Clinical and genetic characteristics of 100 consecutive patients with Birt-Hogg-Dubé syndrome in Eastern Chinese region.

BACKGROUND: Although an increasing number of patients with Birt-Hogg-Dubé syndrome (BHD) are being recognized in China, clinical and genetic characteristics are not well-defined. In addition, revised diagnostic criteria for the Chinese population was proposed in 2023, we aimed to explore their utility in clinical practice at a rare lung disease center. METHODS: We retrospectively analyzed the data of 100 consecutive patients with BHD diagnosed according to the revised Chinese BHD criteria, encountered at the First Affiliated Hospital of University of Science and Technology of China from Jan 2017 to June 2023. RESULTS: There were 100 patients (including 63 females) from 65 unrelated families in Eastern China, mostly Anhui Province. The common manifestations were pulmonary cysts (99%), pneumothorax (60%), and skin lesions (77%). Renal cancer and renal angiomyolipoma were detected in 5 patients each. 37% of patients had no family history of BHD. In total, 25 FLCN germline mutations were detected, including 6 novel mutations. In addition to hotspot mutation c.1285delC/dupC (17%), the most common mutations were c.1015 C > T (16%), c.1579_1580insA (14%), and exons 1-3 deletion (11%) in FLCN. Higher risk of pneumothorax was associated with exons 1-3 deletion mutation and c.1177-5_1177-3de1CTC compared to the hotspot mutation c.1285dupC (91% [95% CI: 0.31, 46.82, p = 0.015] and 67% [95% CI: 0.35, 71.9, p = 0.302] vs. 30%, respectively). The average delay in diagnosis was 7.6 years after initial symptoms. Chinese diagnostic criteria were mostly consistent with typical pulmonary presentations with supportive genetic evidence. CONCLUSION: In the Eastern Chinese region, patients with BHD present most commonly with pulmonary cysts associated with pneumothorax and skin lesions. However, low incidence of renal cancer along with unexpected renal angiomyolipoma was observed. Genotypic spectrum differed from that reported from other global regions, and genotype association of pneumothorax warrants further research. The revised Chinese criteria for BHD seem more appropriate in diagnosing BHD in Chinese patients.

A 62-Year-Old Woman With Cough, Dyspnea, and Diffuse Lung Nodules.

CASE PRESENTATION: A 62-year-old woman came to our hospital with worsening cough and dyspnea over the preceding week, during which time she had been treated with azithromycin and prednisone for suspected pneumonia. She had no fever, chills, or sweats, but her cough had become productive of clear to blood-tinged phlegm during the interval. Medical history was significant for insulin-dependent diabetes mellitus and OSA. She had quit smoking 44 years earlier and had no history of lung disease. She was a bank teller residing in southeastern Minnesota and described no relevant inhalational or environmental exposures, drug use, aspiration, or travels preceding her illness.

"Bubbly lung", a honeycombing variant with more favorable outcome.

BACKGROUND: Although radiologic honeycombing is generally associated with progressive fibrosis and a dismal prognosis, some patients display an unexpectedly indolent clinical course. We aimed to assess for variants of honeycombing associated with a more favorable prognosis. METHODS: A computer-assisted search was conducted to identify patients encountered at Mayo Clinic from 1998 to 2022 who had undergone chest CT that manifested exuberant honeycombing. Medical records and chest imaging studies were reviewed to identify clinical, pulmonary function and radiologic features. RESULTS: Among 136 patients with exuberant honeycombing, 23 patients were identified with CT features of what we termed "bubbly lung" characterized by extensive macrocystic fibrosis; 17 (74%) were female with a median age of 71 years (range, 32-88) at baseline. Underlying diagnoses were ANCA associated vasculitis (22%), overlap CTD (22%), rheumatoid arthritis (17%), IPF (17%), IPAF (9%), systemic sclerosis (4%), undifferentiated CTD (4%), and dermatomyositis (4%). Median FVC was 78% predicted (range 35-112), median DLco was 41% predicted (range 10-92), and median TLC was 73% predicted (range 57-116). Serial FVC measurements were available for 19 (83%) patients with a median interval of 4.7 years (range: 0.4-20); median FVC change per year was 23 ml (range -279 to +232) and median FVC % predicted change per year was 0.00% (range -3.20 to +6.79%). The median survival was 7.1 years, 5-year survival was 76% (95% CI: 58%-100%) and 10-year survival was 48%. CONCLUSIONS: "Bubbly lung" is a variant of exuberant honeycombing that is associated with better-than-expected outcome and FVC decline per year.

