Practical management of oral treprostinil in patients with pulmonary arterial hypertension: Lessons from ADAPT, EXPEDITE, and expert consensus.

BACKGROUND: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies. STUDY DESIGN AND METHODS: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use. RESULTS: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76 % female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62 % (78/126) of patients reported headache and diarrhea, and 40 % (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61 % headache, 44 % diarrhea, 70 % nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron, were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6. CONCLUSION: Patient selection for, and initiation and titration of, oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help patients reach higher and more efficacious doses of oral treprostinil.

Unsupervised Exercise in Interstitial Lung Disease: A Delphi Study to Develop a Consensus Preparticipation Screening Tool for Lymphangioleiomyomatosis.

BACKGROUND: Little research is available to provide practical guidance to health care providers for exercise preparticipation screening and referral of patients with interstitial lung diseases (ILD), including lymphangioleiomyomatosis (LAM), to participate in remote, unsupervised exercise programs. RESEARCH QUESTION: What exercise preparticipation screening steps are essential to determine whether a patient with LAM is medically appropriate to participate in a remote, unsupervised exercise program? STUDY DESIGN AND METHODS: Sixteen experts in LAM and ILD participated in a two-round modified Delphi study, ranking their level of agreement for ten statements related to unsupervised exercise training in LAM, with an a priori definition of consensus. Additionally, 60 patients with LAM completed a survey of the perceived risks and benefits of remote exercise training in LAM. RESULTS: Seven of the 10 statements reached consensus among experts. Experts agreed that an in-person clinical exercise test is indicated to screen for exercise-induced hypoxemia and prescribe supplemental oxygen therapy as indicated prior to initiating a remote exercise program. Patients with recent pneumothorax should wait to start an exercise program for at least 4 weeks until after resolution of pneumothorax and clearance by a physician. Patients with high cardiovascular risk for event during exercise, severe resting pulmonary hypertension, or risk for falls may be more appropriate for referral to a rehabilitation center. A LAM-specific remote exercise preparticipation screening tool was developed from the consensus statements and agreed upon by the panelists. INTERPRETATION: A modified Delphi study approach was useful to develop disease-specific recommendations for safety and preparticipation screening prior to unsupervised, remotely administered exercise in LAM. The primary product of this study is a clinical decision aid for providers to use when medically screening patients prior to participation in the newly launched LAMFit remote exercise program. FUNDING: This work was funded by an Established Investigator Award (LAM0130PB07-18) to MBB from The LAM Foundation.

A perfectly imperfect engine: Utilizing the digital twin paradigm in pulmonary hypertension.

Pulmonary hypertension (PH) is a severe medical condition with a number of treatment options, the majority of which are introduced without consideration of the underlying mechanisms driving it within an individual and thus a lack of tailored approach to treatment. The one exception is a patient presenting with apparent pulmonary arterial hypertension and shown to have vaso-responsive disease, whose clinical course and prognosis is significantly improved by high dose calcium channel blockers. PH is however characterized by a relative abundance of available data from patient cohorts, ranging from molecular data characterizing gene and protein expression in different tissues to physiological data at the organ level and clinical information. Integrating available data with mechanistic information at the different scales into computational models suggests an approach to a more personalized treatment of the disease using model-based optimization of interventions for individual patients. That is, constructing digital twins of the disease, customized to a patient, promises to be a key technology for personalized medicine, with the aim of optimizing use of existing treatments and developing novel interventions, such as new drugs. This article presents a perspective on this approach in the context of a review of existing computational models for different aspects of the disease, and it lays out a roadmap for a path to realizing it.

Progressive Dyspnea on Exertion in an 82-Year-Old.

An older patient with hereditary hemorrhagic telangiectasia and right lower lobe segmental pulmonary embolism presented with dyspnea that had worsened over 5 years; physical examination and laboratory testing showed jugular venous distension, a cardiac systolic murmur, right ventricular heave, bilateral lower extremity edema to the knees, and elevated brain-type natriuretic peptide level. What is the diagnosis and what would you do next?

Managing High Cardiac Output Failure in a Patient With Hereditary Hemorrhagic Telangiectasias During Pregnancy.

