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Treatment options for hepatic cystic echinococcosis
International Journal of Infectious Diseases (2005) 9, 69—76
http://intl.elsevierhealth.com/journals/ijid
Treatment options for hepatic cystic echinococcosis Raymond A. Smego Jr.*, Peter Sebanego Department of Medicine, the University of North Dakota, School of Medicine and Health Sciences, Fargo, ND, USA Received 28 April 2004; received in revised form 9 August 2004; accepted 11 August 2004 Corresponding Editor: Marguerite Neill, Pawtucket, USA
KEYWORDS Cystic hepatic echinococcosis; Hepatic hydatid cyst; PAIR; Albendazole; Mebendazole
Summary A number of surgical and non-surgical options exist to treat cystic echinococcosis of the liver. For decades, surgical excision via a conservative or radical approach was the recommended approach for hepatic hydatid cysts. The availability of chemotherapeutic agents with significant activity against Echinococcus granulosis has made it possible to undertake ultrasound- or computed tomography-guided transhepatic percutaneous drainage (termed puncture, aspiration, injection, and re-aspiration (PAIR)) of hydatid cysts. Pre- and post-intervention chemotherapy with albendazole or mebendazole offers the advantage of reducing the risk of disease recurrence and intraperitoneal seeding of infection that may develop via cyst rupture and spillage occurring spontaneously or during surgery or needle drainage. PAIR appears to have greater clinical efficacy (i.e. a higher incidence of cure), lower rates of major and minor complications, mortality, and disease recurrence, and fewer days of hospitalization compared to patients treated surgically. For patients who fail drug therapy alone, PAIR is a safe and effective procedure of choice for patients with hepatic echinococcosis, and perhaps other anatomic sites of infection such as lung, peritoneum, kidney, and other viscera. Surgery should be reserved for patients with hydatid cysts refractory to PAIR because of secondary bacterial infection or for those with difficult-to-manage cyst-biliary communication or obstruction. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
Introduction * Corresponding author. Present address: Tuberculosis Research Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook II, Room 236, MSC 8180, 12441 Parklawn Drive, Rockville, MD 20852-1742, USA. Tel.: +1 301 435 7216; fax: +1 301 402 0993. E-mail address: [email protected] (R.A. Smego Jr.).
Human cystic echinococcosis, or hydatid cyst disease, is a zoonosis caused by the larval cestode Echincoccus granulosus. Hippocrates recognized hydatid disease over 2000 years ago, and the disease remains endemic today in sheep-raising areas of the world including Africa, the Mediterranean region of
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Europe, the Middle East, Asia, South America, Australia, and New Zealand. Dogs are the definitive hosts for E. granulosus and sheep the major intermediate host (yaks, goats, and camels are other relevant intermediate hosts); man is only incidentally infected. The liver is the most frequent site for the cystic lesions seen in hydatid disease, followed by the lung, brain, and other viscera.1 Three therapeutic modalities exist to treat hepatic cystic echinococcosis: chemotherapy, surgery, and percutaneous drainage (with the latter two being performed with or without chemotherapy). Historically, management of hydatid cysts in the liver typically involved an open surgical approach with meticulous operative site packing, and employed a variety of conservative and radical operative techniques.2—4 Percutaneous aspiration of a documented or suspected hydatid cyst was long considered contraindicated in order to avoid the risk of leakage of cyst contents, which can lead to anaphylaxis and seeding of intraperitoneal structures. Since the advent of drug therapy effective against Echinococcus species, the use of pre- and postoperative chemotherapy with albendazole or mebendazole combined with percutaneous drainage (consisting of puncture, aspiration, injection, and re-aspiration, or PAIR) of hepatic hydatid cysts is now widely advocated.4—8 This article reviews the available surgical and non-surgical approaches used to treat cystic echinococcosis of the liver, and summarizes the safety and effectiveness of percutaneous drainage plus antiparasitic drug therapy compared to surgical interventions.
Antiparasitic chemotherapy Mebendazole and albendazole Mebendazole was the first benzimidazole carbamate agent found to have in vivo activity in hydatid disease. The drug interferes with mechanisms of glucose absorption through the wall of the parasite leading to glycogen depletion and subsequent degenerative changes in the mitochondria and endoplasmic reticulum of the germinal cells.9 Albendazole is more active in vitro than mebendazole and has improved gastrointestinal absorption and bioavailability, as well as reports of better clinical results.10—15 After oral administration, albendazole is converted by first-pass hepatic metabolism to the active metabolite, albendazole sulfoxide, achieves variable concentrations in blood, bile, liver tissue, cyst fluid, and cyst wall, and crosses the blood-brain barrier.14,16,17 Although
R.A. Smego Jr., P. Sebanego
orally administered, albendazole results in high serum concentrations (peaking in about four hours, and with a serum half-life of 6—15 hours) and penetration into cyst contents is erratic. Important drug interactions exist for albendazole and dexamethasone,18—20 praziquantel,18—20 cimetidine,21,22 and antiepileptic drugs (phenytoin, carbamazepine, and phenobarbital)23; all increase drug bioavailability with enhanced levels of the active metabolite, albendazole sulfoxide. In contrast, clotrimazole abolishes in vitro microsomal sulfonase activity and results in inhibition of the formation of active and inactive metabolites of albendazole.24 Both drugs may decrease the size of hydatid cysts and may lead to the sterilization of cyst contents in some cases;25 however, without concomitant drainage clinical and radiographic resolution is unpredictable and occurs in less than half of treated patients.10—14,17,26 Percutaneous injection of mebendazole or albendazole sulfoxide without reaspiration has been attempted in both experimental and human subjects and results in effective scolicidal activity with little or no toxicity to the liver or biliary system, and local instillation has been suggested as an adjunctive to systemic chemotherapy.27,28 The usual dose of orally-administered albendazole, with or without PAIR, is 10—15 mg/ kg/day in two divided doses, or as a fixed dose of 400 mg bid. If mebendazole is used, the daily dose is 40—50 mg/kg in three divided doses. Hepatic and hematologic toxicities are the most frequent serious adverse effects of albendazole and mebendazole. For patients receiving drug therapy it is generally recommended to have liver enzymes and complete blood counts monitored every two weeks during drug treatment.29 Treatment of hepatic cystic echinococcosis with mebendazole or albendazole alone is not as effective as a combined chemotherapy—drainage approach. Treatment is typically administered as 1—6 monthly cycles separated by 10—14 day intervals. Clinical and radiographic improvement (in most studies defined as >25% reduction in cyst size, membrane separation, or cyst calcification30) is seen frequently, but complete cure (i.e. cyst disappearance) generally occurs in less than half of patients treated with anti-parasitic monotherapy.10—14,17,26 Franchi and colleagues treated 448 patients with 3—6 month cycles of either albendazole or mebendazole.9 Among 882 evaluable cysts, 74% showed degenerative changes on sonography or CT imaging; the efficacy of albendazole (82%) was superior to that of mebendazole (56%), confirming previously reported experiences.31,32 However, 25% of subjects showed evidence of cyst regeneration, including an increase in size or fluid volume,
Treatment options for hepatic cystic echinococcosis
exogenous vesiculation, or reattachment of the membrane to the cyst wall. The rate of relapse was similar for patients treated with either albendazole or mebendazole but was more frequent for cysts with a daughter cyst than for primary cysts, and for cysts of the liver than those in the lung. More than three quarters of relapses were noted within two years after the end of the treatment, and, importantly over 90% of these cysts regressed on further antiparasitic therapy. Future advances in chemotherapy may be achieved by identifying drugs with higher echinococcal activity. For now, albendazole chemotherapy as the primary treatment may be considered for patients who are not acceptable candidates for surgery, those with inoperable, recurrent, peritoneal, or too many cysts, those with multiple cysts in several organs, those who refuse surgery or percutaneous drainage, and perhaps, for asymptomatic individuals.
