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Atypical Diarrheas
Atypical Diarrheas CARROLL L. BIRCH, M.D., F.A.C.P.*
DIARRHEAL diseases rank high on the list of human complaints. 'fhey are caused by a number of factors and agents including diet, allergy, drugs such as digitalis preparations and some of the antibiotics, psychiatric states, viruses and bacteria, certain protozoa and some helminthic parasites, as well as neoplasms, etc. It is important to establish the cause of a diarrhea before medication is administered and before the patient is given barium for a gastrointestinal x-ray or barium enema. Almost any medication will mask the diagnosis. All too often the etiology is obscured behind an array of therapy. Paregoric does not interfere with the examination and can be used to control severe diarrhea until the stool is examined for pathogens. After the cause is determined, specific therapy can be given. Three patients will be presented today who have suffered from intermittent diarrhea over a period of years.
AMEBIASIS CASE I. The patient is a 27 year old housewife from one of the southern states. She is the mother of 4 children and is 7 months pregnant. Her chief complaint is pain which began 2 days ago. It is located in the right flank, right subcostal region and in the epigastrium. Discomfort is increased by deep breathing and cough. She appears acutely and chronically ill and older than her stated age, is mildly dyspneic with shallow respiration, and grunts continuously. She is unable to tolerate food by mouth and states she has been "running a fever" and having "night sweats," and "running off of the bowels" with 10 to 15 stools a day. The fecal discharge contains mucus and blood. She had colitis in 1948 with liquid stools containing bright red blood. She has never had "yellow jaundice." Her diet has been poor and she denies drinking either whiskey or beer. Physical examination made on admission showed spider angiomas scattered over chest and back. Her tongue was red and smooth. There were patches of cheesy white material on the buccal mucosa and over the tonsillar pillars. She had mild cheilosis. Palmar erythemia was present. She had lost 20 pounds in spite of being pregnant. Examination of the chest showed the right diaphragm elevated and immobile.
From the Department of M edicine, University of Illinois College of Medicine and Research and Educational Hospitals, Chicago.
* Professor of Medicine, University of Illinois College of Medicine; Attending Physician, Research and Educational Hospitals of the University of Illinois. 217
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Breath sounds were diminished at the right base. The abdomen was distended and palpation was painful. The liver was 4 to 5 cm. below the costal margin and extremely tender .. The tip of the spleen could be felt. The uterus was 2 cm. below the umbilicus Active contractions were present. Temperature was 99.8° F., pulse 92, blood pressure 116 systolic, 55 diastolic. Blood findings: Hemoglobin 5.7 grams (40 per cent); hematocrit 26 per cent (normal 42 0= 6) white blood cells 15,200 with 82 per cent neutrophils, 15 per cent lymphcytes; and 5 monocytes; serum albumin 2.8 grams/lOO ml.; serum globulin 2.7 grams/ 100 ml.; bleeding and clotting times normal; prothrombin 50 per cent of normal; blood cultures negative and also the serology. Stools were positive for occult blood and negative for pathogenic bacteria. Bromsulphalein test showed 10.5 per cent retention after 45 minutes. Other tests were made but they have little direct bearing on the diagnosis.
Diagnosis
Even before fecal examination, the first impression was amebic dysentery with associated involvement of the liver, either by hepatitis or abscess. The fecal discharge was liquid and contained mucus and blood. Examination of the warm stool revealed many active trophozoites of Endamoeba histolytica streaming across the microscopic field. There were numerous red blood cells in the cytoplasm of the amebas. The chief factors which suggested the diagnosis of amebiasis were the chronicity of the diarrhea, the character of the stool, the associated liver involvement and the fact that the patient had recently come from the south. About 10 per cent of all persons in the United States carry E. histolytica but the percentage is higher in the south than in the north while in the true tropics 50 per cent of the population is said to carry this infection. Moving from one climate to another with the associated changes in diet often precipitates an acute attack. Epidemiology
Endamoeba histolytica occurs in two forms, the trophozoite or active stage and the cyst or resting stage (Fig. 25). The trophozoite measures from 10 to 60 fJ-, has a clear ectoplasm and a finely granular endoplasm. It multiples abundantly by binary fission. When stained it shows a single nucleus with a fine central karyosome. It moves by pseudopods which are hyaline, explosive and finger-like. Often it puts out a series of pseudopods and travels in a straight line which is known as "directional motility." The trophozoite is found in warm, liquid, freshly passedjeces of acute amebic dysentery (Fig. 26). '"rhese stools contain mucus and blood and red blood cells frequently are found in the cytoplasm of the amebas. The trophozoites invade the mucosa of the colon by producing a proteolytic enzyme which dissolves tissue. When the stool cools the motility of the ameba ceases and the trophozoites round up and die. For this reason liquid stools must be examined immediately after they are passed while they are still warm. Trophozoites play little part in the transmission of amebiasis.
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Fig. 25. A, Trophozoite; B, C, immature cysts; D, mature cysts. (From E. C. Faust, Animal Agents as Vectors of Human Disease, Lea & Febiger, Philadelphia.)
Fig. 26. Unstained trophozoites of E. histolytica in dysenteric stool showing ingested erythrocytes. (From Medical Museum Collection, Armed Forces Institute of Pathology, in Craig and Faust's Clinical Parasitology, Lea & Febiger, Philadelphia.)
