# Blood Flukes and Arterial Damage: A Review of Aneurysm Cases in Patients with Schistosomiasis

Authors: Valeria Silvestri; Vivian Mushi; Mwanahawa Idavas Mshana; Witness M. Bonaventura; Nyanda C. Justine; Deodatus Sabas; Billy Ngasala
Journal: Canadian Journal of Infectious Diseases and Medical Microbiology
 (2022)

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## Abstract

Introduction. Schistosomiasis, caused by trematode worms of the genus Schistosoma, has organ-specific morbidity due to host’s inflammatory response to the oviposition of parasite eggs in vessels and organs. Damage to the cardiovascular system, including aneurysms, has been described in patients. Aims and Methods. Aims of the review of case reports and series published in literature were to describe the occurrence of aneurysm in patients with schistosomiasis. Investigation Outcomes. A total of 13 cases (seven males and six females) with a mean age of 41.3 ± 14.9 years were included. Aneurysm occurred in patients with active or previous infection. In more than half of the cases, an intestinal or hepato-splenic involvement was reported, followed by pulmonary schistosomiasis and urinary or testicular involvement. The most frequently involved arterial district was the pulmonary artery. Immunomodulation and thrombophilia were featuring challenging surgery. Conclusions. More studies are needed to shed light on the vascular complications of schistosomiasis, to ascertain the true burden of aneurysms in patients with schistosomiasis, to establish the pathophysiology of vessel damage and aneurysm formation, and to assess if there is an association between schistosomiasis and aneurysm formation in line with WHO 2021–2030 NTD Roadmap.


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## Body

## 1. Introduction

Schistosomiasis is an infection caused by trematode worms of the genusSchistosoma, which have different geographical distribution [1, 2] as follows: Schistosoma haematobium is endemic in sub-Saharan Africa and Middle East, S. mansoni is endemic in sub-Saharan Africa, South America, and Caribbean’s, and S. japonicum is endemic in People’s Republic of China, Philippines, and Indonesia [1].Globally, over 250 million people are infected worldwide, 201.5 million of them living in Africa, particularly sub-Saharan Africa [3].Infection in humans occurs by contact with fresh water contaminated by free-swimming cercariae that penetrate the intact human skin and enter venous and lymphatic small vessels. A symptomatic acute stage occurs two weeks to three months after exposure [1], and it is caused by systemic hypersensitivity reactions and formation of immune complexes in response to antigens released during schistosomula migration [1]. In the following stage of infection, oviposition by mature adult worms occurs [1]. Eggs reach the lumen of intestine and genitourinary tract via the characteristic spines or through the induction of an inflammatory granulomatous response, triggered by antigenic glycoproteins. In the chronic stages of the disease, eggs that are not excreted can be trapped into granulomas in tissues and can lead to different organ damage according to the infecting Schistosoma spp and its specific preferred sites (intestinal, hepato-splenic, and genito-urinary, but also ectopic sites such as spleen, lungs, skin, and central nervous system) [1, 4, 5].Aneurysms are diagnosed when an increase in abdominal aortic diameter ≥30 mm on ultrasonography or CT imaging is observed [6]. Abdominal aortic aneurysm prevalence in general population is 1-2%. The main complication of aneurysms is rupture; its risk amounts to 30% a year, and it is diameter dependent. Aortic rupture leads to 150,000–200,000 death each year worldwide [6]. Aneurysms have been described in patients with other diseases of parasitological interest, such as amoebiasis [7] or hydatidosis [8, 9]. Cardiovascular system damage has been reported also in Schistosoma infection in the form of cerebrovascular events leading to stroke [10] or aneurysm involvement of several arterial districts [11–19].


## 2. Aims and Methods

This study aimed to describe, through a review of cases in the literature, the occurrence of aneurysm lesions in patients with schistosomiasis.


### 2.1. Search Strategy and Inclusion and Exclusion Criteria

PubMed, Scopus, and Embase were searched, using “Schistosomiasis” OR “Bilharziasis” AND “aneurysm” as keywords. A filter for the English language was applied. Only cases with available full text and data on age, sex, and aneurysm localization were included. We excluded reports that provided aggregated data. A flow chart on the research strategy has been provided in Figure1.Figure 1
Review process flow-chart.


### 2.2. Quality Assessment

Case reports are assessed by making an overall judgement about methodological quality defining the availability of the whole investigator’s experience such as if authors provided clear information on exposure toSchistosoma; if a clear report of patient’s outcome, differential diagnosis, description of challenges; dose-response effect description for treatment, sufficient length of follow-up, details to allow inference-making were provided [20].


### 2.3. Data Analysis

The data were analyzed using the computer software JASP, version 0.14.1. Descriptive statistics (mean, standard deviation, median, and 25th–75th percentile) were used to present continuous variables. Percentages and frequencies were generated for categorical variables. The association statistical test was not performed, given the dis-homogeneity of reports.


## 2.1. Search Strategy and Inclusion and Exclusion Criteria

PubMed, Scopus, and Embase were searched, using “Schistosomiasis” OR “Bilharziasis” AND “aneurysm” as keywords. A filter for the English language was applied. Only cases with available full text and data on age, sex, and aneurysm localization were included. We excluded reports that provided aggregated data. A flow chart on the research strategy has been provided in Figure1.Figure 1
Review process flow-chart.


## 2.2. Quality Assessment

Case reports are assessed by making an overall judgement about methodological quality defining the availability of the whole investigator’s experience such as if authors provided clear information on exposure toSchistosoma; if a clear report of patient’s outcome, differential diagnosis, description of challenges; dose-response effect description for treatment, sufficient length of follow-up, details to allow inference-making were provided [20].


## 2.3. Data Analysis

The data were analyzed using the computer software JASP, version 0.14.1. Descriptive statistics (mean, standard deviation, median, and 25th–75th percentile) were used to present continuous variables. Percentages and frequencies were generated for categorical variables. The association statistical test was not performed, given the dis-homogeneity of reports.


## 3. Investigation Outcomes

### 3.1. Selection Process

A total of 23 cases were retrieved thorough review of the literature. Six cases from a case series of pulmonary aneurysms were excluded because data were reported as aggregated [21]. Four spleen aneurysm cases were excluded because unavailability of the article, not even by contact of the first author, additionally to the language filter applied. The flow chart of the review process has been provided in Figure 1. The median value of Murad case quality score was 2/8 with a minimum of 2 and a maximum of 7.


