Protective effect of human granulocyte colony stimulating factor (hG-CSF) on Candida, infections in normal and immunosuppressed mice

Prophylactic treatment with human granulocyte colony stimulating factor (hG-CSF) affords significant protection against systemic infections caused by C. albicans in cyclophosphamide-treated but not in cortisone-treated mice. Localized candidosis in neutropenic mice does not respond to hG-CSF. Our data show that granulocytes play an important role in the immune defence against deep mycoses, but not against local infections. From our data it is reasonable to assume that prophylactic treatment with hG-CSF may augment the resistance of immunosuppressed patients to deep Candida infection, but it would be of little help against oral candidosis of HIV patients.     

Pseudomembranous tracheobronchial aspergillosis: a rare manifestation of invasive aspergillosis in a non-neutropenic patient with Hodgkin's disease

Pseudomembranous tracheobronchial aspergillosis coincident with systemic pulmonary aspergillosis represents a rare manifestation of fungal infection in immunocompromized hosts. We report on a patient with recurrent Hodgkin's disease, showing this infectious pattern after treatment with corticosteroids within the antineoplastic schedule, whereas neutropenia--the main risk factor for mold infections--had not occurred. An impaired number of helper T lymphocytes was merely detected as an additional, but hypothetical risk factor, when investigating the status of immunosuppression. Treated systemically with amphotericin B, the patient recovered quickly, although reported mortality rates are disastrous. What is crucial for the clinical management is an early diagnosis by bronchoscopy and cultural proof of the pathogen followed by an adequate antifungal treatment.     

Therapy of invasive aspergillosis with itraconazole: improvement of therapeutic efficacy by early diagnosis

We report on the treatment of invasive aspergillosis with the new triazole antimycotic agent itraconazole. All 11 patients suffered from pulmonary invasive aspergillosis. Two patients also had cerebral aspergillosis; in one of these patients the paranasal sinuses were also invaded. Underlying diseases were acute lymphoblastic leukaemia (n = 3), acute myeloid leukaemia (n = 4); one patient underwent allogeneic bone marrow transplantation before he developed aspergillosis; another was transplanted after successful aspergillosis treatment, liver cirrhosis (n = 1), lung infarction after pulmonary embolism (n = 1), chronic bronchitis after pulmonary tuberculosis (n = 1) and AIDS (n = 1). In five cases initial diagnosis was established by means of mycological methods and clinical signs. In six patients invasive pulmonary aspergillosis was initially diagnosed due to the clinical criteria presented in this paper. Secondary mycological confirmation after onset of therapy was achieved in five out of these six patients. All of the patients initially responded to therapy. One female patient experienced a relapse of aspergillosis and died of cerebral involvement and relapsing leukaemia. Two further patients died due to underlying diseases (pulmonary embolism, relapsing leukaemia). Nine patients (82%) were cured of the mycosis, including the patient with cerebral involvement; two underwent surgical resection of residual pulmonary lesions. Itraconazole is a very effective drug for treatment of invasive aspergillosis. Therapeutic efficacy can be optimized by early diagnosis using clinical criteria and prompt start of treatment.     

Antimycotic Therapy with Liposomal Amphotericin-B for Patients Undergoing Bone Marrow or Peripheral Blood Stem Cell Transplantation

