Interstitial macrophage phenotypes in Schistosoma-induced pulmonary hypertension.

Background: Schistosomiasis is a common cause of pulmonary hypertension (PH) worldwide. Type 2 inflammation contributes to the development of Schistosoma-induced PH. Specifically, interstitial macrophages (IMs) derived from monocytes play a pivotal role by producing thrombospondin-1 (TSP-1), which in turn activates TGF-ß, thereby driving the pathology of PH. Resident and recruited IM subpopulations have recently been identified. We hypothesized that in Schistosoma-PH, one IM subpopulation expresses monocyte recruitment factors, whereas recruited monocytes become a separate IM subpopulation that expresses TSP-1. Methods: Mice were intraperitoneally sensitized and then intravenously challenged with S. mansoni eggs. Flow cytometry on lungs and blood was performed on wildtype and reporter mice to identify IM subpopulations and protein expression. Single-cell RNA sequencing (scRNAseq) was performed on flow-sorted IMs from unexposed and at day 1, 3 and 7 following Schistosoma exposure to complement flow cytometry based IM characterization and identify gene expression. Results: Flow cytometry and scRNAseq both identified 3 IM subpopulations, characterized by CCR2, MHCII, and FOLR2 expression. Following Schistosoma exposure, the CCR2+ IM subpopulation expanded, suggestive of circulating monocyte recruitment. Schistosoma exposure caused increased monocyte-recruitment ligand CCL2 expression in the resident FOLR2+ IM subpopulation. In contrast, the vascular pathology-driving protein TSP-1 was greatest in the CCR2+ IM subpopulation. Conclusion: Schistosoma-induced PH involves crosstalk between IM subpopulations, with increased expression of monocyte recruitment ligands by resident FOLR2+ IMs, and the recruitment of CCR2+ IMs which express TSP-1 that activates TGF-ß and causes PH.

Th2 CD4+ T Cells Are Necessary and Sufficient for Schistosoma-Pulmonary Hypertension.

Background Inflammation underlies many forms of pulmonary hypertension (PH), including that resulting from Schistosoma infection, a major cause of PH worldwide. Schistosomiasis-associated PH is proximately triggered by embolization of parasite eggs into the lungs, resulting in localized type 2 inflammation. However, the role of CD4+ T cells in this disease is not well defined. Methods and Results We used a mouse model of schistosomiasis-associated PH, induced by intraperitoneal egg sensitization followed by intravenous egg challenge, with outcomes including right ventricle systolic pressure measured by cardiac catheterization, and cell density and phenotype assessed by flow cytometry. We identified that embolization of Schistosoma eggs into lungs of egg-sensitized mice increased the perivascular density of T-helper 2 (Th2) CD4+ T cells by recruitment of cells from the circulation and triggered type 2 inflammation. Parabiosis confirmed that egg embolization is required for localized type 2 immunity. We found Th2 CD4+ T cells were necessary for Schistosoma-induced PH, given that deletion of CD4+ T cells or inhibiting their Th2 function protected against type 2 inflammation and PH following Schistosoma exposure. We also observed that adoptive transfer of Schistosoma-sensitized CD4+ Th2 cells was sufficient to drive type 2 inflammation and PH. Conclusions Th2 CD4+ T cells are a necessary and sufficient component for the type 2 inflammation-induced PH following Schistosoma exposure.

Esquistosomiasi: una causa infreqüent d'hipertensió pulmonar en el nostre entorn / Esquistosomiasis: una causa infrecuente de hipertensión pulmonar en nuestro medio / Schistosomiasis: a rare cause of pulmonary hypertension in our environment

INTRODUCCIÓ: Una causa infreqüent al nostre entorn d'hipertensió arterial pulmonar (HAP) és l'esquistosomiasi, una parasitosi causada per Schistosoma mansoni I Schistosoma haematobium. És habitual en pacients d'àrees endèmiques, que en alguns casos poden desenvolupar HAP. CAS CLÍNIC: Presentem el cas d'un pacient de 13 anys, originari de Mali, que consulta per dolor toràcic I símptomes vegetatius associats a l'exercici. En l'exploració física destaquen un segon to cardíac augmentat I esplenomegàlia. Es troba en insuficiència cardíaca classe II de la NYHA. L'ecocardiografia mostra dilatació I hipertròfia ventricular dretes, amb signes indirectes d'hipertensió pulmonar, que es confirma per cateterisme. Tenint en compte la procedència del pacient, s'amplia l'estudi etiològic amb la investigació de la presència de Schistosoma en orina I femta, que resulta positiu per S. mansoni I S. haematobium. S'inicia tractament amb praziquantel I sildenafil; la parasitosi es resol I milloren els símptomes. COMENTARIS: La simptomatologia de l'esquistosomiasi varia segons les característiques de la infecció, la durada I la càrrega parasitària. La definició d'HAP associada a esquistosomiasi es basa en la confirmació mitjançant cateterisme juntament amb la presència del paràsit en orina o femta, I l'evidència d'afectació hepatoesplènica mitjançant ecografia. La patogènesi és encara desconeguda I el tractament no està ben establert, de manera que l'estratègia terapèutica és igual a la de l'HAP idiopàtica. Els antiparasitaris no han demostrat que poden canviar el pronòstic. La seva elevada morbiditat en població jove fa que hi hagi interès a millorar el control de l'HAP associada a esquistosomiasi

