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Taste and Smell Disorders in COVID-19 Patients: Role of Interleukin-6

  • Angela P. Cazzolla
    Angela P. Cazzolla
    Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
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  • , 
  • Roberto Lovero
    Roberto Lovero
    AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
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  • , 
  • Lorenzo Lo Muzio
    Lorenzo Lo Muzio
    Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
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  • , 
  • Nunzio F. Testa
    Nunzio F. Testa
    Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
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  • , 
  • Annalisa Schirinzi
    Annalisa Schirinzi
    AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
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  • , 
  • Giuseppe Palmieri
    Giuseppe Palmieri
    Private practice, Bari 70124, Italy
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  • , 
  • Pietro Pozzessere
    Pietro Pozzessere
    AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Emergency Medicine and Surgery Unit, Bari 70124, Italy
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  • , 
  • Vito Procacci
    Vito Procacci
    AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Emergency Medicine and Surgery Unit, Bari 70124, Italy
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  • , 
  • Mariasevera Di Comite
    Mariasevera Di Comite
    Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Human Anatomy Section, Università degli Studi di Bari, Bari 70124, Italy
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  • , 
  • Domenico Ciavarella
    Domenico Ciavarella
    Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
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  • , 
  • Maria Pepe
    Maria Pepe
    AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
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  • , 
  • Caterina De Ruvo
    Caterina De Ruvo
    Maugeri Clinical Research Institutes IRCCS of Bari, Bari 70124, Italy
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  • , 
  • Vito Crincoli
    Vito Crincoli
    Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Human Anatomy Section, Università degli Studi di Bari, Bari 70124, Italy
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  • , 
  • Francesca Di Serio
    Francesca Di Serio
    AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
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  • , and 
  • Luigi Santacroce*
    Luigi Santacroce
    Ionian Department (DJSGEM), Microbiology and Virology Lab, Università degli Studi di Bari, Bari 70124, Italy
    *Luigi Santacroce ([email protected]).
    More by Luigi Santacroce
    Orcidhttp://orcid.org/0000-0001-5671-8124
Cite this: ACS Chem. Neurosci. 2020, 11, 17, 2774–2781
Publication Date (Web):August 4, 2020
https://doi.org/10.1021/acschemneuro.0c00447
Copyright © 2020 American Chemical Society
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Abstract

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The rapid recovery of smell and taste functions in COVID-19 patients could be attributed to a decrease in interleukin-6 levels rather than central nervous system ischemic injury or viral damage to neuronal cells. To correlate interleukin-6 levels in COVID-19 patients with olfactory or gustatory dysfunctions and to investigate the role of IL-6 in the onset of these disorders, this observational study investigated 67 COVID-19 patients with taste or smell disorders or both, who did not require intensive care admission, admitted at COVID Hospital of Policlinico of Bari from March to May 2020. Interleukin-6 was assayed in COVID-19 patients with taste or smell disturbances at the time of admission and at the time of swab negativization. At the same time, patients have been given a specific survey to evaluate the severity of taste and smell disturbances. Of 125 patients with smell or taste dysfunctions at onset of disease, 67 fulfilled the inclusion criteria, while 58 were excluded because 35 of them required intensive care admission, 5 were unable to answer, 5 died, 7 had finished chemotherapy recently, and 5 refused to participate. The evaluation of taste and smell disorders was carried out using a survey performed at the time of admission and at the time of swab negativization. Sinonasal outcome test 22 (SNOT-22) was used as a reference for olfactory function assessment, and Taste and Smell Questionnaire Section of the US NHANES 2011–2014 protocol (CDC 2013b) was used as reference for gustatory function assessment. A venous blood sample was taken for each patient to measure IL-6 levels upon entry and at swab negativization. Interleukin-6 levels in COVID-19 patients in relation to olfactory or gustatory disorders were correlated from the time of their admission to the time of swab negativization. Statistically significant correlations were obtained between the decrease of interleukin-6 levels and the improvement of smell (p value < 0.05) and taste (p = 0.047) functions at swab negativization. The acquired results demonstrate the key role of interleukin-6 in the pathogenesis of chemosensitive disorders in COVID-19 patients.

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  Note

This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

Introduction

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Coronavirus disease 2019 (COVID-19) is a viral pandemic that recently emerged from East Asia and quickly spread to the rest of the world, due to the SARS-associated coronavirus 2 (SARS-CoV-2), first defined as 2019-nCoV.
SARS-CoV-2 is a viral strain of the SARS-CoV species related to SARS, belonging to the Coronaviridae family, discovered around the end of 2019. (1,2) Differing from other human coronaviruses, SARS coronaviruses may induce a severe form of pneumonia, potentially lethal.
The target cells of SARS-CoV-2 are those that express the angiotensin-converting enzyme 2 (ACE-2): (3) type II alveolar cells, (3,4) upper and stratified epithelial cells, absorptive enterocytes from ileum and colon, (4) myocardial cells, proximal tubule cells of kidney, bladder urothelial cells, (3) glial cells and neurons, (5) oral tissues cells (especially epithelial cells of the tongue), (6) and nasal epithelial cells, which display the highest expression of ACE-2 receptor in the respiratory tree. (7)
Due to the wide expression of this receptor, the SARS-CoV-2 may induce different clinical pictures, often contemporary and able to determine a complex, pleomorphic scenario.
Severe alteration of taste and smell without rhinorrhea or nasal obstruction can be prodromal symptoms in the early stage of disease. (8,9)
Loss of taste might be linked to bonding between SARS-CoV-2 and receptors for sialic acid, a component of saliva that protects the glycoproteins responsible for the transport of molecules stimulating taste in the taste pores. As a result of this bond, the degradation of taste particles with an alteration of taste is favored. (10−12)
According to others authors, loss of taste can be linked to loss of smell because the brain combines the perceptions of taste from the mouth with what is known as retronasal olfaction. (13,14)
It has been demonstrated that human coronaviruses invade the central nervous system through the olfactory neuroepithelium and spread to the olfactory bulb using a mode of neuron-to-neuron propagation. (15−17)
Furthermore, SARS-CoV-2 can damage the blood–brain barrier, invade the nervous system through the slow cerebral microcirculation, which the facilitates the interaction between the protein S (spike) and the ACE-2 receptors expressed on the capillary endothelium, and interact with the ACE-2 receptors expressed in neuronal cells. (5)
SARS-CoV-2 binds to receptors present on cells of the lower tract respiratory system with interstitial pneumonia that can develop into a severe acute respiratory distress syndrome (ARDS) or can damage other organs (heart, kidney, liver, brain) with systemic manifestations (ischemias, arrhythmias, encephalitis, seizures, strokes) up to sepsis, septic shock, and patient death.
These clinical manifestations are accompanied by the onset of an inflammatory storm characterized by the release of a wide range of cytokines. (18,19)
A key role in the cytokine storm is played by interleukin-6 (IL-6), which induces a variety of acute-phase proteins (C-reactive protein, serum amyloid A, α1-antichymotrypsin, haptoglobin, fibrinogen, and complement components) and activates coagulation cascade with probable onset of disseminated intravascular coagulation. Elevated levels of IL-6 were significantly related to severe clinical manifestations. (20)
Increased IL-6 levels have been found in serum of patients with hyposmia (21) and transient high-level expression of proinflammatory cytokines (TNF-α, IL-6) was detected in the olfactory bulb and CNS during different human influenza virus infections (1918 H1N1 influenza virus, 2009 H1N1 influenza virus, and HPAI H5N1 virus) (22−24) Experiments have confirmed that virus-infected microglial cells and astrocytes secrete IL-6 (25−27) and primary glial cells cultured in vitro secrete a large number of inflammatory factors, such as IL-6, IL-12, IL-15, and TNF-α after being infected with coronaviruses. (28)
IL-6 could act as an endogenous substance regulating olfactory neuronal activity because it has been shown to regulate neuronal and glial cell activity. In addition, IL-6 can directly inhibit smell function through activating apoptotic pathways using TNF-α or trough neuropoietin (NP), an IL-6 related cytokine that affects signaling through ciliary neurotrophic factor receptor and influences nuclear factor κB73 and adenosine triphosphate–ubiquitin-dependent proteolytic pathways. (21)
At present, few studies have investigated the pathophysiology of chemosensitive disorders in patients with laboratory-confirmed COVID-19 mostly attributing it either to CNS ischemic injury or viral damage to neuronal cells. Nevertheless, the rapid recovery of chemosensitive functions would rule out these hypotheses in favor of other mechanisms, such as the reduction of IL-6 levels, that may explain a faster recovery of these functions.
This is the first study that evaluates IL-6 levels in COVID-19 patients with grading of smell and taste disorders. The aim was to monitor and to correlate IL-6 levels in laboratory-confirmed COVID-19 patients with olfactory or gustatory disorders from the time of their admission to the time of swab negativization. The evaluation of olfactory or gustatory disorders was carried out using a questionnaire performed at the time of admission and at the time of swab negativization. (29,30)

Results and Discussion

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A total of 67 COVID-19 patients, 45 male (67.2%) (age 65 ± 13.1) and 22 female (32.8%) (age 64 ± 15.8), were admitted at COVID hospital of Policlinico, University of Bari. Table 1 shows the clinical characteristics of the patients and symptoms associated with taste and smell disorders. In all patients, smell or taste disorders occurred before the onset of COVID-19 symptoms (4 ± 1 days), while the duration of the disturbance was 21 ± 7 days.
Table 1. General Characteristics, Associated Symptoms, and Associated Pathologies of 67 COVID-19 Patients with Smell and Taste Disorders
inclusion criteriaexclusion criteria
age > 18 yearspatients without a laboratory-confirmed diagnosis of COVID-19 infection
laboratory-confirmed COVID-19 infection (reverse transcription–polymerase chain reaction, RT-PCR)patients in the intensive care unit
patients clinically able to complete the questionnairepatients with olfactory or gustatory dysfunctions before the epidemic due to congenital anosmia, the side effects of drugs (in particular chemotherapy), previous surgery or radiotherapy in the oral and nasal cavities, head injury, sinonasal diseases, allergic rhinitis
 patients with systemic diseases (iron deficiency, autoimmune diseases)
 patients with neurodegenerative disorders (Parkinson’s disease, disease Alzheimer’s disease, dementia)
 patients with major depression
General Characteristics
 n (percent)age (years)
male45 (67.2%)65 ± 13.1
female22 (32.8%)64 ± 15.8
days from COVID-19 symptoms onset4 ± 1 
day of duration chemosensitive disorders21 ± 7 
Associated Symptoms
fever64 (95.5%)
cough59 (88%)
asthenia49 (73.1%)
headache40 (59.7%)
sore throat43 (64.2%)
abdominal symptoms6 (8.95%)
muscle or joint pains61 (91%)
chest pain52 (77%)
nausea39 (58%)
vomit13 (19%)
loss of appetite17 (25%)
felt tired63 (94%)
altered breathing59 (88%)
diarrhea10 (14%)
Associated Pathologies
diabetes12 (17.9%)
hypertension38 (56.7%)
nasal septum deviation5 (7.4%)
respiratory insufficiency9 (13.4%)
gastresophageal reflux disease20 (29.8%)
thyroid diseases15 (22.3%)
A total of 44 patients (65.7%) reported isolated olfactory dysfunctions, while 17 patients (25.4%) reported isolated taste disorders, and 6 patients (8.95%) reported combined smell and taste disorders (Table 2). At the time of the second evaluation, 35 patients (52.2%) reported a complete recovery of the chemosensitive functions, while 32 patients (47.8%) reported very mild or mild disorders. In particular, 21 patients (65.6%) showed very mild smell disorder, 1 (3.2%) presented mild smell disorder, and 10 (31.2%) reported very mild taste disorder (Table 2).
Table 2. Characteristics of Smell or Taste Disorders in 67 COVID-19 Patients at the First and Second Evaluation (Grading of Disorders)
  grading of disorders
 no. of patientsnone (0)very mild (1)mild or light (2)moderate (3)severe (4)bad (5)
First Evaluation
olfactory disorders44 (65.7%)23 (34.3%)04 (9.1%)13 (29.6%)17 (38.6%)10 (22.7%)
taste disorders17 (25.4%)50 (74.6%)03 (17.7%)7 (41.1%)6 (35.3%)1 (5.9%)
olfactory and taste disorders6 (8.95%)61 (91.05%)0001 (16.7%)5 (83.3%)
Second Evaluation
olfactory disorders22 (32.8%)45 (67.2%)21 (95.4%)1 (4.6%)000
taste disorders10 (14.94%)57 (85.1%)10 (100%)0000
olfactory and taste disorders0000000
At the time of the first examination, complete anosmia was detected in 10 cases (22.7%), severe in 17 patients (38.6%), moderate in 13 patients (29.6%), mild or light in 4 patients (9.1%), very mild in no patients, and absence of disorder in 50 patients (52.3%) (Table 2).
In patients with taste disorders, complete ageusia was detected in 1 case (5.9%), severe in 6 patients (35.3%), moderate in 7 patients (41.1%), mild or light in 3 patients (17.7%), very mild in no patients, and absence of disorder in 50 patients (52.3%) (Table 2).
In patients with associated disorders, 5 (83.3%) had bad form and 1 (16.7%) severe one.
The identified subpopulations were correlated with the levels of IL-6 detected at the time of hospitalization and at swab negativization.
The sex distribution of IL-6 levels in hospitalized patients showed an increase in males (99.6 pg/mL vs 88.5 pg/mL) (Figure 1a), while there were no more differences in the sex distribution at the time of swab negativization (6.3 pg/mL vs 5.8 pg/mL) (Figure 1b).

Figure 1

Figure 1. (a) Sex distribution of IL-6 levels at the first evaluation; (b) sex distribution of IL-6 levels at the second evaluation; (c) sex distribution of the delta (values at the first evaluation minus values at the second evaluation) value of IL-6 levels; (d) sex distribution of the delta score of smell; (e) sex distribution of the delta score of taste.

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The distribution of the delta values of IL-6 was mildly higher in females than in males (93.7 pg/mL vs 80.0 pg/mL) (Figure 1c), while the sex distribution of the smell delta score (2044 vs 2045) and of the taste delta score (0.15 vs 0.13) show no significant differences between the two sexes (Figure 1d,e).
The distribution of IL-6 and smell and taste scores in 67 COVID-19 patients was higher at the first evaluation compared to the second one (Figure 2a–c).

Figure 2

Figure 2. (a) IL-6 and (b) smell and (c) taste score distributions in COVID-19 patients at first and second evaluation.

