The case centers on a patient who, after receiving CAR T cell therapy, developed signs of profound neurological injury. Brain magnetic resonance imaging revealed abnormalities characteristic of immune effector cell-associated neurotoxicity syndrome, universally abbreviated as ICANS: fluid-attenuated inversion recovery sequences showed periventricular white matter hyperintensities involving the atrium and temporal horn of the lateral ventricles, while diffusion-weighted imaging demonstrated areas of cytotoxic edema within the hippocampi on both sides. But what made the case exceptional was the spinal imaging. T2-weighted magnetic resonance images of the spine disclosed a longitudinally extensive spinal cord lesion, with abnormal signal intensity extending over more than three vertebral body segments. Critically, the lesion showed no enhancement after gadolinium administration on post-contrast T1-weighted images.

That combination of findings, a long spinal cord lesion that refuses to light up with contrast, is diagnostically treacherous. In clinical practice, a longitudinally extensive T2 hyperintense lesion in the spinal cord is nonspecific and can be produced by infectious, autoimmune, or vascular processes. Acute autoimmune inflammation of the spinal cord, or ischemia-related breakdown of the blood-spinal cord barrier, typically produces contrast enhancement, because the damaged barrier allows the gadolinium to leak into the cord tissue. A non-enhancing lesion therefore sits uneasily with the classic picture of acute inflammatory myelitis. The Paris team reasoned that, given the concurrent brain lesions suggestive of ICANS and the exclusion of infectious causes, the most likely diagnosis was spinal cord involvement as a component of ICANS itself, a manifestation so rare that only a handful of cases have been described in the literature, and those published reports describe similar non-enhancing imaging features.

The first and most urgent diagnostic step the authors emphasize is the systematic exclusion of infectious myelitis. This is not a bureaucratic precaution. Patients who have undergone CAR T cell therapy are profoundly immunocompromised, both from the lymphodepleting chemotherapy that precedes the infusion and from the therapy’s effects on normal B cells and other immune populations. In such patients, opportunistic infections of the central nervous system are a constant threat. The authors single out viral etiologies that must always be considered: cytomegalovirus, herpes simplex virus, varicella-zoster virus, enteroviruses, and human herpesvirus-6, each of which can produce devastating spinal cord disease in the immunosuppressed host. In their patient, cerebrospinal fluid cultures and multiplex polymerase chain reaction testing were negative, making an infectious etiology unlikely and clearing the way for the diagnosis of ICANS-associated myelopathy.

Understanding why this matters requires appreciating what ICANS is and how it usually behaves. Immune effector cell-associated neurotoxicity syndrome is the most feared non-hematological toxicity of CAR T cell therapy, typically emerging days after infusion as the engineered cells expand and release inflammatory cytokines. It usually announces itself with aphasia, confusion, tremor, and, in severe cases, seizures, cerebral edema, and coma. Aseptic meningitis is a common feature, and brain imaging may show transient abnormalities. The syndrome is graded from I to IV, with grade IV representing life-threatening neurotoxicity. Standard management escalates from corticosteroids to the interleukin-1 receptor antagonist anakinra for severe disease. But the spinal cord has been largely absent from this picture, which is precisely why the Paris case is so valuable to the field.

The timing of spinal cord involvement poses its own diagnostic puzzle, and the authors are candid about this uncertainty. In patients with severe ICANS, concomitant severe encephalopathy frequently precludes a complete neurological examination. A patient who is obtunded or comatose cannot report numbness, weakness, or a sensory level, and the examiner cannot reliably test for the signs that would localize a spinal cord lesion. As a result, it is often impossible to determine when spinal cord symptoms first occur, or whether they emerged before, alongside, or after the encephalopathy. In the reported patient, cerebral and spinal cord involvement probably developed simultaneously, a synchrony that itself supports the idea that both represent facets of a single systemic neurotoxic process rather than two independent complications.

Therapeutically, the patient received the recommended treatment for grade IV ICANS: high-dose corticosteroids combined with anakinra, the interleukin-1 receptor antagonist that has become the mainstay of salvage therapy for steroid-refractory neurotoxicity. Beyond this standard regimen, however, the evidence base evaporates. The authors state plainly that there is no clear evidence supporting a specific therapeutic strategy for ICANS-associated myelopathy. Interventions that neurologists might reach for in other forms of acute myelitis, such as intravenous immunoglobulins or plasmapheresis, have no established role here, because the underlying biology of the spinal cord lesion remains obscure. Larger case series, the authors argue, are needed to define the optimal treatment and the prognosis of this rare manifestation.

