Scandinavian Journal of Gastroenterology. 2014; 49: 845–852
ORIGINAL ARTICLE
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Cytomegalovirus infection and postoperative complications in patients with ulcerative colitis undergoing colectomy
MAYA OLAISEN1, ASTRID RYDNING2, TOM CHRISTIAN MARTINSEN1,3, IVAR SKJÅK NORDRUM4,5, PATRICIA MJØNES4 & REIDAR FOSSMARK1,3 1
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, 2Department of Gastrointestinal Surgery, St. Olav’s Hospital, Trondheim, Norway, 3Department of Gastroenterology and Hepatology, St. Olav’s University Hospital, Trondheim, Norway, 4Department of Pathology and Medical Genetics, St Olav’s University Hospital, Trondheim, Norway, and 5Department of Laboratory Medicine, Children and Woman Health, NTNU, Trondheim, Norway
Abstract Background. Ulcerative colitis (UC) can be complicated by reactivation of cytomegalovirus (CMV). CMV reactivation may change the course of UC and may require antiviral treatment. Some risk factors of CMV reactivation have previously been identified, whereas the association between CMV reactivation and postoperative complications has not been examined systematically. Methods. Patients with UC operated with colectomy due to active UC were studied (n = 77). Patient and disease characteristics, as well as postoperative complications were recorded and CMV was detected by immunohistochemical examination of multiple sections from the colectomy specimen. Results. CMV was found in nine (11.7%) colectomy specimens. CMV-positive patients received significantly higher doses of corticosteroids at colectomy than CMV-negative patients (61.1 ± 23 vs 32.5 ± 32 mg/day, p = 0.01). CMV-positive patients were also older, had a higher risk of severe complications, higher American Society of Anesthesiologists (ASA) score, longer preoperative stay, and a higher rate of acute surgery. Complications occurred in 30 (39%) patients after surgery, 8(10.4%) of whom were serious. Two CMV-positive patients (2.6%) died in-hospital after the colectomy. High ASA score was associated with the occurrence of serious complications. Conclusion. A relatively small proportion of patients with UC operated by colectomy were CMV positive. CMV positivity was associated with old age, high dose of corticosteroids at operation, high ASA score, acute surgery, and severe postoperative complications. Patients with such characteristics may be at risk of CMV infection and may require special management.
Key Words: colectomy, corticosteroids, cytomegalovirus, outcome, ulcerative colitis
Introduction The occurrence of cytomegalic inclusions in the colon of a patient with ulcerative colitis (UC) was noted and described more than 50 years ago [1]. The prevalence of cytomegalovirus (CMV) antibodies among adults ranges from 40% in highly industrialized areas to 100% in developing countries [2]. CMV persists lifelong in the organism after primary infection and may reactivate in immunosuppressed patients. It was
earlier proposed that CMV infection may predispose to a fulminant course of UC [3], but during the past years there has been an increasing interest in the role of CMV in UC, particularly in exacerbations. The use of immunosuppressant drugs may lead to CMV reactivation, but severe colitis per se may possibly cause CMV reactivation and that CMV reactivation could be a surrogate marker of severe UC [4]. Despite the uncertainties, the European Crohn’s and Colitis Organisation (ECCO) recommends that CMV colitis
Correspondence: Reidar Fossmark, MD PhD, Department of Gastroenterology and Hepatology, St.Olav’s University Hospital, Prinsesse Kristinas gate 3, 7006 Trondheim, Norway. Tel: +47 06800. E-mail: [email protected]
(Received 1 May 2014; revised 26 May 2014; accepted 26 May 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.929172
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
846
M. Olaisen et al.
should be excluded in immunomodulatory refractory cases of inflammatory bowel disease and initiation of antiviral therapy and discontinuation of immunomodulators is recommended [5]. In support of this approach, there are a few small, nonrandomized studies suggesting that ganciclovir induces remission in UC patients with steroid refractory exacerbations, and the treatment may reduce short-term risk of colectomy [6–11]. The best method for detecting clinically relevant presence of CMV, which should be considered a CMV infection, has not been established. Real-time quantitative polymerase chain reaction (qPCR) tests for CMV load are more sensitive than immunohistochemical (IHC) and haematoxylin and eosin (HE) sections [11]. However, interlaboratory variations are in the range of 2–4 log10 [12] and qPCR may detect low-level reactivation of latent CMV [4] without clinical relevance. IHC detection of CMV increases the sensitivity compared to HE-stained sections [13,14]. Today IHC is considered the current gold standard for the diagnosis of CMV infection, and colonic mucosal CMV infection detected by histopathology appears clinically relevant and appropriate basis for initiation of antiviral therapy [15,16]. The prevalence of CMV infection has been reported to be higher in steroid refractory UC, varying between 25% and 36% [17,18]. CMV reactivation in UC may increase the risk of colectomy, but the influence of CMV infection on postoperative outcome has not been examined systematically in larger groups of patients. In the present study, we have determined the prevalence of CMV in colectomy tissue samples from patients operated due to active UC and identified characteristics of patients with CMV-positive specimens. Further, we have examined the postoperative outcome to identify risk factors for complications, including CMV positivity. Material and methods All patients of age ‡16 years undergoing colectomy at St Olav’s Hospital Trondheim, Norway, because of active UC during the period between 1 January 2000 and 31 December 2010 were identified and included in a retrospective analysis. Patients with active UC were not regularly tested for CMV in preoperative endoscopic colon biopsies at this time. We identified 81 patients diagnosed where a preoperative UC diagnosis was maintained after histopathological examination of the surgical specimen. In one patient, the histopathological examination also revealed a T-cell lymphoma in the colon and three patients were found to have Crohn’s disease during a mean follow up of 7.0 ± 3.5 years. These four patients were excluded
from further analyses, and 77 patients were eligible for further analyses. Patient data were extracted retrospectively from medical records and an institution-based surgical complication register at the Department of Gastrointestinal surgery, St Olav’s Hospital. The following patient and disease characteristics were recorded: age, sex, reason for colectomy, disease duration, disease pattern, disease extension at the time of operation, previous and current treatment, results of blood analyses before colectomy (C-reactive protein, sedimentation rate), duration of the hospital stay and American Society of Anesthesiologists score (ASA score). Disease pattern was classified into two different categories, continuous or intermitting, where intermitting disease was defined as disease where clinical remission was maintained for ‡3 months without other than 5-aminosalicylic acid (5-ASA) and local treatment. The reason for colectomy was subdivided into three groups: 1) steroid dependency (n = 19), as defined by ECCO [19], that is, patients who are unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids, without recurrent active disease, or who have a relapse within 3 months of stopping steroids; 2) treatment resistance (n = 34), defined as persisting active colitis as perceived by the treating physician, despite medical treatment with 5-ASA, glucocorticoids, and other lines of treatment varying from case to case; and 3) fulminant colitis (n = 24), including all patients who fulfilled the Truelove and Witt’s criteria [20]. Systemic glucocorticoid treatment at colectomy was recorded and expressed as milligrams prednisolone/day (cortisone and methylprednisolone were converted into equipotent doses of prednisolone). Highest dose of glucocorticoids throughout medical history and the duration of continuous treatment before colectomy were registered. High-dose glucocorticoid treatment defined as ‡20 mg prednisolone/ day for ‡6 weeks within the year before colectomy was recorded. Previous and current treatments at the time of operation with azathioprine, anti-TNF-a agents, cyclosporine, 5-ASA, and sulfasalazine, as well as local treatment, were registered. Drug doses are presented as mean ± SD. Surgery and complications The surgical procedure was recorded using NCSP/ NCMP. Different surgical procedures were performed: total colectomy and ileostomy (JFH10 or JFH11), proctocolectomy and ileostomy (JFH20), proctocolectomy and ileal pouch anal anastomosis (IPAA) without ileostomy (JFH30), and proctocolectomy and IPAA with loop ileostomy (JFH33). The
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Cytomegalovirus in ulcerative colitis procedures were classified into laparotomy or laparoscopic procedures and the number of laparoscopic procedures that had to be converted to a laparotomy procedure was recorded. The length of postoperative hospital stay was extracted. Medical records and data from the complication registry were reviewed and compared to ensure the data quality. Complications up to 30 days after colectomy were stratified into five different severity groups using the Clavien-Dindo Classification of Surgical Complications [21]. Further, the occurrence of pouchitis during follow up was recorded for patients with an IPAA. The study protocol was approved by the regional committee for Medical and Health Research Ethics in Trondheim. CMV immunohistochemistry and evaluation Formalin-fixed paraffin-embedded tissue from four to six segments of the colon were cut into 4 mm thick sections that were dewaxed and further processed for immunohistochemistry using a DAKO Autostainer Link system (DAKO, Glostrup, Denmark). Antigen retrieval was achieved by using DAKO Target Retrieval Solution pH 9.0 in 97 C for 20 min. Sections were incubated for 1 h with mouse antihuman monoclonal anti-CMV antibody (DAKO M0854) diluted 1:500; the immunoreaction was then visualized using EnVision (DAKO K5007) and DAB+ before counterstaining with hematoxylin. Positive control tissue from a lung CMV infection and negative control incubated with non-immune serum (DAKO IR750), as well as incubation with tissue known to be infected with adenovirus or Epstein– Barr virus, as well as negative control section incubated with non-immune serum (DAKO IR750), were included in all procedures. The tissue sections were blindly reviewed by two pathologists (I.N. and P.M). The presence of characteristic CMV positivity was registered. As practiced by others, CMV positivity was defined as ‡1 cell with immunolabeled and characteristic inclusions, [22,23], and patients were classified as CMV positive or CMV negative. Statistics Descriptive data are presented as mean ± SD, frequency (percentage) or median (range) as found appropriate. Independent T-test for comparisons between groups was used for data following normal distribution. To examine differences between categorical variables the chi-square test and Fisher’s exact probability test were used. P < 0.05 was considered statistically significant using two-sided tests. Data
847
were analyzed using IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA).
