In the first phase of this SR with meta-analysis, 5,743 articles were found in seven databases, but none in the gray literature. After excluding 304 duplicate studies, 5,439 were selected for reading titles and abstracts. 5,420 were excluded according to the established selection criteria (1,829 studies with patients with ODs associated with nasal obstruction or neurological causes; 1,220 due to missing information on treatments; 1,190 without olfactory data; 512 literature reviews; 668 experimental studies; and one Cohort), and 19 articles were selected for full reading. After the reading, six articles were excluded because their samples were composed of patients with obstructive nasal disease (table 1). However, of the 13 studies included in the qualitative analysis (table 2), five studies were unique in their treatment [10, 21–24] and four did not have enough data for quantitative analysis (meta-analysis) [25–28]. Thus, four studies were selected for the meta-analysis involving 336 patients [29–32] (table 3). The entire article selection process is described in figure 1, which shows the PRISMA flow diagram for inclusion.
Risk of bias assessment
Of the 13 included articles, three studies specified the blinding methods of participants and professionals, as well as the blinding of outcome assessors providing enough information to allow judgment [22,24,27].
Most studies presented a risk of uncertain bias, mainly due to the impossibility of judging by the following criteria: random sequence generation and allocation concealment, denoting an important selection bias; and many studies presented risk of uncertain bias for the item blinding of participants/professionals and for the item blinding of outcome assessments, denoting measurement bias.
The study by Reden et al. (2017), reports how Vitamin A was administered in the groups as a limitation ; the study by Poletti et al. (2016), states that possible differences in solubility may interfere in the effect of the molecular weight of odors . The quality analysis of the included articles is shown in table 4.
Regarding the general characteristics of the articles included in the qualitative analysis, seven studies were conducted in Germany and six in other countries (Table 1). Outcome measures were determined by symptom scores and objective methods of olfactory testing – with the Sniffin`Sticks test as the most common test used in the studies. Ten studies compared the mean TDI score ("T" - threshold, "D" - discrimination, "I" - identification) before and after drug treatment in NCSD (total of six drugs) [10, 21–28], while four compared the mean TDI score before and after olfactory training in NCSD [29–32] (table 3). Of the studies with drug treatment, five were the only ones for the drug they proposed to analyze (oral caroverine, oral vitamin A, intranasal insulin, intravenous pentoxifylline and oral lipoic acid) [10,21–24] and four were on intranasal sodium citrate [26–28]; however, studies with sodium citrate did not provide sufficient pre- and post-treatment data for meta-analysis.
Drug treatments for NCSD.
In a randomized controlled study, Quint et al. investigated the use of quinoxaline derivative caroverine to treat various sensorineural ODs, including post-viral NCSD . A total of 77 patients with NCSD were included in the study, 51 received oral caroverine for 4 weeks (120 mg/day) and 26 controls for 1 month. Olfactory sensitivity was assessed before and after treatment, and patients were blinded. The tests included the assessment of the odor threshold of n-butanol (BTT) and odor identification (Sniffin'Sticks test). Caroverine improved the thresholds (p <0.005) and odor identification (p <0.042) in patients with anosmia, and significantly improved the ability to identify odors (p <0.041) in patients with hyposmia.
The results showed that 13 of the 35 patients with anosmia in the treatment group improved the thresholds in BTT (6 responders had post-viral NCSD). Transitory nausea was reported by two patients and transitory headache by one patient. No severe adverse effects were reported.
2- Vitamin A
In a double-blind, controlled and randomized clinical trial with oral vitamin A in 52 patients with post-viral and post-traumatic NCSD, 26 participants received oral vitamin A (10,000 IU/day) and 26 received placebo for three months . The olfactory function was assessed through the Sniffin'Sticks test in which the patients were blinded, and through a standardized questionnaire. Forty-four percent of patients reported smell recovery, and 29% showed significant improvement in olfactory function. However, there was no significant difference between the results of patients who received oral vitamin A or placebo.
In a double-blind, controlled and randomized clinical trial with intranasal insulin in 38 patients with NCSD, 19 participants received intranasal insulin (40 IU), and 19 received placebo (saline) twice a week for four weeks . Olfactory function was assessed through the Connecticut Chemosensory Clinical Research Center (CCCRC) test at onset and four weeks after treatment.
The CCCRC test score in the intervention group was significantly higher in comparison with the placebo group (p = 0.01). Intranasal insulin appears to be effective in the treatment of NCSD.
