Immune check-point inhibitor-related pneumonitis: acute lung injury with rapid progression and organising pneumonia with less severe clinical disease.

AIMS: To improve understanding of the pathology of immune check-point inhibitor (ICI)-related pneumonitis, clinical, radiographic and histopathological features and outcomes were investigated in a cohort of patients who were treatment-naive before receiving ICI inhibition, who underwent lung biopsy, and in whom other potential causes of lung injury were excluded. METHODS: Patients were retrospectively identified via searches of institutional pathology and clinical records. Patients treated with other modalities for cancer and patients with lung infections or other aetiologies that could cause pneumonitis were excluded. Clinical records were reviewed by pulmonologists. Imaging studies at presentation and follow-up were reviewed by a thoracic radiologist. Pathology was reviewed by thoracic pathologists. RESULTS: Six patients with ICI-related pneumonitis were identified. Two patients presented with respiratory failure requiring mechanical ventilation, diffuse ground glass opacities (GGOs) on chest computed tomography (CT) and acute lung injury (ALI) pattern on transbronchial lung biopsies and had fatal outcomes, despite treatment. The remaining four patients presented with less severe symptoms, predominantly consolidations and patchy ground glass and part solid opacities on chest CT, organising pneumonia (OP) or chronic interstitial inflammation histologically, and showed favourable responses to treatment and remission within months. CONCLUSIONS: This study highlights two radiological-pathological patterns of ICI-related pneumonitis with different behaviour: (1) severe respiratory symptoms and diffuse GGOs on imaging correlating with ALI pattern histologically and poor prognosis; and (2) mild respiratory symptoms and consolidations or patchy subsolid opacities on imaging correlating histologically with OP or chronic interstitial inflammation and good outcomes.

Utility of Bronchoscopy with Bronchoalveolar Lavage among Hematologic Transplant Recipients in the Era of Noninvasive Testing.

BACKGROUND: Pulmonary complications are common among hematologic stem cell transplant (HSCT) recipients. Their evaluation can be pursued through bronchoscopy with bronchoalveolar lavage (BAL) and a variety of available noninvasive studies, which include newer molecular markers for detecting a variety of infectious agents. OBJECTIVE: The objective of this study is to evaluate the diagnostic yield of BAL among HSCT patients relative to the yield of noninvasive testing. METHOD: This is a retrospective analysis of HSCT recipients who underwent both BAL and noninvasive testing at a cancer center in 2013 and 2014. RESULTS: There were 210 diagnostic results among 98 HSCT recipients. There were 84 unique findings on noninvasive testing that were not evident on BAL, and 36 unique findings on BAL that were not evident on noninvasive testing. Noninvasive testing tended to yield bacterial and viral infections more commonly, while BAL yielded mycobacterial isolates more commonly. CONCLUSION: While both noninvasive testing and BAL are helpful in this population, each appeared more precise than the other with individual lung diseases. Bronchoscopy with BAL and noninvasive testing should be considered complementary strategies in the workup of pulmonary complications among HSCT patients.

Outcomes after long-term mechanical ventilation of cancer patients.