Results Patient and disease characteristics are presented in Table I. Of the 77 patients, 25 (32.5%) were female and the age at colectomy was 42.0 ± 17.4 years. ASA scores were distributed as following: ASA 1: 3.9% (n = 3), ASA 2: 71.4% (n = 55), ASA 3: 20.8% (n = 16), and ASA 4: 3.9% (n = 3). Disease duration before surgery was 6.1 ± 7.0 years and 54 (70%) patients had continuous disease activity pattern. Total colitis was diagnosed in 58 (75%) patients, whereas 15 (19.7%) had left-sided colitis and 4 (5.3%) had Table I. Characteristics of patients with ulcerative colitis operated with colectomy. Patient characteristics, n = 77 (%) Male 52 (67.5%) Female 25 (32.5%) 29 (38.7%) Smokers, n = 75 (%)a Age (years) at colectomy, mean ± SD 42.0 ± 17.4 Disease duration (years), mean ± SD 6.1 ± 7.0 Reason for colectomy, n = 77 (%) Steroid-dependant 19 (24.7%) Treatment-resistant 34 (44.2%) Fulminant colitis 24 (31.2%) Disease distribution, n = 77 (%) Rectosigmoid involvement 4 (5.2%) Left-sided colitis 15 (19.5%) Total colitis 58 (75.3%) American Society of Anesthesiologists classification, n=77 (%) Class 1 3 (3.9%) Class 2 55 (71.4%) Class 3 16 (20.8%) Class 4 3 (3.9%) Follow-up time (years), mean ± SD 7.0 ± 3.5 Surgical procedure, n = 77 Colectomy and ileostomy 60 (77.9%) Proctocolectomy and ileostomy 7 (9.1%) Proctocolectomy and ileoanal 2 (2.6%) anastomosis without ileostomy Proctocolectomy and ileoanal 8 (10.4%) anastomosis with loop ileostomy Laparotomy or Laparoscopy, n = 77 Laparotomy 66 (85.7%) Laparoscopy 7 (9.1%) Laparoscopy converted to laparotomyb 4 (5.2%) Elective vs. acute, n = 77 Elective 37 (48.1%) Acute 40 (51.9%) Length of hospital stay (days), [median, range] Postoperative stay (days) 11 (5–30) Preoperative stay (days) 6 (0–36) a
Information available only in 75 patients, smokers are defined as current and previous smokers. The surgical procedure was converted to proctocolectomy with ileostomy in one of four patients and in three of four patients, it was converted to a total colectomy and ileostomy. b
848
M. Olaisen et al.
rectosigmoid involvement. Immediate reason for colectomy was fulminant colitis in 24 (31.2%) cases.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Medication The medication history is presented in Table II. All patients had been using corticosteroids during the course of disease. Thirty-two (41.6%) had received high-dose treatment with corticosteroids during the year before colectomy. The corticosteroid dose at colectomy was 35 ± 32 mg/day, and duration of continuous treatment before colectomy was 11.0 ± 14 months. Five patients received azathioprine at operation (mean dose 123 ± 70 mg/day), one patient received cyclosporine (dose 200 mg) at operation and two patients received adalimumab at operation (mean dose 40 mg ± 0 mg/day). Surgery and complications Surgical procedures are presented in Table I and surgical complications are presented in Figure 1. Most patients underwent colectomy with ileostomy (n = 60). Ten patients were operated with Table II. Current and previous medications in ulcerative colitis patients operated with colectomy. Medication Corticosteroids, n (%) Dose at operationa High-doseb Durationc 5-ASA n (%)d All-time users Dose at operation (g) Sulfasalazine n (%) All-time users Dose at operation (g) Azathioprine n (%) All-time users Azathioprine at operation Dose at operation Anti-TNF treatment n (%) Adalimumab, all-time users Infliximab, all-time users Adalimumab at operation Dose at operation (n = 2) Cyclosporine n (%) All-time users At operation Dose at operation (n = 1) Local treatment n (%) All-time users a
35 ± 32 mg 32 (41.6%) 11 ± 14 months 67 (87%) 2.2 ± 0.8 19 (24.7%) 2.1 ± 0.6 14 (18.2%) 5 (6.5%) 123 ± 70 mg 2 (2.6%) 1 (1.3%) 2 (2.6%) 40 mg/2w 1 (1.3%) 1 (1.3%) 200 mg 52 (67.5%)
Information available only in 76 patients. High dose was defined as: ‡20 mg prednisolone/day ‡6 weeks within the past year before colectomy. c Information available only in 75 patients. d Information available only in 76 patients. Abbreviation: 5-ASA: 5-aminosalicylic acid. b
proctocolectomy and IPAA in one surgical intervention, two of these without ileostomy and eight with a diverting loop ileostomy. Thirty-nine patients got an IPAA during the follow up, one patient a Kock’s pouch and 22 patients underwent proctectomy left with a permanent ileostoma. Ten patients retained their proctum, three patients died before proctectomy was performed whereas two patients were lost to long-term follow up. Complications within 30 days after colectomy occurred in 30 of 77 patients (39%). Twenty-two (73.3%) of these were grade 1 and grade 2 complications, that is, complications handled bedside and with pharmacological treatment, and which did not demand intervention (surgical, endoscopic, or radiological) or an IC/intensive care unit (ICU) management. Serious complications (grades 3–5) occurred in eight (10.4%) patients, two (2.6%) of these died in hospital after colectomy, classified as severity grade 5. No patients developed grade 4 complications. The type of surgical procedure did not influence the risk of postoperative complications significantly (24 of 66 patients operated with laparotomy developed complications versus 5 of 7 patients with laparoscopy versus 1 of 4 patients converted from laparoscopy to laparotomy, p = 0.18). Mean postoperative stay was 11.2 ± 4.5 days. Out of the 40 (51.9%) patients who received a reservoir later on, 19 (47.5%) patients were diagnosed with pouchitis during follow up. Of the 11 CMVpositive patients, 6 did not receive a reservoir. Of the three CMV-positive patients with an IPAA, two developed pouchitis during follow up. Patients with high ASA score (3 and 4) had higher occurrence of serious complications (grades 3–5) than patients with low ASA score (p = 0.002). Age at colectomy, high-dose glucocorticoids, duration of glucocorticoid treatment, fulminant colitis, and acute operation were not associated with more complications, neither of all types or serious complications. However, patients with fulminant colitis had longer postoperative stay compared to patients with steroid dependency and treatment resistance as indication for colectomy (p = 0.03). CMV immunohistochemistry CMV was found in nine patients (11.7%). Strong immunohistochemical labeling is illustrated in Figure 2. In four patients, CMV inclusions were found only in the ascending or transverse colon of the surgical specimen and for the remaining five patients CMV inclusions were found in all segments of the colon. Characteristics of CMV-positive and CMV-negative patients are presented in Table III.
