Karolina Raczkowska-Łabuda1, Justyna Kawa-Szeląg2, Jakub Jędrzychowski3, Justyna Popczyńska3, Martyna Kaplińska3, *Lidia Zawadzka-Głos1, Ernest Kuchar2
Olfactory disorders in children in the era of COVID-19 infection
Zaburzenia węchu u dzieci w dobie infekcji COVID-19
1Department of Pediatric Otolaryngology, Medical University of Warsaw, Poland
Head of Department: Associate Professor Lidia Zawadzka-Głos, MD, PhD
2Pediatrics with Clinical Decisions Unit, Second Medical Faculty, Medical University of Warsaw, Poland
Head of Department: Associate Professor Ernest Kuchar, MD, PhD
3Students’ Medical Association of Pediatric Otorhinolaryngology „OTORHINO”, Medical University of Warsaw, Poland
Streszczenie
Wstęp. Zaburzenia węchu i smaku, występujące niezależnie od nieżytu nosa, należą do charakterystycznych, wczesnych objawów zakażenia wirusem SARS-CoV-2. Manifestacja i nasilenie objawów różni się w zależności od wieku pacjenta czy chorób współwystępujących.
Cel pracy. Celem poniższego opracowania było zbadanie funkcji węchu w populacji pediatrycznej dotkniętej infekcją SARS-CoV-2, w celu pogłębienia wiedzy na temat odrębności symptomów tej choroby u dzieci.
Materiał i metody. Przeprowadzono prospektywne badanie kohortowe na grupie 51 pacjentów Oddziału Obserwacyjno-Izolacyjnego z potwierdzoną testem COVID-19 RT-PCR aktywną infekcją, które odniesiono do wyników równolicznej grupy kontrolnej – pacjentów Oddziału Laryngologii Dziecięcej WUM, bez potwierdzonej w wywiadzie infekcji SARS-CoV-2. Badanie przeprowadzono w okresie od stycznia 2022 do stycznia 2024 roku. Do oceny funkcji narządu węchu posłużono się 11-punktową skalą VAS (badanie subiektywne) oraz testem psychofizycznym Sniffin’ Sticks z adaptacją międzykulturową według Sorokowskiej i wsp.
Wyniki. Grupa dzieci młodszych wskazywała na lepszą kondycję węchu w skali VAS w przebiegu COVID-19, w stosunku do grupy nastolatków (p = 0,004). Podobnie, dzieci poniżej 12. roku życia osiągały lepszy poziom VAS w ocenie węchu po przebyciu infekcji COVID-19 (p = 0,02). Nie było statystycznie istotnych różnic dla kondycji zmysłu powonienia w okresie sprzed i po pandemii.
Dla testów IT oraz TT, w obu grupach wiekowych, poziom p-wartości jest większy niż standardowy próg istotności statystycznej 0,05, co oznacza, że nie mamy wystarczających dowodów, aby odrzucić hipotezę zerową mówiącą o tym, że obie próbki pochodzą z tego samego rozkładu. Innymi słowy, fakt przejścia infekcji COVID-19, w rocznej obserwacji, nie przekłada się na pogorszenie wyniku w teście IT i TT. Dla testu DT zaobserwowano statystycznie istotne różnice pomiędzy grupą badaną a kontrolną, w obu przedziałach wiekowych, uzyskując odpowiednio p-wartość: 0,0015 < 0,05 oraz p-wartość: 0,0175 < 0,05.
Wnioski. Nasze obserwacje sugerują pozytywną prognozę dla czułości węchu po infekcji SARS-CoV-2 w populacji pediatrycznej. Zaobserwowano tendencję do szybkiego wycofywania się zaburzeń węchu u dzieci. Zaburzenia zmysłu powonienia wyraźniej deklaruje młodzież (dzieci > 12. r.ż.) niż dzieci wczesnoszkolne czy przedszkolne.
Summary
Introduction. Olfactory and taste disorders, occurring independently of rhinitis, are among the characteristic early symptoms of SARS-CoV-2 virus infection. The manifestation and severity of symptoms varies depending on the age of the patient or comorbidities.
Aim. The aim of the following study was to investigate olfactory function in a pediatric population affected by SARS-CoV-2 infection, with the aim of improving knowledge of the distinctiveness of symptoms of this disease in children.
Material and methods. A prospective cohort study was conducted on a group of 51 patients of the Pediatric Observation and Isolation Department WUM with active infection confirmed by the COVID-19 RT-PCR test, which was related to the results of an equal control group – patients of the Pediatric ENT Department of WUM, without a history of confirmed SARS-CoV-2 infection. The study was carried out from January 2022 to January 2024. An 11-point VAS scale ( subjective examination) and the Sniffin’ Sticks psychophysical test with cross-cultural adaptation according to Sorokowska et al. were used to assess olfactory function.
