Efficacy and safety of caspofungin for the treatment of invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease

Abstract

Objectives

We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA).

Methods

Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin.

Results

An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants.

Conclusions

Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a prevalent and increasingly common disease that poses a significant threat to human health. Its incidence is increasing, leading to high rates of mortality and morbidity both in China and globally.^1–3 Recent studies suggested a potential association between COPD and an increased risk of invasive pulmonary aspergillosis (IPA). The use of corticosteroids, along with structural and functional impairments in the lungs, further contribute to the susceptibility to IPA. Additionally, comorbidities such as malnutrition and diabetes also increase the risk of IPA in patients with COPD.^4–6

There is currently a scarcity of clinical data regarding morbidity and mortality rates among individuals concurrently affected by IPA and COPD, and the safety and efficacy of antifungal treatments in these individuals have not been clarified. In our hospital, data from 8 October 2009 to 8 October 2010 revealed that among 2342 patients admitted for acute exacerbation of COPD (AECOPD), 37 were diagnosed with proven IPA (unpublished data). These patients were treated with voriconazole, itraconazole, caspofungin, or amphotericin B lipid formulations.

Despite voriconazole traditionally serving as the primary treatment for IPA, the crucial role of caspofungin has been emphasized, as it often functions as the primary antifungal agent, especially in patients with impaired renal function. Recognized as a potent echinocandin antifungal medication, caspofungin holds a significant recommendation from the Infectious Diseases Society of America (IDSA) as a pivotal salvage therapy for IPA. ⁷ Although voriconazole is typically recommended as the primary treatment for IPA, caspofungin is often used as a primary antifungal agent, especially in patients with IPA and impaired renal function. A recent large-scale study conducted in Japan found that micafungin, another echinocandin, was as effective as voriconazole when used as a primary therapy for chronic pulmonary aspergillosis in severely immunocompromised patients while offering superior safety compared with voriconazole. ⁸ Several studies have demonstrated the efficacy and good safety profile of caspofungin in patients with IPA and hematologic disorders or oncological conditions.^9–11 Among these studies, an administered caspofungin dosage of 200 mg/day was determined to be well tolerated and safe. ¹¹ However, the efficacy of caspofungin in patients with COPD and IPA has not been clearly established. Additionally, comorbidities have a significant impact on the efficacy and safety of caspofungin. ¹²

Based on the aforementioned considerations, our study evaluated the efficacy of caspofungin in the treatment of IPA in hospitalized patients with COPD. The primary objective of the study was to assess the efficacy of a 3-week course of caspofungin when used as either a primary or salvage therapy in this patient population. Secondary outcomes of interest included the monitoring and evaluation of adverse events associated with caspofungin therapy, the overall response to 2 weeks of caspofungin treatment, factors influencing patient responses to caspofungin therapy (such as whether it was used as a primary or salvage therapy), the certainty of the IPA diagnosis, the severity of COPD, exposure to systemic corticosteroids and/or broad-spectrum antibiotics, and complications and comorbidities associated with COPD such as malnutrition and diabetes.

Materials and methods

Study design

This prospective, open-label, single-arm, single-center clinical trial study investigated the efficacy and safety of caspofungin in treating IPA in patients with COPD. The lead research center for this study was the Guangzhou Institute of Respiratory Health, formerly known as the Guangzhou Institute of Respiratory Diseases. In error, we did not prospectively register this trial, but we have now registered it retrospectively at the Research Registry (https://www.researchregistry.com/, registration number ChiCTR2400079780).

During the study, enrolled patients participated in the study for approximately 3 weeks and underwent four clinical evaluations at the hospital. A study flowchart is presented in Figure 1.

Figure 1.

Study flowchart.

Subject screening and selection

Patients with AECOPD complicated by proven or probable IPA were recruited between 1 July 2011 and 1 August 2017. The study received ethical approval from the Ethics Committee of Guangzhou Institute of Respiratory Health (code of ethics No. 2011-081).

