Humans ; Adult ; Invasive Pulmonary Aspergillosis ; Pneumonia, Viral/complications* ; Risk Factors ; Pulmonary Aspergillosis/complications*

BACKGROUND: Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. METHODS: A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. RESULTS: The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. CONCLUSION Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.
Humans ; Aspergillosis, Allergic Bronchopulmonary/complications* ; Aspergillus fumigatus/genetics* ; Asthma/genetics* ; Aspergillus ; Mutation/genetics* ; CARD Signaling Adaptor Proteins/genetics*

Aspergillosis, Allergic Bronchopulmonary ; complications ; diagnosis ; Humans

Asthma ; complications ; therapy ; Humans ; Invasive Pulmonary Aspergillosis ; complications ; drug therapy ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive ; complications ; therapy

Airway Obstruction ; diagnosis ; etiology ; Aspergillosis ; complications ; diagnosis ; Humans ; Laryngeal Diseases ; complications ; diagnosis ; microbiology ; Larynx

Aspergillosis ; complications ; Aspergillus ; Chemical and Drug Induced Liver Injury ; complications ; microbiology ; Humans

BACKGROUNDCritically ill chronic obstructive pulmonary disease (COPD) patients admitted to an intensive care unit (ICU) due to respiratory failure are at particularly high risk of Aspergillus infection. The serum galactomannan index (GMI) has proven to be one of the prognostic criteria for invasive pulmonary aspergillosis (IPA) in classical immunocompromised patients. However, the prognostic value of serum GMI in critically ill COPD patients needs evaluation. The purpose of this study is to investigate the prognostic value of serum GMI in patients with severe COPD.

METHODSIn this single-center prospective cohort study, serum samples for GMI assay were collected twice a week from the first day of ICU admission to the day of the patients' discharge or death. Patients were divided into two groups according to their clinical outcome on the 28th day of their ICU admission. Univariate analysis and survival analysis were tested in these two groups.

RESULTSOne hundred and fifty-three critically ill COPD patients were included and were divided into survival group (106 cases) and non-survival group (47 cases) according to their outcome. Univariate analysis showed that the highest GMI level during the first week after admission (GMI-high 1st week) was statistically different between the two groups. Independent prognostic factors for poor outcome in severe COPD patients were: GMI-high 1st week >0.5 (RR: 4.04, 95% CI: 2.17-7.51) combined with accumulative dosage of corticosteroids >216 mg before the RICU admission (RR: 2.25, 95% CI: 1.11-4.56) and clearance of creatinine (Ccr) ≤ 64.31 ml/min (RR: 2.48, 95% CI: 1.22 ± 5.07).

CONCLUSIONSThe positive GMI-high 1st week (>0.5) combined with an accumulative dosage of corticosteroids >216 mg before the ICU admission and a low Ccr may predicate a poor outcome of critically ill COPD patients.

Aged ; Aged, 80 and over ; Critical Illness ; Female ; Humans ; Invasive Pulmonary Aspergillosis ; blood ; complications ; pathology ; Male ; Mannans ; blood ; Middle Aged ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive ; blood ; etiology ; pathology

Drug Therapy, Combination ; Echinocandins ; administration & dosage ; therapeutic use ; Humans ; Invasive Pulmonary Aspergillosis ; complications ; drug therapy ; Lipopeptides ; Liver Failure ; complications ; drug therapy ; microbiology ; Male ; Middle Aged ; Voriconazole ; administration & dosage ; therapeutic use

We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462)
14-alpha Demethylase Inhibitors/adverse effects/therapeutic use ; Adolescent ; Adult ; Aged ; Antifungal Agents/adverse effects/*therapeutic use ; Aspergillosis/complications/*drug therapy ; Candidiasis/complications/*drug therapy ; Coccidioidomycosis/complications/drug therapy ; Febrile Neutropenia/complications/drug therapy ; Female ; Hematologic Neoplasms/complications/drug therapy/*microbiology ; Humans ; Itraconazole/adverse effects/*therapeutic use ; Male ; Mannans/blood ; Middle Aged ; Prospective Studies ; Treatment Outcome ; Young Adult

A 45-year-old-male who had underlying ulcerative colitis and presented with fever and dry cough. Initially, the patient was considered to have invasive aspergillosis due to a positive galactomannan assay. He was treated with amphotericin B followed by voriconazole. Nevertheless, the patient deteriorated clinically and radiographically. The lung biopsy revealed eosinophilic pneumonia, and ELISA for Toxocara antigen was positive, leading to a diagnosis of pulmonary toxocariasis. After a 10-day treatment course with albendazole and adjunctive steroids, the patient recovered completely without any sequelae. Pulmonary toxocariasis may be considered in patients with subacute or chronic pneumonia unresponsive to antibiotic agents, particularly in cases with eosinophilia.
Albendazole/therapeutic use ; Animals ; Anthelmintics/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Antigens, Helminth/analysis ; Colitis, Ulcerative/*complications ; Diagnosis, Differential ; Enzyme-Linked Immunosorbent Assay ; Humans ; Lung/pathology ; Lung Diseases, Parasitic/*diagnosis/*pathology ; Male ; Middle Aged ; Pulmonary Aspergillosis/diagnosis/pathology ; Steroids/therapeutic use ; Toxocara/*isolation & purification ; Toxocariasis/*diagnosis/*pathology ; Treatment Outcome