INTRODUCCIÓN: Una causa infrecuente en nuestro medio de hipertensión arterial pulmonar (HAP) es la esquistosomiasis, una parasitosis causada por Schistosoma mansoni y Schistosoma haematobium. Es habitual en pacientes de áreas endémicas, pudiendo desarrollar en algunos casos HAP. CASO CLÍNICO: Presentamos el caso de un paciente de 13 años, originario de Mali, que consulta por dolor torácico y síntomas vegetativos asociados al ejercicio. En la exploración física destacan un segundo tono cardiaco aumentado y esplenomegalia. Se encuentra en insuficiencia cardiaca clase II de la NYHA. La ecocardiografía muestra dilatación e hipertrofia ventricular derechas, con signos indirectos de hipertensión pulmonar, que se confirma por cateterismo. Dada la procedencia del paciente, se amplía el estudio etiológico investigando la presencia de Schistosoma en orina y heces, que resulta positivo para S. mansoni y S. haematobium. Se inicia tratamiento con prazicuantel y sildenafilo; la parasitosis se resuelve y mejoran los síntomas. COMENTARIOS: La sintomatología de la esquistosomiasis varía según las características de la infección, la duración de la misma y la carga parasitaria. La definición de HAP asociada a esquistosomiasis se basa en la confirmación de ésta mediante cateterismo junto con la presencia del parásito en orina o heces, y la evidencia de afectación hepatoesplénica mediante ecografía. Su patogénesis es aún desconocida y el tratamiento no está bien establecido, y la estrategia terapéutica es igual a la de la HAP idiopática. Los antiparasitarios no han demostrado cambiar el pronóstico. Su elevada morbilidad en población joven hace que haya interés en mejorar el control de la HAP asociada a esquistosomiasis

INTRODUCTION: Schistosomiasis, a parasitosis caused by Schistosoma mansoni and Schistosoma haematobium may cause pulmonary arterial hypertension (PAH). While common in endemic areas, schistosomiasis is an uncommon cause of PAH in our environment. CASE REPORT: We present the case of a 13-year-old male, originally from Mali, who consulted for chest pain and vegetative symptoms associated with exercise. Physical examination revealed an increased second heart tone and splenomegaly, consistent with NYHA class II heart failure. Echocardiography showed dilatation and right ventricular hypertrophy, with indirect signs of pulmonary hypertension, which was confirmed by catheterization. Given the origin of the patient, diagnostic studies were expanded to investigate the presence of Schistosoma spp. in urine and feces, which resulted positive for S. mansoni and S. haematobium. Treatment with praziquantel and sildenafil was started, resulting in resolution of the parasitosis and improvement of the symptoms. COMMENTS: The symptoms of schistosomiasis may vary depending on the characteristics of the infection, the duration of the disease and the parasitic load. The definition of PAH associated with schistosomiasis is based on the confirmation of PAH by catheterization along with the presence of the parasite in urine or feces, and the evidence of hepatosplenic involvement by ultrasound. Its pathogenesis is still unknown and the treatment is not well established, although same principles of management of idiopathic PAH are recommended. Antiparasitic drugs have not shown to impact prognosis. Its high morbidity in young population justify the interest in improving the control of PAH associated with schistosomiasis

Pulmonary arterial response to Angiostrongylus vasorum in naturally infected dogs: echocardiographic findings in two cases.

