Symposium on Diseases of the Liver
Spontaneous Bacterial Peritonitis in Cirrhosis: Endemic or Epidemic? Jose Pinto Correia, M.D.,* and Harold O. Conn, M.D.**
Previous reports from this hospitaP' 4 have suggested thatspontanebacterial peritonitis is a common complication of cirrhosis. Although we had reported 29 patients with this disorder, 27 of whom had been encountered at a single hospital during a 12 year period, we were concerned about the relative rarity of reports of such cases from elsewhere. At that time we were able to locate only 42 other cases reported in the world's literature. Furthermore, the disease was virtually unknown to many knowledgeable physicians. Our concern was increased by the fact that our encounters with this syndrome continued and, in fact, sharply accelerated. Was this an endemic, limited in some strange way to our institution? Were we merely more aware of this disorder and discovering it earlier in its course, or was the incidence of this hitherto uncommon disease rapidly increasing elsewhere as well? Other investigators have recently reported that they too have observed this serious syndrome7' 12, 14-16 with greater frequency than has been generally appreciated. The present investigation was undertaken to review our recent experience with spontaneous peritonitis and to compare our voluminous experience during the past 4 years with our earlier findings in the hope of solving some of these mysteries. OHS
METHODS AND MATERIALS During the 12V2 year period from January 1958 to July 1970 we encountered 25 bacteriologically proved episodes of spontaneous peritonitis in 23 patients at the West Haven Veterans Administration Hospital. These have been described in detail in an earlier report.4 The same chronologic identification numbers used in the earlier publication were retained. Four additional patients with bacteriologically unconfirmed "Associate Professor of Medicine, Hospital Escolar Sta Maria, Lisbon, Portugal; Formerly Visiting Associate Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut ''''Professor of Medicine, Yale University School of Medicine; Chief, Hepatic Diseases Unit, Veterans Administration Hospital, West Haven, Connecticut Supported in part by the Stratfield Fund. Medical Clinics of North America- Vol. 59, No. 4, July 1975
963
964
JOSE PINTO CORREIA AND HAROLD
O.
CONN
spontaneous peritonitis were encountered during this period. These 4 patients (numbers 25, 26,27,28) were presented in the earlier publication but are excluded from this analysis. During the 4 year period from July 1970 to June 1974 the diagnosis of spontaneous bacterial peritonitis has been proved bacteriologically in 25 patients who experienced 29 episodes at the West Haven Veterans Administration Hospital. These patients were chronologically assigned identification numbers from 30 to 54. In addition, 7 patients with bacteriologically unproved spontaneous peritonitis were observed during this interval. Thus, the increased incidence of spontaneous peritonitis was also seen in the more frequent diagnosis of "probable" cases as well as in the proved cases. Our analyses, however, will be restricted to comparison of the proved cases during the two periods. No patients with proved spontaneous peritonitis have been excluded. Bacteriologic examinations were performed with standardized techniques in the clinical bacteriology laboratory. These methods haw not changed significantly during the tenure of these investigations. Ex· aminations of ascitic fluid and blood were performed in the clinical microscopic laboratory using routine methods. The protein concentration of ascitic fluid was measured by the CUS04 method in the first series and by the Technicon SMA biuret technique during most of the second series. The latter method gives lower values than the former. Liver function tests and serum electrolytes were performed using the Technicon Autoanalyzer SMA 18. Serum alkaline phosphatase levels have been reported in international units during the past 4 years. For purposes of comparison, the alkaline phosphatase levels which had been reported in both Bodansky and King-Armstrong units in our previous publications, have been converted to international units by multiplying by factors of 20 and 7, respectively.
REVIEW OF PRESENT EXPERIENCE The chronologic appearance of spontaneous bacterial peritonitis for the whole 16 year period is shown in Figure 1. Starting as a bare trickle, the cases have become an awesome flood. During the past 4 years we have seen an average of 6.2 patients with neritonitis per year compared with an average of 1.8 during the previous period-a three to four-fold increase. CLINICAL FEATURES OF CIRRHOSIS. All 25 patients had cirrhosis, which had been established histologically in 22 (88 per cent). All but one had histories of excessive alcohol consumption and were considered to have alcoholic cirrhosis. The exception had post-hepatitis cirrhosis. Twenty-four were men and one was a woman. The mean age was 49.3 years with a range of 33 to 61 years. Twenty-four of the 25 patients died during the same admission in which peritonitis developed. Autopsies were performed in 15 of the 24 patients who died (62 per cent). One patient had lung cancer in addition to cirrhosis. CLINICAL FEATURES OF PERITONITIS (Table 1). Fever was present in 17 episodes (63 per cent), abdominal pain in 7 (27 per cent), rebound tenderness in 11 (42 per cent), and hypoactive bowel sounds in 10 (50
965
SPONTANEOUS BACTERIAL PERITONITIS IN CIRRHOSIS
7
S
NO.OF PATIENTS 4
3
1958 '59 'SO 'SI 'S2 'S3 'S4 '65 '66 '67 '68 '69 '70 '71 '72 '73 '74 (6mosl
(6mos)
Chronologic appearance of spontaneous peritonitis at the VA Hospital, West Haven, Connecticut. The progressive rise in the number of patients with peritonitis Figure l.
