Diarrhea
by Mark Bowers
Diarrhea is the greatest source of morbidity and mortality worldwide.
It is also a common complaint in HIV disease. Christina Surawicz, MD,
writing for Scientific American Medicine, estimates that diarrhea
occurs in up to 80% of persons with AIDS.
There are many possible causes of diarrhea, including common bacterial
and parasitic infections, and uncommon opportunistic infections such as
cryptosporidiosis, microsporidiosis, Mycobacterium avium complex
(MAC) and cytomegalovirus (CMV) colitis. Diarrhea may follow a course
of antibiotics, it may be a side effect of several drugs used to treat
HIV, or it may simply accompany HIV infection, particularly during primary
HIV infection. In the later stages of HIV infection, diarrhea is thought
to be a reflection of changes in the way the intestinal tract absorbs
nutrients, and may be an important component of HIV-related wasting. In
all cases, diarrhea is a clear symptom of an underlying problem.
The cause of diarrhea needs to be determined before treatment begins.
There are many choices of antidiarrheal drugs, each appropriate in certain
circumstances. Some alternative strategies may be chosen to control occasional
mild diarrhea. Over-the-counter medications can control limited bouts
of diarrhea in certain circumstances. Chronic, severe diarrhea always
requires a physician's immediate attention. Widely accepted strategies
can correct the dehydration and electrolyte imbalances that may accompany
diarrhea. This article includes more information about each of these issues.
What is Diarrhea?
Diarrhea refers to increased water content in the stool as compared with
usual individual patterns. Frequency and volume of stool are also increased.
Most people's experience with short-term diarrhea comes after drinking
contaminated water or eating contaminated food ("food poisoning"),
and the condition spontaneously clears up in a few days. Chronic diarrhea
interferes with activities of daily living, may produce light-headedness
or pain, and may be accompanied by fever or nausea. Chronic diarrhea lasting
more than 3 days requires consultation with a physician.
Diarrhea is usually a response to infection with one of many bacteria,
mycobacteria, parasites or viruses. Intestinal infections are common in
people with HIV, so physicians try to isolate and treat them. Simple infections
in people with compromised immune systems may not resolve quickly, as
they do normally, and intestinal flora (normal bacteria) that are no problem
for HIV uninfected individuals can be very difficult to control in people
who are HIV positive.
Diarrhea can be caused by changes or infection at any level of the digestive
tract. After food is swallowed, it passes down the esophagus into the
stomach, where it is broken up by hydrochloric acid to become chyme, a
semi-liquid that moves on to the duodenum (the first part of the small
intestine). Here, digestive enzymes from the gallbladder, liver and pancreas
break the chyme down further. The contents next move to the remainder
of the small intestine, where nutrients are absorbed, moving into blood
vessels and lymph vessels lining the intestine. Malabsorption creates
the potential for diarrhea at this stage. Most of the water is removed
from undigested material in the large intestine, the final stretch before
the rectum, from which excrement is expelled. Material remains in the
large intestine from 10 hours to several days.
Infection or inflammation of the digestive tract is named for the site
where it occurs. Esophagitis is infection of the esophagus, or swallowing
tube. Enteritis describes infection of the small intestine, and usually
involves diarrhea. Colitis is infection of the colon (large intestine)
that causes diarrhea, usually with visible blood and mucus. Proctitis
is inflammation of the rectum, usually caused by gonorrhea or another
sexually transmitted disease.
Food is propelled through the digestive tract by peristalsis, rhythmic
contractions of muscles surrounding the digestive tube. An increase in
the overall rate of peristalsis can result in diarrhea, because it leaves
insufficient time for the large intestine to extract water from food passing
through the digestive tract. Some prescription drugs slow the rate of
peristalsis to compensate for shortened "transit time," the
time required for food to be completely processed and waste expelled from
the body. Use of these drugs is largely confined to diarrhea of a non-infectious
origin, since slowing peristalsis would allow some infections to thrive
and can lengthen the time a person has symptoms.
