The diagnostic pathway for patients with interstitial lung disease: a mixed-methods study of patients and physicians.

OBJECTIVES: The diagnostic process for patients with interstitial lung diseases (ILD) remains complex. The aim of this study was to characterise the diagnostic care pathway and identify barriers and potential solutions to access a timely and accurate ILD diagnosis. DESIGN: This mixed-method study was comprised of a quantitative chart review, patient and physician surveys and focus groups. RESULTS: Chart review was completed for 97 patients. Median time from symptom onset to ILD diagnosis was 12.0 (IQR 20.5) months, with 46% diagnosed within 1 year. Time from first computed tomography (CT) scan to respirology referral was 2.4 (IQR 21.2) months. Referrals with a prior CT were triaged sooner than referrals without (1.7±1.6 months vs 3.9±3.3 months, p=0.013, 95% CI 0.48 to 2.94). On patient surveys (n=70), 51% felt that their lung disease was not recognised early enough. Commonly reported challenges to timely diagnosis included delayed presentation to primary care, initial misdiagnoses and long wait-times for specialists. Forty-five per cent of physicians (n=20) identified diagnostic delays, attributed to delayed presentations to primary care (58%), initial misdiagnoses (67%) and delayed chest imaging (75%). Themes from patient and respirologist focus groups included patient-related, healthcare provider-related and system-related factors leading to delays in diagnosis. CONCLUSIONS: This mixed-methods study identified patient and system-related factors that contribute to diagnostic delays for patients with ILD, with most delays occurring prior to respirology referral. ILD awareness and education, earlier presentation to primary care, expedited access to chest imaging and earlier referral to respirology may expedite diagnosis.

The Clinical Frailty Scale for Risk Stratification in Patients With Fibrotic Interstitial Lung Disease.

BACKGROUND: Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD). RESEARCH QUESTION: Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD? STUDY DESIGN AND METHODS: Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS score 1-3), vulnerable (CFS score 4), and frail (CFS score 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort was used to establish prognostic performance. Trajectories of functional tests were compared using joint models. RESULTS: Of the 1,587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) were vulnerable, and 329 (21%) were frail. Frailty was a risk factor for early mortality (hazard ratio, 5.58; 95% CI, 3.64-5.76, P < .001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Patients in the frail subgroup had larger annual declines in FVC % predicted than patients in the fit subgroup (-2.32; 95% CI, -3.39 to -1.17 vs -1.55; 95% CI, -2.04 to -1.15, respectively; P = .02). INTERPRETATION: The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice.

Lung imaging patterns in connective tissue disease-associated interstitial lung disease impact prognosis and immunosuppression response.

OBJECTIVES: Interstitial lung disease (ILD) in connective tissue diseases (CTD) have highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality and immunosuppression response. METHODS: Patients with CTD-ILD had high-resolution chest computed tomography (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern (usual interstitial pneumonia [UIP]; non-specific interstitial pneumonia [NSIP]; organizing pneumonia [OP]; fibrotic hypersensitivity pneumonitis [fHP]; and other). Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment. RESULTS: Of 645 CTD-ILD patients, the frequent CTDs were systemic sclerosis (n = 215), rheumatoid arthritis (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with UIP, FVC decline was slower for NSIP (1.1%/year, 95%CI 0.2, 1.9) and OP (3.5%/year, 95%CI 2.0, 4.9), and mortality was lower for NSIP (HR 0.65, 95%CI 0.45, 0.93) and OP (HR 0.18, 95%CI 0.05, 0.57), but higher in fHP (HR 1.58, 95%CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95%CI 1.4, 2.8), with no change for UIP or fHP. CONCLUSION: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP.

Patient and Physician Assessments of Clinical Status: A Mixed-methods Study of Interstitial Lung Disease.

