Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection.

Chronic ethanol consumption is a leading cause of mortality worldwide, with higher risks to develop pulmonary infections, including Aspergillus infections. Mechanisms underlying increased susceptibility to infections are poorly understood. Chronic ethanol consumption induced increased mortality rates, higher Aspergillus fumigatus burden and reduced neutrophil recruitment into the airways. Intravital microscopy showed decrease in leukocyte adhesion and rolling after ethanol consumption. Moreover, downregulated neutrophil activation and increased levels of serum CXCL1 in ethanol-fed mice induced internalization of CXCR2 receptor in circulating neutrophils. Bone marrow-derived neutrophils from ethanol-fed mice showed lower fungal clearance and defective reactive oxygen species production. Taken together, results showed that ethanol affects activation, recruitment, phagocytosis and killing functions of neutrophils, causing susceptibility to pulmonary A. fumigatus infection. This study establishes a new paradigm in innate immune response in chronic ethanol consumers.

Alcoholism is a chronic disease that has many damaging effects on the body. Over long periods, excessive alcohol intake weakens the immune system, putting consumers at increased risk of getting lung infections such as pneumonia. Some forms of pneumonia can be caused by the fungus Aspergillus fumigatus. This microbe does not tend to be a problem for healthy individuals, but it can be fatal for those with impaired immune systems. Here, Malacco et al. wanted to find out why excessive alcohol consumers are more prone to pneumonia. To test this, the researchers used two groups of mice that were either fed plain water or water containing ethanol. After 12 weeks, both groups were infected with Aspergillus fumigatus. The results showed that alcohol-fed mice were more susceptible to the infection caused by strong inflammation of the lungs. Normally, the immune system confronts a lung infection by activating a group of defense cells called neutrophils, which travel through the blood system to the infection site. Once in the right spot, neutrophils get to work by releasing toxins that kill the fungus. Malacco et al. discovered that after chronic alcohol consumption, neutrophils were less reactive to inflammatory signals and less likely to reach the lungs. They were also less effective in dealing with the infection. Neutrophil released fewer toxins and were thus less able to kill the microbial cells. These findings demonstrate for the first time how alcohol can affect immune cells during infection and pave the way for new possibilities to prevent fatal lung infections in excessive alcohol consumers. A next step would be to identify how alcohol acts on other processes in the body and to find a way to modulate or even revert the changes it causes.

An oral drug for chronic lymphocytic leukemia.

Ibrutinib is a new first-line drug for treating chronic lymphocytic leukemia (CLL), and could change frontline treatment of CLL from traditional IV chemotherapy to oral targeted therapy. Lymphocytosis often worsens with initiation of ibrutinib, but typically resolves over 6 to 18 months. Though patients generally tolerate ibrutinib well, the drug can cause adverse reactions including hypertension, atrial fibrillation, bleeding, and infections such as fungal pneumonia.

Histoplasmosis Following Systemic Immunomodulatory Therapy for Ocular Inflammation.

PURPOSE: Histoplasmosis is a known complication of systemic immunosuppressive therapy, particularly among patients who are receiving tumor necrosis factor α inhibitors. There are limited data on the development of disseminated or pulmonary histoplasmosis among patients who are receiving systemic immunosuppressive medication for noninfectious ocular inflammation. DESIGN: Retrospective case series. METHODS: We reviewed all patients with uveitis or scleritis who subsequently developed pulmonary or disseminated histoplasmosis at the Mayo Clinic in Rochester, Minnesota between September 1, 1994 and July 1, 2017, with a 3:1 age- and sex-matched control cohort who did not develop histoplasmosis. This was a single institutional study examining patients that developed histoplasmosis after the initiation of systemic immunomodulatory therapy (IMT). Patients had to develop either disseminated or pulmonary histoplasmosis while receiving systemic immunosuppressive therapy and have an ophthalmic examination at Mayo Clinic Rochester. The control group was comprised of patients who received systemic IMT for ocular inflammation but did not develop histoplasmosis. RESULTS: Nine cases of histoplasmosis were identified: 2 disseminated and 7 pulmonary. Both patients with disseminated histoplasmosis were taking tumor necrosis factor α inhibitors. Seven of the 9 patients received systemic antifungal medication, including both disseminated cases. Over a median follow-up of 4.4 years, none of the patients died, and there were no recurrences of histoplasmosis. When compared to the control cohort, there was no correlation between length of time on IMT and the risk of histoplasmosis. CONCLUSIONS: Ocular inflammation patients on systemic immunomodulatory therapy may develop pulmonary or disseminated histoplasmosis. Most cases require treatment with systemic antifungal medication, but it might not be necessary to stop systemic immunomodulatory medication for ocular inflammation. Ophthalmologists should be aware that patients receiving systemic immunomodulatory therapy have a higher risk of developing Histoplasma infections. Prompt diagnosis and treatment using the expertise of an infectious diseases specialist may ensure low mortality for these patients.

