Tolerability of oral itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis: A systematic review and meta-analysis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) requires prolonged treatment with itraconazole or voriconazole. However, adverse events (AEs) are common with the use of these agents, with the need to discontinue the offending drug in a significant proportion of the patients. The aim of this study was to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of CPA.
METHODS: We searched Embase and Medline to select clinical studies providing information on AEs to itraconazole or voriconazole for the treatment of CPA from inception to May 2020. Reviews, single case reports, and case series reporting less than 10 patients were excluded. Random effect meta-analysis was performed using STATA 16.0.
RESULTS: We included 9 eligible studies with an overall total of 534 CPA patients enrolled. Of these, 69% (n = 366) were treated with voriconazole and 31% (n = 168) with itraconazole. The median daily dose of both itraconazole and voriconazole used was 400mg. In a pooled analysis, AEs were observed in 36% (95% CI: 20-52%, N = 366) of patients on voriconazole and 25% (95% CI: 18 to 31%, N = 168) in those treated with itraconazole. Discontinuation rate due to AEs was the same for both drugs; 35% (47/366) and 35% (15/168) for voriconazole and itraconazole, respectively. There were 70 AEs reported with itraconazole use, the commonest being cardiotoxicity (29%). Skin AEs (28%) were the most frequent among the 204 AEs reported with voriconazole use. None of the studies compared the tolerability of itraconazole head-to-head with voriconazole.
CONCLUSIONS: AEs due itraconazole and voriconazole are common and may lead to discontinuation of treatment in a significant proportion of patients. This information can be used to educate patients prior to commencement of these antifungal therapies. PROSPERO REGISTRATION NUMBER: CRD42020191627.

Introduction

Chronic pulmonary aspergillosis (CPA) is a progressive lung disease characterised by cavitary lesions with evidence of paracavitary infiltrates, new cavity formation, or expansion of cavity size over time with or without a fungal ball accompanied by chronic pulmonary or systemic symptoms of 3 months duration or more, including at least 1 of the following symptoms: weight loss, productive cough, or hemoptysis [1]. CPA remains a global public health problem with a substantial morbidity and mortality. CPA occurs in patients with underlying structural lung diseases, notably healed pulmonary tuberculosis and chronic obstructive pulmonary diseases [2].

Management of CPA is dependent on the radiological phenotype. Simple aspergilloma requires surgical intervention; however, chronic cavitary pulmonary aspergillosis, which may progress to chronic fibrosing pulmonary aspergillosis, generally requires medical treatment with antifungal agents [3, 4].

Long-term oral antifungal therapy is the cornerstone of management of CPA and is associated with improved quality of life and reduced disease activity [5, 6]. Itraconazole and voriconazole are interchangeably used as first-line agents for the management of CPA with response ranging anywhere between 30 and 90% [4, 7–12]. Adverse events (AE) limit the use of these first line agents in a significant proportion of patients, requiring discontinuation in up to 30% of cases [4]. The precise predictors of these adverse events remain unknown. Rates of AEs may be affected by both the patient’s demographics and co-morbidities [13].

Few studies have reported adverse events to itraconazole and voriconazole from routine use and in clinical trial settings [14]. To-date, no systematic review has been undertaken to comprehensively evaluate AEs in this group of patients.

Therefore, this systematic review and meta-analysis was performed to evaluate the rates of AEs among patients being managed for CPA with itraconazole or voriconazole.

Methods

Search strategy

This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. The PRISMA checklist is available in S1 File. The protocol for conducting this systematic review is registered in the PROSPERO database (registration number: CRD42020191627)

We searched all studies published from inception to May 2020 from EMBASE and Medline databases.

The following search terms were used: “chronic pulmonary aspergillosis,” “CPA,” “Aspergillus nodule,” “simple aspergilloma,” “chronic cavitary pulmonary aspergillosis,” “CCPA,” “chronic fibrosing pulmonary aspergillosis,” “CFPA,” “itraconazole,” “voriconazole,” “adverse events,” “side-effects,” and “toxicities”.

In addition, manual literature search of all the references of the included articles was performed to find relevant studies. The search was limited to human studies and only studies written in English were selected.

The search strategy is available as S2 File.

Study selection criteria

The studies found through databases that were duplicates were removed using the HDAS program (National Institute for Health and Care Excellence, London, United Kingdom). Records were initially screened by title and abstract by two independent reviewers (F.B and R.O) to exclude those not related to the current study. The full text of potentially eligible records was retrieved and examined. Any discrepancies were resolved by consensus.

The PRISMA criteria for searching and selecting studies were used: The following inclusion criteria were applied to identify eligible studies: (i) published in the English language from inception to May 2020; (ii) designed as retrospective or prospective observational study or randomized clinical trial; (iii) reporting adverse events to itraconazole, voriconazole or both during treatment of CPA (iv) providing the incidence of toxicity and whether antifungal therapy was discontinued or not. We excluded studies on other forms of aspergillosis and single case reports and case series reporting less than 10 cases.

Data extraction

The following items were extracted from each article: year of publication, authors, study design, antifungal agent administered, sample size, age, underlying diseases, dose and duration of administration, and safety outcomes including tolerability and the specific AEs. Two reviewers (R.O and F.B) independently extracted the data, and differences were resolved by consensus.

Study outcomes

The study outcomes were the cumulative incidence of AEs and the proportion of patients who discontinued antifungal therapy due to adverse events.