### 3.2. Summary of Cases

A total of thirteen cases were included in the review. Cases are summarised in Tables1 and 2, and findings are summarised in Tables 3 and 4.Table 1
Summary of cases.
NAuthor, yearAge, sexGeographic regionSchistosoma speciesComorbidities and c.v. risk factors in anamnesisSchistosomiasis detailsClinical presentationVascular findingsPharmacological treatment of schistosomiasis1Salah, 199727, MEgyptn.a.SmokePrevious urinary andintestinal schistosomiasis, normal lung parenchimaCardio-vocal Ortner’s syndrome; exertional dyspnoea (2 months), pulmonary hypertensionPulmonary artery-aneurysmand schistosomal, cor pulmonalePrevious treatment with praziquantel for intestinal and urinary schistosomiasis2Vanker, 198619, FSouth-AfricaSchistosoma mansoni (stool and rectal mucosa)NonePulmonary shistosomiasisHaemoptysis; left chest pain, hoarseness, absent left brachial pulse (1 month), haematuriaAortic arch pseudoaneurysm (7 x 2 cm)Not reported3Mucenic, 200245, MLived for 17 years inSchistosoma endemic areaNegative (stool and rectal biopsy)No otherPrevious hepatosplenic schistosomiasis (hematemesis, enterorrhagia, oesophageal varices)Abdominal continuous pain (left hypochondrium)Right portal branch aneurysm (5 x 4 x 4 cm)No previous treatment with praziquantel4Lambertucci, 201066, FBraziln.a.No otherChronic hepato-splenic schistosomiasis (esophago-gastric varices; hematemesis)Routine assessment for hepato-splenic schistosomiasisSaccular aneurysm of the splenic artery; intrahepatic shunt between right portal branch and right hepatic veinBeta-blockers as gastroenteric haemorrhage prophylaxis5Piveta, 201241, FBraziln.a.Alcoholic hepatitis waiting for liver transplantHepato-splenic schistosomiasisIntermittent chest pain; pulmonary hypertension; intrapulmonary shuntPulmonary a. aneurysm (8.3 cm)Not reported6Genzini, 201448, MBraziln.a.Hypertension, thrombo-cytopeniaAdvanced hepatosplenic schistosomiasisRight lumbar painRight renal artery aneurysm 2.5 cmNot reported7Ramadan, 201555, MLower-EgyptSchistosoma mansoni (lung biopsy)Ex-smokerHistory of intestinal and hepato-splenic schistosomiasis. Pulmonary granuloma, positive serologyS. mansoniDyspnoea (one month); fever (2 months) cough and mucoid sputum (10 days) left atrial compression; pleural effusionRight pulmonary artery aneurysm (17 x 11 cm)Previous treatment for intestinal schistosomiasis (20 years previously). Anticoagulation8Abdelnaby, 201850, FEgyptn.a.n.a.Bilharziasis since early childhoodChest pain (recurrent); exertional dyspnoeaRight and left pulmonary a. aneurysm (6.5 cm) and atrial mural thrombusAnticoagulation9Athanazio, 2018n.a., MBrazilSchistosoma mansoni (lung, testis, liver, and large bowl)n.a.Testicular, intestinal and lung schistosomiasisSpontaneous aorto-cutaneous fistulaThoraco-abdominal aortic aneurysm; spontaneous aorto-cutaneous fistulan.a.10Gavilanes, 201838, MBraziln.a.n.a.Chronic schistosomiasis, pulmonary artery hypertensionPalpitations; dyspnoea; exertional syncopeGiant pulmonary artery aneurysm; aorta and left coronary artery compressionn.a.11De Oliveira, 201948, MBraziln.a.Type A aortic dissection ascending aorta substitution (dacron); biological valveHepato-splenic schistosomiasisFeverPorphyromonas pogonae sepsisAortic graft infection and aortic ruptureAntibiotics for associated bacteria12Dyer, 202018, FAustraliaSchistosoma Ag EIAn.aSerology positive for schistosomiasisFever; right upper quadrant pain; liver abscessFasciola hepatica infestationHepatic artery pseudoaneurysm; acute bleeding from the ampulla of VaterPraziquantel13Abdelnaby, 202038, FEgyptn.a.History of bilharziasDyspnoea (5 years) and hoarseness (1 year)Pulmonary artery aneurysm (PAA) with dilatation of both branches and hoarsenessAnticoagulationAnagraphic details, geographic region of patient’s origin/residency, schistosomiasis details, clinical presentation, vascular findings, and pharmacological management are included. M = male; F = female; Ag EIA = antigen enzyme-linked immunosorbent essay; n.a = not available; c.v. = cardiovascular. The most frequently involved arterial district was the pulmonary artery, followed by aortic lesions which included one recurrent lesion on previous aortic surgery and abdominal visceral vessels aneurysms (specifically in splenic, hepatic artery, right portal branch, and renal artery).Table 2
Surgical treatment and outcome of patients.
NAuthor, yearAge, sexVascular findingsSurgical treatmentOutcome2Vanker, 198619, FAortic arch pseudoaneurysm (7 x 2 cm)Aneurysmectomy and direct sutureUnknown3Mucenic, 200245, MRight portal branch aneurysm (5 x 4 x 4 cm)SplenectomyPartial portal vein thrombosis. Alive (reduction of aneurysm size to 1.4 cm and resolution of the vessel thrombosis on follow up)4Lambertucci, 201066, FSaccular aneurysm of the splenic artery; intrahepatic shunt between right portal branch-and right hepatic veinRefused surgery treated with beta-blockersUnknown5Piveta, 201241, FPulmonary artery aneurysm (8.3 cm)Exitus waiting for surgeryExitus (aneurysm rupture and cardiac tamponade)6Genzini, 201448, MRight renal artery aneurysm 2.5 cmNephrectomy, aneurysmectomy and renal reimplantationAlive (creatinine improvement on follow-up)7Ramadan, 201555, MRight pulmonary artery aneurysm (17 x 11 cm)Refused surgery on anticoagulationExitus (massive pulmonary embolization, notwithstanding anti-coagulant therapy)11De Oliveira, 201948, MAortic graft infection and aortic ruptureNot-specified reintervention on previous aortic graft on antibiotic therapyExitus (complications of surgery on 12th day post-operatory, likely due to comorbidities related to hepato-splenic schistosomiasis)12Dyer, 202018, FHepatic artery pseudoaneurysm; acute bleeding from the ampulla of VaterNot specified in therapy with praziquantel andBleeding of aneurysm from Vater ampulla, notwithstanding praziquantel13Abdelnaby, 202038, FPulmonary artery aneurysm with dilatation of both branches and Ortner’s syndromeRefused surgeryDischarged on close follow-upAnagraphical details, aneurysm description, surgical management, and outcome of patients were specified. Fatality was reported in 3/13 patients. F = female; M = male.Table 3
Summary of findings.
Clinical presentationThe most frequently reported symptom at presentation was pain referred to the chest, hypochondrium, or the lumbar region, followed by dyspnoea, fever, hoarseness and Ortner’s syndrome, hyper-eosinophilia, syncope, cardiogenic shock, and anaemiaCardiovascular risk factors and comorbiditiesCardiovascular issues were the most frequent associated comorbidity, including hypertension, previous surgery for type A aortic dissection; oesophageal varices, a history of smoke and alcohol consumption were also described in some patientsTiming of schistosomiasis diagnosis and arterial damage observationA history of previously diagnosed schistosomiasis was reported in the majority of cases or in patients with known chronic schistosomiasis, in an advanced stage with ouverte complications. Cases have been also described in patients that had lived in endemic areas previously to the vascular diagnosis even if negative to parasitological investigations and many years after leaving the endemic countryArterial districts involved by aneurysm lesionsThe most frequently involved arterial district was the pulmonary artery, followed by aortic lesions which included one recurrent lesion on previous aortic surgery and abdominal visceral vessels aneurysms (specifically in splenic, hepatic artery, right portal branch, and renal artery)Laboratory investigationsDiagnosis of actual infection was reached by different methods, including serology, stool sample analysis, biopsy of lung, liver, or testisPharmacological treatmentCase 4: beta-blocker gastro-enteric haemorrhage preventive therapy in splenic artery aneurysm with intrahepatic shuntCase 7: heparin and then anticoagulant in pulmonary artery aneurysmCase 8: anticoagulant for pulmonary artery aneurysm complicated by atrial thrombusCase 11: ciprofloxacin, piperacillin, and tazobactam then switched to meropenem and metronidazole for aortic graft infection and rupture on previous type A dissection surgeryCase 12: praziquantel and triclabendazole for hepatic pseudoaneurysm in hepatic abscessCase 13: antifailure measures and anticoagulantsSurgical treatmentCase 2: aneurysmectomy and direct suture of pseudoaneurysm of aortic archCase 3: splenectomy for right portal branch aneurysm and portal hypertensionCase 6: nephrectomy, aneurysmectomy, and kidney reimplantation for renal artery aneurysmCase 11: nonspecified reintervention for aortic graft infection and aortic ruptureOutcomeCase 3: portal vein thrombosis after splenectomy, resolved after 4 years follow-up. In 3 cases exitus was reportedCase 5: comorbidities did not allow surgery for pulmonary artery aneurysm and cardiac tamponadeCase 7: massive pulmonary embolism complicating a pulmonary artery aneurysm for which treatment had been refusedCase 11: heart failure in the late postoperatory period for reintervention on previous aortic graftCase 12: hepatic artery bleeding through ampulla of Vater notwithstanding pharmacological therapy with praziquantelCase 13: alive, refused surgery, discharged on anticoagulant and antifailure measuresThe clinical presentation, cardiovascular risk factors and comorbidities, timing of schistosomiasis diagnosis and arterial damage observation, arterial districts commonly involved, the diagnostic and therapeutic management, and outcome of patients are summarised.Table 4
Summary of findings with frequencies and percentages.
Anagraphic detailsMean ± SDRangeAge41.0 ± 14.318–66SexN%Male753.8Female646.1Cardiovascular risk factors and comorbiditiesCardiovascular comorbidity (Hypertension, previous type A aortic dissection, and pulmonary valve steno-insufficiency)323.1Oesophageal varices215.4Ex-smoker215.4Alcohol abuse17.7Schistosomiasis detailsPrevious history of schistosomiasis861.5Actual positivity for schistosomiasis (stool, antigen test, or histology)430.8Type of schistosomiasisIntestinal-hepatosplenic753.8Pulmonary538.5Urinary or testicular215.4Clinical presentationPain (chest, hypochondrium, and lumbar)646.1Dyspnoea641.6Fever323.1Hoarseness323.1Hyper-eosinophilia215.4Syncope/cardiogenic shock215.4Anaemia17.7Artery involvedPulmonary641.6Aortic arch17.7Thoraco-abdominal17.7Portal17.7Hepatic17.7Renal17.7Splenic17.7Rupture on previous aortic graft17.7TreatmentNo surgery (3 refusals, 1 exitus, 1 n.s)538.5Splenectomy17.7Nephrectomy, aneurysmectomy, and renal reimplantation17.7Aneurysmectomy (aortic arch)17.7Not-specified procedure (aortic rupture on previous graft)17.7OutcomeNot specified641.6Alive430.8Exitus323.1Anagraphic details, cardiovascular risk factors and comorbidities, schistosomiasis details (previous history or actual positivity) and type of schistosomiasis according to the apparatus involved, clinical presentation (signs and symptoms), arterial segment involved, treatment (conservative or surgical), and outcome are summarised, providing mean and standard deviation (for age) and number of cases and percentage for other factors. SD = standard deviation.


