Typhoid fever: causes, symptoms, diagnosis, treatment, prognosis, and prevention

Typhoid fever is an acute intestinal infectious disease caused by Salmonella typhi, but is a systemic disease that is not limited to intestinal lesions. The basic pathological features of typhoid fever are persistent bacteremia and septicemia, and the proliferative response of the mononuclear phagocyte system, especially lymphoid hyperplasia, swelling, necrosis, and ulceration in the terminal ileum. The clinical manifestations are persistent fever, systemic poisoning symptoms, gastrointestinal symptoms, relative bradycardia, roseola, hepatosplenomegaly, and leukopenia. Intestinal hemorrhage and intestinal perforation are the most serious complications.


Causes

Salmonella typhi is the pathogen of this disease and is a 2 - 3μm long, 0.4 - 0.6μm wide, rod-shaped, motile, unencapsulated, non-pore-forming, Gram-negative bacillus. Salmonella typhi can grow in the ordinary culture medium, forming medium-sized, translucent, neatly arranged colonies, with smooth surfaces. The bacterium can decompose glucose, but not lactose, sucrose, and rhamnose, and can produce acid but not gas. In bile-containing medium, Salmonella typhi can grow easily. Salmonella typhi has strong vitality in the natural environment, can survive for 2 - 3 weeks in water and 1 - 2 months in stools, can withstand low temperatures, and can survive for several months in frozen environments. However, the resistance to sunlight, dryness, heat, and disinfectants is weak. The bacteria can survive for several hours in direct sunlight and for 30 minutes at 60 °C, and die immediately in boiling water. The bacteria can be eliminated in 3% phenol in 5 minutes, but can survive and reproduce in food such as milk.

Salmonella typhi only infects humans and does not infect animals under natural conditions. Salmonella typhi does not produce exotoxin. When the cells are lysed, endotoxin is released, which plays an important role in the pathogenesis of this disease.

Source of infection

Salmonella typhi only infects humans, and the only source of infection is patients or carriers. Pathogens in the feces are excreted from humans. Patients can excrete bacteria in the whole duration of the disease.

Mode of transmission

Typhoid fever can be transmitted by contaminated water or foods, daily contact, and flies or cockroaches. Salmonella typhi in the feces is excreted from the infected persons, and enters the body of the susceptible persons through the mouth, which is termed fecal-oral transmission.

Pathogenesis

Infection and severity after exposure is associated with the amount of the bacteria, the virulence of bacterial strains, and the immune status of the host. Salmonella typhi enters the digestive tract from the mouth, and most bacteria are killed by gastric acid. However, if the amount of the bacteria is large or the defense barrier function such as gastric acid secretion and normal intestinal microflora is destroyed, the bacteria can enter the small intestine and invade the intestinal mucosa.

Salmonella typhi proliferates in the small intestine and passes through the intestinal mucosal epithelial cells to the intestinal lamina propria. Some pathogens engulfed by macrophages reproduce in the cytoplasm, and some bacteria enter the aggregated lymphoid nodules, solitary lymphatic nodules, and mesenteric lymph nodes through lymphangion to grow and reproduce, and then enter the bloodstream through the thoracic duct, causing transient bacteremia, that is, primary bacteremia. 1 - 3 days after the ingestion, the pathogens in the bloodstream are rapidly engulfed by the mononuclear phagocyte system in the liver, spleen, bone marrow, and lymph nodes. Primary bacteremia persists shortly, and patients are still asymptomatic and are in a clinical incubation period.

After engulfed by the mononuclear phagocyte system, the bacteria still reproduce in the cells and then enter the blood circulation again, causing second severe bacteremia, persisting for several days to several weeks, and patients have corresponding clinical manifestations. The bacteria disseminate to the whole body, invading liver, gallbladder, spleen, kidney, bone marrow, and other organs and tissues, releasing endotoxin. Clinically, patients present with fever, general malaise, obvious poisoning symptoms, hepatosplenomegaly, and roseola. Blood and bone marrow cultures are often positive. Salmonella typhi reproduces in the biliary tract, the bacteria in the bile are excreted to the intestine, and some bacteria in the feces are excreted to the outside of the body. Some bacteria reinvade the intestinal lymphatic tissue through the intestinal mucosa, causing severe inflammation of the previously sensitized intestinal lymphoid tissue. Swelling, necrosis, and exfoliation of lymphatic tissue result in ulceration. Involvement of blood vessels can cause intestinal hemorrhage, and muscular and serosal involvement can cause intestinal perforation, which are serious clinical complications.

