Defining the pathway to timely diagnosis and treatment of interstitial lung disease: a US Delphi survey.

INTRODUCTION: Timely diagnosis of interstitial lung disease (ILD) is limited by obstacles in the current patient pathway. Misdiagnosis and delays are common and may lead to a significant burden of diagnostic procedures and worse outcomes. This Delphi survey aimed to identify consensus on the key steps that facilitate the patient journey to an accurate ILD diagnosis and appropriate management in the US. METHODS: A modified Delphi analysis was conducted, comprising three online surveys based on a comprehensive literature search. The surveys spanned five domains (guidelines, community screening, diagnosis, management and specialist referral) and were completed by a panel of US physicians, including primary care physicians and pulmonologists practising in community or academic settings. A priori definitions of consensus agreement were median scores of 2-3 (agree strongly/agree), with an IQR of 0-1 for questions on a 7-point Likert scale from -3 to 3, or ≥80% agreement for binary questions. RESULTS: Forty-nine panellists completed the surveys and 62 statements reached consensus agreement. There was consensus agreement on what should be included in the primary care evaluation of patients with suspected ILD and the next steps following workup. Regarding diagnosis in community pulmonology care, consensus agreement was reached on the requisition and reporting of high-resolution CT scans and the appropriate circumstances for holding multidisciplinary discussions. Additionally, there was consensus agreement on which symptoms and comorbidities should be monitored, the frequency of consultations and the assessment of disease progression. Regarding specialist referral, consensus agreement was reached on which patients should receive priority access to ILD centres and the contents of the referral package. CONCLUSIONS: These findings clarify the most common issues that should merit further evaluation for ILD and help define the steps for timely, accurate diagnosis and appropriate collaborative specialty management of patients with ILD.

A 52-Year-Old Man Who Smokes With Rapidly Progressive Respiratory Failure.

CASE PRESENTATION: A 52-year-old White man, who currently smokes, was admitted to the medical ICU with worsening shortness of breath. The patient was dyspneic for a month and had been clinically diagnosed with COPD by his primary care doctor and started on bronchodilators and supplemental oxygen. He had no known medical history or recent illness. His dyspnea worsened rapidly over the next month, prompting admission to the medical ICU. He was on high-flow oxygen followed by noninvasive positive pressure ventilation and then mechanical ventilation. He denied cough, fever, night sweats, or weight loss at the time of admission. There was no history of work-related or occupational exposures, drug intake, or recent travel. Review of systems was negative for arthralgia, myalgia, or skin rash.

Chronic dyspnea with Raynaud's phenomenon and elevated ANA: A diagnosis of systemic sclerosis sine scleroderma.

Systemic sclerosis (SSc) should be considered in all patients initially diagnosed with idiopathic interstitial lung disease (ILD), even in the absence of classical scleroderma cutaneous features. Systemic sclerosis sine scleroderma (ssSSc) is a rare subtype of SSc, and the diagnosis requires the absence of characteristic skin thickening but the presence of the three following criteria: (A) Raynaud's phenomenon or the equivalent of abnormal nail fold capillaries, (B) positive antinuclear antibody (ANA), typically with nucleolar or speckled immunofluorescence pattern, and (C) at least one internal organ involvement of ILD, renal dysfunction, esophageal/bowel dysmotility or pulmonary arterial hypertension; in the absence of an alternative rheumatological diagnosis. The radiological and histopathological features of systemic sclerosis sine scleroderma-associated interstitial lung disease (ssSSc-ILD) are commonly those of non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) that cannot help distinguish between idiopathic interstitial pneumonia, different types of connective tissue diseases, or even different subsets of SSc. Therefore, other than chest imaging, the use of nail fold capillaroscopy, positive serum ANA antibody, echocardiogram, and esophagram are essential, in conjunction with the clinical presentation for facilitating the diagnosis of ssSSc. We present a case of a 58-year-old woman presenting with chronic dyspnea, a positive review of systems for Raynaud's phenomenon, and found to have elevated nucleolar immunofluorescence pattern of ANA with chest imaging consistent with the diagnosis of ssSSc-ILD. The uniqueness of this case is that despite symptomatic alleviation with oral mycophenolate therapy, our patient's restrictive lung disease on pulmonary function tests continued to decline, requiring initiation of oral nintedanib therapy leading to stability and improvement. However, due to the rarity of ssSSc, the use of oral nintedanib for systemic sclerosis-associated ILD has only been formally assessed on patients with diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis.