Analysis

A random-effects meta-analysis was performed using metaprop command [16] in STATA 16.0. Heterogeneity across studies was assessed using the I2 index. Publication bias was assessed using a funnel plot and sensitivity analysis performed. P<0.05 was considered statistically significant at the 95% confidence interval. Descriptive statistics were used to summarise individual patient data. A narrative synthesis was also used to present the results and discussion of the study.

Results

Characteristics of studies

A total of 9 studies [4, 5, 11, 17–22] were included in the systematic review and 8 studies were eligible for meta-analysis, . summarizes the characteristics of studies included in the review and meta-analysis. Of the 10 studies, 6 were retrospective [4, 5, 11, 17, 18, 22], 1 randomised clinical trial [19] and 2 prospective, multicentre studies [20, 21]. Majority of the studies were from the United Kingdom (UK, n = 4) [4, 5, 11, 17] and France (n = 2) [20, 22]. Overall, the studies had 534 patients with mean/median age ranging from 36 to 66 years. Patients in 8 studies [4, 5, 11, 17, 18, 20–22]were treated with voriconazole (n = 366, 69%) and with itraconazole (n = 168, 31%) in two studies [4, 19], .

Adverse events

Voriconazole

AEs to voriconazole was analysed in 8 studies. AE incidence rates ranged from 13% to 86%, Table 1. Overall, pooled incidence rates of AE in patients who received voriconazole for CPA treatment was 36% (95% CI: 20–52%; I2 = 91.94%, P<. 001), .

Table 1

Characteristics of the eligible studies.

Study (Year)	Study Type	Country	Patients (N = 534)	Age (Median or Mean)	Intervention	Dosage	AE (n)	Discontinued: n (%)
Bongomin (2019) [17]	Retrospective Observational	UK	21	66	Voriconazole	300-500mg/day, Mean: 400mg/day	18	10 (56)
Bongomin (2018) [4]	Retrospective Observational	UK	151	65	Itraconazole	100-600mg/day, Median: 400mg/day	35	15 (43)
Bongomin (2018) [4]	Retrospective Observational	UK	43	65	Voriconazole	200-500mg/day; Median: 400mg/day	10	5 (50)
Cucchetto (2015) [18]	Retrospective Observational	Italy	21	52	Voriconazole	LD: 800mg, then 400mg/day	6	6 (100)
Al-Shair (2013) [5]	Prospective Longitudinal	UK	122	59	Voriconazole		46	9 (20)
Agarwal (2013) [19]	Open-labelled, Randomised Control Trial	India	17	36	Itraconazole	400mg/day for 6 months	8	0 (0)
Cadranel (2012) [20]	Prospective Non-Comparative Multicentre study	France	48	58	Voriconazole	100-200mg twice daily	7	7 (100)
Saito (2012) [21]	Prospective Non-Comparative Multicentre study	Japan	71	66	Voriconazole	6mg/kg twice daily	39	2 (5)
Camuset (2007) [22]	Retrospective Observational	France	24	59	Voriconazole	-	3	3 (100)
Jain (2005) [11]	Retrospective Observational	UK	16	-	Voriconazole	150-200mg twice daily	5	5 (100)

Abbreviations: UK- United Kingdom; AE- Adverse Event; LD- Loading Dose.

A funnel plot was generated to show the distribution of the included studies, S1 Fig. A sensitivity analysis was then performed using 3 studies that were under the funnel [5, 11, 18]. Pooled proportion of patients with AE from these studies was 36% (95%CI: 28% - 43%, I: 0.00%, P = .64). The forest plot for the sensitivity analysis is available as S2 Fig.

All studies except Camuset et al [22] reported frequencies of individual AEs that were observed in patients. A total of 204 AEs was reported. The commonest AEs were skin toxicity (n = 57, 27.9%), visual disturbances (n = 49, 24.0%), hepatotoxicity (n = 20, 9.8%), gastrointestinal disturbances (n = 20, 9.8%) and mental disorders (n = 11, 5.4%), .

Itraconazole

Only two studies reported AE following oral itraconazole use in patients with CPA [4, 19]. In one study [19], AE incidence rate was 47% and 23% in a UK study [4]. Overall pooled incidence rate of AE following oral itraconazole from the two studies was 25% (95% CI: 18–31%; I2 = 0.00% p<. 001). A total of 70 AEs was reported. The most common AEs were cardiotoxicities (n = 20, 28.6%), gastrointestinal disturbance (n = 17, 24.3%) and peripheral neuropathy (n = 10, 14.3%), .

Discontinuation from therapy

Table 1 summarizes the proportion of patients who discontinued voriconazole or itraconazole due to AEs. Of 134 patients who experienced AEs to voriconazole, 35% (n = 47) patients were discontinued. Discontinuation rates ranged from 5 to 100% of those who had AEs across studies. Overall, 35% (n = 15) of the 43 patients treated with itraconazole who developed AEs discontinued treatment.

Discussion

CPA is a debilitating progressive disease that highly affects the quality of life of the patients. Antifungal therapies have shown to improve symptoms and quality of life in up to two-thirds of patients [5, 23]. Itraconazole and voriconazole are used interchangeably as first-line agents for the long-term management of CPA [3, 6, 8]. However, voriconazole is preferred for patients with more severe disease or those with intra-cavitary fungal balls [4]. The reported efficacy of itraconazole and voriconazole varies from study-to-study, with a range of 30–93% and 50-67%, respectively [19]. Intravenous agents like amphotericin B and echinocandins have also shown comparable response rates in the treatment of CPA [24]. In a trial where CPA patients were initially stabilised with intravenous antifungals, oral voriconazole maintenance therapy showed better effectiveness than oral itraconazole for clinical improvement in CPA patients [7].

