Schistosomiasis - An Unusual Cause of Ureteral Obstruction

Abstract

A male, 32 years of age, presented with dysuria and abdominal pain, but no gross hematuria. He emigrated three years earlier from Somalia, East Africa, and was currently employed as a poultry processor in a rural Wisconsin community. The patient denied any trauma, sexual activity, or family history of significant illness. Abdominal and genitourinary exams were normal with negative tests for gonococcus and chlamydia. Urinalysis demonstrated microhematuria. A urogram and retrograde pyelogram revealed a mildly dilated right ureter down to the ureterovesical junction. Cystoscopy showed punctate white lesions on the bladder urothelium. Ureteroscopy was used to biopsy abnormal tissue in the distal ureter and bladder. Biopsy tissue demonstrated deposits of Schistosoma haematobium eggs. No ova were seen in collected urine specimens. The patient was successfully treated with praziquantel and will be monitored for sequelae of the disease.

Schistosomiasis (Bilharziasis) can be expected to be seen with increasing frequency in the United States with the continuing influx of immigrants and refugees, as well as the return of travelers and soldiers from endemic areas. While no intermediate snail host exists for the transmission of Schistosoma sp. in the United States, the continued importation of exotic animals including snails from Africa, as well as the ability of schistosomes to shift host species warrants concern. Additionally, increasing disease associated with non-human bird schistosomes of the same genus seen in the midwestern United States is occurring throughout Europe. One should be aware that praziquantel may not always be available or effective in the treatment of schistosomiasis. It behooves the practicing clinician to remain updated on the status of this widespread zoonosis.

INTRODUCTION

The population demographics of the United States are changing. As an example, the population of political refugees within Wisconsin has risen from 30,000 in 1990 to more than 60,000 in 2002 and continues to increase.¹ Most of these refugees originate from Southeast Asia, Eastern Europe, and Africa.

We present the case of a ureteral obstruction in a Somalian refugee caused by a disease entity not commonly seen in the American Midwest. The case serves to emphasize the importance of knowledge of tropical medicine, even in the northern tier of the United States.

CASE REPORT

A male, 32 years of age, presented with dysuria and abdominal pain. He had no other gastrointestinal symptoms. There had been no gross hematuria. The patient denied any trauma or sexual activity. The patient had been treated at another clinic with Rocephin^® and oral antibiotics. Review of symptoms was negative for any ophthalmic or rheumatologic complaints. Family history was negative for any significant illnesses. The patient was a non-smoker and had been working at a poultry processing plant since emigrating from Somalia 3 years ago. Physical exam revealed a healthy male. Abdominal and genitourinary exam were normal.

Urinalysis demonstrated 6 to 10 WBCs, trace leukocyte esterase, microhematuria, and negative nitrates. A urine culture was negative. Polymerase chain reaction (PCR) testing was negative for gonococcus and chlamydia. Because of the microscopic hematuria, an intravenous urogram was obtained. Pertinent findings include a mildly dilated right ureter down to the ureterovesical junction (figure 1). A cystoscopic examination showed that the bladder urothelium was dotted with punctate white lesions. A retrograde pyelogram demonstrated irregularity in the distal 2 cm of the right ureter (figure 2). Ureteroscopy showed irregular, heaped-up tissue in the distal ureter. This tissue, as well as the abnormal tissue in the bladder, was biopsied. Pathologic examination of the biopsy tissue showed classic bilharzial ova (figure 3). Collected urine was not found to have any ova.

Figure 1.

An intravenous urogram displays a mildly dilated right ureter (arrow) down to the ureterovesical junction.

Figure 2.

Retrograde pyelogram demonstrating irregularity in the distal 2 cm of the right ureter.

Figure 3.

Histopathology of the abnormal urinary tract tissue obtained on ureteroscopy reveals Schistosoma haematobium eggs with their characteristic terminal spine (arrow).

