To give you a brief outline of this CME session I'm going to touch upon a little bit upon

Transcription

1 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 1 Today we are going to talk about an important topic in chronic liver disease, cirrhosis of the liver. This CME activity is titled Infection Challenges in the Patient with Cirrhotic Cirrhosis of the liver. To give you a brief outline of this CME session I'm going to touch upon a little bit upon complications of cirrhosis of the liver and its natural history. We'll see how extensive is the problem or the scope of the problem. We'll talk a little bit about clinical management and when to use bacterial prophylaxis and how to treat infections in cirrhosis. and then we'll try and address this controversial area potential preventive approaches. Now cirrhosis is the 12th leading cause of the mortality among U.S. adults. And if you look at the other chronic disease such as diabetes this is responsible for as many fatalities as diabetes. On the other hand, if you look at a select age group, i.e. 45 to 54 years of age this becomes even a more important cause of death and clearly this accounts for a large fraction of healthcare costs today in the United States. It's humbling to admit that even today 10% of patients who are actually admitted to the hospital will actually not make it during that hospital stay. Now if you look at the "conventional complications of cirrhosis" these are the ones listed there: portal hypertension / variceal bleeding; ascites? spontaneous bacterial peritonitis; hepatorenal syndrome; hepatic encephalopathy; coagulopathy; hepatocellular carcinoma. They are aware of complications such as the hepatopulmonary syndrome and portal primary hypertension. But you can see infections are nowhere in this list, and clearly I think this list of "complications of cirrhosis" will need to be revised in the years to come.

2 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 2 Now looking at the natural history of cirrhosis I think this is the best way to do it, and I use this slide to talk to my patients because clearly compensated cirrhosis has a very different outlook as compared to decompensated cirrhosis. So if a patient has compensated cirrhosis the overall survival exceeds 10 years, on the other hand once a patient develops decompensated cirrhosis you can see the overall survival will drop and the 2 year survival is roughly less than 50%. And how do we define decompensated cirrhosis? This is again a very useful slide to talk to my patients. You can see this the cumulative risk of development of each of these complications in a patient with established cirrhosis of the liver. The first thing that will come up is esophageal varices, over time the next complication is ascites and then hepatic encephalopathy and hepatocellular carcinoma. As you can see, the graphs for hepatic encephalopathy and HEC are pretty much parallel to each other and this is the teaching, whenever we see a patient with new onset of encephalopathy we always screen for early or established hepatocellular carcinoma. Now moving on to the topic of infections. It's fair to summarize that cirrhosis is considered as an immunocompromised state, and ultimately this will lead to a variety of infections which account for a much higher mortality as compared to the patient without infection. Based on data approximately 1 out of 3 patients who will develop an infection ultimately will not survive. I think apart from early recognition and better treatment of spontaneous bacterial peritonitis leading to better survival there's been little improvement in the overall survival rates in recent decades. And hence again a humbling statistic cirrhosis with infection still accounts for a 4-fold increase in mortality among patients with

3 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 3 cirrhosis. But clearly the patient who is hospitalized is at the highest risk of developing infection, especially in those with GI bleeding. Bacterial infections occur anywhere from 30% of admitted patients with cirrhosis and clearly up to 45% in patients with GI hemorrhage. And if you look at these infection rates as compared to other infection rates in hospitalized patients these are clearly higher because the usual infection rate is somewhere between 5 and 7% in a patient who is hospitalized. Now which are the most common infections? In order of frequency, spontaneous bacterial peritonitis accounts for 1/4 of infections, another 1/5 are accounted for by urinary tract infection and then comes community acquired pneumonia. Now these are rare infections that I've listed over here, pathogens such as Microbacterium tuberculosis, C-difficile, cryptococcus, vibrio vulnificus, yersinia enterocolitica and listeria are more common and virulent in the patient with cirrhosis as compared to the general population. Again because of the high morbidity and mortality of infections in cirrhosis this would be the key message, prevention, early diagnosis and proper management of these infections are necessary to improve patient survival. Now another new entity that is being talked about these days is acute-on-chronic liver failure. I'm not going to spend much time defining this entity but it's fair to say that bacterial infections are the leading cause of mortality in patients with acute and chronic liver failure in end stage liver disease. And we all know what are the consequences of an infection. This is what I've listed here, clearly once a patient with cirrhosis is infected with prolonged hospitalization this can lead to acute kidney

