Potential pharmacologic treatments for COVID-19 smell and taste loss: A comprehensive review

Authors: Elnaz Khani,aSajad Khiali,aSamineh Beheshtirouy,a and Taher Entezari-Malekia,b,∗

Eur J Pharmacol. 2021 Dec 5; 912: 174582.Published online 2021 Oct 19. doi:  10.1016/ j.ejphar.2021.174582 PMCID: PMC8524700PMID: 34678243

Abstract

The acute loss of taste and smell following COVID-19 are hallmark symptoms that affect 20–85% of patients. However, the pathophysiology and potential treatments of COVID-19 smell and taste loss are not fully understood. We searched the literature to review the potential pathologic pathways and treatment options for COVID-19 smell and taste loss. The interaction of novel coronavirus with ACE-2 receptors expressed on sustentacular cells and taste buds results in direct damage to the olfactory and gustatory systems. Also, the invasion of the virus to the olfactory neurons and consequent local inflammation are other proposed mechanisms. Therefore, COVID-19 patients with smell or taste loss may benefit from neuroprotective, anti-inflammatory, or depolarizing agents. Based on the current evidence, phosphodiesterase inhibitors, insulin, and corticosteroids can be promising for the management of COVID-19 smell and taste loss. This review provided crucial information for treating COVID-19-related smell and/or taste loss, urging to perform large clinical trials to find optimum treatment options.Keywords: Ageusia, Anosmia, COVID-19, Therapeutics.

1. Introduction

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more than 210 million cases and 4 million deaths have been reported worldwide. Despite the considerable progress in treatment tools of the disease, effective therapies for managing the long-lasting complications of the novel coronavirus disease (COVID-19) are still lacking. It is now clear that COVID-19 is not just a respiratory disease and affects other parts of the body. The common manifestations of COVID-19 are fever, cough, and fatigue, which are nonspecific and make the diagnosis challenging (Huang et al., 2020). The acute loss of taste and smell are key diagnostic criteria supposed to be used as screening tools based on the National Institute on Deafness and Other Communication Disorders (NIDCD), and the Global Consortium for Chemosensory Research (GCCR) reports (Gerkin et al., 2021Lovato et al., 2020National Institute on Deafness and Other Communication Disorders, 2021Parma et al., 2020).

Anosmia and ageusia are categorized as neurological complications of the SARS-CoV-2 infection. Previous studies revealed that approximately 20–85% of COVID-19 patients experienced olfactory and gustatory dysfunctions (Bilinska and Butowt, 2020Mao et al., 2020). Although the clear causes of these complications are not fully understood, angiotensin-converting enzyme 2 (ACE2) expression and local inflammation have been considered key mechanisms (Giacomelli et al., 2020Lechien et al., 2020Spinato et al., 2020). Other suggested mechanisms were infecting olfactory non-neuronal cells and sensory neurons (Brann et al., 2020de Melo et al., 2021).

Given to paramount findings of COVID-19 smell and taste loss and lack of effective treatments, we aimed to review the potential treatments of COVID-19 smell and taste loss based on clinical pharmacology principles.

2. Pathophysiology of anosmia

Numerous probable mechanisms have been suggested for the COVID-19-related anosmia, such as nasal obstruction and rhinorrhea, olfactory cleft syndrome, local cytokine storm, damage to the olfactory centers in the brain, direct damage of olfactory receptor neurons (ORNs), also called olfactory sensory neurons (OSNs), or sustentacular cells (SUSs). However, most of them have been ruled out subsequently.

2.1. Damages to SUS and ORNs

In the normal olfactory system, odorant particles bind to the olfactory receptors; the ORN sends the smell sensation signal through the cribriform plate (bone) to the olfactory bulb, where they synapse to the dendrites of mitral and tufted cells. The normal function of ORNs depends on sustentacular cells (SUSs) of the olfactory epithelium (OE). In this regard, SUSs protect the ORNs through metabolizing volatile chemicals via expressing the cytochrome P450 family enzymes. Besides, SUSs could endocytose the complexes of odorant-binding proteins−odorant after initiation of signal transduction at the neurons’ cilia to let the next series of odorants bind to the receptors. Lastly, SUSs supply ORNs cilia with additional glucose, where olfactory receptors are found (Heydel et al., 2013Villar et al., 2017).

It is well-known that SARS-CoV-2 infectivity depends on the binding of spike (S) proteins to the host cells receptors of ACE2 and transmembrane protease serine 2 (TMPRSS2). After interaction with host cells receptors, the S proteins of the SARS-CoV-2 undergo conformational changes that lead to viral cell entry.

It has been shown that SUSs express ACE2 and TMPRSS2 that could result in the SARS-CoV-2 entry and consequential damages to the SUSs. Whereas ORNs do not express the entry proteins for the virus. Therefore, the direct damage to the SUSs could result in olfactory dysfunction without transfer to ORNs due to the functional and anatomical link between SUSs and ORNs. Moreover, Brann et al. showed that SARS-CoV-2 infection of non-neuronal cell types leads to olfactory dysfunction in COVID-19 patients (Brann et al., 2020Fodoulian et al., 2020).

Recently, in a study by de Melo et al., olfactory mucosa sampling revealed that SARS-CoV-2 invades both ORNs and SUSs in human and Syrian hamster models with COVID-19-related anosmia and ageusia. By investigating cell death in the olfactory neuroepithelium, this study considered the apoptosis of mature ORNs as the most relevant cause of anosmia in COVID-19 patients. Notably, they found that SARS-CoV-2 presents in the ORNs of COVID-19 patients with long-lasting anosmia even after six months from diagnosis. Although this study supported the ORNs damage and possible neuroinvasion as anosmia causes, further studies should precisely determine the olfactory bulb dysfunction using larger sample sizes and control groups (de Melo et al., 2021).

Bryche et al. have evaluated the effects of SARS-CoV-2 infection on the olfactory system in golden Syrian hamsters’ model. They observed considerable damage to the OE and loss of smell after two days of nasal instillation of the virus. However, they showed that, unlike the SUSs, the virus did not affect olfactory neurons and olfactory bulbs. They suggested that infiltrated immune cells in the OE may lead the OE to be desquamated and damaged. The restoration of the OE was achieved within 14 days after infection. Thus, this in-vivo study supported that sudden anosmia results from infected SUSs, leading to extended and quick damage to the OE and lamina propria due to immune cells (Bryche et al., 2020).

Meinhardt et al. investigated the brain samples of 32 patients who died of COVID-19. This study suggested that the virus affects the ORNs. However, by single immunocytochemical imaging, especially in old samples that were taken lately after death, the differentiation between neuronal and non-neuronal cells cannot be performed obviously. Moreover, the ribonucleic acid (RNA) of the virus was detected in only 3 of the olfactory bulb samples that did not strongly support the viral diffusion to the brain by the olfactory nerve. Also, lacking data about which patients experienced anosmia limits the interpretation of the results (Meinhardt et al., 2021).

2.2. Inflammation

Along with the damage to the SUSs, a rapid immune response in microvillar cells (MVCs) and a subset of ORNs leads to activation and infiltration of macrophages and lymphocytes into the OE, the release of pro-inflammatory cytokines, and occurrence of cytokine storm, which all may explain the sudden anosmia in patients with COVID-19. Notably, it seems that progenitor/stem cell infection is responsible for COVID-19 induced long-term dysosmia. It has been shown that a local excessive immune response and cytokine storm could lead to olfactory dysfunction even in patients with a milder form of the disease. Of note, to date, no adequate data support the rapid harm to the olfactory cortical areas in the brain; therefore, it is unlikely that excessive systemic immune response and inflammation in the brain have an essential role in the anosmia development (Baxter et al., 2021). In a study by Torabi et al., the direct role of inflammatory cytokines in acute olfactory dysfunction has been highlighted. In this study, the levels of tumor necrosis factor-alpha (TNF-α) in the OE were significantly higher in COVID-19 patients compared to the control group, whereas interleukin-1-beta (IL-1β) levels were similar between groups.

Furthermore, in other studies, SARS-CoV-2-induced infiltration of immune cells, including macrophages and granulocytes, into the OE has been reported (Bryche et al., 2020Meinhardt et al., 2021Torabi et al., 2020). Also, de Melo et al. considered local inflammation a key factor in COVID-19 patients with long-lasting olfactory dysfunction. They showed a high IL-6 expression and myeloid cells in the olfactory mucosa of these patients (de Melo et al., 2021).

2.3. Other probable mechanisms

Nasal obstruction and rhinorrhea, which could block nasal air-flow, are suggested to be much less common and have been ruled out as a cause of SARS-CoV-2 induced anosmia (Salmon Ceron et al., 2020). The interaction of SARS-CoV-2 with sialic acid receptors expressed in nasal mucosa can be another entry pathway other than ACE2 receptors, which might have a role in the complications of the virus, such as anosmia (Kuchipudi et al., 2021Milanetti et al., 2020).

The virus infiltration to the brain is another suggested mechanism in which the OSN is considered a direct route to the brain through anterograde axonal transport (Fenrich et al., 2020). Also, the reports of meningitis and encephalitis in some COVID-19 patients could support the idea that SARS-CoV-2 might invade the central nervous system (CNS). Magnetic resonance imaging could provide information about the olfactory bulb and possible CNS invasion of the virus. The olfactory bulb volume was normal in the first report of olfactory bulb magnetic resonance imaging in a patient with COVID-19-related anosmia (Galougahi et al., 2020). However, further studies showed changes in the volume and shape of the olfactory bulb in COVID-19 patients with anosmia (Altundag et al., 2020Kandemirli et al., 2021Politi et al., 2020).

