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acute diarrhea🚧 施工中
acute diarrhea
Keith W. Hamilton, MD
CHIEF COMPLAINT
PATIENT
Mr. C is a 35-year-old man who comes to your outpatient office complaining of 3 days of diarrhea.
What is the differential diagnosis of diarrhea? How would you frame the differential?
CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
A first step in assessing diarrhea is to categorize the frequency and duration of bowel movements. Diarrhea is defined as at least 3 loose bowel movements per day. Often patients and clinicians will mislabel loose bowel movements as diarrhea solely because the stool is loose. If a patient does fit the clinical criteria for diarrhea, the diarrhea can be further characterized as acute, persistent, or chronic. Acute diarrhea has a duration of less than 14 days, persistent diarrhea 14–29 days, and chronic diarrhea at least 30 days. The differential diagnosis varies significantly based on the duration of symptoms. This chapter focuses specifically on diagnosis and treatment of acute diarrhea.
Acute diarrhea can be further subcategorized into infectious and noninfectious causes, with infectious causes accounting for the majority of cases of acute, self-limited diarrheal illnesses.
Several factors are important in reasoning through a case of acute diarrhea including (1) associated signs and symptoms, (2) duration of symptoms, (3) exposure history, (4) history of immunosuppressive conditions, and (5) epidemiology of specific infectious pathogens.
A detailed history of symptoms and exposures helps guide the evaluation and treatment of acute diarrhea. Noninfectious diarrhea is typically characterized by lack of constitutional symptoms and presence of a culprit medication, supplement, food, or other condition (eg, pancreatic insufficiency). Therefore, taking a thorough history of medications, supplements, diet, and underlying medical conditions is essential to prioritize an initial differential diagnosis for acute diarrhea.
Infectious diarrhea can be associated with symptoms such as fever, myalgias, severe abdominal cramping, nausea, vomiting, and stool with blood or mucus. However, lack of any of these symptoms does not rule out a diagnosis of infectious diarrhea. Symptoms of infectious diarrhea may also suggest whether the diarrhea originates in the large or small bowel, which can narrow the likelihood of specific pathogens. Patients with large volume, watery bowel movements, nausea, vomiting, abdominal cramping, bloating, and gas are more likely to have gastroenteritis and the pathogens most commonly associated with this condition. Mucus or blood in the stool is rarely present in gastroenteritis. In contrast, patients with tenesmus and passage of many small-volume stools with blood and/or mucus are more likely to have colitis and the pathogens more commonly associated with this condition.
Figure 13-1 presents a clinical algorithm and a broad differential diagnosis using this framework.
Figure 13-1. Diagnostic approach to diarrhea.
A. Noninfectious diarrhea
1. Medications and other ingestible substances (some with osmotic effect)
a. Sorbitol (gum, mints, pill fillers)
b. Mannitol
c. Fructose (fruits, soft drinks)
d. Fiber (bran, fruits, vegetables)
e. Lactulose
2. Magnesium-containing medications
a. Nutritional supplements
b. Antacids
c. Laxatives
3. Malabsorption
a. Lactose intolerance
b. Pancreatitis
4. Medications causing diarrhea through nonosmotic means
a. Metformin
b. Antibiotics
c. Colchicine
d. Digoxin
e. Selective serotonin reuptake inhibitor antidepressants
B. Infectious diarrhea
1. Gastroenteritis
a. Viral (most common)
(1) Caliciviruses (including norovirus)
(2) Rotovirus
b. Bacterial
(1) Vibrio cholera
(2) Escherichia coli
(3) Shigella species
(4) Salmonella species
(5) Campylobacter species
(6) Yersinia enterocolitica
c. Preformed toxin-mediated
(1) Staphylococcus aureus
(2) Clostridium perfringens
(3) Bacillus cereus
2. Colitis
a. Shigella species
b. E coli
c. Campylobacter species
d. Salmonella species
e. Y enterocolitica
f. Clostridium difficile
g. Cytomegalovirus
h. Adenovirus
The first symptom the patient noted was loss of appetite while eating breakfast. He was unable to finish his usual cup of coffee and bowl of cereal. During his 20-minute drive to work he became nauseated and diaphoretic. Upon arriving at work, he had a low-grade fever and abdominal cramping and then soon after had an episode of vomiting. Over the next 24 hours, diarrhea developed with 5 bowel movements during that time. He describes the stool being watery and brown without any blood. He has no medical problems and takes no medications or supplements. He has had no recent changes in his diet.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
Naming the problem in the most descriptive possible way, taking into account the pivotal points in the presentation, is an important first step in prioritizing a differential diagnosis. In this case, the problem could be called acute-onset, watery diarrhea, or even acute-onset gastroenteritis. Correspondingly, the differential diagnosis should focus on causes of acute diarrhea and gastroenteritis. The presence of constitutional symptoms and the lack of concurrent medical conditions, offending foods, supplements, and medications make causes of noninfectious diarrhea much less likely. When prioritizing a differential diagnosis, assessing the epidemiology, or frequency of diagnoses in the population of interest, is helpful. In cases of acute diarrhea, at least 87% result from infectious causes. Therefore, based on the epidemiology of acute diarrhea, an infectious etiology is more likely. The presence of nausea and vomiting and lack of colitis-associated symptoms of mucous, blood, and tenesmus makes pathogens that cause gastroenteritis more probable.