4 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 4 injury and its consequences. Clearly we talked about mortality. And then for those of you who work at a transplant center these patients will now be removed or be de-listed from the liver transplant wait list. And there is also data that once a patient with cirrhosis gets infected this patient is now more susceptible to future further infections. Now diagnosis of infections in cirrhosis is clearly very difficult as compared to the non-cirrhotic patient population. And why? Cirrhosis as we all know has a background of what we would call a partial systemic inflammatory response, also known as SIRS. Hence it is very difficult to use the conventional definitions of infection in this patient population. Another kind of confounding factor is our usual modes or methods of infection diagnosis such as cultures could be negative in up to 50% of this patient population. And lastly, the lack of multicenter studies limits how we generalize what we have available for us at this time. So just to summarize, up to 1/3 of all hospitalized patients with cirrhosis are infected. With sepsis mortality increases to more than 50% and it's associated with significant costs. There is a 4-fold increase of death in infected cirrhosis patients and ICU mortality of patients with cirrhosis has remained unchanged over the last 50 years unlike other illnesses like cardiac failure where mortality has clearly decreased. We clearly have a lot of room for improvement in this area. Hence it's fair to say that the prevention, diagnosis and management of infections of infections in patients with end stage liver disease form the large unmet need.

5 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 5 What is the scope of this problem? And again as I outlined data is not easily available. Now the magnitude of the problem in cirrhosis is not quantifiable for many reasons. I already touched upon this, infections are difficult to recognize because 30 to 50% of patients with infection such as SBP can remain culture negative. Also conventional risk scoring strategies such as the SIRS criteria cannot reliably differentiate the SIRS plus infection from the noninfectious SIRS. There are also difficulties in diagnosing the presence o infections especially in hospitalized patients with cirrhosis, hence time appropriate strategies are needed to suspect infections and send cultures early so as to initiate appropriate antimicrobial therapy. A heightened suspicion of potentially resistant organisms is required in order to change therapy as needed. Now based on data in the U.S. from 20% of acute care hospitals this is the data available. This looked at approximately 65,000 patients in 2006 who had a discharge diagnosis of cirrhosis. Clearly you can see the costs out there, approximately $14 billion U.S. per year, and approximately 26,000 patients had presumed infection and required ICU support as identified by mechanical ventilation and invasive cardiovascular monitoring. The in-house mortality in this patient population who was hospitalized was 53%. The mean length of hospitalization was about 14 days. And once again I've highlighted the costs as listed over there. This is basically a U.S. nationwide inpatient sample study called the NIS study. In this study C- difficile infection in patients with cirrhosis was associated with a significantly higher mortality, length of stay and total cost compared with patients admitted with cirrhosis without C-difficile and

6 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 6 patients with C-difficile without cirrhosis. This data can be replicated almost anywhere in the world. Looking at a Korean national database patients with cirrhosis and bacteremia were more significantly likely to die than those without cirrhosis. Also bacteremia in patients with cirrhosis was more likely to occur due to intraabdominal infections and klebsiella pneumoniae was less likely to be due to coag-negative staph. Overall multivariate analysis confirmed that cirrhosis is an independent risk factor for mortality with an odds ratio of almost 2. This is another U.S. based study, the North American Consortium for the study of end stage liver disease. This includes about 12 centers from North America which are prospectively collecting data on infections in patients with cirrhosis. To date about 176 patients have been analyzed from these 9 sites. Once again the same there, common infections include SBP, UTI, spontaneous bacteremia, skin infections, respiratory tract infections and C-difficile. This is the spectrum of infections. grampositive and gram-negative infections account for 1/3 of overall infections, fungal infections are rare but you need to keep a very high index of suspicion because in this patient population 4% of infections were fungal in etiology. And once again another common these, 30% of infections had no identifier organisms. Clearly the mortality rate is different for different infections. Respiratory infections account for the highest mortality rate up to 44%, bacteremia approximately 40%, C- difficile 40%. The other infections have a slightly lower mortality rate averaging about 20 to 30% such as UTI, skin infections and SBP.