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The Wilcoxon signed-rank test, used to evaluate the values of IL-6 and the scores related to smell and taste dysfunctions, provided a good indication of the sample. There are statistically significant differences between the values obtained when patients entered the hospital compared to the values obtained at swab negativization (p < 0.05) (Table 3a).
Table 3. Values of the (a) Wilcoxon Test and (b) Pearson’s Correlation Coefficients between All the Variables of the Dataset Considered
(a) Wilcoxon Signed-Rank Test
variableWilcoxon testp value
IL-6 level (first evaluation) vs IL-6 level (second evaluation)2278<0.05
score smell dysfunction (first evaluation) vs score smell dysfunction (second evaluation)1225<0.05
score taste dysfunction (first evaluation) vs score taste dysfunction (second evaluation)325<0.05
(b) Pearson’s Linear Correlation Coefficients
variablePearson coefficient (r)95% confidence intervalsp value
delta IL-6 vs delta score smell0.580.33 to 0.68<0.05
delta IL-6 vs delta score taste0.240.003 to 0.450.047
delta score taste vs delta score smell–0.38–0.567 to −0.15<0.05
To determine a statistically significant correlation between the delta of IL-6 levels and the delta of smell and taste disorders, the Pearson correlation coefficient was calculated.
Significant correlations between IL-6 levels and type of dysfunctions have been found. The olfactory and gustatory dysfunctions had a higher score in patients with higher levels of IL-6. Also, the patients with the association of both disorders had even higher levels of IL-6.
An excellent correlation between the delta of IL-6 levels and the delta score of smell dysfunction has been found (r = 0.58, p < 0.05).
The delta taste score also showed a statistically significant correlation with the delta of IL-6 levels (p = 0.047). These correlations showed that the recovery of chemosensitive functions occurs when IL-6 levels return to normal values (1–7 pg/mL) at the time of swab negativization.
A statistically significant inverse correlation between the delta score taste and the delta score smell has been found (p < 0.05) (Table 3b).
Coronaviruses have been identified as a family of viruses that may be associated with anosmia, (31) and SARS-CoV-2 can cause taste and smell dysfunctions without rhinorrhea or nasal obstruction like prodromal symptoms.
Different papers have investigated the occurrence of anosmia/hyposmia and dysgeusia/ageusia in patients with laboratory-confirmed COVID-19, the timing of dysfunction, and associated symptoms, but to our knowledge, no papers have investigated the correlation between severity and timing of these dysfunctions and the levels of IL-6.
In the present study, chemosensitive dysfunctions are more frequent in males (67.2%) and the prevalence of olfactory dysfunction is higher than that of taste dysfunction (65.7% vs 25.4%). (32)
Smell and taste disorders occurred before the onset of COVID-19 symptoms (4 ± 1 days), while the duration of the disturbance was 21 ± 7 days.
The Wilcoxon signed-rank test provided statistically significant differences between (a) levels of IL-6 at the first and at the second assessment (p < 0.05), (b) the smell score at the first and at the second assessment (p < 0.05), and (c) the taste score at the first and at the second evaluation (p < 0.05).
The delta of IL-6 levels correlated with the delta smell score (p value < 0.05) and with the delta taste score (p = 0.047), and the delta score taste showed a significant inverse correlation with the delta score smell (p < 0.05). These results would demonstrate that smell and taste disorders in COVID-19 patients might be linked to high levels of IL-6.
The exact pathophysiology of taste and smell dysfunctions is not well understood, and only hypotheses can be made based on studies regarding other coronaviruses. Various mechanisms have been hypothesized: (a) a central involvement linked to the ability of the human coronavirus to invade the olfactory bulb and, therefore, to spread to the central nervous system, (31) or (b) linked to the capacity of the virus to enter into cerebral microcirculation and to damage the brain, (5) or (c) a peripheral involvement of the nasal epithelium with direct damage to the olfactory receptor neurons.
Recent reports have shown a high recovery rate of the olfactory function within 1–2 weeks after the onset of dysfunction, a very short time to achieve complete neuronal regeneration. (32−34) Therefore, it has been hypothesized that olfactory disorders are not related to viral damage to neuronal cells but to non-neuronal cells that express ACE-2 receptors such as sustainable cells of the olfactory epithelium, microvillar cells, Bowman’s gland cells, horizontal basal cells, and olfactory bulb pericytes. (35) Turski et al. have supposed that the loss of smell is due to the infection of the support cells and vascular pericytes of the olfactory epithelium and bulb with consequent alteration of the function of the olfactory neurons. (35)
The central involvement theory is supported by studies conducted in mouse models that have demonstrated the penetration of SARS-CoV trans-neuronally through the olfactory bulb and the rapid spread of the virus in connected areas of the brain. The authors demonstrated an important presence of SARS-CoV at 60–66 h after infection in the olfactory bulb and subsequently in the regions of the brainstem (midbrain–dorsal raphe), of the thalamus, of the basal ganglia (globus pallidus, ventral and lateral preoptic regions), and of the cortex (piriform and infralimbic cortex), connected to the olfactory bulb. These authors, detecting any signs of inflammatory infiltration, hypothesized that neuronal death occurs due to a cytokine storm, in particular IL-6, produced by neurons under stimulation of the viral N spikes. (36)
The data collected in this study demonstrate a close correlation between the levels of IL-6 and the trend of taste and smell dysfunctions: the reduction of disturbances is accompanied by a progressive reduction of IL-6 levels, which return to normal values when the disturbances disappear.
The improvement of the sensory functions over time would suggest the action of local inflammatory phenomena on the receptors of the olfactory and gustatory cells, rather than permanent cellular damage linked to the action of the virus.
The dysfunctions might be linked to peripheral action of the IL-6 at the level of cell receptors infected by the virus and to central action of IL-6 at the level of intermediate stations of taste and olfactory pathways, especially in the thalamus. In fact, at the thalamic level, both the gustatory path (posteromedial ventral nucleus) and the olfactory path (dorsomedial nucleus, that intervenes in the conscious analysis of odors) converge. These centers are close to the hypothalamus, where the thermoregulatory center, target of IL-6, resides. The transient increase in IL-6 produced by microglial cells and astrocytes in the olfactory bulb and other areas of the central nervous system during this infection could justify the progress of these disorders.
In addition, recent studies have shown that taste cells produce, in response to inflammatory stimuli, high levels of various molecules associated with internal defense responses, including multiple inflammatory cytokines. Excessive production of inflammatory cytokines can cause cell death and inhibit cell renewal in the taste buds, which can contribute to the development of taste disorders associated with various diseases, also due to the paracrine activity of some inflammatory mediators, especially if sepsis occurs. (37−39)
Due to these references and the data obtained, it could be hypothesized that in the pathogenesis of taste and smell dysfunctions, not fully clarified, a key role is played by IL-6, the main cytokine of the inflammatory cascade, with central and peripheral action.
Several papers suggest that sensory dysfunctions in COVID-19 patients are linked to viral damage to neuronal cells or to a central nervous system ischemic injury. Such mechanisms would result in a longer recovery time for these functions. (40,41)
On the contrary, this study has shown that the recovery times are shorter than those of possible neurological or ischemic damage and that the recovery of these functions is accompanied by the simultaneous swab negativization and by the return to normal of the levels of IL- 6.
To date, COVID-19 remains an important medical and social issue (42) that requires several translational studies to fully understand its molecular bases and to define correct and effective therapy protocols. In fact, we are continuously understanding the main mechanisms of this multifaceted condition, but we do not know its direct and indirect long-term sequelae; also several hypotheses have been proposed about this matter and especially for neurologic, (43,44) nutritional, (45) immunological (46,47) and cardiovascular consequences. (48,49)

Methods

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This observational study was conducted from March 1 to May 31, 2020, following the provisions of the Declaration of Helsinki. The study was approved by the Ethics committee of the AOU Policlinico Consorziale di Bari (Italy) (No. 6388 COVID19 DOM - protocol number 0034687/12-05-2020) and written informed consent was obtained.
Of 125 patients admitted at COVID hospital of Policlinico, University of Bari, with smell or taste dysfunction or both at onset of disease, 67 (45 men and 22 women) fulfilled the inclusion criteria, while 58 were excluded (35 because of required intensive care admission, 5 who were unable to answer, 5 who died, 7 who had finished chemotherapy recently, and 5 who refused to participate). Inclusion and exclusion criteria are reported in Table 1. Therefore, we mainly included mild to moderate COVID-19 patients, who did not require intensive care admission.
The survey, submitted to each patient, consisted of two parts: the first, for health care professionals, included general questions (age, sex, residence, work activity) and the presence of systemic diseases (hypertension, diabetes, and gastrointestinal and thyroid pathologies) and local diseases (nasal septum deviation); the second, for the patient, investigated taste dysfunctions with 11 questions and smell dysfunctions with 13 questions upon entry and after swab negativization.
The survey examined the onset of associated symptoms concerning the appearance of olfactory and gustatory dysfunctions, timing of the dysfunction (time of onset and duration of the disorder), and the extent of the alteration. Sinonasal outcome test 22 (SNOT-22) was used as a reference for olfactory function assessment. (29) SNOT-22 classified the severity of symptoms as none (0), very mild (1), mild or light (2), moderate (3), severe (4), or bad (5).
Taste and Smell Questionnaire Section (CSQ) of the US NHANES 2011–2014 protocol (CDC 2013b) was used as reference for gustatory function assessment, (30) and the severity of symptoms was classified using the scores none (0), very mild (1), mild or light (2), moderate (3), severe (4), or bad (5). In the presence of the association of both symptoms, severity was classified using the scores none (0), very mild (1), mild or light (2), moderate (3), severe (4), or bad (5).
A venous blood sample was taken for each patient to measure IL-6 levels upon entry and at swab negativization. The sample was collected in 5 mL Vacutainer tubes without anticoagulants. Blood samples were centrifuged (1000 × g, 15 min, 4 °C), and the serum was removed and immediately stored at −80 °C until analysis. The IL-6 assay was performed with the chemiluminescence assay using Cobas e801 (Roche Instrumentation).

Statistical Analysis

All analyses were performed using R, version 3.53 (R Foundation for Statistical Computing). The variables age, sex, symptom associated, and olfactory and taste disorders are reported in numerals and percentages of the total. The delta score (value at the first evaluation minus value at the second evaluation) has been calculated for the following parameters: IL-6 levels and olfactory and taste dysfunction scores, obtained from the questionnaires administered at the first and the second evaluation. Descriptive statistics for quantitative variables are given as the mean ± SD.
The statistical analysis of differences between the first evaluation and the second evaluation for the parameters IL-6 level and olfactory and taste disease was performed using nonparametric tests (Wilcoxon signed-rank test). In order to evaluate the correlation between the delta IL-6 levels, the delta score of olfactory dysfunction, and the delta score taste dysfunction, Pearson’s linear correlation coefficient was applied. For all the tests used, a p-value threshold of 5% was adopted.

Conclusion

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This study based on clinical evidence and laboratory data highlighted the importance of IL-6 in the pathogenesis of chemosensitive disorders. Further studies would be necessary to investigate any other mechanisms of action of IL-6 both in the appearance of taste or smell disturbances and in the clinical manifestations of COVID-19 patients in order to ensure better clinical and pharmacological management of these patients.

Author Information

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  • Corresponding Author
  • Authors
    • Angela P. Cazzolla - Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
    • Roberto Lovero - AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
    • Lorenzo Lo Muzio - Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
    • Nunzio F. Testa - Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
    • Annalisa Schirinzi - AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
    • Giuseppe Palmieri - Private practice, Bari 70124, Italy
    • Pietro Pozzessere - AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Emergency Medicine and Surgery Unit, Bari 70124, Italy
    • Vito Procacci - AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Emergency Medicine and Surgery Unit, Bari 70124, Italy
    • Mariasevera Di Comite - Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Human Anatomy Section, Università degli Studi di Bari, Bari 70124, Italy
    • Domenico Ciavarella - Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia 71122, Italy
    • Maria Pepe - AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
    • Caterina De Ruvo - Maugeri Clinical Research Institutes IRCCS of Bari, Bari 70124, Italy
    • Vito Crincoli - Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Human Anatomy Section, Università degli Studi di Bari, Bari 70124, Italy
    • Francesca Di Serio - AOU Policlinico Consorziale di Bari - Ospedale Giovanni XXIII, Clinical Pathology Unit, Bari 70124, Italy
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors express their gratitude to Santomauro Silvana, RN, for her dedication to the patients and in performing nasal swabs to them and to Paparella Vincenzo, the photographer that helped to create the TOC of this manuscript for free.

References

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This article references 49 other publications.

