149 Typhoid Fever

Typhoid fever is a systemic infection caused by the bacterium Salmonella typhi, usually manifested by the slow onset of a sustained fever and a variety of other symptoms including headache, cough, diges­tive disturbances, abdominal pain, and profound weakness.

A variant illness, called paratyphoid fever, has many of the same features as typhoid fever, but is caused by members of the Salmonella bacterial fam­ily other than S. typhi. Typhoid and paratyphoid fevers are sometimes lumped together under the term enteric fever.

Etiology

The microorganism responsible for typhoid fever is a member of one of the largest and most widespread families of bacteria on Earth with over 1,700 serotypes recognized. The salmonellae are rod­shaped bacteria that have a cell wall and flagella, which give the bacterium motility.

Salmonellae can colonize the gastrointestinal tract of a broad range of animal hosts including mammals, birds, reptiles, amphibians, fish, and in­sects. Some types of salmonellae are highly adapted to specific animals; others have a wide range of hosts. Because of this versatility and the enormous consequent animal reservoir, the eradication of all salmonellosis would be essentially impossible.

Salmonellosis is generally a mild disease in hu­mans, characterized by a few hours or days of vomit­ing and diarrhea (gastroenteritis), followed by weeks to months during which the organism is shed asymptomatically in the feces.

Almost unique among the salmonellae, the ty­phoid bacillus is adapted to human beings alone. S. typhi also possesses a protective envelope, called the “virulence antigen” or Vi antigen, which appears to help the organism resist the immunologic defenses of the host. The exclusive adaptation of S. typhi to human beings makes control possible through public health measures.

Epidemiology

Typhoid fever is spread by the fecal-oral route: Bac­teria shed in the stool by infected persons can be ingested by someone else, usually through contami­nated food or water.

Control of typhoid fever depends on maintaining a separation between sewage and drinking water. In certain areas of the world, as many as 3 percent of adults may be shedding S. typhi. Thus with poor sanitation, the population is continuously exposed, and the disease is constantly present. Such areas are termed endemic. Many of the least developed regions of the world are highly endemic for typhoid fever.

In contrast, where effective sanitation barriers are suddenly breached, transmission follows an epi­demic pattern with a sudden rise in the incidence of a disease within a limited geographic area. For exam­ple, typhoid fever is almost unknown in Switzerland; yet contamination of Zermatt’s water supply in 1963 resulted in 280 cases in a brief period of time. Ten years later, a similar compromise of the water sup­ply of a migrant laborers’ camp in Florida permitted an outbreak of 222 cases, with a single carrier as the apparent origin.

The other main vehicle for typhoid transmission is food. Though denied another animal host, S. typhi can grow well on many types of food, and contami­nated foods have been responsible for large-scale outbreaks.

Foodbome transmission may be important in maintaining high levels of endemicity in areas where drinking water is pure. In Santiago, Chile, 10 percent of water samples from the irrigation canals are positive for S. typhi, and contamination of pro­duce, rather than drinking water, appears to be an important factor in the city’s typhoid problem.

In fact, even when food is initially free of S. typhi, handling by persons who shed the bacillus can be enough to produce disease in those who eat it, par­ticularly where refrigeration is absent and basic standards of hygiene are not maintained.

Minor roles in S. typhi transmission are also played by shellfish harvested from contaminated wa­ters and flies lighting first on excrement and then on food. Transmission may also occur accidentally in the microbiology laboratory while workers are han­dling infected human specimens.

The percentage of persons who develop typhoid fever after exposure to the bacillus depends upon a number of factors, among them the virulence and number of organisms ingested, and the host’s health and immune status.

Experiments conducted with adult volunteers dem­onstrate that the attack rate of typhoid fever de­pends directly on the number of organisms ingested. Illness was produced in about 25 percent of volun­teers each ingesting 100,000 bacilli; ingestion of 10 million bacilli resulted in illness in 50 percent; and ingestion of 1 billion organisms virtually guaran­teed the development of typhoid fever. The incuba­tion period varied inversely: The larger the dose, the shorter the incubation period. Some strains, how­ever, are able to produce disease at very low num­bers: Only 10 organisms of the type involved in the 1963 Zermatt epidemic were needed to make half of volunteers ill.

