Invasive Aspergillus infections in hematologic malignancy patients

The incidence of invasive Aspergillus (IA) infections in patients with hematologic malignancies continues to increase. The most common species include Aspergillus fumigatus (approximately 90% of cases), A. flavus, A. niger, A. terreus, and A. nidulans. Most infections involve the pulmonary parenchyma, though systemic dissemination of the fungus from a primary pulmonary focus or the paranasal sinuses after hyphal invasion into blood vessels is frequent. Early diagnosis and initiation of appropriate antifungal therapy has been shown to improve the prognosis of patients afflicted with this condition. The definitive diagnosis of IA is based on showing the hyphal invasion in tissue specimens together with a positive culture for Aspergillus species from the same specimen. The detection of circulating fungal antigens and DNA seems to be a promising, rapid, and sensitive diagnostic tool for early diagnosis of aspergillosis. The current antifungals available for the treatment of IA include amphotericin B deoxycholate and lipid formulations, itraconazole and caspofungin acetate. New investigational antifungal drugs include the triazoles voriconazole, posaconazole and ravuconazole, liposomal nystatin, and 2 echinocandin derivatives (anidulafungin [VER-002] and micafungin [FK463]). Preventive measures include reduction of environmental exposure of patients from sources of infection and anti-fungal prophylaxis. Specialized air-handling systems capable of excluding Aspergillus spores, such as high-efficiency particulate air (HEPA) filtration with or without laminar air flow ventilation has proven to be very efficacious. Targeted antifungal prophylaxis for hematologic patients who are at high risk for developing invasive fungal infections is not currently standardized.     

Nosocomial invasive aspergillosis in a heart transplant patient acquired during a break in the HEPA air filtration system

We report a case of nosocomially acquired invasive aspergillosis (IA) in a low-risk heart transplant recipient due to a break in the air conditioning system. A high overload of Aspergillus spores in the intensive care unit room led this patient to acquire IA. Identical environmental and patient isolates allowed our hypothesis to be confirmed and a very precise incubation time to be estimated.     

Aspergillus infections in allogeneic stem cell transplant recipients: have we made any progress?

Invasive aspergillosis (IA) is common in allogeneic SCT recipients, with an incidence of 4-10%. The majority of these infections are diagnosed several months after SCT and they are frequently associated with GVHD. The diagnosis is difficult and often delayed. Established IA is notoriously difficult to treat with a death rate of 80-90%. This review summarises recent data on this problem to assess whether there has been any progress. Effective prophylactic measures are still lacking. Severe immunosuppression is the main obstacle to the success of therapy. Recent and ongoing developments in diagnostic measures and new antifungal agents may improve treatment results to some extent, but Aspergillus infections still remain a formidable problem in allogeneic transplantation. Further studies in this field will focus on the role of various cytokines and combinations of antifungal agents.     

Nosocomial Acinetobacter pneumonia

Acinetobacter spp. (A. baumannii is the prevalent genomic species, but others may cause infection) has become an increasingly important cause of nosocomial pneumonia, particularly in mechanically ventilated patients (VAP). This organism has intrinsic resistance to some antimicrobials but easily acquires resistance to many others; Acinetobacter spp. can survive for long periods of time in the environment. All of these characteristics have contributed to protracted outbreaks associated with significant morbidity and mortality. High rates of colonization are found in debilitated hospitalized patients. Infecting or colonizing organisms in nosocomial infections are more likely to be from cross-transmission or from the hospital environment than from endogenous sources. VAP caused by Acinetobacter spp. is emerging as a prominent hospital complication. The incidence of this microorganism varies from site to site, but it is the second commonest aetiological agent among the gram-negative bacteria. Longer periods of hospitalization, longer time on mechanical ventilation and prior use of antibiotics are the recognized factors increasing the risk of VAP due to Acinetobacter spp. Treatment needs to clearly differentiate infection from colonization, and the agents with the most antimicrobial activity are imipenem/cilastatin, amikacin, colistin, ampicillin/sulbactam and tigecycline. Monotherapy can be adequate if the patient does not have significant comorbidities. Infection control procedures have a major role to play in preventing transmission of this microorganism. Emphasis on initial control measures should, however, be on strict isolation of infected or colonized patients to limit dissemination of outbreak strains in the environment. The variety of potential sources of contamination with Acinetobacter spp. in the hospital environment makes control of these outbreaks one of the more difficult challenges. Persistence of Acinetobacter spp. in the environment provides ample opportunities for contamination of patients and staff and may explain continuing long-term outbreaks.     