is evident. The 5 patients represented for 1974 were seen in the first 6 months of the year.
per cent). There were local signs of peritonitis in 12 episodes (46 per cent). There were no abdominal signs in 14 episodes (54 per cent), and in three patients the abdominal findings were not even mentioned. Peritonitis was not suspected in 10 patients. The suspicion of peritonitis was stimulated by a fluid leak from an umbilical hernia in 2, fever in 2, hypothermia in 2, and a rise in the leukocyte count of the ascitic fluid in 1 patient. Table 1.
Clinical Features of Spontaneous Peritonitis 1970-1974 REAB DO M- BOUND
PATIENT NO.
30 31 32 33 34 35A 35B 36 37A 37B 38 39 40A 40B 41 42 43 44 45 46A 46B 47 48 49 50 51 52 53 54
INAL INITIALS
R.S.
AGE
J.S. G.O.'B. W.J.T. P.P.
33 46 58 56 36 38
J.A.K. A.V.G.
56 43
N.H. M.F. A.S.T.
44 53 61
J.E.B. J .j-
>-l l"J
:>(")
ttI
rtl
0 d
l"J
Z >-l :>Z
0
"cl
rn
970
JOSE PINTO CORREIA AND HAROLD
O.
CONN
ase activity were each evaluated on 21 occasions (72 per cent). Serum albumin levels were less than 3.0 gm per 100 ml on 24 occasions (89 per cent). Serum urea levels were elevated (> 25 mg per 100 ml) in 18 episodes (62 per cent). PREDISPOSING AND PRECIPITATING FACTORS (Table 4). All patients had had overt ascites prior to and at the time peritonitis developed. The overwhelming majority had esophageal varices and other evidence of portal-systemic shunting. In all 6 who had had ammonia tolerance tests performed, the tests were grossly abnormal. Virtually all had advanced cirrhosis with seriously deranged liver function. Two patients (nos. 39 and 40A) had leakage of ascitic fluid through erosions of large umbilical hernias. A third had had a leaking hernia in which peritonitis did not develop; several months later, after the hernia had healed, peritonitis developed. Previous paracentesis had been performed in 10 of 29 episodes from 2 to 175 days before the onset of peritonitis (mean 52 days). Six of the 10 had preceded the peritonitis by more than 1 month. Two patients (nos. 39 and 40B) had had portacaval anastomoses 13 and 20 days prior to the appearance of peritonitis, respectively. In no other instances had the integrity of the body cavities been recently violated. In 7 patients significant infections with the same organism preceded the peritonitis or were simultaneously present. Five had had pneumonia, 3 with pneumococci (nos. 34, 44, and 45), one with Klebsiella (no. 37B) and one with Pasteurella multocida (no. 33). Two had urinary tract infections caused by an E. coli with the same antibiotic sensitivity pattern. Two had had intra-arterial catheters placed 3 and 15 days before peritonitis (nos. 30 and 51), and one had had an umbilical vein catheterization (no. 33) 25 days previously. Sigmoidoscopy and gastroscopy had been performed in 1 patient several days before the peritonitis was detected (no. 41). This patient had also had a barium enema. Six patients had had enemas within a week before the onset of peritonitis. Adrenocortical steroids had been given to 5 patients. Broad-spectrum antibiotics had been administered to 3 patients and short courses of oral neomycin to 5 others. TREATMENT. Successful treatment, defined as disappearance of fever and abdominal symptoms and signs, the return to normal of the number of leukocytes in the ascitic fluid, and the disappearance of bacteria from the ascitic fluid, was observed in 14 episodes (48 per cent). Treatment was unsuccessful in 12 additional cases (41 per cent), including 5 patients who died within 24 hours despite the institution of appropriate antibiotic therapy. Three episodes were untreated; in all three the patients died within 24 hours. Only one patient survived. Fifteen (60 per cent) probably died as a direct consequence of the peritonitis.