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    Epidemiology, virology, and clinical features of severe acute respiratory syndrome -coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19)
    Park Su Eun
    Clinical and experimental pediatrics (2020), 63 (4), 119-124 ISSN:.
    A cluster of severe pneumonia of unknown etiology in Wuhan City, Hubei province in China emerged in December 2019. A novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was isolated from lower respiratory tract sample as the causative agent. The current outbreak of infections with SARS-CoV-2 is termed Coronavirus Disease 2019 (COVID-19) by the World Health Organization (WHO). COVID-19 rapidly spread into at least 114 countries and killed more than 4,000 people by March 11 2020. WHO officially declared COVID-19 a pandemic on March 11, 2020. There have been 2 novel coronavirus outbreaks in the past 2 decades. The outbreak of severe acute respiratory syndrome (SARS) in 2002-2003 caused by SARS-CoV had a case fatality rate of around 10% (8,098 confirmed cases and 774 deaths), while Middle East respiratory syndrome (MERS) caused by MERSCoV killed 861 people out of a total 2,502 confirmed cases between 2012 and 2019. The purpose of this review is to summarize known-to-date information about SARS-CoV-2, transmission of SARS-CoV-2, and clinical features.
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  2. 2
    Mousavizadeh, L. and Ghasemi, S. (2020) Genotype and phenotype of COVID-19: Their roles in pathogenesis. J. Microbiol Immunol Infect.  DOI: 10.1016/j.jmii.2020.03.022
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    Zou, X., Chen, K., Zou, J., Han, P., Hao, J., and Han, Z. (2020) Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 14 (2), 185– 192,  DOI: 10.1007/s11684-020-0754-0
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    Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection
    Zou Xin; Chen Ke; Zou Jiawei; Hao Jie; Han Zeguang; Han Peiyi
    Frontiers of medicine (2020), 14 (2), 185-192 ISSN:.
    It has been known that, the novel coronavirus, 2019-nCoV, which is considered similar to SARS-CoV, invades human cells via the receptor angiotensin converting enzyme II (ACE2). Moreover, lung cells that have ACE2 expression may be the main target cells during 2019-nCoV infection. However, some patients also exhibit non-respiratory symptoms, such as kidney failure, implying that 2019-nCoV could also invade other organs. To construct a risk map of different human organs, we analyzed the single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems, including the respiratory, cardiovascular, digestive, and urinary systems. Through scRNA-seq data analyses, we identified the organs at risk, such as lung, heart, esophagus, kidney, bladder, and ileum, and located specific cell types (i.e., type II alveolar cells (AT2), myocardial cells, proximal tubule cells of the kidney, ileum and esophagus epithelial cells, and bladder urothelial cells), which are vulnerable to 2019-nCoV infection. Based on the findings, we constructed a risk map indicating the vulnerability of different organs to 2019-nCoV infection. This study may provide potential clues for further investigation of the pathogenesis and route of 2019-nCoV infection.
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    Zhang, H., Kang, Z., Gong, H., Xu, D., Wang, J., Li, Z., Cui, X., Xiao, J., Meng, T., Zhou, W., Liu, J., and Xu, H. (2020) The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv,  DOI: 10.1101/2020.01.30.927806 (Available at https://www.biorxiv.org/content/10.1101/2020.01.30.927806v1, last accessed June 30, 2020).
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    Baig, A. M., Khaleeq, A., Ali, U., and Syeda, H. (2020) Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host–virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci. 11 (7), 995– 998,  DOI: 10.1021/acschemneuro.0c00122
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    5
    Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms
    Baig, Abdul Mannan; Khaleeq, Areeba; Ali, Usman; Syeda, Hira
    ACS Chemical Neuroscience (2020), 11 (7), 995-998CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    A review. The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and a scare of an epic proportion related to its potential to spread and infect the humans' globe wide. As we are in the midst of an ongoing near pandemic outbreak of the COVID-19, the scientists are struggling to understand how it resembles and varies with the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreaks, it has been shown that like SARS-CoV, the COVID-19 exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurol. tissue and the possible contribution of neurol. tissues damages to the morbidity and mortality of COIVD-19. Here, we investigate the d. of the expression levels of ACE2 in the CNS, the host-virus interaction and relate it to the pathogenesis and complications seen in the recent cases of COVID-19 outbreak. Also, we debate the need for a model of staging COVID-19 based on neurol. tissue involvement.
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  6. 6
    Xu, H., Zhong, L., Deng, J., Peng, J., Dan, H., Zeng, X., Li, T., and Chen, Q. (2020) High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral Sci. 12 (1), 8,  DOI: 10.1038/s41368-020-0074-x
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    High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa
    Xu, Hao; Zhong, Liang; Deng, Jiaxin; Peng, Jiakuan; Dan, Hongxia; Zeng, Xin; Li, Taiwen; Chen, Qianming
    International Journal of Oral Science (2020), 12 (1), 8CODEN: IJOSFA; ISSN:2049-3169. (Nature Research)
    It has been reported that ACE2 is the main host cell receptor of 2019-nCoV and plays a crucial role in the entry of virus into the cell to cause the final infection. To investigate the potential route of 2019-nCov infection on the mucosa of oral cavity, bulk RNA-seq profiles from two public databases including The Cancer Genome Atlas (TCGA) and Functional Annotation of The Mammalian Genome Cap Anal. of Gene Expression (FANTOM5 CAGE) dataset were collected. RNA-seq profiling data of 13 organ types with para-carcinoma normal tissues from TCGA and 14 organ types with normal tissues from FANTOM5 CAGE were analyzed in order to explore and validate the expression of ACE2 on the mucosa of oral cavity. Further, single-cell transcriptomes from an independent data generated inhouse were used to identify and confirm the ACE2-expressing cell compn. and proportion in oral cavity. The results demonstrated that the ACE2 expressed on the mucosa of oral cavity. Interestingly, this receptor was highly enriched in epithelial cells of tongue. Preliminarily, those findings have explained the basic mechanism that the oral cavity is a potentially high risk for 2019-nCoV infectious susceptibility and provided a piece of evidence for the future prevention strategy in dental clin. practice as well as daily life.
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  7. 7
    Sungnak, W., Huang, N., Bécavin, C., Berg, M., Queen, R., Litvinukova, M., Talavera-López, C., Maatz, H., Reichart, D., Sampaziotis, F., Worlock, K. B., Yoshida, M., and Barnes, J. L. (2020) HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat. Med. 26 (5), 681– 687,  DOI: 10.1038/s41591-020-0868-6
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    7
    SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes
    Sungnak, Waradon; Huang, Ni; Becavin, Christophe; Berg, Marijn; Queen, Rachel; Litvinukova, Monika; Talavera-Lopez, Carlos; Maatz, Henrike; Reichart, Daniel; Sampaziotis, Fotios; Worlock, Kaylee B.; Yoshida, Masahiro; Barnes, Josephine L.; HCA Lung Biological Network
    Nature Medicine (New York, NY, United States) (2020), 26 (5), 681-687CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
    We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-assocd. genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells' potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clin. samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.
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    Santacroce, L., Charitos, I. A., and Del Prete, R. (2020) COVID-19 in Italy: An Overview from the First Case to Date. Electron J. Gen Med. 17 (6), em235  DOI: 10.29333/ejgm/7926
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    Passarelli, P. C., Lopez, M. A., Mastandrea Bonaviri, G. N., Garcia-Godoy, F., and D’Addona, A. (2020) Taste and smell as chemosensory dysfunctions in COVID-19 infection. Am. J. Dent. 33 (3), 135– 137
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    Taste and smell as chemosensory dysfunctions in COVID-19 infection
    Passarelli Pier Carmine; D'Addona Antonio; Lopez Michele Antonio; Mastandrea Bonaviri Giuseppe Niccolo; Garcia-Godoy Franklin; Garcia-Godoy Franklin
    American journal of dentistry (2020), 33 (3), 135-137 ISSN:0894-8275.
    PURPOSE: To review the literature on the presence of two clinical manifestations in patients presenting COVID-19 (SARS-CoV-2) infection: loss of taste (ageusia) and loss of smell (anosmia). METHODS: PubMed and EMBASE were searched and studies were selected starting from November, 2019 until April 2020; also, the references of the selected articles were evaluated for methodological quality. RESULTS: Of the 19 studies analyzed, five were included to evaluate the presence of ageusia and/or anosmia as symptoms in patients who were tested and resulted positive for the SARS-CoV-2 virus. In a total of 10,818 patients, 8,823 presented ageusia (81.6%; range 5.6%-88%) and 8,088 presented anosmia (74.8%; range 5.1-85.6%). Only one study recorded both symptoms with a percentage of 18.6%. CLINICAL SIGNIFICANCE: This systematic review demonstrated significant presence of ageusia and anosmia in the patients with COVID-19 infection. These symptoms may be considered as the first manifestation of the infection.
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    Milanetti, E., Miotto, M., Di Rienzo, L., Monti, M., Gosti, G., and Ruocco, G. (2020) In-Silico evidence for two receptors based strategy of SARS-CoV-2, bioRxiv  DOI: 10.1101/2020.03.24.006197 (Available at https://www.biorxiv.org/content/biorxiv/early/2020/04/06/2020.03.24.006197.full.pdf, last access June 30, 2020).
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    There is no corresponding record for this reference.
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    Witt, M. and Miller, I. J., Jr (1992) Comparative lectin histochemistry on taste buds in foliate, circumvallate and fungiform papillae of the rabbit tongue. Histochemistry 98 (3), 173– 182,  DOI: 10.1007/BF00315876
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    11
    Comparative lectin histochemistry on taste buds in foliate, circumvallate and fungiform papillae of the rabbit tongue
    Witt, M.; Miller, I. J., Jr.
    Histochemistry (1992), 98 (3), 173-82CODEN: HCMYAL; ISSN:0301-5564.
    Taste buds (TB) in the foliate, circumvallate and fungiform papillae of the rabbit tongue were examd. with lectin histochem. by means of light (LM) and electron (EM) microscopy. Biotin- and Au-labeled lectins were used for the detection of carbohydrate residues in TB cells and s.c. salivary glands. At the LM level, the lectins of soybean (SBA) and peanut (PNA) react with material of the foliate and circumvallate taste pores only after pretreatment of the section with neuraminidase. This indicates that the terminal trisaccharide sequences are as follows: Sialic acid-Gal-GalNAc in O-glycosylated glycoproteins or Sialic acid-Gal-GlcNAc in N-glycosylated glycoproteins. In fungiform taste buds the lectins of Dolichos biflorus (DBA) and Helix pomatia (HPA), also specific to GalNAc residues, are reactive without preincubation with neuraminidase. Wheat germ agglutinin (WGA), specific to GlcNAc, reacts with TBs of all papillae; and the lectin from Ulex europaeus (UEA I), specific to fucose binds to individual TB cells. The presence of sialic acid may protect mucus or other glycoproteins in TB cells and inside the taste pore from premature enzymic degrdn. In a post-embedding EM procedure on LR-White-embedded tissue sections, only Au-labeled HPA was found to bind esp. on membrane surfaces of the microvilli which protrude into the taste pore; however, HPA did not bind to the electron-dense mucus inside the taste pore. The mucus situated in the trough and at the top of the adjacent epithelial cells also is strongly HPA-pos., but is of different origin and compn. than that found in the taste pore. These results demonstrate distinct carbohydrate histochem. differences between fungiform and circumvallate/foliate taste buds. The different configuration of galactosyl residues and the occurrence of mannose in circumvallate and foliate TBs imply that the lectin reactivities of TBs are not only due to the presence of mucins, but also to N-linked glycoproteins, possibly with a hormonelike, paraneuronal function. A possible relationship to von Ebner glands in these papillae is discussed.
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  12. 12
    Pushpass, R. G., Pellicciotta, N., Kelly, C., Proctor, G., and Carpenter, G. H. (2019) Reduced Salivary Mucin Binding and Glycosylation in Older Adults Influences Taste in an In Vitro Cell Model. Nutrients 11 (10), 2280,  DOI: 10.3390/nu11102280
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    12
    Reduced salivary mucin binding and glycosylation in older adults influences taste in an in vitro cell model
    Pushpass, Rose-Anna G.; Pellicciotta, Nicola; Kelly, Charles; Proctor, Gordon; Carpenter, Guy H.
    Nutrients (2019), 11 (10), 2280CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
    Background: Taste loss is a significant problem in older adults, affecting quality of life and nutrition. Altered salivary rheol. and loss of mucin function may contribute to taste loss by reducing mucosal defences in the oral cavity, impairing sensitivity to oral stimulants. This study aimed to investigate the effects of salivary rheol. on taste loss in ageing. Salivary mucin glycosylation and binding to the oral epithelium was investigated in older and younger adults. A cell-based model was utilized to consider the role of saliva in taste loss. Methods: Human subjects aged >60 years (n = 25) and 18-30 (n = 30) provided saliva samples which were analyzed for viscosity, mucin compn. and mucin binding to oral epithelial cells (TR146/MUC1). Oral epithelial cells (TR146/MUC1 and SCC090) provided models for taste receptor activation. Results: Reduced levels and sialylation of MUC7 were evident in saliva of older adults which may lead to reduced viscoelasticity, while viscosity is unaffected. Impaired muco-adhesion of saliva from older adults was also obsd. Saliva from older adults facilitated the bitter taste receptor activation less well than saliva from younger adults. The causes of taste dysfunction in older adults are unknown, but this study supports a role of saliva in facilitating the activation of taste receptors.
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    Deems, D. A., Doty, R. L., Settle, R. G., Moore-Gillon, V., Shaman, P., Mester, A. F., Kimmelman, C. P., Brightman, V. J., and Snow, J. B., Jr (1991) Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch. Otolaryngol., Head Neck Surg. 117 (5), 519– 528,  DOI: 10.1001/archotol.1991.01870170065015
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    13
    Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center
    Deems D A; Doty R L; Settle R G; Moore-Gillon V; Shaman P; Mester A F; Kimmelman C P; Brightman V J; Snow J B Jr
    Archives of otolaryngology--head & neck surgery (1991), 117 (5), 519-28 ISSN:0886-4470.
    Smell and taste disorders are common in the general population, yet little is known about their nature or cause. This article describes a study of 750 patients with complaints of abnormal smell or taste perception from the University of Pennsylvania Smell and Taste Center, Philadelphia. Major findings suggest that: chemosensory dysfunction influences quality of life; complaints of taste loss usually reflect loss of smell function; upper respiratory infection, head trauma, and chronic nasal and paranasal sinus disease are the most common causes of the diminution of the sense of smell, with head trauma having the greatest loss; depression frequently accompanies chemosensory distortion; low body weight accompanies burning mouth syndrome; estrogens protect against loss of the sense of smell in postmenopausal women; zinc therapy may provide no benefit to patients with chemosensory dysfunction; and thyroid hormone function is associated with oral sensory distortion. The findings are discussed in relation to management of patients with chemosensory disturbances.
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    Prescott, J. (2012) Multimodal chemosensory interactions and perception of flavor, in The Neural Bases of Multisensory Processes (Murray, M. M., and Wallace, M. T., Eds.), CRC Press/Taylor & Francis, Boca Raton FL.
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    Dubé, M., Le Coupanec, A., Wong, A. H., Rini, J. M., Desforges, M., and Talbot, P. J. (2018) Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J. Virol. 92 (17), e00404-18  DOI: 10.1128/JVI.00404-18
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    Koyuncu, O. O., Hogue, I. B., and Enquist, L. W. (2013) Virus infections in the nervous system. Cell Host Microbe 13 (4), 379– 393,  DOI: 10.1016/j.chom.2013.03.010
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    Virus Infections in the Nervous System
    Koyuncu, Orkide O.; Hogue, Ian B.; Enquist, Lynn W.
    Cell Host & Microbe (2013), 13 (4), 379-393CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
    A review. Virus infections usually begin in peripheral tissues and can invade the mammalian nervous system (NS), spreading into the peripheral (PNS) and more rarely the central (CNS) nervous systems. The CNS is protected from most virus infections by effective immune responses and multilayer barriers. However, some viruses enter the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathol. Most viruses in the NS are opportunistic or accidental pathogens, but a few, most notably the alpha herpesviruses and rabies virus, have evolved to enter the NS efficiently and exploit neuronal cell biol. Remarkably, the alpha herpesviruses can establish quiescent infections in the PNS, with rare but often fatal CNS pathol. Here we review how viruses gain access to and spread in the well-protected CNS, with particular emphasis on alpha herpesviruses, which establish and maintain persistent NS infections.
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    Desforges, M., Le Coupanec, A., Dubeau, P., Bourgouin, A., Lajoie, L., Dubé, M., and Talbot, P. J. (2020) Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?. Viruses 12 (1), 14,  DOI: 10.3390/v12010014
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    Zhou, G., Chen, S., and Chen, Z. (2020) Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies. Front Med. 14 (2), 117– 125,  DOI: 10.1007/s11684-020-0773-x
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    Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies
    Zhou Guangbiao; Chen Saijuan; Chen Zhu
    Frontiers of medicine (2020), 14 (2), 117-125 ISSN:.
    Since the outbreak of the COVID-19 pandemic in early December 2019, 81 174 confirmed cases and 3242 deaths have been reported in China as of March 19, 2020. The Chinese people and government have contributed huge efforts to combat this disease, resulting in significant improvement of the situation, with 58 new cases (34 were imported cases) and 11 new deaths reported on March 19, 2020. However, as of March 19, 2020, the COVID-19 pandemic continues to develop in 167 countries/territories outside of China, and 128 665 confirmed cases and 5536 deaths have been reported, with 16 498 new cases and 817 new deaths occurring in last 24 hours. Therefore, the world should work together to fight against this pandemic. Here, we review the recent advances in COVID-19, including the insights in the virus, the responses of the host cells, the cytokine release syndrome, and the therapeutic approaches to inhibit the virus and alleviate the cytokine storm. By sharing knowledge and deepening our understanding of the virus and the disease pathogenesis, we believe that the community can efficiently develop effective vaccines and drugs, and the mankind will eventually win this battle against this pandemic.
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    Wan, S., Yi, Q., Fan, S., Lv, J., Zhang, X., Guo, L., Lang, C., Xiao, Q., Xiao, K., Yi, Z., Qiang, M., Xiang, J., Zhang, B., and Chen, Y. (2020) Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP), MedRxiv  DOI: 10.1101/2020.02.10.20021832 (Available at https://www.medrxiv.org/content/10.1101/2020.02.10.20021832v1, last accessed June 30, 2020).
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    Tanaka, T., Narazaki, M., and Kishimoto, T. (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspect. Biol. 6 (10), a016295  DOI: 10.1101/cshperspect.a016295
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    Henkin, R. I., Schmidt, L., and Velicu, I. (2013) Interleukin 6 in hyposmia. JAMA Otolaryngol Head Neck Surg. 139 (7), 728– 34,  DOI: 10.1001/jamaoto.2013.3392
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    Interleukin 6 in hyposmia
