Spectrum of pulmonary fungal pathogens, associated risk factors, and anti-fungal susceptibility pattern among persons with presumptive tuberculosis at Gombe, Nigeria.

Background: Pulmonary mycosis (PM) poses a great diagnostic challenge due to the lack of pathognomonic and radiological features, especially in the absence of mycology laboratory tests. This study was aimed to isolate, phenotypically identify, determine the prevalence of pulmonary fungal pathogens and antifungal susceptibility pattern of isolates of presumptive tuberculosis (PTB) patients attending Federal Teaching Hospital (FTH) Gombe, Nigeria. Methods: After ethical approval, three consecutive early morning sputa were collected from 216 participants with presumptive of PTB attending FTH Gombe, between May 2, 2017 and May 30, 2018. Samples were processed using standard mycological staining, microscopy, sugar biochemistry, and antifungal susceptibility test protocols. Sociodemographic variables and risk factors of pulmonary fungal infection were assessed through structured questionnaires. Pulmonary fungal infection was defined by the positive culture in at least two sputa. PTB was defined by Genexpert® nested polymerase chain reaction. Results: Of the 216 participants, 19.9% had PTB and 73.6% had pulmonary fungal pathogens. Among the isolated pulmonary fungal pathogens, Aspergillus fumigatus made the highest occurrence, while 6.5% had PTB-fungal co-infection. No significant association existed between the prevalence of PM with age and sex of participants (P < 0.05). Cigarette smoking (adjusted odds ratio [aOR] = 15.9 [95% confidence interval (CI): 0.9-268.8]), prolong antibiotic use (aOR = 77.9 [95% CI: 4.7-1283]) and possession of domestic pet (aOR = 77.9 [95% CI: 4.7-1283]) were significant risk factors of PM (P < 0.05). Penicillium citrinum, Mucor spp. and Aspergillus flavus are more susceptible to voriconazole, and Candida albicans was found to be more susceptible to Nystatin. Of the 159 fungal isolates, 92.5% were resistant to fluconazole. Conclusion: Findings from this study revealed high level pulmonary fungal pathogens, especially among PTB patients. A majority of fungal isolates were resistant to fluconazole. It's recommended that persons should do away with or minimize risk factors for pulmonary fungal pathogens identified in this study.

Tratamiento de la discinecia ciliar primaria / Treatmen of ciliary primary discinesia

At present, there is no specific treatment for primary ciliary dyskinesia, nor controlled and randomized clinical trials to determine how the management and monitoring of these patients should be considered. The therapeutic options are extrapolated from other diseases, such as cystic fibrosis, or non-cystic fibrosis bronchiectasis. However, the implementation of specific groups of experts, both in the USA (PDC-foundation) and in Europe (BESTCILIA or BEAT-PD), are helping to increase knowledge of the disease, opening research channels and seeking new treatments. Until we have therapies capable of correcting the basic defect of the disease, the pillars of treatment are the daily cleansing of the airways and aggressive antibiotherapy against respiratory infections. Multidisciplinary care in specialized centers where pulmonary function is monitored and the infection is prevented and treated will improve, as in cystic fibrosis, the results of patients.

En la actualidad no existe un tratamiento específico para la discinesia ciliar primaria, ni se cuenta con ensayos clínicos controlados y randomizados que permitan determinar cómo debe plantearse el manejo y seguimiento de estos pacientes. Las opciones terapéuticas son extrapoladas de otras enfermedades, como la fibrosis quística, o las bronquiectasias no fibrosis quística. Sin embargo, la puesta en marcha de grupos específicos de expertos, tanto en USA (PDC-foundation) como en Europa (BESTCILIA o BEAT-PD), están permitiendo incrementar el conocimiento de la enfermedad, abriendo vías de investigación y buscando nuevos tratamientos. Hasta contar con terapias capaces de corregir el defecto básico de la enfermedad, los pilares del tratamiento son la limpieza diaria de las vías aéreas y la antibioterapia agresiva frente a las infecciones respiratorias. La atención multidisciplinar en centros especializados donde se monitorice la función pulmonar y se prevengan y traten las infecciones mejorará, como en la fibrosis quística, los resultados de los pacientes.

