Are we adequately prepared for the emergence of Salmonella enterica serovar Paratyphi A?

Typhoid fever is a life-threatening systemic disease caused by the bacterium Salmonella enterica serovar Typhi (S Typhi). Years of focused research have resulted in a detailed, but not complete, understanding of the disease caused by this organism. Diagnostics, host susceptibility, and vaccine responses need further research and investment, but recent technological advances in immunology and high-throughput genomics are providing new insights.1Baker S Holt KE Clements ACA et al.Combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission.Open Biol. 2011; 1: 110008Crossref PubMed Scopus (87) Google Scholar, 2Liang L Juarez S Nga TVT et al.Immune profiling with a Salmonella Typhi antigen microarray identifies new diagnostic biomarkers of human typhoid.Sci Rep. 2013; 3: 1043PubMed Google Scholar Indeed, the burden of typhoid fever might be falling in parts of Asia, and the potential introduction of Vi-polysaccharide-conjugate vaccines could reduce the burden even more.3Mai NL Phan VB Vo AH et al.Persistent efficacy of Vi conjugate vaccine against typhoid fever in young children.N Engl J Med. 2003; 349: 1390-1391Crossref PubMed Scopus (105) Google ScholarOther Salmonella serovars and pathovars also cause invasive disease in human beings, which can be difficult to distinguish clinically from typhoid. Invasive infections with S enterica serovars Typhimurium and Enteritidis in young children and also adults living with HIV in parts of sub-Saharan Africa have been reported.4Kingsley RA Msefula CL Thomson NR et al.Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype.Genome Res. 2009; 19: 2279-2287Crossref PubMed Scopus (383) Google Scholar However, S enterica serovar Paratyphi (S Paratyphi) A, the main alternative cause of typhoid-like infections in most of the world, has received little attention. This knowledge gap has the potential to become an Achilles' heel in the global battle against enteric (typhoid) fever.At the turn of the millennium, S Paratyphi A caused about 20% of the global burden of enteric fever.5Crump JA Luby SP Mintz ED The global burden of typhoid fever.Bull World Health Organ. 2004; 82: 346-353PubMed Google Scholar In many areas, this proportion has steadily increased. In Patan Hospital in Kathmandu, Nepal, standardised surveillance of blood cultures during the past 10 years has shown annual increases in the proportions of individuals with S Paratyphi A. More than two-thirds of the culture-confirmed cases of enteric fever are now caused by this serovar. Increases in the proportion of enteric fever cases caused by S Paratyphi A have also been reported in India, Pakistan, China, and Cambodia.6Crump JA Mintz ED Global trends in typhoid and paratyphoid Fever.Clin Infect Dis. 2010; 50: 241-246Crossref PubMed Scopus (596) Google Scholar In some locations, the proportion of enteric fever caused by S Paratyphi A is now greater than that caused by S Typhi. There is a real threat that S Paratyphi A could replace S Typhi as the main global cause of enteric fever. Clinicians often believe that S Paratyphi A infections are less severe than are those caused by S Typhi. However, in the largest comparison to date,7Maskey AP Day JN Phung QT et al.Salmonella enterica serovar Paratyphi A and S. enterica serovar Typhi cause indistinguishable clinical syndromes in Kathmandu, Nepal.Clin Infect Dis. 2006; 42: 1247-1253Crossref PubMed Scopus (139) Google Scholar no significant differences were shown between disease severity, duration, or outcomes for infection caused by these organisms.Both pathogens are transmitted through the faecal-oral route by ingestion of contaminated food or water. Ingestion is followed by colonisation of the small intestine, invasion of the gastrointestinal mucosal surface, and dissemination throughout the body into the liver, spleen, and bone marrow. Crucially, S Typhi and S Paratyphi A infect only human beings, and no other Salmonella serovar entirely mimics the infection in other hosts. Much of the understanding of pathogenesis is derived from the mouse infection model of S enterica serovar Typhimurium, which does not adequately replicate human infection. The absence of a suitable animal model has impaired the ability of researchers to develop diagnostic tests that take into account the specific biology of host–pathogen interactions. Researchers, therefore, rely almost solely on specimens collected from patients infected with these pathogens to understand the disease and investigate immunological responses.S Paratyphi A could have a large effect if Vi-polysaccharide-conjugate vaccines are introduced in Asia. The absence of the Vi-polysaccharide capsule in S Paratyphi A is the most important microbiological discrepancy between S Paratyphi A and S Typhi; vaccines based on Vi-polysaccharide do not provide any cross-serovar immunity. At present no vaccines specific to S Paratyphi A are available. Conjugate vaccines using the O antigen as the main immunological component are under development.8Sahastrabuddhe S Carbis R Wierzba TF Ochiai RL Increasing rates of Salmonella Paratyphi A and the current status of its vaccine development.Expert Rev Vaccines. 