Examining Miliary Disease Etiology in a Coccidioides-Endemic Center: A Retrospective Cohort Study.

Background: A miliary pattern on chest imaging is often attributed to tuberculosis (TB) infection. However, a myriad of conditions can cause a miliary pattern, many of which are imminently life-threatening. Research Question: The primary aim of our study is to elucidate the potential causes of miliary chest imaging patterns to improve workup and empiric therapy selection. The secondary aims are to discern the predictors of miliary disease etiology and to determine whether appropriate empiric antimicrobial therapies were given. Study Design and Methods: In this retrospective cohort study, we searched a radiology database for patients with chest imaging studies described by the word "miliary". Subjects were excluded if they were under 18 years of age and if there were insufficient objective data to support a miliary disease etiology. A radiologist independently reviewed all imaging studies, and studies that did not appear to have a true miliary pattern were excluded. The collected data include patient demographics, immunocompromising risk factors, conditions associated with miliary disease, ß-D-glucan levels, serum eosinophil count, and empiric therapies received. Results: From our 41-patient cohort, 22 patients (53.7%) were clinically diagnosed with coccidioidomycosis, 8 (19.5%) with TB, 7 (17.1%) with metastatic solid cancer, 1 (2.4%) with lymphoma, 1 (2.4%) with other (Mycobacterium simiae), and 3 (7.3%) with unknown diseases (the sum equals 42 patients because one individual was diagnosed with both coccidioidomycosis and TB). All six patients with greater than 500 eosinophils/µL were diagnosed with coccidioidomycosis. Of the 22 patients diagnosed with coccidioidomycosis, 20 (90.91%) were empirically treated with an antifungal regimen. Of the eight patients with TB, six were empirically treated for TB. Interpretation: Based on our data from a Coccidioides-endemic region with close proximity to tuberculosis-endemic areas, the leading cause of miliary disease is coccidioidomycosis, although TB and cancer are also common etiologies. Serum eosinophilia and elevated ß-D-glucan levels were strongly predictive of coccidioidomycosis in our patient cohort with a miliary chest imaging pattern.

Outcomes of Venovenous Extracorporeal Membrane Oxygenation in Viral Acute Respiratory Distress Syndrome.

Our study assessed the relationship between the duration of venovenous extracorporeal membrane oxygenation (V-V ECMO) and patient outcomes. We studied patients undergoing V-V ECMO support for acute respiratory distress syndrome (ARDS) between 2009 and 2017 who were reported to the Extracorporeal Life Support Organization registry. We evaluated survival, major bleeding, renal failure, pulmonary complications, mechanical complications, neurologic complications, infection, and duration of V-V ECMO support. Multivariable regression modeling assessed risk factors for adverse events. Of the 4,636 patients studied, the mean support duration was 12.2 ± 13.7 days. There was a progressive increase in survival after the initiation of V-VECMO, peaking at a survival rate of 73% at 10 days of support. However, a single-day increase in V-V ECMO duration was associated with increased bleeding events (odds ratio [OR] 1.038; 95% confidence interval [CI]: 1.029-1.047; p < 0.0001), renal failure (OR 1.018; 95% CI: 1.010-1.027; p < 0.0001), mechanical complications (OR 1.065; 95% CI: 1.053-1.076; p < 0.0001), pulmonary complications (OR 1.04; 95% CI: 1.03-1.05; p < 0.0001), and infection (OR 1.04; 95% CI: 1.03-1.05; p < 0.0001). V-V ECMO progressively increases survival for ARDS over the first 10 days of support. Thereafter, rising complications associated with prolonged durations of support result in a progressive decline in survival.

Lung Spatial Profiling Reveals a T Cell Signature in COPD Patients with Fatal SARS-CoV-2 Infection.

People with pre-existing lung diseases such as chronic obstructive pulmonary disease (COPD) are more likely to get very sick from SARS-CoV-2 disease 2019 (COVID-19). Still, an interrogation of the immune response to COVID-19 infection, spatially throughout the lung structure, is lacking in patients with COPD. For this study, we characterized the immune microenvironment of the lung parenchyma, airways, and vessels of never- and ever-smokers with or without COPD, all of whom died of COVID-19, using spatial transcriptomic and proteomic profiling. The parenchyma, airways, and vessels of COPD patients, compared to control lungs had (1) significant enrichment for lung-resident CD45RO+ memory CD4+ T cells; (2) downregulation of genes associated with T cell antigen priming and memory T cell differentiation; and (3) higher expression of proteins associated with SARS-CoV-2 entry and primary receptor ubiquitously across the ROIs and in particular the lung parenchyma, despite similar SARS-CoV-2 structural gene expression levels. In conclusion, the lung parenchyma, airways, and vessels of COPD patients have increased T-lymphocytes with a blunted memory CD4 T cell response and a more invasive SARS-CoV-2 infection pattern and may underlie the higher death toll observed with COVID-19.

