Pearls for the diagnosis and possible pathophysiological mechanisms of valproic acid-induced lupus erythematosus: A literature review.

Background: Drug-induced lupus erythematosus (DILE) accounts for 10-15% of systemic lupus erythematosus (SLE) cases, with more than 100 pharmaceutical agents implicated in its development. Depending on the offending drug, clinical and serological manifestations present great variability and, thus, DILE may be overlooked in clinical practice. Valproic acid (VPA) - induced lupus erythematosus has not been analytically reported in the literature, rendering the recognition of such cases even more difficult.Objective: The aim of this study was to analyze VPA - induced lupus features and to discuss possible pathophysiological mechanisms.Materials and Methods: This literature review was conducted in PubMed and Embase databases in June 2021, in search of DILE cases induced by VPA. We found 164 manuscripts, out of which 140 articles regarding other adverse effects or drugs were discarded. Finally, 15 cases fulfilled the eligibility criteria to be included in this review.Results: Although SLE is more common in females, VPA-induced lupus presented a male predilection. Patients developed DILE within the first three months of treatment with VPA at a percentage of 50%, whereas four patients from one to five years after VPA initiation. DILE frequently presented with mild symptoms. In most patients, serositis manifested with polyarthritis, pleural effusion or pericarditis. Notably, one patient presented with Rowell's syndrome, a rare subtype of lupus erythematosus with erythema multiforme and speckled pattern of antinuclear antibodies (ANAs). Central nervous system, renal and skin involvement was scarcely observed. Cytopenia was noted in 7 patients. Immunological findings included positive ANAs in the vast majority of the patients (86.7%), positive anti-histone antibodies in five, positive anti-dsDNA antibodies in three and hypocomplementemia in two patients. Despite the prompt resolution of clinical symptoms after VPA discontinuation, serological abnormalities persisted up to 18 months. Apart from the discontinuation of VPA administration for the resolution of DILE, treatment included corticosteroids in 8 cases.Conclusion: Valproic acid has been implicated in several cases of DILE. Clinicians should be aware of this entity and recognize it promptly to ensure a favorable outcome. Possible pathophysiologic associations may be extrapolated, but a clearer understanding of this syndrome is to be gained by further studies.

The presence of insomnia and depression contributes to the acceptance of an initial treatment trial of continuous positive airway pressure therapy in patients with obstructive sleep apnea.

The presence of comorbid insomnia and sleep apnea (COMISA) reduces the initial acceptance of continuous positive airway pressure (CPAP) therapy in 39-58% of patients with obstructive sleep apnea (OSA). Depressive disorders are reported in 5 to 63% of patients with OSA. Here we studied the co-occurrence of depression and insomnia in OSA patients and its impact on treatment acceptance in a real-life controlled trial. METHODS: In this prospective, uncontrolled study, participants were recruited from January to December 2018, among adult patients who visited our sleep lab. Participants underwent polysomnography study and completed the Epworth Sleepiness Scale (ESS), Athens Insomnia Scale (AIS), and Zung Depression Rating Scale (ZDRS). All subjects were categorized into 8 groups: no OSA/no depression (apnea-hypopnea index [AHI] < 5/h, n = 34), mild OSA/no depression (AHI = 5-14/h, n = 22), moderate OSA/no depression (AHI = 15-29/h, n = 44), severe OSA/no depression (AHI ≥ 30/h, n = 45), no OSA/mild depression (AHI < 5/h, n = 31), mild OSA/mild depression (AHI = 5-14/h, n = 24), moderate OSA/mild depression (AHI = 15-29/h, n = 31), and severe OSA/mild depression (AHI ≥ 30/h, n = 40). RESULTS: Over the one-year period, 272 participants (200 men, mean age 52.9 ± 13.0 years, BMI 33.6 ± 7.2 kg/m2) were enrolled. When the above 8 groups were subcategorized into the presence or absence of insomnia, we found no differences in CPAP trial acceptance between subgroups except in patients from the mild depression/severe OSA/insomnia subgroup who denied CPAP therapy more frequently (chi-squared test p = 0.016). We found, with a moderate efficiency indicated by the ROC curve, that patients with AHI > 15/h, AIS ≥ 11, and ZDRS > 44 were more likely to refuse an initial trial of CPAP treatment because of COMISA and depression (ROC curve area = 0.710, p = 0.049). CONCLUSION: This study demonstrates that it is important to recognize a depressive mood disorder in patients with moderate/severe OSA and COMISA as the coexistence of these comorbidities impairs the rate of initial acceptance of CPAP treatment. Additionally, our study suggests the cut-off values from the AIS and ZDRS questionnaires to help lead clinicians to an early diagnostic evaluation of COMISA patients for the presence of depressive mood disorder.