An Analysis of the Clinical Benefit of 37 Bronchoalveolar Lavage Procedures in Patients with Hematologic Disease and Pulmonary Complications.

Objective Since pulmonary complications are a major cause of mortality in patients with hematologic diseases, their rapid detection and treatment are essential. Bronchoalveolar lavage (BAL) is widely performed to diagnose pulmonary infiltrates not evident with non-invasive investigations; however, reports on its clinical benefits for patients with hematologic diseases are limited. The aim of our study was to investigate the utility of diagnostic bronchoscopy with BAL for those patients. Methods We retrospectively reviewed the clinical records of 37 consecutive BAL procedures in 33 adult patients with hematological diseases and pulmonary infiltrates with at least 6 months of follow-up between August 2013 and September 2017 (total 747 BAL procedures). The BAL results, ensuing treatment modifications, treatment outcomes, survival times, and adverse events were evaluated. Results Microbiological findings were detected in 11 (29.7%), even though wide-spectrum antibiotics and antifungal drugs had been empirically administered to most patients (>70%) prior to the bronchoscopy procedure. Overall, 25 of the 37 BAL procedures (67.6%) had some impact on the diagnosis of pulmonary diseases. Patients without specific diagnostic findings from BAL had a significantly poorer survival than those with diagnostic findings via BAL (30-day survival: 33.3% vs. 92.0%; 180-day survival: 8.3% vs. 64.0%). Four patients (12.1%) experienced complications associated with bronchoscopy; there were no procedure-related deaths. Conclusion BAL seems still important for diagnosing pulmonary infiltrates and/or excluding some of the important respiratory tract pathogens in patients with hematological diseases; furthermore, negative specific diagnostic findings from BAL may be associated with poor prognoses.

Pulmonary and sinus fungal diseases in non-immunocompromised patients.

The human respiratory tract is exposed daily to airborne fungi, fungal enzymes, and secondary metabolites. The endemic fungi Histoplasma capsulatum, Coccidioides spp, Blastomyces dermatitidis, and Paracoccidioides brasiliensis, and occasionally Aspergillus fumigatus, are primary pulmonary pathogens of otherwise healthy people. Such infections resolve in most people, and only a few infections lead to disease. However, many fungi are directly allergenic by colonising the respiratory tract or indirectly through contact with cell wall constituents and proteases, causing or exacerbating allergic disease. Increasing evidence implicates high indoor fungal exposures as a precipitant of asthma in children and in worsening asthma symptoms. Lung or airways infection by endemic fungi or aspergillus can be diagnosed with respiratory sample culture or serum IgG testing. Sputum, induced sputum, or bronchial specimens are all suitable specimens for detecting fungi; microscopy, fungal culture, galactomannan antigen, and aspergillus PCR are useful tests. Antifungal treatment is indicated in almost all patients with chronic cavitary pulmonary infections, chronic invasive and granulomatous rhinosinusitis, and aspergillus bronchitis. Most patients with fungal asthma benefit from antifungal therapy. Adverse reactions to oral azoles, drug interactions, and azole resistance in Aspergillus spp limit therapy. Environmental exposures, genetic factors, and structural pulmonary risk factors probably underlie disease but are poorly understood.

Caspofungin Treatment for Pulmonary Invasive Fungal Disease in Hematology Patients: A Retrospective Study in a Clinical Practice Setting in China.