Suspected deep or systemic mycosis in patients undergoing high-dose therapy and autologous or allogeneic bone marrow transplantation (BMT) requires an immediate systemic antimycotic therapy. Intravenous therapy with the standard drug conventional amphotericin-B is associated with severe adverse effects like nephrotoxicity and chills. Furthermore, BMT patients often receive other potential nephrotoxic drugs such as CsA or virustatics. In this study, we report 74 BMT-patients treated with liposomal amphotericin-B for culture-documented aspergillosis (n = 5) or candidiasis (n = 6), or for serologically (n = 35) or clinically suspected mycosis or as prophylaxis (n = 2). Therapy was initiated with a median dose of 2.8 (0.64-5.09) mg/kg body-weight and continued for 13 (1-55) days. The drug was excellently tolerated and only in one was therapy stopped due to severe chills and fever. Severe organ impairment was not obserded under therapy with liposomal amphotericin-B. Creatinine decreased in five patients after an increase under preceding therapy with the conventional formulation. Influence of liposomal amphotericin-B on bilirubin and transaminases was difficult to evaluate due to therapy-related toxicity, veno-occlusive disease (VOD), and graft-versus-host disease (GvHD). 10/11 culture-positive patients died from aspergillosis (5/5) or candidiasis (5/6), but in 9/11 of these subjects the immunity was additionally compromised by GvHD, steroid therapy, and VOD. Liposomal amphotericin-B was effective in preventing relapse of systemic mycosis in 10/12 patients with a history of aspergillosis (n = 11) or candidiasis (n = 1). We conclude, that favourable toxicity of liposomal amphotericin-B should encourage dose escalation studies of liposomal amphotericin-B randomised against the conventional formulation and that the comparison of patients undergoing BMT with patients under standard chemotherapy might be difficult because of additional risk factors of the BMT-patients.     

Caspofungin plus posaconazole as salvage therapy of invasive fungal infections in immunocompromised patients

Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients. Substantial improvements of treatment have been achieved by the introduction of new antifungal agents including azoles (e.g. posaconazole) and echinocandins (e.g. caspofungin). However, mortality associated with treatment-refractory aspergillosis remains high. Preliminary data suggest that the combination of azoles and echinocandins may increase activity against refractory IA. The objective of the present study was to evaluate efficiency and safety of caspofungin plus posaconazole for salvage therapy in immunocompromised patients. In this monocentric, retrospective study, 31 hospitalised haematopoietic stem cell transplant recipients with IA refractory to primary treatment were treated with a combination therapy of caspofungin 50 mg a day and posaconazole 200 mg four times per day. Efficacy was assessed by signs, symptoms and the degree of pulmonary infiltrate regression. A favourable response was seen in the majority of patients (77%). In two patients (6%), clinical improvement, but no decline in pulmonary infiltrates, was observed. Five patients (16%) did not respond to combination therapy with a fatal outcome in four of them. Combination therapy was well tolerated. No patient discontinued treatment due to toxicity. This study indicates that the combination of caspofungin and posaconazole may provide an effective and tolerable therapy of IA in immunocompromised patients refractory to primary treatment.     

Voriconazole - applications and perspectives

Voriconazole (Vfend) is a new broadspectrum antifungal agent belonging to the group of triazole drugs. In vitro and in vivo efficacy was demonstrated against a large variety of yeasts with excellent activity against all Candida species but as well against Cryptococcus neoformans. Furthermore, voriconazole has shown excellent activity against many moulds in particular against Aspergillus species, but endemic fungi such as Histoplasma capsulatum are in the spectrum as well. Clinical efficacy was demonstrated in several large phase II/III studies in diseases such as oral and oesophageal candidosis, acute invasive aspergillosis or chronic invasive aspergillosis. New adverse events such as visual disturbancies has been described together with the use of voriconazole, but the majority of adverse events are similar to other triazole drugs and in particular not life-threatening. With the introduction of voriconazole a great progress in the therapy of invasive fungal infections was achieved. In the therapy of invasive aspergillosis, voriconazole is significantly more effective compared to amphotericin B desoxycholate.     

Invasive aspergillosis in patients with solid tumors

Invasive aspergillosis (IA) has been reported only rarely among patients with solid tumors. In the current study, the authors retrospectively identified 13 episodes of definite or probable IA (using European Organization for Research and Treatment of Cancer criteria) occurring in patients with solid tumors who were treated between 1994-2003. Nine patients had pulmonary IA and three patients were found to have IA of the brain. Seven patients (54%) had primary or metastatic brain tumors and 6 patients (46%) received systemic steroids within 30 days prior to the diagnosis of IA. The majority of patients (69%) had a lymphocyte count < 500/microL but only 1 patient was neutropenic within the 30 days before the diagnosis of IA was made. Nodular infiltrates and cavities were the most common radiologic findings. Seven patients (54%) responded to antifungal treatment.     

