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The significance of shigella alkalescens (andrewes)
T H E S I G N I F I C A N C E OF S t t I G E L L A A L K A L E S C E N S (ANDI~EWES) A
CLINICAL APPRAISAL O.I0 NINE
CASES FRo~ WHICH
THE ORGANIS.lV[ W A S ISOLATED
PAu~ V. WOOLLEn, JR., M.D., AND MARIAN SWEET BosTon, MASS. HdlGELLA
a l k a t e s c e n s was described in 1918 b y Andrewes, 1 who
id not a t t a c h p a t h o g e n i c i m p o r t a n c e to it, considering it only as an o r g a n i s m easily confused with the v i r u l e n t d y s e n t e r y types. Since then a few isolated r e p o r t s of h u m a n infection have a p p e a r e d in the literature. We wish to r e p o r t a series of nine patients f r o m w h o m this o r g a n i s m was recovered. I~ITF~R, ATUR,E
The first report of human infection was made by Smith and Fraser 2 in 1928. They recovered the organism from the blood, stools, urine, a n d uterine discharge of a w o m a n in the p o s t p a r t u m period. The a u t o g e n o u s strain w a s a g g l u t i n a t e d in 1:480 dilution of the p a t i e n t ' S serum. H e r r e c o v e r y was complete w i t h o u t specific t h e r a p y . Three y e a r s l a t e r Popoff a n d S p a n s w i c k 3 observed a p a t i e n t with pyelon e p h r i t i s during p r e g n a n c y and cultured the organism f r o m the stool a n d urine. They d e m o n s t r a t e d a g g l u t i n i n s in a dilution of 1:640 of the p a t i e n t ' S serum. The organisms d i s a p p e a r e d following abortion. I n 1934 S t a r k e y 4 r e c o r d e d an instance of pyelitis with the S h i g e l l a a l k a l e s c e n s in the stool, blood, and urine. A g g l u t i n a t i n g antibodies were not d e m o n s t r a t e d b u t " p r e c i p i t i n s " were present. The same year, 1ViacKenzie and R a t h e r 5 noted a n o t h e r p a t i e n t f r o m whom alkalescens was r e c o v e r e d in the blood, stool, and urine. This p a t i e n t showed evidence of severe septicemia and p y e l o n e p h r i t i s b u t r e c o v e r e d a f t e r a severe course. The a g g l u t i n a t i o n tests w e r e not conclusive in this instance. M u r r a y and Pike 6 r e c o v e r e d the o r g a n i s m f r o m the urine of an inf a n t w i t h acute pyelitis and f o u n d a g g l u t i n i n s to be p r e s e n t in the s e r u m at a dilution of 1:640. The only epidemiologic r e p o r t w a s m a d e b y Welch and Miekle, w who studied an o u t b r e a k of mild d y s e n t e r y a m o n g the students of a~l eastern university. S h i g e l l a a l k a l e s c e n s was r e c o v e r e d f r o m the stools of all those infected as well as f r o m a food h a n d l e r who was s y m p t o m - f r e e . These a u t h o r s also studied f o u r strains isolated f r o m p a t i e n t s with chronic u r i n a r y t r a c t infection. Well, s in :From the Departrflent of Pediatrics, IZIarvard 1VIedieaI School, and the I n f a n t s ' and Children's I-IospJtals, ]9oston. 596
WOOLLEY AND SWE~T:
S~IIGEI~LA ALKALESCEI~S
597
Germany, has noted the organism in one patient with pyuria. S n y d e r and Harmer 9 have recently contributed another r e p o r t of pyuria due to Shigella alkalescens. BACT%I~IOLOGY
In morphology the Shigella alkalescens offers n o t h i n g to differentiate it f r o m the r e m a i n d e r of the genus, being nonmotile, Gram-negative, and coliform in shape. The colonies are of average size after twentyf o u r h o u r s ' g r o w t h on agar, blood agar, or eosin-methy]ene blue plates, and they are round, smooth, translucent, and slightly elevated. In b r o t h medium there is a rapid and uniform clouding with the formation of sediment on the second day. Acid is f o r m e d on Russell'S slant w i t h o u t the f o r m a t i o n of gas. Dextrose, maltose, mannite, arabinose, cellobiose, duleite, xylose, and galactose are acidified readily, tRhamnose is f e r m e n t e d only after thirty-six hours" incubation. Lactose, sucrose, salicin, raffinose, and inosite remain unaffected. Dextrin and sorbite are utilized irregularly, the first of these being f e r m e n t e d readily b y several of the strains studied in this series as well as by two strains obtained t h r o u g h the courtesy of Dr. H. Welch and Dr. F. L. Mickle. The reaction varies f r o m n e u t r a l to strong alkalinity following complete growth in litmus milk. The m e t h y l red test is positive, the Voges-Proskauer reaction negative, and indol is formed f r o m peptone. Immunologic studies by Welch and Miekle 7~ demonstrated an antigenie fraction common to alkaleseens, and a m a j o r i t y of the F~exner strains. This is in accord with our observations since all of the strains were agglutinated in subtiter dilutions b y polyva]ent F l e x n e r group sera. However, no one of the F i e x n e r strains which we used was agglutinated b y alkalescens serum, a p h e n o m e n o n previously demonstrated b y Welch and Mickle for both a]kaleseens 7~ and dispard b The same authors showed the close relationship of a]kaleseens and the F l e x n e r types t h r o u g h the use of the S h w a r t z m a n phenomenon. All the strains secured from the patients in this series were agglutinated in low dilutions of high titer (1:10,000) t y p h o i d sera, and again the t y p h o i d organism remained unaffected in a]kaleseens serum. Identification of the organism and its separation f r o m the remainder of the mannite-fermenting d y s e n t e r y group can be accomplished t h r o u g h the f e r m e n t a t i o n of dulcite and rhamnose, the neutral or alkaline reaction in litmus milk, the agglutination in snbtiter dilution by p o l y v a l e n t F l e x n e r serum, and finally by the use of specific diagnostic sera. The routine procedures for the identificat~ou of this organism which we employ are as follows : An organism giving the typical typhoid-dysentery reaction on the Russell slant is inoculated into dextrose, mannit% lactose, rhamnose, and saeeharose. A broth tube is inoculated at the same time and allowed to remain at room temperature for the determination of motility at six, twelve, and eighteen hours.