Results. The group of younger children indicated better olfactory performance on the VAS scale during the course of COVID-19, compared to the group of teenagers (p = 0.004). Similarly, children younger than 12 years of age achieved a better VAS level in olfactory assessment after COVID-19 infection (p = 0.02). There were no statistically significant differences for olfactory conditioning in the pre- and post-pandemic periods.
For the IT and TT tests, in both age groups, the p-value level is greater than the standard threshold for statistical significance: 0.05, which means that we do not have enough evidence to reject the null hypothesis that the two samples come from the same distribution. In other words – the fact of passing COVID-19 infection, at one-year follow-up, does not translate into a worsening of the score in the IT and TT test. For the DT test, statistically significant differences were observed between the test and control groups, in both age ranges, obtaining p-value: 0.0015 < 0.05 and p-value: 0.0175 < 0.05, respectively.
Conclusions. Our observations suggest a positive prognosis for olfactory sensitivity after SARS-CoV-2 infection in the pediatric population. We observed a trend of rapid withdrawal of olfactory impairment in children. The declaration of a disorder of the sense of smell is more clearly declared by adolescents (children > 12 years of age) than by early childhood, or preschool children.
Introduction
Coronavirus-19 infection (COVID-19) is a multisystem, infectious disease with primary manifestation in the upper respiratory tract, caused by SARS-CoV-2 (severe acute respiratory syndrome – coronavirus-2) (1).
Already during the first wave of infection, it was observed that children are less susceptible to the disease, the course of infection in the pediatric population is milder and the prognosis is more optimistic than in adults (2, 3). Nowadays, it is a well-known fact that the characteristic symptom of the disease-often preceding other symptoms (in the case of virus variants preceding Omicron), is dysfunction of the sense of smell (4, 5). It should be noted that olfactory dysfunction is noted with different frequency in adults and children. While loss of smell is one of the most common symptoms in the general population, it accounts for only about 8% of cases in children (6).
In some situations, the lack of clear-cut symptoms can lead to an underestimation of the prevalence of the condition, hence the importance of exploring the nature of olfactory problems in the pediatric population. Undoubtedly, a challenge for the diagnostician is the difficulty in communicating with a patient with a poorer vocabulary and experience, or the lack of dedicated tests.
Aim
The aim of the following study was to investigate olfactory function in children affected by SARS-CoV-2 infection, in order to improve knowledge of the manifestation of this disease in the pediatric population.
Material and methods
Participants
A group of 51 patients of the Observational-Isolation Clinical Department of the Warsaw Medical University with active SARS-CoV-2 infection confirmed by COVID-19 RT-PCR (reverse transcription-polymerase chain reaction) test between January 2022 and January 2023 and a 51-patient control group of patients of the Pediatric Otolaryngology Clinical Department of the Warsaw Medical University with a negative test, within the same time frame, were recruited for the study.
The inclusion criteria were:
– age > 5 years,
– SARS-CoV-2 infection confirmed by RT-PCR test,
– consent of legal guardians to the minor’s participation in the study, and, for children ≥ 16 years of age, consent of the child.
Exclusion criteria are:
– age < 5 years,
– mental impairment that prevents cooperation with the olfactory examination,
– lack of willingness or ability to participate in the study,
– chronic sinusitis with a history of olfactory impairment,
– exacerbation of allergic rhinitis.
In the course of the study, the parents of patients and/or patients were presented with a written consent form for participation in olfactory testing. All testing was conducted in accordance with the Declaration of Helsinki. Due to the acute inflammatory state the patients were in at the time of the study, approval was obtained from the Bioethics Committee of the Warsaw Medical University.
Visual Analog Scale (before-during-after COVID-19 infection)
The participants in the study group were divided into two age categories: children under 12 and adolescents 12-18. All were then asked about the function of the olfactory organ in three periods: 1) before, 2) during, 3) after COVID-19 infection. An 11-point VAS scale was used to rank the responses, where it was assumed: „0” – total absence of olfactory impairment (excellent olfactory sensitivity), „10” – total absence of smell (anosmia).
Olfactometry (Psychophysical olfactory test)
The olfactory test was conducted using the Sniffin’ Sticks test® method (Burghardt®, Wedel, Germany). It was conducted by a physician recruiter (test and control group) and a group of three, physician-trained students (control group). During the study, the presenter removed the cap of the pen for about 3 seconds, during which time there was a 2-second presentation of the scent from a distance of about 2 cm from the patient’s anterior nostrils. The interval between the presentation of each pen was about 3 seconds. A triplet pen test was conducted for 3 tests in the order of Discrimination Test (DT), Identification Test (IT) and Threshold Test (TT).
