General Considerations

Salmonellae are gram-negative rods that frequently cause food-borne gastroenteritis and occasionally bacteremic infection of bone, meninges, and other foci. Approximately 2400 serotypes of Salmonella enterica are recognized. Salmonella typhimurium is the most frequently isolated serotype in most parts of the world. Although 54,000 cases were reported in 2010, it is estimated that 100 or more occur for each one reported. This yields an estimate or more than 5 million cases yearly in the United States.

Salmonellae are able to penetrate the mucin layer of the small bowel and attach to epithelial cells. Organisms penetrate the epithelial cells and multiply in the submucosa. Infection results in fever, vomiting, and watery diarrhea; the diarrhea occasionally includes mucus and polymorphonuclear neutrophils in the stool. Although the small intestine is generally regarded as the principal site of infection, colitis also occurs. S typhimurium frequently involves the large bowel.

Salmonella infections in childhood occur in two major forms: (1) gastroenteritis (including food poisoning), which may be complicated by sepsis and focal suppurative complications; and (2) enteric fever (typhoid fever and paratyphoid fever) (see section on Typhoid Fever and Paratyphoid Fever). Although the incidence of typhoid fever has decreased in the United States, the incidence of Salmonella gastroenteritis has greatly increased in the past 15–20 years. The highest attack rates occur in children younger than age 6 years, with a peak in the age group from 6 months to 2 years.

Salmonellae are widespread in nature, infecting domestic and wild animals. Fowl and reptiles have a particularly high carriage rate. Transmission results primarily from ingestion of contaminated food. Transmission from human to human occurs by the fecal-oral route via contaminated food, water, and fomites. Numerous foods, including meats, milk, cheese, ice cream, chocolate, contaminated egg powder, and frozen whole egg preparations used to make ice cream, custards, and mayonnaise are associated with outbreaks. Eggs with contaminated shells that are consumed raw or undercooked have been incriminated in outbreaks and sporadic cases. Animal contact also can be a source for Salmonella.

Because salmonellae are susceptible to gastric acidity, the elderly, infants, and patients taking antacids or H₂-blocking drugs are at increased risk for infection. Most cases of Salmonella meningitis (80%) and bacteremia occur in infancy. Newborns may acquire the infection from their mothers during delivery and may precipitate outbreaks in nurseries. Newborns are at special risk for developing meningitis.

Clinical Findings

A. Symptoms and Signs

There is a very wide range of severity of infection. Infants usually develop fever, vomiting, and diarrhea. The older child also may complain of headache, nausea, and abdominal pain. Stools are often watery or may contain mucus and, in some instances, blood, suggesting shigellosis. Drowsiness and disorientation may be associated with meningismus. Convulsions occur less frequently than with shigellosis. Splenomegaly occasionally occurs. In the usual case, diarrhea is moderate and subsides after 4–5 days, but it may be protracted.

B. Laboratory Findings

Diagnosis is made by isolation of the organism from stool, blood, or, in some cases, from urine, CSF, or pus from a suppurative lesion. The WBC count usually shows a polymorphonuclear leukocytosis but may show leukopenia. Salmonella isolates should be reported to public health authorities for epidemiologic purposes.

Differential Diagnosis

In staphylococcal food poisoning, the incubation period is shorter (2–4 hours) than in Salmonella food poisoning (12–24 hours). Fever is absent, and vomiting rather than diarrhea is the main symptom. In shigellosis, many polymorphonuclear leukocytes usually are seen on a stained smear of stool, and the peripheral WBC count is more likely to slow a marked left shift, although some cases of salmonellosis are indistinguishable from shigellosis. Campylobacter gastroenteritis commonly resembles salmonellosis clinically. Culture of the stools is necessary to distinguish the causes of bacterial gastroenteritis.

Complications

Unlike most types of infectious diarrhea, salmonellosis is frequently accompanied by bacteremia, especially in newborns and infants. Septicemia with extraintestinal infection is seen, most commonly with Salmonella choleraesuis but also with Salmonella enterica, typhimurium, and paratyphi serotypes. The organism may spread to any tissue and may cause arthritis, osteomyelitis, cholecystitis, endocarditis, meningitis, pericarditis, pneumonia, or pyelonephritis. Patients with sickle cell anemia or other hemoglobinopathies have a predilection for the development of osteomyelitis. Severe dehydration and shock are more likely to occur with shigellosis but may occur with Salmonella gastroenteritis.

Prevention

Measures for the prevention of Salmonella infections include thorough cooking of foodstuffs derived from contaminated sources, adequate refrigeration, control of infection among domestic animals, and meticulous meat and poultry inspections. Raw and undercooked fresh eggs should be avoided. Food handlers and child care workers with salmonellosis should have three negative stool cultures before resuming work. Asymptomatic children, who have recovered from Salmonella infection, do not need exclusion.

Treatment

A. Specific Measures

In uncomplicated Salmonella gastroenteritis, antibiotic treatment does not shorten the course of the clinical illness and may prolong convalescent carriage of the organism. Colitis or secretory diarrhea due to Salmonella may improve with antibiotic therapy.

Because of the higher risk of sepsis and focal disease, antibiotic treatment is recommended in infants younger than age 3 months, in severely ill children, and in children with sickle cell disease, liver disease, recent gastrointestinal surgery, cancer, depressed immunity, or chronic renal or cardiac disease. Infants younger than age 3 months with positive stool cultures or suspected salmonellosis sepsis should be admitted to the hospital, evaluated for focal infection including cultures of blood and CSF, and given treatment intravenously. A third-generation cephalosporin is usually recommended due to frequent resistance to ampicillin and TMP-SMX. Older patients developing bacteremia during the course of gastroenteritis should receive parenteral treatment initially, and a careful search should be made for additional foci of infection. After signs and symptoms subside, these patients should receive oral medication. Parenteral and oral treatment should last a total of 7–10 days. Longer treatment is indicated for specific complications. If susceptibility tests indicate resistance to ampicillin, third-generation cephalosporins or TMP-SMX should be given. Fluoroquinolones also are efficacious but are not approved for administration to children. Fluoroquinolones or azithromycin are used for strains resistant to multiple other drugs.