The patient was treated with praziquantel 20 mg/kg every 6 hours for 1 day. He vomited with the first course of praziquantel, losing some of the dose, so the course was repeated. Approximately one month later symptoms of right lower quadrant and flank pain had returned with sweating, urinary frequency, and occasional urgency, likely the result of infection and/or recurrence of ureteral stenosis that will require further management after assessment by intravenous urogram. He is also being monitored for sequelae of this disease.

A follow-up intravenous pyelogram was performed six months after initial presentation and treatment. No evidence of obstruction or filling defect was noted.

DISCUSSION

Incidence

Schistosoma sp. infect 250 million people worldwide.² Schistosomiasis (also called Bilharziasis after the German tropical disease specialist, Theodore M. Bilharz, 1829–1862) is second only to malaria in parasitic disease morbidity. Approximately 500 to 600 million people in tropical and subtropical countries are at risk, and of those infected, 120 million are symptomatic with 20 million having severe manifestations.³ Schistosomiasis is endemic in many countries, not only in sub-Saharan Africa, but the far East, South and Central America, and the Caribbean.

Endemic distribution

Ten species of schistosomes can infect humans, but a vast majority of infections are caused by Schistosoma mansoni, S. japonicum, and S. haematobium.⁴ Of all people suffering from schistosomiasis, 85% live in sub-Saharan Africa where S. mansoni, S. haematobium, and S. intercalatum are endemic.^5,6 S. mansoni, S. intercalatum, and S. japonicum largely cause hepatobiliary and gastrointestinal symptoms, while S. haematobium causes urogenital symptoms.

Bilharziasis is endemic throughout Africa, but its distribution is focal and constantly shifting as open irrigation canals spread.^7–9 The Bill and Melinda Gates Foundation is funding a 4-year schistosomiasis control initiative in Uganda, Tanzania, Zambia, Mali, Burkina Faso, and Niger during which 15 million people will be treated.¹⁰

As recently as 2000, an article published in the New England Journal of Medicine stated that schistosomiasis, particularly S. haematobium, is not thought to occur in Somalia.¹¹ However, review of the tropical medicine literature reveals that S. haematobium is endemic to Somalia and presents a long-standing health problem there.^9,12–19

Shifting demographics

In the United States, it is estimated that at least 400,000 individuals are infected. Most of these are immigrants, but travelers including military, expatriates, and civilian contractors have been infected as well.^20–31 Southern Iraq is an area endemic for S. haematobium, and it may be expected that returning military personnel, while stationed there, may have contracted infections upon exposure to fresh water.^27,32–35

Within the past decade, the United States has seen a large influx of refugees from Somalia as a consequence of continuing civil war.^36,37 Minneapolis, Minnesota, is believed to have the largest Somali immigrant population in the United States with between 6,000 and 30,000 people from that nation, most of whom arrived within the last 12 years.³⁸ Initially placed by religious aid agencies, Minnesota's draw has been through available jobs and low housing costs. In Somali refugee camps worldwide, the word “Minneapolis” has come to symbolize a shot at the American dream. Somalis who first located elsewhere in the United States moved to the state because of the growing community there, the decent cost of living, and good job opportunities.

Lately, the slowing economy and housing shortages are driving some of these refugees to Columbus, Ohio, which is believed to have the second largest Somali immigrant population in the country, estimated at 15,000. In Milwaukee, there is a Somalian community of between 250 and 500 people. In Barron, Wisconsin, population of 3,000, more than 300 Somalian immigrants have settled to work year-round at a turkey processing plant.^39,40 Further increases in this population can be expected as the United States opens its borders to close relatives of those already here.⁴¹ Along with the influx of people, the manifestation of diseases endemic to that part of the world can be expected to be seen in the United States.