3. Ageusia pathophysiology

Due to the close connection between olfactory and gustatory functions, it might be possible that the concomitant presence of olfactory dysfunction adversely influences the ability of taste perception in COVID-19 patients. However, different pathways have also been suggested, including direct damage to taste buds and salivary glands, binding to sialic acid receptors, and inflammation.

It has been shown that the taste buds and salivary glands have a high number of ACE2 receptors (Doyle et al., 2021Song et al., 2020). Furthermore, the essential role of the renin-angiotensin-aldosterone system (RAAS) in the perception of flavors has been confirmed previously. Similarly, the cases of gustatory dysfunction have been reported in patients receiving angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in a dose-dependent manner. It has been suggested that ACE2 inhibitors inactivate the G protein-coupled proteins and sodium-ion channels located in the taste receptors. Similarly, it has been suggested that SARS-CoV-2-induced ACE2 down-regulation and the consequent RAAS impairment are associated with gustatory dysfunction in patients with COVID-19 (Luchiari et al., 2021). Also, early detection of SARS-CoV RNA in saliva before lung injury confirms that salivary glands might be the initial target for the virus.

Previously, it has been shown that the Middle East respiratory syndrome coronavirus (MERS-CoV) binds to the sialic acid receptors, the pathway that has also recently been indicated for SARS-CoV-2 (Milanetti et al., 2020Park et al., 2019). Sialic acid is a substantial factor of the salivary mucin and has protective effects on glycoproteins that transport taste molecules inside taste pores from early enzymatic metabolism (Witt and Miller, 1992). Thus, SARS-CoV-2 could block the binding sites of sialic acid on the taste buds, increasing the destruction rate of the taste molecules and cause ageusia.

As the entranceway of SARS-CoV-2 to the host cells, ACE2 receptors are also present in the oral mucosa. By binding to these receptors, inflammation and consequent cytokine signaling pathways in taste buds might affect the sense of taste. As in acute respiratory distress syndrome, this pathway could be induced through the interaction between Toll-like receptors and the virus. Also, inflammatory cytokines such as interferons can cause apoptosis and alter the turnover of taste buds (Wang et al., 2009Xu et al., 2020).Go to:

4. Potential therapeutic agents against olfactory and gustatory dysfunctions

We categorized the literature according to the American College of Cardiology/American Heart Association Clinical Practice Guidelines Recommendation Classification System (Halperin et al., 2016). This system evaluates medications based on the strength of recommendation (strong = I, IIa = moderate, IIb = weak, and III = moderately no benefit or strongly harmful) and quality of evidence (A = high quality randomized clinical trials, B-R = moderate-quality randomized clinical trial, B-NR = moderate-quality non-randomized clinical trial, C-LD = limited data, and C-EO = expert opinion). The summary of the promising agents against COVID-19-related smell and/or taste loss is shown in Table 1 and Fig. 1 .

Table 1

Categorization of the proposed medications for COVID-19 smell and taste loss.

MedicationMechanism of actionOutcomes (study design)Class of recommendation/Level of evidenceReferences
PentoxifyllinePDE inhibitorPromising results in smell loss (post-marketing surveillance study), No beneficial effects in patients with post-traumatic anosmia (case series)IIb/B-NR(Gudziol and Hummel, 2009Whitcroft et al., 2020)
CaffeinePDE inhibitor, Adenosine receptors antagonistDirect correlation between coffee consumption and smell scores in patients with Parkinson’s disease (retrospective cohort), 65 mg of caffeine showed no beneficial effects in patients with hyposmia related with upper respiratory tract infection or sinus node dysfunction (RCT)IIb/B-R(Meusel et al., 2016Siderowf et al., 2007)
TheophyllinePDE inhibitorImproved the smell and taste dysfunction caused by various diseases (two non-RCT)IIb/B-NR(Henkin et al., 20092012)
Intranasal insulinNeuroprotectiveBeneficial effects in olfactory dysfunction caused by infection (non-RCT), COVID-19 (non-RCT), and other diseases (RCT)IIa/B-R(Mohamad et al., 2021Rezaeian, 2018Schöpf et al., 2015)
StatinsNeuroprotective, anti-inflammatoryImproved anosmia in mice models (two animal studies)IIb/C-EO(Kim et al., 20102012)
MinocyclineNeuroprotectiveInhibit apoptosis of OSNs in rat models (Histological analysis)IIb/C-EOKern et al. (2004b)
ZincTrace element, growth factorReports of anosmia with intra-nasal zinc gluconate, No beneficial effects of zinc sulfate in chemotherapy-induced taste and smell loss (RCT)III/B-R(Davidson and Smith, 2010Lyckholm et al., 2012)
Intranasal vitamin AAnti-neurodegenerativeBeneficial effects in post-infectious smell dysfunction (retrospective cohort study)IIb/C-LDHummel et al. (2017)
Omega-3NeuroprotectiveBeneficial effects in olfactory loss caused by tumors (RCT)IIb/B-RYan et al. (2020)
Intranasal mometasoneAnti-inflammatoryNo beneficial effects in COVID-19 smell loss (RCT)III/B-RAbdelalim et al. (2021)
Intranasal fluticasoneAnti-inflammatoryBeneficial effects in COVID-19 smell loss (non-RCT)IIa/B-NRSingh et al. (2021)
Oral triamcinolone pasteAnti-inflammatoryBeneficial effects in COVID-19 dysgeusia (non-RCT)IIa/B-NRSingh et al. (2021)
MelatoninNeuroprotective, anti-inflammatoryInhibit apoptosis of OSNs in rat models (animal study)IIb/C-EOKoc et al. (2016)

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PDE, phosphodiesterase; RCT, randomized clinical trial.

Fig. 1

Fig. 1

The potential mechanistic pathways and treatments suggested for COVID-19-related smell loss. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters nasal epithelium, particularly with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) receptors on sustentacular cells (SUSs). Damage to the olfactory sensory neurons (OSNs) could lead to a decrease in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate cGMP levels, which can be inhibited by phosphodiesterase inhibitors (pentoxifylline, caffeine, and theophylline). Neuroprotective agents such as statins, minocycline, intranasal vitamin A, intranasal insulin, omega-3, and melatonin could regenerate olfactory receptor neurons (ORNs). Also, the inflammatory effects of the virus in the nasal epithelium can be blocked by corticosteroids, statins, and melatonin. BG, bowman’s gland; GC, granule cell; MC, mitral cell; MVC, microvillar cell.

4.1. Pentoxifylline (IIb/B-NR)

Signal transduction begins while an odorant binds to the receptors of an ORN. The odor-receptor complex results in the intracellular activation of type 3 adenylate cyclase by a G protein, leading to an elevated intracellular cyclic adenosine monophosphate (cAMP). An increased level of intracellular cAMP leads to calcium influx and depolarization of the neuron, consequently. Of note, it has been confirmed that in patients suffering from anosmia and ageusia, the salivary and nasal mucus growth factors, including cAMP and cyclic guanosine monophosphate (cGMP), were lower than healthy individuals (Henkin and Velicu, 20082011). In the cilia of OSNs, cAMP is metabolized by phosphodiesterase 1C2 (Henkin et al., 2007Nakamura, 2000). Pentoxifylline is a methylxanthine derivative that acts as a phosphodiesterase inhibitor. Thus, it could be reasonable to consider that pentoxifylline-induced inhibition of phosphodiesterase 1C2 can increase intracellular cAMP levels. Also, pentoxifylline reduces TNF-α and other inflammatory cytokines such as IL-1, leading to immunomodulatory effects (Hassan et al., 2014). The effect of pentoxifylline on olfactory function has been evaluated in Gudziol and Hummel’s (2009)prospective post-marketing surveillance. A total of 19 patients were included in the study. Of them, 15 patients were assigned to receive 200 mg of pentoxifylline intravenously, two times per day, and 4 patients received 200 mg of pentoxifylline orally 3 times per day. The mean (SD) of the age of patients was 51 (19.9), and 52.6% of them were female. Data analysis showed a significant reduction in odor threshold after treatment with pentoxifylline (P = 0.01). This reduction was markedly more in younger patients than in older patients (P = 0.001). However, the nasal airflow did not significantly change by pentoxifylline (P = 0.84). Of note, although the oral pentoxifylline has smaller bioavailability, of 4 patients who received the oral forms, half of them showed a clinically significant reduction in odor threshold (Gudziol and Hummel, 2009). The prospective design and small sample size of this study increase the risk of bias for accurate interpretation of these results. Furthermore, the patients in this study have diseases other than COVID-19 that led to olfactory loss. Conversely, a case series of 6 patients with post-traumatic anosmia showed that administration of oral pentoxifylline (200 mg 3 times daily for 3 weeks) did not significantly improve the odor threshold, discrimination, and identification scores (P-values = 0.3, 0.06, and 0.1, respectively) (Whitcroft et al., 2020). Due to the different results, conducting larger double-blinded clinical trials, which directly evaluate the pentoxifylline role in COVID-19 patients with olfactory or gustatory dysfunctions, is recommended.

4.2. Caffeine (IIb/B-R)

Caffeine is a CNS stimulant that belongs to the methylxanthine class. The pharmacologic effects of methylxanthine derivatives can be caused by phosphodiesterase inhibition and blocking of adenosine receptors. Particularly, caffeine could affect the CNS by antagonizing different subtypes of adenosine (A1, A2A, A2B, and A3) receptors in the brain (Ribeiro and Sebastião, 2010). Previously, it has been shown that in rodents, the genes of the adenosine A2A receptors are highly expressed in the granular cells of the accessory olfactory bulb (Abraham et al., 2010Kaelin-Lang et al., 1999Nunes and Kuner, 2015).