The imaging findings deserve close attention from clinicians who will face similar dilemmas. The pattern reported here, a long T2-hyperintense cord lesion without contrast enhancement, occurring in a patient with hippocampal cytotoxic edema and periventricular white matter changes, effectively constitutes a signature that others can look for. The hippocampal involvement is particularly suggestive, because bilateral cytotoxic edema in the hippocampi has been described in severe CAR T cell neurotoxicity and reflects the vulnerability of this region to the inflammatory and possibly vascular disturbances that ICANS produces. When such brain findings are accompanied by a non-enhancing longitudinal cord lesion in a recently infused patient, ICANS-associated myelopathy moves to the top of the differential diagnosis, provided infection has been rigorously excluded.

The broader significance of the case lies in the growing recognition that CAR T cell neurotoxicity is not confined to the brain. As the therapy expands from refractory lymphomas and multiple myeloma into earlier lines of treatment and into autoimmune diseases, the population of exposed patients is growing rapidly, and rare complications become clinically meaningful at scale. Reports such as this one, published as part of the journal’s imaging series with practical tips for intensivists, serve as sentinels. They alert critical care physicians, neurologists, and hematologists that when a CAR T cell recipient deteriorates neurologically, the evaluation must extend beyond the cranial vault. Spinal imaging, cerebrospinal fluid analysis with multiplex pathogen testing, and careful correlation of brain and cord findings should be part of the diagnostic armamentarium.

For now, the message from the Paris team is one of disciplined caution. Infectious myelitis must be systematically ruled out before attributing a cord lesion to ICANS, because the treatments differ fundamentally and the stakes are enormous. The non-enhancing character of the lesion, while atypical for classic autoimmune myelitis, appears consistent across the few published cases of ICANS-associated myelopathy and may reflect a distinct pathophysiology, perhaps one that does not disrupt the blood-spinal cord barrier in the way conventional inflammation does. Until larger series clarify the mechanism, the optimal treatment, and the long-term prognosis of this unusual complication, the case stands as both a warning and a guide: the engineered immune cells that save lives can, in rare instances, reach beyond the brain, and clinicians must be ready to recognize when they do.

Subject of Research: Acute myelopathy as a rare manifestation of CAR T cell therapy-associated neurotoxicity

Article Title: Acute myelopathy following chimeric antigen receptor (CAR) T cell therapy: an unusual diagnostic challenge

Article References: Bois, A., Provost, C., Decroocq, J., & Benghanem, S. (2026). Acute myelopathy following chimeric antigen receptor (CAR) T cell therapy: an unusual diagnostic challenge. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08617-w

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08617-w

Keywords: CAR T cell therapy, ICANS, neurotoxicity, myelopathy, spinal cord, immune effector cell, MRI, encephalopathy, anakinra, corticosteroids, immunocompromised, intensive care

The research team, led by Xuetong Zhu and Jiancheng Xu of the First Hospital of Jilin University in Changchun, China, together with colleagues from several Jilin institutions, assembled an unusually large immunological dataset. The analysis included 112 peripheral blood mononuclear cell samples, which allowed the investigators to probe T-cell responses, and 3,202 serum samples, which provided the statistical power needed to characterize antibody profiles across health and disease states. Using enzyme-linked immunosorbent assay to quantify antibody titers and enzyme-linked immunospot assay to measure cellular reactivity, the researchers built a two-pronged picture of what remains of vaccinia-induced immunity years after the last dose was administered.

The cellular arm of the study delivered a sobering message. Among individuals with historical smallpox vaccination, T-cell responses were limited, and — perhaps most strikingly — no significant differences were observed between healthy participants and those living with disease. In other words, the cellular memory that once formed a critical line of defense against variola virus and its relatives has thinned to a low, relatively flat baseline across the population studied. This matters because cell-mediated immunity is generally considered the more durable component of protection against orthopoxviruses, and its scarcity in previously vaccinated adults suggests that historical vaccination status alone cannot be assumed to confer meaningful cellular protection today.

The humoral picture was more nuanced and more clinically revealing. Vaccinated individuals with comorbidities had significantly lower immunoglobulin G titers against the vaccinia virus Tianan strain than their healthy counterparts, a difference that reached strong statistical significance with P values below 0.001. When the researchers broke the disease groups down into chronic disease subgroups, the variations persisted, indicating that the erosion of antibody memory is not a uniform process but one shaped by the specific burden of illness a person carries. Antibody titers are the standard surrogate for neutralizing capacity against orthopoxviruses, so lower titers in comorbid groups translate directly into a plausible reduction in protective buffering.

