Cerebral aspergillosis in the critically ill: two cases of successful medical treatment

Objective Invasive aspergillosis is associated with a poor prognosis, especially in critically ill patients with cerebral involvement. We present two cases of cerebral invasive aspergillosis successfully treated in the intensive care unit with combination antifungal therapies and without surgery.Case presentation The first patient was a 49-year-old man with rheumatoid arthritis who received corticosteroid and cyclophosphamide treatment and developed pulmonary and cerebral invasive aspergillosis. After failure of voriconazole the patient had a successful outcome with voriconazole and liposomal amphotericin B therapy. The patient returned home after an 8-month hospital stay. The second patient was a 54-year-old woman with pulmonary neoplasia and corticosteroid treatment who developed pulmonary and cerebral invasive aspergillosis. After failure of voriconazole and liposomal amphotericin B therapy the patient had a favorable outcome with liposomal amphotericin B and caspofungin therapy. The patient died 10 months after initial diagnosis of cardiac tamponade unrelated to fungal infection.Discussions These cases illustrate the improving prognosis of invasive aspergillosis due to the availability of new treatments, especially in cases of cerebral involvement. It also demonstrates that the outcome of critically ill patients requiring mechanical ventilation for invasive aspergillosis can be favorable. The treatment of patients with invasive cerebral aspergillosis in the intensive care setting should be encouraged.     

艾滋病患者医院真菌感染回顾性调查

目的：调查与分析艾滋病患者医院真菌感染状况。方法：回顾性分析该院2005-2008年1463例AIDS患者真菌感染的临床资料。结果：1463佣真菌感染部位以口咽部为主,占82．09％。真菌种类白色假丝酵母菌属占首位,为71．09％,其次是新型隐球酵母菌,占19．06％。住院时间、需要HAART治疗、使用广谱抗生索、侵袭性操作。抗真菌的不规范治疗是真菌感染的危险因素。结论;控制感染的危险因素,合理使用抗生索,减少侵入性操作,提高患者机体的免疫力是预防艾滋病患者真菌感染的主要措施。     

Voriconazole-induced photosensitivity

Voriconazole is a broad-spectrum triazole antifungal agent indicated for invasive aspergillosis, refractory Candida infections, and other emerging invasive fungal infections. Adverse cutaneous reactions associated with voriconazole therapy occur in fewer than 10% of treated patients and range from mild erythematous eruptions to life-threatening reactions such as the Stevens-Johnson syndrome and toxic epidermal necrolysis. Photosensitivity reactions are an uncommon but characteristic dermatitis in voriconazole recipients, particularly following chronic administration. We report a case of voriconazole-induced phototoxicity in a 50-year-old male with Candida parapsilosis endocarditis that reversed on discontinuation of the drug.     

气道侵袭性曲霉感染19例分析

目的 探讨气道侵袭性曲霉感染的临床表现、诊断及治疗方法。方法 对1999年12月至2003年12月间经病原学和（或）病理学证实的19例气道侵袭性曲霉感染患者的临床资料进行回顾性分析。结果 所有病例均有基础疾病．主要为原发肺部肿瘤（12例）、肺转移瘤（3例）、支气管结核（4例），其中因气道狭窄行支架植入术9例。感染的常见诱因有低蛋白血症（9例）、长期使用广谱抗生素（7例）、糖皮质激素（2例）及免疫抑制剂（10例）和化疗后粒细胞减少或缺乏（3例）；感染的病原菌以烟曲霉为主（14例，73．7％）；临床主要表现为咳嗽、咳痰（84．2％），痰为白色或黄色胶胨样，或为刺激性干咳，近半数患者伴咯血（47．4％）、胸闷、气急（26．3％）等，9例（47．4％）患者有发热；白细胞增高者12例（63．2％）。分别采用两性霉素B、两性霉素B脂质体、伊曲康唑全身用药，结合支气管镜腔内局部治疗，有效率为47．4％。结论 气道侵袭性曲霉感染是一种特殊类型的真菌感染，近年来呈逐年增加的趋势，这与长期大剂量广谱抗生素、大剂量糖皮质激素以及免疫抑制剂应用、肿瘤化疗等密切相关，也与检测技术的提高尤其是支气管镜腔内诊治技术的广泛开展有关；感染的病原以烟曲霉为主。治疗非常棘手，除全身应用抗真菌药物外，还须联合支气管镜腔内局部治疗。     