Opaganib in Coronavirus Disease 2019 Pneumonia: Results of a Randomized, Placebo-Controlled Phase 2a Trial.

Background: Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe coronavirus disease 2019 (COVID-19) pneumonia. The objective of the study was to evaluate the safety of opaganib and its effect on supplemental oxygen requirements and time to hospital discharge in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods: This Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in 8 sites in the United States. Forty-two enrolled patients received opaganib (n = 23) or placebo (n = 19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo. Results: There were no safety concerns arising in this study. The incidence of ≥Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. A numerical advantage for opaganib over placebo was observed in in this nonpowered study reflected by total supplemental oxygen requirement from baseline to Day 14, the requirement for supplemental oxygen for at least 24 hours by Day 14, and hospital discharge. Conclusions: In this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib had a similar safety profile to placebo-treated patients, with preliminary evidence of benefit for opaganib as measured by supplementary oxygen requirement and earlier hospital discharge. These findings support further evaluation of opaganib in this population.

Incidence and risk factors for secondary pulmonary infections in patients hospitalized with coronavirus disease 2019 pneumonia.

BACKGROUND: Secondary pulmonary infections (SPI) have not been well described in COVID-19 patients. Our study aims to examine the incidence and risk factors of SPI in hospitalized COVID-19 patients with pneumonia. METHODS: This was a retrospective, single-center study of adult COVID-19 patients with radiographic evidence of pneumonia admitted to a regional tertiary care hospital. SPI was defined as microorganisms identified on the respiratory tract with or without concurrent positive blood culture results for the same microorganism obtained at least 48 h after admission. RESULTS: Thirteen out of 244 (5%) had developed SPI during hospitalization. The median of the nadir lymphocyte count during hospitalization was significantly lower in patients with SPI as compared to those without SPI [0.4 K/uL (IQR 0.3-0.5) versus 0.6 K/uL (IQR 0.3-0.9)]. Patients with lower nadir lymphocyte had an increased risk of developing SPI with odds ratio (OR) of 1.21 (95% CI: 1.00 to 1.47, p = 0.04) per 0.1 K/uL decrement in nadir lymphocyte. The baseline median inflammatory markers of CRP [166.4 mg/L vs. 100.0 mg/L, p = 0.01] and d-dimer (18.5 mg/L vs. 1.4 mg/L, p<0.01), and peak procalcitonin (1.4 ng/mL vs. 0.3 ng/mL, p<0.01) and CRP (273.5 mg/L vs. 153.7 mg/L, p<0.01) during hospitalization were significantly higher in SPI group. CONCLUSIONS: The incidence of SPI in hospitalized COVID-19 patients was 5%. Lower nadir median lymphocyte count during hospitalization was associated with an increased OR of developing SPI. The CRP and d-dimer levels on admission, and peak procalcitonin and CRP levels during hospitalization were higher in patients with SPI.

Indications, Clinical Utility, and Safety of Bronchoscopy in COVID-19.

BACKGROUND: Bronchoscopy is an aerosol-generating procedure and routine use for patients with coronavirus disease 2019 (COVID-19) has been discouraged. The purpose of this review was to discuss the indications, clinical utility, and risks associated with bronchoscopy in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. METHODS: A literature search was performed by using appropriate key terms to identify all relevant articles from medical literature databases up to August 1, 2021. RESULTS: Twelve cohorts (9 retrospective and 3 prospective) reported the performance of 2,245 bronchoscopies in 1,345 patients with COVID-19. The majority of the subjects were male. Nearly two thirds of the bronchoscopies (62%) were performed for therapeutic indications; the rest (38%) were for diagnostic purposes. Bronchoalveolar lavage had an overall yield of 33.1% for SARS-CoV-2 in subjects with negative results of real-time polymerase chain reaction on nasopharyngeal specimens. The incidence of a secondary infection ranged from 9.3% to as high as 65%. Antibiotics were changed in a significant number of the subjects (14%-83%) based on the bronchoscopic findings. Bronchoscopy was well tolerated in most subjects except those who required noninvasive ventilation, in whom the intubation rate after the procedure was 60%. The rate of transmission of SARS-CoV-2 among health-care workers was minimum. CONCLUSIONS: Bronchoscopy in patients with COVID-19 results in a significant change in patient management. Transmission of SARS-CoV-2 seems to be low with consistent use of appropriate personal protective equipment by health-care workers. Therefore, bronchoscopic evaluation should be considered for all diagnostic and therapeutic indications in this patient population.

