An Unusual Etiology of Fluorodeoxyglucose Avid Intrathoracic Lymph Nodes.

A middle-aged man in his 50s, active smoker, presented to the pulmonary office for lung cancer evaluation. On a low-dose computed tomography for lung cancer screening, he was found to have an 8 mm endobronchial lesion in the right main stem bronchus. A PET-CT revealed no endobronchial lesion, but incidentally, fluorodeoxyglucose (FDG) avidity was present in the right hilar (SUV 13.2) and paratracheal lymph nodes (LNs). He underwent bronchoscopy and EBUS-TBNA of station 7 and 10 R LNs. The fine needle aspiration (FNA) revealed necrotizing epithelioid granuloma. The acid-fast bacilli (AFB) and Grocott methenamine silver (GMS) stains were negative. He had suffered from pneumonic tularemia 13 months ago and immunohistochemical staining for Francisella tularensis on FNA samples at Center for Disease Control and Prevention was negative. The intense positron emission tomography (PET) avidity was attributed to prior tularemic intrathoracic lymphadenitis without active tularemia, a rare occurrence. To the best of our knowledge, PET-positive intrathoracic lymph node beyond one year without evidence of active tularemia has not been previously reported.

Vaping Associated Acute Eosinophilic Pneumonia: A Clinical and Radiologic Mimicker of COVID-19.

Acute eosinophilic pneumonia (AEP) is a rare cause of respiratory failure. It is primarily a disease of smokers, either a new smoker or an existing one with a recent increase in cigarette consumption. Other risk factors include toxic gas exposure, inhalational illicit drugs, and smoking marijuana. AEP has also been reported in patients with e-cigarette or vaping associated lung injury (EVALI). We present the case of a 20-year-old male who presented to the hospital with acute respiratory failure. The patient has been vaping heavily for the past three months and started smoking three days before presenting to the emergency department. He was hypertensive, tachycardic, tachypneic, and required high-flow nasal cannula to maintain SpO2 > 92%. His condition deteriorated in the first 24 hours following hospitalization requiring noninvasive positive pressure ventilation. Bronchoalveolar lavage revealed an eosinophil count of 36%. Bronchoalveolar lavage (BAL) cytology revealed lipid-laden macrophages. He was diagnosed with AEP due to EVALI, and the patient was treated with high dose corticosteroid with subsequent improvement. Before the bronchoscopic evaluation, the clinical and radiologic findings were consistent with COVID-19, and the patient was tested twice for SARS-CoV-2 PCR. In the appropriate clinical setting, AEP should be considered in the differential diagnoses of community-acquired pneumonia, acute respiratory distress syndrome (ARDS), and COVID-19, especially in this pandemic era.

Bioengineering of a tumour-stroma 3D-tumouroid co-culture model of hypopharyngeal cancer.

Head and neck cancer (HNC) differs at anatomical sites and hypopharyngeal cancer (HPC) is a type of HNC. The non-surgical treatment option for advanced cases of HPC is radiotherapy (RT) with or without chemotherapy but survival is poor. Thus, new treatment approaches in combination with RT are essential. Yet, obtaining post-RT treated tumour specimens and lack of animal models with identical anatomical sites are the major translational research barriers. To overcome these barriers, for the first time, we have developed a tumour-stroma based in vitro three-dimensional (3D)-tumouroid co-culture model of HPC by growing FaDu and HS-5 cells together to mimic the complex tumour-microenvironment in a Petri dish. Before growing the cells together, imaging flow cytometry revealed distinct epithelial and non-epithelial characteristics of the cells. Growth rate of the 3D-tumouroid co-culture was significantly higher compared to the tumouroid monoculture of FaDu. Histology and morphometric analysis were done for the characterisation as well as the development of hypoxia was measured by CAIX immunostaining in this 3D-tumouroid co-culture. Taken together, this innovative in vitro 3D model of HPC resembles many features of the original tumour. The wider application of this pre-clinical research tool is in understanding newer combination (e.g. immunotherapy) treatment approaches with RT in HPC and beyond.

Updates in idiopathic pulmonary hemosiderosis in 2022: A state of the art review.

