Thursday, November 10, 2011

Typhoid Fever

Typhoid fever is a substantive global health problem with wide geographic distribution and significant morbidity and mortality. Typhoid fever should not be confused with typhus, which is a vector-borne rickettsial disease covered previously at Infection Landscapes. The clinical presentation is, however, somewhat similar with respect to neurologic symtpoms, which led to their similar nomenclature when early physicians would have difficulty distinguishing based on signs and symptoms alone. Nevertheless, these two diseases are otherwise quite distinct with respect to the causative organism, pathogenicity, mode of transmission, and landscape epidemiology. In fact, typhoid fever is more correctly known as enteric fever, though the former term is still very much in wide use.

The Pathogen. The causative agent for enteric fever is another serovar of Salmonella enterica enterica. The serovar responsible for enteric fever is Salmonella Typhi, while Salmonella Paratyphi causes a milder form of enteric fever (often referred to as paratyphoid fever). This organism is a gram negative bacillus with paritrichous flagella:

Salmonella Typhi

The bacteria target epithelial cells and microfold cells of the small intestine in the distal ileum in close proximity to the the Peyer's patches, which are important lymphoid tissue in the gut. Much like the other Salmonella serovars discussed previously, Salmonella Typhi employs a type III secretion system to inject proteins into the host cell, altering its cytoskeletal structure and inducing the uptake of the bacterium into the cytoplasm of the host cell. However, this serovar's pathogenicity is more invasive. Because of the location of infection in the small intestine, Salmonella Typhi typically invades the Peyer's patches and thereby accesses the lymphatic system, which ultimately leads to more widespread dissemination by way of the general circulation. Once in circulation, these Salmonellae can target cells in multiple organ systems. Most importantly, they infect macrophages, in which they replicate and are able to disseminate throughout the reticuloendothelial system.

The Disease. The clinical manifestation of enteric fever presents a diagnostic puzzle. Most of the symptoms are non-specific and often mimic other infections even when complicated. Indeed, the cognate, typhus, describes a very different infection, but nevertheless shares some similarities with the neurologic involvement and rash of enteric fever and thus the historical confusion between the two. Both typhoid and typhus are derived from the Greek word meaning stupor.

There are four clinical stages of enteric fever, each  roughly one weak, though not all (or any) stages need present in a particular infection.

The first stage, when infection is symptomatic, may include malaise, dry coughing, headache, myalgia, and a fever of steadily increasing temperature. However, the other symptoms will often precede the fever. While fever is a classic symptom of enteric fever, it will not always occur in symptomatic cases, which can further complicate the diagnosis.

In the second stage of symptomatic infection, the fever typically levels off at a high temperature (between 39 and 40 degrees C) and is maintained over a prolonged period, often until the fourth week of infection. During this stage, hepatomegaly and/or splenomegaly appear with or without associated abdominal pain. Diarrhea and/or constipation are common gastroenteritis signs in the second stage, though diarrhea is more common in children and constipation is more common in adults. Delirium is also a frequent characteristic of enteric fever that usually manifests around the second week of infection in about 20% of symptomatic cases. In about 30% of cases, a mild rash consisting of flat rose spots appears on the chest and abdomen. Elevated liver enzymes, leukopenia, thrombocytopenia, and anemia are common laboratory findings by this stage.

The third stage, if it occurs, typically coincides with the 3rd week of infection. This is the time when more serious complications can present. A more intensive delirium is a common complication with individuals demonstrating increasing agitation and advanced stupor. Intestinal bleeding is common (up to 20% of cases), and intestinal perforation, while not as common (up to 3% of cases), is associated with high case-fatality because of the septicemia that follows. Encephalitis, meningitis, osteitis, endocarditis, and pericarditis are all potential complications of enteric fever, reflecting the wide dissemination and broad tropism exhibited by Salmonella Typhi.

The fourth stage is characterized by recovery. The fever and delirium begin to recede during this stage at week four (or even toward the end of the third week) in a slow progressive convalescence, which can last up to 2 or more months.