Pleural abnormalities in COVID-19: a narrative review.

OBJECTIVE: This narrative review aims to provide a detailed overview of pleural abnormalities in patients with coronavirus disease 19 or COVID-19. BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is a novel beta coronavirus responsible for COVID-19. Although pulmonary parenchymal and vascular changes associated with COVID-19 are well established, pleural space abnormalities have not been the primary focus of investigations. METHODS: Narrative overview of the medical literature regarding pleural space abnormalities in COVID-19. The appropriate manuscripts were identified by searching electronic medical databases and by hand searching the bibliography of the identified papers. Pleural abnormalities on transverse and ultrasound imaging are discussed. The incidence, clinical features, pathophysiology, and fluid characteristics of pleural effusion are reviewed. Studies reporting pneumothorax and pneumomediastinum are examined to evaluate for pathogenesis and prognosis. A brief comparative analysis of pleural abnormalities among patients with COVID-19, severe acute respiratory syndrome (SARS), and Middle Eastern respiratory syndrome (MERS) has been provided. CONCLUSIONS: Radiologic pleural abnormalities are common in COVID-19, but the incidence of pleural effusion appears to be low. Pneumothorax is rare and does not independently predispose the patient to worse outcomes. SARS-CoV-2 infects the pleural space; however, whether the pleural fluid can propagate the infection is unclear.

Interstitial Lung Disease Associated with Connective Tissue Diseases.

Pulmonary manifestations of connective tissue diseases (CTD) carry high morbidity and potential mortality, and the most serious pulmonary type is interstitial lung disease (ILD). Identifying and promptly intervening CTD-ILD with immune suppressor therapy will change the natural course of the disease resulting in survival improvement. Compared to idiopathic pulmonary fibrosis, the most common presentation of idiopathic interstitial pneumonia (IIP), CTD-ILD carries a better prognosis due to the response to immune suppressor therapy. Nonspecific interstitial pneumonia (NSIP) is the most common type of CTD-ILD that is different from the fibrotic classical presentation of IPF, known as usual interstitial pneumonia (UIP). An exception is rheumatoid arthritis that presents more frequently with UIP type. Occasionally, IPF may not have typical radiographic features of UIP, and a full assessment to differentiate IPF from CTD-ILD is necessary, including the intervention of a multidisciplinary team and the histopathology. Interstitial pneumonia with autoimmune features (IPAF) shows promising advantages to identify patients with ILD who have some features of a CTD without a defined autoimmune disease and who may benefit from immune suppressors. A composition of clinical, serological, and morphologic features in patients presenting with ILD will fulfill criteria for IPAF. In summary, the early recognition and treatment of CTD-ILD, differentiation from IPF-UIP, and identification of patients with IPAF fulfill the assessment by the clinician for an optimal care.

Sjogren's Syndrome and Pulmonary Disease.

Sjogren's syndrome is an autoimmune connective tissue disease targeting the exocrine glands and frequently affecting the respiratory system. The pulmonary disease is the most important extra-glandular manifestation as it carries most of the morbidity and mortality. Typically, it affects the small airways ranging from mild to severe respiratory symptoms. The upper airways are also commonly involved, predisposing sinusitis to occur more frequently than in the normal population. Lymphocytic interstitial pneumonia was initially thought to be the prevailing parenchymal disease; however, multiple cohorts report non-interstitial pneumonia to be the most frequent subtype of interstitial lung disease. In the review of high-resolution computed tomography scans, cystic lesions are commonly found and associate with both the small airways and parenchymal disease. Under their presence, amyloidosis or lymphomas should be considered in the differential. Overall, Sjogren's syndrome has a higher risk for lymphoma, and in lungs this condition should be thought of, especially when the images reveal pulmonary nodularity, lymphocytic interstitial pneumonia and lymphadenopathy. Although, pulmonary artery hypertension was traditionally and exceptionally linked with Sjogren's syndrome, together with systemic lupus erythematosus, they are now acknowledged to be the most common pulmonary vascular disease in east Asian populations, even over patients with systemic sclerosis. Although there are no controlled prospective trials to treat pulmonary disease in Sjogren's syndrome, the mainstay treatment modality still falls on glucocorticoid therapy (systemic and inhaled), combined with immune modulators or alone. Most of the evidence sustains successful outcomes based on reported cases or case series.

