Spontaneous Hemoptysis in a Patient With COVID-19.

CASE PRESENTATION: A 65-year-old man presented with shortness of breath, gradually worsening for the previous 2 weeks, associated with dry cough, sore throat, and diarrhea. He denied fever, chills, chest pain, abdominal pain, nausea, or vomiting. He did not have any sick contacts or travel history outside of Michigan. His medical history included hypertension, diabetes mellitus, chronic kidney disease, morbid obesity, paroxysmal atrial fibrillation, and tobacco use. He was taking amiodarone, carvedilol, furosemide, pregabalin, and insulin. The patient appeared to be in mild respiratory distress. He was afebrile and had saturation at 93% on 3 L of oxygen, heart rate of 105 beats/min, BP of 145/99 mm Hg, and respiratory rate of 18 breaths/min. On auscultation, there were crackles on bilateral lung bases and chronic bilateral leg swelling with hyperpigmented changes. His WBC count was 6.0 K/cumm (3.5 to 10.6 K/cumm) with absolute lymphocyte count 0.7 K/cumm (1.0 to 3.8 K/cumm); serum creatinine was 2.81 mg/dL (0.7 to 1.3 mg/dL). He had elevated inflammatory markers (serum ferritin, C-reactive protein, lactate dehydrogenase, D-dimer, and creatinine phosphokinase). Chest radiography showed bilateral pulmonary opacities that were suggestive of multifocal pneumonia (Fig 1). Nasopharyngeal swab for SARS-CoV-2 was positive. Therapy was started with ceftriaxone, doxycycline, hydroxychloroquine, and methylprednisolone 1 mg/kg IV for 3 days. By day 3 of hospitalization, he required endotracheal intubation, vasopressor support, and continuous renal replacement. Blood cultures were negative; respiratory cultures revealed only normal oral flora, so antibiotic therapy was discontinued. On day 10, WBC count increased to 28 K/cumm, and chest radiography showed persistent bilateral opacities with left lower lobe consolidation. Repeat respiratory cultures grew Pseudomonas aeruginosa (Table 1). Antibiotic therapy with IV meropenem was started. His condition steadily improved; eventually by day 20, he was off vasopressors and was extubated. However, on day 23, he experienced significant hemoptysis that required reintubation and vasopressor support.

Invasive aspergillosis in critically ill patients: Review of definitions and diagnostic approaches.

Invasive aspergillosis (IA) is an increasingly recognised phenomenon in critically ill patients in the intensive care unit, including in patients with severe influenza and severe coronavirus disease 2019 (COVID-19) infection. To date, there are no consensus criteria on how to define IA in the ICU population, although several criteria are used, including the AspICU criteria and new consensus criteria to categorise COVID-19-associated pulmonary aspergillosis (CAPA). In this review, we describe the epidemiology of IA in critically ill patients, most common definitions used to define IA in this population, and most common clinical specimens obtained for establishing a mycological diagnosis of IA in the critically ill. We also review the most common diagnostic tests used to diagnose IA in this population, and lastly discuss the most common clinical presentation and imaging findings of IA in the critically ill and discuss areas of further needed investigation.

Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes.

Asthma is a common disease in paediatrics and adults with a significant morbidity, mortality, and financial burden worldwide. Asthma is now recognized as a heterogeneous disease and emerging clinical and laboratory research has elucidated understanding of asthma's underlying immunology. The future of asthma is classifying asthma by endotype through connecting discernible characteristics with immunological mechanisms. This comprehensive review of the immunology of asthma details the currently known pathophysiology and clinical practice biomarkers in addition to forefront biologic and targeted therapies for all of the asthma endotypes. By understanding the immunology of asthma, practitioners will be able to diagnose patients by asthma endotype and provide personalized, biomarker-driven treatments to effectively control patients' asthma.

Epidemiology of invasive pulmonary aspergillosis in patients with liver failure: Clinical presentation, risk factors, and outcomes.

