Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists. METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519. FINDINGS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study. INTERPRETATION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control. FUNDING: AstraZeneca.

Daptomycin-induced eosinophilic pneumonia.

ABSTRACT: Daptomycin-induced eosinophilic pneumonia (DIEP) is a rare complication of daptomycin use. Manifestations most commonly include fever, hypoxia, dyspnea, cough, eosinophilia, and lung changes on radiographs and CT. Patients typically have had recent daptomycin exposure and develop fever, dyspnea, infiltrates on chest radiograph, more than 25% eosinophils on bronchoalveolar lavage, and improvement of symptoms after withdrawal of daptomycin. Treatment includes discontinuation of daptomycin, corticosteroids, and supportive measures such as supplemental oxygen. Clinicians should have a high index of suspicion for DIEP in patients who develop new onset of pulmonary and systemic signs and symptoms after initiation of daptomycin.

Daptomycin Exposure as a Risk Factor for Daptomycin-Induced Eosinophilic Pneumonia and Muscular Toxicity.

BACKGROUND: High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin. METHODS: All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model. RESULTS: From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L. CONCLUSIONS: We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested.

Hypersensitivity reactions to COVID-19 vaccines: a case of Eosinophilic pneumonia following Sinovac/CoronaVac vaccination.

Summary: Hypersensitivity reactions has been reported with COVID-19 vaccines. Acute eosinophilic pneumonia has not been reported yet after Sinovac/CoronaVac vaccine. A 73-year-old woman presented with maculopapular rash, cough and dyspnea following Sinovac/CoronaVac injection. The complete blood count (CBC) indicated eosinophilia and further evaluation of the eosinophilia with CT and bronchoscopy confirmed a diagnosis of acute eosinophilic pneumonia. After methylprednisolone therapy, her rash resolved with marked improvement of the dyspnea. She is still on treatment and on the follow up period, we plan to continue steroid treatment at least 3 months.

Vaping Associated Acute Eosinophilic Pneumonia: A Clinical and Radiologic Mimicker of COVID-19.

Acute eosinophilic pneumonia (AEP) is a rare cause of respiratory failure. It is primarily a disease of smokers, either a new smoker or an existing one with a recent increase in cigarette consumption. Other risk factors include toxic gas exposure, inhalational illicit drugs, and smoking marijuana. AEP has also been reported in patients with e-cigarette or vaping associated lung injury (EVALI). We present the case of a 20-year-old male who presented to the hospital with acute respiratory failure. The patient has been vaping heavily for the past three months and started smoking three days before presenting to the emergency department. He was hypertensive, tachycardic, tachypneic, and required high-flow nasal cannula to maintain SpO2 > 92%. His condition deteriorated in the first 24 hours following hospitalization requiring noninvasive positive pressure ventilation. Bronchoalveolar lavage revealed an eosinophil count of 36%. Bronchoalveolar lavage (BAL) cytology revealed lipid-laden macrophages. He was diagnosed with AEP due to EVALI, and the patient was treated with high dose corticosteroid with subsequent improvement. Before the bronchoscopic evaluation, the clinical and radiologic findings were consistent with COVID-19, and the patient was tested twice for SARS-CoV-2 PCR. In the appropriate clinical setting, AEP should be considered in the differential diagnoses of community-acquired pneumonia, acute respiratory distress syndrome (ARDS), and COVID-19, especially in this pandemic era.

Anti-IL5 mepolizumab minimally influences residual blood eosinophils in severe asthma.

Neutralising antibodies against the cytokine interleukin (IL)5 have become widely used for the control of severe eosinophilic asthma. Remarkably, patients receiving neutralising anti-IL5 biological therapies retain a very stable population of residual blood eosinophils. Whether these residual eosinophils are endowed with particular biological activity has not yet been studied, but is of importance in predicting potential long-term effects of IL5 neutralisation in patients. To tackle the effect of IL5 depletion on residual eosinophils, we used a comparative RNA-sequencing approach and compared the gene expression programme of eosinophils arising in IL5-depleted or IL5-replete human or murine hosts, at steady-state in vivo and following in vitro stimulation with the eosinophil-activating alarmin IL33. We compared blood eosinophils from patients with severe allergic eosinophilic asthma treated with anti-IL5 mepolizumab therapy to those of healthy controls and matched asthma patients receiving anti-IgE omalizumab therapy. We made similar comparisons on bone marrow eosinophils from mice genetically deficient or not for IL5. We report that restriction of IL5 availability did not elicit any detectable transcriptional response in steady-state residual eosinophils in mepolizumab-treated patients or IL5-deficient mice, and influenced only a handful of genes in their response to IL33. Together, these results support the notion that treatment with IL5 neutralising antibodies spares a pool of circulating residual eosinophils largely resembling those of healthy individuals.

