Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Clinical and Functional Outcomes Associated with Quality of Life in Patients with Lymphangioleiomyomatosis: A Cross-Sectional Study.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare (twenty-one per million female inhabitants) neoplastic cystic lung disease that impairs health-related quality of life (HRQoL). However, the factors associated with impaired quality of life in patients with LAM are poorly understood. OBJECTIVE: To assess the clinical, psychosocial, and functional characteristics associated with impaired quality of life in patients with LAM. METHODS: This was a cross-sectional study performed on two nonconsecutive days. HRQoL (SF-36 and CRQ), lung function tests, anxiety and depression symptoms (HADS), maximal (CPET and ISWT), and submaximal exercise capacity (6MWT) were assessed. Linear associations among outcomes were assessed using Pearson's correlation and multivariate tests. RESULTS: Forty-five women with LAM (46 ± 10.years; FEV1,74%pred) were evaluated. The lowest SF-36 scores were observed for general health and vitality and the highest for the physical and social domains. The lowest CRQ scores were observed for dyspnea and fatigue, and the highest were for the emotional function and self-control domains. Sixteen (35%) women had anxiety, and 8 (17%) had depression symptoms. Most of the SF-36 and CRQ domains were associated with anxiety and depression symptoms (from r = 0.4 to r = 0.7; p < 0.05) and exercise capacity (from r = 0.3 to r = 0.5; p < 0.05). Lung function parameters were weakly or not associated with quality of life domains. After multiple linear regression, HRQoL was independently associated with depression symptoms and physical capacity but not with lung function. CONCLUSION: Our results show that aerobic capacity and depression symptoms are the main factors, rather than lung function, related to quality of life in patients with LAM.

Diagnosis of renal tumors in Birt-Hogg-Dube syndrome: Clinical presentation and risk factors in a single-center retrospective cohort.

BACKGROUND: Birt-Hogg-Dube (BHD) syndrome is a rare genetic condition associated with the development of renal tumors. This study aims to determine typical age ranges for detecting renal abnormalities, risk factors for tumor development, and long-term outcomes based on current surveillance strategies. METHODS: A single-center multi-site retrospective cohort study was performed on all patients with BHD diagnosed from 2000 to 2023. Baseline demographics, pulmonary function, laboratory, radiologic, and histopathologic findings were collected. Logistic regression was used to assess predictor variables for the development of renal tumors with survival analysis evaluated from the date of BHD diagnosis to date of death or last known follow-up. RESULTS: The study included 149 patients with BHD, 39 (26%) with diagnosed renal tumors, of which 28 had histopathologic confirmation. Mean age at renal tumor detection was 53.61 years. Older age and male sex were predictive of renal tumor development ((odds ratio 1.05; 95% CI, 1.01-1.08, P = 0.002) and (odds ratio 2.59; 95% CI, 1.17-5.73, P = 0.02), respectively). Time to all-cause mortality appeared shorter in those with renal tumors (Log-rank P = 0.02), though no deaths were from cancer or cancer-related complications. CONCLUSIONS: Current screening protocols for renal tumors in BHD suggest the most common presenting age range for presentation is late 40s to early 50s, with older age and male sex as risk factors for tumor development.

Retinoic Acid-Mediated Control of Energy Metabolism Is Essential for Lung Branching Morphogenesis.

