RESUMO
Hepcidin regulates iron homeostasis by controlling the level of ferroportin, the only membrane channel that facilitates export of iron from within cells. Binding of hepcidin to ferroportin induces the ubiquitination of ferroportin at multiple lysine residues and subsequently causes the internalization and degradation of the ligand-channel complex within lysosomes. The objective of this study was to identify components of the ubiquitin system that are involved in ferroportin degradation. A HepG2 cell line, which inducibly expresses ferroportingreen fluorescent protein (FPN-GFP), was established to test the ability of small interfering (siRNA) directed against components of the ubiquitin system to prevent BMP6- and exogenous hepcidin-induced ferroportin degradation. Of the 88 siRNA directed against components of the ubiquitin pathway that were tested, siRNA-mediated depletion of the alternative E1 enzyme UBA6 as well as the adaptor protein NDFIP1 prevented BMP6- and hepcidin-induced degradation of ferroportin in vitro. A third component of the ubiquitin pathway, ARIH1, indirectly inhibited ferroportin degradation by impairing BMP6-mediated induction of hepcidin. In mice, the AAV-mediated silencing of Ndfip1 in the murine liver increased the level of hepatic ferroportin and increased circulating iron. The results suggest that the E1 enzyme UBA6 and the adaptor protein NDFIP1 are involved in iron homeostasis by regulating the degradation of ferroportin. These specific components of the ubiquitin system may be promising targets for the treatment of iron-related diseases, including iron overload and anemia of inflammation.
Assuntos
Proteínas de Transporte de Cátions , Sobrecarga de Ferro , Proteínas de Membrana , Enzimas Ativadoras de Ubiquitina , Animais , Proteínas de Transporte/genética , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Ferro/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteólise , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND AND OBJECTIVES: Carbon monoxide (CO) poisoning is responsible for nearly 50,000 emergency department visits and 1200 deaths per year. Compared to oxygen, CO has a 250-fold higher affinity for hemoglobin (Hb), resulting in the displacement of oxygen from Hb and impaired oxygen delivery to tissues. Optimal treatment of CO-poisoned patients involves the administration of hyperbaric 100% oxygen to remove CO from Hb and to restore oxygen delivery. However, hyperbaric chambers are not widely available and this treatment requires transporting a CO-poisoned patient to a specialized center, which can result in delayed treatment. Visible light is known to dissociate CO from carboxyhemoglobin (COHb). In a previous study, we showed that a system composed of six photo-extracorporeal membrane oxygenation (ECMO) devices efficiently removes CO from a large animal with CO poisoning. In this study, we tested the hypothesis that the application of hyperbaric oxygen to the photo-ECMO device would further increase the rate of CO elimination. STUDY DESIGN/MATERIAL AND METHODS: We developed a hyperbaric photo-ECMO device and assessed the ability of the device to remove CO from CO-poisoned human blood. We combined four devices into a "hyperbaric photo-ECMO system" and compared its ability to remove CO to our previously described photo-ECMO system, which was composed of six devices ventilated with normobaric oxygen. RESULTS: Under normobaric conditions, an increase in oxygen concentration from 21% to 100% significantly increased CO elimination from CO-poisoned blood after a single pass through the device. Increased oxygen pressure within the photo-ECMO device was associated with higher exiting blood PO2 levels and increased CO elimination. The system of four hyperbaric photo-ECMO devices removed CO from 1 L of CO-poisoned blood as quickly as the original, normobaric photo-ECMO system composed of six devices. CONCLUSION: This study demonstrates the feasibility and efficacy of using a hyperbaric photo-ECMO system to increase the rate of CO elimination from CO-poisoned blood. This technology could provide a simple portable emergency device and facilitate immediate treatment of CO-poisoned patients at or near the site of injury.
