At the end of 1995, approximately 200,000 patients with end-stage renal failure were receiving dialysis in the United States1. Of these, 21,563 (10.8%) were treated with continuous ambulatory peritoneal dialysis (CAPD) and 10,113 (5.1%) with continuous cycling peritoneal dialysis (CCPD). Peritonitis is a major complication of peritoneal dialysis. The signs and symptoms of peritonitis associated with peritoneal dialysis include one or more of the following: cloudy peritoneal dialysis effluent, abdominal pain, nausea, vomiting, fever, and chills. Peritonitis usually is caused by bacterial infection, but sterile peritonitis does occur. Sterile peritonitis, which also is described as aseptic, chemical, or culture-negative peritonitis, is usually caused by a chemical or foreign body irritant. In 1977, an outbreak of sterile peritonitis among peritoneal dialysis patients was attributed to intrinsic endotoxin contamination of dialysate solution, where suspected lots had endotoxin levels in the range of 2 to 2.5 endotoxin units (EU)/ml2. Other reported causes of sterile peritonitis include vancomycin, amphotericin B, and methylene blue3,4,5. In this report, we describe an outbreak of sterile peritonitis occurring in CCPD patients.
Background
From July 1 through August 15, 1996, an outpatient dialysis center at Hospital University of Pennsylvania (HUP) noted an increased number of CCPD patients with peritonitis. All patients received CCPD at home and reported using 5-liter bags of dialysis solution and tubing sets supplied by a single manufacturer (Fresenius Medical Care, North America, formerly called Fresenius, USA Inc., Ogden, Utah, USA).1 When an initial investigation at HUP did not identify the cause of the outbreak, assistance was requested from the Hospital Infection Program, Centers for Disease Control and Prevention (CDC). The objectives of our investigation were to confirm the presence of an outbreak, assess risk factors, and implement control measures to terminate the outbreak. During the same period that the outbreak occurred at HUP, CDC received reports of similar episodes of sterile peritonitis among CCPD patients using peritoneal dialysis solution (PDS) from the same manufacturer at other outpatient dialysis centers in several states (that is, California, Michigan, North Carolina, New Jersey, New York, Wisconsin). On August 16, 1996, the company recalled 53 lots of PDS.
METHODS
Case definition and ascertainment
A case-patient was defined as any patient receiving CCPD at HUP outpatient dialysis center from July 1 through August 15, 1996, (that is, the epidemic period) with (a) cloudy peritoneal fluid or abdominal pain; (b) peritoneal fluid white cell count > 100 mm3; and (c) negative peritoneal fluid cultures for bacteria or fungi. Case-patients were identified from chart and laboratory record review.
Epidemiologic studies
To determine whether an outbreak had occurred, the rates of sterile peritonitis per patient month were compared in all HUP peritoneal dialysis patients during the epidemic and pre-epidemic (January 1995-June 1996) periods.
To identify risk factors for sterile peritonitis, we conducted a retrospective cohort study of all CCPD patients treated at HUP during the epidemic period. We assessed demographic factors, geographic location of the patient's home, type and lot number of dialysis solution and tubing, dialysis procedures and protocols, type of dialysis machines, and medications received. The lot numbers for the dialysis solution and tubing sets were provided by the manufacturer, and, in some instances, directly from patients through phone interviews and/or home visits.
We reviewed the manufacturer's manual, guidelines, and instructions for CCPD provided by the staff at the dialysis center. The nursing staff at HUP outpatient dialysis center conducted a simulated instruction class to illustrate how patients are taught to perform CCPD.
Laboratory evaluation
Peritoneal fluid cell counts and cultures were performed at the HUP microbiology laboratory; 5 to 10 ml of peritoneal fluid were cultured for bacteria and fungi using the Bactec System (Becton Dickinson, Towson, MD, USA). Tubing sets and samples of dialysis fluid were obtained from the patients, HUP, and the manufacturer and sent to CDC for endotoxin assay by the limulus lysate turbidimetric method6.
Manufacturers' phone survey
During July to August 1996, personnel from the manufacturer contacted by phone all dialysis centers caring for patients who had, according to company records, received a recalled lot of PDS. For each patient, data were collected on the lots received, geographic region, dialysis center, shipment dates, whether peritonitis had occurred, and, if so, the date of onset.