A confirmed case of IPA required histopathologic evidence of lung or airway tissue invasion with hyphae consistent with Aspergillus species or a positive culture of Aspergillus spp. These diagnoses were made through invasive procedures such as transbronchial lung biopsy, percutaneous lung biopsy, or open-lung biopsy performed from a sterile site (pleural fluid and/or biopsied airway or lung specimen).

Probable IPA cases were determined according to clinicoradiological evidence suggestive of acute IPA in patients with severe or very severe COPD that did not respond to at least 3 days of intravenous extended-spectrum antibiotics. Additional criteria included the recovery of Aspergillus spp. from respiratory fluids, a positive blood A. galactomannan antigen test, and radiological manifestations of the halo sign, air-crescent sign, or multiple cavitary lesions.

Inclusion and exclusion criteria

Inclusion criteria

The study inclusion criteria were as follows:

1. Inpatients with AECOPD who were diagnosed with proven or probable IPA based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria.

2. Age > 18 years.

3. Admission to the hospital.

4. Provision of written informed consent by patients or their legal representatives.

5. A negative urine pregnancy screening test for women of childbearing age, who also agreed to use safe and effective contraceptive measures throughout the study.

6. No participation in other clinical research studies within the past 14 days.

7. No receipt of echinocandin antifungal therapy within 72 hours prior to enrollment.

8. No receipt of prophylactic intravenous antifungal therapy prior to enrollment, excluding fluconazole or oral antifungal drugs.

Concomitant treatment

All non-study drugs, whether prescription or over-the-counter, including topical antifungal agents, regardless of whether they were being used prior to the study or after they have been tested, were required to be discontinued. The use of any concomitant medication was recorded in the case report form (CRF).

Exclusion criteria

The study excluded subjects who met any of the following criteria:

1. A history of allergies or intolerance to echinocandin antifungal agents.

2. Suspected allergy to the study drug or its associated components.

3. Pregnancy or lactation in women, as well as women of childbearing age who refused to use appropriate contraceptive methods during the study.

4. Prior use of antifungal drugs or requirement of multiple antifungal drugs, with the exception of topical medications.

5. Diagnosis of malignant tumors, active viral hepatitis, severe renal insufficiency (serum creatinine clearance <30 mL/min), severe liver dysfunction or severe hepatic insufficiency, human immunodeficiency virus infection, central nervous system fungal infection, or a serious uncontrolled bacterial infection.

6. Presence of other serious systemic diseases that could potentially affect the outcomes of the study, as determined by the investigator’s judgment.

Informed consent

All patients underwent an assessment by a doctor to determine their eligibility for the study. Following this assessment, a medical officer from the trial team spoke with the patients adhering to the guidelines set forth by the International Council for Harmonisation for good clinical practice. During this conversation, patients were given ample time to thoroughly consider whether they desired to participate in the trial and to ask any questions they had from the investigators. Willing participants provided written informed consent to participate in the trial.

Treatment

The treatment protocol consisted of a loading dose of 70 mg of intravenous caspofungin for the initial 24 hours, followed by a maintenance dose of 50 mg once daily for the subsequent 20 days. Additionally, all patients received supplemental oxygen therapy, systemic corticosteroids, bronchodilators, extended-spectrum antibiotics, and other treatments recommended for AECOPD as outlined by the Global Initiative for Chronic Obstructive Lung Disease guidelines. ¹³

Evaluation

Outcome measurements

Primary outcome

This study evaluated the clinical efficacy of 3 weeks of caspofungin treatment in patients with proven or probable IPA complicated by AECOPD. Clinical efficacy was defined as the proportion of patients exhibiting recovery or significant improvement.

The assessment of clinical efficacy was based on the degree of recovery categorized as follows:

1. Healing: Complete or near-complete absence of signs and symptoms of IPA, as evidenced by chest imaging results (if available).

2. Marked improvement: Absence of most signs of IPA, with at least 50% improvement or complete disappearance of imaging findings.

3. Progression: Moderate improvement (less than 50%) in chest imaging findings.

4. Ineffective: No change or worsening of symptoms related to IPA.

Secondary outcomes

The secondary outcomes of this study included the safety of caspofungin and its clinical efficacy in patients with AECOPD and proven or probable IPA over a 1-week period. After 1 week, patients were assessed according to the EORTC/MSG criteria as follows:

• Treatment success: This category included both complete response and partial response.

