Typhoid fever is a bacterial infection caused by the Salmonella Typhi strain. This disease is most common in developing countries, such as India, Pakistan, and China (CDC). Most cases in the US occur in people who return from these developing countries after traveling. The transmission vessel for this bacterium is fecal matter in which the virus is shed; this explains why this infectious disease is common in developing countries, as they have less access to properly sanitized water. Typhoid fever is usually contracted through oral-fecal contamination, through improper sanitation after using the bathroom, contaminated water, or improperly prepared food (CDC). The symptoms of typhoid include weakness, stomach pain, headache, diarrhea or constipation, cough, loss of appetite, as well as a high fever that can persist for about a month if not treated (CDC). Overall, typhoid fever affects around 22 million people per year (CDC), especially in developing countries, making it an important disease to fully understand.

One of the first historical developments with typhoid fever occurred in 1873 with William Budd, a doctor in Bristol who was interested in cholera and in intestinal fevers. He discovered that the bacteria could be transmitted by a specific toxin present in human feces and that the contamination of water by the feces of patients was responsible for the propagation and spread of the disease (Marineli et al 2019). Later, in 1879, Karl Joseph Eberth discovered the bacillus in the abdominal lymph nodes and the spleen of a patient. At the time of this discovery, 10% of typhoid fever cases were fatal, with the most effected group being impoverished people who lived in large cities (Marineli et al 2019). The vaccine for this disease did not become available until 1911, with effective antibiotics not available until 1948 (Marineli et al 2019).

In the modern day, typhoid fever is an uncommon disease in developed countries. Because these countries, like the United States, have more developed water and food sanitation, it is more difficult to contract typhoid fever, as there is minimized contact with the bacteria. But, in places like Southeast Asia, typhoid fever remains very common. In 2000, it was estimated that over 2.16 million episodes of typhoid occurred worldwide, resulting in 216,000 deaths, and that more than 90% of this morbidity and mortality occurred in Asia (WHO). This is due in part to the poor water sanitation in Southeast Asia, but also the challenge of getting people vaccinated in more rural areas (WHO). These infectious cases can be widespread, especially in times after flooding, where contaminated water is able to move about, allowing the bacteria to widen its scope. Typhoid fever is especially harmful to those with weaker immune systems, such as people with compromised immune systems, the elderly, and children. This being said, typhoid fever still affects a large number of healthy adults. Because of this, it is imperative to understand typhoid fever as a disease, completely, in order to be able to limit the number of outbreaks and overall cases that afflict those in Southeast Asia.

1. Typhi as a Successful Pathogen

One of the reasons that it is important to study typhoid fever is this bacterial infection is extremely successful at infecting hosts. To be considered a successful pathogen, a pathogen must be able to survive transmission through multiple hosts, attach and penetrate host tissue, be able to withstand the host immune response, and disrupt normal function of cells that it infects. In the case of typhoid fever, all of these criteria are met. Due to these capabilities that the S. Typhi bacteria has, infection from this disease has the ability to easily infect host and cause chronic illness. Because of this danger that typhoid fever poses, it is important to understand not only the effects of the disease, but also how it is able to be transmitted and what happens once a host has been infected.

One important facet to typhoid fever’s success as a pathogen is its ease of transmission. In Asia, water sanitation is minimal, as these developing countries do not have the developed systems that are able to remove these harmful bacteria from the water supply, especially when this water is coming from rivers and other natural water sources (WHO). In many cases, these natural water sources are lifelines to people that live in more rural areas. These people use these waterways to gather water, wash clothes, and dispose of waste (WHO). This easily allows for the bacteria responsible for typhoid fever to move from host to host, as it is shed in fecal matter, which moves into the water system. Once someone gathers this contaminated water, and ingests it without sanitizing it, the bacteria are able to enter the body and create an infection (CDC). Due to the lack of sanitation systems to protect against the danger of ingesting contaminated water, it is very easy for the bacteria to move from host to host, as it infects the whole water source. Due to this ease of transmission, typhoid fever is able to infect a greater number of hosts, making it a more successful pathogen.

