Lessons learnt from the 2017/2018 plague outbreak in

Pr André SPIEGEL and Plague IPM Group Directeur de l’Institut Pasteur de Madagascar

29th European Society of Clinical Microbiology and Infectious Diseases Symposium Global health: African update ESCMIDAmsterdam, Netherlands eLibrary 3th-16th April 2019 © by author Plague Y pestis / rodents / fleas and… humans Rodents Humans and Secondary fleas Pneumonic form Yersinia Person to person transmission pestis Possible evolution to Flea

Bubonic form Infected rodent ESCMID eLibrary 2 © by author Plague in Madagascar 1898 : introduction of the Plague in Madagascar (Toamasina)

• 1898 : Toamasina epidemic • 24 november 1898 : 1th cas

• 1921 : • Following the construction railways

• Spread in Madagascar

• Endemic to the present day ESCMID eLibrary 3 © by author Plague in Madagascar Rural / seasonal / bubonic

• Endemic area • Rural areas of the Central highlands • Natural foci of plague • Altitude > 800 m

ESCMID eLibrary 4 © by author Plague in Madagascar Rural / seasonal / bubonic : Reservoirs and Vectors (1) (1) (2) Urban coast

Rural area C C (1) B B

A A B B (2)

Urban highland ESCMID(1) (2) eLibrary(1) A : Rattus rattus (1) : Xenopsylla cheopis B : Rattus norvegicus (2) : Synopsyllus fonquerniei 5 C : Suncus©murinus by author Plague in Madagascar Rural / seasonal / bubonic • Seasonal : October to April • Cases • 500 / year • Bubonic form predominant > 85% notified cases (1998 – 2016)

1998 - 2016

ESCMID eLibrary

6 (Andrianaivoarimanana© V et al,by EID 2019,25,220 -228)author Plague in Madagascar Biological diagnosis • Clinical suspected case or dead suspected case suspicion

• Biological specimen: bubo, sputum, blood

• 3 biologics tests

• Rapid Diagnosis Test : AgF1 (RDT-F1) • Molecular biology: cPCR and qPCR • Bacteria : Culture (antibiotic resistance)

• Strategy

• Health facility : TDR ESCMID• Institut Pasteur de Madagascar : TDR,eLibraryPCR (RTPCR), Culture 7 © by author Plague in Madagascar Definitions (WHO 2006) • Suspected case • All clinically-suspected plague cases that meet the clinical and epidemiological criteria as per WHO recommendations • Probable case • Clinically-suspected cases, with • RDT + or • PCR + • Confirmed case • Clinically-suspected cases, with • Culture + or ESCMID• RDT + and PCR + eLibrary 8 © by author Plague in Madagascar Alert : 11 September 2017

• Toamasina • Health car worker • Cough, fever • Admitted : 10/09 • Deceased : 11/09

• Phone investigation • Contact with patient • Unknown disease ESCMID• Rapidly deceased eLibrary 9 © by author Plague outbreak, Madagascar 2017 Investigation : index case

ANKAZOBE

26/08 90 km Ankazobe Toamasina

Antananarivo Male, 31 years Ankazobe 25/08 : first signs ANTANANARIVO

27/08 100 km

28/08 ESCMIDMORAMANGA eLibrary100 km TOAMASINA 10 © by author Plague outbreak, Madagascar 2017 Investigation : index case (contacts in taxi-bus)

Vohémar 2 1 Funeral was Toamasina Antananarivo 1 carried at 3 Toamasina 30/08/2017 2 3 Male, 26 yrs, student Native of Vohémar Male, 3 yrs Contacts in the taxi- 01/09 : first signs Native of Antananarivo bus to Toamasina : 02/09 : Death in Toamasina 30/08 : first signs Interhuman transmission No treatment 02/09 : hosp :Toamasina 03/09 : Death ESCMIDThe body  Antananarivo (car) NoeLibrary treatment  Vohémar (plane) After a death watch the body transported to Antananarivo by 11 © by authorcar on 04/09 Plague outbreak, Madagascar 2017 Investigation : the beginning Index case

1 2 2 cases in 1 case in Vohémar 3 5 1 case in 9 cases in Toamasina which 2 deaths Tsiroanomandidy Respiratory distress evolved 4 1 case in Analavory rapidly to death

6

Source: Géomatique, Epidémiologie, IPM.