Statistical analysis
Data for the cohort study at HUP were collected on standardized forms, entered, and analyzed using Epi-Info 6.027. Preliminary data collected by the manufacturer during the phone contact of the dialysis centers were entered into a computer file and analyzed using the SAS for personal computers (SAS Institute, Inc., Cary, NC, USA). Categorical variables were compared using the Chi-square or the Fisher's exact test. Relative risk (RR) and 95% confidence intervals were calculated. Multivariate analyses were performed by constructing logistic regression models.
RESULTS
Epidemiologic studies
The rate of sterile peritonitis at the HUP outpatient dialysis center was significantly higher in the epidemic versus the pre-epidemic period (14 episodes during 45 patient months vs. 3 episodes during 525 patients months, P < 0.001).
The 14 epidemic-period case-patients ranged in age from 24 to 64 (median 49) years; five (36%) were female, ten (71%) were black, and four (29%) were white. None of the 14 case-patients had an episode of peritonitis in the preceding three months. Case-patient signs and symptoms included cloudy peritoneal fluid (N = 13; 93%), abdominal pain (N =10; 71%), chills (N = 6; 43%), fever (N = 4; 29%), nausea and vomiting (N = 3; 21%), and/or exudate around the catheter site (N = 4; 29%). Ten (71%) case-patients first presented to the dialysis center, while four (29%) presented to the emergency room. The peritoneal fluid cell count ranged from 114 to 999 (median = 283) cells/mm3.
There was no significant association between sterile peritonitis and gender or exposure to any one of 12 separate lots of dialysis tubing (Table 1). Exposure to either of two specific lots (lots A and B) of PDS had a relative risk >2, but the results were not statistically significant. However, receipt of 
1 lot of recalled dialysis fluid was a significant risk factor for sterile peritonitis (14 of 22 vs. 0 of 6, P = 0.016). Also, the more recalled lots received by a patient, the higher the attack rate (Table 1). When case-patients resumed CCPD using PDS from non-recalled lots, they had no further symptoms.
Table 1 - TABLE 1. Potential risk factors for sterile peritonitis, HUP, July 1 to August 15, 1996.
Full table (39K)Results of manufacturer's phone survey
Of the 53 recalled lots of PDS, 19 were sent to another supplier and data on their clinical effect are not available. The remaining 34 lots were distributed directly by the manufacturer to CCPD patients at 515 dialysis centers. Of the 1,905 patients who received 1 recalled lot of PDS, 260 (13.6%) were reported to have sterile peritonitis.
Of the 34 lots, 12 were significantly associated with sterile peritonitis in univariate analysis. Because some of the patients received >1 lot, a logistic regression model was constructed, and 9 lots remained as independent risk factors for sterile peritonitis (Table 2).
Table 2 - TABLE 2. Endotoxin levels and relative risk for selected lots of peritoneal dialysis solution.
Full table (60K)The phone survey indicated that sterile peritonitis occurred in 6 of 24 (25%) HUP CCPD patients who had received PDS from subsequently recalled lots. In contrast, our on-site investigation documented a 14 of 22 (64%) attack rate.
Procedure review
Patients received 15 to 30 boxes (each box contained two 5-liter bags) of dialysis solution and 4 to 10 boxes of tubing sets per delivery, depending on the patient's individual needs. All on-site CCPD patients at HUP used the Fresenius Freedom Cycler P. D. dialysis machine. Patients were trained to perform CCPD at the dialysis center by the nursing staff for one to two weeks. Patients were instructed to wash their hands for three minutes before the start of dialysis, wear a mask during set-up for dialysis, and maintain sterility during connection. The patients were trained to examine their dialysis solution bags before use for any discoloration or leakage and to check the expiration date. Patients were instructed to follow the manufacturer's protocol for setting-up the machine, initiating dialysis, and setting-up equipment for the next treatment. These practices were reinforced at each patient clinic visit. Neither patients nor staff reported any changes from or non-adherence to these procedures.
Microbiology
All cultures of case-patients' peritoneal dialysis fluid were negative for bacteria. Peritoneal fluids from 10 case-patients also were cultured for fungi and mycobacteria; all were negative. Some patients had initial cultures at outside hospitals/emergency facilities that did not look for fungi and mycobacteria.
Five of 36 lots of PDS tested had measurable amounts of endotoxin detected at CDC ranging from 47.3 to 429 EU/per 5-liter bag (0.0095 to 0.086 EU/ml; Table 2). Only one bag had >350 EU [the threshold pyrogenic dose for a 70-kg man (5 EU/kg/hr)]. There was no correlation between PDS bag endotoxin level and risk of peritonitis. However, endotoxin was detected more commonly in recalled than non-recalled lots (5 of 19 vs. 0 of 17, P = 0.047).
