Human Hydatidosis in the Central Andes of Peru: Evolution of the Disease over 3 Years

Transcription

1 807 Human Hydatidosis in the Central Andes of Peru: Evolution of the Disease over 3 Years Pedro L. Moro, Robert H. Gilman, Manuela Verastegui, Caryn Bern, Bernave Silva, and Juan J. Bonilla From the Asociación Benefica Proyectos en Informatica, Salud, Medicina y Agricultura (PRISMA), Lima, Peru; Department of International Health, The Johns Hopkins School of Hygiene & Public Health, Baltimore, Maryland, USA; Department of Pathology, Universidad Peruana Cayetano Heredia, Lima, Peru; Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Department of Radiology, Hospital Nacional Arzobispo Loayza, Lima, Peru; and Policlinico Peruano-Japones, Lima, Peru To document the natural history of Echinococcus granulosus infection and response to treatment of human hydatidosis, we reexamined 28 of 37 subjects with E. granulosus infection diagnosed in an epidemiological study conducted in Twenty-six (70%) of those 37 subjects underwent abdominal ultrasonography, chest radiography, and enzyme-linked immunoelectrotransfer blot assay in Medical records from two additional individuals were reviewed. Eight patients had their cysts surgically removed during the 3-year follow-up interval; no surgical complications or recurrences occurred. Among eight patients with cystic disease not treated by surgery, four had cyst-growth ranging from 0.4 to 1.4 cm during the 3-year interval. One patient developed a new cyst and another s simple cyst became septate; two developed new calcifications. Of 12 seropositive subjects with no cysts present in 1994, 10 reverted to seronegative, a finding that suggests a significant proportion of seropositive subjects in echinococcus-endemic regions may have only transient infection without disease. When cysts do develop, their growth rates and time courses are highly variable; over the 3-year period, we observed growth, septation, degeneration, and calcification of cysts. Received 17 November 1998; revised 13 May Financial support: This study was funded in part by the National Institutes of Health (grant no. U01-A135894, awarded to The Johns Hopkins University), the RG-ER Fund, and Consejo Nacional de Ciencia y Tecnología (CONCYTEC; Lima, Peru). Reprints or correspondence: Prof. Robert H. Gilman, Department of International Health, The Johns Hopkins School of Hygiene and Public Health, 615 Wolfe Street, Baltimore, Maryland (rgilman@jhsph.edu). Clinical Infectious Diseases 1999;29: by the Infectious Diseases Society of America. All rights reserved /99/ $03.00 Human hydatidosis, caused by Echinococcus granulosus, is a major health problem in areas where sheep-raising is widely practiced [1 3]. The advent of portable ultrasonography and the development of an enzyme-linked immunoelectrotransfer blot (EITB) assay to detect infection have facilitated the study of hydatid disease in regions of endemicity in Peru [4]. In 1994, we surveyed 407 residents of the Andean farming cooperative of Tupac Amaru with use of portable ultrasonography, radiography, and the EITB assay. Human hydatid disease was defined by the presence of a cystic image on portable ultrasonography and/or chest radiography. Human hydatid infection was defined by a positive EITB assay without evidence of cysts. In this 1994 study we found the prevalence of human hydatid disease and human hydatid infection to be 9.1%, collectively. Hydatid disease was found in 5.7% (23 of 407) and hydatid infection in 3.4% (14 of 407) [4]. This study and other similar surveys using portable ultrasonography have provided valuable data about prevalence of cystic hydatid disease [5]; however, few studies have attempted to objectively reevaluate human echinococcosis cases detected as part of these surveys [6]. Field-based studies that incorporate serial evaluation of individuals with hydatidosis are important, as they (1) elucidate the natural history of hydatid disease; (2) monitor the response to medical or surgical treatment; (3) record growth rates and changes in morphology of cysts over time; and (4) detect the appearance of new cysts in previously cyst-negative seropositive subjects. To ascertain the status of persons with hydatidosis diagnosed in our 1994 survey, we reexamined these individuals in 1997 and 1998 with use of the same three diagnostic methods of portable ultrasonography, radiography, and the EITB assay. In addition, we reviewed their medical histories to verify findings at the time of surgery for hydatid disease. Materials and Methods Study site and subjects. Tupac Amaru is a farming cooperative in the central Peruvian Andes, 120 km from the city of Huancayo, at altitudes ranging from 3,600 to 4,300 m above sea level. Of the 37 persons who had hydatid infection or hydatid disease diagnosed during the 1994 survey [4], 28 were successfully contacted and asked to participate in the study. The ethical review boards of the Asociación Benefica PRISMA (Lima), the Universidad Peruana Cayetano Heredia (Lima), and The Johns Hopkins University (Baltimore) and the council