Regression analyses sharpened the risk stratification. Chronic disease was associated with lower odds of high antibody positivity, with an odds ratio of 0.67 and a 95 percent confidence interval of 0.44 to 0.98. Cancer carried an even stronger signal, with an odds ratio of 0.58 and a confidence interval of 0.37 to 0.90. These figures suggest that people with cancer who were vaccinated decades ago are roughly 40 percent less likely to maintain high-level antibody positivity than comparable healthy individuals. At the same time, the proportion of individuals with negative neutralizing antibody responses decreased with age — consistent with more of the oldest cohort having been vaccinated — but remained higher among disease groups than among healthy participants at every comparison point.

Beyond clinical diagnoses, the study uncovered associations between routine laboratory markers and antibody levels, offering a biochemical window into why some vaccinated individuals retain stronger humoral memory than others. High-density lipoprotein cholesterol, often called good cholesterol, showed a positive association with antibody levels, as did aspartate aminotransferase, an enzyme commonly monitored as a marker of liver and cellular turnover. Cholinesterase, by contrast, displayed an inverse association with antibody titers. While such correlations do not establish causation, they hint that metabolic and hepatic status may modulate the persistence of vaccine-induced humoral immunity, and they raise the possibility that routinely collected blood chemistry could help clinicians estimate residual orthopoxvirus protection without specialized immunological testing.

The second half of the study moved from measurement to simulation. The team constructed an exploratory susceptible-infected-recovered-dead model — a classic epidemiological framework that tracks individuals through states of susceptibility, infection, recovery, and death — parameterized with published epidemiological values rather than observed outbreak data. Within this framework, they simulated hypothetical transmission scenarios among immunocompromised populations to explore how reduced immune competence might alter the shape of an orthopoxvirus outbreak. The authors are careful to frame this modeling as exploratory and hypothetical, but the exercise provides a structured way to think about vulnerability that cannot ethically or practically be studied in real outbreaks.

The simulated scenarios produced an age-stratified pattern that public health planners will recognize as a double burden. In the model, immunocompromised individuals aged 15 to 19 years showed higher simulated infection proportions, suggesting that younger immunocompromised people — many of whom were never vaccinated and may have weakened immune systems due to disease or treatment — could contribute disproportionately to transmission in a hypothetical outbreak. At the other end of the age spectrum, individuals aged 70 and above showed higher simulated mortality proportions, reflecting the compounding of advanced age, waning or absent immunity, and reduced physiological reserve. Together, the two ends of the simulated curve sketch a scenario in which an orthopoxvirus introduction could simultaneously stress pediatric and adolescent transmission control and geriatric intensive care capacity.

The authors conclude that individuals with historical smallpox vaccination do show detectable residual immune responses, but that these responses vary meaningfully across comorbidity groups and correlate with measurable laboratory markers. They further suggest that immunocompromised individuals may warrant further evaluation for potential orthopoxvirus susceptibility — a recommendation that carries practical weight given that mpox clade outbreaks continue to evolve and that smallpox vaccines, including modern non-replicating formulations, are being redeployed in some settings. The study does not claim that previously vaccinated people are unprotected, nor does it establish that the modeled outbreak dynamics would occur in reality; its value lies in quantifying the heterogeneity of residual immunity and in providing a transparent, parameterized starting point for preparedness planning.

What emerges from the combined evidence is a portrait of a partially protected world. The generation vaccinated before routine smallpox immunization ended carries measurable but uneven antibody memory, eroded most in those with chronic disease and cancer, and supported by cellular responses too limited to distinguish the sick from the healthy. Meanwhile, younger immunocompromised people who never received the vaccine represent a structurally susceptible population in whom simulated outbreaks spread more readily. As the authors note, these findings may inform future orthopoxvirus preparedness and prevention strategies — from targeted serological screening of comorbid vaccinees to prioritized vaccination of immunocompromised cohorts — and they underscore a broader lesson of post-eradication immunology: population immunity is not a switch that stays on, but a gradient that shifts with age, health, and time.

