Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular disorder. The prevalence of pulmonary hypertension (PH) in the course of the disease is considered to be lower than 10% [1–4]. As previously reported, the increase in pulmonary arterial pressure in this setting may result from different mechanisms: isolated high flow state; PH due to left heart disease secondary to high cardiac output in the presence of hepatic arteriovenous malformations (post-capillary PH, clinical classification group 2); or pulmonary vascular remodelling (pre-capillary PH) [1–3]. For the latter mechanism, a diagnosis of heritable pulmonary arterial hypertension (group 1.2) could be applicable, as genetic mutations in the transforming growth factor-β (TGF-β) signalling pathway () are always found [5].

Some patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis exhibit a progressive clinical phenotype. These chronic progressive fibrosing ILDs have a variety of underlying diseases, and their prevalence is currently unknown. Here we carry out the first systematic review of literature on the prevalence of fibrosing ILDs and progressive fibrosing ILDs using data from physician surveys to estimate frequency of progression among different ILDs. We searched MEDLINE and Embase for studies assessing prevalence of ILD, individual ILDs associated with fibrosis and progressive fibrosing ILDs. These were combined with data from previously published physician surveys to obtain prevalence estimates of each chronic fibrosing ILD with a progressive phenotype and of progressive fibrosing ILDs overall. We identified 16 publications, including five reporting overall ILD prevalence, estimated at 6.3–76.0 per 100,000 people in Europe (four studies) and 74.3 per 100,000 in the USA (one study). In total, 13–40% of ILDs were estimated to develop a progressive fibrosing phenotype, with overall prevalence estimates for progressive fibrosing ILDs of 2.2–20.0 per 100,000 in Europe and 28.0 per 100,000 in the USA. Prevalence estimates for individual progressive fibrosing ILDs varied up to 16.7 per 100,000 people. These conditions represent a sizeable fraction of chronic respiratory disorders and have a high unmet need.

Vascular involvement in coronavirus disease 2019 (COVID-19) has been suggested by several observations, such as the high rate of pulmonary embolism [1], the prothrombotic state and the proinflammatory biological profile [2, 3], as well as the pathological findings of severe endothelial injury and diffuse thrombosis [4]. Dual-energy computed tomography (DECT) allows specific imaging of the iodinated contrast agent distribution within the lung, which has been demonstrated as a surrogate marker of lung perfusion [5, 6]. Therefore, our goal was to assess pulmonary microvascular involvement in patients with COVID-19 pneumonia by using DECT and to determine whether vascular changes vary during the course of the disease.

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects ( = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients ( < 0.0001). Rates of angiomyolipomas >3 cm ( = 0.0119), growing lesions ( = 0.0439), and interventions for angiomyolipomas ( = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with and mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.

Initial combination therapy plays a central role in managing pulmonary arterial hypertension (PAH) [1–4]. Patients with low- or intermediate-risk of 1-year mortality at diagnosis should be treated with initial combination therapy with an endothelin receptor antagonist (ERA) and phosphodiesterase type-5 inhibitor (PDE5i) [2–4]. Benefits of initial therapy with the ERA ambrisentan and PDE5i tadalafil were demonstrated in AMBITION [1]; prospective evidence for other treatment combinations within these drug classes is needed.

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.

Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) vs. mutations, after stratification for levels of IA, in a large, international cohort.

Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ<50]). Chi-square tests were used to test associations between ID and TAND manifestations. The association between TAND and age (children vs. adults), sex (male vs. female), and genotype ( vs. ) stratified by IA levels were examined using the Cochran–Mantel–Haenszel tests.