PURPOSE: Invasive fungal disease (IFD) is a serious complication in patients with hematologic malignancies. Caspofungin is the first approved inhibitor of fungal ß-1,3-glucan synthesis. The aim of the present study was to evaluate the effectiveness of caspofungin in the treatment of IFD in patients with hematologic malignancies. METHODS: In this retrospective study, data from the electronic medical records of 1118 inpatients who were admitted to 10 hospitals in China between 2013 and 2014 were analyzed. Inclusion criteria were hematologic disorder and IFD diagnosed during the hospitalization, based on clinical manifestations or evidence of pulmonary invasion, as well as caspofungin treatment for at least 7 days. The primary end point was the favorable response rate at the end of caspofungin as initial therapy for proven/probable/possible pulmonary IFD. The secondary end point was the survival rate after the completion of the caspofungin treatments. FINDINGS: A total of 704 patients were included, of whom 122 had IFD classified as probable/possible and 582 had unclassified IFD. The most frequent hematologic diseases were acute myeloid leukemia (42.8%), followed by acute lymphatic leukemia (18.8%), non-Hodgkin lymphoma (8.8%), aplastic anemia (7.1%), and others (22.5%). The rates of favorable caspofungin response were 57.2% in all patients, 58.2% in the probable/possible IFD group, and 57.0% in the unclassified IFD group. Caspofungin as initial monotherapy led to a favorable response rate of 62.2% in the probable/possible IFD group. Uni- and multivariate analyses revealed that not recovering from neutropenia during antifungal treatment, and advanced age, were significant factors for unfavorable outcomes. The overall IFD-related mortality rate was 4.1%. IMPLICATIONS: The results of our study show that caspofungin treatment of IFD in hematology patients was reasonable, with an overall rate of favorable response of 57.2% with each caspofungin treatment strategy.

Pulmonary manifestations in adult patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by failure of superoxide production in phagocytic cells. The disease is characterised by recurrent infections and inflammatory events, frequently affecting the lungs. Improvement of life expectancy now allows most patients to reach adulthood. We aimed to describe the pattern of pulmonary manifestations occurring during adulthood in CGD patients. This was a retrospective study of the French national cohort of adult patients (≥16 years old) with CGD. Medical data were obtained for 67 adult patients. Pulmonary manifestations affected two-thirds of adult patients. Their incidence was significantly higher than in childhood (mean annual rate 0.22 versus 0.07, p=0.01). Infectious risk persisted despite anti-infectious prophylaxis. Invasive fungal infections were frequent (0.11 per year per patient) and asymptomatic in 37% of the cases. They often required lung biopsy for diagnosis (10 out of 30). Noninfectious respiratory events concerned 28% of adult patients, frequently associated with a concomitant fungal infection (40%). They were more frequent in patients with the X-linked form of CGD. Immune-modulator therapies were required in most cases (70%). Respiratory manifestations are major complications of CGD in adulthood. Noninfectious pulmonary manifestations are as deleterious as infectious pneumonia. A specific respiratory monitoring is necessary.

Factors predicting outcome in high risk febrile neutropenia in patients receiving intensive chemotherapy for acute sleukemia: A prospective, observational study from South India.

BACKGROUND: Outcome of febrile neutropenia (FN) in acute leukemia patients undergoing intensive chemotherapy from India is scanty. MATERIALS AND METHODS: A prospective, observational, single institutional study was conducted to evaluate the clinical features, microbiological aspects, risk factors influencing the outcome of high risk FN during intensive therapy in acute leukemia. RESULTS: Among 115 febrile episodes, though 94 (81.7%) had indwelling central venous catheter (CVC) at the time of diagnosis of FN, infective foci clinically were identified in 70.4% of episodes, with lung as the major site (25.2%) followed by CVC (17.4%). Microbiological documentation was possible in 33% (n = 40) episodes. Gram-negative bacteria isolates were 58.3% and Gram-positive isolates were 41.7% of which Pseudomonas was the predominant Gram-negative and Staphylococcus aureus was the most common Gram-positive isolate. Piperacillin-tazobactam + amikacin were used as first line antibiotic in 93% episodes and second line antibiotics were necessary in 73% episodes. Granulocyte colony stimulating factor was used in 60.9% episodes of high risk FN mostly in acute myeloid leukemia consolidation patients. Eighteen episodes (15.7%) were assigned to have invasive fungal disease. Eleven (9.6%) out of 115 high risk FN had a fatal outcome. Presence of pulmonary infection predicted for fatal outcome (P = 0.02). CONCLUSION: This study reports the outcome of high risk FN in patients with acute leukemia undergoing intensive chemotherapy. Gram-negative isolates are highly sensitive to piperacillin-tazobactum and hence in a cost restraint scenario, carbapenems needs to be judiciously used. Focus of Infection in lungs during FN predicted higher fatal outcomes.

