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41.2 Typhoid fever and other salmonella infections

CHRISTOPHER S. GRANT AND A. S. DAAR

INTRODUCTION

Salmonella infections occur worldwide and the practising surgeon should be familiar with their protean manifestations. The surgical complications, while infrequent, often require prompt diagnosis and treatment. Human infection usually presents in two distinctive clinical forms: typhoid and paratyphoid fevers (sometimes collectively termed enteric fever), and non-typhoidal salmonella infection (enterocolitis) (see  Table 1 627).

TYPHOID FEVER

Typhoid fever is a major health problem worldwide, particularly in developing countries: an estimated 33 million cases occur each year. The infection is caused by Salmonella typhi, a strict human pathogen which is invariably acquired by ingestion of food or water contaminated with excreta from a patient with typhoid or from a convalescing or chronic carrier. S. typhi, unlike other salmonella species, possesses a polysaccharide Vi (virulence) surface antigen which enhances its invasiveness. The disease remains endemic because of inadequate sewage disposal and lack of safe water supplies.

Pathogenesis

Some features of the pathogenesis have not been completely elucidated. Essentially, after ingestion the bacilli penetrate the intestinal mucosa, multiply within the mesenteric lymph nodes, and spread via the lymphatics (through the thoracic duct) and blood stream to the reticuloendothelial system in the liver, spleen, and bone marrow where continued multiplication takes place during an incubation period of about 10 to 14 days  (Fig. 1) 2648. Re-entry of typhoid bacilli into the bloodstream marks the onset of clinical typhoid fever. During the second or third week of the illness heavy reinfection of the gut occurs through bile or bacteraemic spread. The bacilli localize in the Peyer's patches in the lower ileum, although the lymphoid tissue in the jejunum, caecum, appendix, and ascending colon may sometimes be affected.

Peyer's patches and solitary lymphoid follicles become swollen and red, and mesenteric adenitis also occurs. The main inflammatory cells involved in the process are macrophages and lymphocytes; polymorphonuclear leucocytes are virtually absent. Necrosis of Peyer's patches with ulceration of the intestinal mucosa occurs in the long axis of the bowel. This heals with minimal fibrosis. Intestinal haemorrhage from the necrotic patch or perforation of the bowel with resultant peritonitis may occur. These intestinal complications generally occur in the second week of the illness.

Inflammatory lesions are widespread: the liver, spleen, and bone marrow are affected, as are the kidneys. Extraintestinal organs, including the skin, brain, bone, joints, myocardium, and heart valves, are often involved. Osteomyelitis may occur in immunosuppressed patients and in those with sickle-cell anaemia.

Although S. typhi is excreted in the bile, acute cholecystitis is uncommon. However, chronic typhoid cholecystitis often develops after S. typhi infection; while this is often symptomless, it may be associated with formation of gallstones. Chronic typhoid carriers excrete large numbers of bacilli in the faeces and are the major reservoir for spread of the infection.

The pathogenesis of the prolonged fever and toxic symptoms seen in typhoid fever is unclear. Circulating endotoxins have been strongly suspected but have not been directly demonstrated in patients with typhoid. The prolonged fever may be attributable to prolonged and diffuse inflammation in the reticulendothelial system with release of interleukin-1 and tumour necrosis factor.

Immunity

Experimental work has shown both humoral and cell-mediated immunity to be important in resistance to Salmonella infection. Cell-mediated immune responses are thought to be more important, especially in the recovery process. Patients immunocompromised by chronic diseases or malnutrition are liable to suffer more complications of typhoid. It is not clear yet which antigens are important in eliciting the immune response.

Clinical features

Typhoid fever is generally regarded as a disease of older children and young adults. However, a recent study suggests that infection in infants is also common and, for reasons that are not entirely clear, may not present clinically as typhoid fever. The incubation period is about 10 to 14 days after ingestion of the organism. The onset is insidious with fever, headache, abdominal discomfort or pain, cough, malaise, and anorexia. The fever characteristically increases in a stepwise fashion over many days, but this pattern is not always present. Pea-soup diarrhoea may occur after the first week, although constipation is more common in the initial stages. In severe cases mental changes are often a prominent feature and include clouding of consciousness (tuphos in Greek means smoke or stupor), coma vigil (in which the patient, muttering, is semi-conscious with eyes open), and other psychotic features which could lead to admission to a psychiatric unit. Meningism may be present but meningitis is rare.