Objective Invasive pulmonary aspergillosis (IPA) is a severe and often lethal infection. The possible risk factors, clinical presentation, and treatment of patients with simultaneous liver failure and IPA have received little attention in previous studies. The aim of this study was to investigate the epidemiology of IPA in patients with liver failure in an effort to reduce patient mortality. Methods The patients with liver failure (including acute liver failure , sub-acute liver failure , acute-on-chronic liver failure and chronic liver failure) were recruited from 2011 to 2016. The clinical data of these patients were retrieved for the study. Results In total, 1077 patients with liver failure were included in this study. Of the 1077 patients, 53 (4.9%) had IPA. Forty-four (83%) patients with IPA died. Independent risk factors for IPA were male sex (hazard ratio [HR] = 2.542), hepatorenal syndrome (HR = 2.463), antibiotic use (HR = 4.631), and steroid exposure (HR = 18.615). Conclusions IPA is a fatal complication in patients with liver failure. Male sex, hepatorenal syndrome, antibiotic use, and steroid exposure were independent risk factors for IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be cautious about the possibility of IPA.

Profiling of volatile organic compounds produced by clinical Aspergillus isolates using gas chromatography-mass spectrometry.

Volatile organic compounds (VOCs) in exhaled breath may identify the presence of invasive pulmonary aspergillosis. We aimed to detect VOC profiles emitted by in vitro cultured, clinical Aspergillus isolates using gas chromatography-mass spectrometry (GC-MS). Three clinical Aspergillus isolates and a reference strain were cultured while conidiation was prevented. Headspace samples were analyzed using a standardized method. Breath samples of patients from which the cultures were obtained were checked for the presence of the VOCs found in vitro. Each Aspergillus isolate produced a distinct VOC profile. These profiles could not be confirmed in exhaled breath in vivo.

Invasive Aspergillosis After Kidney Transplant-Treatment Approach.

AIM: Aim of the article was to present a case of post transplantation invasive aspergillosis, successfully treated with conservative and surgical treatment. CASE REPORT: Patient, male, 44 years old, with second kidney transplant, required special preparation therapy, because he was sensitized, with concentration of Panel Reactive Antibody (PRA) class I 11% and PRA class II 76%. On the day of transplantation, induction was done with anti-thymocyte globulin (ATG) and glucocorticosteroids. After transplantation, plasmapheresis with ATG was performed. On the fourth day patient was anuric. Fine-needle biopsy of the graft was performed and showed positive CD4 antibodies for peritubular capillaries and humoral rejection. 14 plasmaphereses through 14 days, were negative and ATG treatment was suspended completely. Full therapeutic dosage of tacrolimus and mycophenolate mofetil were given during treatment. Four days after treatment patient was stable, but next day clinical status had worsened with dyspnea and fever. In sputum, spores of Aspergillus species were microscopically found, and radiologically by computerised tomography. Caspofungin was administered for seven days. Voriconazole therapy was given for first ten days by intravenous route and after then orally. Even with this treatment, there was no improvement in clinical picture, while CT scan of the lungs showed abscess collection in right lung. Lobectomy was performed and pus collection was found. After graft-nephroctomy, patient was treated with continous veno-venous hemodiafiltration (CV-VHDF) dialyses, with constant voriconazole therapy for the next three months (200mg two times per day). After one month of diagnosis, Galactomannan (GM) test was negative. CONCLUSION: Although highly sensitized patients, those who are on hemodialysis, in preparation for transplantation, receive intensive immunosuppressive therapy that suppress the immune system. Occurrence of secondary fungal infections especially infection by aspergillosis, is cause of high mortality of infected. Application GM test that detects existence of antibodies against Aspergillus antigens and usage of different type of immunosuppressive preparation can increase longevity of graft and patients in solid organ transplantation program. Aspergillosis is treated with voriconazole and surgery, and sometimes graft-nephrectomy if needed. Recommendation is that in all immunocompromised hosts and organ transplant recipient should have been tested with GM test.

Successful long-term extracorporeal membrane oxygenation for invasive pulmonary aspergillosis: a case report.