Praziquantel A third antiparasitic agent, praziquantel, has had limited use in the treatment of hydatid cysts of the liver. The drug, an isoquinolone derivative, increases the permeability of the parasite’s cell membrane to calcium, resulting in strong contractions and paralysis of the musculature leading to detachment from host tissue.33 Praziquantel is an effective scolicide in vitro and in animal models; in humans, it has favorable pharmacokinetics when given in a dose of 50 mg/kg either once weekly or every two weeks.33 There are few clinical studies documenting the efficacy of praziquantel in humans,34—38 however, several of these have suggested that the use of praziquantel in combination with mebendazole37 or albendazole34,38 is more effective and perhaps, more rapid than with the benzimidazoles alone. For 41 patients with hepatic hydatid cysts treated with either albendazole alone or albendazole plus praziquantel, albendazole resulted in the complete disappearance of the cyst in 36.4% of subjects with treatment periods ranging from six months to two years (four of these also required endoscopic treatment for cure), while the combination led to the complete disappearance of cysts in 47.4% after only 2—6 months of drug therapy.34 In a patient cohort with intra-abdominal hydatidosis, a significantly greater number of patients treated preoperatively with albendazole plus praziquantel had nonviable protoscolices at the time of surgery compared to patients receiving albendazole alone, at doses of both 10 mg/kg/day (p = 0.004) and 20 mg/kg/day (p = 0.03).38 Albendazole sulfoxide levels in serum
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and in cyst fluid were higher in patients given combination therapy than in those who received only albendazole (10 mg/kg/day: p = 0.016; 20 mg/kg/day: p = 0.034).
Surgical options The goals of surgery in hydatid disease are to inactivate the cestode parasites, evacuate the cyst cavity, remove the germinal layer, and obliterate the residual cavity. Surgical interventions consist of conservative, radical, and laparoscopic approaches. Conservative techniques involve simple tube drainage, marsupialization (i.e. surgical exteriorization of a cyst by resection of the anterior wall and suture of the cut edges of the remaining cyst to the adjacent edges of the skin, thereby establishing a pouch of what was formally an enclosed cyst), capitonnage (i.e. surgical closure of a cyst cavity by applying sutures so as to cause approximation of the opposition surfaces), deroofing, partial simple cystectomy, or open or closed total cystectomy with or without omentoplasty. Radical procedures include total pericystectomy, partial hepatectomy, or lobectomy. In the last decade, there has been a shift towards radical surgical procedures because they appear to result in fewer postoperative complications, fewer relapses, and lower mortality than conservative techniques.2,39 Laparoscopic drainage of hepatic hydatid cysts is a ‘minimally invasive’ surgical technique that appears safe and effective.40—45 Whichever technique is used, a benzimidazole agent is best used before any surgery in an attempt to sterilize the cyst contents and reduce the risk of anaphylaxis and dissemination.25 Meticulous packing of the operative field is necessary irrespective of the surgical technique employed, as is the use of solutions that kill the infective scoleces and protoscolices of the parasite residing within the hydatid cyst, or potentially leaking from the cyst during surgical manipulation. Various scolicidal solutions used in surgical (and percutaneous) approaches include: hypertonic saline, povidone iodine, hydrogen peroxide, iodine, formalin, silver nitrate, and albendazole. These scolicides can be used alone or in combination. The type of scolicide used does not by itself significantly influence the outcome of the surgical or non-surgical intervention, but different solutions have their own advantages and relative contraindications (see percutaneous drainage below). Potential major complications associated with the surgical treatment of hepatic hydatid cysts include postoperative hemorrhage, bile exudation from the residual cyst cavity, incisional fistula for-
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mation, cholangitis, wound infection, sepsis, incisional fistulae, pulmonary complications such as pneumonia and pulmonary embolization,46 complications of anesthesia, and death.39,47—49 The surgical intervention associated with the most complications, longest mean hospital stay (about 20—28 days),47,49 and worst overall outcome is percutaneous tube drainage.
Percutaneous drainage The availability of chemotherapeutic agents with significant activity against Echinococcus granulosis has made it possible to undertake transhepatic percutaneous drainage of hydatid cysts. Several techniques for percutaneous drainage for hydatid cysts have been described,50—55 but here the literature is summarized for experience with the technique known as the PAIR procedure (percutaneous drainage consisting of puncture, aspiration, injection, and re-aspiration of scolicidal solutions). PAIR treatment satisfies all the goals of surgery in hydatid disease but substitutes germinal membrane sclerosing and separation using scolicides for surgical removal. Patients undergoing PAIR typically receive oral albendazole or mebendazole for seven days before and 28 days after drainage. Percutaneous drainage of hepatic hydatid cysts without drug therapy has been reported.6—8,56—58 However, concomitant preand post-interventional chemotherapy with albendazole or mebendazole offers the advantage of reducing the risk of disease recurrence and intraperitoneal seeding of infection that may develop via cyst rupture and spillage occurring spontaneously or during needle puncture of cysts. The procedure is typically performed in three steps: puncture and needle aspiration of the cyst, instillation and in-dwelling of a scolicidal solution for about 20—30 minutes, and cyst re-aspiration and final irrigation (complete cyst aspiration is generally performed a single time, but in certain subjects aspiration may be repeated until the aspirate is clear). Facilities permitting, PAIR drainage is performed under continuous ultrasonographic or CT guidance with close monitoring for complications such as anaphylaxis, bronchospasm, and laryngeal edema. Different scolicidal solutions can be used in PAIR, although hypertonic saline is most commonly employed. Hypertonic saline (in 5—30% concentrations) exerts its scolicidal effect by creating a strong osmotic gradient across the outer cuticular membrane of the protoscolex, which causes its lysis. A unique advantage of hypertonic saline is its high density and attenuation on CT imaging which allows
R.A. Smego Jr., P. Sebanego