Results in clinical practice in the treatment of severe eosinophilic asthma with mepolizumab: a real-life study.

OBJECTIVE: Add-on therapy with monoclonal antibodies is the recommended therapy for severe asthmatic patients refractory to maintenance treatment. In randomized control trials, mepolizumab reduced the number of exacerbations, the need of oral corticosteroids (OCS), increased asthma control, and lung function in a population of uncontrolled severe eosinophilic asthmatic patients. In this piece of work, we aimed to assess mepolizumab efficacy and safety in a cohort of patients with severe eosinophilic asthma in real-life conditions. METHODS: A retrospective study was carried out at eight hospitals from Asturias (Spain). The sample included patients treated with mepolizumab from 1 January 2016 to 31 March 2019. Demographic and clinical variables were collected, including OCS use, asthma control, lung function, and exacerbation rate. RESULTS: Sixty-nine patients (72% women) with mean age 56 ± 13 years were included. Annual exacerbation rate decreased from 4.7 (SD 3.7) to 1.3 (SD 2.5) (p < 0.001). The number of patients requiring OCS treatment decreased from 25 patients (36%, mean prednisone dose = 18 mg/day) to 13 patients (19%, mean prednisone dose = 9 mg/day) (p < 0.001). Twelve patients (48%) stopped OCS treatment. Forced expired volume in one second (FEV1) as percentage increased from 68% (SD 20) to 76% (SD 21) (p < 0.001). Fifty-six patients (81%) were considered responders to mepolizumab. No serious adverse events were detected during the study period. CONCLUSIONS: Overall, this study demonstrates mepolizumab efficacy and safety in a cohort of patients with uncontrolled severe eosinophilic asthma in routine clinical practice.

Ustekinumab associated chronic eosinophilic pneumonia.

INTRODUCTION: Ustekinumab-induced eosinophilic pneumonia is rare and to our knowledge, this is the fifth reported case of such an entity. CASE STUDY: A 60-year-old female was admitted with worsening shortness of breath and a nonproductive cough for 4 months. Her past medical history was significant for Crohn's disease and psoriatic arthritis that was previously managed with adalimumab and switched to ustekinumab 2 months before symptoms. Initial diagnostic workup showed 10% peripheral eosinophilia and a CT chest showed numerous 5 mm nodules scattered throughout the lungs along with some peripheral reticulations. Her BAL fluid analysis showed abnormally high eosinophil count (67%), greatly limiting her potential diagnoses to eosinophilic pneumonia, EGPA, and tropical pulmonary eosinophilia (TPE). AEP typically causes more severe disease with a rapid onset, and there was low suspicion for TPE based on history, leaving EGPA and CEP. Based on her negative autoimmune serology, a negative biopsy of the nasal mucosa (no vasculitis/granulomata or eosinophils), and negative infectious workup, the patient was diagnosed with CEP secondary to ustekinumab and the drug was stopped. She was started on high dose prednisone and after a prolonged taper over 5 months, her symptoms and nodules and reticulations on her CT scan resolved. DISCUSSION: This case exemplifies the importance of identifying drug-induced lung diseases which in many cases might not have a strong temporal association with the symptom onset. It also highlights that some drugs owing to their long elimination half-time can remain in the system for a prolonged period and continues to cause symptoms despite their cessation and require prolonged treatment and reassurance. CONCLUSION: The association of eosinophilic pneumonia with ustekinumab, a drug used in the treatment of psoriasis and other autoimmune diseases, is rare and there is a paucity of literature regarding this association.

Critical role of IL-33, but not IL-25 or TSLP, in silica crystal-mediated exacerbation of allergic airway eosinophilia.

Silica crystals (silica), which are a major mineral component of volcanic ash and desert dust, contribute to the pathogenesis of pulmonary disorders such as asthma and fibrosis. Although administration of silica or sand dust to rodents exacerbates development of ovalbumin-induced or house dust mite-induced asthma-like airway inflammation, the detailed mechanisms remain unclear. Here, using murine models, we found that silica can induce IL-33 expression in pulmonary epithelial cells. IL-33, but not IL-25 or TSLP, and type 2 cytokines such as IL-5 and IL-13 were critically involved in silica's exacerbation of OVA-induced airway eosinophilia in mice. Innate lymphoid cells (ILCs), but not T, B or NKT cells, were also involved in the setting. Moreover, a scavenger receptor that recognized silica was important for silica's exacerbating effect. These observations suggest that IL-33 induced in epithelial cells by silica activates ILCs to produce IL-5 and/or IL-13, contributing to silica's exacerbation of OVA-induced airway eosinophilia in mice. Our findings provide new insight into the underlying mechanisms of exacerbation of pulmonary disorders such as asthma following inhalation of silica-containing materials such as volcanic ash and desert dust.