This manuscript reports the recent advances in idiopathic pulmonary hemosiderosis (IPH), a rare cause of diffuse alveolar hemorrhage in children and adults. This narrative review of the literature summarizes different aspects of IPH, including proposed pathogenesis, patient demographics, clinical and radiological characteristics, treatment, and prognosis. Additionally, the association between Celiac Disease (CD) and IPH is carefully evaluated. IPH is a frequently misdiagnosed disease. The delay in the diagnosis of IPH is often significant but fortunately, appears to have decreased in recent years. IPH in adults and children have distinct demographic preferences. The autoantibodies are common in IPH but with a definite difference between the adult and pediatric populations. The definitive diagnosis of IPH requires lung biopsy and careful exclusion of all competing diagnoses, even with lung biopsy showing bland pulmonary hemorrhage. The presence of nonspecific inflammatory cells or lymphoid aggregates may suggest a secondary immunologic phenomenon and needs careful evaluation and follow-up. A substantial number of patients suffer from coexisting CD, also known as Lane-Hamilton syndrome (LHS), and all patients with IPH need to be evaluated for LHS by serology. Although strict gluten free diet can manage the majority of patients with LHS, other patients generally require immunosuppressive therapy. The corticosteroids are the backbone of IPH therapy. Recently utilized experimental treatment options include mesenchymal stem cell transplant, liposteroid and bronchial artery embolization. The immunosuppression should be adjusted to achieve optimal disease control. Patients may progress to end-stage lung disease despite all measures, and lung transplantation may be the only viable option.

Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy.

Cisplatin-based chemo-radiotherapy (CRT) is the standard treatment for advanced cervical cancer (CC) but the response rate is poor (46-72%) and cisplatin is nephrotoxic. Therefore, better treatment of CC is urgently needed. We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. All inhibitors alone caused concentration-dependent cytotoxicity. Low ATM and DNA-PKcs levels were associated with greater VE-821 cytotoxicity. Cisplatin induced ATR, CHK1 and WEE1 activity in all of the cell lines. Cisplatin only activated PARP in S-phase cells, but RT activated PARP in the entire population. Rucaparib was the most potent radiosensitiser and VE-821 was the most potent chemosensitiser. VE-821, PF-47736 and MK-1775 attenuated cisplatin-induced S-phase arrest but tended to increase G2 phase accumulation. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting.

Pressure-dependent persistent air leak in a patient with secondary spontaneous pneumothorax.

An air leak lasting more than 5-7 days (persistent air leak, PAL) can complicate up to 40% of patients with secondary spontaneous pneumothorax. Chronic obstructive pulmonary disease is the most common cause of secondary spontaneous pneumothorax, and early surgical intervention has been recommended for patients with PAL. Bullectomy or blebectomy with concomitant mechanical pleurodesis by medical thoracoscopy or video assisted thoracoscopic surgery is considered definitive therapy. Unfortunately, the perioperative course following lung resection can also be complicated by air leaks leading to worse clinical outcomes. Post lung resection air leak can be pressure independent or pressure dependent (also known as drainage-related air leak). The distinction between these two entities is crucial as the management varies drastically. Pleural manometry may play an important role in the early diagnosis of pressure-dependent PAL preventing further unnecessary surgical procedures from being performed.

The Spectrum of Autoantibodies in Adult Patients With Idiopathic Pulmonary Hemosiderosis: A Brief Review of the Literature.

While autoimmune antibodies or autoantibodies have been reported sporadically in adult patients with idiopathic pulmonary hemosiderosis (IPH), their true prevalence is unknown. The question as to whether any difference exists between antibody-positive and negative patients has not been explored. The primary objective of this paper was to assess the spectrum of autoantibody testing and its positivity rate. The other objectives included a comparative analysis of demographics, symptom onset, clinical manifestations, and differences in clinical outcomes between antibody-positive (cohort A) and negative (cohort B) patients. To that end, we conducted a retrospective review of the relevant published literature. Multiple databases were searched to retrieve studies published between 1990 and 2022. A total of 35 studies, involving 38 patients, were identified. Five of these patients had a positive autoantibody. Patients in cohort A were older and more likely to be male. The frequencies of testing for these antibodies were as follows: antineutrophil cytoplasmic antibody (ANCA): 37/38 (97.4%), antinuclear antibody (ANA): 31/38 (81.6%), and anti-glomerular basement membrane antibody (anti-GBM): 30/38 (78.9%); 5/38 (13.2%) patients tested positive for an autoantibody, and two of these patients were positive for ANA, two for antithyroid antibody, and one patient tested positive for ANCA, rheumatoid factor (RF), and granulocyte monocyte-colony stimulating factor (GM-CSF) antibody. There was no difference between the cohorts regarding their clinical presentations, recurrence risks, and survival. The occurrence of autoantibodies is uncommon in adult IPH patients. This is in contrast with the pediatric IPH patient population, where the prevalence is much higher (26.4% vs. 13.2%), and the antibodies are more diverse. Unlike pediatric patients, adult patients with autoantibodies do not necessarily have worse outcomes.