• Treatment failure: This category encompassed stable disease, disease progression, and death.

• Treatment success rate = (number of successful treatment cases/total number of patients) × 100%.

Adverse events

Subjects (or their legal representatives) were asked to report adverse events during the trial. Investigators collected, monitored, and reported all adverse events occurring during the trial in accordance with established procedures.

Laboratory tests

During the caspofungin treatment phase, safety-oriented laboratory tests, including routine blood tests, blood biochemistry, and routine urine tests, were conducted in the first and third weeks. Additionally, the safety index was reassessed on day 7 (±2 days) after treatment discontinuation.

All clinically significant changes in the test parameters were documented in the adverse events table in the CRF. At the end of the study, the investigators evaluated whether subjects experienced significant changes in laboratory tests and determined whether these changes were within normal variations, whether levels returned to baseline, whether levels remained stable, and whether these events were unrelated to the treatment regimen.

Auxiliary examinations, such as X-ray, B-ultrasound, magnetic resonance imaging, computed tomography, or electrocardiogram, were conducted at the discretion of the researchers to determine their necessity. However, an electrocardiogram was required for follow-up at baseline and after treatment.

Statistical analysis

The modified intention-to-treat population was defined as patients with COPD and IPA who had received at least one dose of caspofungin. The per-protocol population was defined as patients treated with a minimum of 14 doses of caspofungin. The safety analysis included the modified intention-to-treat population.

The chi-square test was conducted to compare response rates based on the severity of COPD, exposure to systemic corticosteroids or extended-spectrum antibiotics, malnutrition or diabetes, certainty of the diagnosis, and receipt of primary or salvage therapy. Logistic regression was used to determine the potential impact of various factors, such as the severity of COPD, exposure to systemic corticosteroids or extended-spectrum antibiotics, malnutrition or diabetes, proven or probable IPA, and the receipt of primary or salvage therapy, on the response to caspofungin. P < 0.05 indicated statistical significance.

Results

Subject enrollment and distributions

The study was conducted between July 2011 and August 2017. In total, 321 subjects were screened, of whom 51 met the inclusion criteria. However, seven subjects were excluded because they refused therapy (Figure 1). Therefore, 44 patients were recruited for the study. Unfortunately, two additional subjects were excluded because of loss to follow-up. Eventually, 42 patients received caspofungin, with 11, 18, and 13 patients completing 1, 2, and 3 weeks of treatment, respectively. Consequently, the safety analysis set consisted of 42 patients, whereas the intention analysis and program data analysis set included 31 patients.

Demographics and baseline characteristics

Forty-four patients were enrolled in the study from November 2011 to August 2017 (Table 1). Among them, two patients were lost to follow-up, leaving 42 patients included in both the intention-to-treat set and safety analysis set. These 42 patients had complete clinical data and demonstrated good compliance. All patients were scheduled to receive treatment and follow-up. The enrolled patients included 40 men (90.91%) and 4 women (9.09%) with a mean age of 69.84 ± 10.39 years.

Table 1.

Characteristics of the enrolled patients.

Characteristics	Values
No. of subjects	44
Age, years	69.84 ± 10.39
Duration of COPD, years	14 (6–21)
GOLD Stage n (%)
Stage 2	14 (31.81)
Stage 3	20 (45.45)
Stage 4	10 (22.72)
Male sex, n (%)	40 (90.91)
BMI, kg/m2	20.1 ± 3.9
Diabetes, n (%)	9 (20.45)
Smoking history, n (%)	41 (93.1)
Smoking index (pack-years)	24.8 ± 9.4
FEV1 (L)	1.41 ± 0.87
Inhaled steroids n (%)	42 (95.45)
Oral steroids given before IPA diagnosis n (%)	20 (45.45)
Oral steroids given before IPA diagnosis (prednisone acetate, range of doses, mg)	13.14 ± 7.21
Oral steroids continued after IPA diagnosis n (%)	8 (18.18)
Oral steroids continued after IPA diagnosis (prednisone acetate, range of doses, mg)	11.31 ± 6.33
Time from hospital admission to study enrollment, days	4.4 ± 2.1
Ventilated n (%)
Non-invasive ventilation	6 (13.63)
Invasive ventilation	0

BMI, body mass index; FEV₁, forced expiratory volume in 1 s; IPA, invasive pulmonary aspergillosis.

