Authors: Masamitsu Hamakawa, Machiko Arita, Hiroshi Takahashi, Akihiko Amano, Nobuyoshi Hamao, Ayaka Tanaka, Akihiro Ito, Tadashi Ishida
Categories: Case Report, Asthma, CEP, Chronic eosinophilic pneumonia, Mepolizumab
Source: Respiratory Medicine Case Reports
Authors: Masamitsu Hamakawa, Machiko Arita, Hiroshi Takahashi, Akihiko Amano, Nobuyoshi Hamao, Ayaka Tanaka, Akihiro Ito, Tadashi Ishida
The efficacy of mepolizumab as an alternative to glucocorticoids for treating idiopathic chronic eosinophilic pneumonia (ICEP) has been reported. However, various questions remain unanswered, such as the most appropriate dose and dosage interval of mepolizumab for ICEP, how long efficacy is maintained, how long administration should be continued, and whether and when discontinuation can be considered. We present herein three cases of refractory ICEP treated with mepolizumab at a dose of 100 mg every 4 or 8 weeks. No recurrences were observed after 77 months of treatment in Case 1 and after 45 months in Case 2. Case 3 was treated with mepolizumab for 33 months, but ICEP relapsed 42 months after discontinuation of mepolizumab. In conclusion, mepolizumab for refractory ICEP should be continued for as long as possible, considering disease status, glucocorticoid-related adverse events, and the financial situation of the patient.
The efficacy and safety of mepolizumab as an alternative to glucocorticoids in the treatment of idiopathic chronic eosinophilic pneumonia (ICEP) have recently been reported [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. While the long-term efficacy and safety of mepolizumab for severe asthma have been mostly verified, no reports have validated the situation for ICEP alone [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]]. Most previous reports have described the clinical course of ICEP with less than 36 months of mepolizumab treatment (Table 1, Table 2) [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. Various questions remain unanswered, such as what dose and dosage interval of mepolizumab are most appropriate for ICEP, how long efficacy is likely to be maintained, how long mepolizumab should be continued, and whether and when mepolizumab can be discontinued.Table 1Summary of case reports of idiopathic chronic eosinophilic pneumonia treated with mepolizumab.Table 1CaseAuthorsAge (years)/SexFollow-up (months)aMain purpose of mepolizumabMepolizumab regimenDiscontinuation of mepolizumabOutcomes1To et al., 201865/M13Alternative to glucocorticoids100 mg every 4 weeksNANo relapseImprovement of symptoms and chest imaging2Robert et al., 201948/F27Alternative to glucocorticoids100 mg every 4 weeksNADiscontinuation of glucocorticoidsImprovement of symptoms, respiratory function, and chest imaging3Tomyo et al., 201960/F13To improve symptomsNANANo relapseImprovement of symptoms, respiratory function and chest imaging4Otoshi et al., 202057/FNAAlternative to glucocorticoids100 mg, single doseNANo relapseImprovement of symptoms and chest imaging5Kisling et al., 202055/F24Alternative to glucocorticoids300 mg every 4 weeksNADecrease in glucocorticoid dosageImprovement of symptoms6Ciuffreda et al., 202059/F10Alternative to glucocorticoids100 mg every 4 weeksNANo relapseImprovement of respiratory function and chest imaging7Sato et al., 202124/M36Prevention of recurrence100 mg every 4 weeks for 14 doses, then every 14 weeksNANo relapseDiscontinuation of glucocorticoidsImprovement of respiratory function and chest imaging8Sato et al., 202126/F24Alternative to glucocorticoids100 mg every 4 weeks for 12 doses, then every 8 weeksNANo relapseDiscontinuation of glucocorticoidsImprovement of respiratory function and chest imaging9Eldaabossi et al., 202156/F15Alternative to glucocorticoids100 mg every 4 weeksNANo relapseDiscontinuation of glucocorticoidsImprovement of symptoms, respiratory function and chest imaging10Eldaabossi et al., 202148/M6Alternative to glucocorticoids100 mg every 4 weeksNANo relapseDiscontinuation of glucocorticoidsImprovement of symptoms, respiratory function and chest imaging11Tashiro et al., 202274/M19Alternative to glucocorticoids100 mg every 4 weeksNANo