A study by Prediger et al. aimed to assess the efficacy of caffeine on age-related olfactory deficiency in rats. This study demonstrated that caffeine could improve olfactory dysfunction with doses of 3, 10, and 30 mg/kg through blocking A2A receptors (P = 0.001) (Prediger et al., 2005). Furthermore, cAMP and cGMP have substantial effects on olfactory function. Thus, increasing the intracellular levels of cAMP and cGMP by phosphodiesterase inhibitors with less adverse effects can be suggested as potential treatment approaches for anosmia and ageusia/dysgeusia.

Several studies have evaluated the association between caffeinated coffee consumption and various clinical outcomes. For example, a retrospective cohort on 173 patients with Parkinson’s disease (mean age = 58.1 years, 69% female) showed that higher coffee consumption significantly improved the scores of smell test with means of 30.4, 32.6, 33.1, and 34.4 for consuming <1, 1, 2 to 3, and ≥4 cups daily (P = 0.009); this improvement was more noticeable among men. Also, this study showed that the rate of hyposmia is greater among patients whose daily coffee consumption was ≤1 cup compared to patients with more than 1 cup of coffee consumption (26% versus 8%; OR = 0.026; 95% CI, 0.10, 0.67; P = 0.007) (Siderowf et al., 2007). Although these results were adjusted for some confounding factors, the study’s observational design still cannot confirm the exact role of coffee consumption on hyposmia.

A double-blinded, placebo-controlled study was carried out on 76 patients with hyposmia due to either upper respiratory tract infection (n = 48) or sinus node dysfunction (n = 26) to evaluate the effects of caffeine on olfactory dysfunction. The mean age of patients was 57 years, with a mean duration of 14 months for olfactory loss. Patients were assigned to receive 65 mg caffeine in one cup of espresso (n = 39) or a placebo (n = 38). The evaluations before and 45 min after intervention could not support the beneficial effects of coffee in patients suffering hyposmia (odor discrimination: t = 0.03, P = 0.97; odor threshold: t = 0.05, P = 0.96; discrimination and threshold combination score: t = 0.79, P = 0.83) (Meusel et al., 2016). This study only evaluates the short-term effects of coffee on olfactory dysfunction; however, the result may differ with a longer duration of coffee consumption or higher dose. Another limitation was the small sample size of the study that can increase the risk of bias. Despite several types of studies about the role of caffeine in olfactory and gustatory dysfunctions, lacking data on COVID-19 patients makes it difficult to define whether it improves anosmia or ageusia. However, coffee consumption might be a safe way to resolve these complications in patients without caffeine sensitivity.

4.3. Theophylline (IIb/B-NR)

As previously discussed, cAMP and cGMP have key roles in the normal olfactory and gustatory functions (Henkin et al., 2007). As a phosphodiesterase inhibitor, theophylline administration has been evaluated on 312 patients with smell loss. Based on the measurement prior to the study, the reason for patients’ smell loss was related to the lower levels of cAMP and cGMP in the nasal and salivary mucus. In this study, patients received 200–800 mg of theophylline orally for 2–8 months. The results showed that the administration of theophylline was associated with smell function improvement in 50.3% of patients. The doses of 600 and 800 mg showed better results than 200 or 400 mg. Therefore, high doses of oral theophylline are required to elevate cAMP and cGMP levels; however, the high doses might result in increased adverse events such as tachycardia, tremor, restlessness, and gastrointestinal disorders. Also, theophylline has a life-threatening narrow therapeutic window that needs regular blood level monitoring (Henkin et al., 2009Skinner, 1990).

Therefore, another trial evaluated the intranasal theophylline effects on 10 patients from 312 patients of the previous study; these patients were selected due to their lower than expected response for oral theophylline or experiencing adverse effects. The mean age of patients was 64 years. They had a smell or taste loss for several reasons: post-viral olfactory dysfunction, allergic rhinitis, head trauma, and congenital olfactory dysfunction. While the serum level of theophylline became unmeasurable after 3–12 weeks of the oral drug discontinuation, the intranasal theophylline was administered with a dose of 20 μg daily for 4 weeks. The improvement of smell and taste perception has occurred in 8 patients after intranasal administration, which was greater than the oral theophylline. Moreover, no adverse effects were observed after the intranasal theophylline administration (Henkin et al., 2012). However, it should be noted that this trial was primarily conducted to assess the safety of intranasal theophylline use. Thus, the studies with a larger sample size and the placebo group should evaluate the efficacy of intranasal theophylline.

4.4. Intranasal insulin (IIa/B-R)

The intranasal pathway is a well-known drug delivery system for the CNS; particularly for insulin, the mechanism of brain delivery was fully understood. In mice models, fluorescent and electron microscopy imaging of olfactory tissues showed that intranasal insulin affects the brain through the olfactory nerve pathway (Renner et al., 2012). Insulin can be involved in olfactory function through receptors presented on MCs of the olfactory bulb. Furthermore, it has neuroprotective effects and could regenerate the olfactory mucosa (Fadool et al., 2011Lacroix et al., 2011). In a study bySchopf et al. (2015), 10 patients with post-infectious olfactory loss were included to receive 20 units of insulin in each nostril (a total of 40 units). The function of the olfactory system was assessed 30 min after insulin administration. After a year from the first intervention, the patients were asked to receive 0.4 ml of intranasal saline as a placebo. The mean age of patients was 46.5 years, and the mean body mass index for them was 27.1 kg/m2. According to the measurements of olfactory functions, 60% and 28.5% of patients showed an improvement in odor threshold and sensitivity after intranasal insulin and saline administration, respectively. The intensity of the odor perception was significantly higher after insulin application than the placebo (P = 0.04). Of note, the higher body mass index resulted in significantly better odor identification after insulin administration (P < 0.01) (Schöpf et al., 2015). However, the small sample size and non-randomized design of this study limited the interpretation of results.

In a randomized clinical trial by Rezaeian (2018), the role of intranasal insulin in olfactory function has been assessed in patients with mild to severe hyposmia that lasts more than 6 months. Totally, 38 patients underwent randomization to receive either 40 units of intranasal protamine insulin (n = 19) or 20 mL of normal saline as a placebo (n = 19) two times per week for 4 weeks. The mean age of patients and the mean duration of hyposmia in the insulin and placebo groups were 37.3 versus 35.7 years and 2.3 versus 3.0 years, respectively. The mean (±SD) score of the insulin-treated group was significantly higher than the placebo group (5.0 ± 6 0.7 versus 3.8 ± 6 1.0, P = 0.01) (Rezaeian, 2018). Recently, Mohamad et al. (2021) formulated intranasal insulin films to evaluate their effectiveness in managing SARS-CoV-2 induced anosmia. Of 40 patients who underwent randomization, 20 patients were assigned to receive intranasal insulin films, and 20 were assigned to the placebo group. The comparison of the olfactory function between the two groups showed better scoring test results for the insulin-treated group regarding both odor detection (7.9 ± 1.2 versus 3 ± 0.8) and discrimination (6.7 ± 0.5 versus 2.8 ± 1). Moreover, comparing scores before and after intervention showed that, unlike the placebo group, insulin administration resulted in significantly higher scores after intervention (Mohamad et al., 2021).

4.5. Statins (IIb/C-EO)

Statins are known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that are widely used in cases of hypercholesterolemia. Besides their lipid-lowering activity, they have multiple beneficial properties, including anti-inflammatory, immunomodulatory, and neuroprotective effects (Saee di Saravi et al., 2017). Previously, it has been shown that statins could improve the proliferation and neurogenesis of injured OE through immunohistochemical staining investigations. In this study, statin-treated (10 mg/kg for 4 weeks) rats showed a higher rate of OE proliferation and better regeneration of neurons than both prednisolone-treated (1 mg/kg for 2 weeks) or control groups (Kim et al., 2010). In another study on anosmia using mouse models, the improvement of the olfaction system was observed among 75% of mice with oral administration of 10 mg/kg atorvastatin versus 16.6% of control groups (P = 0.004) (Kim et al., 2012). These studies show the neuroprotective and anti-inflammatory effects of statins to improve the COVID-19 related anosmia. Of note, the adverse effects of the statins such as arthralgia and hepatotoxicity should be taken into account, and the pros and cons of treatment should be evaluated cautionary.

4.6. Minocycline (IIb/C-EO)

Minocycline belongs to the tetracycline class of antibiotics approved to manage a wide variety of infections such as skin, respiratory tract, and sexually transmitted infections. Furthermore, minocycline exerts several effects, including anti-inflammatory, anti-apoptotic, and anti-angiogenesis activities. The interference with apoptosis, particularly in neurons, makes minocycline the most neuroprotective agent among tetracycline derivatives. The beneficial effects of minocycline have been indicated in several neurodegenerative disorders such as Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, and degeneration of photoreceptor cells. Besides, the beneficial effects of minocycline against olfactory dysfunction have been reported. Histological analysis of animal olfactory tissue showed that minocycline could inhibit apoptosis of OSN in rat models with bulbectomy (Kern et al., 2004b). The balance between OSN apoptosis and regeneration is vital in maintaining a normal sensory function (Kern et al., 2004a). Thus, this may be a rationale for raising the number of OSNs by inhibiting apoptosis by using well-tolerated medication minocycline.

4.7. Zinc (III/B-R)

Zinc is a trace element that contributes as one of the growth factors in taste and smell function. It has been shown that growth factors activate stem cells in both taste buds and olfactory epithelial cells. Zinc is a constituent of the salivary enzyme carbonic anhydrase VI, which plays a vital role in the maintenance of taste and smell function. Therefore, zinc deficiency could result in anosmia and dysgeusia (Komai et al., 2000Wrobel and Leopold, 2004). Also, Equils et al. (2021)suggested that a reduction of nasal zinc level is a common nasal immune reaction to acute viral infections such as SARS-CoV-2 and involves the pathogenesis of anosmia.

