The European Organisation for Research and Treatment of Cancer and the Mycoses Study Group, whose joint criteria have anchored invasive fungal disease research for decades, sort suspected cases into three tiers: possible, probable, and proven invasive aspergillosis. Host factors such as neutropenia, steroid exposure, and prior stem cell transplantation are weighed alongside mycological evidence, typically galactomannan antigen detection or culture, and clinical imaging features like the halo sign or air-crescent sign on computed tomography. In the Istanbul cohort, only a single patient, 0.6 percent, met the strictest proven category. Fifty-one patients, 31.9 percent, were classified as probable, while 87 patients, 54.4 percent, fell into the possible category. Critically, 21 patients, or 13.1 percent, could not be classified at all despite clinical suspicion strong enough that the investigators judged no alternative etiology could explain their findings.

That unclassified group is the study’s most provocative finding. These were patients whom experienced infectious diseases physicians believed had invasive pulmonary aspergillosis, yet they failed to satisfy the formal criteria, often because they lacked the canonical host factors or the characteristic radiological patterns. The authors argue that such cases indicate the EORTC/MSG criteria should be reviewed, particularly for patients outside the classical hematologic risk groups, because rigid application risks delaying clinical decision-making. In a disease where every day of delayed antifungal therapy can be fatal, a diagnostic framework that leaves more than one in ten clinically suspected cases in limbo is more than an academic inconvenience; it is a potential barrier to timely treatment.

The cohort itself reflected the changing face of the disease. Of the 160 patients, 97 were male and the mean age was 51.39 years, with a standard deviation of 14.27. Three quarters of the patients, 120 in total, had an underlying hematologic diagnosis, and within this group 38 had received allogeneic stem cell transplants while 25 had undergone autologous transplantation. Yet the remaining 40 patients had no hematologic condition at all, representing the non-classical populations, including critically ill and otherwise immunocompromised individuals, in whom aspergillosis is increasingly recognized. Graft-versus-host disease, the immunological complication of allogeneic transplantation in which donor immune cells attack recipient tissues, was significantly more frequent among patients classified as proven or probable, a statistically meaningful association with a p value of 0.042 that fits the biology, since graft-versus-host disease and its steroid treatment compound immunosuppression.

Imaging told its own nuanced story. Computed tomography findings consistent with the EORTC/MSG clinical criteria were present in 144 patients, 90 percent of the cohort, which on the surface suggests the radiological arm of the framework performs well. But the details mattered. Cavity formation, a late and destructive pattern of fungal invasion, was significantly more frequent among patients with mycological evidence of infection, with a p value of 0.037. More troubling was the finding that prolonged corticosteroid use was associated with non-criteria CT patterns, with a p value of 0.048. In other words, patients on long-term steroids, a growing population spanning transplant recipients, oncology patients, and those with autoimmune disease, often did not display the textbook halo signs and nodules the criteria expect. Their infections presented atypically, slipping through the radiological net.

Treatment patterns in the cohort also tracked with the diagnostic categories. Voriconazole, the triazole antifungal that guidelines favor as first-line therapy for invasive aspergillosis, was more often chosen as initial treatment in patients with clinical imaging evidence, a statistically significant association with a p value of 0.034. This suggests that clinicians anchor their therapeutic decisions on visible pulmonary lesions, which may explain why patients lacking criteria-consistent imaging face diagnostic and therapeutic delays. The authors also highlight a practical constraint: invasive diagnostic procedures such as bronchoscopy with bronchoalveolar lavage are often difficult or impossible in the sickest patients, underscoring the need for reliable non-invasive diagnostic methods that could confirm infection without subjecting fragile patients to risky procedures.

The mortality data are sobering. Six-week all-cause mortality stood at 21.2 percent and 12-week mortality at 31.9 percent, figures broadly consistent with published hematologic-malignancy cohorts, which typically report mortality in the range of 25 to 35 percent. But over the full follow-up period, 107 of the 160 patients died, a 66.9 percent overall mortality rate, with a median survival of 240 days. The authors note that this figure is higher than in hematologic cohorts but comparable to intensive care unit and non-hematologic populations, reinforcing the point that aspergillosis arising in atypical hosts carries a prognosis at least as grim as the classical one. The comparison also implies that deaths in this heterogeneous group were driven not only by the fungus itself but by the burden of underlying disease, a distinction with real consequences for how trials and outcome measures are designed.