Cytomegalovirus in ulcerative colitis 0%
849
3%
5% 2% None, n = 47 17%
Severity grade 1, n = 9 Severity grade 2, n = 13 Severity grade 3a, n = 2 Severity grade 3b, n = 4 61%
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
12%
Severity grade 4, n = 0 Severity grade 5, n = 2
Figure 1. Postoperative complications within 30 days after colectomy in patients with ulcerative colitis are shown.
76-year-old man who after colectomy developed postoperative pulmonary embolism due to fulminant colitis and was re-operated due to suspected intraabdominal leak from the remaining rectum. He subsequently developed clinical sepsis and multiorgan failure, including acute respiratory distress syndrome, and died 20 days after colectomy. The second patient was a 52-year-old woman who was operated due to fulminant colitis after direct transfer from a local hospital. The patient had severe chronic obstructive pulmonary disease (GOLD stage 4) and after surgery she developed a pseudomonas lung infection and died from respiratory failure at the ICU 9 days after colectomy.
CMV-positive patients were significantly older, received a higher dose of glucocorticoids at operation, and had a higher ASA score. CMV-positive patients had a longer preoperative stay, were more likely to have non-elective colectomy and more often developed serious postoperative complications than CMV-negative patients. Two patients who died after colectomy were CMV-positive. There was no significant difference between CMV-positive and CMVnegative patients as regard disease duration, duration of glucocorticoid treatment, fulminant colitis as indication for colectomy, or the occurrence of all complications overall. Two patients died within 30 days after colectomy. One patient was a A
B
C
D
Figure 2. Colectomy specimen from a patient with ulcerative colitis with positive immunolabeling of cytomegalovirus (CMV) at (A) 200 and (B) 400 magnification. Sections with positive control tissue from a CMV lung infection (C) and negative control (D) were included in all immunohistochemical procedures.
850
M. Olaisen et al.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Table III. Comparison of CMV-positive and CMV-negative patients with ulcerative colitis undergoing colectomy, with data presented as mean ± SD or n (%).
Age at operation (years) Gender, female (%) Disease duration (years) High ASA score (3 and 4), n (%) Glucocorticoid dose (mg) at colectomy Duration prednisolone (months) High-dose glucocorticoidsa, n (%) Azathioprine at operation, n (%) Preoperative stay (days) Postoperative stay (days) Complications, all types, n (%) Serious complications, n (%) Death in hospital after colectomy, n (%) Acute operation, n (%) Fulminant colitis, n (%)
CMV-positive (n = 9)
CMV-negative (n = 68)
53.8 ± 18.3 4 (44.4%) 3.1 ± 4.0 5 (55.5%) 61.1 ± 22.6 4.3 ± 3.4 6 (66.7%) 0 16.9 ± 9.9 12.8 ± 6.0 5 (55.5%) 3 (33.3%) 2 (22.2%) 8 (88.9%) 5 (55.5%)
40.4 ± 16.8 20 (30.8%) 6.5 ± 7.2 14 (20.5%) 32.5 ± 31.8 11.9 ± 14.5 26 (38.2%) 5.9 (4) 8.3 ± 8.7 10.9 ± 4.3 25 (36.8%) 5 (7.4%) 0 32 (47.1%) 19 (27.9%)
p-Value 0.029 0.275 0.167 0.022 0.011 0.123 0.104 0.007 0.233 0.271 0.016 0.018 0.093
High-dose glucocorticoids: ‡20 mg/day ‡6 weeks within the past year before colectomy. Abbreviation: ASA: American Society of Anesthesiologists.
a
Discussion The clinical significance of CMV in UC is still uncertain. However, accumulating evidence suggest that colonic CMV reactivation and infection affect the clinical course of UC and this has been recognized in recent European [5] and American [24] practice guidelines. Treatment of suspected CMV disease is, therefore, recommended [5,24,25], whereas the knowledge about how to select patients for antiviral treatment is insufficient. In the current study we have determined the prevalence of CMV infection in colectomy specimens of UC patients who underwent surgery due to active disease. We have identified patient and disease characteristics associated with CMV infection as well as postoperative complications. In studies of colectomy specimens using IHC, the prevalence of CMV infection has been 4.6–50% [22,23,26,27]. In the current study we found a prevalence of 11.7%. The variation in CMV prevalence may be explained by differences in patient population as well as lack of standardized IHC procedures and interpretation [22]. The degree of inflammatory activity also matters and, in UC patients undergoing colectomy due to dysplasia or cancer, the prevalence of CMV is very low [28]. In the current study, we found that all CMVpositive patients were using corticosteroids at colectomy and also received a higher dose of glucocorticoids at operation compared to CMV-negative patients. The association between CMV and glucocorticoid use has been noted previously [22,26,29] and CMV was also seem to be more common in steroid
refractory patients, prevalence varying from 25% to 36% [10,17,18,23,30]. We found that CMV was related to the dose of glucocorticoids used at operation, but not to the duration of glucocorticoid use, similar to previous findings [23]. It has been suggested that CMV reactivation has a direct role in the resistance to steroids in UC patients and that antiviral treatment can improve the response to steroids in patients infected with CMV [31]. The association between CMV disease and glucocorticoid use is also seen in solid organ transplant recipients treated with immunosuppression according to standardized protocols [32,33], which indicates that the association between CMV and glucocorticoids in UC patients is due to the immunosuppressant drug and not the UC severity. In a prospective study, CMV was only observed in patients on glucocorticoid therapy but not in patients with active disease before starting steroid treatment [17]. Various definitions [17,19], or lack of definition [18,30], of steroid refractory UC have been used in the literature, which makes it difficult to compare studies. In our patient group, it tended to be a higher proportion of CMV-positive patients (66.7%) than CMV-negative patients (38.2%) who received high-dose steroid treatment before operation, although this did not meet statistic significance. We also found that CMV-positive patients had higher preoperative ASA score and higher age and more often underwent an acute colectomy but still had a longer preoperative stay. It has previously been observed that high age [10,22,28] and the need for emergency surgery is associated with CMV infection [22,29], and all the factors above may negatively affect
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Cytomegalovirus in ulcerative colitis the patients’ immunocompetency and thereby increase the risk of CMV reactivation. To the best of our knowledge the association between postoperative complications and CMV has not been described systematically before. We found that complications within 30 days after colectomy occurred in 30 of 77 patients (39%) – a frequency of complications comparable to other reports [34,35]. A mortality rate of 2 of 77 patients (2.6%) is also similar to recent reports from the past decade, being in the range 1.5–1.8% [36,37]. The two patients who died after colectomy had substantial comorbidity. We found that both these patients had CMV-positive colectomy specimens, but the significance of colonic CMV infection on subsequent mortality in these patients is uncertain. We also found that CMVpositive patients had more serious postoperative complications. As could be expected, postoperative complications were more prevalent in smokers and in patients with high ASA score. Pouchitis is the most common long-term complication after proctocolectomy and IPAA, occurring in up to 50%. The etiology of pouchitis in unknown, but CMV may be one of the triggering factors [38]. It has been reported that 54.5% (6/11) of CMV-positive patients with IPAA developed pouchitis during a follow-up time of 53 months, ranging 8–95 [23]. In our study, most of the CMV-positive patients did not receive an IPAA, but out of the three patients who did, two developed pouchitis. These numbers are too small to draw any conclusions about CMV positivity and pouchitis. Limitations of the current study are the low number of patients (n = 77), although it is one of the largest case series published [15], making multivariate analysis difficult, as well as the retrospective study design. High age and ASA score were both found to be risk factors for CMV positivity. Most likely some risk factors for CMV as well as for postoperative complications are interdependent. Conclusion In conclusion, we have found that CMV-positive patients received a higher dose of corticosteroids at colectomy, were older, and were more likely to have an acute operation, which are factors that most likely are related to each other. CMV-positive patients also had a higher risk of postoperative complications. CMV reactivation could occur in patients with reduced defense mechanisms, either due to higher doses of corticosteroids, older age, or in severe disease leading to acute colectomy. These findings do not clarify whether the presence of CMV infection contributes to treatment resistance and leads to
851
colectomy or if the presence of CMV is a so-called innocent bystander. Prospective cohort studies of UC patients as well as randomized studies on the effect of antiviral treatment are needed to answer important questions.
