Yellow fever vaccine-associated adverse events following extensive immunization in Argentina

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ARTICLE IN PRESS Model

VAC 14994 1–7

Vaccine xxx (2014) xxx– xxx

Contents lists available at ScienceDirect

Vaccine

jou rn al hom ep age: www.elsev ier .com/ locat e/vacc ine

ellow fever vaccine-associated adverse events following extensivemmunization in Argentina

ristián Biscayarta,∗, María Eugenia Pérez Carregaa, Sandra Sagradinia, Ángela Gentileb,aniel Stecherc, Tomás Ordunad, Silvia Bentancourte, Salvador García Jiménezf,uis Pedro Flynng, Gabriel Pirán Arceh, María Andrea Uboldi i, Laura Bugnai,aría Alejandra Morales j, Clara Digilio j, Cintia Fabbri j, Delia Enría j,áximo Diosquea, Carla Vizzotti a

Programa Nacional de Control de Enfermedades Inmunoprevenibles, Ministerio de Salud de la Nación, ArgentinaSociedad Argentina de Pediatría, ArgentinaSociedad Argentina de Infectología, ArgentinaSociedad Latinoamericana de Medicina del Viajero, ArgentinaAdministración Nacional de Medicamentos, Alimentos y Tecnología Médica, ArgentinaPan American Health Organization, ArgentinaSanatorio Británico, Rosario, ArgentinaSanatorio Rivadavia, San Luis, ArgentinaDirección Provincial de Promoción y Prevención de la Salud, Provincia de Santa Fe, ArgentinaInstituto Nacional de Enfermedades Virales Humanas “Dr. Julio I. Maiztegui”, Pergamino, Argentina

r t i c l e i n f o

rticle history:eceived 1 April 2013eceived in revised form 7 January 2014ccepted 8 January 2014vailable online xxx

eywords:

a b s t r a c t

As a consequence of YF outbreaks that hit Brazil, Argentina, and Paraguay in 2008–2009, a significantdemand for YF vaccination was subsequently observed in Argentina, a country where the usual vaccinerecommendations are restricted to provinces that border Brazil, Paraguay, and Bolivia. The goal of thispaper is to describe the adverse events following immunization (AEFI) against YF in Argentina duringthe outbreak in the northeastern province of Misiones, which occurred from January 2008 to January2009. During this time, a total of nine cases were reported, almost two million doses of vaccine were

ellow fever vaccineafetyrgentinaevere adverse events

administered, and a total of 165 AEFI were reported from different provinces. Case study analyses wereperformed using two AEFI classifications. Forty-nine events were classified as related to the YF vaccine(24 serious and 1 fatal case), and 12 events were classified as inconclusive. As the use of the YF 17Dvaccine can be a challenge to health systems of countries with different endemicity patterns, a carefulclinical and epidemiological evaluation should be performed before its prescription to minimize seriousadverse events.

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. Introduction

Argentina’s northeastern provinces are considered yellow feverYF) transitional areas [1]. Wild YF occurs through a cycle sus-ained by mosquitoes of the genera Haemagogus and Sabethes [2–4].egarding the role of non-human primates of the New World inhe infection cycle, it is known that howler monkeys (Alouatta spp.)uickly succumb to YF infection; thus they are considered sentinels

Please cite this article in press as: Biscayart C, et al. Yellow fever vaccine-assoVaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.01.015

f sylvatic YF activity [5]. Nonetheless, large epizootics have onlyecently been reported in this region.

∗ Corresponding author. Tel.: +54 11 4379 9018; fax: +54 11 4379 4806.E-mail address: [email protected] (C. Biscayart).

264-410X/$ – see front matter © 2014 Published by Elsevier Ltd.ttp://dx.doi.org/10.1016/j.vaccine.2014.01.015

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© 2014 Published by Elsevier Ltd.

Between December 2007 and April 2009, YF outbreaks affectedcentral and southern states in Brazil [6], Paraguay [7], and Argentina[8]. Increased vaccination demand occurred, particularly from trav-elers to beach resorts in Brazil for whom vaccination was notrecommended by the public health authorities, and especially frompeople who were not due to travel. Until the occurrence of thisoutbreak, Argentina had not a large experience using the YF 17Dvaccine. In 2007, it was incorporated into the routine vaccinationcalendar of provinces in the North after epizootics in Rio Grandedo Sul [9], a Brazilian state that borders the provinces of Corrientesand Misiones in Argentina, were confirmed.

ciated adverse events following extensive immunization in Argentina.

