Clinical manifestations, associated risk factors and treatment outcomes of Chronic Pulmonary Aspergillosis (CPA): Experiences from a tertiary care hospital in Lahore, Pakistan.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) has a wide spectrum of illnesses depending on the progression of the disease and comorbid conditions. However, there is an inadequacy of investigations regarding clinical, laboratory, risk factor and prognostic data on CPA. The current study is aimed to consider the clinical manifestations, risk factors and outcomes of CPA.
METHODOLOGY: Retrospective records of all patients with a confirmed diagnosis of CPA who sought treatment at Gulab Devi Chest Hospital Lahore, Pakistan from January 2017 to December 2019 were evaluated. Data regarding demographics, clinical manifestations, comorbidities, radiographic and microbiological findings, length of hospital stay (LOS) and intensive care unit (ICU) admission was collected and analyzed to identify the factors associated with mortality. The independent factors associated with mortality were also identified by appropriate analyses.
RESULTS: A total of 218 CPA patients were included in this study. The mean age was 45.75 ± 6.26 years. Of these, 160 (73.4%) were male, and 65 (29.8%) had diabetes. The mean LOS was 18.5 ± 10.9 days. The most common type of CPA was simple aspergilloma (56%) followed by chronic cavitary pulmonary aspergillosis (CCPA) (31.2%). About one half of the patients had a history of pulmonary tuberculosis (TB) and treatment response rates were low in patients with active TB. The overall mortality rate was 27.1%. ICU admission was required for 78 (35.8%) patients. Diabetes mellitus (DM), hematological malignancies and chronic kidney disease (CKD) were the common underlying conditions predicting a poor outcome. Mean LOS, hematological malignancies, consolidation and ICU admission were identified as the independent factors leading to mortality.
CONCLUSIONS: CPA had a significant association with TB in the majority of cases. Treatment response rates in cases with active TB were comparatively low. Cases with high mean LOS, hematological malignancies, consolidation, ICU admission, CKD and DM experienced poor outcomes. High mean LOS, hematological malignancies, consolidation and ICU stay were identified as independent risk factors for mortality. Future large prospective studies, involving aspergillus specific immunoglobulin G (IgG) antibody testing, are required for a better understanding of CPA in Pakistan.

Introduction

Aspergillus species are ubiquitous in the environment and exposure to the conidia is common. However, only a minority of people develop clinical disease, and the development of disease is often determined by host characteristics, e.g., immune status, genetic predisposition, underlying lung pathology and prior pulmonary infection such as tuberculosis (TB) [1].

Classically, chronic pulmonary aspergillosis (CPA) in immunocompetent patients presents as a saprophytic infection in a pre-existing cavity, often following an infection such as TB or prior lung surgery [2]. The key features of CPA include steady destruction of lung tissue showing progressive cavity formation, fibrosis, and pleural thickening. The syndrome is mostly seen in patients with lung cavitation diseases or structural pulmonary abnormalities [3].

There are a number of recognized manifestations of CPA: subacute invasive pulmonary Aspergillosis (SAIA) (which may be referred to as chronic necrotizing pulmonary aspergillosis (CNPA)), chronic cavitary pulmonary aspergillosis (CCPA), and chronic fibrosing pulmonary aspergillosis (CFPA) [4]. SAIA occurs in the cases with some degree of immune compromise, and may present with nodules, consolidation or cavitation upon chest imaging, and a more rapidly progressing clinical course. CCPA presents with single or multiple cavities, with or without aspergilloma(s), and CFPA has the same appearance with the added features of pulmonary fibrosis, which may be progressive and destructive [2].

Estimates of the incidence and prevalence of CPA are difficult; however, the global burden of disease is increasing [5, 6]. The prevalence of CPA has been estimated at 3,000,000 cases worldwide [7]. In 2017, a review encompassing data from 43 countries revealed the highest incidence was estimated in Russia (126.9 cases/100,000) followed by Philippines, Nigeria (78 cases/100,000), Pakistan (70 cases/100,000) and Vietnam (61 cases/100,000). The overall incidence for all the countries included in the study was 22 cases/100,000 (14.2–30.59, 95% CI) [8]. In Pakistan, the risk of development of CPA is high because CPA is regarded as the most severe sequelae of Pulmonary Tuberculosis (PTB) [5], and Pakistan ranks 5th among the countries with the highest PTB burden [9]. The most recent burden estimate of CPA in Pakistan was 39 cases/100,000 people [10].

This data makes CPA as a disease of significant concern for a high pulmonary TB burden countries like Pakistan. The situation is made more complicated by the poor fungal diagnostic capabilities in most of the laboratories in Pakistan, the emergence of antifungal resistance, a lack of antimicrobial stewardship, poor infection control practices and the lack of availability of essential antifungal agents [11]. There is a paucity of data on CPA and very few studies are available providing data regarding clinical manifestations, underlying conditions and risk factors [10, 12]. Therefore, a retrospective study was designed at a tertiary care hospital in Lahore, Pakistan to highlight the clinical manifestations, underlying conditions, predictors associated with mortality and risk factors of CPA.

Methods

Study design and settings

This was a retrospective study conducted at Gulab Devi Chest Hospital, which is a tertiary care facility in Lahore, Pakistan. All of the following patients who enrolled for treatment at the facility from January 1st 2017 to December 30th 2019 were included in this study: (1) those aged 18 years or above; (2) with a CPA diagnosis, including all of its types, i.e., simple aspergilloma, CCPA, SAIA and CFPA; (3) with positive bronchoalveolar lavage (BAL) and/or sputum cultures for Aspergillus Spp. and/or positive pulmonary histopathology suggesting the presence of Aspergillus Spp; and (4) with a chest CT scan/ X-Ray suggestive of aspergillosis.