### 3.3. Stage of Schistosomiasis at Aneurysm Diagnosis

Vascular lesions were diagnosed at any stage of infestation. In some cases, they occurred in patients with activeSchistosoma infection. In these cases, the diagnosis of Schistosoma infection was reached by serological investigations [22], stool sample assessment, rectal biopsy [19], and histology of lung [17] or of liver and testis [23].Aneurysm occurred also in patients with known chronic schistosomiasis [12], in an advanced stage with clinically manifest complications, such as oesophageal varices [14], hepato-splenic schistosomiasis [16, 24, 25], in one case waiting for liver transplant [16] and in pulmonary schistosomiasis [12].Finally, cases were described in patients that had lived in endemic areas [12, 15]. Diagnosis of arterial lesion also occurred in these cases of patients that were negative to parasitological investigations (Kato-Katz and rectal biopsy) [15], many years after leaving the endemic country [15]. Interestingly, other chronic changes related to the portal system in patients with the neglected tropical disease have been reported in refugees, as in the case of tropical splenomegaly, which may persist also months after leaving an endemic country and which suggest a possible underlying persistent infection and immune response as a cause of chronic arterial damage [26] (Tables 3 and 4).


### 3.4. Age of Patients at Diagnosis

When we analysed the age at which patients were diagnosed with an aneurysm, we observed that young patients can be affected. The youngest patient included in our review was 18-years old, and overall, five patients were below 40 years [13, 18, 19, 22, 27]. This differs from the usual age at diagnosis of atherosclerotic aneurysms and suggests the need for an increased clinical suspicion of aneurysm as differential diagnosis when assessing patients of young age with compatible clinical presentation in endemic areas (Tables 3 and 4).


### 3.5. Pathophysiology of Arterial Damage in Schistosomiasis

Vascular complications in schistosomiasis can be caused by several pathophysiological mechanisms. Haemodynamic impairment is secondary to the chronic granulomatous inflammation of embolized eggs reaching the arteriolar districts of perfused organs. The hemodynamic mechanism is well described by Zaky in 1962 in a case series of pulmonary aneurysms in schistosomiasis patients. Schistosomiasis is considered one of the main causes of pulmonary artery aneurysms [13]. According to his report, aneurysms are a late result of the local weakening of the vessel wall associated with a rise of pressure due to repeated implantation of Schistosoma ova [13]. This leads to increased share stress due to the onset of pulmonary hypertension, right ventricular dilatation, and cor pulmonale [17]. Schistosome eggs embolization may cause direct damage to the walls of arteries through additional mechanisms, including vasa vasorum obliterative endarteritis, direct endothelium damage, or inducing atheromatic degeneration [19]. Vanker describes these mechanisms. Eggs of Schistosoma mansoni spread from the left upper lobe of the lung to the adjacent pleura and the aortic thoracic sheath, causing endarteritis obliterans of its vasa vasorum and aneurysm [19]. Interestingly, this physio-pathological mechanism is shared by other infectious diseases associated with thoracic aortic aneurysms, such as tertiary syphilis [28].Visceral aneurysms may also share physio-pathological mechanisms behind pulmonary lesions through hemodynamic impairment due to hepatic fibrosis and portal hypertension or as direct damage to the artery wall due to local inflammation [14, 15]. In the monocentric experience by Lambertucci et al., which included 82 patients with hepatosplenic schistosomiasis, only one case (1.2%) of visceral aneurysm (splenic artery aneurysm and intrahepatic shunt) was observed, a finding that was at first missed during ultrasound examination [14].A pictorial view of the pathophysiology leading to pulmonary artery and visceral arteries is shown in Figures2 and 3.Figure 2
Aneurysms and schistosomiasis. Physiopathology behind aortic aneurysm and pulmonary artery aneurysm formation. (1)Schistosoma eggs may seed pulmonary arteries, leading to lung inflammatory reaction and granuloma formation. Direct damage to vessels may occur as a result of inflammation of tissues surrounding vessels. (2) Pulmonary inflammation due to Schistosoma eggs seeding of pulmonary arteries may lead to pulmonary hypertension. Damage to vessels may be due to hemodynamic changes. (3) Schistosoma eggs may seed major vessels wall through vasa vasorum, causing cystic medial necrosis and loss of wall integrity.Figure 3
Aneurysms and schistosomiasis. Physiopathology behind portal branch aneurysm and splenic artery aneurysm formation. (1) Seeding of hepatic vessels bySchistosoma eggs may lead to inflammatory reaction in hepatic parenchyma, fibrosis, and direct damage to vessels. (2) Inflammatory reaction and portal fibrosis due to Schistosoma oviposition in hepatic vessels may lead to portal hypertension, which may induce aneurysms by hemodynamic mechanisms in visceral vessels. (3) Splenic artery aneurysm may be secondary to portal hypertension. (4) Schistosoma eggs may seed arterial wall through vasa vasorum, inducing direct damage and predisposing to aneurysm formation. Splenic a. = splenic artery. Figures 2 and 3 are original art work by the author V.S.


### 3.6. Histological Findings

Where available, histological findings supported the aforementioned physiopathological mechanisms. A histological report was available for three of the included cases. In case 2 reported by Vanker, of an aortic arch pseudoaneurysm,Schistosoma eggs were found on histological examination in pulmonary parenchyma, pleura, and arterioles, where they appear surrounded by a granulomatous reaction [19].In case 9, of a thoraco-abdominal aortic aneurysm, histology revealed eggs in liver and large bowl and calcified eggs in lung and testis [23].In case 3, of a right portal branch aneurysm, splenic, and liver fibrosis, destruction of portal vein branches was observed. In this case though, histology failed to detectSchistosoma eggs in the samples [15].


### 3.7. Immunomodulation and Infectious Complications

Schistosomes, specifically in the egg stage, have strong immunomodulatory effects on the immune system of their hosts and impair those immune responses necessary to combat other pathogens and to develop a protective antibody response [29]. Immune impairment could favour the occurrence of vascular damage in affected patients, as described for other disease of infectious interest [30]. This can be especially true in patients with pre-existing cardiovascular conditions or a history of previous vascular surgery as in case 11, reported by Romero de Oliveira, of an aortic rupture occurring on an aortic graft infection due to Porphyromonas pogonae [24].


### 3.8. Schistosomiasis and Thrombophilia

Thrombophilia has been reported as a complication in schistosomiasis patients with aneurysms. In case 8, by Abdelnaby et al., a pulmonary artery aneurysm was complicated by atrial mural thrombus [12], and in case 7, by Abo-Salem and Ramadan, a massive pulmonary embolism complicated a pulmonary artery aneurysm after the patient’s refusal of surgical treatment [17]. Also, in case 3, reported by Mucenic, the postoperatory for splenectomy in a patient with hepatic artery aneurysm was complicated by partial spleen vein thrombosis. Inflammation-induced thrombophilia, associated with schistosomiasis, has been suggested as the feature favouring the formation of thrombus in the aneurysm lumen. Secondary thrombophilia should thus be considered an additional cardiovascular risk factor in this setting [12].Pathophysiological mechanisms that lead to aneurysm in patients with schistosomiasis are described in Figures2 and 3.