The chart below depicts some typical clinical symptoms of enteric fever, all of which are non-specific:

The Epidemiology and the Landscape. Enteric fever constitutes a significant global burden of disease with approximately 22 million cases per year and 200,000 deaths, which is substantively more than the burden represented by cholera. The case-fatality of untreated enteric fever is approximately 15%, but with appropriate antibiotic therapy it is, on average, less than 1%. However, in some parts of Asia and Africa where advanced resistance to antibiotic treatment has emerged, current case-fatality may be as high as 30%. The map below from CHU Rouen shows the global distribution of enteric fever with the brown and red shades highlighting endemic and hyperendemic countries, respectively.

The high risk regions typically experience greater than 100 incident cases per 100,000 persons in the population each year, while medium risk regions experience between 10 and 100 incident cases per 100,000 persons each year. Unlike most of the global burden of diarrheal disease covered at Infection Landscapes, enteric fever's greatest burden is not experienced by the youngest children in at risk populations. Rather, the disease is concentrated in older children aged 5 to 19 years. Nevertheless, in hyperendemic regions children aged 1 to 5 years can still experience a significant burden of disease. In addition, when enteric fever does occur in young children, especially those younger than 1 year of age, complications are much more common in the clinical course and the mortality is higher.

Humans are the only reservoir for both Samonella Typhi and Salmonella Paratyphi. Once infected, individuals are infectious beginning at some point during the subclinical period before symptoms present, and until the first week of recovery (i.e. stage 4 described above). However, 10% of those infected who do not receive treatment will continue shedding viable bacteria for up to 3 months following recovery. Up to 5% of untreated infected persons become chronic carries, potentially shedding Salmonella Typhi for the rest of their lives. This extended pathogen carriage following recovery, whether for the sizable proportion who shed bacteria for several months or the smaller proportion who shed bacteria for much of their lives, is one of the critical epidemiologic characteristics of enteric fever. Extended carriage ensures an ongoing source of contamination and, thus, maintains the primary mode of transmission in those regions where this disease is endemic.

Transmission is through the fecal-oral route, and ingestion of feces-contaminated water and food is the primary mode of transmission in most settings where enteric fever is endemic. Direct person to person contact can also be an important mode of transmission, but contaminated water and/or food is consistently the major source of new infections in endemic regions. As such, the geography of endemicity follows the lines of poverty, which, as with other gut infections we have covered at Infection Landscapes, are delineated by areas of poor sanitation and poor water infrastructure.

Control and PreventionControl and prevention of enteric fever begins by following the usual guidelines: improving sanitation in resource poor areas and maintaining vigilance in personal hygiene. In most settings in the world where enteric fever is endemic, improved infrastructure that can maintain adequate water resources is a first priority in prevention.

Secondarily, personal hygiene at the individual level, especially in the context of food preparation, can also be very important in preventing enteric fever: consistent hand washing, boiling water, and thoroughly cooking food are all important in stopping the chain of transmission

Vaccination against enteric fever should also be an important component to control and prevention in endemic regions. There are currently 2 vaccines recommended by the World Health Organization. The Ty21a  is a live attenuated vaccine that is administered orally, and the Vi antigen vaccine is an inactivated vaccine that is administered intramuscularly or subcutaneously. The live vaccine induces both humoral and cell-mediated immunity and requires a 3 to 4 dose schedule, whereas the inactivated vaccine is a one-time injection and induces only a humoral response with significant antibody production, but no memory cells. The efficacy of the live vaccine approaches 80%, but some studies have shown it to be as low as 50%. The range of efficacy for the inactivated vaccine is similar (55% to 77%). As expected, the immunity from the live vaccine is longer lived (approximately 5 years) than that induced by the inactivated vaccine (approximately 2 years), necessitating booster vaccines in both when immunity wanes.

Here is a good summary of prevention strategy from a Kenyan physician:


  1. Typhoid symptoms are so non-specific at first, i imagine it is difficult to diagnose unless there is a current outbreak to arouse your index of suspicion. I wonder if typhoid is one of those illnesses that a health care provider would recognize easily if he or she worked in a highly endemic environment. In any event, this disease, like most of the diarrheal illnesses, is best combatted through public health efforts targeting hygiene and clean water.