Breakthrough disseminated zygomycosis induced massive gastrointestinal bleeding in a patient with acute myeloid leukemia receiving micafungin

A 69-year-old man, who had been receiving prednisolone for 11 months for treatment of interstitial pneumonia, was diagnosed with acute myeloid leukemia. During induction therapy, he developed severe pneumonia. Although meropenem and micafungin were started, he died of circulatory failure owing to massive gastrointestinal bleeding. Autopsy specimens obtained from the stomach revealed fungal hyphae, which had invaded diffusely into submucosal vessels and caused the massive gastric bleeding. The same hyphae were also observed in both lungs. A diagnosis of disseminated zygomycosis was confirmed by its characteristic histopathological findings. Because zygomycetes are spontaneously resistant to the newer antifungal agents, such as voriconazole or micafungin, it seems likely that the prevalence of zygomycosis as a breakthrough infection may increase in the future. Zygomycosis is a rare, but life-threatening, deep fungal infection that appears in immunologically or metabolically compromised hosts. Its manifestations are clinically similar to those of invasive aspergillosis. In addition to the well-established epidemiology of zygomycosis, this case suggests the following new characteristics. (1) Although the gastrointestinal manifestation of zygomycosis is relatively rare, it is observed more frequently than invasive aspergillosis. (2) Gastrointestinal zygomycosis occasionally leads to the development of necrotic ulcers and may induce hemorrhagic shock.(3) We should be cautious of an occurrence of breakthrough zygomycosis when we use echinocandins for patients with known risk factors, especially steroid use and neutropenia. (4) For patients who are receiving broad-spectrum antibiotics and echinocandins, who are negative for culture studies and aspergillus antigen, and who present with unresolved fever, it is important to make a prompt clinical diagnosis of zygomycosis.     

Voriconazole: therapeutic review of a new azole antifungal

The new triazole antifungal, voriconazole (Vfend, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).     

Co-infection with invasive pulmonary aspergillosis and Pneumocystis jirovecii pneumonia after corticosteroid therapy

A 95-year-old man with chronic obstructive pulmonary disease and chronic hepatitis C virus infection was treated for acute lung injury caused by Chlamydophila pneumoniae with antibiotics and high-dose corticosteroids. In total, 7,500 mg methylprednisolone and 680 mg prednisolone were administered over 21 days. However, respiratory failure progressed, and chest computed tomography (CT) scan showed bilateral ground-glass opacity and cavity-forming consolidation in the right upper lobe. Despite intensive therapy, the patient died of multiple organ failure on day 7. CT-guided necropsy was performed, and pathological examination revealed invasive pulmonary aspergillosis and Pneumocystis jirovecii pneumonia. Invasive pulmonary aspergillosis and P. jirovecii pneumonia are both life-threatening opportunistic fungal infections. Co-infection of these organisms is rare but possible if the patient is in an extremely immunocompromised state. Short-term but high-dose systemic corticosteroid therapy was considered to be the risk factor in this case. We should pay more attention to immunocompromised hosts who might be suffering from co-infection of opportunistic infections. Moreover, we need to consider preventive measures in such high-risk cases.     