Two predictors of death emerged from the analysis. Patients who died were significantly older than survivors, with a p value of 0.029, consistent with the accumulated vulnerabilities of advanced age. More intriguingly, pleural effusion, the accumulation of fluid in the space surrounding the lung, visible on chest CT, was associated with death, with an odds ratio of 2.326 and a 95 percent confidence interval of 1.156 to 4.681, yielding a p value of 0.018. However, the association lost significance when the analysis was restricted to the 6-week and 12-week timepoints. The authors interpret this pattern carefully: pleural effusion appears to signal a comorbidity-driven rather than IPA-specific prognostic risk, marking patients whose overall physiological reserve is compromised rather than those in whom the fungal infection itself is uniquely aggressive. It is a subtle but important distinction for clinicians weighing prognosis at the bedside.

The study’s design carries the usual caveats of retrospective cohort research. Classification depended on records assembled for clinical rather than research purposes, and the single-center design limits generalizability, even if the center is a major referral hospital. The authors received no external funding and declared no competing interests, and the work was approved by the Clinical Research Ethics Committee of Istanbul University Istanbul Faculty of Medicine. Still, the scale of the cohort, 160 patients with findings unexplained by any other etiology, gives the findings weight, and the message is consistent with a growing international conversation about whether diagnostic criteria built around neutropenic hematology patients can serve an era in which aspergillosis strikes influenza patients, COVID-19 survivors, steroid-treated transplant recipients, and the critically ill.

What emerges from Istanbul is a portrait of a disease outpacing its diagnostic tools. The EORTC/MSG criteria remain indispensable for standardizing clinical trials and enabling comparison across studies, but this real-world cohort shows their limits: most patients cluster in the weakest possible category, a substantial minority escape classification entirely, and the radiological signatures the criteria demand may be absent precisely in the growing population of corticosteroid-treated patients. With overall mortality approaching 67 percent and median survival measured in months, the stakes of closing that gap are high. The authors’ call is twofold: maintain vigilance and early diagnosis even when criteria are not met, and invest in non-invasive diagnostics that can confirm infection quickly in patients who cannot undergo invasive sampling. Until then, clinicians facing a suspicious lung lesion in an atypical host may need to trust their clinical judgment as much as the checklist.

Subject of Research: Real-world performance of EORTC/MSG diagnostic criteria and mortality predictors in invasive pulmonary aspergillosis

Article Title: Invasive pulmonary aspergillosis in a heterogeneous patient cohort: real-world performance of EORTC/MSG criteria and predictors of mortality

Article References: Alp, E., Bali, E. A., Evlice, O., Çağatay, A., Yavuz, S. Ş., & Eraksoy, H. (2026). Invasive pulmonary aspergillosis in a heterogeneous patient cohort: real-world performance of EORTC/MSG criteria and predictors of mortality. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14567-x

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14567-x

Keywords: invasive pulmonary aspergillosis, EORTC/MSG criteria, fungal infection, diagnostic criteria, mortality, pleural effusion, corticosteroids, computed tomography, voriconazole, stem cell transplantation, hematologic malignancy, survival analysis

The research team, led by Elahe Meftah and colleagues at Amir Oncology Teaching Hospital in Shiraz, combed through medical records of immunocompromised children under 18 who were screened for invasive pulmonary aspergillosis between April 2016 and December 2023. Their analysis focused on 141 children classified as having proven or probable disease according to established diagnostic criteria. The median age was just eight years, and nearly two thirds of the patients were male. Only a small fraction, 14.2 percent, had definitively proven infection confirmed by direct demonstration of the fungus, underscoring how difficult this diagnosis remains even in specialized centers. Cases labeled as possible aspergillosis were analyzed separately and descriptively, keeping the main cohort diagnostically rigorous.

One of the study’s central questions was what chest computed tomography actually reveals in children with this infection, and how those images relate to survival. Radiologists reviewed the available scans using predefined criteria, and a clear hierarchy of findings emerged. Pulmonary nodules, rounded shadows that mark where the fungus has invaded lung tissue, were by far the most common abnormality, present in 75 of the 141 patients. Consolidation, the dense opacification of lung tissue typically seen in pneumonia, came second at 44 patients. The famous halo sign, a nodule surrounded by a rim of ground-glass opacity that radiologists consider a hallmark of early invasive aspergillosis, appeared in 37 patients. Ground-glass opacities and pleural effusion, fluid around the lungs, each turned up in 16 patients.

The pattern of co-occurrence was equally informative. When children had nodules, those nodules most frequently appeared alongside the halo sign, with 33 patients showing both features simultaneously. This makes biological sense: the halo represents hemorrhage around a fungal lesion, and its frequent pairing with nodules reflects the angioinvasive nature of Aspergillus, which seeds blood vessels and starves surrounding tissue. For diagnostic purposes, the study confirms that CT remains a cornerstone of disease detection and characterization, giving clinicians a visual map of how far the infection has spread. What the scan could not do, however, was predict who would survive.