Lung branching morphogenesis relies on intricate epithelial-mesenchymal interactions and signaling networks. Still, the interplay between signaling and energy metabolism in shaping embryonic lung development remains unexplored. Retinoic acid (RA) signaling influences lung proximal-distal patterning and branching morphogenesis, but its role as a metabolic modulator is unknown. Hence, this study investigates how RA signaling affects the metabolic profile of lung branching. We performed ex vivo lung explant culture of embryonic chicken lungs treated with DMSO, 1 µM RA, or 10 µM BMS493. Extracellular metabolite consumption/production was evaluated by using 1H-NMR spectroscopy. Mitochondrial respiration and biogenesis were also analyzed. Proliferation was assessed using an EdU-based assay. The expression of crucial metabolic/signaling components was examined through Western blot, qPCR, and in situ hybridization. RA signaling stimulation redirects glucose towards pyruvate and succinate production rather than to alanine or lactate. Inhibition of RA signaling reduces lung branching, resulting in a cystic-like phenotype while promoting mitochondrial function. Here, RA signaling emerges as a regulator of tissue proliferation and lactate dehydrogenase expression. Furthermore, RA governs fatty acid metabolism through an AMPK-dependent mechanism. These findings underscore RA's pivotal role in shaping lung metabolism during branching morphogenesis, contributing to our understanding of lung development and cystic-related lung disorders.

Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population.

PURPOSE: Penetrance estimates of Birt-Hogg-Dubé syndrome (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a health care system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes. METHODS: Exomes from 135,990 patient-participants in Geisinger's MyCode cohort were assessed for P/LP truncating FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between P/LP FLCN variants and BHD-related phenotypes was assessed using Firth's logistic regression. RESULTS: P/LP truncating FLCN variants were identified in 35 individuals (1 in 3234 unrelated individuals), 68.6% of whom had BHD-related phenotype(s), including cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). A total of 4 (11.4%) individuals had prior clinical BHD diagnoses. CONCLUSION: In this health care population, the frequency of P/LP truncating FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes, a minority were previously clinically diagnosed, likely because cutaneous manifestations, pneumothoraces, and kidney cancer were observed at lower frequencies than in clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.

Computer grading of lung disease severity in patients with lymphangioleiomyomatosis referred for transplantation.

OBJECTIVES: Lymphangioleiomyomatosis (LAM) patients with severe lung disease may be considered for lung transplantation. Clinical, physiologic, and quality of life data are usually employed for referral. The aim of this study was to determine whether computed tomographic measurement of lung volume occupied by cysts (cyst score) complemented clinical and physiologic data in supporting referral for transplantation. METHODS: Forty-one patients were studied. Pre-referral clinical data, pulmonary function tests, exercise testing, and high-resolution computed tomography (HRCT) scans were obtained. From HRCT, a computer-aided diagnostic program was employed to calculate cyst scores. These data were compared to those of 41 age-matched LAM patients not referred for lung transplantation. RESULTS: Cyst score, and % predicted FEV1 and DLCO were respectively, 48.1 ± 9.4%, 36.5 ± 9.1%, and 35.0 ± 10.7%. For the control group, cyst score, FEV1, and DLCO were respectively, 14.8 ± 8.3%, 77.2 ± 20.3%, and 66.7 ± 19.3%. Cyst score values showed a normal distribution. However, the frequency distribution of FEV1 was skewed to the right while the distribution of DLCO was bimodal. Correlations between cyst score and FEV1 and DLCO for the study group were respectively, r = - 0.319 and r = - 0.421. CONCLUSIONS: LAM patients referred for lung transplantation had nearly 50% of lungs occupied by cysts. Correlations between cyst score and FEV1 or DLCO were weak; as shown previously, DLCO was better related to cyst number while FEV1 had a better association with cyst size. Given its normal distribution, cyst score measurements may assist in evaluation of pre-transplant severity of lung disease before referral for transplantation.

Bilateral congenital pulmonary airway malformation presenting in adulthood with a review of the literature.

We report a rare case of congenital pulmonary airway malformation (CPAM) in a middle-aged female patient with bilateral involvement. In view of its presentation in adulthood, it presents a rare picture of a disease often diagnosed in early childhood. Until now, 65 cases of this disease have been reported in adults, including 3 cases with bilateral involvement. A classical radiological picture of CPAM can often be confused with bronchiectasis or pulmonary sequestration. A definite treatment with surgical resection poses a challenge in bilateral involvement. We highlight a rare case with its challenges in diagnosis and management. A review of literature of cases of CPAM with bilateral involvement is conducted in an effort to better understand this entity in adulthood.