Since 2001, when the first reports of YF vaccine-associated vis-cerotropic disease (YEL-AVD) were published [10], safety aspectsregarding the use of this live-attenuated vaccine have emerged.YF vaccine-associated neurological disease (YEL-AND) had

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reviously been reported in infants who were administered therench neurotropic vaccine which was grown in mouse brains11]. Subsequent surveillance revealed that neurologic events withhe 17D vaccine could also occur, especially in infants <6 monthsf age [12]. The extensive use of YF vaccine during the outbreakf 2008–2009 in Argentina encouraged surveillance for adversevents following immunization (AEFI). The purpose of this paper iso present and describe Argentina’s health system experience withF vaccine AEFI after its exceptional use in a short period of time.

. Methods

AEFI is defined as any untoward medical occurrence in a per-on following immunization. Argentina’s AEFI surveillance systems passive, and was initiated in 2005 by a formal AEFI studyommittee. Notification is sent to the National Food, Drug and Med-cal Technology Regulatory Agency (ANMAT) and/or the Nationalmmunization Program (ProNaCEI) after a health worker detects aase and fills out a case report form (including patient demographicata, date of vaccination, vaccine, batch, date of expiration, site andoute of administration, description of the disease, date of onset,linical manifestations and course, diagnostic tests, management,nd follow-up aspects). A case investigation and preliminary anal-sis is conducted by the local immunization program, and analysisnd final case classification is done by a national AEFI committeeesigned by the ministry of health. Committee members includexperts in different fields (e.g., public health, immunization, inter-al medicine, neurology, and pharmacology).

To analyze AEFIs linked to YF vaccine in this context, causal-ty was reviewed by an ad hoc committee led by authoritiesrom ProNaCEI and ANMAT, with the participation of experts froman American Health Organization (PAHO), National Institute foruman Viral Infections (INEVH), and scientific societies such as

he Latin American Society for Travel Medicine (SLAMVI), Infec-ious Diseases Society of Argentina (SADI), and Pediatrics Societyf Argentina (Sociedad Argentina de Pediatría – SAP).

Each event was analyzed according to the PAHO classification13]: (1) coincidental event (i.e., illness caused by another etiol-gy); (2) vaccine-related event, including errors related to vaccineandling (program error) or to vaccine components; (3) inconclu-ive event, in which the available evidence prevents unequivocalonclusions from being made about the etiology. Events were sub-lassified into four categories: mild (no interference with everydayctivities), moderate (some interference with routine activities;eed of medical assistance and/or medication prescription), serioushospitalization, sequelae), and fatal.

Because the PAHO classification does not include specific eventselated to the YF vaccine, cases were further classified as follows:1) mild to moderate: presence of a flu-like syndrome defined as

yalgia, in addition to headache or fever, according to the defini-ions by Bastos Camacho [14]; and (2) serious and fatal: YEL-AVD,EL-AND, and anaphylactic reactions. For YEL-AVD and YEL-AND,he Yellow Fever Vaccine Safety (YFVS) Working Group case defini-ions [11] were used. Anaphylaxis was defined according to Kelso15]. First analysis was made in 2008–2009; for the purpose of thisublication a revision was done in 2010, after the YFVS Workingroup released new case definitions [16].

When feasible, serum, cerebrospinal fluid (CSF), and tissue sam-les were sent to the INEVH. Laboratory diagnosis of YEL-AVD waserformed through genome amplification of YF virus (17D vaccinetrain) RNA using Nested reverse transcription (nRT)–PCR assay.