Moreover, they proposed that patients with zinc deficiency have long-lasting anosmia and severe COVID-19 (Equils et al., 2021;Ozlem Equils, 2020). Previously, several reports of anosmia caused by the zinc-containing nasal product (Zicam) forced the U.S. Food and Drug Administration (FDA) to recall them. Moreover, Davidson and Smith (2010) suggested that intranasal zinc gluconate can cause anosmia or hyposmia in patients (Davidson and Smith, 2010). Also, intranasal zinc sulfate (5%) is well known to induce anosmia in animal models (Cancalon, 1982McBride et al., 2003). In a double-blinded, placebo-controlled, randomized clinical trial, administration of 50 mg elemental zinc sulfate two times per day showed no significant improvements in chemotherapy-induced taste and smell dysfunctions in comparison with the placebo group. However, the small sample size (n = 58), lacked standard methods to evaluate sensory variations, and various concurrent medication used in patients increased the risk of bias in this study (Lyckholm et al., 2012).

4.8. Intranasal vitamin A (IIb/C-LD)

The active metabolite of vitamin A, retinoic acid, participates in various biological situations, including olfactory system embryogenesis, cell growth, and differentiation. Also, retinoic acid has immunomodulatory properties that might improve cell turnover and protection, mainly in the OE, which is susceptible to several inflammatory particles. Due to the regenerative and immunomodulatory effects of Vitamin A on ORNs, some studies were conducted to evaluate intranasal vitamin A effects on olfactory dysfunction (Rawson and LaMantia, 2007).

In a retrospective cohort study, 170 patients with post-infectious and post-traumatic smell complaints were treated with smell training and topical vitamin A (n = 124) or smell training alone (n = 46). Of note, patients with other causes of olfactory dysfunction such as congenital anosmia and/or aged younger than 18 years were not included in this study; the dose of intranasal vitamin A drop was 10 000 units per day for 2 months. Also, smell training was carried out for 3 months. The mean ± SD of the age of patients was 55 ± 14 years, and approximately 59% of them were female. After nearly 10 months of follow-up, the rise of smell distinction score was markedly higher in the vitamin A group than the control group (P = 0.008). In patients with post-infectious olfactory dysfunction, 37% and 23% were clinically improved in the vitamin A and control groups, respectively (P = 0.03). The comparison of the groups in the post-traumatic patients showed no significant changes in the olfactory function (P = 0.29) (Hummel et al., 2017). Although this study supported the beneficial effects of vitamin A in infection-induced olfactory dysfunction, further studies are required to directly evaluate the efficacy and safety in SARS-CoV-2 induced olfactory dysfunction. Also, the duration and the dose of vitamin A administration in this study were based on expert opinion. Moreover, the possible adverse events were not indicated in this study.

4.9. Omega-3 (IIb/B-R)

Omega-3 polyunsaturated fatty acids are vital parts of membrane phospholipids that have substantial effects on gene expression. The low levels of docosahexaenoic acid (DHA), an essential omega-3 fatty acid found in fish oil, exert signs of olfactory dysfunction (Greiner et al., 2001). A multi-institutional, prospective, randomized controlled trial has evaluated the effects of omega-3 administration on olfaction. This trial included 110 patients with sellar or parasellar tumors who underwent endoscopic resection were assigned to receive either nasal saline irrigations (n = 55) or nasal saline irrigations combined with omega-3 supplements with a total dose of 2000 mg per day (n = 55). According to the results, omega-3 administration was found to have beneficial effects on olfactory loss after controlling for multiple confounding variables (odds ratio [OR] 0.05; 95% CI 0.003–0.81; P = 0.03) (Yan et al., 2020). This study did not declare whether patients used other medications with potential benefits on olfactory function, such as corticosteroids, limiting the interpretation. Moreover, it is noteworthy that omega-3 supplements should be used with caution in patients with fish allergy, hepatic failure, and bleeding risk, particularly in patients on concomitant antiplatelet or anticoagulant medications.

4.10. Corticosteroids (mometasone: III/B-R; fluticasone: IIa/B-NR; oral triamcinolone paste: IIa/B-NR)

Corticosteroids could combat the local inflammatory response in the nasal area and taste buds, which may occur during the anosmia and ageusia caused by COVID-19. In addition, corticosteroids could directly improve the olfactory function by modifying the sodium-potassium adenosine triphosphatase (Na/K-ATPase) present on ORNs. Na/K-ATPase is also a key factor of the salivary glands, which is required for the secretion of saliva in the glandular acini, along with later alteration in the ducts (Catana et al., 2013Kim et al., 2016).

Abdelalim et al. (2021) evaluated the use of mometasone nasal spray for the treatment of COVID-19-related anosmia in a randomized clinical trial. Patients with RT-PCR confirmed COVID-19 who aged 18 years or older and experienced recent anosmia and/or ageusia entered the study. Besides, previous use of systemic steroids and pregnancy were exclusion criteria of the study. Patients in the intervention group (n = 50) received mometasone furoate nasal spray with a dose of 100 μg per day for three weeks plus olfactory training. In comparison, patients in the control group (n = 50) were managed by olfactory training alone. The median age of patients was 29.0 years, and 54% were men; mostly (94%) suffered from mild or moderate COVID-19 symptoms. The comparison of smell scores showed no significant difference between the groups after 1, 2, and 3 weeks of treatment (P = 0.10, 0.08, and 0.16, respectively). Also, the duration of anosmia was statistically similar between both groups, with the mean (SD) of 26.41 (7.99) days versus 26.15 (5.07) days for the intervention and control groups, respectively (P = 0.88) (Abdelalim et al., 2021). Although the results of this study did not support the beneficial effects of topical steroids in anosmia caused by COVID-19, the small sample size and unblinded design of the study should be taken into account in the interpretation of the results. Also, some patients received systemic steroids during the study period, which may affect the results.

Another clinical trial in COVID-19 patients assessed the efficacy of topical fluticasone and triamcinolone on anosmia and taste dysfunction, respectively. Of the 120 patients enrolled in the study, 60 patients received two puffs of fluticasone nasal spray for anosmia and triamcinolone paste three times daily for dysgeusia. On day five of the intervention, the smell and taste perceptions were significantly improved compared to the first day (Singh et al., 2021). In this study, saline irrigations or gargles were also administered that might affect the results. Also, the limited sample size and non-randomized design of the study increased the risk of bias.

4.11. Melatonin (IIb/C-EO)

Melatonin is recognized as an anti-inflammatory, antioxidative, and immune-enhancing medication with a great safety profile. Due to melatonin’s small size and amphiphilic properties, it has high cell diffusion ability and permeability through biological compartments, including the blood-brain barrier (BBB). Melatonin renovates BBB homeostasis preventing microvascular hyperpermeability and thus making it a favorable agent to combat SARS-CoV-2 induced neuroinvasion. Also, the neuroprotective effects of melatonin on OSNs were previously indicated in rat models (Koc et al., 2016Romero et al., 2020). However, more clinical data are needed to explore the role of melatonin in smell and taste loss following COVID-19.

5. Discussion

The current study has reviewed the suggested pathways for the anosmia and ageusia caused by SARS-CoV-2 infection and summarized some of the agents to treat them based on pharmacology principles. This summary can be used in designing further clinical trials in the era of COVID-19.

The anosmia and ageusia caused by SARS-CoV-2 have some important properties. First, the notable proportions of COVID-19 patients experience these symptoms that can be the only features of the disease. Second, the symptoms suddenly start and mostly persist for a short period of time. Third, mostly they are not associated with nasal congestion (Butowt and von Bartheld, 2020Lechien et al., 2020). These symptoms are not life-threatening; however, they affect the quality of life and are associated with depression, anxiety, and increased suicidal thoughts(Elkholi et al., 2021Yom-Tov et al., 2021). The precise pathophysiology of anosmia and ageusia is unclear, but several studies suggest multiple causations. Among the suggested mechanisms, direct damage in the SUSs and the local inflammation are the most likely causations for the SARS-CoV-2 induced anosmia. Previously, neuronal damage, including direct damage to ORNs is considered as the least probable reason from two reasons: first, ACE2 and TMPRSS2 are not expressed in ORNs; second, the time required for clinical recovery is faster than the regeneration of ORNs in most cases (Printza and Constantinidis, 2020). However, nasal samples and magnetic resonance imaging results showed that ORN infection and CNS invasion play a key role in COVID-19-related anosmia. The neuronal damage should be particularly taken into account in COVID-19 patients with long-lasting anosmia (Boscolo-Rizzo et al., 2020Butowt and von Bartheld, 2020de Melo et al., 2021Kandemirli et al., 2021Meinhardt et al., 2021Politi et al., 2020). Considering the correlation between olfactory and gustatory systems, the mechanistic pathways contributing to anosmia could also cause ageusia. However, some unique pathways have also been suggested for ageusia/dysgeusia. Similar to anosmia, among the suggested pathways for ageusia, the participation of the central nervous system looks less probable since the appearances of this participation, such as meningitis and encephalitis, are experienced rarely in COVID-19 (Butowt and von Bartheld, 2020Finsterer and Stollberger, 2020Luchiari et al., 2021).

Taken together, several medications have been suggested to treat anosmia and ageusia. Previously, olfactory training was recommended as an effective and safe way for olfactory dysfunction. However, there is no medication approved to treat olfactory dysfunction. Among the discussed medications, corticosteroids are the most studied in COVID-19. However, it should be noted that the use of systemic corticosteroids for the SARS-CoV-2-mediated olfactory and gustatory dysfunctions might have additional risks and could reduce the viral clearance from the body (Tlayjeh et al., 2020). Other medications mentioned in this review were mostly neuroprotective used for different causes of anosmia and/or ageusia.