Life cycle

The life cycle and pathophysiology of S. haematobium has been reviewed extensively in the literature.⁴² Briefly, when eggs are excreted into fresh water, they hatch to release motile, ciliated miracidia (embryos) that penetrate aquatic bulinid snails, the intermediate host. Cercaria (larvae) emerge from the snails and penetrate the skin of humans in contact with the water (figure 4). The cercariae migrate to the lungs and liver, and after 6 weeks, the mature worms mate and migrate into the pelvic veins to begin oviposition. The eggs penetrate small, thin-walled vessels in the genitourinary system. During the active phase viable adult worms deposit eggs that induce a granulomatous response with the formation of polypoid lesions. During this phase eggs are excreted. An inactive phase follows the death of the adult worms.²¹ No viable eggs are present in the urine, and large numbers of calcified eggs are present in the wall of the bladder and other affected tissues. As fibrosis progresses, polypoid patches flatten into finely granular patches.⁴³

Figure 4.

Eggs are eliminated with feces or urine 1. Under optimal conditions the eggs hatch and release miracidia 2, which swim and penetrate specific snail intermediate hosts 3. The stages in the snail include 2 generations of sporocysts 4 and the production of cercariae 5. Upon release from the snail, the infective cercariae swim, penetrate the skin of the human host 6, and shed their forked tail, becoming schistosomulae 7. The schistosomulae migrate through several tissues and stages to their residence in the veins (8, 9). Adult worms in humans reside in the mesenteric venules in various locations, which at times seem to be specific for each species 10. For instance, S. japonicum is more frequently found in the superior mesenteric veins draining the small intestine A, and S. mansoni occurs more often in the superior mesenteric veins draining the large intestine B. However, both species can occupy either location, and they are capable of moving between sites, so it is not possible to state unequivocally that one species only occurs in one location. S. haematobium most often occurs in the venous plexus of bladder C, but it can also be found in the rectal venules. The females (size 7 to 20 mm; males slightly smaller) deposit eggs in the small venules of the portal and perivesical systems. The eggs are moved progressively toward the lumen of the intestine (S. mansoni and S. japonicum) and of the bladder and ureters (S. haematobium), and are eliminated with feces or urine, respectively 1. Pathology of S. mansoni and S. japonicum schistosomiasis includes: Katayama fever, hepatic perisinusoidal egg granulomas, Symmers' pipe stem periportal fibrosis, portal hypertension, and occasional embolic egg granulomas in the brain or spinal cord. Pathology of S. haematobium schistosomiasis includes: hematuria, scarring, calcification, squamous cell carcinoma, and occasional embolic egg granulomas in brain or spinal cord.

Human contact with water is thus necessary for infection by schistosomes. Various animals, such as dogs, cats, rodents, pigs, horse and goats, serve as reservoirs for S. japonicum, and dogs for S. mekongi.

Geographic Distribution:

Schistosoma mansoni is found in parts of South America and the Caribbean, Africa, and the Middle East; S. haematobium in Africa and the Middle East; and S. japonicum in the Far East. Schistosoma mekongi and S. intercalatum are found focally in Southeast Asia and central West Africa, respectively.

(Figure provided by Alexander J. da Silva and Melanie Moser for copyright-free dissemination through the Public Health Image Library of the Centers for Disease Control and Prevention. Legend obtained through the Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention.)

Symptomatic effects

A very vivid description of the symptomatic effects of S. haematobium infection was provided in an early case report. In 1944, Dr. Claude H. Barlow infected himself with schistosomiasis in order to bring viable eggs to Johns Hopkins University for study. He reported the consequences of his voluntary infection with S. haematobium in 1949.⁴⁴ His intense suffering is well described. In the early stages of infection, cough, headache, loss of appetite, various aches and pains, and often difficulty in breathing followed the initial skin irritation. In more advanced infection, nausea was common, accompanied by hematuria and in some cases renal obstruction.

Clinical findings of hematuria, leukocyturia, urinary tract complaints, tender abdomen, and supra-pubic tenderness are associated with S. haematobium infections,⁴⁵ but the clinical outcome of infection is variable, ranging from mild symptoms to chronic iron deficiency and anemia, to scarring and deformity of the ureters and bladder, to chronic bacterial superinfection, to severe damage of urinary tract organs, and ultimately to renal failure.^46–50

Duration of infection

After maturing, schistosome worm pairs live in their definitive host venous system and engage in egg-laying for many years, even decades.^51,52 This means that patients may present with symptoms years after having immigrated from or visited endemic regions.²¹ The eggs, rather than the adult worms, play a crucial role in the pathogenesis of schistosome infection.