Background: The SARS-CoV-2 pandemic necessitated novel health care delivery for patients with interstitial lung disease (ILD), including reduced in-person appointments and physiologic testing to minimize transmission. Clinicians often have been required to rely on patients' subjective assessments of their clinical status during phone follow-up appointments. It is unknown how accurate a patient's self-assessment is compared with that of their physician during an in-person evaluation. Research Question: Are patients' self-assessments of their clinical status in agreement with their physicians' assessments, and are telemedicine vs in-person visits acceptable? Study Design and Methods: Patients were enrolled prospectively from the University of Calgary ILD clinic. Participants were asked by phone before the in-person appointment and after the appointment to rate their clinical status on a five-point Likert scale. Physicians then rated the patient's clinical status after the appointment on a similar five-point Likert scale, masked to patient responses. Patients and physicians were asked if an in-person appointment was necessary or if telemedicine would have sufficed. Clinical variables associated with physician assessments were assessed. Results: Fifty patients with mean age of 67 ± 11.8 years participated. Mean time since last follow-up was 5.0 ± 3.0 months. No correlation was found between the preclinical patient self-assessment and postclinical physician assessment (P = .18; κ = 0.28). Correlation of postclinical assessment was statistically significant (P < .001), with moderate agreement (κ = 0.49). Physicians thought telephone visits were acceptable for 58% of appointments, whereas only 12% of patients preferred telephone visits. Physician's assessment of clinical status seemed to be driven by change in diffusion capacity of the lungs for carbon monoxide (P = .039). Interpretation: Telemedicine may improve access to care for patients during pandemic management, in rural communities, and for those with impaired mobility. Despite these benefits, our data support that patients and physicians may not agree on determination of clinical status and that patients generally prefer in-person patient-physician interactions.

Peripheral blood monocyte count and outcomes in patients with interstitial lung disease: a systematic review and meta-analysis.

BACKGROUND: Peripheral blood monocyte counts have been associated with poor outcomes in interstitial lung disease (ILD). However, studies are limited by variable biomarker thresholds, analytic approaches and heterogenous populations. This systematic review and meta-analysis characterised the relationship between monocytes and clinical outcomes in ILD. METHODS: Electronic database searches were performed. Two reviewers screened abstracts and extracted data. Pooled estimates (hazard ratios (HRs)) of monocyte count thresholds were calculated for their association with mortality using ≥0.6×109 and >0.9×109 cells·L-1 for unadjusted models and ≥0.95×109 cells·L-1 for adjusted models, using random effects, with heterogeneity and bias assessed. Disease progression associated with monocytes >0.9×109cells·L-1 was also calculated. RESULTS: Of 3279 abstracts, 13 were included in the systematic review and eight in the meta-analysis. The pooled unadjusted HR for mortality for monocyte counts ≥0.6×109 cells·L-1 was 1.71 (95% CI 1.34-2.19, p<0.001, I2=0%) and for monocyte counts >0.90×109 cells·L-1 it was 2.44 (95% CI 1.53-3.87, p=0.0002, I2=52%). The pooled adjusted HR for mortality for monocyte counts ≥0.95×109 cells·L-1 was 1.93 (95% CI 1.24-3.01, p=0.0038 I2=69%). The pooled HR for disease progression associated with increased monocyte counts was 1.83 (95% CI 1.40-2.39, p<0.0001, I2=28%). CONCLUSIONS: Peripheral blood monocyte counts were associated with an increased risk of mortality and disease progression in patients with ILD.

Integration and Application of Radiologic Patterns From Clinical Practice Guidelines on Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without direction on whether or how to apply these approaches concurrently within a single patient. RESEARCH QUESTION: How can we integrate guideline-defined radiologic patterns to diagnose interstitial lung disease (ILD) and what are the pitfalls associated with described patterns that require reassessment in future guidelines? STUDY DESIGN AND METHODS: Patients from the Canadian Registry for Pulmonary Fibrosis underwent detailed reevaluation in standardized multidisciplinary discussion. CT scan features were quantified by chest radiologists masked to clinical data, and guideline-defined patterns were assigned. Clinical data then were provided to the radiologist and an ILD clinician, who jointly determined the leading diagnosis. RESULTS: Clinical-radiologic diagnosis in 1,593 patients was idiopathic pulmonary fibrosis (IPF) in 26%, fHP in 12%, connective tissue disease-associated ILD (CTD-ILD) in 34%, idiopathic pneumonia with autoimmune features in 12%, and unclassifiable ILD in 10%. Typical and probable UIP patterns corresponded to a diagnosis of IPF in 66% and 57% of patients, respectively. Typical fHP pattern corresponded to an fHP clinical diagnosis in 65% of patients, whereas compatible fHP was nonspecific and associated with CTD-ILD or IPAF in 48% of patients. No pattern ruled out CTD-ILD. Gas trapping affecting > 5% of lung parenchyma on expiratory imaging was an important feature broadly separating compatible and typical fHP from other patterns (sensitivity, 0.77; specificity, 0.91). INTERPRETATION: An integrated approach to guideline-defined UIP and fHP patterns is feasible and supports > 5% gas trapping as an important branch point. Typical or probable UIP and typical fHP patterns have moderate predictive values for a corresponding diagnosis of IPF and fHP, although occasionally confounded by CTD-ILD; compatible fHP is nonspecific.