With typhoid, whatever the degree of community exposure, maintaining personal hygiene, boiling drinking water, and cooking food just before eating it play an important role in preventing typhoid fe­ver. Predisposing factors for the development of all Salnwnella infections include red cell breakdown diseases (e.g., sickle-cell disease, malaria), immuno­deficiency (e.g., AIDS), malignancy, or dysfunction of various organs such as stomach, liver, or kidney. Other conditions such as gastric hypoacidity and the use of antibiotics that inhibit normal gut bacterial flora are risk factors that favor Salmonella infec­tions. Adults in endemic areas are more resistant to typhoid than are children in the same area or previ­ously unexposed persons from other areas.

A distinctive feature of the epidemiology of ty­phoid is the existence of a large number of asympto­matic carriers: persons who excrete S. typhi yet manifest no signs of illness.

In the normal course of typhoid fever, fecal excre­tion of the organism persists for a few weeks, but about 2 percent of infected persons will never clear the bacillus from their stools. In such persons, the organism appears to colonize the biliary tract - that is, the tubules that conduct bile from the liver and the gallbladder. Persons with preexisting disease of the biliary tract-for example, inflammation or gallstones - are at risk for becoming carriers. S. typhi appears to have a particular affinity for bile and gallstones. It grows best on media enriched with bile by-products. Once a stone is infected, it forms a focus of infection sheltered from antibiotics and the host’s immune system.

The likelihood of becoming a carrier increases with age and peaks at 55 years of age, with women carriers outnumbering their male counterparts 3 to 1 - a pattern similar to that seen in biliary disease, but contrasting sharply with acute typhoid fever, which is a disease of the young and which affects both sexes equally.

Distribution and Incidence

Since the beginning of the twentieth century, ty­phoid fever has been largely a disease of the develop­ing world, and the same factors that interfere with the provision of health care in these regions also interfere with the gathering of health statistics.

For northern Europe, North America, Japan, and Australia, the annual incidence of typhoid fever is less than 1 case per 100,000 persons, and half of these cases are acquired by foreign travel rather than by indigenous exposure. The annual incidence in southern and eastern Europe averages about 10 per 100,000, whereas in the developing world it is 40 in Egypt, 100 in Chile, 850 in rural South Africa, and ranges from 500 to 1,000 for some areas of South and Southeast Asia.

These crude estimates in turn suggest that the global incidence averages 300 cases of typhoid fever per 100,000 persons per year or 15 million cases of typhoid fever each year.

Regarding age, sex, and race, the following gener­alizations can be made: In endemic areas, 75 percent of cases of typhoid fever occur in persons 3 to 18 years old. Typhoid is only rarely described in chil­dren younger than 2 years, although studies in Chile indicate that typhoid fever may be unsuspected clini­cally because the characteristic features of the dis­ease are blurred in this age group. For acute typhoid fever, the ratio of the sexes is equal, but three- quarters of carriers are women; no susceptibility to typhoid fever has been identified by race.

Poverty is usually associated with poor sanitation and poor health care, and thus constitutes a risk factor for acquisition of typhoid. Blacks in South Africa have four times the incidence of typhoid, with eight times the mortality rate of whites.

In endemic areas, typhoid tends to peak in the summer months. Whether this pattern is due to greater consumption of water or enhanced prolifera­tion of the bacteria in food is unknown. In the devel­oped world, to judge by the United States, sea­sonality reflects foreign travel patterns, with peaks in January and February and again in the summer months.

Pathology

Most ingested typhoid bacilli are killed by stomach acid. Factors that reduce stomach acid (antacids) and speed transit time through the stomach (in­fancy, surgery, water rather than food as a bacterial vehicle) enhance the chances of infection.

Once in the small intestine, the bacilli penetrate the mucosal lining and are ingested by white cells located in gut lymph nodes. Perhaps because of its protective envelope (Vi antigen), S. typhi resists in­tracellular digestion and proceeds to multiply within the cells that normally destroy bacteria. Bac­teria multiply and pass into the bloodstream. Ini­tially, they are cleared from the blood by white cells located in the liver and spleen, but there, too, the bacilli multiply intracellularly, and reenter the bloodstream. It is during this second period of bacteremia that the clinical symptoms of typhoid begin.