    Henkin Robert I; Schmidt Loren; Velicu Irina
    JAMA otolaryngology-- head & neck surgery (2013), 139 (7), 728-34 ISSN:.
    IMPORTANCE: Olfaction is a complex sensory process that has not been fully studied. Elevated plasma levels of interleukin 6 (IL-6) have been found in patients with several acute and chronic diseases but have not been reported in patients with smell loss (hyposmia). OBJECTIVE: To determine IL-6 levels in patients with hyposmia. DESIGN: Retrospective study. All measurements were made without reference to the origin of any collected sample. SETTING An ambulatory private practice at The Taste and Smell Clinic in Washington, DC. PARTICIPANTS: Fifty-nine consecutive patients who presented to the clinic between 2005 and 2008 for evaluation and treatment of various degrees of hyposmia were studied. Nine volunteers with normal sensory function served as controls. MAIN OUTCOMES AND MEASURES: Levels of IL-6 were measured in samples of plasma, urine, saliva, and nasal mucus. RESULTS: All biological fluid samples studied contained IL-6. Mean (SEM) levels in plasma, saliva, and nasal mucus in patients were significantly higher than in controls (0.95 [0.10] vs 0.12 [0.03] pg/mL, 0.57 [0.05] vs 0.30 [0.01] pg/mL, and 29.7 [3.8] vs 11.6 [0.5] pg/mL, respectively; all P < .001). The concentration of IL-6 in nasal mucus in patients was significantly higher than in controls and was more than 30 times higher than in any other biological fluid. Mean (SEM) levels in urine were not significantly different: 0.92 (0.17) pg/mL for patients and 1.26 (0.41) pg/mL for controls (P > .50). CONCLUSIONS AND RELEVANCE: Compared with controls, IL-6 in patients was significantly elevated in plasma, saliva, and nasal mucus. Because IL-6 is a proinflammatory cytokine, these changes can relate to local or systemic inflammatory processes, which can be a cause or a result of pathological processes associated with hyposmia. These results support the concept that hyposmia has a biochemical basis and IL-6 may play a role in biochemical pathological processes underlying hyposmia and its treatment.
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    Mori, I. (2018) 1918 H1N1 Influenza Virus Infection–Induced Proinflammatory Cytokines in the Olfactory Bulb Could Trigger Lethargic Disease. J. Infect. Dis. 218 (10), 1686– 1687,  DOI: 10.1093/infdis/jiy380
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    1918 H1N1 Influenza Virus Infection-Induced Proinflammatory Cytokines in the Olfactory Bulb Could Trigger Lethargic Disease
    Mori Isamu
    The Journal of infectious diseases (2018), 218 (10), 1686-1687 ISSN:.
    There is no expanded citation for this reference.
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    de Wit, E., Siegers, J. Y., Cronin, J. M., Weatherman, S., van den Brand, J. M., Leijten, L. M., van Run, P., Begeman, L., van den Ham, H. J., Andeweg, A. C., Bushmaker, T., Scott, D. P., Saturday, G., Munster, V. J., Feldmann, H., and van Riel, D. (2018) 1918 H1N1 influenza virus replicates and induces proinflammatory cytokine responses in extrarespiratory tissues of ferrets. J. Infect. Dis. 217 (8), 1237– 1246,  DOI: 10.1093/infdis/jiy003
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    1918 H1N1 influenza virus replicates and induces proinflammatory cytokine responses in extrarespiratory tissues of ferrets
    de Wit, Emmie; Siegers, Jurre Y.; Cronin, Jacqueline M.; Weatherman, Sarah; van den Brand, Judith M.; Leijten, Lonneke M.; van Run, Peter; Begeman, Lineke; van den Ham, Henk-Jan; Andeweg, Arno C.; Bushmaker, Trenton; Scott, Dana P.; Saturday, Greg; Munster, Vincent J.; Feldmann, Heinz; van Riel, Debby
    Journal of Infectious Diseases (2018), 217 (8), 1237-1246CODEN: JIDIAQ; ISSN:1537-6613. (Oxford University Press)
    The 1918 Spanish H1N1 influenza pandemic was the most severe recorded influenza pandemic with an estd. 20-50 million deaths worldwide. Even though it is known that influenza viruses can cause extrarespiratory tract complications-which are often severe or even fatal-the potential contribution of extrarespiratory tissues to the pathogenesis of 1918 H1N1 virus infection has not been studied comprehensively. Here, we performed a time-course study in ferrets inoculated intranasally with 1918 H1N1 influenza virus, with special emphasis on the involvement of extrarespiratory tissues. Respiratory and extrarespiratory tissues were collected after inoculation for virol., histol., and immunol. anal. Infectious virus was detected at high titers in respiratory tissues and, at lower titers in most extrarespiratory tissues. Evidence for active virus replication, as indicated by the detection of nucleoprotein by immunohistochem., was obsd. in the respiratory tract, peripheral and central nervous system, and liver. Proinflammatory cytokines were up-regulated in respiratory tissues, olfactory bulb, spinal cord, liver, heart, and pancreas. Conclusions. 1918 H1N1 virus spread to and induced cytokine responses in tissues outside the respiratory tract, which likely contributed to the severity of infection. Moreover, our data support the suggested link between 1918 H1N1 infection and central nervous system disease.
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    De Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J., Chau, T. N., Hoang, D. M., Van Vinh Chau, N., Khanh, T. H., Dong, V. C., Qui, P. T., Van Cam, B., Ha, D. Q., Guan, Y., Peiris, J. S., Chinh, N. T., Hien, T. T., and Farrar, J. (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12 (10), 1203– 1207,  DOI: 10.1038/nm1477
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    Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia
    de Jong, Menno D.; Simmons, Cameron P.; Thanh, Tran Tan; Hien, Vo Minh; Smith, Gavin J. D.; Chau, Tran Nguyen Bich; Hoang, Dang Minh; Nguyen, Van Vinh Chau; Khanh, Truong Huu; Dong, Vo Cong; Qui, Phan Tu; Van Cam, Bach; Ha, Do Quang; Guan, Yi; Peiris, J. S. Malik; Chinh, Nguyen Tran; Hien, Tran Tinh; Farrar, Jeremy
    Nature Medicine (New York, NY, United States) (2006), 12 (10), 1203-1207CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Lab. expts. suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, the authors performed virol. and immunol. studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was assocd. with higher pharyngeal viral loads. The authors obsd. low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex assocd. with mammalian adaptation and virulence. The authors' observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clin. management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.
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    Hanisch, U. K. (2002) Microglia as a source and target of cytokines. Glia. 40 (2), 140– 155,  DOI: 10.1002/glia.10161
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    Microglia as a source and target of cytokines
    Hanisch Uwe-Karsten
    Glia (2002), 40 (2), 140-55 ISSN:0894-1491.
    Cytokines constitute a significant portion of the immuno- and neuromodulatory messengers that can be released by activated microglia. By virtue of potent effects on resident and invading cells, microglial cyto- and chemokines regulate innate defense mechanisms, help the initiation and influence the type of immune responses, participate in the recruitment of leukocytes to the CNS, and support attempts of tissue repair and recovery. Microglia can also receive cyto- and chemokine signals as part of auto- and paracrine communications with astrocytes, neurons, the endothelium, and leukocyte infiltrates. Strong responses and modulatory influences can be demonstrated, adding to the emerging view that microglial behavior is highly dependent on the (cytokine) environment and that reactions to a challenge may vary with the stimulation context. In principle, microglial activation aims at CNS protection. However, failed microglial engagement due to excessive or sustained activation could significantly contribute to acute and chronic neuropathologies. Dysregulation of microglial cytokine production could thereby promote harmful actions of the defense mechanisms, result in direct neurotoxicity, as well as disturb neural cell functions as they are sensitive to cytokine signaling.
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    Frei, K., Malipiero, U. V., Leist, T. P., Zinkernagel, R. M., Schwab, M. E., and Fontana, A. (1989) On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur. J. Immunol. 19 (4), 689– 694,  DOI: 10.1002/eji.1830190418
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    On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases
    Frei, Karl; Malipiero, Ursula V.; Leist, Thomas P.; Zinkernagel, Rolf M.; Schwab, Martin E.; Fontana, Adriano
    European Journal of Immunology (1989), 19 (4), 689-94CODEN: EJIMAF; ISSN:0014-2980.
    Interleukin 6 (IL6) was in the central nervous system (CNS) of ICR +/+ mice infected with lymphocytic choriomeningitis virus (LCMV) or with vesicular stomatitis virus (VSV). When infecting athymic ICR nu/nu mice which cannot develop T cell-mediated meningitis after LCMV infection, no synthesis of IL6 was detected in the CNS. IL6 was produced intrathecally in ICR nu/nu mice infected with VSV, which causes a T cell-independent acute encephalitis. This suggested that IL6 may also originate from cells not belonging to the T cell compartment. In vitro assays showed that both virus-infected microglial cells and astrocytes secreted IL6. In addn. to its effect on the development of B cell immunity in the brain, IL 6 may be involved in repair mechanisms initiated in the course of viral-induced tissue damage. IL6 induced an increase of the secretion of a neurotrophic factor, nerve growth factor, by astrocytes. The intrathecal synthesis of IL6 may be part of the host response to infection favoring immune-mediated elimination of the infectious agent as well as trophic support for neurons.
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    Righi, M., Mori, L., De Libero, G., Sironi, M., Biondi, A., Mantovani, A., Donini, S. D., and Ricciardi-Castagnoli, P. (1989) Monokine production by microglial cell clones. Eur. J. Immunol. 19 (8), 1443– 1448,  DOI: 10.1002/eji.1830190815
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    Monokine production by microglial cell clones
    Righi, Marco; Mori, Lucia; De Libero, Gennaro; Sironi, Marina; Biondi, Andrea; Mantovani, Alberto; Donini, Suzanne Denis; Ricciardi-Castagnoli, Paola
    European Journal of Immunology (1989), 19 (8), 1443-8CODEN: EJIMAF; ISSN:0014-2980.
    Cytokines have been suggested to act as intermediates between the immune and the central nervous system, but little is known about the type of cells synthesizing them in the brain. Primary brain cell cultures from mouse embryos were immortalized with oncogenic retroviruses and clones of microglial cells were generated that have been characterized. Three of the clones studied produce interleukin 1 (IL1), IL6, and tumor necrosis factor-α as assessed by biol. assays and by Northern blot anal. These data raise the question on the role of these cytokines in the brain and suggest that early resident microglial cells might play an important role in developmental processes and in the adult brain.
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    Bilinska, K. and Butowt, R. (2020) Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism. ACS Chem. Neurosci. 11, 2152,  DOI: 10.1021/acschemneuro.0c00406
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    Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism
    Bilinska, Katarzyna; Butowt, Rafal
    ACS Chemical Neuroscience (2020), 11 (15), 2152-2155CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    A review. It has become clear since the pandemic broke out that SARS-CoV-2 virus causes redn. of smell and taste in a significant fraction of COVID-19 patients. The olfactory dysfunction often occurs early in the course of the disease, and sometimes it is the only symptom in otherwise asymptomatic carriers. The cellular mechanisms for these specific olfactory disturbances in COVID-19 are now beginning to be elucidated. Several very recent papers contributed to explaining the key cellular steps occurring in the olfactory epithelium leading to anosmia/hyposmia (collectively known as dysosmia) initiated by SARS-CoV-2 infection. In this Viewpoint, we discuss current progress in research on olfactory dysfunction in COVID-19 and we also propose an updated model of the SARS-CoV-2-induced dysosmia. The emerging central role of sustentacular cells and inflammatory processes in the olfactory epithelium are particularly considered. The proposed model of anosmia in COVID-19 does not answer unequivocally whether the new coronavirus exploits the olfactory route to rapidly or slowly reach the brain in COVID-19 patients. To answer this question, new systematic studies using an infectious virus and appropriate animal models are needed.
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    Hopkins, C., Gillett, S., Slack, R., Lund, V. J., and Browne, J. P. (2009) Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 34 (5), 447– 454,  DOI: 10.1111/j.1749-4486.2009.01995.x
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    Psychometric validity of the 22-item Sinonasal Outcome Test
    Hopkins C; Gillett S; Slack R; Lund V J; Browne J P
    Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery (2009), 34 (5), 447-54 ISSN:.
    OBJECTIVES: We set out to determine the psychometric validation of a disease-specific health related quality of life instrument for use in chronic rhinosinusitis, the 22 item Sinonasal Outcome Test (SNOT-22), a modification of a pre-existing instrument, the SNOT-20. DESIGN, SETTING AND PARTICIPANTS: The National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis was a prospective cohort study collecting data on 3128 adult patients undergoing sinonasal surgery in 87 NHS hospitals in England and Wales. Data were collected preoperatively and at 3 months after surgery, and analysed to determine validity of the SNOT-22. Test-retest reliability was assessed in a separate cohort of patients in a single centre. MAIN OUTCOME MEASURES: The SNOT-22, a derivative of the SNOT-20 was the main outcome measure. Patients were also asked to report whether they felt better, the same or worse following surgery. To evaluate the SNOT-22, the internal consistency, responsiveness, known group differences and validity were analysed. RESULTS: Preoperative SNOT-22 scores were completed by 2803 patients. 3-month postoperative SNOT-22 scores were available for 2284 patients of all patients who completed a preoperative form (81.5% response rate). The Cronbach's alpha scores for the SNOT-22 were 0.91 indicating high internal consistency. The test-retest reliability coefficient was 0.93, indicating high reliability of repeated measures. The SNOT-22 was able to discriminate between patients known to suffer with chronic rhinosinusitis and a group of healthy controls (P < 0.0001, t = 85.3). It was also able to identify statistically significant differences in sub-groups of patients with chronic rhinosinusitis. There was a statistically significant (P < 0.0001, t = 39.94) decrease in patient reported SNOT-22 scores at 3 months. At 3 months the overall effect size in all patients was 0.81, which is considered large. We found the minimally important difference that is the smallest change in SNOT-22 score that can be detected by a patient, to be 8.9 points. CONCLUSIONS: We have found the SNOT-22 to be valid and easy to use. It can be used to facilitate routine clinical practice to highlight the impact of chronic rhinosinusitis on the patient's quality of life, and may also be used to measure the outcome of surgical intervention. The minimally important difference allows us to interpret scores in a clinical context, and may help to improve patient selection for surgery.
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    Rawal, S., Hoffman, H. J., Honda, M., Huedo-Medina, T. B., and Duffy, V. B. (2015) The Taste and Smell Protocol in the 2011–2014 US National Health and Nutrition Examination Survey (NHANES): Test-Retest Reliability and Validity Testing. Chemosens. Percept. 8 (3), 138– 148,  DOI: 10.1007/s12078-015-9194-7
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    The Taste and Smell Protocol in the 2011-2014 US National Health and Nutrition Examination Survey (NHANES): Test-Retest Reliability and Validity Testing
    Rawal Shristi; Honda Mallory; Huedo-Medin Tania B; Duffy Valerie B; Hoffman Howard J
    Chemosensory perception (2015), 8 (3), 138-148 ISSN:1936-5802.
    INTRODUCTION: The US NHANES 2011-2014 protocol includes a taste and smell questionnaire (CSQ) in home-based interviews and brief assessments in mobile exam centers. We report the short- and longer-term test-retest reliability and validity of this protocol against broader chemosensory measures. METHODS: A convenience sample of 73 adults (age=39.5±20.8 years) underwent the NHANES protocol at baseline, 2 weeks and 6 months. For taste, participants rated intensities of two tastants (1 M NaCl, 1 mM quinine) applied to the tongue tip and three tastants (1 M NaCl, 1 mM quinine, 0.32 M NaCl) sampled with the whole mouth. Smell function was assessed with a Pocket Smell Test® (PST; eight-item odor identification test). The CSQ asked about chemosensory problems, distortions, and age-related changes. Broader baseline measurements were a 40-item olfactometer-generated identification task and additional whole-mouth taste intensities (1 M sucrose, 32 mM citric acid, 3.2 mM propylthiouracil). RESULTS: Intraclass correlations (ICCs) for NHANES taste measures showed moderate-to-good agreement after 2 weeks and 6 months (ICCs 0.42-0.71). Whole-mouth quinine intensity was significantly correlated with other taste intensities, supporting its utility as a marker for overall taste functioning. Olfactory classification from PSTs agreed for 98.5 % of participants across 2 weeks (κ=0.85; 95 % CI 0.71-0.99) and had good correspondence with the olfactometer task. CSQ items showed good-to-excellent agreement over 6 months (ICCs 0.66-0.90). CONCLUSIONS: These findings further support that the NHANES chemosensory protocol has moderate-to-good test-retest reliability when administered to healthy, educated adults. Despite being a brief procedure with limited measures, the NHANES taste and smell assessments provided good information when compared to broader measures of taste and smell function.
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    Suzuki, M., Saito, K., Min, W. P., Vladau, C., Toida, K., Itoh, H., and Murakami, S. (2007) Identification of viruses in patients with postviral olfactory dysfunction. Laryngoscope 117 (2), 272– 277,  DOI: 10.1097/01.mlg.0000249922.37381.1e
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    Identification of viruses in patients with postviral olfactory dysfunction
    Suzuki Motohiko; Saito Koichi; Min Wei-Ping; Vladau Costin; Toida Kazunori; Itoh Hirotaka; Murakami Shingo
    The Laryngoscope (2007), 117 (2), 272-7 ISSN:0023-852X.
    OBJECTIVE: Causative viruses of postviral olfactory dysfunction (PVOD) have not yet been identified. The aim of this study was to investigate causative viruses in patients with PVOD. STUDY DESIGN AND METHODS: Nasal discharge was collected from 24 patients with PVOD. We investigated the presence of 10 viruses in nasal discharge and examined the time course, with regard to changes in olfactory dysfunction and nasal obstruction in patients with PVOD, using questionnaires, acoustic rhinometry, and olfactory tests. RESULTS: Rhinoviruses were detected in 10 patients by electrophoresis. Rhinoviruses were also confirmed in four patients by nucleotide sequences. Viral serotypes were identified to be human rhinovirus (HRV)-40, HRV-75, HRV-78, and HRV-80. One of the four patients complained of anosmia, whereas another complained of dysosmia. Olfactory testing did not show significant improvement at 4, 8, 11, and 24 weeks after the first visit in the four patients, although results of acoustic rhinometry significantly improved. Two of the four patients complained of olfactory dysfunction even 6 months after the first visit. Coronavirus and parainfluenza virus were detected in one patient each, and Epstein-Barr viruses were detected in three patients. CONCLUSIONS: This study for the first time detected rhinovirus, coronavirus, parainfluenza virus, and Epstein-Barr virus in nasal discharge of patients with PVOD. Furthermore, the present study suggests that rhinoviruses can cause olfactory dysfunction through mechanisms other than nasal obstruction and that rhinoviruses can induce various severities and different time courses of olfactory dysfunction.
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    Vaira, L. A., Deiana, G., Fois, A. G., Pirina, P., Madeddu, G., De Vito, A., Babudieri, S., Petrocelli, M., Serra, A., Bussu, F., Ligas, E., Salzano, G., and De Riu, G. (2020) Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases. Head Neck. 42 (6), 1252– 1258,  DOI: 10.1002/hed.26204
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    Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases
    Vaira Luigi Angelo; Ligas Enrica; De Riu Giacomo; Deiana Giovanna; Fois Alessandro Giuseppe; Pirina Pietro; Madeddu Giordano; De Vito Andrea; Babudieri Sergio; Petrocelli Marzia; Serra Antonello; Bussu Francesco; Salzano Giovanni
    Head & neck (2020), 42 (6), 1252-1258 ISSN:.
