Typhoid fever outbreak with severe complications in Yucatan, Mexico
Authors: Mussaret Bano-Zaidi, Mónica Aguayo-Romero, Freddy D Campos, Jorge Colome-Ruiz, María Elena Gonzalez, Irma Moo Piste, Claudia Puch Magaña, Miguel Gamboa y Gamboa
Journal: The Lancet Global Health (2018)

Typhoid fever—a systemic, life-threatening infection caused by Salmonella enterica serovar Typhi (S Typhi)—causes a considerable burden of disease worldwide. Recent studies1Buckle GC Fischer Walker CL Black RE Typhoid fever and paratyphoid fever: systemic review to estimate global morbidity and mortality for 2010.J Glob Health. 2012; 2: 010401Crossref PubMed Google Scholar, 2Dougan G Baker S Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever.Annu Rev Microbiol. 2014; 68: 317-336Crossref PubMed Scopus (161) Google Scholar estimate that 27 million cases and 200 000 deaths from S Typhi occur annually. Large outbreaks are common in Africa and Asia, but are rare in Latin America.1Buckle GC Fischer Walker CL Black RE Typhoid fever and paratyphoid fever: systemic review to estimate global morbidity and mortality for 2010.J Glob Health. 2012; 2: 010401Crossref PubMed Google Scholar, 2Dougan G Baker S Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever.Annu Rev Microbiol. 2014; 68: 317-336Crossref PubMed Scopus (161) Google Scholar In Mexico, the last major S Typhi outbreak, with more than 10 000 cases, occurred in the early 1970s.3Datta N Olarte J R factors in strains of Salmonella typhi and Shigella dysenteriae 1 isolated during epidemics in Mexico: classification by compatibility.Antimicrob Agents Chemother. 1974; 5: 310-317Crossref PubMed Scopus (41) Google Scholar Recently, Central American media channels have reported large typhoid fever outbreaks, although scientific information is scarce. This year, local newspapers reported more than 100 cases in El Salvador4Rivas I Confirman más de 100 casos de fiebre tifoidea en San Salvador y La Libertad.https://www.laprensagrafica.com/elsalvador/Confirman-mas-de-100-casos-de-fiebre-tifoidea-en-San-Salvador-y-La-Libertad-20180222-0120.htmlDate accessed: April 24, 2018Google Scholar and a major outbreak in Guatemala during 2017, which affected more than 60 patients and caused two deaths.5Alvarez C Aumentan a 60 casos de fiebre tifoidea en Guatemala.https://www.telesurtv.net/news/Aumentan-a-60-casos-de-fiebre-tifoidea-en-Guatemala-20170808-0001.htmlDate accessed: March 10, 2018Google Scholar Approximately 300 000–400 000 people—the majority of whom are from Honduras, El Salvador, and Guatemala—cross the southern Mexican border each year.6International Organization for MigrationIOM study highlights plight of young Central American migrants in Mexico's southern border region.https://www.iom.int/news/iom-study-highlights-plight-young-central-american-migrants-mexicos-southern-border-regionDate accessed: September 1, 2018Google Scholar In 2017, the state of Yucatan in southeast Mexico witnessed a sudden and substantial increase in the number of typhoid fever cases, many with severe complications. We did a retrospective analysis at two referral hospitals in Merida, the state capital, which detected 110 cases of typhoid fever between July 18, 2017, and May 24, 2018 (the epidemic period; figure). By comparison, only three positive cultures had been reported from 2000 to 2016. Patients' ages ranged from 1 to 70 years, with 80% of patients aged between 5 and 29 years. All 110 patients were hospitalised with at least 5 days of fever higher than 38·5°C, generalised weakness, and gastrointestinal symptoms. Patients were classified as confirmed cases if they had a positive blood (n=46), bone marrow (n=6), or stool culture (n=4) for S Typhi, or if they were previously healthy with at least 10 days of fever, gastrointestinal symptoms, and non-traumatic perforation of the distal ileum (n=10). The remaining 44 cases that were not confirmed by culture were classified as probable cases on the basis of their clinical presentation and negative tests for other differentials; all of them had positive Widal reactions (>1:320). 37 (34%) patients presented with severe complications, including gastrointestinal bleeding (n=12 [11%]), intestinal perforation (n=10 [9%]), encephalopathy (n=9 [8%]), cardiovascular collapse (n=8 [7%]), acute renal failure (n=7 [6%]), pneumonitis (n=7 [6%]), hepatic failure (n=6 [5%]), severe anaemia (defined as haemoglobin <70 g/L, n=4 [4%]), haematophagocytic syndrome (n=4 [4%]), and pancreatitis (n=1 [1%]). 30 (81%) of these patients with severe complications had been ill at least 2 weeks before admission. To date, we have registered three deaths in previously healthy people aged 11, 20, and 32 years. Serotyping according to the Kauffmann-White scheme confirmed all isolates as S Typhi; we identified no Paratyphi serovars. All isolates were susceptible to co-trimoxazole, tetracycline, ciprofloxacin, ceftriaxone, and aminoglycosides by disk diffusion and automated Vitek (bioMerieux, Marcy l'Etoile, France) antimicrobial susceptibility testing systems; only one isolate was resistant to ampicillin and one to chloramphenicol. Minimum inhibitory concentrations, as determined by agar dilution, were 0·03 mg/L for ciprofloxacin and 0·06–0·12 mg/L for ceftriaxone, for all isolates except one obtained in early May, 2018, which was resistant to nalidixic acid and had a minimum inhibitory concentration