Lymph nodes in the small intestine become par­ticularly laden with bacilli, occasionally to such an extent that they and the surrounding tissues die, leading to intestinal hemorrhage or perforation- the major causes of mortality in typhoid. The biliary tract is infected, and the patient may begin shedding S. typhi in the stool. Delirium, inflammation of the heart, and shock may occur and are caused not by direct infection but, rather, by toxins released either by the bacilli or by the white cells. Over a period of weeks, the body’s intracellular immune system rec­ognizes the typhoid bacillus, permitting the host to destroy the invader.

Clinical Manifestations

Typhoid fever is an illness characterized by fever and headache. Other early symptoms that may occur are abdominal distension or tenderness, constipa­tion and a few loose bowel movements, cough or bronchitis, and “rose spots” - a transient rash that usually begins on the abdomen. As the illness pro­gresses, the headache may be more severe and be associated with mental confusion or stupor, the liver and spleen usually become enlarged, and complica­tions such as intestinal hemorrhage, intestinal perfo­ration, and pneumonia may occur.

If the disease is untreated, mortality ranges be­tween 10 and 20 percent; 1 in 5 persons experiences gastrointestinal hemorrhage, and 1 in 50 suffers from perforation of the gut. Relapse occurs in about 10 percent of patients, usually after a week free of illness, but the symptoms are frequently milder and the duration shorter than during the original attack.

With early effective antibiotic treatment and sup­portive care, the course of the disease is markedly changed: Fever is usually gone within 3 days, and mortality is cut to less than 1 percent.

Diagnosis

Signs and symptoms so distinctive of typhoid as to render a clinical diagnosis secure are present only in a minority of patients. Particularly at the onset where fever may be the only complaint, typhoid is easily confused with a host of other diseases that share its geographic patterns: malaria, hepatitis, tu­berculosis, brucellosis, and typhus, to name a few.

The usual method of diagnosis is the culture of S. typhi from some part of the body. In persons with typhoid fever, culture of bone marrow is positive in 80 to 90 percent, and blood cultures are positive in 70 percent. Cultures of duodenal fluid are positive in 50 percent. Stool and urine cultures have positivity rates of only 30 and 10 percent, respectively.

In 1896, Fernand Widal determined that most per­sons infected with S. typhi develop antibodies to its cell wall (O antigen) and Aagellae (H antigen). Since that time, the Widal test for O and H antibodies in the blood has been used extensively to diagnose typhoid fever. But although the test uses inexpensive materi­als and is rapid, it is not always reliable. Persons with typhoid fever may never show a rise in antibody lev­els, and past exposure to S. typhi (such as is common among adults in endemic areas) can mean a positive Widal test, whatever the patient’s current ailment. In unimmunized children in endemic areas, however, the Widal test may be of value.

Treatment

Until 1948, little other than supportive measures could be offered the typhoid patient, but with the discovery of the antibiotic chloramphenicol, mortal­ity was markedly reduced. For 20 years chloram­phenicol was an entirely effective treatment, but resistance to it emerged in the early 1970s almost simultaneously in Mexico and Vietnam. Within a few years, 75 percent of all isolates of S. typhi in Vietnam were resistant. In developed areas, where infections were less frequent and antibiotic use was more tightly controlled, the percentage of resistant strains remained below 5 percent. Antibiotics such as trimethoprim, sulfamethoxazole, ampicillin, and others are now the drugs of choice for typhoid fever.

Control

Strategies for control of typhoid are divided into three categories:

Elimination of the Reservoir

Identification of carriers in an endemic population is difficult, and eradication of the carrier state costly. This option appears impractical.

Interruption of Transmission

Where pure water and food can be assured, typhoid transmission is minimal. Solely by improvement of sanitary conditions in the past century in developed countries, the incidence of typhoid fever has declined from 1 in 200 to 1 in 250,000. Mathematical models suggest that the building of privies in endemic areas would be among the least costly methods of reducing typhoid prevalence. Unfortunately, the pace of prog­ress in making such sanitary improvements is slow.

