The research, led by Florian Wyler and colleagues at Bern University Hospital and the University of Bern in Switzerland, tackles a problem that has long frustrated clinicians and researchers alike. The main outputs of a washout test are the lung clearance index, or LCI, which measures how many lung turnovers are needed to clear the resident nitrogen, and the functional residual capacity, or FRC, the volume of air remaining in the lungs at the end of a normal breath out. Irregular breathing behaviors can bias both numbers, but the current gold standard for judging whether a measurement is trustworthy is expert quality control: a trained physician, nurse, or scientist visually inspects the signals and decides whether to accept or reject the test. That judgment is slow, requires rare expertise, and, crucially, is subjective.

The subjectivity is not a minor nuisance. Washout measurements typically last several minutes and are routinely performed in awake children from preschool age onward, so measurements full of minor, ambiguous irregularities are the norm rather than the exception. Two experienced raters can disagree about whether a given test should be kept, especially when the irregularities fall into a grey zone between clearly acceptable and clearly unusable. Existing guidelines also rely on fixed empirical thresholds, such as allowable variation in end-expiratory lung volume, without any direct way of estimating what those deviations actually do to the LCI or FRC. The Bern team set out to replace that guesswork with a quantitative, reproducible estimate of impact.

The core of the new approach is a mathematical model of how nitrogen is diluted during the washout. For any given breath, the model relates an input of breathing behavior to an expected output of nitrogen dilution, taking into account the current end-expiratory lung volume, physiological and machine dead spaces, and the fact that washout efficiency declines as the test proceeds, because well-ventilated lung regions empty first while poorly ventilated regions hold on to their nitrogen longer. The model’s parameters are estimated individually from each measurement, using the carbon dioxide and flow signals to locate dead space and fitting a linear efficiency curve over the course of the washout.

With this model in place, the algorithm runs paired simulations for each measurement. One simulation uses the observed breathing behavior, including whatever irregularities occurred; the other uses an idealized version in which the behavior in question, say a drifting end-expiratory lung volume, is replaced by a stable target. If the two simulations produce nearly identical LCI and FRC values, the irregularity was harmless. If they diverge, the size of the divergence, expressed as a percentage, becomes a behavior-specific quality control outcome. The team built seven such tests, covering changes in end-expiratory lung volume, tidal volume variability and size, leaks or trapped gas, the method used to determine end-tidal nitrogen concentration, signal synchronization, and breath detection. A measurement was deemed acceptable if no single test exceeded an estimated impact of 15 percent.

To validate the tool, the researchers re-analyzed an extraordinary dataset: 2,471 nitrogen washout measurements from 84 children with cystic fibrosis, collected between 2012 and 2019 across 754 visits, each visit including at least three completed measurements. The algorithm ran successfully on every single measurement without any manual intervention, taking roughly four seconds per test on an ordinary office computer. That speed matters, because expert quality control is one of the practical barriers to wider adoption of washout testing in clinical routine. The overall acceptance rate was 76 percent of visits, and the mean per-visit variance of LCI dropped from 0.72 turnovers when all measurements were included to 0.39 turnovers when only algorithm-accepted measurements were counted.

The most striking finding is how much of the natural variability in washout results can be attributed to quality control factors. The combined impact estimate from all tests explained around 45 percent of the within-visit variability of LCI in the children with cystic fibrosis, and the median Pearson correlation between estimated impact and observed within-visit LCI variation was 0.83. The largest single effect on LCI came from leaks or trapped gas, which exceeded the acceptability threshold in 31 percent of measurements, followed by changes in end-expiratory lung volume at 23 percent and variations in breath size around the end of the test at 19 percent. Leaks and trapped gas are particularly common in cystic fibrosis because the disease produces extended washout tails, in which the end-tidal nitrogen concentration hovers near the end-of-test threshold and occasionally ticks upward as poorly ventilated pockets of gas are slowly released.

The team also compared the automated judgments with human experts using a second dataset of 100 measurements from six-year-old children, half with cystic fibrosis and half healthy, drawn from the Bern and Swiss infant lung development cohorts. Agreement between the algorithm and expert raters was moderate, with Cohen’s kappa ranging from 0.32 against the rating made on the day of the test to 0.46 against a retrospective rating. Notably, that level of agreement was comparable to the agreement between two experienced human raters themselves, which stood at 0.65. Some disagreements were instructive: current guidelines instruct raters to reject any measurement with a leak, no matter how small, whereas the automated system tolerates minor leaks as long as their estimated impact on outcomes remains negligible. Conversely, experts sometimes struggled to judge visually whether a transient shift in end-expiratory lung volume mattered, while the model could quantify it directly.

The implications extend beyond cystic fibrosis clinics. Because the algorithm judges every irregularity on the same scale, its estimated impact on the primary outcomes, it replaces a patchwork of device-specific and behavior-specific thresholds with a single interpretable metric. The threshold itself can be tuned to the purpose of the test: a strict 15 percent cutoff for research repeatability, or a looser criterion when a clinical LCI is already far above the upper limit of normal and a modest bias would not change the diagnosis. The tool can also be applied retrospectively when measurements are re-analyzed with updated algorithms, and it inherently distinguishes between signal anomalies caused by genuine leaks and those fully explained by the patient’s underlying breathing pattern, a distinction that is especially valuable in patients who cannot achieve high-quality tidal breathing.

Limitations remain. The algorithm was developed for nitrogen washout data from the Ecomedics Exhalyzer D and relies on carbon dioxide, tracer gas, and flow signals; some tests are specific to that device setup, though the authors note that only minor adaptations would be needed for sulfur hexafluoride measurements or other devices. The current implementation runs after the measurement is complete, so a live version that warns operators mid-test to restart a compromised measurement would require further development. Still, the study demonstrates a feasible, fast, and reproducible method for assigning impact estimates to breathing irregularities, and it explains a substantial share of the measurement noise that has long plagued washout testing. For a technique whose value depends on detecting subtle changes in ventilation inhomogeneity over years of follow-up, an objective quality control standard could make the difference between a noisy research tool and a dependable clinical instrument.