Empiric therapy of gram-negative meningitis is with meropenem (120 mg/kg/d) intravenously in three divided doses or cefepime (150 mg/kg/d) in three divided doses with adjustment based on culture and susceptibility testing.

Often ampicillin (200–300 mg/kg/d intravenously in four to six divided doses) or a third-generation cephalosporin (cefotaxime, ceftriaxone) is used for 4–6 weeks to complete therapy.

Outbreaks on pediatric wards are difficult to control. Strict hand washing, cohorting of patients and personnel, and ultimately closure of the unit may be necessary.

B. Treatment of the Carrier State

About half of patients may have positive stool cultures after 4 weeks. Infants tend to remain convalescent carriers for up to a year. Antibiotic treatment of carriers is not effective.

C. General Measures

Careful attention must be given to maintaining fluid and electrolyte balance, especially in infants.

Prognosis

In gastroenteritis, the prognosis is good. In sepsis with focal suppurative complications, the prognosis is more guarded. The case fatality rate of Salmonella meningitis is high in infants. There is a strong tendency to relapse if treatment is not continued for at least 4 weeks.

TYPHOID FEVER & PARATYPHOID FEVER

General Considerations

Typhoid fever is caused by the gram-negative bacillus Salmonella typhi. Paratyphoid fevers, which are usually milder but may be clinically indistinguishable, are caused by S paratyphi A, Salmonella schottmülleri, or Salmonella hirschfeldii (formerly S paratyphi A, B, and C). Children have a shorter incubation period than do adults (usually 5–8 days instead of 8–14 days). The organism enters the body through the walls of the intestinal tract and, following a transient bacteremia, multiplies in the reticuloendothelial cells of the liver and spleen. Persistent bacteremia and symptoms then follow. Reinfection of the intestine occurs as organisms are excreted in the bile. Bacterial emboli produce the characteristic skin lesions (rose spots). Typhoid fever is transmitted by the fecal-oral route and by contamination of food or water. Unlike other Salmonella species, there are no animal reservoirs of S typhi; each case is the result of direct or indirect contact with the organism or with an individual who is actively infected or a chronic carrier.

About 460 cases per year were reported in the United States in 2010, 80% of which are acquired during foreign travel.

Clinical Findings

A. Symptoms and Signs

In children, the onset of typhoid fever usually is sudden rather than insidious, with malaise, headache, crampy abdominal pains and distention, and sometimes constipation followed within 48 hours by diarrhea, high fever, and toxemia. An encephalopathy may be seen with irritability, confusion, delirium, and stupor. Vomiting and meningismus may be prominent in infants and young children. The classic lengthy three-stage disease seen in adult patients often is shortened in children. The prodrome may last only 2–4 days, the toxic stage only 2–3 days, and the defervescence stage 1–2 weeks.

During the prodromal stage, physical findings may be absent, but abdominal distention and tenderness, meningismus, mild hepatomegaly, and minimal splenomegaly may be present. The typical typhoidal rash (rose spots) is present in 10%–15% of children. It appears during the second week of the disease and may erupt in crops for the succeeding 10–14 days. Rose spots are erythematous maculopapular lesions 2–3 mm in diameter that blanch on pressure. They are found principally on the trunk and chest and they generally disappear within 3–4 days. The lesions usually number fewer than 20.

B. Laboratory Findings

Typhoid bacilli can be isolated from many sites, including blood, stool, urine, and bone marrow. Blood cultures are positive in 50%–80% of cases during the first week and less often later in the illness. Stool cultures are positive in about 50% of cases after the first week. Urine and bone marrow cultures also are valuable. Most patients will have negative cultures (including stool) by the end of a 6-week period. Serologic tests (Widal reaction) are not as useful as cultures because both false-positive and false-negative results occur. Leukopenia is common in the second week of the disease, but in the first week, leukocytosis may be seen. Proteinuria, mild elevation of liver enzymes, thrombocytopenia, and DIC are common.

Differential Diagnosis

Typhoid and paratyphoid fevers must be distinguished from other serious prolonged fevers. These include typhus, brucellosis, malaria, tularemia, tuberculosis, psittacosis, vasculitis, lymphoma, mononucleosis, and Kawasaki disease. The diagnosis of typhoid fever often is made clinically in developing countries, but the accuracy of clinical diagnosis is variable. In developed countries, where typhoid fever is uncommon and physicians are unfamiliar with the clinical picture, the diagnosis often is not suspected until late in the course. Positive cultures confirm the diagnosis.

Complications

The most serious complications of typhoid fever are gastrointestinal hemorrhage (2%–10%) and perforation (1%–3%). They occur toward the end of the second week or during the third week of the disease.

Intestinal perforation is one of the principal causes of death. The site of perforation generally is the terminal ileum or cecum. The clinical manifestations are indistinguishable from those of acute appendicitis, with pain, tenderness, and rigidity in the right lower quadrant.

Bacterial pneumonia, meningitis, septic arthritis, abscesses, and osteomyelitis are uncommon complications, particularly if specific treatment is given promptly. Shock and electrolyte disturbances may lead to death.

About 1%–3% of patients become chronic carriers of S typhi. Chronic carriage is defined as excretion of typhoid bacilli for more than a year, but carriage is often lifelong. Adults with underlying biliary or urinary tract disease are much more likely than children to become chronic carriers.

Prevention

Routine typhoid vaccine is not recommended in the United States but should be considered for foreign travel to endemic areas. An attenuated oral typhoid vaccine produced from strain Ty21a has better efficacy and causes minimal side effects but is not approved for children younger than age 6 years. The vaccine is repeated after 5 years. A capsular polysaccharide vaccine (ViCPS) requires one intramuscular injection and may be given to children age 2 years and older. (See Chapter 10.)