X-ray microtomosynthesis of unstained pathology tissue samples.

In pathology protocols, a tissue block, such as one containing a mouse brain or a biopsy sample from a patient, can produce several hundred thin sections. Substantial time may be required to analyse all sections. In cases of uncertainty regarding which sections to focus on, noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sub-10 µm resolution. We explored a novel x-ray tomosynthesis method as a way to maximise contrast-to-noise ratio, a determinant of tissue visibility. It provided a z-stack of thousands of images at 7.3 µm resolution (10% contrast, half-period of 68.5 line pairs/mm), in scans of 5-15 minutes. When compared with micro-CT scans, the straight-line tomosynthesis scan did not need to rotate the sample, which allowed flat samples, such as paraffin blocks, to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this mode maximised the photon flux density through the sample, which helped in maximising the contrast-to-noise ratio. The tradeoff of tomosynthesis is incomplete 3D information. The microtomosynthesis scanner has scanned 110 unstained human and animal tissue samples as part of their respective pathology protocols. In all cases, the z-stack of images showed tissue structures that guided sectioning or provided correlative structural information. We describe six examples that presented different levels of visibility of soft tissue structures. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.

A microscopy version of the imaging method for 3D luggage screening has been adapted to image unstained pathology samples. Pathology tests of tissue samples are used for clinical diagnosis and for biomedical research. The tissue samples are often embedded in paraffin blocks and sectioned into many thin slices, which are then stained with the appropriate agents for light microscopy. Since each tissue block can produce several hundred thin sections, much time and labour is required to analyse all sections. Noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sufficient resolution. X-ray imaging is a promising tool to meet the challenge since x-rays can penetrate thick samples that are opaque to visible light. With x-ray imaging, a determinant of tissue visibility is the flux density of photons that illuminate the sample. We explored a novel x-ray tomosynthesis method as a way to maximise this factor. It provided a stack of thousands of cross-sectional images at 7.3 µm resolution (half-period of 68.5 line pairs/mm) in scans of 5-15 minutes. When compared with micro-CT scans (a widely used laboratory technology), this method did not need to rotate the sample, which allowed flat samples such as paraffin blocks to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this method maximised the photon flux density through the sample, which helped in improving the visibility of unstained tissue under x-ray. The tradeoff of the method is incomplete 3D information. Over 100 unstained human and animal tissue samples have been scanned with this method as part of their respective pathology protocols. In all cases, the stack of cross-sectional images showed tissue structures that guided pathology analysis or provided correlative structural information. We describe six examples that presented different levels of tissue visibility. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.

Isolated Cystic Lung Disease: An Algorithmic Approach to Distinguishing Birt-Hogg-Dubé Syndrome, Lymphangioleiomyomatosis, and Lymphocytic Interstitial Pneumonia.

OBJECTIVE. Birt-Hogg-Dubé (BHD) syndrome, lymphangioleiomyomatosis (LAM), and lymphocytic interstitial pneumonia (LIP) frequently present as isolated cystic lung disease and can be challenging to distinguish. If imaging findings are otherwise unremarkable, the radiologist is unaided by ancillary CT findings in narrowing the diagnosis. We hypothesized that the distribution and morphologic features of lung cysts could be used to differentiate BHD syndrome, LAM, and LIP. Therefore, the purpose of this study was to characterize the CT appearances of these conditions and create a practical CT-based algorithm to differentiate among them. MATERIALS AND METHODS. The study was a retrospective review of the CT images of 16 patients with BHD syndrome, 17 patients with LAM, and 14 patients with LIP. On the basis of the data collected, a CT-based algorithm was created, and the CT images were reviewed again. RESULTS. Lower lung-predominant cysts were significantly more likely to be found in patients with BHD syndrome (100% of patients) or LIP (71-93% of patients) than in patients with LAM (6-12% of patients), who were more likely to have diffuse cysts. Compared with patients with LIP or LAM, patients with BHD syndrome were significantly more likely to have elliptical (floppy) paramediastinal cysts (88-94% of patients with BHD syndrome, 36-43% of patients with LIP, and 6-12% of patients with LAM) or a disproportionate number of paramediastinal cysts (69-88% of patients with BHD syndrome, 0-14% of patients with LIP, and 0-6% of patients with LAM). Our algorithm enabled differentiation of BHD syndrome, LAM, and LIP with a high level of accuracy and high interreader agreement (κ = 0.809). CONCLUSION. Radiologists can use the proposed CT-based algorithm to prospectively and confidently suggest one of these disorders as the favored diagnosis. Of importance, this will allow diagnosing the disorder early and accurately, screening for comorbidities, and prevention of potential complications.