Assuntos
Intoxicação por Monóxido de Carbono , Monóxido de Carbono , Animais , Intoxicação por Monóxido de Carbono/complicações , Intoxicação por Monóxido de Carbono/terapia , Carboxihemoglobina , Hemoglobinas , Humanos , Oxigênio , Fototerapia/métodosRESUMO
BACKGROUND AND OBJECTIVES: Carbon monoxide (CO) inhalation is the leading cause of poison-related deaths in the United States. CO binds to hemoglobin (Hb), displaces oxygen, and reduces oxygen delivery to tissues. The optimal treatment for CO poisoning in patients with normal lung function is the administration of hyperbaric oxygen (HBO). However, hyperbaric chambers are only available in medical centers with specialized equipment, resulting in delayed therapy. Visible light dissociates CO from Hb with minimal effect on oxygen binding. In a previous study, we combined a membrane oxygenator with phototherapy at 623 nm to produce a "mini" photo-ECMO (extracorporeal membrane oxygenation) device, which improved CO elimination and survival in CO-poisoned rats. The objective of this study was to develop a larger photo-ECMO device ("maxi" photo-ECMO) and to test its ability to remove CO from a porcine model of CO poisoning. STUDY DESIGN/MATERIALS AND METHODS: The "maxi" photo-ECMO device and the photo-ECMO system (six maxi photo-ECMO devices assembled in parallel), were tested in an in vitro circuit of CO poisoning. To assess the ability of the photo-ECMO device and the photo-ECMO system to remove CO from CO-poisoned blood in vitro, the half-life of COHb (COHb-t1/2 ), as well as the percent COHb reduction in a single blood pass through the device, were assessed. In the in vivo studies, we assessed the COHb-t1/2 in a CO-poisoned pig under three conditions: (1) While the pig breathed 100% oxygen through the endotracheal tube; (2) while the pig was connected to the photo-ECMO system with no light exposure; and (3) while the pig was connected to the photo-ECMO system, which was exposed to red light. RESULTS: The photo-ECMO device was able to fully oxygenate the blood after a single pass through the device. Compared to ventilation with 100% oxygen alone, illumination with red light together with 100% oxygen was twice as efficient in removing CO from blood. Changes in gas flow rates did not alter CO elimination in one pass through the device. Increases in irradiance up to 214 mW/cm2 were associated with an increased rate of CO elimination. The photo-ECMO device was effective over a range of blood flow rates and with higher blood flow rates, more CO was eliminated. A photo-ECMO system composed of six photo-ECMO devices removed CO faster from CO-poisoned blood than a single photo-ECMO device. In a CO-poisoned pig, the photo-ECMO system increased the rate of CO elimination without significantly increasing the animal's body temperature or causing hemodynamic instability. CONCLUSION: In this study, we developed a photo-ECMO system and demonstrated its ability to remove CO from CO-poisoned 45-kg pigs. Technical modifications of the photo-ECMO system, including the development of a compact, portable device, will permit treatment of patients with CO poisoning at the scene of their poisoning, during transit to a local emergency room, and in hospitals that lack HBO facilities.
Assuntos
Intoxicação por Monóxido de Carbono , Venenos , Animais , Monóxido de Carbono , Intoxicação por Monóxido de Carbono/terapia , Carboxihemoglobina/metabolismo , Humanos , Fototerapia/métodos , Ratos , SuínosRESUMO
BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator. In-vitro studies report that NO donors can inhibit replication of SARS-CoV-2. This multicenter study evaluated the feasibility and effects of high-dose inhaled NO in non-intubated spontaneously breathing patients with Coronavirus disease-2019 (COVID-19). METHODS: This is an interventional study to determine whether NO at 160 parts-per-million (ppm) inhaled for 30 min twice daily might be beneficial and safe in non-intubated COVID-19 patients. RESULTS: Twenty-nine COVID-19 patients received a total of 217 intermittent inhaled NO treatments for 30 min at 160 ppm between March and June 2020. Breathing NO acutely decreased the respiratory rate of tachypneic patients and improved oxygenation in hypoxemic patients. The maximum level of nitrogen dioxide delivered was 1.5 ppm. The maximum level of methemoglobin (MetHb) during the treatments was 4.7%. MetHb decreased in all patients 5 min after discontinuing NO administration. No adverse events during treatment, such as hypoxemia, hypotension, or acute kidney injury during hospitalization occurred. In our NO treated patients, one patient of 29 underwent intubation and mechanical ventilation, and none died. The median hospital length of stay was 6 days [interquartile range 4-8]. No discharged patients required hospital readmission nor developed COVID-19 related long-term sequelae within 28 days of follow-up. CONCLUSIONS: In spontaneous breathing patients with COVID-19, the administration of inhaled NO at 160 ppm for 30 min twice daily promptly improved the respiratory rate of tachypneic patients and systemic oxygenation of hypoxemic patients. No adverse events were observed. None of the subjects was readmitted or had long-term COVID-19 sequelae.