Some people with chronic diarrhea have irritable bowel syndrome, Crohn's
disease, food intolerance or food allergy syndromes. Along with processing
and transporting nutrients from the gut to the blood or lymph systems,
the epithelium (lining) of the gastrointestinal tract has concentrated
regions of immune cells called Peyer's patches that continuously sample
the contents of the gut for antigens.
Reactions to these antigens range from immediate, severe responses (such
as life-threatening anaphylaxis) to delayed hypersensitivity and increased
permeability (leakiness) of the gut wall. Reaction to HIV antigens may
similarly cause increased permeability, and the gut may leak nutrients
rather than absorb them. Watery stools are characteristic of increased
permeability. Blood in the diarrhea is worrisome, and should be evaluated
by a physician. High fat content in the diarrhea (steatorrhea) suggests
malabsorption or chronic pancreatic disease. A first and frequently successful
strategy to relieve diarrhea in people with these conditions is diet revision.
Diagnosing the Cause
Looking at symptoms can help determine the origin of diarrhea. Frequent
small-volume stools with blood and pus, lower abdominal pain and an unproductive
urge to defecate suggest colitis, while infections of the small intestine
more commonly produce large-volume diarrhea without blood, generalized
abdominal cramps and possible dehydration.
The evaluation of chronic diarrhea is based on whether it is watery,
bloody, full of fat or accompanied by fever. For diarrhea that is watery,
HIV-experienced physicians will look for the presence of white blood cells
and may do a stool culture. If there are substantial numbers of white
cells, it is likely that the cause of diarrhea is a bacterial infection,
for example with Salmonella, Shigella, Listeria, Campylobacter
or Escherichia coli. Since it is difficult to distinguish these
bacteria from one another without laboratory testing, many physicians
presumptively begin treatment (with a fluoroquinolone antibiotic [such
as ciprofloxacin] or with trimethoprim-sulfamethoxazole [Bactrim or Septra]).
If the diarrhea and other symptoms clear up in response to the medication,
no further investigation is usually necessary.
Diarrhea that can be traced to Clostridium difficile infection
is common among HIV positive people who have just completed a course of
antibiotic therapy. Relapses are also common. Diagnosis of C. difficile
infection depends on finding a specific toxin in stool cultures. HIV physicians
tend to treat C. difficile aggressively with oral metronidazole
(Flagyl), 250 mg 4 times a day for 10 days. Vancomycin is an expensive
alternative, but a better option if a patient is taking ritonavir, because
of the potential for drug interactions with metronidazole.
ANTIBIOTICS
THAT COMMONLY PRECIPITATE CLOSTRIDIUM DIFFICILE DIARRHEA
Often: ampicillin/amoxicillin, cephalosporins
(Keflex, others), Clindamycin (Cleocin) Sometimes:
erythromycin, tetracyclines, trimethoprim, sulfonamides
An increasingly important infectious cause of diarrhea among HIV positive
individuals is Escherichia coli (E. coli), particularly
the O157:H7 strain. E. coli normally live in most people's digestive
tract. Each strain produces a characteristic toxin, and most people are
unreactive to the strains of E. coli usually found in their community.
Community outbreaks of E. coli are usually traced to food (e.g.,
undercooked hamburger meat, salami or unpasteurized milk or juice) contaminated
with strains to which most people have not developed resistance. The incubation
period (the time during which the infection is established) is several
days, characterized by pain in the left side. A special laboratory test
is run to diagnose E. coli. The usefulness of treatment of the
infection is not clear, however treatment for electrolyte imbalance, dehydration
and possible kidney failure may be necessary.
Salmonella and Campylobacter are usually acquired by
eating contaminated or undercooked food, especially poultry, eggs and
dairy products. The incubation period is 1-6 days, during which there
are severe, intermittent cramps and watery, foul-smelling stools. There
may be pus and blood in the stool, nausea and vomiting, and chills and
fever (100.5-102 degrees F). Symptoms are considerable for 6-8 hours,
but diarrhea and other symptoms may last for 7-10 days. Dehydration can
become an important issue (see below). Drugs that slow peristalsis are
not usually given since they may produce intestinal paralysis and may
increase or extend fever. Food handlers must have a documented resolution
of Salmonella infection before they return to work.