Comparative Analysis of Adult Patients With Idiopathic Pulmonary Hemosiderosis and Lane-Hamilton Syndrome: A Systematic Review of the Literature in the Period 1971-2022.

Idiopathic pulmonary hemosiderosis (IPH) causes diffuse alveolar hemorrhage (DAH) by a yet unknown mechanism. The coexistence of IPH and celiac disease (CD), also known as Lane-Hamilton syndrome (LHS), has been reported in both pediatric and adult patients. The objective of this study was to compare demographics, clinical and radiologic findings, treatment, and outcomes between adult patients with IPH and LHS. This is a systematic review of the literature. Multiple databases were searched using appropriate formulas to identify relevant articles. A total of 60 studies reporting 65 patients were included in the review. Forty-nine of these patients had IPH and 16 had LHS. The prevalence of anti-CD antibodies among tested patients was 13/22 (59%). The symptom onset and diagnosis of IPH occurred earlier in patients with LHS. The median delay in diagnosis was the same between the two groups (52 weeks). The classic triad was more likely to be present in patients with LHS. Only 20% of patients in the LHS cohort had any significant gastrointestinal (GI) symptoms at the time of IPH diagnosis. A gluten-free diet alone was effective in the majority of patients. Fewer patients in the LHS cohort received systemic corticosteroid than the IPH cohort. The recurrence and mortality in patients with LHS appear to be less than in the IPH cohort. The prevalence of CD is 25% in adult patients with IPH. Patients with LHS may have a milder course than patients without CD. Serologic testing for CD should be performed in all patients diagnosed with IPH.

Proposed Pathogenesis of Diffuse Alveolar Hemorrhage in Idiopathic Pulmonary Hemosiderosis.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease that causes diffuse alveolar hemorrhage (DAH). The latest data suggests an immunologic origin of IPH, and a new name, immune mediated pulmonary hemosiderosis (ImPH), has been proposed. However, the exact immunologic mechanism has remained elusive for nearly eight decades despite extensive research, including detailed histopathologic analysis. Although several hypotheses have been proposed to describe the pathobiology of IPH, none of them explain the clinical and histopathologic findings conclusively. In this manuscript, we have presented a new hypothesis for the pathogenesis of DAH in IPH. We hypothesize that DAH in IPH is not immunocomplex mediated but due to histamine, eosinophilic cationic protein (ECP), and possibly vascular endothelial growth factor (VEGF). These bioactive proteins induce endothelial and alveolar epithelial damage, leading to the peri-capillary and intraalveolar escape of RBCs. The deformability of the RBC likely also plays a role. The supranormal secretion of histamine, ECP and VEGF occurs in genetically predisposed individuals with an aberrant immunologic response. The histamine is released from the basophils and possibly the mast cells in response to cytokines secreted by activated lymphocytes. The lymphocyte activation occurs after exposure to a known (gluten) or unknown antigen. The same lymphocyte-derived cytokines also induce eosinophilic degranulation of ECP and VEGF in the pulmonary circulation. We believe that our hypothesis unifies the observed clinical variabilities and histopathologic findings in IPH, and we hope that would promote future research in the field of IPH.

A 49-year-old man with ischemic cardiomyopathy and persistent hemoptysis for eighteen months.

Idiopathic pulmonary hemosiderosis (IPH) is a rare cause of recurrent episodes of diffuse alveolar hemorrhage (DAH). IPH commonly manifests with hemoptysis, radiologic chest infiltrates and anemia. The etiology of IPH is unknown, but an immunologic mechanism is widely speculated. The definitive diagnosis of IPH requires a thorough exclusion of other causes of DAH, such as infections, inflammation, malignancy, cardiac diseases, drug and toxin exposure, and medications. Due to the rarity of the disease, a diagnosis is often delayed by years. We present the case of a 49-year-old man with ischemic cardiomyopathy who presented with hemoptysis for eighteen months. Serologic workup was negative for vasculitides and autoimmune diseases. Bronchoscopy revealed DAH. A surgical lung biopsy showed 'bland pulmonary hemorrhage.' A right heart catheterization ruled out cardiac causes of DAH. The patient was diagnosed with IPH and started on systemic corticosteroids with rapid improvement of hemoptysis.

