Invasive Pulmonary Aspergillosis in Chronic Obstructive Pulmonary Disease Exacerbations.

Nowadays, reports in the literature support that patients with severe chronic obstructive pulmonary disease (COPD) are at higher risk to develop invasive pulmonary aspergillosis (IPA). However, the interpretation of Aspergillus-positive cultures from the airways in critically ill COPD is still a challenge. Indeed, as the patient could be merely colonized, tissue samples are required to ascertain IPA diagnosis but they are rarely obtained before death. Consequently, diagnosis is often only suspected on the basis of a combination of three elements: clinical characteristics, radiological images (mostly thoracic CT scan), and microbiological, and occasionally serological, results. To facilitate the analysis of these data, several algorithms have been developed, and the best effectiveness has been demonstrated by the Clinical algorithm. This is of importance as IPA prognosis in these patients remains presently very poor and using such an algorithm could promote prompter diagnosis, early initiation of treatment, and subsequently improved outcome.While the most classical presentation of IPA in critically ill COPD patients features a combination of obstructive respiratory failure, antibiotic-resistant pneumonia, recent or chronic corticosteroid therapy, and positive Aspergillus cultures from the lower respiratory tract, the present article will also address less typical presentations and discuss the most appropriate treatments which could alter prognosis.

Allergic bronchopulmonary aspergillosis with aspergilloma: an immunologically severe disease with poor outcome.

BACKGROUND AND AIMS: The association between allergic bronchopulmonary aspergillosis (ABPA) and aspergilloma has been proposed as a severe form of ABPA. However, this conclusion is based on single-patient case reports. In this study, we describe the clinical details and immunological findings of this association and compare patients of ABPA with aspergilloma and those without. METHODS: This is a retrospective analysis of data of patients with ABPA managed in the Chest Clinic. We compared the clinical, radiological and immunological profile of patients with ABPA and central bronchiectasis, with and without the presence of aspergilloma on HRCT scan. RESULTS: There were 98 men and 81 women with a mean (SD) age of 33.6 (12.2) years. Eight patients were diagnosed to have aspergilloma. Sputum cultures grew Aspergillus fumigatus in all these eight patients. The aspergilloma was solitary in six patients, and two each in two patients. Patients with aspergilloma had higher IgE levels (both total and A. fumigatus specific) than those without aspergilloma. Bronchiectasis was also more extensive in patients with aspergilloma. Overall, 70 % of the ABPA patients experienced relapse during the median (interquartile range) follow-up of 27 (19-39) months. The number of relapses was significantly higher in patients with aspergilloma (p = 0.0001). On a multivariate linear regression analysis, high-attenuation mucus and aspergilloma were independent predictors of relapse frequency. CONCLUSIONS: The concurrent presentation of ABPA and aspergilloma is associated with an immunologically severe disease and risk of recurrent relapses.

Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

Aspergillus spp. cultured in specimens from the airways of chronic obstructive pulmonary disease (COPD) patients are frequently considered as a contaminant. However, growing evidence suggests that severe COPD patients are at higher risk of developing invasive pulmonary aspergillosis (IPA), although IPA incidence in this population is poorly documented. Some data report that COPD is the underlying disease in 1% of patients with IPA. Definitive diagnosis of IPA in COPD patients is often difficult as tissue samples are rarely obtained before death. Diagnosis is therefore usually based on a combination of clinical features, radiological findings (mostly thoracic computed tomography scans), microbiological results and, sometimes, serological information. Of 56 patients with IPA reported in the literature, 43 (77%) were receiving corticosteroids on admission to hospital. Breathlessness was always a feature of disease and excess wheezing was present in 79% of patients. Fever (>38 degrees C) was present in only 38.5%. Chest pain and haemoptysis were uncommon. Six out of 33 (18%) patients had tracheobronchitis observed during bronchoscopy. The median delay between symptoms and diagnosis was 8.5 days. The mortality rate was high: 53 out of 56 (95%) patients died despite invasive ventilation and antifungal treatment in 43 (77%) of them. In chronic obstructive pulmonary disease patients, invasive pulmonary aspergillosis currently carries a very poor prognosis. Outcome could perhaps be improved by more rapid diagnosis and prompt therapy with voriconazole.

Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases.