The cysts measure from 5 to 20 J.l, are spherical or oval, are surrounded . by cyst walls and when mature contain four nuclei. In cases of chronic amebiasis and in the carrier stage cysts are discharged rhythmically, not every day. Cysts form when the environment becomes unfavorable for the trophozoite. They occur usually in solid stools and are never
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found in tissues. Cysts are quite resistant to environmental change and are chiefly responsible for the transmission of the disease from person to person. Cysts in drinking water cause most of the epidemics. Endemic amebiasis is continued by infected food handlers, contaminated uncooked vegetables, and fruits and flies which feed indiscriminately on feces and food. Cysts are sensitive to drying but will live for a month in water and will survive at freezing temperature for 90 days. Man is the principal reservoir host. Endamoeba histolytica is well adjusted to the life of a parasite of man. It multiplies abundantly in the atmosphere of man's tissues and the juices of his gastrointestinal tract. It is amazing how man allows the little amebas to flourish at his expense. In parts of the world where sanitation is lacking and hygienic standards low and human night soil is used as fertilizer, amebiasis is common but this infection is found all over the world even in the best circles of society. There is no recognized immunity to E. histolytica and immunization is not available. When the cyst is ingested by man it passes through the stomach unchanged. In the alkaline secretions of the small intestine excystation takes place. This is a fairly long process. Immediately after excystation there is a division into four small amebas which are. swept along in the fecal stream. When the cecum is reached the current is slowed and the tiny amebas come in contact with the mucosa. Here by lytic action they penetrate, grow to maturity and multiply. Types of Infection
Infection with E. histolytica presents a variety of responses from the host depending upon the virulence of the amebas, the magnitude of the infection and the resistance of the host. Malnutrition, anemia and other infections contribute to the host reaction. 1. Acute Amebic Dysentery. The onset usually is sudden with chills, low fever, headache, nausea, vomiting, leukocytosis, severe abdominal cramps and dysentery of 10 to 20 stools daily. The fecal discharge is liquid, contains mucus and blood. On examination of the freshly passed, warm stool trophozoites of E. histolytica are found characteristically. ~rhe colon is the site of pathologic action. Amebas penetrate the mucosa and cause ulceration in the region of the cecum in 85 per cent of cases, the sigmoid is involved in 40 per cent; the ascending, transverse and descending colon is less frequently involved. Rarely the entire colon is ulcerated. The ulcers are flask-shaped and have necrotic bases with normal mucosa in between. Secondary bacterial infection causes inflammatory reaction of the mucosa. In severe cases there is gangrene of the colon and hemorrhage. Death may result from heart failure or peritonitis from perforation of the colon.
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2. Chronic Amebic Dysentery. This condition is usually the result of inadequate and repeated treatment of acute dysentery. The colon often is deformed by scarring. Chronic diarrhea is the rule which leads to malnutrition. Amebas may be difficult to find. 3. Amebic Diarrhea. This is characterized by bouts of diarrhea alternating with constipation. During the diarrheal period there are four or five unformed stools daily accompanied by abdominal cramps. Repeated stool examinations selecting the small flecks of mucus or blood usually reveal the amebas. 4. Cyst Passers. Here a balance has been established between the host and the parasite. Some carriers have recovered from an acute attack. Some have never had symptoms. Others suffer from hypochromic anemia, easy fatigue, lassitude, flatulence and fullness in the right lower quadrant. Often these persons are considered neurasthenics. Cyst carriers are always potential candidates for an acute attack of dysentery or hepatitis or liver abscess as well as being public health hazards. These infections may last for years. It may be necessary to examine several stools before the cysts are found. Three stool examinations at 48 hour intervals are suggested. If these are negative stools should be examined after a saline purge to obtain the material from the region of the cecum. The stool may be negative one day and loaded with cysts the next. Concentration techniques, especially the zinc sulfate flotation method, are used to demonstrate cysts. Trophozoites cannot be concentrated. Complications
Extraintestinal amebiasis may occur in the liver, lung, skin, brain and other organs. The most common site for metastasis is the liver. Amebic hepatitis acts like an acute inflammatory reaction, the liver is enlarged, tender and painful. There is a polymorphonuclear leukocytosis, increase in sedimentation rate, and increase in alpha-globulin. Such reactions are not found in intestinal amebiasis. A series of sedimentation rates is an effective guide to the adequacy of treatment. On adequate antialnebic treatment it should subside. Without treatment or on unsatisfactory treatment the process may go on to abscess formation. Amebic abscess of the liver is usually single and is located in the right lobe in 84 per cent of the cases. Liver abscesses may be huge and contain large amounts of creamy material often reddish brown in color. Amebas are not found in the aspirated material but are abundant on the inner aspect of the advancing margin of the abscess wall. [.lung abscess occurs less frequently and is almost always associated \vith liver abscess. It usually involves the right lower lobe. It may result from extension of the liver abscess through the diaphragm. Abscesses in other organs including the brain are rare. Amehic infection of the skin may occur in infected persons, about the
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anus or postoperative abdominal incisions. Also the presence of a skin abrasion may attract flies which deposit amebic cysts in their dejecta and eructation and carry cysts on legs or mouth parts. The skin lesions have overhanging margins and necrotic bases. E. histolytica may be found in scrapings from under the advancing margin. Besides the extraintestinal sites of amebic involvement there are other complications including secondary infections, perforation of the bowel leading to peritonitis, overwhelming toxemia, heart failure and hemorrhage. Recently there have been two new and interesting developments in the ancient disease amebiasis. Allergic reactions such as asthma and urticaria are sometimes attributable to the proteolytic action of E. histolytica. Sensitization to the heterogenous protein produced by autolysis causes the allergic manifestations. After successful treatment for amebiasis the allergic symptoms disappear (Ristic, L. and Brojovic, R., Acta med. Iugoslavia, 10: 63-92, 1956). Drs. A. E. Braley and H. E. Hamilton (A.M.A. Arch. Ophthalmol. 58: 1-14 [July] 1957) have emphasized a relationship between amebiasis and a central or macular lesion of the eye. When the amebas are cleared from the body by adequate treatment the eye lesions heal. H. Krummel (Arch f. Hyg. u. Bakt. 140:253-263 [June] 1956) found unidentified amebas in three enucleated eyes. TreatDlent
Specific treatment is veered in two directions. The first is toward the tissue-abiding amebas with effective drug levels in the liver and the wall of the intestine. The most effective tissue amebacides are emetine hydrochloride and chloroquine. The second direction is toward the lumenabiding amebas and cysts with effective drug levels in the bowel. The lumen amebacides include diodoquin, chiniofon, carbarsone and erythromycin. Emetine hydrochloride is a toxic drug producing fall in blood pressure, weakness, paralysis of skeletal muscles, nausea, vomiting and diarrhea in sensitive persons or in overdosage. Patients receiving emetine should first have an electrocardiogram to make sure there is no cardiac involvement and should remain in bed, preferably in a hospital. Emetine is given intramuscularly in 6 per cent aqueous solution usually in 1 cc. ampules (65 mg.; 1. grain). 'I'he dose is 1 mg. per kilogram of body weight (but not to exceed ()5 mg.) intramuscularly daily for three to five days; maximum total 195 to 260 mg. Formerly larger doses were used and toxic symptoms were more frequent. The results produced by emetine are almost miraculous in dysentery, amebic hepatitis and abscess. Emetine is a tissue amebacide only, exerts little influence on intestinal amebiasis, and does not destroy cysts. It must be accompanied or follo\ved by the administration of a lumen amebacide.