598
T~[E J O U I % N A L O F PEDIATRICS DEXT.
3/IANIg.
LACT.
RHAIVL
NACC.
~/[OTILITY
Typhoid Ylexner
Ac Ac
Ac Ae
0 0
0 0
+ 0
Sonne
Ac
Ac
0 0 (rarely Ac) Ac
0
0
Alkaleseens
Ac
Ac
Ac
0
0
Ac (late) 0
(36 hr.)
This preliminary separation is confirmed by the use of type specific Sonne and alkalescens sere (prepared by tile injection of rabbits with increasing doses of formalin killed organisms), and commercial polyvalent Flexner and typhoid sera. The formation of indol is determined, but the reaction in litmus milk is not routinely investigated. lCEPORT ON CASES CASE 1.--R. D., six-and-one-half-year-old female. Diagnosis: Acute pyelonephritis. A child with irrelevant past and family history was admitted because of frequency of urination of one week's duration with drowsiness and fever for four days. The temperature had remained around 104 ~ F. for the three days prior to entry, and mild abdominal pain had been present during the same perio d . There had been no similar complaints by other members of the household. The entrance examination showed her to be listless and to have a temperature of 104 ~ F. There was marked bilateral costovertebral tenderness. The Urine contained white blood cells, and there was a leucocytosls (13,500 per c.mm.) with 73 per cent polymorphonuclear forms. Pure growths of Shigella alkaleseens were obtained in five cultures from the urine (catheterized) and three stool cultures. The temperatm'e continued to range as high as 105 ~ F. during the first five days in the hospital, and examinations of the urine, obtained by catheter, throughout the same period revealed many white cells. The fever abated on the ninth day of illness, but the pyuria persisted until the instigation of a ketogenic diet. No abnormalities were demonstrated by pyelogr a p h y or kidney function tests. Two years a f t e r this admission she again acquired acute pyelonephritis with the colon bacillus as the offender. At the time of writing she is reported to be free from symptoms. CASE 2.--]3. E., five-month-old female. Diagnosis: Acute pyelonephritis. This previously well i n f a n t was admitted because of fever and fretfulness of one d a y ' s duration. Six days prior to entry she became irritable and refused her food. Following this she was in good health until the day of admission. Her physical examination revealed a temperature of t04 ~ F. and extreme restlessness. The urine contained many white cells, and there was a slight trace of albumin. A moderate polynucleosls was present with a total white blood cell count of 14,000 per c.mm. She was acutely ill during the first nine days, and the temperature fluctuated between 100 and 104" F. while large numbers of white cells were present in all specimens of urine. Culture of the urine showed pure growth of Shigetla alkaleseens on three occasions, while a negative culture was obtained from the stools. The temperature returned to normal on the tenth day, but the pyurla persisted until a f t e r t r e a t m e n t with methenamine. Intravenous pyelogrums were suggestive of a right hydronephresls, but further investigation was deferred. She has been in good health since discharge, and the urine has been normal on several examinations. CASK 3.--A. J., twenty-one-month-old female. Diagnosis: Acute pyelonephritis. This i n f a n t was admitted because of pain on urination and fever of ten d a y s ' duration. The past and family history w~s not contributory. The onset was sudden, and the fever, anorexia, and dysuria persisted for five days without change. During the next five days there was a n increase in the severity of symptoms as well as con-
WOOLLEu AND S~VE]~T: SttIGE~,LA ALKALESCE~NS
599
siderable abdominal pain. She appeared acutely ill at the time of admission with a temperature of 103 ~ F. The urine contained many leucocytes, and the white blood cell count was elevated to 19,000 per c.mm., 70 per cent of which were polymorphonuclear cells. Shigella a~ka~escens was cultured from two specimens of urine as well as from the stools. She was acutely ill for six days, and the temperature remained between 100 and 104.5 ~ F. The urine began to clear by the end of the first week in t h e h o s p i t a l , and improvement followed. Intravenous pyelograms~ cystograms, and kidney function tests were all within normal limits. Agglutinins against the organism were present in the serum at dilutions of 1:1280. The total period of hospitalization was four weeks, and she has been free from symptoms since discharge. CASE 4.--L. McD., slxteen-month-old female. Diagnosis: Acute pyelonephritis. This infant was entirely well until three weeks before admission when she developed fever, listlessness, and irritability. These complaints persisted unchanged for two weeks and then increased in severity. Pyuria was found, and a course of methenamine given outside of the hospital without relief. She appeared pale but was afebrile at entry. The urine contained a large number of cells and Shigella cdkaleseens was obtained from it by culture. The white blood cells were not elevated in number. On the t h i r d day in the hospital the temperature rose to 103 ~ F. 1V[ethenamine and ammonium chloride were given with excellent results. The urine cleared steadily, and she was discharged on the twenty-fifth day. Intravenous pyelograms and kidney function tests were normal. Agglutlnlns were not demonstrable in her serum, and the organisms were not recovered from the stools. CASE 5.--L. 1~., eleven-year-old female. Diagnosis: Dysentery, Oxyuris infestation. The girl was admitted because of abdominal paln and vomiting of sixteen hours' duration. She had been well in the past, and there had been no similar complaints in the household. Three days before entry she had a mild diarrhea without other symptoms. She awakened with headache and dizziness on the day of admission, and these symptoms were followed by vomiting and abdominal pain. Abdominal symptoms became more marked during the course of the day, and the vomiting persisted. The temperature was 102 ~ F. and the pulse rate 110. The abdomen was spastic and diffusely tender, the latter finding being confirmed by rectal examination. The white blood cell count was 26,000 per e.mm., and 90 per cent of these were polymorphonuclear forms. A ]aparotomy was performed, and a normal appearing appendix removed. Sections of this showed infestation with Oxyuris vermieularis but were without evidence of acute inflammation. The postoperative course was uneventful until the fourth day when the temperature suddenly rose to t04 ~ F. and she passed seven watery green stools within a few hours. Culture of these showed Shige~la aIkaleseens in large numbers. On the following day the temperature began to fall and the diarrhea to subside. The remainder of her stay was uneventful~ and the organisms gradually disappeared from the stools. CASE 6.--F. C., slx-year-o]d male. Diagnosis: Enteric infection. This patient had been well until three days before entry. A t that time he began to vomit and complain of intense abdominal pain which was crampIike in nature and severe enough to keep him awake at night. There were no deviations from the normal physical findings except for a temperature of 102 ~ F. Laboratory data were not helpful until large numbers of Shigella a~ka~escens were found by stool culture. The fever abated on the fourth day of the illness, and the abdominal symptoms disappeared. Repetitions of the stool culture showed a constantly diminishing number of the organisms.