### 3.9. Considerations on Surgical Treatment

Different kinds of approaches have been described according to the location of the aneurysm.Aneurysmectomy and direct suture have been used to treat an aortic arch pseudoaneurysm by D. A. Athanazio and P. R. F. Athanazio [23]. Nephrectomy, aneurysmectomy, and renal reimplantation have been successfully described in a renal artery aneurysm [25]. Splenectomy has been considered in a portal branch aneurysm associated with portal hypertension. By reducing portal hypertension, splenectomy favoured the reduction of aneurysm size to 1.4 cm at 4 year follow up [15], suggesting that the excessive venous inflow from the splenic vein was contributing to portal hypertension and vessel dilatation [15].Aneurysm lesions may be prone to reduction in size when the haemodynamic condition that favours their development is treated. Recently, transjugular intrahepatic portosystemic shunt has been suggested as a reversible and a far less invasive alternative to surgery in patients with portal hypertension, including those due toSchistosoma infection, preserving spleen and its immunologic function [31]. The limited availability in an endemic setting, the high cost, and marginal indications in guidelines challenge the assessment of the safety and effectiveness of this technique in this specific setting [32] (Tables 3 and 4).


### 3.10. Outcome

Some specific features of aneurysms in patients with schistosomiasis have to be considered when it comes to giving surgical indication. Aneurysms wall local weakening due to the rise of pressure and to the implantation ofSchistosoma ova has been described [21]. These features could make aneurysms lesions in this context highly prone to rupture [16]. In case 5, exitus was reported while waiting for surgery for a pulmonary artery aneurysm, due to rupture and cardiac tamponade [16]. Rupture also occurred in a hepatic aneurysm in a patient with hepatic abscess, which occurred notwithstanding the pharmacological management with praziquantel [22]. Thrombophilia related complications have to be considered when planning surgery; partial portal vein thrombosis complicated splenectomy in the case by Mucenic et al. [15] and exitus occurred in case 7 because of massive embolization from a pulmonary artery aneurysm, notwithstanding anticoagulant treatment [17].Finally, general conditions can be impaired by the high prevalence of pulmonary or portal hypertension but will also be secondary to effects of immune-modulation [24], favouring overlap of infections, as in the case of hepatic aneurysm in a patient with schistosomiasis and Fasciola hepatica infection [16] and occurrence of sepsis complications, as in the aortic graft infection in a patient with chronic schistosomiasis and history of aortic repair for type A aortic dissection [24]. Additionally, clinical features can be exacerbated by malnutrition, which can be significantly prevalent in endemic areas [21] (Tables 3 and 4).


## 3.1. Selection Process

A total of 23 cases were retrieved thorough review of the literature. Six cases from a case series of pulmonary aneurysms were excluded because data were reported as aggregated [21]. Four spleen aneurysm cases were excluded because unavailability of the article, not even by contact of the first author, additionally to the language filter applied. The flow chart of the review process has been provided in Figure 1. The median value of Murad case quality score was 2/8 with a minimum of 2 and a maximum of 7.