Acknowledgment The authors thank Bjørn Munkvold for performing immunohistochemical labeling. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Powell RD, Warner NE, Levine RS, Kirsner JB. Cytomegalic inclusion disease and ulcerative colitis; report of a case in a young adult. Am J Med 1961;30:334–40. [2] Krech U. Complement-fixing antibodies against cytomegalovirus in different parts of the world. Bull World Health Organ 1973;49:103–6. [3] Cooper HS, Raffensperger EC, Jonas L, Fitts WT Jr. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterology 1977;72:1253–6. [4] Lawlor G, Moss AC. Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander? Inflamm Bowel Dis 2010;16:1620–7. [5] Rahier JF, Ben-Horin S, Chowers Y, Conlon C, De Munter P, D’Haens G, et al. European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2009;3:47–91. [6] Roblin X, Pillet S, Oussalah A, Berthelot P, Del Tedesco E, Phelip JM, et al. Cytomegalovirus load in inflamed intestinal tissue is predictive of resistance to immunosuppressive therapy in ulcerative colitis. Am J Gastroenterol 2011;106: 2001–8. [7] Leveque N, Brixi-Benmansour H, Reig T, Renois F, Talmud D, Brodard V, et al. Low frequency of cytomegalovirus infection during exacerbations of inflammatory bowel diseases. J Med Virol 2010;82:1694–700. [8] Vega R, Bertran X, Menacho M, Domenech E, Moreno de Vega V, Hombrados M, et al. Cytomegalovirus infection in patients with inflammatory bowel disease. Am J Gastroenterol 1999;94:1053–6. [9] Kou T, Nakase H, Tamaki H, Kudo T, Nishio A, Chiba T. Cytomegalovirus infection in patients with ulcerative colitis diagnosed by quantitative real-time PCR analysis. Dig Dis Sci 2006;51:1052–5. [10] Wada Y, Matsui T, Matake H, Sakurai T, Yamamoto J, Kikuchi Y, et al. Intractable ulcerative colitis caused by cytomegalovirus infection: a prospective study on prevalence, diagnosis, and treatment. Dis Colon Rectum 2003;46: S59–65. [11] Yoshino T, Nakase H, Ueno S, Uza N, Inoue S, Mikami S, et al. Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with
852
[12]
[13]
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
[14]
[15]
[16]
[17]
[18]
[19]
[20] [21]
[22]
[23]
[24]
M. Olaisen et al. ulcerative colitis refractory to immunosuppressive therapies. Inflamm Bowel Dis 2007;13:1516–21. Pang XL, Fox JD, Fenton JM, Miller GG, Caliendo AM, Preiksaitis JK. Interlaboratory comparison of cytomegalovirus viral load assays. Am J Transplant 2009;9:258–68. de Castro ML, Tardio A, del Campo V, Estevez A, Pineda JR, Dominguez F, et al. A comparative study of two histological techniques for the identification of cytomegalovirus infection in colorectal biopsies from patients with chronic inflammatory bowel disease. Rev Esp Enferm Dig 2009;101:697–705. Beaugerie L, Cywiner-Golenzer C, Monfort L, Girard PM, Carbonnel F, Ngo Y, et al. Definition and diagnosis of cytomegalovirus colitis in patients infected by human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14:423–9. Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol 2006;101: 2857–65. Ayre K, Warren BF, Jeffery K, Travis SP. The role of CMV in steroid-resistant ulcerative colitis: a systematic review. J Crohn’s Colitis 2009;3:141–8. Domenech E, Vega R, Ojanguren I, Hernandez A, GarciaPlanella E, Bernal I, et al. Cytomegalovirus infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy. Inflamm Bowel Dis 2008;14: 1373–9. Kambham N, Vij R, Cartwright CA, Longacre T. Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. Am J Surg Pathol 2004;28:365–73. Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 1: definitions and diagnosis. J Crohn’s Colitis 2012;6:965–90. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041–8. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. Kuwabara A, Okamoto H, Suda T, Ajioka Y, Hatakeyama K. Clinicopathologic characteristics of clinically relevant cytomegalovirus infection in inflammatory bowel disease. J Gastroenterol 2007;42:823–9. Maconi G, Colombo E, Zerbi P, Sampietro GM, Fociani P, Bosani M, et al. Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection. Dig Liver Dis 2005;37:418–23. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of G. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology,
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32] [33]
[34]
[35]
[36]
[37]
[38]
Practice Parameters Committee. Am J Gastroenterol 2010; 105:501–23.quiz 24. Pola S, Patel D, Ramamoorthy S, McLemore E, Fahmy M, Rivera-Nieves J, et al. Strategies for the care of adults hospitalized for active ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:1315–25.e4. Takahashi Y, Tange T. Prevalence of cytomegalovirus infection in inflammatory bowel disease patients. Dis Colon Rectum 2004;47:722–6. Kaufman HS, Kahn AC, Iacobuzio-Donahue C, Talamini MA, Lillemoe KD, Hamilton SR. Cytomegaloviral enterocolitis: clinical associations and outcome. Dis Colon Rectum 1999;42:24–30. Kojima T, Watanabe T, Hata K, Shinozaki M, Yokoyama T, Nagawa H. Cytomegalovirus infection in ulcerative colitis. Scand J Gastroenterol 2006;41:706–11. Eyre-Brook IA, Dundas S. Incidence and clinical significance of colonic cytomegalovirus infection in idiopathic inflammatory bowel disease requiring colectomy. Gut 1986;27:1419–25. Cottone M, Pietrosi G, Martorana G, Casa A, Pecoraro G, Oliva L, et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol 2001;96:773–5. Pillet S, Pozzetto B, Jarlot C, Paul S, Roblin X. Management of cytomegalovirus infection in inflammatory bowel diseases. Dig Liver Dis 2012;44:541–8. Rubin RH. Impact of cytomegalovirus infection on organ transplant recipients. Rev Infect Dis 1990;12:S754–66. Matas AJ, Kandaswamy R, Humar A, Payne WD, Dunn DL, Najarian JS, et al. Long-term immunosuppression, without maintenance prednisone, after kidney transplantation. Ann Surg 2004;240:510–16.discussion 6-7. Ma C, Crespin M, Proulx MC, DeSilva S, Hubbard J, Prusinkiewicz M, et al. Postoperative complications following colectomy for ulcerative colitis: a validation study. BMC Gastroenterol 2012;12:39. Gu J, Stocchi L, Remzi F, Kiran RP. Factors associated with postoperative morbidity, reoperation and readmission rates after laparoscopic total abdominal colectomy for ulcerative colitis. Colorectal Dis 2013;15:1123–9. de Silva S, Ma C, Proulx MC, Crespin M, Kaplan BS, Hubbard J, et al. Postoperative complications and mortality following colectomy for ulcerative colitis. Clin Gastroenterol Hepatol 2011;9:972–80. Teeuwen PH, Stommel MW, Bremers AJ, van der Wilt GJ, de Jong DJ, Bleichrodt RP. Colectomy in patients with acute colitis: a systematic review. J Gastrointest Surg 2009; 13:676–86. Navaneethan U, Shen B. Secondary pouchitis: those with identifiable etiopathogenetic or triggering factors. Am J Gastroenterol 2010;105:51–64.
