Aliment Pharmacol Ther 2005; 22: 685700.

doi: 10.1111/j.1365-2036.2005.02645.x

Systematic review: tuberculous peritonitis presenting features, diagnostic strategies and treatment
F. M. SANAI & K. I. BZEIZI Division of Hepatology, Department of Internal Medicine, Riyadh, Saudi Arabia
Accepted for publication 27 July 2005

SUMMARY

The peritoneum is one of the most common extrapulmonary sites of tuberculous infection. Peritoneal tuberculosis remains a signicant problem in parts of the world where tuberculosis is prevalent. Increasing population migration, usage of more potent immunosuppressant therapy and the acquired immunodeciency syndrome epidemic has contributed to a resurgence of this disease in regions where it had previously been largely controlled. Tuberculous peritonitis frequently complicates patients with underlying end-stage renal or liver disease that further adds to the diagnostic difculty. The diagnosis of this disease, however, remains a challenge because of its insidious nature, the variability of its presentation and the limitations of available diagnostic tests. A high index of suspicion is needed whenever confronted with unexplained ascites, particularly in high-risk patients.

Based on a systematic review of the literature, we recommend: tuberculous peritonitis should be considered in the differential diagnosis of all patients presenting with unexplained lymphocytic ascites and those with a serum-ascites albumin gradient (SAAG) of <11 g/L; culture growth of Mycobacterium of the ascitic uid or peritoneal biopsy as the gold standard test; further studies to determine the role of polymerase chain reaction, ascitic adenosine deaminase and the BACTEC radiometric system for acceleration of mycobacterial identication as means of improving the diagnostic yield; increasing utilization of ultrasound and computerized tomographic scan for the diagnosis and as a guidance to obtain peritoneal biopsies; low threshold for diagnostic laparoscopy; treatment for 6 months with the rst-line antituberculous drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) in uncomplicated cases.

INTRODUCTION

The rst documented case of ancient tuberculosis (TB) peritonitis was described in humans in 1843.1 Introduction of antituberculous chemotherapy and more importantly, the improvement in the socioeconomic status, led to a decline in all forms of TB, including tuberculous peritonitis (TBP). Although abdominal TB continues to be a signicant health problem in the
Correspondence to: Dr F. M. Sanai, Division of Hepatology (A41), Department of Internal Medicine, Armed Forces Hospital, PO Box 7897, Riyadh 11159, Saudi Arabia. E-mail: faisalsanai@hotmail.com 2005 Blackwell Publishing Ltd

developing world, recently there has been an increase in the number of patients diagnosed with abdominal TB in parts of the world where TB generally was rare. This is partly a result of increasing travel and migration and also to the rising number of HIV patients who are susceptible to opportunistic infections.2 There has been a cumulative evidence of relative increase in the incidence of the extrapulmonary TB.35 Abdominal TB may involve the gastrointestinal tract, peritoneum or the mesenteric lymph nodes. Occasional overlaps between these forms have also been described. Peritoneum and its reections are common sites of tuberculous involvement of the abdomen and it is the
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sixth most common extrapulmonary site in the United States.5 It occurs in up to 3.5% of cases of pulmonary TB and comprises 3158% of cases of abdominal TB.69 In western Europe and North America, a frequent association between TBP and cirrhosis has been described.1012 Other groups of patients at increased risk of developing TBP include chronic renal failure patients on continuous ambulatory peritoneal dialysis (CAPD) and HIV patients.13, 14 Several reports have also highlighted the remarkable similarity between this illness and ovarian carcinoma,15 carcinomatosis peritonii16 and complicated portal hypertensive ascites. The diagnosis of this disease continues to pose signicant challenges. This is partly due to the lack of specic clinical features that would otherwise help in pursuing the diagnosis when suspected and also to the limited yield of the commonly used diagnostic tests. Isolation of mycobacteria from the ascitic uid is difcult and frequently laparoscopy is needed for the diagnosis. In this review we aim to address the variability of disease presentation, the associated risk factors of the disease and will review the current knowledge of the diagnostic measures available and treatment options. Search strategy for identication of studies We reviewed the literature available on this subject by performing a Medline search limited to the English language (January 1966October 2004). The search terms used were: tuberculous peritonitis, peritoneal tuberculosis, tuberculosis and ascites, abdominal tuberculosis and tuberculosis and laparoscopy. Abstracts of the articles selected in each of these multiple searches were identied and those dealing particularly with the subject were recorded and reviewed in full form. Reference lists from trials previously selected by electronic searching were manually searched to identify further relevant trials. Other publications known to the authors were also reviewed. In addition, we electronically scanned major gastroenterology journals for the most recent studies dealing with the subject. Studies including paediatric subjects were not excluded.
EPIDEMIOLOGY

The reported incidence of TBP among all forms of TB varies from 0.1% to 0.7% worldwide.17 Both sexes are equally affected and the disease is seen most commonly in patients between 35 and 45 years of age.