Posaconazole and isavuconazole are alternative agents for the management of CPA in patients who may not tolerate or have developed resistance to first-line drugs [17, 25, 26]. However, multiple adverse drug reactions have been reported with the use of triazoles, ranging from mild AE like nausea and vomiting to severe life-threatening AE like hepatotoxicity and cardiotoxicity.

In the present study, we synthesize the incidence of AEs following oral itraconazole and voriconazole reported in available studies. Our study shows that patients may better tolerate oral itraconazole than voriconazole in the treatment of CPA. The discontinuation rates due to AE are comparable across studies. However, a randomised clinical trial is required to confirm these findings.

AEs are commonly observed in patients on itraconazole. Transient elevation of liver enzymes (1.5 to 2 times) was observed in two patients in the first 2-3 months of treatment. In this study, most of the AE were mild and none required discontinuation from therapy [19]. Of the 23.1% (n = 35) of the patients who experienced AE in another UK retrospective, up to 37% were switched to a different azole (voriconazole and posaconazole) and 43% (n = 15) required discontinuation of therapy over a 12-month period of therapy [4]. The most common AE reported include heart failure as a result of cardiac toxicity, gastrointestinal disturbances and peripheral neuropathies. Life threatening AE like rhabdomyolysis have also been reported [4].

We observed AEs to voriconazole ranging from 12.5% to 85.7% among individual studies. In a recent study, up to 86% of the patients who received a median dose of 400mg/day of voriconazole experienced at least one AE, 56% of the patients had to be discontinued from therapy [17]. In our study, voriconazole-related skin toxicity, ocular toxicity and gastrointestinal disturbances were the most frequently observed AE which is in line with other studies reporting voriconazole related AEs [27]. Photosensitivity leading to erythematous rashes were reported in up to 6 studies [4, 5, 11, 18, 20, 22] but were prevented by use of sunscreens. Voriconazole-induced photosensitivity reactions include erythematous eruptions like facial erythema, cheilitis, skin hyperpigmentation, exfoliative dermatitis, discoid lupus erythematous, Steven-Johnson Syndrome, toxic epidermal necrolysis [28, 29]. Skin toxicities may lead to a melanoma and non-melanoma skin cancers, which calls for pharmacovigilance especially when initiating immunocompromised patients on voriconazole [30].

Patients also experienced visual disturbances like blurred vision, retinal flashes and photophobia; however, no study has reported blindness as a result of voriconazole use. Animal studies have demonstrated that voriconazole ocular toxicities could be due to the blockage of TRPM1 cation channels in retinal ON-bipolar cells [31]. Up to 83% of patients in a double-blind randomised controlled study suffered at least one visual AE following voriconazole therapy [32]. Other neurological conditions such as paraesthesia [11], vertigo [20] were also observed. Hepatotoxicity ranging from mild to severe was frequently reported in studies. Grade 3 liver toxicity was described in 2 patients, which led to discontinuation of therapy [20]. Derangement of liver enzymes was also observed in all the 8 studies that reported voriconazole use for CPA. Psychological symptoms like hallucination and memory disorders were also reported in some studies [18, 21]. The gastrointestinal AEs were mostly mild; included loss of appetite, nausea, vomiting and diarrhoea and did not necessitate discontinuation from treatment. Other AEs like QT prolongation, cytolysis, cholestasis, insomnia and general symptoms like headache were also observed.

We observed a very high rate of discontinuation of itraconazole (35%) or voriconazole (35%) due to AEs. This presents an issue as such patients are at risk of deterioration in their quality of life or relapse of CPA. Recently, we showed that over 40% of CPA patients who discontinue antifungals do relapse within the first 6 months [33]. Patients with bilateral diseases and those who had had short duration of antifungal treatment before discontinuing treatment were more likely to relapse.

Itraconazole and voriconazole have variable pharmacokinetics with significant drug-drug and drug-food interactions [34]. This results into varied serum drug levels and tissue exposures among patients. In most cases, AEs to these agents are dose dependent and therefore therapeutic drug monitoring should be a standard of care for patients on long-term treatment to optimise care and minimise AEs [34].

Our study however faces some limitations. The heterogeneity of the study has to be taken into consideration while interpreting the results of this study. Most of the patients in this study are from diverse ethnical origin, co-morbidities, different drug dosages and duration of therapy. Some studies also had incomplete reports of AE and were not taken into consideration during the analysis. However, results from a less heterogeneous group in a sensitivity analysis were consistent with the overall results.

Conclusion

From this study, treatment related AE occurred in between 20 and 52% of patients commenced on voriconazole and between 18% and 31% of patients commenced on itraconazole. Our study suggests that oral itraconazole may be a more tolerable agent compared to voriconazole for the treatment of CPA. However, to date no study has directly compared the tolerability of itraconazole and voriconazole. Cardiac toxicities with itraconazole use particularly require ardent monitoring of the patients to avoid adverse events like heart failure, which predisposes to increased mortality. Randomised trials are encouraged to guide appropriate selection of a safe and efficacious first-line antifungals for the management of CPA.

Funnel plot for voriconazole studies.