7 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 7 Overall the index infection was healthcare associated in more than half our patients in this patient population or nosocomial in about 20%. One thing that I alluded to earlier, 30% of patients will develop a second infection during the period of hospitalization. And the overall mortality in this group was about 25%. Clearly patients who ultimately died were much sicker, meaning they had a higher model for end stage liver disease score at admission, 25 versus 20, and they were more likely to have hepatic encephalopathy, hepatorenal syndrome or more likely to be ventilated and have an ICU stay during the hospitalization. We talked about this earlier, there was a higher incidence of second infections during hospitalization in patients who died as compared to those who survived. Patients who developed a second infection were more likely to have a gram-negative first infection, an ICU stay, a lower serum albumin, a greater length of hospitalization and a higher MELD score. Multivariate analysis showed that only second infection and MELD score were associated with death. I think I hope I've been able to convince you that there is a need to develop early diagnostic and prognostic markers including biomarkers for a better understanding of infections so that we can improve the outcomes in this patient population. Let us now look at some clinical scenarios of infections in cirrhosis. We'll talk a little bit more about the two entities listed there, GI bleeding, associated infections and prophylaxis. And then spontaneous bacterial peritonitis. Some of the other infections which I would like to cover are listed above, UTI, pneumonia, soft tissue infections, endocarditis, tuberculosis, C-difficile and then

8 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 8 emerging infections such as drug resistant infections and fungal infections. And then we'll touch upon a few peculiar infections in certain specific liver diseases such as genetic hemochromatosis and primary sclerosing cholangitis. Let's talk a little bit about GI bleeding because this is fairly common in our patient population with decompensated cirrhosis. GI bleeding is associated with an increased incidence of infection, roughly anywhere from 17 to 45% will develop an incidence of SBP or bacteremia following a GI bleed. Conversely, the presence of infection has also been found to increase the risk of early bleeding. Now what we use here is short term antibiotic prophylaxis, meaning prophylaxis with antibiotics only during the episode of GI bleeding. Most infections are caused by gram-negative bacteria and are preventable with selective decontamination of the GI tract with Quinolones. This is a recommendation that's put forward by the AASLD in patients with advanced cirrhosis, 1 gram intravenous Ceftriaxone for 7 days after the bleeding episode would be effective in preventing the bacterial infection. Clearly these patients are not going to be taking anything orally and hence one cannot use the oral agent Norfloxacillin. Now it's been shown by using this approach antibiotic prophylaxis significantly reduces rates of infection, rebleeding as well as mortality. Now a slightly controversial area is the use of nonselective beta blockers. These are commonly used to lower portal hypertension and prevent the initial variceal bleeding. There is also evidence that nonselective beta blockers can decrease bacterial translocation during an episode of acute

9 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 9 hemorrhage. Beta blockers increase gut motility, reduce bacterial translocation thereby reducing the incidence of infection. There is good evidence that in the post-surgical setting a nonselective beta blocker such as Propranolol reduces infections from 40% to about 15%. However, a word of caution, the use of beta blockers in patients with refractory ascites may limit the compensatory increase in cardiac output and increase actually the vulnerability in complications such as septic shock and renal failure. And hence I'm not sure we can propose this to be advocated for this particular indication. Moving on to SBP. The prevalence of spontaneous bacterial peritonitis in patients with cirrhosis and ascites admitted to the hospital ranges anywhere from 10 to 30%. Half of cases are present at the time of hospitalization and another half were actually developed during the hospital stay. The inhouse mortality from SBP again 30%. This is the current recommendation, when to perform a diagnostic paracentesis in a patient with cirrhosis. All patients who have ascites must undergo a diagnostic paracentesis at the time of a hospital admission. Clearly those who manifest symptoms of peritoneal infection it's easy to justify a diagnostic paracentesis. Also patients who have systemic signs of infection, unexplained hepatic encephalopathy and rapid impairment in renal function when hospitalized should undergo a diagnostic paracentesis. This is the definition or the criteria for SBP. The diagnostic cutoff is a PMN count of 250 cells while the highest specificity is reached at 500 cells. Again to highlight up to 65% of patients with clinical evidence of SBP will have negative cultures. How can you increase the yield? A bedside

10 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 10 inoculation of 10 ml of ascites fluid has shown to improve the sensitivity of picking up a positive blood culture to approximately 80%. I would certainly advocate for this practice. Now one thing that always comes up is how to distinguish spontaneous bacterial peritonitis from secondary bacterial peritonitis. Clearly you have to use your clinical judgment over here, however when the ascites fluid in a patient with cirrhosis is found to have a PMN count greater than or equal to 250 cells and there is a high suspicion for secondary peritonitis, one should also test the ascites fluid for total protein, LDH, glucose, gram stain, a CEA, and alkaline phosphatase and this would potentially help in differentiating SBP from secondary peritonitis. Clearly common causes of secondary peritonitis are entities such as a perforated viscus, it could be appendicitis, acute diverticulitis, etc. One should keep a very low threshold for performing abdominal imaging such as a CT scan of the abdomen. Now sometimes the differentiation between SBP and secondary peritonitis such as bacterial peritonitis caused by perforation or an acute inflammation of an organ as highlighted earlier can be quite difficult. It's important to remember that you need to keep a very high index of suspicion for secondary peritonitis because if you miss secondary peritonitis that patient is not going to do well. Luckily secondary peritonitis accounts for only 4.5% of all patients with peritonitis in a patient with cirrhosis. And this should be suspected in the following situations. Clearly a patient who is not doing clinically well despite the use of antibiotics, the presence of a polymicrobial infection in the ascites fluid is a good clue. So two or more organisms which are isolated in the ascites fluid