600
T:HE JOUI~NAD O/P PE,DIATRICS
CAS~: 7.--E. A., six-and-one-half-year-old female. Diagnosis: Enteric infection. This girl was admitted because of vomiting and delirium of twenty-four hours' duration. She had bee~ vaccinated te~ days before entry, and a primary take had resulted. This caused her little discomfort, and she remained well until the onset of unusually severe and persistent vomiting. Her face was flushed at admission, she was completely disoriented, and there was severe ketosis. Laboratory data were not unusual except for large amounts of acetone in the urine. A lumbar puncture was made, and normM cerebrospinM fluid was obtained. Stool cultures showed an almost pure growth of Shigella al]~aleseen8. A f t e r several intravenous infusions of glucose were administered, the temperature fell from 103 ~ F. to normal within forty-eight hours. The ketosis also disappeared by the end of this period, and orientation was reestablished. The stool cultures continued to show SMgella alkalescens for several weeks, always, however, in diminishing number. Agglutinins were demonstrable in her serum for both the antogenous and stock antigens, a titer of 1:320 being reached during the fourth week. The Flexner antigens were not affected. CASE 8.---M. L., ten-month-old male. Diagnosis: Dysentery. This infant was admitted because of diarrhea and vomiting of seventy-two hours' duration. There had been a questionable exposure to contaminated drinking water ten days before the onset of symptoms. Three days prior to entry he began having liquid green stools and vomiting. These symptoms persisted mltil admission. Physical findings wore essentially those of dehydration and ketosis. The white blood cell count was 9,800 per c.mm., and there was a slight lymphoeytosis. The stools gave a chemicM test for blood even though none was found microscopically. :Fluids were provided parenterally during the first week because of the persistence of vomiting and diarrhea. Large ~umbers of Shigella all~alescens were recovered from cultures of the stools during the diarrheal period, but these rapidly disappeared with the subsidence of symptoms. Agglutinins were demonstrable in dilutions of only 1:40 of the patient's serum. Case 9.--13. W., twenty-year-old female. Diagnosis: Acute enteritis. A nurse on ward duty was suddenly stricken with diarrhea and ~omiting. Laboratory data and. physical findings, were within normal limits. Large numbers of Nhigella allcalescens were obtained from several cultures of the stools. The vomiting ceased a f t e r twenty-four hours, but the diarrhea persisted for three days. Agglutination tests were not made.
