While COVID is known for affecting the respiratory system, another more common symptom, anosmia, or the loss of smell, directs attention towards the brain. Anosmia is the total or partial loss of smell. It is the most common neurological symptom reported among patients with COVID and serves as a strong predictor for having the virus. COVID patients usually develop anosmia early on and most recover within several weeks. However, in some cases, a patient's sense of smell takes much longer to recover and there is the possibility of permanently losing their sense of smell.
Try out PMC Labs and tell us what you think. Learn More. The aim of the study was to conduct a systematic review of the literature to investigate the time of onset and duration of symptoms of loss of smell and taste in patients diagnosed with COVID The time of onset and duration of symptoms were considered primary outcomes. The sex and age of individuals, the geographical location of the study, the prevalence of symptoms, other associated symptoms, associated comorbidities, and the impact on quality of life and eating habits were considered secondary outcomes.
Our search generated 17 articles. Many of the studies reported that the onset of anosmia and ageusia occurred 4 to 5 days after the manifestation of other symptoms of the infection and that these symptoms started to disappear after one week, with more significant improvements in the first two weeks.
The present study concludes that the onset of symptoms of loss of smell and taste, associated with COVID, occurs 4 to 5 days after other symptoms, and that these symptoms last from 7 to 14 days. Findings, however, varied and there is therefore a need for further studies to clarify the occurrence of these symptoms.
This would help to provide early diagnosis and reduce contagion by the virus. The spread of the virus was very rapid, reaching pandemic status in early [ 2 ]. By the end of August , the World Health Organization WHO had registered 24,, confirmed cases and , confirmed deaths [ 3 ]. According to the WHO, by the end of August , Brazil had registered 3,, confirmed cases and , deaths [ 3 ]. The most prevalent symptoms in the first patients included fever, cough, myalgia and shortness of breath [ 4 ].
However, as the pandemic spread to more countries and the numbers of infected individuals increased, other signs and symptoms came to be viewed as clinical manifestations of the disease [ 5 ].
One unusual symptom in particular began to appear in an increasing number of patients: dysfunction of smell and taste - loss of sensitivity to taste and smell [ 6 ]. In South Korea, China and Italy, a large percentage of infected patients developed anosmia or hyposnomy [ 4 ]. In Italy, about More than two-thirds of those infected in Germany developed anosmia [ 4 ]. In Brazil, a study carried out with recovered patients, showed that had experienced sudden-onset anosmia and had developed loss of smell accompanied by nonspecific inflammatory symptoms [ 6 ].
Sudden changes in smell thus came to be seen as initial signs of COVID [ 7 ] and, anosmia, in the absence of other symptoms, such as rhinorrhea or nasal congestion, may be an indicator of SARS-CoV-2 infection [ [8] , [9] , [10] , [11] , [12] ]. In view of this, the Center for Disease Control and Prevention CDC added the loss of taste and smell to the list of signs and symptoms that may arise from the second to the fourteenth day after exposure to the virus.
During this time, there are generally no specific clinical manifestations, because it is the viral incubation period [ 1 ]. The Brazilian Academy of Rhinology and the Brazilian Association of Otorhinolaryngology and Cervical-Facial Surgery duly issued a warning that cases of anosmia, with or without concomitant ageusia, may indicate the presence of infection by COVID [ 6 ]. However, despite being a very prevalent symptom in patients with COVID, the onset time and duration of these symptoms has not been well established.
Understanding of this issue would contribute greatly to early diagnosis, thereby enabling prevention of further contagions and possible complications. We thus performed a systematic review of the literature to investigate the time of onset and duration of symptoms of loss of smell and taste in patients diagnosed with COVID A third reviewer BARBOSA, DAM was consulted when necessary and acted as a mediator in decisions regarding inclusion or exclusion criteria, on occasions when there was no agreement between the reviewers.
Data extraction was performed according to the eligibility criteria established for the study. Studies were excluded if they did not explain in detail the outcomes investigated in the present review or if they did not provide detailed explanation of their methodology. Case-reports, letters to the editor, literature reviews, systematic reviews, meta-analyses, and in vitro and animal studies were also excluded.
There were no restrictions regarding language or year of publication. The studies were evaluated using a list of twenty-six items, divided into nine evaluation criteria: study question, study population, subject comparability, exposure or intervention, measured results, statistical analysis, results, discussion, and funding or sponsorship [ 14 , 15 ].
The primary outcomes for reviewing the literature on loss of smell and taste in patients diagnosed with COVID were the time of onset and duration of symptoms. Secondary outcomes included the sex and age of individuals, the geographical location of the study, prevalence of symptoms, other associated symptoms, associated co-morbidities, and the impact on quality of life and eating habits.
