Typhoid fever in China

Description of typhoid fever

Typhoid fever is a life-threatening illness caused by the bacterium Salmonella enterica serovar typhi, which is spread through contaminated food, drink, or water. The bacteria enter the bloodstream through the intestine and spread to the intestinal lymph nodes, gallbladder, liver, and spleen, where they proliferate and cause infection.

Typhoid fever is common in most parts of the world, with exception to industrialized regions such as the United States, Canada, western Europe, Australia, and Japan. Therefore, travelers are urged to take precautions when visiting less-developed countries. Over the past 10 years, travelers from the U.S. to Asia, Africa, and Latin America have been especially at risk. Although typhoid fever is common in developing countries, less than 400 cases are reported in the U.S. each year, most of which are brought into the country from abroad. In the U.S. about 400 cases occur each year, and 75% of these are acquired while traveling internationally. Typhoid fever is still common in the developing world, where it affects about 21.5 million persons each year. Typhoid fever can be prevented and can usually be treated with antibiotics. If you are planning to travel outside the United States, you should know about typhoid fever and what steps you can take to protect yourself.

Symptoms

Early symptoms
• Fever
• Malaise
• Abdominal pain
• Rash or “rose spots” (often on the abdomen and chest)
• Diarrhea

Late symptoms:
• Severe headache
• Fever (>103F)
• Loss of Appetite
• General discomfort, uneasiness, or ill feeling (malaise)
• Rash (rose spots) appearing on the lower chest and abdomen during the second week of the fever
• Abdominal tenderness
• Constipation, then diarrhea
• Bloody stools
• Slow, sluggish, lethargic
• Fatigue
• Weakness
• Nosebleed
• Chills
• Delirium
• Confusion
• Agitation
• Fluctuating mood
• Difficulty paying attention (attention deficit)
• Hallucinations

Treatment

Intravenous fluids and electrolytes may be given. Appropriate antibiotics are given to kill the bacteria. There are increasing rates of antibiotic resistance throughout the world, so the choice of antibiotics should be a careful one.

Description of Salmonella enterica serovar typhi

Salmonella typhi is a rod-shaped gram negative bacterium that belongs to the family Enterobacteriaceae, which also contains the other well-known pathogenic Salmonella and E. coli strains. The genome of Salmonella enteric serovar typhi has been sequenced by the Sanger Centre and consists of one circular chromosome and up to two plasmids, pHCM1 and pHCM2. The chromosome is 4,809,037 nucleotides (nts) long with approximately 52% GC content. pHCM1 is an incHI1 type plasmid which confers multiple drug resistance to chloramamphenicol, tetracycline, sulfonamide and trimethropim, as well as resistance to mercury toxicity. pHCM2 was sequenced from S. typhi strain CT18 from Vietnam and is found in many Southeast Asian strains, but is largely absent in other regions. About half of the plasmid shows 97% identity to the virulence plasmid pMT1 of Yersinia pestis, the causative agent of bubonic plague. pHCM2, however, does not contain the operonsoperon essential for Y. pestis virulence. The importance of pHCM2 is as of yet unknown, though sequencing analysis has shown that pHCM2 encodes many phage-related nucleic acid metabolism genes. S. typhi infects humans using two Type III secretion systems, TTSI and TTSII. TTSI is responsible for injecting effectors into the host gut epithelial cells that allow engulfment of the bacteria into otherwise non-phagocytic cells. Upon vesicularization into the host cell cytoplasm, TTSI expression is down regulated, and TTSII expression is up regulated. TTSII, which is expressed in the cell’s polar regions, releases effectors into the host cell that induce microtubule formation. These microtubules form a scaffold onto which the bacteria attach and divide on.

Prevention

Vaccines are recommended for travel outside of the U.S., Canada, northern Europe, Australia, and New Zealand, and during epidemic outbreaks. Immunization is not always completely effective and at-risk travelers should drink only boiled or bottled water and eat well- cooked food. Experimentation with an oral live attenuated typhoid vaccine is now underway and appears promising. Adequate water treatment, waste disposal, and protection of food supply from contamination are important public health measures. Carriers of typhoid must not be allowed to work as food handlers.