Endemic Fungi Presenting as Community-Acquired Pneumonia: A Review.

In endemic areas, dimorphic fungal infections due to Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides posadasii/immitis account for up to 30% of cases of community-acquired pneumonia. Because respiratory manifestations are often indistinguishable from common bacterial causes of pneumonia, the diagnosis of pulmonary histoplasmosis, blastomycosis, and coccidioidomycosis is often delayed and associated with antibiotics overuse. In addition to being highly endemic to certain regions of North America, dimorphic fungi have global significance due to established areas of endemicity in all six inhabited continents, an increasingly interconnected world of travelers and transported goods, and a changing epidemiology as a result of global heating and anthropomorphic land utilization. In this review, we discuss the epidemiology, pathogenesis, clinical presentation, diagnostic modalities, and treatment strategies for histoplasmosis, blastomycosis, and coccidioidomycosis.

Comparison of three anti-coccidioides antibody enzyme immunoassay kits for the diagnosis of coccidioidomycosis.

Coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. Clinical presentations range from self-limited disease to severe, disseminated disease. As such, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic testing has variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from patients with coccidioidomycosis and controls were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using the MVista Coccidioides antibody detection EIA and two commonly used commercial enzyme immunoassay (EIA) kits: the IMMY Omega EIA and the Meridian Premier EIA. The sensitivity of the IgG antibody detection was 87.4% using the MVista test compared to 46.6% for IMMY and 70.9% for Meridian. The sensitivity for IgM antibody detection was 61.2% for the MVista test, 22.3% for IMMY and 29.1% for Meridian. For IgG antibody detection, specificity was 90% for the MVista EIA, 94.6% for IMMY, 96.4% for Meridian. For IgM antibody detection, specificity was 95.3% for the MVista test 98.2% for IMMY and 99.1% for Meridian. The MVista Coccidioides antibody EIA offers improved sensitivity, including among high-risk patient populations, for the detection of IgG and IgM antibodies in comparison to other currently available EIAs.

Characterization of an Uncinocarpus reesii-expressed recombinant tube precipitin antigen of Coccidioides posadasii for serodiagnosis.

Early and accurate diagnosis of coccidioidomycosis, also known as Valley fever, is critical for appropriate disease treatment and management. Current serodiagnosis is based on the detection of patient serum antibodies that react with tube precipitin (TP) and complement fixation (CF) antigens of Coccidioides. IgM is the first class of antibodies produced by hosts in response to coccidioidal insults. The highly glycosylated ß-glucosidase 2 (BGL2) is a major active component of the TP antigen that stimulates IgM antibody responses during early Coccidioides infection. The predominant IgM epitope on BGL2 is a unique 3-O-methyl-mannose moiety that is not produced by commonly used protein expression systems. We genetically engineered and expressed a recombinant BGL2 (rBGL2ur), derived from Coccidioides, in non-pathogenic Uncinocarpus reesii, a fungus phylogenetically related to the Coccidioides pathogen. The rBGL2ur protein was purified from the culture medium of transformed U. reesii by nickel affinity chromatography, and the presence of 3-O-methyl mannose was demonstrated by gas chromatography. Seroreactivity of the purified rBGL2ur protein was tested by enzyme-linked immunosorbent assays using sera from 90 patients with coccidioidomycosis and 134 control individuals. The sensitivity and specificity of the assay with rBGL2ur were 78.8% and 87.3%, respectively. These results were comparable to those obtained using a proprietary MiraVista Diagnostic (MVD) IgM (63.3% sensitivity; 96.3% specificity), but significantly better than the ID-TP assay using non-concentrated patient sera (33.3% sensitivity; 100% specificity). Expression of rBGL2ur in U. reesii retains its antigenicity for coccidioidomycosis serodiagnosis and greatly reduces biosafety concerns for antigen production, as Coccidioides spp. are biological safety level 3 agents.