The role of immunotherapy in patients with lung cancer and brain metastases: a narrative review of the literature.

Worldwide, approximately half of the patients diagnosed with lung cancer (LC) will develop, simultaneously or asynchronously, brain metastases (BMs). The existence of BMs negatively affects the quality of life and constitutes a poor prognostic factor, linked with high mortality. Locoregional therapy with surgery or radiation is, until now, the treatment of choice, especially for symptomatic patients; however, both options are linked to a high complication rate. The question arising here is whether, in asymptomatic patients, the benefit outweighs the risk and whether an alternative method can be used to treat this special category of patients. Over the last decade, immune checkpoint inhibitors (ICIs) have represented a major breakthrough in the field of oncology, and several molecules have been approved as a treatment option for LC. This review tried to analyze the tumor microenvironment of both the primary lung tumor and the BMs in order to evaluate the intracranial activity of ICIs, outline the main challenges of including these agents in the treatment of LC with BMs, highlight the available information from the main clinical trials, and mark the potential positive effect of choosing a combination therapy. In conclusion, it appears that immunotherapy has a positive effect, inhibiting the progression of BMs, but more data should be published specifically for this category of patients.

Celiac disease and idiopathic pulmonary hemosiderosis: a literature review of the Lane-Hamilton syndrome.

Lane-Hamilton syndrome (LHS) presents a medical emergency, with 14% mortality due to Idiopathic Pulmonary Hemosiderosis (IPH) in acute phase. Despite the clinical severity of this entity, there has been no published review in the international literature, resulting in lack of awareness and delayed diagnosis.A rigorous search of international databases yielded a total of 80 LHS cases from January 1971 to August 2020. We analyzed 44 children (8.56 ± 4.72 years, 21 boys) and 36 adults (33.61 ± 13.41 years, 12 men) to present the clinical manifestations, radiological and immunological pattern, therapeutic approaches and outcome of LHS. We also elaborated on clinical and laboratory findings' associations to propose diagnostic indexes and clarified differences based on age distribution.Celiac disease (CD) and IPH diagnosis was made concurrently in 46 patients, whereas in 21 patients, the diagnosis of LHS was delayed for 2.5y (3 months-11 years). Hemoptysis (n = 56, 70%), dyspnea (n = 47, 58.8%), anemia (n = 72, 90%), and iron deficiency (n = 54, 67.5%) were most commonly observed. Medical history revealed recurrent episodes of hemoptysis (n = 38) and persistent iron deficiency anemia (n = 25) in need of multiple blood transfusions or iron supplementation. Patchy infiltrate opacities to consolidation predominated in children, whereas bilateral diffuse ground-glass opacities in adults. Duodenal biopsy was performed in 66 cases (diagnostic 87.8%), BAL in 51 (diagnostic 74.5%), and surgical lung biopsy in 20. Anti-tTG titer was positive in all 24 (54.6%) children and 19 (52.8%) adults that documented this assay. Prednisone or methylprednisolone pulse therapy and GFD were initiated in the acute phase, whereas chronic therapy included GFD, along with long-term prednisone in refractory cases. Three cases with severe respiratory failure or hemodynamic instability were intubated and a further three succumbed.A thorough understanding of LHS may reveal further diagnostic indexes and a consensus on therapy guidelines. Screening for CD is essential in all IPH cases for timely recognition and favorable outcome.

