PULMONARY ASPERGILLOSIS IN ASSOCIATION WITH TUBERCULOSIS AND HIV IN UGANDA

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Abstract

Thesis submitted to The University of Manchester in 2015 by Iain Dunsmuir Page for the degree of Doctor of Philosophy entitled “Pulmonary aspergillosis in association with tuberculosis and HIV in Uganda”.Chronic pulmonary aspergillosis (CPA) is a serious disease that occurs secondary to tuberculosis and is estimated to affect 1.2 million persons globally. Pulmonary aspergillosis is found in 2-3% of all AIDS autopsies, but 90% of cases go undiagnosed ante-mortem. Here the sensitivity and specificity of optimal diagnostic thresholds for CPA have been defined in relation to six Aspergillus-specific IgG assays. The prevalence of CPA in an area of high tuberculosis prevalence has been measured.Receiver operating characteristic (ROC) curves were used to compare results of testing with six Aspergillus-specific IgG assays in 241 patients with CPA and 100 healthy controls. ThermoFisher Scientific ImmunoCAP and Siemens Immulite had ROC area under curve (AUC) results of 0.995 and 0.991 respectively. Both were statistically significantly superior to all other assays. Both had a sensitivity of 96% and specificity of 98% using diagnostic cut offs of 20 mg/L and 10 mg/L respectively. Eighty patients with allergic bronchopulmonary aspergillosis (ABPA) were also assessed. ROC AUC results were 0.959 for ImmunoCAP and 0.932 for Immulite. The new thresholds produced specificities of 98% for both assays and sensitivities of 78% and 81% respectively. Levels in ABPA patients were also compared to asthmatic controls.398 patients with treated tuberculosis in Gulu, Uganda were assessed in a cross-sectional survey. CCPA diagnostic criteria were; 1 – Cough or haemoptysis for one month, 2 – Progressive cavitation on serial chest X-ray or either paracavitary fibrosis or aspergilloma on CT scan and 3 – Raised Siemens Immulite Aspergillus-specific IgG. All three were required for diagnosis. CCPA was present in 5.7% of patients and simple aspergilloma in 0.7% of patients. There was a non-significant trend to less frequent CCPA in HIV positive patients (p=0.18). Aspergillus-specific IgG levels were measured in stored sera from two adult in patient groups at Mulago Hospital, Kampala, Uganda. 26% of 39 patients with HIV infection and subacute respiratory illness and no diagnosis after extensive investigation had raised levels. 47% of 57 patients with proven active pulmonary tuberculosis had raised levels.The Immulite and ImmunoCAP assays both have good sensitivity and specificity for the diagnosis of CPA. New diagnostic thresholds improve the performance of all assays. CCPA has been shown to complicate pulmonary tuberculosis in Gulu, Uganda. Subacute invasive pulmonary aspergillosis is likely to affect many patients with AIDS and subacute respiratory illness. CPA may begin during active pulmonary tuberculosis infection. CPA associated with tuberculosis constitutes a significant unrecognized public health problem, which is probably being incorrectly identified as ‘smear-negative tuberculosis’ clinically and in public health data. Prospective studies are now needed to confirm the prevalence of CPA secondary to tuberculosis and define the optimal strategy for routine CPA screening, followed by studies to define optimal treatment regimes for use in research poor-settings, where most cases of CPA are likely to occur.

Keyword(s)

Aspergillus; CPA; Chronic Pulmonary Aspergillosis

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