(DOCX)

Click here for additional data file.

Sensitivity analysis forest plot for voriconazole.

(PNG)

Click here for additional data file.

PRISMA checklist.

(DOCX)

Click here for additional data file.

Search strategy.

(DOCX)

Click here for additional data file.

Risk of bias assessment.

(DOCX)

Click here for additional data file.

3 Aug 2020

PONE-D-20-17016

Tolerability of Oral Itraconazole and Voriconazole for The Treatment of Chronic Pulmonary Aspergillosis: A Systematic Review and Meta-Analysis

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Reviewer #1: This review aimed to to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis. This is the first meta-analysis that discuss this point. I have some comments that will enhance the quality of this review:

General

1- The whole manuscript needs extensive revision for language mistakes.

Abstract

2- Sections of results and conclusions need to be paraphrased.

3- Mention all searched databases as reported in the methods.

Introduction

4- The third paragraph (lines 64 to 69) is very confusing; try to make it simple for reading.

5- The efficacy (response rate) of Itraconazole and voriconazole needs further references.

Methods

6- PubMed is a search engine not database (You searched MEDLINE through PubMed.

7- Cite the manifacure info of HDAS program; try to repeat this step (remove duplicates) with other program such as Mendeley or EndNote as I have some doubts with the results of HDAS program (It removed more than 90% of the downloaded citations!!!).

8- Write the initials of the reviewers involved in the data extraction process

9- Which random model you used in your analysis?

Results

10- Add a section of the findings of the potential source of bias assessment in the results.

11- Add a forest plot figure for the sensitivity analysis of Voriconazole in the supplementary file

Reviewer #2: This is an interesting study and the authors compared the safety, efficacy, and risks of Oral Itraconazole and Voriconazole in the treatment of chronic pulmonary aspergillosis. The paper is generally well written and structure. The quality of the manuscript is scientifically sound. Chronic pulmonary aspergillosis requires extensive and long-term treatment with anti-fungal medications. Adverse events are very common with the use of those medications. Many systematic reviews and metaanlyses investigated each of the treatment but none compared the efficacy of the both drugs in the treatment of chronic pulmonary aspergillosis. The authors found that most of the adverse events were observed in about one-fourth of patients treated with itraconazole and just over two-third of patients treated with voriconazole. This information can be used to educate patients prior to commencement of these antifungal therapies but also to guide the future clinical trials to investigate both treatment together. I think that systematic review will serve as an additional to the management of chronic pulmonary aspergillosis.

Reviewer #3: The authors performed a systematic review to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis. They concluded that AEs were observed in about one-fourth of patients treated with itraconazole, and just over two-thirds of patients treated with voriconazole. I have few concerns:

Abstract

1) Methods

- It is a random-effects model, not “Random effect”

- Also, the databases searched are inconsistent with the manuscript text, please recheck

2) Results: No need for I2 and P values.

Methods

* Search strategy

- Were MESH terms used?

- The authors mentioned, “The search was limited to human studies and only studies written in English were selected”, were databases filters used to choose these studies?

- Did not the authors check the abstracts of articles not in English? Some relevant studies may have been missed.

- Why did not the authors assess the efficacy of both drugs, along with assessing the safety outcomes? (I.e., Overall, Clinical, Radiological, responses ... etc.)

- Line 118: replace “Qualitative assessment” with the risk of bias assessment

- Line 133: It is a random-effects model, not “Random effect”

Results

- Line 142: “A total of 10 studies”, add references for the included studies.

- Line 144: “Of the 10 studies, 7 were retrospective [4, 5, 12-15]”, these citations are for 6 studies, not 7.

- Add a paragraph about the results of the “risk of bias assessment.”

- Please interpret the funnel plot.

- Figure 1: How is it possible that records retrieved after the removal of duplicates (n = 56), and the records screened (n = 21) !! please recheck.

Discussion

- I would recommend that basic information about the antifungal therapies should be moved to the introduction.

Language: The entire manuscript needs extensive professional revision for grammatical errors and stylistic editing to improve the quality of English. For example:

Line 33: “case reports and case series”, consider inserting a comma before “and”

Line 46: “compared tolerability”, an article is missing before the word tolerability

Line 50: two-thirds not “two-third”

Line 247: “is varies” the verb “varies” does not work with “is” in this sentence

Line 260: “in the treatment of with CPA”, incorrect preposition use, etc.

Reviewer #4: Reviewer report on the manuscript PONE-D-20-17016_titled " Tolerability of Oral Itraconazole and Voriconazole for The Treatment of Chronic Pulmonary Aspergillosis: A Systematic Review and Meta-Analysis". The present research was aimed to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of CPA. I have some major limitations that that should be considered for considering publication of this manuscript, these include:

1. In the abstract

a. (line 37-38) the sentence started with" We included 10 eligible studies, in 8 studies, 366 patients were treated with voriconazole (69%) and 168 with itraconazole (31%) in 2 studies" was ended with 2 studies???.. it should be rephrased to be understandable. I understand that, the 366 patients were enrolled in the 8 studies but what about the two other studies???? What were the differences between the 8 and the 2 studies?

b. Lines 40 and 42, the authors should include the number of patients between brackets adjacent to the 36% and 25%.

c. Lines 42 and 43, the author should not start the sentence with numbers and both sentences should sentences should be lined to avoid repetition of verbs.

d. The whole abstract should be rephrased particularly the % and (number of patients) in order to presented in more clearly and understandable way.