Removal of duplicate articles reduced the total to , which title and abstract screening reduced further to 22 articles. These 22 studies underwent full-text analysis, resulting in the exclusion of 5 studies and generating a final total of 17 articles included for analysis, as shown in the flowchart presented in Fig. Table 1 shows the evaluation of the articles according to the points highlighted by West [ 14 ]. Evaluation of quality criteria revealed methodological shortcomings in some articles, including: failure to justify the sample size all articles included in the review ; failure to detail inclusion and exclusion criteria [ 8 , 9 , 12 , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] ]; analysis of individuals who were not tested for COVID [ [18] , [19] , [20] , [21] ]; failure to address the limitations of the study [ 15 , 21 ]; and failure to cite sources of financing, even if these did not exist [ 8 , 10 , 15 , 19 , 20 , [24] , [25] , [26] , [27] ].
The level of agreement between reviewers regarding analysis of data extraction and risk of bias was almost perfect Kappa: 0. Characterization of studies according to evaluation criteria highlighted by West et al. Kappa: 0. The results of studies of the time of onset and duration of symptoms of loss of smell and taste in patients diagnosed with COVID, as well as the sex and age of individuals, the geographical location of the study, the prevalence of symptoms, associated symptoms, associated comorbidities, and the impact on quality of life and eating habits, are summarized in Table 2.
All 17 articles provided data on the age and sex of individuals, although only five articles found an association between sex and alterations in the sense of taste or smell [ 10 , 12 , 15 , 24 , 25 ], with women presenting a higher prevalence of such alterations.
Only four articles found an association between age and olfactory and gustatory symptoms, [ 10 , 15 , 24 , 25 ], although these results were inconsistent. Two studies found that younger people presented a higher prevalence of these symptoms [ 10 , 25 ]; one study found that adults with a mean age of The studies covered by the present review provided data for countries on three continents, three articles were from Asia [ 21 , 23 , 24 ], five from North America [ 9 , 16 , 17 , 20 , 22 ], and 10 from Europe [ [8] , [9] , [10] , 12 , 15 , 18 , 19 , [25] , [26] , [27] ].
All articles reported alterations in the sense of smell and taste in patients with COVID, although, in Asian countries, the prevalence of olfactory and gustatory dysfunction reported was lower compared to North America and Europe. In China, the prevalence of such symptoms was 5. In North America and Europe, the prevalence varied from Many studies, however, reported that the onset of anosmia and ageusia occurred 4 to 5 days after the appearance of other symptoms of the infection [ 15 , 26 , 27 ].
The findings were inconsistent but, generally speaking, the symptoms begin to disappear after one week [ 9 , 15 , 24 ], and, in the first two weeks, significant improvement occurred [ [17] , [18] , [19] ]. This study looked only at individuals who had already presented with anosmia [ 9 ].
In relation to taste disorders, six studies reported a prevalence greater The most commonly mentioned were: fever [ 8 , 12 , 16 , 17 , [19] , [20] , [21] , [22] , [23] , [25] , [26] , [27] ], cough [ 8 , 10 , 12 , 15 , [19] , [20] , [21] , [22] , [23] , [25] , [26] , [27] ], headache [ 8 , 10 , 15 , 20 , 22 , 26 , 27 ], and fatigue [ 12 , 16 , 17 , 26 ].
Some studies also reported gastrointestinal symptoms [ 8 , [15] , [16] , [17] , 20 , 22 , 26 , 27 ]. Five of the studies covered by our review investigated co-morbidities present in patients diagnosed with COVID [ 10 , 22 , 23 , 25 , 26 ]. The most prevalent co-morbidities were systemic arterial hypertension [ 10 , 22 , 23 , 25 , 26 ], rhinitis [ 10 , 25 ], asthma [ 10 , 25 , 26 ], and cardiovascular disease [ 22 , 23 , 26 ].
The spread of COVID around the world has been accompanied by the appearance of symptoms that differ from a common flu [ 29 , 30 ].
Changes in smell and taste have been strongly associated with a positive diagnosis of infection by the new coronavirus [ 31 ]. However, the time of onset time and duration of these symptoms has yet to be clearly established. The present systematic review thus aimed to establish the time of onset and duration of symptoms of loss of smell and taste in patients diagnosed with COVID The tool used to assess risk of bias AHRQ [ 14 ] found that the articles reviewed were effectively addressed the proposed study question.
However, this probably occurred due to the lack of information on the prevalence of this novel disease. We also observed that the studies analyzed employed a variety of different methods and presented their findings in different ways, making it impossible to carry out a meta-analysis. All articles included in this review investigated both female and male individuals, but only five articles found any association between sex and changes in taste and smell [ 10 , 12 , 15 , 24 , 25 ].
Although men have a less favorable prognosis for COVID [ 33 ], the prevalence in women of changes in smell and taste was higher in the five studies reviewed [ 10 , 12 , 15 , 24 , 25 ]. The average age range was 38 to 65 years, with a predominance of adults and elderly people affected by the infection. One study cited working outside the home during the pandemic as an important risk factor for the transmission of the disease among adults, as this occasions more contact with people and, consequently, greater exposure to the virus [ 37 ].
