Epidemics of Non-typhoidal Salmonella Sepsis and Meningitis in

AfricaMeningitis & Septicaemia in Children and Adults

November 2015

Rob HeydermanDivision of Infection & Immunity, UCL

Epidemic Meningococcal Meningitis>150,000 cases and 16,000 deaths in 1996

Meningitis belt

See review: Greenwood Trans Roy Soc Trop Med 1999; 3:341-353

Clin Infect Dis 2005; 40:17

0

100

200

300

400

500

600

700

Jan - Jun 1998

Jul - Dec 1998

Jan - Jun 1999

Jul - Dec 1999

Jan - Jun 2000

Jul - Dec 2000

Jan - Jun 2001

Jul - Dec 2001

Jan - Jun 2002

Jul - Dec 2002

Jan - Jun 2003

Jul - Dec 2003

Jan - Jun 2004

Jul - Dec 2004

no.

isola

tes

0102030405060708090100

% M

DR

S. Enteritidis isolates S. Typhimurium isolates

% S. Enteritidis MDR % S Typhimurium MDR

Epidemics of Invasive NTS serovars in Malawi

Gordon et al Clin infect Dis 2008

Community-acquired

BSI in Africa

West & Central Africa

North Africa

East Africa

Southern Africa

Adapted from Lancet Infect Dis. 2010Reddy, Shaw & Crump

Salmonella in Africa Consensus MeetingBlantyre, MalawiHeyderman & Crump EID and CID 2015

Malawi

Kenya

Mozambique

Tanzania

The Gambia

Burden of Invasive NTS Disease

Crump EID 2015 (Systematic Review)

• Case fatality ratio 20%• Estimated deaths annually 681,316

Clinical Features of Invasive NTS Disease

Feasey Lancet 2012; 379: 2489–99

• 278 cases; 45% Salmonella Typhimurium

• 54% <15 years

• Disease of HIV-infected adults and largely HIV-uninfected neonates

• Mortality 47%

• Death associated with GCS ≤13 (adj OR 18.7; 95% CI 3–119)

Clin Infect Dis 2015;61(S4):S272–82

Non-typhoidal Salmonella (NTS) Challenges to Established Dogma

• Clinical illness due to NTS is most commonly self-limited gastroenteritis

• Animals are the reservoir

• Transmission from animal contaminated unprocessed & processed foods

• All NTS strains are equal

Kingsley, Msefula et al Genome Res. 2009

The Molecular Basis of Epidemic Salmonella Typhimurium

Novel sequence type (ST313)

Virulence & Antibiotic Resistance Plasmid (pSLT-BT) = transferable

pSLT-BT

Typhi

Intercontinental spread of Salmonella Typhimurium path variants

Lineage I:~52yrs agoHIV emergence

Lineage II:~35yrs agoChloramphenicol resistance

Okoro et al Nature Genetics 2012

Molecular Basis of Epidemic Salmonella

Enteritidis

Feasey submitted

Reduction in BSI and in-patient case fatality in adults with roll-out of ART

1997/8 [Peters et al 2004]

2009/10 [Feasey et al unpublished]

n % n % z- test (p-

value)

All-cause mortality 502/2789 18.0 269/2184 12.3 <0.001

Blood culture-confirmed BSI 171/433 39.5 32/229 14.0 <0.001

Nontyphoidal Salmonellae 54/164 32.9 9/84 10.8 <0.001

S. pneumoniae 49/136 36.0 4/56 8.9 <0.001

Blood-culture negative/contaminated

331/2356 14.0 237/1955 12.1 0.066

2014][Gordon et al 2001]

Falling Childhood NTS in Malawi

Smoothed Structural Equation Model

iNTS Malaria

Feasey Neg Trop Dis 2015

Cas

es/

mo

nth

Case

s/year

• 2009 - Ceftriaxone resistant NTS emerged

• 2010 - 6.2% (2/32 isolates)

• 2012 - 57% (13/23 isolates)

Clin Infect Dis 2015;61(S4):S310–6

Salmonella BSI in Blantyre (Nov 2010-Oct 2014)C

ase

s/m

on

th%

of S. Typ

hi w

hich

are M

DR

Month Feasey Neg Trop Dis 2015; Feasey CID 2015;Pfitzer CID 2015

Global dissemination of S. Typhi H58

Fiji

Emerged ~30 years ago

~ 1,800 isolates63 countries6 continents

Wong Nature Genetics 2015

Conclusions

• iNTS disease is an important cause of death in Africa

• Three epidemics of Salmonella bloodstream infection in Malawi since 1999

• Epidemics of MDR iNTS disease = novel clades

• Reservoirs of disease and modes of transmission are unknown

• Concerted efforts are required if Public Health interventions including vaccines are to be developed and implemented

AcknowledgmentsGordon DouganRobert KingsleyChinyere Okoro

Vanesa WongNick ThomsonJulian Parkhill

Cal MacLennan

Co-authors of CID Supplement

Chisomo MsefulaNick FeaseyMelita GordonMavuto MukakaTonney NyirendaMike MooreBrigitte Denis

Theresa AllainJoep van OosterhoutAngela HoustonDan KomrowerThandie Mwalukomo

Malcolm MolyneuxElizabeth MolyneuxTerrie Taylor

Stephen GordonChris ParryDavid LallooBrian Faragher

Lysin Tent HaniAndreas JohnRemco Peters