Considering the involvement of the neuronal pathway in COVID-19-induced anosmia and/or ageusia, neuroprotective agents, including intranasal vitamin A, intranasal insulin, omega-3, statins, minocycline, and melatonin, might have beneficial effects in patients with long-lasting anosmia by inducing regeneration of the ORNs. Also, phosphodiesterase inhibitors can activate olfactory function through depolarization of the neurons. However, further studies are required to assess the effects of theophylline, pentoxifylline, and caffeine on SARS-CoV-2 induced anosmia and/or ageusia. Different formulations of zinc have also resulted in completely different results. Some of the zinc-containing products were recalled by the U.S. FDA since there were several cases with compliance of anosmia with them. The precise association between SARS-CoV-2 infection and zinc level, either in the systemic or in the local level, is not fully understood. There are hypotheses that low zinc levels are linked with anosmia and dysgeusia, and additional clinical trials are required for further consideration (Equils et al., 2021). Finally, the medications’ safety issues, adverse reactions, contraindications, and drug interactions, should be considered before administration.

5.1. Limitation

Our study might have some limitations. First, due to the lack of data in the era of COVID-19 mediated anosmia and/or ageusia, the proposed medications have a low level of evidence to support their application in treating anosmia and ageusia following SARS-CoV-2 infection. Second, similar to most review articles, some studies may be missed to enter our review.

6. Conclusion

We searched the literature to review the potential mechanistic pathways and treatments in COVID-19-related anosmia and/or ageusia. According to available data, there are limited studies about possible treatments of COVID-19 taste and smell loss, which need further clinical trials. This review can provide basic information to direct future clinical trials according to clinical pharmacology principles.Go to:

Author agreement

We certify that all authors have seen and approved the final version of the manuscript (EJP-59088R1) being submitted to the European Journal of Pharmacology. We warrant that the article is the authors’ original work, has not received prior publication, and is not under consideration for publication elsewhere.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data statement

Declaration of competing interest

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Smell and Taste Loss Recovery Time in COVID-19 Patients and Disease Severity

Authors: Athanasia Printza,1,*Mihalis Katotomichelakis,2Konstantinos Valsamidis,1Symeon Metallidis,3Periklis Panagopoulos,4Maria Panopoulou,5Vasilis Petrakis,4 and Jannis Constantinidis1

J Clin Med. 2021 Mar; 10(5): 966.Published online 2021 Mar 2. doi: 10.3390/jcm10050966 PMCID: PMC7957474PMID: 33801170

Abstract

A significant proportion of people infected with SARS-CoV-2 report a new onset of smell or taste loss. The duration of the chemosensory impairment and predictive factors of recovery are still unclear. We aimed to investigate the prevalence, temporal course and recovery predictors in patients who suffered from varying disease severity. Consecutive adult patients diagnosed to be infected with SARS-CoV-2 via reverse-transcription–polymerase chain reaction (RT-PCR) at two coronavirus disease-2019 (COVID-19) Reference Hospitals were contacted to complete a survey reporting chemosensory loss, severity, timing and duration, nasal symptoms, smoking, allergic rhinitis, chronic rhinosinusitis, comorbidities and COVID-19 severity. In a cross-sectional study, we contacted 182 patients and 150 responded. Excluding the critically ill patients, 38% reported gustatory and 41% olfactory impairment (74% severe/anosmia). Most of the patients (88%) recovered their sense of smell by two months (median: 11.5 days; IQR: 13.3). For 23%, the olfactory loss lasted longer than a month. There were no significant differences in the prevalence and duration of chemosensory loss between groups of varying COVID-19 severity, and sexes (all p > 0.05). Moderate hyposmia resolved quicker than more severe loss (p = 0.04). Smell and taste loss are highly prevalent in COVID-19. Most patients recover fast, but nearly one out of ten have not recovered in two months.

1. Introduction

Since the coronavirus disease-2019 (COVID-19) pandemic outbreak, many studies have demonstrated that a significant proportion of people who test positive for COVID-19 have a new onset of smell or taste loss [1,2,3,4]. The Centers for Disease Control and Prevention, the World Health Organization, and National Public Health Authorities added ‘new loss of taste or smell’ to the list of symptoms related to COVID-19. The pathogenesis of anosmia related to SARS-CoV-2 has not been defined and most studies have shown that COVID-19-related olfactory dysfunction demonstrates distinct characteristics differentiating it from post-viral olfactory loss related to other viral causes [1,5]. The olfactory loss is of sudden onset, usually profound, and comes early in the disease process [3,4,6,7]. The duration of the smell and taste disorders in COVID-19 disease is still unclear. Many studies reported a quick recovery in the majority of patients [1,8,9]. However, chronic symptoms after COVID-19 disease, including persisting fatigue and loss of taste and smell, have been reported by patients even several months after the onset of the disease [10,11]. The long-term recovery and the influence of the COVID-19 severity or the chemosensory dysfunction severity on the outcome are not clear. We aimed to investigate the longer-term recovery of smell and taste loss in COVID-19 patients who suffered from varying disease severity and chemosensory impairment severity.

2. Materials and Methods

A telephone survey was conducted on consecutive adult patients diagnosed as being infected with SARS-CoV-2 at two COVID-19-Reference University Hospitals, in March and April 2020, in a cross-sectional study. All patients had been diagnosed via a reverse-transcription–polymerase chain reaction (RT–PCR). The study had ethics approval by the two institutional review boards. Three call attempts for each participant were made. All participants provided verbal consent during the interviews. Patients who were not reachable or reported that they did not recall the relevant period events were excluded. Olfactory or/and gustatory disorders before COVID-19 and cognitive disorders were also exclusion criteria. We did not collect data for the deceased patients. The patients were contacted and asked to complete a survey related to taste and smell impairment related to COVID-19 (Table 1. The telephone survey content). It included questions about impairment of smell and taste, nasal congestion, and rhinorrhea. The patients were asked to rate the severity of every symptom on an ordinal scale with the following response options: 0: no loss/absence of the symptom; 1: mild; 2: moderate; 3: severe; 4: extremely severe. The survey also included questions about the timing and duration of symptoms, smoking, history of allergic rhinitis, and chronic rhinosinusitis (CRS). Demographic characteristics (sex and age) and comorbidities were also recorded. Information on severity ratings of COVID-19 was collected from the medical records. The clinical severity of COVID-19 was defined as described by WHO [12] as mild, moderate, severe, and critical. The mild disease includes symptomatic patients meeting the case definition for COVID-19 without evidence of viral pneumonia or hypoxia, moderate patients not exhibiting signs of severe pneumonia, severe patients with clinical or radiographic signs of severe pneumonia including SpO2 < 90% on room air or respiratory rate > 30 breaths/min, and critical ICU-treated patients.

Table 1

The telephone survey content.

During Your COVID-19 Illness
1. Did you experience loss/impairment of smell?The severity in an ordinal scale 0–4
2. Did you experience loss/impairment of taste?The severity in an ordinal scale 0–4
3. Did you experience nasal congestion/obstruction?The severity in an ordinal scale 0–4
4. Did you experience rhinorrhea?The severity in an ordinal scale 0–4
5. When did you first notice the loss of smell?Before/After diagnosis
6. Did the loss/impairment of smell resolve and when?Yes ● No     Days from onset
7. Did the loss/impairment of taste resolve and when?Yes ● No     Days from onset
8. Are you smoking?Yes ● No ● Ex-smoker ● Electronic
9. Do you have a history of allergic rhinitis?Yes ● No
10. Do you have a history of chronic rhinosinusitis?Yes ● No

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Statistical Analysis

Data were analyzed with IBM SPSS Statistics for Windows version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were obtained; continuous variables are expressed as means with standard deviation, while categorical variables are presented as frequencies (percentages). The normality of the variables was ascertained with the Kolmogorov–Smirnov and Shapiro–Wilk test when the number of data was more or less than 50 respectively. Differences between not normally distributed quantitative data were assessed with the use of the Mann–Whitney U test for independent samples. For differences of qualitative parameters between groups, the Chi-square test was applied. For multiple comparisons between more than two groups of not normally distributed quantitative and qualitative variables, Kruskal–Wallis and Chi-square tests were performed, respectively. No post hoc pairwise comparisons were performed. Correlations between two categorical variables were evaluated either with the use of the Chi-square test or Fisher’s Exact test (in the case of dichotomous categorical variable), and logistic regression was applied to check associations between a categorical and a continuous variable. A p value of <0.05 was considered as the statistical significance level.

3. Results

We contacted 182 patients. Twenty-six were not reachable, five declined to participate, one had a history of hyposmia. The study cohort consisted of 150 patients (all Caucasian), with a mean age of 51.6 ± 16.8 (ranging from 18 to 89 years). The patients’ demographic and clinical characteristics are presented in Table 2.

Table 2

The patients’ demographic and clinical characteristics.

Patients, n = 150, n (%)
Age, years18–89
Mean ± SD51.6 ± 16.8
Sex
Male93 (62)
Female57 (38)
Smoking21 (14)
Allergic rhinitis11 (7)
Chronic rhinosinusitis3 (2)
Comorbidities
No medical history86 (57)
Hypertension30 (20)
Diabetes16 (11)
Cardiopathy9 (6)
Covid-19 severity
Mild56 (37)
Moderate50 (33)
Severe34 (23)
Critical (ICU-treated)10 (7)
Hospitalized94 (63)

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n: number of patients; %: percentage, SD: standard deviation.

The median time from the disease onset to the patients’ survey was 61 days (IQR:13). More than half of the participants had no other medical history (57%) while the most common comorbidities were hypertension, diabetes, and cardiac diseases. The study cohort consisted of patients who had suffered from all disease severity levels.