Rose spots (a maculopapular rash) may appear, typically on the upper abdomen and lower chest, in the second or third week and fade away after 2 or 3 days. These spots occur in only one-third of patients and are rarely seen in dark-skinned people. Abdominal tenderness and distension are common as the disease progresses. The spleen and the liver are palpable in about 25 per cent of adults and rather more frequently in children. Relative bradycardia occurs in less than 50 per cent of patients.

The presence of leucopenia has been exaggerated. More often there is an absence of leucocytosis, with the mean white blood cell count in the region of 6000 to 7000. Anaemia is due to haemorrhage, marrow suppression (in long-standing infection), and rarely to haemolysis. Thrombocytopenia may occur.

If untreated, the illness lasts for 3 to 4 weeks, and the fever remits in a stepwise fashion. Major sequelae arise through infection of other organs, or more seriously, as a result of intestinal complications, which may be lethal. Differential diagnosis in the early stages includes malaria, brucellosis, amoebic liver abscess, and typhus. When bloody diarrhoea occurs, the picture may resemble bacillary or amoebic dysentry.

Complications

Although typhoid fever affects many organ systems, the most serious complications occur in the gastrointestinal tract  (Table 2) 628. Gastrointestinal haemorrhage and intestinal perforation are serious complications of typhoid fever and are responsible for most of the fatalities. In one study, gross haemorrhage occurred in 0.8 per cent of hospital inpatients, although others have reported an incidence of up to 5 per cent. Perforation occurs in approximately 5 per cent. However, there are geographical variations in the reported incidence of typhoid perforations (range 0–39 per cent).

Intestinal haemorrhage

This usually occurs following sloughing of typhoid ulcers in the ileum, or less frequently in the caecum and ascending colon, during the second or third week of the disease. It is often insidious and presents as increasing anaemia and tachycardia. Rarely, erosion of large vessels may produce acute massive lower gastrointestinal bleeding. The onset of bleeding should alert the physician to the possibility of an imminent intestinal perforation as the two sometimes occur together.

Intestinal perforation  (Fig. 2) 2649

This typically occurs during the second or third week of the disease and is more common in males than females (4:1 in one recent large Bangladeshi series and 2.3:1 in a Nigerian series), and in adults than children. There is no clear explanation for these observations. Acute perforation is signalled by sudden or increasing abdominal pain, often beginning in the right iliac fossa or lower abdomen and spreading. The pain is associated with tenderness, rigidity, guarding, and loss of liver dullness, and is accompanied by tachycardia and hypotension. Abdominal distension is frequently present but about one-third of patients may have a scaphoid abdomen in spite of gross peritoneal contamination. These signs, however, may be obscured in severely toxic patients, in whom radiology and repeated abdominal examinations are necessary to avoid missing the diagnosis.

Other complications

Many of the other complications of typhoid are also of surgical interest  (Table 2) 628. The liver is frequently affected. About 50 per cent of patients show impairment of liver function: this reverts to normal after recovery. Clinical jaundice due to intrahepatic cholestasis is more frequently observed in children than in adults. Pancreatic enzyme disturbances have recently been reported to be common, but acute pancreatitis is rare.

Pneumonia is a serious complication which is seen frequently in children. Altered mental status, in the form of confusion, delirium, or stupor, is frequently observed. Seizures are frequent in young children. A host of other abnormalities affecting the central nervous system, all rare, have been reported. Acute nephritis and cystitis may occur and acute renal failure, which may require dialysis, is a rare complication. Electrocardiographic abnormalities are sometimes observed; toxic myocarditis and rarely endocarditis are seen more frequently in children than in adults. Deep vein thrombosis occurs in a minority of patients.

Other complications of typhoid that have become rare since the introduction of antibiotics include acute acalculous cholecystitis, osteomyelitis, arthritis, splenic abscess, and purpura. Most of these extraintestinal complications of typhoid fever are reported to be more frequent in patients who are immunocompromised or suffer from chronic disease or malnutrition. Prolonged (up to 2 years) salmonella septicaemia may occur in patients who have schistosomiasis as the bacteria grow in the gut and on the skin of the worm. Treatment should include specific treatment against both the salmonella and the parasite.

Diagnosis

The diagnosis is often strongly suggested by the clinical presentation and a history of residence or recent visit to an endemic area. In endemic areas an experienced clinician can make the correct diagnosis solely on clinical grounds in up to 80 per cent of patients. Nevertheless, a definitive diagnosis of typhoid fever is made by isolation of S. typhi, usually from the blood.