Another reason why typhoid fever is a successful pathogen is due to the bacteria’s ability to invade the host cells and evade the immune response that follows. Once the S. Typhi bacteria is ingested, it moves into the intestinal lining, where the bacteria bind to podocalyxin-like protein 1 (PODXL) receptors (Khan Academy) within the epithelial cells and begins to produce toxins (Safefood 2018). Once these bacteria begin making AB toxins, which damage DNA and stop the cell cycle in infected cells (Hentzen), the body triggers an immune response. Once this response is triggered, immune cells enter the infected tissue and enclose the infection, forming an abscess (Universität Basel 2014). While some bacteria are caught in these abscesses and killed, some S. Typhi bacteria are able to escape and continue to infect the host. This allows bacteria to continue to harm the body, until organ damage occurs, usually resulting in death. This strategy to evade the immune system further allows for typhoid fever to be considered a successful pathogen, as it is able to continue to infect and reproduce in the body for a longer period of time.

One study that looked specifically at the immune response was a study conducted by Khanam et al (2015). The goal of this study was to look at typhoid fever patients in different age groups and look at the differences in antigens produced by each age group of children (1-5 years), older children (6-17 years), and adults (18-59 years). This study was looking to find more information as to if this difference in immune response is the reason children are more likely to become ill from typhoid fever. The study first took blood from suspected typhoid patients and data on the levels of MP-IgA, plasma antibodies, and T cell proliferative response. Overall, the study found that there was no significant difference between the immune response of the different age groups, meaning all groups have a similar response. This suggests that there is some other factor that leads to children being infected with typhoid more often than adults.

Overall, typhoid fever is a successful disease, due to its ease of transmission, ability to attach to the host cell and evade the host immune response, as well as being able to disrupt normal cell function. Because of this success that S. Typhi has as a pathogen, and the inherent danger it poses because of this, it is important to look at the immune response for future studies, as that is where the severity of the disease is determined. It could be advantageous for scientists to look into a way to lower the number of bacteria that escapes the abscesses created by the immune cells, in order to lower the severity of the disease. Because of the possibilities for future development in understanding what makes typhoid fever so successful as a pathogen, there is an obvious importance to continue research into this topic.

Environmental Effects

Southeast Asia offers the perfect breeding ground for typhoid fever. Firstly, much of Southeast Asia is located near the equator, so the average temperature for these areas is relatively warm, which allows for bacteria to reproduce. Additionally, Southeast Asia has a very wet climate, with a multitude of water sources. This is advantageous for the S. Typhi bacterium, as it heavily relies on water as a transmission method. This combination of wet and warm climate offers an ideal climate for typhoid fever to flourish, as these factors make it very easy for bacteria to move from reservoir to reservoir, and thus increase the overall rate of transmission.

One of the contributing factors that affects the number of cases of typhoid fever is the time of year and the relative amount of precipitation. In Asia, there are two seasons: the monsoon, or rainy, season (typically April to October) and the dry season (November to March). A study conducted by Pham Thanh et al. (2016) intended to look at the overall change in number of cases of typhoid fever during different times of the year to try to find the correlation between precipitation and number of cases of typhoid fever. To do this, blood samples were taken from patients from the province of Siem Reap in Cambodia between January 2007 and December 2014. The cases that occurred were then tracked and plotted, to look at the correlation between time of infection and overall number of cases. The study found that there was seasonal variation in the number of typhoid cases, with the majority of the cases (68%) occurring during the early monsoon months of April, May, June and July. Meanwhile, in the later monsoon months of August to October, the number of cases declined to less than two cases per month and remained below this threshold in the dry season months of November to March. The study notes that patients from around the country come to this hospital to receive care, meaning that these results show the overall trends for the entirety of Cambodia, and perhaps the entirety of Southeast Asia, as the overall same wet and dry seasons remain in these regions. According to the study, this influx of cases in the wet season makes sense, as the heavier amounts of rainfall allow for reservoirs to expand. This increase in rainfall creates flooding, which allows contaminated water to mix with clean water, thus creating more reservoirs and sources from which infection can occur. The study suggests that more emphasis should be put on creating more complete spatial information on presence and absence of typhoid throughout areas where outbreaks of typhoid fever occur, in order to predict and prepare for when outbreaks occur.