Treatment

A. Specific Measures

Third-generation cephalosporins such as cefotaxime (150 mg/kg divided in three doses), azithromycin (10 mg/kg on day 1, followed by 5 mg/kg for 7 days), or a fluoroquinolone are used for presumptive therapy. Antimicrobial susceptibility testing and local experience are used to direct subsequent therapy. Equally effective regimens for susceptible strains include the following: TMP-SMX (10 mg/kg trimethoprim and 50 mg/kg sulfamethoxazole per day orally in two or three divided doses), amoxicillin (100 mg/kg/d orally in four divided doses), and ampicillin (100–200 mg/kg/d intravenously in four divided doses). Aminoglycosides and first- and second-generation cephalosporins are clinically ineffective regardless of in vitro susceptibility results. Ciprofloxacin or other fluoroquinolones are efficacious but not approved in children, but may be used for multiply resistant strains. Treatment duration is 14–21 days. Patients may remain febrile for 3–5 days even with appropriate therapy.

B. General Measures

General support of the patient is exceedingly important and includes rest, good nutrition and hydration, and careful observation, with particular regard to evidence of intestinal bleeding or perforation. Blood transfusions may be needed even in the absence of frank hemorrhage.

Prognosis

A prolonged convalescent carrier stage may occur in children. Three negative cultures after all antibiotics have been stopped are required before contact precautions are stopped. With early antibiotic therapy, the prognosis is excellent, and the mortality rate is less than 1%. Relapse occurs 1–3 weeks later in 10%–20% of patients despite appropriate antibiotic treatment.

SHIGELLOSIS (BACILLARY DYSENTERY)

General Considerations

Shigellae are nonmotile gram-negative rods of the family Enterobacteriaceae and are closely related to E coli. The genus Shigella is divided into four species: S dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei. Approximately 15,000 to 20,000 cases of shigellosis are reported each year in the United States. S sonnei followed by S flexneri are the most common isolates.

S dysenteriae, which causes the most severe diarrhea of all species and the greatest number of extraintestinal complications, accounts for less than 1% of all Shigella infections in the United States.

Shigellosis may be a serious disease, particularly in young children, and without supportive treatment an appreciable mortality rate results. In older children and adults, the disease tends to be self-limited and milder. Shigella is usually transmitted by the fecal-oral route. Food- and water-borne outbreaks are increasing in occurrence, but are less important overall than person-to-person transmission. The disease is very communicable—as few as 200 bacteria can produce illness in an adult. The secondary attack rate in families is high, and shigellosis is a serious problem in day care centers and custodial institutions. Shigella organisms produce disease by invading the colonic mucosa, causing mucosal ulcerations and microabscesses. A plasmid-encoded gene is required for enterotoxin production, chromosomal genes are required for invasiveness, and smooth lipopolysaccharides are required for virulence. An experimental vaccine is under development and is safe and immunogenic in young children.

Clinical Findings

A. Symptoms and Signs

The incubation period of shigellosis is usually 2–4 days. Onset is abrupt, with abdominal cramps, urgency, tenesmus, chills, fever, malaise, and diarrhea. Hallucinations and seizures sometimes accompany high fever. In severe forms, blood and mucus are seen in small stools (dysentery), and meningismus and convulsions may occur. In older children, the disease may be mild and may be characterized by watery diarrhea without blood. In young children, a fever of 39.4–40°C is common. Rarely there is rectal prolapse. Symptoms generally last 3–7 days.

B. Laboratory Findings

The total WBC count varies, but often there is a marked shift to the left. The stool may contain gross blood and mucus, and many neutrophils are seen if mucus from the stool is examined microscopically. Stool cultures are usually positive; however, they may be negative because the organism is somewhat fragile and present in small numbers late in the disease, and because laboratory techniques are suboptimal for the recovery of shigellae.

Differential Diagnosis

Diarrhea due to rotavirus infection is a winter rather than a summer disease. Usually children with viral gastroenteritis are not as febrile or toxic as those with shigellosis, and the stool does not contain gross blood or neutrophils. Intestinal infections caused by Salmonella or Campylobacter are differentiated by culture. Grossly bloody stools in a patient without fever or stool leukocytes suggest E coli O157:H7 infection. Amebic dysentery is diagnosed by microscopic examination of fresh stools or sigmoidoscopy specimens. Intussusception is characterized by an abdominal mass (so-called currant jelly stools) without leukocytes, and by absence of initial fever. Mild shigellosis is not distinguishable clinically from other forms of infectious diarrhea.

Complications

Dehydration, acidosis, shock, and renal failure are the major complications. In some cases, a chronic form of dysentery occurs, characterized by mucoid stools and poor nutrition. Bacteremia and metastatic infections are rare but serious complications. Febrile seizures are common. Fulminating fatal dysentery and hemolytic-uremic syndrome occur rarely. Reiter syndrome may follow S flexneri infection.

Treatment

A. Specific Measures

Resistance to TMP-SMX (10 mg/kg/d trimethoprim and 50 mg/kg/d sulfamethoxazole, given in two divided doses orally for 5 days) and ampicillin (100 mg/kg/d divided in four doses) is common and limits the use of these drugs to cases where results of susceptibility testing are known. Amoxicillin is not effective. Parenteral ceftriaxone is effective. Azithromycin (12 mg/kg/d on day 1, then 6 mg/kg/d for 2 days) is effective, but laboratories do not routinely perform susceptibility testing for azithromycin. Ciprofloxacin (500 mg, given twice daily for 5 days) is efficacious in adults but is not approved for use in children. However, it may be used in children who remain symptomatic and in need of therapy, and when multiply resistant strains limit other preferred choices. Successful treatment reduces the duration of fever, cramping, and diarrhea and terminates fecal excretion of Shigella. Presumptive therapy should be limited to children with classic shigellosis or known outbreaks. Afebrile children with bloody diarrhea are more commonly infected with EHEC. Antimicrobial therapy of EHEC may increase the likelihood of hemolytic-uremic syndrome, and is not recommended.

B. General Measures

In severe cases, immediate rehydration is critical. A mild form of chronic malabsorption syndrome may supervene and require prolonged dietary control.