4- Alpha-lipoic acid
A prospective, uncontrolled clinical trial investigated 23 patients with post-viral NCSD treated with oral alpha-lipoic acid. The administered regimen included alpha-lipoic acid (600 mg/day), for approximately 4.5 months ; there was no control group. The olfactory function was assessed through the Sniffin'Sticks test and the patients were blinded. Of the treated patients, 26% showed a moderate improvement in the TDI score (1.5≤TDI <5.5 points), and 35% showed a notable improvement (TDI≥5.5). The recovery of olfactory function appeared to be more evidenced (t = 2.56 [p = 0. 018]) in younger patients than in patients over 60 years (the age of 60 was the average of the group). Oral alpha-lipoic acid appears to be effective in the treatment of post-viral NCSD.
In a longitudinal study with pentoxifylline to treat diseases of the inner ear, 19 patients received intravenous pentoxifylline (400mg/day) . Olfactory function was assessed through the Sniffin'Sticks test before and after drug treatment. After pentoxifylline administration, patients demonstrated a decrease in the odor threshold towards lower odor concentrations (p = 0.01) and was increased in younger patients than in the elderly adults.
6- Sodium citrate
In the first randomized clinical trial by Whitcroft et al. (2016), with 57 patients with NCSD (post-viral, post-traumatic or idiopathic), one nostril was treated with sodium citrate (3.5g /140ml) and the other nostril with 0.9% sodium chloride . The Sniffin 'Sticks test was performed separately in each nostril. The patients were blinded to the side of the sodium citrate application. Compared with placebo, there was a significant improvement in the identification scores of participants with post-viral NCSD after treatment with sodium citrate. In the second clinical trial by Whitcroft et al. (2016) with 49 patients with post-viral NCSD, one nostril was treated with sodium citrate (3.5g/140ml) and the other nostril with 0.9% sodium chloride . The Sniffin 'Sticks test was performed separately in each nostril. The patients were blinded to the side of the sodium citrate application. There was a statistically significant improvement in olfactory thresholds after treatment with sodium citrate compared with placebo in all patients (mean improvement of 0.87 ± 2.68 points, p = 0.04) and in the analysis of subgroups in those with hyposmia (mean improvement of 1.15 ± 2.37 points, p = 0.02).
In a randomized clinical trial with 31 patients with NCSD (post-viral, post-traumatic or idiopathic), each patient’s olfaction was assessed twice . On the first day, olfaction was tested before and after intranasal administration of 0.9% sodium chloride in each nostril; on the third day, the same patients’ olfaction was tested before and after intranasal administration of sodium citrate (3.5g/140ml). The olfactory function was assessed through the Sniffin'Sticks test. Thirty patients (96.8%) improved their scores in less than an hour after using sodium citrate.
In a randomized, double-blind clinical trial with 55 patients with NCSD (post-viral, post-traumatic or idiopathic), 31 participants received intranasal sodium citrate (3.5g/140ml), and 24 received 0.9% sodium chloride . The olfactory thresholds were assessed through a test using phenylethyl alcohol (roses), 1-butanol (pear), acetic acid (vinegar) and eucalyptol (menthol), previously validated by the same authors. A significant effect was observed in the intervention group for phenylethyl alcohol and 1-butanol and eucalyptol when compared to control group (p <0.05); 32% of patients treated with sodium citrate showed an improvement in sensitivity to some of the odors.
Thus, intranasal sodium citrate appears to be effective in the treatment of NCSD, including post-viral cases, with a temporary effect lasting between 30 and 60 minutes.
Effect of olfactory training on NCSD
On the topic olfactory training, four articles and 336 patients were selected; the articles studied olfactory training with four odors: phenyl ethanol (rose), menthol (mint), citronellal (lemon) and eugenol (clove), twice a day (morning and night), instructing the patient to smell each substance for 10 seconds, and 10 seconds of interval between them.
The research carried out the meta-analysis of the four articles that performed olfactory training for at least three months; the improvement in olfaction (increase in mean TDI score) after olfactory training (SMD = 5.99; 95% confidence interval (CI) [4.68, 7.31], p <0.00001) was statistically higher than in pre-training (fig. 2). Considering the causes of NCSD in these articles, all studies had patients with sequelae after viral infection, and in one of them, the sample was also composed of patients with post-traumatic sequelae and idiopathic causes ; therefore, a subgroup meta-analysis was carried out with the three studies whose sample was composed with only post-viral NCSD cases and with the data referring to the group with post-viral NCSD from the study with mixed sample; this subgroup meta-analysis also showed an improvement in olfaction (increased mean TDI score) after olfactory training (SMD = 5.18; 95% confidence interval (CI) [4.12, 6.23], p <0.00001) was statistically higher than in the pre-training (fig.3); the data from the used olfactory training and the results can be seen in table 2. The olfactory training improved the mean TDI score in all studies, and especially in patients with post-viral NCSD.