Variable methods have been used to study TB worldwide and this might explain the discrepancies of data available. Increasing migration and also the constant changes of disease pattern are other factors that made accurate assessments of the extent of this disease even more complex. Examples of the methods used to study TB prevalence include, mortality data, tuberculin skin test and eld surveillance by chest X-ray and sputum cultures. BCG vaccination has limited the usefulness of tuberculin skin testing in the diagnosis of TB because a signicant proportion of vaccinated but uninfected patients will return a positive skin reaction.18 Similarly, deriving meaningful epidemiological data on this disease by Mantoux skin testing has also become difcult because of the vaccination programmes undertaken in the third world. This trend is observed across all age groups where non-vaccinated subjects had lower rates of positive Mantoux test in uninfected patients than those who had received BCG vaccination.18 The peak prevalence of a positive skin reaction in those who had previously been vaccinated occurs in 70% for the age groups between 45 and 64 years. It is expected that the rate of positive skin test for future generations will be signicantly higher as current immunization programmes in most of the third world countries include BCG vaccination at child-birth. The newly developed interferon (IFN)-c-based test would help overcome this problem of detecting latent infection since previous BCG vaccination does not affect its results.19 However, at present there is no large-scale epidemiological data available utilizing this test. A signicant correlation exists between the socioeconomic status and disease prevalence. Poor hygiene and overcrowding have consistently been shown to have a causative relationship with TB. Ingestion of unpasteurized milk might also be another reason for the increased prevalence of this disease in the rural populations. On the contrary, the effective tuberculin testing of dairy herds and a shift from the norm of drinking unpasteurized milk in cities, has most likely contributed to the overall reduction in cases of primary abdominal TB. Alcoholic liver disease (ALD) is frequently linked to increased incidence of TBP particularly in the western countries. In one study, 62% of patients with TBP had an underlying ALD,10 a contrast to the ndings of studies from developing countries where the reported underlying liver diseases was found in <13% of patients with TBP.2023
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The recent dramatic increase in the number of TB cases globally is linked to the HIV/AIDS pandemic.24 About 9% of all new TB cases (31% in Africa) in adults were attributable to HIV/AIDS.24 TB accounts for about 13% of all HIV-related deaths worldwide.24, 25 The incidence of extrapulmonary TB in Unites States over a 5-year period has risen to 20% compared with the incidence of 3% for pulmonary TB.26 Of the 5.1 million HIV patients in India, about half of them are co-infected with TB.27 In India, it is estimated that 1520% of all TB cases are extrapulmonary in site amongst the HIV-negative adult population.28 Similarly, Saudi Arabia reported increasing rates of extrapulmonary TB (abdominal TB 16%) from 1993 at which point the incidence was 1.7 cases per 100 000 population, to 4.7 cases in 1997. During the same time frame, reported pulmonary TB was decreasing.29
PATHOGENESIS

Infection of the peritoneum is usually secondary to haematogenous spread of tubercles from a pulmonary focus. Although an abnormal chest X-ray (CXR) is frequently seen, however coexistent active pulmonary disease is rare30 (Table 2). Spread of the mycobacteria may rarely occur from lesions in the adjacent organs such as the intestine or the fallopian tubes. Intestinal TB occurs as a result of ingesting contaminated milk or from swallowing the sputum of active lung disease.31 Alcoholic liver disease is a signicant risk factor of developing TBP.1012 Shakil et al. found that alcohol was the underlying cause in 90% of patients with cirrhosis who developed TBP.10 The mechanism behind the increased susceptibility of ALD patients to this disease remains unknown. Unlike spontaneous bacterial peritonitis, factors such as impaired opsonization, complement deciency, low immunoglobulin levels in the ascitic and low serum albumin level do not appear to explain the onset of TBP, which is related to impaired cell-mediated immunity. Also, there is no evidence to suggests that the impaired humoral immunity of cirrhosis would play any role in the evolution of this opportunistic infection. Theoretically, the presence of stagnant ascitic uid could potentially predispose to the onset of opportunistic infections, as might be the case with patients on CAPD. Against that is the fact that cellular immunity is impaired in patients with uraemia and this would be a likely explanation for the increased susceptibility to TB. Tuberculosis is more common in
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haemodialysis patients than in patients undergoing CAPD (28% vs. 4.8%),13, 32, 33 which further negates the hypothesis that the stagnant ascitic uid is a signicant risk factor of TBP. Malnutrition frequently develops in cirrhotic patients and is more prominent in patients ALD due to a number of reasons. Previous studies have documented the poorer nutritional health of patients with ALD in comparison with non-alcoholics.34 Additionally, these patients demonstrate cutaneous anergy to a variety of antigens, suggesting impaired T cell-dependent functions, and this immune defect is again more commonly seen in ALD compared with cirrhosis from other causes.35 Therefore, it is likely that an interaction between immunological dysfunction and malnutrition produces the higher prevalence of TBP in patients with cirrhosis. The HIV infection is the strongest of all known risk factors for the development of TB. HIV patients have impaired Th1 type immune response, a crucial defence against Mycobacterium tuberculosis.36, 37 The interaction between TB and HIV is synergistic. The relative risk of death and development of other opportunistic infections is higher in the HIVTB co-infected patients when compared with CD4+ count-matched HIV-infected controls without TB.38
CLINICAL MANIFESTATIONS

TBP is a subacute disease and its symptoms evolve over a period of several weeks to months. Presence of comorbid conditions such as cirrhosis result in atypical presentations that may lead to delayed diagnosis. Elderly patients with TBP may manifest minimal constitutional symptoms, which again might cause a delay in the diagnosis. The disease can present in three different forms which are: the wet-ascitic, brotic-xed and the dry-plastic form.39 They have similar clinical manifestations except for abdominal distension which does not occur in the dry-plastic form. A considerable degree of overlap does occur, whereby more than one form may coexist. The clinical features of this illness from 35 different studies of TBP have been tabulated and presented in Table 1. Systemic and constitutional symptoms are common. Low-grade fever occurs in about 59% of the cases and it is usually accompanied by night sweats. Patients may not report fever and in 49% of the cases it is only documented during hospitalization.7, 11, 40 Other systemic features of the disease