Hemorrhagic telangiectasias is a rare genetic vascular disorder that may complicate pregnancy. We report a case of a pregnant hemorrhagic telangiectasias patient with innumerable hepatic arteriovenous malformations that developed high output cardiac failure necessitating delivery. Postpartum, the patient was treated with bevacizumab that resulted in clinical improvement.

A 28-Year-Old Woman With Nail Discoloration, Recurrent Bronchitis, and Left-Sided Facial Swelling.

CASE PRESENTATION: A 28-year-old woman with a history of congenital hip dysplasia was referred for evaluation of recurrent bronchitis. She had undergone left hip replacement with titanium implants 11 years prior to presentation. The patient reported frequent bouts of bronchitis, sinusitis, and left-sided nontender facial swelling that started after the hip replacement surgery. She also reported nail discoloration of her left first toenail 1 year after this procedure, and nail discoloration of her right first toenail 3 years after the procedure. She was treated for onychomycosis without improvement. Review of symptoms was positive for chronic dry cough and facial tenderness but was negative for dyspnea, wheezing, or chest tightness. She previously had been diagnosed with common variable immunodeficiency based on low immunoglobulin levels, and the condition was maintained with monthly IV immunoglobulins but without any improvement or change in the frequency of sinusitis, bronchitis, or facial swelling. She did not use tobacco, and her family history was unremarkable.

Postpartum Chylothorax: A Case Report and Review of the Literature.

Idiopathic postpartum chylothorax is an uncommon finding, with only four cases described in the literature. We present the case of a 37-year-old female who was diagnosed with chylothorax three days after the delivery of her baby. Chylothorax was managed with chest tube placement, a low-fat diet, and octreotide. As opposed to the current literature, her chylothorax resolved with medical management and chest tube insertion without further surgical intervention. The chest tube was removed 11 days after chest tube placement, and she was discharged in stable condition. We also review the most recent literature on postpartum chylothorax.

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high-output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left-sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

Intralobar pulmonary sequestration presenting as recurrent left lower lobe pneumonia.

This case discusses the diagnosis and management of pulmonary sequestration. Typically discovered incidentally on imaging, it can be a cause of recurrent pulmonary infections causing severe morbidity to the patient. Surgical management is indicated when found to prevent the complications of recurrent infections, including pulmonary necrosis, abscess, or fistula formation.

Systemic capillary leak syndrome secondary to decompression sickness.

Systemic capillary leak syndrome is a rare derangement of endothelial function characterised by extravasation of plasma and proteins into the interstitial space. Primary capillary leak syndrome is a rare, episodic medical illness of unknown molecular pathology while secondary capillary leak syndrome may be precipitated by any number of inflammatory and infectious syndromes. Decompression sickness, a disorder of depressurisation, has been identified as a very rare trigger. We present a structured case report of systemic capillary leak syndrome secondary to decompression sickness following deep diving, informing physicians of this potential complication. No pharmacological therapy has substantial evidence in the treatment of acute systemic capillary leak syndrome. By review of current recommendations for acute management, we also emphasise an observed positive response to judicious fluid resuscitation and an oral cyclic AMP-elevating agent (ie, terbutaline).

A 43-Year-Old Woman With Pleuritic Chest Pain, Shortness of Breath, and Weakness of All Extremities.

CASE PRESENTATION: A 43-year-old woman with a medical history of hypothyroidism, psoriasis, and tobacco abuse (30-pack year history) who had quit smoking several months prior to presentation presented with pleuritic chest pain. She also noted a 2-year history of progressive numbness and weakness in her bilateral upper and lower extremities that now prevented her from completing her activities of daily living. She had worsening exertional dyspnea and a subjective 50-lb weight loss over the past year.

Precapillary pulmonary arterial hypertension in a patient with Proteus syndrome.

Proteus syndrome is a rare progressive multisystem disorder characterized by asymmetric, disproportionate overgrowth of bone, skin, and other tissue types. Molecular pathogenesis has been identified as somatic activating mutations of the AKT1 gene. The presentation of Proteus syndrome is exceptionally variable. Respiratory complications include emphysematous lung disease and predisposition to pulmonary emboli, the latter of which is a significant source of mortality. Pulmonary hypertension due to longstanding hypoxic lung disease as well as chronic thromboembolic events has been observed in this population. In contrast, precapillary pulmonary arterial hypertension in the absence of chronic pulmonary emboli and parenchymal lung disease has not been described in the literature on patients with Proteus syndrome. We report such a case in a young patient with Proteus syndrome, reviewing subsequent management and emphasizing the need for a detailed investigation of dyspnea.