Assuntos
Tratamento Farmacológico da COVID-19 , Hospitalização , Óxido Nítrico/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Respiração/efeitos dos fármacos , Administração por Inalação , COVID-19/complicações , COVID-19/virologia , Relação Dose-Resposta a Droga , Humanos , Óxido Nítrico/farmacologia , Óxido Nítrico/uso terapêutico , Pneumonia Viral/complicaçõesRESUMO
TRPV1 mediates pain occurring during sickling episodes in sickle cell disease (SCD). We examined if hemin, a porphyrin released during intravascular hemolysis modulates TRPV1. Calcium imaging and patch clamp were employed to examine effects of hemin on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1 and TRPA1. Hemin induced a concentration-dependent calcium influx in DRG neurons which was abolished by the unspecific TRP-channel inhibitor ruthenium red. The selective TRPV1-inhibitor BCTC or genetic deletion of TRPV1 only marginally impaired hemin-induced calcium influx in DRG neurons. While hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by BCTC, patch clamp recordings only showed potentiated proton- and heat-evoked currents. This effect was abolished by the PKC-inhibitor chelerythrine chloride and in protein kinase C (PKC)-insensitive TRPV1-mutants. Hemin-induced calcium influx through TRPV1 was only partly PKC-sensitive, but it was abolished by the reducing agent dithiothreitol (DTT). In contrast, hemin-induced potentiation of inward currents was not reduced by DTT. Hemin also induced a redox-dependent calcium influx, but not inward currents on hTRPA1. Our data suggest that hemin induces a PKC-mediated sensitization of TRPV1. However, it also acts as a photosensitizer when exposed to UVA-light used for calcium imaging. The resulting activation of redox-sensitive ion channels such as TRPV1 and TRPA1 may be an in vitro artifact with limited physiological relevance.
Assuntos
Gânglios Espinais/metabolismo , Hemina/farmacologia , Neurônios/metabolismo , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/fisiologia , Animais , Cálcio/metabolismo , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Canal de Cátion TRPA1/efeitos dos fármacos , Canal de Cátion TRPA1/genética , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/genéticaRESUMO
OBJECTIVES: To test the feasibility, safety, and efficacy of intratracheal delivery of nitric oxide (NO) generated from air by pulsed electrical discharge via a Scoop catheter. STUDY DESIGN: We studied healthy 3- to 4-month-old lambs weighing 34 ± 4 kg (mean ± SD, n = 6). A transtracheal Scoop catheter was inserted through a cuffed tracheostomy tube. U46619 was infused to increase mean pulmonary arterial pressure (mPAP) from 16 ± 1 to 32 ± 3 mmHg (mean ± SD). Electrically generated NO was delivered via the Scoop catheter to awake lambs. A sampling line, to monitor NO and nitrogen dioxide (NO2) levels, was placed in the distal trachea of the lambs. The effect of varying doses of electrically generated NO, produced continuously, on pulmonary hypertension was assessed. RESULTS: In awake lambs with acute pulmonary hypertension, NO was continuously delivered via the Scoop catheter at 400 ml/min. NO induced pulmonary vasodilation. NO2 levels, measured in the trachea, were below 0.5 ppm at intratracheal NO doses of 10-80 ppm. No changes were detected in the levels of methemoglobin in blood samples before and after 5 min of NO breathing. CONCLUSIONS: Continuously delivering electrically generated NO through a Scoop catheter produces vasodilation of the pulmonary vasculature of awake lambs with pulmonary hypertension. Transtracheal NO delivery may provide a long-term treatment for patients with chronic pulmonary hypertension as an outpatient without requiring a mask or tracheal intubation.
