Discussion
This is the first study describing clinical features and outcome of pulmonary aspergillosis from a tertiary care hospital from Pakistan. The prevalence of fungal infection has dramatically increased over recent years due to underlying risk factors.9 Culture remains a gold standard for the diagnosis of aspergillosis but has low sensitivity. Culture positivity does not always reflect infection as these organisms could also occur as colonisers or contaminants. We have reported a higher culture positivity rate (66.7%) of sputum/BAL compared with 23.3% from an Indian study.10 This high positivity rate could also reflect colonisation or contamination; however in these cases growth of Aspergillus spp. was reported only after assessing significance. In addition, the laboratory strictly monitors culture contamination rate as a quality indicator, also all specimens were processed in safety cabinet to avoid contamination within laboratory during processing. Furthermore clinical evaluation of these cases also confirmed the significance of the growth. Recent advances of diagnosis of invasive aspergillosis include antigen detection tests; galactomannan and β-D-glucan (component of cellular wall). Both these tests are approved by the US Food and Drug Administration (FDA) for the diagnosis of IPA. They help in the early diagnosis and confirmation of IPA and are also helpful in the assessment of the evolution of infection during treatment with serial levels.11 Unfortunately, the antigen detection tests were not available at our centre during the study period and the rates of aspergillosis reported could be an underestimate.
Majority of patients in this study were men and the commonest isolated species was A. fumigatus similar to the previous literature2 ,10 followed by A. flavus, A. niger and A. terreus. We found CPA as the most common pulmonary manifestation. In the literature the commonest form of CPA is CCPA.5 However, the incidence of aspergilloma was more common than CCPA in our study; this may be because ours is a tertiary care hospital and patients are referred for interventions. Patients with pulmonary insults like COPD, chronic fibrocystic healed TB, interstitial lung disease (ILD), pneumoconiosis and cystic fibrosis are well-known risk factors for CPA.12 In our study majority of patients had a history of TB as reported previously.4 ,10 ,13 ,14 One of the reason being that TB is endemic in Pakistan and majority of these patients developed CPA as a post-TB sequel. It is interesting to note that some of the patients also had active TB along with Aspergillus infection; the association of active TB with Aspergillus infection is rarely seen and reported only in few case reports.15 ,16
The commonest underlying systemic condition among our patients was DM; increased incidence of TB among patients with diabetes is well known due to impaired immunity and associated with aggressive course and outcomes.17 ,18 Previous literature has reported that patients with DM with TB had more severe clinical manifestation (cavitation), severe treatment and post treatment outcomes like failure and death, death and relapse.19 ,20 The majority of patients with SAIA also had underlying diabetes. So diabetes was identified as an important risk factor for pulmonary aspergillosis for SAIA and CPA.
DM has been rarely associated with IPA and reported only in few case reports.21 ,22 In our study the majority of cases had probable IPA but the revised definition of IPA has some limitations as it only included immunocompromised patients.6 A study in 172 critically ill patients showed that 83 had invasive disease while 60% had no risk factors for IPA.23 Critically ill patients are prone to develop disturbances in immunoregulation, which makes them vulnerable for fungal infections. Thus besides neutropaenia, haematopoietic stem cell transplant, DM, renal failure, COPD, liver failure are important risk factors in ICU.
Patients with aspergillosis usually presents with non-specific constitutional symptoms such as fever, cough, haemoptysis and weight loss or rarely may be asymptomatic in CPA.24 In this study patients mostly had non-specific symptoms. Radiographic presentation is also variable from rounded densities, pleural-based infiltrates to cavitation while pleural effusion is rarely seen. Greene25 found 94% of patients with IPA had at least one nodular lesion. In a study IPA in patients with neutropaenia who underwent stem cell transplantation had nodules 67%, ground glass 56% and consolidation 44%,26 while halo sign and air crescent sign were usually non-specific.27 In CPA, patients had pleural thickening and cavitation while fungal ball (mycetoma) can be seen in 50%.28 In our study majority of the patients had nodular infiltrates 42.2%, followed by fungal ball (mycetoma), cavitation and consolidation.
Overall mortality was 72.2% and was higher in IPA and SAIA compared with CPA. Mortality in CPA ranges from 10% to 30%, low in simple aspergilloma compared with CCPA.4 However, severity of the underlying pulmonary disease and the extent of lung destruction are important predictors of mortality and outcomes among patients with CPA. Limited data is available for SAIA while in IPA reported morality ranged from 50% to 80%.29 ,30 Majority of these patients developed hypoxic respiratory failure and had bilateral consolidations. Hypoxic respiratory failure is well known in patients with neutropaenia during the recovery phase with IPA, likely secondary to neutrophil influx.31 ,32 Interestingly, in our study only 8.69% patients were neutropaenic. This is most likely due to low feasibility of performing invasive procedures to collect appropriate samples for culture and the absence of antigen detection tests during the study period at our institute. Besides respiratory failure 14.5% developed pneumothorax. Empyema was a rare complication33 seen in 2.89% patients in this study.
The mean LOS is variable in patients with pulmonary aspergillosis and available data is also limited. As in our study population majority of the patients had CPA, therefore it is difficult to compare the results with the available data which is particularly on IPA.
Our study has added important information on pulmonary aspergillosis particularly from Pakistan but there are certain limitations of this study. (1) It is a retrospective study and we cannot standardise the diagnostic and treatment approaches in these patients. (2) It is a single centre study and study results cannot be generalised. (3) Galactomannan and β-D-glucan assays were not available during this study period and could not be used to diagnose patients in whom invasive sampling could not be performed. We recommend large multicentre prospective studies using β-D-glucan and galactomannan as an adjunctive diagnostic aid as both are now incorporated in the revised European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria for diagnosing IPA6 and recommended for CPA in BAL by European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society (ESCMID/ERS).5