A case of allergic bronchopulmonary aspergillosis leading to pneumonia with unusual organisms

We describe the case of a 50-year-old male with a history of asthma and seizure disorder who presented with a 5-month history of dyspnea. The patient had been treated with multiple courses of antibiotics for presumed community-acquired pneumonia before being determined to have allergic bronchopulmonary aspergillosis (ABPA) by serologic and radiographic criteria. Inflammation resulting from this disease had potentiated a postobstructive pneumonia caused by Nocardia asteroides and Stenotrophomonas maltophilia. Therapy with corticosteroids, trimethoprim sulfa, and voriconazole failed to prevent subsequent destruction of the right upper lobe and the patient required surgical intervention. The discussion emphasizes the diagnostic criteria for ABPA including historic, serologic, and radiographic findings; staging, and treatment. Other possible diagnoses, such as invasive pulmonary aspergillosis, chronic necrotizing aspergillosis, and hyper-IgE syndrome are also briefly reviewed.     

Voriconazole: therapeutic review of a new azole antifungal

The new triazole antifungal, voriconazole (Vfend^®, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan^®, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).     

Acute isolated Aspergillus appendicitis in pediatric leukemia

Aspergillus is a widespread fungus in the environment, usually invades through the respiratory tract. Invasive aspergillosis is a fatal disseminated infection in immunocompromised hosts. Appendicitis occurs scarcely in patients with leukemia. We report a case of Aspergillus appendicitis that underwent an urgent appendectomy. An 11-year-old boy received the diagnosis of acute myeloid leukemia, because of the bone pain and results of the bone marrow study. He obtained a complete remission after cancer chemotherapy and received peripheral blood stem cell transplantation from a histocompatible sibling. Leukemia relapsed 5 months post-transplant. Induction therapy with etoposide, cytarabine and mitoxantrone was started on Candida prophylaxis. Fifteen days after the end of chemotherapy, he presented with febrile neutropenia and abdominal pain, that did not respond to broad-spectrum antibiotics. Serum levels of C-reactive protein, β-D-glucan and procalcitonin were unremarkable. Computed tomography scan revealed a swollen appendix and the adjacent tissue inflammation. An urgent appendectomy led to a tentative diagnosis of Aspergillus appendicitis based on the histopathological findings of many fungal hyphal forms. Panfungal polymerase chain reaction using DNA extracted from the lesion determined the pathogen of Aspergillus niger. There was no evidence of invasive aspergillosis. During the prolonged anti-fungal therapy, he achieved a remission of leukemia and underwent the second hematopoietic cell transplantation. To our knowledge, Aspergillus appendicitis was reported to occur in 5 leukemia patients. Four of them survived after appendectomy and one died from intestinal perforation. Early surgical intervention is mandatory for a cure of Aspergillus appendicitis in neutropenic patients on Candida prophylaxis.     

Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis.

Emergence of resistance to antifungal drugs during therapy for invasive aspergillosis has received scant attention. We recovered Aspergillus isolates from six patients with invasive aspergillosis, who were receiving amphotericin B before fungal isolation. Although isolates were susceptible to amphotericin B in vitro, none of the patients survived. The MIC of amphotericin B for isolates was similar to that for isolates from 35 patients with no prior exposure to amphotericin B. Laboratory attempts to produce amphotericin B resistance in Aspergillus were unsuccessful. These data indicate that emergence of resistance to amphotericin B is uncommon during therapy for invasive aspergillosis.     

以咯血为突出表现的COPD并侵袭性肺曲霉病误诊一例

目的 分析慢性阻塞性肺疾病（COPD）并侵袭性肺曲霉病（IPA）的临床特征及误诊原因,以期提高早期诊治水平.方法 对以咯血为突出表现的COPD并IPA误诊1例的临床资料进行回顾性分析.结果 本例以咯血为突出表现,经相关医技检查拟诊为肺部感染、支气管扩张症,予广谱抗生素、糖皮质激素治疗无效且病情加重,3次痰培养提示曲霉菌感染,真菌葡聚糖及内毒素检查阴性,行抗真菌治疗后,临床治愈.确诊为COPD并IPA.结论 COPD并IPA临床诊断较困难,综合分析患者临床表现及多次行影像学、微生物学、血清学检查是提高该病诊断率、改善患者预后的有效手段.     