BACKGROUND: Angiostrongylus vasorum is a nematode living in the pulmonary arteries of canids. Infected dogs develop severe pulmonary lesions which can potentially lead to pulmonary hypertension (PH). However, reports of PH in natural infected dogs are scant. One of the possible causes of the low prevalence of PH in A. vasorum-infected dogs could be the establishment of large diameter intrapulmonary arteriovenous anastomoses (IPAVAs), which attenuate pulmonary vascular resistance, thus reducing the pulmonary arterial pressure. The present report describes the pulmonary arterial pressure (PAP) response to A. vasorum natural infection in two dogs, assessed by echocardiography and by the saline contrast echocardiographic test (SCE). RESULTS: Both dogs showed clinical signs of respiratory disease. At presentation, case 1 did not show echocardiographic signs of PH and the SCE test was positive proving the presence of IPAVAs. However, at the follow-up visit, despite A. vasorum infection resolution, the same dog showed PH and the SCE test resulted negative, which ruled out the presence of IPAVAs. Case 2 suffered from severe pulmonary arterial hypertension and right-side congestive heart failure since the day of presentation. Saline contrast echocardiography was negative both at the time of presentation and at the follow-up visit. CONCLUSIONS: In the two cases described above, the PH was not associated with IPAVAs. During A. vasorum infection, IPAVAs recruitment mechanism is able to contrast the rise of PAP until a certain level. It probably represents an initial escape mechanism of PH that, over time, exhausts its compensatory capacities allowing PAP to rise and to be detectable on echocardiography.

[Etiological diagnosis of pulmonary hypertension: A cause of difficult diagnosis]. / Diagnostic étiologique de l'hypertension pulmonaire : une cause de diagnostic difficile.

INTRODUCTION: Schistosomiasis associated pulmonary arterial hypertension belongs to group 1 of the pulmonary hypertension classification and should be considered in any patient with pulmonary hypertension returning from an endemic area. CASE REPORT: A 17-year-old patient was hospitalized for pulmonary hypertension detected during the initial assessment of viral hepatitis B-related cirrhosis with portal hypertension. The initial assessment established the diagnosis of pulmonary hypertension secondary to viral hepatitis B-cirrhosis. The patient's hepatic and haemodynamic condition deteriorated and he was treated with intravenous epoprostenol. This allowed subsequent performance of a liver transplantation. Epoprostenol could then be discontinued. Unexpectedly, histology of the liver explant revealed florid schistosomiasis in addition to hepatitis B cirrhosis. CONCLUSION: The diagnosis of pulmonary arterial hypertension associated with schistosomiasis may be difficult. It is necessary to repeat the serological studies and, sometimes, to obtain a rectal biopsy. The treatment of pulmonary arterial hypertension associated with schistosomiasis is based on specific therapies and antiparasitic treatment.

Aberrant migration and surgical removal of a heartworm (Dirofilaria immitis) from the femoral artery of a cat.

A cat was evaluated for an acute-onset of right pelvic limb paresis. Thoracic radiographs revealed normal cardiac size and tortuous pulmonary arteries. Abdominal ultrasound identified a heartworm (HW) extending from the caudal abdominal aorta into the right external iliac artery and right femoral artery. The cat was HW-antigen positive. Echocardiography revealed a HW within the right branch of the main pulmonary artery and evidence of pulmonary hypertension. An agitated-saline contrast echocardiogram revealed a small right to left intracardiac shunt at the level of the atria. Surgical removal of the HW was performed with no substantial postoperative complications. There was return of blood flow and improved motor function to the limb. The cat remains mildly paretic on the affected limb with no other clinical signs.

[Schistosomiasis and pulmonary hypertension]. / Sistosomiyazis ve pulmoner hipertansiyon.

Schistosomiasis is one of the most prevelant parazitic diseases in the world. It is endemic in more than 70 countries, and more than 200 million people worldwide are infected with Schistosoma. Pulmonary hypertension (PHT) is one of the chronic complications of schistosomiasis. The exact pathogenesis of schistosomiasis-associated pulmonary hypertension (S-PHT) remains unclear, although several mechanisms such as parazitic arterial embolisation, pulmonary arteriopathy, and portopulmonary hypertension have been suggested. Pathological pulmonary vascular changes in S-PHT were found similar to those in idiopathic pulmonary arterial hypertension (IPAH). The fact that schistosomiasis is one of the most common causes of pulmonary arterial hypertension (PAH), particularly in the developing countries, underlines the importance of enhancing our knowledge on this disease. Developments in the treatment of PAH have resulted in improved prognosis and significant increase in life expectancy and quality of life in the last two decades, which has enhanced the importance of S-PHT. Schistosomiasis is treated with praziquantel. Nevertheless, there is limited evidence that this treatment is effective for PHT. Although antihelmintic medications do not lead to significant improvement, they have beneficial effects and may slow down disease progression. Using PAH-specific treatments in the patients with schistosomiasis-associated PAH (S-PAH) can improve prognosis. However, inadequate clinical studies and limited sources in the endemic regions restrict extensive usage of these expensive medications. Further studies are required to determine the efficacy of these treatment modalities.