Predictors of Oxygenator Exchange in Patients Receiving Extracorporeal Membrane Oxygenation.

Thrombosis within the membrane oxygenator (MO) during extracorporeal membrane oxygenation (ECMO) can lead to sudden oxygenator dysfunction with deleterious effects to the patient. The purpose of this study was to identify predictors of circuit exchange during ECMO. This is a single-center, retrospective study of all patients who received ECMO at our institution from January 2010 to December 2015. Changes in potential markers were compared on Day 3 vs. Day 0 before MO exchange. Of the 150 patients who received ECMO, there were 58 MO exchanges in 35 patients. Mean ECMO duration was 21.1 (±12.7) days. D-dimer (DD) (µg/mL) (mean difference -2.6; 95% confidence interval [CI]: -4.2 to -1.1; p = .001) increased significantly in the 3 days leading up to MO exchange, whereas fibrinogen (mg/dL) (mean difference 90.7; 95% CI: 41.8-139.6; p = .001), platelet (PLT) count (1,000/µL) (mean difference 23.3; 95% CI: 10.2-36.4; p = .001), and heparin dose (units/h) (mean difference 261.7; 95% CI: 46.3-477.1; p = .02) decreased. Increasing DD or decreasing fibrinogen, PLT count, or heparin dose may indicate an impending need for MO exchange in patients receiving ECMO. Early identification of these changes may help prevent sudden MO dysfunction.

The Association of Non-Cardiac ECMO With Influenza Incidence: A Time Series Analysis.

BACKGROUND: The 2009 H1N1 influenza epidemic saw a rise in the use of extracorporeal membrane oxygenation (ECMO) as a supportive therapy for refractory ARDS. We sought to determine whether ECMO utilization follows a seasonal pattern that matches the influenza season, and whether it can further be explained by the incidence of each influenza subtype. METHODS: We performed a longitudinal analysis of non-cardiac and cardiac-associated ECMO cases from the National In-patient Sample from 2005 to 2014, using overdispersed Poisson regression to evaluate associations with influenza incidence categorized by influenza-like illness and total positive influenza tests divided by subtype from the Centers for Disease Control and Prevention. RESULTS: Non-cardiac ECMO use was positively associated with influenza-like illness incidence in the current month (incidence risk ratio [IRR] 1.11, 95% confidence interval [CI] 1.07-1.15, P < .001) and with influenza-like illness in the previous month (IRR 1.09, 95% CI 1.05-1.14, P < .001). The 2009 H1N1 subtype had the strongest association with non-cardiac ECMO (IRR 1.19, 95% CI 1.09-1.31, P < .001). Cardiac ECMO was also positively associated with the incidence of influenza-like illness (IRR 1.05, 95% CI 1.01-1.09, P = .02). CONCLUSION: Non-cardiac and cardiac ECMO use in the United States were significantly associated with influenza incidence. The influenza A, H1N1 2009, subtype had the strongest association.

Peripheral VA-ECMO with direct biventricular decompression for refractory cardiogenic shock.

Cardiogenic shock and cardiac arrest are life-threatening emergencies that result in high mortality rates. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) via peripheral cannulation is an option for patients who do not respond to conventional therapies. Left ventricular (LV) distention is a major limitation with peripheral VA-ECMO and is thought to contribute to poor recovery and the inability to wean off VA-ECMO. We report on a novel technique that combines peripheral VA-ECMO with off-pump insertion of a trans-apical LV venting cannula and a right ventricular decompression cannula.

Diagnosis and Management of Coccidioidomycosis.

Coccidioidomycosis is a leading cause of community-acquired pneumonia within its traditional endemic zone in the Southwestern United States and portions of Mexico and Central and South America. Its incidence has increased dramatically within the endemic region; its presence outside of the region, facilitated by a mobile society, is also now substantial. Although only a fraction of the incident disease progresses beyond subclinical illness, this proportion is large in absolute terms and causes substantial disease burden. Diagnosis often depends on serologic interpretation. Treatment has been revolutionized by azole therapy. Controversy remains regarding the decision to treat in less severe disease.

Suspected Heparin-Induced Thrombocytopenia in Patients Receiving Extracorporeal Membrane Oxygenation.