Please cite this article in press as: Biscayart C, et al. Yellow fever vaccine-assoVaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.01.015

he (nRT)–PCR assay was performed as described by Sanchez-eco et al. [17], employing the primers Flavi1+, Flavi1− (1◦ round)nd YF2+ and Flavi2− (2◦ round). The amplicon of the expectedize (505 bp) was cut from the agarose gel, purified by using

PRESS xxx (2014) xxx– xxx

QIAquick kit (Qiagen) according to the manufacturer’s proto-col, and sequenced directly from both strands of each reversetranscription-PCR product for verification. The analysis of the

nucleotide sequence of 407 bp fragment of a genomic region ofthe NS5 protein was performed to classify the virus as wild-typeor vaccine-derived, comparing the amplified product with otherYFV strain sequences deposited in GenBank. Sequences were editedand aligned with BioEdit program by ClustalW method (availablefrom http://www.mbio.ncsu.edu/BioEdit/bioedit.html). The phy-logeny of the sequences was constructed using Neighbor JoiningMethod by MEGA 5 Software [18].

Viral isolation was attempted as described in [19]. Briefly, 20%homogenate of liver tissue was prepared and cultured in Vero cellsfor 14 days. Cultures were examined daily for evidence of viral cyto-pathic effect and evaluated by immunofluorescent assay (IFA) [20]for flavivirus antigen, by using fluorescein isothiocyanate-labeledflavivirus polyclonal antisera (Centers for Disease Control and Pre-vention, Puerto Rico), and for YFV antigen by using the specificmonoclonal antibody Mab FA 2D12). Cultures were blindly pas-saged one more time onto fresh Vero monolayers.

YEL- AND laboratory diagnosis was made when positive CSFYF virus IgM results were obtained by MAC-ELISA. IgM detectionwas made also in the acute sera sample by MAC ELISA employingDengue (DENV), Saint-Louis Encephalitis Virus (SLEV), West NileVirus (WNV) and YF virus antigens [21]. Serological cross reactionwas evaluated by PRNT [22] performed in paired serum samples forYF virus, DEN-1, DEN-2, DEN-3, DEN-4, SLEV, and WNV, the mostprevalent flaviviruses in Argentina in the last years [23–26]. Serum

was considered positive to a virus species when it reduced at least90% of the formation of plaques of this virus at ≥1:20 dilutions andits neutralizing antibody titer was ≥four-fold greater than whatwas observed for the other tested flaviviruses.

Epi Info TM software version 7.0.8.0 was employed for descrip-tive analysis.

3. Results

Between January 1, 2008, and January 31, 2009, 1,943,000doses of 17DD YF vaccine (Bio-Manguinhos/FIOCRUZ, Brazil) wereadministered, and 165 AEFI were reported (i.e. 84.9/1,000,000doses). The median age of cases was 38 years old (range 1–92), and55% were male. AEFI were not associated with a particular vaccinebatch.

There were 35 serious events (i.e.18/1,000,000 doses), of which28 (80%) were male. Two of these were coincidental, nine wereinconclusive, and twenty-four were vaccine-related.

3.1. Coincidental cases

Four events were coincidental, including the two afore-mentioned serious cases; namely, one septic shock caused byEscherichia coli (case #3), and one status epilepticus in a patientwho was diagnosed with a brain tumor. In addition, there was onecase of pharyngitis, and one case of headache and malaise withclinical onset a week before vaccination.

3.2. Program errors

ciated adverse events following extensive immunization in Argentina.

One hundred program errors were registered from a clusterof 100 consecutive subjects vaccinated with multi-dose vials. Allreceived 10 times the usual dose. Of note, 35 were people >60 yearsof age. There were no reports of adverse events.

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.3. Inconclusive events

Twelve cases (8 males -66.6%-; range: 7–56 years), were clas-ified as inconclusive since YF viral testing was not performed.mong these, there was a fatal case (#38) of a previously healthy3-year-old man who developed fever, myalgia, purpuric rash, andbdominal pain 6 days after vaccination. He was prescribed anti-istamines and methylprednisone with no improvement, requiringospitalization and intensive care. Blood, urine, and CSF cultures

or bacteria, mycobacteria, and fungi, and serologies (HIV, HCV,DRL) were negative. A skin biopsy revealed vasculitis. He died 8ays after admission. Besides, there was one serious adverse eventSAE) classified as inconclusive. It was the case of a 54-year-oldoman (case #19) with a history of presumable alcohol-related

iver disease and gallbladder lithiasis, and who required admissionor ascites, mild transaminase elevation, and marked hyperbiliru-inemia 3 days after vaccination. She was treated, and the eventas favorably resolved.