Acute phase proteins and markers of oxidative stress to assess the severity of the pulmonary hypertension in heartworm-infected dogs.

BACKGROUND: Canine heartworm infection is characterized by pulmonary endarteritis and pulmonary hypertension (PH). The aim of the present study was to evaluate the relationship between PH with the concentrations of different positive (C-reactive protein [CRP] and haptoglobin [Hp]) and negative (albumin and paraoxonase-1 [PON-1]) acute phase proteins (APP), as well as the oxidative stress, by measuring glutathione peroxidase (GPx) and total antioxidant capacity (TAC) in 27 heartworm-infected dogs on Day 0 (diagnosis) and Day 120 (1 month after the last adulticide injection). Presence/absence of PH was determined by the Right Pulmonary Artery Distensibility (RPAD) Index. RESULTS: On Day 0, 62.9% of the dogs showed PH. Concentrations of CRP and Hp were higher in dogs with PH, especially in dogs with moderate-severe PH (P < 0.005 and P < 0.05, respectively). Albumin and PON-1 concentrations were higher in dogs without PH (P < 0.05 for albumin). On Day 120, 59.2% of the dogs presented with PH; CRP decreased while Hp increased (P < 0.005 and P < 0.05, respectively). Also, albumin and PON-1 rose, especially in absence of PH. There were not significant changes in the serum values of GPx and TAC. CONCLUSIONS: CRP and Hp have a potential prognostic role in dogs with dirofilariasis because increases in positive APP correlated with presence and severity of PH. CRP decreased, but Hp persisted at an elevated level in dogs with PH 1 month after the end of the adulticide treatment. CRP and Hp could work as early biomarkers of PH and be useful to stage the disease and to monitor the evolution of the patient and indirectly evaluate the persistence of arterial damage after the parasites have been eliminated. Albumin and PON-1 also showed potential value as markers of PH, although further research is necessary to determine its utility.

TGF-ß activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-ß signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-ß blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-ß is regulated at the level of activation, but how TGF-ß is activated in this disease is unknown. Here we show TGF-ß activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-ß activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-ß could thus be a therapeutic approach in TGF-ß-dependent vascular diseases.

Identification of Biomarkers for Schistosoma-Associated Pulmonary Arterial Hypertension Based on RNA-Seq Data of Mouse Whole Lung Tissues.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease, and the molecular mechanism of PAH has not been clarified clearly. The objective of this study was to identify possible biomarkers and explore the potential mechanisms of Schistosoma-induced PAH. METHODS: GSE49114 RNA-Seq data developed from mouse whole lung tissues were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between control samples and schistosomiasis-induced PAH samples were identified by the edgeR software. Gene Ontology (GO) and pathway enrichment analysis of DEGs were performed, followed by metabolic pathway network construction. Moreover, pathways with higher connectivity degrees in the metabolic pathway network were identified. RESULTS: Totally, 877 up- and 520 downregulated DEGs were screened. The upregulated DEGs such as IL-4 (Interleukin-4) were significantly related with immune system process, transmembrane signaling receptor activity, and signal transducer activity. Downregulated DEGs (i.e., Smad9 (SMAD family member 9), BMPR2 (bone morphogenetic protein type 2 receptor), and Eng (endoglin)) were significantly enriched in signal transducer activity, growth factor binding, and signal transduction. The top 10 metabolic pathways with highest connectivity degree were screened, including leishmaniasis (degree = 26), antigen processing and presentation (degree = 20), hematopoietic cell lineage (degree = 20), chemokine signaling pathway (degree = 18), and JAK-STAT signaling pathway (degree = 18). CONCLUSIONS: Smad9, BMPR2, Eng and IL4, and their relative functions such as signal transduction, signal transducer activity, and immune system process might play important roles in schistosomiasis-induced PAH. Moreover, the interaction of metabolic pathways was critical in the development of schistosomiasis-PAH.

Pulmonary hypertension in dogs with heartworm before and after the adulticide protocol recommended by the American Heartworm Society.