Toll-deficient Drosophila flies as a fast, high-throughput model for the study of antifungal drug efficacy against invasive aspergillosis and Aspergillus virulence

Invasive aspergillosis (IA) is the most important opportunistic mycosis in immunosuppressed patients. The lack of a sufficient number of effective antifungals and our incomplete understanding of the pathogenesis of IA contribute to its overall unfavorable prognosis. Studies of drug efficacy against IA and Aspergillus virulence rely on conventional animal models that are laborious and use limited numbers of animals; alternative, less cumbersome in vivo models are desirable. Using different inoculation models of IA, we found that Toll-deficient Drosophila flies exposed to voriconazole (VRC), the preferred drug for the treatment of IA in humans, had significantly better survival rates and lower tissue fungal burdens than did those not exposed to VRC. Furthermore, Toll-deficient Drosophila flies infected with an alb1-deleted hypovirulent Aspergillus mutant had significantly better survival rates than did those infected with a wild-type Aspergillus strain. Therefore, the Drosophila fly is a fast, high-throughput in vivo model for the study of drug efficacy against IA and Aspergillus virulence.     

Aspergillus-associated hypersensitivity respiratory disorders

The mould Aspergillus is responsible for a gamut of respiratory diseases ranging from saprobic colonisation to rapidly invasive disseminated disease. The clinical spectrum of Aspergillus-associated hypersensitivity respiratory disorders includes Aspergillus induced asthma, allergic bronchopulmonary aspergillosis (ABPA), allergic Aspergillus sinusitis (AAS) and hypersensitivity pneumonitis. Inhalant allergens, in patients with allergic asthma, play a key role in bringing about the inflammation present in the airways, and fungi are increasingly being recognised as important inhalant allergens. Aspergillus is linked to asthma in more ways than one. In the asthmatic subjects, the fungal spores are trapped in the thick and viscid secretions that are usually present in the airways. This generally develops in atopic subjects and is sustained by continuous inhalation of Aspergillus antigens, triggering asthma that may be more severe in form. Aspergillus induced asthma is yet to receive the recognition that it deserves. Allergic bronchopulmonary aspergillosis is the best known form of allergic aspergillosis and is an emerging disease in India. An immunologically mediated lung disease, ABPA occurs predominantly in patients with asthma. A set of diagnostic criteria is required as there is no single test that establishes the diagnosis apart from demonstration of central bronchiectasis with normal tapering bronchi, a feature considered to be pathognomonic of ABPA. Radiologically, ABPA is characterised by 'transient pulmonary infiltrates' or 'fleeting shadows', often confused with pulmonary tuberculosis. A comparatively more recently recognised clinical entity, AAS is characterised by mucoid impaction in the paranasal sinuses which is akin to that in ABPA. Although it appears that the patient with ABPA provides a favourable milieu for the occurrence of AAS, it is perhaps surprising that in spite of similar histopathological features the co-existence of both these diseases has not often been reported. Aspergilloma, a fungal ball that appears in a pre-existing cavity due to saprobic colonisation of Aspergillus species, can often present with asthma. The association of ABPA and aspergilloma is also known. Although cavitation can occur in ABPA, the co-existence of ABPA with aspergilloma is rather uncommon. Aspergillomas may function as a nidus for antigenic stimulation in a genetically predisposed individual resulting in the occurrence of ABPA. Contemporaneous occurrence of ABPA, AAS and aspergilloma has also been reported. Screening all asthmatic subjects for Aspergillus sensitisation could identify those with a severe form of the disease as well as those at risk for developing ABPA. Furthermore, concomitant occurrence of ABPA and AAS is now being increasingly recognised, and AAS must be excluded in all patients with ABPA.     