Brain Abscesses Due to Aspergillus nidulans Infection During Induction Chemotherapy for Acute Lymphoblastic Leukemia.

We present the case of a 3-year-old boy who was diagnosed with cerebral abscesses due to Aspergillus nidulans infection on day 28 of induction chemotherapy for acute lymphoblastic leukemia. He responded well to treatment with voriconazole and caspofungin, making a full recovery. There are very few cases of invasive aspergillosis reported in children during induction chemotherapy for acute leukemia and A. nidulans is rare in the absence of chronic granulomatous disease.

T. asahii pulmonary infection as a complication of TNF-inhibitor and steroids: posaconazole pharmacotherapy and risk analysis.

We report the first documented Trichosporon asahii infection in a patient with connective tissue disease treated with a Tumor Necrosis Factor (TNF) inhibitor and describe an institutional root cause analysis for TNF inhibitor-associated infections. Fourteen patients with incident fungal infections during TNF inhibitor treatment were identified. They were matched with uncomplicated patients receiving TNF inhibitors or with rheumatoid arthritis (RA) patients managed without TNF inhibitors. We found that patients acquiring fungal infections were more likely to have graft versus host disease (GVHD) (p<0.05). Furthermore, infected patients were more likely (OR=24.4) to have multiple immunosuppressive therapies over the controls as well as several risk factors identified by the Infectious Disease Society ofAmerica (IDSA). The 3 patient deaths in our study were associated with GVHD and infliximab. Trichosporon was isolated in 1 patient receiving adalimumab. Our results suggest that these high risk patients be monitored closely for fungal infection.

[Opportunistic co-infection in a patient with Crohn's disease during infliximab (anti-TNFalpha) therapy]. / Coinfección oportunista durante el tratamiento con infliximab (antifactor de necrosis tumoral alfa) en un paciente con enfermedad de Crohn.

BACKGROUND: The biological therapies for chronic inflammatory diseases of autoimmune origin, particularly drugs inhibiting cytokines, such as the antagonists of the tumoral necrosis factor alpha (TNFalpha), are acceptably well tolerated in patients suffering rheumatologic, dermatologic and gastrointestinal pathologies. Nevertheless, pharmacologic vigilance studies have clarified several aspects of their security in daily clinical use. The adverse effects associated with inhibitors of TNFalpha can be related to the target (or class) and to the agent. The adverse effects related to the target include those potentially attributable to the inherent immunosuppressive state due to the blockade of the main cytokine, phenomenon that could increase the susceptibility to the infections and cancer. AIMS: To expound the potential risk of serious infections, opportunistic or not, inherent to the use of biological therapies and, specifically, antagonistic drugs of TNFalpha, from the description of a case of invasive fungal infection. METHODS: Revision of clinical records, obtained from the chronic inflammatory disease of autoimmune origin patient database, candidates or recipients of the new biological therapies, and study of the microbiological isolates. RESULTS: A case of dual opportunistic infection (nocardiosis and aspergillosis) with a difficult diagnosis and complex management in an immunosupressed patient with Crohn's disease, triggered off after the administration of infliximab (monoclonal antibody anti-TNFalpha) is presented. CONCLUSIONS: Invasive fungal infections, with isolated or associated clinical presentation to other opportunistic infections, are emerging in new groups-at-risk as they are the recipients of anti-cytokine biological therapies, regulators of inflammation and immunity. They can be potentially serious in their evolution and a high index of suspicion is needed sometimes for their prompt diagnosis. Possible preventive measures in patients with a high risk of suffering them will have to be investigated.