A 36-Year-Old Woman With Recurrent Pneumothoraces.

CASE PRESENTATION: A 36-year-old woman with no significant medical history was referred to our institution for evaluation of recurrent pneumothoraces. She had had approximately 16 right-sided pneumothoraces over the prior 3 years. Her pneumothoraces were accompanied by chest pain, and they all presented within 3 days of her menstrual period. She had had three pleurodeses over the prior 3 years. Additionally, she underwent video-assisted thoracic surgery (VATS) exploration, and her diaphragm was reported as normal. She had had a lung biopsy done, which only revealed normal lung parenchyma.

A 26-Year-Old Woman With Retinal Telangiectasias, Onychodystrophy, and Persistent Dyspnea.

CASE PRESENTATION: A 26-year-old woman with no significant past medical history sought treatment for worsening dyspnea and hypoxia. The exertional dyspnea began 2 years prior and was associated with substernal chest discomfort. She did not report myalgia, edema, or worsening of dyspnea on supine or upright position. The patient reported no personal history of tobacco or illicit drug use. Family history was unremarkable. She was started on supplemental oxygen at 3 L/min. Initial workup included CT scan angiography of the chest, which showed no pulmonary embolism and normal lung parenchyma. Transthoracic echocardiography showed unremarkable results. She was not given a clear diagnosis for hypoxia and was treated empirically with antibiotics and bronchodilators without improvement. Over the course of 2 years, her condition progressed to requiring 6 L/min nasal canula at rest and associated dyspnea with minimal exertion and a 30-pound unintentional weight loss. During this time, pulmonary function tests noted normal spirometry results and lung volumes, but a decreased diffusing capacity for carbon monoxide of 33%. She also was discovered incidentally to be leukopenic and thrombocytopenic, with subsequent bone marrow biopsy revealing hypocellularity of 30% to 40%. The patient concurrently demonstrated bilateral visual impairment secondary to retinal telangiectasias with increased severity of deficit in the right eye. She subsequently was referred to our institution for further evaluation.

Opportunistic Infection Associated With Elevated GM-CSF Autoantibodies: A Case Series and Review of the Literature.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to play a key role in enhancing multiple immune functions that affect response to infectious pathogens including antigen presentation, complement- and antibody-mediated phagocytosis, microbicidal activity, and neutrophil chemotaxis. Reduced GM-CSF activity and immune response provides a mechanism for increased infection risk associated with autoimmune pulmonary alveolar proteinosis (aPAP) and other disorders involving the presence of GM-CSF autoantibodies. We present a case series of five patients with persistent or unusual pulmonary and central nervous system opportunistic infections (Cryptococcus gattii, Flavobacterium, Nocardia) and elevated GM-CSF autoantibody levels, as well as 27 cases identified on systematic review of the literature.

A 31-Year-Old Man With Asthma, Chest Discomfort, and Shortness of Breath.

CASE PRESENTATION: A 31-year-old man with a medical history of well-controlled asthma presented with a 3-week history of midsternal chest pressure and shortness of breath. His symptoms were associated with malaise, weakness, 40-pound weight loss over several months, and intermittent fever up to 38.3ºC. A week and half earlier, he started experiencing a productive cough with white sputum and arthralgias in his knees. He denied any exacerbating or relieving factors for his symptoms. Additionally, he had a pruritic rash on his thighs for the last year that remained unresolved despite antifungal medication.

Pulmonary renal syndrome: a clinical review.

The term "pulmonary renal syndrome" describes a clinical syndrome which is characterised by the presence of both diffuse alveolar haemorrhage and glomerulonephritis. It encompasses a group of diseases with distinctive clinical and radiological manifestations, as well as different pathophysiological processes. The most common diseases implicated are anti-neutrophil cytoplasm antibodies (ANCA)-positive small vessel vasculitis and anti-glomerular basement membrane (anti-GBM) disease. Prompt recognition is required as respiratory failure and end-stage renal failure can rapidly occur. Treatment includes a combination of glucocorticoids, immunosuppression, plasmapheresis and supportive measures. The use of targeted treatments has significantly reduced mortality. Thus, an understanding of pulmonary renal syndrome is essential for the respiratory physician.