Mesothelioma: A Case in a Diagnostic Timeline and the Efficiency of Robot-Assisted Surgery.

We present a case of a 65-year-old male with a difficulty to diagnose mesothelioma. To be specific, three attempts were made to diagnose the disease, and only with a large sample performed with robot-assisted surgery, our pathologists were able to identify the malignancy. The novelty for our case is mostly based on the timeline of the diagnosis along with the tissue samples where we present the course of the transformation from benign to malignancy. All tissue biopsies were checked by two independent pathologists. Conclusively, diagnosis for small local lesions should be performed with an endoscopic method, video-assisted or robot-assisted.

Radial Endobronchial Ultrasound for Lung Cancer Diagnosis: Tips and Tricks.

Introduction: Endoscopic techniques have been upgraded in the recent 10 years. We can use the radial endobronchial ultrasound to reach distal nodules in the periphery of the lungs, but also we can use it in order to make biopsies in lesions without endobronchial findings. Patients and Methods: We included in our study 248 patients with pulmonary nodules up to 4 cm. We use a radial endobronchial system from FUJI, a PENTAX bronchoscope and a C-ARM. We recorded the cancer type, biopsy method, time of each procedure, cell blocks and slices from cell blocks. Results: Two thirds of patients belonged to males (61.7%), forceps was the main tissue extraction technique (118, 47.6%) and tumors sized 1 to 2 cm were the most encountered (96, 38.7%). Samples with tissue content were present in 175 patients (70.6%) and one cell block dominated in the samples (109, 43.9%). Less than 20 minutes were needed to complete the operative procedure for the half patients (127, 51.2%), the C-Arm implementation concerned 117 persons (47.2%) and the majority of tumors was located in the central area of the lungs (178, 71.8%). Less time was necessary for central lesions and larger biopsy samples were acquired without the extensive use of C-ARM. Conclusion: The larger the nodule ≥2cm and in periphery the less we use the C-ARM and the time of the procedure is between 20-40 minutes. Moreover; we have more tissue sample and cell block slices.

Clinical and pathophysiological characteristics of valproate-induced pleural effusion.

INTRODUCTION: Valproic acid is a carboxylic acid derivative commonly prescribed for several types of seizure disorders or for acute manic episodes in patients with bipolar disorder. Several cases of valproate-induced pleural effusion have been reported, although the precise pathophysiological mechanism remains unknown. OBJECTIVE: To describe the presentation of pleural effusion associated with valproate use and to categorize published case reports according to clinical, immunological, and pleural effusion cell type. METHODS: PubMed/MEDLINE and Embase databases were systematically searched from January 1970 until November 2020 using the following search terms: "valproic acid" OR "valproate" OR "pleural fluid" OR "exudative effusion" OR "transudative effusion" OR "valproic lung adverse events". These searches yielded 171 references of which 135 articles were considered irrelevant, leaving 36 potentially relevant references which were carefully scrutinized. Twenty-eight cases of valproate-induced pleural effusion were identified after excluding two articles reporting five patients with lung parenchymal adverse reactions to treatment with valproic acid; two articles reporting three patients in whom the pleural effusion could not be attributed to valproic acid alone; one case discussing valproate therapy and fungal pleural effusion; and one describing a patient who suffered from severe cardiac failure. There were also two cases, in an abstract form, with pericardial and pleural effusion, but without any further informative details, and, thus, they were also excluded from this survey. EXUDATIVE EOSINOPHILIC PLEURAL EFFUSION: This was the most common type of valproate-induced pleural effusion reported in 17 out of 28 cases (60.7%), with concurrent peripheral eosinophilia in ten. Acute hypersensitivity reaction, inflammation of the pleural cavity induced by the drug, drug toxicity, and damage to mesothelial cells due to oxidants, comprise the possible pivotal mechanisms. EXUDATIVE LYMPHOCYTIC PLEURAL EFFUSION: This was reported in two cases, with concurrent pericardial effusion in one. Discontinuation of valproate led to resolution of the effusion, although the underlying pathophysiological mechanisms remain abstruse. Interestingly, a patient presented with recurrent pleural effusion characterized by transition from eosinophilic to lymphocytic predominance after readministration of valproate. TRANSUDATIVE PLEURAL EFFUSION: Three out of 28 cases (10.7%) were characterized by neutrophilic transudative pleural effusion after long-term therapy with valproate, while concurrent pericardial effusion was also noted in two. VALPROATE-INDUCED LUPUS ERYTHEMATOSUS WITH PLEURAL EFFUSION: Five patients receiving valproate therapy (17.9% out of the 28 cases) developed drug-induced lupus erythematosus with concurrent pleural effusion that was eosinophilic in three. All patients had positive antinuclear antibodies; anti-histone antibodies were positive in two. CONCLUSIONS: Valproate-induced pleural effusion is rare, but patients receiving treatment with valproic acid who develop respiratory symptoms should be examined for valproate-induced pleural effusion.