11 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 11 particularly anaerobes or fungi may be a clue for secondary peritonitis. Or the presence of at least 2 of the following criteria in the ascites fluid, a low glucose content, a high protein content and LDH which is greater than serum LDH. Clearly one could check ascites fluid CEA or alkaline phosphatase and the criteria are listed above. And as outlined previously you must keep a very low threshold and get a radiologic study such as a CT scan or MRI immediately and possibly even an emergent surgical evaluation or intervention. These are the AASLD guidelines for the diagnosis of SBP. SBP is present in 12% of patients at the time of admission of a patient with cirrhosis and ascites to justify a diagnostic paracentesis. The incidence is lower nowadays because we use preventive approaches in high risk patients. I mentioned the definition of the PMN criteria, and there is new technology available but not easily used as the dip stick testing of the ascites fluid and an automated cell count which may improve early detection of the infection literally within 2 or 3 minutes of performing the paracentesis. Now there are culture, there are entities such as culture negative neutrocytic ascites. This is the treatment algorithm, SBP for all comers should be treated with Cefotaxime 2 gm every 8 yours for a period of 5 days. This is adequate. Clearly you can revise your antibiotic schedule once you get the ascites fluid analysis back. And alternative could be an oral Quinolone such as oral Ofloxacin 400 mg every 12 hours for a period of 8 days. You can adopt the oral approach in patients who are not vomiting, who do not have shock, without grade II encephalopathy or without features of renal failure.

12 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 12 Now it's important to realize that the most common morbidity in patients with SBP is renal failure. Renal impairment develops of approximately 1/3 of all SBP patients and is a strong predictor of mortality during the hospitalization stay. How can we decrease the incidence of renal impairment? This is the approach. Using IV albumen. There is a very elegant study done several - almost a decade ago which showed that using this approach on day 0 and day 3 would decrease the mortality from 30% to 10%. A more recent study has shown that albumen should be given when there is renal impairment, serum creatinine more than 1 mg per deciliter, an elevated BUN or the total protein exceeds 4. Now once a patient is diagnosed with SBP a follow-up paracentesis is usually recommended after 48 hours to assess a response by checking the PMN count and the cultures. Patients with ascites fluid PMN counts greater than or equal to 250 ml millimeters in a nosocomial setting or in the presence of a recent beta-lactam antibiotic exposure all who culture an atypical organism or have atypical clinical responses to treatment are likely to do poorly. This is the overall outcome in a patient with SBP. Recovery from SBP is seen in most patients, so 90% of patients will make a good recovery. The 30 days survival is approximately 80%, however if a patient fails treatment in hospital mortality is very high, about 50 to 80%. And basically in patients where the liver disease will worsen, so rapid deterioration in renal - in liver function in SBP patients carries a very poor prognosis. Now what's humbling here is the 1 year survival after an episode of

13 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 13 SBP which drops to approximately 30%. We used to use SBP as a criteria for putting people on the liver transplant wait list, we don't do that anymore. I think a new trend is there's a recent shift in the microbial etiology of SBP towards cefotaxime-resistant strains and this may complicate survival by delaying resolution of the infection. So to summarize, how do we prevent SBP? In a patient with GI hemorrhage, IV ceftriaxone for 7 days, or twice daily norfloxacin for 7 days. In patients with - this should be given to prevent bacterial infections in patients with cirrhosis and GI hemorrhage. Perhaps a parenteral antibiotic while the patient is still bleeding, and this can be changed to an oral antibiotic for a total of 7 days as a more practical approach. Patients who survive an episode of SBP should receive long term prophylaxis with one of the two approaches listed above. We in this institution prefer trimethoprim and sulfamethoxazole. Another criteria for SBP prevention is listed over there. In patients with cirrhosis and ascites the long term use of antibiotics can be justified if the ascites fluid protein is less than or equal to 1.5 along with impaired renal function defined as creatinine more than 1.2 or BUN more than 25, or a serum sodium less than 130 or liver failure, meaning a Child's score more than 9 or a bilirubin more than 3. Patients who recover from an episode of SBP should be given antibiotics prophylaxis indefinitely. In those without antibiotic prophylaxis the rate of recurrence of SBP is 43% at 6 months, and almost 70% at 1 year and 75% at 2 years after the initial episode. This is why you need to prophylax your