.4. Vaccine-related events

Forty-nine AEFI were classified as YF vaccine-related. Theedian age was 37 years (range 1–69); 38 patients (77.5%) wereale. Twelve events (24.5%) were mild (8 male -66.6%-; age range:

3–59); 13 (26.5%) moderate (10 male -76.9%-; age range: 14–69),3 (47%) serious (20 male -87%-; range: 1–67), and one (2%) fatals determined by the PAHO classification.

Fifty percent of SAEs and all fatal cases occurred in people >50ears old; five (20.8%) cases were in people 51–59 years old, andeven (29.2%) were in people >60 years old. The vaccine-relatedAE incidence rate was 12.3/1,000,000 doses. Twelve events werelassified as YEL-AVD (Table 1.) and 12 as YEL-AND (Table 2.). Nonaphylactic reactions were reported.

YEL-AND cases consisted of eight definite neurotropic diseasesfive meningitis, one meningitis with encephalitis, two encephali-is); one event fulfilled level 1 neurologic disease criteria, two YFaccine-associated autoimmune disease with central nervous sys-em involvement (YEL-AAD-CNS), and one YF vaccine-associatedutoimmune disease with peripheral nervous system involvementYEL-AAD-PNS). The last three patients and one case of encephalitisad neurologic sequelae (ratio: 33.3%) as of August 2013.

Only one case (#43) met the criteria for definite YEL-AVD. Thisubject was a 67-year-old male who developed fever, malaise, andatery diarrhea 4 days after YF vaccination. He was admitted to

he hospital with mild transaminase elevation, renal failure, andhrombocytopenia. His clinical status rapidly progressed to multi-le organ dysfunction syndrome, and he required intensive care.e died 48 h after admission. YEL-AVD was confirmed throughNA sequencing from a liver biopsy. Histopathology examinationevealed mid-zonal necrosis, and the presence of Councilman Bod-es. Two attempts at viral isolation were unsuccessful. A RT-PCRerformed from a serum sample was negative.

The medical conditions were described for cases #47 (end-stageenal disease under hemodialysis), #49 (history of allergy), #59hypothyroidism and allergy to penicillin), and #63 (autoimmunenterstitial glomerulonephritis and venous thrombosis). Six proba-le cases met level 1 diagnostic criteria and five cases met level 2riteria.

The definite YEL-AVD rate was 0.5/1,000,000 doses. When prob-ble cases were included, the rate increased to 6/1,000,000 doses.he case fatality ratio for definite YEL-AVD was 100%. If level 1 and

Please cite this article in press as: Biscayart C, et al. Yellow fever vaccine-assoVaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.01.015

evel 2 YEL-AVD events were included, it decreased to 8.3%. TheEL-AND rate was 5.6/1,000,000 doses. If cases that met level 1 cri-eria were included, the rate increased to 6/1,000,000 doses. Thereere no fatal cases of YEL-AND.

PRESS xxx (2014) xxx– xxx 3

4. Discussion

Between January 2008 and January 2009, Argentina’s Northeastregion experienced its first sylvatic YF outbreak in more than 40years, with nine confirmed cases, two of which were fatal. Thelast YF human cases had been recorded in 1966 [27]. Until theoccurrence of the 2001 epizootic, routine immunization of peo-ple living or traveling to Argentina seemed not to be justified, withthe exception of certain travelers going to Iguasu Falls. However,the sylvatic episode led to a tremendous demand for vaccination.In fact, a telephone-based survey revealed that more than 80%of people who went to a travel medicine and infectious diseasesclinic in Buenos Aires to be vaccinated had no justifiable indication[28]. The fact that YF is a strongly feared illness can explain thisphenomenon. In addition, according to Argentina’s immunizationpolicies, YF vaccination can only be denied when medical condi-tions to contraindicate it are present.

Seventy-seven percent of vaccine-related events cases weremale. This percentage was higher (82%) in the subgroup of patientsrequiring hospitalization. Male sex predominance is consistentwith previous reports [12], although the reason remains unclear.In YF sylvatic transmission areas, professional activities are mostlyperformed by men, what could explain this, but most of our caseswere from districts with no YF transmission risk.