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Chloroquine is a good tissue amebacide. The dosage is 0.5 gram twice daily for two days, then 0.25 gram twice daily for 15 days. It is of little value in lumen amebiasis. Toxic symptoms attributable to chloroquine are: headache, dizziness, nausea, vomiting, diarrhea and blurring of vision. Negroes are especially sensitive to this drug. In the author's hands chloroquine has failed in about one-third of the cases. After two or three days of treatment with a tissue amebacide a drug for lumen infection is begun so there will be an overlap in the two treatments. The most commonly used lumen amebacides are: diodoquin (0.65 gram three times a day for 21 days) ; chiniofon (0.25 to 1 gram three times a day for seven or eight days) ; and carbarsone (0.25 gram twice a day for ten days). On the whole, antibiotics and steroids have little amebacidal activity. The effects they produce are brought about primarily by their action on the bacterial flora of the intestinal tract. This may allow resistant, pathogenic bacteria to multiply. Of the antibiotics erythromycin disturbs the bacterial flora least and is the safest to use. Let us now return to our patient. To overcome her anemia she was given 1000 cc. of whole blood. She was placed on chloroquine therapy. After 5 days she showed little clinical improvement and the liver was larger. An area of fluctuation appeared over the liver in the anterior axillary line. This was interpreted as the pointing of a liver abscess. Chloroquine was discontinued and emetine hydrochloride started. The temperature dropped to normal in 24 hours. The abscess was aspirated using syringe and long needle, entering at the point of fluctuation which was the ninth interspace in the anterior axillary line. 800 cc. of a dark creamy fluid was obtained. Following aspiration the edge of the liver rose 4 to 5 cm. It is important not to palpate the abdomen at this time for fear of "fracturing" the abscess capsule. A second aspiration yielded 500 cc. Emetine was given for 5 days. On the third day of treatment diodoquin was begun and continued for 21 days. On the twenty-third hospital day the patient ,vent into labor and was delivered of a premature infant weighing 4~ pounds. Following the birth of the baby she improved rapidly. Her appetite increased and she was placed on a 4000 calorie diet. Stools from the baby were negative for E. histolytica. On discharge the patient had the following findings: She was free from pain and her chest x-ray was normal. Hemoglobin was 7 grams (50 per cent), hematocrit 37.5, white blood cells normal, serum albumin 3.3 grams/lOO m!., globulin 3 grams/lOO m!., prothrombin 100 per cent of normal, stool negative for parasites and blood, Bromsulphalein 1.7 per cent retention in 45 minutes. She was discharged on her forty-eighth hospital day. N ate: The patient was followed for six months. She gained 20 pounds, remained symptom-free and the stools continued to be negative. The baby progressed normally. GIARDIASIS CASE 11. This patient is one of our medical personnel who has consented to appear at our clinic. She is 35 years old, is 5 feet 5 inches tall and weighs 105 pounds. She has had intermittent diarrhea for 12 years. Bouts of diarrhea with
Carroll L. Birch
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Fig. 27. Giardia lamblia. (After Faust, J. Lab. & Clin. Med., in Craig and Faust's Clinical Parasitology, Lea & Febiger, Philadelphia.)
6 to 10 stools daily occur every 4 to 6 weeks. The fecal discharge is watery but never contains blood. It is acid, frothy and contains glaring mucus. These cyclic symptoms are accompanied by abdominal cramps, slight nausea, weakness, loss of appetite and inability to gain weight. She has been on a bland, low residue diet for several years. Three series of gastrointestinal x-rays have been reported negative. Suspecting chronic appendicitis an appendectomy was performed. Belladonna, kaolin and agar-agar were of little help. Careful and repeated examinations of freshly passed stools revealed the presence of an intestinal flagellate called Giardia lamblia (Fig. 27). This organism was present only during the diarrheal attacks. Usually the first and second stools of each attack were negative while the third, fourth and fifth were positive, from the sixth stool on the organisms became progressively fewer.
