Improved outcome in central nervous system aspergillosis, using voriconazole treatment

The mortality of central nervous system (CNS) aspergillosis approaches 100%, requiring improved therapies. Voriconazole gives superior efficacy and survival in invasive aspergillosis, compared with amphotericin B. Also, in contrast to other antifungal drugs, voriconazole penetrates well into the CNS. We evaluated, retrospectively, the outcome and survival of 81 patients who were treated with voriconazole for definite (n = 48) or probable (n = 33) CNS aspergillosis. Complete and partial responses were recorded in 35% of patients and varied by the underlying disease group: hematologic malignancies (54%), other underlying conditions (50%), chronic immunosuppression (45%), solid organ transplantation (36%), and hematopoietic stem cell transplantation (16%). Thirty-one percent of patients survived CNS aspergillosis for a median observation time of 390 days. There were 31 patients who underwent neurosurgical procedures, including craniotomy/abscess resection (n = 14), abscess drainage (n = 12), ventricular shunt (n = 4), and Ommaya-reservoir (n = 1). Multifactorial analysis revealed that neurosurgery was associated with improved survival (P = .02). Patients who underwent hematopoietic stem cell transplantation had a poorer survival (P = .02), but 7 (22%) of 32 survived for a median of 203 days. We conclude from this large cohort of patients that voriconazole treatment together with neurosurgical management, whenever feasible, is currently the best approach to treat patients with CNS aspergillosis.     

中枢神经系统少见真菌感染35例临床分析

目的 了解中枢神经系统少见真菌感染的临床特点.方法 收集1997年至2010年复旦大学附属华山医院收治的中枢神经系统少见真菌感染病例,共35例,对其病原菌种类、临床特点、疗效等进行回顾性分析,统计学方法采用秩和检验和Fisher确切概率法.结果 35例患者中确诊29例,临床诊断6例.30例患者存在一种或多种易感因素,占86%,致病菌主要有曲霉感染16例,念珠菌感染14例.常见的临床表现有发热22例.头痛19例,脑神经受累12例,脑膜刺激征12例.脑脊液变化为WBC增多、蛋白含量升高及糖含量降低.其中曲霉感染患者多存在免疫力低下的基础疾病,常由邻近部位感染或血流播散所致,以头痛和脑神经受累等脑实质损害为主;而念珠菌感染患者多继发于颅脑手术或外伤后,以发热、脑膜刺激征以及脑脊液异常等脑膜炎表现为主.总有效率为77%(27/35),其中曲霉感染患者以颅内病灶手术清除联合抗真菌药物疗效较佳;念珠菌感染由于多继发于颅脑手术.尤其是脑脊液外引流术,抗真菌药物治疗同时更换或拔除引流管可达到较好疗效.结论 近年来曲霉、念珠菌等中枢神经系统少见真菌感染有明显增多趋势,而早期诊断和及时治疗是改善预后的关键.

Abstract：

Objective To analyze the clinical features of patients with uncommon fungal infections in central nervous system (CNS).Methods Thirty-five patients with uncommon CNS fungal infections who were admitted to Huashan Hospital from 1997 to 2010 were retrospectively reviewed.The pathogens,symptoms and signs.treatments of patients were evaluated.The data were analyzed by rank sum test and Fisher'S exact test.Results Twenty-nine of the 35 patients met the definition criteria of prover CNS fungal infections,while the other 6 had probable diagnosis.Predisposing factors were found in 86% of all patients.The most common pathogens were Aspergillus and Candida species.The symptoms and signs commonly occurred including fever(22 cases),headache(19 cases), cranial neuropathy(12 cases),and meningeal irritation sign(12 cases).High white blood cell count,high protein level,and low glucose level were the main findings of cerebrospinal fluid (CSF) analysis.Patients with cerebral aspergillosis were more frequently accompanied with immunocompromised conditions, and they often got CNS aspergillosis from hematogenous dissemination or direct extension of paranasal sinus infection.Cerebral granuloma and abscess were the common clinical characteristics of CNS aspergillosis.Cerebral candidiasis often arose from neurosurgical surgery or traumatic brain injury,and these patients were usually presented with meningitis.All patients were treated with antifungal drugs and (or) surgical intervention and 77%(27/35) of the patients achieved complete or partial responses. Antifungal agents combined with surgical resection might improve outcome of patients with CNS aspergillosis; while removal or replacement of drainage tubes in combination with antifungal treatment showed satisfactory efficacy in patients with cerebral candidiasis who usually had shunt manipulation. Conclusions The incidence of CNS fungal infection, such as cerebral aspergillosis and candidiasis, is increasing. Early diagnose and therapeutic intervention are crucial for improving outcome.     