Subject of Research: Automated model-based quality control for multiple-breath washout lung function testing in children

Article Title: Quality control in multiple-breath washout measurements: an automated, model-based approach quantifies effects on primary outcomes

Article References: Wyler, F., Borer, S., Curdy, M., Bovermann, X., Frauchiger, B. S., & Latzin, P. (2026). Quality control in multiple-breath washout measurements: an automated, model-based approach quantifies effects on primary outcomes. Frontiers in Medical Engineering, 4, Article 1774073. https://doi.org/10.3389/fmede.2026.1774073

Image Credits: AI Generated

DOI: 10.3389/fmede.2026.1774073

Keywords: multiple-breath washout, lung clearance index, quality control, cystic fibrosis, functional residual capacity, pediatric lung function, nitrogen washout, ventilation inhomogeneity, automated algorithm, respiratory medicine, clinical engineering, Bern University Hospital

When he arrived at the Department of Pulmonary and Critical Care Medicine at Shenzhen Longgang District Central Hospital, physicians heard something asthma rarely produces: inspiratory stridor audible over the trachea itself. His vital signs were stable, with a respiratory rate of 18 breaths per minute and oxygen saturation of 97 percent on room air, but the stridor signaled turbulent airflow through a narrowed central airway. Laboratory workup was largely unremarkable—his white cell count, eosinophil fraction, C-reactive protein, and sedimentation rate were all within normal limits—yet Epstein–Barr virus serology told a different story. EBVCA-IgG and EBNA-IgG were strongly positive, plasma EBV DNA was detectable, and his fractional exhaled nitric oxide was elevated at 60 parts per billion, a finding that would have reinforced the asthma hypothesis had the clinical picture not already begun to fracture.

The decisive test was spirometry with flow-volume loop analysis, a technique many clinicians order routinely but whose graphical output is frequently overlooked. In a normal loop, airflow rises steeply to a sharp peak on both expiration and inspiration before declining smoothly. This patient’s loop showed a flattened plateau in both the inspiratory and expiratory limbs, with peak expiratory flow reduced to 2.03 liters per second and peak inspiratory flow to roughly 2.30 liters per second. That biphasic plateau is the physiological signature of a fixed upper airway obstruction: a lesion that narrows the airway to the same degree regardless of respiratory phase, whether the obstruction is intrathoracic or extrathoracic. Asthma, by contrast, produces a scooped expiratory curve reflecting variable, peripheral airway narrowing—and typically spares the inspiratory limb entirely.

The case carries a subtle technical lesson about bronchodilator testing. When the patient inhaled a bronchodilator, his forced expiratory volume in one second jumped from 0.91 liters (22.1 percent predicted) to 1.75 liters (42.6 percent predicted), an absolute gain of 0.84 liters—a 92 percent increase that technically qualified as positive reversibility. But the plateau on the flow-volume loop persisted after bronchodilator administration. The authors explain this apparent paradox: bronchodilators can improve FEV1 through effects on peripheral airways even in the presence of a central lesion, but the characteristic loop morphology—the biphasic plateau—remains diagnostic of fixed airway obstruction. The persistence of that pattern, not the reversibility numbers, was the observation that redirected the diagnostic workup toward imaging and bronchoscopy.

Chest computed tomography revealed a polypoid mass protruding from the anterior wall of the cervical trachea at the C3–C4 vertebral level. Bronchoscopy went further, identifying a central polypoid mass causing approximately 95 percent occlusion of the tracheal lumen—a near-complete blockage of the windpipe in a man who had been walking around with an inhaler. Surgeons electrosnared the mass endoscopically in a procedure that served two purposes: decompressing the airway to relieve the life-threatening narrowing, and obtaining tissue for pathological diagnosis. It was explicitly not intended as definitive treatment.

What the pathologists found under the microscope was a tumor of extraordinary rarity. Histopathology showed nests and sheets of malignant epithelial cells surrounded by a dense infiltrate of lymphocytes—the defining architecture of lymphoepithelioma-like carcinoma, or LELC. Immunohistochemistry demonstrated diffuse cytoplasmic positivity for CK5/6 and P40, markers of squamous differentiation, while staining for Napsin A, TTF-1, Syn, and CgA was negative, excluding lung adenocarcinoma and neuroendocrine tumors. The Ki-67 proliferative index was 70 percent, indicating a rapidly dividing malignancy. Most tellingly, in situ hybridization for EBV-encoded small RNAs (EBER) revealed strong nuclear positivity, confirming the tumor’s intimate association with Epstein–Barr virus. This immunoprofile established the diagnosis of primary tracheal LELC.

The rarity here is difficult to overstate. Primary tracheal malignancies account for less than 0.1 percent of all cancers, and roughly two-thirds of those are squamous cell carcinoma or adenoid cystic carcinoma. LELC represents less than 2 percent of tracheal tumors, and primary tracheal LELC has been documented only in isolated case reports worldwide. The subtype is characterized histologically by undifferentiated epithelial tumor cells embedded in dense lymphocytic infiltration and is strongly associated with EBV infection, particularly in Asian populations. Among previously published cases the authors could identify in their literature search, the youngest patient was a 22-year-old male—making this 30-year-old one of the youngest adults ever described with the disease.

Before declaring the tracheal tumor primary, the team had to exclude a nasopharyngeal origin, since LELC arises far more commonly in the nasopharynx. Fiberoptic laryngoscopy and nasoendoscopy found no abnormality in the upper aerodigestive tract, and 18F-FDG PET/CT demonstrated no hypermetabolic lesion in the nasopharynx or anywhere outside the trachea and regional mediastinal lymph nodes. The authors acknowledge a diagnostic limitation: dedicated nasopharyngeal biopsy was not performed because no suspicious lesion was identified. Subsequent PET/CT did detect residual mediastinal lymph node metastasis, prompting salvage video-assisted thoracoscopic surgery (VATS) tracheal resection-anastomosis with systematic lymphadenectomy. Pathology confirmed negative resection margins—the closest margin approximately 0.2 centimeters from the tumor—with 11 mediastinal lymph nodes resected, of which two were positive for metastatic carcinoma. The primary tumor measured roughly 2 by 1.2 by 0.5 centimeters and had invaded the cricoid cartilage without extending beyond the adventitia. In the absence of a validated TNM staging system specific to tracheal LELC, the tumor was classified as pT2N2M0, Stage IIIA, by reference to existing systems.