2. In the introduction

a. "line 77" the sentence started with "Few studies have reported adverse events …….etc) however, the authors did not make citation, therefore, the author should inserted the appropriate citation for these few studies.

b. Abbreviations should be defined at first mention and used consistently thereafter. In line 77, the author should replace adverse events with the abbreviation (AEs) as previously indicated.

c. There are a lot of relevant literature are available and I recommend the authors to be include them in both introduction and discussion sections, examples

i. Bongomin F, Asio LG, Baluku JB, Kwizera R, Denning DW. Chronic Pulmonary Aspergillosis: Notes for a Clinician in a Resource-Limited Setting Where There Is No Mycologist. J Fungi (Basel). 2020;6(2):75. Published 2020 Jun 2. doi:10.3390/jof6020075.

ii. Jenks JD, Hoenigl M. Treatment of Aspergillosis. J Fungi (Basel). 2018;4(3):98. Published 2018 Aug 19. doi:10.3390/jof4030098

iii. Alastruey-Izquierdo A, Cadranel J, Flick H, et al. Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives. Respiration. 2018;96(2):159-170. doi:10.1159/000489474

iv. Maghrabi F, Denning DW. The Management of Chronic Pulmonary Aspergillosis: The UK National Aspergillosis Centre Approach. Curr Fungal Infect Rep. 2017;11(4):242-251. doi:10.1007/s12281-017-0304-7

v. Baxter CG, Marshall A, Roberts M, Felton TW, Denning DW. Peripheral neuropathy in patients on long-term triazole antifungal therapy. J Antimicrob Chemother. 2011;66(9):2136-2139. doi:10.1093/jac/dkr233

vi. Sambatakou H, Dupont B, Lode H, Denning DW. Voriconazole treatment for subacute invasive and chronic pulmonary aspergillosis. Am J Med. 2006;119(6):527.e17-527.e5.27E24. doi:10.1016/j.amjmed.2005.11.028

3. Type of article should be changed from" Research article" to "review article) since it was meta-analysis and in silico study

Therefore, and according to the above mentioned remarks I advised minor revision of this manuscript under its current status.

Reviewer #5: - Line 13: This affiliation is missing at the author's list

- The number of studies included are considered to be small. Eight studies and some of them are providing data for one of the two drugs only. This affects the estimation of variation between studies.

- I suggest the authors to be more focused on serious AEs that necessitate the discontinuation of treatment.

- What is the explanation of having more patient treated with voriconazole than those treated with itraconazole (Results line 38) although the second is considered to be the first line.

- In conclusion section, the authors are suggesting the use of itraconazole over the use of voriconazole while it is already known for itraconazole to be the first line of treatment.

- Line 323: which, which

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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Submitted filename: report PONE-D-20-17016.docx

Click here for additional data file.

11 Aug 2020

Authors’ Responses

Editor

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Authors’ Response:

The manuscript has been re-formatted according to PLOS Ones guidelines. Thank you.

2. We note that 516 manuscripts were identified through database searching but that only 56 records (or only about 10% of records) remained after duplicates were removed. Please double check your duplicate removal strategy and confirm that the several hundred records removed were indeed duplicates.

Authors’ Response:

We apologise for this error in data extraction from the HDSA output. We had only 17 results from embase and 7 from Medline, and 5 additional from searching references of the selected articles. The Prisma flow diagram and the highlighted search strategy are provided.

3. Please provide the date(s) when the databases used in this study were last accessed.

Authors’ Response:

The databases were accessed on the May 12th, 2020 as indicated in the search strategy file.

4. Please report the heterogeneity analysis results across studies (assessed using Q statistics) and comment on the appropriateness of a meta-analysis.

Authors’ Response:

Heterogeneity was assessed using both Q statistics (chi-square = 86.88, p<0.001 and I2 statistics (i2 = 91.94, p<0.001). However, only the I2 statistics was reported in the manuscript since it is superior to Q statistics especially in meta-analyses with fewer studies. The interpretation and implication of the notable heterogeneity has been discussed as a limitation in the discussion section.

Authors’ Response:

5. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary).

Authors’ Response:

Thank you. The authors’ list and affiliations have been amended appropriately.

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Authors’ Response:

Thank you. The captions have been added according to the journal guidelines.

Reviewer #1: This review aimed to to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis. This is the first meta-analysis that discuss this point. I have some comments that will enhance the quality of this review:

General

1- The whole manuscript needs extensive revision for language mistakes.

Authors’ response:

Thank you. The manuscript was sent to a native English speaker for proof-reading and grammatical editing. We believe the paper can now be understood clearly.

Abstract

2- Sections of results and conclusions need to be paraphrased.

Authors’ response: Thank you. We may have revised these sections

3- Mention all searched databases as reported in the methods.

Authors’ response:

Thank you. All the searched databases reported in the methodology have been indicated as suggested.

Introduction

4- The third paragraph (lines 64 to 69) is very confusing; try to make it simple for reading.

Authors’ response: Thank you, this paragraph has been revised.

5- The efficacy (response rate) of Itraconazole and voriconazole needs further references.

Authors’ response: Many thanks, this has been amended.

Methods

6- PubMed is a search engine not database (You searched MEDLINE through PubMed.

Authors’ response:

Thank you. This has been rectified as suggested.

