Clinical Analysis Of Pulmonary Cryptococcosis In HIV-Negative Hosts Without Hematological Or Malignant Tumor

【Objective】To describe the clinical characteristics,epidemiology status quo and treatment of pulmonary cryptococcosis in the HIV-negative patients without hematological or malignant tumor.【Methods】The medical records of 47 HIV-negative adult patients diagnosed with pulmonary cryptococcosis at Zhongshan Hospital affiliated to Fudan University between Jan.2003 and Dec.2008 were reviewed retrospectively.Reference to the consensus revised definitions draft VI of EORTC/MSG in 2005,and the diagnostic criteria and therapeutic principle of invasive pulmonary ftmgal infection(protocol) of China in 2006,all of the cases were diagnosed by pathology,microbiology,or coherence examination.The exclusion criteria includes as follows:(1) the AIDS patients,(2) the patients with hematological or malignant tumor,(3) solid organ transplant or bone marrow transplant recipient.Schedule tables were made to record the detail information of each patient with pulmonary cryptococcosis to investigate the demography of the patients compromising the study, evidences of diagnosis including the host factors,clinical features,chest CT, microbiological examination,latex agglutination test of cryptococcus and pathological examination,therapeutic regimens and prognostic evaluation.Compare the differences between the different sexes,ages,host factors,symptoms and iconography types.The continuous data were expressed as means±standard deviation for those with a normal distribution,and as the median for those without a normal distribution.Discrete data were expressed as percentages.Student's unpaired t-test was used to compare continuous variables,the Mann-Whitney U-test to compare continuous variables with non-normal distribution,and the Pearson Chi-squared or Fisher's exact test was used to compare proportions.Statistical analysis was conducted using SPSS for Windows(version 15.0). Significance was defined as P＜0.05 with two-sided analysis.【Results】(1) The patients consisted of 28 males and 19 females.The mean(±SD) age of them was (44.62±12.39) years(range,16 to 70 years),and 74.47%of whom were in the age between 30 and 60 years.There was no significant deviation of age between sexes(Fisher exact test 4.016,P=0.573).(2) From the year 2003 to 2008,the annual number of patients diagnosed with pulmonary cryptococcosis was increased,while the percentage of diagnosis by operation was decreasing,and the positive rate of fiberoptic bronchoscope or TBLB and TNAB were 75.0%and 82.4%.(3) 33 cases(70.21%) of whom had no host factors,and among the patients who had some underlying diseases,the use of steroid hormones is the most common risk factor(n=7; 50.00%),and others were diabetes mellitus(n=4;28.57%),Chronic Hepatitis B(n=3; 21.43%),Bronchial Asthma(n=2;14.29%) and so on.There were no significant deviations of sex and age between the two groups with or without host factors.(4) 13 patients(27.66%) were asymptomatic,who had abnormal chest radiographs during a routine physical examination.34 patients(73.34%) complained of respiratory or constitutional symptoms,as follows:cough(n=29,61.70%),expectoration(n=19;40.43%), fever(n=13;27.66%),chest pain(n=8;17.02%) and dyspnea(n=9;19.15%).All symptoms were mild,and they often show a self-limiting tendence.All patients had no neurologic symptoms.There were no significant deviations of sex,age and host factors between the two groups with or without symptoms.(5) The chest CT demonstrated abnormal findings in all patients.The most common radiologic finding was single or multiple nodules or masses(n=21;52.5%),the next was patchy infiltrates or consolidation(n=11;27.5%),the remaining presented widespread and mixed patterns(n=8;20%).Other associated findings included mediastinal lymphadenopathy(n=9;22.5%),pleural effusion(n=4;10%) and ground-glass change around the lesions(n=12;30%).The diameter of the lymph nodes were almost less than 1 cm,and only 1 case was 1.2cm.The geographic distribution of the nodule or mass lesions mainly on the unilateral lung and especially the right lung;the patchy infiltrates or consolidation could be seen on all lung lobes,and the widespread and mixed patterns in bilateral lung,with ill-defined margins.Multiple lesions were more to see in the females than the males(76.4%vs 43.48%,χ~2=4.354,P=0.037).And the lesions of males often presented the unilateral lung involved(100%vs 47.06%,continuity correctionχ~2=12.822,P =0.000).The nodule or mass lesions are more to see in the males,as the mixed lesions in the females(Fisher exact test 9.456,P=0.008).There were no significant deviations of morphologic characteristics and the associated findings between the sex(P＞0.05).There also were no significant deviations of the number of lesions,the involved lung lobe distribution,the lesion type and the morphologic characteristics between the groups with or without symptoms(P＞0.05),so were the groups with or without host factors(P＞0.05).