Management of invasive fungal infections: a role for polyenes

The spectrum of invasive fungal infections (IFIs) continues to evolve with the emergence of rare and resistant fungal pathogens. Clinicians are faced with difficult diagnostic and treatment challenges in the management of immunocompromised patients at high risk of developing IFIs. Early and appropriate antifungal therapy is essential for a successful outcome when treating invasive mycoses. The armamentarium of antifungal drugs continues to grow; the three main classes of commonly administered drugs are the polyenes, azoles and echinocandins. The newer triazoles and the echinocandins have changed primary treatment options for some fungal infections, such as aspergillosis and candidiasis. However, despite their toxic potential, the oldest antifungal drugs, polyenes, remain useful in the treatment of IFIs because of their broad-spectrum activity, low rates of resistance and established clinical record, particularly in immunocompromised patients with breakthrough fungal infections. This review highlights important issues in the treatment of IFIs for consideration by clinicians.     

26例儿童深部真菌感染的临床病例分析

目的探讨儿童深部真菌感染种类及导致感染的危险因素.方法 回顾性调查分析2005～2010年间26例已确诊为深部真菌感染的住院儿童临床资料,分析其深部真菌感染种类及危险因素.结果 真菌感染种类:在26例真菌感染患者中,白色念珠菌20例,占76.92%;热带念珠菌4例,占15.38%;毛霉菌和新型隐球菌感染各1例,各占3.85%.危险因素分析:在26例感染患者中,进行过侵入性操作,占92.30%;使用了2种及2种以上广谱抗生素≥4 d,占88.46%;在使用了2种及2种以上广谱抗生素≥4 d后体温在38 ℃以上的,占65.38%;手术患者,占50%;应用过呼吸机,占50%.26例经抗真菌治疗:治愈21例占,80.77%;自动出院2例,占7.7%;死亡3例,占11.54%.结论住院儿童深部真菌感染与各种侵入性操作、长时间使用多种抗生素、手术和使用呼吸机等多种危险因素有关.早期诊断及合理选用抗真菌药物是治愈的关键.     

老年患者侵袭性肺部真菌感染的高危因素分析

目的 分析老年患者侵袭性肺部真菌感染的高危因素及防治措施.方法 对76例侵袭性肺部真菌感染的老年患者的临床资料进行回顾性分析.结果 76例老年患者平均年龄72.4岁,共分离真菌117株,其中念珠菌属占94.8%;均有基础疾病重、长期应用广谱抗生素、大剂量使用激素、机械通气和使用各种有创导管等高危因素;早期、足量药物治疗效果良好.结论 重视消除或避免侵袭性肺部真菌感染的高危因素,采取积极有效的防治措施,有助于降低临床病死率.     

A neonatal case of chronic granulomatous disease,initially presented with invasive pulmonary aspergillosis

Chronic granulomatous disease (CGD) often presents with infectious illness, such as repeating bacterial and fungal infections, due to the inability to generate superoxide, which would destroy certain infectious pathogens, and is usually diagnosed in childhood.We describe a CGD case diagnosed in neonatal period, who initially presented with invasive aspergillosis. Neonatal invasive pulmonary aspergillosis is very rare and, to the best of our knowledge, this might be the youngest case in Japan.     