儿童白血病化疗后合并播散性曲霉菌病三例并文献复习

目的 探讨儿童白血病化疗后合并播散性曲霉菌病的临床特征、诊断、治疗及预后.方法 回顾性分析3例白血病化疗后合并播散性曲霉菌病患儿的临床特征及诊治过程.结果3例患儿的基础疾病均为白血病,存在多个侵袭性真菌病的高危因素,临床特征包括:反复发热而抗生素治疗无效,皮下硬性结节,肺部CT提示结节影、空洞,磁共振成像提示肝、脾、肾散在低密度灶(T2加权),血清半乳甘露聚糖(GM)试验阳性,均通过病理组织学检查确诊.确诊后,2例予两性霉素B脂质体抗真菌治疗超过4周,并在临床症状好转、中性粒细胞恢复及影像学提示病灶好转或无进展情况下恢复化疗,同时予口服伏立康唑维持治疗,随访6~12个月,播散性曲霉菌病达治愈标准.1例白血病持续完全缓解,截至随访结束仍生存;1例因家属要求暂停化疗,白血病复发死亡;1例因治疗无效或严重药物不良反应,多次调整抗真菌治疗方案后感染仍无法控制,且因长时间暂停化疗,白血病复发,最终死亡.结论 白血病患儿化疗后反复发热,并有多发皮下硬性结节、肺部结节或空洞、肝脾肾散发性低密度灶、GM试验阳性,应考虑合并播散性曲霉菌病.有效且足疗程的抗真菌治疗,并在适当时机兼顾化疗,有望改善患者预后.     

Fatal haemoptysis associated with invasive pulmonary aspergillosis treated with high-dose amphotericin B and granulocyte-macrophage colony-stimulating factor (GM-CSF)

Opportunistic pulmonary infections are a leading cause of morbidity and mortality in patients with chemotherapeutically treated neoplasias. With increasingly aggressive cytotoxic regimens causing prolonged neutropenia, the risk of systemic mycoses and in particular of invasive pulmonary aspergillosis has increased. We review the case of a 10-year-old child suffering from relapsed lymphoblastic leukaemia and from high-dose amphotericin B-treated invasive pulmonary aspergillosis acquired during long-standing neutropenia in the initial phase of remission induction chemotherapy. The patient died in remission after GM-CSF-induced bone marrow recovery and clinical and radiological improvement with stable plasmatic coagulation and normal thrombocyte count. Peracute massive pulmonary bleeding caused by the simultaneous arrosion of a greater pulmonary artery and a lobar bronchus by a liquefactive fungal focus was responsible. In patients with chemotherapeutically induced neutropenia and invasive aspergillosis, bone marrow recovery may lead to the liquefaction of pulmonary foci, and, in view of the well-known vasotropic nature of the infection, to a potentially lethal arrosion bleeding. With the emerging use of colony-stimulating factors for shortening and overcoming neutropenia, this so far rare complication may become of increasing importance.     

血液肿瘤并发侵袭性肺曲霉菌病的诊断及治疗进展

 侵袭性肺曲霉菌病（IPA）在造血干细胞移植受者和接受强烈化疗的血液恶性肿瘤患者中发病率较高。由于早期诊断困难、治疗不及时,其病死率较高。文章综述近年来IPA的诊治进展。     

Cerebral infection complicating systemic aspergillosis in acute leukemia: clinical and radiographic presentation