Eight hundred and ninety four of the 2,211 participants had formal IQ assessments. There was a significant association ( < 0.05) between levels of IA and the majority of TAND manifestations, except impulsivity ( = 0.12), overactivity ( = 0.26), mood swings ( = 0.08), hallucinations ( = 0.20), psychosis ( = 0.06), depressive disorder ( = 0.23), and anxiety disorder ( = 0.65). Once controlled for IA, children had higher rates of overactivity, but most behavioral difficulties were higher in adults. At the psychiatric level, attention deficit hyperactivity disorder (ADHD) was seen at higher rates in children while anxiety and depressive disorders were observed at higher rates in adults. Compared to females, males showed significantly higher rates of impulsivity and overactivity, as well as autism spectrum disorder (ASD) and ADHD. No significant age or sex differences were observed for academic difficulties or neuropsychological deficits. After controlling for IA no genotype-TAND associations were observed, except for higher rates of self-injury in individuals with mutations.

Findings suggest IA as risk marker for most TAND manifestations. We provide the first evidence of male preponderance of ASD and ADHD in individuals with TSC. The study also confirms the association between and IA but, once controlling for IA, disproves the previously reported association with ASD and with most other TAND manifestations.

We used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs).

Subjects in the two INPULSIS trials had a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) while subjects in the INBUILD trial had a progressive fibrosing ILD other than IPF and met protocol-defined criteria for ILD progression despite management. Using data from the placebo groups, we compared the rate of decline in forced vital capacity (FVC) (mL·year) and mortality over 52 weeks in the INBUILD trial with pooled data from the INPULSIS trials.

The adjusted mean annual rate of decline in FVC in the INBUILD trial (n=331) was similar to that observed in the INPULSIS trials (n=423) (−192.9 mL·year and −221.0 mL·year, respectively; nominal p-value=0.19). The proportion of subjects who had a relative decline in FVC >10% predicted at Week 52 was 48.9% in the INBUILD trial and 48.7% in the INPULSIS trials, and the proportion who died over 52 weeks was 5.1% in the INBUILD trial and 7.8% in the INPULSIS trials. A relative decline in FVC >10% predicted was associated with an increased risk of death in the INBUILD trial (hazard ratio 3.64) and the INPULSIS trials (hazard ratio 3.95).

These findings indicate that patients with fibrosing ILDs other than IPF, who are progressing despite management, have a subsequent clinical course similar to patients with untreated IPF, with a high risk of further ILD progression and early mortality.

Prolidase is a ubiquitous enzyme that plays a major role in the metabolism of proline-rich proteins. Prolidase deficiency is a rare autosomal recessive inborn metabolic and multisystemic disease, characterized by a protean association of symptoms, namely intellectual disability, recurrent infections, splenomegaly, skin lesions, auto-immune disorders and cytopenia. To our knowledge, no published review has assembled the different clinical data and research studies over prolidase deficiency. The aim of this study is to summarize the actual state of the art from the descriptions of all the patients with a molecular diagnosis of prolidase deficiency reported to date regarding the clinical, biological, histopathological features, therapeutic options and functional studies.

Systemic sclerosis (SSc) is a systemic autoimmune disease affecting multiple organ systems, including the lungs. Interstitial lung disease (ILD) is the leading cause of death in SSc.

There are no valid biomarkers to predict the occurrence of SSc-ILD, although auto-antibodies against anti-topoisomerase I and several inflammatory markers are candidate biomarkers that need further evaluation. Chest auscultation, presence of shortness of breath and pulmonary function testing are important diagnostic tools, but lack sensitivity to detect early ILD. Baseline screening with high-resolution computed tomography (HRCT) is therefore necessary to confirm an SSc-ILD diagnosis. Once diagnosed with SSc-ILD, patients' clinical courses are variable and difficult to predict, although certain patient characteristics and biomarkers are associated with disease progression. It is important to monitor patients with SSc-ILD for signs of disease progression, although there is no consensus about which diagnostic tools to use or how often monitoring should occur. In this article, we review methods used to define and predict disease progression in SSc-ILD.

There is no valid definition of SSc-ILD disease progression, but we suggest that either a decline in forced vital capacity (FVC) from baseline of ≥10%, or a decline in FVC of 5–9% in association with a decline in diffusing capacity of the lung for carbon monoxide of ≥15% represents progression. An increase in the radiographic extent of ILD on HRCT imaging would also signify progression. A time period of 1–2 years is generally used for this definition, but a decline over a longer time period may also reflect clinically relevant disease progression.