Three other strains have been recorded in this laboratory. Two were f r o m patients with chronic p y u r i a in whom this species occurred as a t r a n s i t o r y or secondary invader. In one of these the streptococcus appeared to be tile p r i m a r y offender, while it was the colon bacillus in the other. The third strain was sent to us for identification by a neighboring hospital. It had been recovered f r o m tile urine of a f o r t y year-old woman with postoperative pyelitis. The organism was cult u r e d several times before a satisfactory response to methenamine t h e r a p y was obtained. DISCUSSION AND ~U~3s
This series, while composed of only nine eases, represents a larger n u m b e r than heretofore r e p o r t e d and brings out several i m p o r t a n t features. F o u r of these patients represent instances of infection of the g e n i t o u r i n a r y t r a c t with the organism appearing in the urine in
~VOOL,LEY A N D S W E E T :
SllIGELLA
ALKALESCE~NS
()0]
p u r e culture. The case reports in the l i t e r a t u r e are p r i m a r i l y instances of g e n i t o u r i n a r y infection r a t h e r t h a n g a s t r o i n t e s t i n a l disease such as we o r d i n a r i l y associate with the p a r a d y s e n t e r y organisms. D u r i n g the same period of time over which these p a t i e n t s were seen, there were t h i r t y - s e v e n cases of dysentery, p r o v e d bacteriologically, adm i t r e d to the hospital. These were all due to either the F t e x n e r or Sonne type. Only one of these showed evidence of pyuria, and rep e a t e d urine cultures failed to d e m o n s t r a t e the organism. E x c e p t for the cases e n u m e r a t e d in this paper, the d y s e n t e r y organism was not obtained f r o m a n y p a t i e n t with p y u r i a a d m i t t e d over the same period of time. The f o u r cases herein r e p o r t e d were c o m p a r a b l e in severity to the acute p y e l o n e p h r i t i s seen in the same age group and due to the colon bacillus. Three of t h e m were t r e a t e d with either a ketogenie diet or m e t h e n a m i n e , and all recovered w i t h o u t subsequent demonstrable d a m a g e of the g e n i t o u r i n a r y tract. Blood cultures were not t a k e n in these cases, and there was no evidence of septicemia as described b y other writers. R e p o r t s in the ]iterature consistently fail to p r o v e the presence of gastroenterie disorders due to Shigella alkalescens. The one exception to this is the single epidemic we have m e n t i o n e d a b o v e d ~ Boyd, ~~ in his extensive s t u d y of the m a n n i t e - f e r m e n t i n g g r o u p of bacilli, did not observe d y s e n t e r y a t t r i b u t a b l e to Shigella alkalescens. Two different sets of s y m p t o m s were p r e s e n t e d b y five of the p a t i e n t s in this series. P a t i e n t s eight and nine suffered f r o m profuse diarrhea, similar in s e v e r i t y to instances of mild d y s e n t e r y due to other p a r a d y s e n t e r y types. In three of the other p a t i e n t s vomiting" was an outstanding s y m p t o m a n d was severe enough in one instance to require r e p e a t e d a d m i n i s t r a t i o n s of p a r e n t e r a l fluid to combat the ketosis. Abdominal p a i n was a p r o m i n e n t s y m p t o m and was severe enough in one case to suggest the need f o r l a p a r o t o m y . The o r g a n i s m was p r e s e n t in large n u m b e r s in each of these patients d u r i n g the height of the s y m p t o m s and then decreased with clinical i m p r o v e m e n t . D i a r r h e a was present in only one of the three patients. An a g g l u t i n a t i o n test was made on only one of these three and was then positive in dilutions of 1:320'. I t is not justifiable to conclude f r o m three cases t h a t Shigella alkalescens is an etiologic f a c t o r in such s y m p t o m s ; y e t it should be emphasized t h a t it was the only organism p r e s e n t to which the etiology could be attributed. Others of the enteric group do give rise to s i m i l a r findings, and the m o r e liberal use of stool cultures f r o m such patients m a y establish the f a c t of the p a t h o g e n i c i t y of the Shigellc~ alkalescens. I n the past we have regarded pa.tients h a r b o r i n g Shigella alkalescens in the same light as those f r o m w h o m i n d i s p u t a b l y v i r u l e n t species have been recovered, m a i n t a i n i n g enteric technique and requiring nega-
602
TI-I~ JOUaNA~
O~ P~DI~TmCS
tire stool cultures before release. This survey has modified our concept. The observations of Gilbert and Coleman 11 and of Brown and
A n d e r s o n 12 have shown the organism to be widely distributed throughout the community. It is f o u n d in an appreciable portion of the population, and yet enteric symptoms are encountered but rarely. It would seem probable t h a t the state of the host was of more importance t h a n the presence of the organism. Our present tendency would be to r e g a r d it more as we do the M o r g a n bacillus, the group described b y Fothergill, 13 and several other enteric organisms. They are all pathogenic at times but are encountered f a i r l y f r e q u e n t l y in the asymptomatie population. The single r e c o r d e d epidemic suggests that certain strains are endowed at times with increased virulence and are then pathogenic for an appreciable p e r c e n t a g e of individuals. The absence of f u r t h e r epidemiologie r e p o r t s makes this possibility infrequent enough to be ignored so f a r as individual carriers are concerned. S,UMMAI~u
A description of Shigdla. alkalescens has been presented, with an outline for its detection and differentiation. In comparison to the r e m a i n d e r of the p a r a d y s e n t e r y group this f o r m has a predilection f o r the u r i n a r y t r a c t r a t h e r than being the cause of clinical dysentery. Its presence should be considered in any case of u r i n a r y infection due to a manuite-fermenting member of the d y s e n t e r y group. Occasional cases of mild d y s e n t e r y are attributable to the species. The organism was r e c o v e r e d from the stools of three children with abdominal pain and severe vomiting. Gastroenterie symptoms are infrequent, and an appreciable portion of the population h a r b o r the organism. I t would therefore seem unnecessary to isolate the individual carrier except in the rare instance of an epidemic or d u r i n g hospitalization. I~EI~ERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Andrewes, F . W . " Lancet 1: 560, 1918. Smith, 5., and Fraser, A . M . : J. Path. & t~act. 31: 511, 1928. Popoff, N. W., and Spanswiek, M . P . : J. Lab. & Clin. Med, 16: 437, 1931. Starkey, D. It.: Canad. M. A. J. 31: 42, 1934. MacKenzie, D. W., and l~atner, IV[.: J. UroL 31: 671, 1934. l~furray, 1Vi. F., and Pike, 1~. M.: Clin. Misc., Mary L Bassett I-Iosp. 1: 68, 1934. Welch, I-I., and Mickle, F . L . : (a) Am. 5. Pub. Itealth 24: 219, 1934. (b) J. Infect. Dis. 50: 524, 1932. Well, A. 5.: Zentralbl. f. Bakt. 12: 376, 199,9 (orig.). Snyder, N. L., and Hanner, 5. P.: J. Infect. Dis. 60: 51, 1937. Boyd, J. S. 1~.: J. Roy. A r m y M. Corps 5 9 : 2 4 1 (331), ]932. Gilbert, 1~., and Coleman, IV[.: Am. J. Pub. Health 24: 449, 1934. Brown, M. It., and Anderson, E . A . : Canad. Pub. Health J. 27: 560, 1936. Fothergill, L . D . : J. Infect. Dis. 45: 393, 1929.