14 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 14 patient indefinitely. There is a study showed that the use of an oral quinolone reduced the recurrence of SBP from 70% to 20%. Now in this institution one could use ciprofloxacin as outlined above rather than 750 mg of ciprofloxacin once a week because we think daily ciprofloxacin is probably more effective. Now moving on to the other infections. Urinary tract infections occur in approximately 15 to 20% of hospitalized patients. This is twice as frequent in patients with cirrhosis compared with matched controls. Clearly women have a higher rate of bacteruria as compared to men. And the organisms that cause UTI are usually a gram negative bacilli such as e-coli and klebsiella. What's comforting here is bacteruria is not associated with an increased risk of sepsis, SBP or other infections which are often seen in patients with cirrhosis. And again treatment with quinolones is usually very effective in approximately 95% of patient population. Moving on to the next infection, pneumonia. Pneumonia is the third leading cause of infections in patients with cirrhosis. Community acquired pneumonia is most often caused by streptococcal pneumoniae and H. influenza. Other organisms which have been implicated include staph aureus, mycoplasma and klebsiella and legionella. Now as opposed to UTI the risk of bacteremia in community acquired pneumonia is increased in a patient who has cirrhosis. Now other procedures that we perform in these patients such as tracheal intubation and esophageal tamponade put these patients even at a higher risk for hospital acquired pneumonia. In the presence

15 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 15 of comorbidities such as cirrhosis treatment is ideal with an IV beta-lactam plus a macrolide or an IV antipneumococcal quinolone. I cannot stress that when you see a patient with cirrhosis in your office you must make sure that they receive their pneumonococcal vaccination and this is a health maintenance recommendation in a patient with cirrhosis of the liver. Soft tissue infections, cellulitis, are clearly more common. And why? Chronic edema, an increased bacterial translocation predispose patient with cirrhosis to soft tissue infections. This accounts for approximately 11% of infections, broad gram positive as well as gram negative bacteria are common causes. Cellulitis is the most frequently observed skin infection and has a recurrence rate of almost 20%. Broad spectrum antibiotics are necessary for proper management of soft tissue infections and sometimes you may need surgical debridement. Overall this sometimes accounts for a prolonged hospital stay or even morbidity and outcome in these populations. Endocarditis, luckily rare. Approximately 10% of patients with infectious endocarditis will have cirrhosis as a predisposing cause. Now why is infective endocarditis common? Because patients with cirrhosis who are hospitalized have a higher risk of bacteremia associated with certain invasive procedures such as the TIPS procedure, upper endoscopy, etc. Now 60% of patients with cirrhosis may have underlying valvular disease which predisposes to endocarditis. Common organisms once again gram-positive bacteria, beta hemolytic streptococci and enterococci are the most commonly isolated organisms. The management of endocarditis is like any other management of endocarditis.

16 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 16 Tuberculosis. You need to keep a very high index of suspicion. Why? The incidence of virulence of Microbacterium tuberculosis infections are increased in patients with cirrhosis. In a study from Denmark the 30 day case fatality rate in patients with TB and liver cirrhosis was almost 30% and the one year fatality rate 50%. Now as opposed to patients without cirrhosis TB patients with cirrhosis show extra pulmonary involvement such as TB peritonitis more frequently. Another problem is the anti-tb drugs have a much higher risk of hepatotoxicity when used in patients with cirrhosis. Other infections such as C-difficile, a recent study of over 80,000 patients with cirrhosis found that C-difficile associated disease has a much higher mortality and a longer length of stay as compared to patients without this infection. And this is very new data, but clearly very important, antibiotics and proton pump inhibitors were independently associated with C-difficile infection. Thus it is now recommended that antibiotic prophylaxis be limited to patients at the highest risk of developing SBP and PPIs should be used very selectively in this patient population. Another emerging problem, drug resistant infections. I think you and I are going to see more and more of this emerging entity. Up to 2/3 of bacterial infections either nosocomial or in the context of antibiotic intervention have been found to be multidrug resistant. Clearly gram negative isolated SBP such as E-coli, klebsiella pneumoniae are being encountered with increasing rates of resistance. Also gram positive pathogens are increasingly common in patients with cirrhosis.