Prognosis

The prognosis is excellent if vascular collapse is treated promptly by adequate fluid therapy. The mortality rate is high in very young, malnourished infants who do not receive fluid and electrolyte therapy. Convalescent fecal excretion of Shigella lasts 1–4 weeks in patients not receiving antimicrobial therapy. Long-term carriers are rare.

CHOLERA

General Considerations

Cholera is an acute diarrheal disease caused by the gram-negative organism Vibrio cholerae. It is transmitted by contaminated water or food, especially contaminated shellfish. Epidemics are common in impoverished areas where hygiene and safe water supply are limited. Typical disease is generally so dramatic that in endemic areas the diagnosis is obvious. Individuals with mild illness and young children may play an important role in transmission of the infection.

Asymptomatic infection is far more common than clinical disease. In endemic areas, rising titers of vibriocidal antibody are seen with increasing age. Infection occurs in individuals with low titers. The age-specific attack rate is highest in children younger than age 5 years and declines with age. Cholera is unusual in infancy.

Cholera toxin is a protein enterotoxin that is primarily responsible for symptoms. Cholera toxin binds to a regulatory subunit of adenylyl cyclase in enterocytes, causing increased cyclic adenosine monophosphate and an outpouring of NaCl and water into the lumen of the small bowel.

Nutritional status is an important factor determining the severity of the diarrhea. Duration of diarrhea is prolonged in adults and children with severe malnutrition.

Cholera is endemic in India and southern and Southeast Asia and in parts of Africa. The most recent pandemic, caused by the El Tor biotype of V cholerae 01, began in 1961 in Indonesia. Epidemic cholera spread in Central and South America, with a total of 1 million cases and 9500 deaths reported through 1994. A severe cholera outbreak is ongoing in Haiti since October 2010. More than 500,000 cases and 6000 deaths are estimated. V cholerae serogroups 0139 has been recognized in Asia as a cause of cholera illness. Cases in the United States occurred in the course of foreign travel or as a result of consumption of contaminated imported food. Cholera is increasingly associated with consumption of shellfish. Interstate shipment of oysters has resulted in cholera in several inland states. Cholera is now rare in the United States with 10 to 15 cases per year reported.

V cholerae is a natural inhabitant of shellfish and cope-pods in estuarine environments. Seasonal multiplication of V cholerae may provide a source of outbreaks in endemic areas. Chronic cholera carriers are rare. The incubation period is short, usually 1–3 days.

Clinical Findings

A. Symptoms and Signs

Many patients infected with V cholerae have mild disease, with 1%–2% developing severe diarrhea. During severe cholera, there is a sudden onset of massive, frequent, watery stools, generally light gray in color (so-called rice-water stools) and containing some mucus but no pus. Vomiting may be projectile and is not accompanied by nausea. Within 2–3 hours, the tremendous loss of fluids results in life-threatening dehydration, hypochloremia, and hypokalemia, with marked weakness and collapse. Renal failure with uremia and irreversible peripheral vascular collapse will occur if fluid therapy is not administered. The illness lasts 1–7 days and is shortened by appropriate antibiotic therapy.

B. Laboratory Findings

Markedly elevated hemoglobin (20 g/dL) and marked acidosis, hypochloremia, and hyponatremia are seen. Stool sodium concentration may range from 80 to 120 mEq/L. Culture confirmation requires specific media and takes 16–18 hours for a presumptive diagnosis and 36–48 hours for a definitive bacteriologic diagnosis.

Prevention

Cholera vaccine is available outside of the United States and provides 50%–75% efficacy. Protection lasts 3–6 months. Cholera vaccine is not generally recommended for travelers. Tourists visiting endemic areas are at little risk if they exercise caution in what they eat and drink and maintain good personal hygiene. In endemic areas, all water and milk must be boiled, food protected from flies, and sanitary precautions observed. Simple filtration of water is highly effective in reducing cases. Thorough cooking of shellfish prevents transmission. All patients with cholera should be isolated.

Chemoprophylaxis is indicated for household and other close contacts of cholera patients. It should be initiated as soon as possible after the onset of the disease in the index patient. Tetracycline (500 mg/d for 5 days) is effective in preventing infection. TMP-SMX may be substituted in children.

Treatment

Physiologic saline or lactated Ringer solution should be administered intravenously in large amounts to restore blood volume and urine output and prevent irreversible shock. Potassium supplements are required. Sodium bicarbonate, given intravenously, also may be needed initially to overcome profound metabolic acidosis from bicarbonate loss in the stool. Moderate dehydration and acidosis can be corrected in 3–6 hours by oral therapy alone, because the active glucose transport system of the small bowel is normally functional. The optimal composition of the oral solution (in milliequivalents per liter [mEq/L]) is as follows: Na⁺, 90; Cl⁻, 80; and K⁺, 20 (with glucose, 110 mmol/L).

Treatment with tetracycline (50 mg/kg/d orally in four divided doses for 2–5 days) or azithromycin (10 mg/kg/d in one dose for 1–5 days) shortens the duration of the disease in children and prevents clinical relapse but is not as important as fluid and electrolyte therapy. Tetracycline resistance occurs in some regions, and ciprofloxacin may be used depending on local resistance patterns. TMP-SMX or azithromycin should be used in children younger than age 9 years.

Prognosis

With early and rapid replacement of fluids and electrolytes, the case fatality rate is 1%–2% in children. If significant symptoms appear and no treatment is given, the mortality rate is over 50%.

CAMPYLOBACTER INFECTION

General Considerations

Campylobacter species are small gram-negative, curved or spiral bacilli that are commensals or pathogens in many animals. Campylobacter jejuni frequently causes acute enteritis in humans. In the 1990s, C jejuni was responsible for 3%–11% of cases of acute gastroenteritis in North America and Europe. In many areas, enteritis due to C jejuni is more common than that due to Salmonella or Shigella. Campylobacter fetus causes bacteremia and meningitis in immunocompromised patients. C fetus may cause maternal fever, abortion, stillbirth, and severe neonatal infection. Helicobacter pylori (previously called Campylobacter pylori) causes gastritis and peptic ulcer disease in both adults and children (see Chapter 21).