Patients with other forms of pulmonary aspergillosis than CPA, and those with incomplete records, were excluded from the study. Patients with positive cultures but suggesting colonization only were also excluded because the colonization by microorganisms does not cause disease by itself [13].

Ethical approval

The study was approved by the Institutional Review Board (IRB) of Gulab Devi Chest Hospital, Lahore. A written informed consent regarding the use of their clinical records was obtained from patients visiting the study site for their treatment. The hospital’s IRB waived the requirement for informed consent from all those patients who were critically ill or deceased.

Data collection

A validated data collection form was used to collect patients’ demographics, associated conditions, underlying lung pathologies, radiological and microbiological findings, length of hospital stay and requirement for ICU admission. The hospital’s computerized record system and patients’ files were evaluated for the purpose of data collection.

Operational definitions

Patients were categorized further on the basis of the types of CPA, namely: CCPA, SAIA, CFPA and aspergilloma. CPA is defined as the presence of the following for at least three months, along with chronic respiratory symptoms: (1) one or more cavities either with or without a fungal ball or nodules/pleural thickening seen on radiographic imaging; (2) direct evidence of infection by Aspergillus Spp. revealed by either microscopy, a culture taken from biopsy, or both; and (3) the presence of an immunological response to Aspergillus antigens and the exclusion of an alternative diagnosis [14]. Simple pulmonary aspergilloma is defined as the presence of a single cavity with a single fungal ball and no spread or progression seen in radiological imaging over the course of at least 3 months of observation. CCPA is defined as the presence of one or multiple cavities in the lungs, possessing one or multiple fungal balls, along with microbiological evidence suggesting the presence of Aspergillus Spp., and sufficient symptomatic and/or radiographic evidence of an increase in number of cavities and/or infiltrates over at least 3 months of observation [12]. SAIA is defined as the radiographic findings suggestive of the presence of hyphae penetrating into the lung tissue [14]. The label CFPA is assigned to cases with one or multiple cavities, either with or without aspergilloma, that have an additional feature of pulmonary fibrosis which may progressively destroy the lung tissue. According to the Fleischner Society: Glossary of Terms for Thoracic Imaging, a nodule is defined as a rounded, opaque, well or poorly defined mass, with a diameter of up to 3 centimeters [2].

Outcomes were defined as the observable or measurable changes in health status, which included ICU admission and mortality. A deterioration of health status was identified among living patients developing respiratory complications and staying in the ICU till the end of the study. Recovered or stable patients were those patients either not requiring ICU admission or those that may have developed respiratory complications and were admitted to the ICU but recovered and were discharged from the ICU before the completion of the study. Both mortality and deterioration were considered to be poor outcomes, while stability of condition or recovery were considered as favorable outcomes.

Diagnosis of CPA

Fungal cultures were carried out by well-trained laboratory technologists and were reviewed by consultant microbiologists in a suitable and well-controlled environment. The culture plates were examined properly for 4 weeks prior to being reported as negative. Aspergillus Spp. was identified on the basis of physical appearance: the microscopic and morphological characteristics of the colonies [15]. The diagnosis made was in accordance with the ICD (International Disease Classification) that is the most extensively used nosology [16]. ICD code B44, that describes the diagnosis of Aspergillosis, was observed.

Statistical methods

SPSS (Release: 23.0, Standard version, Copyright SPSS; 1989–2015) was used to carry out all the statistical analyses. Quantitative variables (age, length of hospital stay) and qualitative variables (such as gender, diet conditions, smoking status, comorbidities, symptoms, risk factors, respiratory complications, microbiological findings, radiographic findings, and requirement for admission into the ICU) were analyzed by descriptive statistics. Comparisons between outcomes (that were Stable/Recovered, Deteriorated and Mortality) as dependent variables and other independent variables were made using the Chi-square test. The parameters for univariate analysis were selected based on their biological and clinical plausibility, and as indicated by the previous literature. The test variables reaching significance on univariate analysis were analyzed via multinomial logistic regression analysis to determine the independent factors predicting the mortality. From the parameter estimates, p-value and odds ratio along with 95% confidence interval (CI) were taken into consideration. All the p-values ≤ 0.05 were considered significant.

Results

Characteristics of patients

A total of 521 cases with confirmed diagnosis of aspergillosis were reviewed. Of these, 218 (41.84%) cases met the inclusion criteria. The mean age of participants was 45.75 ± 6.26 years and 160 (73.4%) were males (. Of the total 218 CPA cases, 122 (56%) were diagnosed with simple aspergilloma, 68 (31.2%) were diagnosed with CCPA and 28 (12.8%) had SAIA. There were no cases of aspergillus nodules and CFPA in our study population (Fig 1).

Fig 1

Enrollment of patients with pulmonary aspergillosis.

Several non-specific clinical manifestations were observed in the current study with a cough being the most common [n = 207 (95%)], followed by fatigue [n = 202 (92.7%)].

Associated lung diseases

PTB was found to be the most common associated lung disease (with n = 137, 62.8%). Out of 137 cases, 96 (70%) previously had tuberculosis and 41 (29.9%) had active TB disease ( Out of the 122 cases with simple aspergilloma, 20 (16.4%) had active TB, out of which 2 (10%) had underlying chronic obstructive pulmonary disorder (COPD). In 68 cases of CCPA and 28 cases of SAIA, the presence of active TB was 14 (20.6%) and 7 (25%), respectively, of which 1 of 14 (7.1%) and 1 of 7 (14.3%) cases respectively had COPD. Furthermore, pulmonary sarcoidosis was seen in 46 (21.1%) cases.

