Stress & strain in mechanically nonuniform alveoli using clinical input variables: a simple conceptual model.

Clinicians currently monitor pressure and volume at the airway opening, assuming that these observations relate closely to stresses and strains at the micro level. Indeed, this assumption forms the basis of current approaches to lung protective ventilation. Nonetheless, although the airway pressure applied under static conditions may be the same everywhere in healthy lungs, the stresses within a mechanically non-uniform ARDS lung are not. Estimating actual tissue stresses and strains that occur in a mechanically non-uniform environment must account for factors beyond the measurements from the ventilator circuit of airway pressures, tidal volume, and total mechanical power. A first conceptual step for the clinician to better define the VILI hazard requires consideration of lung unit tension, stress focusing, and intracycle power concentration. With reasonable approximations, better understanding of the value and limitations of presently used general guidelines for lung protection may eventually be developed from clinical inputs measured by the caregiver. The primary purpose of the present thought exercise is to extend our published model of a uniform, spherical lung unit to characterize the amplifications of stress (tension) and strain (area change) that occur under static conditions at interface boundaries between a sphere's surface segments having differing compliances. Together with measurable ventilating power, these are incorporated into our perspective of VILI risk. This conceptual exercise brings to light how variables that are seldom considered by the clinician but are both recognizable and measurable might help gauge the hazard for VILI of applied pressure and power.

Activation of the Complement and Coagulation Systems in the Small Airways in Asthma.

BACKGROUND: Several studies have shown the importance of the complement and coagulation systems in the pathogenesis of asthma. OBJECTIVES: We explored whether we could detect differentially abundant complement and coagulation proteins in the samples obtained from the small airway lining fluid by collection of exhaled particles in patients with asthma and whether these proteins are associated with small airway dysfunction and asthma control. METHOD: Exhaled particles were obtained from 20 subjects with asthma and 10 healthy controls (HC) with the PExA method and analysed with the SOMAscan proteomics platform. Lung function was assessed by nitrogen multiple breath washout test and spirometry. RESULTS: 53 proteins associated with the complement and coagulation systems were included in the analysis. Nine of those proteins were differentially abundant in subjects with asthma as compared to HC, and C3 was significantly higher in inadequately controlled asthma as compared to well-controlled asthma. Several proteins were associated with physiological tests assessing small airways. CONCLUSIONS: The study highlights the role of the local activation of the complement and coagulation systems in the small airway lining fluid in asthma and their association with both asthma control and small airway dysfunction. The findings highlight the potential of complement factors as biomarkers to identify different sub-groups among patients with asthma that could potentially benefit from a therapeutic approach targeting the complement system.

A mini-whole lung lavage to treat autoimmune pulmonary alveolar proteinosis (PAP).

BACKGROUND: PAP is an ultra-rare respiratory syndrome characterized by the accumulation of surfactant within the alveoli. Whole lung lavage (WLL) is the current standard of care of PAP, however it is not a standardized procedure and the total amount of fluid used to wash each lung is still debated. Considering ICU hospitalization associated risks, a "mini-WLL" with anticipated manual clapping and reduced total infusion volume and has been proposed in our center. The aim of the study is to retrospectively analyze the efficacy of mini-WLL compared to standard WLL at the Pavia center. METHODS: 13 autoimmune PAP patients eligible for WLL were included: 7 patients were admitted to mini-WLL (9 L total infusion volume for each lung) and 6 patients underwent standard WLL (14 L of infusion volume). Functional data (VC%, FVC%, TLC%, DLCO%) and alveolar-arterial gradient values (A-aO2) were collected at the baseline and 1, 3, 6, 12, 18 months after the procedure. RESULTS: A statistically significant improvement of VC% (p = 0.013, 95%CI 3.49-30.19), FVC% (p = 0.016, 95%CI 3.37-32.09), TLC% (p = 0.001, 95%CI 7.38-30.34) was observed in the mini-WLL group in comparison with the standard WLL group, while no significant difference in DLCO% and A-aO2 mean values were reported. CONCLUSION: Mini-WLL has demonstrated higher efficacy in ameliorating lung volumes, suggesting that a lower infusion volume is sufficient to remove the surfactant accumulation and possibly allows a reduced mechanical insult of the bronchi walls and the alveoli. However, no statistically significant differences were found in terms of DLCO% and Aa-O2.