assessment of the dilution of the solution within the hydatid cyst cavity, evaluation of proper contact of the solution with all internal parts of the cyst, and detection of extra-hepatic biliary communications. For multiseptate Type III cysts or large cysts over 6 cm in size, some authors advocate the use of absolute alcohol because it is a more sclerosing agent than hypertonic saline and may destroy daughter cysts not killed by saline and may also result in a more rapid involution of the cyst cavity.16,27,59—65 Alcohol should not be used, however, if pre-existing biliary communication is suspected or documented because the agent may cause a chemical cholangitis. With PAIR, cyst fluid or operative tissue specimens are immediately subjected to cytologic, histopathologic, and parasitologic examinations after aspiration or catheter drainage in order to confirm the diagnosis and assess success of the drainage procedure. Scolices, hooklets, (and/or fragments of laminated membrane) are sought, and the viability of protoscolices is assessed in cytologic/parasitologic (procedural or operative) specimens by observing their motility and their staining pattern using light microscopy and staining with neutral eosin (demonstrating viable parasites) and methylene blue (demonstrating dead organisms).66 With serial sonographic follow-up, the radiographic response to PAIR plus albendazole therapy evolves through a series of progressive changes in echopattern. There is immediate detachment of the germinal layer (endocyst) from the pericyst after injection and aspiration of the scolicidal agent. Subsequently, there is reduction in cyst size, diminution of fluid contents, solidification of internal cyst structure (pseudotumor formation), and in many patients eventual radiologic disappearance. Microscopically, there is concomitant permanent damage to the germinal membrane, and viable protoscolices can be accurately distinguished from non-viable protoscolices. Percutaneous drainage can be performed utilizing a single needle puncture for both univesicular and multivesicular cysts.59,67 Complications arising from PAIR therapy with albendazole or mebendazole are generally well tolerated. Infections can be managed with systemic antimicrobial therapy; leakage during drainage may lead to fever, urticaria, transient hypotension, or anaphylaxis but these can be anticipated and effectively managed with antipyretics, iv fluids, antihistamines, and subcutaneous epinephrine. Cystbiliary communications (biliary rupture and fistula formation) developing after PAIR and caused by cyst decompression, can usually be managed endoscopically.65,68 Cholangiography or endoscopic retrograde cholangiopancreatography (ERCP) is
Treatment options for hepatic cystic echinococcosis
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Table 1 Clinical outcomes in patients undergoing PAIR plus chemotherapy or surgical intervention for hepatic echinococcosis.a,b Clinical outcome
No. of patients (%)
p value
PAIR plus chemotherapy Cure Died Insufficient response Recurrence Re-PAIR or re-operation a b c d
Surgical intervention
c
737/769 (95.8) 1/769 (0.1) 15/769 (2.0) 12/769 (1.6) 9/769d (1.2)
855/952 7/952 30/952 60/952 18/952
(89.8) (0.7) (3.2) (6.3) (1.8)
<0.0001 <0.08 <0.12 <0.0001 <0.23
Reproduced with permission. References 2,3,16,27,46,48,50,51,56,59—65,70—84. Includes re-PAIR in five patients performed to accelerate healing. Includes one patient undergoing endoscopic retrograde cholangiopancreatography (ERCP) for biliary repair.
recommended prior to any percutaneous drainage in order to inject contrast dye and detect connections with the biliary tree. Biliary connections may be hidden prior to ERCP due to the distention of cysts before aspiration, but become visible after injection of the contrast material.
In a recent meta-analysis of 21 comparative or non-comparative studies published from 1990 to 2001 involving a total of 769 albendazole- (15 studies; 663 subjects) or mebendazole-treated (eight studies; 106 subjects) patients, the clinical outcomes and rates of complications were compared
Table 2 Comparison of complications in patients with hepatic echinococcosis treated with PAIR or surgical intervention.a,b No. of patients (%) PAIR (n = 769) Major Cyst infection Liver or intra-abdominal abscess Sepsis Biliary fistula Anaphylaxis Minor Minor (not stated) Fever Allergic reaction, urticaria, or pruritus Pneumonia, pneumothorax, or pulmonary complications (not stated) Pleural effusions Wound infection/dehiscence Prolonged tube drainage Incisional hernia Hemorrhage GI bleed Cholangitis Peritonitis Intraperitoneal leakage Pancreatitis Deep venous thrombosis or pulmonary embolus Paralytic ileus Liver fibrosis or failure Transient hypotension Stroke Transient elevated liver enzymes Other drug-related a b
Reproduced with permission. References 2,3,16,27,47,49,51,52,57,60,61—66,71—85.
61 16 3 — 34 8
(7.9) (2) (0.4)
101 — 42 37 1
(13.1)
4 — 2 — 1 — — — 1 — — — — 2 — 9 8
(4.4) (1.0)
(5.5) (4.8) (0.1) (0.5) (0.3) (0.1)
(0.1)
(0.3) (1.2) (1.0)
Surgery (n = 952)
p value
239 63 34 1 140 1
(25.1) (6.6) (3.6) (0.1) (14.7) (0.1)
<0.0001 <0.0001 <0.0001 NS <0.0001 NS
314 2 24 1 32
(33.0) (0.2) (2.5) (0.1) (3.4)
<0.0001 NS <0.002 <0.0001 <0.0001
(7.0) (6.6) (0.3) (0.2) (1.3) (0.2) (1.6) (6.4)
<0.0001 <0.0001 NS NS <0.008 NS NS <0.0001 NS NS NS NS NS NS NS NS NS
67 63 3 2 12 2 15 61 — 1 4 9 7 — 1 4 4
(0.1) (0.4) (0.9) (0.7) (0.1) (0.4) (0.4)
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for patients undergoing PAIR drainage for hepatic echinococcosis with those of era-matched historical controls undergoing surgical intervention (952 subjects from 14 previously published articles).69 Four hundred and nineteen control patients received albendazole or mebendazole in addition to surgery, while 533 subjects underwent a surgical procedure alone. Clinical and parasitologic cure occurred in 95.8% of patients undergoing PAIR and 89.8% of surgical controls (p < 0.0001), and incomplete response and disease recurrence in 2.0% and 3.2% (p < 0.12) and 1.6% and 6.3% (p < 0.0001), respectively (Table 1). There was one procedure-related death in the PAIR group due to anaphylaxis (0.1%) compared to seven deaths (0.7%) among surgical controls (p < 0.08). Causes of mortality in the controls included pulmonary complications (3 patients), liver failure (1), myocardial infarction (1), generalized peritonitis (1), and spontaneous anaphylaxis (1). Major (i.e. anaphylaxis, cyst infection, liver or intra-abdominal abscess, sepsis, and biliary fistula) and minor non-fatal complications occurred in 7.9% and 13.1% (p < 0.0001) and 25.1% and 33% (p < 0.0001) of PAIR and surgical control subjects, respectively (Table 2). There was no instance of dissemination (peritoneal seeding) using PAIR. Easily managed fever and minor allergic reactions were encountered more frequently in PAIR-treated subjects compared to controls (5.5% and 2.5, p < 0.002; and 4.8% and 0.1%, p < 0.0001, respectively).
Summary In conclusion, compared to patients undergoing surgical intervention for cystic hepatic echinococcosis, PAIR plus albendazole or mebendazole is associated with greater clinical and parasitologic efficacy, less major and minor morbidity, lower rates of mortality and disease recurrence, and a shorter duration of hospitalization. As an initial treatment option or for patients who fail drug therapy alone, PAIR is a safe and effective procedure of choice for patients with hepatic echinococcosis,4,5 and perhaps other anatomic sites of infection such as lung, peritoneum, kidney, and other viscera.86—89 There are considerable potential economic and societal savings inherent in the availability of a safe and effective non-operative treatment modality for hydatid cyst disease that reduces hospital stays by 84%. Surgery may be reserved for patients with hydatid cysts refractory to PAIR because of secondary bacterial infection or with difficult-to-manage cyst-biliary communication or obstruction.4,5
R.A. Smego Jr., P. Sebanego
Conflict of interest: No conflict of interest to declare.