Subject of Research: Residual smallpox vaccine immunity and orthopoxvirus outbreak modeling in immunocompromised populations

Article Title: Residual immune responses after historical smallpox vaccination and exploratory outbreak modeling in immunocompromised populations

Article References: Zhu, X., Wang, J., Wang, X., Tu, Z., Zhou, Q., Zhu, Y., & Xu, J. (2026). Residual immune responses after historical smallpox vaccination and exploratory outbreak modeling in immunocompromised populations. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08907-3

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08907-3

Keywords: smallpox vaccination, orthopoxvirus, mpox, neutralizing antibodies, immunocompromised, vaccinia virus, humoral immunity, cellular immunity, SIRD model, antibody titers, chronic disease, outbreak modeling

The patient’s story began innocuously. He had been treated with rabbit anti-thymocyte globulin and cyclosporine between June and October 2024 for marrow hypoplasia, leaving him profoundly immunosuppressed and neutropenic, with absolute neutrophil counts hovering between 320 and 390 cells per microliter. A non-enhanced chest computed tomography scan performed at an outside facility showed consolidation in the right lung, and he was given empiric ciprofloxacin for presumed pneumonia. Notably, he had no fever and no respiratory symptoms at that stage, and laboratory markers including carcinoembryonic antigen, neuron-specific enolase, beta-D-glucan and Aspergillus antigen all came back unremarkable. In an immunocompromised host, however, consolidation is usually treated as infection until proven otherwise, and the initial workup proceeded along those lines.

The turning point came on Day 14, when a repeat non-enhanced chest CT showed marked worsening of the right lower lobe lesion, with a mixture of ground-glass opacity and consolidation, a new pleural effusion, and scattered nodules surrounded by halo signs. That radiologic pattern, in which a nodule is ringed by a rim of ground-glass attenuation, is classically associated with invasive pulmonary aspergillosis, although mucormycosis could not be excluded. A cough developed around the same time and a single fever of 38.1 degrees Celsius was recorded at admission, but the patient never required supplemental oxygen. Bronchoscopy on Day 15 revealed no endobronchial lesions, and the bronchoalveolar lavage fluid from the right anterior basal segment was xanthochromic, a yellowish discoloration that, in retrospect, signaled occult alveolar hemorrhage linked to infarction rather than the cloudy return typical of pneumonia.

Every microbiologic test came back negative. Bacterial and fungal cultures, galactomannan assays and viral polymerase chain reaction panels were all sterile, and a transbronchial lung biopsy showed only focal organizing pneumonia without fungal elements. Nevertheless, because the parenchymal disease was worsening, the clinical team initiated liposomal amphotericin B and piperacillin-tazobactam, a broad-spectrum antifungal and antibacterial combination. The lung lesion failed to improve. This disconnect between aggressive antimicrobial therapy and persistent radiologic disease should have been the first clear signal that the working diagnosis was wrong, and it set the stage for a more careful look at the pulmonary vasculature.

That look came indirectly. Concerned about the patient’s coexisting chronic kidney disease, clinicians obtained another non-enhanced chest CT on Day 20, which revealed a dilated main pulmonary artery, enlargement of the right-sided cardiac chambers and a pericardial effusion, a triad suggestive of pulmonary hypertension. A contrast-enhanced chest CT on Day 21 then delivered the answer: a low-attenuation filling defect in the right interlobar and lower lobar pulmonary arteries, with associated infarction of the lung tissue downstream. Anticoagulation was started immediately. Because the scan had not been performed with a dedicated pulmonary embolism protocol, CT pulmonary angiography was repeated on Day 27, showing that the filling defect persisted after a week of anticoagulation and had extended into the lobar branches. Its unilateral, expansile appearance raised a new and alarming possibility: pulmonary artery sarcoma, an exceptionally rare malignancy with an estimated incidence of only 0.001 to 0.03 percent.

Distinguishing a chronic organized thrombus from an intraluminal sarcoma is one of the classic dilemmas in pulmonary vascular imaging. Chronic thromboembolic pulmonary hypertension typically produces vessel narrowing or intraluminal webs, whereas sarcoma tends to appear as an expansile, lobulated mass that distends the artery. In this case, fluorodeoxyglucose positron emission tomography on Day 29 showed only mildly heterogeneous uptake within the lesion, with a maximum standardized uptake value of 2.9, a level that favored thrombus over tumor. Endobronchial ultrasound-guided transbronchial needle aspiration of the right lower lobe pulmonary artery, a technique highlighted in the report as a safe route for tissue acquisition, yielded whitish necrotic cores. Pathology described predominantly thrombotic material with only a few atypical cells, insufficient to exclude malignancy. Right heart catheterization confirmed precapillary pulmonary hypertension, and angiography demonstrated total occlusion of the right lower lobe pulmonary artery.