Epidellliology
Giardia lamblia, like E. histolytica, exists in two forms, the trophozoite and cyst. The trophozoite is a flagellate which is adapted to life in a liquid medium, resides in the upper small intestine, the gallbladder and the bile passages, and is found in the stool only during diarrheal attacks. Cysts may be present in solid feces. The trophozoite is bilaterally symmetrical, has two large nuclei with centrally placed karyosomes and eight flagella. They are pyriform in shape and are concavoconvex and measure from 10 to 20 J.L long and 5 to 10 JL wide. This flagellate has no cytostome and no food vacuoles. It absorbs food through the surface of the body as it is bathed in a nutrient fluid. They have a slow tumbling motion. The cysts are oval and measure 8 to 12 JL. When mature they contain t,vo individuals with four nuclei. The retracted flagella can be seen coiled within the cyst. They multiply in the trophozoite and cyst stages by binary fission. In the upper duo-
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denum they thrive until they are numbered in myriads. They plaster themselves with concave surfaces against the mucosa of the duodenum held fast by suction. Here their flattened bodies form a mosiac on the mucosa and interfere with absorption especially of fats which leads to a deficiency of vitamin A. From the duodenum they may enter the common bile duct and infect the gallbladder and bile passages within and outside the liver. Giardia lamblia is found in other mammals including monkeys, rats, mice, guinea pigs, rabbits, dogs and cats. Animals are thought to play little or no part in the transmission of the infection from person to person. Experimental evidence and experience indicate that water contaminated with cysts is the usual mode of transmission. The incubation period is from one to three weeks. The cysts are sensitive to drying but will live for more than three months in water. Excystation usually does not take place in the same body. They escape from the host to ensure infection of others. Giardiasis is a common worldwide infection which requires no intermediate host. Many patients show no symptoms at all, are simply carriers. For this reason some authors have considered Giardia lamblia a nonpathogen, but it must be remembered that there is a carrier phase with many pathogens including E. histolytica and the typhoid bacillus. The infection is seen far more often in children than in adults and most frequently in males under five years. Severe infections acting as a barrier to absorption often lead to the celiac syndrome, severe steatorrhea, anemia, asthenia and low vitamin A content of the blood. In extremely severe cases there may be emaciation, nervousness, hypochlorhydria, bilary colic, bradycardia, low basal metabolism, mental depression, edema, jaundice, and evidence of vitamin A deficiency. Lack of vitamin A may lead to infection of the eye, impairment of vision, night blindness and later xerophthalmia and l<:eratomalacia. The diagnosis is established by finding the trophozoites in the diarrheal stool or the cysts in solid feces. A higher percentage of positives is found in duodenal drainage with the administration of magnesium sulfate. Sometimes Giardia lamblia resides wholly within the liver, perhaps with occasional discharge of cysts into the duodenum. In these cases the stools may be negative at least for many days. Treatment
Intestinal disinfectants do not cure giardiasis because the organisms are found deep in the intestinal glands and in the gallbladder and bile passages within and outside the liver. Many drugs have been and are still being used in the treatment of giardiasis. The best results follow the use of quinacrine (Atrabrine) 0.1 gram compressed tablets. Adult dose is one tablet three times daily by mouth for five days. A second course of treatment may be needed.
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Recovery in longstanding infections often is slow. Supplementary treatment consists of high protein diet with vitamins, especially A. Antibiotics, sulfonamides and chloroquine are of no permanent value. N ate: The patient has been symptom-free for 6 months. She has gained 20 pounds and is now trying to reduce. Her diet is normal and includes raw vegetables and fruits. Her stool is being checked once a month. SCHISTOSOMIASIS Ill. This patient is from Puerto Rico. His chief complaints are bloody diarrhea with abdominal cramps. Stool examinations revealed the presence of large eggs 150 by 60 JJ- with long, sharp, lateral spines (Fig. 28). The diagnosis of schistosomiasis mansoni was made. CASE
Epidemiology
Schistosomiasis is a serious parasitic infection caused by a fluke. The water-abiding cercarial forms penetrate the skin of man, enter the venules and take the heart-lung route through the body to portal blood where the larvae develop into adults. Schistosomes spend their adult lives within the blood vessels of man. Schistosoma mansoni resides in the blood vessels which drain the large bowel. Male and female worms remain together and produce eggs (Fig. 29) which are carried to many places in the body, including the liver and spleen. Large numbers of eggs break through tissue and enter the lumen of the bowel, causing irritation and diarrhea with fecal discharges containing blood, mucus and eggs. The ovum hatches in fresh water, liberating the miracidium which enters the appropriate snail which is the intermediate host. After larval development in the snail the cercaria emerge and penetrate the skin of man. Early there is acute hepatitis and systemic intoxication. Later the infection leads to periportal fibrosis, cirrhosis of the liver, ascites, liver failure and death. These worms live for 20 or 30 years and usually outlive the patient. As citizens from Puerto Rico are coming to the mainland in large numbers, this infection should be considered in their diagnoses. About 10 per cent of Puerto Ricans carry the parasite. Treatment
Treatment is difficult and not satisfactory. It consists of the intravenous injection of sodium or potassium antimony tartrate. The patient should remain in a reclining position for several hours after each injection to avoid respiratory and hepatic irritation. Dose: A freshly prepared 0.5 per cent solution of potassium antimony tartrate in 5 per cent glucose in physiologic saline. Do not autoclave. Filter and sterilize by gentle boiling for five minutes. Introduce slowly and carefully into the cubital vein every other day. In the tissues it causes a slough. First day 8 cc., 3rd day 12 cc., 5th day 16 cc., 7th day
A lyp'£cal
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Fig. 28. Shistosoma, ovum or egg. (From Faust's Human Helminthology, Lea & Febiger, Philadelphia.)
Fig. 29. Shistosoma, adult male and female. (After Gonnert, from Craig and Faust's Clinical Parasitology, Lea & Febiger, Philadelphia.)
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20 cc., 9th, 11th, 13th, 21st, 23rd, 25th, 27th and 29th days 24 cc. T'he cure rate following the first course of treatment is about 84 per cent. If toxic reactions (cough, nausea, vomiting) occur, increase the injection time or increase the interval between doses or temporarily withhold treatment. Potassium antimony tartrate is contraindicated in diseases of the cardiac, respiratory, renal, hepatic and central nervous systems as well as in all febrile states. It should not be given concurrently with other metals or cardiac depressants. This patient was treated six months ago. His stools have remained negative since. WARNING
Beware of drugs used simply for symptomatic relief of diarrhea, cramps, pain and flatulence. These medications for all diarrheas irrespective of etiology may relieve the symptoms but do not remove the cause. They often invite recurrences and complications. Many antibiotics and sulfonamides check the symptoms but do not eradicate the infection. They simply disturb the delicate balance which exists between the parasite and its environment. These altered conditions inactivate the parasites but do not destroy them. When the climate again becomes favorable the parasite becomes active or multiplies and symptoms reappear. It is best to establish a diagnosis before treatment and then administer specific therapy. 840 S. Wood Street Chicago 12, Illinois
DIARRHEAL diseases rank high on the list of human complaints. 'fhey are caused by a number of factors and agents including diet, allergy, drugs such as digitalis preparations and some of the antibiotics, psychiatric states, viruses and bacteria, certain protozoa and some helminthic parasites, as well as neoplasms, etc. It is important to establish the cause of a diarrhea before medication is administered and before the patient is given barium for a gastrointestinal x-ray or barium enema. Almost any medication will mask the diagnosis. All too often the etiology is obscured behind an array of therapy. Paregoric does not interfere with the examination and can be used to control severe diarrhea until the stool is examined for pathogens. After the cause is determined, specific therapy can be given. Three patients will be presented today who have suffered from intermittent diarrhea over a period of years.