Blood cultures are positive in about 80 per cent of patients during the first 2 weeks of the illness; stool, and sometimes urine, cultures become positive normally from the second week on in patients who have not been treated. By the third week blood cultures are often negative, as the organisms are now mainly intracellular. Bone marrow culture is the single most effective method for the isolation of S. typhi. It is positive in 90 per cent of patients, is not affected by recent partial antibiotic therapy, and often remains positive even when the blood cultures have become negative due to antibiotic therapy. A rising titre of agglutinin (the Widal test for antibodies against the flagella (H) and somatic (O) antigen) over a week helps in making the diagnosis, especially when cultures are negative. However, the test is not completely specific. Newer serodiagnostic tests include indirect immunofluorescent antibody test for the Vi antigen and detection of IgM antibody to S. typhi lipopolysaccharide antigen by enzyme-linked immunosorbent assay.

Leucopenia is not generally useful in diagnosis as it occurs in only 12 per cent of patients; an absence of leucocytosis is more common. The presence of both polychromasia and reticulocytosis should alert the physician to intestinal haemorrhage. The diagnosis of intestinal perforation is straightforward in the presence of a typical history of typhoid and classical signs of perforation. An upright chest radiograph, when available, demonstrates free subdiaphragmatic gas in up to 75 per cent of patients. The major diagnostic difficulty is in determining whether patients known or considered to have typhoid, who have equivocal abdominal signs and no free subdiaphragmatic gas on radiographic examination, have suffered a perforation. An abdominal paracentesis is helpful when positive, but a negative tap does not exclude perforation. Repeated abdominal examination may be helpful but if doubt persists laparotomy should not be delayed.

Medical treatment

Antimicrobial therapy gives excellent results in uncomplicated typhoid. The first-line drugs of choice are chloramphenicol (adult: 500 mg 4-hourly orally till fever subsides, then 500 mg 6-hourly for a total of 14 days; children: 50 mg/kg.day in divided doses for 21 days), amoxycillin (adults: 1 g 6-hourly orally for 14 days; children 100 mg/kg.day in divided doses for 21 days) and cotrimoxazole in two divided doses (adults: 160 mg trimethoprim + 800 mg sulphamethoxazole (i.e. 2 tablets) 12-hourly orally for 14 days; children: 6 mg trimethoprim plus 30 mg sulphamethoxazole/kg/day for 14 days). Once therapy is initiated there is a rapid improvement in the patient's general condition, but complete defervescence may take up to 7 days. A very rapid return to normal temperature may cast doubt on the diagnosis of typhoid fever. The three drugs are equally efficacious and have similar relapse rates following cessation of treatment. Ampicillin (adults: 1.5 g 6-hourly for 14 days; children 80 mg/kg.day in four divided doses for 14 days) may be used, but it is not as effective as the other drugs. The minimum length of treatment should be 14 days; shorter periods of treatment with any of the drugs are associated with higher relapse rates. Patients should not be discharged home until they have had three negative stool and urine cultures after the end of drug treatment. Chloramphenicol, which was first introduced over 40 years ago, has a small risk of marrow toxicity.

There have recently been reports from India and south-east Asia of strains of S. typhi resistant to chloramphenicol, ampicillin/amoxycillin, and cotrimoxazole. None of these drugs can therefore be presumed to be safe for the treatment of infection acquired in these endemic areas. During a 1989 epidemic of typhoid fever in Calcutta, India, 89.7 per cent of strains showed resistance to two or more antibiotics. There have been isolated reports of resistance to individual drugs from many other countries. Ciprofloxacin (500 mg orally twice daily for 14 days), one of the new quinolone drugs, is regarded as the drug of choice for the treatment of infection with multiresistant S. typhi. However, the new quinolone drugs should be used with caution in children and pregnant women as they can cause irreversible damage to cartilage in the strained joints of young experimental animals. The alternative is to use one of the new cephalosporins, such as cefotaxime, ceftriaxone, and cefoperazone, which give results comparable to those seen with chloramphenicol. Recent reports suggest that, in addition to the antibiotics, high doses of dexamethasone are valuable in severely ill patients with an altered state of consciousness and shock. An initial intravenous dose of 30 mg/kg over 30 min is followed by eight doses of 1 mg/kg 6-hourly.

Management of intestinal haemorrhage

The treatment is generally conservative, with blood transfusion to correct anaemia, which develops over a few days. Acute haemorrhage should be treated promptly with blood transfusion. If the bleeding is massive and persistent, laparotomy is indicated as an erosion of a large vessel has probably occurred. The affected bowel is often easy to identify (eg. thinning of the bowel wall at the site of the ulcers) and to resect.