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20. Takayanagui OM, Lanchote VL, Marques MP, Bonato PS. Therapy for neurocysticercosis: pharmacokinetic interaction of albendazole sulfoxide with dexamethasone. Ther Drug Monit 1997;19:51—5. 21. Nagy J, Schipper HG, Koopmans RP, Butter JJ, Van Boxtel CJ, Kager PA. Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability. Am J Trop Med Hyg 2002;66:260—3. 22. Schipper HG, Koopmans RP, Nagy J, Butter JJ, Kager PA, Van Boxtel CJ. Effect of dose increase or cimetidine co-administration on albendazole bioavailability. Am J Trop Med Hyg 2000;63:270—3. 23. Lanchote VL, Garcia FS, Dreossi SA, Takayanagui OM. Pharmacokinetic interaction between albendazole sulfoxide enantiomers and antiepileptic drugs in patients with neurocysticercosis. Ther Drug Monit 2002;24:338—45. 24. Alvarez AI. Effect of clotrimazole on microsomal metabolism and pharmacokinetics of albendazole. J Pharm Pharmacol 2003;55:757—64. 25. Smego DR, Smego Jr RA. Hydatid cyst: Pre-operative sterilization with mebendazole. South Med J 1986;79: 900—1. 26. Hao W, Pei-Fan Z, Wen-Guang Y, Jian L, Yun-Hai W, Jing-Hui Z, et al. Albendazole chemotherapy for human cystic and alveolar echinococcosis in north-western China. Trans R Soc Trop Med Hyg 1994;88:340—3. 27. Erzurumlu K, Sahin M, Selcuk MB, Yldiz C, Kesim M. Intracystic application of mebendazole solution in the treatment of liver hydatid disease: Preliminary report of two cases. Eur Surg Res 1996;28:466—70. 28. Deger E, Hokelek M, Deger BA, Tutar E, Asil M, Pakdermirli E. A new therapeutic approach for the treatment of cystic echinococcosis: Percutaneous albendazole sulphoxide injection without reaspiration. Am J Gastroenterol 2000;95: 248—54. 29. Smith AL, Rego LP, Williams R. Albendazole monitoring. Am J Health Syst Pharm 1997;54:319—20. 30. Kumar A, Lal BK, Chattapodhay TK. Hydatid disease of the liver—non-surgical options. J Assoc Physicians India 1993;41:437—43. 31. Davis A, Dixon H, Pawlowski Z. Multicentre clinical trials of benzimidazole carbamates in human cystic echinococcosis (phase 2). Bull World Health Organ 1989;67:503—8. 32. Guidelines for treatment of cystic and alveolar echinococcosis in humans. WHO Informal Working Group on Echinococcosis. Bull World Health Organ 1996;74:231—42. 33. Anadol D, Ozgelik U, Kiper N, Gogmen A. Treatment of hydatid disease. Paediatr Drugs 2001;3:123—35. 34. Mohamed AE, Yasawy MI, Al Karawi MA. Combined albendazole and praziquantel versus albendazole alone in the treatment of hydatid disease. Hepatogastroenterology 1998;45: 1690—1694. 35. Yasawy MI, al Karawi MA, Mohamed AR. Combination of praziquantel and albendazole in the treatment of hydatid disease. Trop Med Parasitol 1993;44:192—4. 36. Redzic B, Radulovic S, Stankovic N, Redzic-Rosko Z. Praziquantel in the treatment of human echinococcosis. Vojnosanit Pregl 1995;52:155—9. 37. Salto E, Juarez E, Roiz MP, Abad J. Combined chemotherapy (mebendazole plus praziquantel) in patients with hydatidosis. Enferm Infecc Microbiol Clin 1991;9:527—9. 38. Cobo F, Yarnoz C, Sesma B, Fraile P, Aizcorbe M, Trujillo R, et al. Albendazole plus praziquantel versus albendazole alone as a pre-operative treatment in intra-abdominal hydatisosis caused by Echinococcus granulosus. Trop Med Int Health 1998;3:462—6.
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39. Cirenei A, Bertoldi I. Evolutions of surgery for liver hydatidosis from 1950 to today: Analysis of a personal experience. World J Surg 2001;25:87—92. 40. Yaghan R, Heis H, Bani-Hani K, Matalka I, Shatanawi N, Gharaibeh K, et al. Is fear of anaphylactic shock discouraging surgeons from more widely adopting percutaneous and laparoscopic techniques in the treatment of liver hydatid cyst? Am J Surg 2004;187:533—7. 41. Chowbey PK, Shah S, Khullar R, Sharma A, Soni V, Baijal M, et al. Minimal access surgery for hydatid cyst disease: laparoscopic, thoracoscopic, and retroperitoneoscopic approach. J Laparoendosc Adv Surg Tech 2003;13:159—65. 42. Al-Shareef Z, Hamour OA, Al-Shlash S, Ahmed I, Mohamed AA. Laparoscopic treatment of hepatic hydatid cysts with a liposuction device. JSLS 2002;6:327—30. 43. Altinli E, Saribeyoglu K, Pekmezci S, Uras C, Tasci H, Akcal T. An effective omentoplasty technique in laparoscopic surgery for hydatid disease of the liver. JSLS 2002;6:323—6. 44. Gloor B, Ly Q, Candinas D. Role of laparoscopy in hepatic cyst surgery. Dig Surg 2002;19:494—9. 45. Ertem M, Karahasanoglu T, Yavuz N, Erguney S. Laparoscopically-treated liver hydatid cysts. Arch Surg 2002;137: 1170—3. 46. Utkan NZ, Canturk NZ, Gonullu N, Yildirir C, Dulger M. Surgical experience of hydatid disease of the liver: Omentoplasty or capitonnage versus tube drainage. Hepatogastroenterology 2001;48:203—7. 47. Balik AA, Basoglu M, Celebi F, Oren D, Polat KY, Atamanalp SS, et al. Surgical treatment of hydatid disease of the liver: Review of 304 cases. Arch Surg 1999;134:166—9. 48. Bektas H, Lehner F, Werner U, et al. Surgical therapy of cystic echinococcosis of the liver. Zentralbl Chir 2001;126:369—73. 49. Demirci S, Eraslan S, Anadol E, Bozatli L. Comparison of the results of different surgical techniques in the management of hydatid cysts of the liver. World J Surg 1989;13:88—90. 50. Regev A, Reddy KR, Berho M, et al. Large cystic lesions of the liver in adults: A 15-year experience in a tertiary center. J Am Coll Surg 2001;193:36—45. 51. Agaev RM. Surgical treatment of hepatic echinococcosis and its complications. Khirurgiia (Mosk) 2001;2:32—6. 52. Wang XZ, Shao XL, Liang TZ, Li YS, Wei WH, Gao GM, et al. Elementary research on percutaneous puncture treatment guided by B-ultrasound for cystic echinococcosis. Chin J Ultrasound Med 1991;7:54—5. 53. Wang XZ, Fen SL, Zhao HN. A new type of multi-functional trocar for percutaneous puncture in hydatidosis. Arch Int Hidatidosis 1993;30:404. 54. Wang XZ, Changming Y, Shengli F, Jinshen C, Hui M, Shufang L, et al. Therapy of liver and abdominal cavity echinococcosis with percutaneous drainage and curettage (report of 1,002 cases). (abstract). Arch Int Hidatidosis Lisbon 1997;32:254. 55. Schipper HG, Lame ´ris JS, van Delden OM, Rauws EA, Kager PA. Percutaneous evacuation (PEVAC) of multivesicular echinococcal cysts with or without cystobiliary fistulas which contain non-drainable material: First results of a modified PAIR method. Gut 2002;50:718—23. 56. Filice C, Pirola F, Brunetti E, Dughett S, Strosselli M, Foglieni CS. A new therapeutic approach for hydatid liver cysts. Gastroenterology 1990;98:1366—8. 57. Ben Amor N, Gargouri M, Gharbi HA, Golvan YJ, Ayachi K, Kcouck H. Essai de traitement par ponction des kystes hydatiques abdominaux inoperables. Ann Parasitol Hum Comp 1986;61:689. 58. Simonetti G, Profili S, Sergiacomi GL, et al. Percutaneous treatment of hepatic cysts by aspiration and sclerotherapy. Cardiovasc Intervent Radiol 1993;16:81—4.