Olfactory and gustatory disorders were reported by 58 patients (39%) and 54 patients (36%) respectively. Forty-nine patients (33%) reported olfactory and gustatory disorders, nine isolated smell loss and five isolated taste loss. We analyzed further the chemosensory loss prevalence and characteristics in patients with mild, moderate, and severe disease, excluding ICU-treated patients (n = 10), since this small subgroup was not considered representative of the critically ill patients for reasons that we comment in the discussion. In this cohort, 41% experienced a loss of smell, which was severe or extremely severe for 74% of them and 38% taste loss (extremely severe for 61% of them) (Table 3. Chemosensory loss characteristics). One out of four patients experienced smell loss before other COVID-19 symptoms. Only a small percentage suffered from nasal blockage and rhinorrhea.

Table 3

Chemosensory loss characteristics in patients with mild, moderate, and severe COVID-19 disease.

Patients (n = 140), n (%)
Smell loss57 (41)
Taste loss53 (38)
Smell and taste loss48 (34)
Nasal obstruction16 (11)
Rhinorrhea13 (9)
Allergic rhinitis11 (8)
Chronic rhinosinusitis3 (2)
Smell loss severity
Mild3 (5)
Moderate12 (21)
Severe11 (19)
Extremely severe (anosmia)31 (54)
Taste loss severity
Mild3 (6)
Moderate11 (21)
Severe7 (5)
Extremely severe32 (61)
Smell loss recovery50 (88)
Taste loss recovery42 (79)
Hyposmia before other symptoms15 (26)
Smell loss duration (days), median (IQR)11.5 (13.3)
Taste loss duration (days), median (IQR)10 (8)

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n: number of patients; %: percentage; IQR: Interquartile Range.

Most of the patients (88%) recovered their sense of smell by 61 days. The median recovery time was 11.5 days (IQR: 13.3), (mean: 14.8 ± 11.2). In two weeks, 58% of the patients had an olfactory recovery and in a month 77%. Similarly, 42 patients (79%) recovered their sense of taste by 61 days. The median recovery time was 10 days (IQR: 8), (mean: 13.8 ± 10.6). Figure 1 shows the recovery time after the onset of smell loss.

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Figure 1

Olfactory recovery over time.

No statistically significant differences were noted in the prevalence of smell loss and taste loss and their duration between groups of varying disease severity (mild, moderate, severe), and sexes (all p > 0.05) (Table 4). The percentages of patients who recovered their sense of smell or taste in the subgroups with varying chemosensory loss severity showed no statistically significant differences (all p > 0.05) (Table 5). Patients’ groups with varying olfactory loss severity showed statistically significant differences in the days to smell loss recovery (p = 0.04). In the patients who recovered their sense of smell, patients with moderate loss had a quicker recovery compared to patients with more severe impairment. The smell loss correlated significantly with the taste loss (Chi-square test, p < 0.001), and the presence of rhinorrhea (Chi-square test, p = 0.005).

Table 4

Comparison of the prevalence and duration of hyposmia between groups of varying COVID-19 disease severity and sexes.

Smell Loss Prevalence Patients; n (%)pHyposmia Duration Days; Mean ± SDp *
COVID-19 Disease Severity0.3270.756 **
Mild
Moderate
Severe
19 (33)
23 (46)
15 (44)
13.5 ± 8.3
14.1 ± 12
16.9 ± 13.2
Sex0.3270.874 ***
Male
Female
33 (38)
24 (44)
14.1 ± 9.2
15.7 ± 13.9

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n: number; %: percentage of hyposmic patients in any disease severity or sex subgroup; SD: Standard deviation; p: comparison of hyposmia prevalence in the different subgroups, Chi-square test; p *: comparison of hyposmia duration in the different subgroups; **: Kruskal–Wallis test; ***: Mann–Whitney U test.

Table 5

Comparison of olfactory and gustatory recovery rates and chemosensory loss duration between patients’ groups with varying chemosensory loss severity.

Recovery Rates Patients; n (%)pDays to Recovery Mean ± SDp *
Smell loss severity0.3960.04
Moderate
Severe
Extremely severe
10 (83)
11 (100)
27 (87)
9 ± 6.8
21.2 ± 12.5
14.7 ± 10.3
Taste loss severity0.510.084
Moderate
Severe
Extremely severe
8 (73)
6 (85)
28 (88)
8.5 ± 7
15.8 ± 12.8
14.8 ± 10.7

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n: number; %: percentage of patients in any chemosensory severity subgroup who recovered; SD: standard deviation; p: comparison of recovery rates between groups of different chemosensory severity, Chi-square test; p *: comparison of days to recovery between groups of different chemosensory severity, Kruskal–Wallis test.

A few participants who suffered olfactory loss reported smoking, allergy, and CRS. Therefore, we did not perform a subgroup analysis regarding the olfactory recovery. Eight patients who developed smell loss were smokers, and 88% of them recovered their sense of smell in an average time of 15.4 days. Six patients with smell loss reported a history of allergic rhinitis. Five out of them (82%) recovered olfaction in 5, 5, 7, 16, and 33 days (an average time of 13.2 days). Only one patient in the subgroup of smell loss reported a history of chronic rhinosinusitis. There were no significant associations between olfactory dysfunction and age (logistic regression, p = 0.267), sex (Chi-square test, p = 0.12), smoking (Fisher Exact test, p = 0.919), disease severity (Chi-square test, p = 0.327), allergic rhinitis (Fisher Exact test, p = 0.355), chronic rhinosinusitis history (Fisher Exact test, p = 0.639) and the presence of nasal blockage (Chi-square test, p = 0.059).

4. Discussion

Our cohort exhibited a significant prevalence of smell loss, severe and of sudden onset in most cases. A large proportion of the patients recovered from their chemosensory losses in a month (77%) and even more of them (88%) in two months. A characteristic pattern of quick recovery is evident (six out of ten recovered in two weeks) as it has been reported in other studies [1,13]. However, a small proportion of patients exhibit persisting loss indicating the need to identify predictive factors for persisting hyposmia. No difference was noted in the prevalence of olfactory and gustatory disorders between mild, moderate, and severe COVID-19 disease. Previous studies indicated a greater prevalence of chemosensory deficits in outpatients compared to hospitalized patients [1,14]. It has been postulated that anosmia might be a biomarker of the magnitude of the host’s response to SARS-CoV-2 infection [14]. However, a more detailed analysis of the correlation of smell impairment with disease severity levels is limited to date. We report on a cohort of consecutive patients of all disease severity levels. We did not include the small subgroup of ICU-treated patients in further analysis, because there are serious concerns regarding the validity of self-reporting in this subgroup. The non-ICU-treated patients were representative of home- and hospital-treated patients. Only a small percentage of patients were not reached on the telephone calls, not willing to participate, or presented exclusion criteria. On the contrary, among the critically ill patients, almost half did not survive and a significant proportion of the survivors were excluded from the study because they were still suffering from serious deconditioning. The findings of other research teams are supportive of our results. Recently, a high prevalence of smell impairment (95%) was reported in assisted-breathing patients (ICU-excluded) [15]. Moein et al. also reported no significant relationship between COVID-19 severity and smell impairment in a cohort of hospitalized patients presenting a high prevalence of smell impairment [16].

The majority of our patients had severe loss of smell/anosmia, at onset (74%), in agreement with the findings reported in other studies [1,5]. Our patients’ groups with varying chemosensory loss severity showed no statistically significant differences in recovery rates. Vaira et al. also reported no significant difference in the persistence of impairment between patients with varying olfactory loss severity at baseline evaluation of their cohort [7]. However, regarding the time to recovery in those who recovered their sense of smell, in our study, patients with moderate olfactory loss had a quicker recovery compared to patients with more severe impairment. This is in agreement with findings reported by Lechien et al., who found that a less severe loss of smell was significantly associated with an earlier recovery [5]. In our study, the calculated mean duration of smell loss recovery was smaller for extremely severe than for severe loss; however, our anosmic patients did not have a quicker recovery overall. The days to recovery have been calculated and compared only for the patients who recovered their sense of smell by 61 days. Whereas all patients with severe hyposmia (100%) had recovered their sense of smell by 61 days, a percentage of anosmic patients had not recovered. Therefore, the percentage of anosmic patients who had not recovered by 61 days from smell loss onset and had olfactory impairment for longer than 61 days are not included in this comparison. Regarding individual patients results, it took four patients (out of 11) 33, 35, 36, and 45 days to recover olfaction in the severe loss subgroup and four patients (out of 27) 30, 30, 31, and 47 days in the anosmia subgroup. The main difference between these subgroups is the patients that had not recovered by 61 days. Larger studies on patients with all levels of disease severity will be needed to determine whether there are predisposing factors for developing long-lasting chemosensory disorders.

The prevalence of nasal blockage and rhinorrhea (11.4% and 9.2% respectively) was small, similar to that reported by other studies [17]. There are, though, studies that reported a much higher prevalence of nasal obstruction and rhinorrhea [18]. We found no significant association between olfactory dysfunction and the presence of nasal blockage. Altundag et al., though, reported that nasal congestion was found to be more prevalent in cases with olfactory dysfunction compared to patients without olfactory dysfunction [19]. We found that smell loss significantly correlated with taste loss and rhinorrhea. Other studies have also shown such a correlation [5]. Although the typical COVID-19-related smell impairment usually does not affect patients with significant nasal symptoms, a small percentage of patients might have a component of nasal inflammatory changes contributing to the hyposmia.

Similar to other studies, we found no associations between age, and gender and smell impairment [7]. The prevalence of allergic rhinitis, chronic rhinosinusitis, and smoking were small in our cohort and no association was found with olfactory loss. A few participants who suffered olfactory loss reported smoking, allergy, and CRS. Therefore, we did not perform a subgroup analysis regarding the olfactory recovery, but descriptive statistics suggest similar patterns of recovery in patients with allergic rhinitis and chronic rhinosinusitis with those recorded in the whole cohort of patients with smell loss. Most studies found no association of comorbidities with the persistence of olfactory dysfunction [5,7], but a recent study reported an association of comorbidities with a worse olfactory recovery in patients with allergic rhinitis, smoking, and hypertension [9].