The decision to withhold adjuvant systemic therapy or radiotherapy was an individualized, multidisciplinary one, not a general recommendation. The team weighed the achievement of R0 resection with negative margins, the complete absence of established standard adjuvant therapy for this ultra-rare disease, and the significant long-term toxicities of radiotherapy and chemotherapy in a young patient. After tumor board discussion, the patient chose close surveillance. The authors are careful to note that recent evidence showing PD-1/PD-L1 inhibitor efficacy in locally advanced or metastatic pulmonary LELC cannot be extrapolated to justify routine adjuvant immunotherapy after R0 resection of tracheal LELC—that remains strictly investigational. Similarly, plasma EBV-DNA thresholds used in pulmonary LELC and nasopharyngeal carcinoma have never been validated for the tracheal subtype and should be interpreted only as exploratory surveillance tools. The patient’s postoperative plasma EBV DNA remained detectable at low levels, below 500 copies per milliliter, warranting continued monitoring but not constituting an indication for intervention.

One year after surgery, the results speak for themselves. The patient remains asymptomatic with no evidence of recurrence on imaging, and postoperative pulmonary function testing demonstrated complete normalization of the flow-volume loop morphology. FEV1 improved from 0.91 liters to 3.62 liters—a 298 percent increase reaching 89.7 percent of predicted—while peak expiratory flow rose from 2.03 to 6.76 liters per second, a 233 percent gain. The plateau pattern had resolved entirely, confirming restoration of normal airway dynamics. In his own words, he can now exercise without any shortness of breath for the first time in months, and he is grateful his doctors did not stop at the asthma diagnosis. The teaching point extends well beyond this single extraordinary case: in young, non-smoking patients with asthma-like symptoms, failure to respond to an adequate trial of inhaled corticosteroids—typically four to six weeks—should prompt reconsideration of the initial diagnosis. The flow-volume loop, a non-invasive and cost-effective tool, provides a rapid means of identifying patterns suggestive of central airway obstruction, and a biphasic plateau can unmask rare tracheal malignancies before escalating antiasthma therapy wastes precious time.

Subject of Research: A rare Epstein–Barr virus–associated tracheal cancer in a young non-smoker was misdiagnosed as asthma until a flow-volume loop revealed fixed upper airway obstruction, guiding CT, bronchoscopy, and successful surgical treatment with full lung function recovery.

Article Title: Primary tracheal lymphoepithelioma-like carcinoma in a young non-smoking male: a case report highlighting the diagnostic value of flow-volume loop

Article References: Xiao, S., Chen, S., Ou, J., & Shen, Y. (2026). Primary tracheal lymphoepithelioma-like carcinoma in a young non-smoking male: a case report highlighting the diagnostic value of flow-volume loop. Frontiers in Medicine, 13, Article 1965664. https://doi.org/10.3389/fmed.2026.1965664

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1965664

Keywords: tracheal cancer, lymphoepithelioma-like carcinoma, Epstein-Barr virus, flow-volume loop, asthma misdiagnosis, pulmonary function testing, case report, respiratory medicine, spirometry, airway obstruction, Primary, tracheal

ANCA-associated vasculitis, or AAV, is a family of necrotizing small-vessel diseases driven by pathogenic antineutrophil cytoplasmic antibodies. It encompasses microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. Classically, patients present with striking systemic features—rapidly rising creatinine, pulmonary hemorrhage, palpable purpura, peripheral neuropathy—that trigger an immunological workup and serological testing. Bronchiectasis, by contrast, is rarely considered an inaugural manifestation. When it appears in AAV, it is usually interpreted as structural fallout from established vasculitic inflammation rather than a warning shot, a framing that can postpone ANCA testing until organ damage declares itself elsewhere.

The patient at the center of the report arrived in 2018 with a chronic productive cough and a history of intermittent asthma. High-resolution computed tomography revealed focal bronchiectasis confined to the right middle lobe. Her physicians did what good diagnosticians do: they systematically excluded the usual suspects. Serial sputum cultures and bronchoalveolar lavage were negative for bacterial, mycobacterial, and fungal pathogens. Non-tuberculous mycobacterial infection, cystic fibrosis, primary immunodeficiency, allergic bronchopulmonary aspergillosis, and eosinophilic granulomatosis with polyangiitis were all ruled out. Spirometry was normal. Empiric corticosteroids and macrolides were prescribed for presumed non-infective airway inflammation, and her symptoms improved—but never resolved.

Over the following six years, repeat imaging charted a slow, ominous march. The focal right middle lobe disease progressed to multifocal bilateral bronchiectasis, accompanied by tree-in-bud nodularity and mucus plugging, with new parenchymal nodules appearing along the way. Her antinuclear antibody test was negative. Critically, ANCA serology was never obtained, and the diagnosis remained bronchiectasis of undetermined etiology for seven years. The authors of the report are careful not to overclaim causality, but they highlight a stark, narrower fact: seven years elapsed during which an inexpensive blood test that would have reframed the entire diagnosis was never sent.

Then, in 2025, the systemic disease erupted. The woman developed palpable purpura across both lower extremities, hemoptysis, and hematuria. Imaging showed new multifocal bilateral consolidations superimposed on the established bronchiectasis, though without the ground-glass pattern of diffuse alveolar hemorrhage; her hemoglobin and oxygen saturation remained stable and the hemoptysis resolved spontaneously. Her kidneys told a more urgent story. Serum creatinine had surged from 0.46 mg/dL six weeks earlier to 2.09 mg/dL—an estimated glomerular filtration rate collapsing from 100 to 24 mL/min/1.73 m²—and reached a nadir of 2.19 mg/dL on hospital day three, all while urine output remained preserved.