In addition to looking at the effects of monsoon and dry seasons on the number of cases of typhoid fever, the same study conducted by Pham Thanh et al. (2016) looked at proximity to water as a contributing factor for contraction of typhoid fever. The Siem Reap province is bordered by Tonle Sap Lake, the largest body of freshwater in Southeast Asia. The method for this part of the study looked at how close patients lived to the lake. The study found that the Kampong Kleang commune showed the highest incidence of typhoid fever over the study period with 11.36/1,000 cases. This area is known for its floating villages and is situated on the edge of Tonle Sap Lake. Overall, the study found that closer proximity to the lake increases likelihood of infection. This commune also experiences a lot of flooding from the lake, which further increases likelihood of contraction.

Due to the direct effect that climate has on the epidemiology of typhoid fever, it is important to look at the effect that changes in climate have on this infectious disease. A study conducted by Wu et al. (2015) examined whether changes in climate could have an effect on infectious diseases. The study found that temperature changes, changes in precipitation rates, and extreme weather events could have an effect on the epidemiology of typhoid. According to the study, an increase in temperature could increase the reproduction rate of the bacteria, as bodies of water begin to warm. As temperature between 7 °C and 37 °C are optimal for bacteria to reproduce; this warming of waters could cause more bacteria to be produced, thus increasing the number of bacteria and possibility for infection. The study also states that precipitation change could result in an increase of typhoid fever cases. If precipitation levels increase, this would allow for flooding to occur, which would spread water contaminated with typhoid from one location to other sources of water. Likewise, a decrease in precipitation would also cause an increase in cases, as the concentration of bacteria in a water source would increase, making it more likely to contract the infection. These factors are important to take into account in extreme weather phenomena, such as hurricanes, flooding, and tsunamis, as they often bring about changes in climate that would have an effect on typhoid. Overall, the study suggests that as climate change becomes a more pressing issue, it is important to look at these factors, in order to predict changes in cases of typhoid.

Sociocultural Effects

While many of the factors that lead to the infection of typhoid fever are due to the pathogen and environment itself, there are also some human factors that contribute to the epidemiology of typhoid fever. Because of the low-income nature of many of the countries in Southeast Asia, some families opt to skip treatment, as they cannot afford the burden of cost (Poulos et al. 2011). Additionally, due to the lack of education and general health care in developing countries, the general public isn’t aware of the necessity to treat typhoid. This means that people don’t get treated, which allows chronic symptoms to develop, thus increasing overall mortality of the infection.

A study conducted by Poulos et al. (2011) looked at the overall cost for families that experience a typhoid fever infection. To do this, an extensive survey was given to families that were affected by typhoid fever to evaluate the overall cost to treat a case. The overall cost surveys took into account costs of medical treatment, medicines, laboratory tests, transportation, food, lodging, and the costs of special items such as foods or herbs. The results showed that the average private cost of a non-hospitalized case was 13% of the average monthly household income in Kolkata, 23% in North Jakarta, and 55% in Hechi. The average private cost of a hospitalized case was 35% of the income average monthly income in Kolkata and over 100% in North Jakarta and Hechi. Because of this high expense that families face when receiving treatment, some families opt to not be treated, as the cost will send the family into financial hardship. When the symptoms become more chronic, and the necessity to get treated is much higher, families will experience even more hardship. This can continue the lack of treatment, until complications occur, and the infected person dies. Overall, some effort should be made to offer more aid to families that cannot afford treatment, in order to lower the mortality rate.

Another study (Owais et al. 2011) looked at how maternal education of treatment and prevention options could affect immunization rates. Mothers were given easy-to-understand information, including pictorial guides, in order to convey the benefits and necessity to immunize children. The control group was given general health promotion messages based on Pakistan’s Lady Health Worker, while the intervention group received postcards consisting of three targeted pictorial messages regarding vaccines program curriculum. It was found that in the intervention group 72.1% of children had received all 3 doses of the monitored vaccine, while only 51.7% had received all 3 doses in the control group. Due to the lower literacy rates in these developing countries, simple educational intervention designed for these communities have a significantly beneficial effect on vaccination rates, as parents can easily understand the benefits of vaccines for their children.

Antibiotic Resistance

One of the largest challenges facing the burden of typhoid fever is the increasing amount of antibiotic resistance seen in the S. Typhi bacteria. Typhoid fever is primarily treated by antibiotics, which has created an increased resistance profile. This is a problem, as it limits the number of effective ways to treat typhoid fever. Additionally, antibiotic resistance is not uniform and varies among individual subtypes of the S. Typhi, allowing for resistance to increase, due to difficulties in prescribing the correct and specific antibiotic that is effective against each infection.