The endotoxin released by Salmonella typhi plays an important role in the pathological process of typhoid fever. However, it is believed that the clinical symptoms such as persistent fever and septicemia in typhoid fever are not directly caused by endotoxemia, and the actual cause is more complicated. Endotoxin enhances the inflammatory response of focal lesions, and activates monocytes, macrophages, and neutrophils to produce and release various cytokines. The cytokines and the toxic substances produced by necrotic tissues may be closely related to the clinical manifestations of typhoid fever. In addition, the endotoxin can also induce disseminated intravascular coagulation (DIC) or hemolytic uremic syndrome.

With the enhancement of various immune abilities, especially cellular immunity, the bacteria are gradually eliminated from the blood and organs, the intestinal wall ulcers gradually heal, and the clinical manifestations are gradually improved. The bacteria not eliminated due to insufficient immunity in few patients reproduce again and reinvade the bloodstream, causing recurrence.

The main pathological features of typhoid fever are the systemic mononuclear phagocyte system including liver, spleen, bone marrow, and lymphoid tissue, and the proliferative responses of the mononuclear phagocyte system result in typhoid nodules. The intestinal lesions, especially lesions in the terminal ileum, are most obvious. The pathological process includes four stages of hyperplasia, necrosis, ulcer formation, and ulcer healing. 1 - 2 weeks after onset, proliferation and swelling of the intestinal lymphatic tissue, especially aggregated lymphoid nodules and solitary lymphatic nodules, present button-like protrusion. The mesenteric lymph nodes are also significantly proliferated and enlarged. Other lymph nodes, spleen, bone marrow, and hepatic stellate cells also develop different degrees of hyperplasia. Intestinal lymphoid tissue lesions are intensified, leading to focal nutritional disturbance and necrosis, forming yellow scabs. 3 weeks after onset, decrustation results in oval or round ulcers, distributed along the long axis of the intestine. Necrosis in the blood vessels can cause hemorrhage, and necrosis in the muscular layer and the serosal layer can cause intestinal perforation. Lesions in the terminal ileum are the most serious, and intestinal perforation is also more common. 4 - 5 weeks after onset, the ulcers heal without scars and intestinal stenosis. In light microscopy, the prominent feature of the lesions is the infiltration of inflammatory cells mainly composed of macrophages, abundantly found at the bottom and periphery of the ulcers. The phagocytic ability of macrophages is strong, and the cytoplasm contains engulfed lymphocytes, erythrocyte, Salmonella typhi, and necrotic tissue debris, so that the macrophages are also known as typhoid cells, which is a characteristic feature of this disease. These cells aggregate into clusters, forming typhoid granuloma or typhoid nodules. The severity of intestinal lesions is not necessarily positively related to the severity of clinical symptoms. For example, infants and patients with severe septicemia may not have obvious intestinal lesions.  On the contrary, patients with mild or absent septicemia may develop suddenly intestinal hemorrhage or intestinal perforation.

In the extraintestinal organs, the lesions of the spleen and liver are most prominent. Splenomegaly, expansion and congestion in splenic sinusoids, obvious hyperplasia of splenic pulp, macrophage infiltration, and typhoid nodules are visible. Obvious hepatomegaly, hepatocytes cloudy swelling, degeneration, focal necrosis, sinusoidal dilatation, and typhoid nodules are seen. The gallbladder is mildly inflammatory. In severe septicemia, the cardiac muscle and kidney may be turbid. Roseola results from the capillary congestion and dilation on the surface of the skin, and Salmonella typhi can be found in the skin lesions. Bronchitis is more common, and there may be secondary bronchopneumonia or lobar pneumonia. Occasionally there may be metastatic suppurative lesions in the kidney, meninges, bone marrow, pericardium, lung, and middle ear.


Signs and Symptoms

The incubation period is 5 - 21 days. The duration of the incubation period is related to the amount of infectious bacteria.

The natural duration of typical typhoid fever is about 4 weeks and can be divided into 4 stages.