The serology finally caught up with the disease. Indirect immunofluorescence showed a perinuclear pattern, and antigen-specific ELISA confirmed myeloperoxidase-ANCA, or MPO-ANCA, at 250.2 U/mL against a reference value below 1.0, with proteinase 3-ANCA negative. Urinalysis revealed proteinuria with dysmorphic erythrocytes. A renal biopsy sampling fourteen glomeruli showed pauci-immune crescentic glomerulonephritis with a cellular crescent in one glomerulus, no immune deposits, and more than half of the glomeruli intact—Berden focal class, the histological category carrying the most favorable prognosis. Anti-glomerular basement membrane and anti-double-stranded DNA antibodies were negative, and complement was normal. Together, the findings established microscopic polyangiitis.

Treatment followed current guidelines: three days of intravenous methylprednisolone at 500 mg daily, an oral prednisone taper, and rituximab 1 gram repeated after two weeks and then every six months as maintenance, with Pneumocystis prophylaxis. The response was dramatic on the inflammatory front. Within two months her eGFR peaked at 74, stabilizing at 60 at fifteen months—stage 3a chronic kidney disease, a plateau the authors attribute to residual nephron loss after inflammatory suppression. At five months, high-resolution CT showed near-complete resolution of the consolidations, while the underlying bronchiectasis persisted, exactly as expected for fixed structural airway damage. MPO-ANCA fell from 250.2 to 5.2 U/mL by twelve months with documented B-cell depletion, and she remains asymptomatic at fifteen months, her cough finally resolved.

The literature review embedded in the report gives the case its wider significance. A 2024 systematic review and meta-analysis of 24 studies found a pooled bronchiectasis prevalence of 19 percent in AAV—higher with MPO-ANCA than PR3-ANCA, at 28 percent versus 13 percent—and noted that bronchiectasis may precede, coincide with, or follow the vasculitis. One retrospective cohort of 58 AAV patients found bronchiectasis in 37.9 percent, all MPO-ANCA positive, independently associated with MPO specificity, female sex, and age at diagnosis. Most striking is a multicentre cohort of 61 patients with AAV and bronchiectasis: in 25 of them, bronchiectasis preceded the vasculitis by a median of 16 years, and this bronchiectasis-first group had more microscopic polyangiitis, more MPO-ANCA, and shorter survival. The present patient—female, MPO-positive, with airway disease antedating systemic vasculitis by seven years—fits that phenotype precisely.

Yet the authors resist a simple causal narrative, and the evidence supports their caution. Where bronchiectasis was universally MPO-associated, affected patients actually had less frequent renal involvement than those without it, and bronchiectasis in AAV generally does not respond to immunosuppression—consistent with this patient, whose consolidations melted away while the structural airway disease remained. Whether earlier serology would have changed her outcome is genuinely uncertain. The real gap, they argue, lies in the current diagnostic algorithms. The 2025 European Respiratory Society guideline strongly recommends standardized testing for the underlying cause of bronchiectasis, but ANCA appears only within an etiological algorithm gated behind systemic features—coexisting autoimmune disease, hemoptysis, or signs of vasculitis—and the guideline explicitly states these components are not separate recommendations. A 2025 observational study screening 468 bronchiectasis patients found ANCA positivity in just 3.8 percent and concluded screening should remain individualized. The 2026 American College of Chest Physicians guideline addresses management only. This patient had none of the trigger features before 2025: her gap sits outside current algorithms—culture-negative, radiographically progressive, incompletely corticosteroid-responsive disease without systemic features.

One diagnostic alternative deserved careful exclusion. The combination of MPO-ANCA positivity, long-standing airway disease, and a history of asthma raises eosinophilic granulomatosis with polyangiitis as the leading rival. Applying the 2022 ACR/EULAR classification criteria is instructive: her cumulative score was just 2 points—3 for obstructive airway disease, credited on her asthma history despite normal spirometry, minus 1 for hematuria—far below the 6 required, because the most heavily weighted item, a maximum eosinophil count of at least 1 × 10⁹ per liter, was never met. Eosinophils were 0 percent at presentation and had never been elevated; total IgE, measured in 2024, was 114 kU/L without the marked elevation characteristic of EGPA. Pauci-immune crescentic glomerulonephritis with markedly elevated MPO-ANCA and no tissue or blood eosinophilia settles the question in favor of microscopic polyangiitis. The case also carries a technical lesson in serology: the discordance between her falling MPO-ANCA titers and persistent weak immunofluorescence positivity is compatible with non-MPO perinuclear antibodies during B-cell depletion, reinforcing guidance against basing treatment decisions on titers alone. Limitations remain—alveolar hemorrhage was never definitively confirmed, and the absence of ANCA testing during the airway phase means the timing of seroconversion is unknown. What endures is the clinical message: in a patient with progressive, culture-negative bronchiectasis that resists the usual treatments, the vasculitis may already be knocking, years before the door gives way.

Subject of Research: Bronchiectasis as an early sentinel manifestation of ANCA-associated vasculitis

Article Title: Bronchiectasis as the Sentinel Manifestation of ANCA‐Associated Vasculitis: A Case Report and Literature Review

Article References: Kim, A., Vartany, C., Hegde, S., Lau, K., Tatosyan, L., & Liang, B. (2026). Bronchiectasis as the Sentinel Manifestation of ANCA ‐Associated Vasculitis: A Case Report and Literature Review. Respirology Case Reports, 14(10), Article e70777. https://doi.org/10.1002/rcr2.70777

Image Credits: AI Generated

DOI: 10.1002/rcr2.70777

Keywords: bronchiectasis, ANCA-associated vasculitis, microscopic polyangiitis, MPO-ANCA, case report, glomerulonephritis, rituximab, high-resolution CT, EGPA, clinical guidelines, autoimmune screening, respiratory medicine

Chronic eosinophilic pneumonia, or CEP, occupies a distinctive niche in pulmonary medicine. The disease is characterized by dense infiltration of the lung parenchyma by eosinophils, the white blood cells best known for fighting parasites and driving allergic reactions. It typically strikes middle-aged adults, shows a marked female predominance, and is strongly linked to asthma and atopic disease, with up to two-thirds of patients carrying a history of asthma before the lung disease declares itself. Clinically, CEP follows a subacute to chronic course, unfolding over weeks to months with cough, progressive shortness of breath on exertion, and constitutional symptoms such as weight loss and fatigue. The classic radiological picture is equally recognizable: bilateral consolidations and ground-glass opacities clustered at the periphery of the lungs, hugging the pleural surface in a pattern that experienced radiologists can spot from across the reading room.