Adult patients with idiopathic pulmonary hemosiderosis: a comprehensive review of the literature.

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease without a known incidence or prevalence in adults. Our knowledge of this entity is limited as there is no prospective or retrospective study with a reasonable number of patients. The objective is to describe the demographics, clinical manifestations, diagnosis, treatment, and prognosis of adult patients with IPH. The Medline and Embase databases were searched from inception to 2021 with appropriate search formulas to identify relevant articles following strict inclusion and exclusion criteria. Statistical analyses were performed for the entire cohort and prespecified subgroups. A total of 84 patients were identified. The majority of patients were males 54/84 (64.3%). The median age was 27 years. The manifesting symptoms were present in the following frequencies: anemia 76/83 (91.6%), dyspnea 71/83 (85.5%), hemoptysis 70/84 (83.3%), cough 22/84 (26.2%), and chest pain 9/84 (10.7%). The classic triad was present in 61/84 (79%) patients. The mean hemoglobin during the initial presentation was 8.4 gm/dL. A total of 16/57 (19.5%) tested positive for autoantibodies. The median delay in the diagnosis of IPH was 1.02 years. Immunosuppressive therapy was prescribed in 49/79 (62%) patients, and recurrence occurred in more than half of the patients 36/66 (54.5%). A total of 63/79 (79.7%) patients were alive during the final follow-up. IPH is more common in young adults with a male predominance. A high index of suspicion is necessary to attain an early diagnosis and possibly reduce the short-term mortality of nearly 20% and long-term complications.

Association between idiopathic pulmonary hemosiderosis and celiac disease in pediatric patients: A scoping review of the literature over the past 50 years.

INTRODUCTION: Idiopathic pulmonary hemosiderosis (IPH) is a rare cause of diffuse alveolar hemorrhage, the mechanism of which is currently unknown. Nearly one-third of pediatric patients with IPH test positive for Celiac disease (CD) serology. Several hypothetical mechanisms have been proposed to unify the coexistence of these two entities, also referred to as Lane-Hamilton syndrome (LHS). METHOD: This manuscript is a scoping review of the medical literature. Medline, Embase, and PubMed Central databases were searched between 1971 and 2021 with appropriate search words to identify all cases of pediatric LHS. RESULTS: A total of 20 manuscripts with 23 pediatric patients with LHS were identified. The mean age was 11 years, and 13/23 (56.5%) of the children were boys. Hemoptysis was present in 57% of patients during diagnosis. Bronchoscopy with bronchoalveolar lavage demonstrating hemosiderin laden macrophages was the primary mode of diagnostic confirmation. Only three patients underwent lung biopsy. Any significant GI symptom was reported in a minority of patients (22%). Iron deficiency anemia on presentation was described in 83% of children. The majority of patients were malnourished. Serology for CD was positive in all patients, as was the histopathologic analysis of the small bowel biopsy. No patients had any other autoantibody positivity. The introduction of gluten free diet (GFD) was associated with a positive response in 20/23 patients. CONCLUSION: All pediatric patients with IPH should undergo screening for CD. Low serum ferritin in patients with IPH could be suggestive of coexisting CD. Strict GFD should be tried as the initial therapy.

Indications, Clinical Utility, and Safety of Bronchoscopy in COVID-19.