Treshold test (TT) – consists of 16 triplets, for a total of 48 samples. In each triplet, one of the pen is saturated with an odorant of increasing, along with the sample number, concentration, the other two are unscented. The patient’s task is to identify the pen containing the odorant.
Discrimination test (DT) – consists of 16 triplets, with a total of 48 samples. Two pens contain the same odor, the third pen a different one. The patient’s task is to identify which pen contains a different odor than the other two.
Identification test (IT) – consists of 16 samples. The patient must determine the odor of the sample from among 4 suggestions provided by the tester (older patients could read the odor suggestions to themselves).
The olfactory test took about 40-60 minutes to complete. From each part, the patient received points, which were then summed. The results of the multicenter study by Hummel et al. (8), in which a score equal to or below 15 points was classified as anosmia, a score of 15-30 points as hyposmia, and above, or equal to 30 points as normosmia, were used as normative data.
Statistical analysis
SciPy v1.12.0 software was used for statistical analysis of the data. Some participants were excluded from the analysis due to their inability to cooperate or lack of understanding of the study’s principles.
Mann-Whitney U tests and Kolmogorov-Smirnov tests were performed for the collected data to analyze the differences between the „study group” and the „control group” in each age range. A p-value < 0.05 was considered significant with a 95% confidence interval.
Results
The study enrolled 96 patients (39 females, 57 males) aged between 5 and 18 (mean age: 11 (10.897)). There were 47 minors in the study group, including 20 girls and 27 boys with a mean age of 12 years. The control group consisted of 49 children, 19 girls and 30 boys, with an average age of 10 years (fig. 1).
Fig. 1. Graph showing inclusion and exclusion criteria for the study
Subjective assessment of olfactory organ condition
A group of younger children indicated a better olfactory condition on the VAS scale during the course of COVID-19, compared to a group of teenagers (p = 0.004). Similarly, children younger than 12 years of age achieved a better VAS level in olfactory assessment after COVID-19 infection (p = 0.02). There were no statistically significant differences for the condition of the sense of smell in the pre- and post-pandemic periods (fig. 2).
Fig. 2. Mean VAS scale score in subjective olfactory assessment before, during and after COVID-19 infection. Group sizes are nm = 21 (patients < 12 years old) and ns = 26 (children 12 years old and older)
The results of the sniff test conducted by the Sniffin’ Sticks test were statistically processed. Statistically significant differences were sought in the distributions of samples of children tested (with confirmed COVID-19 infection – „sick”) and children in the control group „healthy”, in two age ranges: under 12 years old – „young” and 12 years old and older – „elderly”.
Fig. 3. Distribution of TT test scores for successively (from the smallest ordinate) „elderly sick children”, „young sick children”, „elderly healthy children”, „young healthy children”
A Kolmogorov-Smirnov analysis was performed for the Treshold test (TT) (fig. 3), for children ≥ 12 years of age, yielding a p-value: 0.102 > 0.05. The test statistic indicates a difference between the distribution functions for the two samples. The p-value level is greater than the standard threshold for statistical significance: 0.05, which means that we do not have enough evidence to reject the null hypothesis that the two samples come from the same distribution. In other words, based on our analysis, we do not find statistically significant differences in the distributions of the two samples. That is, the fact that COVID-19 infection passed, at one-year follow-up, does not translate into a worsened score in the TT test.
For the younger children, Mann-Whitney and Kolmogorov-Smirnov U-analyses were performed, yielding a p-value of: 0.155 and a p-value of: 0.165, respectively. In both cases, the test result confirms that there is insufficient statistical evidence to conclude that there are differences in the distributions between the compared samples. Which brings us to the identical conclusion as for the group of older children: COVID-19 infection does not translate in a statistically significant way into TT test results.
Fig. 4. Distribution of DT test results for successively (from the smallest ordinate) „young sick children”, „elderly sick children”, „young healthy children”, „elderly healthy children”
For the Discrimination Test (DT) (fig. 4), a Mann-Whitney U-test was performed for children ≥ 12 years of age, which was then confirmed by the Kolmogorov-Smirnov test, obtaining a p-value of 0.0015 < 0.05 and a p-value of 0.0175, respectively. As with the Mann-Whitney U-test, the results of the Kolmogorov-Smirnov test confirm that the samples are not from the same distribution and the differences between them are statistically significant. This means that, based on the test performed, we can reject the null hypothesis that the distributions of the two samples are identical. Thus, in this age group, overtreatment with COVID-19 results in a worse DT test result.
For younger children, both analyses were also carried out, obtaining p-values of 0.00028 < 0.05 and p-values of 0.0027 < 0.05, respectively. In both cases, the test result confirms that there is sufficient statistical evidence to find differences in the distributions between the compared samples. Which brings us to the identical conclusion as for the group of older children: COVID-19 infection translates in a statistically significant way into DT test results.