To prioritize the differential diagnosis, a thorough travel, exposure, medical, and sexual history is essential. International travel is especially important given the regional differences in epidemiology of infectious pathogens. Exposure history should include detailed dietary history, water exposures through drinking or swimming, healthcare exposure, antibiotic exposure, contact with animals, known sick contacts, and exposure to childcare settings. Table 13-1 lists specific exposures and corresponding pathogens. Past medical history should focus on known history of immunocompromising conditions, medications, or history of past infections that would raise suspicion of an immunocompromising condition such as HIV. The most common pathogens associated with diarrhea in immunocompetent persons are also the most common in immunosuppressed persons, but opportunistic pathogens—such as parasites (eg, Cryptosporidium, Giardia, Cyclospora, Cystoisospora) and microsporidia; bacteria (eg, Mycobacterium avium complex); and viruses (eg, cytomegalovirus)—increase in prevalence.
Table 13-1. Exposures and corresponding pathogens.
Timing of onset of symptoms relative to a potential culprit food exposure may also help determine a potential causative pathogen. Diarrheal illness caused by preformed toxins often cause symptoms within several hours of exposure, whereas non-toxin–mediated diarrheal illnesses have incubation periods of at least 24 hours.
Mr. C is otherwise in good health. He reports no recent illnesses or antibiotic exposures. There have been no recent changes in his diet and he has eaten only food prepared at home for the last week. He lives with his wife. He works as a bus driver. He has not traveled out of New York City, where he lives and works. He reports no known sick contacts, but he has a 2-year-old child in daycare that he drops off and picks up every weekday. He has no pets at home and has had no recent contact with animals.
The physical exam is notable for temperature, 38.2°C; BP is 110/80 mm Hg and pulse is 100 bpm while lying down; BP is 90/72 mm Hg and pulse is 126 bpm while standing; RR, 12 breaths per minute. Sclera and conjunctiva are normal. The abdomen is soft and diffusely tender with hyperactive bowel sounds. The rectal exam shows brown, heme-negative stool.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Table 13-2 lists the differential diagnosis for Mr. C.
Table 13-2. Diagnostic hypotheses for Mr. C.
Leading Hypothesis: Norovirus
Textbook Presentation
Acute vomiting is usually the presenting symptom. The onset of diarrhea typically follows the vomiting. Mild abdominal cramping and low-grade fever are common. Symptoms typically resolve by 3 days.
Disease Highlights
A. Calciviruses, of which norovirus and closely related viruses such as sapovirus are the most common cause of adult viral gastroenteritis, account for about 80% of cases.
B. Most commonly occurs in winter.
C. Transmission
1. Norovirus is easily transmissible via the fecal-oral route, airborne droplets, food, and fomites.
2. Norovirus is the most common cause of foodborne diarrhea, and numerous outbreaks have been reported in restaurants, catered events, and cruise ships.
3. Norovirus is very stable in the environment, resisting chlorine and alcohol disinfectants.
4. Attack rates as high as 50% have been documented in outbreaks.
D. Incubation period is 1–2 days.
Evidence-Based Diagnosis
A. In almost all cases, norovirus should be diagnosed clinically based on consistent symptoms as well as ruling out exposures or risk factors that would make diagnostic testing necessary.
B. Polymerase chain reaction (PCR) testing is available to confirm a diagnosis, but testing should be reserved for public health investigations and in patients who have reasons for diagnostic testing (see Figure 13-1).
C. PCR is available as a part of some molecular multipathogen stool panels, which are increasing in clinical use. However, testing should not be performed as most cases of norovirus can be diagnosed clinically.
Treatment
A. Supportive care
1. Most patients with acute diarrhea require only supportive care. Supportive care is meant to provide rehydration and symptom relief.
2. Rehydration
a. Oral rehydration is generally sufficient.
b. For patients with mild diarrhea and little volume depletion, oral fluids (eg, sports drinks, pediatric electrolyte drinks, and soup broth) are appropriate rehydration.
c. For patients with more significant volume depletion, oral rehydration solutions should contain NaCl, KCl, HCO3 or citrate, and glucose. The World Health Organization oral rehydration solution has the following composition:
(1) Sodium: 75 mmol/L
(2) Chloride: 65 mmol/L
(3) Glucose: 75 mmol/L
(4) Potassium: 20 mmol/L
(5) Citrate: 10 mmol/L
d. If this solution is not available, patients can be instructed to mix the following in 1 L of water
(1) One-half teaspoon of salt
(2) One-quarter teaspoon of baking soda
(3) 8 teaspoons of sugar
e. In patients who cannot tolerate oral rehydration or who are very volume depleted, intravenous fluids (lactated Ringer solution or normal saline) are indicated.
3. Antidiarrheals (such as loperamide) are safe and effective for patients without bloody diarrhea (dysentery) or concern for C difficile infection. Using antidiarrheals in a patient with dysentery or C difficile may lead to:
a. Prolonged fever
b. Toxic megacolon and colonic perforation
c. Hemolytic uremic syndrome in patients with Shiga toxin–producing E coli (STEC).
4. Antiemetics
5. Diet
a. BRAT diet (banana, rice, applesauce, toast) is often recommended.
b. Dairy products should be avoided. (See discussion below).
B. Antimicrobial therapy
1. Treatment other than supportive care is not necessary for norovirus-like illnesses.
2. Empiric antimicrobial therapy is recommended for diarrheal infections only in limited circumstances (see Figure 13-1).