BACKGROUND: The probability of weaning and of long-term survival of chronically mechanically ventilated cancer patients is unknown, with incomplete information available to guide therapeutic decisions. We sought to determine the probability of weaning and overall survival of cancer patients requiring long-term mechanical ventilation in a specialized weaning unit. METHODS: A single-institution retrospective review of patients requiring mechanical ventilation outside of a critical care setting from 2008 to 2012 and from January 1 to December 31, 2018, was performed. Demographic and clinical data were recorded, including cancer specifics, comorbidities, treatments, and outcomes. Overall survival was determined using the Kaplan-Meier approach. Time to weaning was analyzed using the cumulative incidence function, with death considered a competing risk. Prognostic factors were evaluated for use in prospective evaluations of weaning protocols. RESULTS: Between 2008 and 2012, 122 patients required mechanical ventilation outside of a critical care setting with weaning as a goal of care. The cumulative incidence of weaning after discharge from the intensive care unit was 42% at 21 days, 49% at 30 days, 58% at 60 days, 61% at 90 days, and 61% at 120 days. The median survival was 0.16 years (95% CI, 0.12 to 0.33) for those not weaned and 1.05 years (95% CI, 0.60 to 1.34) for those weaned. Overall survival at 1 year and 2 years was 52 and 32% among those weaned and 16 and 9% among those not weaned. During 2018, 36 patients at our institution required mechanical ventilation outside of a critical care setting, with weaning as a goal of care. Overall, with a median follow-up of 140 days (range, 0-425 days; average, 141 days), 25% of patients requiring long-term mechanical ventilation (9 of 36) are alive. CONCLUSIONS: Cancer patients can be weaned from long-term mechanical ventilation, even after prolonged periods of support. Implementation of a resource-intensive weaning program did not improve rates of successful weaning. No clear time on mechanical ventilation could be identified beyond which weaning was unprecedented. Short-term overall survival for these patients is poor.

Gut Microbiota Predict Pulmonary Infiltrates after Allogeneic Hematopoietic Cell Transplantation.

RATIONALE: Pulmonary complications (PCs) cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Shifts in gut microbiota have been linked to HCT outcomes; however, their effect on PCs is unknown. OBJECTIVES: To investigate whether changes in gut microbiota are associated with PCs after HCT. METHODS: A single-center observational study was performed on 94 patients who underwent HCT from 2009 to 2011 and who were previously enrolled in a protocol for 16S ribosomal RNA sequencing of fecal microbiota. The primary endpoint, PC, was defined by new abnormal parenchymal findings on chest imaging in the setting of respiratory signs and/or symptoms. Outcomes were collected up to 40 months after transplant. Clinical and microbiota risk factors for PCs and mortality were evaluated using survival analysis. MEASUREMENTS AND MAIN RESULTS: One hundred twelve PCs occurred in 66 (70.2%) subjects. A high comorbidity index (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.30-4.00; P = 0.004), fluoroquinolones (HR, 2.29, 95% CI, 1.32-3.98; P = 0.003), low baseline diversity (HR, 2.63; 95% CI, 1.22-5.32; P = 0.015), and γ-proteobacteria domination of fecal microbiota (HR, 2.64; 95% CI, 1.10-5.65; P = 0.031), which included common respiratory pathogens, predicted PCs. In separate analyses, low baseline diversity was associated with PCs that occurred preengraftment (HR, 6.30; 95% CI, 1.42-31.80; P = 0.016), whereas γ-proteobacteria domination predicted PCs postengraftment (HR, 3.68; 95% CI, 1.49-8.21; P = 0.006) and overall mortality (HR, 3.52; 95% CI, 1.28-9.21; P = 0.016). Postengraftment PCs were also independent predictors of death (HR, 2.50; 95% CI, 1.25-5.22; P = 0.009). CONCLUSIONS: This is the first study to demonstrate prospective changes in gut microbiota associated with PCs after HCT. Postengraftment PCs and γ-proteobacteria domination were predictive of mortality. This suggests an adverse relationship between the graft and lung, which is perhaps mediated by bacterial composition in the gut. Further study is warranted.

Radiation recall pneumonitis from immune checkpoint inhibitors after extra pulmonary radiation.

Radiation recall is an unpredictable, poorly understood inflammatory reaction within the confines of previously irradiated tissue that occurs following exposure to a systemic agent. In this article, we will focus on a subcategory of radiation recall, called radiation recall pneumonitis (RRP), precipitated by immune checkpoint inhibitors (ICI). Historically, RRP can develop weeks to years after radiation treatment to the lung, most commonly after receiving certain chemotherapeutic agents, but more recently has been recognized in association with immunotherapy agents (ICIs). Up until now, RRP following exposure to ICIs has been described in patients who have received radiation to the lung itself. Here we present three cases of RRP in patients who received radiation to areas adjacent to the lung parenchyma, and developed pulmonary infiltrates in an area adjacent to the radiation field while on ICI therapy. Since ICI induced RRP is treatable and steroid sensitive, early recognition and treatment are important.