The diagnostic architecture of CEP rests on a tripod of findings. Because no universally accepted diagnostic criteria exist, clinicians generally require a compatible subacute clinical course, characteristic peripheral-predominant pulmonary infiltrates on imaging, and evidence of eosinophilic inflammation, either in the blood or in bronchoalveolar lavage fluid, while systematically excluding secondary causes of pulmonary eosinophilia such as drugs, parasites, and systemic autoimmune disease. In typical cases, the lavage findings are dramatic. BAL eosinophilia is usually marked, often reaching 40 percent or more of the recovered cells, and peripheral blood eosinophil counts commonly exceed 1,000 cells per microliter. When the clinical picture, the imaging, and the cellular evidence all align, lung biopsy is generally considered unnecessary, reserved for the minority of cases in which features are atypical or inconclusive. That reserve clause, as this case demonstrates, is where diagnostic danger lives.

The patient at the center of the report was a 61-year-old ex-smoker who arrived with two months of progressively worsening breathlessness on exertion and two weeks of a productive cough that would not relent, accompanied by weight loss. His medical history included asthma, managed with inhaled fluticasone furoate and vilanterol, along with type 2 diabetes treated with empagliflozin and metformin and hyperlipidaemia controlled with simvastatin for more than a decade. He reported no recent travel abroad and no consumption of raw or undercooked food, closing off the most common routes to parasitic lung infection. On examination, doctors heard bilateral fine inspiratory crackles but no wheezing, and they found none of the peripheral stigmata, purpura, mechanic’s hands, Gottron papules, Raynaud phenomenon, synovitis, or neurological deficits, that would suggest a connective tissue disease or vasculitis masquerading as lung disease.

Laboratory testing initially seemed to confirm the suspicion of CEP. The patient’s peripheral blood showed eosinophilia of 15 percent, corresponding to 1,314 cells per microliter, comfortably above the threshold commonly associated with eosinophilic lung disease. Chest radiography revealed bilateral peripheral patchy opacities with an upper-lobe predominance, and high-resolution computed tomography went further, demonstrating multifocal peripheral consolidations and ground-glass opacities with a subpleural predilection, along with traction bronchiectasis indicating that the process had been smoldering long enough to begin remodeling the lung’s architecture. Taken together, the subacute course, the blood eosinophilia, and the textbook peripheral distribution of disease made CEP the leading diagnosis on admission, and a reasonable one by any standard.

Then the bronchoscope told a different story. Bronchoalveolar lavage of the patient’s lung returned a cellular differential that was 85 percent neutrophils and only 6 percent eosinophils, a profile that belongs to bacterial pneumonia, not to eosinophilic lung disease. Autoimmune serology, including antinuclear antibody, proteinase 3-antineutrophil cytoplasmic antibody, and myeloperoxidase-antineutrophil cytoplasmic antibody, came back negative, and the total IgE level of 289 kU/L offered no signal of an allergic driver. Urinalysis showed neither haematuria nor proteinuria, and renal function was normal, further arguing against a systemic vasculitis. Confronted with neutrophil-predominant lavage fluid, the clinical team reasonably pivoted to an infectious explanation and initiated empirical treatment with amoxicillin and clavulanate. The antibiotics failed. Symptoms persisted, radiographic abnormalities did not budge, follow-up lavage microbiological cultures were negative, cytological examination identified no parasitic organisms, and stool examination for parasites was also unrevealing.

With the non-invasive pathway exhausted, the team turned to video-assisted thoracoscopic surgery, resecting a wedge of the left lower lobe for histopathological examination. What the pathologist found rewrote the case entirely. The tissue demonstrated an organizing pneumonia pattern, defined by intra-alveolar proliferation of fibroblastic foci, the plug-like clusters of immature connective tissue known as Masson bodies, accompanied by active immature fibrosis. Critically, woven through the interstitial and peribronchiolar regions was a prominent eosinophilic inflammatory infiltrate, with plasma cells and scattered lymphocytes in attendance. The alveolar architecture was relatively preserved, and, importantly, a blood vessel examined in the specimen showed an intact wall with no histological evidence of vasculitis, excluding one of the most dangerous mimics. Integrating the clinical course, the peripheral eosinophilia, the radiological findings, the histopathological features, and a thorough assessment for secondary causes, the physicians made the diagnosis of chronic eosinophilic pneumonia.

Treatment followed the established playbook for CEP. Intravenous methylprednisolone was commenced at 40 milligrams daily, a dose equivalent to prednisolone at 1 milligram per kilogram of body weight per day, then converted to oral methylprednisolone before discharge and gradually tapered over approximately two months. The response was swift and convincing. Symptoms improved progressively, and a chest radiograph obtained after roughly one month of corticosteroid therapy showed resolution of the bilateral peripheral opacities that had dominated the initial films. The trajectory underscores why making the correct diagnosis matters so much: corticosteroids, which are useless against bacterial pneumonia and potentially harmful, are precisely the right weapon against CEP, and delays in reaching the diagnosis translate directly into prolonged symptoms and unnecessary exposure to antibiotics.