Invasive fungal infection (IFI) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT); however, we have little information on its clinical features after reduced intensity cord blood transplantation (RICBT) for adults. We reviewed medical records of 128 patients who underwent RICBT at Toranomon Hospital between March 2002 and November 2005. Most of the patients received purine-analogbased preparative regimens. Graft-versus-host disease (GVHD) prophylaxis was a continuous infusion of either tacrolimus 0.03 mg/kg or cyclosporine 3 mg/kg. IFI was diagnosed according to the established EORTC/NIH-MSG criteria. IFI was diagnosed in 14 patients. Thirteen of the 14 had probable invasive pulmonary aspergillosis and the other had fungemia resulting from Trichosporon spp. Median onset of IFI was day 20 (range: 1-82), and no patients developed IFI after day 100. Three-year cumulative incidence of IA was 10.2%. Four of the 13 patients with invasive aspergillosis (IA) developed grade II-IV acute GVHD, and their IA was diagnosed before the onset of acute GVHD. The mortality rate of IFI was 86%. Multivariate analysis revealed that the use of prednisolone >0.2 mg/kg (relative risk 7.97, 95% confidence interval 2.24-28.4, P = .0014) was a significant risk factor for IA. This study suggests that IFI is an important cause of deaths after RICBT, and effective strategies are warranted to prevent IFI.

Role of collectins in innate immunity against aspergillosis.

The protective role of lung surfactant proteins SP-A, SP-D and MBL in the host defense against both allergic and invasive aspergillosis was identified and established by a series of in vitro and in vivo studies. Therapeutic administration of SP-D and MBL proteins in a murine model of pulmonary invasive aspergillosis rescued mice from death. In mice mimicking human allergic bronchopulmonary aspergillosis, SP-A and SP-D suppressed IgE levels, eosinophilia, pulmonary cellular infiltration and cause a marked shift from a pathogenic Th2 to a protective Th1 cytokine profile. SP-A and SP-D knock-out mice studies made significant contributions in understanding the mechanisms by which SP-A and SP-D modulate the host defense response in patients suffering from pulmonary allergies and infections. The results suggested that individuals with any structural or functional defects in these innate immune molecules due to genetic variations might be susceptible to aspergillosis. SNPs in SP-A2 and MBL genes showed significant associations with patients of allergic bronchopulmonary aspergillosis in an Indian population. The patients carrying either one or both of GCT and AGG alleles of SP-A2 and patients with A allele at position 1011 of MBL had markedly higher eosinophilia, total IgE antibodies and lower FEV1 (the clinical markers of ABPA). Our results show that collectins play an important role in Aspergillus mediated allergies and infections.

Invasive pulmonary aspergillosis.

In susceptible patients, invasive aspergillosis has a high incidence and a mortality of up to 80%. The diagnosis of this condition is difficult, especially in the early stages of the disease and, as a consequence, antifungal therapy, despite its expense and toxicity, is often initiated empirically. Until recently, there were very few effective antifungal agents for established invasive aspergillosis, but the introduction of two new drugs, voriconazole and caspofungin, has increased the treatment options. These newer antifungal therapies, combined with improved early diagnosis due to the introduction of newer microbiologic techniques, offer the hope that there will be a significant improvement in the substantial morbidity and mortality associated with invasive aspergillosis over the next 5 years.

Invasive pulmonary aspergillosis in solid organ and bone marrow transplant recipients.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) remains a major cause of mortality in transplant recipients. New strategies in therapy are needed. METHODS: We prospectively followed all solid organ and bone marrow transplant recipients from January 1998 to January 2003 who showed pulmonary infiltrates. We retrospectively analyzed all of the patients diagnosed as having IPA. Clinical and epidemiological data were collected. Influence of new treatment strategies on survival was also analyzed. RESULTS: Thirty-one cases of API were found: 8 definite, 18 probable, 5 possible among recipients of liver (11), bone marrow (9), kidney (7), kidney-pancreas (3), and heart (1) transplants. Five patients (16%) were previously receiving antifungal prophylaxis. The most common symptoms were fever (74%) and dyspnea and dry cough (48%). Six cases (19%) showed dissemination to extrapulmonary sites: central nervous system (CNS) in five and bone in one. The most common radiographic patterns were alveolar infiltrates (58%); the lesions were usually diffuse and bilateral (58%). The most common Aspergillus species identified was A. fumigatus (74%). The test to detect Aspergillus antigen (galactomannan) in serum performed in 13 cases, was positive in eight (61%). The crude mortality rate was 61% (19 of 31), but in patients on mechanical ventilation, it was 94% (OR 88, IC 95%: 7.1-1094), and in patients with CNS involvement, it was 100%. The influence of the different treatment regimens on survival was analyzed in definite and probable cases: Group 1 (12) included patients who received conventional monotherapy and group 2 (12) patients received combination antifungal therapy or liposomal amphotericin B (1-AMB) at high doses. The mortality in group 1 was 83% (10 of 12), and in group 2 it was 42% (5 of 12) (P < 0.05). CONCLUSIONS: The mortality rate of IPA remains high, especially among patients with CNS involvement or those under mechanical ventilation. Combined antifungal therapy or monotherapy with 1-AMB at high doses significantly reduced mortality compared with conventional monotherapy.

