S. Typhi and S. Paratyphi A B and C - Disease prevalence report 2019-2021
Typhoid and paratyphoid fever are caused by Salmonella Typhi and Salmonella Paratyphi A, B or C, respectively. Registered typhoid and paratyphoid fever infections were most recently reported in EPI-NEWS 11/19 (covering the 2014-2018 period). Typhoid and paratyphoid fever are individually notifiable conditions for the treating physician using the clinical notification system via the Danish Health Data Authority’s Electronic Notification System (SEI2). (As the last of the Danish regions, the Region of South Denmark will shift from using Form 1515 to SEI2 on 4 July 2022). Additionally, until recently the diagnosing laboratories of clinical microbiology had a duty to notify any findings of typhoid and paratyphoid fever via the laboratory notification system, but the monitoring of laboratory findings of S. Typhi/S. Paratyphi is now done by data extraction directly from the MiBa.
This statement covers the 2019-2021 period, during which a total of 47 notified cases of S. Typhi (22) and S. Paratyphi (25) were recorded. For comparison, the previous three-year period (2016-2018) recorded a total of 65 cases. The decline is presumably owed to reduced travel activity due to travel restrictions imposed during the COVID-19 pandemic.
Among the 47 cases, 25 were notified clinically. Among these cases, three were only notified clinically, which probably reflects that the diagnosis was made abroad. A total of 44 cases were registered via the laboratory monitoring system. Table 1 presents the distribution of clinical notifications and laboratory registrations by serotype.
Among the 44 laboratory-registered cases, half (22) were notified clinically. Two cases were notified clinically with another serotype than was detected in the samples at serotyping. This applied to a case of laboratory-registered S. Paratyphi A, which was notified clinically as an S. Paratyphi B case, and for another laboratory-registered S. Paratyphi case, which was notified as S. Typhi. The reason for these deviations was presumably typing error in the clinical notifications.
The 2019-2021 period saw a decline in the number of S. Typhi and S. Paratyphi registered in the laboratory monitoring system, Figure 1.
No clinical notification of S. Paratyphi C was received in the notification period, which was also the case in the previous period from 2014 to 2018. Even so, Figure 1 shows that 2019 saw two registered cases of S. Paratyphi C in the laboratory monitoring system. The two persons had become infected at approx. the same time and had both travelled to Africa.
Sex, age and country of infection
Among the 47 registered cases, the sex distribution was even (23 women and 24 men), and the patient’s age ranged from three to 60 years with a median age in the group of 28 years (interquartile range 21-38), Figure 2.
Information was provided of the presumed country of infection for 24 of the 25 clinical notifications and for 22 of the 44 laboratory registrations. The most frequently stated countries of infection were Pakistan (nine cases) and Cambodia (six cases), whereas Denmark and India were both stated as country of infection of more than one case. Other countries of infection were Iraq, Iran, Kenya, Morocco, Uganda, Indonesia, Brazil and Bangladesh. Three cases were registered with presumed infection in Africa, South America and Asia, respectively, with no further details being provided.
In some cases, there was no match between the country of infection stated in the clinical notification and the registration in the laboratory system. Among the laboratory-registered cases, one was assessed to have been infected in Denmark, but this case was notified clinically, stating Pakistan as the country of infection. Among the clinically notified cases, two were presumably infected in Denmark, including one patient who was registered as having an affiliation with an African country.
Whole-genome sequencing
In some cases, the samples submitted to Statens Serum Institut had already been serotyped by the laboratory of clinical microbiology. Since 2017, the SSI has conducted whole genome sequencing as part of the national Salmonella laboratory monitoring, whereby, among others, serotype and multi-locus sequence typing (MLST) sequence type (ST) may be characterised.
Among the 44 laboratory-registered cases, some had bacteria with same sequence type and also shared the presumed country of infection. For example, five persons with S. Typhi ST 1 had presumably all been infected in Pakistan. Such findings may be explained by the fact that the detected sequence types are endemic or sequence types that are endemic in the geographic area in question. By detailed comparison of the genomes of the bacteria, it can be established how likely the persons are to have become infected by the same source. Four of these five S. Typhi ST 1 isolates were located to a genetically closely related cluster, which may mean that the persons had been infected by the same source. The four persons were not seemingly related to each other and roughly occurred in the course of a year; the first case presented in the spring of 2019 and the final case in the spring of 2020. The S. Typhi ST 1 cluster in question also comprised a fifth isolate registered with unknown country of infection. It seems likely that this person will also have been infected in Pakistan - possibly by the same source of infection.
By including whole genome sequencing as part of the monitoring, it has become possible to identify links between infection cases what would not necessarily have been established based on epidemiological data from the clinical notifications alone. In the period 2019-2021, whole genome sequencing served to identify isolates that were related to a total of six minor travel-related clusters, including the above-mentioned S. Typhi ST 1 cluster related to Pakistan.
Antibiotic resistance
In Denmark, empirical treatment of patients admitted with typhoid fever is ceftriaxone, a third-generation cephalosporin. This is so because of the high global occurrence of S. Typhi with resistance to fluoroquinolones (e.g., ciprofloxacin), which was previously used empirically. Even so, a high prevalence has been observed, particularly in Pakistan, of XDR (extensively drug-resistant) S. Typhi, which is resistant to third-generation cephalosporins. Thus, it may be indicated to select an alternative empirical antibiotic if you learn that a patient admitted with typhoid fever has recently been travelling in Pakistan.
Figure 2 presents the resistance pattern for a selection of relevant antibiotics among the registered cases of S. Typhi and S. Paratyphi in the 2019-2021 period as presented in the MiBa, the Danish Microbiological Database (which must therefore have been assessed based on disk diffusion testing or determination of the minimal inhibitory concentration).
Generally, most cases (31 of the 41 tested) were resistant to ciprofloxacin, whereas all of those tested were susceptible to meropenem and azithromycin. Four cases were consistent with XDR S. Typhi and were resistant to third-generation cephalosporins, among others. All of these cases belonged to the above-mentioned cluster of S. Typhi ST 1 for which Pakistan was the presumed country of infection (one case registered with unknown country of infection). This means that bacterial isolates from at least one third of the registered S. Typhi cases from Pakistan were non-susceptible to the empirical antibiotic we use against S. Typhi in Denmark.
Studies have shown that travellers living with relatives in their country of origin/home country have a much higher risk than the average traveller of becoming infected with a range of infections. This also applies to typhoid fever/paratyphoid fever. We therefore propose that travellers who will be visiting relatives in areas of the world where typhoid fever is endemic are vaccinated against typhoid fever before embarking on their journey, regardless of the expected duration of their travelling activities. Additionally, vaccination of other types of travellers may be indicated, e.g., in connection with travels lasting more than two weeks to the Indian Subcontinent. In the 2019-2021 period, the most frequently observed country of infection was Pakistan and a third of the cases from Pakistan were XDR S. Typhi. Cambodia was the second most frequent country of infection. Notably, from this country all cases were S. Paratyphi A, against which typhoid fever vaccination is not effective.
This annual report is also described in EPI-NEWS no. 26/2022.