Friday, December 8, 2023
| Characteristic | Aseptic meningitis, n = 24 | Encephalitis, n = 8 | Guillain-Barré syndrome, n = 3‡ | Myelitis, n = 2‡ | ADEM, n = 2‡ | Unclassified† n = 3‡ |
|---|---|---|---|---|---|---|
| Age, y, median (IQR) [range] | 36 (23.75–46.75) | 40 (30.25–58.25) | 59 (43–73) | 33 [25–41] | 37 [22–52] | 28 [25–50] |
| Sex, no (%) | ||||||
| F | 7 (29) | 5 (62) | 1 (33) | 2 (100) | 1 (50) | 0 |
| M | 17 (71) | 3 (38) | 2 (67) | 0 | 1 (50) | 3 (100) |
| Vaccine–symptom interval, d, median (IQR) [range] | 17 (7.75–20.00) | 7 (3.50–17.25) | 16 [14–31] | 11.5 [0–23] | 10 [5–15] | 13 [3–29] |
| No. full/fractional/unknown doses | 18/4/2 | 5/3/0 | 3/0/0 | 1/1/0 | 1/1/0 | 2/0/1 |
| YF virus IgM in CSF, reactive/total tested | 10/17 | 4/7 | 0/2 | 0/1 | 1/2 | 0/1 |
| YF virus in CSF detected by PCR, detected/total tested | 0/17 | 0/6 | 0/2 | 0/1 | 0/1 | 0/1 |
| BC level of diagnostic certainty, no. cases | ||||||
| Level 1 | 17 | 0 | 1 | 0 | 2 | NA |
| Level 2 | 7 | 8 | 2 | 2 | 0 | NA |
| Brazil MoH/CDC classification, no. cases | Level 1 NRL: 21; level 2 NRT: 1; definite NRT: 1; suspected NRT: 1 | Level 1 NRL: 2; level 2 NRT: 3; definite NRT: 2; suspected NRT: 1 | Level 2 PNS: 1; probable PNS:2 | Level 1 NRL: 2 | Probable CNS: 2 | Level 1 NRL: 3 |
Table 1. Diagnostic certainty, clinical, epidemiologic, and immunologic investigations for 42 patients with suspected yellow fever vaccine–associated neurologic disease, according to Brighton Collaboration classification criteria, São Paulo, Brazil, 2017–2018*
*ADEM, acute disseminated encephalomyelitis; BC, Brighton Collaboration; CDC, Centers for Disease Control and Prevention); CNS, autoimmune neurologic disease with central nervous system involvement; CSF, cerebrospinal fluid; IQR, interquartile range; NA, not applicable; NRL, neurologic disease; NRT, neurotropic disease; MoH, Ministry of Health; PNS, autoimmune neurologic disease with peripheral nervous system involvement; YF, yellow fever.
†Includes 1 case of ataxia, 1 of opsoclonus-myoclonus-ataxia, 1 case of optic neuritis.
‡In groups with <5 cases, range is substituted for IQR.
| Variable | Aseptic meningitis, n = 24 | Encephalitis, n = 8 | Guillain-Barré syndrome, n = 3‡ | Myelitis, n = 2‡ | ADEM, n = 2‡ | Unclassified,† n = 3‡ |
|---|---|---|---|---|---|---|
| CSF parameters§ | ||||||
| Leukocytes >5, no. (%) | 24 (100) | 7 (87.5) | 1 (33) | 0 | 1 (50) | 1 (33) |
| Leukocytes, total/mm3, median (IQR) [range] | 76.50 (53–207.5) | 30 (13–70) | 1 [0–32] | 1 [0–2] | 4.5 [2–7] | 2 [1–12] |
| Lymphocytes, median (IQR) [range] | 73 (65.5–88.0) | 85 (71–93) | 51.5 [3 –71] | 75 [75–75] | 79,5 [79–80] | 80 [73–92] |
| Neutrophils, median (IQR) [range] | 10 (3.5–25.0) | 3 (0.5–6.0) | 23.5 [13–34] | 16 [16–16] | 19.5 [19–20] | 2 [1–3] |
| Erythrocytes, total/mm3, median (IQR) [range] | 2 (1–12) | 5.5 (1–640.50) | 302 [249–355] | 26 [1–52] | 985.5 [131–1,840] | 0 [0–3] |
| Total protein, mg/dL, median (IQR) [range] | 53.5 (48–71.5) | 60 (47.5–67) | 53 [31–66] | 27.5 [23–32] | 61 [41 – 81] | 46 [26–51] |
| Total glucose, mg/dL, median (IQR) [range] | 60 (52.5–64.5) | 66 (54.5–92.5) | 60.5 [50–71] | 72 [66–78] | 62.5 [54–71] | |
| MRI findings, no. cases | Leptomeningeal enhancement, 1; unremarkable, 3 | Leptomeningeal enhancement, 1; unremarkable, 5 | Facial nerve enhancement, 1; unremarkable, 1 | Longitudinally extensive myelitis,1; partial myelitis, 1 | White matter abnormalities and extensive myelitis,1; brainstem and cerebellar peduncles abnormalities, 1 | Bilateral optic nerve abnormalities,1; unremarkable, 1 |
| EEG/EMG findings, no. cases | EEG: disorganized background, 2; unremarkable, 2 | EEG: disorganized background, 6 | EMG: AMAN, 1 | ND | ND | ND |
Table 2. Laboratory, neurophysiologic, and imaging characteristics for 42 patients with suspect YEL-AND, according to classification with the Brighton Collaboration criteria, São Paulo, Brazil, 2017–2018*
*ADEM, acute disseminated encephalomyelitis; AMAN, axonal motor polyneuropathy; CSF, cerebrospinal fluid; EEG, electroencephalography; EMG, electromyography; IQR, interquartile range; ND, not done; YF, yellow fever.