Effect of granulocyte colony-stimulating factor combination therapy on efficacy of posaconazole (SCH56592) in an inhalation model of murine pulmonary aspergillosis.

Using an inhalation model of pulmonary aspergillosis, we observed modest differences in the survival rates of mice treated with granulocyte colony-stimulating factor (G-CSF) and posaconazole (POS) and those treated with POS alone. This finding is in contrast to a previous report that suggested that G-CSF had a significant antagonistic effect on the antifungal activity of POS.

Comparison of real-time PCR, conventional PCR, and galactomannan antigen detection by enzyme-linked immunosorbent assay using bronchoalveolar lavage fluid samples from hematology patients for diagnosis of invasive pulmonary aspergillosis.

An iCycler iQ real-time PCR assay targeting 18S rRNA Aspergillus-specific sequences was developed for the diagnosis of invasive pulmonary aspergillosis (IPA). Positive findings were obtained for 18 of 20 (90%) bronchoalveolar lavage (BAL) fluid specimens from patients with probable or confirmed IPA and were obtained for none of the 24 BAL samples from patients with no clinical evidence of aspergillosis. These results were concordant with those of a nested PCR assay, which detected 90% of the patients with IPA, while galactomannan ELISA revealed positivity for 100% of these patients, suggesting that combined use of methods might improve the diagnosis of IPA.

Variation in virulence of Aspergillus fumigatus strains in a murine model of invasive pulmonary aspergillosis.

The diversity in virulence of different Aspergillus fumigatus strains was studied in an experimental murine model of invasive pulmonary aspergillosis (IPA) and the results were correlated with possession of a putative molecular marker of virulence. Seven strains from different patients with non-invasive or invasive aspergillosis and four environmental strains were typed by PCR with specific primers and scored as positive or negative, according to whether or not a 0.95-kb DNA fragment was amplified. Immunosuppressed mice were inoculated intranasally with A. fumigatus conidia from these different strains. The mortality curves revealed differences in virulence between the strains. The environmental strains produced a weaker infection than the strains from patients and the 0.95-kb-positive patient strains caused significantly higher mortality rates in mice than the 0.95-kb-negative patient strains. These findings support the hypothesis that certain isolates of A. fumigatus are more virulent than others and that their virulence appears to be associated with the 0.95-kb molecular marker.

Tratamiento médico de la aspergilosis pulmonar intracavitaria (API) no quirúrgica / Medical treatment for intracavitary aspergillosis pulmonary non surgical

En la aspergilosis pulmonar intracavitaria (API), el tratamiento de elección es el quirúrgico, aunque no siempre es posible por causas relacionadas con patologías pulmonares preexistentes o por asociaciones morbosas. Entre 1979 y l989 se registraron en el Hospital "San Juan de Dios" de La Plata (Pcia. de Buenos Aires) 37 casos de API no quirúrgica , que fueron tratados con una o dos drogas antifúngicas bajo cuatro esquemas de tratamiento: 1)anfotericina B en nebulizaciones, 2)flucitosina oral, 3)ketoconazol oral y 4)anfotericina B nebulizaciones y flucitosina por vía oral. Todos los pacientes presentaron lesiones radiólogicas bilaterales con cavidad (BCC). La mayoría presentó un patrón ventilatorio mixto o restrictivo, y se registró la mayor incidencia de API no quirúrgica en los grupos etarios más afectados por tuberculosis pulmonar (TBC), además se detectó un elevado número de aspergilomas (35,l4%). Se obtuvo el aislamiento de Aspergillus fumigatus en el 83,8% de los casos, con un excelente rendimiento tanto de los cultivos cuanto de la serología. La mortalidad general fue del 10.81% y la atribuible a API del 2,70%. El abandono del tratamiento alcanzó el 35,l4% y se logró la negativización en 7 pacientes (33,40% de los tratamientos cumplidos). Los factores principales que influyeron en el resultado exitoso fueron: la duración prolongada del tratamiento y el esmero por parte del grupo de trabajo en la asistencia y seguimiento de los pacientes

Sarcoidosis and aspergilloma. The role of surgery.

