Typhoid Fever

Typhoid fever is an acute intestinal infectious disease caused by Salmonella typhi. It is characterized by persistent bacteremia and toxemia, and a proliferative response of the mononuclear phagocyte system, with hyperplasia, swelling, necrosis, and ulceration mainly in the lymphoid tissue of the distal ileum as the basic pathological features. Typical clinical manifestations include persistent high fever, systemic toxic symptoms and gastrointestinal symptoms, relative bradycardia, rose spots, hepatosplenomegaly, and leukopenia. This disease is also known as enteric fever. However, the clinical manifestations are mainly caused by hematogenous dissemination of the pathogen to organs throughout the body rather than by local intestinal lesions. Intestinal bleeding and intestinal perforation are the most important serious complications that may occur.

Common Symptoms

Irregular fever; maculopapular rash; garrison physician; abdominal discomfort; intestinal perforation; apathetic expression; intestinal bleeding; stupor; fatigue; toxemia; slowed response

Causes and Pathogenesis

Salmonella typhi is the pathogen of this disease, isolated by Gaffky from the spleen of a patient in Germany in 1884. It belongs to group D of the genus Salmonella, appearing as a short rod-shaped, Gram-negative bacillus with peritrichous flagella, motility, no capsule, and no spore formation, 2 to 3 μm long and 0.4 to 0.6 μm wide. Salmonella typhi can grow on ordinary media, forming medium-sized, colorless, translucent, smooth-surfaced colonies with regular edges; it can ferment glucose but not lactose, sucrose, or rhamnose, producing acid without gas. Salmonella typhi grows more readily on media containing bile. It is relatively hardy in the natural environment, surviving 2 to 3 weeks in water and up to 1 to 2 months in feces; it tolerates low temperatures and can persist for months in frozen environments. However, its resistance to sunlight, drying, heat, and disinfectants is weak: it is killed by several hours of direct sunlight; it dies immediately at boiling or after 30 min at 60°C; it is killed within 5 min in 3% phenol; and residual chlorine of 0.2 to 0.4 mg/L in water can rapidly kill it. It can survive and even multiply in foods such as milk. Salmonella typhi infects only humans and does not infect animals under natural conditions. Salmonella typhi does not produce exotoxin; upon bacterial lysis it releases endotoxin, which plays an important role in the pathogenesis of this disease. Salmonella typhi possesses somatic (O) antigen, flagellar (H) antigen, and surface (Vi) antigen; after infecting humans it induces corresponding antibodies, none of which are protective antibodies. The O and H antigens are strongly immunogenic; the Widal test (typhoid serum agglutination test) can detect O and H antibodies in serum specimens, which is of some help in clinical diagnosis. Newly isolated Salmonella typhi from typhoid patients carries Vi antigen, which interferes with serum bactericidal activity and phagocytosis, enhancing bacterial invasiveness and is an important determinant of virulence. Because Vi antigen is weakly immunogenic, the agglutination titer of the Vi antibody it induces is low and short-lived, giving little value for clinical diagnosis; after the pathogen is cleared from the body, Vi antibody also disappears, which helps in detecting Salmonella typhi carriers. Salmonella typhi carrying Vi antigen can be lysed by specific phages, allowing classification into more than 100 phage types; phage typing aids epidemiological investigation and tracing of the infection source. Salmonella typhi enters the digestive tract through the mouth and is usually killed by gastric acid; however, if the invading bacterial load is high, or if defensive barriers such as gastric acid secretion and normal intestinal flora are impaired, Salmonella typhi can enter the small intestine and invade the intestinal mucosa. Salmonella typhi multiplies in the small intestine and passes through intestinal epithelial cells to reach the lamina propria. Some bacteria are phagocytosed by macrophages and multiply within their cytoplasm; some enter the ileal Peyer's patches, solitary lymphoid follicles, and mesenteric lymph nodes via lymphatics to grow and multiply, then enter the bloodstream through the thoracic duct, causing transient bacteremia, i.e., the primary bacteremia phase. Within 1 to 3 days after ingestion, the bacteria entering the bloodstream are rapidly phagocytosed by the mononuclear-macrophage system in the liver, spleen, bone marrow, and lymph nodes; the primary bacteremia phase is short, the patient is still asymptomatic, and is in the clinical incubation period. After being phagocytosed by mononuclear-macrophages, Salmonella typhi still multiplies intracellularly and then re-enters the blood circulation, causing a second, more severe bacteremia lasting days to weeks, during which corresponding clinical manifestations gradually appear. Salmonella typhi disseminates throughout the body, invades organs and tissues such as the liver, biliary tract, spleen, kidney, and bone marrow, and releases endotoxin; clinically, fever, general malaise, marked toxic symptoms, hepatosplenomegaly, and cutaneous rose spots appear, corresponding to the 1st to 2nd week of