Protozoans are parasites of the intestinal tract that account for the
highest percentage of detectable infections that lead to diarrhea in people
with HIV in developed countries. Cryptosporidia and microsporidia each
account for about 20% of cases, while Giardia lamblia accounts
for 4.9%, Entamoeba histolytica for 2.6% and Isospora belli
for 1.5%. Physicians request that 3 stool samples (1 per day for
3 days) be tested for ova and parasites (O & P) to detect these pathogens.
The detection of Isospora belli requires a special staining procedure
and sometimes a small bowel biopsy. Strongyloides is a parasitic
infection that can be a severe problem in people with compromised immune
systems and may be accompanied by bloating, pain and blood in the stool.
A viral infection that sometimes produces problematic diarrhea in people
with HIV is cytomegalovirus (CMV) colitis (particularly among those with
fewer than 100 CD4 cells/mm3), a disease characterized by perforations,
ulcerations or diffuse bleeding in or beneath the surface of the mucous
membrane of the colon or rectum. Bleeding, weight loss, anorexia (lack
of appetite) and fever often accompany CMV colitis. A colonoscopy procedure,
in which a flexible viewing tube is inserted into the rectum, will often
be performed to obtain tissue samples that can be tested for the presence
of CMV.
Another opportunistic infection that frequently results in diarrhea is
Mycobacterium avium complex (MAC). MAC usually occurs among people
with fewer than 50 CD4 cells/mm3, although it has been diagnosed
in people whose CD4 cell counts have recently risen as a result of combination
therapy with a protease inhibitor. MAC diarrhea is usually non-inflammatory
and is accompanied by fever, abdominal pain and unwanted weight loss (wasting).
Drugs and other causes account for significant short-term and long-term
diarrhea in susceptible HIV positive individuals. Diarrhea is the side
effect most commonly associated with the protease inhibitor drug nelfinavir
(Viracept, from Agouron Pharmaceuticals). Agouron reports that over-the-counter
medications such as Imodium AD control diarrhea until people get used
to the medication, at which time the symptom resolves. Ritonavir (Norvir,
from Abbott Pharmaceuticals) is also associated with significant rates
of diarrhea, at least initially, as are ddI (Videx) and macrolide antibiotics
such as clarithromycin (Biaxin) or azithromycin (Zithromax).
Although it might seem a reasonable strategy to solve the problem of
drug-associated diarrhea by simply stopping the drug, this may not be
wise. Protease inhibitor drugs must be taken on schedule if they are to
be effective and if the development of drug-resistant HIV is to be avoided.
Drug holidays make it easier for HIV to mutate and develop resistance
to the drug, so most HIV physicians either substitute another protease
inhibitor drug or "treat through" short bouts of diarrhea, giving
mild antidiarrheal agents until the symptom resolves, usually in a few
weeks.
REPORTED
RATES OF DIARRHEA AS A SIDE EFFECT OF ANTI-HIV DRUGS
(generic drug name, brand name, rate of diarrhea)
Foscarnet (Foscavir) -- 30%.
Interferon alfa (Roferon, Intron) -- 29%
Nelfinavir (Viracept) -- 25-30%. Usual treatment: OTC preparations
ddI (Videx) -- 17-28%
Ritonavir (Norvir) -- 12-18%. Usual treatment: OTC preparations
ddC (Hivid) 10%
DIARRHEA
CAUSED BY BACTERIAL AND OTHER INFECTIONS IN AIDS
In order of most to least prevalent
Cryptosporidium parvum -- treatment: paromomycin (Humatin),
bovine colostrum*, nitazoxanide*, GM-CSF* (Leukine), allicin*; symptomatic
relief: octreotide, anti-motility agents
Microsporidia
- E. bieneusi -- treatment: no standard
- S. intestinalis -- treatment: albendazole*; symptomatic relief:
anti-motility agents
Cytomegalovirus (colitis) -- treatment: ganciclovir, foscarnet combinations,
cidofovir
Mycobacterium avium complex (MAC) -- treatment: rifabutin (prophylactic),
clarithromycin or azithromycin plus ethambutol
Giardia lamblia -- treatment: metronidazole (flagyl)
Entamoeba histolytica -- treatment: metronidazole (flagyl);
symptomatic relief: loperamide
Campylobacter -- treatment: erythromycin or ciprofloxacin, norfloxacin
or azithromycin; symptomatic relief: loperamide
Salmonella -- treatment: ciprofloxacin or TMP-SMX; symptomatic
relief: loperamide
Shigella -- treatment: ciprofloxacin or TMP-SMX; symptomatic
relief: loperamide
Clostridium difficile -- treatment: metronidazole (flagyl);
symptomatic relief: avoid anti-motility agents
Isospora belli -- treatment: TMP-SMX
E. coli -- treatment: ciprofloxacin
Chlamydia trachomatis -- treatment: ceftriaxone plus azithromycin,
or doxycycline
Vibrio parahaemolyticus -- treatment: doxycycline, ciprofloxacin
or TMP-SMX
Herpes simplex -- treatment: acyclovir
* indicates experimental therapy, not FDA-approved
DIAGNOSTIC
QUESTIONS A PHYSICIAN MAY ASK
Question: Have you had diarrhea for more than 1 week?