Ureteral involvement

Obstructive uropathy is the most common and dangerous complication of S. haematobium infection of the interstitial and juxtavesicular portions of the ureter.^{21,24,53–56} Chronic renal failure and immune-complex-mediated glomerulonephritis may result.^57–59 The urinary collecting system, the ureters, bladder, seminal vesicles, prostate gland, urethra, vas deferens, and testes may become involved.^60,61

In the ureter, mostly the lower portion is affected because of the blood supply anatomy. Eggs are found in all layers of the ureter, and cause mural fibrosis, loss of the muscle layer, and fibrosis. Stricture may occur.

Acute symptoms may include renal colic with pyelonephritis and hydronephrosis.⁶² Long-standing obstruction may present with silent obstruction or anuria. Most cases of ureteral involvement also have bladder involvement.

Diagnosis

Diagnosis of urinary tract schistosomiasis is based on history and clinical suspicion followed by laboratory studies. These may include the enzyme-linked immunosorbent assay (ELISA), serum antigens, and demonstration of ova in the urine. Many cases are diagnosed by endoscopy and biopsy.

Traditionally for S. haematobium, microscopic examination of urine and seminal fluids reveal eggs with characteristic species-specific morphology.^11,44,63,64 For best results, urine collections should be made between 10:00 am and 2:00 pm to ensure maximum yield.⁶⁵ Another way to increase yield of eggs in the urine is to have the patient go for a short run or walk just before the urine is passed to facilitate the shedding of the eggs from the bladder mucosa.²⁹ Samples may be centrifuged or filtered on membranes to enhance the chances of finding eggs.^66–68

Detection of eggs in stool samples is typically used in the diagnosis of S. mansoni,⁶⁹ but S. haematobium eggs may also occasionally be found in the stool. Egg production can be low and sporadic so the risk of missing the diagnosis by egg detection alone is high.⁴⁵

Ultrasonography has been used as a diagnostic technique for assessment of urinary tract morbidity.^{49,50,70–73} Bladder pathology can include thickening, the presence of polyps, or the existence of masses protruding into the lumen. Kidney dilation may occur unilaterally or bilaterally. Urograms can reveal filling defects.²²

Cystoscopic examination generally reveals masses and/or punctuate white calcifications without ulceration or necrosis. Similar lesions are seen in the uterus upon pelviscopic examination when the reproductive tract is involved.²¹ Urinary eosinophil cationic protein has been shown to correlate well with the extent of bladder pathology in S. haematobium infections.⁷⁴

Immunodiagnostic assays have been developed to detect circulating antibodies to semi-purified or fractionated antigens^75–81 and parasite circulating antigens in different host body fluids.^82–88 Falcon assay screening test (FAST)-ELISA and immunoblot assays for specific antibodies to S. mansoni and S. haematobium adult worm microsomal antigens are highly specific for both species.^89,90 However, positive results in antibody assays do not necessarily correlate with the worm burden, as measured by egg output. Also, it is not possible to distinguish previous exposure from current infections or reinfections.^45,91–93 A PCR method has been developed as a highly sensitive and specific technique to detect Schistosoma sp. DNA.⁹⁴

Medical treatment

Until the late 1970s, fouadin, a trivalent antimony preparation, and potassium antimony tartrate were the only treatments available, and the cure involved suffering more intense than that caused by the disease.⁴⁴ Metrifonate (Trichlorfon: CASRN: 52-68-6) has been used for the treatment of S. haematobium,^15,16,95 but it has some severe human neurological side effects.⁹⁶