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Table 1. Cumulative data of clinical features compiled from 35 studies of tuberculous peritonitis (TBP) Clinical feature Abdominal pain Fever Weight loss Diarrhoea Constipation Ascites Abdominaltenderness Hepatomegaly Splenomegaly Number of cases 12841, 7, 1113, 15, 2023, 3941, 44, 45, 47, 51, 52, 60, 94104 13931, 7, 1013, 2023, 40, 41, 44, 45, 47, 51, 52, 60, 94105 7741, 7, 1013, 2023, 3941, 51, 52, 9599, 106 6301, 7, 11, 12, 21, 23, 40, 94, 96, 98, 104 31911, 12, 21, 40, 47 14051, 7, 1012, 15, 2023, 39, 40, 41, 44, 45, 47, 51, 52, 94105, 3297, 11, 12, 20, 22, 40, 9496 3197, 1012, 20, 39, 40, 95, 103 18910, 11, 39, 40, 52, 103 Average (%) 64.5 59 61 21.4 11 73 47.7 28.2 14.3

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include weight loss, anorexia and malaise. The superimposition of this illness on other chronic conditionslike uraemia, cirrhosis and AIDS make these symptoms more difcult to quantify. Weight loss is seen in about 61% of cases and investigators have reported reversibility of this manifestation as one of the markers of disease resolution.7 Abdominal pain is a common presenting symptom and frequently accompanied by abdominal distension. It is usually non-localized and vague in nature. The pain is largely due to the tuberculous inammation of the peritoneum and mesentery. Less often, it could be a manifestation of intermittent subacute intestinal obstruction, a result of matted bowel loops caused by adhesions of the mesentery and omentum. The matted bowel loops could be felt as palpable masses on abdominal examination. Abdominal symptoms such as vomiting, diarrhoea and constipation are uncommon. The pathophysiology of diarrhoea is unknown and it is very unlikely to be due to direct intestinal involvement as TBP rarely occurs simultaneously with tuberculous enteritis.1, 11, 41 Khuroo and Khuroo42 suggested that the stagnation in dilated segments of intestinal loops caused by adhesions between mesentery and small bowel may result in small bowel bacterial overgrowth. The evidence for this plausible mechanism is however, not yet available. Tenderness on palpation is common in TBP and occurs in almost 48% of the cases and this might help in differentiating it from spontaneous bacterial peritonitis, which complicates portal hypertensive ascites.43 Rebound tenderness is rare as the presence of ascitic uid prevents approximation of the parietal with the visceral peritoneum. Ascites is the predominant nding and it is present in about 73% of the patients. A smaller percentage of

patients (513%) present with the classical doughy abdomen. This is described as the dry or plastic type of TBP and the patients have very little ascites, which can only be detected by ultrasonography or during laparoscopy.39, 44 The ascitic uid is usually straw coloured, and although red blood cells are frequently seen on microscopic examination, however, frank haemorrhagic uid is seen only in 9% of the cases.21 The dialysate uid of patients on CAPD becomes cloudy upon infection with TBP and this could be the earliest sign of the infection. Interestingly, from the cumulative data of six large series compiled by Marshall, it evolved that in 18% of patients, ascites was detected primarily by radiological means or at the time of surgery.30 The inaccuracy of detecting ascites combined with the vague nature of the abdominal pain and the paucity of other abdominal signs may erroneously cause the condition to be mislabelled as a mental illness. Therefore, a high index of suspicion is required in diagnosing these patients and a liberal utilization of imaging studies may be warranted. An enlarged liver or splenomegaly is uncommon (Table 1), and presence of hepatomegaly suggests a direct involvement of the liver.7 Splenomegaly is likely to reect presence of portal hypertension. Hepatosplenomegaly is common in patients with an underlying ALD except in advanced cirrhosis which results in a shrunken liver.10, 11, 40
DIAGNOSIS

The insidious nature of this disease makes the diagnosis a clinical challenge. With the ever-increasing demographic shift, more cases are now seen in areas of the world where TB was a rarity. Unless a high degree of suspicion is maintained, the diagnosis can easily be missed or inappropriately delayed. The indolent nature of this
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disease was illustrated by the recent case series, which consistently reported a prolonged period of symptoms before the diagnosis was established.13, 4547 In areas of high prevalence, it is a routine practice to screen for Mycobacterium by the special staining and culture of the ascitic uid. It would be impractical to perform this test routinely in areas of the world where TBP is rare except of course in cases where TB is considered in the differential diagnosis. The reported incidence of TBP as a cause for ascites is only 2%.48 However, the index of suspicion should be high if the patient has lived or traveled from an endemic area. The same applies for patients with ALD and those who are immunosuppressed or undergoing CAPD. Patients with ascites who have an abnormal CXR or had prior exposure to open TB should also be screened for TB.17, 40 The sensitivity patterns of various tests used to diagnose TBP have been compiled in a tabulated form based on the cumulative data of 39 series. Laboratory investigations Haematological indices. Changes of haematological indices are non-specic and therefore of little diagnostic yield. Mild to moderate normochromic, normocytic anaemia and thrombocytosis are frequent ndings.10, 21, 30 The white cell count (WBC) is usually normal but, lymphomonocytosis is not uncommon.11, 21 The erythrocyte sedimentation rate is almost always raised but in at least 50% of the cases, the values do not exceed 60 mm/h.21 Raising the cut-off value does not