The case’s most instructive twist lies in what the lavage fluid did and did not reveal. Although BAL eosinophilia is usually prominent in CEP, the authors note that considerable variability has been reported across published series, with eosinophil proportions ranging from as low as 12 percent to as high as 95 percent. There is a technical reason for this scatter: bronchoalveolar lavage samples only a limited portion of the distal airways and alveolar compartment, a tiny and possibly unrepresentative window onto a patchy disease process. A normal or atypical BAL differential, the authors emphasize, does not exclude microscopic abnormalities elsewhere in the lung tissue. The cellular profile of lavage fluid should therefore be interpreted in conjunction with the clinical and radiological findings rather than wielded in isolation, and when the lavage results clash with the broader picture, surgical lung biopsy may be justified in selected patients to establish the diagnosis definitively.

The report also untangles a second source of confusion, the relationship between CEP and cryptogenic organizing pneumonia. The two conditions share several clinical and radiological features, including subacute respiratory symptoms, pulmonary consolidation, and ground-glass opacities, which can complicate their distinction even for experienced clinicians. Histologically, however, organizing pneumonia is a non-specific pattern of lung injury that may occur in a variety of pulmonary disorders, CEP among them. Although eosinophilic infiltration of the alveolar spaces and interstitium is the characteristic histopathological hallmark of CEP, foci of organizing pneumonia with intra-alveolar fibroblastic plugs may also be present within it. The presence of an organizing pneumonia pattern on biopsy, in other words, does not automatically signify cryptogenic organizing pneumonia. In this patient, the combination of that pattern with prominent eosinophilic infiltration, alongside compatible clinical, radiological, and peripheral blood findings, anchored the diagnosis firmly in eosinophilic territory. For clinicians navigating the eosinophilic lung diseases, the message is blunt: lavage fluid is a supporting witness, not the judge, and when the evidence conflicts, the tissue still holds the final word.

Subject of Research: Diagnosis of chronic eosinophilic pneumonia with atypical bronchoalveolar lavage findings and an organizing pneumonia pattern on lung biopsy

Article Title: Chronic Eosinophilic Pneumonia: A Diagnostic Challenge With Atypical Bronchoalveolar Lavage Findings and an Organizing Pneumonia Pattern

Article References: Lin, Y.-T., Ou, W.-F., Liang, S.-Y., Hu, Y.-H., Chen, W.-C., & Chan, M.-C. (2026). Chronic Eosinophilic Pneumonia: A Diagnostic Challenge With Atypical Bronchoalveolar Lavage Findings and an Organizing Pneumonia Pattern. Respirology Case Reports, 14(10), Article e70780. https://doi.org/10.1002/rcr2.70780

Image Credits: AI Generated

DOI: 10.1002/rcr2.70780

Keywords: chronic eosinophilic pneumonia, bronchoalveolar lavage, organizing pneumonia, lung biopsy, eosinophilia, interstitial lung disease, corticosteroids, high-resolution computed tomography, cryptogenic organizing pneumonia, respiratory medicine, case report, differential diagnosis

Mycobacterium avium complex pulmonary disease, often abbreviated MAC-PD, belongs to a family of infections caused by non-tuberculous mycobacteria, organisms that are widespread in soil and water and that can colonize the lungs of susceptible individuals, particularly older women with certain structural lung characteristics and people with compromised immune defenses. Unlike tuberculosis, MAC-PD is not generally transmitted from person to person, but it shares a troubling feature with its more famous cousin: treatment is long, burdensome, and frequently followed by relapse. Patients typically endure multidrug antibiotic regimens lasting many months or years, and even those who achieve conversion of their sputum cultures to negative face a substantial probability that the infection will reappear. The recurrence rate is high enough that clinicians increasingly describe MAC-PD not as an acute infection to be eradicated but as a chronic disease requiring long-term management strategies, yet no intervention has ever been prospectively proven to reduce the risk of recurrence after cure.

It is this therapeutic vacuum that the new trial aims to fill, and the choice of candidate is deliberate. Bailing capsule is a fermented preparation of Cordyceps sinensis, a fungus that has been used in Chinese medicine for centuries and that has already been granted approval in China for the treatment of chronic bronchitis and chronic obstructive pulmonary disease. The research team points to previous studies suggesting that the preparation exerts immunomodulatory effects, meaning that rather than attacking bacteria directly, it may help recalibrate the host immune system that failed to clear the mycobacteria in the first place. This concept, known as host-directed therapy, has attracted growing interest in infectious disease research because it offers a way to bolster the body’s own defenses in situations where antibiotics alone are insufficient, toxic, or undermined by resistance. If the immune environment of the lung can be shifted toward one that resists re-infection or reactivation, the logic goes, the cycle of cure and relapse might finally be broken.

The design of the study reflects an unusually high standard of rigor for research in complementary medicine. The investigators plan to recruit 300 participants who have achieved microbiologically cured MAC-PD, confirmed by laboratory testing, and to assign them randomly in a one-to-one ratio to receive either Bailing capsule or an indistinguishable placebo. Neither the patients nor the treating clinicians and assessors will know who is receiving the active preparation, a double-blind arrangement that guards against bias in symptom reporting and outcome assessment. Both groups will take four capsules three times per day by mouth for twelve consecutive months, a dosing schedule and duration chosen to provide sustained exposure while remaining feasible for patients to adhere to over the long treatment period.

Monitoring during the trial will be intensive. Participants will return for follow-up visits every month, at which they will complete quality-of-life questionnaires, undergo blood analyses, and receive radiologic examinations of the chest. The primary outcome measure is the rate of MAC-PD recurrence within twelve months, and the investigators have specified a demanding diagnostic standard for detecting it: recurrence must be confirmed either by culture of mycobacteria or by sequencing-based detection, ensuring that the endpoint rests on objective microbiological evidence rather than on clinical impression alone. This matters because respiratory symptoms in patients with prior MAC-PD can fluctuate for many reasons, and attributing worsening to recurrence without laboratory confirmation risks overstating both disease activity and treatment effects.