Iron therapy as a novel treatment of scleroderma-related pulmonary hypertension: A case report and literature review.

Pulmonary arterial hypertension (PAH) is the leading cause of death in patients with systemic sclerosis (SSc), with a 3-year mortality of 40%-50% despite optimal therapy. Treatment mirrors that of idiopathic PAH and is often ineffective. This is a case report of a patient with SSc evaluated for progressive dyspnoea with exertion and found to have elevated pulmonary artery systolic pressures (PASPs). She received ferritin-targeted iron infusions as a novel treatment of suspected SSc-associated PAH, with subsequent resolution of respiratory symptoms and PASPs that normalized. We review PAH especially associated with SSc, its treatment and identify a possible novel therapeutic approach for those with PAH-SSc.

Algorithmic Approach to the Diagnosis of Organizing Pneumonia: A Correlation of Clinical, Radiologic, and Pathologic Features.

Organizing pneumonia (OP), characterized histopathologically by patchy filling of alveoli and bronchioles by loose plugs of connective tissue, may be seen in a variety of conditions. These include but are not limited to after an infection, drug reactions, radiation therapy, and collagen vascular diseases. When a specific cause is responsible for this entity, it is referred to as "secondary OP." When an extensive search fails to reveal a cause, it is referred to as "cryptogenic OP" (previously called "bronchiolitis obliterans with OP"), which is a clinical, radiologic, and pathologic entity classified as an interstitial lung disease. The clinical presentation of OP often mimics that of other disorders, such as infection and cancer, which can result in a delay in diagnosis and inappropriate management of the underlying disease. The radiographic presentation of OP is polymorphous but often has subpleural consolidations with air bronchograms or solitary or multiple nodules, which can wax and wane. Diagnosis of OP sometimes requires histopathologic confirmation and exclusion of other possible causes. Treatment usually requires a prolonged steroid course, and disease relapse is common. The aim of this article is to summarize the clinical, radiographic, and histologic presentations of this disease and to provide a practical diagnostic algorithmic approach incorporating clinical history and characteristic imaging patterns.

Sarcoidosis presenting as hiccups.

Hiccups are common; however, hiccups caused by sarcoidosis have rarely been reported. An unusual case involving a patient with persistent hiccups possibly caused by hilar/mediastinal lymph node enlargement due to sarcoidosis prompted us to perform a literature search. Eight case reports relating hiccups to sarcoidosis were found and in only one case were the hiccups thought to be due to thoracic lymphadenopathy (LAD). Most cases were attributed to involvement of the central nervous system (CNS) with sarcoidosis. Management of hiccups in general is unclear and only chlorpromazine is approved by the Food and Drug Administration (FDA) for treatment; multiple other pharmacological agents have been advocated mostly being ineffective. This case report describes a patient whose hiccups were likely caused by thoracic sarcoidosis. It reviews the mechanisms of hiccups, explores co-morbid conditions associated with hiccups (including sarcoidosis), and provides some recommended treatments.

MAC Attack: Clinical Correlates of Mycobacterium avium Complex Infection Among Patients With and Without Cancer.