Utility of flexible bronchoscopy in the evaluation of pulmonary infiltrates in the hematopoietic stem cell transplant population -- a single center fourteen year experience.

INTRODUCTION: Pulmonary infiltrates are common within the hematopoietic stem cell transplant (HSCT) population and unfortunately portend an increased mortality. Bronchoscopy is often utilized as an initial diagnostic tool, but the literature supporting its diagnostic utility and effect on clinical management varies significantly. The aim of this study was to investigate the diagnostic ability, complication rate, and clinical impact of flexible bronchoscopy (FB) in evaluating pulmonary infiltrates in a large HSCT population. PATIENTS AND METHOD: Retrospective review of all patients undergoing FB after HSCT in the Bone Marrow Transplant Unit from 1996 to 2009. RESULTS: FB was performed 162times in 144patients with pulmonary infiltrates yielding positive results in 52.5%. The most common positive results were bacterial pneumonia (31%), fungal pneumonia (15%), and alveolar hemorrhage (11%). Treatment changes occurred in 44% of patients after FB. Treatment changes included antibiotic modification (59%), addition of corticosteroids (21%), antifungal modification (12%), and antiviral modification (7%). The overall complication rate associated with FB was 30%, although 84% of these complications were considered minor. CONCLUSIONS: FB in patients with pulmonary infiltrates after HSCT should still be considered a valuable tool in the evaluation and management of pulmonary infiltrates in the HSCT population. Future prospective, multicenter randomized studies are needed to evaluate the overall clinical impact that bronchoscopic results and management changes have in this unique population.

How I manage pulmonary nodular lesions and nodular infiltrates in patients with hematologic malignancies or undergoing hematopoietic cell transplantation.

Pulmonary nodules and nodular infiltrates occur frequently during treatment of hematologic malignancies and after hematopoietic cell transplantation. In patients not receiving active immunosuppressive therapy, the most likely culprits are primary lung cancer, chronic infectious or inactive granulomata, or even the underlying hematologic disease itself (especially in patients with lymphoma). In patients receiving active therapy or who are otherwise highly immunosuppressed, there is a wider spectrum of etiologies with infection being most likely, especially by bacteria and fungi. Characterization of the pulmonary lesion by high-resolution CT imaging is a crucial first diagnostic step. Other noninvasive tests can often be useful, but invasive testing by bronchoscopic evaluation or acquisition of tissue by one of several biopsy techniques should be performed for those at risk for malignancy or invasive infection unless contraindicated. The choice of the optimal biopsy technique should be individualized, guided by location of the lesion, suspected etiology, skill and experience of the diagnostic team, procedural risk of complications, and patient status. Although presumptive therapy targeting the most likely etiology is justified in patients suspected of serious infection while evaluation proceeds, a structured evaluation to determine the specific etiology is recommended. Interdisciplinary teamwork is highly desirable to optimize diagnosis and therapy.

Disseminated penicilliosis in a Korean human immunodeficiency virus infected patient from Laos.

Penicillium marneffei may cause life-threatening systemic fungal infection in immune-compromised patients and it is endemic in Southeast Asia. A 39-yr-old HIV-infected male, living in Laos, presented with fever, cough, and facial vesiculopapular lesions, which had been apparent for two weeks. CT scans showed bilateral micronodules on both lungs; Pneumocystis jirovecii was identified by bronchoscopic biopsy. Despite trimethoprim-sulfamethoxazole and anti-tuberculosis medications, the lung lesions progressed and the facial lesions revealed central umbilications. Biopsy of the skin lesions confirmed disseminated penicilliosis, with the culture showing P. marneffei hyphae and spores. The P. marneffei was identified by rRNA PCR. A review of the bronchoscopic biopsy indicated penicilliosis. The patient completely recovered after being prescribed amphotericin-B and receiving antiretroviral therapy. This is the first case of penicilliosis in a Korean HIV-infected patient. It is necessary to consider P. marneffei when immunocompromised patients, with a history of visits to endemic areas, reveal respiratory disease.