Physiological dead space and alveolar ventilation in ventilated infants.

BACKGROUND: Dead space is the volume not taking part in gas exchange and, if increased, could affect alveolar ventilation if there is too low a delivered volume. We determined if there were differences in dead space and alveolar ventilation in ventilated infants with pulmonary disease or no respiratory morbidity. METHODS: A prospective study of mechanically ventilated infants was undertaken. Expiratory tidal volume and carbon dioxide levels were measured. Volumetric capnograms were constructed to calculate the dead space using the modified Bohr-Enghoff equation. Alveolar ventilation (VA) was also calculated. RESULTS: Eighty-one infants with a median (range) gestational age of 28.7 (22.4-41.9) weeks were recruited. The dead space [median (IQR)] was higher in 35 infants with respiratory distress syndrome (RDS) [5.7 (5.1-7.0) ml/kg] and in 26 infants with bronchopulmonary dysplasia (BPD) [6.4 (5.1-7.5) ml/kg] than in 20 term controls with no respiratory disease [3.5 (2.8-4.2) ml/kg, p < 0.001]. Minute ventilation was higher in both infants with RDS or BPD compared to the controls. VA in infants with RDS or BPD was similar to that of the controls [p = 0.54]. CONCLUSION: Prematurely born infants with pulmonary disease have a higher dead space than term controls, which may influence the optimum level during volume-targeted ventilation. IMPACT: Measurement of the dead space was feasible in ventilated newborn infants. The physiological dead space was a significant proportion of the delivered volume in ventilated infants. The dead space (per kilogram) was higher in ventilated infants with respiratory distress syndrome or evolving bronchopulmonary dysplasia compared to term controls without respiratory disease. The dead space volume should be considered when calculating the most appropriate volume during volume-targeted ventilation.

Fisiopatología de la enfermedad COVID-19 / Pathophysiology of COVID-19 / Fisiopatologia da doença COVID-19

La enfermedad por coronavirus es una infección respiratoria causada por el virus SARS-CoV 2, el cual genera una cascada de eventos sistémicos, afectando diferentes órganos y tejidos. El entendimiento de la fisiopatología del COVID-19 es indispensable no solo al momento de brindar tratamiento a los pacientes, sino que también para comprender las causas de las complicaciones que presentan un número importante de pacientes recuperados. El objetivo de este trabajo es presentar una revisión actualizada de los efectos de la infección en diferentes órganos y sistemas principales que sea de utilidad como material de referencia para profesionales y estudiantes de la salud. Para ello se realizó una búsqueda bibliográfica en los portales PubMED, Scielo, Google Scholar, Cochrane y Springer Link, así como en las bases de repositorios científicos pre-publicación bioRxiv ("bioarchives") y medRxiv ("med-archives") y sobre un total de cerca de 200 mil artículos, se seleccionaron 100 artículos para esta revisión en base a su relevancia o sugerencias de parte de profesionales especializados.

Coronavirus disease is a respiratory infection caused by the SARS-CoV-2 virus, which causes a cascade of systemic events, affecting various organs and tissues. Understanding the pathophysiology of COVID-19 is essential to treat patients and understand the causes of the complications in a significant number of recovered patients. This article presents a review of the effects of infection on various organs and systems that will be useful as reference material for healthcare professionals and medical students. To this end, a literature search was conducted in PubMED, Scielo, Google Scholar, Cochrane, and Springer Link portals, as well as in the pre-publication scientific repositories bioRxiv ("bioarchives") and medRxiv ("med-archives") databases. From about 200,000 papers, 100 articles were selected for this review based on their relevance or suggestions from experts in the field.