    BACKGROUND: The first European case series are detecting a very high frequency of chemosensitive disorders in COVID-19 patients, ranging between 19.4% and 88%. METHODS: Olfactory and gustatory function was objectively tested in 72 COVID-19 patients treated at University Hospital of Sassari. RESULTS: Overall, 73.6% of the patients reported having or having had chemosensitive disorders. Olfactory assessment showed variable degree hyposmia in 60 cases and anosmia in two patients. Gustatory assessment revealed hypogeusia in 33 cases and complete ageusia in one patient. Statistically significant differences in chemosensitive recovery were detected based on age and distance from the onset of clinical manifestations. CONCLUSION: Olfactory and gustatory dysfunctions represent common clinical findings in COVID-19 patients. Otolaryngologists and head-neck surgeons must by now keep this diagnostic option in mind when evaluating cases of ageusia and nonspecific anosmia that arose suddenly and are not associated with rhinitis symptoms.
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    Lechien, J. R., Chiesa-Estomba, C. M., De Siati, D. R., Horoi, M., Le Bon, S. D., Rodriguez, A., Dequanter, D., Blecic, S., El Afia, F., Distinguin, L., Chekkoury-Idrissi, Y., Hans, S., Delgado, I. L., Calvo-Henriquez, C., Lavigne, P., Falanga, C., Barillari, M. R., Cammaroto, G., Khalife, M., Leich, P., Souchay, C., Rossi, C., Journe, F., Hsieh, J., Edjlali, M., Carlier, R., Ris, L., Lovato, A., De Filippis, C., Coppee, F., Fakhry, N., Ayad, T., and Saussez, S. (2020) Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur. Arch Otorhinolaryngol. 277 (8), 2251– 2261,  DOI: 10.1007/s00405-020-05965-1
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    Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study
    Lechien Jerome R; Chiesa-Estomba Carlos M; De Siati Daniele R; El Afia Fahd; Distinguin Lea; Chekkoury-Idrissi Younes; Delgado Irene Lopez; Calvo-Henriquez Christian; Lavigne Philippe; Falanga Chiara; Barillari Maria Rosaria; Cammaroto Giovanni; Hsieh Julien; Fakhry Nicolas; Ayad Tareck; Saussez Sven; Lechien Jerome R; Journe Fabrice; Saussez Sven; Lechien Jerome R; El Afia Fahd; Distinguin Lea; Chekkoury-Idrissi Younes; Hans Stephane; Lechien Jerome R; Horoi Mihaela; Le Bon Serge D; Rodriguez Alexandra; Dequanter Didier; Saussez Sven; Chiesa-Estomba Carlos M; De Siati Daniele R; Blecic Serge; Delgado Irene Lopez; Calvo-Henriquez Christian; Lavigne Philippe; Ayad Tareck; Falanga Chiara; Barillari Maria Rosaria; Cammaroto Giovanni; Khalife Mohamad; Saussez Sven; Leich Pierre; Souchay Christel; Rossi Camelia; Hsieh Julien; Edjlali Myriam; Edjlali Myriam; Carlier Robert; Ris Laurence; Lovato Andrea; De Filippis Cosimo; Coppee Frederique; Fakhry Nicolas
    European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery (2020), 277 (8), 2251-2261 ISSN:.
    OBJECTIVE: To investigate the occurrence of olfactory and gustatory dysfunctions in patients with laboratory-confirmed COVID-19 infection. METHODS: Patients with laboratory-confirmed COVID-19 infection were recruited from 12 European hospitals. The following epidemiological and clinical outcomes have been studied: age, sex, ethnicity, comorbidities, and general and otolaryngological symptoms. Patients completed olfactory and gustatory questionnaires based on the smell and taste component of the National Health and Nutrition Examination Survey, and the short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS). RESULTS: A total of 417 mild-to-moderate COVID-19 patients completed the study (263 females). The most prevalent general symptoms consisted of cough, myalgia, and loss of appetite. Face pain and nasal obstruction were the most disease-related otolaryngological symptoms. 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders (p < 0.001). Olfactory dysfunction (OD) appeared before the other symptoms in 11.8% of cases. The sQO-NS scores were significantly lower in patients with anosmia compared with normosmic or hyposmic individuals (p = 0.001). Among the 18.2% of patients without nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0%. Females were significantly more affected by olfactory and gustatory dysfunctions than males (p = 0.001). CONCLUSION: Olfactory and gustatory disorders are prevalent symptoms in European COVID-19 patients, who may not have nasal symptoms. The sudden anosmia or ageusia need to be recognized by the international scientific community as important symptoms of the COVID-19 infection.
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    Yan, C. H., Faraji, F., Prajapati, D. P., Boone, C. E., and DeConde, A. S. (2020) Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms. Int. Forum Allergy Rhinol. 10 (7), 806– 813,  DOI: 10.1002/alr.22579
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    Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms
    Yan Carol H; Faraji Farhoud; Prajapati Divya P; DeConde Adam S; Prajapati Divya P; Boone Christine E
    International forum of allergy & rhinology (2020), 10 (7), 806-813 ISSN:.
    BACKGROUND: Rapid spread of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and concern for viral transmission by ambulatory patients with minimal to no symptoms underline the importance of identifying early or subclinical symptoms of coronavirus disease 2019 (COVID-19) infection. Two such candidate symptoms include anecdotally reported loss of smell and taste. Understanding the timing and association of smell/taste loss in COVID-19 may help facilitate screening and early isolation of cases. METHODS: A single-institution, cross-sectional study evaluating patient-reported symptoms with a focus on smell and taste was conducted using an internet-based platform on adult subjects who underwent testing for COVID-19. Logistic regression was employed to identify symptoms associated with COVID-19 positivity. RESULTS: A total of 1480 patients with influenza-like symptoms underwent COVID-19 testing between March 3, 2020, and March 29, 2020. Our study captured 59 of 102 (58%) COVID-19-positive patients and 203 of 1378 (15%) COVID-19-negative patients. Smell and taste loss were reported in 68% (40/59) and 71% (42/59) of COVID-19-positive subjects, respectively, compared to 16% (33/203) and 17% (35/203) of COVID-19-negative patients (p < 0.001). Smell and taste impairment were independently and strongly associated with COVID-19 positivity (anosmia: adjusted odds ratio [aOR] 10.9; 95% CI, 5.08-23.5; ageusia: aOR 10.2; 95% CI, 4.74-22.1), whereas sore throat was associated with COVID-19 negativity (aOR 0.23; 95% CI, 0.11-0.50). Of patients who reported COVID-19-associated loss of smell, 74% (28/38) reported resolution of anosmia with clinical resolution of illness. CONCLUSION: In ambulatory individuals with influenza-like symptoms, chemosensory dysfunction was strongly associated with COVID-19 infection and should be considered when screening symptoms. Most will recover chemosensory function within weeks, paralleling resolution of other disease-related symptoms.
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    Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2
    Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, Stanley
    Journal of Virology (2008), 82 (15), 7264-7275CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurol. sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, esp. those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.
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    Wang, H., Zhou, M., Brand, J., and Huang, L. (2007) Inflammation activates the interferon signaling pathways in taste bud cells. J. Neurosci. 27 (40), 10703– 10713,  DOI: 10.1523/JNEUROSCI.3102-07.2007
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    Inflammation activates the interferon signaling pathways in taste bud cells
    Wang, Hong; Zhou, Minliang; Brand, Joseph; Huang, Liquan
    Journal of Neuroscience (2007), 27 (40), 10703-10713CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    Patients with viral and bacterial infections or other inflammatory illnesses often experience taste dysfunctions. The agents responsible for these taste disorders are thought to be related to infection-induced inflammation, but the mechanisms are not known. As a first step in characterizing the possible role of inflammation in taste disorders, we report here evidence for the presence of interferon (IFN)-mediated signaling pathways in taste bud cells. IFN receptors, particularly the IFN-γ receptor IFNGR1, are coexpressed with the taste cell-type markers neuronal cell adhesion mol. and α-gustducin, suggesting that both the taste receptor cells and synapse-forming cells in the taste bud can be stimulated by IFN. Incubation of taste bud-contg. lingual epithelia with recombinant IFN-α and IFN-γ triggered the IFN-mediated signaling cascades, resulting in the phosphorylation of the downstream STAT1 (signal transducer and activator of transcription protein 1) transcription factor. I.p. injection of lipopolysaccharide or polyinosinic:polycytidylic acid into mice, mimicking bacterial and viral infections, resp., altered gene expression patterns in taste bud cells. Furthermore, the systemic administration of either IFN-α or IFN-γ significantly increased the no. of taste bud cells undergoing programmed cell death. These findings suggest that bacterial and viral infection-induced IFNs can act directly on taste bud cells, affecting their cellular function in taste transduction, and that IFN-induced apoptosis in taste buds may cause abnormal cell turnover and skew the representation of different taste bud cell types, leading to the development of taste disorders. To our knowledge, this is the first study providing direct evidence that inflammation can affect taste buds through cytokine signaling pathways.
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    Wang, H., Zhou, M., Brand, J., and Huang, L. (2009) Inflammation and taste disorders: mechanisms in taste buds. Ann. N. Y. Acad. Sci. 1170, 596– 603,  DOI: 10.1111/j.1749-6632.2009.04480.x
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    Inflammation and taste disorders: mechanisms in taste buds
    Wang, Hong; Zhou, Minliang; Brand, Joseph; Huang, Liquan
    Annals of the New York Academy of Sciences (2009), 1170 (International Symposium on Olfaction and Taste, 2008), 596-603CODEN: ANYAA9; ISSN:0077-8923. (Wiley-Blackwell)
    Taste disorders, including taste distortion and taste loss, neg. impact general health and quality of life. To understand the underlying mol. and cellular mechanisms, we set out to identify inflammation-related mols. in taste tissue and to assess their role in the development of taste dysfunctions. We found that 10 out of 12 mammalian Toll-like receptors (TLRs), type I and II interferon (IFN) receptors, and their downstream signaling components are present in taste tissue. Some TLRs appear to be selectively or more abundantly expressed in taste buds than in nongustatory lingual epithelium. Immunohistochem. with antibodies against TLRs 1, 2, 3, 4, 6, and 7 confirmed the presence of these receptor proteins in taste bud cells, of which TLRs 2, 3, and 4 are expressed in the gustducin-expressing type II taste bud cells. Administration of TLR ligands, lipopolysaccharide, and double-stranded RNA polyinosinic:polycytidylic acid, which mimics bacterial or viral infection, activates the IFN signaling pathways, upregulates the expression of IFN-inducible genes, and downregulates the expression of c-fos in taste buds. Finally, systemic administration of IFNs augments apoptosis of taste bud cells in mice. Taken together, these data suggest that TLR and IFN pathways function collaboratively in recognizing pathogens and mediating inflammatory responses in taste tissue. This process, however, may interfere with normal taste transduction and taste bud cell turnover and contributes to the development of taste disorders.
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    Olfactory dysfunction in chronic stroke patients
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    BMC neurology (2015), 15 (), 199 ISSN:.
    BACKGROUND: The aim of the study was to investigate odor identification performance in patients one year after hospital admittance due to stroke. Predictors for olfactory dysfunction were investigated as well as self-reported olfactory function and pleasantness of olfactory items. METHODS: A 1-year prospective study was performed. Stroke location, classification and comorbidities were registered at hospital admission. One year after admission, olfactory function was assessed using standardized olfactory methods (screening for loss of detection sensitivity and an odor identification test). A group of matched controls was derived from a population-based study to compare odor identification performance between groups. Patients were asked for their personal judgment regarding their olfactory function and pleasantness of odorous items. In addition, global cognitive function and symptoms of depression were assessed. RESULTS: A total of 78 patients were enrolled (46 males, 32 females; mean age 68 years) of which 28.2% exhibited reduced olfactory function (hyposmia) and 15.4% exhibited loss of olfactory function (10.3% functional anosmia, 5.1% complete anosmia). Patients showed significantly lower olfactory performance compared to age- and sex-mated matched controls. Predictors of impaired olfactory function were age and NIHSS score. Self-reports indicated no significant differences between patients with normal olfactory function and those with reduced function. Yet, patients having an olfactory dysfunction rated odorous items as significantly less pleasant compared to patients without dysfunction. CONCLUSIONS: Olfactory dysfunction seems to occur frequently after stoke even one year after initial admission. The deficits seem to relate to hyposmia and functional anosmia, and less to a complete loss of smell sensitivity.
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    Disorders of smell, taste, and food intake in a patient with a dorsomedial thalamic infarct
    Rousseaux M; Muller P; Gahide I; Mottin Y; Romon M
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    BACKGROUND: We report that a lasting deficit in the hedonic character of olfactory and gustatory perception can be observed in bilateral dorsomedial and intralaminar thalamic lesions. CASE DESCRIPTION: A 68-year-old patient abruptly presented with vigilance disorders associated with a reduction of olfactory and gustatory perceptions. A severe drop in appetite for foods and a weight loss of 10 kg were observed, which were partially reversed with time. Two years later, the main persisting disorder was a change in the quality of perceptions: odors and taste were perceived either in a neutral way, their pleasant character having disappeared, or as unpleasant. However, identification was preserved. MRI showed that lesions principally involved the dorsomedial thalamic nuclei and the adjacent part of the intralaminar nuclei. CONCLUSIONS: This case suggests that the dorsomedial thalamus may play a role in the hedonic perception of food, thus affecting short-term regulation of food intake, and may possibly have a role in the long-term control of body weight.
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    The recent paper of Gudi, et al, has highlighted certain aspects of COV-ID-19. In particular, the attention for social and economic consequences of this emergency, usually underestimated, has been clearly and widely described.
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    Troyer, E. A., Kohn, J. N., and Hong, S. (2020) Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain, Behav., Immun. 87, 34– 39,  DOI: 10.1016/j.bbi.2020.04.027
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    Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms
    Troyer, Emily A.; Kohn, Jordan N.; Hong, Suzi
    Brain, Behavior, and Immunity (2020), 87 (), 34-39CODEN: BBIMEW; ISSN:0889-1591. (Elsevier Inc.)
    A review. The coronavirus disease 19 (COVID-19) pandemic is a significant psychol. stressor in addn. to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future ppt. anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addn. to pandemic-assocd. psychol. distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunol. response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunol. underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunol. into epidemiol. studies of pandemics.
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    Serrano-Castro, P. J., Estivill-Torrús, G., Cabezudo-García, P., Reyes-Bueno, J. A., Ciano Petersen, N., Aguilar-Castillo, M. J., Suárez-Pérez, J., Jiménez-Hernández, M. D., Moya-Molina, MÁ, Oliver-Martos, B., Arrabal-Gómez, C., and Rodríguez de Fonseca, F. (2020) Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?. Neurologia. 35 (4), 245– 251,  DOI: 10.1016/j.nrl.2020.04.002
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    Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?
    Serrano-Castro P J; Estivill-Torrus G; Suarez-Perez J; Oliver-Martos B; Arrabal-Gomez C; Rodriguez de Fonseca F; Cabezudo-Garcia P; Reyes-Bueno J A; Ciano Petersen N; Aguilar-Castillo M J; Jimenez-Hernandez M D; Moya-Molina M A
    Neurologia (Barcelona, Spain) (2020), 35 (4), 245-251 ISSN:.
    INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. DEVELOPMENT: We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. CONCLUSIONS: SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.
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    Butler, M. J. and Barrientos, R. M. (2020) The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain, Behav., Immun. 87, 53– 54,  DOI: 10.1016/j.bbi.2020.04.040
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    The impact of nutrition on COVID-19 susceptibility and long-term consequences
    Butler, Michael J.; Barrientos, Ruth M.
    Brain, Behavior, and Immunity (2020), 87 (), 53-54CODEN: BBIMEW; ISSN:0889-1591. (Elsevier Inc.)
    A brief review with commentary. While all groups are affected by the COVID-19 pandemic, the elderly, underrepresented minorities, and those with underlying medical conditions are at the greatest risk. The high rate of consumption of diets high in satd. fats, sugars, and refined carbohydrates (collectively called Western diet, WD) worldwide, contribute to the prevalence of obesity and type 2 diabetes, and could place these populations at an increased risk for severe COVID-19 pathol. and mortality. WD consumption activates the innate immune system and impairs adaptive immunity, leading to chronic inflammation and impaired host defense against viruses. Furthermore, peripheral inflammation caused by COVID-19 may have long-term consequences in those that recover, leading to chronic medical conditions such as dementia and neurodegenerative disease, likely through neuroinflammatory mechanisms that can be compounded by an unhealthy diet. Thus, now more than ever, wider access to healthy foods should be a top priority and individuals should be mindful of healthy eating habits to reduce susceptibility to and long-term complications from COVID-19.
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    Santacroce, L. (2020) Letter in response to the article “Enhancing immunity in viral infections, with special emphasis on COVID-19: A review (Jayawardena et al.). Diabetes Metab Syndr. 14 (5), 927,  DOI: 10.1016/j.dsx.2020.06.009
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    Letter in response to the article "Enhancing immunity in viral infections, with special emphasis on COVID-19: A review" (Jayawardena et al.)
    Santacroce Luigi
    Diabetes & metabolic syndrome (2020), 14 (5), 927 ISSN:.
    There is no expanded citation for this reference.
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    Elsayed, Y. and Khan, N. A. (2020) Immunity-Boosting Spices and the Novel Coronavirus. ACS Chem. Neurosci. 11 (12), 1696– 1698,  DOI: 10.1021/acschemneuro.0c00239
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    Immunity-Boosting Spices and the Novel Coronavirus
    Elsayed, Yehya; Khan, Naveed Ahmed
    ACS Chemical Neuroscience (2020), 11 (12), 1696-1698CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Although there is no reported genetic predisposition in contracting coronavirus disease 2019 (COVID-19), the mortality rate varies among different ethnic groups. Here we detd. potential correlation between COVID-19 and spice consumption. The data from 163 countries including total cases, total deaths, and total recovered were analyzed. It was obsd. that there is a clear interrelated prevalence between the total no. of COVID-19 cases per million population tested and the gram of spice supply per capita per day. Nations with lower consumptions of spices per capita showed greater no. of COVID-19 cases per million population. This is not surprising as herbs and spices are well-known to boost immunity. Although the precise mol. mechanisms assocd. with spices and immunity are not completely understood, our findings led us to hypothesize that spice consumption plays a role in our ability to fight COVID-19; however, intensive research is needed to det. the translational value of these findings.
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    Mitrani, R. D., Dabas, N., and Goldberger, J. J. (2020) COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Heart Rhythm  DOI: 10.1016/j.hrthm.2020.06.026
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  • Abstract