Pulmonary hypertension (pH) is a frequent and severe phenomenon in heartworm disease (Dirofilaria immitis). There is a lack of studies assessing the evolution of the proliferative endarteritis and pH caused by D. immitis after the death of the parasites, so this study evaluated the influence that the elimination of the worms exerts over the pulmonary pressure and therefore evolution of the endarteritis, through the evaluation of the Right Pulmonary Artery Distensibility (RPAD) Index and other echocardiographic measurements in 2D mode, M-mode and Doppler echocardiography in 34 dogs naturally infected by D. immitis on day 0, and one month after the last adulticide dose (day 120). pH, based on the determination of the RPAD Index, was present in 68% of the dogs (n=23) on day 0 and on day 120. No significant differences were observed between the RPAD Index between the two measurements, and only significant differences were found in pulmonary deceleration time, ejection time, and left ventricular internal diameter in telediastole when measurements from day 0 and day 120 were compared. There was not any worsening in the development of pH after the elimination of the parasites, independently of the parasite burden. During the adulticide treatment, the death of the worms causes thromboembolism and tends to worsen the vascular damage and presence of pH . It seems that following the adulticide protocol recommended by the American Heartworm Society with the previous elimination of Wolbachia and reduction of microfilariae followed by the stepped death of the worms did not cause a significant aggravation of the pulmonary damage of the treated dogs. Neither is present any significant improvement in the RPAD Index on day 120; probably, more time is needed before appreciating some positive changes after the elimination of the worms and Wolbachia from the vasculature and further studies are necessary.

Intrapulmonary arteriovenous anastomoses in dogs with severe Angiostrongylus vasorum infection: clinical, radiographic, and echocardiographic evaluation.

BACKGROUND: In both humans and dogs the pulmonary vasculature is able to recruit large-diameter anatomical intrapulmonary arteriovenous anastomoses (IPAVAs). In healthy people the opening of these anastomoses affects the degree of exercise-induced increase in pulmonary arterial pressure. The presence of these IPAVAs can be demonstrated using saline contrast echocardiography. OBJECTIVES: The aims of the present study were to characterize severely affected, naturally infected dogs with Angiostrongylus vasorum, to evaluate if these dogs can open IPAVAs, and to assess if the recruitment of such anastomoses affects the severity of pulmonary hypertension (PH). ANIMALS: Eight client-owned dogs with severe A. vasorum infection were recruited. METHODS: Dogs with A. vasorum infection that presented with severe dyspnea and/or syncope were prospectively screened by echocardiography for the presence of PH and IPAVAs. Only severely affected dogs, based on a combination of clinical, radiographic and echocardiographic abnormalities, were enrolled. RESULTS: Opening of IPAVAs could be demonstrated in three dogs with no to moderate PH, and could not be demonstrated in five dogs with severe PH. In two dogs thoracic radiographs showed only mild interstitial changes, while computer tomography and postmortem examination revealed severe pulmonary interstitial and vascular disease. CONCLUSIONS: These results suggest that dogs may open IPAVAs and that opening of such anastomoses may play a regulatory role in the development of PH. There may be a marked discrepancy between radiographic changes and disease severity in A. vasorum.

Irreversible pulmonary hypertension associated with Troglostrongylus brevior infection in a kitten.

A four month-old kitten was referred at the Veterinary Teaching Hospital of Teramo, Italy. Physical examination, echocardiography, thoracic radiography, copromicroscopy and biomolecular assays led to a diagnosis of severe parasitic bronchopneumonia by Troglostrongylus brevior complicated by pulmonary hypertension. A single administration of a spot on solution containing imidacloprid 10%/moxidectin 1% was effective in stopping larval shedding but clinical, radiographic and echocardiographic signs of bronchopneumonia and pulmonary hypertension still persisted after further follow-ups.While cases of pulmonary hypertension are known in infections by Aelurostrongylus abstrusus, this is the first report of irreversible pulmonary hypertension in a kitten with troglostrongylosis.

Hepatic Shunting of Eggs and Pulmonary Vascular Remodeling in Bmpr2(+/-) Mice with Schistosomiasis.