2 808 Moro et al. CID 1999;29 (October) of Tupac Amaru approved the study; informed consent was obtained from all participants. Ultrasonographic examination. Subjects were examined in the supine position with use of an Aloka SDL MHz portable ultrasonograph (Aloka, Tokyo, Japan), with liquid paraffin as the transducing medium. Cysts were classified as solitary fluid-filled hepatic cysts (type 1); fluid-filled cysts with membrane detachment (type 2); fluid-filled cysts with septa (daughter cysts) (type 3); lesions with a heterogeneous echographic pattern (type 4); or calcified cysts (type 5) [7]. All examinations took place at the cooperative health post during December EITB assay. An EITB assay that identifies three antigens of 8, 16, and 21 kda was performed on serum samples as previously described [8]. A positive result, indicating hydatid disease, was defined as the presence of any of the above bands. This EITB assay has 10% cross-reactivity with sera of patients with Taenia solium cysticercosis [8]. Chest radiography. Posterior-anterior portable radiographs were obtained at the Hospital Daniel Carrion in Huancayo, Peru, in February Films were read by a radiologist (B. S.) blinded to serological and ultrasonographic findings. Beggs criteria of lung hydatid disease were used for diagnosis of pulmonary hydatidosis [9]. Centrally located, closed, welldefined round images were interpreted as unruptured cysts. Treatment of patients with hydatid disease. All cooperative workers and their dependents are covered by the national health insurance system of Peru, but they must be evaluated first at the local health post before referral to one of the national hospitals for surgery or other treatment. Most patients who had hydatid disease diagnosed were asymptomatic when examined in Only three presented with hepatomegaly. All patients were informed of the findings, as was the national health insurance physician at the local health post. All subjects with active disease were referred to the major hospitals in Oroya or Huancayo City by the physician at the health post. Seven had surgery, while eight declined surgical treatment. Surgical removal of hydatid cysts remains the treatment of choice in Peru. Benzimidazole compounds are used to some extent but have not yet gained widespread acceptance; percutaneous treatment is not yet performed in Peru. Review of hospital charts. Hospital charts of consenting subjects who had had presumptive hydatid disease diagnosed were reviewed. Relevant clinical information such as medical treatment received, surgical findings if a procedure was performed, and other ultrasonographic and chest radiographic examinations were also recorded. Results Of the 37 people with hydatid infection or disease diagnosed in 1994, 26 (70%) underwent ultrasonography, chest radiography, and EITB assay in Two additional participants consented to a review of their medical records but were not reexamined. Table 1. Natural history of hydatid infection detected in 1994 in patients who were reexamined in 1997 (Tupac Amaru, Peru). Case no. Patient s sex/age (y) in 1997 EITB assay Classification 1 M/66 Pos Neg Infected, seroreverted 2 F/9 Pos Neg Infected, seroreverted 3 M/13 Pos Neg Infected, seroreverted 4 F/53 Pos Neg Infected, seroreverted 5 M/35 Pos Neg Infected, seroreverted 6 F/9 Pos Neg Infected, seroreverted 7 F/43 Pos Neg Infected, seroreverted 8 M/12 Pos Neg Infected, seroreverted 9 F/63 Pos Neg Infected, seroreverted 10 F/34 Pos Neg Infected, seroreverted 11 M/12 Pos Pos Infected 12 F/30 Pos Pos Infected NOTE. Radiographic findings were normal in 1994 and 1997 for all 12 of these patients. EITB enzyme-linked immunoelectrotransfer blot assay; F female; M male; neg negative; pos positive; seroreverted reverted to seronegativity for Echinococcus granulosus. Among the 28 individuals on whom we obtained follow-up information, 8 had presumed hydatid cysts in 1994 (7 were asymptomatic and 1 was symptomatic with hepatomegaly) but refused any treatment; 1 had liver and lung cysts and received albendazole treatment; 7 had cysts surgically removed; and 12 were seropositive in 1994 but had no cyst demonstrated by imaging. Twenty persons with hydatid infection or disease diagnosed in our 1994 survey did not receive treatment following diagnosis. Performing follow-up examinations in 1997 allowed us to assess the natural history of infection and disease in this community with highly endemic hydatidosis (tables 1 and 2). Twelve subjects with hydatid infection in 1994 had no evidence of cysts revealed by imaging in 1997 (cases 1 12); 10 of the 12 (83%) had reverted to negative EITB-assay status in In three patients with liver cysts in 1994 (cases 17, 18, and 19), cyst-growth of between 0.4 and 1.4 cm occurred over the 3 years of follow-up. The simple liver cyst seen in case 18 had also developed septa by Four patients with hydatid disease in 1994 demonstrated no evidence of cyst growth upon reexamination in 1997 (cases 13, 14, 15, and 16). Other findings in 1997 consisted of new liver cysts (cases 20 and 28) and a new liver calcification (case 16). Two patients (cases 13 and 14) had the same calcified cysts in 1994 and 1997, and one patient had a viable cyst that remained unchanged in size (case 15). Only one patient (case 28) had both lung and liver cysts. He refused surgical treatment in 1994 but received four cycles of albendazole in 1995 and 1996 (10 mg/[kg d] for 28 days per cycle). Despite medical treatment, his liver cysts had enlarged by 1997, and he had developed a new cyst in the left lung (figure 1).