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    Figure 1

    Figure 1. (a) Sex distribution of IL-6 levels at the first evaluation; (b) sex distribution of IL-6 levels at the second evaluation; (c) sex distribution of the delta (values at the first evaluation minus values at the second evaluation) value of IL-6 levels; (d) sex distribution of the delta score of smell; (e) sex distribution of the delta score of taste.

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    Figure 2

    Figure 2. (a) IL-6 and (b) smell and (c) taste score distributions in COVID-19 patients at first and second evaluation.

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    This article references 49 other publications.

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      Henkin, R. I., Schmidt, L., and Velicu, I. (2013) Interleukin 6 in hyposmia. JAMA Otolaryngol Head Neck Surg. 139 (7), 728– 34,  DOI: 10.1001/jamaoto.2013.3392
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      Interleukin 6 in hyposmia
      Henkin Robert I; Schmidt Loren; Velicu Irina
      JAMA otolaryngology-- head & neck surgery (2013), 139 (7), 728-34 ISSN:.
      IMPORTANCE: Olfaction is a complex sensory process that has not been fully studied. Elevated plasma levels of interleukin 6 (IL-6) have been found in patients with several acute and chronic diseases but have not been reported in patients with smell loss (hyposmia). OBJECTIVE: To determine IL-6 levels in patients with hyposmia. DESIGN: Retrospective study. All measurements were made without reference to the origin of any collected sample. SETTING An ambulatory private practice at The Taste and Smell Clinic in Washington, DC. PARTICIPANTS: Fifty-nine consecutive patients who presented to the clinic between 2005 and 2008 for evaluation and treatment of various degrees of hyposmia were studied. Nine volunteers with normal sensory function served as controls. MAIN OUTCOMES AND MEASURES: Levels of IL-6 were measured in samples of plasma, urine, saliva, and nasal mucus. RESULTS: All biological fluid samples studied contained IL-6. Mean (SEM) levels in plasma, saliva, and nasal mucus in patients were significantly higher than in controls (0.95 [0.10] vs 0.12 [0.03] pg/mL, 0.57 [0.05] vs 0.30 [0.01] pg/mL, and 29.7 [3.8] vs 11.6 [0.5] pg/mL, respectively; all P < .001). The concentration of IL-6 in nasal mucus in patients was significantly higher than in controls and was more than 30 times higher than in any other biological fluid. Mean (SEM) levels in urine were not significantly different: 0.92 (0.17) pg/mL for patients and 1.26 (0.41) pg/mL for controls (P > .50). CONCLUSIONS AND RELEVANCE: Compared with controls, IL-6 in patients was significantly elevated in plasma, saliva, and nasal mucus. Because IL-6 is a proinflammatory cytokine, these changes can relate to local or systemic inflammatory processes, which can be a cause or a result of pathological processes associated with hyposmia. These results support the concept that hyposmia has a biochemical basis and IL-6 may play a role in biochemical pathological processes underlying hyposmia and its treatment.
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    22. 22
      Mori, I. (2018) 1918 H1N1 Influenza Virus Infection–Induced Proinflammatory Cytokines in the Olfactory Bulb Could Trigger Lethargic Disease. J. Infect. Dis. 218 (10), 1686– 1687,  DOI: 10.1093/infdis/jiy380
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      1918 H1N1 Influenza Virus Infection-Induced Proinflammatory Cytokines in the Olfactory Bulb Could Trigger Lethargic Disease
      Mori Isamu
      The Journal of infectious diseases (2018), 218 (10), 1686-1687 ISSN:.
      There is no expanded citation for this reference.
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    23. 23
      de Wit, E., Siegers, J. Y., Cronin, J. M., Weatherman, S., van den Brand, J. M., Leijten, L. M., van Run, P., Begeman, L., van den Ham, H. J., Andeweg, A. C., Bushmaker, T., Scott, D. P., Saturday, G., Munster, V. J., Feldmann, H., and van Riel, D. (2018) 1918 H1N1 influenza virus replicates and induces proinflammatory cytokine responses in extrarespiratory tissues of ferrets. J. Infect. Dis. 217 (8), 1237– 1246,  DOI: 10.1093/infdis/jiy003
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      1918 H1N1 influenza virus replicates and induces proinflammatory cytokine responses in extrarespiratory tissues of ferrets
      de Wit, Emmie; Siegers, Jurre Y.; Cronin, Jacqueline M.; Weatherman, Sarah; van den Brand, Judith M.; Leijten, Lonneke M.; van Run, Peter; Begeman, Lineke; van den Ham, Henk-Jan; Andeweg, Arno C.; Bushmaker, Trenton; Scott, Dana P.; Saturday, Greg; Munster, Vincent J.; Feldmann, Heinz; van Riel, Debby
      Journal of Infectious Diseases (2018), 217 (8), 1237-1246CODEN: JIDIAQ; ISSN:1537-6613. (Oxford University Press)
      The 1918 Spanish H1N1 influenza pandemic was the most severe recorded influenza pandemic with an estd. 20-50 million deaths worldwide. Even though it is known that influenza viruses can cause extrarespiratory tract complications-which are often severe or even fatal-the potential contribution of extrarespiratory tissues to the pathogenesis of 1918 H1N1 virus infection has not been studied comprehensively. Here, we performed a time-course study in ferrets inoculated intranasally with 1918 H1N1 influenza virus, with special emphasis on the involvement of extrarespiratory tissues. Respiratory and extrarespiratory tissues were collected after inoculation for virol., histol., and immunol. anal. Infectious virus was detected at high titers in respiratory tissues and, at lower titers in most extrarespiratory tissues. Evidence for active virus replication, as indicated by the detection of nucleoprotein by immunohistochem., was obsd. in the respiratory tract, peripheral and central nervous system, and liver. Proinflammatory cytokines were up-regulated in respiratory tissues, olfactory bulb, spinal cord, liver, heart, and pancreas. Conclusions. 1918 H1N1 virus spread to and induced cytokine responses in tissues outside the respiratory tract, which likely contributed to the severity of infection. Moreover, our data support the suggested link between 1918 H1N1 infection and central nervous system disease.
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    24. 24
      De Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J., Chau, T. N., Hoang, D. M., Van Vinh Chau, N., Khanh, T. H., Dong, V. C., Qui, P. T., Van Cam, B., Ha, D. Q., Guan, Y., Peiris, J. S., Chinh, N. T., Hien, T. T., and Farrar, J. (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12 (10), 1203– 1207,  DOI: 10.1038/nm1477
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      Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia
      de Jong, Menno D.; Simmons, Cameron P.; Thanh, Tran Tan; Hien, Vo Minh; Smith, Gavin J. D.; Chau, Tran Nguyen Bich; Hoang, Dang Minh; Nguyen, Van Vinh Chau; Khanh, Truong Huu; Dong, Vo Cong; Qui, Phan Tu; Van Cam, Bach; Ha, Do Quang; Guan, Yi; Peiris, J. S. Malik; Chinh, Nguyen Tran; Hien, Tran Tinh; Farrar, Jeremy
      Nature Medicine (New York, NY, United States) (2006), 12 (10), 1203-1207CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
      Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Lab. expts. suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, the authors performed virol. and immunol. studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was assocd. with higher pharyngeal viral loads. The authors obsd. low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex assocd. with mammalian adaptation and virulence. The authors' observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clin. management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.
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      Hanisch, U. K. (2002) Microglia as a source and target of cytokines. Glia. 40 (2), 140– 155,  DOI: 10.1002/glia.10161
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      25
      Microglia as a source and target of cytokines
      Hanisch Uwe-Karsten
      Glia (2002), 40 (2), 140-55 ISSN:0894-1491.
      Cytokines constitute a significant portion of the immuno- and neuromodulatory messengers that can be released by activated microglia. By virtue of potent effects on resident and invading cells, microglial cyto- and chemokines regulate innate defense mechanisms, help the initiation and influence the type of immune responses, participate in the recruitment of leukocytes to the CNS, and support attempts of tissue repair and recovery. Microglia can also receive cyto- and chemokine signals as part of auto- and paracrine communications with astrocytes, neurons, the endothelium, and leukocyte infiltrates. Strong responses and modulatory influences can be demonstrated, adding to the emerging view that microglial behavior is highly dependent on the (cytokine) environment and that reactions to a challenge may vary with the stimulation context. In principle, microglial activation aims at CNS protection. However, failed microglial engagement due to excessive or sustained activation could significantly contribute to acute and chronic neuropathologies. Dysregulation of microglial cytokine production could thereby promote harmful actions of the defense mechanisms, result in direct neurotoxicity, as well as disturb neural cell functions as they are sensitive to cytokine signaling.
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    26. 26
      Frei, K., Malipiero, U. V., Leist, T. P., Zinkernagel, R. M., Schwab, M. E., and Fontana, A. (1989) On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur. J. Immunol. 19 (4), 689– 694,  DOI: 10.1002/eji.1830190418
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      On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases
      Frei, Karl; Malipiero, Ursula V.; Leist, Thomas P.; Zinkernagel, Rolf M.; Schwab, Martin E.; Fontana, Adriano
      European Journal of Immunology (1989), 19 (4), 689-94CODEN: EJIMAF; ISSN:0014-2980.
      Interleukin 6 (IL6) was in the central nervous system (CNS) of ICR +/+ mice infected with lymphocytic choriomeningitis virus (LCMV) or with vesicular stomatitis virus (VSV). When infecting athymic ICR nu/nu mice which cannot develop T cell-mediated meningitis after LCMV infection, no synthesis of IL6 was detected in the CNS. IL6 was produced intrathecally in ICR nu/nu mice infected with VSV, which causes a T cell-independent acute encephalitis. This suggested that IL6 may also originate from cells not belonging to the T cell compartment. In vitro assays showed that both virus-infected microglial cells and astrocytes secreted IL6. In addn. to its effect on the development of B cell immunity in the brain, IL 6 may be involved in repair mechanisms initiated in the course of viral-induced tissue damage. IL6 induced an increase of the secretion of a neurotrophic factor, nerve growth factor, by astrocytes. The intrathecal synthesis of IL6 may be part of the host response to infection favoring immune-mediated elimination of the infectious agent as well as trophic support for neurons.
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    27. 27
      Righi, M., Mori, L., De Libero, G., Sironi, M., Biondi, A., Mantovani, A., Donini, S. D., and Ricciardi-Castagnoli, P. (1989) Monokine production by microglial cell clones. Eur. J. Immunol. 19 (8), 1443– 1448,  DOI: 10.1002/eji.1830190815
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      Monokine production by microglial cell clones
      Righi, Marco; Mori, Lucia; De Libero, Gennaro; Sironi, Marina; Biondi, Andrea; Mantovani, Alberto; Donini, Suzanne Denis; Ricciardi-Castagnoli, Paola
      European Journal of Immunology (1989), 19 (8), 1443-8CODEN: EJIMAF; ISSN:0014-2980.
      Cytokines have been suggested to act as intermediates between the immune and the central nervous system, but little is known about the type of cells synthesizing them in the brain. Primary brain cell cultures from mouse embryos were immortalized with oncogenic retroviruses and clones of microglial cells were generated that have been characterized. Three of the clones studied produce interleukin 1 (IL1), IL6, and tumor necrosis factor-α as assessed by biol. assays and by Northern blot anal. These data raise the question on the role of these cytokines in the brain and suggest that early resident microglial cells might play an important role in developmental processes and in the adult brain.
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    28. 28
      Bilinska, K. and Butowt, R. (2020) Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism. ACS Chem. Neurosci. 11, 2152,  DOI: 10.1021/acschemneuro.0c00406
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      28
      Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism
      Bilinska, Katarzyna; Butowt, Rafal
      ACS Chemical Neuroscience (2020), 11 (15), 2152-2155CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      A review. It has become clear since the pandemic broke out that SARS-CoV-2 virus causes redn. of smell and taste in a significant fraction of COVID-19 patients. The olfactory dysfunction often occurs early in the course of the disease, and sometimes it is the only symptom in otherwise asymptomatic carriers. The cellular mechanisms for these specific olfactory disturbances in COVID-19 are now beginning to be elucidated. Several very recent papers contributed to explaining the key cellular steps occurring in the olfactory epithelium leading to anosmia/hyposmia (collectively known as dysosmia) initiated by SARS-CoV-2 infection. In this Viewpoint, we discuss current progress in research on olfactory dysfunction in COVID-19 and we also propose an updated model of the SARS-CoV-2-induced dysosmia. The emerging central role of sustentacular cells and inflammatory processes in the olfactory epithelium are particularly considered. The proposed model of anosmia in COVID-19 does not answer unequivocally whether the new coronavirus exploits the olfactory route to rapidly or slowly reach the brain in COVID-19 patients. To answer this question, new systematic studies using an infectious virus and appropriate animal models are needed.
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    29. 29
      Hopkins, C., Gillett, S., Slack, R., Lund, V. J., and Browne, J. P. (2009) Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 34 (5), 447– 454,  DOI: 10.1111/j.1749-4486.2009.01995.x
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      Psychometric validity of the 22-item Sinonasal Outcome Test
      Hopkins C; Gillett S; Slack R; Lund V J; Browne J P
      Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery (2009), 34 (5), 447-54 ISSN:.