AMEBIASIS CASE I. The patient is a 27 year old housewife from one of the southern states. She is the mother of 4 children and is 7 months pregnant. Her chief complaint is pain which began 2 days ago. It is located in the right flank, right subcostal region and in the epigastrium. Discomfort is increased by deep breathing and cough. She appears acutely and chronically ill and older than her stated age, is mildly dyspneic with shallow respiration, and grunts continuously. She is unable to tolerate food by mouth and states she has been "running a fever" and having "night sweats," and "running off of the bowels" with 10 to 15 stools a day. The fecal discharge contains mucus and blood. She had colitis in 1948 with liquid stools containing bright red blood. She has never had "yellow jaundice." Her diet has been poor and she denies drinking either whiskey or beer. Physical examination made on admission showed spider angiomas scattered over chest and back. Her tongue was red and smooth. There were patches of cheesy white material on the buccal mucosa and over the tonsillar pillars. She had mild cheilosis. Palmar erythemia was present. She had lost 20 pounds in spite of being pregnant. Examination of the chest showed the right diaphragm elevated and immobile.
From the Department of M edicine, University of Illinois College of Medicine and Research and Educational Hospitals, Chicago.
* Professor of Medicine, University of Illinois College of Medicine; Attending Physician, Research and Educational Hospitals of the University of Illinois. 217
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Breath sounds were diminished at the right base. The abdomen was distended and palpation was painful. The liver was 4 to 5 cm. below the costal margin and extremely tender .. The tip of the spleen could be felt. The uterus was 2 cm. below the umbilicus Active contractions were present. Temperature was 99.8° F., pulse 92, blood pressure 116 systolic, 55 diastolic. Blood findings: Hemoglobin 5.7 grams (40 per cent); hematocrit 26 per cent (normal 42 0= 6) white blood cells 15,200 with 82 per cent neutrophils, 15 per cent lymphcytes; and 5 monocytes; serum albumin 2.8 grams/lOO ml.; serum globulin 2.7 grams/ 100 ml.; bleeding and clotting times normal; prothrombin 50 per cent of normal; blood cultures negative and also the serology. Stools were positive for occult blood and negative for pathogenic bacteria. Bromsulphalein test showed 10.5 per cent retention after 45 minutes. Other tests were made but they have little direct bearing on the diagnosis.
Diagnosis
Even before fecal examination, the first impression was amebic dysentery with associated involvement of the liver, either by hepatitis or abscess. The fecal discharge was liquid and contained mucus and blood. Examination of the warm stool revealed many active trophozoites of Endamoeba histolytica streaming across the microscopic field. There were numerous red blood cells in the cytoplasm of the amebas. The chief factors which suggested the diagnosis of amebiasis were the chronicity of the diarrhea, the character of the stool, the associated liver involvement and the fact that the patient had recently come from the south. About 10 per cent of all persons in the United States carry E. histolytica but the percentage is higher in the south than in the north while in the true tropics 50 per cent of the population is said to carry this infection. Moving from one climate to another with the associated changes in diet often precipitates an acute attack. Epidemiology
Endamoeba histolytica occurs in two forms, the trophozoite or active stage and the cyst or resting stage (Fig. 25). The trophozoite measures from 10 to 60 fJ-, has a clear ectoplasm and a finely granular endoplasm. It multiples abundantly by binary fission. When stained it shows a single nucleus with a fine central karyosome. It moves by pseudopods which are hyaline, explosive and finger-like. Often it puts out a series of pseudopods and travels in a straight line which is known as "directional motility." The trophozoite is found in warm, liquid, freshly passedjeces of acute amebic dysentery (Fig. 26). '"rhese stools contain mucus and blood and red blood cells frequently are found in the cytoplasm of the amebas. The trophozoites invade the mucosa of the colon by producing a proteolytic enzyme which dissolves tissue. When the stool cools the motility of the ameba ceases and the trophozoites round up and die. For this reason liquid stools must be examined immediately after they are passed while they are still warm. Trophozoites play little part in the transmission of amebiasis.
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Fig. 25. A, Trophozoite; B, C, immature cysts; D, mature cysts. (From E. C. Faust, Animal Agents as Vectors of Human Disease, Lea & Febiger, Philadelphia.)
Fig. 26. Unstained trophozoites of E. histolytica in dysenteric stool showing ingested erythrocytes. (From Medical Museum Collection, Armed Forces Institute of Pathology, in Craig and Faust's Clinical Parasitology, Lea & Febiger, Philadelphia.)