The prevalence of smell and taste dysfunction appeared to be lower in Asia, compared to North America and Europe. It is thus possible to identify a change in the profile of the main symptoms as the disease passes through different countries. This may be related to the different strains of the virus that have been circulating since the beginning of the COVID pandemic. A meta-analysis carried out with cases of COVID in China, the country that presented the first cases of the disease, showed that the main symptoms were fever, cough, fatigue, sputum and dyspnea [ 39 ].
When the disease reached European countries, a change in symptoms occurred and olfactory and gustatory changes began to appear as clinical signs. Such signs may prove a great aid to diagnosis of COVID, since they are predominant symptoms in people affected by the virus [ 40 ].
Most patients with Sars-CoV-2 infection are considered asymptomatic and do not require hospitalization [ 10 ]. Symptomatic patients have symptoms such as fever, dry cough, shortness of breath, gastrointestinal symptoms and also symptoms that mainly affect smell and taste, in which there is a significant reduction in these senses.
Such symptoms have been reported mainly in countries in Europe and America [ 25 ]. Furthermore, a survey of patients found a prevalence of these symptoms of Even with these divergences, the presence of the two associated symptoms in individuals with suspected COVID is of great importance for the diagnosis of this infection, It can, in fact, be seen from the articles included in this review that, in patients with a positive or negative diagnosis, these changes in smell and taste were more likely to be present in patients with a positive diagnosis of the disease.
This association has also been observed in other studies of adult individuals with a positive diagnosis of COVID [ 42 , 43 ]. Some of the authors indicate that these changes may precede the development of other common symptoms of the disease, such as fever, shortness of breath, dry cough and fatigue [ 8 , 10 , 12 ].
This ranged from five days to four weeks, with an average of one to two weeks for recovery. More detailed investigation of the duration of these symptoms is, however, still required.
Two of the studies reviewed reported persistence of symptoms, even after recovery from the disease [ 10 , 15 ]. Furthermore, the impact of this persistence of olfactory and gustatory loss after the end of COVD infection is still unclear. We therefore stress the importance of conducting research that analyzes the time and persistence of symptoms associated with olfactory and gustatory disorders in patients with COVID, since the results found in the literature are scarce and present divergent findings.
The scientific literature considers a number of hypotheses regarding the pathogenic mechanisms associated with changes in smell and taste in patients with COVID and some of these takes into account the duration of sensory dysfunctions. One such hypothesis is that these disorders occur due to direct damage caused by the virus to olfactory and gustatory receptors [ 44 ].
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Any use of this site constitutes your agreement to the Terms and Conditions and Privacy Policy linked below. A single copy of these materials may be reprinted for noncommercial personal use only. Instead, ACE2 is expressed in cells that provide metabolic and structural support to olfactory sensory neurons, as well as certain populations of stem cells and blood vessel cells. The findings suggest that infection of nonneuronal cell types may be responsible for anosmia in COVID patients and help inform efforts to better understand the progression of the disease.
This implies that in most cases, SARS-CoV-2 infection is unlikely to permanently damage olfactory neural circuits and lead to persistent anosmia, Datta added, a condition that is associated with a variety of mental and social health issues, particularly depression and anxiety. Analyses of electronic health records indicate that COVID patients are 27 times more likely to have smell loss but are only around 2. Some studies have hinted that anosmia in COVID differs from anosmia caused by other viral infections, including by other coronaviruses.
For example, COVID patients typically recover their sense of smell over the course of weeks—much faster than the months it can take to recover from anosmia caused by a subset of viral infections known to directly damage olfactory sensory neurons. In addition, many viruses cause temporary loss of smell by triggering upper respiratory issues such as stuffy nose. They began by analyzing existing single-cell sequencing datasets that in total catalogued the genes expressed by hundreds of thousands of individual cells in the upper nasal cavities of humans, mice and nonhuman primates.
The team focused on the gene ACE2 , widely found in cells of the human respiratory tract, which encodes the main receptor protein that SARS-CoV-2 targets to gain entry into human cells. The analyses revealed that both ACE2 and TMPRSS2 are expressed by cells in the olfactory epithelium—a specialized tissue in the roof of the nasal cavity responsible for odor detection that houses olfactory sensory neurons and a variety of supporting cells.
Neither gene, however, was expressed by olfactory sensory neurons. By contrast, these neurons did express genes associated with the ability of other coronaviruses to enter cells.
The researchers found that two specific cell types in the olfactory epithelium expressed ACE2 at similar levels to what has been observed in cells of the lower respiratory tract, the most common targets of SARS-CoV-2, suggesting a vulnerability to infection.
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