300 LONGWOOD AVENUE
CLINICAL APPRAISAL O.I0 NINE
CASES FRo~ WHICH
THE ORGANIS.lV[ W A S ISOLATED
PAu~ V. WOOLLEn, JR., M.D., AND MARIAN SWEET BosTon, MASS. HdlGELLA
a l k a t e s c e n s was described in 1918 b y Andrewes, 1 who
id not a t t a c h p a t h o g e n i c i m p o r t a n c e to it, considering it only as an o r g a n i s m easily confused with the v i r u l e n t d y s e n t e r y types. Since then a few isolated r e p o r t s of h u m a n infection have a p p e a r e d in the literature. We wish to r e p o r t a series of nine patients f r o m w h o m this o r g a n i s m was recovered. I~ITF~R, ATUR,E
The first report of human infection was made by Smith and Fraser 2 in 1928. They recovered the organism from the blood, stools, urine, a n d uterine discharge of a w o m a n in the p o s t p a r t u m period. The a u t o g e n o u s strain w a s a g g l u t i n a t e d in 1:480 dilution of the p a t i e n t ' S serum. H e r r e c o v e r y was complete w i t h o u t specific t h e r a p y . Three y e a r s l a t e r Popoff a n d S p a n s w i c k 3 observed a p a t i e n t with pyelon e p h r i t i s during p r e g n a n c y and cultured the organism f r o m the stool a n d urine. They d e m o n s t r a t e d a g g l u t i n i n s in a dilution of 1:640 of the p a t i e n t ' S serum. The organisms d i s a p p e a r e d following abortion. I n 1934 S t a r k e y 4 r e c o r d e d an instance of pyelitis with the S h i g e l l a a l k a l e s c e n s in the stool, blood, and urine. A g g l u t i n a t i n g antibodies were not d e m o n s t r a t e d b u t " p r e c i p i t i n s " were present. The same year, 1ViacKenzie and R a t h e r 5 noted a n o t h e r p a t i e n t f r o m whom alkalescens was r e c o v e r e d in the blood, stool, and urine. This p a t i e n t showed evidence of severe septicemia and p y e l o n e p h r i t i s b u t r e c o v e r e d a f t e r a severe course. The a g g l u t i n a t i o n tests w e r e not conclusive in this instance. M u r r a y and Pike 6 r e c o v e r e d the o r g a n i s m f r o m the urine of an inf a n t w i t h acute pyelitis and f o u n d a g g l u t i n i n s to be p r e s e n t in the s e r u m at a dilution of 1:640. The only epidemiologic r e p o r t w a s m a d e b y Welch and Miekle, w who studied an o u t b r e a k of mild d y s e n t e r y a m o n g the students of a~l eastern university. S h i g e l l a a l k a l e s c e n s was r e c o v e r e d f r o m the stools of all those infected as well as f r o m a food h a n d l e r who was s y m p t o m - f r e e . These a u t h o r s also studied f o u r strains isolated f r o m p a t i e n t s with chronic u r i n a r y t r a c t infection. Well, s in :From the Departrflent of Pediatrics, IZIarvard 1VIedieaI School, and the I n f a n t s ' and Children's I-IospJtals, ]9oston. 596
WOOLLEY AND SWE~T:
S~IIGEI~LA ALKALESCEI~S
597
Germany, has noted the organism in one patient with pyuria. S n y d e r and Harmer 9 have recently contributed another r e p o r t of pyuria due to Shigella alkalescens. BACT%I~IOLOGY
In morphology the Shigella alkalescens offers n o t h i n g to differentiate it f r o m the r e m a i n d e r of the genus, being nonmotile, Gram-negative, and coliform in shape. The colonies are of average size after twentyf o u r h o u r s ' g r o w t h on agar, blood agar, or eosin-methy]ene blue plates, and they are round, smooth, translucent, and slightly elevated. In b r o t h medium there is a rapid and uniform clouding with the formation of sediment on the second day. Acid is f o r m e d on Russell'S slant w i t h o u t the f o r m a t i o n of gas. Dextrose, maltose, mannite, arabinose, cellobiose, duleite, xylose, and galactose are acidified readily, tRhamnose is f e r m e n t e d only after thirty-six hours" incubation. Lactose, sucrose, salicin, raffinose, and inosite remain unaffected. Dextrin and sorbite are utilized irregularly, the first of these being f e r m e n t e d readily b y several of the strains studied in this series as well as by two strains obtained t h r o u g h the courtesy of Dr. H. Welch and Dr. F. L. Mickle. The reaction varies f r o m n e u t r a l to strong alkalinity following complete growth in litmus milk. The m e t h y l red test is positive, the Voges-Proskauer reaction negative, and indol is formed f r o m peptone. Immunologic studies by Welch and Miekle 7~ demonstrated an antigenie fraction common to alkaleseens, and a m a j o r i t y of the F~exner strains. This is in accord with our observations since all of the strains were agglutinated in subtiter dilutions b y polyva]ent F l e x n e r group sera. However, no one of the F i e x n e r strains which we used was agglutinated b y alkalescens serum, a p h e n o m e n o n previously demonstrated b y Welch and Mickle for both a]kaleseens 7~ and dispard b The same authors showed the close relationship of a]kaleseens and the F l e x n e r types t h r o u g h the use of the S h w a r t z m a n phenomenon. All the strains secured from the patients in this series were agglutinated in low dilutions of high titer (1:10,000) t y p h o i d sera, and again the t y p h o i d organism remained unaffected in a]kaleseens serum. Identification of the organism and its separation f r o m the remainder of the mannite-fermenting d y s e n t e r y group can be accomplished t h r o u g h the f e r m e n t a t i o n of dulcite and rhamnose, the neutral or alkaline reaction in litmus milk, the agglutination in snbtiter dilution by p o l y v a l e n t F l e x n e r serum, and finally by the use of specific diagnostic sera. The routine procedures for the identificat~ou of this organism which we employ are as follows : An organism giving the typical typhoid-dysentery reaction on the Russell slant is inoculated into dextrose, mannit% lactose, rhamnose, and saeeharose. A broth tube is inoculated at the same time and allowed to remain at room temperature for the determination of motility at six, twelve, and eighteen hours.