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico/farmacologia , Vigília/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administração & dosagem , Administração por Inalação , Ar , Animais , Eletricidade , Hipertensão Pulmonar/induzido quimicamente , Infusões Intravenosas , Óxido Nítrico/administração & dosagem , Óxido Nítrico/análise , Ovinos , Traqueia/química , Vasodilatação/efeitos dos fármacosRESUMO
BACKGROUND & AIMS: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive vs active chronic infection. Interferon alfa may convert hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. METHODS: Hepatitis B surface proteins were measured before and during peginterferon alfa-2a therapy in serum from 127 Asian patients with HBeAg-positive CHB. Sustained response was defined as HBeAg seroconversion 24 weeks post-treatment. RESULTS: Mean total HBs levels were significantly lower in responders vs nonresponders at all time points (P < .05) and decreased steadily during the initial 24 weeks treatment (by 1.16 vs 0.86 ng/mL in responders/nonresponders respectively) with unchanged relative proportions. Genotype B had a two-fold higher proportion of LHBs than genotype C (13% vs 6%). HBV DNA, HBeAg, HBsAg and HBs protein levels predicted response equally well but not optimally (area under the receiver operating characteristic curve values >0.70). CONCLUSIONS: Hepatitis B surface protein levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa-2a therapy in HBeAg-positive patients.
Assuntos
Antígenos E da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Antígenos de Superfície da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Proteínas de Membrana , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
This prospective study investigated viral and host markers after stopping long-term therapy with nucleos(t)ide analogues in noncirrhotic patients with hepatitis B e antigen-negative chronic hepatitis B. After stopping therapy, 13 of 15 patients experienced a virological relapse. Rebound of hepatitis B virus DNA and hepatitis B core-related antigen was associated with induction of plasma tumor necrosis factor, interleukin (IL) 10 , IL-12p70, CXCL10 and subsequent decline in hepatitis B surface antigen (HBsAg), with 20% HBsAg loss after long-term follow-up. The peak levels of hepatitis B virus DNA and hepatitis B core-related antigen after cessation of therapy were positively correlated with the level of HBsAg decline at week 48. Thus, stopping or interrupting NA treatment should be further investigated as a strategy to accelerate HBsAg loss.
Assuntos
Antivirais/administração & dosagem , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Nucleosídeos/administração & dosagem , Nucleotídeos/administração & dosagem , Suspensão de Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocinas/sangue , DNA Viral/sangue , Feminino , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Hepatite B Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RecidivaRESUMO
OBJECTIVES: Cases of chronic hepatitis E virus (HEV) infection have been described in HIV-infected patients. There are several commercial anti-HEV assays, but anti-HEV seroprevalence rates differ largely depending on the assay used. The aim of this study was to (1) compare two commercial anti-HEV assays in a German cohort of HIV-positive individuals, and (2) determine whether HEV takes chronic courses in controlled HIV infection. METHODS: 246 HIV patients were tested for both HEV RNA and HEV antibodies. All patients received antiretroviral therapy, if this was indicated, according to European guidelines. All but 19 individuals had CD4+ counts above 200/µl. Anti-HEV IgG was determined by two independent commercial assays (Wantai and MP). RESULTS: None of the patients tested HEV RNA positive. Anti-HEV IgG was detected more frequently by the Wantai assay (26%) than the MP assay (1.6%, p < 0.001). Patients born in Europe tested more frequently positive for anti-HEV (p = 0.047) than individuals from other regions. Increasing age but not CD4 count correlated with a higher likelihood of anti-HEV positivity (R = 0.313, p < 0.001). CONCLUSIONS: About one quarter of HIV-infected patients show evidence of previous HEV contact. The risk of developing chronic HEV infection is very low in individuals receiving appropriate antiretroviral therapy. The large variability in HEV seroprevalence rates determined by different assays requires consideration for the diagnostic workup of HIV patients.