Follow up: Do you have it when you are under emotional stress? (Continued
stress may cause diarrhea in some people.)
Question: Is there blood in your stool?
Follow-up: Is the blood black and tarry or red? (A follow-up test will
be done to confirm.)
Question: Are you nauseous or vomiting and have you had a fever?
Follow-up: Did you eat any questionable foods, go camping or travel abroad
recently? (You may have "travelers' diarrhea.")
Question: Have you recently started taking any new medicines or herbal
preparations?
Follow-up: Will you let the laboratory analyze a sample? (You may need
to change over-the-counter drugs or stop taking herbs.)
Question: Have you recently eaten food that could have turned bad or
to which you might be allergic?
Follow-up: Have others who ate the same food also developed diarrhea?
(You may have "food poisoning.")
Treatment Choices
There are many strategies to control diarrhea. In HIV disease, most clinicians
who suspect an infectious source for diarrhea begin immediate empirical
antibiotic therapy for diarrhea within 3 days of the onset. Choice of
antibiotic therapy is frequently difficult. The first choice for treatment
is often one of the fluoroquinolones, usually ciprofloxacin (Cipro). The
second choice is trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim or Septra).
Both drugs successfully treat the underlying bacterial infections most
commonly associated with diarrhea, Shigella, Salmonella and Campylobacter.
The severity of diarrhea helps to determine an appropriate response.
Mild diarrhea, defined as fewer than 4 unformed stools per day, is usually
not treated. Fluids such as Gatorade are given to assure that electrolytes
remain in balance and dehydration does not become a problem (see "Other
Concerns," below). Moderate diarrhea, or 4 or more unformed stools
a day with some other symptoms, is often treated with bulk-forming agents
(such as psyllium [Metamucil]) or antimotility agents that slow the rate
of peristalsis. Severe diarrhea is treated with appropriate antibiotics.
An important exception is the treatment of diarrhea associated with C.
difficile colitis. Antibiotics other than metronidazole are discontinued,
if possible. (Note that when alcohol is consumed within 24 hours of taking
metronidazole, severe vomiting results; ritonavir contains alcohol, and
patients taking ritonavir should not be given metronidazole.) Relapses
are treated with metronidazole again, or with 125 mg of Vancomycin 4 times
a day, 25 units of bacitracin 4 times a day or 4 grams of cholestyramine
4 times a day. Cholestyramine and vancomycin are not given together.
Moderate diarrhea can often be managed with over-the-counter medications.
Bismuth subsalicylate (Pepto-Bismol), attapulgite (Kaopectate) and loperamide
(Imodium AD) may be tried first, followed by prescription drugs such as
codeine, diphenoxylate (Lomotil) or paregoric (tincture of opium). For
more severe cases of diarrhea, particularly when a patient is hospitalized,
a physician may administer octreotide (Sandostatin) 50-200 mcg 3 times
a day by subcutaneous injection or through an intravenous line at a rate
of 1 mcg/hour. Another strategy is to provide bowel rest through total
parenteral nutrition.