RATIONALE: Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein type-II receptor (BMPR-II) are the commonest genetic cause of PAH. OBJECTIVES: To determine whether Bmpr2(+/-) mice are more susceptible to schistosomiasis-induced pulmonary vascular remodeling. METHODS: Wild-type (WT) and Bmpr2(+/-) mice were infected percutaneously with Schistosoma mansoni. At 17 weeks postinfection, right ventricular systolic pressure and liver and lung egg counts were measured. Serum, lung and liver cytokine, pulmonary vascular remodeling, and liver histology were assessed. MEASUREMENTS AND MAIN RESULTS: By 17 weeks postinfection, there was a significant increase in pulmonary vascular remodeling in infected mice. This was greater in Bmpr2(+/-) mice and was associated with an increase in egg deposition and cytokine expression, which induced pulmonary arterial smooth muscle cell proliferation, in the lungs of these mice. Interestingly, Bmpr2(+/-) mice demonstrated dilatation of the hepatic central vein at baseline and postinfection, compared with WT. Bmpr2(+/-) mice also showed significant dilatation of the liver sinusoids and an increase in inflammatory cells surrounding the central hepatic vein, compared with WT. This is consistent with an increase in the transhepatic passage of eggs. CONCLUSIONS: This study has shown that levels of BMPR-II expression modify the pulmonary vascular response to chronic schistosomiasis. The likely mechanism involves the increased passage of eggs to the lungs, caused by altered diameter of the hepatic veins and sinusoids in Bmpr2(+/-) mice. Genetically determined differences in the remodeling of hepatic vessels may represent a new risk factor for PAH associated with schistosomiasis.

Contrasting cardiopulmonary responses to incremental exercise in patients with schistosomiasis-associated and idiopathic pulmonary arterial hypertension with similar resting hemodynamic impairment.

It has been reported that schistosomiasis-associated PAH (Sch-PAH) has a more benign clinical course compared with idiopathic PAH (IPAH). We therefore hypothesized that Sch-PAH subjects would present with less impaired cardiopulmonary and metabolic responses to exercise than IPAH patients, even with similar resting pulmonary hemodynamic abnormalities. The aim of this study was to contrast physiologic responses to incremental exercise on cycle ergometer between subjects with Sch-PAH and IPAH. We performed incremental cardiopulmonary exercise tests (CPET) in subjects newly diagnosed with IPAH (n = 9) and Sch-PAH (n = 8), within 1 month of the hemodynamic study and before the initiation of specific therapy for PAH. There were no significant between-group differences in cardiac index, pulmonary vascular resistance or mean pulmonary artery pressure. However, mean peak oxygen uptake (VO2) was greater in Sch-PAH than IPAH patients (75.5±21.4 vs 54.1±16.1% predicted, p = 0.016), as well as the ratio of increase in VO2 to work rate (8.2±1.0 vs 6.8±1.8 mL/min/W, p = 0.03). Additionally, the slope of the ventilatory response as a function of CO2 output was lower in Sch-PAH (40.3±3.9 vs 55.6±19.8; p = 0.04), and the heart rate response for a given change in VO2 was also diminished in Sch-PAH compared to IPAH (80.1±20.6 vs 123.0±39.2 beats/L/min; p = 0.02). In conclusion, Sch-PAH patients had less impaired physiological responses to exercise than IPAH subjects with similar resting hemodynamic dysfunction. Our data suggest a more preserved cardiopulmonary response to exercise in Sch-PAH which might be related to its better clinical course compared to IPAH.

Immunopathological aspects of schistosomiasis-associated pulmonary arterial hypertension.

OBJECTIVES: Pulmonary hypertension is a lethal complication of chronic hepatosplenic schistosomiasis. Little is known of the underlying (immuno-)histopathological characteristics of lung vasculopathy. METHODS: We characterized vasculopathy and inflammation in lung tissue of 10 patients with Schistosomiasis-associated PH (SCH-PH) in comparison to 22 idiopathic pulmonary arterial hypertension (IPAH) patients and 10 normal controls. SCH-PH cases were younger than controls. RESULTS: Plexiform lesions and/or angiomatoid lesions were found in 10/10 SCH-PH, and 19/22 IPAH patients (χ² p = 0.22). Lung granulomas with Schistosoma eggs were found in 2/10 of SCH-PH cases. PAH cases had increased peri-arterial density of CD3+ T cells, chymase+ and tryptase+ mast cells when compared to controls (p ≤ 0.047). SCH-PH showed increased density of CD4+ cells when compared to controls (p = 0.025), paralleled by an increased density of dendritic CD83+ cells when compared to both controls and IPAH patients (p ≤ 0.022). CONCLUSION: Both SCH-PH and IPAH feature plexogenic arteriopathy and increased periarterial T cell and mast cell density. SCH-PH and IPAH differ only with respect to the density of dendritic CD83+ cells. These findings imply ongoing antigenic stimulation in SCH-PH, yet a pattern of pulmonary vasculopathy similar to IPAH, suggestive of a final common pathway in their pathogenesis of PAH.