598
T~[E J O U I % N A L O F PEDIATRICS DEXT.
3/IANIg.
LACT.
RHAIVL
NACC.
~/[OTILITY
Typhoid Ylexner
Ac Ac
Ac Ae
0 0
0 0
+ 0
Sonne
Ac
Ac
0 0 (rarely Ac) Ac
0
0
Alkaleseens
Ac
Ac
Ac
0
0
Ac (late) 0
(36 hr.)
This preliminary separation is confirmed by the use of type specific Sonne and alkalescens sere (prepared by tile injection of rabbits with increasing doses of formalin killed organisms), and commercial polyvalent Flexner and typhoid sera. The formation of indol is determined, but the reaction in litmus milk is not routinely investigated. lCEPORT ON CASES CASE 1.--R. D., six-and-one-half-year-old female. Diagnosis: Acute pyelonephritis. A child with irrelevant past and family history was admitted because of frequency of urination of one week's duration with drowsiness and fever for four days. The temperature had remained around 104 ~ F. for the three days prior to entry, and mild abdominal pain had been present during the same perio d . There had been no similar complaints by other members of the household. The entrance examination showed her to be listless and to have a temperature of 104 ~ F. There was marked bilateral costovertebral tenderness. The Urine contained white blood cells, and there was a leucocytosls (13,500 per c.mm.) with 73 per cent polymorphonuclear forms. Pure growths of Shigella alkaleseens were obtained in five cultures from the urine (catheterized) and three stool cultures. The temperatm'e continued to range as high as 105 ~ F. during the first five days in the hospital, and examinations of the urine, obtained by catheter, throughout the same period revealed many white cells. The fever abated on the ninth day of illness, but the pyuria persisted until the instigation of a ketogenic diet. No abnormalities were demonstrated by pyelogr a p h y or kidney function tests. Two years a f t e r this admission she again acquired acute pyelonephritis with the colon bacillus as the offender. At the time of writing she is reported to be free from symptoms. CASE 2.--]3. E., five-month-old female. Diagnosis: Acute pyelonephritis. This previously well i n f a n t was admitted because of fever and fretfulness of one d a y ' s duration. Six days prior to entry she became irritable and refused her food. Following this she was in good health until the day of admission. Her physical examination revealed a temperature of t04 ~ F. and extreme restlessness. The urine contained many white cells, and there was a slight trace of albumin. A moderate polynucleosls was present with a total white blood cell count of 14,000 per c.mm. She was acutely ill during the first nine days, and the temperature fluctuated between 100 and 104" F. while large numbers of white cells were present in all specimens of urine. Culture of the urine showed pure growth of Shigetla alkaleseens on three occasions, while a negative culture was obtained from the stools. The temperature returned to normal on the tenth day, but the pyurla persisted until a f t e r t r e a t m e n t with methenamine. Intravenous pyelogrums were suggestive of a right hydronephresls, but further investigation was deferred. She has been in good health since discharge, and the urine has been normal on several examinations. CASK 3.--A. J., twenty-one-month-old female. Diagnosis: Acute pyelonephritis. This i n f a n t was admitted because of pain on urination and fever of ten d a y s ' duration. The past and family history w~s not contributory. The onset was sudden, and the fever, anorexia, and dysuria persisted for five days without change. During the next five days there was a n increase in the severity of symptoms as well as con-
WOOLLEu AND S~VE]~T: SttIGE~,LA ALKALESCE~NS
599
siderable abdominal pain. She appeared acutely ill at the time of admission with a temperature of 103 ~ F. The urine contained many leucocytes, and the white blood cell count was elevated to 19,000 per c.mm., 70 per cent of which were polymorphonuclear cells. Shigella a~ka~escens was cultured from two specimens of urine as well as from the stools. She was acutely ill for six days, and the temperature remained between 100 and 104.5 ~ F. The urine began to clear by the end of the first week in t h e h o s p i t a l , and improvement followed. Intravenous pyelograms~ cystograms, and kidney function tests were all within normal limits. Agglutinins against the organism were present in the serum at dilutions of 1:1280. The total period of hospitalization was four weeks, and she has been free from symptoms since discharge. CASE 4.--L. McD., slxteen-month-old female. Diagnosis: Acute pyelonephritis. This infant was entirely well until three weeks before admission when she developed fever, listlessness, and irritability. These complaints persisted unchanged for two weeks and then increased in severity. Pyuria was found, and a course of methenamine given outside of the hospital without relief. She appeared pale but was afebrile at entry. The urine contained a large number of cells and Shigella cdkaleseens was obtained from it by culture. The white blood cells were not elevated in number. On the t h i r d day in the hospital the temperature rose to 103 ~ F. 1V[ethenamine and ammonium chloride were given with excellent results. The urine cleared steadily, and she was discharged on the twenty-fifth day. Intravenous pyelograms and kidney function tests were normal. Agglutlnlns were not demonstrable in her serum, and the organisms were not recovered from the stools. CASE 5.--L. 1~., eleven-year-old female. Diagnosis: Dysentery, Oxyuris infestation. The girl was admitted because of abdominal paln and vomiting of sixteen hours' duration. She had been well in the past, and there had been no similar complaints in the household. Three days before entry she had a mild diarrhea without other symptoms. She awakened with headache and dizziness on the day of admission, and these symptoms were followed by vomiting and abdominal pain. Abdominal symptoms became more marked during the course of the day, and the vomiting persisted. The temperature was 102 ~ F. and the pulse rate 110. The abdomen was spastic and diffusely tender, the latter finding being confirmed by rectal examination. The white blood cell count was 26,000 per e.mm., and 90 per cent of these were polymorphonuclear forms. A ]aparotomy was performed, and a normal appearing appendix removed. Sections of this showed infestation with Oxyuris vermieularis but were without evidence of acute inflammation. The postoperative course was uneventful until the fourth day when the temperature suddenly rose to t04 ~ F. and she passed seven watery green stools within a few hours. Culture of these showed Shige~la aIkaleseens in large numbers. On the following day the temperature began to fall and the diarrhea to subside. The remainder of her stay was uneventful~ and the organisms gradually disappeared from the stools. CASE 6.--F. C., slx-year-o]d male. Diagnosis: Enteric infection. This patient had been well until three days before entry. A t that time he began to vomit and complain of intense abdominal pain which was crampIike in nature and severe enough to keep him awake at night. There were no deviations from the normal physical findings except for a temperature of 102 ~ F. Laboratory data were not helpful until large numbers of Shigella a~ka~escens were found by stool culture. The fever abated on the fourth day of the illness, and the abdominal symptoms disappeared. Repetitions of the stool culture showed a constantly diminishing number of the organisms.
