The impact of COVID-19 pandemic on pulmonary hypertension: What have we learned?

The coronavirus 2019 disease (COVID-19) pandemic threatened the Spanish health-care system. Patients with demanding conditions such as precapillary pulmonary hypertension (PH) faced a potentially severe infection, while their usual access to medical care was restricted. This prospective, unicentric study assessed the impact of COVID-19 on PH patients' outcomes and the operational changes in the PH network. Sixty-three PH patients (41 pulmonary arterial hypertension [PAH]; 22 chronic thromboembolic pulmonary hypertension [CTEPH]) experienced COVID-19. Overall mortality was 9.5% without differences when stratifying by hemodynamics or PAH-risk score. Patients who died were older (73.6 ± 5 vs. 52.2 ± 15.4; p = 0.001), with more comorbidities (higher Charlson index: 4.17 ± 2.48 vs. 1.14 ± 1.67; p = 0.0002). Referrals to the PH expert center decreased compared to the previous 3 years (123 vs. 160; p = 0.002). The outpatient activity shifted toward greater use of telemedicine. Balloon pulmonary angioplasty activity could be maintained after the first pandemic wave and lockdown while pulmonary thromboendarterectomy procedures decreased (19 vs. 36; p = 0.017). Pulmonary transplantation activity remained similar. The COVID-19 mortality in PAH/CTEPH patients was not related to hemodynamic severity or risk stratification, but to comorbidities. The pandemic imposed structural changes but a planned organization and resource reallocation made it possible to maintain PH patients' care.

Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes ACVRL1, ENG, SMAD4 and GDF2 can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in GDF2 in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.

Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear. TNIP2 and TRAF2 encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH. Methods: Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting. Results: We discovered a novel missense variant in the TNIP2 gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a de novo protein-truncating variant in the TRAF2. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h. Conclusions: We have identified two rare novel variants in TNIP2 and TRAF2 using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.

Uso de hidroterapia durante el parto: evaluación del dolor, uso de analgesia y seguridad neonatal / Use of hydrotherapy during labour: Assessment of pain, use of analgesia and neonatal safety

OBJETIVO: Evaluar la efectividad del uso de la hidroterapia en la percepción del dolor y solicitud de analgesia en las mujeres que la usen durante el parto e identificar posibles efectos adversos en aquellos neonatos nacidos dentro del agua. MÉTODO: Se ha diseñado un estudio multicéntrico de cohortes prospectivo llevado a cabo entre septiembre de 2014 y abril de 2016. Se incluyeron 200 gestantes, asignadas al grupo hidroterapia (GH) o grupo control (GC) según deseo y disponibilidad de uso, marcando el inicio de la recogida de datos a partir de los 5cm de dilatación. Los instrumentos utilizados han sido: la escala de valoración numérica (EVN), el uso de analgesia, el test de Apgar, el pH de cordón umbilical y el ingreso en UCIN. Los participantes se distribuyeron en: GH (n=111; 50 expulsivo en agua) y GC (n=89). RESULTADOS: La media de dolor a los 30 y 90min de la aplicación de hidroterapia fue menor en el GH que en el GC (EVN 30min 6,7; [DE 1,6] vs.7,8 [DE 1,2] [p < 0,001] y EVN 90min 7,7 [DE 1,2] vs.8,9 [DE 1,1] [p < 0,001]). Durante el expulsivo el dolor fue menor en las gestantes de parto en el agua (EVN GH 8,2 [DE 1,2], n=50; EVN GC 9,5 [DE 0,5], n=89 [p < 0,001]). Relativo a la analgesia, 30 gestantes del GC (33,7%) solicitaron analgesia epidural vs.24 gestantes (21,1%) del GH (p = 0,09). No se modificaron los parámetros neonatales tras el nacimiento en el agua. CONCLUSIÓN: El uso de hidroterapia disminuye el dolor durante el trabajo de parto y durante el expulsivo en aquellas mujeres que realizan un parto en el agua, y la petición de analgesia disminuye en las gestantes multíparas. No se objetivaron efectos adversos en los neonatos nacidos bajo el agua