relapseDiscontinuation of glucocorticoids12Tashiro et al., 202268/M17Alternative to glucocorticoids100 mg every 4 weeksNANo relapseDiscontinuation of glucocorticoids13Daboussi et al., 202321/M12Alternative to glucocorticoids100 mg every 4 weeksNADiscontinuation of glucocorticoidsImprovement of symptoms and chest imaging14Daboussi et al., 202327/M4Alternative to glucocorticoids100 mg every 4 weeksNANo relapseDecrease in glucocorticoid dosageAll authors reported the efficacy and safety of mepolizumab, but none mentioned the timing of discontinuation.F, female; M, male; NA, not applicable.aFollow-up is defined as the period after starting administration of mepolizumab.Table 2Summary of the real-life study by Brenard et al.Table 2AuthorsNumber of patientsSex (M/F)Age, years (median, range)Follow-up, months (median, range)aMepolizumab regimenDiscontinuation of mepolizumabOutcomesBrenard et al., 2020105/548 (22–65)9 (6–12)100 mg every 4 weeks in six patients300 mg every 4 weeks in four patientsNADecrease in annual relapse rateDecrease in glucocorticoid dosagebImprovement of chest imagingcNo secondary eventsThe authors reported on the efficacy and safety of mepolizumab for idiopathic chronic eosinophilic pneumonia, but did not mention the timing of mepolizumab discontinuation.CT, computed tomography; F, female; M, male; NA, not applicable.aFollow-up is defined as the period after initiating administration of mepolizumab.bThree months after receiving mepolizumab, the glucocorticoid dosage was reduced in nine patients. Six months after receiving mepolizumab, only one patient was continuing to receive low-dose glucocorticoid treatment.cSix months after receiving mepolizumab, seven of the eight patients showed complete resolution of abnormalities on chest CT. Two patients evaluated by chest radiography showed no lung lesions.
Case 1A 33-year-old woman was referred to the emergency department with a 2-month history of fever (Fig. 1). She was a never-smoker with a history of asthma and allergic rhinitis. Asthma had developed after pregnancy with her first child at 26 years old. She was being treated with fluticasone furoate at 200 μg/day as inhaled corticosteroid and vilanterol at 25 μg/day as a long-acting β2 agonist. She had no history of allergic bronchopulmonary mycosis (ABPM), atopic dermatitis, eosinophilic chronic rhinosinusitis (ECRS), eosinophilic granulomatosis with polyangiitis (EGPA), or eosinophilic pneumonia (EP). The patient had no apparent history of changes in drug or environmental exposures. Blood and biochemical tests showed a high peripheral blood eosinophil count (12,540/μL) and elevated immunoglobulin (Ig)E (637 IU/mL; normal, <361 IU/mL). Positive antigen-specific serum IgE results were seen for house dust. Negative results were obtained for myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) and FIP1L1-PDGFRA fusion gene. Respiratory function and fractional exhaled nitric oxide (FeNO) had not been evaluated by the referring physician. Computed tomography (CT) of the chest showed upper and right lobe-predominant non-regional consolidation and ground-glass opacities (Fig. 1A). Cell fractions in bronchoalveolar lavage fluid neutrophils, 0 %; eosinophils, 94 %; lymphocytes, 0 %; basophils, 0 %; monocytes, 0 %; and macrophages, 6 %. A rheumatologist examined the patient and diagnosed idiopathic EP rather than EGPA as the cause of symptoms. Prednisolone was started at 25 mg/day, after which subjective symptoms and chest image findings rapidly improved. Prednisolone was then tapered. However, EP flares were seen 7 and 13 months after the initial onset of EP (Fig. 1B and C). At this time, the patient was re-diagnosed with ICEP following EP recurrence. Eighteen months after the initial onset of ICEP, mepolizumab was started at 100 mg every 4 weeks to allow tapering of prednisolone. After starting mepolizumab, no relapses of ICEP were seen. Finally, prednisolone was able to be discontinued 27 months after the initial onset of ICEP. As the disease stabilized, the dosing interval for mepolizumab was changed from every 4 weeks to every 8 weeks at 32 months after the initial onset of ICEP. However, the