A 65-year-old Woman With Persistent Dyspnea, Arthritis, and Raynaud's Phenomenon.

Antisynthetase syndrome (AS) is a rare disease that affects patients with inflammatory myopathies such as polymyositis (PM) and dermatomyositis (DM). In patients with AS, up to 95% of patients develop antisynthetase syndrome-associated interstitial lung disease (AS-ILD). Although AS-ILD commonly occurs in patients with a well-established diagnosis of AS, it can be the first or only manifestation of an occult AS. The frequency of interstitial lung disease (ILD), myopathy, and skin involvement are often dependent on the type of myositis-specific antibodies present. AS-ILD patients who are positive for both anti-Jo-1 and anti-SSA/RO-52 autoantibodies often present with a severe degree of lung restriction on pulmonary function tests and radiologic imaging with an inadequate response toward immunosuppressive therapies. We describe a 65-year-old woman who presents with chronic dyspnea. She was initially diagnosed with corticosteroid-resistant cryptogenic organizing pneumonia based on the radiological findings on her CT chest. Her symptoms did not improve, and she suffered from intolerable corticosteroid-related side effects. Reviews of systems were positive for arthritis and Raynaud's phenomenon. She was found to have elevated inflammatory markers and autoantibodies such as anti-Jo-1, anti-RO-52, and anti-SSA. A diagnosis of AS-ILD resistant to corticosteroid therapy was made. Her lung function improved with combination therapy of mycophenolate and rituximab. Our case highlights that a detailed history and physical exam, compatible radiologic imaging, and autoantibodies are essential for the diagnosis of AS-ILD.

Respiratory Failure Secondary to Diaphragmatic Paralysis from Acute Exacerbation of Dermatomyositis.

Dermatomyositis (DM) is an idiopathic inflammatory disorder that presents with proximal muscle weakness and typical DM skin changes. DM can involve other organs such as the lung, esophagus, and heart. Diaphragmatic muscle paralysis is an unrecognized clinical presentation of acute DM exacerbation. A 58-year-old man with a history of DM presented to the hospital after sustaining a cardiorespiratory arrest. Before arrest, he had been suffering from progressive dyspnea and muscle weakness. Immunosuppressive therapy of tacrolimus for DM was recently discontinued due to renal toxicity. Bedside ultrasound of the diaphragm while intubated revealed evidence of bilateral diaphragmatic paralysis. After extubation, supine and upright pulmonary function tests (PFT) and sniff test results strengthened the diagnosis of diaphragmatic paralysis. The patient was worked up for an acute DM exacerbation as the likely etiology of the severe diaphragmatic muscle weakness (diaphragmatic paralysis) and ventilatory failure. Skin and muscle biopsy confirmed the diagnosis of active DM. The patient was treated with high dose steroids and mycophenolate mofetil, following which he soon recovered.

Type A aortic dissection mimicking saddle pulmonary embolism on CT imaging.

Type A aortic dissection is an uncommon cause of chest pain that carries a high morbidity and mortality rate. A previous history of hypertension and coronary artery bypass grating (CABG) are recognized risk factors for Type A aortic dissection. We present a case of an elderly man who presents with acute onset chest pain and was found to have an acute ruptured Type A aortic dissection that has a "saddle pulmonary embolism"-like appearance on computed tomography (CT) imaging. We also describe the clinical, laboratory, and radiological workup done leading up to the diagnosis of Type A aortic dissection in the emergency setting.

Rapid reversal of diffuse cerebral edema with correction of serum sodium in acute water intoxication.