Successful treatment of disseminated aspergillosis with the combination of voriconazole, caspofungin, granulocyte transfusions, and surgery followed by allogeneic blood stem cell transplantation in a patient with primary failure of an autologous stem cell graft

The treatment of disseminated aspergillus infections in neutropenic patients remains a major challenge in spite of several new antifungal drugs. We report the case of a patient with multiple myeloma in prolonged neutropenia after primary failure of an autologous stem cell graft who developed invasive aspergillosis despite voriconazole monotherapy. He responded to a combination of voriconazole and caspofungin, supported by granulocyte transfusions and surgery. A subsequent allogeneic peripheral blood stem cell transplantation did not lead to recurring aspergillus infection. The patient is well and free of clinical disease with respect to the fungal infection and myeloma more than 18 months after the allogeneic transplantation.     

Antifungal therapy in patients with hematological malignancies: how to avoid overtreatment?

Historically, treatment of invasive fungal infections (IFI) has consisted of amphotericin B. However, new therapeutic agents have recently been introduced. At the same time, the relatively low incidence of IFI and the progress in the diagnostic accuracy of IFI have made routine use of empirical antifungal therapy questionable. OBJECTIVES AND METHODS: With the aim to define the present trends in the use of antifungal agents for the treatment of IFI, we prospectively observed type, safety, and efficacy of given antifungal treatment in patients with hematological malignancies during a recent 18-month period. We also analyzed the impact of restricted use of empirical antifungal therapy on IFI-related mortality. RESULTS: A total of 279 episodes of neutropenia and fever following the chemotherapy were recorded. Treatment of IFI was given during the management of 41 (14%) episodes. Voriconazole (27 episodes) and caspofungin (14 episodes) were the only antifungal agents used as initial therapy. The rate of antifungal therapy success outcome was 78%. The overall 4-week mortality rate was 8%. Two patients died of invasive pulmonary aspergillosis. Empirical antifungal therapy was given in 13 episodes with persistent febrile neutropenia (PFN) and resulted in successful outcome in 92% of cases. In general, antifungal agents were well tolerated and only two patients had to discontinue treatment because of severe adverse event. In 127 episodes of PFN, antifungal therapy was deemed unnecessary and accordingly was not administered. In this subgroup of patients, no IFI-related mortality occurred. CONCLUSION: A better tolerability and efficacy of voriconazole and caspofungin together with the availability of an oral formulation of voriconazole most probably contributed to the observed shift in the use of antifungal agents. A restricted use of empirical antifungal therapy was, in this setting, not associated with an increased IFI-related mortality.     

Successful Treatment of Pulmonary Invasive Aspergillosis with Voriconazole in Patients who Failed Conventional Therapy

Background: The incidence of fungal infections, including those due to Aspergillosis species has continued to increase in recent years. Invasive aspergillosis remains an important cause of morbidity and mortality, despite therapeutics interventions.Patients and Methods: We reported five cases of invasive pulmonary aspergillosis treated with voriconazole failing to respond to conventional treatments.Results: The clinical and radiological resolution of pulmonary aspergillosis reported in these cases following therapy with voriconazole is remarkable, considering the infections had proved refractory to standard antifungal therapies. Long-term therapy (in two cases 1 year, in one case 6 months) was very well tolerated by patients who were unable to tolerate other antifungal agents.Conclusion: Therapy with voriconazole offers a new therapeutic option for otherwise difficult-to-treat infections and the potential to significantly improve the management of Aspergillosis infections.     

Invasive pulmonary aspergillosis complicated by complete atrioventricular block and aspergillus pericarditis after induction chemotherapy in a patient with acute lymphoblastic leukemia

A 50-year-old man developed invasive pulmonary aspergillosis after induction chemotherapy for acute lymphoblastic leukemia. He was treated with 5-fluorocytosine and intravenous amphotericin B (AMPH-B). During antifungal therapy, he developed aspergillus pericarditis and complete atrioventricular (A-V) block. The pericardial effusion was decreased and the A-V block was improved after treatment with intravenous and intrapericardial instillation of AMPH-B. Because the patient's renal function deteriorated, AMPH-B was replaced with itraconazol after the latex agglutination (LA) test for an aspergillus-specific antigen showed a negative result. The patient, however, died from disseminated aspergillosis. Aspergillus DNA was detected in retrospective analysis of the serum which had been negative with the LA test. This case indicates that LA is not sufficient for diagnosis and post therapy evaluation of invasive aspergillosis. PCR or other methods should be used concomitantly with LA. Intrapericardial instillation of AMPH-B might be effective for patients with aspergillus pericarditis in whom surgical treatment is not indicated.     

Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia

Invasive aspergillosis is an increasing problem in patients with acute leukaemia, bone marrow transplantation, immunosuppression after solid organ transplantation, or acquired immunodeficiency syndrome. Despite available antifungal treatment, the mortality approaches 100% in patients with dissemination of the infection into the central nervous system (CNS). Using a novel triazole, voriconazole, we successfully treated an Aspergillus brain abscess in a patient with acute leukaemia. Drug levels above the minimal fungicidal concentration for Aspergillus species were detected in cerebrospinal fluid (CSF) specimens, and the treatment achieved an objective response.     

Pulmonary fungal infections

PURPOSE OF REVIEW: Invasive fungal infections of the lung have historically been associated with an extremely high mortality. This review aims to disseminate the most recent advances in the diagnosis and management of fungal infections of the lung. RECENT FINDINGS: The number and diversity of immunosuppressed populations are growing rapidly. Transplant immunosuppression is becoming more aggressive early in the posttransplant period, potentially increasing the risk of invasive fungal infections. The galactomannan antigen test and the beta-D-glucan test have emerged as methods of serially monitoring at-risk patients for invasive aspergillosis. Their utility has been established in some neutropenic populations but not in solid organ transplant recipients. In-vitro studies, animal studies, and retrospective human studies support the use of combination antifungal therapy for invasive aspergillosis. Unfortunately no randomized clinical trials exist. SUMMARY: Invasive pulmonary aspergillosis will continue to be a major problem in immunocompromised patients in the future. Immense advances in the last 2-3 years are sure to improve outcome. Well-designed multicenter evaluations are still necessary, however, to optimize management as management options widen.     

Aspergillus infection in chronic obstructive pulmonary diseases

Chronic obstructive pulmonary disease (COPD) is a chronic airway non-specific inflammatory disease characterised by airway obstruction and alveolar destruction. In recent years, due to the extensive use of antibiotics, glucocorticoids, immunosuppressants and other drugs, pulmonary fungal infection in patients with AECOPD, especially aspergillus infection, has gradually increased. The forms of aspergillus infection present in COPD patients include sensitisation, chronic pulmonary aspergillosis (CPA) and invasive pulmonary aspergillosis (IPA). This review will summarise diagnostic and treatment of aspergillus in COPD patients.     

Newer antifungal agents for invasive fungal infections in patients with haematological malignancy

Since 2001 five new systemically administered antifungal agents have been approved for clinical use. This represents a major advance for antifungal therapy in haematological malignancy patients undergoing chemotherapy or haematopoietic stem cell transplant (HSCT). The echinocandins are a new class of antifungals with a novel mode of action. Capsofungin has already established itself as a valuable therapy for candidaemia and salvage therapy of invasive aspergillosis. Although both anidulafungin and micafungin are approved for treatment of candidiasis, their role in invasive aspergillosis requires more clinical trial evaluation. Of the two newer triazoles, voriconazole has been recommended in international guidelines as primary therapy for acute invasive aspergillosis. Posaconazole has a broad spectrum of activity in vitro and a potentially key role in antifungal prophylaxis in high-risk HSCT recipients and during prolonged neutropenia. Although some of these drugs have important interactions with other medications, and potential toxicities, they are safer to use and more efficacious than amphotericin B deoxycholate. Their arrival gives more choices to treat rarer mycoses and will facilitate clinical trial assessment of combination therapy of aspergillosis where single agent therapy gives less than 50% success rates.     

Disseminated Invasive Aspergillosis with Cerebral Involvement Successfully Treated with Caspofungin and Voriconazole

Abstract We describe a case of cerebral aspergillosis which was successfully treated with a combination of caspofungin and voriconazole. The patient remains in remission 18 months after stopping antifungal treatment. We discuss primary and salvage therapy of invasive aspergillosis with focus on cerebral involvement. Since historical data showed a fatal outcome in most cases, amphotericin B does not cross the blood brain barrier while voriconazole does, we chose a combination of voriconazole plus caspofungin as primary therapy.     