Epidemiology of MRSA

Staphylococcus aureus is recognized as one of the major causes of infections in humans occurring in both the community and the hospital. Up to now one of the most serious aspects as far as treatment of S. aureus infections is concerned is resistance to methicillin, which in clinical terms indicates resistance to all beta-lactam antibiotics. The growing incidence of methicillin-resistant S. aureus (MRSA) infections worldwide, their multidrug resistance, several reservoirs of resistant strains, the facility to spread also outside hospitals and to cause outbreaks requires efficacious infection control measures. For this reason microbiological and epidemiological studies are of crucial importance.     

Filtering hospital air decreases Aspergillus spore counts.

We performed counts of airborne spores in a hospital with filtered air where a decrease in nosocomial infection with Aspergillus organisms had been documented. For comparison, similar studies were performed at a nearby general hospital in a ward with open windows. The total spore count inside the hospital with filtered air was significantly less than inside the ward with open windows. The total count of Aspergillus organisms in the filtered air was significantly less than that in the room with open windows. We conclude that the decrease in nosocomial infections with Aspergillus organisms in the hospital with filtered air is probably associated with fewer airborne spores.     

Epidemiology and prevention of invasive aspergillosis

Aspergillus species are the most common causes of invasive mold infections in immunocompromised persons. This review examines the available information regarding the rising incidence of invasive aspergillosis in different high-risk groups, including persons with acute leukemia, hematopoietic stem cell transplant recipients, and liver and lung transplant recipients. The risk factors for infection in these groups are discussed. Because Aspergillus species are widespread in the environment, it is difficult to link specific sources and exposures to the development of human infections. However, molecular strain typing and other studies indicate that a significant number of Aspergillus infections are now being acquired outside the health care setting, either before patients are admitted to hospital, or after they have been discharged. The role of environmental control measures and antifungal drug prophylaxis in the prevention of hospital- and community-acquired aspergillosis is discussed.     

Invasive aspergillosis in critically ill patients without malignancy

Using criteria designed for invasive aspergillosis (IA) in patients with cancer, we aimed to determine the impact of IA in patients without malignancy in a medical intensive care unit (ICU). In this retrospective study, 127 patients out of 1,850 admissions (6.9%) hospitalized between 2000 and 2003 had microbiological or histopathologic evidence of Aspergillus during their ICU stay. There were 89 cases (70%) without hematologic malignancy. These patients were classified as proven IA (n = 30), probable IA (n = 37), possible IA (n = 2), or colonization (n = 20). In these patients, mean SAPS II score was 52 with a predicted mortality of 48%. The observed mortality was 80% (n = 71). Mortality of the proven and the probable IA was 97 and 87%, respectively. Postmortem examination was done in 46 out of 71 patients, and 27 autopsies (59%) showed hyphael invasion with Aspergillus. Aspergillus infections occurred in five critically ill patients with proven IA who did not have any predisposing factors according to the currently available definitions. Three of these patients had Child C liver cirrhosis. IA is an emerging and devastating infectious disease in patients in the ICU without malignancy. In those patients, host criteria for probable fungal infections should probably be adapted.     

A solid-phase radioimmunoassay for the measurement of antibody to Aspergillus in invasive aspergillosis.

A solid-phase radioimmunoassay (SPRIA) to measure antibody responses to Aspergillus fumigatus and Aspergillus flavus antigens in invasive aspergillosis (IA) was developed and compared with immunodiffusion (ID) and counterimmunoelectrophoresis (CIE). SPRIA detected significant elevations in levels of aspergillus antibody in 15 (79)% of 19 patients with IA. Fewer patients with IA were positive by ID (give of 19) or CIE (four of 19). Only seven )8%) of 58 subjects with other fungal or bacterial infections were positive by SPRIA, as was one (5%) of 20 by ID and CIE. Weak cross-reactivity between aspergillus and candida antigens was demonstrated by SPRIA. IgG levels in patients with IA and control subjects were equivalent. Thus, an antibody response to Aspergillus can be detected in a greater percentage of patients with IA by SPRIA than by ID or CIE. Although a few patients without aspergillosis had elevated levels of aspergillus antibody, a rise in antibody level was specific for IA.     