patient developed an exacerbation of productive cough 48 months after the initial onset of ICEP. Although chest CT showed no apparent relapse of ICEP, the dosing interval for mepolizumab was changed back to every 4 weeks. The patient has not experienced any flare-ups of EP in the 77 months after starting mepolizumab (Fig. 1D). The patient has also experienced no drug-related adverse events since starting mepolizumab. We decided to continue mepolizumab treatment for this patient.Fig. 1Computed tomography (CT) evaluations of the chest before and after starting mepolizumab in Case 1A–C) Chest CT shows non-regional ground-glass opacities and consolidation in both lung fields at the onset of idiopathic chronic eosinophilic pneumonia (ICEP) (A), at the second episode of ICEP, 7 months after the initial onset of ICEP (B), and at the third episode of ICEP, 13 months after the initial onset of ICEP (C). D) After starting mepolizumab, 68 months after the initial onset of ICEP, chest CT shows no abnormal shadows suggestive of ICEP.Fig. 1
Case 2The patient was a 63-year-old woman with asthma who regularly visited the outpatient clinic. This time, she presented to the emergency department with chief complaints of fever and dyspnea with wheezing (Fig. 2). She was a never-smoker and had developed asthma at 59 years of age. She was being treated with fluticasone propionate at 1000 μg/day as inhaled corticosteroid and salmeterol at 100 μg/day as a long-acting β2 agonist. Her medical history included allergic rhinitis, but not ABPM, atopic dermatitis, EGPA, ECRS, or EP. As biomarkers of type 2 inflammation, IgE was 579 IU/mL (normal, <361 IU/mL) and the peripheral blood eosinophil count was 108/μL. FeNO was unknown because testing was unavailable in Japan at that time. Positive antigen-specific serum IgE was seen for dog, Alternaria, Aspergillus, Candida, Penicillium, and house dust. She was diagnosed with asthma that had worsened as a result of infection. On hospitalization, symptoms improved with systemic glucocorticoids. However, symptoms flared up 3 months after discharge. Chest CT showed diffuse ground-glass opacities, interlobular septal thickening, and consolidation in both lung fields (Fig. 2A). Peripheral blood eosinophil count was increased to 3700/μL. Cell fractions of bronchoalveolar lavage fluid neutrophils, 0 %; eosinophils, 92 %; lymphocytes, 6 %; basophils, 0 %; monocytes, 0 %; and macrophages, 2 %. Negative results were obtained for MPO-ANCA. No changes to drug or environmental exposures were evident. Idiopathic EP was diagnosed, as no vasculitis organ damage suggestive of EGPA was noted. Prednisolone was started at 30 mg/day. After starting prednisolone, subjective symptoms and findings from chest imaging rapidly improved and prednisolone was tapered. However, EP relapsed after each discontinuation or tapering of prednisolone (Fig. 2B–E). The patient was re-diagnosed with ICEP following repeated recurrences of EP. After the 5th episode of ICEP, the patient was started on mepolizumab at a dose of 100 mg every 4 weeks to allow tapering of prednisolone. After starting mepolizumab, prednisolone was able to be discontinued and the patient experienced no relapses of ICEP in the next 45 months (Fig. 2F). The patient has not experienced any drug-related adverse events. We decided to continue mepolizumab treatment for this patient.Fig. 2CT evaluations of the chest before and after starting mepolizumab in Case 2A–E) Chest CT shows non-regional ground-glass opacities, consolidation, and interlobular septal thickening in both lung fields with the first episode of ICEP, 4 months after initial hospitalization (A), with the second episode of ICEP, 18 months after initial hospitalization (B), with the third episode of ICEP, 48 months after initial hospitalization (C), with the fourth episode of ICEP, 89 months after initial hospitalization (D), and with the fifth episode of ICEP, 128 months after initial hospitalization (E). F) After starting treatment with mepolizumab, chest CT at 162 months after initial hospitalization shows no abnormal shadows suggestive of ICEP.Fig. 2
