Enteric fever caused by S. Typhi continues to pose as a health burden globally, with the incidence being highest in low to middle-income countries (LMIC), due to poor infrastructure of public health (11). According to the World Health Organization (12), Pakistan faced the largest outbreak of XDR enteric fever, in Hyderabad in November 2016, followed by a similar outbreak in Karachi. XDR Enteric is a novel strain of S. Typhi which belongs to H58 lineage and has plasmid-encoded resistance and extended-spectrum β-lactamase (ESBL) gene which is responsible for resistance to both first and second-line antibiotics (13).
Out of 1518, total positive blood cultures for enteric fever, 1341 (88%) belonged to children. The median age of affected children was five years (IQR: 2-8 years). Literature from other parts of Pakistan have also reported a higher frequency of infection among children in comparison to adults and found children less than five years of age to be affected more. An investigation of XDR enteric fever in Hyderabad (7) and in Islamabad (14) revealed that 56% and 33% affected children were under five years of age. This high burden of XDR Enteric fever among Pakistani children has resulted in government initiative in the form of efforts to improve water quality and sanitation and initiation of mass vaccination of children for Enteric fever in Hyderabad and Karachi (7). This higher incidence of XDR enteric fever amongst younger children could be explained by the fact that children have lower immunity and require lower bacterial dose for development of infection (15). Most of the participants in our study belonged to East district of Karachi, probably because Indus Hospital lies in the catchment area of this district. Many residential areas located in district East of Karachi, comprise of peri-urban slums, having unhygienic conditions, inadequate sewerage facilities and consumption of pipe-borne portable water supply by the people. The high burden of disease in these areas could be due to contaminated drinking water and mixing of drinking and sewage water, a finding which was also observed in Hyderabad (6).
Enteric fever has been associated with considerable seasonal variations in different parts of the world (16) In Pakistan MDR Enteric peaks have been noted in May-June and in October. The seasonality was linked to increased consumption of contaminated local drinks and ice-cream during the hot season and post-monsoon contamination of drinking water with rainwater (17). We also observed two peak seasons of XDR Enteric cases, one in February-May 2018 and second in August-October 2018. This observation is contrary to previous epidemiological findings of Enteric fever in Karachi, which identified a clear relation of Enteric fever with monsoon rains. An epidemiological survey has shown that Sindh province, including Karachi, remained generally dry throughout 2018 (18), which makes post-monsoon contamination of water a less likely cause in our study. However, the timing of peak cases in our study was very similar to those observed in Lahore in 2018. In Lahore, increased numbers of cases of XDR Enteric fever were observed from January - April 2018 (19), while XDR peak in our study was from February-May 2018. The most probable explanation for the seasonal similarity of XDR cases between Karachi and Lahore is the intercity travelling of people.
Electrolyte imbalances were the most common complications observed. Hyponatremia was seen in 74 (11%) children and hypokalemia in 59 (9%). This electrolyte imbalance was one of the commonest reasons for hospital admission and can be attributed to vomiting and diarrhea seen in our patients. The hypovolemic shock was seen in 5 (0.7%) children. All children with shock responded to fluids and inotropes except for one child who expired. We observed neurological complications in 15 children. All of these children had seizures. Three children with fits had hyponatremia, 4 had encephalitis, and eight had encephalopathy. Daniel et al. (20) have reported 48 cases of enteric fever with encephalopathy. They found strong correlation of encephalopathy with dehydration and low white blood cell count (p-value <0.001). They postulated that in severe enteric infection immune response may be exaggerated leading to neurological complications. In our study, five children with encephalopathy had a severe clinical course. There is a possibility they had immunological mediated neuronal injury .
Four children developed aphasia, out of which 3 had encephalitis, and one had encephalopathy. All children recovered completely without any deficit. Few cases of aphasia caused by enteric fever have been reported (21, 22) Literature reports multiple factors like electrolyte imbalance, cerebral injury and neurotoxins-associated injury in the Broca’s speech as the cause of motor aphasia in Enteric fever (21).
We observed mortality in 4 children. Reasons for death were identified as encephalitis in one child and shock with multi-organ dysfunction in 3 children. Mortality in all children was observed in the third week of illness and could be due to delayed presentation, which may have delayed treatment. One case of vertical transmission was observed, and the newborn died of the infection in second-week life.
Any child who failed to show up for one month after the initial visit and could not be contacted over the phone was considered lost to follow up. Three hundred fifty-one children were lost to follow up in our study. The most probable explanation for this could be poverty; as most of our study participants belonged to low socio-economic strata. These patients may find it challenging to afford travelling expenses.
In our study, the most successful single drug was Azithromycin, which cured 78 cases (82%) followed by Meropenem, which cured 15 cases (16%). Tayyaba et al. studied antibiotic susceptibility of XDR Enteric in Karachi and found equal susceptibility of XDR strains to both Azithromycin (95%) and Meropenem (97%) (23). Other studies also reported equal cure rates with both the drugs (24, 25). We found Azithromycin superior to Meropenem probably because a majority of the patients were treated as out-patients and were given oral Azithromycin.
Seventy-six patients (48%) were successfully treated with a combination of Azithromycin and Meropenem. Children who received a combination of Azithromycin and Meropenem achieved fever defervescence two days earlier compared to children who received a single antibiotic. We can infer that these two antibiotics may have synergic action against XDR-Enteric fever. This synergism among various antibiotics has been observed in MDR Enteric fever also (26).
Eight children were cured on single drugs, although they were resistant to those antibiotics. Since we did not determine the minimum inhibitory concentration (MIC), therefore, there is a possibility that these strains were sensitive to antibiotics with a higher MIC breakpoint, and were falsely interpreted them as resistant strains.
The strength of this study is that it is the only extensive study in our knowledge which examines the clinical course, outcomes and complications of XDR strain of S. Typhi amongst the pediatric population within Pakistan. The study also determined response to antibiotics in XDR Enteric fever. The limitations of this study include lack of use of minimum inhibitory concentration (MIC) for culture and sensitivity, along with an absence of molecular mapping, which would have provided a more comprehensive picture of the disease. We did not routinely perform stool cultures and hence could not identify carriers. Retrospective data had missing information on socio-demographics like drinking water quality, hygiene practices and the number of people in the household.