A doença coronavírus é uma infecção respiratória causada pelo vírus SARS-CoV-2, que gera uma cascata de eventos sistêmicos, afetando diferentes órgãos e tecidos. Compreender a fisiopatologia da COVID-19 é essencial não apenas no tratamento de pacientes, mas também para compreender as causas das complicações que um número significativo de pacientes recuperados apresenta. O objetivo deste trabalho é apresentar uma revisão atualizada dos efeitos da infecção em diferentes órgãos e principais sistemas que seja útil como material de referência para profissionais de saúde e estudantes. Para isso, foi realizada uma pesquisa bibliográfica nos portais PubMED, Scielo, Google Scholar, Cochrane e Springer Link, bem como nos repositórios científicos de pré-publicação bioRxiv ("bioarquivos") e medRxiv ("arquivos med"). Num total de cerca de 200 mil artigos, 100 artigos foram selecionados para esta revisão por sua relevância ou sugestões de profissionais especializados.

Pulmonary Fibroelastotic Remodelling Revisited.

Pulmonary fibroelastotic remodelling occurs within a broad spectrum of diseases with vastly divergent outcomes. So far, no comprehensive terminology has been established to adequately address and distinguish histomorphological and clinical entities. We aimed to describe the range of fibroelastotic changes and define stringent histological criteria. Furthermore, we wanted to clarify the corresponding terminology in order to distinguish clinically relevant variants of pulmonary fibroelastotic remodelling. We revisited pulmonary specimens with fibroelastotic remodelling sampled during the last ten years at a large European lung transplant centre. Consensus-based definitions of specific variants of fibroelastotic changes were developed on the basis of well-defined cases and applied. Systematic evaluation was performed in a steps-wise algorithm, first identifying the fulcrum of the respective lesions, and then assessing the morphological changes, their distribution and the features of the adjacent parenchyma. We defined typical alveolar fibro-elastosis as collagenous effacement of the alveolar spaces with accompanying hyper-elastosis of the remodelled and paucicellular alveolar walls, independent of the underlying disease in 45 cases. Clinically, this pattern could be seen in (idiopathic) pleuroparenchymal fibro-elastosis, interstitial lung disease with concomitant alveolar fibro-elastosis, following hematopoietic stem cell and lung transplantation, autoimmune disease, radio-/chemotherapy, and pulmonary apical caps. Novel in-transit and activity stages of fibroelastotic remodelling were identified. For the first time, we present a comprehensive definition of fibroelastotic remodelling, its anatomic distribution, and clinical associations, thereby providing a basis for stringent patient stratification and prediction of outcome.

A rare association between group A Streptococcus purpura fulminans and diffuse alveolar hemorrhage in a young girl: A case report.

We report the case of a 7-year-old girl with septic shock and coagulopathy associated with purpura fulminans (PF) and diffuse alveolar hemorrhage (DAH) due to group A Streptococcus (GAS) infection identified with 16S ribosomal RNA analysis performed on the skin biopsy. GAS infection with PF associated with DAH is rare in healthy young children but pediatricians should be aware of this condition because of the poor prognosis. The initial treatment for circulatory failure and severe disseminated intravascular coagulation as well as the prompt initiation of antibiotic treatment may be crucial for the outcomes of S. pyogenes PF.

Hemoptysis in a cannabis user.

A healthy young man presented to the emergency department with mild hemoptysis associated with cannabis abuse. He was on no medications and cocaine abuse was ruled out by both history and negative toxicology screens. There were neither signs of an infection, nor of a systemic or cardiac disease. Imaging studies were consistent with diffuse alveolar hemorrhage, a reported, albeit rare adverse drug reaction of tetrahydrocannabinol (Naranjo score 6). The patient improved spontaneously within a few days, hemoptysis stopped and repeat imaging was entirely normal. With the increase in cannabis abuse and enhanced cannabis potency worldwide clinicians may increasingly encounter even unusual cannabis-associated adverse drug reactions, including associated diffuse alveolar hemorrhage.

Ventilation Heterogeneity in Asthma and COPD: The Value of the Poorly Communicating Fraction as the Ratio of Total Lung Capacity to Alveolar Volume.

