Wednesday, December 6, 2023
| Characteristic | Patient | ||||||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | |
| Age,y/sex | 28/F | 37/F | 55/F | 20/F | 57/M | 31/F | 27/F |
| Days from illness onset | 3 | 2 | 10 | 5 | 3 | 4 | 3 |
| Medical history | Uncontrolled hyperthyroidism | Unremarkable | Influenza A(H3N2) virus encephalitis in 2012 | Treated for Russell−Silver syndrome | Unremarkable | Recent breast implants | Unremarkable |
| Leukocyte count, cells/mm3 | 2 | 2 | 10 | 5 | 2 | 3 | 13 |
| CSF | |||||||
| Protein, g/L | 0.143 | 0.270 | 2.305 | 0.251 | 0.313 | 0.162 | 7.156 |
| Glucose, g/L | 0.61 | 0.50 | 0.74 | 1.07 | 0.55 | 0.71 | 1.22 |
| Chloride, g/L | ND | ND | 7.60 | 6.78 | 7.10 | 6.80 | 7.02 |
| Virus type | B seq EPI_ISL_179707 | B seq EPI_ISL_179711 | B | B | B seq EPI_ISL_182519 | B | B seq EPI_ISL_182518 |
| Cerebral imaging result | MRI, abnormal† | CT, normal | MRI, abnormal‡ | MRI, normal | MRI, normal | NA | MRI, abnormal§ |
| Diagnosis | Confirmed encephalitis | Possible encephalitis | Confirmed encephalitis | Confirmed encephalitis | Possible encephalitis | Cerebellar ataxia | Confirmed encephalitis |
| Length of hospitalization, d | 7 | 9 | 18 | 17 | 10 | 5 | 3 |
| Outcome | Died | Complete resolution | Complete resolution | Complete resolution | Complete resolution | Complete resolution | Died |
| Clinical findings | Fever, headache, sleepiness, left upper limb motor deficit, coma, GCS score 3–4 | Fever, headache, sleepiness, photophobia, vertigo, stiff neck, positive Romberg sign | Fever, confusion, photophobia, dizziness, right facial paralysis, aphasia, stiff neck, coma, GCS score 8 | Fever, agitation, nystagmus, stiff neck, coma, GCS score 9–10 | Fever, headache, dysarthria, right side motor deficit, vomiting | Fever, headache, vomiting, vertigo, photophobia, ataxia, positive Romberg sign, movement and balance disorder | Fever, headache, vomiting, lethargy, aphasia, upward deviation of eyes, seizures, coma, GCS score 3 |
Table. Characteristics of 7 patients with neurologic complications of influenza B virus infection, Romania*
*All patients showed negative RT-PCR results for influenza B virus in CSF. CSF, cerebrospinal fluid; CT, computed tomography; GCS, Glasgow coma scale; MRI, magnetic resonance imaging; NA, not available; ND, not determined.
†MRI on day 3. See Figure 1 for a detailed description.
‡MRI on day 8. See Figure 2 for a detailed description.
§MRI on day 2 showed multiple areas of hyperintensities.
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We report an unusually high number of adults infected with influenza B virus who had neurologic complications at a tertiary care facility in Romania. Influenza B neurologic manifestations have been reported mainly in children. In Japan in 1998–1999, an outbreak of influenza-associated encephalitis/encephalopathy (148 cases, mostly linked with influenza A/H3N2 infection, only 17 with influenza B viruses) was observed primarily in children <5 years of age.[16] In a 2-year National British Surveillance study, 25 cases (21 in children) of neurologic disorders were identified in patients with influenza in the United Kingdom, but only 4 of these patients (all children) were infected with influenza B virus.[17] Eleven cases of neurologic complications in children with influenza B virus infection were reported in Taiwan in 2006.[18] Other cases were also reported: 1 case of influenza B virus–associated optic neuritis after meningoencephalitis in a 10-year-old boy in Italy,[19] and 1 case of influenza B virus–associated acute necrotizing encephalopathy in a 3-year-old boy in North America.[20]
Sporadic cases of influenza B virus with neurologic manifestations in adults have also been reported: 2 adults with influenza B virus–associated encephalopathy,[21] 1 person with nonconvulsive epilepticus after influenza virus B infection,[22] and 6 of 15 patients with influenza B virus–associated encephalitis.[7] In our study, we report 7 case-patients with influenza B virus–associated neurologic complications; 2 of these case-patients died. In Romania during the 2014–15 influenza season, the mortality rate for patients with confirmed influenza B virus infections was 1.7%.[12] In the tertiary care facility we studied, the overall mortality rate for patients infected with influenza B virus was 9.3% (3/32 confirmed case-patients), and the mortality rate for patients with influenza B virus–related neurologic complications was 28.5% (2/7 adult case-patients). All patients with neurologic complications admitted to the ICU who required intubation and mechanical ventilation did not have respiratory complications, the 2 deaths were caused by neurologic manifestations, not respiratory failure.