BACKGROUND: Extracorporeal membrane oxygenation is an established life-saving procedure for severe acute respiratory failure due to various causes. In general, the duration of extracorporeal membrane oxygenation ranges from 1 to 2 weeks, with withdrawal recommended if no improvement is noted. We report a successful case of long-term extracorporeal membrane oxygenation management for respiratory failure due to invasive pulmonary Aspergillus infection. CASE PRESENTATION: A 64-year-old Asian man with no previous underlying medical conditions was transferred to our hospital for fever and dyspnea. On admission, he presented with bilateral diffuse infiltration shadow on X-ray and chest computed tomography readings, and severe hypoxemia with a partial pressure of oxygen in arterial blood/fraction of inspired oxygen ratio of 55. He was intubated and underwent mechanical ventilation. A bronchial-alveolar lavage was performed prior to administration of antibiotics, and as the bacterial culture was positive for Aspergillus fumigatus, antifungal treatment was then initiated. His respiratory status deteriorated on the 11th admission day, with no improvement on any mechanical ventilator settings. Venous-venous extracorporeal membrane oxygenation was introduced. Extracorporeal membrane oxygenation was used for an extended period of time, with respiratory improvement delayed until the 39th admission day. Extracorporeal membrane oxygenation discontinuation was possible on the 44th day, and he was removed from the ventilator on the 64th day. CONCLUSIONS: Long-term extracorporeal membrane oxygenation might be considered if the primary causes of respiratory failure necessitating extracorporeal membrane oxygenation can be expected to be resolved, such as in the case of effective antimicrobial therapy for a definite pathogen. Our case indicates that extracorporeal membrane oxygenation can be used during treatment of respiratory failure due to invasive aspergillosis for the recommended treatment duration of 4 to 8 weeks.

Treatment of Cyclosporin A retains host defense against invasive pulmonary aspergillosis in a non-immunosuppressive murine model by preserving the myeloid cell population.

Cyclosporin A (CsA) is widely used as an immunosuppressive agent for organ transplant recipients. CsA inhibits calcineurin, which is highly conserved in mammals and fungi, and thus affects both types of organism. In mammals, the immunosuppressive effect of CsA is via hampering T cell activation. In fungi, the growth inhibitory effect of CsA is via interference with hyphal growth. The aim of this study was to determine whether CsA renders mice susceptible to invasive pulmonary aspergillosis (IPA) and whether it can protect immunosuppressed mice from infection. We therefore examined both the antifungal and the immunosuppressive activity of CsA in immunosuppressed and in immunocompetent mice infected with Aspergillus fumigatus to model IPA. We found that daily injections of CsA could not produce an antifungal effect sufficient to rescue immunosuppressed mice from lethal IPA. However, a 100% survival rate was obtained in non-immunosuppressed mice receiving daily CsA, indicating that CsA did not render the mice vulnerable to IPA. The lymphocyte subset was significantly suppressed by CsA, while the myeloid subset was not. Therefore, we speculate that CsA does not impair the host defense against IPA since the myeloid cells are preserved.

Caspofungin Increases Fungal Chitin and Eosinophil and γδ T Cell-Dependent Pathology in Invasive Aspergillosis.

The polysaccharide-rich fungal cell wall provides pathogen-specific targets for antifungal therapy and distinct molecular patterns that stimulate protective or detrimental host immunity. The echinocandin antifungal caspofungin inhibits synthesis of cell wall ß-1,3-glucan and is used for prophylactic therapy in immune-suppressed individuals. However, breakthrough infections with fungal pathogen Aspergillus fumigatus are associated with caspofungin prophylaxis. In this study, we report in vitro and in vivo increases in fungal surface chitin in A. fumigatus induced by caspofungin that was associated with airway eosinophil recruitment in neutropenic mice with invasive pulmonary aspergillosis (IA). More importantly, caspofungin treatment of mice with IA resulted in a pattern of increased fungal burden and severity of disease that was reversed in eosinophil-deficient mice. Additionally, the eosinophil granule proteins major basic protein and eosinophil peroxidase were more frequently detected in the bronchoalveolar lavage fluid of lung transplant patients diagnosed with IA that received caspofungin therapy when compared with azole-treated patients. Eosinophil recruitment and inhibition of fungal clearance in caspofungin-treated mice with IA required RAG1 expression and γδ T cells. These results identify an eosinophil-mediated mechanism for paradoxical caspofungin activity and support the future investigation of the potential of eosinophil or fungal chitin-targeted inhibition in the treatment of IA.

Is Bulpa criteria suitable for the diagnosis of probable invasive pulmonary Aspergillosis in critically ill patients with chronic obstructive pulmonary disease? A comparative study with EORTC/ MSG and ICU criteria.