Tracheal fistula repair with stent placement after failure of reconstruction with muscle tissue. A lung cancer surgery complication.

A report a case of a 63 year old male diagnosed with lung cancer adenocarcinoma. The patient had a right paratracheal mass diagnosed with EBUS-TBNA 22G. The patient had surgery, however 7 days after the billau catheter was removed pneumothorax was diagnosed which did not resolved. Bronchoscopy reveled two minor fistulas in the interior wall of the trachea. An additional surgery was performed in order to add muscle patches on the exterior part of the trachea. Unfortunately additional stent placement was placed after a silicon stent since the muscle patches failed. We chose a metallic auto expandable stent since after three months of follow up a small metastatic lesion was observed in the liver. Stent placement is an option for these patients and the right stent has to be placed for each case.

Interventional bronchoscopy for HPV 16 and 66 with the use of spraying interferon-α (2b) plus bevacizumab and anti-reflux agent.

A fifty year old male was diagnosed with bronchial HPV. He was treated with local interventional treatment argon plasma coagulation and subcutaneous injections bevacizumab. Spraying of the regions followed with a specially designed catheter with interferon-α (2b). Systematic treatment of esomeprazole was also administered. After six months the patient is disease free and on close follow-up.

Lymphadenopathy and granulomas: benignancy of malignancy and differential diagnosis with endobronchial ultrasound-transbronchial needle biopsy 19G needle fine-needle aspiration biopsy.

Endobronchial ultrasound (EBUS) is a very useful tool for the diagnosis of lymphadenopathy of the mediastinum. Nowadays, EBUS can substitute video-assisted thoracic surgery when a 19G needle is used. Several studies have provided data for efficient diagnosis not only for lung cancer, but for also sarcoidosis, tuberculosis and lymphoma. We present five cases of EBUS-transbronchial needle biopsy 19G needle used for the diagnosis of mediastinum lymphadenopathy. We present not only the pathological diagnosis, but also the steps for the differential clinical and pathological differential diagnosis for sarcoidosis, tuberculosis, cancer metastasis, respiratory infection and lymphoma.

Perinatal management of enlarged bronchogenic cyst causing hydrops fetalis.

Bronchogenic cysts are rare congenital anomalies that they are usually diagnosed prenatally during the routine second trimester scan. We present such a rare case of bronchogenic cyst in a fetus. Our initial scan demonstrated a big cystic mass, which enlarged progressively causing shifting of the mediastinum and compression of the fetal heart. Consequent hydrops fetalis was treated with thoracoamniotic shunt and the pregnancy continued with no further complications. Pontnatal period, surgery and long term follow-up was uneventful.

Bronchogenic cyst or lung cancer. Only biopsy can tell.

Bronchogenic cysts are rare congenital malformations which derive from primitive ventral foregut. They are usually observed in intrathoracically. A fifty year old male was admitted for the investigation of a three month chest pain. Computed tomography scan of the thorax revealed a lesion around the esophagus and left stem bronchus. Endobronchial ultrasound with convex probe and a 19G needle biopsy revealed a bronchogenic cystic which was removed with video assisted thoracic surgery. Initial radiologic assessment although was thought to be lung cancer because of the smoking habit it turned out to be benignancy. EBUS-TBNAB with 10G needle is safe and absolutely necessary for these lesions, as they take large samples.