In terms of diagnosis, 5 patients were diagnosed through pathology, whereas 39 patients were diagnosed clinically. There were no specific symptoms or signs. However, most of the patients experienced respiratory symptoms such as cough, shortness of breath, and difficulty breathing. Rhonchi (21, 47.73%) and moist rales (30, 68.18%) were commonly heard in the lungs of most of the patients. Additionally, most patients had undergone various iatrogenic interventions, including deep vein catheterization, indwelling catheter, indwelling gastric tube, and fiberoptic bronchoscopy (Supplementary Tables 1–2).

The rate of pathogen acquisition was relatively low. Specifically, 17 cases of A. fumigatus and three cases of other untyped Aspergillus were identified. Serological examination revealed a significant increase in positivity in the 1, 3-β-d-glucan test. Among all patients, 17 (38.6%) tested positive in the 1, 3-β-d-glucan test, whereas only two (4.6%) tested positive in the galactomannan test. Patients with COPD and IPA exhibited diverse imaging findings in their lungs, including pulmonary exudation, consolidation nodules, cavities, and pleural effusions. Pulmonary exudation was the most commonly observed sign (38, 86.4%; Supplementary Tables 3–4).

Efficacy results

The average duration of treatment with caspofungin was 13.9 ± 6.4 days, and no adjustments were made to the dosage during the treatment period. To analyze the results, it should be noted that two patients were lost to follow-up, leaving 42 patients in the final data analysis set. All 42 patients were followed-up for a minimum of 3 weeks, permitting the evaluation of the clinical efficacy of both 1- and 3-week treatment durations.

Primary outcome results

Based on the efficacy evaluation criteria, none of the patients treated with caspofungin for 3 weeks achieved recovery or complete response at the treatment endpoint. Of all patients, 16 (38.10%) exhibited a partial response, whereas 26 (61.90%) exhibited stable disease or disease progression. Therefore, the final effective rate for the 3-week treatment duration was 38.10% (Table 2).

Table 2.

Treatment response in the first and third weeks in the modified intention-to-treat dataset (n = 42).

Response	Number (%)
One week
Complete recovery	0
Complete response	0
Partial response	14 (33.33%)
Stable disease or disease  progression	28 (66.67%)
Three weeks
Complete recovery	0
Complete response	0
Partial response	16 (38.10%)
Stable disease or disease  progression	26 (61.90%)
EORTC/MSG criteria (third week)
Success	16 (38.10%)
Complete recovery	0
Complete response	0
Partial response	16
Failure	26 (61.90%)
Stable	14
Disease progression	11
Death	1

EORTC/MSG, European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium.

Secondary outcomes

According to the EORTC/MSG criteria, after 1 week of treatment, 33.33% (14/42) of patients had a partial response, whereas 66.67% (28/42) exhibited stable disease or disease progression. Additionally, as previously mentioned, a final success rate of 38.10% was achieved (Table 2).

Evaluation efficacy between different subgroups

To assess further differences in efficacy, the chi-squared test was conducted for statistical analysis. The original plan was to compare response rates among different subgroups based on factors such as the severity of COPD, glucocorticoid use, broad-spectrum antibiotic usage, malnutrition, concomitant diabetes, confirmed/clinical diagnosis, initial treatment, and remedial treatment. However, it was determined that the severity of COPD and history of corticosteroid use could not be used for grouping statistics for multiple reasons. First, most patients were seriously ill at the time of enrollment, and some older patients were unable to undergo pulmonary function tests. Second, all enrolled patients had received corticosteroid treatment, including intravenous, oral, inhaled, and other forms.