BACKGROUND: Bronchoscopy is an aerosol-generating procedure and routine use for patients with coronavirus disease 2019 (COVID-19) has been discouraged. The purpose of this review was to discuss the indications, clinical utility, and risks associated with bronchoscopy in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. METHODS: A literature search was performed by using appropriate key terms to identify all relevant articles from medical literature databases up to August 1, 2021. RESULTS: Twelve cohorts (9 retrospective and 3 prospective) reported the performance of 2,245 bronchoscopies in 1,345 patients with COVID-19. The majority of the subjects were male. Nearly two thirds of the bronchoscopies (62%) were performed for therapeutic indications; the rest (38%) were for diagnostic purposes. Bronchoalveolar lavage had an overall yield of 33.1% for SARS-CoV-2 in subjects with negative results of real-time polymerase chain reaction on nasopharyngeal specimens. The incidence of a secondary infection ranged from 9.3% to as high as 65%. Antibiotics were changed in a significant number of the subjects (14%-83%) based on the bronchoscopic findings. Bronchoscopy was well tolerated in most subjects except those who required noninvasive ventilation, in whom the intubation rate after the procedure was 60%. The rate of transmission of SARS-CoV-2 among health-care workers was minimum. CONCLUSIONS: Bronchoscopy in patients with COVID-19 results in a significant change in patient management. Transmission of SARS-CoV-2 seems to be low with consistent use of appropriate personal protective equipment by health-care workers. Therefore, bronchoscopic evaluation should be considered for all diagnostic and therapeutic indications in this patient population.

HCV Activates Somatic L1 Retrotransposition-A Potential Hepatocarcinogenesis Pathway.

Hepatitis C virus (HCV) is a common cause of hepatocellular carcinoma (HCC). The activation and mutagenic consequences of L1 retrotransposons in virus-associated-HCC have been documented. However, the direct influence of HCV upon L1 elements is unclear, and is the focus of the present study. L1 transcript expression was evaluated in a publicly available liver tissue RNA-seq dataset from patients with chronic HCV hepatitis (CHC), as well as healthy controls. L1 transcript expression was significantly higher in CHC than in controls. L1orf1p (a L1 encoded protein) expression was observed in six out of 11 CHC livers by immunohistochemistry. To evaluate the influence of HCV on retrotransposition efficiency, in vitro engineered-L1 retrotransposition assays were employed in Huh7 cells in the presence and absence of an HCV replicon. An increased retrotransposition rate was observed in the presence of replicating HCV RNA, and persisted in cells after viral clearance due to sofosbuvir (PSI7977) treatment. Increased retrotransposition could be due to dysregulation of the DNA-damage repair response, including homologous recombination, due to HCV infection. Altogether these data suggest that L1 expression can be activated before oncogenic transformation in CHC patients, with HCV-upregulated retrotransposition potentially contributing to HCC genomic instability and a risk of transformation that persists post-viral clearance.

Bronchoscopy During Coronavirus Disease 2019 Pandemic: A Bronchoscopist's Perspective.

Bronchoscopy is a safe and commonly performed procedure for diagnostic as well as therapeutic indications. Bronchoscopy is also an aerosol-generating procedure, and due to the risk of severe acute respiratory syndrome coronavirus 2 transmission during the procedure, routine bronchoscopy has been discouraged by multiple professional societies, despite any solid evidence. There are only a few reports of bronchoscopy in patients with coronavirus disease 2019 in the literature. Bronchoscopy in this patient population plays a crucial role not only in the diagnosis of coronavirus disease 2019 but also in the identification of secondary bacterial or fungal infections and in directing appropriate antimicrobial therapy. Bronchoscopy with therapeutic interventions may be lifesaving. Based on the literature, the risk of coronavirus disease 2019 transmission appears to be low among bronchoscopists and other healthcare workers when appropriate personal protective equipment is used. Bronchoscopy in patients with coronavirus disease 2019 should be strongly considered when clinically indicated.

Unilateral Diffuse Alveolar Hemorrhage Due to Selective Directionality of Mitral Regurgitant Jet in a Patient With Severe Aortic Stenosis.

Diffuse alveolar hemorrhage (DAH) in cardiac diseases results from pulmonary capillary stress failure due to pulmonary venous hypertension. The most common cardiac causes of DAH are heart failure and mitral valvular disease. Patients typically manifest with hemoptysis, radiologic chest abnormalities, and anemia. The chest infiltrates are generally bilateral, similar to pulmonary edema. Rarely, the chest infiltrates can be unilateral, mimicking an infectious etiology. We present the case of an 88-year-old female with critical aortic stenosis, who presented with shortness of breath, unilateral right lung infiltrates, and mild leukocytosis. The patient was misdiagnosed with pneumonia as pulmonary edema or DAH was expected to be a bilateral finding on chest imaging. The patient deteriorated and DAH was eventually diagnosed by bronchoscopy.