2013; 12: 1021-1031Crossref PubMed Scopus (40) Google Scholar However, these vaccines are some way from being licensed and made available to use in endemic locations. Whether they will provide sufficient protective efficacy and herd immunity to be a cost-effective intervention for public health remains to be established.In the absence of improvements in sanitation, clean water, and systematic vaccination, antimicrobial therapy for acute infection is the only intervention that can contribute to control of community transmission. Available data suggest that infections with S Typhi and S Paratyphi A both respond equally well to antimicrobials when the bacteria are susceptible.9Arjyal A Basnyat B Koirala S et al.Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial.Lancet Infect Dis. 2011; 11: 445-454Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar Unfortunately, antimicrobial resistance in all invasive Salmonella species is a growing threat, and S Paratyphi A seems to have a greater propensity than does S Typhi to develop resistance to antimicrobials.10Khan MI Soofi SB Ochiai RL et al.Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan.J Infect Dev Ctries. 2012; 6: 704-714PubMed Google Scholar Multidrug resistance and intermediate susceptibility to ciprofloxacin is common in S Paratyphi A, and full resistance to fluoroquinolones, azithromycin, and ceftriaxone is of increasing concern. The world is not prepared for the emergence of S Paratyphi A. Although many lessons from research into S Typhi are applicable to S Paratyphi A, this neglected but emergent pathogen is a global health issue that needs the urgent attention of the enteric-fever research community.We declare that we have no competing interests. This work was funded by the Wellcome Trust of Great Britain. Stephen Baker is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society ( 100087/Z/12/Z ). Typhoid fever is a life-threatening systemic disease caused by the bacterium Salmonella enterica serovar Typhi (S Typhi). Years of focused research have resulted in a detailed, but not complete, understanding of the disease caused by this organism. Diagnostics, host susceptibility, and vaccine responses need further research and investment, but recent technological advances in immunology and high-throughput genomics are providing new insights.1Baker S Holt KE Clements ACA et al.Combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission.Open Biol. 2011; 1: 110008Crossref PubMed Scopus (87) Google Scholar, 2Liang L Juarez S Nga TVT et al.Immune profiling with a Salmonella Typhi antigen microarray identifies new diagnostic biomarkers of human typhoid.Sci Rep. 2013; 3: 1043PubMed Google Scholar Indeed, the burden of typhoid fever might be falling in parts of Asia, and the potential introduction of Vi-polysaccharide-conjugate vaccines could reduce the burden even more.3Mai NL Phan VB Vo AH et al.Persistent efficacy of Vi conjugate vaccine against typhoid fever in young children.N Engl J Med. 2003; 349: 1390-1391Crossref PubMed Scopus (105) Google Scholar Other Salmonella serovars and pathovars also cause invasive disease in human beings, which can be difficult to distinguish clinically from typhoid. Invasive infections with S enterica serovars Typhimurium and Enteritidis in young children and also adults living with HIV in parts of sub-Saharan Africa have been reported.4Kingsley RA Msefula CL Thomson NR et al.Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype.Genome Res. 2009; 19: 2279-2287Crossref PubMed Scopus (383) Google Scholar However, S enterica serovar Paratyphi (S Paratyphi) A, the main alternative cause of typhoid-like infections in most of the world, has received little attention. This knowledge gap has the potential to become an Achilles' heel in the global battle against enteric (typhoid) fever. At the turn of the millennium, S Paratyphi A caused about 20% of the global burden of enteric fever.5Crump JA Luby SP Mintz ED The global burden of typhoid fever.Bull World Health Organ. 