Isolation of Aspergillus in critically ill patients: a potential marker of poor outcome

OBJECTIVE: Recent reports have suggested a rising incidence of pulmonary aspergillosis in intensive care unit (ICU) patients. The aim of this study was to determine the clinical significance of isolating Aspergillus from respiratory samples of critically ill patients. DESIGN: Retrospective review of medical records. SETTING: Tertiary medical center that has a large cancer center. PATIENTS: All patients admitted to the ICU between January 1998 and August 2004, in whom Aspergillus was isolated from respiratory samples or lung tissue. INTERVENTION: None. RESULTS: The charts of 104 patients were reviewed. Aspergillus was isolated for a mean of 6.6 days after ICU admission. Thirty-three percent of patients had hematological malignancy, 10% had absolute neutropenia, 14% had bone marrow transplant, 11% had HIV infection, and 22% had chronic obstructive pulmonary disease. Upon admission to ICU, 79%, 43%, and 19% were on antibiotics, corticosteroids, or immunosuppressive therapy, respectively. Ninety percent of patients required mechanical ventilation. The mean Acute Physiologic and Chronic Health Evaluation II score on ICU admission was 20.6, with predicted mortality of 35.5%. However, the actual ICU mortality rate for the cohort was 50%. Twenty-eight percent of patients were diagnosed with probable or definite invasive pulmonary aspergillosis, and 72% had Aspergillus colonization. On univariate analysis, the significant clinical differences between the 2 groups were the presence of neutropenia (P < .05), immunosuppressants (P < .05), antibiotics (P < .05), or bone marrow transplant (P < .05). The differences in Acute Physiologic and Chronic Health Evaluation II score, the need for mechanical ventilation, ICU length of stay, and ICU mortality were not statistically significant. On multivariate analysis, the following factors were independently associated with invasive diseases, bone marrow transplantation (P < .01), hematological malignancy (P = .02), and broad-spectrum antibiotics (P = .02). CONCLUSION: Isolation of Aspergillus in critically ill patients is a poor prognostic marker and is associated with high mortality irrespective of invasion or colonization. Those who are neutropenic, on immunosuppressive therapy, on broad-spectrum antibiotics, or had bone marrow transplantation are more likely to have invasive pulmonary aspergillosis.     

Role of innate immune receptors in paradoxical caspofungin activity in vivo in preclinical aspergillosis

This study investigated the possible mechanisms underlying the paradoxical caspofungin activity in vivo in preclinical aspergillosis. We evaluated the activity of escalating doses of caspofungin in vivo in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors. The therapeutic efficacy of caspofungin in experimental invasive aspergillosis was strictly dose dependent, being observed at doses of 0.1 and 1 mg/kg of body weight depending on the experimental models. Paradoxical increase in pulmonary fungal burden as well as inflammatory pathology was observed at the highest dose of caspofungin (5 mg/kg), occurred independently of the so-called Eagle effect and susceptibility to caspofungin in vitro, and was contingent upon the presence of TLR2, Dectin-1, and TLR9. Increased expression of Dectin-1 and TLR9 were observed upon exposure to caspofungin in vitro and in vivo. Together, these findings suggest that the net activity of caspofungin in vivo is orchestrated by the activation, directly or indirectly, of multiple innate immune receptors.     

Transurethral passage of Aspergillus fungus balls in acute myelocytic leukemia.

A patient with acute myelocytic leukemia who had a chronic febrile illness during the induction of remission of leukemia developed asymptomatic discrete pulmonary infiltrates which rapidly evolved into cavities containing homogeneous opacities. Over the next five weeks, the cavities resolved without specific treatment. The patient subsequently passed large fungus balls in the urine, and the diagnosis of disseminated aspergillosis was made. A course of intravenous amphotericin B therapy was completed without complications. This case demonstrates the importance of culturing urine specifically for fungal organisms in the immunosuppressed host.     

Numerous granulocyte transfusions to a patient with severe aplastic anemia without severe complication

One of the most important morbidity causes of aplastic anemia is invasive fungal infections. It could not be possible to take control of infection without neutrophils despite the recent developments in the antifungals. In this presented case, a patient with severe aplastic anemia, granulocyte transfusion were administered as 46 times because of the presence of widely invasive aspergillosis and resistance. Only fever reaction was observed as a complication of transfusion amongst the other complications such as acute lung damage, alloimmunisation, and graft-versus-host disease. Granulosit transfusions should not be avoided in patients who had an indication for.