The final results, as presented in Table 3, indicated that only the number of broad-spectrum antibiotics used and the malnutrition indicators displayed statistically significant differences in all parameters reflecting the therapeutic effect. There was no significant difference in efficacy observed between patients with and without diabetes mellitus (P = 0.658; Table 3).

Table 3.

Factors associated with the response to caspofungin treatment (n = 42).

Factors	Logistic Regression
	Success, n/N (%)	P
Diagnosis of IPA at the start of treatment	2 (6.90%)
Proven	5 (11.90)	0.832
Probable	37 (88.10%)
Line of treatment
First-line	23 (54.76%)	0.914
Salvage	19 (45.24%)
COPD stage	–	–
Group I–II	–	–
Group III–IV	–	–
Prior antifungal therapy	11 (37.93%)	0.134
≤2 types of broad-spectrum antibiotics	28 (66.67%)
≥3 types of broad-spectrum antibiotics	14 (33.33%)
Prior GC therapy	–	–
Diabetes mellitus	9 (21.43%)	0.932
Malnutrition	15 (35.71)	0.009
Invasive ventilation	9 (21.43%)	0.215

IPA, invasive pulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; GC, glucocorticoid.

Regression analysis of factors affecting efficacy

The potential effects of caspofungin were assessed by considering various factors, including the severity of COPD, the use of glucocorticoids and broad-spectrum antibiotics, malnutrition, diabetes, confirmed or clinically diagnosed IPA, initial treatment, remedial treatment, and multivariate logistic regression analysis. The results of this analysis are presented in Supplementary Table 3.

Based on the model fitting information, the multifactor model did not reveal any significant differences (Table 3). However, it is important to note that the sample size in this study was relatively small (n = 42). Therefore, these results should be interpreted with caution, and further investigations with larger sample sizes are needed to confirm these findings.

Safety analyses

Adverse events

In the safety analysis set, which consisted of 42 patients receiving caspofungin treatment, 10 adverse events were observed during the course of treatment. It is important to note that these adverse events were carefully evaluated through clinical assessment and dynamic monitoring. The evaluation considered the progression of the patients’ underlying disease and excluded any adverse events that were not directly related to the use of caspofungin. Additionally, both serious and non-serious clinical adverse events were excluded from the analysis (Supplementary Table 5).

Safety laboratory inspection

During the drug treatment phase, safety laboratory tests were conducted at two time points, namely after 1 and 3 weeks of treatment. These tests included routine blood tests, blood biochemistry, and routine urine tests.

Blood tests

During the initial screening, one patient had moderate anemia with a low red blood cell count (1.58 × 10⁹/L), low hemoglobin levels (45 g/L), and a low platelet count (81 × 10⁹/L). This was likely attributable to upper gastrointestinal bleeding prior to administration. However, after receiving symptomatic treatment such as acid suppression, the patient’s blood parameters returned to normal levels within 3 weeks of follow-up.

During the treatment phase, eight cases of mild anemia (hemoglobin levels of 63–88 g/L) were observed. There was no significant difference in hemoglobin levels between the treatment follow-up period and weekly assessments.

Three patients had platelet counts lower than 100/L during the course of treatment. However, in two of these patients, the platelet count returned to normal ranges without discontinuing or reducing the use of caspofungin, as it was determined that the decrease was not related to the study drug. In one case, the platelet count decreased from 76/L to 29/L after 1 week of treatment. Considering the clinical manifestations, it was suspected that the patient developed a serious infection and probable disseminated intravascular coagulation.

No cases of leukopenia were observed during treatment. However, one patient experienced an increase in the white blood cell count from 22.9 × 10⁹/L to 43.75 × 10⁹/L after 1 week of treatment. As the combined bacterial infection was not controlled, this patient unfortunately died after treatment. There was no direct relationship between the study drug and the patient’s outcome (Supplementary Figure 1).

