Modalities For The Diagnosis Of Spontaneous Bacterial Peritonitis Biology Essay

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Spontaneous bacterial peritonitis is a life threatening complication in patients with cirrhosis. It has been defined as an ascitic fluid infection without an evident intraabdominal surgically treatable source. [1] The prevalence of SBP in hospitalized patients with liver cirrhosis and ascites is high, ranging between 10% and 30%. Notably, in-hospital mortality rates range between 30% and 50%. [2, 3] SBP therefore, requires timely diagnosis that is usually based on cytobacteriological examination of ascetic fluid. An absolute polymorphonuclear leukocyte (PMN) cell count in ascetic fluid of > 250mm, irrespective of the ascetic fluid culture is currently considered as the standard criterion of diagnosis of SBP. [4, 5] Manual laboratory counting of ascetic PMN cell count is not always available all the time in every hospital and it results in diagnostic delay and appropriate antibiotic therapy. [6] that is why alternative methods to diagnose SBP rapidly are urgently needed. Some studies focused on diagnosing SBP based on bedside leukocyte estrase strips that can be read with the help of spectrophotometer, reducing the time from paracentesis to a presumptive diagnosis of SBP from few hours to few seconds. [6, 7] These tests have the ability to detect esterase activity of PMN cells and provide indirect evidence of the presence of PMN cells in ascetic fluid. [8] Based on these tests we can get prompt diagnosis and initiate antibiotic therapy in patients with SBP and cirrhosis which has otherwise high morbidity and mortality. [9] Numerous studies have used reagent strips to diagnose SBP and most have shown high sensitivity and specificity.[10,11] The sensitivity, specificity, positive and negative predictive values of the leukocyte esterase reagent strips in one such study were found out to be; 93%, 100%, and 98%, respectively. [12]

Bacterial infections often occur in patients with cirrhosis and are a major cause of death in these patients.' Activation of the complement system is pivotal in the host defence against bacterial infections. There are three main effector mechanisms by which complement eliminates bacteria: (1) direct killing by the terminal C5b-9 complement complex (TCC); (2) recruitment of phagocytic cells to sites of infection by release of anaphylatoxins; and (3) generation of opsonins which contribute to immune recognition of microbes. [22]Intact opsonisation is essential for efficient phagocytosis and subsequent intracellular killing of bacteria. [23]Consequently, complement deficiencies are associated with recurrent bacterial infections. [24]

In the past studies have focused on measuring the complement levels of different factors in the plasma and ascitic fluid to reach at the diagnosis of infections including SBP. It was proposed that decrease in circulating complement concentrations which is seen patients with severe chronic liver disease is one of the factors that predisposes to high incidence of bacterial infections in patients with cirrhosis. [13] Patients who develop SBP have decrease opsonic and bactericidal activity both before and during infection reflecting low concentration of C3 and C4 in ascites [14, 15]. Low complement levels in plasma and ascitic fluid could be due to impair synthetic function of the diseased liver, activation of complement or altered clearance of complement from plasma. G Bird and associates demonstrated in their study that low complement levels were due to activation of the classical pathway rather than impaired synthetic capacity of the liver. IgM and IgG complexes in patients with SBP can trigger the activation of classical pathway and indicate the systemic nature of infection. [16] These findings are compatible with those of previous studies which showed normal or reduced C3 concentrations in patients with chronic liver disease and that patients with low ascetic proteins are at highest risk of developing SBP. [17, 18]

Bacterial DNA translocation is another area of study where researchers have demonstrated that it is associated with a significant inflammatory reaction as manifested by increased plasma and AF levels of proinflammatory cytokines (TNF-_, INF-_, and IL-12) and NO metabolites, suggesting that translocation of products of bacterial origin has a proinflammatory effect as intense as that induced by translocation of viable bacteria, So bactDNA translocation-associated cytokine response is indistinguishable from that in patients with spontaneous bacterial peritonitis and is dependent on bactDNA concentration.[19,]. Recently proteomic analysis tools detected the presence of bacterial peptides in acitic fluid (AF) from patients with advanced cirrhosis and culture negative ascites. Their presence in turn, associated with a marked inflammatory response significantly higher than that caused by bacterial genomic fragments per se.[20] The immune response associated with the presence of bacterial DNA is significantly higher than in patients without bacterial DNA as shown in previous study [19]. The simultaneously presence of several bacterial products including bact.DNA and bact.Peptides can lead to enhance inflammatory response.[20] Higher inflammatory response has been associated with hemodynamic disturbances, hepatorenal syndrome and death in patients with SBP even after the infection has been cured.[21]. Furthermore patients with bacterial peptides show a trend towards more advanced liver disease (i.e. lower albumin and quick index, higher bilirubin and Child-Pugh score). And greater impact in the inflammatory, hemodynamic and prognostic status of the patients with decompensated cirrhosis. [20]

Hepatic Venous Pressure Gradient (HVPG) is currently is the method of choice to diagnose portal hypertension (PH) which in turn lead to ascites and consequently the patient at risk for spontaneous bacterial peritonitis. HVPG of more than 10 mmHg increases the risk for complications of Portal Hypertension. Although this method is used to assess the progression of PH in patients with severe liver disease however, reduction in PH of more than 20% or, 12 mmHg due to drug therapy decreases the risk of bleeding, ascites, SBP and increased survival [25].