That was the study’s most striking twist. Among the 136 patients included in the survival analysis, 41 deaths occurred during follow-up. The researchers estimated survival at 96 percent at four weeks after diagnosis, but that figure fell to 66.3 percent by the end of follow-up, a sobering trajectory that illustrates the delayed toll the infection takes on fragile patients. When the team fed CT variables, including the presence of nodules, the total nodule burden, and nodule size, into multivariable Cox proportional hazards models alongside laboratory markers, none of the radiological features showed a significant association with survival. The pictures told doctors where the fungus was, but not where the patient was headed.

The blood tests told a different story. Higher serum galactomannan, a sugar molecule released by growing Aspergillus hyphae and detected through a widely used enzyme immunoassay, independently predicted mortality, with a hazard ratio of 1.06 and a 95 percent confidence interval of 1.02 to 1.10, statistically significant at p below 0.001. In practical terms, every incremental rise in galactomannan corresponded to a measurable increase in the risk of death, likely reflecting the sheer fungal load multiplying inside the lungs and spreading through the bloodstream. Because galactomannan is shed by viable fungus, serial measurements essentially track the living enemy in real time, a capability no static imaging study can match.

C-reactive protein, the classic inflammatory sentinel produced by the liver in response to systemic inflammation, proved to be an equally powerful prognostic marker. Each unit increase in CRP carried a hazard ratio of 1.02, with a confidence interval of 1.01 to 1.03 and p below 0.001. While a hazard ratio per single unit may sound modest, CRP values in sick children routinely range across hundreds of units, so the cumulative effect on risk is substantial. Elevated CRP in this setting signals an uncontrolled inflammatory storm accompanying the infection, a process known to drive tissue damage and organ failure independent of the pathogen itself. Together, the two biomarkers capture both sides of the lethal equation: how much fungus is present and how violently the body is responding.

The authors’ conclusion is carefully framed and clinically meaningful. Chest CT, they write, primarily supported disease detection and radiologic characterization, whereas serum galactomannan and CRP demonstrated greater prognostic value for mortality risk stratification within diagnosed invasive pulmonary aspergillosis. This distinction matters because diagnostic and prognostic tools serve different purposes at the bedside. A scan answers the question of whether the disease is present and what it looks like; biomarkers answer the question of how the patient is likely to fare. The study suggests that once a diagnosis is established, clinicians should look to repeated blood tests, not follow-up imaging, to gauge trajectory and intensity of therapy.

Several secondary analyses enriched the picture. The researchers examined predictors of nodules and nodule burden, probing which factors drove the most characteristic radiologic manifestation of the disease. While the source data abstracts these details, their inclusion signals the team’s effort to understand the biology behind imaging findings rather than merely cataloging them. Kaplan-Meier survival estimates anchored the mortality analysis, providing clear time-to-event curves that clinicians can interpret intuitively, and the Cox models adjusted for multiple variables simultaneously to isolate the independent contribution of each marker.

The study carries the usual caveats of retrospective, single-center research. All patients came from one oncology hospital in Shiraz, and practice patterns, host populations, and diagnostic thresholds elsewhere may differ. Not every child had a CT scan available for review, and biomarker values were drawn from routine clinical testing rather than a standardized protocol. Still, the cohort size of 141 children with proven or probable disease is substantial for a condition that remains rare and hard to diagnose, and the consistency of the statistical findings lends weight to the conclusions. For a disease in which early risk stratification can mean the difference between aggressive antifungal therapy and a fatal outcome, the message is potent: in children with invasive pulmonary aspergillosis, what is in the blood may matter more than what is on the scan.

Subject of Research: Prognostic value of chest CT findings and serum biomarkers for mortality in pediatric invasive pulmonary aspergillosis

Article Title: Chest CT findings and biomarker predictors of mortality in pediatric invasive pulmonary aspergillosis: a retrospective cohort study

Article References: Meftah, E., Mirbagheri, S. S., Reihani, Y., Jafarian, H., Hamzavi, S. S., Abbasi, A., Khajeh, S., Naseri, A., Nazemosadat, S. M. A., Habibzadeh, A., Haghshenas, A., Abdipour Mehrian, S. R., & Amanati, A. (2026). Chest CT findings and biomarker predictors of mortality in pediatric invasive pulmonary aspergillosis: a retrospective cohort study. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14512-y

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14512-y

Keywords: invasive pulmonary aspergillosis, pediatric oncology, chest CT, galactomannan, C-reactive protein, mortality, fungal infection, immunocompromised children, halo sign, prognostic biomarkers, retrospective cohort, Aspergillus