ORIGINAL ARTICLE
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Cytomegalovirus infection and postoperative complications in patients with ulcerative colitis undergoing colectomy
MAYA OLAISEN1, ASTRID RYDNING2, TOM CHRISTIAN MARTINSEN1,3, IVAR SKJÅK NORDRUM4,5, PATRICIA MJØNES4 & REIDAR FOSSMARK1,3 1
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, 2Department of Gastrointestinal Surgery, St. Olav’s Hospital, Trondheim, Norway, 3Department of Gastroenterology and Hepatology, St. Olav’s University Hospital, Trondheim, Norway, 4Department of Pathology and Medical Genetics, St Olav’s University Hospital, Trondheim, Norway, and 5Department of Laboratory Medicine, Children and Woman Health, NTNU, Trondheim, Norway
Abstract Background. Ulcerative colitis (UC) can be complicated by reactivation of cytomegalovirus (CMV). CMV reactivation may change the course of UC and may require antiviral treatment. Some risk factors of CMV reactivation have previously been identified, whereas the association between CMV reactivation and postoperative complications has not been examined systematically. Methods. Patients with UC operated with colectomy due to active UC were studied (n = 77). Patient and disease characteristics, as well as postoperative complications were recorded and CMV was detected by immunohistochemical examination of multiple sections from the colectomy specimen. Results. CMV was found in nine (11.7%) colectomy specimens. CMV-positive patients received significantly higher doses of corticosteroids at colectomy than CMV-negative patients (61.1 ± 23 vs 32.5 ± 32 mg/day, p = 0.01). CMV-positive patients were also older, had a higher risk of severe complications, higher American Society of Anesthesiologists (ASA) score, longer preoperative stay, and a higher rate of acute surgery. Complications occurred in 30 (39%) patients after surgery, 8(10.4%) of whom were serious. Two CMV-positive patients (2.6%) died in-hospital after the colectomy. High ASA score was associated with the occurrence of serious complications. Conclusion. A relatively small proportion of patients with UC operated by colectomy were CMV positive. CMV positivity was associated with old age, high dose of corticosteroids at operation, high ASA score, acute surgery, and severe postoperative complications. Patients with such characteristics may be at risk of CMV infection and may require special management.
Key Words: colectomy, corticosteroids, cytomegalovirus, outcome, ulcerative colitis
Introduction The occurrence of cytomegalic inclusions in the colon of a patient with ulcerative colitis (UC) was noted and described more than 50 years ago [1]. The prevalence of cytomegalovirus (CMV) antibodies among adults ranges from 40% in highly industrialized areas to 100% in developing countries [2]. CMV persists lifelong in the organism after primary infection and may reactivate in immunosuppressed patients. It was
earlier proposed that CMV infection may predispose to a fulminant course of UC [3], but during the past years there has been an increasing interest in the role of CMV in UC, particularly in exacerbations. The use of immunosuppressant drugs may lead to CMV reactivation, but severe colitis per se may possibly cause CMV reactivation and that CMV reactivation could be a surrogate marker of severe UC [4]. Despite the uncertainties, the European Crohn’s and Colitis Organisation (ECCO) recommends that CMV colitis
Correspondence: Reidar Fossmark, MD PhD, Department of Gastroenterology and Hepatology, St.Olav’s University Hospital, Prinsesse Kristinas gate 3, 7006 Trondheim, Norway. Tel: +47 06800. E-mail: [email protected]
(Received 1 May 2014; revised 26 May 2014; accepted 26 May 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.929172
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
846
M. Olaisen et al.
should be excluded in immunomodulatory refractory cases of inflammatory bowel disease and initiation of antiviral therapy and discontinuation of immunomodulators is recommended [5]. In support of this approach, there are a few small, nonrandomized studies suggesting that ganciclovir induces remission in UC patients with steroid refractory exacerbations, and the treatment may reduce short-term risk of colectomy [6–11]. The best method for detecting clinically relevant presence of CMV, which should be considered a CMV infection, has not been established. Real-time quantitative polymerase chain reaction (qPCR) tests for CMV load are more sensitive than immunohistochemical (IHC) and haematoxylin and eosin (HE) sections [11]. However, interlaboratory variations are in the range of 2–4 log10 [12] and qPCR may detect low-level reactivation of latent CMV [4] without clinical relevance. IHC detection of CMV increases the sensitivity compared to HE-stained sections [13,14]. Today IHC is considered the current gold standard for the diagnosis of CMV infection, and colonic mucosal CMV infection detected by histopathology appears clinically relevant and appropriate basis for initiation of antiviral therapy [15,16]. The prevalence of CMV infection has been reported to be higher in steroid refractory UC, varying between 25% and 36% [17,18]. CMV reactivation in UC may increase the risk of colectomy, but the influence of CMV infection on postoperative outcome has not been examined systematically in larger groups of patients. In the present study, we have determined the prevalence of CMV in colectomy tissue samples from patients operated due to active UC and identified characteristics of patients with CMV-positive specimens. Further, we have examined the postoperative outcome to identify risk factors for complications, including CMV positivity. Material and methods All patients of age ‡16 years undergoing colectomy at St Olav’s Hospital Trondheim, Norway, because of active UC during the period between 1 January 2000 and 31 December 2010 were identified and included in a retrospective analysis. Patients with active UC were not regularly tested for CMV in preoperative endoscopic colon biopsies at this time. We identified 81 patients diagnosed where a preoperative UC diagnosis was maintained after histopathological examination of the surgical specimen. In one patient, the histopathological examination also revealed a T-cell lymphoma in the colon and three patients were found to have Crohn’s disease during a mean follow up of 7.0 ± 3.5 years. These four patients were excluded
from further analyses, and 77 patients were eligible for further analyses. Patient data were extracted retrospectively from medical records and an institution-based surgical complication register at the Department of Gastrointestinal surgery, St Olav’s Hospital. The following patient and disease characteristics were recorded: age, sex, reason for colectomy, disease duration, disease pattern, disease extension at the time of operation, previous and current treatment, results of blood analyses before colectomy (C-reactive protein, sedimentation rate), duration of the hospital stay and American Society of Anesthesiologists score (ASA score). Disease pattern was classified into two different categories, continuous or intermitting, where intermitting disease was defined as disease where clinical remission was maintained for ‡3 months without other than 5-aminosalicylic acid (5-ASA) and local treatment. The reason for colectomy was subdivided into three groups: 1) steroid dependency (n = 19), as defined by ECCO [19], that is, patients who are unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids, without recurrent active disease, or who have a relapse within 3 months of stopping steroids; 2) treatment resistance (n = 34), defined as persisting active colitis as perceived by the treating physician, despite medical treatment with 5-ASA, glucocorticoids, and other lines of treatment varying from case to case; and 3) fulminant colitis (n = 24), including all patients who fulfilled the Truelove and Witt’s criteria [20]. Systemic glucocorticoid treatment at colectomy was recorded and expressed as milligrams prednisolone/day (cortisone and methylprednisolone were converted into equipotent doses of prednisolone). Highest dose of glucocorticoids throughout medical history and the duration of continuous treatment before colectomy were registered. High-dose glucocorticoid treatment defined as ‡20 mg prednisolone/ day for ‡6 weeks within the year before colectomy was recorded. Previous and current treatments at the time of operation with azathioprine, anti-TNF-a agents, cyclosporine, 5-ASA, and sulfasalazine, as well as local treatment, were registered. Drug doses are presented as mean ± SD. Surgery and complications The surgical procedure was recorded using NCSP/ NCMP. Different surgical procedures were performed: total colectomy and ileostomy (JFH10 or JFH11), proctocolectomy and ileostomy (JFH20), proctocolectomy and ileal pouch anal anastomosis (IPAA) without ileostomy (JFH30), and proctocolectomy and IPAA with loop ileostomy (JFH33). The
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Cytomegalovirus in ulcerative colitis procedures were classified into laparotomy or laparoscopic procedures and the number of laparoscopic procedures that had to be converted to a laparotomy procedure was recorded. The length of postoperative hospital stay was extracted. Medical records and data from the complication registry were reviewed and compared to ensure the data quality. Complications up to 30 days after colectomy were stratified into five different severity groups using the Clavien-Dindo Classification of Surgical Complications [21]. Further, the occurrence of pouchitis during follow up was recorded for patients with an IPAA. The study protocol was approved by the regional committee for Medical and Health Research Ethics in Trondheim. CMV immunohistochemistry and evaluation Formalin-fixed paraffin-embedded tissue from four to six segments of the colon were cut into 4 mm thick sections that were dewaxed and further processed for immunohistochemistry using a DAKO Autostainer Link system (DAKO, Glostrup, Denmark). Antigen retrieval was achieved by using DAKO Target Retrieval Solution pH 9.0 in 97 C for 20 min. Sections were incubated for 1 h with mouse antihuman monoclonal anti-CMV antibody (DAKO M0854) diluted 1:500; the immunoreaction was then visualized using EnVision (DAKO K5007) and DAB+ before counterstaining with hematoxylin. Positive control tissue from a lung CMV infection and negative control incubated with non-immune serum (DAKO IR750), as well as incubation with tissue known to be infected with adenovirus or Epstein– Barr virus, as well as negative control section incubated with non-immune serum (DAKO IR750), were included in all procedures. The tissue sections were blindly reviewed by two pathologists (I.N. and P.M). The presence of characteristic CMV positivity was registered. As practiced by others, CMV positivity was defined as ‡1 cell with immunolabeled and characteristic inclusions, [22,23], and patients were classified as CMV positive or CMV negative. Statistics Descriptive data are presented as mean ± SD, frequency (percentage) or median (range) as found appropriate. Independent T-test for comparisons between groups was used for data following normal distribution. To examine differences between categorical variables the chi-square test and Fisher’s exact probability test were used. P < 0.05 was considered statistically significant using two-sided tests. Data
847
were analyzed using IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA).