Trypacidin, a spore-borne toxin from Aspergillus fumigatus, is cytotoxic to lung cells.

Inhalation of Aspergillus fumigatus conidia can cause severe aspergillosis in immunosuppressed people. A. fumigatus produces a large number of secondary metabolites, some of which are airborne by conidia and whose toxicity to the respiratory tract has not been investigated. We found that spores of A. fumigatus contain five main compounds, tryptoquivaline F, fumiquinazoline C, questin, monomethylsulochrin and trypacidin. Fractionation of culture extracts using RP-HPLC and LC-MS showed that samples containing questin, monomethylsulochrin and trypacidin were toxic to the human A549 lung cell line. These compounds were purified and their structure verified using NMR in order to compare their toxicity against A549 cells. Trypacidin was the most toxic, decreasing cell viability and triggering cell lysis, both effects occurring at an IC50 close to 7 µM. Trypacidin toxicity was also observed in the same concentration range on human bronchial epithelial cells. In the first hour of exposure, trypacidin initiates the intracellular formation of nitric oxide (NO) and hydrogen peroxide (H2O2). This oxidative stress triggers necrotic cell death in the following 24 h. The apoptosis pathway, moreover, was not involved in the cell death process as trypacidin did not induce apoptotic bodies or a decrease in mitochondrial membrane potential. This is the first time that the toxicity of trypacidin to lung cells has been reported.

Influence of oral beclomethasone dipropionate on early non-infectious pulmonary outcomes after allogeneic hematopoietic cell transplantation: results from two randomized trials.

Early non-infectious pulmonary complications represent a significant cause of mortality after hematopoietic cell transplantation (HCT). We tested the hypothesis that oral beclomethasone dipropionate (BDP) is effective for preventing early non-infectious pulmonary complications after allogeneic HCT. We retrospectively reviewed the medical records of 120 patients, 60 in each treatment arm, to identify non-infectious and infectious pulmonary events and pulmonary function test results from all patients who participated in two randomized trials of oral BDP for treatment of acute gastrointestinal GVHD. 17-Beclomethasone monopropionate (17-BMP), the active metabolite of BDP, was evaluated in blood from the right atrium in four patients. Thirty-three of 42 (79%) placebo-treated patients experienced a decrease of the DL(CO) from pretransplant to day 80 after transplant, compared with 27 of 49 (55%) BDP-treated patients (P=0.02). In the first 200 days after randomization, there were no cases of non-infectious pulmonary complications in BDP-treated patients, vs four cases among placebo-treated patients (P=0.04). Levels of 17-BMP were detected in atrial blood at steady state. Delivery of a potent glucocorticoid such as 17-BMP to the pulmonary artery after oral dosing of BDP may be useful in modulating pulmonary inflammation and preventing the development of non-infectious pulmonary complications after allogeneic HCT.

Zygomycosis in children: a systematic review and analysis of reported cases.