Campylobacter colonizes domestic and wild animals, especially poultry. Numerous cases have been associated with sick puppies or other animal contacts. Contaminated food and water, improperly cooked poultry, and person-to-person spread by the fecal-oral route are common routes of transmission. Outbreaks associated with day care centers, contaminated water supplies, and raw milk have been reported. Newborns may acquire the organism from their mothers at delivery.

Clinical Findings

A. Symptoms and Signs

C jejuni enteritis can be mild or severe. In tropical countries, asymptomatic stool carriage is common. The incubation period is usually 1–7 days. The disease usually begins with sudden onset of high fever, malaise, headache, abdominal cramps, nausea, and vomiting. Diarrhea follows and may be watery or bile-stained, mucoid, and bloody. The illness is self-limiting, lasting 2–7 days, but relapses may occur. Without antimicrobial treatment, the organism remains in the stool for 1–6 weeks.

B. Laboratory Findings

The peripheral WBC count generally is elevated, with many band forms. Microscopic examination of stool reveals erythrocytes and pus cells.

Isolation of C jejuni from stool is not difficult but requires selective agar, incubation at 42°C rather than 35°C, and incubation in an atmosphere of about 5% oxygen and 5% CO₂ (candle jar is satisfactory).

Differential Diagnosis

Campylobacter enteritis may resemble viral gastroenteritis, salmonellosis, shigellosis, amebiasis, or other infectious diarrheas. Because it also mimics ulcerative colitis, Crohn disease, intussusception, and appendicitis, mistaken diagnosis can lead to unnecessary diagnostic testing or surgery.

Complications

The most common complication is dehydration. Other uncommon complications include erythema nodosum, convulsions, reactive arthritis, bacteremia, urinary tract infection, and cholecystitis. Guillain-Barré syndrome may follow C jejuni infection by 1–3 weeks.

Prevention

No vaccine is available. Hand washing and adherence to basic food sanitation practices help prevent disease. Hand washing and cleaning of kitchen utensils after contact with raw poultry are important.

Treatment

Treatment of fluid and electrolyte disturbances is important. Antimicrobial treatment with erythromycin in children (30–50 mg/kg/d orally in four divided doses for 5 days), azithromycin (10 mg/kg/d orally once daily) for 3 days, or ciprofloxacin terminates fecal excretion. Fluoroquinolone-resistant C jejuni are now common worldwide. Therapy given early in the course of the illness will shorten the duration of symptoms but is unnecessary if given later. Antimicrobials used for shigellosis, such as TMP-SMX and ampicillin, are inactive against Campylobacter. Supportive therapy is sufficient in most cases.

Prognosis

The outlook is excellent if dehydration is corrected and misdiagnosis does not lead to inappropriate diagnostic or surgical procedures.

TULAREMIA

General Considerations

Tularemia is caused by Francisella tularensis, a gram- negative organism usually acquired directly from infected animals (principally wild rabbits) or by the bite of an infected tick. Occasionally infection is acquired from infected domestic dogs or cats; by contamination of the skin or mucous membranes with infected blood or tissues; by inhalation of infected material; by bites of fleas or deer flies that have been in contact with infected animals; or by ingestion of contaminated meat or water. The incubation period is short, usually 3–7 days, but may vary from 2 to 25 days.

Ticks are the most important vector of tularemia and rabbits are the classic vector. It is important to seek a history of rabbit hunting, skinning, or food preparation in any patient who has a febrile illness with tender lymphadenopathy, often in the region of a draining skin ulcer.

Prevention

Children should be protected from insect bites, especially those of ticks, fleas, and deer flies, by the use of proper clothing and repellents. Because rabbits are the source of most human infections, the dressing and handling of such game should be performed with great care. Rubber gloves should be worn by hunters or food handlers when handling carcasses of wild rabbits. If contact occurs, thorough washing with soap and water is indicated. For postexposure prophylaxis from an intentional release of F tularensis (bioterrorism), a 14-day course of doxycycline or ciprofloxacin is recommended (children less than 8 years should not receive doxycycline unless benefits outweigh risks; in children less than 18 years ciprofloxacin is not approved for this indication—weigh benefits and risk).

Clinical Findings

A. Symptoms and Signs

Several clinical types of tularemia occur in children. Sixty percent of infections are of the ulceroglandular form and start as a reddened papule that may be pruritic, quickly ulcerates, and is not very painful. Soon, the regional lymph nodes become large and tender. Fluctuance quickly follows. There may be marked systemic symptoms, including high fever, chills, weakness, and vomiting. Pneumonitis occasionally accompanies the ulceroglandular form or may be seen as the sole manifestation of infection (pneumonic form). A detectable skin lesion may be absent, and localized lymphoid enlargement may exist alone (glandular form). Oculoglandular and oropharyngeal forms also occur. The latter is characterized by tonsillitis, often with membrane formation, cervical adenopathy, and high fever. In the absence of a primary ulcer or localized lymphadenitis, a prolonged febrile disease reminiscent of typhoid fever can occur (typhoidal form). Splenomegaly is common in all forms.

B. Laboratory Findings

F tularensis can be recovered from ulcers, regional lymph nodes, and sputum of patients with the pneumonic form. However, the organism grows only on an enriched medium (blood-cystine-glucose agar), and laboratory handling is dangerous owing to the risk of airborne transmission to laboratory personnel. Immunofluorescent staining of biopsy material or aspirates of involved lymph nodes is diagnostic, although it is not widely available.

The WBC count is not remarkable. Agglutinins are present after the second week of illness, and in the absence of a positive culture their development confirms the diagnosis. A tube agglutination antibody titer of 1:160 or greater or a microagglutination titer of 1:128 or higher is considered presumptively positive for the diagnosis of tularemia. Confirmation of disease is established by demonstration of a fourfold antibody titer rise between acute and convalescent serum samples. PCR of blood, lymph node aspirate, or tissue may be available through State Health Departments.