Prevalence, Risk Factors, and Outcomes of Adult Interstitial Lung Abnormalities: A Systematic Review and Meta-Analysis.

Rationale: Incidental parenchymal abnormalities detected on chest computed tomography scans are termed interstitial lung abnormalities (ILAs). ILAs may represent early interstitial lung disease (ILD) and are associated with an increased risk of progressive fibrosis and mortality. The prevalence of ILAs is unknown, with heterogeneity across study populations. Objectives: Estimate the pooled prevalence of ILAs in lung cancer screening, general population-based, and at-risk familial cohorts using meta-analysis; identify variables associated with ILA risk; and characterize ILA-associated mortality. Methods: The study protocol was registered on PROSPERO (CRD42022373203), and Meta-analyses of Observational Studies in Epidemiology recommendations were followed. Relevant studies were searched on Embase and Medline. Study titles were screened and abstracts reviewed for full-text eligibility. Random effect models were used to pool prevalence estimates for specified subgroups and ILA-associated mortality risk. Risk of ILAs was estimated based on age, sex, and FVC. Quality assessment was conducted using an adapted Assessment Tool for Prevalence Studies. Measurements and Main Results: The search identified 9,536 studies, with 22 included, comprising 88,325 participants. The pooled ILA prevalence was 7% (95% confidence interval [CI], 0.01-0.13) in lung cancer screening, 7% (95% CI, 0.04-0.10) in general population, and 26% (95% CI, 0.20-0.32) in familial cohorts. Pooled mortality risk was increased in those with ILAs (odds ratio, 3.56; 95% CI, 2.19-5.81). Older age, male sex, and lower FVC% were associated with greater odds of ILA. Conclusions: Populations undergoing imaging for non-ILD indications demonstrate high ILA prevalence. Standardized reporting and follow-up of ILAs is needed, including defining those at greatest risk of progression to ILD.

Pregnancy Considerations for Patients With Interstitial Lung Disease.

Advances in our understanding of interstitial lung disease (ILD) pathophysiology and natural history have led to the development of guidelines for the diagnosis and management of several of these complex diseases. The demographics of patients with ILD indicate the disease is not restricted to older adults. Connective tissue disease-associated ILD, familial pulmonary fibrosis, and post-COVID-19 fibrosis may affect women of child-bearing age. Recent trials have excluded pregnant women, thereby limiting the applicability of contemporary therapeutic advances to these patients. This review synthesizes the current knowledge of pregnancy outcomes in those with ILD, with a focus on connective tissue disease-associated ILD, and potential treatment implications for patients with ILD who are pregnant or considering pregnancy. Pregnancy considerations for patients with ILD include the need for preconception counseling and planning to ensure disease stability, medication and vaccination optimization, and multidisciplinary involvement of a patient's pulmonologist, obstetrician, and, when indicated, rheumatologist and genetic counselor. Evidence to date suggests that women with ILD can have safe and healthy pregnancies but that complications may occur in those with severe ILD.

Perceptions of Genetic Testing: A Mixed-Methods Study of Patients with Pulmonary Fibrosis and Their First-Degree Relatives.

Rationale: Genetic testing is an emerging tool in interstitial lung disease (ILD) as several ILD subtypes have potential genetic causes or predispositions with resultant clinical implications. There is a need to understand the perceptions of patients and their first-degree relatives of genetic testing for ILD. Objectives: The objective of this study was to investigate patients with ILD and their first-degree family members' understanding of the genetic risks associated with ILD and their interest and/or concerns about genetic testing. Methods: This mixed-methods study included patients with ILD and their first-degree relatives. Data were obtained from an online survey and three focus groups. Categorical data were reported with descriptive frequencies. Chi-square analyses were used to measure associations. Focus group discussions were transcribed, coded, and analyzed according to the grounded theory principle. Results: A total of 188 respondents completed the survey; 119 patients, 52 first-degree relatives, and 17 who were both patients and who also reported being a first-degree relative to someone with ILD. Most (79%) patients had idiopathic pulmonary fibrosis. The majority of patients and first-degree relatives were unsure if there was a genetic cause, whereas 71% of those who were both patient and first-degree relative thought there could be a genetic cause to their ILD. Fifty-nine percent of respondents worried their family members could be affected, and 72% of respondents were interested in genetic testing. Interest in genetic testing was associated with sex (P = 0.03), post-secondary education (P = 0.047), and having a family member with ILD (P = 0.02). The primary motivators were understanding risk to family members and contributing to research. First-degree relatives were concerned about insurance issues (60%) and personal stress (60%) more often than patients (40% and 28%, respectively); 29% of first-degree relatives anticipated changing their health behavior based on results. Focus group themes included disease knowledge, understanding the role of genetics in ILD, testing concerns, and how to use genetic testing information. Conclusions: This study provides insight into the perceptions of patients and first-degree relatives of ILD-related genetic testing. These findings inform the need for additional patient resources, yet a better understanding of the clinical applications of ILD genetic testing and how testing may impact diagnostics, therapeutics, and prognostication.