7- Cite the manufacture info of HDAS program; try to repeat this step (remove duplicates) with other program such as Mendeley or EndNote as I have some doubts with the results of HDAS program (It removed more than 90% of the downloaded citations!!!).

Authors’ response:

The manufacture of HDAS program has been duly cited.

8- Write the initials of the reviewers involved in the data extraction process

Authors’ response:

Thank you. The initials o the reviewers have been included in the main text as suggested.

9- Which random model you used in your analysis?

Authors’ response:

A random-effects model was used for meta-analysis. The metaprop command used (Command: metaprop n N, random) specifies a random-effects model using the method of DerSimonian and Laird, with the estimate of heterogeneity being taken from the inverse-variance fixed-effect model (Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Archives of Public Health. 2014 Dec 1;72(1):39.).

Results

10- Add a section of the findings of the potential source of bias assessment in the results.

Authors’ response:

A paragraph on the risk of bias assessment has been added in the results section as suggested. Thank you.

11- Add a forest plot figure for the sensitivity analysis of Voriconazole in the supplementary file

Authors’ response:

Thank you. The forest plot for the sensitivity analysis has been submitted as a supplementary file and cited in-text.

Reviewer #2: This is an interesting study and the authors compared the safety, efficacy, and risks of Oral Itraconazole and Voriconazole in the treatment of chronic pulmonary aspergillosis. The paper is generally well written and structure. The quality of the manuscript is scientifically sound. Chronic pulmonary aspergillosis requires extensive and long-term treatment with anti-fungal medications. Adverse events are very common with the use of those medications. Many systematic reviews and metanalyses investigated each of the treatment but none compared the efficacy of the both drugs in the treatment of chronic pulmonary aspergillosis. The authors found that most of the adverse events were observed in about one-fourth of patients treated with itraconazole and just over two-third of patients treated with voriconazole. This information can be used to educate patients prior to commencement of these antifungal therapies but also to guide the future clinical trials to investigate both treatments together. I think that systematic review will serve as an additional to the management of chronic pulmonary aspergillosis.

Authors’ response:

Thank you so much for the kind words.

Reviewer #3: The authors performed a systematic review to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis. They concluded that AEs were observed in about one-fourth of patients treated with itraconazole, and just over two-thirds of patients treated with voriconazole. I have few concerns:

Abstract

1) Methods

- It is a random-effects model, not “Random effect”

- Also, the databases searched are inconsistent with the manuscript text, please recheck

Authors’ response:

Thank you. The suggestions have been accepted and changed accordingly in the abstract.

2) Results: No need for I2 and P values.

Authors’ response:

Thank you. I2 and P values have been eliminated from the abstract as suggested.

Methods

* Search strategy

- Were MESH terms used?

Authors’ response:

The full search strategy used was ((((ITRACONAZOLE/ OR (Itraconazole).ti,ab OR (voriconazole).ti,ab OR VORICONAZOLE/) AND ("chronic pulmonary aspergillosis" OR "chronic cavitary aspergillosis" OR "chronic fibrosing pulmonary aspergillosis" OR "simple aspergilloma").ti,ab) AND ((adverse ADJ3 (reaction* OR effect OR affect)).ti,ab OR (toxic*).ti,ab OR "DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS"/ OR ("side effect*").ti,ab)) NOT ("invasive aspergillosis" OR "allergic aspergillosis").ti,ab. The strategy used Medline MESH terms where possible, in this case for Intraconazole, Voriconazole and Drug related side effects and adverse reactions.

- The authors mentioned, “The search was limited to human studies and only studies written in English were selected”, were databases filters used to choose these studies?

Authors’ response:

Database filters were used to limit to English language papers and human only studies.

- Did not the authors check the abstracts of articles not in English? Some relevant studies may have been missed.

Authors’ response: We limited our search strategy only to published English literature.

- Why did not the authors assess the efficacy of both drugs, along with assessing the safety outcomes? (I.e., Overall, Clinical, Radiological, responses ... etc.)

Authors’ response: Many thanks for these suggestions. We sought to answer a single hypothesis on safety. However, efficacy studies would be a good subject for future meta-analysis.

- Line 118: replace “Qualitative assessment” with the risk of bias assessment

Authors’ response:

Thank you. The suggestion has been accepted and change accordingly.

- Line 133: It is a random-effects model, not “Random effect”

Authors’ response:

Thank you. The suggestion has been accepted and changed accordingly.

Results

- Line 142: “A total of 10 studies”, add references for the included studies.

- Line 144: “Of the 10 studies, 7 were retrospective [4, 5, 12-15]”, these citations are for 6 studies, not 7.

Authors’ response:

Thank you for this observation. The references have been added as suggested. There was an obvious error in counting the number of eligible studies that we realised immediately after submission. The study by Bongomin et al , 2018 reported adverse events for both itraconazole and voriconazole. This was unfortunately counted as two studies. A total of 9 studies were eligible instead. The error has been corrected throughout the manuscript. Therefore, only 6 studies were retrospective.

- Add a paragraph about the results of the “risk of bias assessment.”

Authors’ response:

Thank you. A paragraph has been added as suggested.

- Please interpret the funnel plot.

Authors’ response:

Thank you. The funnel plot has been interpreted.

- Figure 1: How is it possible that records retrieved after the removal of duplicates (n = 56), and the records screened (n = 21) !! please recheck.