Protozoal infections, when properly identified, are treated with a variety
of drugs. Entamoeba histolytica (amebas) is treated with 500
mg of paromomycin (Humatin) 3 times a day for a week. Iodoquinol (Yodoquinol),
available from Glenwood Inc. (83 Summit Street, Tenafly NJ 07670; phone
201 569-0050), is another option, although treatment times are typically
much longer -- 20 days or more. Another option is 500 mg of Diloxanide
furoate (Furamide) 3 times a day for 10 days.
Cryptosporidial diarrhea that does not respond to the standard or experimental
therapies may become chronic and severe. An option for such individuals
is octreotide at 50-200 mcg 3 times a day injected subcutaneously, or
intravenously at 1 mcg/hour. Patients taking octreotide should be monitored
carefully, because the drug can induce malabsorptive diarrhea. Recent
studies of the experimental drug nitazoxanide suggest that it significantly
decreased Cryptosporidium-associated diarrhea. Most encouragingly,
investigators from France, Australia and Rhode Island reported at the
4th Conference on Retroviruses and Opportunistic Infections in January
that combination antiretroviral therapy including a protease inhibitor
drug (either ritonavir or indinavir) stopped cryptosporidial diarrhea
and cleared the infection in 18 people.
Microsporidia are parasites that are increasingly recognized as a cause
of diarrhea in HIV positive individuals. Two species, Enterocytozoon
bieneusi and Septata intestinalis, are prevalent in HIV-infected
individuals. Clinical studies show that albendazole is promising for S.
intestinalis, but there is no standard therapy for E. bieneusi.
A low-fat, low-residue diet with simple carbohydrates reduced stool volume
and frequency in 8 of 9 people with E. bieneusi in whom this
strategy was tried. From 200-400 mg of albendazole twice a day for 1 month
was reported to reduce the average number of stools per day from 7 to
3.8.
CMV colitis is treated with ganciclovir (Cytovene) or foscarnet (Foscavir).
Foscarnet causes diarrhea in up to 30% of people who take it, so ganciclovir
may have a clear advantage in the treatment of colitis. CMV disease has
not yet been convincingly shown to respond well to combination therapy
with protease inhibitor drugs.
MAC disease is most common among individuals with fewer than 50-75 CD4
cells/mm3. Combinations of drugs have varying degrees of success
in treating MAC (see MAC article in the
December 1996 issue of BETA). Recent reports suggest that MAC can be a
problem even when CD4 cell counts rise above the "danger zone"
in response to combination antiretroviral therapy, suggesting that physicians
should look for unrecognized or subclinical MAC in patients who are about
to start protease inhibitors. Another complication is that rifabutin,
a cornerstone MAC prophylaxis, interacts unfavorably with protease inhibitor
drugs.
Common bacterial pathogens can be more problematic in HIV positive people
than in others. See the chart on page 31 for treatment recommendations.
Note that not all possible treatments are mentioned, and that potential
drug interactions are not addressed. Do not self-medicate; consult
your physician before treating diarrhea with antibiotics or over-the-counter
medications.
Prevention
Prevention of infections that may cause diarrhea is important. Through
safer sex and use of clean needles, most infections that have diarrhea
as a symptom can be avoided. Sex partners should be notified of infections
and treated to prevent reinfection and further spread. Travelers, backpackers
and hikers can reduce their chances of infection by relying on bottled
water and avoiding previously peeled fruits and salads containing leafy
vegetables. Safe food handling can reduce the risk of infection with many
common diarrhea-producing pathogens (see Food Safety
Guidelines in this issue).
Complementary and Dietary Treatment Options
The long history of diarrhea among human beings is accompanied by an
equally long history of attempts to control the condition by any means
available.
Saccharomyces boulardii is a yeast that has been effective in
decreasing diarrhea associated with C. difficile infection. It
is available in buyers' clubs and some health food stores. Clinical data
are scant, but collected anecdotal evidence suggests wide use in community
settings. Naturopaths recommend preventing diarrhea by taking acidophilus
capsules and organic garlic capsules. Acidophilus culture (similar to
yogurt) "replaces and fortifies normal intestinal flora." Peppermint
oil, tea and extract and linden tea have all been used to control diarrhea.