The cysts measure from 5 to 20 J.l, are spherical or oval, are surrounded . by cyst walls and when mature contain four nuclei. In cases of chronic amebiasis and in the carrier stage cysts are discharged rhythmically, not every day. Cysts form when the environment becomes unfavorable for the trophozoite. They occur usually in solid stools and are never
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found in tissues. Cysts are quite resistant to environmental change and are chiefly responsible for the transmission of the disease from person to person. Cysts in drinking water cause most of the epidemics. Endemic amebiasis is continued by infected food handlers, contaminated uncooked vegetables, and fruits and flies which feed indiscriminately on feces and food. Cysts are sensitive to drying but will live for a month in water and will survive at freezing temperature for 90 days. Man is the principal reservoir host. Endamoeba histolytica is well adjusted to the life of a parasite of man. It multiplies abundantly in the atmosphere of man's tissues and the juices of his gastrointestinal tract. It is amazing how man allows the little amebas to flourish at his expense. In parts of the world where sanitation is lacking and hygienic standards low and human night soil is used as fertilizer, amebiasis is common but this infection is found all over the world even in the best circles of society. There is no recognized immunity to E. histolytica and immunization is not available. When the cyst is ingested by man it passes through the stomach unchanged. In the alkaline secretions of the small intestine excystation takes place. This is a fairly long process. Immediately after excystation there is a division into four small amebas which are. swept along in the fecal stream. When the cecum is reached the current is slowed and the tiny amebas come in contact with the mucosa. Here by lytic action they penetrate, grow to maturity and multiply. Types of Infection
Infection with E. histolytica presents a variety of responses from the host depending upon the virulence of the amebas, the magnitude of the infection and the resistance of the host. Malnutrition, anemia and other infections contribute to the host reaction. 1. Acute Amebic Dysentery. The onset usually is sudden with chills, low fever, headache, nausea, vomiting, leukocytosis, severe abdominal cramps and dysentery of 10 to 20 stools daily. The fecal discharge is liquid, contains mucus and blood. On examination of the freshly passed, warm stool trophozoites of E. histolytica are found characteristically. ~rhe colon is the site of pathologic action. Amebas penetrate the mucosa and cause ulceration in the region of the cecum in 85 per cent of cases, the sigmoid is involved in 40 per cent; the ascending, transverse and descending colon is less frequently involved. Rarely the entire colon is ulcerated. The ulcers are flask-shaped and have necrotic bases with normal mucosa in between. Secondary bacterial infection causes inflammatory reaction of the mucosa. In severe cases there is gangrene of the colon and hemorrhage. Death may result from heart failure or peritonitis from perforation of the colon.
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2. Chronic Amebic Dysentery. This condition is usually the result of inadequate and repeated treatment of acute dysentery. The colon often is deformed by scarring. Chronic diarrhea is the rule which leads to malnutrition. Amebas may be difficult to find. 3. Amebic Diarrhea. This is characterized by bouts of diarrhea alternating with constipation. During the diarrheal period there are four or five unformed stools daily accompanied by abdominal cramps. Repeated stool examinations selecting the small flecks of mucus or blood usually reveal the amebas. 4. Cyst Passers. Here a balance has been established between the host and the parasite. Some carriers have recovered from an acute attack. Some have never had symptoms. Others suffer from hypochromic anemia, easy fatigue, lassitude, flatulence and fullness in the right lower quadrant. Often these persons are considered neurasthenics. Cyst carriers are always potential candidates for an acute attack of dysentery or hepatitis or liver abscess as well as being public health hazards. These infections may last for years. It may be necessary to examine several stools before the cysts are found. Three stool examinations at 48 hour intervals are suggested. If these are negative stools should be examined after a saline purge to obtain the material from the region of the cecum. The stool may be negative one day and loaded with cysts the next. Concentration techniques, especially the zinc sulfate flotation method, are used to demonstrate cysts. Trophozoites cannot be concentrated. Complications
Extraintestinal amebiasis may occur in the liver, lung, skin, brain and other organs. The most common site for metastasis is the liver. Amebic hepatitis acts like an acute inflammatory reaction, the liver is enlarged, tender and painful. There is a polymorphonuclear leukocytosis, increase in sedimentation rate, and increase in alpha-globulin. Such reactions are not found in intestinal amebiasis. A series of sedimentation rates is an effective guide to the adequacy of treatment. On adequate antialnebic treatment it should subside. Without treatment or on unsatisfactory treatment the process may go on to abscess formation. Amebic abscess of the liver is usually single and is located in the right lobe in 84 per cent of the cases. Liver abscesses may be huge and contain large amounts of creamy material often reddish brown in color. Amebas are not found in the aspirated material but are abundant on the inner aspect of the advancing margin of the abscess wall. [.lung abscess occurs less frequently and is almost always associated \vith liver abscess. It usually involves the right lower lobe. It may result from extension of the liver abscess through the diaphragm. Abscesses in other organs including the brain are rare. Amehic infection of the skin may occur in infected persons, about the
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anus or postoperative abdominal incisions. Also the presence of a skin abrasion may attract flies which deposit amebic cysts in their dejecta and eructation and carry cysts on legs or mouth parts. The skin lesions have overhanging margins and necrotic bases. E. histolytica may be found in scrapings from under the advancing margin. Besides the extraintestinal sites of amebic involvement there are other complications including secondary infections, perforation of the bowel leading to peritonitis, overwhelming toxemia, heart failure and hemorrhage. Recently there have been two new and interesting developments in the ancient disease amebiasis. Allergic reactions such as asthma and urticaria are sometimes attributable to the proteolytic action of E. histolytica. Sensitization to the heterogenous protein produced by autolysis causes the allergic manifestations. After successful treatment for amebiasis the allergic symptoms disappear (Ristic, L. and Brojovic, R., Acta med. Iugoslavia, 10: 63-92, 1956). Drs. A. E. Braley and H. E. Hamilton (A.M.A. Arch. Ophthalmol. 58: 1-14 [July] 1957) have emphasized a relationship between amebiasis and a central or macular lesion of the eye. When the amebas are cleared from the body by adequate treatment the eye lesions heal. H. Krummel (Arch f. Hyg. u. Bakt. 140:253-263 [June] 1956) found unidentified amebas in three enucleated eyes. TreatDlent
Specific treatment is veered in two directions. The first is toward the tissue-abiding amebas with effective drug levels in the liver and the wall of the intestine. The most effective tissue amebacides are emetine hydrochloride and chloroquine. The second direction is toward the lumenabiding amebas and cysts with effective drug levels in the bowel. The lumen amebacides include diodoquin, chiniofon, carbarsone and erythromycin. Emetine hydrochloride is a toxic drug producing fall in blood pressure, weakness, paralysis of skeletal muscles, nausea, vomiting and diarrhea in sensitive persons or in overdosage. Patients receiving emetine should first have an electrocardiogram to make sure there is no cardiac involvement and should remain in bed, preferably in a hospital. Emetine is given intramuscularly in 6 per cent aqueous solution usually in 1 cc. ampules (65 mg.; 1. grain). 'I'he dose is 1 mg. per kilogram of body weight (but not to exceed ()5 mg.) intramuscularly daily for three to five days; maximum total 195 to 260 mg. Formerly larger doses were used and toxic symptoms were more frequent. The results produced by emetine are almost miraculous in dysentery, amebic hepatitis and abscess. Emetine is a tissue amebacide only, exerts little influence on intestinal amebiasis, and does not destroy cysts. It must be accompanied or follo\ved by the administration of a lumen amebacide.