Case 3The patient was a 78-year-old woman referred from another hospital for treatment of pneumonia (Fig. 3). She was a never-smoker with a history of asthma since childhood. However, she had made the decision to discontinue treatment since she had been symptom-free for the last 4 years. She had not been diagnosed with ABPM, atopic dermatitis, allergic rhinitis, EGPA, ECRS, or EP and reported no changes in drug or environmental exposures. As biomarkers of type 2 inflammation, IgE was 11 IU/mL (normal, <361 IU/mL) and the peripheral blood eosinophil count was 1370/μL. FeNO was unknown because testing was not available in our hospital at that time. Negative results were obtained for MPO-ANCA. Chest CT showed ground-glass opacities and consolidation in the upper lobe (Fig. 3A). The patient was initially diagnosed with infectious pneumonia and treated with ceftriaxone and azithromycin. However, symptoms of fever and dyspnea remained unimproved. Bronchoscopy was performed to review the diagnosis. Cell fractions in bronchoalveolar lavage fluid neutrophils, 15 %; eosinophils, 33 %; lymphocytes, 15 %; basophils, 0 %; monocytes, 0 %; and macrophages, 37 %. Examination by a rheumatologist did not reveal any findings suspicious of EGPA-related vasculitis. The patient was diagnosed with idiopathic EP and administered methylprednisolone pulse therapy as remission induction therapy, followed by prednisolone as maintenance therapy. However, she was not started on inhaled corticosteroids. After starting this treatment, symptoms and chest imaging findings quickly improved and prednisolone was tapered. However, EP flares occurred 5 and 8 months after the initial onset of EP (Fig. 3B and C) and she was re-diagnosed with ICEP. Cyclosporin A was started in combination with prednisolone 13 months after the initial onset of ICEP, but was discontinued 12 months later after fungal sinusitis developed. At 39 months after the initial onset of ICEP, a fourth episode of ICEP developed (Fig. 3D). Mepolizumab was started 44 months after the initial onset of ICEP, at a dose of 100 mg every 4 weeks. By 13 months after starting mepolizumab, ICEP had flared up only once. Mepolizumab was discontinued after 33 months (Fig. 3E), then prednisolone was tapered off and discontinued. Although the patient had seemed completely cured of ICEP (Fig. 3F), a fifth episode developed 19 months after discontinuing prednisolone (Fig. 3G). Treatment with prednisolone was followed by a resumption of mepolizumab.Fig. 3CT and radiographic evaluations of the chest before and after starting mepolizumab in Case 3A–C, E) Chest CT shows non-regional ground-glass opacities, consolidation, and interlobular septal thickening at the onset of ICEP (A), at the second episode of ICEP, 5 months after the initial onset of ICEP (B), and at the third episode of ICEP, 8 months after the initial onset of ICEP (C). D) Chest radiograph at the fourth episode of ICEP, 39 months after the initial onset of ICEP, shows infiltration shadows in the right lower lung field. E) Chest CT at the fifth episode of ICEP, 57 months after the initial onset of ICEP, shows non-regional ground-glass opacities, consolidation, and interlobular septal thickening. F) At 98 months after the initial onset of EP, chest CT shows no abnormal shadows suggestive of ICEP. G) Chest CT at the sixth episode of ICEP, 98 months after the initial onset of ICEP and 21 months after discontinuing mepolizumab, again shows non-regional ground-glass opacities, consolidation, and interlobular septal thickening.Fig. 3
ICEP is a rare disease characterized by infiltration of eosinophils into the lungs [14]. Although the pathogenic mechanisms remain unclear, previous reports have described increased levels of chemokines such as CC chemokine receptor (CCR)3/CCR5 ligands, cytokines such as interleukin (IL)-5, lipid mediators such as leukotriene B4, damage-associated molecular pattern molecules, and extracellular matrix proteins in bronchoalveolar lavage fluid in patients with eosinophilic pneumonia [14]. Among these, IL-5 is a well-known cytokine associated with eosinophilic inflammation due to roles in priming and promoting the survival of eosinophils [14].
