Can transbronchial lung cryobiopsy benefit adaptive treatment strategies in connective tissue disease-associated interstitial lung disease?

BACKGROUND: Some patients with connective tissue disease (CTD)-associated interstitial lung disease (ILD) progress to pulmonary fibrosis over their disease course despite initial improvement, potentially indicating a poor prognosis. Transbronchial lung cryobiopsy (TBLC) is a new bioptic approach used in diffuse parenchymal lung diseases. This study of CTD-ILD assessed the utility of TBLC in determining therapeutic decision-making strategies. METHODS: We analyzed medical records of 31 consecutive CTD-ILD patients who underwent TBLC focusing on radio-pathological correlation and disease course. A TBLC-based usual interstitial pneumonia (UIP) score was used that assessed three morphologic descriptors: i) patchy fibrosis, ii) fibroblastic foci, and iii) honeycombing. RESULTS: Among the patients with CTD-ILD, 3 had rheumatoid arthritis, 2 systemic sclerosis, 5 polymyositis/dermatomyositis, 8 anti-synthetase syndrome, 6 Sjögren's syndrome, and 5 had microscopic polyangiitis. Pulmonary function test results showed a mean %FVC of 82.4% and %DLCO of 67.7%. Among the 10 CTD patients and TBLC-proven pathological UIP, 3 patients had prominent inflammatory cells in addition to a framework of UIP, and pulmonary function of most patients improved with anti-inflammatory agents. Six (40%) of 15 patients with TBLC-based UIP score ≥ 1 had a progressive disease course during follow-up, of whom 4 patients received anti-fibrotic agents. CONCLUSIONS: TBLC in patients with CTD-ILD can help determine an appropriate medication strategy, particularly when UIP-like lesions are present. TBLC may be useful when judging which agents to prioritize, anti-inflammatory or anti-fibrotic, is difficult. Moreover, additional information from TBLC may be beneficial when considering early intervention with anti-fibrotic agents in clinical practice.

Prognostic value of radiological findings indeterminate for UIP pattern and anterior upper lobe honeycomb-like lesion in chronic fibrosing interstitial lung disease associated with MPO-ANCA.

BACKGROUND: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is often positive in patients with interstitial lung disease (ILD), which is also often present in patients with microscopic polyangiitis (MPA). A possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. The objective of this study was to determine whether high-resolution computed tomography (HRCT) classification based on recent idiopathic pulmonary fibrosis guideline and specific CT findings can obtain new knowledge of prognostic factors in all MPO-ANCA-positive patients with ILD including both idiopathic ILD and MPA-ILD. METHODS: We analyzed 101 consecutive MPO-ANCA-positive patients with respiratory disease. We assessed the diagnostic accuracy of CT findings, HRCT pattern, and specific radiological signs. Prognostic predictors were determined using Cox regression models. RESULTS: Subjects with chronic ILD included 22 patients with MPA-ILD and 39 patients with ILD but without MPA. A quarter of the patients were radiological indeterminate for usual interstitial pneumonia (UIP) pattern, which resulted in a better prognosis than that for UIP pattern. "Increased attenuation around honeycomb and traction bronchiectasis" and "anterior upper lobe honeycomb-like lesion" were found to be highly frequent radiological findings (39% and 30%, respectively). In addition, the latter finding was a significant negative prognostic factor. CONCLUSIONS: Radiological indeterminate for UIP was a useful HRCT classification in MPO-ANCA-positive patients with ILD. In addition, anterior upper lobe honeycomb-like lesion was found to be specific radiological finding that was a significant prognostic factor. The present results might aid in the assessment of appropriate strategies of diagnosis in these patients.