BACKGROUND: The ventilation heterogeneity (VH) is reliably assessed by the multiple-breath nitrogen washout (MBNW), which provides indices of conductive (Scond) and acinar (Sacin) VH as well as the lung clearance index (LCI), an index of global VH. VH can be alternatively measured by the poorly communicating fraction (PCF), that is, the ratio of total lung capacity by body plethysmography to alveolar volume from the single-breath lung diffusing capacity measurement. OBJECTIVES: Our objective was to assess VH by PCF and MBNW in patients with asthma and with COPD and to compare PCF and MBNW parameters in both patient groups. METHOD: We studied 35 asthmatic patients and 45 patients with COPD. Each patient performed spirometry, body plethysmography, diffusing capacity, and MBNW test. RESULTS: Compared to COPD patients, asthmatics showed a significantly lesser degree of airflow obstruction and lung hyperinflation. In asthmatic patients, both PCF and LCI and Sacin values were significantly lower than the corresponding ones of COPD patients. In addition, in both patient groups, PCF showed a positive correlation with LCI (p < 0.05) and Sacin (p < 0.05), but not with Scond. Lastly, COPD patients with PCF >30% were highly likely to have a value ≥2 of the mMRC dyspnea scale. CONCLUSIONS: These results showed that PCF, a readily measure derived from routine pulmonary function testing, can provide a comprehensive measure of both global and acinar VH in asthma and in COPD patients and can be considered as a comparable tool to the well-established MBNW technique.

Hermansky-Pudlak syndrome-2 alters mitochondrial homeostasis in the alveolar epithelium of the lung.

BACKGROUND: Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood. METHODS: We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2). RESULTS: We observed widespread changes in mitochondrial homeostasis in HPS-2 cells, including the acquisition of abnormally shaped mitochondria, with reduced number of cristae, and markedly reduced activity of the electron transport chain and the tricarboxylic acid cycle. We also found that mitochondrial redox imbalance and activity of the mitochondrial unfolded protein response were dysregulated in HPS-2 cells and this associated with various other changes that appeared to be compensatory to mitochondrial dysfunction. This included an increase in glycolytic activity, an upregulation in the expression of mitochondrial biogenesis factors and enhanced activation of the energy-conserving enzyme AMP-activated protein kinase. CONCLUSION: In summary, our findings indicate that mitochondrial function is dramatically altered in HPS-2 lung tissues, suggesting dysfunction of this organelle might be a driver of HPS lung disease.

Evaluation of Pulmonary Hypoplasia in Various Congenital Anomalies with a Comparison of Two Conventional Methods of Assessment: Radial Alveolar Count (RAC) and Lung Weight: Body Weight Ratio (LBW).

OBJECTIVE: Pulmonary hypoplasia is common in the perinatal period and causes death in newborn infants. It is commonly associated with a number of malformation syndromes. Various parameters are used to estimate pulmonary hypoplasia at fetal autopsy including Lung Weight Body Weight ratio (LW:BW), Radial Alveolar Count (RAC) and DNA estimation. MATERIAL AND METHOD: This study was carried out as a retrospective analysis of 108 lung specimens of fetuses with congenital anomalies for a period of five years. All terminated fetuses with anomalies were received with 10% formalin. An inverted Y-shaped incision was made on the fetus to remove the lungs. Lung weight and body weight were measured and the ratio was calculated. Morphometric estimation of RAC was done microscopically by counting the number of alveoli using the Q capture software. RAC was calculated based on gestational age. RESULTS: Among the restrictive lung diseases, pulmonary hypoplasia by the LW:BW ratio was prevalent in 43% while the same by RAC was 19%. Similarly, pulmonary hypoplasia by the LW:BW ratio was prevalent in 35% while the same by RAC was 26% among cases with non restrictive lung diseases. Oligohydramnios showed the highest prevalence of pulmonary hypoplasia (23.7%), followed by renal anomalies (16.9%) and CNS anomalies (15.2%). CONCLUSION: Pulmonary hypoplasia is a common occurrence in many congenital anomalies, premature rupture of membranes, and hydrops fetalis. Identifying the anomaly during the intrauterine period will help to anticipate and accordingly manage the baby in the postpartum period. Early diagnosis of correctable condition like oligohydramnios will also help in the early intervention and prevention of pulmonary hypoplasia.

Massive Vespa basalis stings induce an envenoming syndrome.