DISCUSSION Is the incidence of spontaneous bacterial peritonitis rising? We shall attempt to answer this question by asking a series of other questions. Is This an Endemic Disease Limited to our Institution? Only a few new reports have been published about spontaneous peritonitis
n.w.
+ + + + + + + + +
0 0
+ + +
0
+ + + + +
0 0
0 0
+
0 0 0 0 0
+ +
0 0 0
+ +
*Number represents interval in days before appearance of peritonitis.
S.T. V.W.R. S.J.A. S.C. G.C.S. C.F. J.H.L. W.B.
J.K.F. J.H.J. C.T.N. N.W.M. J.K.C.
0
0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0
+
0
0
42 43 44 45 46A 46B 47 48 49 50 51 52 53 54 30
7
35
0 0
+
+
J.E.B.
0 0
+
+
41
175
0
0
60
0
55
+
0 0 0 0 0 0
13,19 2, 7 50 90
+ + +
0 0
+ + + +
AZOTEMIA NEOMYCIN
0 0
S.T.
40A 40B
0
0 0 0 0 0
+ +
DIARRHEA
PRIOR PARACENTESIS"
Pulmonary
Pulmonary Pulmonary
Urinary
Pulmonary Urinary Pulmonary
Pulmonary Pulmonary
INFECTION
Potential Pathogenetic Factors
+ +
+ +
N.R. M.F.
38 39
+ + + + + + + + +
JAUNDICE
+
J.A.K. V.G.
J.S. G.O'B. W.J.T. P.P.
R.S.
INITIALS
37B
30 31 32 33 34 35A 36B 36 37A
PATIENT NO.
Table 4. *
Intra-arterial catheter, 3
Thoracentesis Steroids
Enemas
Enemas
Enemas, steroids, 30 Umbilical hernia leakage, splenorenal shunt, 13 Umbilical hernia leakage Portacaval shunt, 20, Intraarterial catheter, 15 Enemas, sigmoidoscopy, esophagoscopy, steroids
Enemas
Steroids
Umbilical vein catheter, 22
Intra-arterial catheter, 3 Enemas, steroids
MISCELLANEOUS
'Cl
"'"'
~
.....
Cfl
>-
-
Spontaneous Bacterial Peritonitis in Cirrhosis: Endemic or Epidemic? Jose Pinto Correia, M.D.,* and Harold O. Conn, M.D.**
Previous reports from this hospitaP' 4 have suggested thatspontanebacterial peritonitis is a common complication of cirrhosis. Although we had reported 29 patients with this disorder, 27 of whom had been encountered at a single hospital during a 12 year period, we were concerned about the relative rarity of reports of such cases from elsewhere. At that time we were able to locate only 42 other cases reported in the world's literature. Furthermore, the disease was virtually unknown to many knowledgeable physicians. Our concern was increased by the fact that our encounters with this syndrome continued and, in fact, sharply accelerated. Was this an endemic, limited in some strange way to our institution? Were we merely more aware of this disorder and discovering it earlier in its course, or was the incidence of this hitherto uncommon disease rapidly increasing elsewhere as well? Other investigators have recently reported that they too have observed this serious syndrome7' 12, 14-16 with greater frequency than has been generally appreciated. The present investigation was undertaken to review our recent experience with spontaneous peritonitis and to compare our voluminous experience during the past 4 years with our earlier findings in the hope of solving some of these mysteries. OHS
METHODS AND MATERIALS During the 12V2 year period from January 1958 to July 1970 we encountered 25 bacteriologically proved episodes of spontaneous peritonitis in 23 patients at the West Haven Veterans Administration Hospital. These have been described in detail in an earlier report.4 The same chronologic identification numbers used in the earlier publication were retained. Four additional patients with bacteriologically unconfirmed "Associate Professor of Medicine, Hospital Escolar Sta Maria, Lisbon, Portugal; Formerly Visiting Associate Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut ''''Professor of Medicine, Yale University School of Medicine; Chief, Hepatic Diseases Unit, Veterans Administration Hospital, West Haven, Connecticut Supported in part by the Stratfield Fund. Medical Clinics of North America- Vol. 59, No. 4, July 1975
963
964
JOSE PINTO CORREIA AND HAROLD
O.