Currently, medical management of bilharziasis relies on praziquantel, sometimes in combination with oxamniquine. Praziquantel (Biltricide^®, Bayer AG, Germany) a heterocyclic prazino-isoquinoline, is highly effective against all species of schistosomes pathogenic to humans.^97,98 However, since its first use, praziquantel treatment has been noted not to be 100% effective in eliminating S. haematobium infection.⁹⁹ In adult schistosomes, praziquantel induces vesication, vacuolization, and disintegration of the tegument.^100–104 It also causes mature schistosome eggs to hatch.^105,106 Immature eggs remain unaffected and continue to develop to maturity.¹⁰⁷ In longitudinal studies, bladder wall pathology and hydronephrosis have been found to regress upon treatment, especially in active phases of the infection.^24,108,109 However, if chronic stricture of the ureters has occurred, no significant reduction of the renal collecting system may result.¹¹⁰ In such a case, surgical intervention including mechanical dilation, resection, re-implantation, formation of an ileal ureter, and even nephroureterectomy may be required.²⁴

Drug availability

It behooves the medical community to keep the continuing needs for such drugs in their collective consciousness. Not long ago, Bayer Corporation Pharmaceutical Division had decided to withdraw praziquantel from the United States market for lack of sales. A campaign of letters, faxed messages, and telephone calls from members of the American Society of Tropical Medicine and Hygiene, the International Society of Travel Medicine, and the Infectious Disease Society of America served to increase the corporate awareness of the unique role for this drug in the treatment of immigrants, refugees, and returned travelers.¹¹¹ As a consequence, Bayer reversed its earlier discontinuation decision, and therefore praziquantel was available for treatment of the present case. With the vagaries of the current climate of global drug import, export and reimport, it is difficult to predict, however, whether this will always be the case.^112–114

Drug resistance

Another concern with respect to the future of praziquantel treatment is the ever-present worry over the emergence of drug resistance.¹¹⁵ Praziquantel has been in use for almost 25 years, during which time it has been the drug of choice for many human and veterinary parasitic infections worldwide.^116–118 The European Commission has established an International Initiative on Praziquantel Use to review reports of low efficacy in clinical trials in Senegal and Egypt, and reports of resistant S. mansoni strains isolated in the laboratory.^{115,119–129} While investigations suggest that no emergence of praziquantel resistance in S. haematobium has yet occurred, mathematical models predict that such resistance can be expected to occur as soon as 2010.¹³⁰ As a consequence new drugs are being actively investigated.^131,132

Adverse reactions

In healthy, uninfected humans, clinical trials showed no clinically relevant drug-related changes.^133,134 However, in humans infected with S. mansoni or S. japonicum, abdominal pain, nausea, vomiting, anorexia, diarrhea, and bloody stools have been reported.^135–138 These symptoms occur immediately after treatment and are correlated with the intensity of infection, suggesting an anaphylactic response due to parasite and egg antigens released in response to praziquantel.

In S. japonicum-infected mice, intestinal mast cells infiltrate into the intestine. When praziquantel is administered by injection, mature eggs hatch and the mast cells are activated to release histamine and other biogenic amines. This mast cell response plays a pivotal role in the pathogenesis of post-praziquantel anaphylactic signs. Additionally, antigenic components from the hatched eggs, rather than from adult worms play a major role as allergens in the pathogenesis of adverse effects in praziquantel-treated mice.¹³⁹

Severe symptoms occur more frequently in patients given high dosages of praziquantel than in those given relatively low, divided dosages.¹³⁷ Thus, while single doses are more convenient, treatment with two or more praziquantel administrations, each at a low dosage, may reduce antigen release, and has been suggested as a way to minimize the occurrence of severe adverse effects.¹³⁹

Vaccines

No effective vaccine is yet available against any of the Schistosoma species. However, this may soon change. The Schistosoma Genome Project, created in 1992, has begun to yield comprehensive understanding of the molecular mechanism involved in schistosome nutrition and metabolism, host-dependent development and maturation, immune evasion, and invertebrate evolution.^2,140 New potential vaccine candidates and drug targets are emerging.^141–146

Co-infection

It is also important to be aware that persons infected with S. haematobium can be simultaneously infected with S. mansoni and other geohelminths.^50,147–149 Evidence also suggests that the type 2 immunological response (interleukin (IL)-4 and IL-5) induced by S. haematobium may weaken the type 1 response (interferon-γ) making individuals more susceptible to mycobacterial infections.¹⁵⁰