Voriconazole in the management of invasive aspergillosis in two patients with acute myeloid leukemia undergoing stem cell transplantation

The management of invasive aspergillosis in patients with hematological malignancies remains controversial. A major problem is how to manage patients who had invasive aspergillosis during remission induction and consolidation therapy and then undergo SCT. Indeed in these patients the mortality rate related to invasive aspergillosis recurrence remains unacceptably high. We report two cases of patients who underwent remission induction for AML, developed invasive aspergillosis during antifungal prophylaxis with itraconazole, failed amphotericin B deoxycholate and liposomal amphotericin B treatment, were successfully treated with voriconazole and eventually underwent SCT with voriconazole prophylaxis without reactivation of invasive aspergillosis.     

Prophylaxis of invasive aspergillosis with voriconazole or caspofungin during building work in patients with acute leukemia

Background

Invasive aspergillosis is a common life-threatening infection in patients with acute leukemia. The presence of building work near to hospital wards in which these patients are cared for is an important risk factor for the development of invasive aspergillosis. This study assessed the impact of voriconazole or caspofungin prophylaxis in patients undergoing induction chemotherapy for acute leukemia in a hematology unit exposed to building work.

Design and Methods

This retrospective cohort study was carried out between June 2003 and January 2006 during which building work exposed patients to a persistently increased risk of invasive aspergillosis. This study compared the cumulative incidence of invasive aspergillosis in patients who did or did not receive primary antifungal prophylaxis. The diagnosis of invasive aspergillosis was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria.

Results

Two-hundred and fifty-seven patients (213 with acute myeloid leukemia, 44 with acute lymphocytic leukemia) were included. The mean age of the patients was 54 years and the mean duration of their neutropenia was 21 days. Eighty-eight received antifungal prophylaxis, most with voriconazole (n=74). The characteristics of the patients who did or did not receive prophylaxis were similar except that pulmonary antecedents (chronic bronchopulmonary disorders or active tobacco use) were more frequent in the prophylaxis group. Invasive aspergillosis was diagnosed in 21 patients (12%) in the non-prophylaxis group and four (4.5%) in the prophylaxis group (P=0.04). Pulmonary antecedents, neutropenia at diagnosis and acute myeloid leukemia with high-risk cytogenetics were positively correlated with invasive aspergillosis, whereas primary prophylaxis was negatively correlated. Survival was similar in both groups. No case of zygomycosis was observed. The 3-month mortality rate was 28% in patients with invasive aspergillosis.

Conclusions

This study suggests that antifungal prophylaxis with voriconazole could be useful in acute leukemia patients undergoing first remission-induction chemotherapy in settings in which there is a high-risk of invasive aspergillosis.     

Invasive fungal disease in allogeneic hematopoietic stem cell transplant recipients: an autopsy-driven survey

Abstract: Invasive mycoses are pre-eminent causes of morbidity and mortality in the allogeneic stem cell transplant setting. In spite of novel diagnostic modalities, the timely and specific identification of invasive mycoses still remains challenging. We analyzed the case history of 97 consecutive patients receiving 103 allogeneic stem cell transplants between January 2003 and October 2006 performed by a single team at 2 transplant centers in Budapest, Hungary. All patients with febrile neutropenia not responding to broad-spectrum antibacterial therapy received amphotericin B deoxycholate empirically. In cases of proven or probable invasive aspergillosis, intravenous voriconazole was instituted. Patients who failed to improve on initial therapy were treated with an antifungal combination, while responders were switched to oral voriconazole. A total of 38 patients died following allografting. Both centers had an autopsy rate of 100% due to central health care regulations. An infectious cause of death could be identified in 15 cases, invasive fungal disease being the most prevalent and accounting for 10 fatalities. Six patients died of invasive aspergillosis, while invasive candidiasis and mucormycosis led to a fatal outcome in 2 cases each. Despite the regular use of galactomannan antigen detections and imaging, an ante mortem diagnosis of proven/probable invasive fungal disease could only be established in 4 of 10 autopsy-verified cases (aspergillosis: 3, candidiasis: 1, mucormycosis: 0). In the remaining 6 patients, deep mycoses were missed clinically and were revealed only by postmortem histology. Present diagnostic and therapeutic strategies still seem to be suboptimal for the management of invasive fungal diseases in the high-risk allogeneic stem cell transplant population.     

Graded isavuconazole introduction in a patient with voriconazole allergy

Triazole antifungal drugs may rarely cause serious allergic reactions including angioedema. No standardized tests are available to predict cross‐reactivity within the azole class and little guiding information exists on whether to change therapy within the class or to another class after a serious allergic reaction. Herein we report the first successful use, to our knowledge, of graded isavuconazole introduction for treatment of aspergillosis in a liver transplant recipient with severe voriconazole allergy.     