†Includes 1 case of ataxia, 1 of opsoclonus-myoclonus-ataxia, and 1 of optic neuritis.
‡In groups with <5 cases, range was substituted for IQR.
§All patients underwent lumbar puncture and CSF analysis.
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Yellow fever (YF) vaccine can cause neurologic complications. We examined YF vaccine–associated neurologic disease reported from 3 tertiary referral centers in São Paulo, Brazil, during 2017–2018 and compared the performance of criteria established by the Yellow Fever Vaccine Working Group/Centers for Disease Control and Prevention and the Brighton Collaboration. Among 50 patients who met inclusion criteria, 32 had meningoencephalitis (14 with reactive YF IgM in cerebrospinal fluid), 2 died, and 1 may have transmitted infection to an infant through breast milk. Of 7 cases of autoimmune neurologic disease after YF vaccination, 2 were acute disseminated encephalomyelitis, 2 myelitis, and 3 Guillain-Barré syndrome. Neurologic disease can follow fractional vaccine doses, and novel potential vaccine-associated syndromes include autoimmune encephalitis, opsoclonus-myoclonus-ataxia syndrome, optic neuritis, and ataxia. Although the Brighton Collaboration criteria lack direct vaccine causal assessment, they are more inclusive than the Centers for Disease Control and Prevention criteria.
Yellow fever (YF) is an acute febrile illness caused by a mosquito-borne arbovirus of the family Flaviviridae. The disease is endemic to the tropical forests of South America and Africa, periodically causing outbreaks and epidemics. The clinical manifestations of YF range from asymptomatic to severe with jaundice and hemorrhage[1]. The primary preventive strategy is vaccination. The 3 substrains of the 17D vaccine virus currently used for vaccine production (17DD, 17D-204, and 17D-213) have similar safety and immunogenicity profiles[1,2]. The main YF vaccine available in Brazil is 17DD, which is produced by Bio-Manguinhos-Fiocruz (https://www.bio.fiocruz.br). YF vaccine–associated neurologic disease (YEL-AND) is a rare but potentially severe adverse event following immunization (AEFI). The incidence of YEL-AND varies between studies; in the United States and Brazil, the estimated range is 0.2–0.94 cases/100,000 doses[3–6].
In 2002, the Centers for Disease Control and Prevention (CDC) formed the Yellow Fever Vaccine Safety Working Group, a panel of vaccine safety experts, which proposed a surveillance case definition for YEL-AND. The clinical manifestations included in YEL-AND are meningoencephalitis (neurotropic disease), Guillain-Barré syndrome (GBS), and acute disseminated encephalomyelitis (ADEM)[7].
In 2004, the Brighton Collaboration (BC) was commissioned as a vaccine safety research network to develop standardized case definitions for AEFI[8]. The first BC case definition of aseptic meningitis was issued in 2007[9]. Subsequent BC criteria were established for encephalitis, ADEM[10], and myelitis[10], all distinct from aseptic meningitis[9] and each other.
There are fundamental differences between the BC and CDC case definitions. The CDC criteria require that acute brain lesions or dysfunction be evidenced by electroencephalography (EEG) or magnetic resonance imaging (MRI) and exclude causality when the vaccine–symptom interval exceeds 30 days. These criteria render them poorly suited to diagnose YEL-AND in resource-limited settings or during massive vaccination campaigns. The BC criteria encompass a broader range of neurologic syndromes, including aseptic meningitis and myelitis. However, in contrast to the CDC criteria, they lack specific criteria to determine vaccine causality (YF virus IgM in cerebrospinal fluid [CSF]). Both criteria focus on major neurologic syndromes and overlook the rare and atypical ones. Although recent publications used the newer BC criteria[6], CDC case definitions are still used routinely by the Brazil Ministry of Health, as seen in the Epidemiologic Surveillance of Post-Vaccination Adverse Events manual[11].
During 2017 and 2018, YF virus transmission increased in the southeastern region of Brazil (states of Rio de Janeiro, Espírito Santo, and those parts of São Paulo where the vaccination schedule did not include YF vaccine). In response to this outbreak, the National Immunization Program launched a massive vaccination campaign in the São Paulo metropolitan area. During 2017–2018, a total of 6 million full doses (0.5 mL) and 4 million fractional doses (0.1 mL) of 17DD were administered throughout the São Paulo metropolitan area (E. Gatti Fernandes, unpub. data). We describe suspected YEL-AND cases from tertiary centers in the city of São Paulo during the 2017–2018 vaccination campaign, identify differences between the CDC and BC classification criteria, and describe novel atypical syndromes.