Imm uniza tion

Exposure to the typhoid bacillus appears to confer some degree of protection against subsequent in­fection. Volunteer trials in the twentieth century verified this, and the extent of protection was quan­tified at 75 percent. However, the immunity was relative; it seemed to decay after a number of years, and could be overcome, at any stage, by the adminis­tration of a sufficient number of bacilli. Neverthe­less, a relative immunity was better than none, and attempts to induce it artificially began almost as soon as the bacillus was isolated in the last decades of the nineteenth century. Since that time, most clinical vaccine trials indicate a protective effect of about 75 percent. At present, three major formula­tions exist:

Injection of Killed S. typhi Bacilli. This version contributed to the elimination of typhoid from the British and American armies during World War I, and, when administered to Thai schoolchildren in the 1970s, it was apparently instrumental in decreas­ing endemic typhoid fever. It is cheap and easy to produce, but there is a high rate of adverse reactions (fever, pain at the site of injection), as well as the need for refrigeration, sterile administration, and one to two boosters.

Injection of Vi Antigen. Vi Antigen (the protective polysaccharide envelope of S. typhi) provides, for persons in endemic areas, a degree of protection that is similar to that of the killed vaccine. The efficacy of this vaccine in Western travelers is not known. Only one dose is required, no refrigeration is needed, and no adverse effects have been noted. It requires sterile administration and is relatively expensive.

Oral Vaccine. This vaccine consists of a mutant strain of S. typhi incapable of causing typhoid fever. Studies in Egypt and Chile have documented its efficacy, with no adverse reactions observed. Refrig­eration, but not sterile administration, is required. Disadvantages include the problems of storage and administration of a live vaccine, the need for at least three doses, and the higher cost.

Although control of typhoid fever is best accom­plished with improvement of sanitary conditions, immunization with the more acceptable oral and polysaccharide vaccines may play an important pub­lic health role in developing countries.

History

Antiquity Through The Seventeenth Century Typhoid fever has surely been a disease of human beings since prehistory, but for ancient physicians its nonspecific symptoms did not make it distinct from other illnesses. Hippocrates described a case of what appears to have been typhoid, and Caesar Au­gustus was cured of a fever with the characteristics of typhoid by the use of cold baths, a remedy that persisted well into the twentieth century.

Although meaningful reports from ancient and medieval times are lacking, the early mercantile and colonial enterprises of European expansion were clearly affected by typhoid epidemics. In the early seventeenth century, 6,500 out of 7,500 colonists at Jamestown, Virginia, died most likely from typhoid fever.

At about the same time this epidemic was occur­ring, the Belgian anatomist Adriaan van den Spieghel (Spigelius) described lesions in the lym­phoid tissue of the small intestine of a patient who had died of a protracted fever, the first report of the characteristic pathological findings of typhoid. Later in the century, a British physician, Thomas Willis, cataloged the symptoms, signs, and course of a dis­ease he called “putrid malignant fever,” which was clearly typhoid.

Eighteenth Through Nineteenth Century

In the mid-eighteenth century, the Frenchman Fran­cois Boissier de Sauvages consolidated a variety of ailments, including what Willis had called putrid malignant fever, into the term “typhus.” In the 1830s, Pierre Louis, dissatisfied with the heterogene­ity of the concept of typhus, proposed isolating a particular constellation of symptoms under the name “typhoid fever,” or typhus-like fever. Later the American William W Gerhard, studying an epi­demic in Philadelphia, established typhoid fever as an entity independent of typhus, a term that now refers only to diseases caused by the rickettsial fam­ily ofbacteria.

Though the illness now had a clinical definition, its mode of transmission was still in dispute. Some­what earlier in the century, Pierre Bretonneau had argued that typhoid was contagious and that an attack conferred immunity. In the 1840s, the En­glishman William Budd virtually inaugurated the science of epidemiology by his demonstration that typhoid was spread from infected individuals to new hosts by means of water and food. Budd’s position was actively opposed by those who believed in spon­taneous generation, and little was done to imple­ment his recommendations of public health mea­sures. As a result, the annual incidence in Europe at that time remained as high as 1 per 200 people.

Finally, in 1875 Budd’s warnings were heeded, and the British Public Health Act was passed, radi­cally improving sanitary practices. Within a decade, typhoid mortality was cut in half. This lesson was not lost on other developed nations who enacted sani­tary laws of their own. Since that time, the incidence of typhoid in the developed world has steadily de­clined to its current annual rate of 1 case per 250,000 individuals.