MAKING A DIAGNOSIS
At the time of the patient’s initial visit he was beginning to feel better. He still noted an “upset stomach” and was having watery diarrhea every 2–3 hours. He had not had any vomiting in about 6 hours and was able to tolerate fluids.
Have you crossed a diagnostic threshold for the leading hypothesis, norovirus? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
In this case, given the classic symptoms, childcare exposure, and epidemiologic likelihood of norovirus as a cause of community-acquired gastroenteritis, it is the most likely diagnosis. The clinical history, lack of suspicious exposures, and the lower frequency of other causes in community-acquired gastroenteritis (see Table 13-3) make other causes less likely. Although toxin-mediated gastroenteritis is a consideration, there is no commercially available diagnostic testing, and treatment is supportive. There are sporadic cases of other causes of infectious diarrhea such as Salmonella, but almost all of these infections resolve spontaneously. No diagnostic testing is warranted in this case due to lack of severe symptoms or risk factors for complication. In fact, only 2–15% of tests for bacterial pathogens are positive and only 0.4–0.7% of tests for ova and parasites are positive in resource-rich settings. Patients and settings that indicate need for evaluation include the following:
Table 13-3. Infectious causes of diarrhea in the United States.
A. Patients with bloody diarrhea
B. Outbreak is suspected
C. Patients at high risk for infecting others, including:
1. Residents of long-term–care facilities
2. Daycare workers
3. Food service workers
4. Healthcare workers
D. Patients with severe disease (dehydration, toxic appearance, high fever) or risk factors for poor outcome (immunosuppression, severe comorbid illnesses).
E. Patients with prolonged diarrhea (>7 days)
Must not miss diagnoses include those that would indicate a more significant predisposing immunosuppressive condition that could progress if not diagnosed (eg, HIV). Other must not miss diagnoses are infections that would present a public health concern in people who have the potential to easily spread them such as healthcare workers, childcare workers, and food handlers. Finally, other must not miss diagnoses include those that could progress rapidly to life-threatening infections, including C difficile, Vibrio species, and enteric fever caused by Salmonella typhi and Salmonella paratyphi. However, in almost all cases, these diagnoses can be ruled out by a careful history, and additional testing is not warranted unless associated characteristics and risks are identified.
In this case, no compelling reason for diagnostic testing or treatment is present.
In most patients with an acute diarrheal illness, diagnostic testing is not helpful to the patient but may be important from a public health standpoint.
Alternative Diagnosis: Toxin-Mediated Gastroenteritis
Textbook Presentation
The presentation of this syndrome, most commonly caused by S aureus or C perfringens, usually includes acute-onset vomiting and crampy abdominal pain. Vomiting is the predominant symptom with diarrhea being mild and watery. If present, fever is only low grade. Because of the very short lag between ingestion and illness (1–16 hours), the culprit meal is usually the last one eaten. Recovery is very rapid (12–48 hours).
Disease Highlights
A. Toxin-mediated gastroenteritis (often referred to as food poisoning) is not an infection; it occurs when a preformed toxin, produced by bacteria, is ingested.
B. Although S aureus, B cereus, and C perfringens are the most common causes of toxin-mediated gastroenteritis, they account for only about 1% of foodborne diarrheal illnesses.
1. Viral causes account for most foodborne infections.
2. Salmonella, Campylobacter, and E coli are the most common bacterial causes of foodborne infections.
C. S aureus, C perfringens, and B cereus can often be recognized by the clinical and exposure history. Table 13-4 describes the clinical syndromes of these infections.
Table 13-4. Clinical syndromes of toxin-mediated gastroenteritis.
Illnesses presenting with the acute onset of vomiting and constitutional symptoms, often with abdominal cramping, are usually caused by viruses or bacteria that elaborate toxins.
Evidence-Based Diagnosis
A. There are no diagnostic tests for toxin-mediated gastroenteritis available for routine clinical use.
B. Toxin-mediated gastroenteritis should be considered in any patient with acute gastrointestinal symptoms and recent suspicious food intake.
Treatment
Treatment is supportive care.
Alternative Diagnosis: Gastroenteritis Caused by Salmonella Species
Textbook Presentation
The onset of disease is usually subacute with nausea, fever, and diarrhea. Fever and nausea often resolve over 1–2 days while diarrhea persists for 5–7 days. Patients usually have watery diarrhea with 6–8 bowel movements each day. Salmonella gastroenteritis may cause higher fevers than viral or preformed toxin disease. Dysentery (characterized by the passage of blood and mucus often with tenesmus and fever) may occur.
Disease Highlights
A. Salmonella species cause 3 major types of disease.
1. Diarrheal illnesses
a. Gastroenteritis
(1) Most common Salmonella-related disease in the United States
(2) Estimated annual incidence of Salmonella: 1.23 million cases
b. Dysentery
2. Bacteremia
a. Develops in approximately 5% of patients
b. Endovascular infections and osteomyelitis may complicate bacteremia.
3. Typhoid (enteric) fever
a. A systemic illness characterized by fever and abdominal pain caused by Salmonella enterica of both typhi and paratyphi serotypes.
b. It is distinct from gastroenteritis, which is caused by nontyphoidal Salmonella.
c. Not generally considered a diarrheal illness; however, diarrhea may be predominant symptom in some patients.
d. While typhoid fever is a major problem worldwide, in the United States, it is seen most often in unvaccinated travelers.
e. Typhoid fever should be considered in the differential diagnosis of a traveler with a febrile illness.