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59. Khuroo MS, Wani NA, Javid G, et al. Percutaneous drainage compared with surgery for hepatic hydatid cysts. N Engl J Med 1997;337:881—7. 60. Gargouri M, Ben Amor N, Ben Chehida F, et al. Percutaneous treatment of hydatid cysts (Echinococcus granulosus). Cardiovasc Intervent Radiol 1990;12:169—73. 61. Acunas B, Rozanes I, Celik L, et al. Purely cystic hydatid disease of the liver: Treatment with percutaneous aspiration and injection of hypertonic saline. Radiology 1992;182:541—3. 62. Giorgio A, Tarantino L, Francica Gl. Unilocular hydatid liver cysts: Treatment with US-guided, double percutaneous aspiration and alcohol injection. Radiology 1992;184:705—10. 63. Bastid C, Azar C, Doyer M, Sahel J. Percutaneous treatment of hydatid cysts under sonographic guidance. Dig Dis Sci 1994;39:1576—80. 64. Akhan O, Ozmen MN, Dincer A, Sayek I, Gocmen A. Liver hydatid disease: Long-term results of percutaneous treatment. Radiology 1996;198:259—64. 65. Filice C, Brunetti E. Use of PAIR in human cystic echinococcosis. Acta Trop 1997;64:95—107. 66. Gori S, Campatelli A, Luchi S, Paladini A, Savalli E, Scasso A. Cytology in the percutaneous treatment of hydatid cysts. A report of four cases. Acta Cytol 1993;37:423—6. 67. Khuroo MS. Percutaneous drainage of hydatid cysts (letter response to Schipper et al.). N Engl J Med 1998;338:391—3. 68. Al Karawi MA, El-Sheikh Mohamed AR, Yasawy MI. Advances in diagnosis and management of hydatid disease. Hepatogastroenterology 1990;37:327—31. 69. Smego Jr RA, Bhatti S, Khaliq AA, Beg MA. Percutaneous aspiration-injection-re-aspiration (PAIR) plus albendazole or mebendazole for hepatic echinococcosis: A meta-analysis. Clin Infect Dis 2003;37:1073—83. 70. Turkcapar AG, Ersoz S, Gungor C, Aydinuraz K, Yerdel MA, Aras N. Surgical treatment of hepatic hydatidosis combined with perioperative treatment with albendazole. Eur J Surg 1997; 163:923—8. 71. Mikic D, Trnjak Z, Bojic I, et al. Personal experience in the diagnosis and treatment of hepatic echinococcosis. Vojnosanit Pregl 1998;55:489—99. 72. Tan A, Yakut M, Kaymakcioglu N, Ozerhan IH, Cetiner S, Akdeniz A. The results of surgical treatment and percutanous drainage of hepatic hydatid disease. Int Surg 1998;83:314—6. 73. Uhl W, Loffler H, Zimmermann A, Tcholakov O, Gloor B, Buchler MW. Chirurgische therapie der leber-echinokokkose. Swiss Surg 1999;5:126—32.
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74. Erzurumlu K, Hokelek M, Gonlusen L, Tas K, Amanvermez R. The effect of albendazole on the prevention of secondary hydatidosis. Hepatogastroenterology 2000;47:247—50. 75. Sayek I, Onat D. Diagnosis and treatment of uncomplicated hydatid cyst of the liver. World J Surg 2001;25:21—7. 76. Demirbilek S, Sander S, Atayurt HF, Aydin G. Hydatid disease of the liver in childhood: The success of medical therapy and surgical alternatives. Pediatr Surg Int 2001;17:373—7. 77. Anadol D, Gocmen A, Kiper N, Ozcelik U. Hydatid disease in childhood: A retrospective analysis of 376 cases. Pediatr Pulmonol 1998;26:190—6. 78. Ustunsoz B, Akhan O, Kamiloglu MA, Somuncu I, Ugurel MS, Cetiner S. Percutaneous treatment of hydatid cysts of the liver: Long-term results. Am J Roentgenol 1999;172:91—6. 79. Men S, Hakimoglu B, Yucesoy C, Arda IS, Beran I. Percutaneous treatment of hepatic hydatid cysts: An alternative to surgery. Am J Radiol 1999;172:83—9. 80. Pelaez V, Kugleer C, Correa D, et al. PAIR as percutaneous treatment of hydatid liver cysts. Acta Trop 1997;75:197— 202. 81. Kabaalioglu A, Karaali K, Apaydin A, Melikoglu M, Sindel T, Luleci E. Ultrasound-guided percutaneous sclerotherapy of hydatid liver cysts in children. Pediatr Surg Int 2000;16:346— 50. 82. Grigorov N, Golemanov B, Mitova R, et al. Khirurgiia (Sofia) 2000;56:28—31. 83. Odev K, Paksoy Y, Arslan A, et al. Sonographically-guided percutaneous treatment of hepatic hydatid cysts: Long-term results. J Clin Ultrasound 2000;28:469—74. 84. Aygun E, Sahin M, Odev K, Vatansev C, et al. The management of liver hydatid cysts by percutaneous drainage. Can J Surg 2001;44:203—9. 85. Akhan O, Dincer A, Gokoz A, et al. Liver hydatid disease: Percutaneous treatment of abdominal hydatid cysts with hypertonic saline and alcohol. Invest Radiol 1993;28: 121—7. 86. Akhan O, Ozmen MN, Dincer A, Gocmen A, Kalyoncu F. Percutaneous treatment of pulmonary hydatid cysts. Cardiovasc Intervent Radiol 1994;17:271—5. 87. Mawhorter S, Temeck B, Chang R, Pass H, Nash T. Nonsurgical therapy for pulmonary hydatid cyst disease. Chest 1997;112:1432—6. 88. Akhan O, Ustunsoz B, Somunco L, Ozmen MN, Oner A, Alemdaroglu A. Percutaneous renal hydatid cyst treatment: Longterm results. Abdom Imaging 1998;23:209—13.