Beyond the primary endpoint, the trial will track a battery of secondary outcomes designed to capture the fuller clinical picture. These include the time it takes for recurrence to occur, the rate of other respiratory tract infections, quality of life as measured by validated instruments, respiratory symptoms, and adverse events. The inclusion of adverse event surveillance is particularly important for a widely used over-the-counter-style preparation, since large randomized cohorts are among the best settings in which to detect side effects that smaller or shorter studies might miss. The parallel-group design, in which the two arms proceed simultaneously under identical conditions, further strengthens the trial’s ability to isolate the effect of the capsule from seasonal variation in respiratory infections and from differences in care across the participating hospitals.

The scale and structure of the study also speak to a broader ambition. According to the investigators, this is the first trial to prospectively evaluate any specific intervention for reducing the recurrence of MAC-PD, a claim that underscores how little evidence-based guidance currently exists for the post-cure phase of this disease. The authors describe the rigid design and large sample size as key features boosting the statistical power of the study, and they frame the project as an effort to establish traditional Chinese medicine as a legitimate form of host-directed therapy in the long-term management of chronic infectious disease. They also acknowledge that questions will remain even if the trial succeeds, noting that further research will be needed to determine the optimal duration of treatment, since twelve months of capsules may represent only one point on a longer dosing curve.

The institutional backing behind the study lends it additional weight. The trial is coordinated through the National Center for Respiratory Medicine and the State Key Laboratory of Respiratory Health and Multimorbidity at the China-Japan Friendship Hospital, one of China’s leading respiratory institutions, and draws co-investigators from Capital Medical University, Shanghai University of Traditional Chinese Medicine’s Longhua Hospital, Shanghai Pulmonary Hospital affiliated with Tongji University, Guangzhou Chest Hospital, Beijing Chest Hospital, Anhui Chest Hospital, and Jiangxi Provincial Chest Hospital. The protocol has received ethics approval from the ethics committee of the China-Japan Friendship Hospital under approval number 2025-KY-004-2, and the investigators state that the trial will be conducted in accordance with the Good Clinical Practice guideline and the Declaration of Helsinki. The authors declare no competing interests, and the work is supported by a grant from the National Science and Technology Major Project.

For patients, the stakes are considerable. MAC-PD predominantly affects people who already carry significant respiratory burden, and each episode of recurrence can mean another round of toxic multidrug antibiotic therapy, repeated hospital visits, and mounting anxiety about a disease that seems to keep returning. A safe, orally administered adjunct that meaningfully reduced recurrence would transform the outlook for this population, shifting the post-cure period from watchful waiting to active prevention. It would also represent a notable milestone for the scientific evaluation of traditional Chinese medicine, demonstrating that a classical fungal preparation can be tested against the same gold-standard criteria applied to any modern pharmaceutical.

Caution remains warranted, as it always does at the protocol stage. A published trial design is a promise of evidence to come, not a result, and the history of medicine is littered with promising hypotheses that dissolved under the scrutiny of randomized data. The true test will arrive when the 300 participants have completed their twelve months of capsules and monthly follow-ups, and when the culture and sequencing results reveal whether the Bailing group truly experienced fewer recurrences than those receiving placebo. Until then, the study stands as a carefully constructed experiment at the intersection of ancient pharmacology and modern immunology, one whose outcome could reshape how clinicians think about preventing relapse not only in MAC-PD but potentially in chronic infections more broadly. If the fungus that has been a fixture of Chinese apothecaries for centuries does prove its worth in a double-blind trial, it will do so not on the strength of tradition, but on the strength of data.

Subject of Research: A randomized controlled trial of Bailing (Cordyceps sinensis) capsule for preventing recurrence of Mycobacterium avium complex pulmonary disease

Article Title: The effect of Bailing (Cordyceps sinesis) capsule in preventing recurrence of mycobacterium avium complex pulmonary disease: a protocol of multicenter, randomized, double-blind, placebo-controlled trial

Article References: Gu, S., Cui, X., Lu, Z., Gu, J., Chen, P., Nie, L., Wang, H., & Zhong, F. (2026). The effect of Bailing (Cordyceps sinesis) capsule in preventing recurrence of mycobacterium avium complex pulmonary disease: a protocol of multicenter, randomized, double-blind, placebo-controlled trial. BMC Complementary Medicine and Therapies. https://doi.org/10.1186/s12906-026-05614-w

Image Credits: AI Generated

DOI: 10.1186/s12906-026-05614-w

Keywords: Mycobacterium avium complex, non-tuberculous mycobacteria, Cordyceps sinensis, Bailing capsule, traditional Chinese medicine, host-directed therapy, pulmonary disease recurrence, randomized controlled trial, immunomodulation, respiratory medicine, clinical trial protocol, placebo-controlled

Inhaled corticosteroids are the cornerstone of modern asthma management. Unlike in COPD, where steroid inhalers are reserved for a specific subgroup of patients with an eosinophilic phenotype, international guidelines from the Global Initiative for Asthma recommend inhaled corticosteroids at every step of asthma severity, from mild disease treated on an as-needed basis to severe disease requiring daily maintenance therapy. That ubiquity is precisely why the question of interclass safety differences matters so much in asthma: unlike in COPD, where a concerning safety profile might prompt a clinician to simply withdraw the steroid, withdrawing inhaled corticosteroids from a patient with asthma is not a realistic therapeutic option. Any meaningful difference in pneumonia risk between drug classes would therefore have immediate and unavoidable implications for prescribing decisions worldwide.

The motivation for the study traces back to a robust body of COPD literature. Systematic reviews and meta-analyses have consistently found that budesonide/formoterol combinations are associated with fewer pneumonia events than salmeterol/fluticasone combinations, and subsequent nationwide cohort studies have reinforced the conclusion that fluticasone propionate raises pneumonia risk relative to budesonide in that population. A repeat systematic review published nine years after the first reached the same conclusion, describing a likely clinically important interclass difference. Researchers have even documented downstream economic consequences, with patients treated with fluticasone incurring higher COPD-related, pneumonia-related, and all-cause health care costs than those treated with budesonide. Whether this pharmacological divergence extended to asthma, however, remained genuinely uncertain.