Liver function

Only one patient experienced a new-onset liver injury, including elevated levels of alanine aminotransferase (ALT, 56 U/L), aspartate aminotransferase (57 U/L), total bilirubin (30.9 μmol/L), and direct bilirubin (22.6 μmol/L), for a duration of 1 week. Based on clinical considerations, we concluded that the patient developed infection-related multiorgan injury. Prior to treatment, eight patients already had abnormal liver function (ALT: 41.1–79.2 U/L). Despite not discontinuing or reducing the dosage of caspofungin, these patients received symptomatic treatment for liver protection. During follow-up, liver enzyme levels either improved or slightly increased, with no statistically significant difference observed. This suggested no direct relationship between the study drug and the observed liver enzyme changes (Supplementary Figure 2).

Renal function

Before treatment, only one patient exhibited a clinically significant increase in serum creatinine levels (154.6 μmol/L). However, during the course of treatment, the patient’s creatinine levels decreased to 122.6 μmol/L. It is important to note that this decrease was not directly attributed to the study drug (Supplementary Figure 3).

Serious adverse events and deaths

No serious adverse events or deaths were reported during the 3-week study period.

Important rare serious adverse events

No rare serious adverse events were reported during the 3-week study period.

Severe adverse events

There was one fatality attributed to bacterial infection.

Pregnancies

No pregnant subjects were found during the study period. Female subjects were tested for human chorionic gonadotropin, and contraceptive measures were strictly followed during the course of treatment.

Discussion

COPD currently ranks among the top three causes of mortality globally. In 2012, more than 3 million deaths were attributed to COPD, representing 6% of the total global mortality. As a consequential complication, the prevalence of IPA is estimated to range between 1.3% and 3.9% in patients with COPD in China, with the associated mortality rates at approximately 71.7%. ¹⁴ Several studies revealed that severe COPD is a significant risk factor for the development of IPA. However, there is limited documentation on the frequency of IPA in the Chinese population.^4,15,16 Cohort studies reported that COPD is the underlying cause in 1% of patients with IPA. Diagnosing IPA in patients with COPD is challenging, and it typically relies on a combination of clinical features, radiological findings, and microbiological and serological assessments. However, microbial cultures require several days or weeks to grow, and invasive sampling for histopathological examinations is not feasible for many patients.^17,18

Our center’s medical records (unpublished data) revealed an increase in the admission rates of patients with COPD and IPA. This increase in the admission rate of patients with COPD complicated by IPA necessitates further studies to better understand the factors contributing to these increases in disease prevalence and treatment. Additionally, there is a lack of clinical data regarding the incidence and mortality of IPA in patients with COPD, as well as the efficacy and safety of antifungal therapy in this population. A recent study involving 261 patients with AECOPD identified five patients with IPA (1.91%), with a mortality rate as high as 80% (four of five).^17,18 However, it is likely that the incidence of IPA in patients with COPD is underestimated, particularly in high-risk patients during periods of AECOPD.

Current evidence supports the use of intravenous voriconazole as the recommended primary treatment for IPA, although liposomal amphotericin B has also demonstrated excellent clinical efficacy. ¹⁹ Studies conducted on IPA in patients with COPD described the significant therapeutic effects of voriconazole, a triazole-based antifungal, as a first-line treatment. ²⁰ However, voriconazole has limitations such as low bioavailability and high toxicity, requiring continuous monitoring of plasma drug levels.^6,7 Therefore, the development of new antifungal therapies as alternative or adjunctive treatments for IPA is necessary. Caspofungin, an echinocandin antifungal, has been recommended as a salvage therapy for IPA in patients with COPD. ²¹ It belongs to a new class of antifungals that inhibit fungal cell wall synthesis by disrupting 1, 3-β-d-glucan synthase, resulting in a broad-spectrum antifungal effect. Because of its safety and tolerability, caspofungin has been recommended by the IDSA for the treatment of IPA. ⁷ It is commonly used in clinical settings as an antifungal agent for IPA treatment in patients with impaired renal function, and recent studies have explored its use as a first-line treatment for IPA.^17,18 A prospective study involving 11 countries confirmed the efficacy and tolerability of caspofungin in high-risk populations with IPA, such as those with blood diseases or tumors. ²² Similarly, a German multicenter study determined that a daily caspofungin dose of 200 mg was safe for in vivo use. ¹¹