Underlying conditions

Diabetes mellitus was reported as the most common underlying condition with n = 65 (29.8%) followed by chronic kidney disease (n = 61, 28%). Hematological malignancies and chronic liver disease were present in 36 (16.5%) and 12 (5.5%) cases, respectively ( Out of 68 patients with CCPA, 23 (33.8%) had diabetes. Out of 28 patients with SAIA and 122 patients with simple aspergilloma, 8 (28.6%) and 34 (27.9%) had diabetes, respectively.

Steroid use (n = 147; 67.4%) was a common associated condition. Out of 147 cases with steroid use, 115 (78.2%) received oral prednisolone, with a mean dose of 35.1 ± 8.3 milligrams for 4.5 ± 1.1 weeks, followed by a tapered dose. Inhaled corticosteroids were used in 32 out of 147 (21.7%) patients, with a mean duration of 3.5 ± 0.6 months, out of which 13 (40.6%) received fluticasone at the mean initial dose of 134.6 ± 47.3 micrograms with the mean maximum dose of 546.1 ± 210.6 micrograms, and 19 (59.4%) received beclomethasone at the mean initial dose of 66.8 ± 22.1 micrograms with a mean maximum dose of 480 ± 127.7 micrograms, and with the dose tapered thereafter.

Laboratory, microbiological and radiological findings

Microbiological findings revealed that BAL/sputum cultures were positive for Aspergillus Spp. in 185 (84.9%) cases while 111 (50.9%) cases had positive histopathology. A total of 11 (5.04%) cases had positive histopathology only, while 85 (38.99%) cases had positive BAL/sputum cultures only. Both histopathology and cultures were positive in 100 (45.9%) cases. Aspergillus fumigatus was the most common isolate (n = 100, 45.9%) (.

Inflammatory markers, i.e., Erythrocyte sedimentation rate (ESR) and C-Reactive protein (CRP), were also elevated, with a median of 13.7 mg/L (IQR: 9.3–17.5) and 67 mm/h (IQR: 55–78), respectively. Upon chest imaging, 143 (65.6%) showed fungal balls, and nodular infiltrates were seen in 93 (42.7%) cases. Consolidation was present in 73 (33.5%) cases. Pleural thickening was observed in 53 (24.3%) cases and bronchiectasis was seen in 33 (15.1%) cases. A single cavity was present in 123 (56.4%) cases, and 95 (43.6%) cases had two or multiple cavities. In 95 (43.6%) cases, the cavities were bilaterally located. Cavities in the left and right lobes were observed in 65 (29.8%) and 58 (26.6%) cases, respectively (.

Antifungal therapy and outcomes

Out of 218 cases, itraconazole was used in 152 (69.7%) cases and 51 (23.4%) were treated with amphotericin B. In the remaining 15 (6.9%) cases, voriconazole was used as an anti-fungal agent. The median duration of treatment was 6.5 (IQR: 6.0–8.0) months. The duration of treatment in 114 (52.3%) cases was more than 6 months, while 95 (43.6%) received treatment for at least 6 months. The median duration of follow up remained 7.5 (IQR: 6.0–8.5) months. Improvement in symptoms was observed in 122 (52.3%) cases. Radiographic changes such as pleural thickening and nodular infiltrates were observed in 41 (18.8%) and 71 (33%) cases, respectively, as compared to the presence of pleural thickening and nodular infiltrates in 53 (24.3%) and 93 (42.7%) cases, respectively, before the initiation of therapy. A decline in inflammatory markers, i.e., ESR and CRP, was seen in 188 (86.2%) and 177 (81.2%) cases, respectively (.

Respiratory complications were developed in 129 (59.2%) cases. Hypoxic respiratory failure was the most common respiratory complication, followed by pneumothorax. ICU admission was required in 78 (35.8%) cases. Stability or recovery was observed in 119 (54.6%) patients, whereas the clinical conditions of 40 (18.3%) patients were deteriorated. Mortality was seen in 59 (27.1%) patients. Out of the CPA variants, the highest mortality was seen in SAIA [n = 9/28, (32.1%)] (.

Adverse effects associated with anti-fungal therapy

Adverse effects related to antifungal therapy were observed, which led to the discontinuation of treatment in 8 (3.7%) cases after a median of 2.5 months (IQR: 2.1–3.05). The majority of adverse effects were related to GIT, such as nausea (n = 51; 23.4%), diarrhea (n = 26; 11.9%) and anorexia (n = 60; 27.5%). Hepatotoxicity (liver transaminase level of ≥ 120 IU/L) was observed in 17 (7.8%) cases (.

Impact of prognosis in patients with TB

A proportion of our study population (n = 41; 18.8%) had active tuberculosis disease. The mean age of patients with the collective presence of TB and CPA was 45.9 years. Amphotericin B was the antifungal agent of choice for CPA in all the 41 cases with active tuberculosis disease. All the cases with active TB disease received standard anti-TB therapy, i.e., a combination of Ethambutol HCL, Rifampicin, Isoniazid and Pyrazinamide. The treatment response rate, based on the alleviation of symptoms, in the patients with co-existing tuberculosis was 51.2%, as compared to 56.3% and 58% in the patients having tuberculosis previously and in those with no tuberculosis, respectively. Out of 41 patients, respiratory complications were developed in 23 (56%) cases. ICU admission was required in 15 (36.6%) cases and mortality was seen in 11 (26.8%) patients (.

Factors associated with mortality

Underlying conditions such as hematological malignancies (p = 0.03), chronic kidney disease (p = 0.03), and diabetes mellitus (p = 0.04) were significant factors associated with mortality. Admission to ICU (p = <0.001) was also found to be significantly associated with mortality, as 29 (49.2%) out of 59 cases ending in mortality required ICU admission, and only 10 (12.8%) out of 78 patients requiring ICU admission recovered. Hypoxic respiratory failure (p = 0.028) was the most significant factor leading to ICU admission.