17 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 17 In a recent study MRSA was noted to account for approximately 25% of patients with nosocomial SBP. Enterococcal infections such as E. faecalis, E. faecium are now isolated anywhere from 10 to 25% of patients in the setting of cirrhosis. And enterococcal infections are pretty bad, 25% mortality rate. Clearly 1/3 of these patients with enterococcal bacteremia will have vancomycin resistance and the mortality rate clearly goes up very steeply. I talked about fungal infections earlier. You need to keep a very high index of suspicion because you need to send the blood culture or the ascites fluid for special fungal cultures to pickup these infections. As mentioned earlier liver cirrhosis is an underlying condition in approximately a third of non-hiv cryptococcemia cases and is a stronger independent predictor of the 30 day mortality than in those in patients with AIDS. Cryptococcus neoformans may infect the ascites and cause SBP. Unlike SBP spontaneous cryptococcal peritonitis presents with an elevation in the lymphocyte count and because usually you and I do not detect these patients early this has a very high mortality rate, almost 70%. Other liver diseases that predispose to fungal infections are primary sclerosing cholangitis. We'll now address liver infections in certain specific liver diseases: iron overload or genetic hemochromatosis. Now iron overload impairs your cell mediated response and enhances the growth of various pathogens such as E-coli, vibrio and listeria. Patients with genetic hemochromatosis face a 30-fold higher risk of acquiring V. vulnificus bacteremia. Luckily this is rare. This bacterium is acquired through ingestion of contaminated raw oysters. Clearly this vibrio septicemia has a very

18 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 18 high mortality rate in patients with liver disease as well as people who develop localized wound infections. Another infection is yersinia in this patient population, once again if it leads to bacteremia it can cause hepatic abscesses with a very high mortality rate. Primary sclerosing cholangitis, this is a separate liver disease with it's own infection bag. PSC is a risk factor for ascending cholangitis which itself is associated with a 16% mortality rate. Generally ascending cholangitis is relatively uncommon unless there's been some kind of intervention, mechanical intervention in the biliary tree, a procedure such as an ERCP or PTC. The most common infections are ERCP are caused by gram-negative bacteria such as E-coli, klebsiella and Enterobacter. Clearly if cholangitis occurs without intervention in PSC one should suspect the presence of CBD stones, a common bile duct stricture or the development of cholangiole carcinoma. In a study of explanted livers with PSC bacteria were isolated almost in 60% of this patient population and the common bacteria are listed above, alpha-hemolytic streptococci, enterococci and staphylococci. Let's now move on to potential preventive approaches in this patient population. I'll highlight some of our challenges and then future directions in this patient population in prevention of bacterial infection. As highlighted earlier the studies currently are limited because of single center experiences, poly-pharmacy is a predictor of infections, we'll talk a little bit about the role of intensive care management of cirrhosis and sepsis, we'll touch a little bit upon the concept or the changing concept of acute kidney injury and its role in infections in cirrhosis. We clearly highlight

19 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 19 the healthcare associated issues and nosocomial infections, and then the problem of multidrug resistant organism. These are the proposed categories of nosocomial infections in patients with cirrhosis. Spontaneous bloodstream infection that is not related to intervention or infection at other sites, urinary tract infections, pulmonary infections and SBP. To complete this list we would add C-difficile and then of course infections related to interventions such as urinary catheterization, mechanical ventilation, central line placement, paracentesis, thoracentesis, renal replacement therapy, interventional radiology procedures and use of IV nutrition. Now what's proposed - what predisposes to bacterial infections in patients with cirrhosis would be bacterial translocation. Changes in gut bacteria in cirrhosis can lead to bacterial overgrowth and subsequent enhanced bacterial translocation from the gut to the systemic circulation and ascites. Hence it's fair to say that bacterial translocation is a major pathogenetic factor for infections. This process is also facilitated by acid suppression and increased intestinal permeability in patients with cirrhosis, especially with advanced disease. Sepsis as a result of bacterial translocation and small bowel bacterial overgrowth is a key component of the natural history of infections. As highlighted earlier one of the key modulators of outcomes of infections as the underlying immune status which is negatively affected at multiple levels in