CONN
spontaneous peritonitis were encountered during this period. These 4 patients (numbers 25, 26,27,28) were presented in the earlier publication but are excluded from this analysis. During the 4 year period from July 1970 to June 1974 the diagnosis of spontaneous bacterial peritonitis has been proved bacteriologically in 25 patients who experienced 29 episodes at the West Haven Veterans Administration Hospital. These patients were chronologically assigned identification numbers from 30 to 54. In addition, 7 patients with bacteriologically unproved spontaneous peritonitis were observed during this interval. Thus, the increased incidence of spontaneous peritonitis was also seen in the more frequent diagnosis of "probable" cases as well as in the proved cases. Our analyses, however, will be restricted to comparison of the proved cases during the two periods. No patients with proved spontaneous peritonitis have been excluded. Bacteriologic examinations were performed with standardized techniques in the clinical bacteriology laboratory. These methods haw not changed significantly during the tenure of these investigations. Ex· aminations of ascitic fluid and blood were performed in the clinical microscopic laboratory using routine methods. The protein concentration of ascitic fluid was measured by the CUS04 method in the first series and by the Technicon SMA biuret technique during most of the second series. The latter method gives lower values than the former. Liver function tests and serum electrolytes were performed using the Technicon Autoanalyzer SMA 18. Serum alkaline phosphatase levels have been reported in international units during the past 4 years. For purposes of comparison, the alkaline phosphatase levels which had been reported in both Bodansky and King-Armstrong units in our previous publications, have been converted to international units by multiplying by factors of 20 and 7, respectively.
REVIEW OF PRESENT EXPERIENCE The chronologic appearance of spontaneous bacterial peritonitis for the whole 16 year period is shown in Figure 1. Starting as a bare trickle, the cases have become an awesome flood. During the past 4 years we have seen an average of 6.2 patients with neritonitis per year compared with an average of 1.8 during the previous period-a three to four-fold increase. CLINICAL FEATURES OF CIRRHOSIS. All 25 patients had cirrhosis, which had been established histologically in 22 (88 per cent). All but one had histories of excessive alcohol consumption and were considered to have alcoholic cirrhosis. The exception had post-hepatitis cirrhosis. Twenty-four were men and one was a woman. The mean age was 49.3 years with a range of 33 to 61 years. Twenty-four of the 25 patients died during the same admission in which peritonitis developed. Autopsies were performed in 15 of the 24 patients who died (62 per cent). One patient had lung cancer in addition to cirrhosis. CLINICAL FEATURES OF PERITONITIS (Table 1). Fever was present in 17 episodes (63 per cent), abdominal pain in 7 (27 per cent), rebound tenderness in 11 (42 per cent), and hypoactive bowel sounds in 10 (50
965
SPONTANEOUS BACTERIAL PERITONITIS IN CIRRHOSIS
7
S
NO.OF PATIENTS 4
3
1958 '59 'SO 'SI 'S2 'S3 'S4 '65 '66 '67 '68 '69 '70 '71 '72 '73 '74 (6mosl
(6mos)
Chronologic appearance of spontaneous peritonitis at the VA Hospital, West Haven, Connecticut. The progressive rise in the number of patients with peritonitis Figure l.
is evident. The 5 patients represented for 1974 were seen in the first 6 months of the year.
per cent). There were local signs of peritonitis in 12 episodes (46 per cent). There were no abdominal signs in 14 episodes (54 per cent), and in three patients the abdominal findings were not even mentioned. Peritonitis was not suspected in 10 patients. The suspicion of peritonitis was stimulated by a fluid leak from an umbilical hernia in 2, fever in 2, hypothermia in 2, and a rise in the leukocyte count of the ascitic fluid in 1 patient. Table 1.
Clinical Features of Spontaneous Peritonitis 1970-1974 REAB DO M- BOUND
PATIENT NO.
30 31 32 33 34 35A 35B 36 37A 37B 38 39 40A 40B 41 42 43 44 45 46A 46B 47 48 49 50 51 52 53 54
INAL INITIALS
R.S.
AGE
J.S. G.O.'B. W.J.T. P.P.
33 46 58 56 36 38
J.A.K. A.V.G.
56 43
N.H. M.F. A.S.T.
44 53 61
J.E.B. J .j-
>-l l"J
:>(")
ttI
rtl
0 d
l"J
Z >-l :>Z
0
"cl
rn
970
JOSE PINTO CORREIA AND HAROLD
O.