600
T:HE JOUI~NAD O/P PE,DIATRICS
CAS~: 7.--E. A., six-and-one-half-year-old female. Diagnosis: Enteric infection. This girl was admitted because of vomiting and delirium of twenty-four hours' duration. She had bee~ vaccinated te~ days before entry, and a primary take had resulted. This caused her little discomfort, and she remained well until the onset of unusually severe and persistent vomiting. Her face was flushed at admission, she was completely disoriented, and there was severe ketosis. Laboratory data were not unusual except for large amounts of acetone in the urine. A lumbar puncture was made, and normM cerebrospinM fluid was obtained. Stool cultures showed an almost pure growth of Shigella al]~aleseen8. A f t e r several intravenous infusions of glucose were administered, the temperature fell from 103 ~ F. to normal within forty-eight hours. The ketosis also disappeared by the end of this period, and orientation was reestablished. The stool cultures continued to show SMgella alkalescens for several weeks, always, however, in diminishing number. Agglutinins were demonstrable in her serum for both the antogenous and stock antigens, a titer of 1:320 being reached during the fourth week. The Flexner antigens were not affected. CASE 8.---M. L., ten-month-old male. Diagnosis: Dysentery. This infant was admitted because of diarrhea and vomiting of seventy-two hours' duration. There had been a questionable exposure to contaminated drinking water ten days before the onset of symptoms. Three days prior to entry he began having liquid green stools and vomiting. These symptoms persisted mltil admission. Physical findings wore essentially those of dehydration and ketosis. The white blood cell count was 9,800 per c.mm., and there was a slight lymphoeytosis. The stools gave a chemicM test for blood even though none was found microscopically. :Fluids were provided parenterally during the first week because of the persistence of vomiting and diarrhea. Large ~umbers of Shigella all~alescens were recovered from cultures of the stools during the diarrheal period, but these rapidly disappeared with the subsidence of symptoms. Agglutinins were demonstrable in dilutions of only 1:40 of the patient's serum. Case 9.--13. W., twenty-year-old female. Diagnosis: Acute enteritis. A nurse on ward duty was suddenly stricken with diarrhea and ~omiting. Laboratory data and. physical findings, were within normal limits. Large numbers of Nhigella allcalescens were obtained from several cultures of the stools. The vomiting ceased a f t e r twenty-four hours, but the diarrhea persisted for three days. Agglutination tests were not made.
Three other strains have been recorded in this laboratory. Two were f r o m patients with chronic p y u r i a in whom this species occurred as a t r a n s i t o r y or secondary invader. In one of these the streptococcus appeared to be tile p r i m a r y offender, while it was the colon bacillus in the other. The third strain was sent to us for identification by a neighboring hospital. It had been recovered f r o m tile urine of a f o r t y year-old woman with postoperative pyelitis. The organism was cult u r e d several times before a satisfactory response to methenamine t h e r a p y was obtained. DISCUSSION AND ~U~3s
This series, while composed of only nine eases, represents a larger n u m b e r than heretofore r e p o r t e d and brings out several i m p o r t a n t features. F o u r of these patients represent instances of infection of the g e n i t o u r i n a r y t r a c t with the organism appearing in the urine in
~VOOL,LEY A N D S W E E T :
SllIGELLA
ALKALESCE~NS
()0]
p u r e culture. The case reports in the l i t e r a t u r e are p r i m a r i l y instances of g e n i t o u r i n a r y infection r a t h e r t h a n g a s t r o i n t e s t i n a l disease such as we o r d i n a r i l y associate with the p a r a d y s e n t e r y organisms. D u r i n g the same period of time over which these p a t i e n t s were seen, there were t h i r t y - s e v e n cases of dysentery, p r o v e d bacteriologically, adm i t r e d to the hospital. These were all due to either the F t e x n e r or Sonne type. Only one of these showed evidence of pyuria, and rep e a t e d urine cultures failed to d e m o n s t r a t e the organism. E x c e p t for the cases e n u m e r a t e d in this paper, the d y s e n t e r y organism was not obtained f r o m a n y p a t i e n t with p y u r i a a d m i t t e d over the same period of time. The f o u r cases herein r e p o r t e d were c o m p a r a b l e in severity to the acute p y e l o n e p h r i t i s seen in the same age group and due to the colon bacillus. Three of t h e m were t r e a t e d with either a ketogenie diet or m e t h e n a m i n e , and all recovered w i t h o u t subsequent demonstrable d a m a g e of the g e n i t o u r i n a r y tract. Blood cultures were not t a k e n in these cases, and there was no evidence of septicemia as described b y other writers. R e p o r t s in the ]iterature consistently fail to p r o v e