Filarial tropical pulmonary eosinophilia: a condition masquerading asthma, a series of 12 cases.

INTRODUCTION: Tropical pulmonary eosinophilia (TPE) is a form of occult filariasis, clinically characterized by paroxysmal cough, wheezing and dyspnea which is often misdiagnosed and treated as asthma. These manifestations result from a host immune response to trapped antigens of the microfilarial parasites Wuchereria bancrofti or Brugia malayi in the pulmonary microcirculation. CASE STUDY: We describe three rare presentations of TPE (cor pumonale, cystic lung disease and respiratory distress mimicking acute severe asthma) in our series of 12 cases. All cases were from filaria endemic areas and presented with cough, wheezing and dyspnea, either alone or in combination. Subsequent work-up revealed peripheral eosinophilia, raised serum IgE levels and positive serum filarial antibody and/or antigen in all the cases. RESULTS: All patients were treated with diethylcarbamazine (DEC), while few required inhaled/systemic corticosteroid. Prompt improvement in clinical symptoms with a decrease in eosinophil count was seen in all. Two cases relapsed requiring a second course of DEC. Long-term outcome was good, however, there was a persistence of restrictive lung function and echocardiographic feature of pulmonary hypertension in the patients with cystic lung disease and cor pulmonale, respectively. CONCLUSION: TPE should always be considered in patients from filaria endemic areas presenting with cough, dyspnea or wheezing. High eosinophil count (>3 × 109 cells) with raised IgE level (>1000 IU/mL) in such cases should alert the physician to look for TPE. Early diagnosis and treatment can prevent disease progression and complications.

Pulmonary lobectomy techniques in infants and children.

Thoracoscopic pulmonary lobectomy (TPL) techniques in infants and children are presented practically with concise descriptions and numerous illustrations. TPL is the treatment of choice for congenital pulmonary airway malformation and intralobar pulmonary sequestration, both now commonly diagnosed prenatally. Timing of surgery is somewhat controversial in asymptomatic cases with small isolated lesions. Incomplete fissures and history of chest infections are most problematic. Thorough understanding of anatomic relations preoperatively is vital for successful outcome and thin-slice computed tomography with 3D reconstruction of vessels is valuable. Judicious placement of trocars and switching instruments between trocars improves visualization and safety. Specific techniques for all commonly performed TPL are included.

Perinatal features of congenital cystic lung diseases: results of a nationwide multicentric study in Japan.

PURPOSE: The current study aimed to assess the perinatal risk and clinical features of congenital cystic lung diseases (CCLD). MATERIALS AND METHODS: Of the 874 CCLD patients identified in a nationwide survey, 428 patients born between 1992 and 2012 and treated at 10 high-volume centers, were retrospectively reviewed. RESULTS: Fetal hydrops was visualized using MRI in 9.2 % of the patients. Prenatal interventions were described for 221 of the 428 patients, including the maternal administration of steroid and pleuro-amniotic shunting. Postnatally, a right-to-left shunt flow through a persistent ductus arteriosus was observed in 7.8 % of the patients. The fetal lung lesion volume ratio (LVR) was significantly higher among these symptomatic patients (2.04 ± 1.71 vs. 0.98 ± 0.50, P < 0.00071), and decreased to a greater degree in non-CCAM patients compared with CCAM patients during the late gestational period (from 1.37 ± 1.28 to 1.14 ± 0.84 in CCAM and from 1.08 ± 0.47 to 0.46 ± 0.64 in non-CCAM). CONCLUSIONS: An estimated 8-9 % of prenatally diagnosed patients carry the highest risk of perinatal respiratory distress. Fetal LVR remaining at a high level during the late gestational period seems to predict a high risk.