20 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 20 cirrhosis. I've highlighted some of the other theories over here. There is clearly more work to be done in this area. Let me stress a little bit upon the use of PPIs in SBP. Single center studies have shown - associated the use of PPIs with SBP and C-difficile. An important observation is that PPIs are overprescribed in our patients with cirrhosis and it's been found that an appropriate indication for a PPI sometimes may exist in less than 50% of our patient population. As highlighted earlier PPIs predispose to bacterial overgrowth and adversely affect your immune function. The controversy about nonselective beta blockade. There is contradictive association on the effect of nonselective beta blockers on the negative outcomes in cirrhosis. While a metaanalysis showed a reduced development of SBP in previous studies there is data recently emerging in a nonrandomized study that patients who received nonselective beta blockers actually had a worse survival, especially in the patients with subsets of refractory ascites. Also nonselective beta blockers increased the risk for hepatorenal syndrome and death in patients with cirrhosis and SBP. Hence this new data has led to the window hypothesis on the effect of nonselective beta blockers. This is probably new evidence that suggests that nonselective beta blockers only improve outcomes in a narrow window of cirrhosis natural history between those who have medium to large varices before the development of end stage liver disease. Clearly we need more studies to elucidate the clinical role of nonselective beta blockers in cirrhosis.

21 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 21 I would like for you to read this editorial by Bruce Runyon in Gastroenterology which kind of highlights when should the beta blocker window in cirrhosis be closed? You can see on the left in early cirrhosis beta blockers are not indicated, in the middle the window opens so beta blockers are clearly indicated for the primary prophylaxis of variceal bleeding, secondary prophylaxis of variceal bleeding. On the other hand, the window once again closes and will not reopen and it's been said today that beta blockers are potentially contraindicated in refractory ascites, systolic pressures less than 100, mean arterial pressure less than 82, acute kidney injury, hepatorenal syndrome, SBP, sepsis, poor medical follow-up and patients with medical noncompliance. A little bit about prognosis and management in the ICU. As outlined previously there are several precipitating factors associated with worsening in cirrhosis leading to multisystem organ failure. These include infection, GI bleeding, acute alcoholic hepatitis, superimposed viral hepatitis, drug induced liver injury and surgery in a patient with cirrhosis. The response to infection in patients with cirrhosis is often exaggerated leading to admission to the ICU because of sepsis, severe sepsis and septic shock. The key areas that you should work with with your ICU team in the management of patients with cirrhosis is the following. Prevention of nosocomial and second infections, reduction of unnecessary instrumentation, the judicious use of antibiotics and antifungal agents and then more studies need to be done on the validation of prognostic scores that take into account the underlying liver disease severity.

22 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 22 And I put here today a list of additional areas need to be addressed. Should we be using albumen and is albumen the preferred volume expander? How should coagulopathy be corrected? Which is the optimal vasopressor support? The methodology for determining adrenal insufficiency, the situations in which steroids should be given and what dosage should be used, and finally the role of artificial and bioartificial liver support devices needs to be determined in this patient population. A few slides upon the prevention and treatment of acute kidney injury in this patient population. Clearly the definition of acute kidney injury in patients with cirrhosis is rapidly evolving. A critical need is required to prevent and adequately treat renal dysfunction in patients with infected cirrhosis. This is because renal disfunction with acute kidney injury has emerged as the major determinant of mortality in patients with cirrhosis. Acute kidney injury including hepatorenal syndrome is associated with a markedly shorter survival. In patients with decompensated cirrhosis admitted to the hospital an increased creatinine concentration within 24 hours is associated with poor survival. Even more profound is the requirement for renal replacement therapy which has almost a higher than 90% in-hospital mortality. Now you are all familiar with the definitions of the criteria for type 1 and type 2 hepatorenal syndrome. I've listed these on the slides above and these are the standard definitions for type 1 and type 2 hepatorenal syndrome. It's fair to say today that the most common precipitating factor for type 1 hepatorenal syndrome is a bacterial infection. This may occur despite the clearance of the bacterial infection. And why is that? The inflammatory response to bacterial infections increases

23 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 23 the systemic arterial vasodilatation with further reduction in the effective arterial blood volume and further renal vasoconstriction leading to the renal failure. Now I highlighted the association between SBP and renal failure. SBP was the first bacterial infection recognized to be associated with a high incidence of renal failure in cirrhosis. This occurs in approximately 1/3 of patients despite resolution of the infection and has an in-hospital mortality rate of up to 60%. Any bacterial infection can precipitate renal failure in cirrhosis. Patients who develop renal failure with bacterial infections clearly have a much higher MELD score and lower mean arterial pressure. Other infections associated with renal failure and cirrhosis are listed above. These include biliary and GI infections, we talked about SBP earlier, urinary tract infection, pneumonia and skin infections. Now look at the statistic over here, once renal failure sets in the probability of survival at 3 months is only 30% and clearly this will be even lower with a higher MELD score. Hence I hope I've been able to convince you that any measure that can prevent renal failure in cirrhosis will go a long way, especially in the setting of infection. And what can we do right now? Use IV albumen in a patient with SBP. The use of a vasopressor agent such as Terlipressin in SBP has been proposed. This agent is not FDA approved right now in the United States. The use of a vasoconstrictor should be investigated as a potential alternative or an additive to albumen in the prevention of renal failure in SBP.