## 3.2. Summary of Cases

A total of thirteen cases were included in the review. Cases are summarised in Tables1 and 2, and findings are summarised in Tables 3 and 4.Table 1
Summary of cases.
NAuthor, yearAge, sexGeographic regionSchistosoma speciesComorbidities and c.v. risk factors in anamnesisSchistosomiasis detailsClinical presentationVascular findingsPharmacological treatment of schistosomiasis1Salah, 199727, MEgyptn.a.SmokePrevious urinary andintestinal schistosomiasis, normal lung parenchimaCardio-vocal Ortner’s syndrome; exertional dyspnoea (2 months), pulmonary hypertensionPulmonary artery-aneurysmand schistosomal, cor pulmonalePrevious treatment with praziquantel for intestinal and urinary schistosomiasis2Vanker, 198619, FSouth-AfricaSchistosoma mansoni (stool and rectal mucosa)NonePulmonary shistosomiasisHaemoptysis; left chest pain, hoarseness, absent left brachial pulse (1 month), haematuriaAortic arch pseudoaneurysm (7 x 2 cm)Not reported3Mucenic, 200245, MLived for 17 years inSchistosoma endemic areaNegative (stool and rectal biopsy)No otherPrevious hepatosplenic schistosomiasis (hematemesis, enterorrhagia, oesophageal varices)Abdominal continuous pain (left hypochondrium)Right portal branch aneurysm (5 x 4 x 4 cm)No previous treatment with praziquantel4Lambertucci, 201066, FBraziln.a.No otherChronic hepato-splenic schistosomiasis (esophago-gastric varices; hematemesis)Routine assessment for hepato-splenic schistosomiasisSaccular aneurysm of the splenic artery; intrahepatic shunt between right portal branch and right hepatic veinBeta-blockers as gastroenteric haemorrhage prophylaxis5Piveta, 201241, FBraziln.a.Alcoholic hepatitis waiting for liver transplantHepato-splenic schistosomiasisIntermittent chest pain; pulmonary hypertension; intrapulmonary shuntPulmonary a. aneurysm (8.3 cm)Not reported6Genzini, 201448, MBraziln.a.Hypertension, thrombo-cytopeniaAdvanced hepatosplenic schistosomiasisRight lumbar painRight renal artery aneurysm 2.5 cmNot reported7Ramadan, 201555, MLower-EgyptSchistosoma mansoni (lung biopsy)Ex-smokerHistory of intestinal and hepato-splenic schistosomiasis. Pulmonary granuloma, positive serologyS. mansoniDyspnoea (one month); fever (2 months) cough and mucoid sputum (10 days) left atrial compression; pleural effusionRight pulmonary artery aneurysm (17 x 11 cm)Previous treatment for intestinal schistosomiasis (20 years previously). Anticoagulation8Abdelnaby, 201850, FEgyptn.a.n.a.Bilharziasis since early childhoodChest pain (recurrent); exertional dyspnoeaRight and left pulmonary a. aneurysm (6.5 cm) and atrial mural thrombusAnticoagulation9Athanazio, 2018n.a., MBrazilSchistosoma mansoni (lung, testis, liver, and large bowl)n.a.Testicular, intestinal and lung schistosomiasisSpontaneous aorto-cutaneous fistulaThoraco-abdominal aortic aneurysm; spontaneous aorto-cutaneous fistulan.a.10Gavilanes, 201838, MBraziln.a.n.a.Chronic schistosomiasis, pulmonary artery hypertensionPalpitations; dyspnoea; exertional syncopeGiant pulmonary artery aneurysm; aorta and left coronary artery compressionn.a.11De Oliveira, 201948, MBraziln.a.Type A aortic dissection ascending aorta substitution (dacron); biological valveHepato-splenic schistosomiasisFeverPorphyromonas pogonae sepsisAortic graft infection and aortic ruptureAntibiotics for associated bacteria12Dyer, 202018, FAustraliaSchistosoma Ag EIAn.aSerology positive for schistosomiasisFever; right upper quadrant pain; liver abscessFasciola hepatica infestationHepatic artery pseudoaneurysm; acute bleeding from the ampulla of VaterPraziquantel13Abdelnaby, 202038, FEgyptn.a.History of bilharziasDyspnoea (5 years) and hoarseness (1 year)Pulmonary artery aneurysm (PAA) with dilatation of both branches and hoarsenessAnticoagulationAnagraphic details, geographic region of patient’s origin/residency, schistosomiasis details, clinical presentation, vascular findings, and pharmacological management are included. M = male; F = female; Ag EIA = antigen enzyme-linked immunosorbent essay; n.a = not available; c.v. = cardiovascular. The most frequently involved arterial district was the pulmonary artery, followed by aortic lesions which included one recurrent lesion on previous aortic surgery and abdominal visceral vessels aneurysms (specifically in splenic, hepatic artery, right portal branch, and renal artery).Table 2
Surgical treatment and outcome of patients.
NAuthor, yearAge, sexVascular findingsSurgical treatmentOutcome2Vanker, 198619, FAortic arch pseudoaneurysm (7 x 2 cm)Aneurysmectomy and direct sutureUnknown3Mucenic, 200245, MRight portal branch aneurysm (5 x 4 x 4 cm)SplenectomyPartial portal vein thrombosis. Alive (reduction of aneurysm size to 1.4 cm and resolution of the vessel thrombosis on follow up)4Lambertucci, 201066, FSaccular aneurysm of the splenic artery; intrahepatic shunt between right portal branch-and right hepatic veinRefused surgery treated with beta-blockersUnknown5Piveta, 201241, FPulmonary artery aneurysm (8.3 cm)Exitus waiting for surgeryExitus (aneurysm rupture and cardiac tamponade)6Genzini, 201448, MRight renal artery aneurysm 2.5 cmNephrectomy, aneurysmectomy and renal reimplantationAlive (creatinine improvement on follow-up)7Ramadan, 201555, MRight pulmonary artery aneurysm (17 x 11 cm)Refused surgery on anticoagulationExitus (massive pulmonary embolization, notwithstanding anti-coagulant therapy)11De Oliveira, 201948, MAortic graft infection and aortic ruptureNot-specified reintervention on previous aortic graft on antibiotic therapyExitus (complications of surgery on 12th day post-operatory, likely due to comorbidities related to hepato-splenic schistosomiasis)12Dyer, 202018, FHepatic artery pseudoaneurysm; acute bleeding from the ampulla of VaterNot specified in therapy with praziquantel andBleeding of aneurysm from Vater ampulla, notwithstanding praziquantel13Abdelnaby, 202038, FPulmonary artery aneurysm with dilatation of both branches and Ortner’s syndromeRefused surgeryDischarged on close follow-upAnagraphical details, aneurysm description, surgical management, and outcome of patients were specified. Fatality was reported in 3/13 patients. F = female; M = male.Table 3