Assuntos
Infecções por HIV/complicações , Vírus da Hepatite E/imunologia , Hepatite E/epidemiologia , Adolescente , Adulto , Idoso , Doença Crônica , Feminino , Alemanha/epidemiologia , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite E/genética , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Estudos Retrospectivos , Estudos Soroepidemiológicos , Adulto JovemRESUMO
BACKGROUND: Surgical aortic valve replacement (SAVR) is an established therapy for severe calcific aortic stenosis. Enhanced recovery after cardiac surgery (ERACS) protocols have been shown to improve outcomes for elective cardiac procedures. The COVID-19 pandemic prompted early extubation post-elective surgeries to preserve critical care resources. AIM OF THIS STUDY: To investigate the effects of extubating patients within 6 h post-elective SAVR on hospital and ICU length of stay, mortality rates, ICU readmissions, and postoperative pneumonia. STUDY DESIGN AND METHODS: The retrospective analysis at the University Hospital Aachen, Germany, includes data from 2017 to 2022 and compares a total of 73 elective SAVR patients. Among these, 23 patients were extubated within 6 h (EXT group), while 50 patients remained intubated for over 6 h (INT group). RESULTS: The INT group experienced longer postoperative ventilation, needed more vasopressor support, had a higher incidence of postoperative pneumonia, and longer ICU length of stay. No significant differences were noted in overall hospital length of stay, mortality, or ICU readmission rates between the groups. CONCLUSION: This study demonstrates that early extubation in high-risk, multimorbid surgical aortic valve replacement patients is safe, and is associated with a reduction of pneumonia rates, and with shorter ICU and hospital length of stays, reinforcing the benefits of ERACS protocols, especially critical during the COVID-19 pandemic to optimize intensive care use.
Assuntos
Extubação , COVID-19 , Procedimentos Cirúrgicos Eletivos , Implante de Prótese de Valva Cardíaca , Tempo de Internação , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Masculino , Feminino , Estudos Retrospectivos , Idoso , Implante de Prótese de Valva Cardíaca/métodos , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Estenose da Valva Aórtica/cirurgia , Idoso de 80 Anos ou mais , Valva Aórtica/cirurgia , Pessoa de Meia-Idade , Alemanha/epidemiologia , SARS-CoV-2 , PandemiasRESUMO
Background: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a critical intervention for patients with severe lung failure, especially acute respiratory distress syndrome (ARDS). The weaning process from ECMO relies largely on expert opinion due to a lack of evidence-based guidelines. The ventilatory ratio (VR), which correlates with dead space and mortality in ARDS, is calculated as [minute ventilation (mL/min) x arterial pCO2 (mmHg)]/[predicted body weight × 100 × 37.5]. Objectives: The aim of this study was to determine whether the VR alone can serve as a reliable predictor of safe or unsafe liberation from VV-ECMO in critically ill patients. Methods: A multicenter retrospective analysis was conducted, involving ARDS patients undergoing VV-ECMO weaning at Massachusetts General Hospital (January 2016 - December 2020) and at the University Hospital Aachen (January 2012-December 2021). Safe liberation was defined as no need for ECMO recannulation within 48 h after decannulation. Clinical parameters were obtained for both centers at the same time point: 30 min after the start of the SGOT (sweep gas off trial). Results: Of the patients studied, 83.3% (70/84) were successfully weaned from VV-ECMO. The VR emerged as a significant predictor of unsafe liberation (OR per unit increase: 0.38; CI: 0.17-0.81; p = 0.01). Patients who could not be safely liberated had longer ICU and hospital stays, with a trend towards higher mortality (38% vs. 13%; p = 0.05). Conclusions: The VR may be a valuable predictor for safe liberation from VV-ECMO in ARDS patients, with higher VR values associated with an elevated risk of unsuccessful weaning and adverse clinical outcomes.