Furthermore, higher LOS (p = 0.007), consolidation (p = 0.02) and development of respiratory complications (p = 0.03) were also significant factors associated with mortality. In light of the analysis performed, recovery was seen in 11 out of 16 patients for which the length of hospital stay was < 10 days. Among 124 patients with LOS in the range of 10–19 days, recovery was seen in 81 (65.3%) cases. Whereas the recovery rates significantly declined once the length of stay in hospital was over 20 days. Age distribution (p = 0.012), chronic liver disease (p = 0.003), consolidation (p = 0.016) and diabetes mellitus (p = 0.05) were the significant factors leading to prolonged LOS. Among respiratory complications, hypoxic respiratory failure was the most significant factor associated with mortality (p = 0.04). Independent factors associated with mortality on logistic regression analysis were mean LOS, hematological malignancies, consolidation and ICU admission (.

Discussion

This study provided valuable information regarding the clinical manifestations, underlying conditions, associated risk factors and outcomes of CPA. The literature suggests that out of all the forms of CPA, CCPA is the most common [14]. However, in this study, the most encountered form was simple aspergilloma. The reason for this is the site of the study which was a tertiary care hospital, because simple aspergilloma is a late and progressed feature of CPA and the majority of cases are referred for further interventions in a tertiary care hospital [17].

Microbiological findings revealed that the percentage of positive sputum/BAL cultures was 84.9%, which was higher than the previous study carried out at a tertiary care hospital in Karachi, Pakistan, that reported 66.7% positive sputum/BAL cultures [12]. The high percentage may also be attributed to colonization or in-process contamination. In an attempt to reduce and possibly eliminate the risk of colonization affecting the culture results to some extent, the results were concluded after duly accessing the significance of growth. The risk of contamination was significantly reduced by carrying out microbiological processes under a controlled environment and using safety cabinets. Furthermore, the most common isolate was Aspergillus fumigatus, which was the same as found by previous research [18-21].

According to the literature, risk factors for CPA include a history of mycobacterial illness, COPD, asthma and interstitial pneumonia [12, 22–24]. In our study, a history of steroid use was also found as a common associated condition, and association between corticosteroid use and development of pulmonary aspergillosis is also reflected by the previous studies [25, 26]. This study revealed that the majority of patients developed CPA as a post-TB sequel, which is also supported by a number of previous studies [5, 18, 22, 27, 28]. But a rare condition, that is the collective presence of active PTB and CPA, was also revealed, which was previously reported in very few studies [29-31]. DM was found to be the most significant comorbidity, as 29.8% cases were diabetic. CCPA had the highest percentage of patients with diabetes (33.8%) compared to other forms of CPA. The previous studies have also reported the association between DM and pulmonary aspergillosis infections, and individuals with DM are more prone to getting pulmonary aspergillus infections, even when the other risk factors are not present [32]. The increase in occurrence of tuberculosis is attributed to DM, possibly due to the deteriorated immune status of diabetic patients, and thus the clinical manifestations are worsened and treatment outcomes are adversely affected due to the collective presence of DM and TB [33-35]. In our study, 21.1% of patients had a history of pulmonary sarcoidosis, and it has also been documented that CPA can occur, complicating the pulmonary sarcoidosis [36]. The symptoms observed in this study were non-specific such as cough, fever, fatigue, weight loss and hemoptysis, as indicated in previous studies, and in a few cases, CPA has also been found to be asymptomatic [37, 38].

Radiographic findings revealed that the majority of patients had fungal balls. Nodular infiltrates, consolidation, bronchiectasis and pleural thickening were also observed. The presence of fungal balls was reported in 90% of CPA patients in a recent study [39]. A total of 56.4% CPA patients in our study had a single cavity as compared to 86% reported by a previous study, and most of the cavities in our study were bilaterally present unlike in the previous study [40]. The number of cases with nodular infiltrates and pleural thickening declined as a response to treatment.

The most common respiratory complication was hypoxic respiratory failure because CPA is a progressive lung disease. In CCPA, the compromised respiratory system is already well-documented [41]. Mortality rates vary significantly between the studies because mortality is linked to the severity of the disease, various complications and delayed diagnosis. In a previous study, a mortality rate of 8% was reported with a median follow-up time of 10 months [42]. A comparatively recent study revealed a high mortality rate of 50% with a median follow-up time of 27.8 months [43]. This study revealed an overall mortality rate of 27.1% with a median follow-up time of 7.5 months.

In a previous study, based on the alleviation of symptoms, the overall treatment response rates involving the use of voriconazole in about 99% of the study population was 73% [40], as compared to 56% in our study. Antifungal therapy remained adequately acceptable for most of the patients as treatment discontinuation was seen in only 3.7% of cases as compared to 10% in a recent study [40]. Our study population had a considerable number of patients with co-existing tuberculosis; thus, Amphotericin B was considered as an anti-fungal agent of choice due to major interactions among triazoles and first line anti-tubercular drugs [14]. In the patients with co-existing pulmonary tuberculosis, the treatment response rate based on alleviation of symptoms was 51.2%, which was low compared to the treatment response rate in patients having TB previously and patients having no TB.

Mean LOS, admission to ICU, presence of hematological malignancies and consolidation were independent factors associated with the mortality, whereas in a previous study hypoxic respiratory failure, DM and mean LOS were the risk factors associated with mortality [12]. The presence of invasive fungal infections in patients with hematological malignancies is already well documented as the evidence of fungal infections at autopsy has already been found in 20–50% of the patients with such malignancies [44, 45]. This is possibly due to the enhanced risk of infection in patients with hematological malignancies leading to morbidity and mortality [46]. In our study, the non-survivors appeared to have a longer stay at hospital and required ICU admission, which is also evident in a recent study [12]. Due to the scarcity of data regarding mean LOS and ICU stay in patients with chronic pulmonary aspergillosis, a clear comparison is very difficult to make as most of the available data was related to the IPA.