[Daptomycin-induced eosinophilic pneumonia associated with an early endoprosthesis infection]. / Daptomycin-induzierte eosinophile Pneumonitis im Rahmen eines Endoprothesenfrühinfektes.

Acute eosinophilic pneumonia (AEP) is a rare disease characteristically involving eosinophilic infiltration of lung parenchyma as well as fever, dyspnea, and coughing. A differentiation is made between primary and secondary AEP depending on the underlying etiology. Substances that most frequently cause secondary AEP are antibiotics, such as the lipopeptide daptomycin. This is a case report about a 69-year-old female patient who underwent antibiotic treatment with daptomycin for an infection of a knee prosthesis. During the treatment, signs of pneumonia developed and included the increased dependence on mechanical ventilation of the previously intubated patient, infiltrates on a chest X­ray, fever, and an increase in serum inflammation markers. Proof of bacteria as an underlying pathogen was not possible. A thoracic computed tomography (CT) scan showed opacities that are commonly seen in interstitial lung disease. Termination of daptomycin treatment due to renal failure led to an improvement of pulmonary symptoms. Re-exposure to daptomycin resulted in a recurrence of the symptoms. The diagnostic criteria for AEP according to Uppal et al. include 1) current exposure to daptomycin, 2) dyspnea with increased oxygen requirements or necessity for mechanical ventilation, 3) new infiltrates on chest X­ray or CT scan, 4) bronchoalveolar lavage with eosinophilia >25%, 5) improvement of clinical symptoms following daptomycin withdrawal, and 6) fever. With 5 out of the 6 criteria by Uppal et al. positive-an eosinophilia >25% being the only unmet criteria-an AEP induced by daptomycin was diagnosed. Withdrawal of daptomycin as well as high-dose cortisol bolus treatment led to a rapid recovery.

Chronic cough and an atypical pattern of peripheral pulmonary opacities: A case report secondary to suspected drug onset.

INTRODUCTION: Chronic eosinophilic pneumonia (CEP) is an idiopathic interstitial lung disease with nonspecific symptoms that involves a complex inflammatory cascade. CASE STUDY: A 36-year-old prisoner with a history of psoriasis presented with progressive worsening dyspnea, chest pain, and cough. His symptoms started 2-months after starting adalimumab, a tumor necrosis factor (TNF)-inhibitor, for psoriasis treatment. RESULTS: Initial workup revealed 27% eosinophils on complete blood count, elevated IgE levels on bronchoalveolar lavage, and bilateral peripheral lung opacities on imaging. The patient's symptoms and eosinophilia improved markedly after starting corticosteroids. Based on these findings, the patient was diagnosed with CEP. CONCLUSION: To our knowledge, this is the first case of asthma and CEP in a patient taking adalimumab. We suspect adalimumab unmasked the Th2 cell pathway response that was otherwise suppressed by psoriasis, a primarily Th1 cell pathway disease. The patient's pulmonary changes can be attributed to an eosinophilic asthma phenotype with adalimumab putatively indirectly causing CEP.

Eosinophilic pneumonia induced by non-steroidal anti-inflammatory drugs: An underestimated risk.

INTRODUCTION: Eosinophilic pneumonia (EP) is a rare but serious adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: We describe the second published case of EP induced by oral diclofenac. We also reviewed the literature as well as French pharmacovigilance database. Case presentation A 63 year-old woman with polyarthralgia had taken diclofenac for three days for analgesic purposes. Progressively, the patient presented weakness, dyspnea and fever. Computed tomography (CT) scan revealed bilateral interstitial infiltration. Broncho-alveolar lavage (BAL) showed an elevated level of eosinophils. After ruling out all other possible etiologies, drug-induced EP was diagnosed and treatment by corticosteroid was initiated. The patient recovered in three months. RESULTS: In the French pharmacovigilance database, six cases of EP were recorded (3 with naproxen, 2 with ibuprofen, 1 with piroxicam). In the literature, twenty-six cases of EP with NSAIDs were published. The most commonly involved drug was naproxen (n=8), followed by fenbufen (n=4), ibuprofen (n=3) and diclofenac (n=2). A high level of eosinophils was systematically observed in the blood cell count or BAL. Corticosteroid therapy was started in eleven cases. All patients recovered. CONCLUSION: Complete history taking and examination should be done to rule out other etiological diagnoses. BAL is sufficient to diagnose EP. Corticosteroid therapy should be indicated for more severe or refractory cases. This adverse drug reaction is underestimated, healthcare professionals should be informed.