Presenting clinical and imaging features of patients with clinically amyopathic interstitial lung disease associated with myositis-specific autoantibodies.

Background: Lung involvement in the context of idiopathic inflammatory myopathies has significant impact on outcome; early and accurate diagnosis is important but can be difficult to achieve. In particular, patients without clinically evident muscle involvement pose a significant diagnostic challenge. Methods: A computer-assisted search was conducted to identify patients with amyopathic interstitial lung disease associated with the presence of myositis-specific autoantibodies. Medical records and chest imaging studies were reviewed to identify clinical and radiologic features at presentation. Results: Of the 35 patients with amyopathic interstitial lung disease associated with myositis-specific autoantibodies, the median age was 65 years (range 43-78) and 20 were women (57%). Of the patients, 34% had previously visited the rheumatology department. Presenting symptoms consisted of dyspnea (94%), cough (43%), and arthritis (23%). Raynaud phenomenon, "mechanic hands," Gottron papules, and inspiratory crackles were present in 23, 31, 9, and 74% of patients, respectively. After a detailed history, none of the patients reported muscle weakness, while four (11%) exhibited increased CK levels; of these four, two had a concomitant increase in aldolase levels. Median FVC was 79% predicted (range: 49-135) and median DLco was 50% predicted (range: 17-103). HRCT pattern was suggestive of an alternative to UIP pattern in 31/33 (94%) patients; the most common imaging patterns were NSIP (49%) and NSIP/OP (39%). Conclusion: In patients with NSIP and NSIP/OP pattern, the presence of amyopathic interstitial lung disease associated with myositis-specific autoantibodies should be considered even in the absence of clinical evident myositis.

Diagnosis of interstitial lung diseases: from Averill A. Liebow to artificial intelligence.

Histopathologic criteria of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) were defined over the years and endorsed by leading organizations decades after Dr. Averill A. Liebow first coined the term UIP in the 1960s as a distinct pathologic pattern of fibrotic interstitial lung disease. Novel technology and recent research on interstitial lung diseases with genetic component shed light on molecular pathogenesis of UIP/IPF. Two antifibrotic agents introduced in the mid-2010s opened a new era of therapeutic approaches to UIP/IPF, albeit contentious issues regarding their efficacy, side effects, and costs. Recently, the concept of progressive pulmonary fibrosis was introduced to acknowledge additional types of progressive fibrosing interstitial lung diseases with the clinical and pathologic phenotypes comparable to those of UIP/IPF. Likewise, some authors have proposed a paradigm shift by considering UIP as a stand-alone diagnostic entity to encompass other fibrosing interstitial lung diseases that manifest a relentless progression as in IPF. These trends signal a pendulum moving toward the tendency of lumping diagnoses, which poses a risk of obscuring potentially important information crucial to both clinical and research purposes. Recent advances in whole slide imaging for digital pathology and artificial intelligence technology could offer an unprecedented opportunity to enhance histopathologic evaluation of interstitial lung diseases. However, current clinical practice trends of moving away from surgical lung biopsies in interstitial lung disease patients may become a limiting factor in this endeavor as it would be difficult to build a large histopathologic database with correlative clinical data required for artificial intelligence models.