Initial stage

Initial stage is the first week of the disease. Slow onset is present in most patients. Fever is the earliest symptom, often accompanied by general malaise, fatigue, anorexia, headache, and abdominal discomfort. As the condition gradually worsens, the body temperature rises stepwise, reaching 39 - 40 °C within 5 to 7 days. Fever may be preceded by chills and occasionally shaking chills. At the end of the stage, the swollen spleen and liver are often palpable.

Critical stage

Critical stage is the second to third week of the disease. The typical manifestations of typhoid fever and complications such as intestinal hemorrhage and intestinal perforation can be present in this stage.

The typical fever is continuous fever, and few patients may have remittent or irregular fever. High fever often lasts for about 2 weeks, with peaks of 39 - 40 °C or more than 40 °C.

Patients may present with anorexia, abdominal distension, and abdominal discomfort or dull pain, especially in the right lower abdomen, but also mild tenderness. Most patients have constipation, and few may have diarrhea.

Patients may present with asthenia, trance, apathy, lethargy, unresponsiveness, and hearing loss. In severe cases, deliration and coma can occur. Meningismus may occur. These manifestations are associated with severe septicemia, and as the body temperature drops, the symptoms are gradually improved.

Relative bradycardia or dicrotism may occur. If there is complicated myocarditis, the relative bradycardia is not obvious.

The swollen spleen and liver are often palpable, soft, with mild tenderness. Hepatosplenomegaly is usually mild and gradually returns to normal as the condition recovers. If obvious toxic hepatitis is present, the liver dysfunction such as jaundice and increased alanine aminotransferase is visible.

On the 7th to 12th day of the disease, few, pinhead sized, blanching, slightly raised, pale red papules occur in groups, mostly in the chest and abdomen, as well as in the back and extremities, subsiding in 2 - 4 days. In addition, patients with hyperhidrosis can develop miliaria cystallina.

Remission stage

Remission stage is the third to fourth week of the disease. Body temperature fluctuates and gradually drops. Patients still feel weak, but the appetite is recovery, and abdominal distention is relieved. The swollen spleen and liver recover, and tenderness is regressed. Various complications, including serious complications such as intestinal hemorrhage and intestinal perforation, may still occur in this stage.

Convalescent stage

Convalescent stage is the fifth week of the disease. The body temperature returns to normal, the appetite is improved, and symptoms and signs return to normal.

In addition to the typical clinical manifestations, the disease can be divided into some types.

Mild typhoid fever

About 38 °C of fever, mild septicemia, and short duration are present, and patients usually recover in 1 - 3 weeks. Absent typical typhoid manifestations are easy to cause misdiagnosis and missed diagnosis.

Fulminant typhoid fever

Acute onset, severe septicemia, critical condition, rapid progression, chills, high fever, abdominal pain, diarrhea, shock, toxic encephalopathy, toxic myocarditis, toxic hepatitis, and toxic tympanites can be seen. DIC may occur. If with early diagnosis and prompt treatment, the disease can be cured.

Protracted typhoid fever

The initial manifestations are the same as those of the typical typhoid fever. Due to the low immunity, remittent or intermittent fever can last for several months. Hepatosplenomegaly is also significant. Typhoid fever patients with chronic schistosomiasis often have these manifestations. Antibiotic treatment is not satisfactory in these patients, and combination therapy with anti-schistosomiasis medications is required.

Ambulatory typhoid fever

With mild systemic symptoms, patients often live and work as usual, and do not notice the disease. Some patients may have a sudden onset of intestinal hemorrhage or intestinal perforation.

Abortive typhoid fever

Rapid onset is similar to the typical typhoid fever, but the symptoms such as fever quickly subside in about 1 week, and patients are cured.

Infantile typhoid fever

The clinical process of typhoid fever in children is not typical. Rapid onset and serious condition are present. Gastrointestinal symptoms such as vomiting, abdominal pain, and diarrhea are common. Irregular high fever, convulsions, and fast pulses are present. Roseola is less common. The count of peripheral leukocytes is elevated. Bronchitis or pneumonia often occurs. School-age children are mostly with mild or abortive typhoid fever, with manifestations similar to those of adults. Mild symptoms, short duration, merely relative bradycardia, and normal count of leukocytes are present. Intestinal lesions are also mild, and complications such as intestinal hemorrhage and intestinal perforation are also less common.

Typhoid fever in elderly adults

Atypical symptoms and obvious infirmity are present. Bronchopneumonia and cardiac insufficiency may occur. Persistent gastrointestinal dysfunction and memory loss are present. The prolonged duration, slow recovery, and high mortality rate can be visible.