Impact of radiological honeycombing in rheumatoid arthritis-associated interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is the most common and important pulmonary manifestation of rheumatoid arthritis (RA). A radiological honeycomb pattern has been described in diverse forms of ILD that can impact survival. However, the clinical course and sequential radiological changes in the formation of the honeycomb pattern in patients with RA-ILD is not fully understood. METHODS: We evaluated the sequential changes in computed tomography findings in 40 patients with chronic forms of RA-ILD without the honeycomb pattern at initial diagnosis. We classified the patients into the Non-honeycomb group and Honeycomb group, and then analyzed the characteristics and prognosis of the two groups. The term "honeycomb formation" indicated a positive finding of honeycombing on any available follow-up CT. RESULTS: Our RA-ILD cohort included patients with probable usual interstitial pneumonia (UIP) (35%), nonspecific interstitial pneumonia (NSIP) (20%), and mixed NSIP/UIP (45%). Among all RA-ILD patients, 16 (40%) showed honeycomb formation on follow-up CT (median time between initial and last follow-up CT was 4.7 years). Patient characteristics and prognosis were not significantly different between the Non-honeycomb and Honeycomb groups. However, Kaplan-Meier survival curve for the time from the date of honeycomb formation to death showed a poor median survival time of 3.2 years. CONCLUSIONS: A certain number of patients with RA-ILD developed a honeycomb pattern during long-term follow-up, regardless of whether they had UIP or NSIP. Prognosis in the patients with characteristics of both progressive ILD and honeycomb formation could be poor. Although radiological findings over the disease course and clinical disease behavior in RA-ILD are heterogenous, clinicians should be alert to the possibility of progressive disease and poor prognosis in patients with RA-ILD who form a honeycomb pattern during follow-up observation.

Pilot study for risk assessment of aspiration pneumonia based on oral bacteria levels and serum biomarkers.

BACKGROUND: Aspiration pneumonia is a serious problem among elderly patients; it is caused by many risk factors including dysphagia, poor oral hygiene, malnutrition, and sedative medications. The aim of this study was to define a convenient procedure to objectively evaluate the risk of aspiration pneumonia in the clinical setting. METHODS: This prospective study included an aspiration pneumonia (AP) group, a community-acquired pneumonia (CAP) group, and a control (Con) group (patients hospitalized for lung cancer chemotherapy). We used the Oral Health Assessment Tool (OHAT), which assesses oral hygiene, and evaluated performance status, body mass index, serum albumin levels, substance P values in plasma, and oral bacterial counts. RESULTS: The oral health as assessed by the OHAT of the aspiration pneumonia group was significantly impaired compared with that of the CAP group and the control (5.13 ± 0.18, 4.40 ± 0.26, 3.90 ± 0.22, respectively; p < 0.05). The oral bacterial count in the aspiration pneumonia group (7.20 ± 0.11) was significantly higher than that in the CAP group (6.89 ± 0.12), consistent with the OHAT scores. Oral bacterial count was significantly reduced by oral care. CONCLUSIONS: OHAT and oral bacterial counts can be a tool to assess the requirement of taking oral care and other preventive procedures in patients at high risk of aspiration pneumonia.

Nintedanib allows retreatment with atezolizumab of combined non-small cell lung cancer/idiopathic pulmonary fibrosis after atezolizumab-induced pneumonitis: a case report.

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor that efficiently slows the progression of idiopathic pulmonary fibrosis (IPF) and has an acceptable tolerability profile. In contrast, immune checkpoint inhibitors (ICIs) such as programmed death 1 and programmed death ligand 1 inhibitors have shown clinical activity and marked efficacy in the treatment of non-small cell lung cancer. However, it is unclear whether nintedanib reduces the risk of ICI-induced pneumonitis in IPF. CASE PRESENTATION: A 78-year-old man with squamous cell lung carcinoma in IPF underwent second-line treatment with pembrolizumab. He was diagnosed as having pembrolizumab-induced pneumonitis after two cycles. He was administered prednisolone (PSL) and then improved immediately. Thereafter, his lung cancer lesion enlarged despite treatment with TS-1. Atezolizumab was then administered as 4th-line chemotherapy, but he immediately developed atezolizumab-induced pneumonitis after 1 cycle. The re-escalated dosage of PSL improved the pneumonitis, and then nintedanib was started as additional therapy. Under careful observation with nintedanib, atezolizumab was re-administered on day 1 of an every-21-day cycle. After three cycles, it remained stable without exacerbation of drug-induced pneumonitis. CONCLUSION: This case indicates the possibility that the addition of nintedanib to ICI therapy might prevent drug-induced pneumonitis or acute exacerbation of IPF. However, whether anti-fibrotic agents such as nintedanib are actually effective in preventing ICI-induced pneumonitis in ILD remains unknown and additional research is greatly needed to identify effective therapies for ILD combined with lung cancer.