Study limitations

Though plenty of useful clinical information was extracted from this study, it had a few limitations, which should be considered while interpreting the results. Findings produced by a study conducted in a single center cannot be generalized, and the nature of the study was retrospective, so standardization was not ensured [2]. The latest diagnostic methods, particularly antigen detection techniques, were not available. Nowadays, a variety of diagnostic methods are available to detect fungal infections of the lungs. These methods include the antigen detection techniques, polymerase chain reactions (PCR) and various serological methods [47]. Neither the galactomannan (GM) tests from bronchoalveolar lavage fluid (BALF) nor the serum GM antigen tests have shown significant efficacy in the case of CPA [48, 49]. A research study concluded that the combination of GM and β-D-Glucan (βDG) tests performed on BALFs of those with a suspected infection was a more useful approach for the diagnosis of CPA compared to any test used alone [50-52]. Due to the unavailability of antigen detection techniques, we had to rely on culture tests, despite their low sensitivity, because culture positivity does not always confirm the presence of infection, owing to the undeniable fact that organisms may be either contaminants or colonizers, as described by Iqbal et al. [12]. It should be noted that colonization is distinguishable from infection: colonization means only the existence of microorganisms without any induction of disease or anomaly, whereas infection refers to the induction of disease or anomaly due to the presence of pathogenic microorganisms, which are the etiological agents of the caused disease [13, 53]. Further studies involving the latest diagnostic techniques are required to overcome the gaps in terms of diagnosis, and standardized, multi-center studies should be conducted to overcome the lack of standardization.

Conclusions

CPA had a significant association with PTB in the majority of the cases., The co-existence of CPA along with active PTB was also seen in some cases. In the later cases, treatment response rates were comparatively low. Mortality had a significant relationship with mean LOS, consolidation, hematological malignancies and stay at ICU, chronic renal failure, respiratory complications and DM. Increased mean LOS, hematological malignancies, presence of consolidation and stay at ICU were the independent factors associated with mortality. The unavailability of antigen detection techniques made diagnosis delayed and questionable. Further multi-center prospective studies involving antigen detection techniques are required for better understanding of the disease.

Enrollment of patients having pulmonary aspergillosis.

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1 Feb 2021

PONE-D-20-37556

Clinical Manifestations, Associated Risk Factors and Treatment Outcomes of Chronic Pulmonary Aspergillosis (CPA): An Experience from Tertiary Care Hospital in Lahore, Pakistan

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Reviewer #1: This is a fairly straightforward retrospective study of outcomes in pulmonary aspergillosis. Overall it provides helpful granular information regarding risk of mortality and complications for various types of pulmonary aspergillosis and as such is of value to the literature.

Major comments:

1. There are many grammatical and spelling errors and the document would benefit from an edit by a native english speaker.

2. Mortality is discussed but I don't see any discussion of the average duration of follow up for cases. Mortality is 100% if the follow up period is long enough.

3. I don't know if it adds anything to say that longer LOS and ICU admission predict mortality as hospitalization and ICU admission tend to proceed mortality and are outcomes themselves.

Reviewer #2: The manuscript by Akram et al descibes clinical characteristics of a cohort of patients with pulmonary aspergillosis. The strenght of the study is the large number of patients with postTB aspergilloma. However, the topic has been extensively reviewed in the last years and the manuscript does not add information to current knowledge. The english academic language needs some corrections.

Reviewer #3: The study investigated the clinical manifestations, associated risk factors and treatment outcomes of chronic pulmonary aspergillosis in a tertiary care hospital in Pakistan. It’s important. However, there are several issues in the study.

1.The dosage and course of steroid, and respiratory complications (Table 4) were not clearly described in the study.

2.Age distribution, treatment choice, and the impact on prognosis in patients with tuberculosis is not well analyzed.

3.Moreover, many factors such as underlying conditions and treatment medications may also impact the alarming mortality rate. More detailed analysis is needed.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Chao Wu

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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12 Apr 2021

Reviewer 1: I have incorporated all of your suggestions into my revision. They were helpful. Thank you.

Reviewer 2: I have incorporated all of your suggestions into my revision. They were helpful. Thank you.

Reviewer 3: I have incorporated all of your suggestions into my revision. They were helpful. Thank you.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

6 May 2021

PONE-D-20-37556R1

Clinical Manifestations, Associated Risk Factors and Treatment Outcomes of Chronic Pulmonary Aspergillosis (CPA): An Experience from Tertiary Care Hospital in Lahore, Pakistan

PLOS ONE

Dear Dr. Akram,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Please review comments made by the reviewer and provide point by point response in your revised manuscript..

==============================

Please submit your revised manuscript by June 5th, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The manuscript has been greatly improved. The description of statistical analysis needs further clarification regarding the multiple regression analysis and how parameters were selected. In the tables it should be clarified whether range, IQR or SD is presented.

The are still a number of spelling errors.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #2: No

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17 Jun 2021

Respected Editor,

We have received revision for our submitted manuscript. We have hereby addressed all the concerns of the reviewer and all the suggestions made by the reviewer have been duly acknowledged. We are hopeful that the concerns of the reviewer will be satisfied by revised version of the manuscript. We have attached point-by-point response to the concerns of the reviewer and the revised version of manuscript has been highlighted in order to make the changes evident. Please let us know if there are any other suggestions or if any further changes are required.

We are thankful to the editor and the reviewers for their time and efforts in putting their valuable suggestions and recommendations to make this manuscript more scientifically elegant and technically sound.

Journal Requirements:

1. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: There is no retracted reference in our article. We did some changes to the reference list in the previous revision. Following are the new references that were added:

Number in References References Added

25. Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax. 2015;70(3):270-7.