Authors’ response: Many thanks for spotting this. This was an error in extraction of HDAS output. We had only 17 results from embase and 7 from Medline, and 5 additional from searching references of the selected articles. The Prisma flow diagram and the highlighted search strategy are provided.

Discussion

- I would recommend that basic information about the antifungal therapies should be moved to the introduction.

Authors’ response:

Thanks for this suggestion. However, we thought the discussion section was a good place to explain the pharmacology of these agents. So We have left it as is .

Language: The entire manuscript needs extensive professional revision for grammatical errors and stylistic editing to improve the quality of English. For example:

Line 33: “case reports and case series”, consider inserting a comma before “and”

Line 46: “compared tolerability”, an article is missing before the word tolerability

Line 50: two-thirds not “two-third”

Line 247: “is varies” the verb “varies” does not work with “is” in this sentence

Line 260: “in the treatment of with CPA”, incorrect preposition use, etc.

Authors’ response:

Thank you for the concerns. The above outlined errors have been corrected as suggested. The manuscript was also sent to a native English speaker to make grammatical corrections on the whole paper. We believe the science in the paper can now be understood clearly by the readers.

Reviewer #4: Reviewer report on the manuscript PONE-D-20-17016_titled " Tolerability of Oral Itraconazole and Voriconazole for The Treatment of Chronic Pulmonary Aspergillosis: A Systematic Review and Meta-Analysis". The present research was aimed to evaluate the frequency of adverse events of itraconazole and voriconazole for the treatment of CPA. I have some major limitations that that should be considered for considering publication of this manuscript, these include:

1. In the abstract

a. (line 37-38) the sentence started with" We included 10 eligible studies, in 8 studies, 366 patients were treated with voriconazole (69%) and 168 with itraconazole (31%) in 2 studies" was ended with 2 studies??? it should be rephrased to be understandable. I understand that, the 366 patients were enrolled in the 8 studies but what about the two other studies???? What were the differences between the 8 and the 2 studies?

Authors’ response:

Thank you. The statements have been rephrased and is now clear. In all the eligible studies included, a combined total of 534 patients were enrolled. 366 (69%) were treated with voriconazole and 168 (31%) with itraconazole. 8 studies reported patients treated with voriconazole and 2 studies reported those treated with itraconazole.

b. Lines 40 and 42, the authors should include the number of patients between brackets adjacent to the 36% and 25%.

Authors’ response:

Thank you. This has been included as suggested.

c. Lines 42 and 43, the author should not start the sentence with numbers and both sentences should sentences should be lined to avoid repetition of verbs.

Authors’ response:

Thank you. The two sentences have been corrected as suggested by the reviewer.

d. The whole abstract should be rephrased particularly the % and (number of patients) in order to presented in more clearly and understandable way.

Authors’ response:

The entire abstract has been rephrased to present the results more clearly and in a comprehensible manner. Thank you.

2. In the introduction

a. "line 77" the sentence started with "Few studies have reported adverse events …etc) however, the authors did not make citation, therefore, the author should insert the appropriate citation for these few studies.

Authors’ response:

Thank you for this important observation. Citations supporting the statement have been added.

b. Abbreviations should be defined at first mention and used consistently thereafter. In line 77, the author should replace adverse events with the abbreviation (AEs) as previously indicated.

Authors’ response:

Thank you. This has been rectified.

c. There are a lot of relevant literature are available and I recommend the authors to be include them in both introduction and discussion sections, examples

i. Bongomin F, Asio LG, Baluku JB, Kwizera R, Denning DW. Chronic Pulmonary Aspergillosis: Notes for a Clinician in a Resource-Limited Setting Where There Is No Mycologist. J Fungi (Basel). 2020;6(2):75. Published 2020 Jun 2. doi:10.3390/jof6020075.

ii. Jenks JD, Hoenigl M. Treatment of Aspergillosis. J Fungi (Basel). 2018;4(3):98. Published 2018 Aug 19. doi:10.3390/jof4030098

iii. Alastruey-Izquierdo A, Cadranel J, Flick H, et al. Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives. Respiration. 2018;96(2):159-170. doi:10.1159/000489474

iv. Maghrabi F, Denning DW. The Management of Chronic Pulmonary Aspergillosis: The UK National Aspergillosis Centre Approach. Curr Fungal Infect Rep. 2017;11(4):242-251. doi:10.1007/s12281-017-0304-7

v. Baxter CG, Marshall A, Roberts M, Felton TW, Denning DW. Peripheral neuropathy in patients on long-term triazole antifungal therapy. J Antimicrob Chemother. 2011;66(9):2136-2139. doi:10.1093/jac/dkr233

vi. Sambatakou H, Dupont B, Lode H, Denning DW. Voriconazole treatment for subacute invasive and chronic pulmonary aspergillosis. Am J Med. 2006;119(6):527.e17-527.e5.27E24. doi:10.1016/j.amjmed.2005.11.028

Authors’ response:

Thank you for the valuable suggestions. We have reviewed the above papers and found them excellent and relevant for our paper. They have been included appropriately.

3. Type of article should be changed from" Research article" to "review article) since it was meta-analysis and in silico study

Authors’ response:

Thanks for this suggestions. However, PLoS one considers SR and MA as Original Articles

Reviewer #5:

- Line 13: This affiliation is missing at the author's list.

The affiliation has been updated in the authors’ list. Thank you for the keen observation.

- The number of studies included are considered to be small. Eight studies and some of them are providing data for one of the two drugs only. This affects the estimation of variation between studies.