We acknowledge that there is currently no published study on the efficacy of caspofungin in patients with COPD and IPA. Therefore, this study was conducted to evaluate the effects of caspofungin in this specific patient population. The findings of the study suggest that caspofungin is an effective treatment for IPA in patients with COPD (Table 2). However, it is important to note that the overall effective rate of the 3-week treatment was 38.10% (Table 2). According to the efficacy evaluation criteria, none of the patients treated with the 3-week caspofungin regimen achieved full recovery or complete response. Sixteen patients (38.10%) had a partial response, whereas 26 patients (61.90%) had stable disease or disease progression (Table 2). The study findings also revealed a relatively linear dose–response relationship with a slight slope in the treatment effectiveness of caspofungin. Increasing the treatment duration from 1 week to 3 weeks resulted in a 1.14-fold increase in the treatment efficacy rate.

In this study, the evaluation considered the progression of the patient’s underlying disease and excluded any adverse events that were not directly related to the use of caspofungin. Our results indicated that following 1 week of treatment, a clinical efficacy rate of 33.33% (14/42) was observed, and this slightly increased to 38.10% (16/42) after 3 weeks. At the end of the study, 16 patients achieved some degree of treatment efficacy, resulting in a success rate of 38.10% (Table 2). The lower therapeutic efficacy observed might be attributable to concomitant diseases, as it has been reported that the effectiveness of caspofungin is influenced by such factors. ¹² However, other factors did not significantly affect the therapeutic effect of caspofungin (Table 4).

Table 4.

Differences in therapeutic efficacy between different subgroups in the intention-to-treat dataset (n = 42).

Subgroups	% (n/N)	Chi-squared test
		χ2/z-value	P
Diagnosis of IPA at the start of treatment
Proven	5 (11.90)	0.09	0.926
Probable	37 (88.10%)
Line of treatment
First-line	23 (54.76%)	0.023	0.879
Salvage	19 (45.24%)
COPD stage	–	–	–
Group I–II	–	–	–
Group III–IV	–
Broad-spectrum antibiotics therapy
≤2 types of broad-spectrum antibiotics	28 (66.67%)	5.048	0.025
≥3 types of broad-spectrum antibiotics	14 (33.33%)
Prior GC therapy	–	–	–
Diabetes mellitus	9 (21.43%)	0.196	0.658
Malnutrition	15 (35.71)	6.067	0.014

IPA, invasive pulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; GC, glucocorticoid.

Our study found that the treatment efficacy of caspofungin was higher as a first-line therapy than as a salvage therapy (54.76% vs. 45.24%). However, this difference was not statistically significant (P = 0.914, Table 3). Previous studies also recommended the use of caspofungin as a salvage therapy or in combination with other antifungal agents. Guidelines have also suggested caspofungin as a drug for salvage therapy or combined therapy. However, our findings regarding the effect of caspofungin as a first-line monotherapy were consistent with those observed in salvage therapy. Therefore, we suggest that caspofungin could be used as a single first-line drug in patients with COPD and IPA.

In previous studies on the use of caspofungin for the treatment of IPA in patients with COPD, caspofungin was also employed as salvage therapy. For instance, Maertens et al. conducted a study of 83 patients with proven IPA who were intolerant or refractory to amphotericin B, lipid formulations of amphotericin B, and triazoles. ¹¹ These patients received caspofungin treatment for a minimum of 28 days, with an additional 7 to 14 days of a loading dose of 70 mg on day 1, followed by a daily dose of 50 mg for the rest of the treatment period. The study reported a positive response rate of 45%.

Caspofungin is extremely safe.^22,23 Our investigation into both local and systemic adverse effects revealed that all patients tolerated the caspofungin dose well. Although our study had a small sample size, we observed that some patients experienced benefits from the treatment. However, many patients only achieved a partial response or experienced disease progression without any evidence of short-term cure. It is important to note that these findings are not definitive because of the limited sample size and study duration. Therefore, the data cannot be generalized to the entire population of patients with IPA and COPD. To gain a better understanding of the clinical efficacy of caspofungin for treating IPA in patients with COPD, further randomized clinical trials should be conducted.