26. Ader F, Nseir S, Le Berre R, Leroy S, Tillie-Leblond I, Marquette C, et al. Invasive pulmonary aspergillosis in chronic obstructive pulmonary disease: an emerging fungal pathogen. Clinical Microbiology and Infection. 2005;11(6):427-9.

36. Uzunhan Y, Nunes H, Jeny F, Lacroix M, Brun S, Brillet P-Y, et al. Chronic pulmonary aspergillosis complicating sarcoidosis. European Respiratory Journal. 2017;49(6).

Apart from that, in this revision, a duplicated reference has been removed. The reference present at number 47 in the previous version, was also present at number 12. Below are the details of that particular reference:

Number in previous version. Reference Removed

47. Iqbal N, Irfan M, Zubairi ABS, Jabeen K, Awan S, Khan JA. Clinical manifestations and outcomes of pulmonary aspergillosis: experience from Pakistan. BMJ open respiratory research. 2016;3(1).

2. Please ensure that you refer to Table 4 in your text as, if accepted, production will need this reference to link the reader to the Table.

Response: The revised manuscript has followed the direction.

3. Please upload a copy of Supporting information Figure S1 which you refer to in your text on line 586.

Response: The revised manuscript has followed the direction.

Reviewer 2: Reviewer Comments

Reviewer: The manuscript has been greatly improved. The description of statistical analysis needs further clarification regarding the multiple regression analysis and how parameters were selected. In the tables it should be clarified whether range, IQR or SD is presented.Theere are still a number of spelling errors.

Response: Respected reviewer, we are pleased to know that you have seen great improvements in our revised manuscript. Your concern towards our manuscript is really appreciated and we are thankful that you are taking pains to recommend further improvements.

Concern 1: The description of statistical analysis needs further clarification regarding the multiple regression analysis and how parameters were selected.

Response 1: Respected reviewer, prior to performing the multivariate analysis, univariate analyses of the independent variables with the outcomes (that were stable/recovered, Deteriorated, and Mortality) were conducted. For the univariate analysis, all the parameters/variables that were clinically and biologically plausible, and all those indicated by previous literature, were selected. The variables reaching significance on univariate analyses, i.e., p ≤ 0.05, were selected for multinomial logistic regression analysis, in order to determine the independent factors associated with mortality. Furthermore, in regression output, the redundant parameters were excluded from the model. The results were presented in tables as p-value and odds ratio, along with 95% confidence intervals. For your convenience, we have highlighted the text in methodology, in which we have mentioned that how the variables were selected.

Concern 2: In the tables it should be clarified whether range, IQR or SD is presented.

Response 2: Respected reviewer, the mentioned aspect has been clarified and highlighted in tables.

Concern 3: Theere are still a number of spelling errors.

Response 3: Respected reviewer, all the spelling errors have been corrected and the manuscript has been subjected to a review by a native speaker. We expect that the revised version will satisfy this concern.

Respected reviewer,

We have tried our best to improve the manuscript and have made and highlighted the recommended changes in the manuscript. In this point-by-point response document, we did not list all the changes, but the changes are marked in the revised version. We are hopeful that this revision will meet with approval.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

15 Jul 2021

PONE-D-20-37556R2

Clinical Manifestations, Associated Risk Factors and Treatment Outcomes of Chronic Pulmonary Aspergillosis (CPA): An Experience from Tertiary Care Hospital in Lahore, Pakistan

PLOS ONE

Dear Dr. Khan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: Please review comments ​made by the reviewer and address them in your revised manuscript. Specifically language editing is required prior to acceptance of the manuscript.

==============================

Please submit your revised manuscript by August 14th, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Explanation of the statistical analyses has greatly improved. The document is still somewhat difficult to read and it would benefit from a once over by a native english speaking editor, but I think the data and conclusions are sound.

Reviewer #2: The manuscript has been greatly improved. Comments have been addressed. However the academic language needs revision.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Brett Williams

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

12 Aug 2021

Respected Editor,

We have received further revision for our submitted manuscript. The concerns of the reviewers have been duly acknowledged. We are hopeful that the concerns of the reviewers will be satisfied by this version of the manuscript. We have attached point-by-point response to the concerns of the reviewers and the revised version of manuscript has been highlighted in order to make the changes evident.

We are greatly thankful to the editor and the reviewers for their time and efforts in putting their valuable suggestions and recommendations to make this manuscript scientifically elegant, technically sound and comprehendible.

Reviewer Comments

Reviewer 1: Explanation of the statistical analyses has greatly improved. The document is still somewhat difficult to read and it would benefit from a once over by a native english speaking editor, but I think the data and conclusions are sound.

Response: Respected reviewer, we are pleased to know that you are satisfied with the explanation of statistical analyses. The manuscript has been subjected to review by a native English-speaking editor and Proofreading certificate is attached. We are hopeful that the revised version will satisfy this concern.

Respected reviewer,

We have tried our best to improve the manuscript by subjecting it to an extensive review by a native English speaking editor. We are hopeful that this revision will meet with approval.

Reviewer 2: The manuscript has been greatly improved. Comments have been addressed. However the academic language needs revision.

Response: Respected reviewer, we are pleased to know that you have seen great improvements in the manuscript. The manuscript has been subjected to review by a native English-speaking editor and Proofreading certificate is attached. We are hopeful that the revised version will satisfy this concern.

Respected reviewer,

We have tried our best to improve the manuscript by subjecting it to an extensive review by a native English-speaking editor. We are hopeful that this revision will meet with approval.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

27 Oct 2021

Clinical Manifestations, Associated Risk Factors and Treatment Outcomes of Chronic Pulmonary Aspergillosis (CPA): Experiences from a Tertiary Care Hospital in Lahore, Pakistan

PONE-D-20-37556R3

Dear Dr. Khan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All comments have been addressed

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The manuscript has been greatly improved.