Cerebral fungal infection is becoming an increasingly recognized entity in immunocompromised patients on post-mortem examination. In order to determine the frequency of clinically significant cerebral fungal infection and define its clinical characteristics in a cohort of immunocompromised patients at high risk of fungal infection, the records of 118 patients with acute leukemia were examined for 57 clinical and laboratory features. The characteristics of 26 patients with systemic aspergillosis and acute leukemia were compared to 92 patients with acute leukemia in a control group. Eight of 118 patients (7%) had cerebral infection (seven Aspergillus, on Candida). Patients with systemic aspergillosis were more likely than patients in the control group to have focal neurologic findings (p = 0.02), confusion (p = 0.04), and abnormal computerized tomography (CT) of the brain characterized by single or multiple, enhancing or non-enhancing hypodense lesions (p = 0.02). Patients with systemic aspergillosis were more likely to die in complete remission than patients in the control group (p = 0.003); three of six patients with aspergillosis who died in remission expired as a consequence of cerebral infection. Cerebral infection complicated systemic Aspergillus infection in seven of 26 patients (27%), versus one of 16 patients with systemic Candida infection (6%) (p = NS). The authors conclude, therefore, that systemic aspergillosis complicating acute leukemia is more likely to be associated with confusion, focal neurologic findings, and and abnormal CT scan of the brain, and that these findings suggest the presence of cerebral infection. In addition, cerebral infection commonly complicates the course of systemic aspergillosis, and is a significant cause of morbidity and mortality in patients with acute leukemia. A high index of suspicion is needed to insure early diagnosis and appropriate therapy, particularly in those who achieve remission of their leukemia.Parts of this paper have been presented at the Sixth International Symposium on Infections in the Immunocompromised Host, June 3–6, 1990, Peebles, Scotland.     

Chronic pulmonary aspergillosis

Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases usually presenting with prolonged and relapsing cough, dyspnoea and weight loss. Acute symptoms such as haemoptysis and bronchial or pulmonary haemorrhage may occasionally occur. CPA affects patients with underlying pulmonary conditions, for example, chronic obstructive pulmonary disease or mycobacteriosis or common immunosuppressive conditions such as diabetes. Precise epidemiology is unknown, and while prevalence is considered low the chronic and relapsing nature of the disease challenges the treating physician. Diagnostics largely rely on serologic Aspergillus precipitins and findings on thoracic computed tomography. The latter are manifold comprising cavity formation, pleural involvement and sometimes aspergilloma. Other markers for aspergillosis are less helpful, in part due to the non‐ or semi‐invasive nature of these forms of Aspergillus infection. Various antifungals were shown to be effective in CPA treatment. Azoles are the most frequently applied antifungals in the outpatient setting, but are now compromised by findings of Aspergillus resistance. Long‐term prognosis is not fully elucidated and may be driven by the underlying morbidities. Prospective registry‐type studies may be suitable to systematically broaden our CPA knowledge base. This article gives an overview of the available literature and proposes a clinical working algorithm for CPA management.     

Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications

BACKGROUND: Assessing the outcome of patients with invasive pulmonary aspergillosis by using conventional criteria is difficult, particularly when clinical and radiologic worsening coincides with neutrophil recovery. Usually, it is assumed that this deterioration is related to progressive aspergillosis, prompting changes in patient management. However, its temporal relation with neutrophil recovery suggests that it may be caused by an immune reconstitution syndrome (IRIS). Galactomannan is an Aspergillus-specific polysaccharide that is released during aspergillosis and is detected by the serum galactomannan test, which has been approved by the United States Food and Drug Administration for the diagnosis of invasive aspergillosis. In this study, the authors used sequential galactomannan testing to distinguish IRIS responses from progressive aspergillosis. METHODS: From April 2001 to December 2006, patients with hematologic malignancies underwent galactomannan screening during periods when they were at risk. The clinical and laboratory findings from patients who had >or=2 consecutive positive galactomannan assays (optical density, >or=0.5) were reviewed. RESULTS: Nineteen neutropenic patients with aspergillosis developed clinical and radiologic pulmonary deterioration during neutrophil recovery. Deterioration coincided with microbiologic response, as documented by rapid normalization of serum galactomannan, and, in 16 patients, was followed by complete clinical response and survival at 3 months, although there were no changes in antifungal therapy. The 3 patients who died during the first month had no evidence of aspergillosis at autopsy examination. CONCLUSIONS: The authors propose that IRIS was responsible for the current findings and provide a definition for the syndrome. They also recommend serial galactomannan testing to guide aspergillosis management. Declining galactomannan values imply IRIS with an aspergillus response and obviate the need for invasive procedures and alternative antifungal therapies, whereas persistent galactomannan elevation indicates progressive aspergillosis and requires prompt treatment modification.     

