Fungal invader strikes diabetic patients: review maps deadly aspergillosis risk

Invasive aspergillosis has long been understood as a menace confined to the profoundly immunosuppressed: patients battling leukaemia, enduring months of neutropenia, or recovering from solid organ transplantation. A new scoping review published in BMC Infectious Diseases now forces clinicians to widen that mental map. Drawing on four and a half decades of published cases, researchers from Makerere University’s School of Medicine in Kampala, Uganda, have assembled the most systematic picture to date of a fungus that appears to exploit diabetes mellitus as a gateway into the human body, often with devastating consequences for the sinuses, the skull base and the brain.

The review, led by Kaweesi Calvin Nantalaga and Alice Nantege, followed the PRISMA extension for scoping reviews and searched PubMed/MEDLINE for records published between 1980 and 2026, supplementing the primary search with the Web of Science Core Collection, Scopus and hand-searching of reference lists. After screening 1322 records in PubMed/MEDLINE and a further 3949 unique records retrieved by the supplementary searches, the team identified 55 cases of invasive aspergillosis in which diabetes mellitus stood as the principal risk factor. Each case was assessed against the 2020 EORTC/MSGERC definitions, the internationally accepted standard for classifying invasive fungal disease, with a crucial modification: because diabetes is not a recognised EORTC/MSGERC host factor, probable cases had to be classified using modified criteria.

The demographic profile of the affected patients is striking. The median age was 63 years, with cases ranging from a child of six to adults as old as 84. Among patients whose sex was reported, 65.3 percent were male. Geographically, the literature is dominated by Asia, which accounted for 60 percent of all cases, a distribution the authors suggest may reflect both genuine epidemiological patterns, including the enormous and often underdiagnosed diabetic populations of South and East Asia, and publication practices that have concentrated case reporting in certain regions.

Perhaps the most clinically consequential finding concerns anatomy. Invasive aspergillosis in diabetic patients shows a marked predilection for the nose, paranasal sinuses and orbit: rhino-orbital and sinonasal disease accounted for 43.6 percent of cases, far ahead of pulmonary disease at 14.5 percent and central nervous system involvement at 12.7 percent. This pattern echoes what clinicians have observed for decades with another fungus, the mould Rhizopus, which causes mucormycosis, a feared complication of diabetic ketoacidosis. The new review suggests that Aspergillus behaves in a disturbingly similar fashion when it encounters the metabolic terrain of poorly controlled diabetes, ascending from the nasal mucosa along vessels and nerves toward the orbit and cranial cavity.

The technical reason for this tropism lies in the interplay between fungal virulence and diabetic physiology. Aspergillus species, above all Aspergillus fumigatus, the most frequently identified organism in this review, invade tissue through angioinvasion, colonising and destroying blood vessels, which produces infarction, necrosis and rapid spread. Hyperglycaemia impairs neutrophil chemotaxis, phagocytosis and oxidative killing, the very cellular defences that normally hold inhaled conidia in check. Acidosis, which accompanies decompensated diabetes, further disables complement activity and iron sequestration. Where glycaemic status was documented in the reviewed cases, most patients had poorly controlled diabetes, reinforcing the association between metabolic derangement and fungal invasion.

Diagnostic practice across the 55 cases revealed a sobering gap between modern non-culture diagnostics and the realities of this population. Galactomannan testing and Aspergillus polymerase chain reaction, the assays that anchor mycological evidence in haematology patients, contribute little here, partly because diabetic patients with rhino-orbital disease often present with localised, tissue-destructive infection rather than the angioinvasive pulmonary disease in which these tests perform best. The authors conclude that tissue-based diagnosis, obtained by biopsy where it can be done safely, is likely to be of decisive value, since histopathological demonstration of septate hyphae with acute-angle branching, combined with culture or molecular identification, was the pathway by which the overwhelming majority of cases achieved diagnostic certainty.

That certainty is not trivial. In this review, 90.9 percent of cases were proven invasive aspergillosis under EORTC/MSGERC criteria, with the remaining 9.1 percent classified as probable using the modified framework. This unusually high proportion of proven diagnoses reflects the fact that most reported patients underwent surgical debridement or biopsy, procedures that simultaneously provide tissue for the laboratory and remove necrotic, infected material. The review thus implicitly outlines a standard of care for diabetic patients with suspected sinonasal fungal invasion: urgent imaging of the sinuses, orbits and brain, followed by prompt tissue acquisition and early antifungal therapy, typically with voriconazole, which remains the guideline-endorsed first-line agent against Aspergillus.

The outcome data carry a clear warning. All-cause mortality across the 51 cases with a known outcome was 33.3 percent, meaning one in three patients died. Death clustered in the most aggressive anatomical presentations: cardiovascular involvement, disseminated disease, and pulmonary aspergillosis carried the highest fatality. The numbers also illustrate a bias inherent to scoping reviews of published cases, since fatal and spectacular cases are more likely to be written up than routine recoveries. Even allowing for that bias, the mortality figure for an infection classically considered rare outside haematology units demands that emergency physicians, ophthalmologists, otolaryngologists and endocrinologists alike reconsider how quickly they entertain the diagnosis.

The clinical message distilled by the authors is a plea for suspicion. A diabetic patient, frequently one whose glucose control has slipped, presenting with invasive sinonasal, cerebral or pulmonary disease should be regarded as a potential aspergillosis case until proven otherwise. Warning signs include facial pain and numbness, proptosis, vision loss, cranial nerve palsies, black necrotic turbinate mucosa, and pulmonary infiltrates that fail to respond to antibacterial therapy. In such patients, delaying antifungal therapy while pursuing alternative explanations can be fatal, because angioinvasion converts every day of delay into additional irreversible tissue death.

The review also exposes gaps in the evidence base that only prospective research can fill. Fifty-five cases across four decades is a small and heterogeneous corpus, assembled largely from case reports and case series, and the authors deliberately excluded reviews, non-invasive fungal forms, COVID-19-associated aspergillosis and cases driven by competing immunosuppression such as neutropenia or transplantation. The absence of diabetes from the EORTC/MSGERC host-factor list means that probable cases in this population exist in a diagnostic grey zone, a limitation the modified criteria only partly resolve. Larger multinational registries, standardised reporting of glycaemic control and antifungal regimens, and outcome data free from publication bias would sharpen the picture considerably. Until then, this scoping review stands as the clearest account yet of a fungal threat that diabetes quietly unlocks, and as a reminder that in medicine the most dangerous infections are sometimes the ones appearing in patients no one thought to worry about.

Subject of Research: Invasive aspergillosis complicating diabetes mellitus, characterised by rhino-orbital predominance, tissue-based diagnosis and substantial mortality.

Article Title: Invasive aspergillosis complicating diabetes mellitus: a scoping review

Article References: Nantalaga, K. C., & Nantege, A. (2026). Invasive aspergillosis complicating diabetes mellitus: a scoping review. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14503-z

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14503-z

Keywords: invasive aspergillosis, diabetes mellitus, rhino-orbital aspergillosis, Aspergillus fumigatus, scoping review, EORTC/MSGERC criteria, mortality, fungal infection, poorly controlled diabetes, tissue-based diagnosis, BMC Infectious Diseases, Invasive