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Chloroquine is a good tissue amebacide. The dosage is 0.5 gram twice daily for two days, then 0.25 gram twice daily for 15 days. It is of little value in lumen amebiasis. Toxic symptoms attributable to chloroquine are: headache, dizziness, nausea, vomiting, diarrhea and blurring of vision. Negroes are especially sensitive to this drug. In the author's hands chloroquine has failed in about one-third of the cases. After two or three days of treatment with a tissue amebacide a drug for lumen infection is begun so there will be an overlap in the two treatments. The most commonly used lumen amebacides are: diodoquin (0.65 gram three times a day for 21 days) ; chiniofon (0.25 to 1 gram three times a day for seven or eight days) ; and carbarsone (0.25 gram twice a day for ten days). On the whole, antibiotics and steroids have little amebacidal activity. The effects they produce are brought about primarily by their action on the bacterial flora of the intestinal tract. This may allow resistant, pathogenic bacteria to multiply. Of the antibiotics erythromycin disturbs the bacterial flora least and is the safest to use. Let us now return to our patient. To overcome her anemia she was given 1000 cc. of whole blood. She was placed on chloroquine therapy. After 5 days she showed little clinical improvement and the liver was larger. An area of fluctuation appeared over the liver in the anterior axillary line. This was interpreted as the pointing of a liver abscess. Chloroquine was discontinued and emetine hydrochloride started. The temperature dropped to normal in 24 hours. The abscess was aspirated using syringe and long needle, entering at the point of fluctuation which was the ninth interspace in the anterior axillary line. 800 cc. of a dark creamy fluid was obtained. Following aspiration the edge of the liver rose 4 to 5 cm. It is important not to palpate the abdomen at this time for fear of "fracturing" the abscess capsule. A second aspiration yielded 500 cc. Emetine was given for 5 days. On the third day of treatment diodoquin was begun and continued for 21 days. On the twenty-third hospital day the patient ,vent into labor and was delivered of a premature infant weighing 4~ pounds. Following the birth of the baby she improved rapidly. Her appetite increased and she was placed on a 4000 calorie diet. Stools from the baby were negative for E. histolytica. On discharge the patient had the following findings: She was free from pain and her chest x-ray was normal. Hemoglobin was 7 grams (50 per cent), hematocrit 37.5, white blood cells normal, serum albumin 3.3 grams/lOO m!., globulin 3 grams/lOO m!., prothrombin 100 per cent of normal, stool negative for parasites and blood, Bromsulphalein 1.7 per cent retention in 45 minutes. She was discharged on her forty-eighth hospital day. N ate: The patient was followed for six months. She gained 20 pounds, remained symptom-free and the stools continued to be negative. The baby progressed normally. GIARDIASIS CASE 11. This patient is one of our medical personnel who has consented to appear at our clinic. She is 35 years old, is 5 feet 5 inches tall and weighs 105 pounds. She has had intermittent diarrhea for 12 years. Bouts of diarrhea with
Carroll L. Birch
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Fig. 27. Giardia lamblia. (After Faust, J. Lab. & Clin. Med., in Craig and Faust's Clinical Parasitology, Lea & Febiger, Philadelphia.)
6 to 10 stools daily occur every 4 to 6 weeks. The fecal discharge is watery but never contains blood. It is acid, frothy and contains glaring mucus. These cyclic symptoms are accompanied by abdominal cramps, slight nausea, weakness, loss of appetite and inability to gain weight. She has been on a bland, low residue diet for several years. Three series of gastrointestinal x-rays have been reported negative. Suspecting chronic appendicitis an appendectomy was performed. Belladonna, kaolin and agar-agar were of little help. Careful and repeated examinations of freshly passed stools revealed the presence of an intestinal flagellate called Giardia lamblia (Fig. 27). This organism was present only during the diarrheal attacks. Usually the first and second stools of each attack were negative while the third, fourth and fifth were positive, from the sixth stool on the organisms became progressively fewer.