3 CID 1999;29 (October) Evolution of Human Hydatidosis in Peru 809 Table 2. Natural history of hydatid disease detected in 1994 in patients who were reexamined in 1997 (Tupac Amaru, Peru). Case no. Patient s sex/age (y) in 1997 Radiographic findings (size of lesion, in cm) EITB assay Classification (cyst growth, in cm) 13 M/41 1 L-lung cyst (1.3) 1 Calcified L-lung cyst (1.3) Pos Pos No progression, inactive 14 M/39 1 Calcification in liver, R lobe (0.5) 1 Calcification in liver, R lobe (0.6) Neg Neg No progression, inactive 15* M/19 1 Multilobular liver cyst, L lobe (5.7) 1 Multilobular liver cyst, L lobe (5.7) Pos Pos No progression, active 16 M/29 1 Calcification in liver, R lobe (2.0) 2 Calcifications in liver, R lobe (2.0, Pos Pos Inactive 0.9) 17 F/55 1 Heterogeneous liver cyst, L lobe (4) 1 Heterogeneous liver cyst, L lobe (4.4) Pos Pos Progression (0.4) 18 M/12 1 Simple liver cyst, R lobe (1.4) 1 Liver cyst with septa, R lobe (2) Pos Pos Progression (0.6) 19 M/42 5 Liver cysts, R and L lobes (7, 7, 4, 5 Liver cysts, R and L lobes (8.4, 6, 4, Pos Pos Progression (1.4, 1) 4, 1) 4, 2) 20 M/56 1 Calcification in liver, R lobe (0.9) 1 Calcification in liver, R lobe (0.9); 1 new calcification in liver, R lobe (0.3); 1 new simple liver cyst, L lobe (1.1) Neg Neg Progression (new lesions) NOTE. EITB enzyme-linked immunoelectrotransfer blot; F female; L left; M male; neg negative; pos positive; R right. * Case 15 had surgery after the 1997 examination. Seven patients underwent surgery for hydatid disease: four for liver cysts and three for lung cysts. The diagnosis was confirmed by surgical findings in all seven cases (table 3). Only two of these patients were symptomatic with hepatomegaly when first examined in 1994 (cases 23 and 25). One patient with a lung cyst (case 27) was asymptomatic in 1994 but presented with mild hemoptysis and a productive cough with purulent sputum 2 years later. The patient was referred by the health post physician to a hospital in Huancayo for surgical treatment. Patient 15, although still asymptomatic, had surgical treatment after being reexamined in 1997 (table 2). Two liver hydatid cysts were removed at surgery. Five of the seven who underwent surgery had postoperative imaging examinations in 1997; none had recurrent cysts. Five of the seven patients who had surgery received albendazole treatment before surgery, but only one completed the full course (three 28-day cycles of 10 mg/[kg d]). Among those patients who underwent surgical treatment, preoperation imaging studies accurately predicted the extent of disease. However, ultrasonography did miss an omental cyst (case 15) and a small daughter cyst in each of two other patients (cases 22 and 23). Figure 1. Chest radiographs of a young boy in Peru who had hydatid disease. Left, a radiograph obtained in March 1995 showed a hydatid cyst in the right lung. Right, a radiograph obtained in February 1998 showed calcification of the right-lung hydatid cyst and a new presumptive hydatid cyst in the left lung (arrowhead).