All relevant comments have been met.

The manuscript merits publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

3 Nov 2021

PONE-D-20-37556R3

Clinical Manifestations, Associated Risk Factors and Treatment Outcomes of Chronic Pulmonary Aspergillosis (CPA): Experiences from a Tertiary Care Hospital in Lahore, Pakistan

Dear Dr. Khan:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Muhammad Adrish

Academic Editor

PLOS ONE

Table 1

Characteristics of patients with chronic pulmonary aspergillosis.

Characteristics of patients.	Out of 218 (%)
Mean age ± SD (years)	45.75 ± 6.26
Gender:
Male	160 (73.4%)
Female	58 (26.6%)
Smoking status:
Non-smokers	106 (48.6%)
Ex-smokers	64 (29.4%)
Current smokers	48 (22%)
Symptoms:
Cough	207 (95%)
Fatigue	202 (92.7%)
Sputum production	197 (90.4%)
Fever	187 (85.8%)
Hemoptysis	130 (59.6%)
Weight loss	76 (34.9%)
Dyspnea	39 (17.9%)
Chest pain	22 (10.1%)
Associated Conditions:
Diabetes mellitus	65 (29.8%)
Chronic kidney disease	61 (28%)
Hematological malignancies	36 (16.5%)
Chronic liver disease	12 (5.5%)
Neutropenia	19 (8.7%)
Steroid use	147 (67.4%)
Inhaled	32/147 (21.8%)
Oral	115/147 (78.2%)
Chemotherapy	16 (7.3%)
Pulmonary Tuberculosis:
Previous TB	96 (44%)
Active TB	41 (18.8%)
Other Respiratory Conditions:
Pulmonary sarcoidosis	46 (21.1%)
Bronchiectasis	33 (15.1)
Asthma	23 (10.6%)
COPD	23 (10.6%)
ILD	10 (4.6%)
Types of CPA Encountered:
Simple Aspergilloma.	122 (56%)
CCPA	68 (31.2%)
SAIA	28 (12.8%)

TB: Tuberculosis, COPD: Chronic obstructive pulmonary disorder.

ILD: Interstitial Lung Disease, CPA: Chronic Pulmonary Aspergillosis. CCPA: Chronic Cavitary Pulmonary Aspergillosis, SAIA: Subacute Invasive Aspergillosis. SD: Standard Deviation.

Table 2

Laboratory, microbiological and radiological findings.

Characteristics	Out of 218 (%)
Laboratory Findings:
C-Reactive Protein [Median (IQR)] (mg/L)	13.7 (9.3–17.5)
CRP >3–9	26 (11.9%)
CRP >9–18	149 (68.3%)
CRP >18	43 (19.7%)
Erythrocyte Sedimentation Rate [Median (IQR)] (mm/h)	67 (55–78)
ESR > 20–50	21 (9.6%)
ESR > 50–80	147 (67.4%)
ESR > 80–100	45 (20.6%)
ESR >100	5 (2.3%)
Positive Cultures:
Sputum/BAL	185 (84.9%)
Histopathology	111 (50.9%)
Sputum/BAL only	85 (38.99%)
Histopathology only	11 (5.04%)
Both sputum/BAL and Histopathology	100 (45.9%)
Isolated Aspergillus spp.
Aspergillus fumigatus	100 (45.9%)
Aspergillus flavus	81 (37.2%)
Aspergillus niger	20 (9.2%)
Aspergillus terreus	17 (7.8%)
Radiological Findings:
Fungal ball	143 (65.6%)
Nodular infiltrates	93 (42.7%)
Consolidation	73 (33.5%)
Pleural thickening	53 (24.3%)
Bronchiectasis	33 (15.1%)
Number of cavities:
1	123 (56.4%)
≥2	95 (43.6%)
Location of cavities:
Bilateral	95 (43.6%)
Left lobe	65 (29.8%)
Right lobe	58 (26.6%)

BAL: Bronchoalveolar Lavage, CRP: C-Reactive Protein, ESR: Erythrocyte Sedimentation Rate. IQR: Interquartile Range.

Table 3

Responses to therapy and outcomes.

Characteristics	Out of 218 (%)
Antifungal agent used
Itraconazole	152 (69.7%)
Amphotericin B	51 (23.4%)
Voriconazole	15 (6.9%)
Duration of Treatment [Median (IQR)] (Months)	6.5 (6.0–8.0)
<6 Months	9 (4.1%)
At least 6 months	95 (43.6%)
>6 Months	114 (52.3%)
Mean LOS ± SD (Days)	18.5 ± 10.9
<10	16 (7.3%)
10–19	124 (56.9)
20–29	20 (9.2%)
30–40	46 (21.1%)
>40	12 (5.5%)
Changes after treatment
Improvement in symptoms	122 (56%)
Pleural thickening	41 (18.8%)
Nodular infiltrates	72 (33%)
Decrease in CRP	177 (81.2%)
Decrease in ESR	188 (86.2%)
Negative conversion of sputum/BAL cultures	67/185 (36.3%)
Respiratory complications	129 (59.2%)
Hypoxic respiratory failure	59 (27.1%)
Pneumothorax	51 (23.4%)
Bronchopleural fistula	4 (1.8%)
Empyema	4 (1.8%)
Outcomes
Deteriorated	40 (18.3%)
Stable/Recovered	119 (54.6%)
Overall mortality	59 (27.1%)
Mortality in SA	29 out of 122 (23.8%)
Mortality in CCPA	21 out of 68 (30.9%)
Mortality in SAIA	9 out of 28 (32.1%)
Adjunctive surgical resection	19 (8.7%)
ICU admission	78 (35.8%)
Follow up duration [Median (IQR)] (Months)	7.5 (6.0–8.5)
Adverse effects due to antifungal therapy
Nausea	51 (23.4%)
Diarrhea	26 (11.9%)
Anorexia	60 (27.5%)
Hepatotoxicity	17 (7.8%)

LOS: Length of stay at hospital, SD: Standard deviation, IQR: Interquartile Range

ICU: intensive care unit, SA: Simple aspergilloma, CCPA: Chronic cavitary pulmonary aspergillosis, SAIA: Subacute invasive aspergillosis CRP: C-Reactive Protein

ESR: Erythrocyte Sedimentation Rate.

