Study The Early And Advanced CT Features Of Invasive Aspergillosis Pulmonary Infection In Immunosuppressed Patients And Experimental Research

[Objectives]1. To invcstigatc the clinical symptoms together with CT signs, so as to obtain thc diagnostic CT features of the invasive pulmonary aspergillosis (IPA) in immunocompromiscd patients, and to provide practicable basis for timely and cffcctive empirical antifungal therapy in the absence of reliable clinical evidence of aspergillus infections.2. To tentatively establish pulmonary aspcrgillosis models on immunocompromised New Zealand white rabbits and to prcliminarily analyze their pulmonary CT findings along with corresponding pathological changes, in order to cxplorc the charactcristic CT features of the early and progrcssivc stage.Material and methods:1. Seventy-six immunocompromised patients with invasive pulmonary aspergillosis infections but not multiple pulmonary infections, admitted to the departments of Clinical Hematogy,Peadiatrics and Kidney transplantion of Nan Fang Hospital between December 2002 and February 2007, were enrolled in our study, which were allocated into experiment group (32 aspergillus infected ones) and control group (44 bacterial infected ones), and were retrospectively analyzed referring to their clinical symptoms as well as CT features. CT manifestations were analyzed in 8 major aspects: (1) CT "Halo sign." (2) "Fruits-on-branch sign"; (3) "Air crescent sign "; (4) wedge-shaped area Consolidation of pulmonary lobes or segments; (5) Multiple very small nodules; (6) "Ground-Glass syndrome" (7) Mass or Nodule, (8) Solitary or Multifocal lung nodules. Data were statistically analyzed by means of two independent samplesχ2 test and logistic regression analysis (Backward: conditional) using SPSS13.0(α=0.05). The statistically analytic results were integrated with our clinical expertise in attempt to obtain the characteristic CT features useful for the diagnosis of invasive pulmonary aspergillosis aspergillosis in the early and progressive stage.2. The establishment of immunocompromised white rabbit models with invasive pulmonary aspergillosis infections: 8 New Zealand rabbits (CL) weighting from 2.0 to 5.0 kg were distributed into experiment group (n=6) and control group (n=2), all of which were given high-dose eprednisone via ear vein, i. v., 25mg/kg, bid, until they all evaluated as immunocompromised by immune functional parameter. In addition, six rabbits in experiment group were inoculated with Aspergillus by endotracheally infusing 1.0ml treated Aspergillus sporus suspension (10~7/ml) with sterile injection syringes, and underwent chest CT scans, PI. bid. The last CT scans were obtained 5 to 8 days after endotracheal inoculation, when they all successively showed symptoms of shock. Then all rabbits were executed and had lung tissues taken for histologic examination. Results1. The primarily underlaying disease of Invasive pulmonary aspergillosis in immunocompromised patientsBetween December 2002 and February 2007, of all the immunocompromised patients admitted to the Nan fang hospital, 76 cases (36 men, 40 women; mean age, 40 years; range, 3-77 years) whose etiology of pulmonary infection were clear were enrolled in our study. The others were not included because of complicating multiple infections or free from infection. The 76 patients were divided into two groups. Group A (32 patients) with invasive pulmonary aspergillosis infections; the controls (group B: 44 patients) with secondary pulmonary bacterial infections. The primaryily underlaying disease were acute lymphocytic leukemia(n=19), acute non-lyphocytic leukemia(36), chornic myelocytic leukemia(10), acute mixed lineage leukemia(5), marrow paraplasm syndrome(1), mediterranean anemia(1), aplastic anemia(1), systemic lupus erythematosus(1), multiple myeloma(1), kidney transplantion(1). Regarding the opportunity of onsets, elderly leukemia patients, resistant leukemia patients that cannot be alleviated with repeated chemotherapies and patients 1-2 months post stem cell transplantation are subject to secondary aspergillus infections.2.The pulmonary CT feature of immunocompromised patients with invasive pulmonary aspergillosis infections:The frequency and period of the appearing of the 8 CT signs in non-HIV immunocompromised patients with invasive pulmonary aspergillosis infections were: (1) CT "Halo sign" appeared in approximately 68.8% patients and emerged generally in the early and progressive stage. (2) "Fruits-on-branch sign" 78.1%; (3) "Air crescent sign" showed up in about 37.5 % cases, but late, that's 2 weeks or so post treatment; (4) wedge-shaped area Consolidation of pulmonary lobes or segments were about 48.3%; (5) Multiple very small nodules 18.8%; (6) "Ground-Glass syndrome" 37.5% (7) Mass or Nodule 87.5% (8) Solitary or Multifocal lung nodules: Multifocal nodules seemed more likely to happen, and were mostly diffusely distributed. But 2～3 CT features always occured in one patients. The most frequent CT findings was "halo sign+fruits-on-branch" 73.4%, and the second was" halo sign+fruits-on-branch+wedge shaped area consolidation "64.6%, and the lastest was "halo sign+fruits-on-branch+ground glass syndrome" 58.3%. Besides, solitary lesion was rare and located mainly in the middle and upper lung.Two independent samplesχ2 test indicated that the frequencies of CT "halo sign" "Fruits-on-branch sign" and "Air crescent sign" were significantly(P=0.000) higher in research group compared with control group. Hence they probably are the expected CT features characteristic of invasive pulmonary aspergillosis infections in immunocompromised patients. The remaining four CT signs were not significantly different in the two groups of patients(P＞0.05). logistic regression analysis (Backward: LR)revealed that four characteristic CT features were significant for the diagnosis of early and progressive invasive pulmonary aspergillosis infections, and the total accuracy of discriminating was 84.2%. The four identified CT features are ordered by the P-value: (1) CT "Halo sign" (2) "Fruits-on-branch sign"; (3) Multifocal lung nodules. (4) "Air crescent sign".2. The establishment of immunocompromised white rabbit models with invasive pulmonary aspergillosis infections and their CT findings: 8 New Zealand rabbits (CL) were included in our experiment, 6 of which were distributed into the experiment group and established the attempted models successfully; unfortunately, they all died 5 to 8 days after inoculation one after another. Their pulmonary CT manifestations were characterized by consolidation of pulmonary segments or "Ground-Glass syndrome", but without lung nodules; and their corresponding pathological changes were pulmonary infarctions, consolidation of pulmonary segments as well as pleural effusion. Both rabbits in the control group showed no spontaneous death.Conclusions:1. Early and progressive CT features of non-HIV immunocompromised patients with invasive pulmonary aspergillosis infections:(1). the etiological factors and pathomechanism of invasive pulmonary aspergillosis infectionsRecently, aspergillosis has the potential of exceeding Candida albicans to become the most common fungus pathogen of invasive pulmonary fungous infections in non-HIV immunocompromised patients. Due to the clinical symptoms of patients with invasive pulmonary aspergillosis infections are similar to those with secondary bacterial infections; clinical diagnoses are often difficult to make, especially for those in their early and progressive stages. A major predisposing factor in non-HIV immunocompromised patients is severe neutropenia (absolute neutrophil count of＜500 cells/L,＞10d). Other risk factors affecting the course of IPA include intensive chemotherapy regimens, allogeneic haemopoietic stem cell transplantation, autologous peripheral blood stem cell transplantation, long-term application of broad-spectrum antibiotics and nosocomialtions. Nevertheless, early diagnosis of IPA is very important, because it enables early onset of antifungal therapy, and thus improves outcome. Therefore, thoracic CT scan, in particular, the application of high-resolution CT scanning has become the vital tool of choice to achieve the earliest and most likely diagnosis of invasive pulmonary aspergillosis in immunocompromised patients. The pathomechanism of invasive pulmonary aspergillosis was that hypha encroach into the pulmonary small vessels and bronchus and then induce hemorrhagic pulmonary infarction. The nodus of pulmonary infarction can develop coagulation necrosis, because their surrounding alveoli pulmonary displayed hemorrhagic rim.(2). The pulmonary CT appearances of non-HIV immunocompromised patients with invasive pulmonary aspergillosis infections:For some of the CT characteristic dominance, for example, it's density resolution, display focal substantivity, et al.The probabilities of CT "Halo sign", "Fruit-on-branch sign" and "Air crescent sign" were significantly (P=0.0001) higher in research group compared with control group. Hence they are probably the characteristic CT features of invasive pulmonary aspergillosis in immunocompromised patients. CT "halo sign" is the main evidence for providing empirical antifungal therapy to patients without reliable clinical evidences of aspergillus infections. "Fruits-on-branch sign" is a kind of pulmonary CT pattern that resembles fruits on branch; actually, it's a large number of lung nodi caused by pulmonary aspergillosis infection, which are usually situated beside pulmonary vessels and tightly connected with them. It is one of the advanced CT features, and is often seen in patients who are not given antifungal treatments in time or accompanied by "Halo sign". Because "Air crescent sign" emerges rather late in the course of the disease, it's of little help to an early diagnosis, but it does provide some useful clues. For example, when it is complicated with other CT features characteristic of a pulmonary aspergillosis infection, it probably hints the infection is in progress. While it follows antifungal therapy, it may be the symbol of effectiveness. Comparing the CT signs of invasive pulmonary aspergillosis infection with bacterial infection, we can find that four characteristic CT features are meaningful for the diagnosis of early and progressive invasive pulmonary aspergillosis in non-HIV immunocompromised patients, and the total accuracy of discriminating is 84.2%. The four CT features are ordered by the P-value: (1) CT "Halo sign." (2) "Fruits-on-branch sign"; (3) Multifocal lung nodules. (4) "Air crescent sign ".wedge-shape consolidation of pulmonary lobes or segments, multiple miliary nodules, "Ground-Glass syndrome", Mass or Nodule can also be found in these patients, but are not significantly different between the two (P＞0.05), and cannot function as the evidence for differential diagnosis.Notwithstanding Wedge-shape consolidation of pulmonary lobes or segments and ground-glass syndrome have no significant statistical difference in the early and progressive stage of IPA and they are usually accompanied by CT halo sign (64.6%) and fruits-on-branch (58.3%). But the early and progressive CT features of IPA were our first consideration while the chest CT scan displayed wedge-sharp or ground-glass syndrome accompanied with "CT halo" or "fruits-on-branch".2. The establishment of immunocompromised white rabbit models with invasive pulmonary aspergillosis infection and their pulmonary CT findings:In our animal models, the CT patterns of early invasive pulmonary aspergillus infection are consolidation of pulmonary segments and "ground-glass syndrome", this results were consistented with the first chapter standpoints. Notwithstanding without CT "halo sign" or "Fruits-on-branch sign". The explanation for this phenomenon maybe the short survival time of our laboratory animals, which died before the emerging of "halo sign", "Fruits-on-branch sign" or "Air crescent sign ". Hence, our approach to establish immunocompromised white rabbit models with invasive pulmonary aspergillosis still need to be further refined.