Bronchial HPV; the good the bad and the unknown.

BACKGROUND: Solitary tracheobronchial papilloma (STBP) is a rare benign tumor. Human papilloma virus (HPV) infection is associated with dysplasia and a high risk of carcinoma. CASE 1: Sixty five year old male with hemoptysis and with coilocytic atypia, indicating the presence of HPV. CASE 2: Thirty two year old female with a polypoid villoglandular bronchial structure and no cytoplasmic or nuclear atypia but prominent microvilli. DISCUSSION: Tissue sample is the best sample in order to determine and distinguish the two entities, local treatment should be considered as first option when possible.

Excessive muscle paralysis due to pulmonary carcinoid -a case report.

We present the case of a 58-year-old woman with a renin secreting typical bronchopulmonary carcinoid. This patient showed hypotension, constipation and fatigue due to extensive hypokaliemia (K =1.9 meq/L). Aldosterone (102.7 ng/100 mL) and renin (46 ng/mL) were excessively elevated at that time, but cortisol level was normal. Routine chest roentgenography and computed tomography revealed a nodular lesion in the upper left lung lobe, which was suspicious for a neurosecretory pulmonary tumor. The final diagnosis was made by using bronchoscopic procedures and the histologically diagnosis was compatible as a typical pulmonary carcinoid. The tumor was resected curatively, and the renin and aldosterone level became normal. A year after the patient looks healthy.

Serratia pneumonia presenting as hemoptysis in a patient with sarcoidosis: a case report.

INTRODUCTION: Serratia marcescens is a Gram-negative bacillus which belongs to the family Enterobacteriaceae. It is a facultative anaerobe and produces red pigment at room temperature. It naturally occurs in soil and water as well as the intestines, and it is responsible for nosocomial infections. There have been few reports about community acquired pneumonia of Serratia. CASE PRESENTATION: This report presents a 37-year-old man with hemoptysis, fever, and shortness of breath. The clinical and laboratory examinations revealed that the patient had pseudohemoptysis due to S. marcescens pneumonia, on an immunocompromised pattern, because of the coexistence of sarcoidosis (stage 1). CONCLUSION: Appropriate antibiotic therapy for Serratia was administered, and the patient's symptoms regressed. The patient is healthy and asymptomatic after 1-year follow-up. To the best of the authors' knowledge, this is the first reported case of a pseudohemoptysis in a patient with pulmonary sarcoidosis.

Penetration of azithromycin in experimental pleural empyema fluid.

There were no data about the extent of azithromycin penetration into the empyemic pleural fluid in humans and in experimental animals. An empyema was created via the intrapleural injection of an Escherichia coli solution into the pleural space of New Zealand white rabbits. After an empyema was verified by thoracocentesis, 24h post inoculation, azithromycin (15 mg/kg) was administered intravenously. Antibiotic levels were determined in samples of pleural fluid and blood serum, collected serially at 2, 8, 24, 48 and 72 h, after administration. Azithromycin levels were estimated using an HPLC analytical method with fluorimetric detection. Azithromycin penetrated well into the empyemic pleural fluid, exhibiting a slower onset and decline compared to the corresponding blood serum levels. Equilibration between pleural fluid and blood serum compartments seemed to occur at 2h, with peak pleural fluid levels (C(maxpf) of 0.48 microg/ml) occurring 24h post administration and decreasing thereafter. Azithromycin peak serum concentration (C(maxserum) of 0.24 microg/ml) was observed 2h after administration and, thereafter, serum antibiotic levels remained lower than the corresponding pleural fluid ones. The area under the concentration versus time curve (AUC) and terminal half-life (T(1/2)) of azithromycin was three- to six fold and twofold higher, respectively, in the pleural fluid compared to the blood serum compartment. After intravenous administration, azithromycin penetrated well into the empyemic pleural fluid, exhibiting pleural fluid levels that are inhibitory for most erythromycin-sensitive pathogens causing empyema.