TPMT and HLA-DQA1-HLA-DRB genetic profiling to guide the use of azathioprine in the treatment of interstitial lung disease: First experience.

BACKGROUND: The choice of immunosuppressive therapy in interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF) is based on safety profile and expected efficacy. Azathioprine is one of the most commonly used agents to treat ILD. The immunosuppressive effect and pancreatitis risk of azathioprine are influenced by the activity of the enzyme thiopurine methyltransferase (TPMT) and by the genetic mutations in HLA-DQA1-HLA-DRB locus, respectively. We hypothesized that systematic genotyping prior to starting azathioprine improves the rate of discontinuation of immunosuppressive therapy and the total incidence of adverse drug reactions (ADRs). METHODS: Eighty-two patients with ILD other than IPF were included in the study. The rate of immunosuppressive therapy discontinuation due to major ADRs and the total incidence of ADRs were compared between a cohort of genotyped patients (n = 49) and an untested cohort of patients (n = 33). RESULTS: Thirty-seven out of 49 patients in the genotyped cohort and 27 out of 33 patients in the untested cohort were started on azathioprine. The rate of immunosuppressive therapy discontinuation due to major ADRs was significantly lower (6/49) in the genotyped cohort compared to the untested cohort (11/33; p = 0.0276). All but one discontinuation due to severe ADRs occurred within a month of therapy. However, the total incidence rate of ADRs was very similar in the 2 cohorts (0.025 in the genotyped cohort vs. 0.023 in the untested cohort). CONCLUSION: In patients with ILD other than IPF, genotyping for azathioprine metabolism prior to starting therapy is associated with a significantly reduced rate of immunosuppressive therapy discontinuation due to major ADRs, with prevention of bone marrow suppression and pancreatitis, but without a reduction of the total incidence of ADRs. While these data support the use of genetic profiling prior to starting azathioprine to treat ILD, its cost effectiveness remains to be established.

Unique ECG Findings in Acute Pulmonary Embolism: STE with Reciprocal Changes and Pathologic Q Wave.

A 68-year-old male presented to the emergency department with retrosternal chest pain, presyncope, and then a pulseless electrical activity cardiac arrest. An ECG prior to his arrest revealed ST elevations in leads V1-V3, Q waves in lead V2, and reciprocal ST depressions in the lateral and inferior leads. He received thrombolytic therapy for a presumptive diagnosis of ST elevation myocardial infarction. Return of spontaneous circulation was achieved and he underwent a coronary angiogram. No critical disease was found and his left ventriculogram showed normal contraction. His ongoing metabolic acidosis and dependence on an intra-aortic balloon pump, despite adequate cardiac output, prompted a CT pulmonary angiogram which showed multiple segmental filling defects. He was treated for a pulmonary embolism and was discharged 5 days later. Acute pulmonary embolism (APE) has variable clinical presentations. To our knowledge, this is the first case report of an APE presenting with these ECG findings suggestive of myocardial ischemia. In this case report, we discuss the underlying physiological mechanisms responsible and offer management suggestions for emergency department and critical care physicians to better expedite the treatment of APE mimicking acute coronary syndrome on ECG.

Does laparoscopy safely improve technicity for complex hysterectomy cases?