Although the 2014–15 influenza season in Romania was severe, older persons were less frequently infected (12.8% of ILI cases recorded were in patients >65 years of age), but hospitalization rates increased with age (from 23.7% in persons <0–1 year of age to 36.7% in persons 15–49 years of age, and 61.5% in persons >65 years of age).[12] The high mortality rate is not necessarily representative of the severity of influenza B virus infection because persons with severe cases are generally referred to the tertiary care facility. However, these data highlight the potentially severe progression of influenza B virus infection in adults. This severe evolution has been reported in children. In the United States in 2010–11, influenza B viruses were involved in 38% of deaths in children caused by influenza.[23] In Japan, a 6-year national surveillance identified 50 patients (median age 4.5 years) with of influenza B virus–associated encephalopathy/encephalitis, of whom 7 (14%) died.[24]
Most patients in our study had no previous concurrent conditions. One patient (patient 3) had a prior episode of influenza-related encephalitis with the same clinical pattern as the present infection (the previous infection was diagnosed at the same hospital in 2012). At that time, the isolated virus was identified as influenza A(H3N2) virus. This isolate was not tested for genetic mutations that might predispose a person to recurrent encephalitis. However, such infections have been reported in a family infected with a virus containing a Ran binding protein 2 mutation, which is autosomal dominantly transmitted.[17,25]
In our study we isolated virus from nasopharyngeal samples; none of the CSF samples were positive for virus nucleic acids. However, influenza viruses are rarely identified in the CSF.[2,26] Abnormal findings for CSF were observed in 3 patients with encephalitis who required hospitalization in the ICU (1 patient died). Two patients, both admitted to the ICU, showed major increases in protein levels in CSF, a profile usually seen in patients with severe cases.[2,26,27] Although influenza virus nucleic acids have been detected in brain tissue, ependymal, and Purkinje cells,[28] several studies have emphasized the role of neuroinflammation in the pathogenesis of neurologic complications mediated by high levels of proinflammatory cytokines in the CSF (cytokine storm), increased systemic inflammatory responses, or blood–brain barrier dysfunction.[29–34] However, neurotropism has been investigated mainly for influenza A viruses; information on neurovirulence caused by influenza B viruses is lacking.
All isolated virus strains belonged to B(Yam)-lineage clade 3, representative strain B/Phuket/3073/2013, which belongs to a distinct antigenic cluster different from that recommended by the World Health Organization for vaccination in the Northern Hemisphere during the 2014–15 influenza season. This strain and the vaccine strain (B/Massachusetts/02/2012–like from the B/Yamagata/16/88 lineage) were cocirculating in Romania during the 2014–15 influenza season.[35] Antigenic mismatch between a vaccine strain and a strain that prevails in a specific influenza season is common for influenza B viruses because of cocirculation of the Victoria and Yamagata lineages,[36] and additional challenges are increased by antigenic drift of the B/Yamagata strain.
None of the patients in our study in whom neurologic complications developed were vaccinated against influenza. Vaccination coverage in Romania was extremely low; only 2.5% of the general population were vaccinated.[12] The efficacy of the 2014–15 vaccine against influenza B virus was modest, ranging from 41% in persons 15–59 years of age to 62% in persons <14 years of age, as reported by a multicenter case–control study in the population in Europe.[37] Some studies support the inclusion of both lineages of influenza B virus in the vaccine to reduce illness,[38] although others suggest a more cautious approach, arguing that addition of a second influenza B virus lineage leads to a modest reduction in influenza-associated outcomes.[39] Recently, a hedging strategy for selection of the influenza B virus lineage included in the standard trivalent vaccine has been suggested as the most effective in terms of long-term protection rates.[40]
This study had several limitations. A cluster of severe cases is not uncommon in a tertiary care facility with an ICU, which might lead to overestimation of the neurologic complication rate. Nevertheless, the hospital admissions we analyzed are representative for Romania (18,710 admissions in 2015 for a 500-bed hospital that covers the capital city of Bucharest and 8 adjacent counties in Romania; ≈3 million inhabitants). Oseltamivir was given to all patients, often with a delay after infection onset because of late presentation. Although neuraminidase inhibitors are considered more effective against influenza A viruses than influenza B viruses, the mechanisms of influenza B virus drug resistance are not well understood.[41] Sequencing the isolated strains was successful for isolates from 4 of the patients. Lack of amplification for the other 3 isolates could be partially associated with low levels of nucleic acids in the clinical specimens and lower sensitivity of the amplification procedures used for sequencing than the techniques used for initial virus detection.
In conclusion, we report that influenza B virus infection can cause a severe clinical course in adults, with neurologic complications in a large number of patients. Continuous evolution of influenza viruses can give rise to virulent strains that escape the immune response, particularly when a large part of the population remains unvaccinated.