http://intl.elsevierhealth.com/journals/ijid
Treatment options for hepatic cystic echinococcosis Raymond A. Smego Jr.*, Peter Sebanego Department of Medicine, the University of North Dakota, School of Medicine and Health Sciences, Fargo, ND, USA Received 28 April 2004; received in revised form 9 August 2004; accepted 11 August 2004 Corresponding Editor: Marguerite Neill, Pawtucket, USA
KEYWORDS Cystic hepatic echinococcosis; Hepatic hydatid cyst; PAIR; Albendazole; Mebendazole
Summary A number of surgical and non-surgical options exist to treat cystic echinococcosis of the liver. For decades, surgical excision via a conservative or radical approach was the recommended approach for hepatic hydatid cysts. The availability of chemotherapeutic agents with significant activity against Echinococcus granulosis has made it possible to undertake ultrasound- or computed tomography-guided transhepatic percutaneous drainage (termed puncture, aspiration, injection, and re-aspiration (PAIR)) of hydatid cysts. Pre- and post-intervention chemotherapy with albendazole or mebendazole offers the advantage of reducing the risk of disease recurrence and intraperitoneal seeding of infection that may develop via cyst rupture and spillage occurring spontaneously or during surgery or needle drainage. PAIR appears to have greater clinical efficacy (i.e. a higher incidence of cure), lower rates of major and minor complications, mortality, and disease recurrence, and fewer days of hospitalization compared to patients treated surgically. For patients who fail drug therapy alone, PAIR is a safe and effective procedure of choice for patients with hepatic echinococcosis, and perhaps other anatomic sites of infection such as lung, peritoneum, kidney, and other viscera. Surgery should be reserved for patients with hydatid cysts refractory to PAIR because of secondary bacterial infection or for those with difficult-to-manage cyst-biliary communication or obstruction. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
Introduction * Corresponding author. Present address: Tuberculosis Research Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook II, Room 236, MSC 8180, 12441 Parklawn Drive, Rockville, MD 20852-1742, USA. Tel.: +1 301 435 7216; fax: +1 301 402 0993. E-mail address: [email protected] (R.A. Smego Jr.).
Human cystic echinococcosis, or hydatid cyst disease, is a zoonosis caused by the larval cestode Echincoccus granulosus. Hippocrates recognized hydatid disease over 2000 years ago, and the disease remains endemic today in sheep-raising areas of the world including Africa, the Mediterranean region of
1201-9712/$30.00. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. doi:10.1016/j.ijid.2004.08.001
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Europe, the Middle East, Asia, South America, Australia, and New Zealand. Dogs are the definitive hosts for E. granulosus and sheep the major intermediate host (yaks, goats, and camels are other relevant intermediate hosts); man is only incidentally infected. The liver is the most frequent site for the cystic lesions seen in hydatid disease, followed by the lung, brain, and other viscera.1 Three therapeutic modalities exist to treat hepatic cystic echinococcosis: chemotherapy, surgery, and percutaneous drainage (with the latter two being performed with or without chemotherapy). Historically, management of hydatid cysts in the liver typically involved an open surgical approach with meticulous operative site packing, and employed a variety of conservative and radical operative techniques.2—4 Percutaneous aspiration of a documented or suspected hydatid cyst was long considered contraindicated in order to avoid the risk of leakage of cyst contents, which can lead to anaphylaxis and seeding of intraperitoneal structures. Since the advent of drug therapy effective against Echinococcus species, the use of pre- and postoperative chemotherapy with albendazole or mebendazole combined with percutaneous drainage (consisting of puncture, aspiration, injection, and re-aspiration, or PAIR) of hepatic hydatid cysts is now widely advocated.4—8 This article reviews the available surgical and non-surgical approaches used to treat cystic echinococcosis of the liver, and summarizes the safety and effectiveness of percutaneous drainage plus antiparasitic drug therapy compared to surgical interventions.
Antiparasitic chemotherapy Mebendazole and albendazole Mebendazole was the first benzimidazole carbamate agent found to have in vivo activity in hydatid disease. The drug interferes with mechanisms of glucose absorption through the wall of the parasite leading to glycogen depletion and subsequent degenerative changes in the mitochondria and endoplasmic reticulum of the germinal cells.9 Albendazole is more active in vitro than mebendazole and has improved gastrointestinal absorption and bioavailability, as well as reports of better clinical results.10—15 After oral administration, albendazole is converted by first-pass hepatic metabolism to the active metabolite, albendazole sulfoxide, achieves variable concentrations in blood, bile, liver tissue, cyst fluid, and cyst wall, and crosses the blood-brain barrier.14,16,17 Although
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orally administered, albendazole results in high serum concentrations (peaking in about four hours, and with a serum half-life of 6—15 hours) and penetration into cyst contents is erratic. Important drug interactions exist for albendazole and dexamethasone,18—20 praziquantel,18—20 cimetidine,21,22 and antiepileptic drugs (phenytoin, carbamazepine, and phenobarbital)23; all increase drug bioavailability with enhanced levels of the active metabolite, albendazole sulfoxide. In contrast, clotrimazole abolishes in vitro microsomal sulfonase activity and results in inhibition of the formation of active and inactive metabolites of albendazole.24 Both drugs may decrease the size of hydatid cysts and may lead to the sterilization of cyst contents in some cases;25 however, without concomitant drainage clinical and radiographic resolution is unpredictable and occurs in less than half of treated patients.10—14,17,26 Percutaneous injection of mebendazole or albendazole sulfoxide without reaspiration has been attempted in both experimental and human subjects and results in effective scolicidal activity with little or no toxicity to the liver or biliary system, and local instillation has been suggested as an adjunctive to systemic chemotherapy.27,28 The usual dose of orally-administered albendazole, with or without PAIR, is 10—15 mg/ kg/day in two divided doses, or as a fixed dose of 400 mg bid. If mebendazole is used, the daily dose is 40—50 mg/kg in three divided doses. Hepatic and hematologic toxicities are the most frequent serious adverse effects of albendazole and mebendazole. For patients receiving drug therapy it is generally recommended to have liver enzymes and complete blood counts monitored every two weeks during drug treatment.29 Treatment of hepatic cystic echinococcosis with mebendazole or albendazole alone is not as effective as a combined chemotherapy—drainage approach. Treatment is typically administered as 1—6 monthly cycles separated by 10—14 day intervals. Clinical and radiographic improvement (in most studies defined as >25% reduction in cyst size, membrane separation, or cyst calcification30) is seen frequently, but complete cure (i.e. cyst disappearance) generally occurs in less than half of patients treated with anti-parasitic monotherapy.10—14,17,26 Franchi and colleagues treated 448 patients with 3—6 month cycles of either albendazole or mebendazole.9 Among 882 evaluable cysts, 74% showed degenerative changes on sonography or CT imaging; the efficacy of albendazole (82%) was superior to that of mebendazole (56%), confirming previously reported experiences.31,32 However, 25% of subjects showed evidence of cyst regeneration, including an increase in size or fluid volume,
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exogenous vesiculation, or reattachment of the membrane to the cyst wall. The rate of relapse was similar for patients treated with either albendazole or mebendazole but was more frequent for cysts with a daughter cyst than for primary cysts, and for cysts of the liver than those in the lung. More than three quarters of relapses were noted within two years after the end of the treatment, and, importantly over 90% of these cysts regressed on further antiparasitic therapy. Future advances in chemotherapy may be achieved by identifying drugs with higher echinococcal activity. For now, albendazole chemotherapy as the primary treatment may be considered for patients who are not acceptable candidates for surgery, those with inoperable, recurrent, peritoneal, or too many cysts, those with multiple cysts in several organs, those who refuse surgery or percutaneous drainage, and perhaps, for asymptomatic individuals.