Summary of findings.
Clinical presentationThe most frequently reported symptom at presentation was pain referred to the chest, hypochondrium, or the lumbar region, followed by dyspnoea, fever, hoarseness and Ortner’s syndrome, hyper-eosinophilia, syncope, cardiogenic shock, and anaemiaCardiovascular risk factors and comorbiditiesCardiovascular issues were the most frequent associated comorbidity, including hypertension, previous surgery for type A aortic dissection; oesophageal varices, a history of smoke and alcohol consumption were also described in some patientsTiming of schistosomiasis diagnosis and arterial damage observationA history of previously diagnosed schistosomiasis was reported in the majority of cases or in patients with known chronic schistosomiasis, in an advanced stage with ouverte complications. Cases have been also described in patients that had lived in endemic areas previously to the vascular diagnosis even if negative to parasitological investigations and many years after leaving the endemic countryArterial districts involved by aneurysm lesionsThe most frequently involved arterial district was the pulmonary artery, followed by aortic lesions which included one recurrent lesion on previous aortic surgery and abdominal visceral vessels aneurysms (specifically in splenic, hepatic artery, right portal branch, and renal artery)Laboratory investigationsDiagnosis of actual infection was reached by different methods, including serology, stool sample analysis, biopsy of lung, liver, or testisPharmacological treatmentCase 4: beta-blocker gastro-enteric haemorrhage preventive therapy in splenic artery aneurysm with intrahepatic shuntCase 7: heparin and then anticoagulant in pulmonary artery aneurysmCase 8: anticoagulant for pulmonary artery aneurysm complicated by atrial thrombusCase 11: ciprofloxacin, piperacillin, and tazobactam then switched to meropenem and metronidazole for aortic graft infection and rupture on previous type A dissection surgeryCase 12: praziquantel and triclabendazole for hepatic pseudoaneurysm in hepatic abscessCase 13: antifailure measures and anticoagulantsSurgical treatmentCase 2: aneurysmectomy and direct suture of pseudoaneurysm of aortic archCase 3: splenectomy for right portal branch aneurysm and portal hypertensionCase 6: nephrectomy, aneurysmectomy, and kidney reimplantation for renal artery aneurysmCase 11: nonspecified reintervention for aortic graft infection and aortic ruptureOutcomeCase 3: portal vein thrombosis after splenectomy, resolved after 4 years follow-up. In 3 cases exitus was reportedCase 5: comorbidities did not allow surgery for pulmonary artery aneurysm and cardiac tamponadeCase 7: massive pulmonary embolism complicating a pulmonary artery aneurysm for which treatment had been refusedCase 11: heart failure in the late postoperatory period for reintervention on previous aortic graftCase 12: hepatic artery bleeding through ampulla of Vater notwithstanding pharmacological therapy with praziquantelCase 13: alive, refused surgery, discharged on anticoagulant and antifailure measuresThe clinical presentation, cardiovascular risk factors and comorbidities, timing of schistosomiasis diagnosis and arterial damage observation, arterial districts commonly involved, the diagnostic and therapeutic management, and outcome of patients are summarised.Table 4
Summary of findings with frequencies and percentages.
Anagraphic detailsMean ± SDRangeAge41.0 ± 14.318–66SexN%Male753.8Female646.1Cardiovascular risk factors and comorbiditiesCardiovascular comorbidity (Hypertension, previous type A aortic dissection, and pulmonary valve steno-insufficiency)323.1Oesophageal varices215.4Ex-smoker215.4Alcohol abuse17.7Schistosomiasis detailsPrevious history of schistosomiasis861.5Actual positivity for schistosomiasis (stool, antigen test, or histology)430.8Type of schistosomiasisIntestinal-hepatosplenic753.8Pulmonary538.5Urinary or testicular215.4Clinical presentationPain (chest, hypochondrium, and lumbar)646.1Dyspnoea641.6Fever323.1Hoarseness323.1Hyper-eosinophilia215.4Syncope/cardiogenic shock215.4Anaemia17.7Artery involvedPulmonary641.6Aortic arch17.7Thoraco-abdominal17.7Portal17.7Hepatic17.7Renal17.7Splenic17.7Rupture on previous aortic graft17.7TreatmentNo surgery (3 refusals, 1 exitus, 1 n.s)538.5Splenectomy17.7Nephrectomy, aneurysmectomy, and renal reimplantation17.7Aneurysmectomy (aortic arch)17.7Not-specified procedure (aortic rupture on previous graft)17.7OutcomeNot specified641.6Alive430.8Exitus323.1Anagraphic details, cardiovascular risk factors and comorbidities, schistosomiasis details (previous history or actual positivity) and type of schistosomiasis according to the apparatus involved, clinical presentation (signs and symptoms), arterial segment involved, treatment (conservative or surgical), and outcome are summarised, providing mean and standard deviation (for age) and number of cases and percentage for other factors. SD = standard deviation.