Leukemic pulmonary infiltrates in chronic lymphocytic leukemia: Clinical and imaging features.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. Although various patterns of lung involvement with CLL have been reported, data on clinicoradiologic presentation are sparse. METHODS: A computer-assisted search was conducted to identify patients encountered at Mayo Clinic from 1998 to 2022 and had leukemic pulmonary infiltrates (LPI) with CLL demonstrated on lung biopsy. Medical records and chest imaging studies were reviewed to identify clinical and radiologic features. RESULTS: Among 13 patients, median age was 77 years (range: 60-88) and included 10 men (77 %). All patients were known to have CLL with a median duration of 96 months (range: 50-408), and none were on treatment. Most common symptoms were dyspnea (62 %), cough (54 %), and fatigue (46 %); 2 patients (15 %) were asymptomatic. Dominant abnormality on CT consisted of single or multiple nodular/mass-like opacities in 10 patients (77 %), while diffuse centrilobular nodules, pleural mass, and diffuse bronchial wall thickening were each seen in one patient, respectively; intrathoracic lymphadenopathy was present in all. After diagnosis of LPI, treatment for CLL was administered to 7 patients (54 %); 6 patients (86 %) exhibited improvement. During follow-up (median 41 months), 8 (62 %) patients died. Causes of death included progressive CLL or treatment-related complications (2 patients), pneumonia (1 patient), unrelated causes (3 patients), and unknown in 2 patients. CONCLUSIONS: LPI in CLL is generally encountered in patients with known untreated CLL. The main imaging feature is single mass-like opacity or multiple nodular/mass-like opacities, associated with intrathoracic lymphadenopathy.

Combined Pulmonary Fibrosis and Emphysema: A Narrative Review.

Combined pulmonary fibrosis and emphysema (CPFE) syndrome refers to co-occurrence of two disease processes in the lung that can be difficult to diagnose but is associated with high morbidity and mortality burden. Diagnosis of CPFE is challenging because the two diseases can counterbalance respective impairments resulting in deceivingly normal-appearing chest radiography and spirometry in a dyspneic patient. Although an international committee published the terminology and definitions of CPFE in 2022, consensus on exact diagnostic criteria and optimal management strategy is yet to be determined. Herein, we provide a narrative review summarizing the literature on CPFE from 1990 to 2022, including historical background, epidemiology, pathogenesis, clinical features, imaging and pulmonary function findings, diagnosis, prognosis, complications, and treatment. Although CPFE was initially conceived as a variant presentation of idiopathic pulmonary fibrosis, it has been recognized to occur in patients with a wide variety of interstitial lung diseases, including connective tissue disease-associated interstitial lung diseases, and hypersensitivity pneumonitis. The affected patients have a heightened risk for pulmonary hypertension and lung cancer. Clinicians need to recognize the characteristic presenting features of CPFE along with prognostic implications of this entity.

A 68-Year-Old Patient With Dyspnea and Hypoxemia After Total Hip Arthroplasty.

CASE PRESENTATION: A 68-year-old patient with obesity (BMI, 4 7 kg/m2) was transferred to the ED of our hospital because of dyspnea and pronounced hypoxemia. The patient underwent total right hip arthroplasty in an outside hospital because of osteoarthritis; there was no history of trauma. After 48 h, she experienced dyspnea with severe hypoxemia. The next day she was transferred to our hospital. Her history was notable for arterial hypertension and depression, but not heart failure. Her medications included candesartan (16 mg once daily) and sertraline (100 mg once daily). Perioperatively, she received enoxaparin 4.000 International Units subcutaneously once daily. There was no family history of respiratory diseases. The patient currently smokes (50 pack-years) with no recent increase in her habit and denied vaping, alcohol consumption, illicit drug use, and any home or occupational exposures. Prior to surgery, the family of the patient reported that she maintained modest mobility despite her osteoarthritis and was able to fulfill her daily activities. Interestingly, she reported a similar event of severe dyspnea and hypoxemia after total knee arthroplasty 3 years earlier; however, no further details were available.

Long-term outcomes among adults with Langerhans cell histiocytosis.

Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms 'diffuse' and 'idiopathic.' We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Risk Stratification in Transthyretin Cardiac Amyloidosis: The Added Value of Lung Spirometry.