This profound revolution in public health had be­gun before the microbial etiology of typhoid, or any other infection, had been established. Yet just 2 years after the Public Health Act was passed in England, the German Robert Koch demonstrated that a microorganism was the cause of anthrax; 3 years later his countrymen Carl Eberth and Edwin Klebs identified the typhoid bacillus in intestinal lymph nodes, making typhoid one of the earliest diseases for which a bacterial agent was known.

The next 2 decades saw an explosion of knowledge about the organism which was then called Eber- thella typhosa in honor of its discoverer. In 1884 Georg Gaffky succeeded in culturing the bacillus from lymph nodes, and shortly thereafter it was iso­lated from blood and stool.

Despite these rapid advances, therapeutic inter­ventions against typhoid were lacking. During the Spanish-American War of 1898, one-fifth of the American army fell ill from typhoid fever, with a mortality six times the number of those who died of wounds. At about this time in England, Almroth Wright developed a vaccine of heat-killed bacilli, which reduced the attack rate among soldiers in India by 75 percent. Despite these impressive re­sults, the vaccine was little used 2 years later in the South African (Boer) War, and the disastrous experi­ence of the American army in the war against Spain was virtually repeated among British troops in South Africa.

Twentieth Century

Early in this century, both the British and American commands ordered mandatory typhoid immuniza­tion and better military sanitation. The effect a de­cade later was dramatic: During World War I, the typhoid attack rate was reduced from 1 in 5, to 1 in 2,000, and since then, perhaps for the first time in human history, typhoid has not played a major role in armed conflicts.

In 1906 George Soper, then a sanitary engineer for the New York Department of Health, was called upon to investigate an outbreak of typhoid. It had occurred in a summer home in Oyster Bay, a well-to- do town where the disease was unknown. Yet 6 of 11 people in the house had become ill. Soper deter­mined that 3 weeks before the outbreak a new cook had been hired but had left after the first persons began falling ill. The cook’s name was Mary Mallon, and she was destined to become inextricably linked with typhoid fever.

Four years earlier, Koch had proposed that a per­son might chronically shed the typhoid bacillus and thus infect others, yet remain healthy and unaf­fected by the disease. His carrier hypothesis lacked adequate supporting evidence and was doubted by many. It occurred to Soper, however, that the perplex­ing cluster of typhoid cases in Oyster Bay might be explained if the cook were a carrier.

Soper’s investigations showed that over the previ­ous 10 years inexplicable typhoid outbreaks had oc­curred in seven of the eight families for which Mary Mallon had worked. A year later, Soper located her working once again in a home where typhoid fever had just broken out. She was removed against her will to a hospital where culture of her stool proved that she was indeed shedding S. typhi in great num­bers. After a 3-year detention on North Brother Is­land in Long Island Sound (a detention that raised many civil liberty questions), she was released on the promise that she would never again handle food. Five years later, however, she was found to be the source of an epidemic of 25 cases of typhoid that occurred at Women’s Hospital in Manhattan. She was arrested and spent the rest of her life on North Brother Island. “Typhoid Mary” had established be­yond scientific doubt that a carrier state existed in typhoid.

In 1933 Eberthella typhosa became Salmonella typhi, thereby joining a family of bacilli named after D. E. Salmon, who in the 1880s had discovered an organism {Salmonella cholerasuis) responsible for bacteremia in humans and diarrhea in swine. The discovery in 1948 of antibiotics active against S. typhi converted typhoid in the developed world from a rare but dread disease to just a rare one, acquired mainly by travel abroad.

On a global scale, however, there has been little evidence that typhoid is fading into obscurity. Al­though inexpensive vaccines place typhoid control within reach of those nations with limited health resources, the huge worldwide reservoir of carriers and the continuation of poor sanitation in endemic areas suggest that it will be some time before the developing nations can significantly reduce the inci­dence of typhoid fever.

Charles W. LeBaron and David W. Taylor

This chapter was written in the authors’ private capacities. No official support or endorsement by the Centers for Disease Con­trol is intended or should be inferred.

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