Invasive pulmonary aspergillosis in patients with neoplastic diseases

Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in granulocytopenic patients. The purpose of this article is to review the current understanding of the microbiology, hospital epidemiology, clinical manifestations, diagnosis, prevention, and treatment of invasive pulmonary aspergillosis. Aspergillus conidia (spores) are inhaled from environmental sources into the paranasal sinuses and lower respiratory tract. Persistent fever, pulmonary infiltrates, and pleuritic pain in granulocytopenic patients receiving antibacterial antibiotics is a common manifestation of invasive pulmonary aspergillosis. Computerized tomographic scans of the chest often reveal characteristic peripheral nodules that also may progress to characteristic cavitary lesions. Hemoptysis may develop due either to hemorrhagic infarction during granulocytopenia or to the rupture of mycotic aneurysms during recovery from granulocytopenia. Aspergillus organisms may extend locally from the lung to involve other thoracic structures, including the heart and chest wall, and may disseminate to extrapulmonary sites, such as the brain, where focal neurological deficits ensue. Early diagnosis of invasive pulmonary aspergillosis may be difficult. Isolation of Aspergillus organisms from respiratory secretions of a persistently febrile granulocytopenic patient is usually indicative of invasive pulmonary aspergillosis and should not be dismissed as a contaminant or saprophyte. Amphotericin B is the treatment of choice; however, high dosages (1.0 to 1.5 mg/kg/day) are often necessary. Aspergillosis may develop in granulocytopenic patients who are already receiving empirical amphotericin B in lower doses (0.5 to 0.6 mg/kg/day). It is hoped that further investigation directed toward an understanding of pathogenesis, improving diagnostic methodology, and developing new therapeutic and preventive strategies will improve the outcome of this life-threatening infection.     

血清半乳甘露聚糖检测诊断侵袭性曲霉病的临床研究

目的 评价血清半乳甘露聚糖(GM)检测对侵袭性曲霉病(IA)的诊断价值.方法 南京军区南京总医院2005年1月至2007年2月确诊的侵袭性真菌感染(IFI)住院患者49例,平均年龄55岁,男34例,女15例,其中IA 11例,其他IFI 20例,曲霉气道定植18例.采用Platelia Aspergillus(法国Bio-Rad公司)双夹心ELISA检测试剂盒检测患者的血清GM吸光度指数(简称GM值),IA患者中6例于治疗后7 d重复检测.正态分布计量资料以-x±s表示,多组间比较采用单因素方差分析,治疗前后比较采用配对t检验,采用SPSS统计软件处理实验数据.结果 IA患者血清GM值为1.63±0.29,其他IFI和曲霉气道定植患者分别为0.96±0.49和0.83±0.43,IA患者与后两者比较差异有统计学意义(F=12.681,P＜0.05).6例IA患者治疗前后GM值分别为1.67±0.24和1.62±0.28(t=0.475,P＞0.05).以GM值为1.5作为诊断阈值诊断IA的敏感度、特异度、阳性预测值和阴性预测值分别为72.7%、84.2%、57.1%和94.1%.结论 血清GM检测对IA具有诊断价值,可区分IA与其他IFI和曲霉气道定植;以GM值为1.5作为诊断阈值诊断IA的敏感度、特异度较理想.     

Missed TB in AIDS unit leads to tighter isolation

The San Francisco General Hospital recently tightened its tuberculosis (TB) policies for isolating HIV-positive patients after learning that active TB patients had been admitted without respiratory protection. The new policy resulted from what was initially believed to be a TB outbreak on the AIDS unit. However, an investigation concluded that the patients were infected outside the hospital. The hospital now automatically screens patients for TB when they are admitted to the AIDS ward. HIV-positive patients who are put on rule-out for TB cannot be admitted to the AIDS unit until they have three negative sputum smears. Low-risk, suspected TB patients now are put in a private room with negative air pressure. This new policy will cost the hospital more money. Using the rapid assay test for sputum-positive cases that are likely to be Mycobacterium avium complex (MAC) would cut isolation time and money. However, the test is only 95 percent sensitive, so one out of 20 patients could be missed. The city will be making a decision about whether the new test will be used under these circumstances.     