alter the specicity of this test as patients with ascites in general may have similarly raised values. Ascitic uid analysis. Ascitic uid analysis is routinely performed in evaluating all patients presenting with ascites. The WBC in TBP varies widely ranging from counts of <100 cells/mm3 to as high as 5000 cells/ mm3.10, 13 Most patients however, have cell counts between 500 and 1500 cells/mm3. The cells are predominantly lymphocytes with the possible exception of patients with underlying renal failure where, for unknown reasons, the cells are mostly neutrophils.13, 49 As such, the possibility of TBP cannot be negated in the presence of a neutrophil-predominant ascitic uid. The cumulative data from 13 series of TBP reviewed by us (Table 2) showed lymphocytic predominance in 68% of patients. A lymphocytic predominance may also be seen in portal hypertensive ascites at the end of diuresis or immediately after antibiotic therapy in previously unrecognized spontaneous bacterial peritonitis. The presence of lymphomonocytic ascites therefore is not a reliable marker for TB and should be considered merely as an indication for further investigations. Ascitic uid biochemistry. Ascitic glucose values is reported to be slightly low in some studies10, 11 however, there is no sufcient evidence to support routine ascitic uid glucose measurement in patients with suspected TBP. Ascitic lactate dehydrogenase (LDH) has been reported to be high in some studies. The ascitic uid concentration of LDH is usually less than half of the serum level in

Table 2. Sensitivity patterns of various diagnostic tests from the cumulative data of 39 studies of TBP Diagnostic test Sensitivity (%) Remarks 1002 patients with TBP1, 1013, 2022, 3941, 44, 45, 47, 51, 52, 60, 9496, 98101 380 patients studied;10, 11, 2022, 39, 40, 51, 52, 96 authors used various induration sizes for positivity 477 patients;10, 11, 13, 20, 23, 40, 41, 44, 45, 47, 51, 61, 96 investigators had differing denitions for predominance 87 patients;10, 11, 51, 52 investigators used varying LDH range 1305 patients studied; 205 with TBP11, 39, 61, 62, 108114 Hillebrand et al.61 used >7 U/L as cut-off 615 patients1, 1013, 2023, 41, 47, 51, 52, 95, 100, 101, 103, 104, 114118 446 patients;1, 1013, 20, 22, 23, 51, 52, 85, 95, 96, 99101, 103, 104, 114116, 118 studies using BACTEC radiometric system not included 397 patients;10, 402 patients;10,
20, 21, 23, 39, 51, 119122 2023, 39, 51, 96, 119121

Abnormal CXR 38 Positive PPD 53.16 Ascitic uid tests Predominant lymph 68.34 LDH ADA (>30 U/L) Smear Culture Laparoscopy Visual diagnosis Histology 77 94 2.93 34.75

92.7 93

most series did not report specicity patients with intent-to-biopsy included

TBP, tuberculous peritonitis; CXR, chest X-ray; LDH, lactate dehydrogenase; ADA, adenosine deaminase. 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 22, 685700

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uncomplicated cirrhotic ascites. In infection, including TBP, the ascitic uid LDH level rises because of the release of LDH from neutrophils. Shakil et al.10 showed that raised LDH above 90 U/L carries a sensitivity of 90% and a specicity of 14% for TBP. Such high degree of sensitivity was not reproduced by another similar study.11 Data tabulated by us from four different studies (Table 2) suggest a sensitivity of 77% for LDH. Raised ascitic LDH with similar degrees of sensitivity also occur in patients with peritoneal carcinomatosis, pancreatic ascites and about 20% of those with cirrhosis or congestive cardiac failure.50 It does appear therefore that ascitic LDH measurement is not of discriminatory value and should not necessary be used routinely. Ascitic uid proteins. Ascitic uid total protein levels >25 g/L is seen in almost 100% of patients with isolated TBP. However, the sensitivity of this test is signicantly reduced (4270%) when TBP complicates cirrhosis.10, 11, 51, 52 Ascitic uid total protein >25 g/L is found in 100% of nephrogenous ascites,53 22% of cirrhotics, almost 100% of cardiac ascites50, 54 and 95% of peritoneal carcinomatosis.54 The serum-ascites albumin gradient (SAAG) has more diagnostic yield than ascitic uid total protein measurement.50 It is calculated by measuring both serum and ascitic uid albumin on the same day and subtracting the ascitic albumin from the serum one. A low SAAG (<11 g/L) is seen in 100% of patients with TBP, although the specicity remains low.10, 51, 52, 54 Moreover, the sensitivity is greatly reduced (2988%) when TBP complicates chronic liver disease leading to further diagnostic confusion.10, 51 The main advantage of calculating the SAAG is in its specicity for portal hypertension induced ascites. SAAG of 11 g/L or greater indicates portal hypertension with 97% of accuracy.54 This is of great signicance as majority of ascites is due to portal hypertension and therefore specic investigation for other aetiologies such as TB could be applied to a small group of patients with unexplained ascites. Elevation of CA-125 has been documented in the majority of patients with TBP and created considerable confusion by mimicking advanced ovarian carcinoma.15, 52 Subsequently, this test was recommended as an indirect marker for TBP. Recent reports have shown that serum and ascitic CA-125 levels are elevated in almost all patients with ascites regardless of the underlying cause.5557 Patients commenced on antituberculous treatment have shown rapid falls in