Acute effect of smoking on plasma Obestatin levels.

BACKGROUND: Smoking and smoking cessation are considered to be associated with weight changes. We have recently shown that smoking acutely increases plasma levels of ghrelin, a known orexigenic hormone. Obestatin is a peptide encoded by the ghrelin gene, which opposes ghrelin effects on food intake. We conducted a study in adult volunteers measuring plasma levels of obestatin immediately after initiation of smoking. METHODS: 31 volunteers (mean age 32.2 +/- 9.2 years and mean BMI 25.7 +/- 4.1), 17 smokers and 14 non-smokers, were enrolled in our study. The 2 groups were matched in age and BMI. Plasma obestatin concentrations were determined at baseline (T0), 2 (T2), 5 (T5), 15 (T15), and 60 (T60) minutes after the initiation of smoking. RESULTS: In all 31 subjects, no significant difference in the mean values of plasma obestatin levels was observed from baseline at T2, T5, T15 and T60 after initiation of smoking (overall p = 0.15). However, a trend for higher obestatin levels was noted in smokers vs non-smokers (overall p = 0.069), which was not related to the pack-years. CONCLUSION: On the contrary with ghrelin's response after smoking initiation, there is no such an acute response of plasma obestatin levels.

Pharmacokinetics of Linezolid and Ertapenem in experimental parapneumonic pleural effusion.

OBJECTIVE: To determine the extent of linezolid and ertapenem penetration into the empyemic fluid using a rabbit model of empyema. METHODS: An empyema was created via the intrapleural injection of Escherichia coli bacteria (ATCC 35218) into the pleural space of New Zealand white rabbits. After an empyema was verified by thoracocentesis, 24 hours post inoculation, linezolid (10 mg/kg) and ertapenem (60 mg/kg) were administered intravenously into 10 and 8 infected empyemic rabbits, respectively. Antibiotic levels were determined in samples of pleural fluid and blood serum, collected serially at 1, 2, 4, 6 and 8 hours, after administration each of the two antibiotics. RESULTS: Linezolid as well as ertapenem penetrate well into the empyemic pleural fluid, exhibiting a slower onset and decline compared to the corresponding blood serum levels. Equilibration between blood serum and pleural fluid compartments seems to occur at 1.5 hours for both linezolid and ertapenem, with peak pleural fluid levels (Cmaxpf of 2.02 +/- 0.73 <>g/ml and Cmaxpf of 3.74 +/- 1.39 <>g/ml, correspondingly) occurring 2 hours post antibiotics administration and decreasing very slowly thereafter. The serum concentrations for both antibiotics were significantly lower from the corresponding pleural fluid ones during the 8 hours collecting data, with the exception of samples collected at the 1st hour (Cmaxserum of 2.1 +/- 1.2 <>g/ml for linezolid and Cmaxserum of 6.26 +/- 2.98 <>g/ml for ertapenem). CONCLUSION: Pleural fluid levels of both antibiotics are inhibitory for common specified pathogens causing empyema.

Sodium valproate as a cause of recurrent transudative pleural effusion: a case report.

INTRODUCTION: There are few reported cases of neutrophilic pleural effusions associated with valproic acid therapy. Most of them are of eosinophilic exudates with or without blood eosinophilia. CASE PRESENTATION: This case study describes a 70-year-old man with recurrent episodes of eosinophilic transudative pleural effusions associated with sodium valproate treatment. The recurrence of effusion after re-administration of the drug is strongly suggestive of an association between them. To the best of our knowledge, this is the first reported case with a pleural effusion with these characteristics caused by sodium valproate. CONCLUSION: This is the first report in the literature, with a full understanding of the etiology but with an unknown drug mechanism. This case report is of interest to different medical specialists (such as pulmonologists, neurologists, cardiologists) and pharmacologists.