Results Patient and disease characteristics are presented in Table I. Of the 77 patients, 25 (32.5%) were female and the age at colectomy was 42.0 ± 17.4 years. ASA scores were distributed as following: ASA 1: 3.9% (n = 3), ASA 2: 71.4% (n = 55), ASA 3: 20.8% (n = 16), and ASA 4: 3.9% (n = 3). Disease duration before surgery was 6.1 ± 7.0 years and 54 (70%) patients had continuous disease activity pattern. Total colitis was diagnosed in 58 (75%) patients, whereas 15 (19.7%) had left-sided colitis and 4 (5.3%) had Table I. Characteristics of patients with ulcerative colitis operated with colectomy. Patient characteristics, n = 77 (%) Male 52 (67.5%) Female 25 (32.5%) 29 (38.7%) Smokers, n = 75 (%)a Age (years) at colectomy, mean ± SD 42.0 ± 17.4 Disease duration (years), mean ± SD 6.1 ± 7.0 Reason for colectomy, n = 77 (%) Steroid-dependant 19 (24.7%) Treatment-resistant 34 (44.2%) Fulminant colitis 24 (31.2%) Disease distribution, n = 77 (%) Rectosigmoid involvement 4 (5.2%) Left-sided colitis 15 (19.5%) Total colitis 58 (75.3%) American Society of Anesthesiologists classification, n=77 (%) Class 1 3 (3.9%) Class 2 55 (71.4%) Class 3 16 (20.8%) Class 4 3 (3.9%) Follow-up time (years), mean ± SD 7.0 ± 3.5 Surgical procedure, n = 77 Colectomy and ileostomy 60 (77.9%) Proctocolectomy and ileostomy 7 (9.1%) Proctocolectomy and ileoanal 2 (2.6%) anastomosis without ileostomy Proctocolectomy and ileoanal 8 (10.4%) anastomosis with loop ileostomy Laparotomy or Laparoscopy, n = 77 Laparotomy 66 (85.7%) Laparoscopy 7 (9.1%) Laparoscopy converted to laparotomyb 4 (5.2%) Elective vs. acute, n = 77 Elective 37 (48.1%) Acute 40 (51.9%) Length of hospital stay (days), [median, range] Postoperative stay (days) 11 (5–30) Preoperative stay (days) 6 (0–36) a
Information available only in 75 patients, smokers are defined as current and previous smokers. The surgical procedure was converted to proctocolectomy with ileostomy in one of four patients and in three of four patients, it was converted to a total colectomy and ileostomy. b
848
M. Olaisen et al.
rectosigmoid involvement. Immediate reason for colectomy was fulminant colitis in 24 (31.2%) cases.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Medication The medication history is presented in Table II. All patients had been using corticosteroids during the course of disease. Thirty-two (41.6%) had received high-dose treatment with corticosteroids during the year before colectomy. The corticosteroid dose at colectomy was 35 ± 32 mg/day, and duration of continuous treatment before colectomy was 11.0 ± 14 months. Five patients received azathioprine at operation (mean dose 123 ± 70 mg/day), one patient received cyclosporine (dose 200 mg) at operation and two patients received adalimumab at operation (mean dose 40 mg ± 0 mg/day). Surgery and complications Surgical procedures are presented in Table I and surgical complications are presented in Figure 1. Most patients underwent colectomy with ileostomy (n = 60). Ten patients were operated with Table II. Current and previous medications in ulcerative colitis patients operated with colectomy. Medication Corticosteroids, n (%) Dose at operationa High-doseb Durationc 5-ASA n (%)d All-time users Dose at operation (g) Sulfasalazine n (%) All-time users Dose at operation (g) Azathioprine n (%) All-time users Azathioprine at operation Dose at operation Anti-TNF treatment n (%) Adalimumab, all-time users Infliximab, all-time users Adalimumab at operation Dose at operation (n = 2) Cyclosporine n (%) All-time users At operation Dose at operation (n = 1) Local treatment n (%) All-time users a
35 ± 32 mg 32 (41.6%) 11 ± 14 months 67 (87%) 2.2 ± 0.8 19 (24.7%) 2.1 ± 0.6 14 (18.2%) 5 (6.5%) 123 ± 70 mg 2 (2.6%) 1 (1.3%) 2 (2.6%) 40 mg/2w 1 (1.3%) 1 (1.3%) 200 mg 52 (67.5%)
Information available only in 76 patients. High dose was defined as: ‡20 mg prednisolone/day ‡6 weeks within the past year before colectomy. c Information available only in 75 patients. d Information available only in 76 patients. Abbreviation: 5-ASA: 5-aminosalicylic acid. b
proctocolectomy and IPAA in one surgical intervention, two of these without ileostomy and eight with a diverting loop ileostomy. Thirty-nine patients got an IPAA during the follow up, one patient a Kock’s pouch and 22 patients underwent proctectomy left with a permanent ileostoma. Ten patients retained their proctum, three patients died before proctectomy was performed whereas two patients were lost to long-term follow up. Complications within 30 days after colectomy occurred in 30 of 77 patients (39%). Twenty-two (73.3%) of these were grade 1 and grade 2 complications, that is, complications handled bedside and with pharmacological treatment, and which did not demand intervention (surgical, endoscopic, or radiological) or an IC/intensive care unit (ICU) management. Serious complications (grades 3–5) occurred in eight (10.4%) patients, two (2.6%) of these died in hospital after colectomy, classified as severity grade 5. No patients developed grade 4 complications. The type of surgical procedure did not influence the risk of postoperative complications significantly (24 of 66 patients operated with laparotomy developed complications versus 5 of 7 patients with laparoscopy versus 1 of 4 patients converted from laparoscopy to laparotomy, p = 0.18). Mean postoperative stay was 11.2 ± 4.5 days. Out of the 40 (51.9%) patients who received a reservoir later on, 19 (47.5%) patients were diagnosed with pouchitis during follow up. Of the 11 CMVpositive patients, 6 did not receive a reservoir. Of the three CMV-positive patients with an IPAA, two developed pouchitis during follow up. Patients with high ASA score (3 and 4) had higher occurrence of serious complications (grades 3–5) than patients with low ASA score (p = 0.002). Age at colectomy, high-dose glucocorticoids, duration of glucocorticoid treatment, fulminant colitis, and acute operation were not associated with more complications, neither of all types or serious complications. However, patients with fulminant colitis had longer postoperative stay compared to patients with steroid dependency and treatment resistance as indication for colectomy (p = 0.03). CMV immunohistochemistry CMV was found in nine patients (11.7%). Strong immunohistochemical labeling is illustrated in Figure 2. In four patients, CMV inclusions were found only in the ascending or transverse colon of the surgical specimen and for the remaining five patients CMV inclusions were found in all segments of the colon. Characteristics of CMV-positive and CMV-negative patients are presented in Table III.