CA-125 levels paralleling clinical response and resolution of ascites. Based on the available evidence, this test does not seem to offer any particular advantage in the diagnosis of TBP. Microbiological diagnosis ZiehlNeelsen (ZN) staining of the ascitic uid for mycobacterial detection is positive in only about 3% of cases with proven TBP (Table 2). To allow for the detection of mycobacteria in stained smears, presence of at least 5000 bacilli/mL of specimen is required, whereas for positive culture as few as 10 organisms might be sufcient for the diagnosis.58, 59 The current gold standard for the diagnosis of TB entails culturing the mycobacteria from clinical specimens. Culture methods based on a combination of liquid or biphasic media, together with solid media, are used to ensure maximum sensitivity of detection. Studies reporting on the microbiological diagnosis have used varied reporting methodology. While most have reported on the regular method of culturing 1050 mL of ascitic uid, others have recommended culturing 1 L of centrifuged uid. This is based on the above principle of increasing yield by increasing the concentration of the bacilli. Culture of the uid by the regular method is positive in 35% based on our cumulative data comprising of 446 patients from 22 case series (Table 2), although the yield has been shown to signicantly improve (6683%) when 1 L of uid is centrifuged and then cultured, either by traditional culture media or the BACTEC system.41, 47, 60 In clinical practice this is not practical as the biggest available aliquots for centrifugation have a capacity of 50 mL. This problem is further compounded by the 48 weeks requirement by the conventional culture media. The recently introduced BACTEC radiometric system is a rapid method for detecting mycobacteria in clinical specimens, with a mean time to detection of 14 days, and can be used to complement conventional methods.47 A further 7 days are required for drug susceptibility testing. Other newer methods of identifying mycobacteria isolates include liquid chromatography and DNA probes for which the typical turnaround time for conrmation is 21 days. Although, the concept of culturing a litre of centrifuged ascitic uid is attractive, it may not be feasible in the regular clinical setting. Hence, at least in resource-rich settings, the BACTEC radiometric system should be made available in routine clinical practice.
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New diagnostic tools Adenosine deaminase. With the persisting diagnostic difculties surrounding TBP, there has been an ongoing search for alternative rapid and non-invasive tests. Amongst these, adenosine deaminase (ADA) activity in the ascitic uid has been studied the most. ADA is an aminohydrolase that converts adenosine to inosine and its activity is more in T than in B lymphocytes, this being proportional to the degree of T-cell differentiation. ADA is increased in tuberculous ascitic uid because of the stimulation of T cells by the mycobacterial antigens. Sensitivity and specicity levels over 90% have been reported (Table 2) with the exception of a study by Hillebrand et al.61 who reported a sensitivity of 59%. They postulated that their lower sensitivity may have been related to the higher incidence of cirrhosis in their group of patients. These observations were countered by Burgess et al.62 when they evaluated cirrhotic patients with TBP in their study and reported a sensitivity of 94%, comparable with the ndings of previous studies. This study also demonstrated that raising the ADA level above 30 U/L did not affect either the sensitivity or the diagnostic efciency of this test. At present, an ascitic ADA activity of 30 U/L is generally accepted as the cut-off level expected to yield the best results. Given its high rate of diagnostic accuracy and easy availability, we do recommend increasing the utilization of this test in the diagnostic work-up of patients with suspected TBP. Gene amplication. Another technological advancement has been the introduction of rapid amplication-based tests for detecting specic regions of bacterial DNA or RNA. The polymerase chain reaction (PCR) is a technique that uses nucleic acid amplication to detect M. tuberculosis in body tissues. Reports suggest that the performance of the various PCR tests is reasonably good with sensitivity reaching up to 95% in smearpositive patients. The same success has not been duplicated in smear-negative patients and the sensitivity attained has been disappointingly low (48%).63 As the ZN stain in patients with TBP is positive in only 3%, these gures suggest that PCR sensitivity would be similarly very low. To date, excluding a few case reports there are no controlled studies of PCR in patients with TBP.6466 The issue of false-positives as a result of cross-contamination of samples has raised concerns of over-diagnosing TB in areas of endemicity.
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Samples from sites with a possible latent infection focus or DNA from dead bacilli may also give a positive reaction. The ligase chain reaction (LCR) DNA amplication method has recently been introduced into practice. This assay has been shown to provide valuable and rapid information for the diagnosis of extrapulmonary TB and with a higher diagnostic accuracy than PCR.67 Further studies are needed to determine the clinical use of PCR and/or LCR in the diagnosis of TBP. The cost of utilizing these techniques will be another major issue to consider particularly in poor countries where TB is endemic. Immunodiagnostic tests. The search for reliable, reproducible and specic serological tests for the diagnosis of TBP has been an area of active research for many years. Various antigens have been targeted in numerous studies, however few have dealt with the issue of TBP. In a South African study dealing with active disease, an enzyme-linked immunosorbent assay to detect IgG to a 43 kDa antigen of M. tuberculosis found it to be highly sensitive (approaching 100%) and 97% specic for pleural and ascitic uids.68 In another report from India, the seropositivity of the IgA and IgG antibody directed against A60 antigen was 88.4% in active gastrointestinal TB.69 However, it is unclear from the methodology if any of these 26 patients had TBP. High IFN-c levels in tuberculous ascites have been reported to be useful diagnostically.70 Although such assays hold great potential, concerns remain regarding costs, low positive predictive value and the ability to distinguish from atypical mycobacterial infection. Tuberculin skin test The utilization of tuberculin skin testing has become controversial and perhaps redundant. Various studies from different parts of the world have reported positivity rates ranging between 24 and 100%, and averaging at 53% based on the reported gures of 10 studies (Table 2). A breakdown along demographic lines of high and low endemicity areas did not reveal any differences in these rates. Surprisingly, studies arising from the same regions have revealed vast differences in their rates of positivity.20, 51, 52 Possible explanations for this may be linked to the method of testing, strength of the reagent utilized and the methodology of interpretation by the investigators in different studies. Unfortunately, none of these study offer any of these details. Generally, about 47% of patients with