Recurrence

The disease is prone to recurrence, and the recurrence rate is generally about 10%. 1 - 3 weeks after fever drops, the clinical symptoms reappear. The symptoms are usually mild, the duration is about 1 - 3 weeks, and blood culture can be positive again. In general, patients have 1 recurrence, and more recurrences are less common. Recurrence is related to the low immune function of the body. Salmonella typhi latent in the macrophages reproduces and invades the blood circulation, causing bacteremia again. Recurrence is more common in patients with inadequate antibacterial therapy.

Recrudescence

In 2nd to 3rd weeks of the disease, the body temperature fluctuates and drops, but has not reached normal, lasting for 5 - 7 days, and fever rises again. Symptoms may be more obvious, and blood cultures may be positive again. The mechanism of recrudescence is similar to that of recurrence.


Diagnosis

Diagnosis is based on the clinical manifestations and results in laboratory examinations, such as bacterial isolation and culture from the blood or stools, enzyme-linked immunosorbent assay (ELISA), PCR, and Widal test.


Treatment

Usually, the preferred antibiotics include ceftriaxone 1g in adults and 25 - 37.5mg/kg in children IM or IV once every 12 hours for 14 days and various fluoroquinolones such as ciprofloxacin 500mg orally twice daily for 10 - 14 days, levofloxacin 500mg orally or intravenously once a day for 14 days, and moxifloxacin 400mg orally or intravenously once a day for 14 days.

Chloramphenicol 500mg orally or intravenously once every 6 hours is still widely used, but resistance is more common. Fluoroquinolones can be used in children, but should be used with caution. For fluoroquinolone-resistant strains, azithromycin 1g orally on the first day, then 500mg once daily for 6 days can be used. Other alternative medications, such as amoxicillin, methoxypyrazine/sulfamethoxazole (TMP/SMX), also have high resistance, so these drugs need to be selected based on in vitro drug susceptibility testing.

In addition to antibiotics, patients with severe poisoning symptoms may also be treated with glucocorticoids, which can often speed defervescence and improve clinical symptoms. Oral prednisone 20 - 40mg/d for the first 3 days of the treatment is generally sufficient. Patients with obvious deliration, coma, or shock can be treated with high-dose glucocorticosteroids such as dexamethasone 3mg/kg intravenously for the first dose, followed by 1mg/kg once every 6 hours for 48 hours.

Intestinal perforation and peritonitis require surgical intervention and broad-spectrum antibiotics against Gram-negative bacteria and bacteroides fragilis.

The treatment for recurrence is the same as the primary disease, but the duration of antibiotics is rarely >5 days.

3 - 12 months after the acute phase, Salmonella typhi can be isolated from patients even if they may not be carriers. Therefore, 3 successive negative stool cultures with an interval of 1 month can be used to exclude the state of carrier.

Antibiotics should be used in carriers with normal biliary tract. Amoxicillin, TMP/SMX, or ciprofloxacin can be administered for 4 - 6 weeks.

Some carriers with gallbladder disease can use methoxypyrazine/sulfamethoxazole plus rifampin to eliminate bacteria. Cholecystectomy does not guarantee the removal of the carrier status, most likely due to residual infection in other parts of the hepatobiliary system.


Prognosis

The prognosis of typhoid fever is related to the condition, age, presence or absence of complications, early or late treatment, treatment regimen, and amount of pathogens. The previous mortality was about 20% due to lack of effective antibacterial drugs, and the mortality rate has been significantly reduced to about 1% - 5% after application of chloramphenicol. However, drug resistance causes increased mortality. Old adults, infants, and young children may have a poor prognosis. Patients with obvious anemia and malnutrition have also poor prognosis. Complications such as intestinal perforation, intestinal hemorrhage, myocarditis, and severe septicemia can lead to high mortality.


Prevention

Water should be purified before drinking, and sewage should be treated effectively. Chronic carriers should avoid processing food and avoid caring for patients or children unless it is proven that the bacteria have been eliminated in the body. Isolation of patients should be implemented.

Tourists in endemic areas should avoid raw leafy vegetables and other foods stored and processed at room temperature and untreated water including ice. Water should be boiled or chlorinated before drinking.

Preventive effect of vaccines is not perfect, so vaccination is recommended only for persons in endemic areas. The vaccine available is Ty21a at present.