Rapid improvement of osseous sarcoidosis after the treatment of pulmonary aspergillosis by itraconazole

Osseous sarcoidosis is relatively uncommon, and treatment with corticosteroids is not always effective. Moreover, patients with an advanced stage of pulmonary sarcoidosis are sometimes infected with aspergillus in the cavities of the pulmonary lesions, and long-term use of corticosteroids should be prohibited to prevent the development of fatal invasive pulmonary aspergillosis. Here, we described a unique case of osseous sarcoidosis with pulmonary aspergillosis, showing a rapid improvement of the osseous symptoms just after the administration of the antifungal agent, itraconazole. Itraconazole is likely to become a candidate among new therapeutic agents for osseous sarcoidosis.     

Pneumonia in febrile neutropenic patients: radiologic diagnosis.

Pneumonia in febrile neutropenic cancer patients should be diagnosed as early as possible, because prompt institution of targeted therapeutic measures might be essential for their prognosis. Conventional chest radiographs frequently fail to detect lung infiltrates at an early stage, meaning that a normal chest radiograph finding must be interpreted with caution. Thoracic computed tomograph scans provide a much higher yield and are therefore recommended in patients at risk for a complicated pulmonary infection. Lung infiltrates documented by computed tomograph scans (eg, nodular infiltrates with or without a halo, ground-glass opacities, or cavitations with or without air crescent signs) open up a wide range of differential diagnoses, such as invasive pulmonary aspergillosis, other types of pneumonia, hemorrhage, infiltration by the underlying malignancy, drug toxicity, alveolar proteinosis, or acute respiratory distress syndrome. High-resolution techniques or magnetic resonance imaging may provide further details to help distinguish inflammatory processes from processes that may not require an antimicrobial intervention. Sequential nonculture-based monitoring for invasive fungal infections, using Aspergillus antigen sandwich enzyme-linked immunosorbent assay, and panfungal or Aspergillus-specific polymerase chain reaction, may add important tools in the early identification of patients who may benefit from systemic antifungal treatment.     

Patho-radiologic correlation of invasive pulmonary aspergillosis in the compromised host

The autopsy findings and antemortem radiographic abnormalities were correlated in 20 patients with invasive pulmonary aspergillosis to define typical radiographic patterns, their progression and anatomic basis. Sixteen (80%) patients had radiographic abnormalities due to aspergillosis. Fifty-nine percent of the specific radiographic abnormalities seen in these patients were caused by anatomic lesions of asperigillosis and 67% of such anatomic lesions were radiographically definable. The most common initial radiographic pattern was a patchy density (single or multifocal) or a well defined nodule. The densities remained stable in half the patients but progressed, over several weeks to either diffuse consolidation or cavitation in the others. Most anatomic lesions were categorized as either nodular ("target") lesions (1-3 cm in diameter) or hemorrhagic infarctions (5-10 cm in diameter), both due to vascular invasion causing thrombosis and ischemic necrosis. Unlike pulmonary candidiasis, which is usually radiographically undetectable, invasive pulmonary asperigillosis frequently caused radiographically visible lesions.     

Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients: Guidelines of the infectious diseases working party of the German Society of Haematology and Oncology