Cytokine profiles associated with disease severity and prognosis of autoimmune pulmonary alveolar proteinosis.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal accumulation of surfactants in the alveoli. Most cases are classified as autoimmune PAP (APAP) because they are associated with autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). However, GM-CSF autoantibody levels are unlikely to correlate with the disease severity or prognosis of APAP. METHODS: We collected clinical records and measured 38 serum cytokine concentrations for consecutive patients with APAP. After exclusion of 21 cytokines because of undetectable levels, 17 cytokine levels were compared between low and high disease severity scores (DSSs). We also compared whole lung lavage (WLL)-free survival with cut-off values defined by receiver operating characteristic (ROC) curves of cytokine levels and WLL administration at 11 months. RESULTS: Nineteen patients with APAP were enrolled in the study. Five were classified as DSS 1 or 2, while the others were classified as DSS 4 or 5. Comparison between DSS 1-2 and 4-5 revealed that the concentrations of IP-10 and GRO increased in the latter groups (p < 0.05). Fifteen patients underwent WLL. Comparison between those who underwent WLL within 11 months and the others showed that IP-10 and TNF-α were tended to be elevated in the former group (p = 0.082 and 0.057, respectively). The cut-off values of IP-10, 308.8 pg/mL and TNF-α, 19.1 pg/mL, defined by the ROC curves, significantly separated WLL-free survivals with log-rank analyses (p = 0.005). CONCLUSIONS: The concentrations of IP-10 and GRO may reflect the DSSs of APAP. A combination of IP-10 and TNF-α levels could be a biomarker to predict WLL-free survival.

Body weight loss is a simple and useful indicator of prognosis and predictive tolerability in the first year of nintedanib therapy in patients with interstitial lung disease.

BACKGROUND: Nintedanib is generally safe and well tolerated and can improve prognosis in patients with various interstitial lung diseases (ILDs). Appropriate management of adverse events of nintedanib is important to ensure its long-term persistent use. Weight loss is a routinely assessed adverse event in clinical practice. This study aimed to elucidate whether body weight change in the first year of nintedanib therapy can indicate prognosis and predict tolerability in patients with ILD. METHODS: We analysed 245 consecutive ILD patients treated with nintedanib. We calculated the slope of body weight change using baseline weight and that recorded closest after the first year and then categorized percent change in body weight at this time. Significant weight loss was defined as that ≥5%. RESULTS: Subjects included 67 patients with idiopathic pulmonary fibrosis (IPF) and 76 with non-IPF progressive fibrosing-ILD including fibrotic hypersensitivity pneumonitis (n = 16), unclassifiable (n = 35), connective tissue disease-ILD (n = 21), and nonspecific interstitial pneumonia (n = 4). Older age, low body weight at initial examination, significant weight loss, and lower %FVC were significant predictors of discontinuation of nintedanib. Patients with weight loss ≥5% over the first year showed worse survival than those with weight loss <5% regardless of whether IPF existed or BMI indicated obesity. CONCLUSIONS: Careful monitoring of body weight change might suggest useful information for predicting long-term use of nintedanib and mortality risk in ILD patients treated with nintedanib. Appropriate body weight management is needed to prevent adverse events of nintedanib itself.

Usefulness of Transbronchial Lung Cryobiopsy When Starting Antifibrotic Treatment and Predicting Progressive Fibrosing Interstitial Lung Disease: Descriptive Research.