Cytomegalovirus in ulcerative colitis 0%
849
3%
5% 2% None, n = 47 17%
Severity grade 1, n = 9 Severity grade 2, n = 13 Severity grade 3a, n = 2 Severity grade 3b, n = 4 61%
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
12%
Severity grade 4, n = 0 Severity grade 5, n = 2
Figure 1. Postoperative complications within 30 days after colectomy in patients with ulcerative colitis are shown.
76-year-old man who after colectomy developed postoperative pulmonary embolism due to fulminant colitis and was re-operated due to suspected intraabdominal leak from the remaining rectum. He subsequently developed clinical sepsis and multiorgan failure, including acute respiratory distress syndrome, and died 20 days after colectomy. The second patient was a 52-year-old woman who was operated due to fulminant colitis after direct transfer from a local hospital. The patient had severe chronic obstructive pulmonary disease (GOLD stage 4) and after surgery she developed a pseudomonas lung infection and died from respiratory failure at the ICU 9 days after colectomy.
CMV-positive patients were significantly older, received a higher dose of glucocorticoids at operation, and had a higher ASA score. CMV-positive patients had a longer preoperative stay, were more likely to have non-elective colectomy and more often developed serious postoperative complications than CMV-negative patients. Two patients who died after colectomy were CMV-positive. There was no significant difference between CMV-positive and CMVnegative patients as regard disease duration, duration of glucocorticoid treatment, fulminant colitis as indication for colectomy, or the occurrence of all complications overall. Two patients died within 30 days after colectomy. One patient was a A
B
C
D
Figure 2. Colectomy specimen from a patient with ulcerative colitis with positive immunolabeling of cytomegalovirus (CMV) at (A) 200 and (B) 400 magnification. Sections with positive control tissue from a CMV lung infection (C) and negative control (D) were included in all immunohistochemical procedures.
850
M. Olaisen et al.
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Table III. Comparison of CMV-positive and CMV-negative patients with ulcerative colitis undergoing colectomy, with data presented as mean ± SD or n (%).
Age at operation (years) Gender, female (%) Disease duration (years) High ASA score (3 and 4), n (%) Glucocorticoid dose (mg) at colectomy Duration prednisolone (months) High-dose glucocorticoidsa, n (%) Azathioprine at operation, n (%) Preoperative stay (days) Postoperative stay (days) Complications, all types, n (%) Serious complications, n (%) Death in hospital after colectomy, n (%) Acute operation, n (%) Fulminant colitis, n (%)
CMV-positive (n = 9)
CMV-negative (n = 68)
53.8 ± 18.3 4 (44.4%) 3.1 ± 4.0 5 (55.5%) 61.1 ± 22.6 4.3 ± 3.4 6 (66.7%) 0 16.9 ± 9.9 12.8 ± 6.0 5 (55.5%) 3 (33.3%) 2 (22.2%) 8 (88.9%) 5 (55.5%)
40.4 ± 16.8 20 (30.8%) 6.5 ± 7.2 14 (20.5%) 32.5 ± 31.8 11.9 ± 14.5 26 (38.2%) 5.9 (4) 8.3 ± 8.7 10.9 ± 4.3 25 (36.8%) 5 (7.4%) 0 32 (47.1%) 19 (27.9%)
p-Value 0.029 0.275 0.167 0.022 0.011 0.123 0.104 0.007 0.233 0.271 0.016 0.018 0.093
High-dose glucocorticoids: ‡20 mg/day ‡6 weeks within the past year before colectomy. Abbreviation: ASA: American Society of Anesthesiologists.
a
Discussion The clinical significance of CMV in UC is still uncertain. However, accumulating evidence suggest that colonic CMV reactivation and infection affect the clinical course of UC and this has been recognized in recent European [5] and American [24] practice guidelines. Treatment of suspected CMV disease is, therefore, recommended [5,24,25], whereas the knowledge about how to select patients for antiviral treatment is insufficient. In the current study we have determined the prevalence of CMV infection in colectomy specimens of UC patients who underwent surgery due to active disease. We have identified patient and disease characteristics associated with CMV infection as well as postoperative complications. In studies of colectomy specimens using IHC, the prevalence of CMV infection has been 4.6–50% [22,23,26,27]. In the current study we found a prevalence of 11.7%. The variation in CMV prevalence may be explained by differences in patient population as well as lack of standardized IHC procedures and interpretation [22]. The degree of inflammatory activity also matters and, in UC patients undergoing colectomy due to dysplasia or cancer, the prevalence of CMV is very low [28]. In the current study, we found that all CMVpositive patients were using corticosteroids at colectomy and also received a higher dose of glucocorticoids at operation compared to CMV-negative patients. The association between CMV and glucocorticoid use has been noted previously [22,26,29] and CMV was also seem to be more common in steroid
refractory patients, prevalence varying from 25% to 36% [10,17,18,23,30]. We found that CMV was related to the dose of glucocorticoids used at operation, but not to the duration of glucocorticoid use, similar to previous findings [23]. It has been suggested that CMV reactivation has a direct role in the resistance to steroids in UC patients and that antiviral treatment can improve the response to steroids in patients infected with CMV [31]. The association between CMV disease and glucocorticoid use is also seen in solid organ transplant recipients treated with immunosuppression according to standardized protocols [32,33], which indicates that the association between CMV and glucocorticoids in UC patients is due to the immunosuppressant drug and not the UC severity. In a prospective study, CMV was only observed in patients on glucocorticoid therapy but not in patients with active disease before starting steroid treatment [17]. Various definitions [17,19], or lack of definition [18,30], of steroid refractory UC have been used in the literature, which makes it difficult to compare studies. In our patient group, it tended to be a higher proportion of CMV-positive patients (66.7%) than CMV-negative patients (38.2%) who received high-dose steroid treatment before operation, although this did not meet statistic significance. We also found that CMV-positive patients had higher preoperative ASA score and higher age and more often underwent an acute colectomy but still had a longer preoperative stay. It has previously been observed that high age [10,22,28] and the need for emergency surgery is associated with CMV infection [22,29], and all the factors above may negatively affect
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
Cytomegalovirus in ulcerative colitis the patients’ immunocompetency and thereby increase the risk of CMV reactivation. To the best of our knowledge the association between postoperative complications and CMV has not been described systematically before. We found that complications within 30 days after colectomy occurred in 30 of 77 patients (39%) – a frequency of complications comparable to other reports [34,35]. A mortality rate of 2 of 77 patients (2.6%) is also similar to recent reports from the past decade, being in the range 1.5–1.8% [36,37]. The two patients who died after colectomy had substantial comorbidity. We found that both these patients had CMV-positive colectomy specimens, but the significance of colonic CMV infection on subsequent mortality in these patients is uncertain. We also found that CMVpositive patients had more serious postoperative complications. As could be expected, postoperative complications were more prevalent in smokers and in patients with high ASA score. Pouchitis is the most common long-term complication after proctocolectomy and IPAA, occurring in up to 50%. The etiology of pouchitis in unknown, but CMV may be one of the triggering factors [38]. It has been reported that 54.5% (6/11) of CMV-positive patients with IPAA developed pouchitis during a follow-up time of 53 months, ranging 8–95 [23]. In our study, most of the CMV-positive patients did not receive an IPAA, but out of the three patients who did, two developed pouchitis. These numbers are too small to draw any conclusions about CMV positivity and pouchitis. Limitations of the current study are the low number of patients (n = 77), although it is one of the largest case series published [15], making multivariate analysis difficult, as well as the retrospective study design. High age and ASA score were both found to be risk factors for CMV positivity. Most likely some risk factors for CMV as well as for postoperative complications are interdependent. Conclusion In conclusion, we have found that CMV-positive patients received a higher dose of corticosteroids at colectomy, were older, and were more likely to have an acute operation, which are factors that most likely are related to each other. CMV-positive patients also had a higher risk of postoperative complications. CMV reactivation could occur in patients with reduced defense mechanisms, either due to higher doses of corticosteroids, older age, or in severe disease leading to acute colectomy. These findings do not clarify whether the presence of CMV infection contributes to treatment resistance and leads to
851
colectomy or if the presence of CMV is a so-called innocent bystander. Prospective cohort studies of UC patients as well as randomized studies on the effect of antiviral treatment are needed to answer important questions.