Heparin-induced thrombocytopenia (HIT) is an immune reaction usually secondary to unfractionated heparin. Anticoagulation management is critical in patients while on extracorporeal membrane oxygenation (ECMO) to prevent thromboembolism and for the optimal functioning of the circuit. We identified five patients with respiratory failure at our hospital managed with ECMO in the last 2 years that were treated for HIT. A brief clinical course and their management are discussed. We also briefly review the literature for best evidence for management of such patients.

Enhanced Antibody Detection and Diagnosis of Coccidioidomycosis with the MiraVista IgG and IgM Detection Enzyme Immunoassay.

Coccidioidomycosis is a common cause of community-acquired pneumonia in areas of the southwestern United States in which the disease is endemic. Clinical presentations range from self-limited disease to severe disseminated disease. Therefore, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic tests have variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from 103 cases of coccidioidomycosis and 373 controls were tested for IgG and IgM antibodies using the MVista anti-Coccidioides antibody enzyme immunoassay. Serum specimens from 170 controls from areas in which the disease is endemic and 44 cases were tested by immunodiffusion at MiraVista Diagnostics. The sensitivity of the MVista antibody assay was 88.3%, and the specificity was 90%. The sensitivity was maintained in the presence of immunocompromising conditions or immunosuppressive therapies. The sensitivity of immunodiffusion was 60.2%, and the specificity was 98.8%. The sensitivity of complement fixation (62 cases) was 66.1%, but the specificity could not be determined. The MVista anti-Coccidioides antibody enzyme immunoassay offers improved sensitivity, compared with immunodiffusion and complement fixation, is not impaired in immunocompromised patients, and permits highly reproducible semiquantification.

Top Questions in the Diagnosis and Treatment of Coccidioidomycosis.

Revised and greatly expanded treatment guidelines for coccidioidomycosis were published last year by the Infectious Diseases Society of America. We have selected 4 questions that commonly arise in the management of patients suspected of this disease and for which there remain divided opinions.

The impact of a comprehensive airway management training program for pulmonary and critical care medicine fellows. A three-year experience.

RATIONALE: Airway management in the intensive care unit (ICU) is challenging, as many patients have limited physiologic reserve and are at risk for clinical deterioration if the airway is not quickly secured. In academic medical centers, ICU intubations are often performed by trainees, making airway management education paramount for pulmonary and critical care trainees. OBJECTIVES: To improve airway management education for our trainees, we developed a comprehensive training program including an 11-month simulation-based curriculum. The curriculum emphasizes recognition of and preparation for potentially difficult intubations and procedural skills to maximize patient safety and increase the likelihood of first-attempt success. METHODS: Training is provided in small group sessions twice monthly using a high-fidelity simulation program under the guidance of a core group of two to three advanced providers. The curriculum is designed with progressively more difficult scenarios requiring critical planning and execution of airway management by the trainees. Trainees consider patient position, preoxygenation, optimization of hemodynamics, choice of induction agents, selection of appropriate devices for the scenario, anticipation of difficulties, back-up plans, and immediate postintubation management. Clinical performance is monitored through a continuous quality improvement program. MEASUREMENTS AND MAIN RESULTS: Sixteen fellows have completed the program since July 1, 2013. In the 18 months since the start of the curriculum (July 1, 2013-December 31, 2014), first-attempt success has improved from 74% (358/487) to 82% (305/374) compared with the 18 months before implementation (P = 0.006). During that time there were no serious complications related to airway management. Desaturation rates decreased from 26 to 17% (P = 0.002). Other complication rates are low, including aspiration (2.1%), esophageal intubation (2.7%), dental trauma (0.8%), and hypotension (8.3%). First-attempt success in a 6-month period after implementation (July 1, 2014-December 31, 2014) was significantly higher (82.1 compared with 70.9%, P = 0.03) than during a similar 6-month period before implementation (July 1, 2012-December 31, 2012). CONCLUSIONS: This comprehensive airway curriculum is associated with improved first-attempt success rate for intensive care unit intubations. Such a curriculum holds the potential to improve patient care.

Positive (1-3) B-d-glucan and cross reactivity of fungal assays in coccidioidomycosis.