Avoiding typhoid fever while traveling:
• Avoid risky foods and drinks.
• Get vaccinated against typhoid fever.
• If you drink water, buy it bottled or bring it to a rolling boil for 1 minute before you drink it. Bottled carbonated water is safer than uncarbonated water.
• Ask for drinks without ice. Avoid popsicles and flavored drinks.
• Eat foods that have been thoroughly cooked and that are still hot and steaming.
• Avoid raw vegetables and fruits that cannot be peeled. Vegetables like lettuce are easily contaminated and are very hard to wash well.
• When you eat raw fruit or vegetables that can be peeled, peel them yourself. (Wash your hands with soap first.) Do not eat the peelings.
• Avoid foods and beverages from street vendors. It is difficult for food to be kept clean on the street, and many travelers get sick from food bought from street vendors.

Remember that you will need to complete your vaccination at least 1 week before you travel so that the vaccine has time to take effect. Typhoid vaccines lose effectiveness after several years and the vaccines are not completely effective.

Why is this disease a problem in China?

China is considered as one of the Asian countries where typhoid fever is endemic. As a gastrointestinal infection that is both waterborne and food-borne, typhoid fever poses a problem in developing countries, such as China, that do not have optimal safe water supply, sanitation conditions, and food hygiene. Because preventative measures, such as public health proceedings and immunization are difficult in developing countries, the fight against the endemic is reliant on antimicrobial chemotherapy, such as the use of ampicillin, chloramphenicol, and co-trimoxzole. However, the prevalence of multi-resistant strains of S. typhi has increased in China; "by 1989, 80 percent of S. typhi isolates in Shanghai were multi-resistant."

Treatment for those infected with the multi-resistant strains can be the use of fluoroquinolones, such as ciprofloxacin or ofloxacin, but ciprofloxacin-resistant strains have already begun to appear. The lack of water and food sanitation and the presence of multi-resistant strains of S. typhi have made typhoid fever a continuing problem in China if preventive measures are not implemented.

Although infections in China have decreased, the endemic is still present with an outbreak of typhoid fever affecting 81 middle school students in Hubei province in December 2008. Another concern that must be noted is the current shift in the cause of typhoid fever, from S. typhi to S. Paratyphi A. In Guangxi, a southern province of China with the highest incidence of typhoid fever, S. Paratyphi A is currently the most common cause of typhoid fever. This new emergence of infections caused by S. Paratyphi A presents two new problems: there is no current vaccine for S. Paratyphi A and multidrug resistance is more common in paratyphoid fever. Almost all S. Paratyphi A strains collected from Guangxi province were resistant to nalidixic acid, which is an indicator of reduced effectiveness of ciprofloxacin treatment. Alarmingly, paratyphoid fever outbreaks occurred more in counties where the typhoid polysaccharide Vi vaccine was used but the cause of this emergence is still unknown. Thus, any preventative measures of typhoid fever involving vaccinations must also take into consideration the possible emergence of S. Paratyphi A infections.

China's response

In response to the increased concern of typhoid fever, China has begun to locally produce the Vi polysaccharide vaccine. Although there are two typhoid vaccines available that have shown to be safe and effective, the stability and efficiency of the Vi vaccine has made it the more appealing choice for developing countries like China. Until recently, however, this vaccination was distributed only to a few high-incidence Chinese provinces for school children and to participants of clinical studies. In a clinical study conducted in Suzhou, Jiangsu, China the vaccine was found to significantly increase antibody titers and revaccination was found to prolong the protective nature of the vaccine.

Epidemiology and Etiology Studies in China and other Asian countries

In addition to medical and pharmaceutical methods of managing this disease, epidemiology and etiological studies are a key component in the control of this disease, especially in developing countries that have high prevalence and incidence of outbreaks due to factors such as lack of sanitation, resources, public awareness, and poor community management.

Recent studies have shown developing Asian countries to be of particularly high risk for typhoid fever, accounting for 90% of global morbidity and mortality of typhoid incidences. One study focusing on typhoid and paratyphoid fever in Ningbo, China was led by the Ningbo Municipal Center for Disease Control and Prevention, from 1988 to 2007, focusing on epidemiology and etiology. Data collection was done on typhoid and paratyphoid fever and examined in market shellfish from the community and examined in patient cases from that marketplace region. From 1988-2007, 19,000 cases of typhoid and paratyphoid were reported, with a total of 7 deaths. The numbers for the annual incidence rate and fatality rate were 17.68 per one hundred thousand and 0.36 per thousand, respectively. The age range was 20-50 years old with a large regional distribution and high incidence seen in winter and spring months. It was seen that from 1990s onward, the advantage strain had changed from Salmonella typhi to Salmonella paratyphi A. The main risk factors involved were raw Andara subcrenata and oysters, where a strain was found on both containing a TEM-1 drug resistance gene. Using PFGE (Pulsified Field Gene Electrophoresis) genotyping, PGE-X2 was the strain found to cause the pandemic in Ningbo. This study states that consuming contaminated substances from the marketplace, primarily contaminated oysters and hairy clams was the main risk factor responsible for the outbreaks. Salmonella paratyphi A was found to be the advantageous pandemic strain in Ningbo. It is recommended that a main focus should be in increased community vigilance in supervision of personal hygiene and increased health education.