Praziquantel A third antiparasitic agent, praziquantel, has had limited use in the treatment of hydatid cysts of the liver. The drug, an isoquinolone derivative, increases the permeability of the parasite’s cell membrane to calcium, resulting in strong contractions and paralysis of the musculature leading to detachment from host tissue.33 Praziquantel is an effective scolicide in vitro and in animal models; in humans, it has favorable pharmacokinetics when given in a dose of 50 mg/kg either once weekly or every two weeks.33 There are few clinical studies documenting the efficacy of praziquantel in humans,34—38 however, several of these have suggested that the use of praziquantel in combination with mebendazole37 or albendazole34,38 is more effective and perhaps, more rapid than with the benzimidazoles alone. For 41 patients with hepatic hydatid cysts treated with either albendazole alone or albendazole plus praziquantel, albendazole resulted in the complete disappearance of the cyst in 36.4% of subjects with treatment periods ranging from six months to two years (four of these also required endoscopic treatment for cure), while the combination led to the complete disappearance of cysts in 47.4% after only 2—6 months of drug therapy.34 In a patient cohort with intra-abdominal hydatidosis, a significantly greater number of patients treated preoperatively with albendazole plus praziquantel had nonviable protoscolices at the time of surgery compared to patients receiving albendazole alone, at doses of both 10 mg/kg/day (p = 0.004) and 20 mg/kg/day (p = 0.03).38 Albendazole sulfoxide levels in serum
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and in cyst fluid were higher in patients given combination therapy than in those who received only albendazole (10 mg/kg/day: p = 0.016; 20 mg/kg/day: p = 0.034).
Surgical options The goals of surgery in hydatid disease are to inactivate the cestode parasites, evacuate the cyst cavity, remove the germinal layer, and obliterate the residual cavity. Surgical interventions consist of conservative, radical, and laparoscopic approaches. Conservative techniques involve simple tube drainage, marsupialization (i.e. surgical exteriorization of a cyst by resection of the anterior wall and suture of the cut edges of the remaining cyst to the adjacent edges of the skin, thereby establishing a pouch of what was formally an enclosed cyst), capitonnage (i.e. surgical closure of a cyst cavity by applying sutures so as to cause approximation of the opposition surfaces), deroofing, partial simple cystectomy, or open or closed total cystectomy with or without omentoplasty. Radical procedures include total pericystectomy, partial hepatectomy, or lobectomy. In the last decade, there has been a shift towards radical surgical procedures because they appear to result in fewer postoperative complications, fewer relapses, and lower mortality than conservative techniques.2,39 Laparoscopic drainage of hepatic hydatid cysts is a ‘minimally invasive’ surgical technique that appears safe and effective.40—45 Whichever technique is used, a benzimidazole agent is best used before any surgery in an attempt to sterilize the cyst contents and reduce the risk of anaphylaxis and dissemination.25 Meticulous packing of the operative field is necessary irrespective of the surgical technique employed, as is the use of solutions that kill the infective scoleces and protoscolices of the parasite residing within the hydatid cyst, or potentially leaking from the cyst during surgical manipulation. Various scolicidal solutions used in surgical (and percutaneous) approaches include: hypertonic saline, povidone iodine, hydrogen peroxide, iodine, formalin, silver nitrate, and albendazole. These scolicides can be used alone or in combination. The type of scolicide used does not by itself significantly influence the outcome of the surgical or non-surgical intervention, but different solutions have their own advantages and relative contraindications (see percutaneous drainage below). Potential major complications associated with the surgical treatment of hepatic hydatid cysts include postoperative hemorrhage, bile exudation from the residual cyst cavity, incisional fistula for-
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mation, cholangitis, wound infection, sepsis, incisional fistulae, pulmonary complications such as pneumonia and pulmonary embolization,46 complications of anesthesia, and death.39,47—49 The surgical intervention associated with the most complications, longest mean hospital stay (about 20—28 days),47,49 and worst overall outcome is percutaneous tube drainage.
Percutaneous drainage The availability of chemotherapeutic agents with significant activity against Echinococcus granulosis has made it possible to undertake transhepatic percutaneous drainage of hydatid cysts. Several techniques for percutaneous drainage for hydatid cysts have been described,50—55 but here the literature is summarized for experience with the technique known as the PAIR procedure (percutaneous drainage consisting of puncture, aspiration, injection, and re-aspiration of scolicidal solutions). PAIR treatment satisfies all the goals of surgery in hydatid disease but substitutes germinal membrane sclerosing and separation using scolicides for surgical removal. Patients undergoing PAIR typically receive oral albendazole or mebendazole for seven days before and 28 days after drainage. Percutaneous drainage of hepatic hydatid cysts without drug therapy has been reported.6—8,56—58 However, concomitant preand post-interventional chemotherapy with albendazole or mebendazole offers the advantage of reducing the risk of disease recurrence and intraperitoneal seeding of infection that may develop via cyst rupture and spillage occurring spontaneously or during needle puncture of cysts. The procedure is typically performed in three steps: puncture and needle aspiration of the cyst, instillation and in-dwelling of a scolicidal solution for about 20—30 minutes, and cyst re-aspiration and final irrigation (complete cyst aspiration is generally performed a single time, but in certain subjects aspiration may be repeated until the aspirate is clear). Facilities permitting, PAIR drainage is performed under continuous ultrasonographic or CT guidance with close monitoring for complications such as anaphylaxis, bronchospasm, and laryngeal edema. Different scolicidal solutions can be used in PAIR, although hypertonic saline is most commonly employed. Hypertonic saline (in 5—30% concentrations) exerts its scolicidal effect by creating a strong osmotic gradient across the outer cuticular membrane of the protoscolex, which causes its lysis. A unique advantage of hypertonic saline is its high density and attenuation on CT imaging which allows