Desquamative interstitial pneumonia: A case report.

Diffuse cystic lung diseases (DCLDs) are a group of heterogeneous lung diseases that are characterized by inflated spaces or cysts within the lung parenchyma. They also exhibit similar imaging characteristics and clinical manifestations compared with those of cystic lesions, such as pulmonary cavities, emphysema, bronchiectasis and honeycomb lung. The most common DCLDs encountered in the clinic include lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, Langerhans cell histiocytosis and lymphocytic interstitial pneumonia. In particular, accurate diagnosis of DCLDs in terms of the different lesions found is important, because their clinical courses, prognoses and treatment strategies vary widely. However, because DCLDs usually have overlapping clinical presentations, diagnosis typically requires a combination of clinical considerations that take into account characteristics of the cyst, its distribution, organ of origin and background parenchymal findings. The present report documents the case of a 73-year-old man diagnosed with desquamative interstitial pneumonia (DIP). The patient was admitted to the hospital due to chest tightness, shortness of breath and intermittent fever. The patient had been a smoker for >60 years and had stopped smoking for 6 months before being admitted. A transbronchial lung biopsy, bronchoscopy and alveolar lavage cytopathogen culture were performed to confirm the diagnosis of desquamative interstitial pneumonia (DIP). The patient was treated with hormonal therapy and advised to abstain from smoking. The diagnosis of DIP in comparison with other DCLDs was summarized for the purpose of providing a clinical basis for the accurate clinical diagnosis of DIP and the development of evidence-based practice guidelines.

Bevacizumab-induced pulmonary cystic disease.

The use of Bevacizumab has significantly advanced the treatment of various malignancies. Bevacizumab's inhibition of angiogenesis is a known mechanism that impedes tumour growth and facilitates chemotherapy delivery; however, its association with the development of cystic lung disease is not fully understood. We report a unique case of a 73-year-old woman with a past medical history of metastatic endometrial adenocarcinoma status post-chemotherapy with bevacizumab that presented with worsening respiratory symptoms. A follow-up chest CT scan post chemotherapy showed the transformation of the metastatic lesions into cystic formations. After further extensive evaluation, she was diagnosed with pulmonary cystic disease secondary to bevacizumab. This case illustrates a rare presentation of secondary pulmonary cystic disease following Bevacizumab therapy in a patient with metastatic endometrial adenocarcinoma. It highlights the importance of recognizing uncommon side effects of targeted immunotherapy and underscores the need for ongoing research to understand the underlying mechanisms and manage such complications effectively.

Computer-aided diagnosis of cystic lung diseases using CT scans and deep learning.