Neue Medikamente zur Behandlung systemischer Mykosen

The past few years have seen the advent of several new antifungal agents. The echinocandin, caspofungin, has greatly expanded the antifungal armamentarium by providing a cell wall-active agent with candidacidal activity as well as demonstrated clinical efficacy in the therapy of aspergillosis refractory to available therapy. In addition, in clinical trials, caspofungin exhibited efficacy comparable to amphotericin B for invasive and/or fluconazole-resistant Candida infections. According to a randomised trial, voriconazole has added a significantly improved therapeutic option for primary therapy of invasive aspergillosis. Additionally, voriconazole may be used successfully as salvage therapy for other fungal infections, i.e. cryptococcosis. Despite the advances offered by each of these drugs, the morbidity and mortality associated with invasive fungal infections remains high. Considering the adverse effects of the available antifungal agents and the considerable costs for their application, meaningful clinical trials for a precise indication in different clinical situations are urgently needed.     

Fatal invasive aspergillosis in an adolescent with cystic fibrosis

We report on a 13-year-old girl with cystic fibrosis (CF) who developed refractory airflow obstruction despite high-dose steroids. She developed invasive aspergillosis and died despite oral and intravenous antifungal therapy. We speculate that the increasing use of immunosuppressive strategies and aggressive antipseudomonal therapy in CF may lead to an increase in aspergillus lung disease, including invasive aspergillosis in the future.     

Persistent poor long-term prognosis of allogeneic hematopoietic stem cell transplant recipients surviving invasive aspergillosis

Background Voriconazole treatment increases early survival of allogeneic hematopoietic stem cell transplant recipients with invasive aspergillosis. We investigated whether this survival advantage translates into an increased long-term survival. DESIGN AND METHODS: This retrospective study involved all patients with an invasive aspergillosis diagnosis transplanted between September 1997 and December 2008, at the Saint-Louis Hospital, Paris, France. The primary end point was survival up to 36 months. Survival analysis before and after 12 weeks, as well as cumulative incidence analysis in a competing risk framework, were used to assess the effect of voriconazole treatment and other factors on mortality. RESULTS: Among 87 patients, 42 received first-line voriconazole and 45 received another antifungal agent. Median survival time was 2.6 months and survival rate at 36 months was 18%. Overall, there was a significant difference in the survival rates of the two groups. Specifically, there was a dramatic difference in survival rates up to ten months post-aspergillosis diagnosis but no significant difference after this time. Over the first 36 months as a whole, no significant difference in survival rate was observed between the two groups. First-line voriconazole significantly reduced aspergillosis-attributable mortality. However, first-line voriconazole patients experienced a significantly higher probability of death from a non-aspergillosis-attributable cause. Conclusions Although the prognosis for invasive aspergillosis after stem cell transplantation has dramatically improved with the use of voriconazole, this major advance in care does not translate into increased long-term survival for these severely immunocompromised patients.     

Opaque hemithorax - An interesting case

ObjectiveTo present an interesting case of left opaque hemithorax in an adult female and discuss its assessment and management.MethodsDesign: Case Report. Setting: Tertiary care hospital. Patient: One.Results44yrs retropositive female admitted with complaints of acute onset dry cough since 15–20 days, sudden breathlesness since 5 days which was progressive in nature, left sided heaviness in chest since 5 days. CECT Thorax showed complete collapse of left lung with cut off of left main bronchus while video bronchoscopy showed left main bronchus completely blocked with very thick necrotic mass and was difficult to dislodge. Debulking with cryo probe was done and left main bronchus was completely cleared off. Allergen panel showed very high serum IgE, high S.IgE against aspergillus and high specific S.IgG against aspergillus. Patient and her Chest X-ray showed significant improvement post cryo debulking and was discharged satisfactorily on oral voriconazole therapy.ConclusionEndobronchial aspergillosis is characterized by massive intrabronchial overgrowth of the aspergillus species, mainly aspergillus fumigatus. Most patients with chronic pulmonary aspergillosis, including those with simple aspergillomas and Aspergillus nodules, have positive Aspergillus IgG antibodies in the blood. We hereby present a case of 44 yrs female presenting with complaints of dry cough and dyspnea and was diagnosed with endobronchial aspergillosis with complete obliteration of left main bronchus by fungal debris in which cryo debulking was done which relieved the symptoms significantly and was discharged in satisfactory condition on oral voriconazole therapy.