Sixteen lots of PDS were tested for endotoxin and were among the 34 recalled lots investigated in the manufacturer's phone survey. Of the 16, 8 were independent risk factors for sterile peritonitis in the logistic regression model. Measurable endotoxin was found more commonly in lots that were independent risk factors than in other lots (4 of 8 vs. 1 of 8, P = 0.3), but the result was not statistically significant.
DISCUSSION
Peritoneal dialysis was first used in the treatment of renal failure in 1923. Infection always has been a serious complication of peritoneal dialysis. Infectious peritonitis and catheter-related infections are the most common cause of morbidity and result in discontinuation of therapy in up to 28% of peritoneal dialysis patients8,9,10. The most common sign and symptom of peritonitis in peritoneal dialysis patients are cloudy dialysate effluent and abdominal discomfort, respectively11,12. Sterile peritonitis, which has a similar clinical picture to bacterial peritonitis, accounts for < 10% of all episodes of peritonitis13. Before 1976, culture-negative peritonitis was assumed to be due to concomitant use of antibiotics, a laboratory error, or caused by a fungus, mycobacteria, virus, or other non-culturable agent. Although these factors may still apply, in 1977 a non-infective etiology for sterile peritonitis was documented during an outbreak traced to an intrinsic contamination of dialysis fluid with endotoxin2.
In 1980, CCPD was introduced as an alternative mode of home dialysis14. In CCPD, fluid is infused into the peritoneum during the early morning and left in the peritoneal cavity during the day. At bedtime, the fluid is drained and cycling of fluid occurs throughout the night. In theory, prolonged dwell times and fewer entries into the sterile system might reduce the risk of infective peritonitis.
On August 16, 1996, the manufacturer recalled 53 lots of PDS after receiving reports of sterile peritonitis. According to the manufacturer, only these 53 lots had routine cultures that showed 1 colony forming units of bacteria per milliliter before terminal sterilization. The organisms cultured from this fluid were Enterobacter taylorae and Kluvera cryocresceus. These presterilization cultures are done by the manufacturer as an internal test procedure; when elevated colony counts are found, general maintenance and cleaning are increased. However, results of presterilization colony counts are not a criteria for releasing the lot. Lots are released if the endotoxin level is < 0.5 EU/ml, which is in keeping with the industry standards. All PDS lots, including those recalled, passed this quality assurance test with endotoxin < 0.5 EU/ml. As a result of this outbreak, the manufacturer has increased the frequency of equipment disinfection and filter exchanges.
Our investigation documents a nationwide outbreak of sterile peritonitis. Our study at one site, HUP, showed that all case-patients were on CCPD and used 5-liter bags of PDS. Our results do not implicate one specific lot of PDS. However, patients who received 1 recalled lot of PDS had a significantly higher risk of sterile peritonitis. Results of the manufacturer's telephone survey revealed that nine lots of PDS were significantly associated with sterile peritonitis in a logistic regression model. Only one of these lots had a borderline association with sterile peritonitis according to our data collected at HUP.
All HUP case-patients were exposed to a subsequently recalled lot of dialysis solution. However, eight patients also exposed to a subsequently recalled lot did not become ill. This may be explained by variability among the lots, bags of the same lot, endotoxin concentration, and potential to cause peritonitis. Also, the stock was not always rotated, that is, the older supplies used before newer ones. Although we determined which patients received subsequently recalled lots, it is uncertain whether these lots were actually used. Patients generally could not report which lots or boxes they had used before developing peritonitis. Furthermore, since the risk of sterile peritonitis increased with receipt of more recalled lots, it is possible that the non-case-patients had insufficient exposure to the implicated lots.
This is the largest reported outbreak of sterile peritonitis in the United States. We received reports of episodes from six states. The manufacturer identified 260 episodes at 515 dialysis centers. However, the manufacturer identified less than half of the case-patients that we identified at HUP. This discrepancy may be due to the fact that the manufacturer had to rely on information reported by personnel at the dialysis centers at the time of the phone contact, while we collected data through an on-site visit. However, the manufacturer's phone survey may have significantly underestimated the number of episodes of sterile peritonitis attributable to this product and the extent of the outbreak.