Regarding the control of clinical symptoms, we found that 19.05% (8/42) of patients exhibited progressive symptom control after 1 week, and this rate increased to 28.57% (12/42) after 3 weeks. These results suggest a limited effect of caspofungin on short-term symptom improvement. However, it is important to note that we did not assess symptom descriptions in detail, and these symptoms were not quantified, which prevented us from conducting effective statistical analyses of symptom control.

Furthermore, we conducted fungal serological tests throughout the study. Upon initial diagnosis, 13 patients (44.83%) tested positive in the 1, 3-β-d-glucan test. After 1 week of treatment, three of these patients tested negative, whereas 10 patients displayed no significant increase in their titers. Additionally, two new patients were positive in this test. One of these patients tested positive in the galactomannan test at the time of the initial diagnosis, and the other patient more tested positive after one week. Unfortunately, because of the challenges in obtaining live pathogens and patients’ refusal to cooperate with sputum collection protocols, we were unable to obtain comprehensive datasets regarding pathogen classification, drug sensitivity, or pathogen clearance rates.

In terms of chest imaging, we observed several characteristics in the majority of patients, including a variety of lesions, a lack of specificity, and prominent signs of chest exudations. The diverse imaging findings made it challenging to quantitatively assess changes in the lesions. Additionally, this study lacked long-term follow-up and quantitative data illustrating changes in imaging after caspofungin treatment.

Furthermore, as outlined in our research protocol, we attempted to perform a subgroup chi-square analysis to assess the efficacy of caspofungin and a logistic regression analysis to identify factors that might affect treatment efficacy. However, because of the limited sample size, these results were not statistically significant, and they can only be used for reference purposes. In terms of drug tolerance, no adverse events associated with caspofungin were reported during the follow-up period. Dynamic monitoring of laboratory tests revealed evidence of liver and kidney dysfunction and abnormal blood composition in some patients prior to enrollment. However, there was no significant worsening or progression of these symptoms after treatment. Patients with abnormal indicators were followed for a minimum of 1 week after discharge, and no relevant organ dysfunction occurred during this time, with no laboratory evidence of progression. This indicates the good safety and tolerability of caspofungin.

It is important to acknowledge the limitations of this study when interpreting our findings and designing future studies. These limitations included the insufficient sample size for many statistical analyses because of the strict inclusion criteria, the single-center, one-arm nature of study, which only provided initial insights into the effects of treatment, and the aforementioned incomplete data collection, including a lack of data on pathogen clearance, a lack of quantification of clinical symptom descriptions, and a failure to assess symptom control. Large-scale, multicenter, placebo-controlled studies are needed to further clarify the efficacy of caspofungin.

Conclusions

This study investigated the therapeutic efficacy and safety of caspofungin as salvage and first-line therapy for the treatment of IPA in patients with COPD. Our findings found that short-term treatment with caspofungin monotherapy for patients with COPD and IPA demonstrated a certain degree of efficacy. However, the overall recovery rate was low. Importantly, the efficacy of caspofungin was less likely to be affected by external factors. Furthermore, caspofungin exhibited low toxicity to organs and was generally well tolerated and safe.

In conclusion, our findings support the results of previous studies suggesting that caspofungin could be an effective treatment option as salvage or first-line therapy for IPA in patients with COPD. However, to reach a conclusive outcome and gain a deeper understanding of the clinical efficacy of caspofungin as salvage or first-line therapy for the treatment of IPA in patients with COPD, it is necessary to conduct multicenter, large sample-sized, randomized, and controlled clinical trials.

Conflicts of interest

The authors declare no conflicts of interest.

Consent for publication

All participants provided informed consent for participation and publication.

Data availability statement

Data are available from the corresponding author upon reasonable request.

Ethical approval and consent to participate

The authors of the study take full responsibility for all aspects of the work, including ensuring the accuracy and integrity of the research. Any questions or concerns related to the accuracy or integrity of any part of the study will be appropriately investigated and resolved.

Supplementary material

Supplemental material for this article is available online.