Management of typhoid perforation

The management of typhoid perforation has been controversial in the absence of controlled prospective trials. Most authors currently advocate operative rather than non-operative treatment, which in many past series has been associated with mortality rates of over 60 per cent. Operative treatment is preferred because typhoid perforation produces fulminating peritonitis and, unlike other perforations, rarely seals up as the omentum seldom migrates to the area of perforation. Occasionally the diagnosis will be wrong, and peritonitis will be due to a perforated appendix or peptic ulcer. An occasional patient with typhoid may occasionally suffer a perforation which seals, and may survive without an operation, justifying non-operative therapy in rare instances.

Patients are usually critically ill with septicaemia, generalized peritonitis, dehydration, and electrolyte imbalance, especially potassium deficiency. They are best resuscitated in an intensive care unit if the facilities exist. Dehydration and electrolyte imbalance should be treated aggressively to restore normal haemodynamics and urine output within a few hours. Blood transfusion is often required to correct severe anaemia.

Parenteral antibiotic therapy is aimed at S. typhi and the common enteric organisms, including anaerobes. A useful practical regimen consists of ciprofloxacin and metronidazole or chloramphenicol and metronidazole, but the local antibiotic resistance pattern must be taken into consideration. Although steroids have been shown to be useful in the treatment of typhoid fever complicated by severe toxaemia, altered mental status, and shock, their role in typhoid perforation has not been evaluated.

Surgical management

At laparotomy, a single perforation is found on the antimesenteric border of the ileum in 80 per cent of patients. Two perforations are found in 15 per cent and more than two in 5 per cent. About 90 per cent of ileal perforations are located within 60 cm of the ileocaecal valve and caecal perforations occur in about 2 per cent of patients. Perforations at sites other than ileum and caecum are extremely rare.

The operative management of perforation remains controversial: a variety of procedures is currently in use  (Table 3) 629. There have been no randomized controlled trials comparing different surgical procedures. The ideal operation would be simple, effective, and tailored to the findings. A simple debridement of the margins of the perforation and meticulous closure in two layers (an inner layer of catgut and an outer layer of silk in a transverse direction to avoid narrowing the bowel), with copious peritoneal lavage, is the procedure of choice. This is within the competence of a district surgeon operating in a remote village in an endemic area. However, when there are more than three perforations which are close together, it is best to resect the affected bowel and perform a primary end-to-end anastomosis. Any areas of apparent impending perforations, if not included in a resection, must be oversewn. A right hemicolectomy is undertaken only for caecal perforations.

Following peritoneal lavage, the abdominal wound is closed, usually without drains. If there is gross faecal contamination, the skin wound may be left open to minimize wound infection. The antityphoid drug therapy should be continued for at least 14 days. The incidence of postoperative complications is high. Wound infection is the most common problem, and is often severe. Other serious common complications include respiratory infections, reperforation, peritonitis, faecal fistula, intraperitoneal abscesses, and wound dehiscence. Long-term complications include incisional hernia and adhesive intestinal obstruction.

Mortality

Typhoid fever is a severe disease whose major complications are potentially lethal. Patients at the greatest risk of death are those with severe toxaemia, an altered state of consciousness, shock, and intestinal perforation. Although the case fatality rate in countries with well-developed health services is less than 2 per cent, in most developing countries, despite the general availability of drugs effective against S. typhi, a mortality rate of 4 to 32 per cent is reported.

Intestinal perforation is the leading cause of death. The mortality rates in reported series of typhoid perforation vary widely. In a collective review of reported series from developing countries the median of the case fatality rates was 43 per cent. Two factors have an important bearing on the prognosis: duration of illness before perforation, and interval between the time of perforation and surgery. Perforations occurring after the third week of the illness are associated with a higher mortality rate than those occurring in the first week. For patients undergoing surgery, the best results are obtained when operations are promptly performed within 24 h of perforation. When surgery is delayed for 24 to 48 h after perforation the case fatality rates increase to above 50 per cent, and even worse rates are observed when the delay is more than 72 h. The number of perforations does not appear to have a consistent bearing on the postoperative prognosis. Mortality from perforation could therefore be minimized by early patient presentation, early diagnosis of perforation, improved critical care, and prompt surgical treatment. Unfortunately, in the endemic countries the medical resources to meet these clinical challenges are scarce.