BACKGROUND: Three diagnostic criteria have been proposed used for invasive pulmonary aspergillosis (IPA) diagnosis, namely EORTC/ MSG criteria, Bulpa criteria and intensive care unit (ICU) criteria. The Bulpa criteria were proposed to diagnose IPA in chronic obstructive pulmonary disease (COPD) patients specially. Our aim is to verify that whether the Bulpa criteria are the most suitable for diagnosing probable IPA in critically ill COPD patients compared with the other two criteria. METHODS: We included critically ill COPD patients admitted to the ICU from April 2006 to August 2013. Patients were classified into four populations: population one (n1 = 59) comprised all included patients; population two (n2 = 24) comprised patients with positive mycological findings (both positive cultures and positive serologic tests); population three (n3 = 18) comprised patients with positive lower respiratory tracts (LRTs) isolation; and population four (n4 = 5) comprised proven IPA patients with histopathology. Patients in four groups were diagnosed as probable IPA using three criteria respectively, and the "diagnostic rate" of each criteria were compared with each other. Then, the reasons for differences in "diagnostic rate" were analyzed in population two. Finally, the modified Bulpa criteria were proposed. RESULTS: Bulpa criteria yielded the highest "diagnostic rate" of probable IPA followed by the ICU criteria, while the EORTC/ MSG criteria provided the lowest rates in four populations (the "diagnostic rate" of probable IPA was 33.9%, 16.9% and 6.8% in population one, p = 0.001; 83.3%, 41.7% and 16.7% in population two, p < 0.001; 100%, 55.6% and 22.2% in population three, p < 0.001; 100%, 60% and 20% in population four, p = 0.036). The reasons for the highest "diagnostic rate" by Bulpa criteria were its less strict requirements regarding the doses/courses of steroid use and typical computed tomography (CT) findings. Finally, the modified Bulpa criteria for probable IPA were proposed for critically ill COPD patients admitted to ICU, mainly involving revised interpretations of microbiological findings. CONCLUSIONS: Among the existing three criteria, the Bulpa criteria are the most suitable for diagnosing probable IPA in critically ill COPD patients admitted to ICU. A modified criteria maybe proposed for better diagnosis,and its clinical validity need to be verified in future studies.

Invasive Aspergillus Pseudomembranous and Obstructive Tracheo-bronchitis in an Immuno-competent Patient.

A 19 year female, presented with life threatening haemoptysis and cough with minimum expectoration for 3 months. Bronchoscopy showed multiple nodules in airway. The direct microscopy and culture of sputum revealed fungal elements and Aspergillus flavus respectively. Serum Galactomannan was positive. Thus diagnosis of invasive aspergillus tracheo-bronchitis made. She responded to voriconazole. Aspergillus tracheo-bronchitis is a rare form of invasive pulmonary aspergillosis in immuno-competent host. Aspergillus spp in respiratory samples should not be routinely discarded as colonization.

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies.

Invasive aspergillosis is a life-threatening infection caused by the opportunistic filamentous fungus Aspergillus fumigatus. Patients undergoing haematopoietic stem cell transplant (HSCT) for the treatment of hematological malignancy are at particularly high risk of developing this fatal infection. The susceptibility of HSCT patients to infection with A. fumigatus is a consequence of a complex interplay of both fungal and host factors. Here we review our understanding of the host-pathogen interactions underlying the susceptibility of the immunocompromised host to infection with A. fumigatus with a focus on the experimental validation of fungal and host factors relevant to HSCT patients. These include fungal factors such as secondary metabolites, cell wall constituents, and metabolic adaptations that facilitate immune evasion and survival within the host microenvironment, as well as the innate and adaptive immune responses involved in host defense against A. fumigatus.

A 68-Year-Old Musician With Cough, Wheezing, and a Lung Mass.

A 68-year-old man was referred to the pulmonary clinic for evaluation of cough and a 5-cm right upper lobe mass. He was in his usual state of health until 1 year prior when he developed intermittent cough, wheezing, and sinus congestion. He denied any sputum production or hemoptysis. He also denied any fevers, chills, or weight loss. He had received various treatments within the prior 6 months, including short courses of oral prednisone, levofloxacin, and bronchodilators, without any relief of his symptoms.