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TBP would have false-negative reactions to tuberculin skin testing. As the tuberculin skin test has many potential sources of error and variability, it has become imperative to standardize the reagent, reading of the test itself, and the interpretations derived. Recent recommendations by the American Thoracic Society and the US Centers for Disease Control and Prevention have placed the cut point for the induration for those at low risk at 15 mm; in people at moderate risk the cut point is 10 mm and those at high risk the cut point is 5 mm.71 Additionally, the issue of tuberculin testing has shifted away from detecting active TB to one of screening for latent infection. Some studies dealing with TBP have addressed the issue of anergy testing reported to be positive in about 9% of the cases.10 Anergy testing was proposed initially to measure the overall ability to mount a delayed-type hypersensitivity response. However, anergy testing as a routine adjunct to tuberculin testing is no longer recommended as it may yield misleading information. Despite the high specicity of this test (between 95 and 99%), the low sensitivity, and the low positive predictive value of 5067% should obviate the clinician from placing undue importance to this test.72 Skin testing is now consigned to detecting latent infection and there are no recommendations for using this test to diagnose active disease like TBP. Diagnosis of TB is a clinical responsibility and tuberculin skin testing, at best, offers only auxiliary support. A major scientic advance in detecting latent infection has been the development of an IFN-c-based test which yielded a sensitivity of 89%.19 Interferon-c test is a quantitative in vitro assay that evaluates the cellmediated immune response to M. tuberculosis. The test is based upon the principle that previously sensitized T lymphocytes release IFN-c in response to stimulation by puried protein derivative (PPD). This assay has been shown to have excellent agreement with tuberculin skin testing. A novel assay that is not widely available, it measures the amount of IFN-c released by T lymphocytes following exposure to the antigen ESAT-6 (normally absent in BCG) and may be useful for diagnosing latent TB in patients previously vaccinated with BCG. Imaging studies Various studies have reported an abnormal CXR in 1983% of cases averaging to about 38% based on our

cumulative data of over 1000 patients (Table 2). Active concomitant pulmonary disease however, occurs in only 14% of patients.30 Although TBP represents one of the disseminated forms of TB, miliary shadowing is rarely seen or even reported in the literature. Aguado et al.,11 found miliary mottling in only one patient out of 20 who had an abnormal CXR. Ultrasound (US) changes include echogenic debris seen as ne mobile strands or particulate matter within the ascitic uid. Calcications in the walls of encysted ascitic uid are rare and when present, could be detected by US imaging.7376 The ascitic uid has high attenuation values on computerized tomographic (CT) imaging (2045 HU). The peritoneum is commonly thickened and nodular (Figure 1).73, 75, 77 The brotic-xed type of TBP is characterized by a hypervascular peritoneum, matting of the loops, and omental masses. CT seems more capable of delineating omental changes which occur in 3682% of cases.74, 75, 7780 Thickened mesentery (>15 mm) with mesenteric lymph nodes is seen in most cases and this combination may be an early sign of abdominal TB.81 Loss of normal mesenteric conguration is better demonstrated by CT scan.74, 75, 77, 80 Several studies have compared US and CT ndings in TBP and found them to be complementary to each other as they provide different information. US is superior to CT in revealing the multiple, ne, mobile septations characteristically found in TBP, while CT can highlight the peritoneal, mesenteric or omental involvement.75, 82 Ha et al.80 reported 69% sensitivity in the diagnosis of TBP by CT scan. On the contrary, another group analysed retrospectively the CT images of their TBP patients over a 3-year period and found that the disease had been missed in all cases.83 The CT abnormalities described above might be seen in other diseases with peritoneal inltration notably peritoneal carcinomatosis. The presence of a smooth peritoneum with minimal thickening and pronounced enhancement on CT suggests TBP, whereas nodular implants and irregular peritoneal thickening suggests carcinomatosis. Imagining modalities are increasingly used to help in obtaining peritoneal biopsies. They provide a safer and inexpensive alternative to diagnostic laparoscopy. Earlier reports had suggested limited diagnostic sensitivity59, 83 but a recent report by Vardareli et al. demonstrated a high diagnostic yield approaching 95% and without any complications.52 This is of vital
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Figure 1. A computerized tomographic (CT) image of a 34-year-old male with fever and abdominal pain showing a thickened peritoneum (arrow) with mild ascites. Histology was consistent with tuberculous peritonitis (TBP).