2004; 82: 346-353PubMed Google Scholar In many areas, this proportion has steadily increased. In Patan Hospital in Kathmandu, Nepal, standardised surveillance of blood cultures during the past 10 years has shown annual increases in the proportions of individuals with S Paratyphi A. More than two-thirds of the culture-confirmed cases of enteric fever are now caused by this serovar. Increases in the proportion of enteric fever cases caused by S Paratyphi A have also been reported in India, Pakistan, China, and Cambodia.6Crump JA Mintz ED Global trends in typhoid and paratyphoid Fever.Clin Infect Dis. 2010; 50: 241-246Crossref PubMed Scopus (596) Google Scholar In some locations, the proportion of enteric fever caused by S Paratyphi A is now greater than that caused by S Typhi. There is a real threat that S Paratyphi A could replace S Typhi as the main global cause of enteric fever. Clinicians often believe that S Paratyphi A infections are less severe than are those caused by S Typhi. However, in the largest comparison to date,7Maskey AP Day JN Phung QT et al.Salmonella enterica serovar Paratyphi A and S. enterica serovar Typhi cause indistinguishable clinical syndromes in Kathmandu, Nepal.Clin Infect Dis. 2006; 42: 1247-1253Crossref PubMed Scopus (139) Google Scholar no significant differences were shown between disease severity, duration, or outcomes for infection caused by these organisms. Both pathogens are transmitted through the faecal-oral route by ingestion of contaminated food or water. Ingestion is followed by colonisation of the small intestine, invasion of the gastrointestinal mucosal surface, and dissemination throughout the body into the liver, spleen, and bone marrow. Crucially, S Typhi and S Paratyphi A infect only human beings, and no other Salmonella serovar entirely mimics the infection in other hosts. Much of the understanding of pathogenesis is derived from the mouse infection model of S enterica serovar Typhimurium, which does not adequately replicate human infection. The absence of a suitable animal model has impaired the ability of researchers to develop diagnostic tests that take into account the specific biology of host–pathogen interactions. Researchers, therefore, rely almost solely on specimens collected from patients infected with these pathogens to understand the disease and investigate immunological responses. S Paratyphi A could have a large effect if Vi-polysaccharide-conjugate vaccines are introduced in Asia. The absence of the Vi-polysaccharide capsule in S Paratyphi A is the most important microbiological discrepancy between S Paratyphi A and S Typhi; vaccines based on Vi-polysaccharide do not provide any cross-serovar immunity. At present no vaccines specific to S Paratyphi A are available. Conjugate vaccines using the O antigen as the main immunological component are under development.8Sahastrabuddhe S Carbis R Wierzba TF Ochiai RL Increasing rates of Salmonella Paratyphi A and the current status of its vaccine development.Expert Rev Vaccines. 2013; 12: 1021-1031Crossref PubMed Scopus (40) Google Scholar However, these vaccines are some way from being licensed and made available to use in endemic locations. Whether they will provide sufficient protective efficacy and herd immunity to be a cost-effective intervention for public health remains to be established. In the absence of improvements in sanitation, clean water, and systematic vaccination, antimicrobial therapy for acute infection is the only intervention that can contribute to control of community transmission. Available data suggest that infections with S Typhi and S Paratyphi A both respond equally well to antimicrobials when the bacteria are susceptible.9Arjyal A Basnyat B Koirala S et al.Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial.Lancet Infect Dis. 2011; 11: 445-454Summary Full Text Full Text PDF PubMed Scopus (45) Google Scholar Unfortunately, antimicrobial resistance in all invasive Salmonella species is a growing threat, and S Paratyphi A seems to have a greater propensity than does S Typhi to develop resistance to antimicrobials.10Khan MI Soofi SB Ochiai RL et al.Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan.J Infect Dev Ctries. 2012; 6: 704-714PubMed Google Scholar Multidrug resistance and intermediate susceptibility to ciprofloxacin is common in S Paratyphi A, and full resistance to fluoroquinolones, azithromycin, and ceftriaxone is of increasing concern. The world is not prepared for the emergence of S Paratyphi A. Although many lessons from research into S Typhi are applicable to S Paratyphi A, this neglected but emergent pathogen is a global health issue that needs the urgent attention of the enteric-fever research community. We declare that we have no competing interests. This work was funded by the Wellcome Trust of Great Britain. Stephen Baker is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society ( 100087/Z/12/Z ).