Pollen-induced oxidative DNA damage response regulates miRNAs controlling allergic inflammation.

A mucosal oxidative burst is a hallmark response to pollen exposure that promotes allergic inflammatory responses. Reactive species constituents of oxidative stress signal via the modification of cellular molecules including nucleic acids. One of the most abundant forms of oxidative genomic base damage is 8-oxo-7,8-dihydroguanine (8-oxoG), which is removed from DNA by 8-oxoguanine DNA glycosylase 1 (OGG1). OGG1 in complex with 8-oxoG acts as a GDP-GTP exchange factor and induces acute inflammation; however, the mechanism(s) by which OGG1 signaling regulates allergic airway inflammation is not known. Here, we postulate that the OGG1 signaling pathway differentially altered the levels of small regulatory RNAs and increased the expression of T helper 2 (Th2) cytokines in ragweed pollen extract (RWPE)-challenged lungs. To determine this, the lungs of sensitized mice expressing or lacking OGG1 were challenged with RWPE and/or with OGG1's excision product 8-oxoG. The responses in lungs were assessed by next-generation sequencing, as well as various molecular and histological approaches. The results showed that RWPE challenge induced oxidative burst and damage to DNA and activated OGG1 signaling, resulting in the differential expression of 84 micro-RNAs (miRNAs), which then exacerbated antigen-driven allergic inflammation and histological changes in the lungs. The exogenous administration of the downregulated let-7b-p3 mimetic or inhibitors of upregulated miR-23a or miR-27a decreased eosinophil recruitment and mucus and collagen production via controlling the expression of IL-4, IL-5, and IL-13. Together, these data demonstrate the roles of OGG1 signaling in the regulation of antigen-driven allergic immune responses via differential expression of miRNAs upstream of Th2 cytokines and eosinophils.

Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone.

Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2-/- mice (devoid of T and B cells), and ILC-deficient Rag2-/-Il2rg-/- mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures.

Collaborative interactions between type 2 innate lymphoid cells and antigen-specific CD4+ Th2 cells exacerbate murine allergic airway diseases with prominent eosinophilia.

Type-2 innate lymphoid cells (ILC2s) and the acquired CD4(+) Th2 and Th17 cells contribute to the pathogenesis of experimental asthma; however, their roles in Ag-driven exacerbation of chronic murine allergic airway diseases remain elusive. In this study, we report that repeated intranasal rechallenges with only OVA Ag were sufficient to trigger airway hyperresponsiveness, prominent eosinophilic inflammation, and significantly increased serum OVA-specific IgG1 and IgE in rested mice that previously developed murine allergic airway diseases. The recall response to repeated OVA inoculation preferentially triggered a further increase of lung OVA-specific CD4(+) Th2 cells, whereas CD4(+) Th17 and ILC2 cell numbers remained constant. Furthermore, the acquired CD4(+) Th17 cells in Stat6(-/-)/IL-17-GFP mice, or innate ILC2s in CD4(+) T cell-ablated mice, failed to mount an allergic recall response to OVA Ag. After repeated OVA rechallenge or CD4(+) T cell ablation, the increase or loss of CD4(+) Th2 cells resulted in an enhanced or reduced IL-13 production by lung ILC2s in response to IL-25 and IL-33 stimulation, respectively. In return, ILC2s enhanced Ag-mediated proliferation of cocultured CD4(+) Th2 cells and their cytokine production, and promoted eosinophilic airway inflammation and goblet cell hyperplasia driven by adoptively transferred Ag-specific CD4(+) Th2 cells. Thus, these results suggest that an allergic recall response to recurring Ag exposures preferentially triggers an increase of Ag-specific CD4(+) Th2 cells, which facilitates the collaborative interactions between acquired CD4(+) Th2 cells and innate ILC2s to drive the exacerbation of a murine allergic airway diseases with an eosinophilic phenotype.

