Asthma in Cystic Fibrosis: Definitions and Implications of This Overlap Syndrome.

PURPOSE OF REVIEW: Cystic fibrosis (CF) is a multisystem, autosomal recessive disease that leads to progressive loss of lung function. Respiratory symptoms for both CF and asthma include cough, wheezing, and dyspnea. There is debate within the CF community on how to best define and distinguish CF-asthma overlap syndrome (CFAOS) from asthma-like features, though CFAOS is well-recognized. We aim to review the epidemiology, diagnosis, and treatment of asthma in CF and explore areas where further research is needed. RECENT FINDINGS: There has been considerable improvement in the understanding and treatment of asthma over the past two decades leading to novel therapies such as biologic agents that target the airway inflammation in asthmatics based on their asthma phenotype. These therapies are being studied in CFAOS and are promising treatments. This review provides a comprehensive overview of the definition, epidemiology, diagnosis, and current treatment of CFAOS.

Disseminated blastomycosis.

Blastomycosis is a fungal infection caused by Blastomyces dermatitidis, a dimorphic fungus endemic in the soils of the Ohio and Mississippi River Vallys, Great Lakes region, and southeastern United States. It most commonly manifests as a pulmonary infection following inhalation of spores, which causes a broad array of clinical manifestations ranging from asymptomatic infection to fulminant sepsis with acute respiratory distress syndrome and death. Extrapulmonary disease occurs in approximately 25-30% of patients following hematogenous spread from the lungs, with skin being the most common site of exytrapulmonary disease. Here we present a case of disseminated blastomycosis in a healthy 48 year old female.

Severe Noncardiogenic Pulmonary Edema Secondary to Massive Verapamil Overdose and Treatment with Venovenous Extracorporeal Membrane Oxygenation.

Calcium channel blocker (CCB) poisoning frequently presents with cardiovascular complications such as cardiogenic shock and arrhythmia. We present a case of massive verapamil overdose causing refractory noncardiogenic pulmonary edema successfully treated with extracorporeal membrane oxygenation. To our knowledge, this is the first case with these features reported in literature. A 27-year-old female patient presented with an overdose of 18,000 mg of verapamil. Her clinical condition deteriorated to severe hypoxic respiratory failure despite being treated with calcium, high-dose insulin, and full invasive ventilation support. She eventually required venovenous extracorporeal membrane oxygenation (VV-ECMO) for three days with full recovery. Large ingestion of verapamil could lead to noncardiogenic pulmonary edema. VV-ECMO might play an important role to support the treatment in severe cases with refractory hypoxia.

Heightened Immune Response to Presumed Loxosceles reclusa Envenomation.

Loxoscelism is a systemic inflammatory reaction in response to a brown recluse spider bite (BRSB). In this case we describe a patient with a heightened inflammatory response to a presumed BRSB, with Coomb's positive hemolysis, cytoplasmic antineutrophil cytoplasmic antibody (cANCA) vasculitis, and features of hemophagocytic lymphohistiocytosis (HLH). A 24-y-old female presented with sudden pain and swelling to her lower back, nausea, fever, and tachycardia after a presumed BRSB. Hemolysis began on hospital day 3 (15.9 g·dL-1) with a nadir on hospital day 5 (6.3 g·dL-1). She had an lactate dehydrogenase of 1415 U·L-1, ferritin of 15534 ng·mL-1, persistent fever, and signs of bone marrow suppression despite hemolysis, with thrombocytopenia (100,000 µL-1) and an inadequate reticulocyte response (1.7%) suggestive of HLH. The patient's blood was Coomb's and cANCA/antiproteinase 3 positive. She had signs of toxin-induced vasculitis, with respiratory failure requiring bilevel positive airway pressure, radiographs with bilateral pulmonary infiltrates, and a desquamating rash. She received 6 U of packed red blood cells, furosemide for pleural and pericardial effusions, antibiotics, and symptomatic treatment during the acute phase of her illness. Hemolysis improved without glucocorticoids by hospital day 6. The patient demonstrated a dysregulated immunologic and complement-mediated response to the presumed BRSB. The triad of Coomb's positive hemolysis, cANCA vasculitis, and HLH-like reaction associated with a presumed BRSB is described for the first time in the literature and brings up questions for future research regarding the role of immune modulators and complement inhibitors in the treatment of severe loxoscelism as well as the genetic factors that predispose certain individuals to such reactions.

Immunomodulatory Cell Therapy to Target Cystic Fibrosis Inflammation.

Cystic fibrosis (CF) is associated with exaggerated and prolonged inflammation in the lungs, which contributes to lung injury, airway mucus obstruction, bronchiectasis, and loss of lung function. This hyperinflammatory phenotype appears to be caused by an imbalance between the pro- and antiinflammatory regulatory pathways, with heightened proinflammatory stimuli, a decreased counter-regulatory response, and reduced effectiveness of immune cell function and inflammatory resolution. Thus, therapies that can target this inflammatory environment would have a major impact on preventing the progression of lung disease. Because of the complex phenotype of CF inflammation, current antiinflammatory regimens have proven to be inadequate for the targeting of these multiple dysregulated pathways and effects. Several approaches using cell therapies have shown potential therapeutic benefit for the treatment of CF inflammation. This review provides an overview of the immune dysfunctions in CF and current therapeutic regimens; explores the field of cell therapy as a treatment for CF inflammation; and focuses on the various cell types used, their immunomodulatory functions, and the current approaches to mitigate the inflammatory response and reduce the long-term damage for patients with CF.

AST to ALT Ratio is elevated in disseminated histoplasmosis as compared to localized pulmonary disease and other endemic mycoses.

Severe pulmonary or disseminated histoplasmosis often necessitates presumptive antifungal treatment while awaiting definitive diagnosis. Histoplasma antigen assays have improved sensitivity but results may lag up to 7 days. In order to increase diagnostic certainty, "soft clues" may be looked for in laboratory and radiologic data, such as elevated alkaline phosphatase or ferritin levels and findings of mediastinal adenopathy or hepatosplenomegaly. To determine if elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is specific to histoplasmosis or a non-specific marker for disseminated fungal infection or sepsis in general, we retrospectively examined records of all patients diagnosed with an endemic fungal infection (EFI) at Rush University Medical Center from January of 1997 to October of 2012, and a cohort of septic patients with elevated liver enzymes. We identified 90 cases of EFIs during the study period that met all inclusion criteria (Histoplasma 21, Blastomyces 56, Coccidioides 12, Paracoccidioides 1). We also evaluated 10 control patients with bacterial sepsis. The mean ratio of AST to ALT in patients with disseminated histoplasmosis was 2.69 (95% CI:1.22, 4.16) while for other EFIs, the mean ratio ranged from 0.38 to 1.14 with disseminated coccidioidomycosis and blastomycosis respectively (P < 0.0001). The ratio in patients with bacterial sepsis was 0.84. We propose the use of the AST/ALT ratio as a clinical "soft clue" suggestive of disseminated histoplasmosis in the appropriate host, and to possibly distinguish cross reactivity of the Histoplasma antigen assay with other EFIs.