Acute water intoxication (AWI) is a disorder of excess water intake that can manifest in neurological injury and death. We describe a case of a 54-year-old man that presents to the emergency department with a generalized toxic-clonic seizure due to AWI. Initial computed tomography of the brain demonstrated diffuse cerebral edema. However, with correction of serum sodium over the one hospital day, the patient's neurological symptoms and imaging completely resolved. Clinicians should recognize of reversibility of this entity with management of hyponatremia.

A Fatal Case of Thrombotic Microangiopathy Without Schistocytosis and Absent Biochemical Markers of Hemolysis.

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia with thrombocytopenia. In addition to the primary TMA syndromes, microangiopathic hemolytic anemia with thrombocytopenia can be seen in many systemic diseases. Transplant associated TMA (TA-TMA) affects patients following stem cell or solid organ transplant. A 48-year-old male who underwent autologous stem cell transplant for nonsecretory multiple myeloma was admitted to our hospital with worsening anemia, thrombocytopenia, renal dysfunction and hepatosplenomegaly. Initial blood work revealed rare schistocytes and normal lactate dehydrogenase and haptoglobin levels. He underwent an extensive workup looking for an infectious, inflammatory or malignant etiology but a definitive diagnosis could not be reached. Over his prolonged stay at the hospital, he suffered from multiorgan failure and eventually passed away. An autopsy revealed TMA involving all clinically affected organ systems and was deemed to be the cause of his demise. The absence of typical blood work suggestive of hemolysis does not rule out a diagnosis of TA-TMA. Knowledge of this rare disease entity will help physicians identify and treat this life-threatening condition early and effectively.

Chronic, Silent Microaspiration Masquerading as Interstitial Lung Disease.

Chronic, silent microaspiration is a common but underrecognized pathologic process in pulmonary medicine. The clinical presentation is variable and diagnosis can be challenging. We present the case of a 55-year-old woman with known emphysema, who was referred to us for progressive respiratory failure that was unresponsive to therapy. The patient had 9 hospital admissions in the preceding 5 months and was treated with multiple courses of antibiotics and systemic steroid therapy for a diagnosis of cryptogenic organizing pneumonia. The steroid therapy was complicated by 51 pounds of weight gain. She had conversational as well as profound exertional shortness of breath. Physical examination revealed a woman in moderate distress and bilateral diffuse wheezing and rhonchi. Computed tomography of the chest revealed areas of bronchocentric consolidation and bronchial wall thickening in the bilateral lower lobes. She underwent surgical lung biopsy and the histopathology was consistent with chronic aspiration pneumonia.

Chronic pleuritis leading to severe pulmonary restriction: a rare complication of Degos disease.

This case demonstrates chronic fibrosing pleuritis, as a rare pulmonary aetiology for mortality in patients with Degos disease or malignant atrophic papulosis (MAP). Knowledge of this unusual complication will help physicians identify this entity early and provide appropriate treatment.Patients with MAP die from gastrointestinal and brain involvement within 2-3 years of diagnosis. This case is unique as the patient survived for 9 years and died secondary to respiratory failure, which had not been reported before. Our patient was a young man, diagnosed with MAP at the age of 17. His skin and gastrointestinal disease were controlled with eculizumab and parenteral treprostinil. The patient developed severe restrictive pulmonary disease, required ventilatory support, and died from respiratory failure. An autopsy revealed chronic fibrosis pleuritis. Longer surviving patients with MAP might suffer from significant respiratory disease. Pulmonary function test should be obtained to identify subclinical respiratory limitation.

Central airway compression by massively dilated pulmonary artery in a patient with pulmonary arterial hypertension: a rare entity.

Patients with pulmonary arterial hypertension (PAH) usually die from progressive right ventricular failure. Mechanical complications due to pulmonary artery (PA) enlargement are rare and include tracheobronchial and left main coronary artery compression, and PA dissection. A 62-year-old female with PAH was seen in our office for follow-up. During the evaluation, spirometry was performed, which revealed a severe obstructive ventilatory limitation. Subsequent workup identified compression of bilateral mainstem bronchi from the dilated PA as the aetiology for the abnormal spirometry. Very few cases of this rare complication have been reported in the literature. A significant dilation of the PA is necessary (>4 cm) for the occurrence of these complications. Dilation of PA is an independent risk factor for sudden unexpected death in patients with PAH.