BACKGROUND: Zygomycosis has emerged as an increasingly important infection with a high mortality especially in immunocompromised patients. No comprehensive analysis of pediatric zygomycosis cases has been published to date. METHODS: We used a PUBMED search for English publications of pediatric (0-18 years) zygomycosis cases and references from major books as well as single case reports or case series. Individual references were reviewed for additional cases. Data were entered into Filemaker-pro database and analyzed by logistic regression analysis. RESULTS: One hundred fifty-seven cases (64% male) were found with median age 5 years (range, 0.16-13). Underlying conditions included neutropenia (18%), prematurity (17%), diabetes mellitus (15%), ketoacidosis (10%), and no apparent underlying condition (14%). The most common patterns of zygomycosis were cutaneous (27%), gastrointestinal (21%), rhinocerebral (18%), and pulmonary (16%). Among 77 culture-confirmed cases, Rhizopus spp. (44%) and Mucor spp. (15%) were most commonly identified. Of 81 patients who were given antifungal therapy, 73% received an amphotericin B formulation only. The remaining patients received mostly amphotericin B in combination with other antifungal agents. Mortality in patients without antifungal therapy was higher than in those with therapy (88% versus 36%, P < 0.0001). Ninety-two (59%) patients underwent surgery. Cerebral, gastrointestinal, disseminated and cutaneous zygomycosis were associated with mortality rates of 100, 100, 88, and 0%, respectively. Independent risk factors for death were disseminated infection (OR: 7.18; 95% CI: 3.02-36.59) and age <1 year (OR: 3.85; 95% CI: 1.05-7.43). Antifungal therapy and particularly surgery reduced risk of death by 92% (OR: 0.07; 95% CI: 0.04-0.25) and 84% (OR: 0.16; 95% CI: 0.09-0.61), respectively. CONCLUSIONS: Zygomycosis is a life-threatening infection in children with neutropenia, diabetes mellitus, and prematurity as common predisposing factors, and there is high mortality in untreated disease, disseminated infection, and age <1 year. Amphotericin B and surgery significantly improve outcome.

Pulmonary dysfunction in pediatric hematopoietic stem cell transplant patients: overview, diagnostic considerations, and infectious complications.

Pulmonary complications are among the most common and serious sequelae seen in hematopoietic stem cell transplantation (HSCT) recipients. This two-part review addresses the incidence and impact of pulmonary complications in pediatric HSCT patients. In this first part we review the available data for the use of diagnostic modalities in this population, including flexible bronchoscopy with bronchoalveolar lavage (BAL) and open lung biopsy (OLB). We also review the many infectious pulmonary complications that may occur in pediatric HSCT recipients, utilizing the traditional chronologic divisions of neutropenic phase (0-30 days following HSCT), early phase (30-100 days), and late phase (>100 days).

[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.

Aerosolised antibiotics: a critical appraisal of their use.

Aerosolised antimicrobial agents have been used in clinical practice since the 1950s. The main advantage of this route of administration is the targeted drug delivery to the site of infection in the lung. Exploitation of this targeted delivery can yield high concentrations at the site of infection/colonisation while minimising systemic toxicities. It is important to note that the ability of a drug to reach the target area in the lung effectively is dependent on a number of variables, including the nebuliser, patient technique, host anatomy and disease-specific factors. The most convincing data to support the use of aerosolised antimicrobials has been generated with tobramycin solution for inhalation (TOBI, Chiron Corp.) for maintenance treatment in patients with cystic fibrosis. In addition to cystic fibrosis, the use of aerosolised antimicrobials has also been studied for the treatment or prevention of a number of additional disease states including non-cystic fibrosis bronchiectasis, ventilator-associated pneumonia and prophylaxis against pulmonary fungal infections. Key studies evaluating the benefits and shortcomings of aerosolised antimicrobial agents in these areas are reviewed. Although the theory behind aerosolised administration of antibiotics seems to be sound, there are limited data available to support the routine use of this modality. Owing to the gaps still existing in our knowledge base regarding the routine use of aerosolised antibiotics, caution should be exercised when attempting to administer antimicrobials via this route in situations falling outside clearly established indications such as the treatment of patients with cystic fibrosis or Pneumocystis pneumonia.

Breakdown of pulmonary host defense in the immunocompromised host: cancer chemotherapy.

The number of immunocompromised patients is steadily increasing due to HIV infection, solid organ and stem cell transplantation, intensified chemotherapy, immunosuppression for autoimmune diseases, and a marked increase in the use of monoclonal antibodies. Prevention strategies for pulmonary infections and diagnostic methods have evolved and patient outcome has improved. However, therapies affecting the immune system are also given to older patients and patients with comorbidities. While the rate of pulmonary complications in HIV patients has dramatically decreased under antiretroviral therapy, we are seeing more patients with pulmonary problems after chemotherapy. Neutropenia is still the most important risk factor for bacterial and fungal infection. Flexible bronchoscopy with BAL remains an important diagnostic method with a low morbidity and high diagnostic yield in patients with pulmonary infiltrates following cancer chemotherapy.