Most of the patients in our study (88%) had recovered their sense of smell by two months, but a small proportion presents persisting hyposmia. Similar results have been reported by Lechien et al., who reported that, at two months, 80% of their cohort had achieved normal levels of olfactory function [5]. However other researchers have reported higher rates of early recovery (86% in a month after the onset of olfactory dysfunction) [17] or worse recovery [20]. Recently 6-month follow-up data were published on a cohort of patients who presented with a sudden loss of smell in March 2020 reporting persisting very severe and complete loss of smell in 11% of the patients [21]. Fatigue and smell loss were the most common symptoms in a cohort of patients questioned for long-term persistence of symptoms post COVID-19, a mean of 125 days after disease onset [22]. Our knowledge regarding SARS-CoV-2-related symptoms is evolving [23]. Another population-based study found that, in a cohort of non-hospitalized subjects contacted for reporting persistent symptoms, 65% reported a loss of smell and 69% loss of taste at diagnosis and 12% reported loss of smell and 10% loss of taste a median of 117 days from disease diagnosis [24].

A strength of our study is the inclusion of a comprehensive cohort of consecutive patients with a confirmed diagnosis of COVID-19 by two reference hospitals, therefore limiting patient selection bias related to age, residence, health-care profession, and information about COVID-19-related smell loss. Our cohort is representative of all disease severity levels. The recovery rate beyond the early four weeks recovery was measured. The chemosensory loss severity was rated at a scale that allowed us to examine the possible correlation of the olfactory and gustatory loss severity with the recovery rate and the time from chemosensory loss onset to recovery.

A limitation of our study is that the chemosensory dysfunction was not documented with olfactory and gustatory tests. Olfactory questionnaires are considered less reliable in comparison to objective tests. Vaira et al. reported that 10.3% of patients who were found to have a disorder on objective testing had self-reported normal function [7], and adversely in a prospective controlled trial that assessed with validated psychophysical tests the patients’ complaints of smell loss, 61% of COVID-19 patients reported a subjective loss in smell, whereas 54% had a positive test [25]. Self-reporting was appropriate given the retrospective type of our study. The research on COVID-19-related hyposmia relies a lot on questionnaires due to the pandemic restrictions and the short duration of the hyposmia [1]. Another limitation of the study is that patient reports are subjected to recall bias. Furthermore, there is a risk of misclassification of severity ratings when self-reporting of olfactory or gustatory function is retrospective. Recall is considered to be good for distinctive disease symptoms [26]. Smell loss is a very distinct symptom. We acknowledge that rating of symptoms’ severity retrospectively can be inaccurate, but in the context of COVID-19-related smell loss, the great majority of patients in all studies report a sudden and severe change of functional status (severe hyposmia or anosmia) [1] and this reduces the risk of inaccurate rating. Asking the patients to recall events at an order, reference to a calendar, and intervening health events can improve recall [26]. During the pandemic, being diagnosed with COVID-19 was a cardinal health event and with the anxiety of whether the mild disease would turn to more serious, a reference to a calendar of events is strong and a timeline exists for patients regarding the disease resolution. Recall reliability can increase by using precise language, and confirming that the patient is not psychologically or physically impaired [26]. Our study followed these recommendations. We developed a short, appropriate-for-telephone-use survey, using simple everyday language. Furthermore, we excluded from this study patients under rehabilitation for serious deconditioning. In studies about COVID-19-related smell loss, the most appropriate methods of data collection were applied, balancing recruitment bias, recall bias, and the research questions. Another limitation of the study is the small sample size of the subgroups of patients with different COVID-19 severity levels and chemosensory loss. Similarly, the sample sizes of the subgroups of patients with different chemosensory loss severity are small. Differences in the recovery might be detectable in larger participants’ groups.

Smell and taste loss is highly prevalent in COVID-19 of all levels of severity. Most patients recover fast, but one out of ten have not recovered in two months. The recovery rates up to two months do not correlate with the COVID-19 and chemosensory loss severity. The time from chemosensory loss to recovery for the patients who recover is associated with the severity of impairment. Less severe hyposmia tends to resolve quicker.Go to:

Acknowledgments

The authors thank Anastasia Nikolaidou, Chatzi Souleiman Ipek, and Maria Zisoglou for assistance with data collection.Go to:

Author Contributions

Conceptualization, A.P. and J.C.; methodology, A.P. and M.K.; formal analysis, K.V.; investigation, A.P., S.M., P.P., V.P., M.P. and M.K.; data curation, A.P., K.V. and M.K.; writing—original draft preparation, A.P.; writing—review and editing, A.P., M.K., K.V., S.M., P.P., V.P., M.P. and J.C.; supervision: A.P.; project administration: A.P. All authors have read and agreed to the published version of the manuscript.Go to:

Funding

This research received no external funding.Go to:

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of two COVID-19 Reference University Hospitals in Greece: Scientific Board of AHEPA University Hospital, Thessaloniki, decision: SB10/347/8.5.2020, and Scientific Board of University Hospital of Alexandroupolis, decision: SB8/9/18065/12.06.2020/25.06.2020).Go to:

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.Go to:

Data Availability Statement

Data are available upon request from the authors.Go to:

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

Highlights

  • Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
  • Reactivation of latent viruses during initial infection may contribute to PASC
  • Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
  • Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells

SUMMARY

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Article Info

Publication History

Accepted: January 19, 2022Received in revised form: December 14, 2021Received: September 29, 2021

Click on Link Below for Complete Study:

https://www.cell.com/cell/pdf/S0092-8674(22)00072-1.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867422000721%3Fshowall%3Dtrue

Covid-19 Vaccine Analysis: The most common adverse events reported so far

Authors: DATED: AUGUST 6, 2021 BY SHARYL ATTKISSON 

As of July 19, 2021 there were 419,513 adverse event reports associated with Covid-19 vaccination in the U.S., with a total of 1,814,326 symptoms reported. That’s according to the federal Vaccine Adverse Event Reporting System (VAERS) database.

Report an adverse event after vaccination online here.

Each symptom reported does not necessarily equal one patient. Adverse event reports often include multiple symptoms for a single patient.

Reporting of illnesses and symptoms that occur after Covid-19 vaccination does not necessarily mean they were caused by the vaccine. The system is designed to collect adverse events that occur after vaccination to uncover any patterns of illnesses that were not captured during vaccine studies.

Read CDC info on Covid-19 vaccine here.

Scientists have estimated that adverse events occur at a rate many fold higher than what is reported in VAERS, since it is assumed that most adverse events are not reported through the tracking system. Reports can be made by doctors, patients or family members and/or acquaintances, or vaccine industry representatives. 

Read: Exclusive summary: Covid-19 vaccine concerns.

Some observers claim Covid-19 vaccine adverse events are not as likely to be underreported as those associated with other medicine, due to close monitoring and widespread publicity surrounding Covid-19 vaccination.

Approximately 340 million doses of Covid-19 vaccine have been given in the U.S. Slightly less than half of the U.S. population is fully vaccinated.

According to the Centers for Disease Control (CDC) and Food and Drug Administration (FDA), the benefits of Covid-19 vaccine outweigh the risks for all groups and age categories authorized to receive it.

Watch: CDC disinformation re: studies on Covid-19 vaccine effectiveness in people who have had Covid-19.

The following is a summary of some of the most frequent adverse events reported to VAERS after Covid-19 vaccination. (It is not the entire list.)

Most common Covid-19 vaccine adverse events reported as of July 19, 2021

Yellow highlighted adverse events are subjects of investigations, warnings or stated concerns by public health officials. For details, click here.

128,370 Muscle, bone, joint pain and swelling including:

  • 39,902 Pain in extremity
  • 37,819 Myalgia, muscle pain, weakness, fatigue, spasms, disorders, related
  • 30,138 Arthralgia, joint pain or arthritis, swelling, joint disease, bone pain, spinal osteoarthritis
  • 14,682 Back pain, neck pain
  • 5,829 Muscle and skeletal pain, stiffness, weakness

119,866 Injection site pain, bleeding, hardening, bruising, etc.

105,332 Skin reddening, at injection site or elsewhere, rash, hives

100,564 Fatigue, lethargy, malaise, asthenia, abnormal weakness, loss of energy

89,302 Headache, incl. migraine, sinus

68,252 Vomiting, nausea

68,064 Fever

63,133 Chills

60,913 Pain

49,574 Dizziness

34,076 Flushing, hot flush, feeling hot, abnormally warm skin

31,785 Lung pain or abnormalities, fluid in lung, respiratory tract or lung congestion or infection, wheezing, acute respiratory failure including:

  • 23,005 Dyspnoea, difficulty breathing
  • 1,398 Pneumonia
  • 1,128 Respiratory arrest, failure, stopped or inefficient breathing, abnormal breathing
  • 563 Covid-19 pneumonia
  • 265 Mechanical ventilation
  • 217 Bronchitis

30,909 Skin swelling, pain, tightness, face swelling, swelling under skin, hives, angioedema including:

  • 7,579 Skin pain, sensitivity, burning, discoloration, tenderness

25,319 Heart failure, heart rhythm and rate abnormalities, atrial fibrillation, palpitations, flutter, murmur, pacemaker added, fluid in heart, abnormal echocardiogram including:

  • 3,105 Heart attack or cardiac arrest, sudden loss of blood flow from failure to pump to heart effectively, cardiac failure, disorder

22,085 Itchiness

29,861 Sensory disturbance including:

  • 8,236 Tinnitus, hearing noise
  • 7,951 Abnormal vision, blindness
  • 6,349 Ageusia, loss of taste, altered taste, disorders
  • 2,249 Anosmia, loss of smell, parosmia (rotten smell)
  • 2,075 Hypersensitivity
  • 1,560 Sensitivity or reaction to light 
  • 890 Hearing loss, deafness

Prevalence of anosmia and ageusia symptoms among long-term effects of COVID-19.