Cavitating lung disease due to concomitant drug resistant tuberculosis and invasive pulmonary Aspergillosis in a post-partum patient: A case report.

Many disorders can present as cavitating lesions in the lung. In this case report, a case of mixed infection with drug resistant tuberculosis and invasive pulmonary aspergillosis in a post-partum patient has been presented.

Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant.

RATIONALE: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers. OBJECTIVES: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing. METHODS: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover. MEASUREMENTS AND MAIN RESULTS: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tract microbial richness and diversity. Fungal populations were typically dominated by Candida in both sites or by Aspergillus in BAL but not OW. 16S outlier analysis identified lung-enriched taxa indicating bacteria replicating in the lower respiratory tract. In some cases this confirmed respiratory cultures but in others revealed enrichment by anaerobic organisms or mixed outgrowth of upper respiratory flora and provided quantitative data on relative abundances of bacteria found by culture. CONCLUSIONS: Respiratory tract microbial communities in lung transplant recipients differ in structure and composition from healthy subjects. Outlier analysis can identify specific bacteria replicating in lung. These findings provide novel approaches to address the relationship between microbial communities and transplant outcome and aid in assessing lung infections.

Manipulation of host angioneogenesis: A critical link for understanding the pathogenesis of invasive mold infections?

Despite progress over the last decade, opportunistic mold infections continue to be associated with high rates of morbidity and mortality in immunocompromised patients. Given the propensity of molds to invade blood vessels, vasculopathy may be a barrier to effective delivery of antifungal drugs to infected tissue. In a recent study (Ben-Ami R et al. Blood, 2009), we found that A. fumigatus suppresses endothelial cell migration, differentiation and capillary tube formation both in vitro and in an animal model system. This effect is mediated by secreted secondary metabolites such as gliotoxin. Herein, I discuss the potential implications of how invasive molds modulate host angiogenesis in experimental and clinical mold infections. Strategies that employ reversal of vasculopathy, neutralization of metabolites that inhibit endothelial function, exploration of pro-angiogenic factors as diagnostic or prognostic markers affected patients will likely be the focus of future studies. This complex, yet emerging field might add another level of knowledge and therapeutic choices in the management of these devastated infections.

Clinical and radiological features of invasive pulmonary aspergillosis in transplant recipients and neutropenic patients.

Invasive pulmonary aspergillosis (IPA) is an important cause of mortality in transplant recipients and in patients with neutropenia. Although IPA has been studied extensively in neutropenic patients, there are limited data on IPA in recipients of solid organ transplants (SOTs). We compared the clinical features and radiologic findings of 27 SOT recipients with IPA with those of 35 neutropenic patients with IPA. The SOT recipients were more likely than neutropenic patients to show peribronchial consolidation (31% vs. 7%; P=0.03) or ground-glass opacity (38% vs. 7%; P=0.007) and less likely to have fever (22% vs. 80%; P<0.001), macro-nodules (35% vs. 67%; P=0.02), mass-like consolidation (27% vs. 67%; P=0.004), halo signs (8% vs. 56%; P<0.001), or air-crescent signs (0% vs. 22%; P=0.01).

Aspergillus and the paediatric lung.

Aspergillus spp produce a wide range of saprophytic and invasive syndromes in the lungs, including allergic bronchopulmonary aspergillosis (ABPA), aspergilloma and invasive pulmonary aspergillosis (IPA). ABPA results from hypersensitivity to the fungus, and mainly affects patients with asthma or cystic fibrosis (CF). The treatment of choice consists of systemic corticosteroids and itraconazole. Aspergilloma is managed by observation or surgery. IPA is predominantly seen in patients with haematological malignancies, chronic granulomatous disease or immunosuppressive treatment. With the use of aggressive therapies for end-stage CF, such as heart-lung transplantation, the potential for a patient to convert from colonization or ABPA to IPA has increased. Suggestive clinical and radiological findings, supplemented with mycological data using serology and molecular biology, have enhanced the capacity to diagnose IPA in paediatric patients. While voriconazole is considered the first-line therapy in IPA, several other antifungal agents may be appropriate alternatives.