Envenoming syndrome induced by massive Vespa basalis stings is a critical condition. Severe systemic reaction may present with hemolytic activity and rhabdomyolysis, leading diffuse alveolar hemorrhage, adult respiratory distress syndrome, coagulopathy, and multiple organs failure. In severe envenoming syndrome population, extracorporeal membrane oxygenation (ECMO) may be considered for unstable hemodynamic status. However, few studies reported ECMO in venom-induced disseminated intravascular coagulation patients. Here, we provide a case presented with pulmonary hemorrhage due to multiple Vespa basalis stings tried to rescue by veno-arterial extracorporeal membrane oxygenation. We also highlight that early recognition of venom-induced disseminated intravascular coagulation by checking coagulation profile in high risk patients may prevent from poor outcome.

The Roborovski Dwarf Hamster Is A Highly Susceptible Model for a Rapid and Fatal Course of SARS-CoV-2 Infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has precipitated an unprecedented and yet-unresolved health crisis worldwide. Different mammals are susceptible to SARS-CoV-2; however, few species examined so far develop robust clinical disease that mirrors severe human cases or allows testing of vaccines and drugs under conditions of severe disease. Here, we compare the susceptibilities of three dwarf hamster species (Phodopus spp.) to SARS-CoV-2 and introduce the Roborovski dwarf hamster (P. roborovskii) as a highly susceptible COVID-19 model with consistent and fulminant clinical signs. Particularly, only this species shows SARS-CoV-2-induced severe acute diffuse alveolar damage and hyaline microthrombi in the lungs, changes described in patients who succumbed to the infection but not reproduced in any experimentally infected animal. Based on our findings, we propose the Roborovski dwarf hamster as a valuable model to examine the efficacy and safety of vaccine candidates and therapeutics, particularly for use in highly susceptible individuals.

Expression of Matrix Metalloproteinase-2, Matrix Metalloproteinase-9, Tissue Inhibitor of Metalloproteinase-1, and Changes in Alveolar Septa in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND This study investigated the relationship between the pathological alteration of alveolar septa and (1) pulmonary function and (2) matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor matrix metalloproteinase 1 (TIMP-1) expression in chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS Sixty patients with pulmonary disease were divided into control (n=20) and COPD (n=40) groups. Postoperative lung tissue specimens were examined. Hematoxylin and eosin and elastin van Gieson staining detected pathological alterations of pulmonary alveolar septa. Septa thickness was measured. MMP-2, MMP-9, and TIMP-1 expression levels were detected by immunohistochemical staining. Correlations were determined by Pearson analysis. RESULTS Forced expiratory volume in 1 s (FEV1), forced vital capacity, FEV1 percent predicted (FEV1%pre), and diffusion capacity of carbon monoxide percent predicted (DLCO%pre) in COPD patients were significantly lower than in those of the control group (P<0.05). MMP-2, MMP-9, and TIMP-1 expression levels were significantly higher in the COPD group than in control, especially the severe group (P<0.05). Septa thickness was negatively correlated with FEV1%pre (r=-0.335; P<0.05) and positively correlated with MMP-2 and TIMP-1 expression (P<0.05). Proportion of collagenous fiber was negatively correlated with FEV1%pre and DLCO%pre (P<0.01), and positively correlated with MMP-2, MMP-9, and TIMP-1 expression (P<0.01). Proportion of elastic fibers was negatively correlated with collagenous fiber. CONCLUSIONS The pathological alteration of alveolar septa was correlated with pulmonary function and expression levels of MMP-2, MMP-9, and TIMP-1, which can play vital roles in COPD progression.

Endothelial activation and dysfunction in metabolic syndrome, type 2 diabetes and coronavirus disease 2019.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 infection is a serious global concern. Increased morbidity and mortality is associated with older age, male gender, cardiovascular disease, diabetes, and smoking. As COVID-19 spreads from coastal borders, both state to state and country to country, our understanding of its pathophysiology has evolved. Age and type 2 diabetes mellitus (T2DM) play especially important roles in COVID-19 progression. T2DM is an age-related disease associated with metabolic syndrome, obesity, insulin resistance (hyperinsulinemia), hyperlipidemia, hypertension, hyperglycemia, and endothelial activation and dysfunction. This review evaluates the relationships and intersection between endothelial cell activation and dysfunction in T2DM and COVID-19. COVID-19 induces multiple injuries of the terminal bronchioles and alveolar blood-gas barrier and associated ultrastructural tissue remodeling. COVID-19 may unmask multiple vulnerabilities associated with T2DM including damage to the endothelial glycocalyx and multiple end-organ macro and microvascular diseases. Unmasking existing vulnerabilities in diabetic patients with COVID-19 is important. Globally, we must come together to better understand why T2DM is associated with increased COVID-19 morbidity and mortality.