BACKGROUND: Although transbronchial lung cryobiopsy (TBLC) is widely used in diagnostic algorithms for various interstitial lung diseases (ILDs), its real-world utility in the therapeutic decision-making strategy for ILD patients remains unclear, in particular, when judging the time to start antifibrotic agents. METHODS: We analyzed medical records of 40 consecutive patients with idiopathic or fibrotic hypersensitivity pneumonitis who underwent TBLC. A TBLC-based usual interstitial pneumonia (UIP) score was used to assess three morphologic descriptors: patchy fibrosis, fibroblastic foci, and honeycombing. RESULTS: In our 40 patients with ILD, the most frequent radiological feature was indeterminate for UIP (45.0%). Final diagnosis included idiopathic pulmonary fibrosis (22.5%), fibrotic nonspecific interstitial pneumonia (5.0%), fibrotic hypersensitivity pneumonitis (35.0%), and unclassifiable ILD (37.5%). Linear mixed-effects analysis showed that declines in the slopes of %FVC and %DLCO in patients with TBLC-based UIP "Score ≥ 2" were significantly steeper than those of patients with "Score ≤ 1." During follow-up of patients with Score ≥ 2 (n = 24), more than half of them (n = 17) received an antifibrotic agent, with most patients (n = 13) receiving early administration of the antifibrotic agent within 6 months after the TBLC procedure. CONCLUSIONS: TBLC-based UIP Score ≥ 2 indicated the increased possibility of a progressive fibrosis course that may prove helpful in predicting progressive pulmonary fibrosis/progressive fibrosing ILD even if disease is temporarily stabilized due to anti-inflammatory agents. Patients may benefit from early introduction of antifibrotic agents by treating clinicians.

Clinical significance of para-carinal air cysts in patients with pleuroparenchymal fibroelastosis: The relationship with pneumomediastinum and pneumothorax.

BACKGROUND: Para-tracheal or para-carinal air cysts (PACs) are often asymptomatic and usually detected incidentally by methods such as computed tomography. Their clinical significance is unclear in patients with pleuroparenchymal fibroelastosis (PPFE). METHODS: We evaluated the clinical significance of PACs in PPFE and their relationship with pneumomediastinum or pneumothorax. RESULTS: In total, 50 patients had PPFE and 34 (68%) had PACs. Most PACs were para-carinal (n = 30). A para-tracheal air cyst was detected in only nine patients, which included five patients having both para-carinal and para-tracheal air cysts. Overall median survival was 24.7 months. Survival was not significantly different between the patients with [PACs(+)] and without PACs (P = 0.268). A high frequency (64%) of the complication of pneumomediastinum or pneumothorax occurred in the overall population during follow-up. Pneumomediastinum/pneumothorax occurred significantly more frequently in patients with PACs(+) than in those without (76.5% vs. 37.5%; P = 0.012). PACs(+) was the only significant risk factor for pneumomediastinum/pneumothorax. CONCLUSIONS: Our data showed that PACs commonly occur in patients with PPFE, and most PACs were para-carinal air cysts. Additionally, PACs(+) was a significant risk factor for pneumomediastinum/pneumothorax; therefore, clinicians should be more aware of these complications during follow-up examination, particular in PACs(+) patients with PPFE.

Impact of progressive fibrosing interstitial lung disease (ILD) in ILD patients complicated with secondary spontaneous pneumothorax.

BACKGROUND: Secondary spontaneous pneumothorax (SSP) in interstitial lung disease (ILD) may influence prognosis of any ILD, and SSP onset predicts poor outcome in idiopathic pulmonary fibrosis (IPF). Recently, progressive fibrosing ILD (PF-ILD) has rapidly acquired importance. OBJECTIVE: We hypothesized that PF-ILD would strongly influence the prognosis of patients with any ILD complicated with SSP. METHODS: We retrospectively surveyed and collected data from patients hospitalized for SSP from January 2016 to June 2020. PF-ILD was defined as the following occurring within 24 months before SSP develops: relative decline in %forced vital capacity (FVC) ≥10% or two of the following: relative decline in %FVC between 5% and 10%, worsening respiratory symptoms, or increased extent of fibrosis on high-resolution computed tomography. RESULTS: We analyzed 32 patients hospitalized for SSP in ILD. This study comprised 18 patients with PF-ILD and 14 patients with non-PF-ILD. PF-ILD patients had lower body mass index (BMI) and %FVC. No significant differences in survival regarding follow-up period from the time of ILD diagnosis and hospitalization for SSP were observed between the PF-ILD and non-PF-ILD patients. Older age and lower BMI were significant predictors of mortality by multivariate Cox regression analysis. ROC analysis showed BMI ≤17.8 kg/m2 to reliably predict poor prognosis. CONCLUSIONS: Regardless of whether patients have PF-ILD, older age and lower BMI in patients with ILD places them at higher risk of developing SSP, and prognosis is poor if SSP develops. Therefore, clinical management of physique is important to improve the prognosis of ILD patients.