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized disease that often results in heart failure and death. Traditionally, biological staging systems are used to stratify disease severity. Reduced aerobic capacity has recently been described as useful in identifying higher risk of cardiovascular events and death. Assessment of lung volume via simple spirometry might also hold prognostic relevance. We aimed to assess the combined prognostic value of spirometry, cardiopulmonary exercise testing (CPET) and biomarker staging in ATTR-CA patients in a multi-parametric approach. We retrospectively reviewed patient records with pulmonary function and CPET testing. Patients were followed until study endpoint (MACE: composite of heart-failure-related hospitalization and all-cause death) or censure (1 April 2022). In total, 82 patients were enrolled. Median follow-up was 9 months with 31 (38%) MACE. Impaired peak VO2 and forced vital capacity (FVC) were independent predictors of MACE-free survival, with peak VO2 < 50% and FVC < 70% defining the highest risk group (HR 26, 95% CI: 5-142, mean survival: 15 months) compared to patients with the lowest risk (peak VO2 ≥ 50% and FVC ≥ 70%). Combined peak VO2, FVC and ATTR biomarker staging significantly improved MACE prediction by 35% compared to ATTR staging alone, with 67% patients reassigned a higher risk category (p < 0.01). In conclusion, combining functional and biological markers might synergistically improve risk stratification in ATTR-CA. Integrating simple, non-invasive and easily applicable CPET and spirometry in the routine management of ATTR-CA patients might prove useful for improved risk prediction, optimized monitoring and timely introduction of newer-generation therapies.

Exons 1-3 deletion in FLCN is associated with increased risk of pneumothorax in Chinese patients with Birt-Hogg-Dubé syndrome.

BACKGROUND: The pathogenic variants responsible for Birt-Hogg-Dubé syndrome (BHDS) in folliculin (FLCN) gene mostly consist of point mutations. Although large intragenic deletions/duplications have been reported in several case reports, the relationship between large intragenic deletions/duplications and phenotype in BHDS remains unclear. METHODS: We retrospectively identified and reviewed patients with a large intragenic deletion spanning exons 1-3 and analyzed their phenotypic features to compare with those of point mutation carriers in our hospital from January 1, 2017 to August 31, 2022. RESULTS: Twenty unique point mutations (including 4 novel mutations) were detected in 62 patients from 45 families (90%). Exons 1-3 deletion were identified in 8 patients from 5 families (10%) that resided in the same region, Feidong County of Anhui Province, China. Breakpoint analysis indicated that all the deletion breakpoints were flanked by Alu repeats. The prevalence of exons 1-3 deletion carriers in Feidong County was 8.1-times higher than that for BHDS in Anhui Province, suggesting a clustered phenomenon of exons 1-3 deletion. Significantly increased risk of pneumothorax was observed in those with exons 1-3 deletion compared with point mutations (91% vs. 58%, p value 0.047). The risk of renal cancer may be higher in those with exons 1-3 deletion than for those with point mutations (18% vs. 4%, p > 0.05). CONCLUSIONS: Large intragenic deletion of exons 1-3 in FLCN was identified as a local aggregation phenomenon in Feidong County, China, and was associated with a significantly higher risk of pneumothorax compared to those with point mutations.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

A 79-Year-Old Man With Recurrent Respiratory and Constitutional Symptoms, Elevated Acute Phase Reactants, and Pancytopenia.

CASE PRESENTATION: A 79-year-old man was examined because of recurrent dyspnea and constitutional symptoms that included malaise, fatigue, fevers, and arthralgias over the past 7 years. He was a nonsmoker who was a retired farmer. Elevated levels of acute phase reactants and C-reactive protein and a high erythrocyte sedimentation rate were noted often in his health records. However, an extensive rheumatologic evaluation, which included serologic studies (antinuclear antibodies, cyclic citrullinated peptide antibodies, antineutrophil cytoplasmic antibodies) and temporal artery biopsy, had not shown an identifiable autoimmune disease. The patient had been treated intermittently with prednisone, with partial symptomatic improvement. Various cytopenias had been present over the preceding years; however, three bone marrow biopsy specimens showed moderately hypercellular bone marrow with no diagnostic findings.