Daptomycin-associated eosinophilic pneumonia with rechallenge: a case report
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PURPOSE: A case of daptomycin-associated acute eosinophilic pneumonia (AEP) with positive rechallenge is reported. SUMMARY: AEP associated with daptomycin is reported in the literature, and the product labeling contains a warning and precaution statement. Criteria for diagnosing daptomycin-induced AEP varies and generally includes bronchoalveolar lavage (BAL) eosinophils ≥ 25%. We report a case of a 70-year-old woman with cough, shortness of breath, and altered mental status who presented ~ 9 days after starting therapy with daptomycin to treat methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. Daptomycin was utilized because of a presumed vancomycin allergy. Aspiration pneumonia was suspected and IV ampicillin and sulbactam was initiated. Clinical status improved initially but ~ 1 week later, her respiratory status declined. During work-up, peripheral eosinophils were abnormal at 11.6%, so daptomycin therapy was discontinued. BAL revealed 5% eosinophils with negative infectious work-up. Respiratory status rapidly improved after discontinuation of daptomycin. Linezolid therapy was initiated. Due to an uncertain association with daptomycin and concerns associated with long-term linezolid therapy, the patient agreed to rechallenge with daptomycin. Within 24 hours, respiratory symptoms returned and daptomycin was permanently discontinued. The patient rapidly recovered without the need for systemic corticosteroid treatment. CONCLUSIONS: Our case supports a broadened definition of pulmonary eosinophilia associated with daptomycin administration. It is important for clinicians to consider daptomycin as an etiology of pneumonia with abnormal eosinophils when other causes have been excluded. Clinicians could also consider peripheral eosinophilia as a possible indication of AEP when BAL is not available or cannot be obtained.
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Eosinophilic pneumonia caused by daptomycin: Six cases from two institutions and a review of the literature.

Here we report six cases of daptomycin (DAP)-induced eosinophilic pneumonia (DIEP) encountered at two medical centers and present a review of 43 DIEP patients from 26 studies to compare the clinical characteristics and radiographic findings of acute and chronic eosinophilic pneumonia (AEP; CEP). Four of the six patients did not exhibit respiratory symptoms, and one patient with only fever was misdiagnosed with DAP-induced fever. According to our literature review and the present findings, male sex and old age were dominant risk factors for DIEP. Fever and fine crackles were the most common clinical manifestations. The DAP dose and duration of administration were not significant risk factors for DIEP, and we also could not find any association between allergic predisposition and DIEP. Among the reviewed patients, 51.8% did not show more than 25% eosinophils in bronchoalveolar lavage, which is a criterion for the diagnosis of drug-induced eosinophilic pneumonia. Chest images of all patients showed CEP patterns such as multiple reticulonodular infiltrates in the subpleural region and diffuse bilateral pulmonary infiltrates with ground-glass opacities. However, 66.7% of patients also exhibited pleural effusion, a feature specific to AEP. All patients showed prompt recovery after DAP withdrawal. Our results suggest that clinicians should consider DIEP as a differential diagnosis when patients receiving DAP therapy, particularly men and elderly patients, present with fever, even in the absence of respiratory symptoms. Furthermore, they should be aware that the occurrence of DIEP is independent of the DAP dose and administration duration, and allergic reaction.

Platelets constitutively express IL-33 protein and modulate eosinophilic airway inflammation.

BACKGROUND: Although platelets play a key role in allergic inflammation in addition to their well-established role in hemostasis, the precise mechanisms of how platelets modulate allergic inflammation are not fully understood. IL-33 is an essential regulator of innate immune responses and allergic inflammation. OBJECTIVE: We sought to determine the expression of IL-33 protein by platelets and its functional significance in airway inflammation. METHODS: IL-33 protein in human platelets, the human megakaryocyte cell line MEG-01, and bone marrow-derived mouse megakaryocytes was detected by using Western blot analysis and fluorescent immunostaining. We examined the functional relevance of IL-33 protein in platelets by comparing platelet-intact and platelet-depleted groups in a murine model of IL-33-dependent airway eosinophilia elicited by intranasal administration of papain. We further compared the additive effect of administration of platelets derived from wild-type versus IL-33-deficient mice on the papain-induced eosinophilia. RESULTS: Platelets and their progenitor cells, megakaryocytes, constitutively expressed IL-33 protein (31 kDa). Papain-induced IL-33-dependent airway eosinophilia in mice was significantly attenuated by platelet depletion. Conversely, concomitant administration of platelets derived from wild-type mice but not IL-33-deficient mice enhanced the papain-induced airway eosinophilia. CONCLUSIONS: Our novel findings suggest that platelets might be important cellular sources of IL-33 protein in vivo and that platelet-derived IL-33 might play a role in airway inflammation. Therefore platelets might become an attractive novel therapeutic target for asthma and probably allergic inflammation.