OBJECTIVE: The minimally invasive surgical (MIS) approach to hysterectomy (vaginal or laparoscopic), when compared with laparotomy, results in shorter length of stay, fewer minor and major complications, and quicker return to normal activity. The complexity of the hysterectomy procedure or pathology may affect the success of an MIS approach. This study examined the indications, complications, and outcomes of all hysterectomies performed, irrespective of the severity of pathology or patient habitus, in a Canadian tertiary level gynaecologic surgical referral service. METHODS: We performed a retrospective chart review of all hysterectomies performed by a single surgeon between September 2007 and June 2011, noting indications, complications, and outcomes. One-way analysis of variance was used to calculate the influence of various factors across surgery types. Significance was set at P < 0.05 for all tests. RESULTS: A total of 305 cases were included; 291 of these (95.4%) were managed through an MIS approach, providing a technicity rate of 95.4%. Mean patient age was 45.5 years, and mean BMI was 28.9. The main indicators for surgery were fibroids (42.0%), pain (38.4%), and heavy menstrual bleeding (37.4%). Eighty-one percent of cases were tertiary referrals. Of the laparoscopic cohort, endometriosis was moderate-severe in 61.2% of patients. Mean length of stay was 1.14 days, mean uterine weight was 277.6 g, and mean estimated blood loss was 179 mL. CONCLUSION: This retrospective study of a tertiary level referral gynaecologic service suggests that complex hysterectomy may be effectively and efficiently managed through an MIS approach.

Objectif : Le recours à une approche chirurgicale à effraction minimale (CEM) aux fins de la tenue d'une hystérectomie (par voie vaginale ou laparoscopique), par comparaison avec le recours à une laparotomie, entraîne une diminution de la durée de l'hospitalisation et du nombre de complications mineures et majeures, ainsi qu'une accélération du retour aux activités normales. La complexité de l'hystérectomie ou de la pathologie pourrait affecter la réussite du recours à une approche CEM. Cette étude s'est penchée sur les indications, les complications et les issues de toutes les hystérectomies menées, sans égard à la gravité de la pathologie ou à l'habitus de la patiente, au sein d'un service canadien d'orientation en chirurgie gynécologique de niveau tertiaire. Méthodes : Nous avons mené une analyse rétrospective des dossiers portant sur toutes les hystérectomies menées par un même chirurgien entre septembre 2007 et juin 2011, en prenant note des indications, des complications et des issues. Une analyse de variance à un critère de classification a été utilisée pour calculer l'influence de divers facteurs sur tous les types de chirurgie. Le niveau de signification a été établi à P < 0,05 pour tous les tests. Résultats : Au total, 305 cas ont été inclus; 291 de ces cas (95,4 %) ont été pris en charge au moyen d'une approche CEM, offrant ainsi un taux de technicité de 95,4 %. L'âge moyen des patientes était de 45,5 ans et l'IMC moyen était de 28,9. Les fibromes (42,0 %), la douleur (38,4 %) et la présence de règles abondantes (37,4 %) constituaient les principaux indicateurs du recours à la chirurgie. Les orientations tertiaires représentaient 81 % des cas. Au sein de la cohorte « laparoscopie ¼, l'endométriose allait de modérée à grave chez 61,2 % des patientes. La durée moyenne de l'hospitalisation était de 1,14 jour, le poids utérin moyen était de 277,6 g et la perte sanguine estimée moyenne était de 179 ml. Conclusion : Cette étude rétrospective ayant porté sur un service d'orientation en chirurgie gynécologique de niveau tertiaire semble indiquer que les cas complexes d'hystérectomie pourraient être pris en charge de façon efficace au moyen d'une approche CEM.

Spot urine protein measurements in kidney transplantation: a systematic review of diagnostic accuracy.

BACKGROUND: Quantification of proteinuria (albuminuria) in renal transplant recipients is important for diagnostic and prognostic purposes. Recent guidelines have recommended quantification of proteinuria by spot protein-to-creatinine ratio (PCR) or spot albumin-to-creatinine ratio (ACR). Validity of spot measurements remains unclear in renal transplant recipients. METHODS: Systematic review of adult kidney transplant recipients. Studies that reported the diagnostic accuracy of PCR or ACR as compared with 24-h urine protein or albumin excretion in renal transplant recipients were included. RESULTS: The search identified 8 studies involving 1871 renal transplant recipients. The correlation of the PCR to 24-h protein ranged from 0.772 to 0.998 with a median value of 0.92. PCR sensitivity ranged from 63 to 99 (50% of sensitivities were >90%); PCR specificity varied from 73 to 99 (50% of specificities were >90%). Only one study reported the bias; percent bias ranged from 12 to 21% and accuracy (within 30% of 24 h urine protein) ranged from 47 to 56% depending on the degree of proteinuria. For the ACR, percent bias ranged from 9 to 21%, and the accuracy (within 30%) ranged from 38 to 80%. CONCLUSIONS: The data regarding diagnostic accuracy of PCR and ACR is limited. Only one report studied the absolute measures of agreement (bias and accuracy). We recommend verifying PCR and ACR measurements with a 24-h protein before making any major diagnostic (e.g. biopsy) or therapeutic (e.g. change in immunosuppressive agents) decisions in this population.