Authors’ response: We agree with the reviewer. We acknowledged that most studies reported on AEs to a single agent and we also acknowledged that there is no published study comparing itra and vori head to head. Bongomin et al 2018 is the only study that reported the use of itra and vori in more than 150 patients. Again this was an observational study. We recommened that more studies are required to provide definitive answers. Thank you

- I suggest the authors to be more focused on serious AEs that necessitate the discontinuation of treatment.

Authors’ response: Many thanks for this. We presented both sides of the data, overall AEs and AEs warranting discontinuation of therapy. We believe both parts of the story is useful to the patients.

- What is the explanation of having more patient treated with voriconazole than those treated with itraconazole (Results line 38) although the second is considered to be the first line.

Authors’ response: this finding also surprised us. We know that the recommendation of itra as first line is based mainly on expert opinions and a single RCT which had less than 20 patients on itra. And the other possible explanation is publication bias, where more studies on Vori are published compared to itra.

- In conclusion section, the authors are suggesting the use of itraconazole over the use of voriconazole while it is already known for itraconazole to be the first line of treatment.

Authors’ response: Thanks for this observation, however, we said “more tolerable” and we didn’t suggest it as a preferred first line. Current guidelines suggest Itra and vori are alternative firstlline agents and the choice of use of itra or vori is based on the clinicians assessment of risks and benefits for each individual patient.

- Line 323: which, which

Authors’ response:

Thank you. This has been rectified accordingly.

Submitted filename: Authors Response to Reviewers - Final.docx

Click here for additional data file.

14 Sep 2020

PONE-D-20-17016R1

Tolerability of oral itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Bongomin,

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

The article is acceptable after addressing our minor comments "shown below".

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

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We look forward to receiving your revised manuscript.

Kind regards,

Ahmed Negida, MD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

1- Please, address the comments of Reviewer 1.

2- I suggest adding publication bias assessment & the funnel plot in the online supplementary files not in the main manuscript. According to Egger et al. the assessment of publication bias in fewer than 10 studies is not statistically reliable. While you information is indicative and informative of the possibility of publication bias, it is not a firm reliable method to judge the current evidence (based on the limited number of analyzed studies). Therefore, I would suggest removing this part to an online supplementary file.

[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

Reviewer #4: All comments have been addressed

**********

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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

Reviewer #4: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

**********

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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

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

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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: The authors addressed all my comments, and I think that the manuscript now is well-written and well-presented; however, I have some concerns about the searching process:

Why you did you exclude the Web of Science and Cochrane library?

Did you repeated the searching and screening process?

How could the number of articles in EMBASE decreased from 516 to 17? Did you applied any filters?

Reviewer #2: The authors addressed all the required comments. Therefore, I think that that the manuscript is suitable for review at PLOS ONE.

Reviewer #4: The review comments have been addressed by authors. all required questions have been answered by authors and the responses meet formatting specification

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Reviewer #1: No

Reviewer #2: No

Reviewer #4: No

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18 Sep 2020

Response to Editor

1- Please, address the comments of Reviewer 1.

Authors’ response: Thank you editor. We have addressed the reviewer 1’s comments below.

2-

2- I suggest adding publication bias assessment & the funnel plot in the online supplementary files not in the main manuscript. According to Egger et al. the assessment of publication bias in fewer than 10 studies is not statistically reliable. While you information is indicative and informative of the possibility of publication bias, it is not a firm reliable method to judge the current evidence (based on the limited number of analyzed studies). Therefore, I would suggest removing this part to an online supplementary file

Authors’ response: Thank you for these insightful suggestions. The bias assessment and the funnel plots have been removed from the main manuscript and transferred to supplementary materials.

Response to reviewer 1

Reviewer #1: The authors addressed all my comments, and I think that the manuscript now is well-written and well-presented; however, I have some concerns about the searching process:

Why you did you exclude the Web of Science and Cochrane library?

Authors’ response: We thank the reviewer for this query: Our specialist medical librarian (LR – an author to this paper) conducted an extensive search inclusive of both WoS and Cochrane library. Howver, she retrieved very few articles from this two databases – all of which were already picked up by Embase and Medline – Therefore WoS and Cochrane library did not contribute any unique search and so we did not include them on the PRISMA flow diagram

Did you repeated the searching and screening process?

Authors’ response: Yes, we did and we got the same output – no new articles were identified. We further confirmed our search output as outlined in Figure 1.

How could the number of articles in EMBASE decreased from 516 to 17? Did you applied any filters?

Authors’ response: Many thanks for this confirmatory question again. As we responded to your comments in the first review, this was an error in extraction of HDAS output. We had only 17 results from embase and 7 from Medline (we have provided the search output as a supplementary material), and 5 additional articles from searching references of the selected articles. Yes, we applied filters – a qualified Medical Librarian did these searches.

Thank you very much for improving the quality of this paper. Much appreciated.

25 Sep 2020

Tolerability of oral itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis: a systematic review and meta-analysis

PONE-D-20-17016R2

Dear Dr. Bongomin,

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.

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Kind regards,

Ahmed Negida, MD

Academic Editor

PLOS ONE

28 Sep 2020

PONE-D-20-17016R2

Tolerability of oral itraconazole and voriconazole for the treatment of chronic pulmonary aspergillosis: a systematic review and meta-analysis

Dear Dr. Bongomin:

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.

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on behalf of

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Academic Editor

PLOS ONE