statistical modeling was used to compare neurological outcomes in the COVID-19 data set with two other groups of people not infected with the virus: a control group of more than 5.6 million patients who did not have COVID-19 during the same time frame; and a control group of more than 5.8 million people from March 2018 to December 31, 2019, long before the virus infected and killed millions across the globe.

The researchers examined brain health over a year-long period. Neurological conditions occurred in 7% more people with COVID-19 compared with those who had not been infected with the virus. Extrapolating this percentage based on the number of COVID-19 cases in the U.S., that translates to roughly 6.6 million people who have suffered brain impairments associated with the virus.

Memory problems—colloquially called brain fog—are one of the most common brain-related, long-COVID symptoms. Compared with those in the control groups, people who contracted the virus were at a 77% increased risk of developing memory problems. “These problems resolve in some people but persist in many others,” Al-Aly said. “At this point, the proportion of people who get better versus those with long-lasting problems is unknown.”

Interestingly, the researchers noted an increased risk of Alzheimer’s disease among those infected with the virus. There were two more cases of Alzheimer’s per 1,000 people with COVID-19 compared with the control groups. “It’s unlikely that someone who has had COVID-19 will just get Alzheimer’s out of the blue,” Al-Aly said. “Alzheimer’s takes years to manifest. But what we suspect is happening is that people who have a predisposition to Alzheimer’s may be pushed over the edge by COVID, meaning they’re on a faster track to develop the disease. It’s rare but concerning.”

Also compared to the control groups, people who had the virus were 50% more likely to suffer from an ischemic stroke, which strikes when a blood clot or other obstruction blocks an artery’s ability to supply blood and oxygen to the brain. Ischemic strokes account for the majority of all strokes, and can lead to difficulty speaking, cognitive confusion, vision problems, the loss of feeling on one side of the body, permanent brain damage, paralysis and death.

“There have been several studies by other researchers that have shown, in mice and humans, that SARS-CoV-2 can attack the lining of the blood vessels and then then trigger a stroke or seizure,” Al-Aly said. “It helps explain how someone with no risk factors could suddenly have a stroke.”

Overall, compared to the uninfected, people who had COVID-19 were 80% more likely to suffer from epilepsy or seizures, 43% more likely to develop mental health disorders such as anxiety or depression, 35% more likely to experience mild to severe headaches, and 42% more likely to encounter movement disorders. The latter includes involuntary muscle contractions, tremors and other Parkinson’s-like symptoms.

COVID-19 sufferers were also 30% more likely to have eye problems such as blurred vision, dryness and retinal inflammation; and they were 22% more likely to develop hearing abnormalities such as tinnitus, or ringing in the ears.

“Our study adds to this growing body of evidence by providing a comprehensive account of the neurologic consequences of COVID-19 one year after infection,” Al-Aly said.

Long COVID’s effects on the brain and other systems emphasize the need for governments and health systems to develop policy, and public health and prevention strategies to manage the ongoing pandemic and devise plans for a post-COVID world, Al-Aly said. “Given the colossal scale of the pandemic, meeting these challenges requires urgent and coordinated—but, so far, absent—global, national and regional response strategies,” he said.

Study Shows Pfizer’s Paxlovid Pill Can Cause Deadly Blood Clots

Authors:  Jim Hoft Published October 13, 2022 

A new study warned that Pfizer’s Paxlovid COVID-19 pill can have harmful interactions with common medications used to treat cardiovascular disease, as what the Gateway Pundit reported in 2021.

Pfizer’s Paxlovid, which contains the drugs nirmatrelvir and ritonavir (NMVr), can interact with several other drugs routinely used to treat cardiovascular disease, according to a study published in the Journal of the American College of Cardiology on Wednesday.

Most of the concerns about drug interactions come from ritonavir, experts said.

“Co-administration of NMVr with medications commonly used to manage cardiovascular conditions can potentially cause significant drug-drug interactions and may lead to severe adverse effects,” according to the reviewed paper.

Paxlovid can cause serious health problems when coupled with common heart disease medication such as statins and blood thinners.

Researchers from Lahey Hospital and Medical Center, Harvard Medical School and other US institutions  found the Covid drug can increase the risk of developing blood clots when taken with blood thinners.

It can also cause an irregular heartbeat when combined with drugs for heart pain and when taken alongside statins it can be toxic to the liver.

Dozens of medications such as aspirin are safe to take with Paxlovid,  the researchers stress. But doctors need to be aware that other drugs can be dangerous and should be discontinued or adjusted while a patient is being treated for Covid.

Dr. Houman Hemmati, Chief Medical Officer of Vyluma, Inc, shared his insights on the study and claimed that people who took Paxlovid are part of the clinical trials.