## 3.3. Stage of Schistosomiasis at Aneurysm Diagnosis

Vascular lesions were diagnosed at any stage of infestation. In some cases, they occurred in patients with activeSchistosoma infection. In these cases, the diagnosis of Schistosoma infection was reached by serological investigations [22], stool sample assessment, rectal biopsy [19], and histology of lung [17] or of liver and testis [23].Aneurysm occurred also in patients with known chronic schistosomiasis [12], in an advanced stage with clinically manifest complications, such as oesophageal varices [14], hepato-splenic schistosomiasis [16, 24, 25], in one case waiting for liver transplant [16] and in pulmonary schistosomiasis [12].Finally, cases were described in patients that had lived in endemic areas [12, 15]. Diagnosis of arterial lesion also occurred in these cases of patients that were negative to parasitological investigations (Kato-Katz and rectal biopsy) [15], many years after leaving the endemic country [15]. Interestingly, other chronic changes related to the portal system in patients with the neglected tropical disease have been reported in refugees, as in the case of tropical splenomegaly, which may persist also months after leaving an endemic country and which suggest a possible underlying persistent infection and immune response as a cause of chronic arterial damage [26] (Tables 3 and 4).


## 3.4. Age of Patients at Diagnosis

When we analysed the age at which patients were diagnosed with an aneurysm, we observed that young patients can be affected. The youngest patient included in our review was 18-years old, and overall, five patients were below 40 years [13, 18, 19, 22, 27]. This differs from the usual age at diagnosis of atherosclerotic aneurysms and suggests the need for an increased clinical suspicion of aneurysm as differential diagnosis when assessing patients of young age with compatible clinical presentation in endemic areas (Tables 3 and 4).


## 3.5. Pathophysiology of Arterial Damage in Schistosomiasis

Vascular complications in schistosomiasis can be caused by several pathophysiological mechanisms. Haemodynamic impairment is secondary to the chronic granulomatous inflammation of embolized eggs reaching the arteriolar districts of perfused organs. The hemodynamic mechanism is well described by Zaky in 1962 in a case series of pulmonary aneurysms in schistosomiasis patients. Schistosomiasis is considered one of the main causes of pulmonary artery aneurysms [13]. According to his report, aneurysms are a late result of the local weakening of the vessel wall associated with a rise of pressure due to repeated implantation of Schistosoma ova [13]. This leads to increased share stress due to the onset of pulmonary hypertension, right ventricular dilatation, and cor pulmonale [17]. Schistosome eggs embolization may cause direct damage to the walls of arteries through additional mechanisms, including vasa vasorum obliterative endarteritis, direct endothelium damage, or inducing atheromatic degeneration [19]. Vanker describes these mechanisms. Eggs of Schistosoma mansoni spread from the left upper lobe of the lung to the adjacent pleura and the aortic thoracic sheath, causing endarteritis obliterans of its vasa vasorum and aneurysm [19]. Interestingly, this physio-pathological mechanism is shared by other infectious diseases associated with thoracic aortic aneurysms, such as tertiary syphilis [28].Visceral aneurysms may also share physio-pathological mechanisms behind pulmonary lesions through hemodynamic impairment due to hepatic fibrosis and portal hypertension or as direct damage to the artery wall due to local inflammation [14, 15]. In the monocentric experience by Lambertucci et al., which included 82 patients with hepatosplenic schistosomiasis, only one case (1.2%) of visceral aneurysm (splenic artery aneurysm and intrahepatic shunt) was observed, a finding that was at first missed during ultrasound examination [14].A pictorial view of the pathophysiology leading to pulmonary artery and visceral arteries is shown in Figures2 and 3.Figure 2
Aneurysms and schistosomiasis. Physiopathology behind aortic aneurysm and pulmonary artery aneurysm formation. (1)Schistosoma eggs may seed pulmonary arteries, leading to lung inflammatory reaction and granuloma formation. Direct damage to vessels may occur as a result of inflammation of tissues surrounding vessels. (2) Pulmonary inflammation due to Schistosoma eggs seeding of pulmonary arteries may lead to pulmonary hypertension. Damage to vessels may be due to hemodynamic changes. (3) Schistosoma eggs may seed major vessels wall through vasa vasorum, causing cystic medial necrosis and loss of wall integrity.Figure 3
Aneurysms and schistosomiasis. Physiopathology behind portal branch aneurysm and splenic artery aneurysm formation. (1) Seeding of hepatic vessels bySchistosoma eggs may lead to inflammatory reaction in hepatic parenchyma, fibrosis, and direct damage to vessels. (2) Inflammatory reaction and portal fibrosis due to Schistosoma oviposition in hepatic vessels may lead to portal hypertension, which may induce aneurysms by hemodynamic mechanisms in visceral vessels. (3) Splenic artery aneurysm may be secondary to portal hypertension. (4) Schistosoma eggs may seed arterial wall through vasa vasorum, inducing direct damage and predisposing to aneurysm formation. Splenic a. = splenic artery. Figures 2 and 3 are original art work by the author V.S.