      OBJECTIVES: We set out to determine the psychometric validation of a disease-specific health related quality of life instrument for use in chronic rhinosinusitis, the 22 item Sinonasal Outcome Test (SNOT-22), a modification of a pre-existing instrument, the SNOT-20. DESIGN, SETTING AND PARTICIPANTS: The National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis was a prospective cohort study collecting data on 3128 adult patients undergoing sinonasal surgery in 87 NHS hospitals in England and Wales. Data were collected preoperatively and at 3 months after surgery, and analysed to determine validity of the SNOT-22. Test-retest reliability was assessed in a separate cohort of patients in a single centre. MAIN OUTCOME MEASURES: The SNOT-22, a derivative of the SNOT-20 was the main outcome measure. Patients were also asked to report whether they felt better, the same or worse following surgery. To evaluate the SNOT-22, the internal consistency, responsiveness, known group differences and validity were analysed. RESULTS: Preoperative SNOT-22 scores were completed by 2803 patients. 3-month postoperative SNOT-22 scores were available for 2284 patients of all patients who completed a preoperative form (81.5% response rate). The Cronbach's alpha scores for the SNOT-22 were 0.91 indicating high internal consistency. The test-retest reliability coefficient was 0.93, indicating high reliability of repeated measures. The SNOT-22 was able to discriminate between patients known to suffer with chronic rhinosinusitis and a group of healthy controls (P < 0.0001, t = 85.3). It was also able to identify statistically significant differences in sub-groups of patients with chronic rhinosinusitis. There was a statistically significant (P < 0.0001, t = 39.94) decrease in patient reported SNOT-22 scores at 3 months. At 3 months the overall effect size in all patients was 0.81, which is considered large. We found the minimally important difference that is the smallest change in SNOT-22 score that can be detected by a patient, to be 8.9 points. CONCLUSIONS: We have found the SNOT-22 to be valid and easy to use. It can be used to facilitate routine clinical practice to highlight the impact of chronic rhinosinusitis on the patient's quality of life, and may also be used to measure the outcome of surgical intervention. The minimally important difference allows us to interpret scores in a clinical context, and may help to improve patient selection for surgery.
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    30. 30
      Rawal, S., Hoffman, H. J., Honda, M., Huedo-Medina, T. B., and Duffy, V. B. (2015) The Taste and Smell Protocol in the 2011–2014 US National Health and Nutrition Examination Survey (NHANES): Test-Retest Reliability and Validity Testing. Chemosens. Percept. 8 (3), 138– 148,  DOI: 10.1007/s12078-015-9194-7
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      The Taste and Smell Protocol in the 2011-2014 US National Health and Nutrition Examination Survey (NHANES): Test-Retest Reliability and Validity Testing
      Rawal Shristi; Honda Mallory; Huedo-Medin Tania B; Duffy Valerie B; Hoffman Howard J
      Chemosensory perception (2015), 8 (3), 138-148 ISSN:1936-5802.
      INTRODUCTION: The US NHANES 2011-2014 protocol includes a taste and smell questionnaire (CSQ) in home-based interviews and brief assessments in mobile exam centers. We report the short- and longer-term test-retest reliability and validity of this protocol against broader chemosensory measures. METHODS: A convenience sample of 73 adults (age=39.5±20.8 years) underwent the NHANES protocol at baseline, 2 weeks and 6 months. For taste, participants rated intensities of two tastants (1 M NaCl, 1 mM quinine) applied to the tongue tip and three tastants (1 M NaCl, 1 mM quinine, 0.32 M NaCl) sampled with the whole mouth. Smell function was assessed with a Pocket Smell Test® (PST; eight-item odor identification test). The CSQ asked about chemosensory problems, distortions, and age-related changes. Broader baseline measurements were a 40-item olfactometer-generated identification task and additional whole-mouth taste intensities (1 M sucrose, 32 mM citric acid, 3.2 mM propylthiouracil). RESULTS: Intraclass correlations (ICCs) for NHANES taste measures showed moderate-to-good agreement after 2 weeks and 6 months (ICCs 0.42-0.71). Whole-mouth quinine intensity was significantly correlated with other taste intensities, supporting its utility as a marker for overall taste functioning. Olfactory classification from PSTs agreed for 98.5 % of participants across 2 weeks (κ=0.85; 95 % CI 0.71-0.99) and had good correspondence with the olfactometer task. CSQ items showed good-to-excellent agreement over 6 months (ICCs 0.66-0.90). CONCLUSIONS: These findings further support that the NHANES chemosensory protocol has moderate-to-good test-retest reliability when administered to healthy, educated adults. Despite being a brief procedure with limited measures, the NHANES taste and smell assessments provided good information when compared to broader measures of taste and smell function.
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    31. 31
      Suzuki, M., Saito, K., Min, W. P., Vladau, C., Toida, K., Itoh, H., and Murakami, S. (2007) Identification of viruses in patients with postviral olfactory dysfunction. Laryngoscope 117 (2), 272– 277,  DOI: 10.1097/01.mlg.0000249922.37381.1e
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      Identification of viruses in patients with postviral olfactory dysfunction
      Suzuki Motohiko; Saito Koichi; Min Wei-Ping; Vladau Costin; Toida Kazunori; Itoh Hirotaka; Murakami Shingo
      The Laryngoscope (2007), 117 (2), 272-7 ISSN:0023-852X.
      OBJECTIVE: Causative viruses of postviral olfactory dysfunction (PVOD) have not yet been identified. The aim of this study was to investigate causative viruses in patients with PVOD. STUDY DESIGN AND METHODS: Nasal discharge was collected from 24 patients with PVOD. We investigated the presence of 10 viruses in nasal discharge and examined the time course, with regard to changes in olfactory dysfunction and nasal obstruction in patients with PVOD, using questionnaires, acoustic rhinometry, and olfactory tests. RESULTS: Rhinoviruses were detected in 10 patients by electrophoresis. Rhinoviruses were also confirmed in four patients by nucleotide sequences. Viral serotypes were identified to be human rhinovirus (HRV)-40, HRV-75, HRV-78, and HRV-80. One of the four patients complained of anosmia, whereas another complained of dysosmia. Olfactory testing did not show significant improvement at 4, 8, 11, and 24 weeks after the first visit in the four patients, although results of acoustic rhinometry significantly improved. Two of the four patients complained of olfactory dysfunction even 6 months after the first visit. Coronavirus and parainfluenza virus were detected in one patient each, and Epstein-Barr viruses were detected in three patients. CONCLUSIONS: This study for the first time detected rhinovirus, coronavirus, parainfluenza virus, and Epstein-Barr virus in nasal discharge of patients with PVOD. Furthermore, the present study suggests that rhinoviruses can cause olfactory dysfunction through mechanisms other than nasal obstruction and that rhinoviruses can induce various severities and different time courses of olfactory dysfunction.
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    32. 32
      Vaira, L. A., Deiana, G., Fois, A. G., Pirina, P., Madeddu, G., De Vito, A., Babudieri, S., Petrocelli, M., Serra, A., Bussu, F., Ligas, E., Salzano, G., and De Riu, G. (2020) Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases. Head Neck. 42 (6), 1252– 1258,  DOI: 10.1002/hed.26204
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      Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases
      Vaira Luigi Angelo; Ligas Enrica; De Riu Giacomo; Deiana Giovanna; Fois Alessandro Giuseppe; Pirina Pietro; Madeddu Giordano; De Vito Andrea; Babudieri Sergio; Petrocelli Marzia; Serra Antonello; Bussu Francesco; Salzano Giovanni
      Head & neck (2020), 42 (6), 1252-1258 ISSN:.
      BACKGROUND: The first European case series are detecting a very high frequency of chemosensitive disorders in COVID-19 patients, ranging between 19.4% and 88%. METHODS: Olfactory and gustatory function was objectively tested in 72 COVID-19 patients treated at University Hospital of Sassari. RESULTS: Overall, 73.6% of the patients reported having or having had chemosensitive disorders. Olfactory assessment showed variable degree hyposmia in 60 cases and anosmia in two patients. Gustatory assessment revealed hypogeusia in 33 cases and complete ageusia in one patient. Statistically significant differences in chemosensitive recovery were detected based on age and distance from the onset of clinical manifestations. CONCLUSION: Olfactory and gustatory dysfunctions represent common clinical findings in COVID-19 patients. Otolaryngologists and head-neck surgeons must by now keep this diagnostic option in mind when evaluating cases of ageusia and nonspecific anosmia that arose suddenly and are not associated with rhinitis symptoms.
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      Lechien, J. R., Chiesa-Estomba, C. M., De Siati, D. R., Horoi, M., Le Bon, S. D., Rodriguez, A., Dequanter, D., Blecic, S., El Afia, F., Distinguin, L., Chekkoury-Idrissi, Y., Hans, S., Delgado, I. L., Calvo-Henriquez, C., Lavigne, P., Falanga, C., Barillari, M. R., Cammaroto, G., Khalife, M., Leich, P., Souchay, C., Rossi, C., Journe, F., Hsieh, J., Edjlali, M., Carlier, R., Ris, L., Lovato, A., De Filippis, C., Coppee, F., Fakhry, N., Ayad, T., and Saussez, S. (2020) Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur. Arch Otorhinolaryngol. 277 (8), 2251– 2261,  DOI: 10.1007/s00405-020-05965-1
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      Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study
      Lechien Jerome R; Chiesa-Estomba Carlos M; De Siati Daniele R; El Afia Fahd; Distinguin Lea; Chekkoury-Idrissi Younes; Delgado Irene Lopez; Calvo-Henriquez Christian; Lavigne Philippe; Falanga Chiara; Barillari Maria Rosaria; Cammaroto Giovanni; Hsieh Julien; Fakhry Nicolas; Ayad Tareck; Saussez Sven; Lechien Jerome R; Journe Fabrice; Saussez Sven; Lechien Jerome R; El Afia Fahd; Distinguin Lea; Chekkoury-Idrissi Younes; Hans Stephane; Lechien Jerome R; Horoi Mihaela; Le Bon Serge D; Rodriguez Alexandra; Dequanter Didier; Saussez Sven; Chiesa-Estomba Carlos M; De Siati Daniele R; Blecic Serge; Delgado Irene Lopez; Calvo-Henriquez Christian; Lavigne Philippe; Ayad Tareck; Falanga Chiara; Barillari Maria Rosaria; Cammaroto Giovanni; Khalife Mohamad; Saussez Sven; Leich Pierre; Souchay Christel; Rossi Camelia; Hsieh Julien; Edjlali Myriam; Edjlali Myriam; Carlier Robert; Ris Laurence; Lovato Andrea; De Filippis Cosimo; Coppee Frederique; Fakhry Nicolas
      European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery (2020), 277 (8), 2251-2261 ISSN:.
      OBJECTIVE: To investigate the occurrence of olfactory and gustatory dysfunctions in patients with laboratory-confirmed COVID-19 infection. METHODS: Patients with laboratory-confirmed COVID-19 infection were recruited from 12 European hospitals. The following epidemiological and clinical outcomes have been studied: age, sex, ethnicity, comorbidities, and general and otolaryngological symptoms. Patients completed olfactory and gustatory questionnaires based on the smell and taste component of the National Health and Nutrition Examination Survey, and the short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS). RESULTS: A total of 417 mild-to-moderate COVID-19 patients completed the study (263 females). The most prevalent general symptoms consisted of cough, myalgia, and loss of appetite. Face pain and nasal obstruction were the most disease-related otolaryngological symptoms. 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders (p < 0.001). Olfactory dysfunction (OD) appeared before the other symptoms in 11.8% of cases. The sQO-NS scores were significantly lower in patients with anosmia compared with normosmic or hyposmic individuals (p = 0.001). Among the 18.2% of patients without nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0%. Females were significantly more affected by olfactory and gustatory dysfunctions than males (p = 0.001). CONCLUSION: Olfactory and gustatory disorders are prevalent symptoms in European COVID-19 patients, who may not have nasal symptoms. The sudden anosmia or ageusia need to be recognized by the international scientific community as important symptoms of the COVID-19 infection.
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    34. 34
      Yan, C. H., Faraji, F., Prajapati, D. P., Boone, C. E., and DeConde, A. S. (2020) Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms. Int. Forum Allergy Rhinol. 10 (7), 806– 813,  DOI: 10.1002/alr.22579
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      34
      Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms
      Yan Carol H; Faraji Farhoud; Prajapati Divya P; DeConde Adam S; Prajapati Divya P; Boone Christine E
      International forum of allergy & rhinology (2020), 10 (7), 806-813 ISSN:.
      BACKGROUND: Rapid spread of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and concern for viral transmission by ambulatory patients with minimal to no symptoms underline the importance of identifying early or subclinical symptoms of coronavirus disease 2019 (COVID-19) infection. Two such candidate symptoms include anecdotally reported loss of smell and taste. Understanding the timing and association of smell/taste loss in COVID-19 may help facilitate screening and early isolation of cases. METHODS: A single-institution, cross-sectional study evaluating patient-reported symptoms with a focus on smell and taste was conducted using an internet-based platform on adult subjects who underwent testing for COVID-19. Logistic regression was employed to identify symptoms associated with COVID-19 positivity. RESULTS: A total of 1480 patients with influenza-like symptoms underwent COVID-19 testing between March 3, 2020, and March 29, 2020. Our study captured 59 of 102 (58%) COVID-19-positive patients and 203 of 1378 (15%) COVID-19-negative patients. Smell and taste loss were reported in 68% (40/59) and 71% (42/59) of COVID-19-positive subjects, respectively, compared to 16% (33/203) and 17% (35/203) of COVID-19-negative patients (p < 0.001). Smell and taste impairment were independently and strongly associated with COVID-19 positivity (anosmia: adjusted odds ratio [aOR] 10.9; 95% CI, 5.08-23.5; ageusia: aOR 10.2; 95% CI, 4.74-22.1), whereas sore throat was associated with COVID-19 negativity (aOR 0.23; 95% CI, 0.11-0.50). Of patients who reported COVID-19-associated loss of smell, 74% (28/38) reported resolution of anosmia with clinical resolution of illness. CONCLUSION: In ambulatory individuals with influenza-like symptoms, chemosensory dysfunction was strongly associated with COVID-19 infection and should be considered when screening symptoms. Most will recover chemosensory function within weeks, paralleling resolution of other disease-related symptoms.
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    35. 35
      Turski, W. A., Wnorowski, A., Turski, G. N., Turski, C. A., and Turski, L. (2020) AhR and IDO1 in pathogenesis of Covid-19 and the “Systemic AhR Activation Syndrome:” Translational review and therapeutic perspectives. Restor. Neurol. Neurosci.  DOI: 10.3233/RNN-201042
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      Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., and Perlman, S. (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 82 (15), 7264– 7275,  DOI: 10.1128/JVI.00737-08
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      36
      Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2
      Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, Stanley
      Journal of Virology (2008), 82 (15), 7264-7275CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
      Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurol. sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, esp. those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.
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    37. 37
      Wang, H., Zhou, M., Brand, J., and Huang, L. (2007) Inflammation activates the interferon signaling pathways in taste bud cells. J. Neurosci. 27 (40), 10703– 10713,  DOI: 10.1523/JNEUROSCI.3102-07.2007
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      37
      Inflammation activates the interferon signaling pathways in taste bud cells
      Wang, Hong; Zhou, Minliang; Brand, Joseph; Huang, Liquan