Molecular Detection of Invasive Aspergillosis in Hematologic Malignancies

BACKGROUND: Aspergillus species are the most frequent causes of invasive mold infections in immunocompromised patients, particularly those who underwent chemotherapy for hematologic malignancies. The aim of this study was to determine the incidence and efficiency of the PCR-enzyme linked immunosorbent assay method (PCR-ELISA) for early detection of Aspergillus species in patients with hematologic malignancies. PATIENTS AND METHODS: From 2004 to 2006, 194 patients with hematologic malignancies (who received chemotherapy) were evaluated for invasive aspergillosis (IA) in Shiraz, southern Iran. Ethylenediaminetetraacetic acid anticoagulant whole blood samples were collected prospectively once a week and stored at -20 degrees C until examination. All collected blood samples were assayed for the presence of the bands on ethidium bromide stained gel and for hybridization. RESULTS: The female-to-male ratio was 61:133, the mean age of patients was 33.7 years, and mean of hospitalization period was 21.2 days. PCR-ELISA was positive in 14 (7.2%) patients who exhibited clinical and radiologic signs of IA. The etiologic agents were Aspergillus flavus (11 cases) and Aspergillus fumigatus (three cases). The mean time of positivity of PCR-ELISA in the blood before the appearance of clinical signs was 12.6 days. PCR was found to be the earliest indicator of IA preceding nonspecific clinical and radiologic findings. The sensitivity, specificity, positive, and negative predictive values of PCR-ELISA to detect DNA-specific for Aspergillus species in patients with proven and probable IA were 66%, 96%, 62.5%, and 97%, respectively. In case patients were treated with antifungal drugs, and the treatment was successful, fungal PCR assay became negative after 14 days and if the treatment failed, assay was positive until death. CONCLUSIONS: We demonstrated, in the present study, the incidence of IA in leukemic patients and the usefulness of molecular assay for early diagnosis and monitoring of the treatment of IA.     

Overview of hepatitis E virus

Hepatitis E virus (HEV) is an enterically transmitted virus usually presenting as an acute self-limiting disease. However, mortality increases dramatically from around 1% to 20% in pregnant women. HEV has been the cause of very large outbreaks of hepatitis in developing countries and is also responsible for a significant number of sporadic cases. It is clear that cases occur outside the endemic areas, and new isolates have been identified. HEV-like viruses have also been found in various animal groups, and it is likely that HEV can be regarded as a zoonotic infection. Preventative measures at the moment depend mainly on the provision of clean water supplies, although a vaccine is now undergoing clinical trials.     

Invasive aspergillosis: a severe infection in juvenile systemic lupus erythematosus patients

Infections are an important cause of morbidity and mortality in juvenile systemic lupus erythematosus (JSLE). Among them, invasive aspergillosis (IA), which is usually related to immunosuppressed patients, has been rarely reported in JSLE. From 1983 to 2011, 5604 patients were followed at our institution and 283 (5%) met the American College of Rheumatology (ACR) classification criteria for SLE. Six (2.1%) of our JSLE patients had IA. One of them was previously reported and five will be described herein. Four of them were female. The median age at JSLE diagnosis was 12 years (8-16) and the median interval between diagnosis of JSLE and IA was 6 months (1-38). All had pulmonary involvement and three of them had systemic involvement. The median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was 19 (7-22). Diagnosis of IA was performed by isolation of Aspergillus spp., two in bronchoalveolar lavage culture and by way of autopsy in the others. All of them were treated with corticosteroids and/or immunosuppressive drugs at IA diagnosis (azathioprine and/or intravenous cyclophosphamide). They all required treatment in the pediatric intensive care unit with mechanical ventilation and antifungal therapy (fluconazole, amphotericin B, itraconazole and/or voriconazole); nonetheless, none of them survived. In conclusion, this was the first report that evaluated the prevalence of IA in a large population of JSLE patients from a tertiary pediatric hospital, and clearly showed the severity of the outcome, especially in patients with active disease and treated with immunosuppressive agents. This study reinforces the importance of early diagnosis and treatment with certain antifungals, especially in critically ill patients.     