Convalescent and chronic typhoid carriers

Typhoid patients who have been inadequately treated may become convalescent carriers. Ciprofloxacin has been shown to reduce the convalescent carrier rate. A chronic carrier has usually had a previous subclinical infection and usually excretes S. typhi in the stools, but sometimes in the urine, over a long period without any symptoms. The gallbladder or biliary tract is the primary site of chronic carriage, although the infection may also persist in an intrahepatic nidus or in the urinary tract, especially if there is a urinary tract abnormality. In countries with endemic urinary schistosomiasis urinary carriers pose a significant health hazard. Eradication of the focus of infection is usually difficult. A prolonged course of amoxycillin or ampicillin or cotrimoxazole is necessary. Ciprofloxacin (750 mg) or norfloxacin (400 mg) twice daily for 28 days is more effective, especially in those with chronic gallbladder disease. In patients with gallstones or chronic cholecystitis, cholecystectomy is the most effective way to eliminate the carrier state, but cholecystectomy alone is inadequate if there is associated infection in the biliary or urinary tract. Carriers should not handle food or water which is to be consumed without further cooking or purification.

Prevention

Typhoid fever remains a global health problem. Its eradication in endemic areas requires major efforts to provide safe water supplies and waste disposal. Health education should include proper ways of cooking and storing food, measures that also minimize other Salmonella infections. The development of effective oral typhoid vaccines promises effective prophylaxis in the future, but vaccines are unlikely substitutes for the more important public health measures. The most promising oral vaccine is the Ty21a, an attenuated non-pathogenic strain of S. typhi which lacks the enzyme UDP-galactose 4-epimerase and the Vi polysaccharide. The Vi capsular polysaccharide is itself an effective vaccine, but it requires intramuscular injection and has significant local and systemic side-effects.

PARATYPHOID FEVER

The infection is caused by S. paratyphi A, B, and C, of which type B is the most common. The organisms, like S. typhi, are also primarily human pathogens although S. paratyphi B has been known to infect cattle.

Paratyphoid fever is similar in most respects to typhoid fever but runs a milder and shorter course than typhoid. Complications and mortality are also less frequent, and effective vaccines against paratyphoid fever are not available.

NON-TYPHOIDAL SALMONELLA INFECTIONS

Enterocolitis (food poisoning) is the most common form of salmonella infection and is caused by Salmonella enteritidis serotypes which, unlike S. typhi and S. paratyphi, are primarily animal pathogens. There are approximately 2000 named serotypes. Infections are usually acquired through ingestion of food or, less often, of water, contaminated by animals, particularly cattle and poultry, for which Salmonella is a primary pathogen. A high infecting dose is normally required for Salmonella serotype infections, although a lower infective dose may cause illness in patients with gastric hypochlorhydria, immunosuppression, or debilitating diseases. The organisms multiply in the small intestine and produce an acute enterocolitis after an incubation period of about 12 to 48 h. The clinical picture varies widely but usually includes abdominal cramps, pain, and diarrhoea that may be bloody and purulent. The infection is normally brief and self-limiting. It is confined to the intestinal tract and often requires no specific therapy. However, in severe cases the bloody diarrhoea may persist and toxic megacolon may rarely occur; the presentation may be confused with ulcerative colitis. Colonic dilation will usually resolve without surgery. Perforation is extremely rare. In other cases ileal involvement may be prominent with right lower quadrant pain and tenderness, mimicking acute appendicitis.

The differential diagnosis includes Campylobacter and Shigella infections, which have similar incubation periods. An incubation period of less than 6 h, absence of fever, a shorter period of diarrhoea, and absence of blood and pus in the faeces tilts the diagnosis towards the toxin-type food poisoning caused by Staphylococcus aureus, Clostridium perfringens, or Bacillus cereus.

In contrast to S. typhi, bacteraemia occurs in only about 5 per cent of all patients with non-typhoidal Salmonella infection  (Table 1) 627 but may lead to metastatic infections. Chronic extraintestinal focal diseases may manifest insiduously in any anatomical site long after a bout of entercolitis and are often associated with other chronic diseases and immunosuppressed status. Osteomyelitis occurs not infrequently in immunosuppressed patients and those with sickle-cell anaemia. Suppurative complications needing surgery are increasingly being encountered in HIV patients. The Salmonella enteritidis serotypes also seem to have a predilection for atherosclerotic lesions, particularly aneurysms; the infection causes acute softening and rapid enlargement of the aneurysm with catastrophic consequences if not treated promptly. In addition, they may cause septic thrombophlebitis and deep vein thrombosis. In developing countries where malaria and schistosomiasis are endemic, Salmonella bacteraemia is an important complication.

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