The evidence in asthma was sparse and contradictory. A Swedish cohort found that fluticasone propionate was associated with increased pneumonia risk, but only when compared against patients with asthma who were not using the drug, not against budesonide users. A Canadian quasi-cohort study suggested that both budesonide and fluticasone were linked to elevated pneumonia risk in asthma. Meanwhile, analyses of randomized trial data found no increased pneumonia risk among patients with asthma taking budesonide at all. Compounding the confusion, studies comparing steroid users with non-users in asthma suffer from a fundamental design flaw: because guidelines recommend maintenance inhaled corticosteroids for all moderate to severe disease, such comparisons effectively pit patients with mild asthma against those with severe disease, confounding drug effects with underlying illness severity.

To sidestep that bias, the research team, led by Wang Chun Kwok and James Chung Man Ho of the University of Hong Kong together with colleagues at the University of South Carolina, restricted their analysis to adults with moderate to severe asthma at Global Initiative for Asthma steps 3 to 5, all of whom required regular maintenance inhaled corticosteroid combined with a long-acting beta-agonist. Drawing on the Clinical Data Analysis and Reporting System of the Hong Kong Hospital Authority, a network covering more than 90 percent of the territory’s population through 43 hospitals and 123 outpatient clinics, the investigators identified 16,170 eligible patients treated in 2018 and followed them through the end of 2023. Of these, 7,169 patients, or 44.3 percent, were prescribed budesonide; 7,853, or 48.6 percent, received fluticasone propionate; and 1,148, or 7.1 percent, received fluticasone furoate. The cohort had a mean age of 63.1 years, was 35.4 percent male, and included just over half of patients at the most severe treatment step.

The researchers evaluated pneumonia across three tiers of severity: all pneumonia events requiring emergency department visits or hospitalization, pneumonia severe enough to require admission to a medical ward, and pneumonia requiring intensive care unit admission. Over the follow-up period, 1,675 patients, or 10.4 percent of the cohort, developed pneumonia, with nearly identical proportions in the two treatment groups: 10.2 percent among budesonide users and 10.5 percent among fluticasone users. Hospitalized pneumonia affected 8.9 percent of patients overall, while only 42 patients, roughly 0.3 percent, developed pneumonia severe enough to require intensive care.

Across every analytical framework the team applied, the results pointed in the same direction. Using budesonide as the reference group, the adjusted odds ratio for all pneumonia events among fluticasone users was 0.95, with a 95 percent confidence interval of 0.85 to 1.06 and a p-value of 0.32. The adjusted incidence rate ratio was 1.05, and the adjusted hazard ratio for time to first pneumonia event was 0.94, none of which reached statistical significance. For hospitalized pneumonia, the adjusted odds ratio was 0.95 and the adjusted hazard ratio 1.03, both non-significant. Even for the rarest and most severe outcome, pneumonia requiring ICU admission, the adjusted odds ratio of 1.08 and hazard ratio of 1.06 were statistically indistinguishable between the drugs. To guard against confounding, the team also performed propensity score matching on age, sex, treatment step, comorbidity burden, steroid dose, and vaccination status for influenza and pneumococcal disease; the matched analysis reproduced the null result. Subgroup analyses isolating fluticasone furoate and fluticasone propionate individually against budesonide likewise found no significant differences.

Why would an interclass difference so prominent in COPD vanish in asthma? The authors point to fundamental differences in the two patient populations. Patients with COPD who qualify for inhaled corticosteroids tend to be older, heavy smokers with multiple comorbidities and a history of exacerbations driven by respiratory pathogens, making them intrinsically vulnerable to pneumonia. Patients with asthma, by contrast, are generally younger, more often non-smokers, and carry fewer comorbidities, and steroid initiation in asthma is dictated by disease severity rather than exacerbation history. With a baseline pneumonia incidence of only about 10 percent over five years in this asthma cohort, the researchers argue that any true interclass difference, if it exists at all, is likely too small to carry meaningful clinical weight, even in a dataset of this size and with follow-up extending across five years.

The study does carry limitations worth noting. The cohort was overwhelmingly Chinese, which may limit generalizability to other populations, although the authors observe that COPD studies of the same question have yielded consistent findings across countries. Lung function parameters and symptom burden were not directly assessed, with treatment step serving as the recognized proxy for asthma severity, and mild pneumonia cases managed entirely in outpatient settings were excluded because such events are inconsistently coded in medical records, a trade-off the investigators made to preserve diagnostic validity. The study also included only adults, leaving pediatric populations, who face distinct viral pneumonia risks, as a target for future research.

For practicing clinicians, the practical message is straightforward. In moderate to severe asthma, the choice between budesonide-based and fluticasone-based fixed-dose combinations should be guided by asthma control, device preferences, and each drug’s broader side-effect profile, not by fear of pneumonia. The shadow cast by COPD safety data, it turns out, does not extend to the asthma clinic, and patients can take some comfort in knowing that the workhorse anti-inflammatory inhalers they depend on daily differ far less in infection risk than the older literature might have suggested.

Subject of Research: Comparative pneumonia risk of budesonide versus fluticasone inhaled corticosteroids among patients with moderate to severe asthma

Article Title: Comparing Pneumonia Risks of Budesonide with Fluticasone Among Patients with Asthma in Hong Kong: A Territory-Wide Retrospective Study

Article References: Kwok, W. C., Zhou, L., Ma, T. F., Ngai, S. M., Leung, R. Y. H., Tam, T. C. C., & Ho, J. C. M. (2026). Comparing Pneumonia Risks of Budesonide with Fluticasone Among Patients with Asthma in Hong Kong: A Territory-Wide Retrospective Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03776-0

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03776-0

Keywords: asthma, inhaled corticosteroids, budesonide, fluticasone, pneumonia, COPD, Hong Kong, GINA guidelines, retrospective cohort study, respiratory medicine, drug safety, propensity score matching