illness. Blood and bone marrow cultures are often positive. Salmonella typhi multiplies in large numbers in the biliary tract and is excreted into the intestine with bile; some is excreted in feces to spread the pathogen externally, and some re-invades the intestinal lymphoid tissue through the mucosa, causing a severe inflammatory reaction in previously sensitized intestinal lymphoid tissue, with mononuclear infiltration, swelling, necrosis, and sloughing of lymphoid tissue to form ulcers. If lesions involve blood vessels, intestinal bleeding may result; if they reach the muscularis and serosa, intestinal perforation may occur, both being serious clinical complications. This lesion process generally corresponds to the 2nd to 3rd week of illness. The endotoxin released by Salmonella typhi plays an important role in the pathological process of typhoid fever, but studies suggest that persistent fever and toxic symptoms in typhoid patients are not directly caused by endotoxemia; the actual cause is far more complex than simple endotoxemia. Endotoxin enhances the inflammatory response in local lesions, activates mononuclear-macrophages and neutrophils to produce and release various cytokines, and toxic substances from necrotic tissue may all be closely related to the clinical manifestations of typhoid fever. In addition, Salmonella typhi endotoxin can also induce DIC or hemolytic uremic syndrome, the latter being a clinical syndrome caused by microvascular coagulation confined to the kidney. After the 4th week, the body's immune capacity gradually strengthens, especially cellular immunity; Salmonella typhi gradually disappears from the blood and organs, intestinal ulcers gradually heal, clinical manifestations gradually recover, and the disease finally resolves. A few patients may, due to insufficient immunity, have surviving pathogens in latent foci multiply again and invade the bloodstream causing relapse. The main pathological feature of typhoid fever is the proliferative response of the systemic mononuclear-macrophage system (including liver, spleen, bone marrow, lymphoid tissue, etc.), forming typhoid nodules. Lesions are most prominent in the intestine, especially the terminal ileum. The lesion process includes four stages: hyperplasia, necrosis, ulcer formation, and ulcer healing. In the 1st to 2nd week, intestinal lymphoid tissue proliferates and swells, showing button-like elevations, most prominent in the Peyer's patches and solitary lymphoid follicles of the terminal ileum; mesenteric lymph nodes also markedly proliferate and enlarge, and lymph nodes, spleen, bone marrow, and hepatic sinusoidal astrocytes at other sites show varying degrees of hyperplasia. As intestinal lymphoid lesions worsen, local nutritional disturbance leads to necrosis and yellow eschar formation. In the 3rd week, eschar sloughs off to form ulcers, which are oval or round and distributed along the long axis of the intestine; necrosis reaching blood vessels may cause bleeding, and invasion of the muscularis and serosa may cause intestinal perforation; since lesions are most severe in the terminal ileum, perforation is also most common at this site. In the 4th to 5th week, ulcers heal without leaving scars or causing intestinal stricture. Under light microscopy, the notable feature of the above lesions is inflammatory cell infiltration dominated by macrophages, abundant at the base and periphery of ulcers; macrophages are highly phagocytic, containing phagocytosed lymphocytes, red blood cells, Salmonella typhi, and necrotic debris in their cytoplasm, hence called typhoid cells, a relatively characteristic finding of this disease. These cells aggregate to form so-called typhoid granulomas or typhoid nodules. The severity of intestinal lesions does not necessarily correlate with the severity of clinical symptoms; especially in infants with severe toxemia, intestinal lesions may be inconspicuous, whereas patients with mild or absent toxic symptoms may suddenly develop intestinal bleeding or perforation. Among extraintestinal organs, splenic and hepatic lesions are most prominent: splenomegaly with dilated, congested splenic sinuses, marked medullary hyperplasia, macrophage infiltration, and visible typhoid nodules; the liver is markedly swollen with cloudy swelling and degeneration of hepatocytes, focal necrosis, dilated sinusoids, and visible typhoid nodules; the gallbladder shows mild inflammation; in severe toxemia, myocardium and kidney may show cloudy swelling. Rose spots are congested, dilated capillaries in the superficial skin with mononuclear infiltration, where Salmonella typhi can be found. In the respiratory system, bronchitis is common, and secondary bronchopneumonia or lobar pneumonia may also occur; migratory suppurative lesions may occasionally occur in the kidney, meninges, bone marrow, pericardium, lung, and middle ear. Whether disease develops after Salmonella typhi infection is closely related to the infectious bacterial load, strain virulence, and the host's immune status. Generally, the larger the viable bacterial load, the greater the chance of disease; strains carrying Vi antigen are more virulent and cause higher attack rates at the same infectious dose; and individuals with weakened immune defense are more susceptible to infection.