Traditional Chinese Medicine (TCM) relies on herbs and acupuncture for
the control of diarrhea. A diagnostic procedure establishes the source
of diarrhea and prescribes mixtures of herbs that may be boiled and drunk
to combat the symptom. A first step is the trial elimination of milk products
to determine if the diarrhea can be traced to lactose intolerance. Diarrhea
that persists is differentiated into as many as 20 types. For each type,
specific acupuncture points may be stimulated or various herbs may be
prescribed. In an attempt to validate or disprove an element of TCM, the
Community Consortium in San Francisco (415-502-0658) is conducting a pilot
study of Chinese herbs (Source Qi, containing 28 different herbs) for
the treatment of chronic diarrhea in people who test negative for pathogens.
Herbalists have assembled a long list of herbs that can slow diarrhea
and promote the formation of normal stool. High fiber treatments that
provide bulk (psyllium) have penetrated the over-the-counter market and
are available in most pharmacies.
Physicians often recommend dietary restriction to patients with chronic
diarrhea. Some recipes are ancient: the BRATT diet (bananas, rice, applesauce,
toast and tea) has been recommended for decades, while the use of rice
water and flaxseed can be traced back thousands of years. A modern understanding
of dietary factors that may worsen diarrhea includes lactose (from milk
products), fructose (from apple juice, pear juice, grapes, honey, dates,
nuts, figs and soft drinks), sucrose (from table sugar), sorbitol, hexol
or mannitol (from Òsugar-freeÓ products), magnesium-containing antacids,
vitamin C and caffeine (from coffee, tea, colas, and headache remedies).
Other Concerns
Dehydration
and Electrolyte Loss
Extensive water loss is potentially a serious problem for anyone with
severe diarrhea, but is particularly life-threatening in infants and small
children. Adults normally lose 1,500-2,000 mL per day of water through
urination and perspiration, even in cold climates. Diarrhea may cause
additional high fluid losses, so the volume of fluid lost should be measured
and an equal amount of electrolyte-balanced fluid should replace it. Water
contains no electrolytes, so fruit juices, soft drinks, soups and similar
liquids should be consumed.
An alternative electrolyte replacement fluid contains 1 teaspoon of table
salt and 4 heaping teaspoons of sugar in a liter of water. Some liquids,
such as tea, coffee and hot chocolate, are diuretics that encourage more
fluid loss, and should be avoided. Urine color is a fairly reliable gauge
of dehydration. Small amounts of dark yellow to orange urine suggest considerable
fluid loss. (Note that rifabutin discolors the urine and renders this
rule of thumb useless.)
Oral rehydration is usually sufficient to counterbalance the fluid losses
due to chronic diarrhea, but intravenous fluids may be needed if the person
is in shock or near shock, vomits persistently, or has ileus (an obstruction
of the bowel). Lost potassium can usually be repleted by drinking 1 cup
of orange juice or eating 2 bananas. Electrolytes must be monitored carefully
in those who experience diarrhea as a result of taking foscarnet.
Malabsorption
A study of 30 men with various stages of HIV disease showed that malabsorption
is more likely in people with AIDS than in asymptomatic, HIV-infected
men. Researchers concluded that:
- The intestines' ability to absorb nutrients deteriorates with AIDS,
usually accompanied by low-grade inflammation.
- Malabsorption in the ileum in people with AIDS may lead to vitamin
B12 deficiency, which can be corrected with regular B12 injections.
- Bile acid malabsorption may also contribute to AIDS-related diarrhea
in some individuals.
Conclusions
Diarrhea is a symptom, not a disease. The underlying cause of diarrhea,
when identified, can often be treated. Acute diarrhea and chronic diarrhea
are treated differently by HIV-experienced physicians. Frequently, but
not always, strategies to control diarrhea treat the underlying infection
and provide symptomatic relief for diarrhea at the same time. Chronic
diarrhea can be an important component in AIDS-related wasting, and diarrhea
control should be part of comprehensive care for people with HIV/AIDS.
Mark Bowers is Managing Editor in the Treatment Education and Advocacy
Department at the San Francisco AIDS Foundation.
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Page last updated 2 July 1997
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