Fungal antigen testing in immunosuppressed patients has emerged as a powerful diagnostic tool. Some assays are relatively nonspecific, and misinterpretation can have severe clinical consequences. Additionally, when new assays become commercially available it is important to evaluate the potential for cross reactivity. We recently observed several immunosuppressed patients with positive (1→3)-ß-D-glucan (BG) who were eventually diagnosed with coccidioidomycosis in the endemic area of Tucson, Arizona. Although the BG assay is known to detect glucans of many fungal pathogens, reports of cross-reactivity with Coccidioides remain sparsely reported. To test the cross-reactivity of fungal antigens in detection assays, serum samples from patients with coccidioidomycosis testing positive for Coccidioides antigen were evaluated for BG. Of 12 samples positive for Coccidioides antigen (≥0.07 ng/ml), 11 (92%) were positive by BG (>80 pg/ml), and of 11 positive for Aspergillus galactomannan, 10 (91%) were positive by BG (>80 pg/ml). We conclude that the BG assay is nonspecific, detecting glucans from many fungal pathogens, including Coccidioides. In the endemic area, a positive BG warrants further specific testing.

Update on the diagnosis of pulmonary coccidioidomycosis.

Coccidioidomycosis is a common cause of community-acquired pneumonia in the southwest United States, Mexico, and South America. The disease has seen a marked increase in incidence in the western United States in the last decade and can be acquired by individuals who travel even briefly through an endemic area, presenting a diagnostic dilemma for clinicians who are not familiar with the disease. The clinical and radiographic manifestations of pulmonary coccidioidomycosis often mimic those of other causes of pneumonia. However, because treatment recommendations and the potential for chronic sequelae of acute infection differ substantially from those for bacterial community-acquired pneumonia, accurate, timely diagnosis of coccidioidomycosis is paramount. A number of diagnostic tests are available with varying sensitivity and specificity, making the approach complex. Radiographic features, although nonspecific, sometimes demonstrate patterns more suggestive of coccidioidomycosis than bacterial community-acquired pneumonias. A routine blood count may reveal eosinophilia. Serologic testing is used most widely but may be negative early in the course of disease, potentially leading to misdiagnosis with subsequent inappropriate treatment and follow-up. The sensitivity of serologic testing is lower in immunocompromised patients, a population at the highest risk for developing severe disease. When clinically appropriate, other biologic specimens, such as sputum, bronchoalveolar lavage fluid, or lung biopsies, may allow for rapid, definitive diagnosis. In light of the significantly increased incidence and complexities in diagnosis of coccidioidomycosis, we examine the diagnostic approach and provide examples of classic clinical and radiographic presentations, discuss the utility of serologic testing, and suggest algorithms that may aid in the diagnosis.

Sleep and non-invasive ventilation in patients with chronic respiratory insufficiency.

OBJECTIVE: Noninvasive ventilation with pressure support (NIV-PS) therapy can augment ventilation; however, such therapy is fixed and may not adapt to varied patient needs. We tested the hypothesis that in patients with chronic respiratory insufficiency, a newer mode of ventilation [averaged volume assured pressure support (AVAPS)] and lateral decubitus position were associated with better sleep efficiency than NIV-PS and supine position. Our secondary aim was to assess the effect of mode of ventilation, body position, and sleep-wakefulness state on minute ventilation (V(E)) in the same patients. DESIGN: Single-blind, randomized, cross-over, prospective study. SETTING: Academic institution. PATIENTS AND PARTICIPANTS: Twenty-eight patients. INTERVENTIONS: NIV-PS or AVAPS therapy. MEASUREMENTS AND RESULTS: Three sleep studies were performed in each patient; prescription validation night, AVAPS or NIV-PS, and crossover to alternate mode. Sleep was not different between AVAPS and NIV-PS. Supine body position was associated with worse sleep efficiency than lateral decubitus position (77.9 +/- 22.9 and 85.2 +/- 10.5%; P = 0.04). V(E) was lower during stage 2 NREM and REM sleep than during wakefulness (P < 0.0001); was lower during NIV-PS than AVAPS (P = 0.029); tended to be lower with greater body mass index (P = 0.07), but was not influenced by body position. CONCLUSIONS: In patients with chronic respiratory insufficiency, supine position was associated with worse sleep efficiency than the lateral decubitus position. AVAPS was comparable to NIV-PS therapy with regard to sleep, but statistically greater V(E) during AVAPS than NIV-PS of unclear significance was observed. V(E) was determined by sleep-wakefulness state, body mass index, and mode of therapy.