In a study conducted by Dutta et al. (2014), a resistance profile was created for the S. Typhi bacteria. To do this, children in Kolkata, India who were diagnosed with enteric fever had blood samples taken​, so that bacteria could be isolated from these samples. Kirby Bauer disc diffusion tests were administered, in order to evaluate resistance to different antimicrobials. Overall, it was found that the antimicrobial NaR had the most resistance against it, and  15 other antimicrobials had some level of resistance built against them. Meanwhile, azithromycin had no resistance built it against it. This suggests that the current antimicrobials being administered to treat typhoid fever should be reviewed, taking into account that azithromycin is effective against typhoid fever completely.

Another study (Mannan et al. 2014) looked at multidrug resistance in Bangladesh. The study first took blood, urine, sputum, and pus samples from hospitalized patients diagnosed with typhoid fever from three different regions. The bacteria were then cultured, and Kirby Bauer disc diffusion tests were ran. It was found that every antimicrobial had some resistance built against it. Additionally, the study found that different regions had different levels of resistance for each antimicrobial. This suggests that resistance profiles need to be developed for specific regions in areas where typhoid fever is present, so doctors can prescribe antibiotics that are effective, and limit increases in antibiotic resistance.  

Reducing Morbidity and Mortality Through Vaccines

Because of the overall success of typhoid fever, due to characteristics of the bacteria, as well as epidemiological factors, there is a high necessity to reduce the morbidity, and subsequently, the mortality of this infectious disease. One of the approaches to do this are the efforts being made to create a vaccine to protect against this infection. While there currently are available vaccines to protect against typhoid fever, they aren’t able to provide overall protection. For example, the Ty21a vaccine only has moderate efficacy and is unsuitable for use in children less than two years of age (Darton et al. 2016). Another vaccine used is the Vi-conjugate vaccine which can be given during infancy but is not considered to be effective for widespread use (Jin et al. 2017).  Because of this problem with the efficacy of current vaccines, continued effort has been put in, in a hope to find a more effective vaccine option.

In trying to develop a new vaccine for typhoid fever, a study (Darton et al. 2016) looked at the efficacy of a developmental vaccine, compared to the effects of a commonly used vaccine and a placebo. First, participants were either given one dose of the trial vaccine, M01ZH09, a placebo, or 3-doses of the open-label vaccine, Ty21a. Then, twenty-eight days after vaccination, participants were exposed to a strain of S. Typhi, following an evaluation of the overall efficacy of the trial vaccine. The study (Darton et al. 2016) found that neither a single dose of the trial vaccine nor three doses of the open-label vaccine given resulted in significant overall protection. While both vaccines did show some protection from typhoid fever, these results were not significant enough to suggest that either vaccine effectively protects against the infection. These results help prove the necessity to continue working to develop an effective vaccine that provides full protection.

Another study (Jin et al. 2017) that looks at the efficacy of vaccines assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S. Typhi. For this study, healthy adult volunteers aged 18-60 years were recruited and given either a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine. Then, participants had blood culture taken over a 2-week period and were diagnosed with typhoid infection if the bacteria were present in the blood. Then, the overall efficacy of the vaccines was evaluated. The study (Jin et al. 2016) found that there was a vaccine efficacy of 54.6% for Vi-TT and 52.0% for Vi-PS. This suggest that both Vi-vaccines have potential to provide overall protection against typhoid fever. This is a significant finding, as it opens up a whole new group of vaccines to protect against typhoid fever.

Implications and Future Progress

Overall, typhoid fever is an infectious disease that poses a continued problem to the developing world. Due to typhoid fever’s success as a pathogen, it easily infects hosts and causes damage within their tissues. While typhoid fever is an effective and successful pathogen, the environmental and sociocultural factors of Southeast Asia magnify the overall success of S. Typhi. Due to the environmental characteristics of Southeast Asia, the bacteria that causes typhoid fever flourishes. This wet, warm climate allows the bacteria to have easy transmission, as well as an ideal environment to reproduce. In addition to these environmental factors, the sociocultural effects of Southeast Asia have a large effect on the overall success of typhoid fever. Factors such as poverty and lack of education have an effect on people’s ability to obtain both preventative measures to protect against typhoid infection, as well as treat typhoid fever. But, there are also inherent problems with treatment, as antibiotic resistance limits the overall efficacy of this common method of treatment.