BACKGROUND: In 2007 the American Thoracic Society (ATS) released guidelines on management of Mycobacterium avium complex (MAC), an increasingly common respiratory organism worldwide. Determining when this represents a true respiratory pathogen remains controversial and becomes increasingly challenging in patients with cancer. This study aims to 1) describe the phenotype that exists among cancer patients with MAC colonization and MAC pulmonary infection when compared to non-cancer patients; 2) assess whether cancer, symptoms, and radiographs, were associated with the decision to treat MAC pulmonary infection with antibiotics. METHODS: We retrospectively analyzed 550 adult, non-human immunodeficiency virus (HIV) patients, among whom MAC was identified in respiratory cultures or tissue. Radiographs, clinical symptoms and cancer status were studied. Patients were categorized as having MAC pulmonary infection based on 2007 ATS guidelines, and antibiotic treatment was thereafter reviewed. Fisher's exact test and Wilcoxon Rank sum assessed differences. RESULTS: Median age of the 550 patients was 68 years; most were female (56%) and white (83%). Symptoms and radiographic abnormalities accompanying MAC isolation were common, occurring among 83% and 99.6% respectively of all patients. There were 444 patients with MAC who had current or inactive cancers, most commonly hematologic (30%) and lung (25%) malignancies, while 106 patients never had cancer. Cancer patients were younger (P = 0.028), less often female (P < 0.001), and had less-frequent pre-existing lung disease (P = 0.017) than those without cancer. There were 196 (35%) patients determined to have MAC pulmonary infection, among whom 49 (9%) received directed antibiotics. Those receiving antibiotics had lower body mass index (BMI) (P < 0.0001), more frequent pre-existing lung disease (P = 0.003) and lower cancer rates (P = 0.008) than those not receiving antibiotics. Patients receiving antibiotics were more likely to have cavitary disease (P = 0.001), cough/dyspnea (P = 0.012), hemoptysis (P < 0.001), and constitutional symptoms (P = 0.001). CONCLUSIONS: In concordance with ATS guidelines, hemoptysis, constitutional symptoms, cough/dyspnea and cavitary disease were associated with highest likelihood to treat with antibiotics. The phenotype in cancer patients was quite different than the classic Lady Windermere syndrome. MAC pulmonary infection was treated less often in cancer patients. This study extends beyond the ATS guidelines to examine the potential import of malignancy on the colonization and potential treatment of MAC.

Pilot Study of Self-care Breath Training Exercise for Reduction of Chronic Dyspnea.

PURPOSE: Dyspnea related to chronic pulmonary disorders is difficult to manage. In this single-arm study, we evaluated feasibility and potential efficacy of a self-care breath training program to reduce dyspnea that persists despite standard treatments in patients with chronic lung disease. METHODS: Adult patients with a chronic pulmonary disorder and stable moderate dyspnea received one 30-min training on specific breathing techniques, followed by audio-guided at-home practice 15 min twice daily for 6 wk, supported with weekly telephone monitoring/coaching. The feasibility endpoints, Baseline and Transition Dyspnea Indexes, 6-min walk test, Hospital Anxiety and Depression Scale, and oxygen saturation at rest and exercise were evaluated at baseline and wk 6. RESULTS: Of the 23 patients enrolled over 2 yr, 19 completed the study. A majority (74%; 95% CI, 49%-91%) completed at least 75% of the home practice sessions. Significant objective improvements in physical performance, defined as distance walked, were observed after 6 wk of intervention. On average, patients walked significantly further in the 6-min walk test (59 ft; 95% CI, 18-99; P = .007). In addition, 53% reported clinically significant (20%, defined a priori) subjective improvement in the Transition Dyspnea Index, although the difference was not statistically significant (0.7; 95% CI, -0.8 to 2.3; P = .3). No significant differences were seen in the Hospital Anxiety and Depression Scale or oxygen saturation. CONCLUSIONS: A low-burden, low-cost, self-care breath training program improved distance walked by patients with chronic dyspnea after 6 wk of home practice. Promising data suggest that a randomized trial of this breath training program is warranted.

Prevalence of COPD in women compared to men around the time of diagnosis of primary lung cancer.