4 810 Moro et al. CID 1999;29 (October) Table 3. Preoperative and postoperative findings in cases in which surgical intervention and/or medical treatment for hydatid disease occurred (Tupac Amaru, Peru). Case no. Patient s sex/age (y) in 1997 Radiographic findings, 1994 (size of lesion, in cm) Medical therapy (with albendazole) EITB assay Mo to surgery Surgical findings (size, in cm) 21 F/46 R-lung cyst (2.5) None Neg ND 4 R hydatid lung cyst (3.0) 22 F/49 Liver cyst, R lobe (5.0) 1 w before and 1 cycle after surgery Neg Neg 2 Hydatid cyst with multiple daughter cysts 23 M/48 1 Liver cyst, R lobe (10); hepatomegaly 24 M/20 Multiple liver cysts, L lobe (7); 7 peritoneal cysts (3) 25 F/35 1 Liver cyst, L lobe (12); hepatomegaly 1 Cycle before and 1 cycle after surgery 3 Cycles before and 1 cycle after surgery 1 Cycle before and 1 cycle after surgery Pos Neg 1.5 Hydatid cyst (10) with multiple daughter cysts Pos Pos 9 Liver cyst, L lobe (10), with multiple daughter cysts; R-lobe cyst (6) Neg Neg 1 Liver cyst, L lobe (14) 26 M/12 R lung cyst (6) 5 d after surgery Neg ND 1 Hydatid lung cyst, R upper lobe (6) 27 M/15 R lung cyst (3.5) 1 w before and Pos Neg 24 Infected R-lung hydatid cyst 3 w after surgery 28 M/12 2 Simple liver cysts, R lobe (3, 2); 1 hydatid cyst, R lung (3) 4 cycles of albendazole; no surgery* Pos Pos... 2 Simple liver cysts, R lobe (6.1; 2.4); 1 calcified cyst, R lung (3); 1 new presumptive hydatid cyst, L lung (1.5) NOTE. EITB enzyme-linked immunoelectrotransfer blot; F female; L left; M male; ND not done; neg negative; pos positive; R right. * Refused surgical treatment. All revealed by ultrasonography and chest radiography in Discussion To our knowledge, this is the first prospective communitybased study of the natural history of hydatid infection and disease with use of serology, chest radiography, and portable ultrasonography. Our data demonstrate that infection with E. granulosus produces a wide spectrum of disease, from seropositivity without demonstrable lesions to multiple-organ involvement with progressive cystic disease. Moreover, when cysts do develop, their growth rates and the time courses of their progression are highly variable. In our case series, some patients had cysts that grew as much as 3 cm in 3 years, while other cysts remained the same size. One cyst altered its morphology from simple to septate, and still others appeared to undergo parasite degeneration and calcification. Our findings lend support to the hypothesis that the course of human hydatidosis is a multistage process, similar to that seen in other cestode infections, such as cysticercosis. The first stage is characterized by exposure to E. granulosus eggs and oncospheres. Growth and proliferation of the parasite characterize the second stage; death of the parasite in the third stage may be spontaneous or medically induced. During the initial exposure to tapeworm eggs, oncospheres may migrate to the liver and/or lung and develop into a hydatid cyst. However, in some hosts, oncosphere infection never advances to the second and third stages, producing only a transient antibody response. This may have occurred in 10 of 12 seropositive subjects without evidence of hydatid disease in 1994 who seroreverted with no evidence of hydatid disease when reexamined in It is also possible that some of these subjects may have developed cysts, undetected by imaging because of their size, that resolved spontaneously. Other field surveys have also observed subjects with antibodies to E. granulosus without evidence of hydatid disease on imaging [5, 10]. The EITB assay is highly specific but has 10% cross-reactivity with patients who have cysticercosis [8]. However, cross-reactivity with T. solium cysticercosis in the study area is unlikely, as the prevalence of cysticercosis in the study area is only 0.2% [3], while the EITB-assay-indicated prevalence of hydatidosis was 2%. The probability of a crossreaction occurring is 1%. In addition, no cross-reactions have been noted when the EITB assay was used in areas of endemic cysticercosis in previous studies [3]. Of the 12 subjects with infection in 1994, all were negative for T. solium antibodies when tested with an EITB assay [4]. Our study suggests that in a community where E. granulosus is endemic, a significant proportion of infected people will never develop hydatid disease. The ability of the parasite to