Differential Diagnosis

The typhoidal form of tularemia may mimic typhoid, brucellosis, miliary tuberculosis, Rocky Mountain spotted fever, and mononucleosis. Pneumonic tularemia resembles atypical or mycotic pneumonitis. The ulceroglandular type of tularemia resembles pyoderma caused by staphylococci or streptococci, plague, anthrax, and cat-scratch fever. The oropharyngeal type must be distinguished from streptococcal or diphtheritic pharyngitis, mononucleosis, herpangina, or other viral pharyngitides.

Treatment

A. Specific Measures

Historically, streptomycin was the drug of choice. However, gentamicin is efficacious, more available, and familiar to clinicians. A 10-day course is usually sufficient, although more severe infections may need longer therapy. Doxycycline is effective, but relapse rates are higher. Doxycycline is not usually recommended for children younger than 8 years of age unless benefits of use outweigh the risk of dental staining. Doxycycline is a static (as opposed to cidal) agent and should be given for at least 14 days. Ciprofloxacin also can be used in patients with less severe disease. Ciprofloxacin is not approved for children younger than 18 years, and is not usually recommended in children unless benefits outweigh risks.

B. General Measures

Antipyretics and analgesics may be given as necessary. Skin lesions are best left open. Glandular lesions occasionally require incision and drainage.

Prognosis

The prognosis is excellent in most cases of tularemia that are recognized early and treated appropriately.

PLAGUE

General Considerations

Plague is an extremely serious acute infection caused by a gram-negative bacillus, Yersinia pestis. It is a disease of rodents that is transmitted to humans by flea bites. Plague bacilli have been isolated from ground squirrels, prairie dogs, and other wild rodents in many of the western and southwestern states in the United States. Most cases have come from New Mexico, Arizona, Colorado, and California. Direct contact with rodents, rabbits, or domestic cats may transmit fleas infected with plague bacilli. Most cases occur from June through September. Human plague in the United States appears to occur in cycles that reflect cycles in wild animal reservoirs.

Prevention

Proper disposal of household and commercial wastes and chemical control of rats are basic elements of plague prevention. Flea control is instituted and maintained with liberal use of insecticides. Children vacationing in remote camping areas should be warned not to handle dead or dying animals. Domestic cats that roam freely in suburban areas may contact infected wild animals and acquire infected fleas. There is no commercially available vaccine for plague.

All persons who have been exposed to plague in the previous 6 days (via personal contact with an infected person, contact with plague infected fleas, or exposure to infected tissues) should be given antimicrobial prophylaxis or be instructed to closely monitor themselves for fever or other symptoms and report any illness or any fever to their physician. Persons who have close personal contact (< 2 m) with a person with pneumonic plague should receive antimicrobial prophylaxis for 7 days from the last exposure. Doxycycline or ciprofloxacin are the recommended agents for prophylaxis. For children younger than 8 years, TMP-SMX is an alternative agent but the efficacy is unknown. Chloramphenicol is also an alternative agent. For persons who have had a known or suspected exposure to plague-infected fleas in the previous week, the same antimicrobial regimen can be used for prophylaxis. Patients on prophylaxis should still seek prompt medical care for onset of fever or other illness.

Clinical Findings

A. Symptoms and Signs

Plague assumes several clinical forms; the two most common are bubonic and septicemic. Pneumonic plague, the form that occurs when organisms enter the body through the respiratory tract, is uncommon.

1. Bubonic plague—Bubonic plague begins after an incubation period of 2–8 days with a sudden onset of high fever, chills, headache, vomiting, and marked delirium or clouding of consciousness. A less severe form also exists, with a less precipitous onset, but with progression over several days to severe symptoms. Although the flea bite is rarely seen, the regional lymph node, usually inguinal and unilateral, is/are painful and tender, 1–5 cm in diameter. The node usually suppurates and drains spontaneously after 1 week. The plague bacillus produces endotoxin that causes vascular necrosis. Bacilli may overwhelm regional lymph nodes and enter the circulation to produce septicemia. Severe vascular necrosis results in widely disseminated hemorrhage in skin, mucous membranes, liver, and spleen. Myocarditis and circulatory collapse may result from damage by the endotoxin. Plague meningitis or pneumonia may occur following bacteremic spread from an infected lymph node.

2. Septicemic plague—Plague may initially present as septicemia without evidence of lymphadenopathy. In some series, 25% of cases are initially septicemic. Septicemic plague carries a worse prognosis than bubonic plague, largely because it is not recognized and treated early. Patients may present initially with a nonspecific febrile illness characterized by fever, myalgia, chills, and anorexia. Plague is frequently complicated by secondary seeding of the lung causing plague pneumonia.

3. Primary pneumonic plague—Inhalation of Y pestis bacilli causes primary plague pneumonia. This form of plague has been transmitted to humans from cats with pneumonic plague and would be the form of plague most likely seen after aerosolized release of Y pestis in a bioterrorist incident. After an incubation of 1–6 days, the patient develops fever, cough, shortness of breath, and the production of bloody, watery, or purulent sputum. Gastrointestinal symptoms are sometimes prominent. Because the initial focus of infection is the lung, buboes are usually absent; occasionally cervical buboes may be seen.

B. Laboratory Findings

Aspirate from a bubo contains bipolar-staining gram- negative bacilli. Pus, sputum, and blood all yield the organism. Rapid diagnosis can be made with fluorescent antibody detection or polymerase chain reaction (PCR) on clinical specimens. Confirmation is made by culture or serologic testing. Laboratory infections are common enough to make bacterial isolation dangerous. Cultures are usually positive within 48 hours. Paired acute and convalescent sera may be tested for a fourfold antibody rise in those cases with negative cultures.

Differential Diagnosis

The septic phase of the disease may be confused with illnesses such as meningococcemia, sepsis caused by other bacteria, and rickettsioses. The bubonic form resembles tularemia, anthrax, cat-scratch fever, streptococcal adenitis, and cellulitis. Primary gastroenteritis and appendicitis may have to be distinguished.