ESCMID11 cases in Faratsiho which 1 death (E) eLibrary

Succession of deaths in same family in Antananarivo alerted health workers on 12 ©11/09/2017. by author Plague outbreak, Madagascar 2017 Investigation : 27/08 au 15/09 From 27/08 to 15/09 7 deaths 24 cases In 8 health districts Vohémar

Mahajanga 1 case Source of outbreak Ankazobe : plague area ANKAZOBE Index case Extension to : • Toamasina Analavory 1 case Toamasina • non endemic plague area Antananarivo • Main commercial seaport • 206,000 hab Tsiroanomandidy 1 case • Antananarivo Faratsiho • Capital • High population density • 24 cases ESCMIDNotification eLibrary to WOH 13/09 according to IHR 13 © by author Plague outbreak, Madagascar 2017 1th Aug to 26 Nov 2017: 2,417 reported cases • 1,878 (78%) PP

• 395 (16%) PB Alert

• 1 septicemic

• 140 unspecified

Alert ESCMID eLibrary Daily number of notified plague cases by case classification 14 (Randremanana© Ret al, Lancet infecbyDis, 2019) author Plague outbreak, Madagascar 2017 1th Aug to 26 Nov 2017: 597 confirmed /probable cases

597 confirmed / probable (25%)

418 / 1,878 139 / 395 39 /140 (22%) (35%) (28%) Pneumonic Bubonic Unknown (32 confirmed) (32 confirmed) (6 confirmed)

•ESCMIDSuspect: clinical presentation + epid eLibrary. context • Probable: RDT + or PCR + • Confirmed: (RDT + and PCR +) or (culture +) 15 © by author Plague outbreak, Madagascar 2017 1th Aug to 26 Nov 2017: cases geographical distribution 69% of PP in Antananarivo and 15% in Toamasina

Pneumonic Bubonic

ESCMID eLibrary 16 © by author Plague outbreak, Madagascar 2017 1th Aug to 26 Nov 2017: clinical signs and CFR • Pneumonic (confirmed) • Median age : 26 years • Male : 72% • 25% used antibiotic before examination • Clinical : cough (81%) fever (75%) chest pain (50%) hemoptysis (48%) • CFR : 25% (probable 8%; suspected 5%)

• Bubonic (confirmed) suspected 2% CFR

• Median age : 15 years probable 6% Bubonic • Male : 59% confirmed 24%

• Clinical : adenopathy (100%) fever 98%) suspected 5%

• CFR : 24% (probable 6%; suspected 2%) probable 8% • ESCMID eLibraryPneumonic confirmed 25% 0% 10% 20% 30% 17 © by author Plague outbreak, Madagascar 2017 Strains profiles • 50 Yersinia pestis strains isolated • 8 from PP, 41 from BP, 1 unspecified form) • All strains susceptible to tested antibiotics

• 37 isolated strains sequenced • Close to the strains isolated in previous years in in endemic district

• Including 8 strains of PP • All different • Important genetic diversity • 1 strain from a case epidemiologically linked to initial PP chain ESCMID• 4 of them associated with BP strains eLibrary 18 Source: Pasteur Institutes© Paris andby Madagascar. Submitted author for publication Plague outbreak, Madagascar 2017 National and international response • Malagasy high-level workgroup, chaired by the prime minister • Coordination health activities in collaboration with partners

• WHO : very strong technical and operational support • GOARN • Mobilisation ressources : UK, , USA

• Institut Pasteur de Madagascar and Institut Pasteur (Paris) • USAID • International Federation of the Red Cross • MDM, MSF,……...

