RESUMO
An elevated blood angiotensin I-converting enzyme (ACE) supports diagnosis of sarcoidosis and Gaucher disease. However, some ACE mutations increase ACE shedding, and patients with these mutations are therefore at risk of being incorrectly diagnosed with sarcoidosis because of elevated serum ACE levels. We applied a novel approach called "ACE phenotyping" to identify possible ACE mutations in 3 pulmonary clinic patients that had suspected sarcoidosis based on elevated blood ACE levels. Conformational fingerprinting of ACE indicated that these mutations may be localized in the stalk region of the protein and these were confirmed by whole exome sequencing. Index patient 1 (IP1) had a mutation (P1199L) that had been previously identified, while the other 2 patients had novel ACE mutations. IP2 had 2 mutations, T887M and N1196K (eliminating a putative glycosylation site), while IP3 had a stop codon mutation Q1124X (eliminating the transmembrane anchor). We also performed a comprehensive analysis of the existing database of all ACE mutations to estimate the proportion of mutations increasing ACE shedding. The frequency of ACE mutations resulting in increased blood ACE levels may be much higher than previously estimated. ACE phenotyping, together with whole exome sequencing, is a diagnostic approach that could prevent unnecessary invasive and/or costly diagnostic procedures, or potentially harmful treatment for patients misdiagnosed on the basis of elevated blood ACE levels.
Assuntos
Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Sarcoidose/sangue , Sarcoidose/diagnóstico , Idoso , Biomarcadores/sangue , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Mapeamento de Peptídeos , Ligação Proteica , Conformação ProteicaRESUMO
A sarcoidosis patient may be refractory to corticosteroid therapy. This may be because corticosteroids are ineffective in relieving the sarcoidosis patient's symptoms/dysfunction or because the clinician has determined that the risks of corticosteroids outweigh their benefits. Interestingly, when corticosteroids truly fail to improve a sarcoidosis patient's condition, it is very rarely because of failure of the drug as an anti-granulomatous agent; rather, it is usually because the patient's symptoms were unrelated to active sarcoid granulomas. In this manuscript, we review the causes of corticosteroid refractory sarcoidosis. The clinician should consider these causes when confronted with a sarcoidosis patient who is either not responding to corticosteroids, developing corticosteroid side-effects, or is at significant risk of developing such side-effects. We believe that determining the cause of corticosteroid refractory sarcoidosis may aid the clinicians in optimizing the care of sarcoidosis patients and clinical researchers in appropriately stratifying patients for clinical trials.
Assuntos
Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Sarcoidose Pulmonar/tratamento farmacológico , Humanos , Cooperação do Paciente , Falha de TratamentoRESUMO
BACKGROUND: Lung injury associated with cannabinoid oil vaping is rapidly becoming a serious public health concern. We describe the clinical and radiographic presentations of 5 patients with lung injury associated with vaping cannabinoid oils seen at a single institution. RESULTS: Of the 5 patients with suspected vaping-associated lung injury seen at our institution, 4 required supplemental oxygen, and all these 4 were admitted to the hospital. Three patients required admission to the intensive care unit. None of the patients required mechanical ventilation. All patients demonstrated a consistent radiologic appearance of diffuse bilateral ground-glass lung opacities that spared the extreme periphery. Three patients underwent bronchoalveolar lavage, which revealed lipid-laden macrophages in 2 of them. All patients were successfully discharged from the hospital. Four received only supportive care, while the fifth required intravenous followed by oral corticosteroids. CONCLUSIONS: We report the clinical and radiographic presentation of 5 patients at our institution with cannabinoid oil vaping-associated lung injury. All patients displayed a consistent chest radiographic pattern of injury. Most responded to supportive care, although one required the addition of corticosteroids. Bronchoalveolar lavage results suggest that this injury may related to a toxic form of lipoid pneumonia.
Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Canabinoides/efeitos adversos , Sistemas Eletrônicos de Liberação de Nicotina , Pulmão/diagnóstico por imagem , Vaping/efeitos adversos , Lesão Pulmonar Aguda/diagnóstico , Adulto , Canabinoides/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óleos/administração & dosagem , Óleos/efeitos adversos , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
OBJECTIVES: The objectives of this study were to 1) assess patterns of early crystalloid resuscitation provided to sepsis and septic shock patients at initial presentation and 2) determine the association between time to initial crystalloid resuscitation with hospital mortality, mechanical ventilation, ICU utilization, and length of stay. DESIGN: Consecutive-sample observational cohort. SETTING: Nine tertiary and community hospitals over 1.5 years. PATIENTS: Adult sepsis and septic shock patients captured in a prospective quality improvement database inclusion criteria: suspected or confirmed infection, greater than or equal to two systemic inflammatory response criteria, greater than or equal to one organ-dysfunction criteria. INTERVENTIONS: The primary exposure was crystalloid initiation within 30 minutes or lesser, 31-120 minutes, or more than 120 minutes from sepsis identification. MEASUREMENTS AND MAIN RESULTS: We identified 11,182 patients. Crystalloid initiation was faster for emergency department patients (ß, -141 min; CI, -159 to -125; p < 0.001), baseline hypotension (ß, -39 min; CI, -48 to -32; p < 0.001), fever, urinary or skin/soft-tissue source of infection. Initiation was slower with heart failure (ß, 20 min; CI, 14-25; p < 0.001), and renal failure (ß, 16 min; CI, 10-22; p < 0.001). Five thousand three hundred thirty-six patients (48%) had crystalloid initiated in 30 minutes or lesser versus 2,388 (21%) in 31-120 minutes, and 3,458 (31%) in more than 120 minutes. The patients receiving fluids within 30 minutes had lowest mortality (949 [17.8%]) versus 31-120 minutes (446 [18.7%]) and more than 120 minutes (846 [24.5%]). Compared with more than 120 minutes, the adjusted odds ratio for mortality was 0.76 (CI, 0.64-0.90; p = 0.002) for 30 minutes or lesser and 0.76 (CI, 0.62-0.92; p = 0.004) for 31-120 minutes. When assessed continuously, mortality odds increased by 1.09 with each hour to initiation (CI, 1.03-1.16; p = 0.002). We observed similar patterns for mechanical ventilation, ICU utilization, and length of stay. We did not observe significant interaction for mortality risk between initiation time and baseline heart failure, renal failure, hypotension, acute kidney injury, altered gas exchange, or emergency department (vs inpatient) presentation. CONCLUSIONS: Crystalloid was initiated significantly later with comorbid heart failure and renal failure, with absence of fever or hypotension, and in inpatient-presenting sepsis. Earlier crystalloid initiation was associated with decreased mortality. Comorbidities and severity did not modify this effect.