Hospital-acquired invasive pulmonary aspergillosis in patients with hepatic failure.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a rapid, progressive, fatal disease that occurs mostly in immunocompromised patients. Patients with severe liver disease are at a heightened risk for infections. Little is known about the clinical presentation including predisposing factors and treatment of IPA in patients with hepatic failure. METHODS: Medical records of patients with hepatic failure between November 2005 and February 2007 were reviewed for lung infection. Nine medical records of definitive diagnosis of IPA and three of probable IPA were identified. RESULTS: The main predisposing factors were found to be prolonged antibiotic therapy and steroid exposure. Clinical signs and radiological findings were non-specific and atypical. Timely use of caspofungin was found to reduce the mortality due to the disease. CONCLUSION: A high index of suspicion is required for early IPA diagnosis in patients with hepatic failure.

Rapid formation of Aspergillus mycetoma in a patient receiving corticosteroid treatment. Serial radiographic observation over two months.

This study presents the case of rapidly progressing pulmonary aspergillosis in a 47-year-old woman who had healed cavitations of pulmonary tuberculosis in the right upper lobe. She had been treated for pulmonary tuberculosis seven years prior to admission. The initial manifestations of the disease on admission included cough, dyspnea, hemoptysis, pulmonary infiltrate, and renal failure. As anti-myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA) were positive, she was diagnosed with ANCA-associated vasculitis and treated with corticosteroids. This treatment resulted in remission of the vasculitis. However, she developed new pulmonary symptoms and an enlarged cavitary lesion associated with the rapid formation of a fungal, ball-shaped shadow that was serially observed by radiological analysis. Pulmonary resection was finally performed because of acute progressive respiratory failure due to massive recurrent hemoptysis. A subsequent pathological analysis revealed a mass of hyphae with acute-angle branching, features consistent with Aspergillus, within the cavitary lesion, and she was diagnosed with pulmonary aspergillosis. The rapid development of pulmonary aspergillosis associated with the formation of an Aspergillus mycetoma should be attributed to the loss of normal immune mechanisms due to immunosuppressive treatment.

[Pulmonary consequences of marijuana smoking]. / Pulmonale konsekvenser af hashrygning.

Based on previously published studies, this review describes the pulmonary consequences of marijuana smoking. Smoking of marijuana is significantly associated with chronic bronchitis (cough and phlegm), but it has not been firmly established whether it also leads to a reduction in lung function. Both epidemiological studies and case reports suggest that regular smokers of marijuana have a higher risk of developing malignancies in both the upper and lower airways. Smoking of marijuana contaminated with fungus spores has been reported to lead to pulmonary aspergillus infections in immunocompromised patients, and sharing of marijuana water pipes has been associated with transmission of tuberculosis.

Effectiveness of amphotericin B lipid complex (ABLC) treatment in allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis (IA).

A total of 85 allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis treated with amphotericin B lipid complex (ABLC) were identified from the Collaborative Exchange of Antifungal Research (CLEAR) database. Of these patients, 78% (66/85) presented with pulmonary aspergillosis. Graft-versus-host disease (GVHD) was present in 24 of 85 patients. The response rate to ABLC was 31% (26/85) overall and 21% (5/24) in patients with GVHD. The overall response rate to first-line ABLC treatment was 41% (11/27). Four of nine (44%) patients with GVHD responded to first-line treatment with ABLC, while only one of 13 (8%) responded to ABLC as second-line therapy. Five of 18 (28%) and four of 14 (29%) patients, respectively, responded to sequential or concurrent treatment with ABLC and itraconazole. None of seven patients responded who continued receiving itraconazole after the start of ABLC therapy. At the end of ABLC therapy, serum creatinine had doubled in 12% of patients (10/85), and 2% (2/85) had developed a requirement for dialysis. These data suggest that ABLC, especially when administered as first-line therapy, can result in clinical response even in the most immunocompromised patients, that is, HCT recipients with GVHD, with minimal effects on renal function.