RESUMO
South American camelids (SAC) are being more and more presented at the veterinary Clinics in Germany. A bad nutritional condition, which can be easily categorized using a body condition score (BCS) of the animals, is often not noticed by the owners. Further anaemia is also often only detected in an advanced stage in SAC. Clinical detection of anaemia can be performed by assessing the FAMACHA©-score (FS), that is adapted from small ruminants. So far, there is only little information available about BCS and FS in SAC. In this study, both clinical scores were assessed in alpacas and llamas presented at the veterinary clinic and compared with the haematological parameters from the animals. The data were extracted retrospectively from the animals' medical records and compared statistically. More than half of the alpacas (60%) and llamas (70%) had a BCS < 3, while 12% of the alpacas and 21% of the llamas had a FS > 2. A decreased BCS was associated with a decrease in haematocrit, haemoglobin, lymphocytes, and eosinophils, as well as an increase in FS and neutrophils. BCS and FS should be assessed regularly in SAC to detect emaciation and anaemia in time.
RESUMO
RATIONALE: Inhalation of nitric oxide (NO) exerts selective pulmonary vasodilation. Nitric oxide also has an antimicrobial effect on a broad spectrum of pathogenic viruses, bacteria and fungi. OBJECTIVES: The aim of this study was to investigate the effect of inhaled NO on bacterial burden and disease outcome in a murine model of Klebsiella pneumonia. METHODS: Mice were infected with Klebsiella pneumoniae and inhaled either air alone, air mixed with constant levels of NO (at 80, 160, or 200 parts per million (ppm)) or air intermittently mixed with high dose NO (300 ppm). Forty-eight hours after airway inoculation, the number of viable bacteria in lung, spleen and blood was determined. The extent of infiltration of the lungs by inflammatory cells and the level of myeloperoxidase activity in the lungs were measured. Atomic force microscopy was used to investigate a possible mechanism by which nitric oxide exerts a bactericidal effect. MEASUREMENTS AND MAIN RESULTS: Compared to control animals infected with K. pneumoniae and breathed air alone, intermittent breathing of NO (300 ppm) reduced viable bacterial counts in lung and spleen tissue. Inhaled NO reduced infection-induced lung inflammation and improved overall survival of mice. NO destroyed the cell wall of K. pneumoniae and killed multiple-drug resistant K. pneumoniae in-vitro. CONCLUSIONS: Intermittent administration of high dose NO may be an effective approach to the treatment of pneumonia caused by K. pneumoniae.
Assuntos
Klebsiella pneumoniae , Pneumonia , Animais , Antibacterianos , Modelos Animais de Doenças , Pulmão , Camundongos , Óxido NítricoRESUMO
Treatment options are limited for patients with respiratory failure due to coronavirus disease 2019. Conventional oxygen therapy and awake proning are options, but the use of high-flow nasal cannula and continuous positive airway pressure are controversial. There is an urgent need for effective rescue therapies. Our aim is to evaluate the role of inhaled nitric oxide 160 ppm as a possible rescue therapy in nonintubated coronavirus disease 2019 patients. DESIGN: Retrospective evaluation of coronavirus disease 2019 patients in respiratory distress receiving nitric oxide gas as rescue therapy. SETTING: Massachusetts General Hospital, between March 18, 2020, and May 20, 2020, during the local coronavirus disease 2019 surge. PATIENTS: Coronavirus disease 2019 patients at high risk for acute hypoxemic respiratory failure with worsening symptoms despite use of supplemental oxygen and/or awake proning. INTERVENTIONS: Patients received nitric oxide at concentrations of 160 ppm for 30 minutes twice per day via a face mask until resolution of symptoms, discharge, intubation, or the transition to comfort measures only. MEASUREMENTS AND MAIN RESULTS: Between March 18, 2020, and May 20, 2020, five patients received nitric oxide inhalation as a rescue therapy for coronavirus disease 2019 at Massachusetts General Hospital. All received at least one dosage. The three patients that received multiple treatments (ranging from five to nine) survived and were discharged home. Maximum methemoglobin concentration after 30 minutes of breathing nitric oxide was 2.0% (1.7-2.3%). Nitrogen dioxide was below 2 ppm. No changes in mean arterial pressure or heart rate were observed during or after nitric oxide treatment. Oxygenation and the respiratory rate remained stable during and after nitric oxide treatments. For two patients, inflammatory marker data were available and demonstrate a reduction or a cessation of escalation after nitric oxide treatment. CONCLUSIONS: Nitric oxide at 160 ppm may be an effective adjuvant rescue therapy for patients with coronavirus disease 2019.