Authors: Moraschini V1Reis D1Sacco R2Calasans-Maia MD3

COVID‐19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that currently presents the greatest, most challenging health concern worldwide. Since the first reports of the disease in December 2019, clinicians and scientists have endeavored to understand the main symptoms, risk factors, and prognosis of the disease (Wynants et al., 2020). Although a significant portion of the infected population remains asymptomatic, many COVID‐19‐infected individuals develop symptoms that vary from mild to severe (Stasi et al., 2020).

Some patients may experience long‐term effects of COVID‐19, which persist for two or more weeks after the onset of the disease (Tenforde et al., 2020). Loss of taste (ageusia) and smell (anosmia) are symptoms that have drawn substantial attention from researchers because of their high prevalence in the early stages of the disease (Eliezer et al., 2020; Gane et al., 2020). However, recent studies have observed persistent dysgeusia and anosmia following recovery from COVID‐19 infection (Andrews et al., 2020; Garrigues et al., 2020; Panda et al., 2020).

The aim of this study was to estimate the prevalence of dysgeusia and anosmia in studies that assessed the long‐term effects of COVID‐19. Four databases (PubMed/MEDLINE, EMBASE, Scopus, and Lilacs) were searched for articles without any restrictions regarding language, and the inclusion criteria were based on the PECO strategy (Morgan et al., 2018). This review included studies that analyzed the prevalence of persistent symptoms (>30 days) of anosmia and dysgeusia in patients who had COVID‐19. There were no language restrictions. Two independent review authors (V.M. and M.D.C.M.) conducted the search‐and‐screening process, commencing with the analysis of titles and abstracts. Next, full papers were selected for careful reading and matched with the eligibility criteria for subsequent data extraction. The search strategy is described in Table S1.

Regarding the quality of the analyzed studies and risk of bias, one study was classified as low quality (Andrews et al., 2020), two as satisfactory (Garrigues et al., 2020; Horvath et al., 2020), and five as of high quality (Carfì et al., 2020; Carvalho‐Schneider et al., 2020; Chopra et al., 2020; Galván‐Tejada et al., 2020; Panda et al., 2020). The analyses can be viewed in Table S2.

The two review authors (V.M. and M.D.C.M.) independently performed risk‐of‐bias and study quality analyses. The Newcastle–Ottawa Scale (Lo et al., 2014) was used in the analysis of non‐randomized studies. For data analysis, the effects reported in one simple arm were estimated by dividing the number of patients with each symptom by the total number of patients with COVID‐19 in the sample and then by multiplying by 100 to estimate the percentage. The prevalence with 95% confidence intervals (CIs) was presented using the software Comprehensive Meta‐Analysis (BioStat).

A total of eight observational studies were selected for this study. Six cohort studies (Andrews et al., 2020; Carfì et al., 2020; Carvalho‐Schneider et al., 2020; Chopra et al., 2020; Horvath et al., 2020; Panda et al., 2020), one cross‐sectional study (Garrigues et al., 2020), and one case–control study (Galván‐Tejada et al., 2020) were included in this study (Figure S1). The studies analyzed 1,483 patients (773 male and 710 female) with a mean age of 48.3 ± 11.2. All patients were diagnosed with COVID‐19 through reverse transcription polymerase chain reaction (RT‐PCR) and exhibited mild, moderate, or severe symptoms. The mean overall follow‐up time was 60.7 days. The main data for each study are shown in Table ​Table11.

For More Information: https://europepmc.org/article/PMC/PMC8242542

Age-dependent appearance of SARS-CoV-2 entry sites in mouse chemosensory systems reflects COVID-19 anosmia-ageusia symptoms

Authors: Julien Brechbühl,Ana Catarina Lopes,Dean Wood,Sofiane Bouteiller,Aurélie de Vallière,Chantal Verdumo, and Marie-Christine Broillet

Abstract

COVID-19 pandemic has given rise to a collective scientific effort to study its viral causing agent SARS-CoV-2. Research is focusing in particular on its infection mechanisms and on the associated-disease symptoms. Interestingly, this environmental pathogen directly affects the human chemosensory systems leading to anosmia and ageusia. Evidence for the presence of the cellular entry sites of the virus, the ACE2/TMPRSS2 proteins, has been reported in non-chemosensory cells in the rodent’s nose and mouth, missing a direct correlation between the symptoms reported in patients and the observed direct viral infection in human sensory cells. Here, mapping the gene and protein expression of ACE2/TMPRSS2 in the mouse olfactory and gustatory cells, we precisely identify the virus target cells to be of basal and sensory origin and reveal the age-dependent appearance of viral entry-sites. Our results propose an alternative interpretation of the human viral-induced sensory symptoms and give investigative perspectives on animal models.

Introduction

The Corona Virus Disease 2019 (COVID-19) has federated worldwide scientific efforts for understanding the viral epidemiological mechanisms of the coronavirus 2 (SARS-CoV-2) that causes this severe acute respiratory syndrome. In humans, the viral syndrome is characterized by an increased mortality rate in aged and/or comorbidity patients associated with the upper respiratory infection symptoms, such as severe respiratory distress13. In addition to its major impact, COVID-19 is associated by its direct alteration of human olfaction and gustation, in absence of substantial nasal inflammation or coryzal signs, resulting to anosmia and ageusia in up to 77% of the patients47. While these sensory symptoms are well established and intensely affect everyday behaviors8,9, the precise related mechanisms remain elusive10.

The target cells of the virus share a molecular signature: the concomitant cellular expression of the angiotensin-converting enzyme 2 (ACE2) and of its facilitating transmembrane serine protease 2 (TMPRSS2), which plays a crucial role for the interaction of viral spike proteins with the host cell1113. Paradoxically, these entry sites seem to be lacking in sensory cells1418, while a direct SARS-CoV-2 contamination has been observed both in humans and rodents19,20, requesting further investigations to explain the sensory-associated symptoms2124. Therefore, the characterization of the animal model is necessary prior to its use to understand the causality underling the viral-induced sensory symptoms.

The use of mice is indeed limited for epidemiological studies due to their absence of hands, which, with aerosols, are the foremost passages of interindividual viral transmission25, as well as their published lack of SARS-CoV-2 ACE2-spike protein affinity26,27. Nevertheless, the ease of production of genetically modified mice and their scientific availability, as well as their well-studied and specialized chemosensory systems2830, make them a valuable ally for the development of potential prophylactic and protective treatments related to these sensory symptoms.

Thus, we aimed here at characterizing the potential viral entry sites across mouse sensory systems. We found SARS-CoV-2 entry cells to be of different origins depending on the sensory systems. In summary, the virus could target cells involved in tissue regulation such as the supporting cells of the olfactory receptor neurons and the regenerative basal cells but also, specifically, the chemosensory cells of both gustatory and olfactory systems. We finally revealed that the emergence of viral entry sites in sensory and basal cells only occurs with age, which could explain both, the observed COVID-19 long-lasting effects and the age-dependent sensory-symptomatology in human.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282876/

COVID-19-Associated Bronchiectasis and Its Impact on Prognosis

Authors: Aasir M. SulimanBassel W. BitarAmer A. FarooqiAnam M. ElarabiMohamed R. AboukamarAhmed S. Abdulhadi

Abstract

Coronavirus disease 2019 (COVID-19), which initially emerged in Wuhan, China, has rapidly swept around the world, causing grave morbidity and mortality. It manifests with several symptoms, on a spectrum from asymptomatic to severe illness and death. Many typical imaging features of this disease are described, such as bilateral multi-lobar ground-glass opacities (GGO) or consolidations with a predominantly peripheral distribution. COVID-19-associated bronchiectasis is an atypical finding, and it is not a commonly described sequel of the disease. Here, we present a previously healthy middle-aged man who developed progressive bronchiectasis evident on serial chest CT scans with superimposed bacterial infection following COVID-19 pneumonia. The patient’s complicated hospital course of superimposed bacterial infection in the setting of presumed bronchiectasis secondary to COVID-19 is alleged to have contributed to his prolonged hospital stay, with difficulty in weaning off mechanical ventilation. Clinicians should have high suspicion and awareness of such a debilitating complication, as further follow-up and management might be warranted.

Introduction

Beginning in December 2019, a series of pneumonia cases were reported in Wuhan City, Hubei Province, China. Further investigations revealed that it was a new type of viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), which was termed coronavirus disease 2019 (COVID-19). Symptoms are variable, nonspecific, and include dry cough, fever, fatigue, myalgia, dyspnea, anosmia, and ageusia [1]. The real-time reverse transcription-polymerase chain reaction (rRT-PCR) test is the current gold standard for confirming infection and is performed using nasal or pharyngeal swab specimens.

Computerized tomography of the thorax (CT thorax), as a routine imaging tool for pneumonia diagnosis, is of great importance in the early detection and treatment of patients affected by COVID-19. Chest CT may detect the early parenchymal abnormalities in the absence of positive rRT-PCR at initial presentation [2]. Since chest CT was introduced as a diagnostic tool for COVID-19 pneumonia, many typical features of this disease were described such as bilateral multi-lobar ground-glass opacification (GGO) with a prevalent peripheral or posterior distribution, mainly in the lower lobes; sometimes, consolidative opacities superimposed on GGOs could be found [3]. To our knowledge, bronchiectasis is not a classical finding in COVID-19 pneumonia, with a paucity of reporting on its development and progression during the disease course.

For More Information: https://www.cureus.com/articles/59350-covid-19-associated-bronchiectasis-and-its-impact-on-prognosis