“The problem is that Paxlovid didn’t have these lengthy phase one, two, and three trials. It was rushed to market under an emergency use authorization, never an approval. And as a result, they’ve skipped a lot of these studies. And so what we’re learning about that drug and its safety is largely based on post-marketing data. What does that mean? It’s people who are actually getting it in the real life, in real-world usage, and then we find out through them,” Hemmati said.\

It’s Not Just the mRNA Vaccines, New Study Shows Pfizer’s Paxlovid Pill Can Cause Deadly Blood Clots

By Jim Hoft
Published October 13, 2022 at 2:00pm
138 Comments

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A new study warned that Pfizer’s Paxlovid COVID-19 pill can have harmful interactions with common medications used to treat cardiovascular disease, as what the Gateway Pundit reported in 2021.

Pfizer’s Paxlovid, which contains the drugs nirmatrelvir and ritonavir (NMVr), can interact with several other drugs routinely used to treat cardiovascular disease, according to a study published in the Journal of the American College of Cardiology on Wednesday.

Most of the concerns about drug interactions come from ritonavir, experts said.

“Co-administration of NMVr with medications commonly used to manage cardiovascular conditions can potentially cause significant drug-drug interactions and may lead to severe adverse effects,” according to the reviewed paper.

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Daily Mail reported:

Paxlovid can cause serious health problems when coupled with common heart disease medication such as statins and blood thinners.

Researchers from Lahey Hospital and Medical Center, Harvard Medical School and other US institutions  found the Covid drug can increase the risk of developing blood clots when taken with blood thinners.

It can also cause an irregular heartbeat when combined with drugs for heart pain and when taken alongside statins it can be toxic to the liver.

Dozens of medications such as aspirin are safe to take with Paxlovid,  the researchers stress. But doctors need to be aware that other drugs can be dangerous and should be discontinued or adjusted while a patient is being treated for Covid.

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Dr. Houman Hemmati, Chief Medical Officer of Vyluma, Inc, shared his insights on the study and claimed that people who took Paxlovid are part of the clinical trials.

“The problem is that Paxlovid didn’t have these lengthy phase one, two, and three trials. It was rushed to market under an emergency use authorization, never an approval. And as a result, they’ve skipped a lot of these studies. And so what we’re learning about that drug and its safety is largely based on post-marketing data. What does that mean? It’s people who are actually getting it in the real life, in real-world usage, and then we find out through them,” Hemmati said.

Watch the video below:

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It can be recalled that Dr. Jill tested positive for Covid AGAIN  in a ‘rebound’ case after taking Paxlovid earlier in August.

When President Joe Biden, 79, tested positive for Covid and started Paxlovid in July, Joe Biden’s doctor said he had stopped heart medications for Biden’s atrial fibrillation and high cholesterol due to his prescribing Paxlovid to treat Biden’s COVID infection. Atrial fibrillation can cause strokes and is treated by blood thinners to reduce the risk of stroke-causing blood clots being formed.

“His apixaban (ELIQUIS) and rosuvastatin (Crestor) are being held during PAXLOVID treatment and for several days after his last dose. During this time, it is reasonable to add low dose aspirin as an alternative type of blood thinner,” said Biden’s personal physician Dr. Kevin O’Connor.

Quadruple vaxxed Pfizer CEO Albert Bourla announced he tested positive for Covid in August. Bourla also said he started a course of Paxlovid.

The U.S. Food and Drug Administration issued an emergency use authorization for Pfizer’s antiviral pill for the treatment of mild-to-moderate COVID-19 infection on December 2021.

The Gateway Pundit reported that the COVID pill could cause life-threatening reactions when used with many common medications in 2021.

Pfizer’s antiviral oral drug Paxlovid that was developed as an early treatment for Covid-19 can cause severe or life-threatening effects if it is taken in tandem with other common medications including some anticoagulants, anti-depressants, and cholesterol-lowering drugs that are used widely across the US, according to a warning from the Food and Drug Administration (FDA).

There are six pages of warnings about this drug. FDA already know about the adverse event, and yet they still push it on people with COVID-19.

As the Gateway Pundit previously reported, more and more reports of patients taking Pfizer’s antiviral pill experienced a second round of Covid-19 shortly after recovering. Experts are still investigating the causes and they are baffled.

Scientific documentation about post-Paxlovid relapse has been available since last fall. Pfizer’s application to the FDA for emergency use authorization of Paxlovid stated that in the placebo-controlled clinical trial — which included 2,246 participants — “several subjects appeared to have a rebound in SARS-CoV-2 RNA levels around Day 10 or Day 14” after beginning treatment, NBC reported.

Following this report, Pfizer released a statement admitting that it failed to reduce the risk of confirmed and symptomatic COVID-19 infection in adults living with someone who had been exposed to the virus.