importance for centres with limited laparoscopic availability or expertise.84 Laparoscopy Laparoscopy is the diagnostic tool of choice in patients with suspected TBP. Not only does it allows inspection of the peritoneum but also offers the option of obtaining specimens for histology. The well-described laparoscopic appearance by Bhargava et al.39 classies it into three types: thickened, hyperaemic peritoneum with ascites and whitish miliary nodules (<5 mm) scattered over the parietal peritoneum (Figure 2), omentum and bowel loops (66%); thickened and hyperaemic peritoneum with ascites and adhesions (21%); markedly thickened parietal peritoneum with possibly yellowish nodules and cheesy material along with multiple thickened adhesions (bro-adhesive type 13%). The diagnostic yield of laparoscopic examination is very high with a sensitivity of the macroscopic appearances approaching 93%. The cumulative data of 402 patients from 11 studies (Table 2) showed impressive sensitivity and specicity rates of 93% and 98% respectively when the macroscopic appearances are combined with the histological ndings (epitheliod granulomata with caseation or mycobacterial identication). Peritoneal biopsies should always be examined whenever possible for culture and sensitivity. It is the gold standard test that provides diagnostic accuracy and
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helps in optimizing the selection of the anti-TB therapy. Surprisingly, few studies from the ones that we reviewed did report results of mycobacterial culture on specimens obtained at laparoscopy. ZN stain was positive 325%10, 11, 39 while the yield of culture sensitivity was between 38 and 92%.10, 39, 85 Peritoneal carcinomatosis, sarcoidosis, starch peritonitis and Crohns disease may occasionally mimic the laparoscopic features of TBP, hence the importance of taking biopsies. Granulomatous changes might be seen in sarcoidosis or Crohns disease, however presence of caseating changes would support the diagnosis of TB. Complications of laparoscopy are rare, seen in <3% of cases including bleeding, infection and bowel perforation. The reported mortality is up to 0.04%.8688 The procedure requires expertise and should only be performed by competent surgeons. Moreover, this procedure requires hospitalization and is more expensive than image-guided peritoneal biopsy. Failure to obtain tissue for microbiological or histological assessment should not deter us from initiating treatment as studies have consistently reported a specicity in excess of 96% on the laparoscopic appearance alone.17 At present there are no randomized-controlled trials comparing image guided biopsy, laparoscopy and laparotomy; and the high number of patients required would make such a trial unlikely in the near future. We believe that laparotomy is unnecessary and is only considered for patients with the

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Figure 2. Laparoscopic image of an 18year-old girl with fever and ascites showing multiple whitish nodules (<5 mm) covering the peritoneum. The biopsy was consistent with caseating granuloma and acid-fast bacilli (courtesy: N. Azzam and A. K. Al-Aska).

bro-adhesive type of TBP when there is an indication for a peritoneal biopsy. Although the ideal diagnostic test requires the demonstration of mycobacteria, however, the characteristic laparoscopic appearance itself, even in the absence of bacteriological conrmation, would be sufcient grounds for the diagnosis of TBP.
TREATMENT

The treatment of TBP is solely pharmacological. The available data strongly suggest that regimens, which are curative for pulmonary TB, are also sufcient for TBP. There are currently ve drugs that are considered rst-line medications: isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), ethambutol (EMB) and streptomycin (SM). Thiacetazone is widely used in the developing world because of its low cost, but has substantial toxicity and limited efcacy. In most circumstances, the treatment regimen for adult patients with previously untreated TB should consist of a 2-month initial phase of INH, RIF, PZA and EMB given on a daily basis. This is followed by a continuation phase where INH and RIF are again given on a daily basis for another 4 months.89 There are various second-line drugs-like rifabutin, uoroquinolones, ethionamide, aminosalicylic acid and cycloserine. The treatment of TBP in HIV-infected adults is the same as that of HIV-uninfected patients, except for the INH-rifapentine once weekly, continuation phase which is contraindicated because of high relapse

rates.89 However, because HIV-infected patients are often taking multiple medications, some of which may interact with antituberculous ones, it is strongly encouraged that experts in the treatment of HIV-related TB be consulted. Response to therapy is manifested by resolution of symptoms and disappearance of ascites. All laboratorybased tests of disease activity return to normal values, usually within 3 months of treatment initiation. The rate of drug resistance varies in different countries and within different ethnic or regional denominations. Overall primary resistance rates to standard rst-line medications in low prevalence areas tends to be below 5%, whereas multidrug resistance rates as high as 48% have been described in high prevalence areas such as Nepal.90 Drug resistance occurs usually when there is a large bacillary population, or when an inadequate drug regimen is prescribed. It also occurs as a result of malabsorption of the antituberculous drug(s). As the type of drugs used in resistant forms need to be modied (along with an extension of the duration of treatment), conducting drug sensitivities to the organism is essential. This should not forestall initiation of treatment because the drugs can be modied as the sensitivity patterns become available. In the presence of resistance to rst-line therapy, a single drug should not be added to the failing regimen. Revising therapy in such instances should be attempted with at least three unused drugs (one of whom is injectable) to which there is in vitro
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695

Clinical features suggestive

Ascites present SAAG 11 g/L Neutrophil dominant Imaging Studies Ascitic fluid analysis Lymphocyte dominant
Spontaneous bacterial peritonitis Rx

Ascites absent

Peritoneal disease (+) SAAG <11 g/L IGPB ADA < 30 IU/L ADA > 30 IU/L Histology conclusive TB culture positive

Peritoneal disease (-)

Histology inconclusive

TB culture negative

Laparotomy

Malignant cells positive Appearance suggestive; histology inconclusive

Anti-TB treatment
Appearance suggestive; histology conclusive

Figure 3. Algorithm for evaluation of patients with suspected tuberculous peritonitis (TBP).