Invasive aspergillosis in liver transplant recipients

Background

Liver transplantation is increasing worldwide with underlying pathologies dominated by metabolic and alcoholic diseases in developed countries.

Methods

We provide a narrative review of invasive aspergillosis (IA) in liver transplant (LT) recipients. We searched PubMed and Google Scholar for references without language and time restrictions.

Results

The incidence of IA in LT recipients is low (1.8%), while mortality is high (∼50%). It occurs mainly early (<3 months) after LT. Some risk factors have been identified before (corticosteroid, renal, and liver failure), during (massive transfusion and duration of surgical procedure), and after transplantation (intensive care unit stay, re-transplantation, re-operation). Diagnosis can be difficult and therefore requires full radiological and clinicobiological collaboration. Accurate identification of Aspergillus species is recommended due to the cryptic species, and susceptibility testing is crucial given the increasing resistance of Aspergillus fumigatus to azoles. It is recommended to reduce the dose of tacrolimus (50%) and to closely monitor the trough level when introducing voriconazole, isavuconazole, and posaconazole. Surgery should be discussed on a case-by-case basis. Antifungal prophylaxis is recommended in high-risk patients. Environmental preventative measures should be implemented to prevent outbreaks of nosocomial aspergillosis in LT recipient units.

Conclusion

IA remains a very serious disease in LT patients and should be promptly sought and, if possible, prevented by clinicians when risk factors are identified.

     

Pumonary aspergillosis during hospital renovation.

During a 4-week period, Aspergillus fumigatus caused disease in 2 patients and colonized a third patient in a renal transplant ward. Our investigation indicated that increased exposure of these patients to spores probably occurred during renovation of the ward one floor above it. Cases were significantly clustered (P = 0.014) during the period when work overhead caused dust to filter down through pores in the acoustical tiles of the false ceiling of the renal transplant ward. Swab cultures demonstrated A. fumigatus in the dust, and air samples showed heavy contamination with A. fumigatus and other fungi at and below a renovation site, but not on 2 distant wards. We concluded that dust can be an important source of aspergilli and that release of dust and spores during activities such as renovation may increase the risk of nosocomial Aspergillus infection in exposed, immunosuppressed patients.     

Allergic bronchopulmonary aspergillosis: an Indian perspective

PURPOSE OF REVIEW: Allergic bronchopulmonary aspergillosis is an immunologically mediated lung disease that is caused by hypersensitivity to antigens of the genus Aspergillus. This review summarizes the clinical presentation, radiologic profile, lung functions and immunologic studies on allergic bronchopulmonary aspergillosis from India. Data regarding Aspergillus sensitization in asthmatics are presented. The association of allergic bronchopulmonary aspergillosis with allergic Aspergillus sinusitis and aspergilloma is also highlighted. RECENT FINDINGS: Allergic bronchopulmonary aspergillosis is now an emerging disease in India. Sensitization to Aspergillus antigens is not uncommon in our patients with asthma. Although asthma commenced in these subjects in their early 20s, allergic bronchopulmonary aspergillosis was recognized more than a decade later. Allergic bronchopulmonary aspergillosis can also occur in patients without clinical asthma. Radiology is crucial to the diagnosis of allergic bronchopulmonary aspergillosis. The remarkable radiological similarity to pulmonary tuberculosis has important clinical implications in our country as patients with allergic bronchopulmonary aspergillosis often receive antituberculous therapy for a long time. Although oral corticosteroids still remain the cornerstone for management, itraconazole has emerged as an adjunct therapy in appropriate situations. Concomitant occurrence of allergic bronchopulmonary aspergillosis and allergic Aspergillus sinusitis is now being increasingly recognized. SUMMARY: All asthmatic subjects with a positive skin prick test to Aspergillus antigens must be evaluated for allergic bronchopulmonary aspergillosis and allergic Aspergillus sinusitis should be excluded.