Patient background and prognosis of chronic pulmonary aspergillosis in fibrosing interstitial lung disease.

Several previous reports have shown interstitial lung disease (ILD) to be a predictor of poor prognosis in patients with chronic pulmonary aspergillosis (CPA). However, there is a lack of clarity regarding patient background and the prognostic factors in CPA associated with ILD (CPA-ILD). Therefore, we assessed these points to obtain valuable information for clinical practice. We retrospectively surveyed and collected data from 459 patients who had serum examination for anti-Aspergillus antibody. Of these patients, we extracted and investigated CPA-ILD patients. We ultimately analyzed 32 CPA-ILD patients. Patient background factors more frequently showed the patients to be older (mean: 74.9 years), male (75.0%), and to have a smoking history (71.9%). Median survival time from the diagnosis of ILD was 76.0 months, whereas that from the diagnosis of CPA-ILD was 25.5 months. No significant differences in survival were found in regard to each ILD pattern and the presence of idiopathic pulmonary fibrosis. A higher level of C-reactive protein was a significant predictor of mortality by Cox regression analysis. CPA complicating ILD is associated with poor prognosis. ILD patients with older age, male sex, and smoking history should be aware of the potential for the development of CPA in ILD. If such patients have elevated markers of inflammation, prompt induction of antifungal treatment may improve their prognosis. Clinicians should be aware of which complications of CPA may lead to a poor prognosis for any ILD not just those limited to idiopathic pulmonary fibrosis or usual interstitial pneumonia pattern.

Successful surgical treatment of epithelioid hemangioendothelioma involving multiple liver lesions and bilateral lung nodules.

Epithelioid hemangioendothelioma (EHE) affects many organs, particularly lung and liver, and typically presents as multiple lesions. Treatment for EHE is not yet standardized, but surgery is appropriate when lesions are resectable. In our patient, radiography revealed multiple bilateral pulmonary nodules, and CT showed several liver tumors. The liver masses and those in the right lung were removed during the initial surgery; pathology of hepatic specimens confirmed the diagnosis of EHE. During the second operation, the left lung nodules were excised, and all were EHEs. Surgical removal of multiorgan multinodular EHE is a viable treatment option, especially for young patients.

A patient with hepatocellular carcinoma who developed invasive pulmonary aspergillosis after corticosteroid treatment.

Lung or head and neck cancer have been indicated as solid cancers associated with invasive pulmonary aspergillosis (IPA), but the relationship with hepatocellular carcinoma (HCC) is unknown. We report a case of HCC in which the presence of cirrhosis and corticosteroid administration may have caused the development of IPA.

Anti-PL-7 antibody-positive dermatomyositis with progressive interstitial pneumonia complicated with tracheal ulcer.

Tracheobronchial lesions are rare extramuscular complications for idiopathic inflammatory myopathies including dermatomyositis. We herein report a 65-year-old woman with tracheal ulcer during the progression of dermatomyositis-associated interstitial lung disease. Treatment with corticosteroids combined with immunosuppressive agents resulted in improvement of the tracheal ulcer and pulmonary involvement. We believe that the tracheal ulceration might reflect the disease behaviour of dermatomyositis and dermatomyositis-associated interstitial pneumonia.

Delayed onset of severe immune thrombocytopenia associated with COVID-19 pneumonia.

A 72-year-old Japanese man was admitted to our hospital for treatment of severe COVID-19 pneumonia and was started on favipiravir, heparin calcium, and methylprednisolone pulse therapy. He recovered from respiratory failure about one month later. However, he soon developed purpura in his lower limbs and thrombocytopenia, and immune thrombocytopenia was subsequently diagnosed. Although immune thrombocytopenia is one of the early complications of COVID-19, the use of corticosteroids for COVID-19 is thought to be a factor in the late onset of immune thrombocytopenia. In cases of severe COVID-19 for which corticosteroids were used for treatment, autoimmune diseases such as immune thrombocytopenia may manifest themselves late in the disease course.

The Usefulness of a Transbronchial Lung Cryobiopsy for Diffuse Bronchiolitis.