Haemoptysis following shallow breath-hold diving in a cannabis user.

We report the first case of a healthy 24-year-old male with a 6-year history of regular cannabis use, who presented with haemoptysis after a shallow 3 m breath-hold dive. Blood investigations showed mild neutrophilia. CT thorax revealed focal ground-glass changes in the superior segment of the lower lobe. With a suspicion of pneumonia, oral antibiotics were initiated to poor effect. Through bronchoscopic visualisation and lavage, a diagnosis of diffuse alveolar haemorrhage was established. The clinical course was benign with resolution of symptoms and changes on CT thorax within 6 weeks of stopping marijuana use. Since all other causes of haemoptysis were excluded, pathophysiology was attributed to cannabis-induced lung parenchymal damage, exacerbated by a shallow breath-hold dive. To ensure appropriate management, a clinician should therefore have a high index of suspicion for drug use and other factors known to cause chronic lung damage in whom other causes of diffuse alveolar haemorrhage are excluded.

Severe diffuse alveolar hemorrhage related to autoimmune disease: a multicenter study.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) occurs during the course of autoimmune disease and may be life threatening. The objective was to assess characteristics and prognosis factors of DAH who required intensive care unit (ICU) admission in patients with autoimmune diseases. METHODS: French multicenter retrospective study including patients presenting DAH related to autoimmune diseases requiring ICU admission from 2000 to 2016. RESULTS: One hundred four patients (54% of men) with median age of 56 [32-68] years were included with 79 (76%) systemic vasculitis and 25 (24%) connective tissue disorders. All patients received steroids, and 72 (69%), 12 (11.5%), and 57 (55%) patients had cyclophosphamide, rituximab, and plasma exchanges, respectively. During ICU stay, 52 (50%), 36 (35%), and 55 (53%) patients required mechanical ventilation, vasopressor use, and renal replacement therapy, respectively. Factors associated with mechanical ventilation weaning were age (HR [95%CI] 0.97 [0.96-0.99] per 10 years, p < 0.0001), vasculitis-related DAH (0.52 [0.27-0.98], p = 0.04), and time from dyspnea onset to ICU admission (0.99 [0.99-1] per day, p = 0.03). ICU mortality was 15%. Factors associated with alive status at ICU discharge were chronic cardiac failure (HR [95%CI] 0.37 [0.15-0.94], p = 0.04), antiphospholipid syndrome-related DAH (3.17 [1.89-5.32], p < 0.0001), SAPS II (0.98 [0.97-0.99], p = 0.007), and oxygen flow at ICU admission (0.95 [0.91-0.99] per liter/min, p = 0.04). CONCLUSION: DAH in autoimmune diseases is a life-threatening complication which requires mechanical ventilation in half of the cases admitted to ICU.

Prognostic factors in chronic hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease resulting from exposure to inhaled environmental antigens. Prognosis is variable, with a subset of patients developing progressive fibrosis leading to respiratory failure and death. Therefore, there is an urgent need to identify factors which predict prognosis and survival in patients with HP. We undertook a narrative review of existing evidence to identify prognostic factors in patients with chronic HP. Patient demographics, smoking history, extent of antigen exposure and comorbidities all have reported associations with disease outcome, and physiological, radiological and laboratory markers have been shown to predict overall survival. While no single marker has been demonstrated to accurately and reliably predict prognosis, older age, more severe impairment of pulmonary function at baseline and established fibrosis on either biopsy or high-resolution computed tomography are consistently associated with worse survival. The vast majority of existing studies are retrospective, and this review identifies a need for prospective longitudinal studies with serial assessment of respiratory health to ascertain factors associated with nonfatal deterioration. Future developments, including the development of HP-specific composite scores may help further improve our ability to predict outcomes for individual patients.