for ciprofloxacin of 2 mg/L. Despite having susceptible phenotypes on their antibiograms, 14 patients had therapeutic failure during their hospital stay, with persistence of fever after 7 days of treatment with ciprofloxacin (five patients) or ceftriaxone (nine patients). Seven of these patients developed severe complications. Pulsed-field gel electrophoresis was used to determine the relatedness among strains; an analysis of the first 29 isolates revealed that almost all belonged to a single clone, with only one isolate presenting a one-band difference (appendix). Our data strongly suggest that the outbreak initiated from a single source, although attempts to identify the origin by multiple food and water cultures were unsuccessful. The recurrence of typhoid fever outbreaks in Mexico after almost half a century is an ominous warning. Although the worst of the outbreak appears to have subsided, its torturous course and the emergence of a ciprofloxacin-resistant strain during the recent months highlight the need for immediate measures to prevent its spread. An improvement in local public health infrastructure and infectious disease surveillance would be crucial first steps. In the state of Yucatan, 50% of the population lives in poverty or extreme poverty.7Instituto Nacional de EstadísticaGeografía MéxicoIndicadores de Bienestar por entidad federativa.www.beta.inegi.org.mx/app/bienestar/?ag=31#graficaDate accessed: February 24, 2018Google Scholar The introduction of S Typhi into such a susceptible population poses a serious risk for an outbreak. Furthermore, because the detected cases in an outbreak are only a fraction of the total number of affected people, we assume that the true number of typhoid fever cases in the region is substantially higher.8WHOFoodborne disease outbreaks. Guidelines for investigation and control. World Health Organization, Geneva2008Google Scholar The lack of diagnostic capacity could be a major contributing factor to the underestimation of incidence. Blood culture bottles are scarce throughout Mexican public hospitals, and are positive in only 50–60% of cases. The Widal test, widely used in Mexico, is an unreliable diagnostic method. The limitations of these diagnostic tests reveal the need for a new rapid and inexpensive assay that can be used at both the hospital and primary care levels. Several immunodiagnostic assays have shown promising results9Islam K Sayeed MA Hossen E et al.Comparison of the performance of the TP test, Tubex, Typhidot and Widal immunodiagnostic assays and blood cultures in detecting patients with typhoid fever in Bangladesh, including using a Bayesian latent class modeling approach.PLoS Neg Trop Dis. 2016; 10: e0004558Crossref PubMed Scopus (35) Google Scholar, 10Wijedom L Malle HS Parry CM Rapid diagnostic tests for typhoid and paratyphoid enteric fever.Cochrane Database Syst Rev. 2017; 5 (CD008892.)Google Scholar and should be further investigated for widespread implementation. Delayed diagnosis might partly explain the unusually high rate of complications, since 81% of the patients we studied had been ill for at least 2 weeks. This finding concurs with a report on a large outbreak in Uganda with a 43% intestinal perforation rate.11Neil KP Sodha SV Lukwago L et al.A large outbreak of typhoid fever associated with a high rate of intestinal perforation in Kasese District, Uganda, 2008–2009.Clin Infect Dis. 2012; 54: 1091-1099Crossref PubMed Scopus (73) Google Scholar Delayed diagnosis and treatment cannot fully account for all such cases, however, because a subset of patients presented with therapeutic failure, despite early use of ciprofloxacin or ceftriaxone. Parry and colleagues12Parry CM Thompson C Vinh H et al.Risk factors for the development of severe typhoid fever in Vietnam.BMC Infect Dis. 2014; 14: 73Crossref PubMed Scopus (39) Google Scholar hypothesised that the particular genotype of an S Typhi strain could determine its disease severity. Genomic analysis of our isolates is underway; their relation to the widely circulating H58 strain in Asia and Africa13Wong VK Baker S Pickard DJ et al.Phylogeographical analysis of the dominant multi-resistant H58 clade of Salmonella Typhi identified inter and intracontinental transmission events.Nat Genet. 2015; 47: 632-639Crossref PubMed Scopus (284) Google Scholar should be determined, as well as the identification of possible new virulence determinants. The concurrent outbreaks in El Salvador, Guatemala, and southeast Mexico represent a major public health threat, exacerbated by the unprecedented influx of migrants fleeing violence and persecution in Central America.14Muggah R Europe's refugee crisis is making headlines, but Latin America's is just as alarming. World Economic Forum.https://www.weforum.org/agenda/2017/03/refugee-crisis-migration-europe-latin-america/Date accessed: March 10, 2018Google Scholar This reality, concomitant with the emergence of ciprofloxacin resistance, merits a forthright and sustained collaborative response from Central American and Mexican governments. We are indebted to Jason Abbott for assistance in preparing the PFGE dendrogram (appendix). MZ has received a grant funds from Pfizer unrelated to this work and serves on an advisory board for Sanofi vaccines. The other authors declare no competing interests. Download .pdf (.26 MB) Help with pdf files Supplementary appendix