It can be argued that DENV could have explained some casesbecause of the presence of DENV IgM. Cross-reactivity when usingELISA technique is frequent, so DENV, SLEV, WNV, and YFV antigenswere employed and compared. PRNT in paired sera was performedwhen it was possible and seroconversion with higher titers wasinterpreted as indicating the causative organism in patients show-ing a primary immune response. Dengue circulation in 2008–2009did not coincide with the time frame of this study and sign,symptoms and laboratory features coincide with typical mild tomoderate adverse events caused by YF vaccine administration,according to the definitions [14]. Thus, cases that fit with mild tomoderate illness and had temporal link to YF vaccination whereclassified as YF vaccine related.

Unfortunately, several cases had to be classified as inconclu-sive. Many reports were incomplete and difficult to reconstruct, forexample case #19: the history of alcohol abuse does not mean thatthe subject had a diagnosis of liver cirrhosis. Even if this diagnosiswas valid, the YF vaccine may also have triggered a decompensa-tion. Furthermore, inadequate data for confirming or ruling out aYF vaccine-related event is illustrated by case #38, where clinicalpicture clearly indicated YEL-AVD, but no viral testing or necropsywere performed. These shortcomings are common with passivesurveillance systems [17].

If the PAHO classification had been strictly followed, the hos-pitalized cases would have been considered serious based onadmittance to the hospital alone. The reasons for admission are het-erogeneous, so further analysis is necessary to validate the severitycriteria. Hospitalization itself as a definition for seriousness couldbe seen as a limitation of the PAHO classification. One strength of it,however, is that it is highly-sensitive for case capture. On the otherhand, case analysis with a classification of high specificity, such asthat currently proposed by the YFVS Working Group, may lead todismissals due to non-compliance with criteria which are difficultto fulfill in certain settings. A YF vaccine AEFI classification thatoffers the best possible balance between sensibility and specificityis needed, as the current proposal is not sensitive enough to includeall possible cases of YEL-AND and YEL-AVD. This is illustratedby case #9 (a 52-year-old male who had fever, malaise, myalgia,

ciated adverse events following extensive immunization in Argentina.

headache and abdominal pain 24 h after vaccination; laboratorytests revealed 3800 WBC/�L and 115,000 platelets/�L) which didnot meet the criteria for YEL-AVD despite clinical features and bonemarrow dysfunction following vaccination. Considering that wild

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Table 1Yellow fever vaccine-associated viscerotropic disease cases.

Case# Age Gender Onset fromvaccination(days)

Pre-existing conditions Clinical features Relevant laboratory/imagefindings

Outcome Observations CDC classification(2010)

2 61 M 4 Allergy to bees Fever (>40 ◦C),tachycardia, malaise,myalgia, dizziness, lossof appetite, chills

WBC 5500; platelets140,000

Recovered Travel to endemic area Level 2 YEL-AVDcriteria

9 52 M 1 No Fever, myalgia,headache, rash,conjunctival injection

WBC 3500; platelets116,000

Recovered Residence in endemicarea

Level 1 YEL-AVDcriteria

27 54 M 5 No Fever, malaise,myalgia, headache,retroorbital pain

platelets 126,000;YF/DENV MAC ELISA (+)(>optical density for YFvirus antigen); RT-PCRYF/DENV (−)

Recovered Travel to endemic area Level 1 YEL-AVDcriteria

29 34 M 4 No Fever, malaise, myalgia No data Recovered Residence in endemicarea

Level 1 YEL-AVDcriteria

37 30 F 1 No Myalgia, headache,petechiae and gingivalbleeding

Platelets 10,000 Recovered Residence in endemicarea

Level 2 YEL-AVDcriteria

43 67 M 4 No Fever, malaise,diarrhea

MODS. Negative cultures(blood–urine–stool). Liverbiopsy YF RT-PCR (+). YFvaccine strain confirmedby RNA sequencing

Dead (10 days after YFvaccination)

Travel to endemic area Definite YEL-AVD

53 60 F 5 No Myalgia, arthalgia WBC 1800; platelets58,000; AST 60;

Recovered Travel to Venezuela Level 2 YEL-AVDcriteria

55 66 M 4 No Fever, malaise,myalgia, orchitis

Hct 23; WBC 2,500;platelets 90,000; ESR 60;LDH 469; blood and urinecultures (−); YF MAC ELISA(+)