the presence of gastroenterie disorders due to Shigella alkalescens. The one exception to this is the single epidemic we have m e n t i o n e d a b o v e d ~ Boyd, ~~ in his extensive s t u d y of the m a n n i t e - f e r m e n t i n g g r o u p of bacilli, did not observe d y s e n t e r y a t t r i b u t a b l e to Shigella alkalescens. Two different sets of s y m p t o m s were p r e s e n t e d b y five of the p a t i e n t s in this series. P a t i e n t s eight and nine suffered f r o m profuse diarrhea, similar in s e v e r i t y to instances of mild d y s e n t e r y due to other p a r a d y s e n t e r y types. In three of the other p a t i e n t s vomiting" was an outstanding s y m p t o m a n d was severe enough in one instance to require r e p e a t e d a d m i n i s t r a t i o n s of p a r e n t e r a l fluid to combat the ketosis. Abdominal p a i n was a p r o m i n e n t s y m p t o m and was severe enough in one case to suggest the need f o r l a p a r o t o m y . The o r g a n i s m was p r e s e n t in large n u m b e r s in each of these patients d u r i n g the height of the s y m p t o m s and then decreased with clinical i m p r o v e m e n t . D i a r r h e a was present in only one of the three patients. An a g g l u t i n a t i o n test was made on only one of these three and was then positive in dilutions of 1:320'. I t is not justifiable to conclude f r o m three cases t h a t Shigella alkalescens is an etiologic f a c t o r in such s y m p t o m s ; y e t it should be emphasized t h a t it was the only organism p r e s e n t to which the etiology could be attributed. Others of the enteric group do give rise to s i m i l a r findings, and the m o r e liberal use of stool cultures f r o m such patients m a y establish the f a c t of the p a t h o g e n i c i t y of the Shigellc~ alkalescens. I n the past we have regarded pa.tients h a r b o r i n g Shigella alkalescens in the same light as those f r o m w h o m i n d i s p u t a b l y v i r u l e n t species have been recovered, m a i n t a i n i n g enteric technique and requiring nega-
602
TI-I~ JOUaNA~
O~ P~DI~TmCS
tire stool cultures before release. This survey has modified our concept. The observations of Gilbert and Coleman 11 and of Brown and
A n d e r s o n 12 have shown the organism to be widely distributed throughout the community. It is f o u n d in an appreciable portion of the population, and yet enteric symptoms are encountered but rarely. It would seem probable t h a t the state of the host was of more importance t h a n the presence of the organism. Our present tendency would be to r e g a r d it more as we do the M o r g a n bacillus, the group described b y Fothergill, 13 and several other enteric organisms. They are all pathogenic at times but are encountered f a i r l y f r e q u e n t l y in the asymptomatie population. The single r e c o r d e d epidemic suggests that certain strains are endowed at times with increased virulence and are then pathogenic for an appreciable p e r c e n t a g e of individuals. The absence of f u r t h e r epidemiologie r e p o r t s makes this possibility infrequent enough to be ignored so f a r as individual carriers are concerned. S,UMMAI~u
A description of Shigdla. alkalescens has been presented, with an outline for its detection and differentiation. In comparison to the r e m a i n d e r of the p a r a d y s e n t e r y group this f o r m has a predilection f o r the u r i n a r y t r a c t r a t h e r than being the cause of clinical dysentery. Its presence should be considered in any case of u r i n a r y infection due to a manuite-fermenting member of the d y s e n t e r y group. Occasional cases of mild d y s e n t e r y are attributable to the species. The organism was r e c o v e r e d from the stools of three children with abdominal pain and severe vomiting. Gastroenterie symptoms are infrequent, and an appreciable portion of the population h a r b o r the organism. I t would therefore seem unnecessary to isolate the individual carrier except in the rare instance of an epidemic or d u r i n g hospitalization. I~EI~ERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Andrewes, F . W . " Lancet 1: 560, 1918. Smith, 5., and Fraser, A . M . : J. Path. & t~act. 31: 511, 1928. Popoff, N. W., and Spanswiek, M . P . : J. Lab. & Clin. Med, 16: 437, 1931. Starkey, D. It.: Canad. M. A. J. 31: 42, 1934. MacKenzie, D. W., and l~atner, IV[.: J. UroL 31: 671, 1934. l~furray, 1Vi. F., and Pike, 1~. M.: Clin. Misc., Mary L Bassett I-Iosp. 1: 68, 1934. Welch, I-I., and Mickle, F . L . : (a) Am. 5. Pub. Itealth 24: 219, 1934. (b) J. Infect. Dis. 50: 524, 1932. Well, A. 5.: Zentralbl. f. Bakt. 12: 376, 199,9 (orig.). Snyder, N. L., and Hanner, 5. P.: J. Infect. Dis. 60: 51, 1937. Boyd, J. S. 1~.: J. Roy. A r m y M. Corps 5 9 : 2 4 1 (331), ]932. Gilbert, 1~., and Coleman, IV[.: Am. J. Pub. Health 24: 449, 1934. Brown, M. It., and Anderson, E . A . : Canad. Pub. Health J. 27: 560, 1936. Fothergill, L . D . : J. Infect. Dis. 45: 393, 1929.
300 LONGWOOD AVENUE