  2. Invasion of the Peyer's patches and dissemination via lymphatic system to all organs makes this bacteria highly dangerous. It causes hepatosplenomegaly which leads to destruction of all cells lines causing anemia, leukopenia and low platelet count. Therefore, the body is left with a suppressed immune system which is no longer capable of defending itself against this organism. Vaccination, live attenuated or inactive, can protect up to 70% for 3 years. I am not sure if vaccination of all people is mandated in highly epidemic areas but as long as proper infrastructures are not built and the water is not treated properly, I believe it is very difficult to fight against this infection.

  3. Many countries that are endemic with Typhoid fever would really benefit from a widespread round of vaccinations. This would be a great method of prevention and containing outbreaks, as mentioned by the Kenyan physician. One thing to consider when choosing to mass vaccinate a group of people is the type of vaccine which will be used. Since the Ty21a is a live attenuated vaccine, it may be dangerous for those who are immune-compromised. Also, it requires a 3-4 dosing schedule and proper storage conditions. The Vi antigen vaccine is only a one time vaccine, that does not require storage at special temperatures- however the immunity may be shorter lived and possibly weaker than the Ty21a. These are important considerations during a mass vaccination plan.

  4. As reported, the chronic carrier state is one of the key epidemiologic characteristics of enteric fever. One of the most famous examples of chronic Salmonella thyphi carriage was Mary Mallon, "Thyroid Mary," during the early 1900s. She worked for families as a cook and infected several household members for whom she worked. About 50 people were infected and 3 died. She was quarantined twice (the second time because she broke her agreement and returned to being a cook). After she died, an autospy revealed she was harboring Salmonella thyphi with her gallbladder. After this story, you can never forgot about chronic carrier state of Salmonella thyphi.

    1. "Typhoid Mary" was the first thing I learned about Salmonella typhi. This was a very informative post. I learned way more about this subject than what I previously knew.

  5. In addition to typhoid fever worsening progressing to the third stage, there are complications that may arise form the second stage symptoms that are not specifically associated with typhoid fever. This means that typhoid fever can be a serious burden even without progressing to the third, most severe stage.

  6. I find the age distribution of the disease to be the most interesting. I wonder why it is that the 5-19 year olds have the highest percentage of cases. And because mortality rates are highest in those under 1, I wonder if the risk of dying continues to decrease as an individual becomes older. I also wonder what percentage of the population has developed immunity. This could definitely explain why the larget burden is seen in those under the age of 20.

  7. In response to Gul, many of these highly epidemic countries most likely can not afford these vaccinations. These same countries also probably have very poor infrastructures and a poor economy. I am sure if they were able to afford these vaccinations it would definitely be mandated for everyone to receive in order to stop the epidemic. Until that time when all of these countries can afford the necessary various medications, or to rebuild their infrastructure, the basic attention to personal hygiene should be every countries goal to aide in decreasing the epidemic of Typhoid fever.

  8. In response to Jennifer, I agree that there should be a mass vaccination campaign, but the way in which the campaign would proceed, presumably through efforts of the WHO or another organization, should be with caution. Along with careful choice of the specific vaccine based on conferred immunity and storage process, we must address the issue of actual bringing vaccines into these area; in some cases there are issues when foreign organizations attempt to enter a country and "force" medicine on a population. It is a sensitive subject and we must look at past attempts at vaccine administration for guidance.

  9. Many of us have agreed that improving infrastructures and vaccinating against particular diseases should be priorities when trying to stop or prevent future outbreaks of infectious diseases. How are certain vaccine schedules prioritized and how is the burden of particular diseases taken into consideration? Pouring funds into developing areas to improve infrastructure will only do so much unless there is a plan to also maintain these infrastructures throughout the future. So where do we really start...with education? with re-building? with vaccinating? In theory, all of these plans seem like the way to go. I am sure, however, that when plans are put in place to eradicate outbreaks of any disease, the disease with the highest impact will take priority. Also, I believe it is easier to put programs in place but to keep them going is the biggest challenge.

  10. Andriane brings up a good point because you want to make a long term impact with any type of intervention. I think that engaging the community is very important for sustainability. A small example are the organizations that provide malaria nets to people in the developing world but make them pay a small amount for them. Some find that when just giving them away, some people will use them to fish or to protect their crops from bugs. When they pay for them they are more likely to take care of them and to use them properly.
    But tackling sustainability is very difficult because there are so many factors that effect public health and they all differ between communities.