Recovered Travel to Thailand Level 2 YEL-AVDcriteria

58 45 M 5 Cardiac valve surgery Fever Hct 39; WBC 2800;platelets 155,000; bloodand urine cultures (−)

Recovered Unknown Level 1 YEL-AVDcriteria

59 26 F 5 Hypo-thyroidism Fever, myalgia,headache

WBC 3,600; AST 621; ALT462; YF MAC ELISA (+)

Recovered Unknown Suspect YEL-AVD

61 1 M 12 No Fever and vomiting Hb 10; WBC 16,800;platelets 480,000; AST 683;ALT 822;HAV-HBV-HCV(−); CMV(−)

Recovered Unknown Suspect YEL-AVD

63 52 M 21 Membrano-proliferativenephropathy;hypertension; cardiacfailure; pulmonaryhypertension;superficial venousthrombosis of leftupper limb

Loss of appetite,myalgia, arthralgia,jaundice, dyspnea,confusion

Platelets 28,000; LDH:625;creatinine 1.98; thorax CT:diffuse ground-glassopacity; TTE: pulmonaryhypertension

Recovered Unknown Level 2 YEL-AVDcriteria

WBC: white blood cells; AST: aspartate aminotransferase; ESR: erythrosedimentation rate; Hct: hematocrit; LDH: lactic dehydrogenase; ALT: alanine aminotransferase; EEG: electroencephalography; MODS: multi-organdysfunction syndrome; HAV: hepatitis A virus; HBV: hepatitis B virus; HCV: hepatitis C virus; CMV: cytomegalovirus; CT: computed tomography; TTE: transthoracic echocardiography.

Please cite

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article in

press

as: B

iscayart C

, et

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vaccine-associated

adverse

events

followin

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in A

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(2014), h

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Table 2Yellow fever vaccine-associated neurologic disease cases.

Case # Age Gender Onset fromvaccination(days)

Pre-existingconditions

Clinical features Laboratory findings Images Outcome Reason forvaccination

CDCClassification

Sample IgM detection (MAC ELISA) PRNTa YFV (90%) PRNTa DENV (90%)

YFV DENV WNV SLEV

1 20 M 13 No Fever, headache,unstable gait, nistagmus,tremor

S1 + − − − 640 ND NA Nistagmus,memoryimpairment

Travel to BrazilSouthern coast

DefiniteYEL-AND

CSF + − − − ND ND24 63 M 10 Hypertension Vomiting, headache,

confusionS1 − − − − ND ND MRI:

demye-natingence-phalo-myelitis

Memoryimpairment

Travel to BrazilSouthernCoast

YEL-AAD-CNS

CSF − − − − ND ND25 29 M 13 No Fever, nausea, vomiting,

myalgia, chills,headache, arthralgia,diarrhea

S1 + − − − 320 ND Recovered Resident inendemic area

DefiniteYEL-AND

CSF + − − − ND ND39 63 M 4 No Encephalitis S1 + − − − ND ND MRI: diffuse

peri-ventri-cularhyper-internsity

Recovered Travel toendemic area

DefiniteYEL-AND

CSF + − − − ND ND42 22 M 15 No Headache, dizziness.

Cognitive impairment,hemiparesis, dysarthria

MRI: T2 whitematterbilateralhyperin-tenseimages; EEG:diffuse lowvoltage,slow-waveactivity

Righthemiparesis

No vaccineindication

YEL-AAS-CNS

46 65 M 19 No Encephalitis No samplesavailable

Recovered No vaccine indication Level1 YEL-AND

47 28 M 26 End-stage renaldisease(hemodyalisis)