Typhoid fever should be suspected in returning traveler with a fever. Diarrhea is not necessarily part of the clinical presentation.
B. Non-typhi Salmonella is transmitted by:
1. Food
a. Eggs and poultry are most common sources.
b. There are reports of infection from almost any type of food.
2. Fecal-oral contact with infected patients
a. Person-to-person transmission is less common than infection from contaminated food.
b. Bacteria commonly remain in the stool for 4–5 weeks after infection.
3. Animals (reptiles and poultry) known to carry Salmonella species.
Evidence-Based Diagnosis
A. Diagnosis of Salmonella gastroenteritis is made by stool culture or multipathogen molecular assay.
B. Multipathogen molecular assays
1. Sensitivity for Salmonella of 79–96% and specificity of 100%.
2. Results are generally available faster than those from stool culture.
C. Stool culture
1. Still considered the gold standard because sensitivity is close to 100%.
2. Remains the only method of performing susceptibility testing in patients that require treatment.
D. Understanding local laboratory protocols is important to determine what tests are performed when a stool culture is ordered.
Treatment
A. Prevention: Cooking food at adequate temperatures and good hand washing practices prevent most infections.
B. Treatment
1. Most Salmonella infections require no treatment.
2. The patients who should receive therapy beyond supportive care are those who have:
a. Severe disease (dehydration, dysentery, high fever)
b. Immunocompromised status
c. Age greater than 65 years
d. Confirmed or high risk of disseminated infection
(1) Bacteremia
(2) Prosthetic joints or hardware
(3) Sickle cell anemia
e. Typhoid fever
C. Although most patients shed bacteria for weeks after infection, antibiotics should not be used in attempts to prevent transmission. Antibiotics do not shorten the duration of carriage.
CASE RESOLUTION
Mr. C was sent home with directions for oral rehydration. He reported sleeping for most of the afternoon and was well enough to return to work the next day. By the following day (day 4 of the presentation), the patient was completely better. He reported that none of his close contacts became ill.
The patient’s symptoms lasted 48–72 hours. He required no specific therapy. There were no suspicious food exposures and nobody else became ill. The case is consistent with a viral gastroenteritis such as that caused by norovirus. The lack of a suspicious diet history makes a toxin-induced foodborne illness (food poisoning) less likely.
FOLLOW-UP OF MR. C
Two weeks later Mr. C comes to see you again. He attributes his recovery to antibiotics that he took on the day he saw you. (The antibiotics were left over from a prescription he was given for a dental infection.) About 5 days after his recovery, he began to feel poorly again. For the last 10 days he has had diarrhea, abdominal bloating, and belching. He denies fever, chills, nausea, vomiting, or tenesmus. There has been no blood in his stool.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
Key elements in the patient’s current presentation include the 10-day duration of the symptoms, lack of constitutional symptoms, recent gastrointestinal illness, and recent exposure to antibiotics. These key features suggest that both infectious and noninfectious causes should be considered. Both the duration of symptoms and the recent gastroenteritis should raise the possibility of lactose intolerance. Lactose intolerance is common after gastroenteritis due to injury to the small bowel mucosa. Other potential diagnoses include recurrent gastroenteritis, side effect of the antibiotic, and C difficile infection. Recurrent infectious gastroenteritis can occur since many of the bacteria that cause diarrhea can persist in the stool after clinical symptoms have resolved. This feature is especially common with Salmonella and Campylobacter. Antibiotics also have been associated with a paradoxical prolonged carriage rate especially in non-typhoidal Salmonella infections, possibly due to their effect on the intestinal microbiome.
Diarrhea is also a common side effect of antibiotics and complicates as much as 25% of antibiotic courses. Given the recent antibiotic exposure, C difficile infection should also be considered. The prolonged nature of the illness should prompt consideration of the less typical pathogens, such as parasites, but if testing is considered necessary, it should focus on pathogens that may be endemic to the specific regions of exposure. Table 13-5 reviews the differential diagnosis for this presentation. A targeted history focused on association with milk and milk-containing foods or new medications as well as any new exposures or symptoms will help further prioritize the differential diagnosis.
Table 13-5. Diagnostic hypotheses for Mr. C’s repeat visit.
The patient describes 3–4 soft bowel movements a day. He has no abdominal pain, but has bloating and belching. He says he goes to the bathroom 3 or 4 additional times each day just to pass gas.
The patient took 3 doses of amoxicillin on the day he first came to see you. He ran out after these 3 doses. The onset of the diarrhea occurred after completing the antibiotics. He has not traveled since his infection and does not note any unusual exposures. He reports that he had kept to the “BRAT diet” for a couple days after recovery, but started to reintroduce more cereal, rice, potatoes, milk, and yogurt as he began to feel better.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Lactose Intolerance
Textbook Presentation
Lactose intolerance commonly presents with symptoms of belching, bloating, flatulence, and diarrhea. Though usually chronic, the symptoms may be acute or subacute in the setting of recent infection or dietary changes. Symptoms are associated with intake of milk or milk-containing products.
Disease Highlights
A. Lactase is the enzyme that metabolizes lactose.
1. Rarely, it can be deficient at birth.
2. More commonly, it can become deficient with age.
B. It is thought that some ethnicities evolved persistent lactase activity because of the importance of milk products as a calorie source in their environments.