  11. In response to Lisa:

    There is great variability in the clinical presentation of typhoid fever defending on age, gastric acidity, immunologic status, specific Salmonella serotype, and geographic area. In addition, the differential diagnosis includes other bacterial gastroenteritis, malaria, amebiasis, dengue fever and leishmaniasis. I would imagine that along with a high index of suspicion, thorough medical history is key. The classic manifestations of relative bradycardia, pulse-temperature dissociation, and salmon-colored “rose spots” may help with the diagnosis if they are present.

  12. In response to Waqas,
    As quoted above, up to 5% of people who contract typhoid may continue to carry the disease after their symptoms are gone, allowing transmission to continue from asymptomatic carriers. Typhoid Mary is indeed the classic example. It is interesting as to how people go about identifying typhoid carriers today, and what type of limitations they experience in their lives. What type of control measures are implemented to protect them from spreading the disease?

  13. In response to Jennifer,
    The importance of vaccination for prevention of diseases, including typhoid fever is obvious. As you mentioned, each vaccine has it's pros and cons in mass vaccination plans. Furthermore, vaccination for typhoid fever, live attenuated or inactive, can unfortunately protect up to 70% for 3 years only. In areas with poor water quality and sanitation, vaccination by itself will not be successful in preventing typhoid fever.

  14. Although the human is the only reservoir for Samonella Typhi, one would expect that this disease be either eliminated or even irradicated by now. The disease has about a 15% case fatality without adequate antibiotic treatment, but with proper treatment, the case fatality is about 1%. Of the untreated cases, about 5% go on to be chronic cases and remain that way for the rest of their lives and keep the organism viable by continuously infecting others. For this reason, Salmonella Typhi and also S. Typhimurium may forever be diseases that cannot be eliminated.

  15. Since certain areas of Africa and Asia are now facing antibiotic-resistant strains,such as is the case with several other diseases we've talked about, I wonder how the focus on prevention and the speed by which measures are implemented has changed in these regions in recent years.

  16. Nicole and Andri: I think you make a great point for sustainability and commmunity involvement in relation to successful interventions. In the case of typhoid, areas that are mostly affected are the ones that carry most of the burden of diarrheal diseases, SEA and SSA. Most people in these endemic areas, believe that water=life. Prevent diarrheal disease not through vaccination, but through community participation. Lets get community members and leaders to build boreholes or throw educational events on treating water and hand hygiene into schools or at the local health clinic.

  17. To add to what Gul and Jennifer said about vaccination, this method of prevention is only about 50-80% effective. The vaccine is recommended for those living in and traveling to endemic areas. The live attenuated form of the vaccine cannot be given to children under 6 years of age and also immunocompromised people. The inactivated vaccine cannot be given to children under 2 years of age. The highest risk of patients are those under 1 year old. With an estimated 22 million cases and 200,000 deaths world wide yearly, the best preventive measure still comes back to access to clean and safe drinking water, adequate hand hygeine, fully cooking foods prior to consumption and improved infrastructure.

  18. I live on an island where typhoid fever is endemic. I am a public health medical officer, has been in the field for 3 months. you can imagine the work we do, day in, day out of typhoid case finding and treatment. we've had an outbreak in a large, poor family. we're treated all of the food handlers as typhoid carriers. I am beginning to think that perhaps, this is how we would manage the carriers from now on. I wonder if any country or anyone has done it. ofcourse, all other issues should be addressed such as water and sanitation. My country depends heavily on foreign aid. We are also looking into getting the vaccines for prevention but that is just a temporary measure. We still need to identify and treat our carriers..i can imagine there are alot out there. Problems such as there are a shortage of health staff and resources are big issues so its unrealistic to identify most of them. hence, why I personally believe that the only way is to treat all the food handlers in a household as carriers.
    Has anyone had this experience or thinking? please share!!