Treatment

Drug therapy, supportive therapy

Preventive Measures

The focus is on strengthening food and drinking water hygiene and fecal management to cut off transmission routes. Patients and carriers are isolated as intestinal infectious disease cases until one week after drug discontinuation, with weekly stool cultures until two consecutive negatives. Long-standing killed vaccines have unsatisfactory protection, and oral attenuated vaccines are under trial. Prevention of this disease should adopt comprehensive measures focused on cutting off transmission routes, adapted to local conditions. 1. Control the source of infection: Isolate and treat patients early; the isolation period should last until clinical symptoms resolve and body temperature returns to normal for 15 days; stool cultures may also be performed once every 5 to 7 days, and isolation can be lifted after two consecutive negatives. The urine, feces, bedpans, eating utensils, clothing, and daily items of patients must be properly disinfected. Management of chronic carriers should be strictly enforced; workers in food, childcare, and water supply industries should be regularly examined to detect carriers early. Chronic carriers should be transferred from such positions, treated, and placed under regular supervision and management. Close contacts should be under medical observation for 23 days; suspected typhoid patients with fever should be isolated and treated early. 2. Cut off transmission routes: This is the key measure for prevention. Provide health education, improve fecal, water source, and food hygiene management, eliminate flies, develop good hygiene habits, wash hands before meals and after using the toilet, avoid eating unclean food, and avoid drinking raw water or raw milk. Improving water supply hygiene and strictly enforcing water hygiene supervision are the most important steps in controlling typhoid epidemics. Water-borne typhoid outbreaks are the most important in many areas, and incidence can drop significantly after water supply hygiene is improved. 3. Protect susceptible individuals: Typhoid vaccination provides some protection to susceptible populations. The typhoid and paratyphoid A, B triple vaccine has unsatisfactory preventive effect and relatively strong reactions, and is not used as routine immunization. Opinions differ on emergency immunization in outbreak areas, though it may play some role in controlling the epidemic. The Ty21a oral attenuated live vaccine was approved for use in the United States in 1989, with fewer adverse reactions and some protective effect.

Department to Visit

It is recommended to visit the Infectious Diseases department; an appointment can be booked on this platform before the visit.

Warm reminder: The above information is for health science reference only and cannot replace professional medical diagnosis. If you have related symptoms, please seek medical attention at a regular hospital promptly.