Patients with neutropenia lasting for more than 10 d, who develop fever and pulmonary infiltrates, are at risk of treatment failure under conventional broad-spectrum antibacterial therapy. Filamentous fungi are predominant causes of failure, however, multi-resistant gram-negative rods such as Pseudomonas aeruginosa or Stenotrophomonas maltophilia may be involved. Prompt addition of mould-active systemic antifungal therapy, facilitated by early thoracic computed tomography, improves clinical outcome. Non-culture-based diagnostic procedures to detect circulating antigens such as galactomannan or 1,3-beta-d-glucan, or PCR techniques to amplify circulating fungal DNA from blood, bronchoalveolar lavage or tissue specimens, may facilitate the diagnosis of invasive pulmonary aspergillosis. CT-guided bronchoalveolar lavage is useful in order to identify causative microorganisms such as multidrug-resistant bacteria, filamentous fungi or Pneumocystis jiroveci. For pre-emptive antifungal treatment, voriconazole or liposomal amphotericin B is preferred. In patients given broad-spectrum azoles for antifungal prophylaxis, non-azole antifungals or antifungal combinations might become first choice in this setting. Antifungal treatment should be continued for at least 14  d before non-response and treatment modification are considered. Microbial isolates from blood cultures, bronchoalveolar lavage or respiratory secretions must be critically interpreted with respect to their aetiological relevance for pulmonary infiltrates.     

The safety of interferon-gamma-1b therapy for invasive fungal infections after hematopoietic stem cell transplantation

BACKGROUND: The restoration of normal immune responses, especially of the T-helper type 1 immune response, is an important predictor of fungal infection outcome in patients with malignant disease who undergo hematopoietic stem cell transplantation (HSCT). The authors sought to evaluate the safety of adjuvant recombinant interferon-gamma-1b as an immune-modulatory therapy HSCT recipients. METHODS: Thirty-two patients received interferon-gamma-1b after undergoing HSCT at the author's institution between 1998 and 2003. A retrospective analysis was undertaken after obtaining permission from the Institutional Review Board. RESULTS: Twenty-six of 32 patients (81%) received allogeneic stem cell grafts. All but 1 patient received interferon-gamma-1b and antifungals to treat infections; the other patients received interferon-gamma-1b to promote autologous graft-versus-tumor effect. Interferon-gamma-1b usually was administered at a dose of 50 mug subcutaneously every other day. The median duration (+/- standard deviation) of interferon-gamma-1b therapy was 6+/-6.5 doses (range, 1-29 doses), and the median cumulative dose was 487+/-453 mug (range, 35-2175 microg). During therapy with interferon-gamma-1b, fever was common (n=9 patients; 28%). In 1 patient (3%), new-onset lymphocytopenia occurred but resolved after cytokine therapy was discontinued; there were no interferon- gamma-1b-related episodes of neutropenia, thrombocytopenia, anemia, or liver dysfunction. Interferon-gamma-1b therapy did not precipitate or exacerbate acute or chronic graft-versus-host disease (GVHD). In fact, in 2 of 7 patients (29%) with acute GVHD and in 3 of 10 patients (30%) with chronic GVHD, significant improvements in GVHD were noted during therapy with interferon-gamma-1b. Among the 26 patients with aspergillosis, 14 patients (54%) died. However, 5 of 10 patients (50%) with presumed pulmonary aspergillosis, 3 of 9 patients (33%) with probable pulmonary aspergillosis, 1 of 2 patients (50%) with definite pulmonary aspergillosis, and 3 of 5 patients (60%) with disseminated aspergillosis responded to antifungals and adjuvant interferon-gamma-1b. CONCLUSIONS: Recombinant interferon-gamma-1b was tolerated without serious adverse reactions in HSCT recipients. A large, prospective, randomized study will be needed to evaluate the efficacy of this cytokine in high-risk HSCT recipients who have invasive mycoses.     

Cloning of granulocyte colony-stimulating factor cDNA from human macrophages and its expression in Escherichia coli

Human granulocyte colony-stimulating factor (hG-CSF) cDNA was cloned, by using a synthetic oligonucleotide probe, from an Okayama-Berg cDNA library of lipopolysaccharide-stimulated human peripheral blood macrophages. The cDNA encodes a polypeptide with an amino acid sequence which completely matches that of the known polypeptide with hG-CSF activity derived from human tumor cell lines. Expression in E. coli of high levels of the protein (about 10% of total cellular proteins) was accomplished under control of the trp promoter, and the purified protein was proved to have hG-CSF activity. Our data provide evidence that human peripheral blood macrophages do produce hG-CSF mRNA when stimulated exogenously, suggesting they are the producer of naturally occurring hG-CSF.