Narcolepsy Incidence Increase During H1N1 Pandemic Period Not Driven by Pandemrix Vaccine, Chinese Report Suggests

Author(s):

Incidence of narcolepsy increased 4.17- and 1.42-fold during and after the 2009 H1N1 pandemic when compared with baseline.

Rolf Fronczek, MD

Using epidemiological data from a Chinese population collected from 1990 to 2017, investigators observed a substantial 3-fold increase in the incidence of narcolepsy during the 2009 H1N1 pandemic period. This was after ruling out a possible confounding factor of non-adjuvanted monovalent 2009 H1N1 vaccination used in the country, albeit at a low vaccination rate.

Led by Xiling Wang, PhD, School of Public Health, Fudan University, the cohort included 2869 eligible patients with narcolepsy enrolled from 15 hospitals known to diagnose cases. Findings showed that the incidence of narcolepsy before, during, and after the 2009 H1N1 pandemic was 0.83 (95% CI, 0.82-0.83), 3.07 (95% CI, 3.04-3.10), and 1.02 (95% CI, 1.01-1.02) per 100,000 person-years (PY), respectively. Incidence of narcolepsy decreased postpandemic, but remained slightly higher than that in the pre-pandemic period in most age groups.

The average annual incidence was 0.79 per 100,000 PY from 1990 to 2017 and 1.08 per 100,000 PY from 2003 to 2017 in mainland China, with the highest incidence observed in 2010 (3.74 per 100,000 PY). Incidence in children aged 5 to 9 years old was the highest among age groups (9.02 per 100,000 PY; 95% CI, 8.96-9.07) while the lowest incidence rate was seen in adults aged 60 years and older, at 0.03 (95% CI, 0.03-0.04) per 100,000 PY. Regarding sex, the incidence rate was higher in males (1.43 [95% CI, 1.43-1.44] per 100,000 PY) than females (0.72 [95% CI, 0.71-0.72] per 100,000 PY).

After adjusting for age group and sex, a Poisson regression model found a statistically significant increase in incidence of narcolepsy during and postpandemic as compared to the prepandemic period (incidence rate ratio [IRR], 4.17 [95% CI, 4.12-4.22]; IRR, 1.42 [95% CI, 1.41-1.44). A sensitivity analysis revealed that the pattern was robust for narcolepsy type 1 (NT1) cases or after excluding the effect of the H1N1 pandemic vaccine, Pandemrix. In some European countries, Pandemrix was widely deployed, and a clear 5-14- and 2-7-fold increased risk of narcolepsy related to the vaccine was observed in children and adults, respectively.²

During and after the pandemic, there was a significant increase in the proportion of NT1 among patients with narcolepsy (P <.001). Additionally, age at onset and diagnosis became 3 and 10 years younger during the pandemic period compared with prepandemic (P <.001). The number of sleep-onset rapid eye movement period (SOREMP) was higher among patients with onset during the pandemic than the rest of the patients (P <.001), and investigators found no statistically significant difference in HLA-DQB1*06:02 positivity rate over time (P = .084).

"This does not seem to leave a lot of room for doubt regarding the autoimmune nature of narcolepsy type 1. It is thus surprising that direct evidence for the suspected autoimmune process is still lacking," Rolf Fronczek, MD, neurologist, Leiden University Medical Center, and colleagues wrote in a related editorial.³

Fronczek et al added, "More than 20 years after the discovery of hypocretin deficiency in narcolepsy with cataplexy the ultimate question remains unsolved. What happens to the hypothalamic hypocretin neurons in narcolepsy type 1? Are the hypocretin neurons of genetically susceptible people indeed unrecoverably killed by T-cells that wrongly elicit an immune response to a self-antigen in hypocretin neurons after an immune trigger (or several triggers)? Or is the immune mechanism in reality aimed at another target outside hypocretin neurons? Are the hypocretin neurons really gone?"

In the data reported by Wang et al, patients with NT1 were 2 years younger than those with type 2 narcolepsy (9 years vs 11 years; P = .002) at onset and 3 years younger at diagnosis (13 years vs 16 years; P = .003). Patients with symptoms of cataplexy, hallucinations, or sleep paralysis accounted for 88%, 41%, and 31%, respectively. Patients with NT1 also demonstrated shorter sleep latency, a greater SOREMP number, and a higher positivity rate of HLA-DBQ1*06:02 than type 2 patients (all P <.001).

REFERENCES
1. Wang X, Xiao F, Wang Y, et al. Changed epidemiology of narcolepsy before, during, and after the 2009 H1N1 pandemic: a nationwide narcolepsy surveillance network study in mainland China, 1990-2017. Sleep. 2023;46(3). doi:10.1093/sleep/zsac325
2. Sarkanen T, Alakuijala APE, Dauvilliers YA, Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: systematic review and meta-analysis. 2018;38:177-186. doi:10.1016/j.smrv.2017.06.006
3. Gool JK, Schinkelshoek MS, Fronczek R. What triggered narcolepsy: H1N1 vaccination, virus, or both? Important lessons learned from China. Sleep. 2023;46(3). doi:10.1093/sleep/zsad005