ESCMID• Cost : $4 million to the response eLibrary 19 © by author Plague outbreak, Madagascar 2017 National and international response • Improvement of the surveillance, to detect and treat early

• Case management and prevention of inter-human transmission

• Social mobilization, health education

• Control in the country and at the borders

• Vector control and rat proofing

ESCMID eLibrary 20 © by author Plague outbreak, Madagascar, 2017 Response : Case management / prevention person to person transmission

Clinical suspicion Isolation if PP suspected Collection of clinical specimen + RDT

Active finding of contacts + Chemoprophylaxis

Presumptive treatment . Pneumonic plague : Streptomycin 8 days ESCMID eLibrary(= 40 IM) Desinfection of house . Bubonic plague : Streptomycin IM 3 days followed by Sulfamethoxazole- trimethoprim 5 days 21 © by author Plague outbreak, Madagascar 2017 Response : safe burial practices

Funeral rites

Funeral secured

Death suspected

ESCMIDActive finding of contacts eLibraryDesinfection of house + Chemoprophylaxis 22 © by author Plague outbreak, Madagascar 2017 Response : other measures • Social mobilization, health education • plague = shameful disease

• Panic in the population and over reaction

• Difficulties to managing rumors and panics

• Control in the country and at the borders ESCMID eLibrary • Vector control and rat proofing 23 © by author Plague outbreak, 2017 Interpretation and experience feedback • Biological diagnostics: no gold standard diagnostic available • Culture • Very specific but no sensitive • Only 8 Y. Pestis strains isolated on PP • Quality of sputum samples ? Transport too long ? Antibiotic treatment before ? • Contamination by commensal flora of the upper respiratory tract • RDT • RDT performance on pneumonic plague samples had not been evaluated • Misuse / misinterpretation in non-endemic areas • PCR • Conventional pla PCR • Insufficient specificity pneumonic plague • PCR pla, inv1. ESCMID• Importance of molecular biology +++eLibrary 24 • Deployment© byof the mobile authorlaboratory Plague outbreak, 2017 Interpretation and experience feedback • High % of suspected cases (78%)

• Pneumonic cases : 23% of notified cases are confirmed / probable • Frequent use of antibiotics • Misdiagnosis : new areas affected, lack of clinical experience • Large number of suspected cases • major hurdle for logistical management of different aspects of the response • Need to change 2006 WHO classification cases • suspect cases with all lab results negative  "non-cases“ ESCMID eLibrary 25 © by author Plague outbreak, 2017 Interpretation and experience feedback • Case management response • Urban context made complex the implementation of usual control measures

• 7289 contacts • Change treatment : streptomycine fluoroquinolones

ESCMID eLibrary 26 © by author Plague outbreak, Madagascar 2017 Conclusion • Unprecedented urban pneumonic plague +++

• Not an epidemic related to a single strain

• Magnitude of PP epidemic smaller than suggested by notifications

• 23% of notified PP cases had ≥1 positive laboratory test

• Laboratory results available for 99.6% of cases.

• Impact for Madagascar +++ (sanitary, economic)

• Economical context of Madagascar

• Highlighted weaknesses of national health system ESCMID eLibrary 27 © by author Plague outbreak, Madagascar 2017 Conclusion • The outbreak was contained and the international spread avoided

• Mobilization of MoH • Mobilization of international partners • Massive use of antibiotics

ESCMID eLibrary 28 © by author Other Supports MoH WHO USAID

Rindra Randremanana, Voahangy Andrianaivoarimanana, Birgit Nikolay, Beza Ramasindrazana, Juliette Paireau, Quirine Astrid ten Bosch, Jean Marius Rakotondramanga, Olivier le Polain de Waroux, Soloandry Rahajandraibe, Soanandrasana Rahelinirina, Fanjasoa Rakotomanana, Feno M Rakotoarimanana, Léa Bricette Randriamampionona, Vaoary Razafimbia, Mamy Jean De Dieu Randria, Mihaja Raberahona, Guillain Mikaty, Anne-Sophie Le Guern, Lamina Arthur Rakotonjanabelo, Charlotte Faty Ndiaye, Voahangy Rasolofo, Eric Bertherat, Maherisoa Ratsitorahina, Simon Cauchemez, Laurence Baril, André Spiegel, Minoarisoa Rajerison

Institut Pasteur, Paris Laboratory for Urgent Response to Biological Threats (ERI-CIBU), MathematicalESCMID Modeling of Infectious Diseases eLibrary Unit Yersinia Research Unit (National Reference Laboratory for Plague 29 © by author *It is normal that there is the plague it is the season

ESCMID eLibrary 30 © by author