Epidellliology
Giardia lamblia, like E. histolytica, exists in two forms, the trophozoite and cyst. The trophozoite is a flagellate which is adapted to life in a liquid medium, resides in the upper small intestine, the gallbladder and the bile passages, and is found in the stool only during diarrheal attacks. Cysts may be present in solid feces. The trophozoite is bilaterally symmetrical, has two large nuclei with centrally placed karyosomes and eight flagella. They are pyriform in shape and are concavoconvex and measure from 10 to 20 J.L long and 5 to 10 JL wide. This flagellate has no cytostome and no food vacuoles. It absorbs food through the surface of the body as it is bathed in a nutrient fluid. They have a slow tumbling motion. The cysts are oval and measure 8 to 12 JL. When mature they contain t,vo individuals with four nuclei. The retracted flagella can be seen coiled within the cyst. They multiply in the trophozoite and cyst stages by binary fission. In the upper duo-
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denum they thrive until they are numbered in myriads. They plaster themselves with concave surfaces against the mucosa of the duodenum held fast by suction. Here their flattened bodies form a mosiac on the mucosa and interfere with absorption especially of fats which leads to a deficiency of vitamin A. From the duodenum they may enter the common bile duct and infect the gallbladder and bile passages within and outside the liver. Giardia lamblia is found in other mammals including monkeys, rats, mice, guinea pigs, rabbits, dogs and cats. Animals are thought to play little or no part in the transmission of the infection from person to person. Experimental evidence and experience indicate that water contaminated with cysts is the usual mode of transmission. The incubation period is from one to three weeks. The cysts are sensitive to drying but will live for more than three months in water. Excystation usually does not take place in the same body. They escape from the host to ensure infection of others. Giardiasis is a common worldwide infection which requires no intermediate host. Many patients show no symptoms at all, are simply carriers. For this reason some authors have considered Giardia lamblia a nonpathogen, but it must be remembered that there is a carrier phase with many pathogens including E. histolytica and the typhoid bacillus. The infection is seen far more often in children than in adults and most frequently in males under five years. Severe infections acting as a barrier to absorption often lead to the celiac syndrome, severe steatorrhea, anemia, asthenia and low vitamin A content of the blood. In extremely severe cases there may be emaciation, nervousness, hypochlorhydria, bilary colic, bradycardia, low basal metabolism, mental depression, edema, jaundice, and evidence of vitamin A deficiency. Lack of vitamin A may lead to infection of the eye, impairment of vision, night blindness and later xerophthalmia and l<:eratomalacia. The diagnosis is established by finding the trophozoites in the diarrheal stool or the cysts in solid feces. A higher percentage of positives is found in duodenal drainage with the administration of magnesium sulfate. Sometimes Giardia lamblia resides wholly within the liver, perhaps with occasional discharge of cysts into the duodenum. In these cases the stools may be negative at least for many days. Treatment
Intestinal disinfectants do not cure giardiasis because the organisms are found deep in the intestinal glands and in the gallbladder and bile passages within and outside the liver. Many drugs have been and are still being used in the treatment of giardiasis. The best results follow the use of quinacrine (Atrabrine) 0.1 gram compressed tablets. Adult dose is one tablet three times daily by mouth for five days. A second course of treatment may be needed.
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Recovery in longstanding infections often is slow. Supplementary treatment consists of high protein diet with vitamins, especially A. Antibiotics, sulfonamides and chloroquine are of no permanent value. N ate: The patient has been symptom-free for 6 months. She has gained 20 pounds and is now trying to reduce. Her diet is normal and includes raw vegetables and fruits. Her stool is being checked once a month. SCHISTOSOMIASIS Ill. This patient is from Puerto Rico. His chief complaints are bloody diarrhea with abdominal cramps. Stool examinations revealed the presence of large eggs 150 by 60 JJ- with long, sharp, lateral spines (Fig. 28). The diagnosis of schistosomiasis mansoni was made. CASE
Epidemiology
Schistosomiasis is a serious parasitic infection caused by a fluke. The water-abiding cercarial forms penetrate the skin of man, enter the venules and take the heart-lung route through the body to portal blood where the larvae develop into adults. Schistosomes spend their adult lives within the blood vessels of man. Schistosoma mansoni resides in the blood vessels which drain the large bowel. Male and female worms remain together and produce eggs (Fig. 29) which are carried to many places in the body, including the liver and spleen. Large numbers of eggs break through tissue and enter the lumen of the bowel, causing irritation and diarrhea with fecal discharges containing blood, mucus and eggs. The ovum hatches in fresh water, liberating the miracidium which enters the appropriate snail which is the intermediate host. After larval development in the snail the cercaria emerge and penetrate the skin of man. Early there is acute hepatitis and systemic intoxication. Later the infection leads to periportal fibrosis, cirrhosis of the liver, ascites, liver failure and death. These worms live for 20 or 30 years and usually outlive the patient. As citizens from Puerto Rico are coming to the mainland in large numbers, this infection should be considered in their diagnoses. About 10 per cent of Puerto Ricans carry the parasite. Treatment
Treatment is difficult and not satisfactory. It consists of the intravenous injection of sodium or potassium antimony tartrate. The patient should remain in a reclining position for several hours after each injection to avoid respiratory and hepatic irritation. Dose: A freshly prepared 0.5 per cent solution of potassium antimony tartrate in 5 per cent glucose in physiologic saline. Do not autoclave. Filter and sterilize by gentle boiling for five minutes. Introduce slowly and carefully into the cubital vein every other day. In the tissues it causes a slough. First day 8 cc., 3rd day 12 cc., 5th day 16 cc., 7th day
A lyp'£cal
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Fig. 28. Shistosoma, ovum or egg. (From Faust's Human Helminthology, Lea & Febiger, Philadelphia.)
Fig. 29. Shistosoma, adult male and female. (After Gonnert, from Craig and Faust's Clinical Parasitology, Lea & Febiger, Philadelphia.)
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20 cc., 9th, 11th, 13th, 21st, 23rd, 25th, 27th and 29th days 24 cc. T'he cure rate following the first course of treatment is about 84 per cent. If toxic reactions (cough, nausea, vomiting) occur, increase the injection time or increase the interval between doses or temporarily withhold treatment. Potassium antimony tartrate is contraindicated in diseases of the cardiac, respiratory, renal, hepatic and central nervous systems as well as in all febrile states. It should not be given concurrently with other metals or cardiac depressants. This patient was treated six months ago. His stools have remained negative since. WARNING
Beware of drugs used simply for symptomatic relief of diarrhea, cramps, pain and flatulence. These medications for all diarrheas irrespective of etiology may relieve the symptoms but do not remove the cause. They often invite recurrences and complications. Many antibiotics and sulfonamides check the symptoms but do not eradicate the infection. They simply disturb the delicate balance which exists between the parasite and its environment. These altered conditions inactivate the parasites but do not destroy them. When the climate again becomes favorable the parasite becomes active or multiplies and symptoms reappear. It is best to establish a diagnosis before treatment and then administer specific therapy. 840 S. Wood Street Chicago 12, Illinois