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assessment of the dilution of the solution within the hydatid cyst cavity, evaluation of proper contact of the solution with all internal parts of the cyst, and detection of extra-hepatic biliary communications. For multiseptate Type III cysts or large cysts over 6 cm in size, some authors advocate the use of absolute alcohol because it is a more sclerosing agent than hypertonic saline and may destroy daughter cysts not killed by saline and may also result in a more rapid involution of the cyst cavity.16,27,59—65 Alcohol should not be used, however, if pre-existing biliary communication is suspected or documented because the agent may cause a chemical cholangitis. With PAIR, cyst fluid or operative tissue specimens are immediately subjected to cytologic, histopathologic, and parasitologic examinations after aspiration or catheter drainage in order to confirm the diagnosis and assess success of the drainage procedure. Scolices, hooklets, (and/or fragments of laminated membrane) are sought, and the viability of protoscolices is assessed in cytologic/parasitologic (procedural or operative) specimens by observing their motility and their staining pattern using light microscopy and staining with neutral eosin (demonstrating viable parasites) and methylene blue (demonstrating dead organisms).66 With serial sonographic follow-up, the radiographic response to PAIR plus albendazole therapy evolves through a series of progressive changes in echopattern. There is immediate detachment of the germinal layer (endocyst) from the pericyst after injection and aspiration of the scolicidal agent. Subsequently, there is reduction in cyst size, diminution of fluid contents, solidification of internal cyst structure (pseudotumor formation), and in many patients eventual radiologic disappearance. Microscopically, there is concomitant permanent damage to the germinal membrane, and viable protoscolices can be accurately distinguished from non-viable protoscolices. Percutaneous drainage can be performed utilizing a single needle puncture for both univesicular and multivesicular cysts.59,67 Complications arising from PAIR therapy with albendazole or mebendazole are generally well tolerated. Infections can be managed with systemic antimicrobial therapy; leakage during drainage may lead to fever, urticaria, transient hypotension, or anaphylaxis but these can be anticipated and effectively managed with antipyretics, iv fluids, antihistamines, and subcutaneous epinephrine. Cystbiliary communications (biliary rupture and fistula formation) developing after PAIR and caused by cyst decompression, can usually be managed endoscopically.65,68 Cholangiography or endoscopic retrograde cholangiopancreatography (ERCP) is
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Table 1 Clinical outcomes in patients undergoing PAIR plus chemotherapy or surgical intervention for hepatic echinococcosis.a,b Clinical outcome
No. of patients (%)
p value
PAIR plus chemotherapy Cure Died Insufficient response Recurrence Re-PAIR or re-operation a b c d
Surgical intervention
c
737/769 (95.8) 1/769 (0.1) 15/769 (2.0) 12/769 (1.6) 9/769d (1.2)
855/952 7/952 30/952 60/952 18/952
(89.8) (0.7) (3.2) (6.3) (1.8)
<0.0001 <0.08 <0.12 <0.0001 <0.23
Reproduced with permission. References 2,3,16,27,46,48,50,51,56,59—65,70—84. Includes re-PAIR in five patients performed to accelerate healing. Includes one patient undergoing endoscopic retrograde cholangiopancreatography (ERCP) for biliary repair.
recommended prior to any percutaneous drainage in order to inject contrast dye and detect connections with the biliary tree. Biliary connections may be hidden prior to ERCP due to the distention of cysts before aspiration, but become visible after injection of the contrast material.
In a recent meta-analysis of 21 comparative or non-comparative studies published from 1990 to 2001 involving a total of 769 albendazole- (15 studies; 663 subjects) or mebendazole-treated (eight studies; 106 subjects) patients, the clinical outcomes and rates of complications were compared
Table 2 Comparison of complications in patients with hepatic echinococcosis treated with PAIR or surgical intervention.a,b No. of patients (%) PAIR (n = 769) Major Cyst infection Liver or intra-abdominal abscess Sepsis Biliary fistula Anaphylaxis Minor Minor (not stated) Fever Allergic reaction, urticaria, or pruritus Pneumonia, pneumothorax, or pulmonary complications (not stated) Pleural effusions Wound infection/dehiscence Prolonged tube drainage Incisional hernia Hemorrhage GI bleed Cholangitis Peritonitis Intraperitoneal leakage Pancreatitis Deep venous thrombosis or pulmonary embolus Paralytic ileus Liver fibrosis or failure Transient hypotension Stroke Transient elevated liver enzymes Other drug-related a b
Reproduced with permission. References 2,3,16,27,47,49,51,52,57,60,61—66,71—85.
61 16 3 — 34 8
(7.9) (2) (0.4)
101 — 42 37 1
(13.1)
4 — 2 — 1 — — — 1 — — — — 2 — 9 8
(4.4) (1.0)
(5.5) (4.8) (0.1) (0.5) (0.3) (0.1)
(0.1)
(0.3) (1.2) (1.0)
Surgery (n = 952)
p value
239 63 34 1 140 1
(25.1) (6.6) (3.6) (0.1) (14.7) (0.1)
<0.0001 <0.0001 <0.0001 NS <0.0001 NS
314 2 24 1 32
(33.0) (0.2) (2.5) (0.1) (3.4)
<0.0001 NS <0.002 <0.0001 <0.0001
(7.0) (6.6) (0.3) (0.2) (1.3) (0.2) (1.6) (6.4)
<0.0001 <0.0001 NS NS <0.008 NS NS <0.0001 NS NS NS NS NS NS NS NS NS
67 63 3 2 12 2 15 61 — 1 4 9 7 — 1 4 4
(0.1) (0.4) (0.9) (0.7) (0.1) (0.4) (0.4)
74
for patients undergoing PAIR drainage for hepatic echinococcosis with those of era-matched historical controls undergoing surgical intervention (952 subjects from 14 previously published articles).69 Four hundred and nineteen control patients received albendazole or mebendazole in addition to surgery, while 533 subjects underwent a surgical procedure alone. Clinical and parasitologic cure occurred in 95.8% of patients undergoing PAIR and 89.8% of surgical controls (p < 0.0001), and incomplete response and disease recurrence in 2.0% and 3.2% (p < 0.12) and 1.6% and 6.3% (p < 0.0001), respectively (Table 1). There was one procedure-related death in the PAIR group due to anaphylaxis (0.1%) compared to seven deaths (0.7%) among surgical controls (p < 0.08). Causes of mortality in the controls included pulmonary complications (3 patients), liver failure (1), myocardial infarction (1), generalized peritonitis (1), and spontaneous anaphylaxis (1). Major (i.e. anaphylaxis, cyst infection, liver or intra-abdominal abscess, sepsis, and biliary fistula) and minor non-fatal complications occurred in 7.9% and 13.1% (p < 0.0001) and 25.1% and 33% (p < 0.0001) of PAIR and surgical control subjects, respectively (Table 2). There was no instance of dissemination (peritoneal seeding) using PAIR. Easily managed fever and minor allergic reactions were encountered more frequently in PAIR-treated subjects compared to controls (5.5% and 2.5, p < 0.002; and 4.8% and 0.1%, p < 0.0001, respectively).
Summary In conclusion, compared to patients undergoing surgical intervention for cystic hepatic echinococcosis, PAIR plus albendazole or mebendazole is associated with greater clinical and parasitologic efficacy, less major and minor morbidity, lower rates of mortality and disease recurrence, and a shorter duration of hospitalization. As an initial treatment option or for patients who fail drug therapy alone, PAIR is a safe and effective procedure of choice for patients with hepatic echinococcosis,4,5 and perhaps other anatomic sites of infection such as lung, peritoneum, kidney, and other viscera.86—89 There are considerable potential economic and societal savings inherent in the availability of a safe and effective non-operative treatment modality for hydatid cyst disease that reduces hospital stays by 84%. Surgery may be reserved for patients with hydatid cysts refractory to PAIR because of secondary bacterial infection or with difficult-to-manage cyst-biliary communication or obstruction.4,5
R.A. Smego Jr., P. Sebanego
Conflict of interest: No conflict of interest to declare.
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