AIM: To evaluate the effectiveness of the use of hydrotherapy in pain perception and requesting analgesia in women who use hydrotherapy during childbirth and to identify possible adverse effects in infants born in water. METHOD: A multicentre prospective cohort study was performed between September 2014 and April 2016. A total of 200 pregnant women were selected and assigned to the hydrotherapy group (HG) or the control group (CG) according to desire and availability of use, data collection started at 5cm dilatation. The instruments used were the numerical rating scale (NRS), use of analgesia, Apgar Test, umbilical cord pH and NICU admission. Participants were distributed into: HG (n=111; 50 water birth) and CG (n=89). RESULTS: Pain at 30 and 90min was lower in the HG than in the CG (NRS 30min 6.7 [SD 1.6] vs 7.8 [SD 1.2] [P<.001] and NRS 90min 7.7 [SD 1.2] vs.8.9 [SD 1.1] [P<.001]). During the second stage of labour, pain was lower in pregnant women undergoing a water birth (NRS HG 8.2 [SD 1.2], n=50; NRS CG 9.5 [SD 0.5], n=89 [P<.001]). Relative to the use of analgesia, in the CG 30 (33.7%) pregnant women requested epidural analgesia vs.24 (21.1%) pregnant women in HG (P=.09). The neonatal parameters after water birth were not modified compared to those born out of water. CONCLUSIONS: The use of hydrotherapy reduces pain during labour, and during second stage in women who undergo a water birth and the demand for analgesia decreases in multiparous pregnant women. No adverse effects were seen in infants born under water

Use of hydrotherapy during labour: Assessment of pain, use of analgesia and neonatal safety. / Uso de hidroterapia durante el parto: evaluación del dolor, uso de analgesia y seguridad neonatal.

AIM: To evaluate the effectiveness of the use of hydrotherapy in pain perception and requesting analgesia in women who use hydrotherapy during childbirth and to identify possible adverse effects in infants born in water. METHOD: A multicentre prospective cohort study was performed between September 2014 and April 2016. A total of 200 pregnant women were selected and assigned to the hydrotherapy group (HG) or the control group (CG) according to desire and availability of use, data collection started at 5cm dilatation. The instruments used were the numerical rating scale (NRS), use of analgesia, Apgar Test, umbilical cord pH and NICU admission. Participants were distributed into: HG (n=111; 50 water birth) and CG (n=89). RESULTS: Pain at 30 and 90min was lower in the HG than in the CG (NRS 30min 6.7 [SD 1.6] vs 7.8 [SD 1.2] [P<.001] and NRS 90min 7.7 [SD 1.2] vs. 8.9 [SD 1.1] [P<.001]). During the second stage of labour, pain was lower in pregnant women undergoing a water birth (NRS HG 8.2 [SD 1.2], n=50; NRS CG 9.5 [SD 0.5], n=89 [P<.001]). Relative to the use of analgesia, in the CG 30 (33.7%) pregnant women requested epidural analgesia vs. 24 (21.1%) pregnant women in HG (P=.09). The neonatal parameters after water birth were not modified compared to those born out of water. CONCLUSION: The use of hydrotherapy reduces pain during labour, and during second stage in women who undergo a water birth and the demand for analgesia decreases in multiparous pregnant women. No adverse effects were seen in infants born under water.

Group B streptococcal bacteriuria during pregnancy as a risk factor for maternal intrapartum colonization: a prospective cohort study.

PURPOSE: Current evidence is inconclusive regarding the intrapartum administration of chemoprophylaxis, merely based on the presence of group B streptococcal (GBS) bacteriuria of any colony count, in the prevention of early-onset neonatal GBS infection. The aim of this study was to assess whether GBS bacteriuria is a risk factor for intrapartum colonization (IPC) regardless of urinary concentration or the results of late third-trimester rectovaginal screening cultures (RVSCs). METHODOLOGY: Six hundred and eight pregnant women, with urine specimens cultured between May 2011 and May 2013, were enrolled in this prospective cohort study. RVSCs were available for 582 women and intrapartum rectovaginal cultures for 246. RESULTS: The prevalence of GBS bacteriuria and positive RVSCs was 10.8 and 16.5 %, respectively. The frequency of IPC was 15.9 % (39/246). Sensitivity, specificity, positive and negative predictive values of urine culture and of RVSC in predicting GBS IPC were 41, 94.7, 59.3 and 89.5 %, and 76.9, 95.4, 76.9 and 95.4 %, respectively. GBS bacteriuria was significantly associated with IPC, overall [relative risk (RR) 5.6] and in women with negative RVSC (RR 8.5), with bacteriuria <104 c.f.u. ml-1 (RR 5.9) or when both circumstances coexisted (RR 8.9). The urinary colony count was <104 c.f.u. ml-1 in 13 of the 16 women with GBS bacteriuria and IPC. CONCLUSION: GBS bacteriuria is a risk factor for IPC, irrespective of urinary GBS concentration or of colonization status at late gestation. Therefore, microbiology laboratories should search, and report, GBS of any colony count in urine from pregnant women, and not only in the presence of ≥104 c.f.u. ml-1 as the 2010 CDC guidelines recommend.