Table 4

Impact on prognosis of patients with TB.

Characteristics	Out of 41 (%)
Mean age ± SD (years)	45.90 ± 6.34
Age distribution
<35	3 (7.3%)
35–45	17 (41.5%)
>45	21 (51.2%)
Treatment Choice:
Amphotericin B	41 (100%)
Improvement in symptoms	21 (51.2%)
Stable/Recovered	20 (48.8%)
Deteriorated	10 (24.4%)
Mortality	11 (26.8%)
Adjunctive surgical resection	6 (14.6%)
Respiratory complications	23 (56.1%)
Hypoxic respiratory failure	12 (29.3%)
ICU admission	15 (36.6%)

SD: Standard Deviation, ICU: Intensive Care Unit.

Table 5

Factors associated with outcomes and independent risk factors associated with Mortality.

Factors	Outcomes			p-value*
	Stable/Recovered (n = 119)	Deteriorated (n = 40)	Mortality (n = 59)
Gender				0.559
Male	84 (70.6%)	30 (75%)	46 (78%)
Female	35 (29.4%)	10 (25%)	13 (22%)
Age Distribution (years)				0.338
<35	6 (5%)	5 (12.5%)	3 (5.1%)
35–45	53 (44.5%)	14 (35%)	21 (35.6%)
>45	60 (50.4%)	21 (52.5%)	35 (59.3%)
Diet conditions				0.396
Well-nourished	20 (16.8%)	8 (20%)	15 (25.4%)
Malnourished	99 (83.2%)	32 (80%)	44 (74.6%)
Smoking status				0.083
Current smoker	22 (18.5%)	6 (15%)	20 (33.9%)
Ex-smoker	33 (27.7%)	15 (37.5%)	16 (27.1%)
Non-smoker	64 (53.8%)	19 (47.5%)	23 (39%)
Mean LOS (± SD) (days)	15.68 (± 9.19)	14.92 (± 08)	26.64 (± 11.7)	0.007
<10	11 (9.2%)	5 (12.5%)	0 (0.0%)
10–19	81 (68.1%)	26 (65%)	17 (28.8%)
20–29	8 (6.7%)	3 (7.5%)	9 (15.3%)
30–40	15 (12.6%)	6 (15%)	25 (42.4%)
>40	4 (3.4%)	0 (0.0%)	8 (13.6%)
Treatment choice				0.584
Itraconazole	87 (73.1%)	25 (62.5%)	40 (67.8%)
Voriconazole	9 (7.6%)	3 (7.5%)	3 (5.1%)
Amphotericin B	23 (19.3%)	12 (30%)	16 (27.1%)
Respiratory complications	63 (52.9%)	23 (57.5%)	43 (72.9%)	0.038
Hypoxic respiratory failure	25 (21%)	11 (27.5%)	23 (39%)	0.040
Pneumothorax	27 (22.7%)	7 (17.5%)	17 (28.8%)	0.412
Bronchopleural Fistula	4 (3.4%)	0 (0.0%)	0 (0.0%)	0.184
Empyema	2 (1.7%)	2 (5%)	0 (0.0%)	0.188
Bronchiectasis	17 (14.3%)	4 (10%)	12 (20.3%)	0.344
Consolidation	33 (27.7%)	12 (30%)	28 (47.5%)	0.028
Pleural thickening	26 (21.8%)	8 (20%)	19 (32.2%)	0.247
Fungal balls	83 (69.7%)	26 (65%)	34 (57.6%)	0.276
ICU Admission	10 (8.4%)	39 (97.5%)	29 (49.2%)	<0.001
Underlying conditions associated with mortality:
Diabetes mellitus	31 (26.1%)	9 (22.5%)	25 (42.4%)	0.043
Hematological malignancies	16 (13.4%)	4 (10%)	16 (27.1%)	0.032
CKD	27 (22.7%)	10 (25%)	24 (40.7%)	0.038
CLD	7 (5.9%)	2 (5%)	3 (5.1%)	0.965
Neutropenia	12 (10.1%)	3 (7.5%)	4 (6.8%)	0.729
Chemotherapy	12 (10.1%)	2 (5%)	2 (3.4%)	0.224
Steroid use	77 (64.7%)	30 (75.0%)	40 (67.8%)	0.484
Tuberculosis				0.778
Active TB	20 (16.8%)	10 (25%)	11 (18.6%)
Previous TB	52 (43.7%)	16 (40%)	28 (47.5%)
COPD	12 (10.1%)	2 (5%)	9 (15.3%)	0.257
Asthma	12 (10.1%)	7 (17.5%)	4 (6.8%)	0.227
Independent factors associated with mortality on logistic regression analysis:
Factors	OR (95% CI)			p-value**
Mean LOS (days)	1.107 (1.063 to 1.154)			<0.01
ICU admission	12.806 (4.614 to 35.542)			<0.01
Hematological malignancies	3.747 (1.336 to 10.510)			0.012
Consolidation	2.753 (1.184 to 6.400)			0.019

*Chi-square.

**Multinomial Logistic Regression.

Bold: Significant, LOS: Length of hospital stay, CKD: Chronic Kidney Disease

CLD: Chronic liver disease, TB: Tuberculosis, COPD: Chronic obstructive pulmonary disease, ICU: Intensive care unit, SD: Standard Deviation.