BACKGROUND: Auxiliary diagnosis of different types of cystic lung diseases (CLDs) is important in the clinic and is instrumental in facilitating early and specific treatments. Current clinical methods heavily depend on accumulated experience, restricting their applicability in regions with less developed medical resources. Thus, how to realize the computer-aided diagnosis of CLDs is of great clinical value. PURPOSE: This work proposed a deep learning-based method for automatically segmenting the lung parenchyma in computed tomography (CT) slice images and accurately diagnosing the CLDs using CT scans. METHODS: A two-stage deep learning method was proposed for the automatic classification of normal cases and five different CLDs using CT scans. Lung parenchyma segmentation is the foundation of CT image analysis and auxiliary diagnosis. To meet the requirements of different sizes of the lung parenchyma, an adaptive region-growing and improved U-Net model was employed for mask acquisition and automatic segmentation. The former was achieved by a self-designed adaptive seed point selection method based on similarity measurement, and the latter introduced multiscale input and multichannel output into the original U-Net model and effectively achieved the lightweight design by adjusting the structure and parameters. After that, the middle 30 consecutive CT slice images of each sample were segmented to obtain lung parenchyma, which was employed for training and testing the proposed multichannel parallel input recursive MLP-Mixer network (MPIRMNet) model, achieving the computer-aided diagnosis of CLDs. RESULTS: A total of 4718 and 16 290 CT slice images collected from 543 patients were employed to validate the proposed segmentation and classification methods, respectively. Experimental results showed that the improved U-Net model can accurately segment the lung parenchyma in CT slice images, with the Dice, precision, volumetric overlap error, and relative volume difference of 0.96 ± 0.01, 0.93 ± 0.04, 0.05 ± 0.02, and 0.05 ± 0.03, respectively. Meanwhile, the proposed MPIRMNet model achieved appreciable classification effect for normal cases and different CLDs, with the accuracy, sensitivity, specificity, and F1 score of 0.8823 ± 0.0324, 0.8897 ± 0.0325, 0.9746 ± 0.0078, and 0.8831 ± 0.0334, respectively. Compared with classical machine learning and convolutional neural networks-based methods for this task, the proposed classification method had a preferable performance, with a significant improvement of accuracy of 10.74%. CONCLUSIONS: The work introduced a two-stage deep learning method, which can achieve the segmentation of lung parenchyma and the classification of CLDs. Compared to previous diagnostic tasks targeting single CLD, this work can achieve various CLDs' diagnosis in the early stage, thereby achieving targeted treatment and increasing the potential and value of clinical applications.

A case of Sjögren's syndrome in which diffuse cystic lung lesions led to an accurate diagnosis.

Key Clinical Message: Even in the absence of other symptoms or other pulmonary manifestations suggesting Sjögren's syndrome (SS), it is necessary to include SS in the differential diagnosis of diffuse cystic lung disease (CLD). Abstract: A case of SS that presented initially with diffuse CLD is reported. This case is considered rare because diffuse pulmonary cysts were observed in the early stage with few symptoms, only cysts were observed without other lung lesions on imaging, cyst formation was histologically considered to be alveolar loss, and airway lesions not observed on imaging were suspected based on lung function testing. The details of this case provide extremely important information to consider for the diagnosis and management of CLD and SS.

Clinical Trial Validation of Automated Segmentation and Scoring of Pulmonary Cysts in Thoracic CT Scans.

In cystic lung diseases such as lymphangioleiomyomatosis (LAM), a CT-based cyst score that measures the percentage of the lung volume occupied by cysts is a common index of the cyst burden in the lungs. Although the current semi-automatic measurement of the cyst score is well established, it is susceptible to human operator variabilities. We recently developed a fully automatic method incorporating adaptive features in place of manual adjustments. In this clinical study, the automatic method is validated against the standard method in several aspects. These include the agreement between the cyst scores of the two methods, the agreement of each method with independent tests of pulmonary function, and the temporal consistency of the measurements in the consecutive visits of the same patients. We found that the automatic method agreed with the standard method as well as the agreement between two trained operators running the same standard method; both methods obtained the same level of correlation with laboratory pulmonary function tests; the automated method had better temporal consistency than the standard method (p < 0.0001). The study indicates that the automatic method could replace the standard method and provide better consistency in assessing the extent of cystic changes in the lungs of patients.

Diffuse Cystic Lung Disease: A Clinical Guide to Recognition and Management.