Treatment

A. Specific Measures

Streptomycin or gentamicin for 7–10 days (or until several days after defervescence) is effective. For patients not requiring parenteral therapy, doxycycline, ciprofloxacin or chloramphenicol may be given. Doxycycline is not usually recommended for children younger than 8 years of age and ciprofloxacin is not usually recommended for children less than 18 years of age unless benefits of use outweigh the risk. However, plague is a potentially life-threatening condition and benefits of use of these agents outweigh potential risks. Plague bacilli that are multiply resistant to antimicrobials are uncommon but of serious concern.

Mortality is extremely high in septicemic and pneumonic plague if specific antibiotic treatment is not started in the first 24 hours of the disease.

Every effort should be made to effect resolution of buboes without surgery. Pus from draining lymph nodes is infectious.

B. General Measures

State health officials should be notified immediately about suspected cases of plague. Pneumonic plague is highly infectious, and droplet isolation is required until the patient has been on effective antimicrobial therapy for 48 hours. All contacts of patients with pneumonic plague should receive antibiotic prophylaxis for 7 days after the last exposure. Contacts should see a physician immediately for any illness or fever.

Prognosis

The mortality rate in untreated bubonic plague is about 50%. The mortality rate for treated pneumonic plague is 50%–60%. Recent mortality rates in New Mexico were 3% for bubonic plague and 71% for the septicemic form.

HAEMOPHILUS INFLUENZAE TYPE B INFECTIONS

General Considerations

H influenzae type b (Hib) has become uncommon because of widespread immunization in early infancy. The 99% reduction in incidence seen in many parts of the United States is due to high rates of vaccine coverage and reduced nasopharyngeal carriage after vaccination. Forty percent of cases occur in children younger than 6 months who are too young to have completed a primary immunization series. Hib may cause meningitis, bacteremia, epiglottitis (supraglottic croup), septic arthritis, periorbital and facial cellulitis, pneumonia, and pericarditis.

Disease due to H influenzae types a, c, d, e, f, or unencapsulated strains is rare, but it now accounts for a larger proportion of positive culture results. Third-generation cephalosporins are preferred for initial therapy of Hib infections. Ampicillin is adequate for culture-proved Hib susceptible strains.

Unencapsulated, nontypeable H influenzae frequently colonize the mucous membranes and cause otitis media, sinusitis, bronchitis, and pneumonia in children and adults. Bacteremia is uncommon. Neonatal sepsis similar to early-onset GBS is recognized. Obstetric complications of chorioamnionitis and bacteremia are usually the source of neonatal cases.

Ampicillin resistance occurs in 25%–40% of nontypeable H influenzae. Beta-lactamase-negative, ampicillin-resistant (BLNAR) H influenzae has emerged as a clinically important pathogen in Europe, Japan, and Canada. In the United States, the prevalence of BLNAR strains currently remains low at around 3%.

Prevention

Several carbohydrate protein conjugate Hib vaccines are currently available (see Chapter 10).

The risk of invasive Hib disease is highest in unimmunized, or partially immunized, household contacts who are younger than 4 years of age. The following situations require rifampin chemoprophylaxis of all household contacts (except pregnant women) to eradicate potential nasopharyngeal colonization with Hib and limit risk of invasive disease: (1) families where at least one household contact is younger than age 4 years and either unimmunized or incompletely immunized against Hib; (2) an immunocompromised child (of any age or immunization status) resides in the household; or (3) a child younger than age 12 months resides in the home and has not received the primary series of the Hib vaccine. Preschool and day care center contacts may need prophylaxis if more than one case has occurred in the center in the previous 60 days (discuss with state health officials). The index case also needs chemoprophylaxis in these situations to eradicate nasopharyngeal colonization unless treated with ceftriaxone or cefotaxime (both are effective in eradication of Hib from the nasopharynx). Household contacts and index cases older than 1 month of age who need chemoprophylaxis should be given rifampin, 20 mg/kg per dose (maximum adult dose, 600 mg) orally, once daily for 4 successive days. Infants who are younger than 1 month should be given oral rifampin (10 mg/kg per dose once daily for 4 days). Rifampin should not be used in pregnant females.

Clinical Findings

A. Symptoms and Signs

1. Meningitis—Infants usually present with fever, irritability, lethargy, poor feeding with or without vomiting, and a high-pitched cry.

2. Acute epiglottitis—The most useful clinical finding in the early diagnosis of Hib epiglottitis is evidence of dysphagia, characterized by a refusal to eat or swallow saliva and by drooling. This finding, plus the presence of a high fever in a toxic child—even in the absence of a cherry-red epiglottis on direct examination—should strongly suggest the diagnosis and lead to prompt intubation. Stridor is a late sign (see Chapter 19).

3. Septic arthritis—Hib is a common cause of septic arthritis in unimmunized children younger than age 4 years in the United States. The child is febrile and refuses to move the involved joint and limb because of pain. Examination reveals swelling, warmth, redness, tenderness on palpation, and severe pain on attempted movement of the joint.

4. Cellulitis—Cellulitis due to Hib occurs almost exclusively in children between the ages of 3 months and 4 years but is now uncommon as a result of immunization. Fever is usually noted at the same time as the cellulitis, and many infants appear toxic. The cheek or periorbital (preseptal) area is usually involved.

B. Laboratory Findings

The WBC count in Hib infections may be high or normal with a shift to the left. Blood culture is frequently positive. Positive culture of aspirated pus or fluid from the involved site proves the diagnosis. In untreated meningitis, CSF smear may show the characteristic pleomorphic gram-negative rods.

C. Imaging

A lateral view of the neck may suggest the diagnosis in suspected acute epiglottitis, but misinterpretation is common. Intubation should not be delayed to obtain radiographs. Haziness of maxillary and ethmoid sinuses occurs with orbital cellulitis.

Differential Diagnosis

A. Meningitis

Meningitis must be differentiated from head injury, brain abscess, tumor, lead encephalopathy, and other forms of meningoencephalitis, including mycobacterial, viral, fungal, and bacterial agents.