CONN
ase activity were each evaluated on 21 occasions (72 per cent). Serum albumin levels were less than 3.0 gm per 100 ml on 24 occasions (89 per cent). Serum urea levels were elevated (> 25 mg per 100 ml) in 18 episodes (62 per cent). PREDISPOSING AND PRECIPITATING FACTORS (Table 4). All patients had had overt ascites prior to and at the time peritonitis developed. The overwhelming majority had esophageal varices and other evidence of portal-systemic shunting. In all 6 who had had ammonia tolerance tests performed, the tests were grossly abnormal. Virtually all had advanced cirrhosis with seriously deranged liver function. Two patients (nos. 39 and 40A) had leakage of ascitic fluid through erosions of large umbilical hernias. A third had had a leaking hernia in which peritonitis did not develop; several months later, after the hernia had healed, peritonitis developed. Previous paracentesis had been performed in 10 of 29 episodes from 2 to 175 days before the onset of peritonitis (mean 52 days). Six of the 10 had preceded the peritonitis by more than 1 month. Two patients (nos. 39 and 40B) had had portacaval anastomoses 13 and 20 days prior to the appearance of peritonitis, respectively. In no other instances had the integrity of the body cavities been recently violated. In 7 patients significant infections with the same organism preceded the peritonitis or were simultaneously present. Five had had pneumonia, 3 with pneumococci (nos. 34, 44, and 45), one with Klebsiella (no. 37B) and one with Pasteurella multocida (no. 33). Two had urinary tract infections caused by an E. coli with the same antibiotic sensitivity pattern. Two had had intra-arterial catheters placed 3 and 15 days before peritonitis (nos. 30 and 51), and one had had an umbilical vein catheterization (no. 33) 25 days previously. Sigmoidoscopy and gastroscopy had been performed in 1 patient several days before the peritonitis was detected (no. 41). This patient had also had a barium enema. Six patients had had enemas within a week before the onset of peritonitis. Adrenocortical steroids had been given to 5 patients. Broad-spectrum antibiotics had been administered to 3 patients and short courses of oral neomycin to 5 others. TREATMENT. Successful treatment, defined as disappearance of fever and abdominal symptoms and signs, the return to normal of the number of leukocytes in the ascitic fluid, and the disappearance of bacteria from the ascitic fluid, was observed in 14 episodes (48 per cent). Treatment was unsuccessful in 12 additional cases (41 per cent), including 5 patients who died within 24 hours despite the institution of appropriate antibiotic therapy. Three episodes were untreated; in all three the patients died within 24 hours. Only one patient survived. Fifteen (60 per cent) probably died as a direct consequence of the peritonitis.
DISCUSSION Is the incidence of spontaneous bacterial peritonitis rising? We shall attempt to answer this question by asking a series of other questions. Is This an Endemic Disease Limited to our Institution? Only a few new reports have been published about spontaneous peritonitis
n.w.
+ + + + + + + + +
0 0
+ + +
0
+ + + + +
0 0
0 0
+
0 0 0 0 0
+ +
0 0 0
+ +
*Number represents interval in days before appearance of peritonitis.
S.T. V.W.R. S.J.A. S.C. G.C.S. C.F. J.H.L. W.B.
J.K.F. J.H.J. C.T.N. N.W.M. J.K.C.
0
0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0
+
0
0
42 43 44 45 46A 46B 47 48 49 50 51 52 53 54 30
7
35
0 0
+
+
J.E.B.
0 0
+
+
41
175
0
0
60
0
55
+
0 0 0 0 0 0
13,19 2, 7 50 90
+ + +
0 0
+ + + +
AZOTEMIA NEOMYCIN
0 0
S.T.
40A 40B
0
0 0 0 0 0
+ +
DIARRHEA
PRIOR PARACENTESIS"
Pulmonary
Pulmonary Pulmonary
Urinary
Pulmonary Urinary Pulmonary
Pulmonary Pulmonary
INFECTION
Potential Pathogenetic Factors
+ +
+ +
N.R. M.F.
38 39
+ + + + + + + + +
JAUNDICE
+
J.A.K. V.G.
J.S. G.O'B. W.J.T. P.P.
R.S.
INITIALS
37B
30 31 32 33 34 35A 36B 36 37A
PATIENT NO.
Table 4. *
Intra-arterial catheter, 3
Thoracentesis Steroids
Enemas
Enemas
Enemas, steroids, 30 Umbilical hernia leakage, splenorenal shunt, 13 Umbilical hernia leakage Portacaval shunt, 20, Intraarterial catheter, 15 Enemas, sigmoidoscopy, esophagoscopy, steroids
Enemas
Steroids
Umbilical vein catheter, 22
Intra-arterial catheter, 3 Enemas, steroids
MISCELLANEOUS
'Cl
"'"'
~
.....
Cfl
>-
-