Lactoferrin is a red iron binding protein present predominantly in breast milk and polymorphonuclear neutrophils. It serves as the defence mechanism of mucosal surfaces and is released from neutrophils during inflammation [26]. Its level in body fluids directly correlates with the flux of neutrophils and it can be used as a marker for neutophilic inflammation [27, 28]. Several studies have shown the role of lactoferrin in body secretions with one study specifically focused on its role in the rapid diagnosis of spontaneous bacterial peritonitis. They found out the sensitivity and specificity of this test to be 95.5% and 79% respectively and proposed that qualitative bedside assays for the measurement of ascetic fluid can be develop in the future to speed the process of diagnosis of SBP [28].

C reactive protein (CRP) is a plasma protein which increases during inflammation and its levels are high in serum of the patients with peritonitis related cirrhosis than sterile portal hypertension related ascites [29]. One recent study suggested that levels of CRP were significantly high in two groups of patients with spontaneous bacterial peritonitis. One group had signs and symptoms of peritonitis with PMN cell count of more than 250mm3 and the other group had signs and symptoms of peritonitis with neutophil count of less than 250 mm3. In third group CRP levels were not high as these patients did not have SBP. These findings require more studies to find out the exact utility of CRP in the diagnosis of SBP [30].

Interleukin-8 (IL-8) is a cytokine that is produced by different cells in response to stimuli such as bacterial lipopolysaccharide. It has strong chemotactic activity on neutrophils. Increased IL 8 levels have been seen in patients with sever infection and alcoholic and non alcholoic patients with cirrhosis [31, 32]. A study to determine IL8 levels in ascitic fluid to distinguish between spontaneous bacterial peritonitis and sterile ascites in patients with cirrhosis has shown that ascetic fluid IL8 levels were higher than plasma in patients with spontaneous bacterial peritonitis suggesting the possible IL8 production in peritoneum in patients with SBP. Also its levels has decrease to baseline after 48 hour of initiation of SBP therapy. This study concludes that IL8 can classify SBP and sterile ascetic patients with cirrhosis [33].

BacT/ALERT is an automated colorimetric microbial detection system that has shown to be faster in the diagnosis of bacteremia than conventional blood cultures. This study compared BacT/ALERT system with conventional culture and conventional blood culture bottles. It proved that 33.3% patients were diagnosed with conventional culture and 73.3% with conventional culture bottles. BacT/ALERT was positive 66.6% of the times compared with conventional cultures and diagnosis of SBP was established in first 12 hours (in 56.6% patients) as compared to conventional cultures where only 13 % were diagnosed in first 12 hours. In conclusion, the BacT/ALERT offers an earlier diagnosis of SBP than conventional blood culture bottles with equal sensitivity [34]

Procalcitonin (PCT) is a precursor of the hormone calcitonin. Calcitonin is involved in calcium hemostasis. The level of procalcitonin in the blood is below the limit of detection in healthy people and rises in response to proinflammatory stimulus especially in bacterial infections. Levels can go high in severe infections with systemic response. It has been shown that serum procalcitonin level with a cut-off of .75ng/ml has sensitiviy of 95% and specificity of 98% in SBP patients. IL 6 with a cut-off of 5000ng/ml in ascitic fluid has a sensitivity and specificity of 100% and 88% respectivelyin SBP patients. Sensitivity and Specificity of C reactive protein and Polymorhonuclear count was low in serum and found out to be 62/92 % and 57/90 %, respectively. Ascitic fluid to serum ratio of TNF-a and IL 6 was greater than 2 as compared to ratio of procalcitonin in ascetic fluid to serum was less than 1. This shows that there is no correlation between procalcitonin and cytokine levels in either ascetic fluid or serum. In conclusive this study has proven that procacitonin is a good marker for the diagnosis of SBP in patients with cirrhosis [35].

Another recent study revealed that Prolactin levels in ascetic fluid in patients with SBP were not significantly differ from those of controls although levels in serum were high. This same study also showed that IL6 levels in asictic fluid were same in SBP group and control group but C reactive protein were high both in serum and ascetic fluid in pateints with SBP [36].

Many studies have observed that opsonic activity is low [37, 39] in patients with cirrhosis which is related with low levels of C3, C4, and Total Protein [38, 40]. This predisposes to SBP in cirrhotic patients. Fibronectin is a glycoprotein that is involved in providing non specific opsonization to bacteria and a number of endogeneous substances [41, 42]. This particular study focused on measurement of ascetic fluid concenteration of fibronectin and correlated it with C3, C4 and total protein, which are known risk factors for SBP [ 17,18]. Fibronectin concenteration was found out to be low in ascetic fluid in pateints who are at risk for SBP and a positive correlation was there with low C3,C4 and Total Protein. This shows the possible role of fibronectin as one of the local defense mechanisms of asitic fluid. FN concentration in ascetic fluid is related to opsonic ability of this fluid, and its concentration in the ascitic fluid may be a risk factor for the development of SBP[43].

One previous study has also shown that levels of fibronectin were found to be high in patients with malignant ascites and low in patients with infectious ascites further supporting this study that low levels in ascetic fluid could be a marker to identify patients who are at risk for development of SBP and need for advance studies to find its role as a diagnostic marker for SBP [44].

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