24 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 24 I'm not going to spend too much time on the management of hepatorenal syndrome. Listed on this slide are the standard published management approaches to HRS type 1. One would use a vasoconstrictor and albumen infusion. The choice of vasoconstrictor depends on local availability. In North America we use midodrine in combinations with octreotide, in most other parts of the world terlipressin is used. Give the overall poor survival in patients with cirrhosis bacterial infections and established renal failure there is now a trend to treating renal impairment at a much earlier stage if you have type 1 HRS. One definition has been to define the early stage of renal dysfunction as we all know serum creatinine is an inaccurate measure of renal function in a patient with cirrhosis. So listed here are the proposed definitions of kidney disease and cirrhosis. Acute kidney disease and chronic kidney disease, acute kidney injury defined as a rise in serum creatinine to more than 50% of baseline or a rise in creatinine to greater than.3 mg in 48 hours. HRS type 1 would be a specific form of acute kidney injury. Chronic kidney disease is the standard definition, GFR less than 60 for more than 3 months and it's fair to say that HRS type 2 is a specific form of chronic kidney disease. Then of course you have another entity, acute-on-chronic kidney disease which is being considered as a rise in serum creatinine of more than 50% from baseline or a rise in creatinine of more than 0.3 in less than 48 hours in a patient with cirrhosis whose GFR is less than 60 for more than 3 months. Moving on to multiresistant organisms and nosocomial infections. I've already highlighted this problem earlier. Infection present in one set of patients who are hospitalized, healthcare associated 30%, nosocomial up to 45%. The common community-acquired infections are usually SBP,

25 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 25 cellulitis. On the other hand the common healthcare associated infections are usually SBP, UTI. Now nosocomial infections are dominated by UTIs and that makes sense. How common is the problem of multidrug resistant organisms? If you look at different patient populations clearly in community-acquired infections there is a much lower resistance of MDR, only about 4%. On the other hand, if you look at nosocomial infections it will go up to as high as 35%. This - the high risk of MDR organisms decreases the efficacy of standard antibiotic regimens and clearly will double the mortality in this patient population. As highlighted earlier, a disturbing trend is the increased isolation of MRSA and enterococcal infections in patients with cirrhosis which clearly accounts for a very high mortality rate. SBP is an important cause of both community-acquired and nosocomial infections in patients with cirrhosis. Whereas community-acquired SBP is more commonly caused by gram-negative rods, nosocomial SBP has an increased prevalence of gram-positive cocci. In addition, nosocomial acquisition increases the risk of resistance to cephalosporins and quinolones and clearly increase mortality. So thus to summarize this important topic. Early diagnosis and proper management of infection in patients with cirrhosis are necessary. Luckily generally speaking intravenous third generation cephalosporins are recommended and are effective as empiric antibiotic therapy for most cases of spontaneous bacterial peritonitis and bacteremia. However, the risk of resistant organisms and

26 KAPIL CHOPRA, MD, DM, FACP, FASSSLD, AGAF 26 unusual organ pathogens should be kept in mind especially in patients with cirrhosis who have been previously receiving quinolone prophylaxis or as specifically with diseases such as genetic hemochromatosis. Auxiliary therapy with intravenous albumen will significantly reduce the morbidity and mortality in patients with spontaneous bacterial peritonitis who are at the highest risk of developing renal failure. The importance of preventive strategies cannot be underscored. Patients with cirrhosis admitted with GI hemorrhage benefit from what I would call short term antibiotic prophylaxis, whereas long term oral antibiotic prophylaxis is recommended in those who have recovered from an episode of SBP. What could be the potential future? Despite recent advances in the understanding of the mechanisms of infection in patients with cirrhosis the outcome of these patients with severe infections still remains poor. Clearly we need further studies into the mechanisms, diagnostic approaches and potential preventive strategies are needed to improve the management of these infections in patients with cirrhosis of the liver. I thank you very much for your attention. Thank you very much.