B. Acute Epiglottitis

In croup caused by viral agents (parainfluenza 1, 2, and 3, respiratory syncytial virus, influenza A, adenovirus), the child has more definite upper respiratory symptoms, cough, hoarseness, slower progression of obstructive signs, and lower fever. Spasmodic croup usually occurs at night in a child with a history of previous attacks. Sudden onset of choking and paroxysmal coughing suggests foreign body aspiration. Retropharyngeal abscess may have to be differentiated from epiglottitis.

C. Septic Arthritis

Differential diagnosis includes acute osteomyelitis, prepatellar bursitis, cellulitis, rheumatic fever, and fractures and sprains.

D. Cellulitis

Erysipelas, streptococcal cellulitis, insect bites, and trauma (including Popsicle panniculitis or other types of freezing injury) may mimic Hib cellulitis. Periorbital cellulitis must be differentiated from paranasal sinus disease without cellulitis, allergic inflammatory disease of the lids, conjunctivitis, and herpes zoster infection.

Complications

A. Meningitis (See CHAPTER 25)

B. Acute Epiglottitis

The disease may rapidly progress to complete airway obstruction with complications owing to hypoxia. Mediastinal emphysema and pneumothorax may occur.

C. Septic Arthritis

Septic arthritis may result in rapid destruction of cartilage and ankylosis if diagnosis and treatment are delayed. Even with early treatment, the incidence of residual damage and disability after septic arthritis in weight-bearing joints may be as high as 25%.

D. Cellulitis

Bacteremia may lead to meningitis or pyarthrosis.

Treatment

All patients with bacteremic or potentially bacteremic Hib diseases require hospitalization for treatment. The drugs of choice in hospitalized patients are a third-generation cephalosporin (cefotaxime or ceftriaxone) until the sensitivity of the organism is known. Meropenem is an alternative choice.

Persons with invasive Hib disease should be in droplet isolation for 24 hours after initiation of parenteral antibiotic therapy.

A. Meningitis

Therapy is begun as soon as bacterial meningitis has been identified and CSF, blood, and other appropriate cultures have been obtained. Empiric intravenous therapy recommended for meningitis (until organism identified) is vancomycin in combination with either cefotaxime or ceftriaxone. Once the organism has been identified as Haemophilus influenza and the susceptibilities are known, the antibiotic regimen can be tailored accordingly. Most isolates will be susceptible to ceftriaxone or cefotaxime. Meropenem is an alternative agent. Therapy should preferably be given intravenously for the entire course. Ceftriaxone may be given intramuscularly if venous access becomes difficult.

Duration of therapy is 10 days for uncomplicated meningitis. Longer treatment is reserved for children who respond slowly or in whom complications have occurred.

Dexamethasone given immediately after diagnosis and continued for 4 days may reduce the incidence of hearing loss in children with Hib meningitis. The use of dexamethasone is controversial, but when it is used the dosage is 0.6 mg/kg/d in four divided doses for 4 days. Starting dexamethasone more than 6 hours after antibiotics have been initiated is unlikely to provide benefits.

Repeated lumbar punctures are usually not necessary in Hib meningitis. They should be obtained in the following circumstances: unsatisfactory or questionable clinical response, seizure occurring after several days of therapy, and prolonged (7 days) or recurrent fever if the neurologic examination is abnormal or difficult to evaluate.

B. Acute Epiglottitis (See Chapter 19)

C. Septic Arthritis

Initial therapy should include an effective antistaphylococcal antibiotic and cefotaxime or ceftriaxone (dosage as for meningitis) until identification of the organism is made. Cefotaxime or ceftriaxone are the usual agents used once the isolate is known to be Haemophilus and susceptibilities are known. Ampicillin resistance is now common in the United States. Occasionally isolates are resistant to third generation cephalosporins. Meropenem, if the isolate is susceptible, can be used as an alternative. If a child is improved following initial intravenous therapy, transition to oral therapy based on susceptibilities can occur. Possible oral agents should be chosen based on susceptibilities but might include amoxicillin/clavulanate (90–100 mg/kg/d of amoxicillin component in four divided doses every 6 hours). Antibiotics should be administered under supervision to complete a 4-week course (longer if complications or signs and symptoms are unresolved). Alternative agents include second- or third-generation cephalosporins. Drainage of infected joint fluid is an essential part of treatment. In joints other than the hip, this can often be accomplished by one or more needle aspirations. In hip infections—and in arthritis of other joints when treatment is delayed or clinical response is slow—surgical drainage is advised. The joint should be immobilized.

D. Cellulitis, Including Orbital Cellulitis

Initial therapy for orbital cellulitis should be broad spectrum antibiotic therapy. The most likely pathogens may include Streptococcus pneumonia, Streptococcus anginosus, Group A Streptococcus, Staphylococcus aureus, Haemophilus influenzae, and anaerobes. Once the organism is known to be H influenzae orbital and susceptibilities are known, cefotaxime, ceftriaxone, or Meropenem can be used depending on susceptibilities for H influenzae coverage. Mixed infections require additional agents. Therapy is given parenterally for at least 3–7 days (some clinicians treat up to 2 weeks intravenously) followed by oral treatment. There is usually marked improvement after 72 hours of treatment. The total antibiotic course will vary with the severity of the infection, response to therapy, whether or not an abscess was present, and whether or not drainage was performed. A minimum course of 21 days is reasonable in uncomplicated cases without abscess and good therapeutic response, assuming all signs of orbital cellulitis have completely resolved. In cases with severe ethmoid sinusitis and evidence of boney destruction at least a 4-week treatment course is advisable. Complicated cases may require longer treatment courses.

Prognosis

The case fatality rate for Hib meningitis is less than 5%. Young infants have the highest mortality rate. One of the most common neurologic sequelae, developing in 5%–10% of patients with Hib meningitis, is sensorineural hearing loss. Patients with Hib meningitis should have their hearing checked during the course of the illness or shortly after recovery. Children in whom invasive Hib infection develops despite appropriate immunization should have tests to investigate immune function and to rule out HIV. The case fatality rate in acute epiglottitis is 2%–5%. Deaths are associated with bacteremia and the rapid development of airway obstruction. The prognosis for the other diseases requiring hospitalization is good with the institution of early and adequate antibiotic therapy.

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