Due to all the factors Southeast Asia possesses that aid in the success of typhoid fever, future work needs to be done to lower the overall morbidity and mortality of the infection. More effort needs to be put into methods to aid communities effected by typhoid fever, such as filtration methods on an individual scale. Additionally, more effort needs to be put into education of typhoid fever, to help individuals understand how to avoid contracting the infection. Along with these preventative measures, there must be some development for the treatment methods of typhoid fever. Firstly, an effort should be made so families can afford treatment for the infection. The expensive antibiotics that are typically used as treatment must also be evaluated for effectiveness on S. Typhi, in order to limit more resistance being built against antimicrobials. The necessity for vaccine development is also high, as continued effort must be put into this subject, to create preemptive protection against the infection. With these future developments, the overall morbidity and mortality of typhoid can be reduced, thus lowering the number of deaths caused by this infectious disease.    

References

(2019). Home | Typhoid Fever | CDC.

Darton, T., Jones, C., Blohmke, C., Waddington, C., Zhou, L., Peters, A., Haworth, K., Sie, R., Green, C., and Jeppesen, C. et al. (2016). Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a. PLOS Neglected Tropical Diseases 10, e0004926.

Dutta, S., Das, S., Mitra, U., Jain, P., Roy, I., Ganguly, S., Ray, U., Dutta, P., and Paul, D. (2014). Antimicrobial Resistance, Virulence Profiles and Molecular Subtypes of Salmonella enterica Serovars Typhi and Paratyphi A Blood Isolates from Kolkata, India during 2009-2013. Plos ONE 9, e101347.

Hentzen, Typhoid Toxin (PDB: 4K6L) from Salmonella enterica. C. doc1.

Jin, C., Gibani, M., Moore, M., Juel, H., Jones, E., Meiring, J., Harris, V., Gardner, J., Nebykova, A., and Kerridge, S. et al. (2017). Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. The Lancet 390, 2472-2480.

Khanam, F., Sayeed, M., Choudhury, F., Sheikh, A., Ahmed, D., Goswami, D., Hossain, M., Brooks, A., Calderwood, S., and Charles, R. et al. (2015). Typhoid Fever in Young Children in Bangladesh: Clinical Findings, Antibiotic Susceptibility Pattern and Immune Responses. PLOS Neglected Tropical Diseases 9, e0003619.

Khan Academy, (2019). Typhoid toxin.

Mannan, A., Shohel, M., Rajia, S., Mahmud, N., Kabir, S., and Hasan, I. (2014). A cross sectional study on antibiotic resistance pattern of Salmonella typhi clinical isolates from Bangladesh. Asian Pacific Journal Of Tropical Biomedicine 4, 306-311.

Marineli, G. (2019). Mary Mallon (1869-1938) and the history of typhoid fever.

Ochiai, R. (2019). A study of typhoid fever in five Asian countries: disease burden and implications for controls.

Owais, A., Hanif, B., Siddiqui, A., Agha, A., and Zaidi, A. (2011). Does improving maternal knowledge of vaccines impact infant immunization rates? A community-based randomized-controlled trial in Karachi, Pakistan. BMC Public Health 11.

Pham Thanh, D., Thompson, C., Rabaa, M., Sona, S., Sopheary, S., Kumar, V., Moore, C., Tran Vu Thieu, N., Wijedoru, L., and Holt, K. et al. (2016). The Molecular and Spatial Epidemiology of Typhoid Fever in Rural Cambodia. PLOS Neglected Tropical Diseases 10, e0004785.

Poulos, C., Riewpaiboon, A., Stewart, J., Clemens, J., Guh, S., Agtini, M., Anh, D., Baiqing, D., Bhutta, Z., and Sur, D. et al. (2011). Cost of illness due to typhoid fever in five Asian countries. Tropical Medicine & International Health 16, 314-323.

Safefood (2018). Salmonella - what you need to know.

Universität Basel (2014). Typhoid fever: A race against time.

Wu, X., Lu, Y., Zhou, S., Chen, L., and Xu, B. (2016). Impact of climate change on human infectious diseases: Empirical evidence and human adaptation. Environment International 86, 14-23.