A 2008 study led by R Leon Ochiai et al. expanded on typhoid and paratyphoid fever in Asian countries, assessing the disease incidence and suggestions to control these outbreaks in other high-risk areas in these five Asian countries: Karachi, Pakistan, Kolkata, India, Jakarta, Indonesia, Hechi, China, and Hue, Vietnam. This study’s object was to educate policy-makers on ways to prevent typhoid, including the use of vaccinations. There are currently two vaccines, Vi polysaccharide and Ty21a that are in the market and have been shown to be safe and effective vaccines, with ongoing research for new vaccinations. This study acknowledges that the primary concern of the community should be making increased efforts to advance the quality of sanitation and water to decrease the risk of contamination from these strains but also that vaccination in these areas should be focused on as a maintenance goal as these conditions are being improved. A problem in vaccine implementation is that policy-makers need to have updated information regarding the incidence in these countries before introducing vaccine programmes into the community. For Asian countries, data on typhoid fever has been collected through routine collection using hospital and government data, with unclear representations of the communities as a whole because of similar symptoms between typhoid and other febrile diseases such as malaria and dengue fever. A better diagnosis would require laboratory resources not seen in these developing regions. Therefore, studies that focused on populations concerning the incidence of culture-confirmed typhoid have been taken from control groups of typhoid fever vaccine trials. This study provided policymakers a 12-month pre-vaccination estimate of the statistics of typhoid episodes in these five regions to help with the implementation of increased vaccination procedures and to plan for the trial use of the effectiveness of the Vi polysaccharide vaccines. The criteria for the selection of the study populations were thus: a large perception of typhoid fever in the region, lack of control programmes against the disease, compliance of community participation, and the high possibility of a vaccination trial that could be later implemented. There were 441,435 participants total in the study under surveillance for one year, their findings showed 21,874 episodes of typhoid fever lasting ≥3 days were detected and 475 people had blood culture-confirmed Salmonella typhi. The Salmonella typhi strain was found in 2% of blood cultures and 57% found in 5-15 year olds. Typhoid incidence as measured annually (per 100,000 person years) for the preceding age group showed variation in Viet Nam and China (24.2 and 29.3 respectively), Indonesia (180.3), Pakistan (412.9) and India (493.5). The percent of isolates found to be multidrug resistant strains was 23% to the following antibiotics: chloramphenicol (an antibiotic once used as the first line of defense against typhoid), ampicillin, and trimethioprim-sulfamethoxazole. The study concludes that there was high variability between sites, highest being in India and Pakistan, medium incidence in Indonesia, and China and Vietnam showing the lowest percentage. These findings emphasize the importance of policy-makers in implementing interventions in these disease laden countries to control this disease as an important intermediate step to improve conditions while acknowledging that increased community based awareness and improving health resources and sanitation is the ultimate long-term goal.

Suggestions on improving the current situation of typhoid fever in China

Because of the emergence of multidrug resistant strains, preventative measures seem to be more effective against the typhoid fever endemic in the long run. As vaccinations prove to decrease typhoid fever incidence, they should be implemented but studies on S. paratyphi A should be done simultaneously in order to prevent paratyphoid fever from becoming endemic. A long term preventative measure would be to provide better water sanitation, which would require funding and possibly even a change in infrastructure. The water and food sanitation can be improved more directly by alerting the public of this endemic and ways to prevent infection, such as boiling all drinking water and cooking all foods. As far as treatment for those already infected, multidrug resistant strains can be treated with fluoroquinolones but as ciprofloxacin-resistant strains have already begun to appear, further studies should be done on other treatment methods.

References

1. Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.
2. Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.
3. Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.

Edited by Garo Akmakjian, Jenny Choi, Hanna Gill, Gihei Kim, Aerin Oh, Crystalline Zapanta, students of Rachel Larsen