Other potential sequelae

Secondary bacterial infection is common in schistosomiasis.¹⁵¹ S. haematobium infections can not only affect the urinary tract, but also other organs of the pelvic floor, especially the reproductive organs, including the prostate and scrotum,⁴⁴ and the uterus and fallopian tubes, which can lead to infertility.^21,152–155 The vulva, vagina, and cervix are affected more commonly than the internal pelvic organs.¹⁵⁶ Genital schistosomiasis may increase the risk of human immunodeficiency virus (HIV) and human papillomavirus (HPV) infection.¹⁵⁷ S. haematobium can also rarely infect the pericardium, central nervous system, synovium, adrenal gland, thyroid gland and other organs.^24,54,158 S. haematobium infection has been associated with squamous cell carcinoma, the only form of bladder cancer with a parasitologic etiology.^159–163

Potential threats to public health in the United States The intermediate host for S. haematobium is the aquatic snail Bulinus abyssinicus. Human transmission of S. haematobium to countries where other susceptible bulinid snails occur is of concern.¹⁶⁴ B. abyssinicus is not present in the United States. Studies have long been undertaken to determine the potential of snails endemic to the United States to transmit schistosomes, and none have thus far proven capable of serving as a vector.^44,165,166 However, it is evident that snail host shifts have played a role in the Schistosoma evolution, so the possibility of an emerging competent schistosome/snail host combination in the United States, while negligible, is present.¹⁶⁷

There is a North American schistosome of which one should be aware, however, and that is the bird schistosome (Trichobilharzia ocellata = T. szidati) that causes cercarial dermatitis (swimmer's itch).^168–170 This causes initial symptoms very similar to Schistosoma sp. infections when the worm enters the skin. Thus far it is found primarily in the upper Midwest, but has also been found in other regions of the United States.¹⁷¹ The transmission of human zoonoses via migratory birds is a growing concern in this area.¹⁷²

The related schistosomes, T. franki and T. regent, are now also spreading via bird vectors throughout Europe and are becoming an emerging zoonoses there.^173–175 In some cases, it causes fever, respiratory and digestive allergic symptoms. Great concern is being expressed over the possibility of central nervous system involvement as well.^176–179 Rodents are being found to be capable intermediate hosts and might be expected to be capable hosts of T. ocellata (T. szidati) in the United States as well.

Another concern is not only the importation of the schistosome from immigrants and travelers, but also the importation of African snails into the country. Recent events have vividly demonstrated that the importation of African plants and animals into this country have caused public health and agricultural concerns in the Midwest, as exemplified by the monkeypox outbreak resulting from the importation of the Giant Gambian Rat in 2003 and giant African snails in 2004.^180–182

Helminthic infections, dengue, leishmaniasis, African trypanosomiasis, malaria, diarrheal diseases, and tuberculosis are reemerging in Africa due to inadequate intervention and control strategies.¹⁸³ All of these need to be considered as potential diseases in African immigrants and travelers.

Another large immigrant population in Wisconsin are the Hmong from Laos.^184,185 Nearly 20,000 Hmong immigrated to Wisconsin in the 1970s.¹⁸⁶ A schistosome similar to S. japonicum, but endemic to a defined area of the Mekong River in Laos and Cambodia is S. mekongi, and it has been reported among the Hmong.^187,188 It is characteristically associated with hepatosplenic disease, but has also been reported to involve the brain.¹⁸⁹

CONCLUSION

While the Centers for Disease Control is developing a strategy for better health assessments of refugees from areas rife with endemic parasitic diseases of public health significance, the chronic nature of schistosomiasis makes it difficult to catch and treat all cases.¹⁹ This means that all practitioners, but especially those in communities with large and growing immigrant populations, need to increase awareness of these diseases. Bilharziasis, although a common disease, is rarely seen in Wisconsin. The diagnosis is straight forward, if suspected, and effective, safe treatment exists at the present time.