## 3.6. Histological Findings

Where available, histological findings supported the aforementioned physiopathological mechanisms. A histological report was available for three of the included cases. In case 2 reported by Vanker, of an aortic arch pseudoaneurysm,Schistosoma eggs were found on histological examination in pulmonary parenchyma, pleura, and arterioles, where they appear surrounded by a granulomatous reaction [19].In case 9, of a thoraco-abdominal aortic aneurysm, histology revealed eggs in liver and large bowl and calcified eggs in lung and testis [23].In case 3, of a right portal branch aneurysm, splenic, and liver fibrosis, destruction of portal vein branches was observed. In this case though, histology failed to detectSchistosoma eggs in the samples [15].


## 3.7. Immunomodulation and Infectious Complications

Schistosomes, specifically in the egg stage, have strong immunomodulatory effects on the immune system of their hosts and impair those immune responses necessary to combat other pathogens and to develop a protective antibody response [29]. Immune impairment could favour the occurrence of vascular damage in affected patients, as described for other disease of infectious interest [30]. This can be especially true in patients with pre-existing cardiovascular conditions or a history of previous vascular surgery as in case 11, reported by Romero de Oliveira, of an aortic rupture occurring on an aortic graft infection due to Porphyromonas pogonae [24].


## 3.8. Schistosomiasis and Thrombophilia

Thrombophilia has been reported as a complication in schistosomiasis patients with aneurysms. In case 8, by Abdelnaby et al., a pulmonary artery aneurysm was complicated by atrial mural thrombus [12], and in case 7, by Abo-Salem and Ramadan, a massive pulmonary embolism complicated a pulmonary artery aneurysm after the patient’s refusal of surgical treatment [17]. Also, in case 3, reported by Mucenic, the postoperatory for splenectomy in a patient with hepatic artery aneurysm was complicated by partial spleen vein thrombosis. Inflammation-induced thrombophilia, associated with schistosomiasis, has been suggested as the feature favouring the formation of thrombus in the aneurysm lumen. Secondary thrombophilia should thus be considered an additional cardiovascular risk factor in this setting [12].Pathophysiological mechanisms that lead to aneurysm in patients with schistosomiasis are described in Figures2 and 3.


## 3.9. Considerations on Surgical Treatment

Different kinds of approaches have been described according to the location of the aneurysm.Aneurysmectomy and direct suture have been used to treat an aortic arch pseudoaneurysm by D. A. Athanazio and P. R. F. Athanazio [23]. Nephrectomy, aneurysmectomy, and renal reimplantation have been successfully described in a renal artery aneurysm [25]. Splenectomy has been considered in a portal branch aneurysm associated with portal hypertension. By reducing portal hypertension, splenectomy favoured the reduction of aneurysm size to 1.4 cm at 4 year follow up [15], suggesting that the excessive venous inflow from the splenic vein was contributing to portal hypertension and vessel dilatation [15].Aneurysm lesions may be prone to reduction in size when the haemodynamic condition that favours their development is treated. Recently, transjugular intrahepatic portosystemic shunt has been suggested as a reversible and a far less invasive alternative to surgery in patients with portal hypertension, including those due toSchistosoma infection, preserving spleen and its immunologic function [31]. The limited availability in an endemic setting, the high cost, and marginal indications in guidelines challenge the assessment of the safety and effectiveness of this technique in this specific setting [32] (Tables 3 and 4).


## 3.10. Outcome

Some specific features of aneurysms in patients with schistosomiasis have to be considered when it comes to giving surgical indication. Aneurysms wall local weakening due to the rise of pressure and to the implantation ofSchistosoma ova has been described [21]. These features could make aneurysms lesions in this context highly prone to rupture [16]. In case 5, exitus was reported while waiting for surgery for a pulmonary artery aneurysm, due to rupture and cardiac tamponade [16]. Rupture also occurred in a hepatic aneurysm in a patient with hepatic abscess, which occurred notwithstanding the pharmacological management with praziquantel [22]. Thrombophilia related complications have to be considered when planning surgery; partial portal vein thrombosis complicated splenectomy in the case by Mucenic et al. [15] and exitus occurred in case 7 because of massive embolization from a pulmonary artery aneurysm, notwithstanding anticoagulant treatment [17].Finally, general conditions can be impaired by the high prevalence of pulmonary or portal hypertension but will also be secondary to effects of immune-modulation [24], favouring overlap of infections, as in the case of hepatic aneurysm in a patient with schistosomiasis and Fasciola hepatica infection [16] and occurrence of sepsis complications, as in the aortic graft infection in a patient with chronic schistosomiasis and history of aortic repair for type A aortic dissection [24]. Additionally, clinical features can be exacerbated by malnutrition, which can be significantly prevalent in endemic areas [21] (Tables 3 and 4).


## 4. Conclusions and Recommendations

Our review of available literature (limited to case reports and case series) has described the co-occurrence of aneurysm lesions in patients with schistosomiasis, suggesting the need to ascertain the true burden of aneurysms in patients with schistosomiasis, to establish the pathophysiology of vessel damage and aneurysm formation and to assess if there is an association between schistosomiasis and aneurysm formation. These studies will be in line with the newly-launched revised WHO 2021–2030 NTD Roadmap, towards the elimination of morbidity related to Neglected Tropical Diseases in all endemic countries by 2030 [2, 10].



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