RESUMO
BACKGROUND: Rescue therapies to treat or prevent progression of coronavirus disease 2019 (COVID-19) hypoxic respiratory failure in pregnant patients are lacking. METHOD: To treat pregnant patients meeting criteria for severe or critical COVID-19 with high-dose (160-200 ppm) nitric oxide by mask twice daily and report on their clinical response. EXPERIENCE: Six pregnant patients were admitted with severe or critical COVID-19 at Massachusetts General Hospital from April to June 2020 and received inhalational nitric oxide therapy. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 39 treatments was administered. An improvement in cardiopulmonary function was observed after commencing nitric oxide gas, as evidenced by an increase in systemic oxygenation in each administration session among those with evidence of baseline hypoxemia and reduction of tachypnea in all patients in each session. Three patients delivered a total of four neonates during hospitalization. At 28-day follow-up, all three patients were home and their newborns were in good condition. Three of the six patients remain pregnant after hospital discharge. Five patients had two negative test results on nasopharyngeal swab for SARS-CoV-2 within 28 days from admission. CONCLUSION: Nitric oxide at 160-200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure.
Assuntos
Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Administração por Inalação , Betacoronavirus , COVID-19 , Feminino , Humanos , Massachusetts , Pandemias , Gravidez , Complicações Infecciosas na Gravidez/virologia , SARS-CoV-2 , Resultado do TratamentoRESUMO
Chronic hepatitis B virus (HBV) infection may follow four different consecutive phases, which are defined by virology as well as biochemical markers and differ in terms of prognosis and need for antiviral treatment. Currently, host responses reflected by immune markers are not considered in this definition. We aimed to study soluble immune markers and their distribution in different phases of chronic HBV infection. In this cross-sectional retrospective study, we investigated a panel of 14 soluble immune markers (SIM) including CXCL10 in 333 patients with chronic HBV infection. In a small cohort of HBeAg positive patients we analyzed SIM before and after HBeAg seroconversion and compared seroconverters to patients with unknown outcome. Significant differences were documented in the levels of several SIM between the four phases of chronic HBV infection. The most pronounced difference among all investigated SIM was observed for CXCL10 concentrations with highest levels in patients with hepatitis. TGF-ß and IL-17 revealed different levels between HBeAg negative patients. HBeAg positive patients with HBeAg seroconversion presented higher amounts of IL-12 before seroconversion compared to HBeAg positive patients with unknown follow up. SIM such as CXCL10 but also IL-12, TGF-ß and IL-17 may be useful markers to further characterize the phase of chronic HBV infection.
Assuntos
Biomarcadores/metabolismo , Hepatite B Crônica/metabolismo , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Pré-Escolar , Estudos Transversais , DNA Viral/metabolismo , Feminino , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Soroconversão/efeitos dos fármacos , Carga Viral/fisiologia , Adulto JovemRESUMO
BACKGROUND: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. METHODS: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). RESULTS: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). CONCLUSION: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.
Assuntos
Biomarcadores/sangue , Hepacivirus/genética , Hepatite C Crônica/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único/genética , Carga Viral/genética , Adulto , Antivirais/uso terapêutico , Feminino , Seguimentos , Genótipo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Interferons , Interleucinas/sangue , Masculino , Prognóstico , Estudos ProspectivosRESUMO
Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.