  19. This blog is a great source of information which is very useful for me. Thank you very much.


  20. George,
    I also thought quite a bit about a more community based approach to dealing with typhoid fever. It is amazing to me that typhoid fever has a higher disease burden than cholera, but does not seem to get quite as much press. Mass vaccine campaigns and improving the infrastructure in every town (as some of the commenters have suggested) will require massive amounts of money. However, I feel as if George's suggestion on interventions to promote water treatment and handling is the most feasible (while mass vaccine campaigns and improving infrastructure would be great) given economic and political circumstances. An education campaign would require less financial support upfront and could potentially create a cultural perpetuation of water treatment/sanitation education within communities and generations.

  21. Are there any good studies that point to what loci are responsible for a person being a carrier and not developing Typhoid? Thanks!

  22. Although, Typhoid fever is vague presentation, one of the characteristic finding is bradycardia with fever (Faget sign). Widal test which tests for antiO and antiH antibodies is fairly sensitive and specific and also pretty cheap. But you need 2 titers 7-10 days apart. Blood culture is always standard but does not grow typhi always. Usually in endemic areas, clinicians can put two and two together but would be difficult to make a diagnosis in developed countries like US.
    Resistance of S typhi against commonly used antibiotics (quinolones and cephalosporins) has become a major problem.

  23. In response to Ms. Stephanie, from current understanding of the disease S typhi can cause carrier state after primary infection. In up to 10% untreated patients, S typhi can shed in feces for 3 months. This fecal shedding comes from bacteria surviving and multiplying in Peyer’s patches.
    In 1-4% of chronic asymptomatic patients, shedding of S typhi in urine and stool occurs for > 1 yr. Of all the sites, bacteria might infect gall bladder is known to harbor for longer. Whether this is secondary to biliary abnormalities is difficult to stay. But women and infants are more susceptible. Even the famous case of NY, “Typhoid Mary” was found to harbor S. typhi in her gall bladder after her death at postmortem. But again, patients may still be a carrier (from liver infection) after gall bladder is removed.
    Studies on carrier state are mostly animal studies and case series.

    This review article may be useful to read –
    Nat Rev Microbiol. 2011 Jan;9(1):9-14. doi: 10.1038/nrmicro2490. Epub 2010 Nov 29.
    Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Gonzalez-Escobedo G, Marshall JM, Gunn JS.

  24. In response to Dr.Dwivedi, I wonder why women are more susceptible to the disease. Is there something in particular that makes women more susceptible ?

  25. Just like most infectious diseases, improved sanitation and proper personal hygiene are essential to prevent and control typhoid fever. However, given the extended pathogen carriage of the disease, public health should pay special attention to the group of chronic carriers, as this group would become a potential source of contamination in their life-time, potentially causing threat to the public just like the case of “Typhoid Mary” in NYC in early 1900s. Moreover, the general public should be educated to seek medical care for typhoid fever rather than left untreated or self-treated which could lead to chronic infection of the disease.

  26. I found this interesting. I caught Typhoid in Nagaland, India and while I am not a doctor, being Allied Health I found several things different in my case.
    Firstly, the Dr treating me there laughed when I said I couldn't have Typhoid because I was immunized. In fact I was not the only person in the NGO I was at who was infected, and one who was tested had a 'different strain' of Typhoid to the typical one in the region. The Dr concerned said their local strains were 'tougher', although I cannot tell whether his comments were medically valid. It responded to Antibiotics. Being water compromised I had boiled all water, but the political system was unstable, no one could leave the place I was at for a week or two and we had to conserve gas and clean water, so I washed my hands in well water, and spat out mouthwash from toothpaste probably compromised with the bacterium. This apparently was enough to catch it, although I can't tell if I was infected from cooking preparations from a carrier.
    I think this raises several questions about whether there needs to be research on Nagaland Typhoid organisms to see if there is immunization that more effectively covers it. It is also difficult to know how to eradicate all risk to persons in an NGO when it is difficult and expensive to ascertain whether all members who are cooking are not infected. Colloquially the people there tell you, none of them get Typhoid (I'm sure this is not true but it's their perception), only people from outside get it, so possibly if they are right that most have had it as a very young child or are passed immunity through their mother's breastmilk, then a substantial percentage of persons of Nagaland descent are probably carriers, making it difficult and expensive to eliminate or prevent.


Note: Only a member of this blog may post a comment.