The conventional treatment for ICEP has been administration of glucocorticoids. However, ICEP is prone to relapse and the treatment period may thus be prolonged. As a result, adverse events associated with prolonged glucocorticoid dosage can be problematic. Several recent reports have shown that mepolizumab achieves efficacy not only against asthma and EGPA, but also against ICEP by inhibiting IL-5 [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. Those reports showed that the main effects of mepolizumab were reducing the frequency of exacerbations, and allowing tapering of glucocorticoids. However, most respiratory physicians have clinical questions regarding the treatment of ICEP with mepolizumab, such as how long and how much mepolizumab should be used, and can mepolizumab be discontinued after ICEP is cured? Mepolizumab shows fewer adverse events than glucocorticoids, but long-term administration may represent a substantial financial burden for patients. Although previous reports have demonstrated the efficacy and safety of mepolizumab, none have described criteria for its discontinuation [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. In addition, the optimal regimen of mepolizumab for ICEP had not been fully established [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. In our Case 1, the patient received mepolizumab at a dose of 100 mg every 4 or 8 weeks for 77 months. In Case 2, the patient received a dose of 100 mg every 4 weeks for 45 months. No drug-related adverse events or obvious recurrences of ICEP were seen during those courses. Most previous reports have described clinical courses for less than 36 months of mepolizumab administration [[1], [2], [3], [4], [5], [6], [7],[9], [10], [11], [12]]. Those reports showed that patients received mepolizumab at a dose of 100 mg every 4 weeks, as in the treatment of severe asthma, while others described doses of 300 mg every 4 weeks, as in the treatment of EGPA [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. We think that mepolizumab is likely to provide continued efficacy and safety in the treatment of ICEP for periods of 36 months or longer. Regarding the optimal dose, 100 mg every 4 weeks may be sufficient. However, since patients diagnosed with ICEP may have had undiagnosed EGPA, a dose of 300 mg every 4 weeks may be more appropriate. In Case 3, the patient discontinued prednisolone after receiving mepolizumab for 33 months. That patient had experienced no recurrences of ICEP for some time and seemed to be cured. However, 19 months after discontinuing prednisolone, the patient experienced a relapse of ICEP. Although ICEP may not flare up for a while after discontinuing mepolizumab, as in this case, mepolizumab is highly unlikely to be curative for ICEP. The role of mepolizumab should be considered only as an alternative to glucocorticoid treatment.
Some limitations should be kept in mind when interpreting the findings in this case report. First, none of the three patients had any history of EGPA, but the possibility remains that symptoms were masked by the use of glucocorticoids, in which case EGPA would not have been diagnosed correctly. Whether the treatment strategy for ICEP can be applied to EP associated with EGPA remains unclear. Second, although mepolizumab is generally considered for use in cases of refractory ICEP, caution is required when administering this agent for mild cases for any reason. Regardless of the administration of mepolizumab, mild cases of ICEP may improve spontaneously. In such cases, early discontinuation of mepolizumab may be possible.
Continuing mepolizumab for as long as possible appears preferable in the treatment of refractory ICEP, although consideration should be given to disease status, glucocorticoid-related adverse events, and the financial situation of the patient.
Masamitsu Hamakawa: Writing – original draft. Machiko Arita: Writing – review & editing. Hiroshi Takahashi: Writing – review & editing. Akihiko Amano: Writing – review & editing. Nobuyoshi Hamao: Writing – review & editing. Ayaka Tanaka: Writing – review & editing. Akihiro Ito: Writing – review & editing. Tadashi Ishida: Writing – original draft.
The authors declare that appropriate written informed consent was obtained for publication of this manuscript and the accompanying images.
This work did not receive any grants from funding agencies in the public, commercial, or not-for-profit sectors.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.