Acknowledgment The authors thank Bjørn Munkvold for performing immunohistochemical labeling. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Powell RD, Warner NE, Levine RS, Kirsner JB. Cytomegalic inclusion disease and ulcerative colitis; report of a case in a young adult. Am J Med 1961;30:334–40. [2] Krech U. Complement-fixing antibodies against cytomegalovirus in different parts of the world. Bull World Health Organ 1973;49:103–6. [3] Cooper HS, Raffensperger EC, Jonas L, Fitts WT Jr. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterology 1977;72:1253–6. [4] Lawlor G, Moss AC. Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander? Inflamm Bowel Dis 2010;16:1620–7. [5] Rahier JF, Ben-Horin S, Chowers Y, Conlon C, De Munter P, D’Haens G, et al. European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2009;3:47–91. [6] Roblin X, Pillet S, Oussalah A, Berthelot P, Del Tedesco E, Phelip JM, et al. Cytomegalovirus load in inflamed intestinal tissue is predictive of resistance to immunosuppressive therapy in ulcerative colitis. Am J Gastroenterol 2011;106: 2001–8. [7] Leveque N, Brixi-Benmansour H, Reig T, Renois F, Talmud D, Brodard V, et al. Low frequency of cytomegalovirus infection during exacerbations of inflammatory bowel diseases. J Med Virol 2010;82:1694–700. [8] Vega R, Bertran X, Menacho M, Domenech E, Moreno de Vega V, Hombrados M, et al. Cytomegalovirus infection in patients with inflammatory bowel disease. Am J Gastroenterol 1999;94:1053–6. [9] Kou T, Nakase H, Tamaki H, Kudo T, Nishio A, Chiba T. Cytomegalovirus infection in patients with ulcerative colitis diagnosed by quantitative real-time PCR analysis. Dig Dis Sci 2006;51:1052–5. [10] Wada Y, Matsui T, Matake H, Sakurai T, Yamamoto J, Kikuchi Y, et al. Intractable ulcerative colitis caused by cytomegalovirus infection: a prospective study on prevalence, diagnosis, and treatment. Dis Colon Rectum 2003;46: S59–65. [11] Yoshino T, Nakase H, Ueno S, Uza N, Inoue S, Mikami S, et al. Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with
852
[12]
[13]
Scand J Gastroenterol Downloaded from informahealthcare.com by University of Newcastle on 01/02/15 For personal use only.
[14]
[15]
[16]
[17]
[18]
[19]
[20] [21]
[22]
[23]
[24]
M. Olaisen et al. ulcerative colitis refractory to immunosuppressive therapies. Inflamm Bowel Dis 2007;13:1516–21. Pang XL, Fox JD, Fenton JM, Miller GG, Caliendo AM, Preiksaitis JK. Interlaboratory comparison of cytomegalovirus viral load assays. Am J Transplant 2009;9:258–68. de Castro ML, Tardio A, del Campo V, Estevez A, Pineda JR, Dominguez F, et al. A comparative study of two histological techniques for the identification of cytomegalovirus infection in colorectal biopsies from patients with chronic inflammatory bowel disease. Rev Esp Enferm Dig 2009;101:697–705. Beaugerie L, Cywiner-Golenzer C, Monfort L, Girard PM, Carbonnel F, Ngo Y, et al. Definition and diagnosis of cytomegalovirus colitis in patients infected by human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 1997;14:423–9. Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol 2006;101: 2857–65. Ayre K, Warren BF, Jeffery K, Travis SP. The role of CMV in steroid-resistant ulcerative colitis: a systematic review. J Crohn’s Colitis 2009;3:141–8. Domenech E, Vega R, Ojanguren I, Hernandez A, GarciaPlanella E, Bernal I, et al. Cytomegalovirus infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy. Inflamm Bowel Dis 2008;14: 1373–9. Kambham N, Vij R, Cartwright CA, Longacre T. Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. Am J Surg Pathol 2004;28:365–73. Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 1: definitions and diagnosis. J Crohn’s Colitis 2012;6:965–90. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2:1041–8. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. Kuwabara A, Okamoto H, Suda T, Ajioka Y, Hatakeyama K. Clinicopathologic characteristics of clinically relevant cytomegalovirus infection in inflammatory bowel disease. J Gastroenterol 2007;42:823–9. Maconi G, Colombo E, Zerbi P, Sampietro GM, Fociani P, Bosani M, et al. Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection. Dig Liver Dis 2005;37:418–23. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of G. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology,
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32] [33]
[34]
[35]
[36]
[37]
[38]
Practice Parameters Committee. Am J Gastroenterol 2010; 105:501–23.quiz 24. Pola S, Patel D, Ramamoorthy S, McLemore E, Fahmy M, Rivera-Nieves J, et al. Strategies for the care of adults hospitalized for active ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:1315–25.e4. Takahashi Y, Tange T. Prevalence of cytomegalovirus infection in inflammatory bowel disease patients. Dis Colon Rectum 2004;47:722–6. Kaufman HS, Kahn AC, Iacobuzio-Donahue C, Talamini MA, Lillemoe KD, Hamilton SR. Cytomegaloviral enterocolitis: clinical associations and outcome. Dis Colon Rectum 1999;42:24–30. Kojima T, Watanabe T, Hata K, Shinozaki M, Yokoyama T, Nagawa H. Cytomegalovirus infection in ulcerative colitis. Scand J Gastroenterol 2006;41:706–11. Eyre-Brook IA, Dundas S. Incidence and clinical significance of colonic cytomegalovirus infection in idiopathic inflammatory bowel disease requiring colectomy. Gut 1986;27:1419–25. Cottone M, Pietrosi G, Martorana G, Casa A, Pecoraro G, Oliva L, et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol 2001;96:773–5. Pillet S, Pozzetto B, Jarlot C, Paul S, Roblin X. Management of cytomegalovirus infection in inflammatory bowel diseases. Dig Liver Dis 2012;44:541–8. Rubin RH. Impact of cytomegalovirus infection on organ transplant recipients. Rev Infect Dis 1990;12:S754–66. Matas AJ, Kandaswamy R, Humar A, Payne WD, Dunn DL, Najarian JS, et al. Long-term immunosuppression, without maintenance prednisone, after kidney transplantation. Ann Surg 2004;240:510–16.discussion 6-7. Ma C, Crespin M, Proulx MC, DeSilva S, Hubbard J, Prusinkiewicz M, et al. Postoperative complications following colectomy for ulcerative colitis: a validation study. BMC Gastroenterol 2012;12:39. Gu J, Stocchi L, Remzi F, Kiran RP. Factors associated with postoperative morbidity, reoperation and readmission rates after laparoscopic total abdominal colectomy for ulcerative colitis. Colorectal Dis 2013;15:1123–9. de Silva S, Ma C, Proulx MC, Crespin M, Kaplan BS, Hubbard J, et al. Postoperative complications and mortality following colectomy for ulcerative colitis. Clin Gastroenterol Hepatol 2011;9:972–80. Teeuwen PH, Stommel MW, Bremers AJ, van der Wilt GJ, de Jong DJ, Bleichrodt RP. Colectomy in patients with acute colitis: a systematic review. J Gastrointest Surg 2009; 13:676–86. Navaneethan U, Shen B. Secondary pouchitis: those with identifiable etiopathogenetic or triggering factors. Am J Gastroenterol 2010;105:51–64.