TOPIC IMPORTANCE: Diffuse cystic lung diseases (DCLDs) represent a group of pathophysiologically heterogeneous entities that share a common radiologic phenotype of multiple thin-walled pulmonary cysts. DCLDs differ from the typical fibroinflammatory interstitial lung diseases in their epidemiology, clinical presentation, molecular pathogenesis, and therapeutic approaches, making them worthy of a distinct classification. The importance of timely and accurate identification of DCLDs is heightened by the impact on patient management including recent discoveries of targeted therapeutic approaches for some disorders. REVIEW FINDINGS: This article offers a practical framework for evaluating patients with DCLD, indicating the most appropriate and current diagnostic and management approaches. We focus on the DCLDs that are most likely to be encountered by practicing pulmonologists: lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and lymphoid interstitial pneumonia. Chest CT scan is the most informative noninvasive diagnostic modality to identify DCLDs. Thereafter, instituting a structured approach to high-yield associated factors (eg, medical, social, and family history; renal and dermatologic findings) increases the likelihood of identifying DCLDs and achieving a diagnosis. SUMMARY: Although the individual diseases that comprise the DCLD family are rare, taken together, DCLDs can be encountered more frequently in clinical practice than commonly perceived. An increased eagerness among general pulmonary physicians to recognize these entities, coupled with a practical and systematic clinical approach to examinations and investigations, is required to improve case findings, allow earlier intervention, and reduce morbidity and mortality.

[Case report of a cystic lung disease: From a rarity to the discovery of an unknown genetic variant]. / À propos d'un cas clinique de maladie kystique pulmonaire : d'une rareté à la découverte d'un variant génétique inconnu.

INTRODUCTION: Cystic lung diseases are rare, with numerous differential diagnoses. Iconographic discovery consequently necessitates medical examinations in view of proposing an etiological orientation. CASE REPORT: A 57-year-old woman consulted in pulmonology following fortuitous detection of a cystic lung disease on an abdominal CT scan. Complementary medical examinations did not allow orientation towards a particular diagnosis. During a follow-up consultation, the patient informed her pulmonologist of the recent detection of a monoallelic variant of a FAT4 gene in one of her daughters, who was suffering from edema of the lower limbs secondary to a disease of the lymphatic system. As our patient had a similar history, she likewise received a genetic analysis. A monoallelic variant not described in the genetic databases was observed, and considered as a probable pathogenic variant (class 4/5 on the pathogenicity scale of genetic variants). CONCLUSION: After analyzing the available literature data, we raise questions about a possible link between this variant of the FAT4 gene, chronic lymphedema and our patient's cystic lung disease.

[Genetic diffuse cystic lung disease in adults]. / Maladies kystiques pulmonaires de l'adulte d'origine génétique.

Multiple cystic lung diseases comprise a wide range of various diseases, some of them of genetic origin. Lymphangioleiomyomatosis (LAM) is a disease occurring almost exclusively in women, sporadically or in association with tuberous sclerosis complex (TSC). Patients with LAM present with lymphatic complications, renal angiomyolipomas and cystic lung disease responsible for spontaneous pneumothoraces and progressive respiratory insufficiency. TSC and LAM have been ascribed to mutations in TSC1 or TSC2 genes. Patients with TSC are variably affected by cutaneous, cognitive and neuropsychiatric manifestations, epilepsy, cerebral and renal tumors, usually of benign nature. Birt-Hogg-Dubé syndrome is caused by mutations in FLCN encoding folliculin. This syndrome includes lung cysts of basal predominance, cutaneous fibrofolliculomas and various renal tumors. The main complications are spontaneous pneumothoraces and renal tumors requiring systematic screening. The mammalian target of rapamycin (mTOR) pathway is involved in the pathophysiology of TSC, sporadic LAM and Birt-Hogg-Dubé syndrome. MTOR inhibitors are used in LAM and in TSC while Birt-Hogg-Dubé syndrome does not progress towards chronic respiratory failure. Future challenges in these often under-recognized diseases include the need to reduce the delay to diagnosis, and to develop potentially curative treatments. In France, physicians can seek help from the network of reference centers for the diagnosis and management of rare pulmonary diseases.