C. Lactose intolerance can be caused by lactase deficiency or lactose malabsorption.
1. Acquired lactase deficiency is most common in people of Asian, African, Middle East, Mediterranean, and Native American ancestry.
2. Secondary lactose malabsorption can occur in the setting of underlying bowel diseases, small intestinal bacterial overgrowth, and infection of the small bowel. This process is more common in people with low levels of lactase activity at baseline.
Lactose intolerance after episodes of gastroenteritis has been reported as high as 50-70% but frequency depends on patient ethnicity.
D. Milk, ice cream, and yogurt have the highest levels of lactose.
E. Foods with high lactose and low fat (skim milk) tend to cause the most symptoms as these foods deliver lactose to the small intestine the fastest.
Evidence-Based Diagnosis
A. The diagnosis of lactose intolerance is made clinically based on a consistent history and resolution of symptoms on a lactose-free diet.
B. More definitive tests, including lactose tolerance test or lactose breath hydrogen test, can be performed in patients in whom the diagnosis is likely but not clear historically.
1. False-negative testing can occur in setting of recent antibiotic use.
2. False-positive testing can occur in the setting of small intestinal bacterial overgrowth.
Treatment
A. Lactose intolerance is treated by decreasing lactose intake.
B. Enzyme supplementation with lactase is often helpful in patients with chronic symptoms.
C. In post-gastroenteritis lactose malabsorption, lactase activity will eventually recover when the intestinal brush border regenerates.
D. Because of the high prevalence of mild lactose intolerance and the frequent exacerbation following gastroenteritis, patients with acute gastroenteritis should be advised to avoid dairy products for 2 weeks after recovery.
MAKING A DIAGNOSIS
On exam he appears well. Vital signs are all normal. His abdominal exam reveals hyperactive bowel sounds with minimal distention. His abdomen is soft and nontender. Rectal exam reveals soft, brown, heme-negative stool.
Have you crossed a diagnostic threshold for the leading hypothesis, lactose intolerance? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Lactose intolerance is most likely, given the high incidence of this condition in patients following episodes of gastroenteritis as well as the history of association with reintroduction of dairy products. The patient is less likely to have an infectious cause of diarrhea due to lack of constitutional signs and symptoms. Although antibiotic side effect should be considered, diarrhea from this cause typically resolves soon after cessation of the antibiotic. Another consideration in a patient who has had a recent antibiotic exposure is C difficile infection. Given the duration of symptoms of greater than 7 days, diarrhea caused by a parasitic infection becomes more of a consideration, but is still unlikely given the low prevalence in the United States.
Alternative Diagnosis: Antibiotic Side Effect
Textbook Presentation
Patients with diarrhea as a side effect of antibiotics typically have watery diarrhea during a course of antibiotics. Upper abdominal symptoms of nausea and vomiting are rare and systemic symptoms should be absent.
Disease Highlights
A. Diarrhea complicates up to 25% of antibiotic courses.
B. Although any antibiotic can be associated with diarrhea, those most commonly responsible for diarrhea are:
1. Clindamycin
2. Cephalosporins
3. Ampicillin, amoxicillin, and amoxicillin-clavulanate
C. Patients with diarrhea caused by side effects of antibiotics usually have mild disease that occurs either during or immediately after a course of antibiotics. Possible causes of this type of diarrhea are numerous:
1. Change in intestinal flora
2. Nonantimicrobial effect of antibiotics such as the promotility effects of erythromycin.
Evidence-Based Diagnosis
A. Diarrhea due to antibiotic use is more likely when certain features are present:
1. History of previous diarrhea associated with antibiotics
2. Mild to moderate symptoms
B. Symptoms almost always resolve shortly after discontinuation of antibiotics.
Treatment
A. Diarrhea as a side effect of antibiotic use usually resolves with discontinuation of antibiotics.
B. Probiotic agents may reduce the risk of antibiotic-associated diarrhea and may shorten an episode once it has occurred.
C. Antidiarrheal agents such as loperamide can provide symptomatic relief.
Alternative Diagnosis: C difficile Infection
Disease Highlights
A. C difficile accounts for 10–20% of diarrhea in the setting of recent antibiotic exposure.
B. C difficile causes diarrhea via toxin-mediated effects on the large bowel, which can present with severe diarrhea, often with abdominal pain and leukocytosis.
C. Risk factors for C difficile include advanced age, hospitalization, antibiotic use, and proton pump inhibitor use.
1. Although C difficile is classically associated with healthcare exposure, the incidence of community-associated C difficile is rising, with up to 41% of all cases of C difficile being community-associated in some areas.
2. C difficile should also be suspected in hospitalized patients with unexplained leucocytosis.
3. C difficile has been associated with almost every antibiotic. Those associated with the highest risk of C difficile include clindamycin, fluoroquinolones, and third- and fourth-generation cephalosporins.
Evidence-Based Diagnosis
1. Polymerase chain reaction (PCR) has become the diagnostic standard with sensitivity ≥ 90% and specificity ≥ 97%. PCR can be performed alone or using an algorithm that includes screening with enzyme immunoassay for glutamate dehydrogenase and toxins A and B.
2. Diagnosis can also be confirmed by direct visualization of pseudomembranous colitis on colonoscopy or sigmoidoscopy.
3. Culture, although highly sensitive and specific, is not frequently used because it is slow and because it also isolates non-toxin–producing strains of C difficile that are not clinically relevant.