Fig. 5. Distribution of IT test scores for successively (from the smallest ordinate) „elderly sick children”, „young sick children”, „elderly healthy children”, „young healthy children”
For the Identification test (IT) (fig. 5), a Kolmogorov-Smirnov analysis was performed for children ≥ 12 years of age, yielding a p-value: 0.0703 > 0.05. The p-value level is greater than the standard threshold for statistical significance: 0.05, which means that we do not have enough evidence to reject the null hypothesis that the two samples come from the same distribution. In other words, based on our analysis, we do not find statistically significant differences in the distributions of the two samples. That is, the fact of passing COVID-19 infection, at one-year follow-up, does not translate into a worsening of the score in the IT test.
An analogous situation was observed in the group of younger children, where Kolmogorov-Smirnov was also used, obtaining a p-value: 0.098 > 0.05. In both cases, the test result confirms that there is insufficient statistical evidence to find differences in the distributions between the compared samples. Which brings us to the identical conclusion as for the group of older children: COVID-19 infection does not translate in a statistically significant way into an IT test result.
Discussion
„Sniffin’ Sticks” test provides a calibrated psychophysical tool for a detailed, semi-objective assessment of the state of the organ of smell. The test requires active cooperation on the part of the patient; it enforces the maintenance of concentration for at least half an hour. For children, a test based on three independent procedures presents a considerable challenge. Hence, the basic criteria for inclusion in the study were age above 5 years, understanding of the test, and willingness to cooperate at each stage of the test. Due to the age of the patients and the cross-cultural adaptation of the test itself, it was necessary to modify some items of the identification subtest (IT). As proposed by Sorokowska and Hummel (9), only verbal discs were used and distractors for four items were modified. For item 2 („leather”) – glue was changed to „chewing gum”; for item 6 („lemon”) – „grapefruit” was changed to „cherry” and peach to „melon”; for item 8 („turpentine”) „menthol” was changed to „grass”; for item 11 („apple”) „melon” was changed to „pineapple”. In addition, for items 2. („leather”), 8. („turpentine”) and 11. („apple”), descriptive information was added in detail. „Leather” – often understood as the outer covering of the skin-was made more specific with the description „shoe leather”, „turpentine” – often a word completely misunderstood by children, was replaced with the expression „paint solvent”, and „apple”, which in Poland is typically associated with a red apple, was made more specific with „green apple”.
The study shows that adolescents – who are more self-aware – declared greater olfactory impairment on the VAS scale, during the course of the infection and after its withdrawal, relative to children under the age of 12. At the same time, the study indicates a discrepancy between the results of subjective tests (VAS) and psychophysical measures of olfactory functioning. Which may suggest a tendency to exaggerate complaints - mainly in the adolescent group (> 12 years old). A corollary of this observation is the conclusion that estimating the degree of olfactory impairment solely on the basis of self-assessment is not a reliable method. A similar observation can be found in the study by Cancellieri et al. (10). Differences in the degree of post-COVID olfactory damage in relation to age are also reported by Malcangi et al. (11). In the article, we find a multitude of theories explaining differences in the intensity of the degree of COVID-19 infection-dependent neurological damage, such as differences in angiotensin-converting enzyme 2 (ACE2) levels in the nasal mucosa, which determines the immune system response, or pre-existing endothelial damage and impaired cellular regeneration.
Overall, our observations suggest a positive prognosis for olfactory sensitivity after SARS-CoV-2 infection in the pediatric population.
We observed a statistically significant difference only for the discrimination test (DT), with no deviation in the identification (IT) and threshold (TT) tests. Similar results were obtained by Gözen et al. (13) for DT and IT in patients declaring and denying subjective sensation of loss of sense of smell. A study by Cancellieri et al. (10) found statistically significant differences in the IT test for the pediatric population.
According to Buonsenso et al. (12), 3 months after corona virus infection, only 2% of children still declared olfactory impairment. Similarly, in the observation of Rusetsky et al. (14), where all pediatric patients (52/52) reported full recovery after 2 months. Both publications are in agreement with our one-year observation.
Conclusions
We fully understand the limitations of our study, which indicates the rationale for deeper research on the function of the sense of slowness in the pediatric population. Loss of smell is a characteristic symptom of COVID-19 infection, although it is less common in the pediatric population than in adults. Declaration of disturbance of the sense of smell is more clearly declared by adolescents (children > 12 years of age) than by early childhood or preschool children. COVID-19 olfactory dysfunction tends to resolve quickly in the pediatric population. At one-year follow-up, there were no statistically significant features of permanent olfactory impairment in children.
Piśmiennictwo
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