      Journal of Neuroscience (2007), 27 (40), 10703-10713CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      Patients with viral and bacterial infections or other inflammatory illnesses often experience taste dysfunctions. The agents responsible for these taste disorders are thought to be related to infection-induced inflammation, but the mechanisms are not known. As a first step in characterizing the possible role of inflammation in taste disorders, we report here evidence for the presence of interferon (IFN)-mediated signaling pathways in taste bud cells. IFN receptors, particularly the IFN-γ receptor IFNGR1, are coexpressed with the taste cell-type markers neuronal cell adhesion mol. and α-gustducin, suggesting that both the taste receptor cells and synapse-forming cells in the taste bud can be stimulated by IFN. Incubation of taste bud-contg. lingual epithelia with recombinant IFN-α and IFN-γ triggered the IFN-mediated signaling cascades, resulting in the phosphorylation of the downstream STAT1 (signal transducer and activator of transcription protein 1) transcription factor. I.p. injection of lipopolysaccharide or polyinosinic:polycytidylic acid into mice, mimicking bacterial and viral infections, resp., altered gene expression patterns in taste bud cells. Furthermore, the systemic administration of either IFN-α or IFN-γ significantly increased the no. of taste bud cells undergoing programmed cell death. These findings suggest that bacterial and viral infection-induced IFNs can act directly on taste bud cells, affecting their cellular function in taste transduction, and that IFN-induced apoptosis in taste buds may cause abnormal cell turnover and skew the representation of different taste bud cell types, leading to the development of taste disorders. To our knowledge, this is the first study providing direct evidence that inflammation can affect taste buds through cytokine signaling pathways.
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    38. 38
      Wang, H., Zhou, M., Brand, J., and Huang, L. (2009) Inflammation and taste disorders: mechanisms in taste buds. Ann. N. Y. Acad. Sci. 1170, 596– 603,  DOI: 10.1111/j.1749-6632.2009.04480.x
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      38
      Inflammation and taste disorders: mechanisms in taste buds
      Wang, Hong; Zhou, Minliang; Brand, Joseph; Huang, Liquan
      Annals of the New York Academy of Sciences (2009), 1170 (International Symposium on Olfaction and Taste, 2008), 596-603CODEN: ANYAA9; ISSN:0077-8923. (Wiley-Blackwell)
      Taste disorders, including taste distortion and taste loss, neg. impact general health and quality of life. To understand the underlying mol. and cellular mechanisms, we set out to identify inflammation-related mols. in taste tissue and to assess their role in the development of taste dysfunctions. We found that 10 out of 12 mammalian Toll-like receptors (TLRs), type I and II interferon (IFN) receptors, and their downstream signaling components are present in taste tissue. Some TLRs appear to be selectively or more abundantly expressed in taste buds than in nongustatory lingual epithelium. Immunohistochem. with antibodies against TLRs 1, 2, 3, 4, 6, and 7 confirmed the presence of these receptor proteins in taste bud cells, of which TLRs 2, 3, and 4 are expressed in the gustducin-expressing type II taste bud cells. Administration of TLR ligands, lipopolysaccharide, and double-stranded RNA polyinosinic:polycytidylic acid, which mimics bacterial or viral infection, activates the IFN signaling pathways, upregulates the expression of IFN-inducible genes, and downregulates the expression of c-fos in taste buds. Finally, systemic administration of IFNs augments apoptosis of taste bud cells in mice. Taken together, these data suggest that TLR and IFN pathways function collaboratively in recognizing pathogens and mediating inflammatory responses in taste tissue. This process, however, may interfere with normal taste transduction and taste bud cell turnover and contributes to the development of taste disorders.
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    39. 39
      Di Serio, F., Lovero, R., D’Agostino, D., Nisi, L., Miragliotta, G., Contino, R., Man, A., Ciccone, M. M., and Santacroce, L. (2016) Evaluation of procalcitonin, Vitamin D and C-reactive protein levels in septic patients with positive emocoltures. Our preliminary experience. Acta Medica Mediterr. 32, 1911– 1914,  DOI: 10.19193/0393-6384_2016_6_182
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      Wehling, E., Naess, H., Wollschlaeger, D., Hofstad, H., Bramerson, A., Bende, M., and Nordin, S. (2015) Olfactory dysfunction in chronic stroke patients. BMC Neurol. 15, 199,  DOI: 10.1186/s12883-015-0463-5
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      40
      Olfactory dysfunction in chronic stroke patients
      Wehling Eike; Hofstad Hakon; Wehling Eike; Wehling Eike; Naess Halvor; Naess Halvor; Naess Halvor; Wollschlaeger Daniel; Hofstad Hakon; Bramerson Annika; Bende Mats; Nordin Steven
      BMC neurology (2015), 15 (), 199 ISSN:.
      BACKGROUND: The aim of the study was to investigate odor identification performance in patients one year after hospital admittance due to stroke. Predictors for olfactory dysfunction were investigated as well as self-reported olfactory function and pleasantness of olfactory items. METHODS: A 1-year prospective study was performed. Stroke location, classification and comorbidities were registered at hospital admission. One year after admission, olfactory function was assessed using standardized olfactory methods (screening for loss of detection sensitivity and an odor identification test). A group of matched controls was derived from a population-based study to compare odor identification performance between groups. Patients were asked for their personal judgment regarding their olfactory function and pleasantness of odorous items. In addition, global cognitive function and symptoms of depression were assessed. RESULTS: A total of 78 patients were enrolled (46 males, 32 females; mean age 68 years) of which 28.2% exhibited reduced olfactory function (hyposmia) and 15.4% exhibited loss of olfactory function (10.3% functional anosmia, 5.1% complete anosmia). Patients showed significantly lower olfactory performance compared to age- and sex-mated matched controls. Predictors of impaired olfactory function were age and NIHSS score. Self-reports indicated no significant differences between patients with normal olfactory function and those with reduced function. Yet, patients having an olfactory dysfunction rated odorous items as significantly less pleasant compared to patients without dysfunction. CONCLUSIONS: Olfactory dysfunction seems to occur frequently after stoke even one year after initial admission. The deficits seem to relate to hyposmia and functional anosmia, and less to a complete loss of smell sensitivity.
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    41. 41
      Rousseaux, M., Muller, P., Gahide, I., Mottin, Y., and Romon, M. (1996) Disorders of Smell, Taste, and Food Intake in a Patient With a Dorsomedial Thalamic Infarct. Stroke 27 (12), 2328– 2330,  DOI: 10.1161/01.STR.27.12.2328
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      41
      Disorders of smell, taste, and food intake in a patient with a dorsomedial thalamic infarct
      Rousseaux M; Muller P; Gahide I; Mottin Y; Romon M
      Stroke (1996), 27 (12), 2328-30 ISSN:0039-2499.
      BACKGROUND: We report that a lasting deficit in the hedonic character of olfactory and gustatory perception can be observed in bilateral dorsomedial and intralaminar thalamic lesions. CASE DESCRIPTION: A 68-year-old patient abruptly presented with vigilance disorders associated with a reduction of olfactory and gustatory perceptions. A severe drop in appetite for foods and a weight loss of 10 kg were observed, which were partially reversed with time. Two years later, the main persisting disorder was a change in the quality of perceptions: odors and taste were perceived either in a neutral way, their pleasant character having disappeared, or as unpleasant. However, identification was preserved. MRI showed that lesions principally involved the dorsomedial thalamic nuclei and the adjacent part of the intralaminar nuclei. CONCLUSIONS: This case suggests that the dorsomedial thalamus may play a role in the hedonic perception of food, thus affecting short-term regulation of food intake, and may possibly have a role in the long-term control of body weight.
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    42. 42
      Santacroce, L., Bottalico, L., and Charitos, I. A. (2020) The Impact of COVID-19 on Italy: A Lesson for the Future. Int. J. Occup. Environ. Med. 11 (3), 151– 152,  DOI: 10.34172/ijoem.2020.1984
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      42
      The impact of COVID-19 on Italy: a lesson for the future
      Santacroce, Luigi; Bottalico, Lucrezia; Charitos, Ioannis Alexandros
      International Journal of Occupational and Environmental Medicine (2020), 11 (3), 151-152CODEN: IJOEBW; ISSN:2008-6814. (NIOC Polyclinics, IJOEM Editorial Office)
      The recent paper of Gudi, et al, has highlighted certain aspects of COV-ID-19. In particular, the attention for social and economic consequences of this emergency, usually underestimated, has been clearly and widely described.
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    43. 43
      Troyer, E. A., Kohn, J. N., and Hong, S. (2020) Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain, Behav., Immun. 87, 34– 39,  DOI: 10.1016/j.bbi.2020.04.027
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      43
      Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms
      Troyer, Emily A.; Kohn, Jordan N.; Hong, Suzi
      Brain, Behavior, and Immunity (2020), 87 (), 34-39CODEN: BBIMEW; ISSN:0889-1591. (Elsevier Inc.)
      A review. The coronavirus disease 19 (COVID-19) pandemic is a significant psychol. stressor in addn. to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future ppt. anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addn. to pandemic-assocd. psychol. distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunol. response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunol. underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunol. into epidemiol. studies of pandemics.
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    44. 44
      Serrano-Castro, P. J., Estivill-Torrús, G., Cabezudo-García, P., Reyes-Bueno, J. A., Ciano Petersen, N., Aguilar-Castillo, M. J., Suárez-Pérez, J., Jiménez-Hernández, M. D., Moya-Molina, MÁ, Oliver-Martos, B., Arrabal-Gómez, C., and Rodríguez de Fonseca, F. (2020) Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?. Neurologia. 35 (4), 245– 251,  DOI: 10.1016/j.nrl.2020.04.002
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      44
      Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic?
      Serrano-Castro P J; Estivill-Torrus G; Suarez-Perez J; Oliver-Martos B; Arrabal-Gomez C; Rodriguez de Fonseca F; Cabezudo-Garcia P; Reyes-Bueno J A; Ciano Petersen N; Aguilar-Castillo M J; Jimenez-Hernandez M D; Moya-Molina M A
      Neurologia (Barcelona, Spain) (2020), 35 (4), 245-251 ISSN:.
      INTRODUCTION: SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100 000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. DEVELOPMENT: We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. CONCLUSIONS: SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.
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    45. 45
      Butler, M. J. and Barrientos, R. M. (2020) The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain, Behav., Immun. 87, 53– 54,  DOI: 10.1016/j.bbi.2020.04.040
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      45
      The impact of nutrition on COVID-19 susceptibility and long-term consequences
      Butler, Michael J.; Barrientos, Ruth M.
      Brain, Behavior, and Immunity (2020), 87 (), 53-54CODEN: BBIMEW; ISSN:0889-1591. (Elsevier Inc.)
      A brief review with commentary. While all groups are affected by the COVID-19 pandemic, the elderly, underrepresented minorities, and those with underlying medical conditions are at the greatest risk. The high rate of consumption of diets high in satd. fats, sugars, and refined carbohydrates (collectively called Western diet, WD) worldwide, contribute to the prevalence of obesity and type 2 diabetes, and could place these populations at an increased risk for severe COVID-19 pathol. and mortality. WD consumption activates the innate immune system and impairs adaptive immunity, leading to chronic inflammation and impaired host defense against viruses. Furthermore, peripheral inflammation caused by COVID-19 may have long-term consequences in those that recover, leading to chronic medical conditions such as dementia and neurodegenerative disease, likely through neuroinflammatory mechanisms that can be compounded by an unhealthy diet. Thus, now more than ever, wider access to healthy foods should be a top priority and individuals should be mindful of healthy eating habits to reduce susceptibility to and long-term complications from COVID-19.
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    46. 46
      Santacroce, L. (2020) Letter in response to the article “Enhancing immunity in viral infections, with special emphasis on COVID-19: A review (Jayawardena et al.). Diabetes Metab Syndr. 14 (5), 927,  DOI: 10.1016/j.dsx.2020.06.009
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      46
      Letter in response to the article "Enhancing immunity in viral infections, with special emphasis on COVID-19: A review" (Jayawardena et al.)
      Santacroce Luigi
      Diabetes & metabolic syndrome (2020), 14 (5), 927 ISSN:.
      There is no expanded citation for this reference.
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    47. 47
      Elsayed, Y. and Khan, N. A. (2020) Immunity-Boosting Spices and the Novel Coronavirus. ACS Chem. Neurosci. 11 (12), 1696– 1698,  DOI: 10.1021/acschemneuro.0c00239
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      47
      Immunity-Boosting Spices and the Novel Coronavirus
      Elsayed, Yehya; Khan, Naveed Ahmed
      ACS Chemical Neuroscience (2020), 11 (12), 1696-1698CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Although there is no reported genetic predisposition in contracting coronavirus disease 2019 (COVID-19), the mortality rate varies among different ethnic groups. Here we detd. potential correlation between COVID-19 and spice consumption. The data from 163 countries including total cases, total deaths, and total recovered were analyzed. It was obsd. that there is a clear interrelated prevalence between the total no. of COVID-19 cases per million population tested and the gram of spice supply per capita per day. Nations with lower consumptions of spices per capita showed greater no. of COVID-19 cases per million population. This is not surprising as herbs and spices are well-known to boost immunity. Although the precise mol. mechanisms assocd. with spices and immunity are not completely understood, our findings led us to hypothesize that spice consumption plays a role in our ability to fight COVID-19; however, intensive research is needed to det. the translational value of these findings.
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    48. 48
      Mitrani, R. D., Dabas, N., and Goldberger, J. J. (2020) COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Heart Rhythm  DOI: 10.1016/j.hrthm.2020.06.026
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      Lasrado, N. and Reddy, J. (2020) An overview of the immune mechanisms of viral myocarditis [published online ahead of print, 2020 Jul 28]. Rev. Med. Virol. e2131  DOI: 10.1002/rmv.2131
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      There is no corresponding record for this reference.
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