Treatment
A. 2018 guidelines recommend oral vancomycin or fidaxomicin for initial episodes of C difficile.
B. Relapse complicates 20–25% of cases of treated C difficile.
1. An initial relapse should be treated with vancomycin or fidaxomicin.
2. For subsequent recurrences, various regimens are recommended including prolonged courses of oral vancomycin with a taper, use of fidaxomicin, or fecal microbiota transplantation.
C. Surgical therapy, such as colectomy, is sometimes necessary for patients with perforation, toxic megacolon, or severe infection.
D. When possible, patients with C difficile infection should discontinue antibiotics.
E. Antidiarrheal medications should be avoided because of risk of development of ileus or toxic megacolon.
Alternative Diagnosis: Giardia lamblia (also known as Giardia intestinalis or Giardia duodenalis)
Textbook Presentation
Giardiasis can present as either acute or chronic diarrhea. It usually occurs in patients with exposure to infected water supplies, although person-to-person transmission can occur. Symptoms usually include diarrhea, nausea, abdominal cramps, bloating, flatulence, and foul-smelling stools. Fever is uncommon.
Disease Highlights
A. Giardia is the most common parasitic cause of diarrhea in the United States.
B. Most infections in the United States result from ingestion of contaminated water from streams and lakes but can also be transmitted by foodborne and fecal-oral routes.
C. Incidence peaks annually during the summer and early fall when people most commonly participate in water sports and camping.
D. Although usually sporadic, there are occasional outbreaks related to contamination of bodies of water used for recreation and drinking supplies.
E. Common symptoms
1. Diarrhea occurs in 96% of cases.
2. Weight loss is present in 62% of cases.
3. Abdominal cramps occur in 61% of cases.
4. Greasy stools are present in 57% of cases.
5. Belching, flatulence, and foul-smelling stools are commonly reported.
F. Fever is uncommon.
Evidence-Based Diagnosis
A. Enzyme immunoassay has a sensitivity of over 90%.
B. Sensitivity of microscopic examination of stool for ova is 50–70% for 1 stool sample and 90% for 3 samples.
Treatment
A. The treatment of choice for G lamblia infection is oral metronidazole.
B. If a patient has recurrence or severe disease with Giardia, immunosuppression (including HIV infection or immunoglobulin deficiency) should be suspected.
CASE RESOLUTION
A lactose-free diet was recommended for the patient. PCR testing for C difficile was negative. The suspicion for a recurrent bacterial infection or a parasitic infection was very low. The patient began a lactose-free diet and was better within 3 days. After 2 weeks, he slowly reintroduced his usual diet without symptoms.
CHIEF COMPLAINT
PATIENT
Mr. V is a 35-year-old man who is admitted to your acute-care hospital after presenting with 4 days of diarrhea. He reports feeling tired and weak. He is having 6–8 bowel movements a day. He says that he has significant abdominal pain. On the day of admission, he began to pass bloody stools. On physical exam, his vital signs are temperature, 38.3°C; BP, 130/84 mm Hg; pulse, 90 bpm; RR, 12 breaths per minute. He is orthostatic. His abdomen has hyperactive bowel sounds. It is diffusely tender, without peritoneal signs. His stool is a mixture of loose brown stool and blood.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
The pivotal points in this case are the presence of bloody diarrhea, abdominal pain, and fever. Bacterial pathogens are much more likely than other pathogens to cause bloody diarrhea. The bacteria that commonly cause bloody diarrhea are Shigella species, Campylobacter species, and E coli. Salmonella species, Y enterocolitica, and C difficile also may cause bloody diarrhea. Noninfectious causes, such as ischemia or an initial presentation of inflammatory bowel disease, should also be considered.
Clinically, it is impossible to differentiate, with certainty, between the different causes of bacterial diarrhea, but a careful history focused on potential exposures and risk factors as well as the knowledge of the epidemiology of the relevant infections can help prioritize the differential diagnosis. Table 13-6 lists the differential diagnosis.
Table 13-6. Diagnostic hypotheses for Mr. V.
The patient’s diarrhea began 4 days prior to admission. The diarrhea was watery and was accompanied by abdominal cramping. He also had a low-grade fever. On the day of admission, he began to have blood in his stool.
Mr. V is an accountant and traveled to a conference in San Diego 7 days ago. He has not had any international travel. He has sex with men only and engages in anal receptive and anal insertive intercourse. He has had three sexual partners in the past 6 months and only occasionally uses barrier protection. He has not eaten any undercooked meat or poultry, and he has not had any animal contact in the past 6 months.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Shigella Infection
Textbook Presentation
Shigella infection often presents with fever and constitutional symptoms. Diarrhea is initially watery and may become bloody. The diarrhea can be frequent. Tenesmus is often present.
Disease Highlights
A. Shigella has been reported to be the most common cause of bloody diarrhea in the United States.
B. There have been outbreaks of Shigella in people who engage in anal-genital or anal-oral sexual intercourse.
C. Although there is a spectrum of disease, a patient who is systemically ill with classic dysentery (frequent bloody stools with tenesmus) is most likely to have Shigella infection.
Evidence-Based Diagnosis
A. Similar to the case with Salmonella (discussed earlier) both PCR testing (as part of multipathogen molecular panels) or stool culture can be used to diagnose Shigella.