(6) The mean leukocyte counts of the patients was(7.52±2.949)×10~9/L,38 cases(80.85%) were normal;the mean neutrophilic granulocyte percentage was(61.67%±9.778%),31 cases(65.96%) were normal.And the counts of neutrophilic granulocyte count of all patients were over 1.5×10~9/L.(7) 30 cases had the latex agglutination test for pulmonary cryptococcosis,and 100%were positive,and the titers ranging from 1:5 to＞1:1280.After the treatment,the titers of 11 cases decreased or turned negative.The patients whose lesion was single nodule or mass in the chest CT,often had a low titer of less than 1:320,which had a significant deviation with the ones with other lesions(Fisher exact test,P=0.041).(8) Pathogenic microorganism examination:The sputum examination:12 cases had the examination of sputum smear to find Cryptococcus Neoformans spores,with the positive rate of 8.33%,and 19 cases had the sputum culture for Cryptococcus Neoformans,with the positive rate of 5.26%.20 cases had the flexible bronchofiberscope examination:two(10%) positive in the suction flow cultures and four(20%) positive in biopsy tissue cultures,and both of the smears of suction flow and biopsy tissue were all negative.The transthoracic needle aspiration biopsy examination:8 had the examination of biopsy tissue smear,with two(20%) positive,and 10 had the cultures,with all negative.The hydrothorax smear or culture and the blood culture were all negative.(9) Histologic section demonstrated extensive granulomatous involvement of the pulmonary parenchyma,and with multinucleated giant cells containing abundant vacuolus yeast forms. The yeast was red after the special stain of periodic acid schiff(PAS),and black after Grocot's methenamine-silver(GMS) stain,and positive rate of both were 92.5%.The yeast showed coccinellin,after the stain of mucicarmine,but in our cases,the stains were all negative.(10)The treatment and prognosis:12 patients received surgical intervention as the initial treatment,and 9 of them received systemic antifungal therapy after the operation (Fluconazole,n=8;Itraconazole,n=1),the remaining 3 asymptomatic patients were observed,and found no new lesions and manifests of meningitis followed up.30 patients received the antifungal therapy of Fluconazole as the initial treatment,and 25 of them improved,while the other 5 patients did not,who had no change of the lesions or the titers, so had to change the drug,and use the Amphotericin B or Liposome.4 patients received the treatment of Itraconazole,and one had Amphotericin B as the initial treatment,all the patients had improved.【Conclusion】(1) The incidence of pulmonary cryptococcosis had increase tendency in the HIV-negative hosts without hematological or malignant tumor.The disease mainly involves the middle ages.It was more to see in the males than the females.And there may be some differences in the imaging appearance between the males and females.(2) The clinical process of this disease is often a chronic or subacute course,with mild or no symptoms,such as slight respiratory symptom or low-grade fever,with no specificity and no signs.The imaging features can be classified to 3 types:nodule or mass type,patchy infiltrates or consolidation type,and widespread or mixed patterns type,and the lesions of nodule or mass and consolidation are more to see.The disease was usually considered to have some self-limit tendency.(3) The sensitivity and specificity of the latex agglutination test for Cryptococcus neoformans were both high.The flexible bronchofiberscope and TNAB had smaller trauma than the surgery,and with a high positive ratio,which can be chosen rely on the location of the lesions.Some cases need surgery intervention to get the tissues for the examination of pathology and microbiology.Non-caseous granulomas is the main characteristic of pathological study(96.7%),with the PAS reaction and GMS staining positive.(4) Fluconazole is preferred to be used in these patients,while Amphotericin B or Liposome is used in the severe cases.