PURPOSES: COPD is a well-known independent risk factor that is associated with primary lung cancer. There is, however, a striking paucity of women in studies demonstrating this association. The purpose of this study was to compare the prevalence of COPD as determined by pulmonary function tests (PFTs) between women and men at around the time of lung cancer diagnosis. METHODS: We retrospectively reviewed patients with newly diagnosed primary lung cancer who had undergone PFTs prior to their treatment. The diagnosis of airflow obstruction was made according to American Thoracic Society guidelines. Comparisons of the prevalence of COPD between men and women were performed using univariate and multivariate logistic regression analysis. RESULTS: Of the 294 patients in the study, 151 patients (51.4%) were men and 143 patient (48.6%) were women. Of the men, 110 patients (72.8%) had COPD compared with 75 patients (52.5%) among the women. This represented a significantly lower prevalence of COPD in women than in men (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.25 to 0.67; p = 0.0003). When adjusted for age and smoking status, a sustained lower prevalence of COPD was noted in women compared to men (OR, 0.44; 95% CI, 0.26 to 0.74; p = 0.002). In a subset of 256 smokers, there remained a lower prevalence of COPD in women compared to men (OR, 0.45; 95% CI, 0.27 to 0.77; p = 0.003). Adjusted analysis to control for age and number of pack-years of smoking in this subset again showed a sustained reduction in the OR for women presenting with COPD (OR, 0.48; 95% CI, 0.28 to 0.83; p = 0.009). CONCLUSIONS: When COPD was examined as an end point among patients who had newly diagnosed lung cancer, a significantly higher proportion of women had normal PFT results. Gender-based differences on PFT results should be considered during the screening of lung cancer, because the stratification of high-risk patients based on the presence of COPD may miss a significant proportion of women with lung cancer.

Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia?

Some macrolides have been found to exert anti-inflammatory effects. Lung diseases such as asthma, panbronchiolitis, cystic fibrosis, and bronchiectasis are thought to respond to the immunomodulatory properties of macrolides. We report three cases of idiopathic bronchiolitis obliterans organizing pneumonia, now called cryptogenic organizing pneumonia, and three cases of radiation-related bronchiolitis obliterans organizing pneumonia that responded to macrolide therapy. An explanation of why macrolides may have anti-inflammatory effects in patients with these syndromes is discussed. These cases help to reinforce accumulating data that macrolides are beneficial as anti-inflammatory agents and organizing pneumonia may be another pulmonary disease that can benefit from such therapy.

A comparison of the pathological, clinical and radiographical, features of cryptogenic organising pneumonia, acute fibrinous and organising pneumonia and granulomatous organising pneumonia.

AIMS: Cryptogenic organising pneumonia (COP) and acute fibrinous and organising pneumonia (AFOP) are recognised patterns of organising pneumonia (OP), a condition that resembles pneumonia but is not caused by infection. We have recognised granulomatous organising pneumonia (GOP) to be a similar histopathological entity where non-necrotising granulomata are intimately associated with the organising connective tissue. To what degree COP, AFOP and GOP represent distinct clinical and pathological disorders is unknown. This cross-sectional study sought to compare the pathological, clinical, and radiographical features of these OP patterns. METHODS: Surgical lung biopsy specimens were reviewed for consecutive patients referred with OP to a metropolitan cancer centre. Clinical information and CT images were acquired from the hospital electronic medical record to determine the clinical and CT characteristics of each OP pattern. RESULTS: Sixty-one patients (35 men, 26 women), mean age 61.5 years (range 8-85 years), were available for analysis. Of these, 43 patients (70%) had at least one prior cancer; 27 (44%) had received chemotherapy and 18 (30%) had received radiation. Approximately, half (32 patients) had respiratory symptoms, most commonly cough, dyspnoea and/or wheezing. While symptoms and mortality rates were not different among OP groups, AFOP patients more commonly had fever (p=0.04). GOP patients less commonly had received chemotherapy (p=0.03) and were more likely to present as masses/nodules (p=0.04). CONCLUSIONS: AFOP and GOP, a newly described OP form, possess clinical and pathological findings that set it apart from a COP, suggesting an emerging spectrum of OP.

Lung cancer prevention: the guidelines.