These results suggest that this outbreak was associated with intrinsic contamination of PDS by a substance released from bacteria. Endotoxin, which has been implicated in previous outbreaks of sterile peritonitis, is the likely cause. All recalled lots of PDS passed the quality control test of <0.5 EU/ml, and only some had detectable endotoxin. Those with measurable amounts of endotoxin had ranges from 47.3 to 429 endotoxin units (EU)/per 5-liter bag, which is equivalent to 0.0095 to 0.086 EU/ml, but well below the release level of 0.5 EU/ml. CCPD patients receive up to 15 liters of dialysis fluid daily, over an 8-hour period, and thus, the maximum dialysate flow rate is approximately 2 liters/hr. Assuming use of a recalled PDS with the highest level of endotoxin detected during our investigation, the maximum exposure of endotoxin to a 70 kg patient would be 172 EU/hr, which is below the recognized threshold pyrogenic dose of 350 EU/hr (5 EU/kg/hr). Thus, it is possible that endotoxin exposure at levels below the commonly accepted pyrogenic threshold dose may cause disease, at least in renal failure patients. This outbreak stopped after the recall of lots of PDS having 1 CFU/ml on presterilization cultures. This suggests that pre-sterilization colony counts may be more sensitive than the current established endotoxin levels (< 0.5 EU/ml) for identifying contaminated product, and that colony counts could be used in conjunction with endotoxin levels as quality control indicators for CCPD solution.
Notes
1 Use of trade names and commercial sources are for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.
References
| 1. | ESRD Facility Survey Data. End Stage Renal Disease Branch, Health Care Financing Administration. 1995; U.S. Department of Health and Human Services, Washington, D.C.. |
| 2. | Karanicolas S, Oreopoulos DG, Izatt SH, Shimizu A, Manning RF, Sepp H, Deveber GA & Darby T. Epidemic of aseptic peritonitis caused by endotoxin during chronic peritoneal dialysis. N Engl J Med 1977; 296: 1336−1337. | PubMed | ChemPort | |
| 3. | Smith T, Baile G & Eisele G. Chemical peritonitis associated with intraperitoneal vancomycin. Ann Pharm 1991; 25: 602−603. |
| 4. | Benevent D, El Akoun N & Lagarde C. Dangers of administration of intraperitoneal amphotericin B in continuous ambulatory peritoneal dialysis. Press Med 1984; 13: 1844. | ChemPort | |
| 5. | Charncy DI & Gouse SF. Chemical peritonitis secondary to intraperitoneal vancomycin. Am J Kidney Dis 1991; 17: 76−79. |
| 6. | Novitsky TJ, Roslansky PF, Siber GR & Warren HS. Turbidimetric method for quantifying serum inhibition of limulus amoebocyte lysate. J Clin Microscopy 1985; 20: 211−216. |
| 7. | Dean Ag, Ja, D, Ka, Dc, Ah, Dicker Ac, Sullivan K, Fagan Rf & Arner Tg. Epi Info, Version 6.02 1994; A word processing database, and statistics program for epidemiology on microcomputers Atlanta, Centers for Disease Control and Prevention. |
| 8. | Oreopoulus DG. Prevention of peritonitis in patients undergoing CAPD. Periton Dial Bull 1986; 6: 2−4. |
| 9. | Williams CC. CAPD in Toronto: an overview. Periton Dial Bull 1983; 3: 56−58. |
| 10. | Report of the National CAPD Registry of National Institute Health. 1986; January 1981- August 1985. |
| 11. | Rubin J, Rogers WA, Taylor HM, Everett ED, Prowant BF, Fruto LV & Nolph KD. Peritonitis during continuous ambulatory peritoneal dialysis. Ann Intern Med 1980; 92: 7−13. | PubMed | ChemPort | |
| 12. | Vas SI. Microbiological aspect of chronic ambulatory peritoneal dialysis. Kidney Int 1983; 23: 83−92. | PubMed | ChemPort | |
| 13. | Anonymous. Diagnosis and management of peritonitis in continuous ambulatory peritoneal dialysis. Working Party of British Society of Antimicrobial Chemotherapy. Lancet 1987; 1: 2−3. |
| 14. | Diaz-Buxo JA, Farmer CD, Walker PJ, Chandler JT & Holt KL. Continuous cyclic peritoneal dialysis: A preliminary report. Artif Organs 1981; 5: 157−161. | PubMed | ChemPort | |