Fever, headache,obtundation

S1 + + − − 160 <20 Recovered Travel toendemic area

DefiniteYEL-AND

S2 ND ND ND ND 320 <40CSF + + − − ND ND

48 M 9 No Encephalitis S1 + − − − 1280 ND Recovered Unknown DefiniteYEL-AND

CSF + − − − ND ND49 11 M 17 Allergy Fever, malaise, vomiting,

myalgia, headacheS2 + + − − 1280 <20 Recovered Resident in

endemic areaDefiniteYEL-AND

CSF + + − − ND ND50 53 M 50 No Fever, malaise,

headache; acutedemyelinatingpolyradiculo-neuropathy

S1 + + − − ND ND Spinal cordMRI: thoracichyper-intenseT2 gray mattersigna

Sphincterdisfunction

Unknown YEL-AAS-PNS

CSF − − − − ND ND52 58 M 21 No Fever, malaise,

headache, somnolenceS1 + + − − 40 <20 Recovered Resident in

endemic areaDefiniteYEL-AND

S2 ND ND ND ND 320 <40CSF + + − − ND ND

62 28 F 19 No Fever, nausea, vomiting,myalgia, retroocularpain. Meningeal signs

S1 + + − − 80 <20 Recovered Unknown DefiniteYEL-AND

CSF + + − − ND ND

S1: sample (acute phase); S2: sample (convalesencet phase); ND: not done; NA: not available; EEG: electroencephalography; S2: sample (convalescent phase); CSF: cerebrospinal fluid; MRI: magnetic resonance imaging.a Reciprocal of serum dilutions.

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F infection encompasses a clinical range from asymptomatic toalignant with up to 60% fatality, the same should be true for

EL-AVD. That is, viscerotropism could be more common than iturrently appears, as all diagnostic criteria to date target only theost serious forms of YEL-AVD.Regarding YEL-AND, case #39 illustrates how diagnostic crite-

ia must be periodically revised based on new available evidence.n 2008–2009, our committee analyzed the case when the patientrst consulted with encephalitis after vaccination. However, as CSFiochemical parameters were normal and a CSF YF IgM was nega-ive, the case was dismissed as YEL-AND since it did not meet theFVS Working Group definitions at the time [17]. Several weeks

ater, since the patient did not have a clear diagnosis or show clini-al improvement, he was transferred from his original province touenos Aires for further study. Another CSF sample was obtained,evealing a lymphocytic pleocytosis and a positive YF ELISA IgM29]. Interestingly, we found this and another YEL-AND case (aongitudinal myelitis with onset 45 days after vaccination [30])s published reports. None of these were reported to the healthuthority. Finally, as another YEL-AND case with a late-onset pre-entation was reported [31], a new revision of the time frame forEL-AND case definition should be considered.

As for risk factors, it is worth noting that case #63 had anutoimmune disorder and a history of renal and thromboticanifestations, and two cases had hypothyroidism. Autoimmune

iseases are increasingly considered to be predisposing factorsoward the development of YF vaccine-related SAE [12]. Pathologyf the thyroid constitutes the most frequent autoimmune disease,nd is much more common in young women [32,33]. At least twoases of YEL-AVD were found to have disorders of this gland [16,34].ore evidence is needed to determine if thyroid disease could have

n association with adverse events after YF vaccination and eveno underlie the higher fatality ratio reported in young women [35].

YEL-AND and AVD rates in this study were slightly higher thanhose previously reported if we included cases that met level 1 and

criteria. Reported rates for YEL-AVD and YEL-AND vary depend-ng on the source. For VAERS, the rate for YEL-AVD and YEL-AND

as estimated in 0.4/100,000 and 0.8/100,000 doses [36]. A higherate (7.9/100,000) for YEL–AVD in a non-endemic population wasocumented from Peru [34].

The case of the patient with definite YEL-AVD is worth expand-ng upon. This patient was due to fly to Sudan to work in areasepicted as endemic for YF transmission [37]. Moreover, before fly-

ng the higher risk of SAE due to his age was explained; howevere decided to be immunized. New YF risk maps were subsequentlyeleased in which those areas were excluded for vaccine recom-endations. It is clear that accurate information is needed to better

efine actual risk areas.An inactivated, whole virus vaccine was proven to be safe and

easonably efficacious in a phase I clinical study [38]. If it is avail-ble in the future, it will help to safely immunize individuals withedical conditions that put them at risk of developing SAEs after

dministration of YF 17D vaccine.In the meantime, a judicious usef this vaccine in countries like Argentina is mandatory, given thathe risk of SAEs could outweigh the potential benefits of vaccina-ion, especially under the exceptional circumstances registered inhe 2008–2009 regional outbreak.

cknowledgement

Conflicts of interest: The authors have no conflicts of interest toeclare.

Please cite this article in press as: Biscayart C, et al. Yellow fever vaccine-assoVaccine (2014), http://dx.doi.org/10.1016/j.vaccine.2014.01.015

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