Lung carcinogenesis is a chronic and multi-step process resulting in malignant lung tumors. This progression from normal to neoplastic pulmonary cells or tissues could be arrested or reversed through pharmacologic treatments, which are known as cancer chemoprevention. These therapeutic interventions should reduce or avoid the clinical consequences of lung cancer by treating early neoplastic lesions before the development of clinically evident signs or symptoms of malignancy. Preclinical, clinical, and epidemiologic findings relating to different classes of candidate chemopreventive agents provide strong support for lung cancer prevention as an attractive therapeutic strategy. Smoking prevention and smoking cessation represent an essential approach to reduce the societal impact of tobacco carcinogenesis. However, even if all the goals of the national antismoking efforts were met, there still would be a large population of former smokers who would be at increased risk for lung cancers. Lung cancer also can occur in those persons who never have smoked. This article focuses on what is now known about pharmacologic strategies for lung cancer prevention. Randomized clinical trials using beta-carotene, retinol, isotretinoin or N-acetyl-cysteine did not show benefit for primary and tertiary lung cancer prevention. There is also evidence that the use of beta-carotene and isotretinoin for lung cancer chemoprevention in high-risk individuals may increase the risk for lung cancer, especially in individuals who continue to smoke. There is a need for relevant in vitro models to identify pathways that activate chemopreventive effects in the lung. An improved understanding of cancer prevention mechanisms should aid in the design of clinical trials and in the validation of candidate chemopreventive targets as well as the discovery of new targets. Until such studies are completed, no agent or combination of agents should be used for lung cancer prevention outside of a clinical trial.

Gender and lung cancer.

Accumulating data suggest that the risks for development of lung cancer are different in women compared with men. An increased susceptibility in women to the adverse effects of tobacco may be due to higher levels of DNA adducts, decreased DNA repair capacity, increased frequency of mutations in tumor suppressor genes, and hormonal differences. There are many sex and gender differences in lung cancer presentation, including a greater proportion of adenocarcinoma among women, a greater representation of women in cohorts of younger patients who have lung cancer, and women who do not smoke are more likely to be diagnosed with lung cancer than men. When guidelines for screening, preventive therapies, and treatment options for lung cancer are outlined these differences should be considered.

Prevention of lung cancer.

This is a review of current concepts in lung cancer prevention including primary or smoking prevention, secondary prevention or smoking cessation and tertiary prevention or chemoprevention of lung cancer.

Pneumocystis carinii pneumonia in patients with and without HIV infection.

Advances in the prevention and treatment of Pneumocystis carinii pneumonia in HIV infected patients have led to a decrease in the incidence and improved outcomes. Pneumocystis carinii pneumonia continues to be problematic in non-HIV infected immunocompromised patients.

Organizing pneumonia as a side effect of ipilimumab treatment of melanoma.

Ipilimumab is one of the newly developed human monoclonal antibodies used in the treatment of metastatic melanoma. Its primary mechanism of action is a specific blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a T-cell receptor responsible for inhibition of lymphocyte activation. By blocking CTLA-4, ipilimumab enhances immune responses against tumor cells, but also exposes normal tissues to an increased risk of autoimmune phenomena as a potential side effect. In this report, we describe the case of a 58-year-old woman with metastatic melanoma who was treated with ipilimumab in the weeks prior to the onset of severe nonresolving dyspnea and cough. Extensive workup revealed organizing pneumonia as the cause of her hypoxemic respiratory failure and treatment with steroids led to a resolution of her pulmonary disease. To our knowledge, this is the first report of pulmonary toxicity caused by ipilimumab, which manifested on pathology as organizing pneumonia.

Diagnostic bronchoscopy in solid-organ and hematopoietic stem cell transplantation.

Fiberoptic bronchoscopy is a valuable diagnostic tool in solid-organ and hematopoietic stem cell transplant recipients presenting with a range of pulmonary complications. This article provides a comprehensive overview of the utility and potential adverse effects of diagnostic bronchoscopy for transplant recipients. Recommendations are offered on the selection of patients, the timing of bronchoscopy, and the samples to be obtained across the spectrum of suspected pulmonary complications of transplantation. Based on review of the literature, the authors recommend early diagnostic bronchoscopy over empiric treatment in transplant recipients with evidence of certain acute, subacute, or chronic pulmonary processes. This approach may be most critical when an underlying infectious etiology is suspected. In the absence of prompt diagnostic information on which to base effective treatment, the risks associated with empiric antimicrobial therapy, including medication side effects and the development of antibiotic resistance, compound the potential harm of delaying targeted management.