[Diagnostic image (92). A man with fever during chemotherapy. Invasive pulmonary mycosis]. / Diagnose in beeld (92). Een man met koorts tijdens chemotherapie. Invasieve pulmonale mycose.

A 64-year-old male was treated for acute myeloid leukemia with idarubicin and cytarabin. He developed pulmonary mycosis (radiologically consistent with aspergillosis), which responded to intravenous amphotericin B.

Prior invasive pulmonary and cerebellar mucormycosis is not a primary contraindication to perform an autologous stem cell transplatation in leukemia.

Mucormycosis infections, caused by fungi of the families Rhizopus, Mucor or Absidia, are typically rapidly progressive and often fatal. We report a 27-year-old male with acute myeloid leukemia (AML) developing an invasive pulmonary-CNS mucormycosis during the neutropenic period after salvage induction chemotherapy; the infection was successfully controlled with surgery and antifungal therapy. The patient received two courses of consolidation chemotherapy and underwent autologous stem cells transplantation (ASCT) while receiving secondary antifungal systemic prophylaxis with liposomal Amphotericin B (L-AMB, Ambisome). There was no clinical, radiological or microbiological evidence of mycotic reactivation during the bone marrow transplantation (BMT) procedure.

Successful allogeneic stem cell transplant after invasive pulmonary zygomycosis.

We report the successful outcome of allogeneic stem cell transplant (SCT) in a patient with acute lymphoblastic leukaemia (ALL) and pulmonary zygomycosis diagnosed prior to transplant. The lesion was surgically excised and SCT proceeded with antifungal therapy, granulocyte transfusions and G-CSF support during the period of neutropenia.

Pulmonary toxicity syndrome following CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) chemotherapy.

We report on three patients with multiple myeloma who developed drug-induced pneumonitis 1-2(1/2) months following maintenance (post autologous transplantation) chemotherapy with CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) and 6-20 months after exposure to carmustine (BCNU) 300 mg/m(2), used in combination with melphalan 140 mg/m(2), as pre-transplant conditioning regimen. All patients had either a proven (two) or suspected (one) fungal pneumonia and were treated with liposomal amphotericin B. Dyspnea, fever and cough were the prominent clinical symptoms, while air-space disease with ground glass appearance was seen radiographically. Histologic features typical for drug-induced lung injury were detected. All patients had a dramatic, clinical and radiographic response to a brief course of corticosteroids. Although CDEP-induced pneumonitis appears to be a rare complication, its early recognition and prompt treatment, as well as its possible association with preceding fungal infection may have important clinical implications.

Chronic obstructive pulmonary disease patients with invasive pulmonary aspergillosis: benefits of intensive care?

OBJECTIVES: Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a cause of acute respiratory failure in patients with chronic obstructive pulmonary disease (COPD) treated with corticosteroids. For these patients admission in intensive care unit (ICU) is often required for life-support and mechanical ventilation. Whether this approach improves outcome is unknown. DESIGN AND SETTING: Retrospective study in a university hospital intensive care unit. PATIENTS: Between November 1993 and December 1997, 23 COPD patients were admitted in our ICU and received antifungal agents for possible IPA. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The clinical features and the outcome were reviewed. Diagnosis of IPA was classified as confirmed (positive lung tissue biopsy and/or autopsy) or probable (repeated isolation of Aspergillus from the airways with consistent clinical and radiological findings). Among the 23 patients treated for Aspergillus, 16 fulfilling these criteria for IPA were studied. Steroids had been administered at home to all patients but one and were increased during hospitalization in all. Twelve patients suffered a worsening of their bronchospasm precipitating acute respiratory failure. During ICU stay all patients required mechanical ventilation for acute respiratory failure. Although amphotericin B deoxycholate was started when IPA was suspected (0.5-1.5 mg/kg per day), all patients died in septic shock (n = 5) or in multiple-organ failure. CONCLUSIONS: The poor prognosis of intubated COPD patients with IPA, in spite of antifungal treatment suggests that further studies are required to define the limits and indications for ICU management of these patients.