B. PCR testing is associated with high sensitivity (93–97%) and specificity (98–100%) for detecting Shigella species.
C. Stool culture allows for susceptibility testing. Because of increasing rates of antibiotic resistance, particularly in men who have sex with men, culture should be performed in addition to molecular testing.
D. Understanding local laboratory protocols is important to determine what tests are performed when a stool culture is ordered.
Treatment
A. Shigella dysentery benefits from treatment, by shortening the duration of symptoms and decreasing bacterial shedding.
B. Ciprofloxacin is a reasonable empiric treatment option, but selection of an antibiotic should be based on susceptibility testing as well as knowledge of local resistance patterns in target populations as a result of increasing antibiotic resistance.
Alternative Hypothesis: Campylobacter Infection
Textbook Presentation
Presenting symptoms of Campylobacter infection are usually diarrhea and abdominal pain. The diarrhea is often profuse and watery and preceded by fever. The fever usually resolves over the first 2 days of the illness, while the diarrhea and abdominal pain may last 4–6 days.
Disease Highlights
A. Campylobacter species are among the most commonly isolated bacterial pathogens in patients with diarrhea and the second most common causes of bloody diarrhea behind Shigella species.
B. Campylobacter species can be carried by domestic animals such as birds and farm animals (eg, pigs), and they can be found in undercooked meat and poultry.
C. Campylobacter rarely can be transmitted from person-to-person, including through genital-anal, oral-anal, and digital-anal contact.
D. Common aspects of the presentation are
1. Constitutional symptoms, including fever, occur before gastrointestinal symptoms.
2. Bloody diarrhea may occur after 2–3 days of watery diarrhea in a small percentage of patients.
3. Diarrhea is often associated with abdominal pain and can be severe, sometimes mimicking appendicitis.
E. Campylobacter infection can rarely be associated with extraintestinal complications, such as reactive arthritis and Guillain-Barré syndrome.
F. Bacteria commonly remain in the stool for 4–5 weeks and reinfection can occur.
Evidence-Based Diagnosis
A. Stool cultures with selective media for Campylobacter can make the diagnosis, but sensitivity is lower compared to other bacterial pathogens (37-70%).
B. PCR testing is increasing in clinical settings and has much higher sensitivity (93-97%) for Campylobacter than culture; however, PCR testing does not provide susceptibility data, which can be performed only on positive cultures.
Organisms that are generally associated with dysentery (Shigella, Campylobacter, Shiga toxin-producing E coli) are at least as likely to cause non-bloody diarrhea and a gastroenteritis-type illness, so the absence of bloody diarrhea does not rule out these diagnoses.
Treatment
A. Most cases of Campylobacter infection do not require antibiotics and are self-limited.
B. Patients with severe symptoms (see Figure 13-1) should be treated with antibiotics.
C. Fluoroquinolone or macrolide antibiotics can be used as empiric therapy, but resistance is increasing so choice should be based on local susceptibility patterns and results of antibiotic susceptibility testing.
Antidiarrheals should never be used for patients with dysentery or signs of invasive infection (tenesmus, blood or mucus in stool, high fever, and severe abdominal pain).
Alternative Diagnosis: Shiga toxin–producing E coli (STEC)
Textbook Presentation
STEC usually presents with diarrhea and abdominal pain. The pain is often worse in the right lower quadrant. Bloody diarrhea is very common, while nausea, vomiting, and fever are not.
Disease Highlights
A. Nomenclature
1. STEC is a strain of E coli that produces Shiga toxin.
2. STEC is also called enterohemorrhagic E coli (EHEC).
3. The most common strain of STEC in the United States is O157:H7.
4. Other than STEC, there are 4 types of E coli that cause diarrheal illness in adults.
a. Enterotoxigenic E coli (ETEC) is a common cause of travelers’ diarrhea that causes symptoms through elaboration of a toxin.
b. Enteropathogenic E coli (EPEC) is a common cause of watery diarrhea in adults and children.
c. Enteroinvasive E coli (EIEC) causes bloody diarrhea with tenesmus similar to Shigella.
d. Enteroaggregative E coli (EAEC) is a common cause of diarrhea in children and travelers’ diarrhea.
B. STEC is most commonly associated with undercooked beef, but it can also be found in fecally contaminated food products such as produce, fruit products, and dairy products.
C. STEC can also be transmitted by direct contact with infected people and livestock.
D. Symptoms of STEC include bloody diarrhea, abdominal pain, and absence of fever.
E. STEC can cause hemolytic uremic syndrome (HUS), a condition that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.
Evidence-Based Diagnosis
A. Patients infected with STEC are significantly more likely than patients infected with other pathogens to:
1. Report bloody diarrhea and provide visibly bloody specimens
2. Lack fever
3. Have abdominal tenderness
4. Have a white blood cell count > 10,000/mcL
B. Positive culture for STEC, detection of Shiga toxin by immunoassay, or detection of Shiga toxin gene by nucleic acid amplification testing is considered diagnostic.
1. Selective culture media for STEC is required for growth.
2. Multipathogen molecular testing panels have demonstrated high sensitivity (91-100%) and specificity (97–100%) for STEC.
C. Some microbiology laboratories perform testing for STEC with routine stool testing, but culture and toxin testing for STEC may need to be specifically requested in other microbiology laboratories.
Treatment
A. Treatment of STEC is controversial.
B. Antibiotics have demonstrated mixed results in studies, but there is a concern for increased risk of HUS with their use.