5 CID 1999;29 (October) Evolution of Human Hydatidosis in Peru 811 cause hydatid disease may depend on the number of challenge infections, the presence of innate and acquired immunity in the host, parasite strain differences, or a combination of these factors. Naturally acquired and artificially induced immunity that blocks the development of hydatid cysts has been demonstrated in sheep [11, 12]. When the infection reaches the second stage, oncospheres successfully implant, grow, and develop into hydatid cysts. Cysts have been reported to grow from 1 to 5 cm per year [13]. However, our study indicates that cyst growth may be much slower than this; in addition, cysts may stop growing altogether and become static or spontaneously degenerate and calcify completely. Our observations are consistent with those of Frider et al. in Argentina, who followed 14 patients with liver hydatid disease over a period of 12 years with use of ultrasonography. Eight of 14 patients had no cyst growth, five had growth of 3 cm, and one had a cyst that enlarged by 4 cm [14]. Similar observations were also reported by Romig et al. with regard to 36 patients harboring 44 cysts. During 18 months of follow-up, variable growth was noted in 29 cysts, 9 remained static, 3 collapsed, and 3 disappeared [15]. This group also reported a greater rate of cyst growth among younger vs. older subjects [15]. The rate of cyst growth may be determined in part by its location; a constrained site will increase the risk of cyst rupture, and lung cysts may be more likely to develop other complications that hasten intervention, such as the secondary bacterial abscess observed in case 27. A rapid rate of growth also may be related to the thinner pericyst wall that surrounds a young developing cyst, in comparison with the thicker wall of an older cyst. Thus, the natural history and clinical course of hydatid disease are quite variable. In addition to enlargement, the natural progression of hydatid disease may include a change in cyst morphology, as in case 18, where a simple cyst became septate during the 3-year period of follow-up. This observation is consistent with the hypothesis that multilobular cysts begin as simple unilocular lesions. After a year follow-up of 16 cysts in 14 patients, Frider et al. [14] reported disappearance of the unilocular pattern (type 1), with some cysts becoming multilocular or calcified. Similar results also have been noted by Caremani et al. [16], who observed a parallel change in cyst morphology in one of 39 untreated patients over a period of 1 9 years. Resolution of hydatid disease may be spontaneous or medically induced. Medical involution has been demonstrated in therapeutic clinical trials of benzimidazole compounds and after percutaneous drainage [16 18]. In contrast, spontaneous resolution of cysts has been more difficult to document. In our 1994 survey, three patients had calcified liver cysts but no history of treatment (cases 14, 16, and 20). In 1997, two cysts observed in 1994 had become calcified (cases 13 and 28), while two other patients had developed new calcifications with antecedent cysts observed (cases 17 and 28). Only case 28 had been medically treated; the other cases demonstrate clearly that degeneration of the parasite and calcification of the cyst may occur spontaneously. Findings similar to ours have also been documented by Romig et al. [15], who observed spontaneous resolution of three of 44 cysts. Caremani et al. [16] observed cyst calcification in two of 39 untreated patients, while 36 patients had calcified cysts that remained unchanged over 9 years of followup. The pattern of degeneration and calcification following parasite death has also been observed in patients with cysticercosis, another tissue cestode infection whose natural history comprises a wide spectrum, from asymptomatic seropositivity to active cystic disease to inactive calcifications [19]. Calcification of hydatid cysts does not always imply degeneration, as some calcified cysts may contain viable protoescolices; however, completely calcified cysts, as observed in this study, indicate dead cysts that are no longer active. In two of three patients who were seropositive in 1994, the postoperative EITB assay was negative, suggesting that the immunologic stimulus had been eliminated. In the past, postsurgical serological follow-up of patients with hydatid disease has been used to detect recurrent cysts that may continue to induce the formation of specific antibodies [20]. Further comprehensive field-based studies in which the EITB assay is used preoperatively and postoperatively for patients with hydatid disease will enable assessment of the assay s ability to detect recurrent cysts. Only through community-based longitudinal studies such as this one can we understand the full spectrum of disease attributable to hydatidosis. Our study confirms that a large proportion of infected individuals have no demonstrable disease. Among those with demonstrable lesions followed over time, the course of hydatid disease includes parasite degeneration and calcification, static but viable cysts, disease progression with highly variable growth rates, and changes in cyst morphology. Acknowledgments The authors thank Drs. R. Black, P. M. Schantz, H. H. Garcia, N. Perez-Palma, R. Lavarello, and D. Bonifacio for helpful comments; Ms. J. Moro for technical assistance; and Ms. J. B. Phu and Ms. D. Sara for editorial assistance. References 1. Schwabe CW. 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