Laparoscopy

susceptibility. Usage of drugs with demonstrated in vitro resistance is not encouraged. It is also preferable to use hospital-based or directly observed therapy.89 Delay in treatment initiation can lead to signicant mortality. Chow et al.47 reported a considerable deterioration in clinical condition of more than 80% of patients during the diagnostic work-up. The overall mortality in this study was 35%, while in the subset of patients with underlying cirrhosis was 73%. Average mortality from the cumulative data of 18 series comprising of more than 800 patients was 19%.17 Although, current recommendation for treatment duration in TBP is only for 6 months, most reported studies have given treatment for 12 months. There is however, no evidence to support a recommendation of treatment beyond 6 months. Some studies that used the 6- or 9-month regimen found almost all of their patients responded equally to the treatment.51, 52 One study compared different durations of treatment (9 months to beyond 12 months) and found no difference in outcome in either group.11 As such, 6 months of phased therapy with the standard rst line of antituberculous medications would be adequate for the treatment of TBP. Role of corticosteroids Corticosteroids reduce the polymorphonuclear inammatory response, and decrease the peripheral blood
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lymphocytes, monocytes, eosinophils and basophils. The inammatory brotic process of the disease results in adhesions and subsequent intestinal obstruction. Adjunctive steroids may offer benet by minimizing the inammation and preventing the postinammatory brosis. Early trials showed that when corticosteroids were given in combination with antituberculous medications there was no progression of the TB.91 Over the decades, this has prompted four trials of adjuvant corticosteroids use in TBP and all of them cited modest benet.40, 51, 60, 85 Alrajhi et al.85 reported considerably low morbidity and complications in those treated with corticosteroids. There is a pending need for prospective, well-controlled clinical trials with long-term follow-ups to identify the category of patients most likely to benet from such therapy. Based on the limited data available, it is presently difcult to make any rm recommendations regarding steroid use in TBP patients. Drug-induced hepatotoxicity One of the main concerns of clinicians in treating TB is the hepatotoxic effect of the antituberculous drugs. The risk is higher in patients with cirrhosis that is commonly associated with TBP. Asymptomatic elevation of aspartate transaminase (AST) occurs in 20% of patients with the standard 4-drug regimen for pulmonary TB.92 According to recent recommendations by the American

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Thoracic Society, Centers for Disease Control and Infectious Disease Society of America, in such situations drug therapy need not be altered but the frequency of clinical and laboratory monitoring should be increased.89 Stoppage of treatment is recommended if AST is elevated vefolds; or threefolds in the presence of symptoms.89 An increase in bilirubin or alkaline phosphatase is also a serious adverse event. Restarting treatment should be attempted when AST values are less than twofolds and the drug to be introduced rst is RIF, followed by introductions of INH and PZA a week apart. Asides from this, it is important to consider other causes of impaired liver functions such as the preexisting liver disease or less commonly, direct dissemination of TB to the liver. Pre-existing liver disease The treatment of TBP in patients with background liver disease is problematic. The incidence of drug-induced hepatitis may be greater and the implications of hepatotoxicity for patients with cirrhosis are potentially serious. One study of patients with TB and underlying liver disease used INH, RIF, EMB and ooxacin for 2 months followed by INH and RIF for 10 months and found 0% hepatotoxicity in this group, while another cohort utilizing a standard regimen developed hepatotoxicity in 26%.93 The aforementioned recent recommendations89 suggested using any of the following four regimens in such a scenario. 1 RIF, PZA and EMB for 6 months. 2 INH, RIF, EMB for 2 months followed by INH and RIF for another 7 months. 3 RIF, EMB, a uoroquinolone, cycloserine/injectible agents for 1218 months. 4 EMB, SM, a uoroquinolone and another second-line oral drug.
CONCLUSION

CAPD. The diagnosis of this disease requires a high index of suspicion because of the subtle nature of the symptoms and signs. TBP should be considered in the differential diagnosis of all patients presenting with a lymphocytic ascites and those with a SAAG of <11 g/L. Ascitic uid analysis is non-specic and culture growth of the Mycobacterium remains the gold standard for diagnosis. Ascitic ADA is a relatively new test with excellent sensitivity and specicity patterns. Further studies are needed to determine its role as a diagnostic tool for TBP. Lately, the advent of molecular biology techniques has led to the introduction of rapid amplication-based tests like PCR and LCR. These are yet to be tested in patients with TBP. The BACTEC radiometric system for acceleration of mycobacterial identication does increase the diagnostic yield and we recommend its wider introduction in clinical practice. Ultrasound and CT scan are increasingly used for the diagnosis of TBP and could help in providing guided peritoneal biopsies. Laparoscopy, however, remains the best means of diagnosing the disease, either by visualization alone or in combination with biopsy and histological examination. It should be considered at an early stage whenever TBP is suspected. It is essential to recognize that a combination of different diagnostic tests is used in order to arrive at the diagnosis of TBP. There is no single test that can consistently yield a diagnosis by itself. Selective screening of ascitic uid samples by more dening tests along with laparoscopic visualization; or histological and microbiological analysis of tissue obtained would be required for denitive disease diagnosis in most cases. The algorithm (Figure 3) outlines the suggested investigational plan of patients with TBP. Six months of treatment with the usual rst-line antituberculous drugs is considered sufcient in uncomplicated cases.
ACKNOWLEDGEMENT

The authors thank Drs MA Al-Karawi and Al-Barrak for critically reviewing the manuscript.
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2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 22, 685700