Fibrocystic pulmonary disease is a common sequel of chronic pulmonary sarcoidosis, and the subsequent development of intracavitary aspergillomas is frequent, especially in black patients. Pulmonary hemorrhage from aspergilloma is second only to cardiorespiratory failure as the cause of death in sarcoidosis. Opinions regarding the role of resectional surgery are conflicting. We report observations on 38 patients with biopsy evidence of antecedent sarcoidosis and cultural or serologic identification of Aspergillus species as cause of the fungus balls. Pulmonary fibrosis was bilateral and extensive in most cases, making surgical treatment perilous. Ten patients had moderate impairment of pulmonary function. Seven had surgical resection with six satisfactory results and one death. Three patients in this category have not required surgery. Twenty-eight patients had severely compromised pulmonary function. Surgery was performed in seven because of intractable bleeding; four survived, but three later died of respiratory failure. Of the 21 in this category not treated by surgery, six survived, four died of hemorrhage and 11 of respiratory failure. Of the 37 patients with aspergilloma whose status is known, 19 are dead, 14 survived with positive precipitins and four, all treated surgically, recovered. It is concluded that surgical treatment of aspergilloma in patients with sarcoidosis should be avoided if possible, but is inescapable in a third of cases.

Late sequelae of allergic bronchopulmonary aspergillosis.

Seven patients with late sequelae of allergic bronchopulmonary aspergillosis (ABPA) are described. All seven had significant chronic symptoms from asthma. At the time of diagnosis of ABPA all patients had marked irreversible pulmonary function abnormalities; symptoms of chronic bronchitis were present in all. Pulmonary fibrosis was present in six of seven patients. Three patients have died from irreversible lung disease with terminal cardiac failure. Despite the difficulty in establishing an early diagnosis of ABPA, its importance must be emphasized in order to attempt to prevent progression of the disease to severe irreversible and potentially fatal end-stage lung disease.

Diagnosis of invasive aspergillosis by passive hemagglutination assay of antibody.

Sheep red cells treated with concanavalin A and sensitized with a partially purified aspergillus antigen were used to detect antibody to Aspergillus by passive hemagglutination (PHA). Sera from eight patients with aspergillomas or allergic aspergillosis had PHA titers of greater than or equal to 1:800 and antibody detectable by immunodiffusion (ID). Of 122 hospitalized cancer patients without invasive aspergillosis, 118 had titers of less than or equal to 1:80, 86 of < 1:10, two of 1:160, and two of 1:320. None had antibody by ID. Antibody was detectable by PHA in sera from 12 of 14 healthy microbiology laboratory workers. Of 55 cancer patients who had sera available for testing within two weeks before diagnosis of invasive aspergillosis, 18 patients seroconverted: 13 by both PHA and ID, two by PHA alone, and three by ID alone. PHA titers rose from < 1:10 to between 1:40 and 1:1,280. In immunosuppressed patients who were at risk of developing invasive aspergillosis, the appearance of antibody correlated with the diagnosis of invasive aspergillosis.

[True and false problems in surgery of pulmonary aspergilloma. Study of 220 cases (author's transl)]. / Vrais et faux problèmes de la chirurgie des aspergillomes pulmonaires. A propos de 220 cas.

Different problems involved in the surgery of 220 cases of pulmonary aspergilloma are analyzed. The operatory blood loss, which was more abundant than usual, did not bring about any complication. The authors believe that pleural cavities were observed for only 6% of the partial excisions, probably because of the complementary thoracoplasties they performed. The true problem is raised by the patients suffering from respiratory failure for whom techniques of direct approach are the only solution.

[True and false problems in surgery of pulmonary aspergilloma. Study of 220 cases (author's transl)]. / Vrais et faux problèmes de la chirurgie des aspergillomes pulmonaires. A propos de 220 cas.

Different problems involved in the surgery of 220 cases of pulmonary aspergilloma are analyzed. The operatory blood loss, which was more abundant than usual, did not bring about any complication. The authors believe that pleural cavities were observed for only 6% of the partial excisions, probably because of the complementary thoracoplasties they performed. The true problem is raised by the patients suffering from respiratory failure for whom techniques of direct approach are the only solution.