MAKING A DIAGNOSIS
Mr. V is given intravenous fluids (because of the orthostatic hypotension) and acetaminophen. A complete blood count and basic metabolic panel are normal. Orthostatic symptoms resolve with intravenous fluids.
Have you crossed a diagnostic threshold for the leading hypothesis, Shigella infection? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Because most infectious diarrhea is self-limited, stool cultures and other directed testing for bacterial pathogens do not need to be performed on every patient. Testing should be selective in order to facilitate pathogen detection in groups that benefit the most, while decreasing likelihood of false-positive testing. Details of testing strategies are included in Table 13-7.
Table 13-7. Testing for specific causative pathogens of diarrhea.
Many laboratories are now using multipathogen gastrointestinal panels, which identify a range of bacterial, viral, and parasitic causes of diarrhea from a single specimen. These tests are often more sensitive than non-molecular tests and do not require clinicians to order different tests for each suspected pathogen. However, these methods are not able to determine antibiotic susceptibility, so some pathogens identified by these panels require a reflex culture.
Patients who may benefit the most from treatment and are highest yield for diagnostic testing include:
A. Patients with severe illness (bloody stool, fever, severe abdominal pain, > 6 bowel movements per day, hypovolemia, and need for hospitalization);
B. Specific exposures that increase risk of pathogens that benefit from treatment (travel, high-risk sexual encounters, antibiotics);
C. Patients with conditions that increase the risk of complications (immunosuppression, inflammatory bowel disease, pregnancy, and advanced age); and
D. Situations with public health implications (confirmed or possible outbreak or patients who are at high risk for spreading disease, such as healthcare workers, food handlers, and childcare workers).
In the past, testing for fecal leukocytes has been recommended in the diagnostic work-up of acute diarrhea with the highest reported sensitivity for infectious or inflammatory diarrhea of 71–73% and specificity of 79–84%. However, the performance characteristics are widely variable in different settings. In addition, this test is not diagnostic of a particular infection and does not generally change management or outcomes. Therefore, fecal leukocyte testing should not be used routinely in the diagnostic work-up of acute diarrhea. Fecal lactoferrin and calprotectin are newer tests that have been used for the diagnosis of inflammatory diarrhea, but there is insufficient evidence to support their routine clinical use for guiding the management and diagnostic testing for acute diarrhea.
Although Shigella infection is most likely in this case, diagnostic testing should be performed because other pathogens including Campylobacter and STEC are still possible, and the management of these pathogens is different.
CASE RESOLUTION
The patient was treated with supportive therapy. Antidiarrheals were withheld because of his bloody diarrhea. Ciprofloxacin was prescribed empirically due to his severe symptoms. His stool was sent for multipathogen molecular testing, which identified Shigella. Reflex culture grew Shigella flexneri that was susceptible to ciprofloxacin.
In this case, the acute and bloody nature of the diarrhea allowed for the differential diagnosis to be focused on specific pathogens using the initial approach presented in this chapter. Epidemiologic factors, symptoms, and exposures allowed for further focusing of the differential diagnosis, which, in turn guided the appropriate diagnostic and therapeutic monitoring.
REVIEW OF OTHER IMPORTANT DISEASES
Travelers’ Diarrhea
Textbook Presentation
Patients with travelers’ diarrhea usually become ill in the first 5 days of their trip from resource-rich regions to resource-limited ones. They usually have mild symptoms of a gastroenteritis-like illness. Patients are often better by the time they return home.
Disease Highlights
A. There are up to 10 million cases in the United States reported yearly.
B. The highest risk destinations for travelers’ diarrhea are in Asia, Africa, and South and Central America.
C. The disease usually occurs in the first 5 days (with a peak onset at 4 days) and resolves in 1–5 days.
D. Symptoms are usually mild to moderate but more severe symptoms can occur.
E. Although the predominant cause of travelers’ diarrhea is enterotoxigenic E coli (ETEC), any bacteria, virus, or parasite can be a causative pathogen. The local epidemiology of gastrointestinal pathogens is important to inform the differential diagnoses in these cases.
Treatment
A. Prevention
1. Ensure clean water
a. Boiled, filtered, or chemically purified local water or bottled water.
b. Ice and mixed drinks can be made with contaminated water.
c. Ensure bottled water is sealed and not just bottled tap water.
2. Fruit, vegetables, and table-top sauces are also sources of travelers’ diarrhea.
3. Gastric acidity is natural prevention; temporarily discontinue proton pump inhibitors or H2-blockers if safe to do so.
4. Prophylactic antibiotics
a. Antibiotic prophylaxis is not typically recommended for travelers unless they are at very high risk for complications, such as those with severe immunosuppression or inflammatory bowel disease.
b. Rifaximin, ciprofloxacin, or bismuth subsalicylate can be used for prophylaxis in high-risk travelers.
c. When used, antibiotics are at least 80% effective at preventing travelers’ diarrhea, but there is increasing antibiotic resistance in many regions of the world.
B. Treatment
1. Antibiotics are effective at decreasing duration of symptoms.
a. Ciprofloxacin and azithromycin are the preferred agents, but ultimate choice should depend on resistance rates in the area of travel.
b. Antibiotics should be provided to travelers to take at first signs of gastrointestinal symptoms.
2. Consider causes of travelers’ diarrhea other than ETEC (such as giardiasis, amebiasis), which require different therapies, especially if symptoms do not respond to empiric treatment.
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