We herein report four cases of diffuse bronchiolitis proven by a transbronchial lung cryobiopsy (TBLC). Based on various aspects, including the pathological findings, we definitively diagnosed two patients with diffuse panbronchiolitis (DPB) and the other two with primary ciliary dyskinesia (PCD). One of the DPB patients had more severe peribronchiolar fibrosis than the other, and the disease course was refractory to macrolide therapy. One of the PCD patients was additionally diagnosed with combined constrictive bronchiolitis. This report highlights the importance of a TBLC in the differentiation of bronchiolitis, suggesting its utility for helping pulmonologists formulate a treatment strategy.

Hairspray Inhalation-induced Interstitial Pneumonitis Evaluated by a Transbronchial Lung Cryobiopsy.

A 60-year-old Japanese woman was admitted to our hospital with a fever and shortness of breath occurring immediately after using hairspray. Chest high-resolution computed tomography (HRCT) showed ground-glass opacities (GGOs) predominantly distributed around the bronchovascular bundles, and a pathological evaluation by a transbronchial lung cryobiopsy (TBLC) revealed fibrotic non-specific interstitial pneumonia (f-NSIP). Her symptoms disappeared without the use of corticosteroids, and GGOs on HRCT improved markedly over time. This case suggests that a pathological evaluation by a TBLC for lung injury due to inhalation pathogen exposure may provide a more accurate diagnosis and a better understanding of the pathology from bronchial to interstitial lesions than transbronchial lung biopsy.

Levetiracetam-induced interstitial lung disease in a patient with advanced lung cancer.

An 85-year-old woman with antibiotics-resistant pneumonia after surgery for metastatic brain tumor from lung cancer was consulted to our department. Chest CT showed diffuse GGO bilaterally. BALF showed elevated ratios of lymphocytes and CD4/CD8. Tests for bacteria, mycobacteria, and fungi were negative. She improved following levetiracetam discontinuance and systemic corticosteroid administration, and we diagnosed levetiracetam-induced lung injury. Although levetiracetam is widely used, few reports of levetiracetam-induced pneumonia exist. Changes in chest images may occur after levetiracetam administration if patients have multiple risk factors for development of drug-induced interstitial lung disease. Bronchoscopy is useful for differential diagnosis if new lung lesions appear after starting levetiracetam.

The potential utility of anterior upper lobe honeycomb-like lesion in interstitial lung disease associated with connective tissue disease.

BACKGROUND: Interstitial lung disease (ILD) is associated with high morbidity and mortality in patients with connective tissue disease (CTD). Because some patients with CTD overlap present with ILD first, with CTD diagnosed later, specific radiologic signs are needed to help differentiate each CTD or CTD-ILD from idiopathic ILD. OBJECTIVES: To determine whether specific CT findings can help differentiate CTD as rheumatoid arthritis (RA), systemic sclerosis (SSc), or polymyositis/dermatomyositis (PM/DM). METHODS: We analyzed 143 consecutive ILD patients with RA, SSc, or PM/DM. We assessed diagnostic accuracy of CT findings of CTD-ILD, CT pattern, and signs including "anterior upper lobe honeycomb-like lesion" and "low attenuation area (LAA) within an interstitial abnormality" for each CTD-ILD. Prognostic predictors were determined using Cox regression models. RESULTS: Subjects were 78 patients with RA-ILD, 38 with SSc-ILD, 24 with PM/DM-ILD, and 3 with overlapping CTD-ILD. High frequency of anterior upper lobe honeycomb-like lesion suggests that CTD-ILD is due to RA-ILD (22%) rather than SSc-ILD (8%) or PM/DM-ILD (8%), whereas LAA within an interstitial abnormality suggests that CTD-ILD is due to SSc-ILD (26%) rather than RA-ILD (4%) or PM/DM-ILD (0%). Multivariate analysis showed that while not associated with survival, current or ex-smoker, honeycombing, and acute exacerbation were negative prognostic factors of mortality. CONCLUSIONS: The tendency is high for RA-ILD, in which anterior upper lobe honeycomb-like lesion is a specific feature, to show UIP or NSIP/UIP pattern, combined emphysema, and honeycombing; SSc-ILD to show NSIP pattern and LAA within an interstitial abnormality; and PM/DM-ILD to show NSIP pattern and non-honeycombing.