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

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.


Introduction
Schistosomiasis is an infection caused by trematode worms of the genus Schistosoma, which have diferent 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 infammatory 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 specifc 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%. Te 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][12][13][14][15][16][17][18][19].

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

Search Strategy and Inclusion and Exclusion Criteria.
PubMed, Scopus, and Embase were searched, using "Schistosomiasis" OR "Bilharziasis" AND "aneurysm" as keywords. A flter 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 fow chart on the research strategy has been provided in Figure 1.

Quality Assessment.
Case reports are assessed by making an overall judgement about methodological quality defning the availability of the whole investigator's experience such as if authors provided clear information on exposure to Schistosoma; if a clear report of patient's outcome, diferential diagnosis, description of challenges; dose-response efect description for treatment, sufcient length of follow-up, details to allow inference-making were provided [20].

Data Analysis.
Te 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. Te association statistical test was not performed, given the dis-homogeneity of reports.

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 frst author, additionally to the language flter applied. Te fow chart of the review process has been provided in Figure 1. Te median value of Murad case quality score was 2/8 with a minimum of 2 and a maximum of 7.

Summary of Cases.
A total of thirteen cases were included in the review. Cases are summarised in Tables 1 and  2, and fndings are summarised in Tables 3 and 4.    In some cases, they occurred in patients with active Schistosoma 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).

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 afected. Te youngest patient included in our review was 18-years old, and overall, fve patients were below 40 years [13,18,19,22,27]. Tis difers from the usual age at diagnosis of atherosclerotic aneurysms and suggests the need for an increased clinical suspicion of aneurysm as diferential diagnosis when assessing patients of young age with compatible clinical presentation in endemic areas (Tables 3 and 4).

Pathophysiology of Arterial Damage in Schistosomiasis.
Vascular complications in schistosomiasis can be caused by several pathophysiological mechanisms. Haemodynamic Table 3: Summary of fndings. Clinical presentation Te 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 anaemia Cardiovascular risk factors and comorbidities Cardiovascular 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 patients Timing of schistosomiasis diagnosis and arterial damage observation A 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 country Arterial districts involved by aneurysm lesions Te 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 (specifcally in splenic, hepatic artery, right portal branch, and renal artery) Laboratory investigations Diagnosis of actual infection was reached by diferent methods, including serology, stool sample analysis, biopsy of lung, liver, or testis Pharmacological treatment Case 4: beta-blocker gastro-enteric haemorrhage preventive therapy in splenic artery aneurysm with intrahepatic shunt impairment is secondary to the chronic granulomatous infammation of embolized eggs reaching the arteriolar districts of perfused organs. Te 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]. Tis 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 physiopathological mechanism is shared by other infectious diseases associated with thoracic aortic aneurysms, such as tertiary syphilis [28]. Anagraphic 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.
Visceral aneurysms may also share physiopathological mechanisms behind pulmonary lesions through hemodynamic impairment due to hepatic fbrosis and portal hypertension or as direct damage to the artery wall due to local infammation [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 fnding that was at frst missed during ultrasound examination [14].
A pictorial view of the pathophysiology leading to pulmonary artery and visceral arteries is shown in Figures 2  and 3. 3.6. Histological Findings. Where available, histological fndings 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 calcifed eggs in lung and testis [23].
In case 3, of a right portal branch aneurysm, splenic, and liver fbrosis, destruction of portal vein branches was observed. In this case though, histology failed to detect Schistosoma eggs in the samples [15].

Immunomodulation and Infectious Complications.
Schistosomes, specifcally in the egg stage, have strong immunomodulatory efects 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 afected patients, as described for other disease of infectious interest [30]. Tis 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].

Schistosomiasis and Trombophilia.
Trombophilia 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. Infammation-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 Figures 2  and 3. 3.9. Considerations on Surgical Treatment. Diferent 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 infow 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 to Schistosoma infection, preserving spleen and its immunologic function [31]. Te limited availability in an endemic setting, the high cost, and marginal indications in guidelines challenge the assessment of the safety and efectiveness of this technique in this specifc setting [32] (Tables 3 and 4).

3.10.
Outcome. Some specifc 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 of Schistosoma ova has been described [21]. Tese 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]. Trombophilia 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 efects 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 signifcantly prevalent in endemic areas [21] (Tables 3 and 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. Tese 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].

Data Availability
All available data have been included in the manuscript.

Conflicts of Interest
Te authors declare that they have no conficts of interest.