With the lesion persisting after nearly a month of anticoagulation and malignancy still on the differential, the team planned a pulmonary endarterectomy, a procedure that could serve as both treatment and definitive biopsy. Because the patient remained clinically stable without oxygen requirement or worsening breathlessness, the operation was scheduled electively. While awaiting surgery, however, his dyspnea gradually worsened and the pleural effusion grew, prompting readmission and an earlier operation on Day 87. Surgeons found extensive material filling the right pulmonary artery and dissected it distally into the lobar branches, consistent with level III disease in the UCSD surgical classification of endarterectomy findings. The decisive result came from histopathology: Brown and Brenn staining revealed Gram-positive cocci within the organizing thrombus, confirming a septic pulmonary artery thrombus. The patient later recalled a remote dental implant infection, a plausible source of the bacteremia that had seeded the vessel. He completed four weeks of ceftriaxone, and after an urgent re-exploration for postoperative bleeding, he recovered without further surgical complications.

The case is remarkable for what it lacked as much as for what it showed. A septic thrombus inside a major pulmonary artery would ordinarily be expected to produce overt sepsis or signs of infective endocarditis, yet this patient had essentially none of the classic systemic features. The report notes that septic pulmonary embolism can present with attenuated systemic manifestations, particularly in patients with prior antimicrobial exposure or immunosuppression, both of which applied here. Antibiotics given for the presumed pneumonia may have partially suppressed the inflammatory response, while the underlying immunosuppressive therapy blunted fever and other warning signs. The result was a vascular infection smoldering silently for weeks, masquerading first as pneumonia and then as an aggressive fungal process, and only unmasked when imaging of the pulmonary arteries was finally performed with contrast.

The authors distill several lessons that extend well beyond this single patient. Pulmonary consolidation that follows an atypical course or fails to respond to appropriate antimicrobials should prompt consideration of pulmonary infarction, and dedicated CT pulmonary angiography should be obtained early once a vascular etiology is suspected, rather than relying on non-enhanced or non-dedicated scans. A unilateral pulmonary artery filling defect that persists despite adequate anticoagulation, especially when accompanied by pulmonary hypertension, warrants evaluation for chronic thromboembolic disease and pulmonary artery malignancy. Metabolic imaging with FDG PET-CT and minimally invasive sampling through EBUS-guided needle aspiration can provide useful clues, but as this case demonstrates, they may remain non-diagnostic, and surgical pathology or endarterectomy may ultimately be required to settle the question.

For clinicians caring for the growing population of immunocompromised patients, the message is a sobering one. The xanthochromic bronchoalveolar lavage fluid, the early CT signs of pulmonary hypertension, and the relentless progression despite broad-spectrum therapy were all, in hindsight, pointing toward a vascular catastrophe rather than an infection. Recognizing those signals sooner could have shortened a diagnostic odyssey that stretched across nearly three months from first scan to definitive surgery. Septic organizing thrombus of the pulmonary artery remains a rare diagnosis, but as this case makes clear, it belongs on the differential for any immunocompromised patient whose lung lesion refuses to behave like pneumonia, and whose arteries tell a story the parenchyma has been hiding all along.

Subject of Research: Septic pulmonary artery thrombus causing pulmonary infarction in an immunocompromised patient

Article Title: Unilateral Pulmonary Artery Lesion in an Immunocompromised Patient

Article References: Lee, S., Lee, K. S., Jeong, D. Y., Lee, B., Lee, J., Jeong, D. S., Chang, S.-A., & Shin, S. H. (2026). Unilateral Pulmonary Artery Lesion in an Immunocompromised Patient. Respirology Case Reports, 14(10), Article e70778. https://doi.org/10.1002/rcr2.70778

Image Credits: AI Generated

DOI: 10.1002/rcr2.70778

Keywords: pulmonary artery thrombus, pulmonary infarction, immunocompromised, myelodysplastic syndrome, pulmonary hypertension, pulmonary endarterectomy, CT pulmonary angiography, FDG PET-CT, EBUS-TBNA, septic pulmonary embolism, pulmonary artery sarcoma, chronic thromboembolic disease

The research team, led by Joanne Reekie and Bette Liu, exploited Australia’s extraordinary national data infrastructure to answer two linked questions: whether the country’s zoster vaccination program actually reduced disease at the population level, and how well the current recombinant zoster vaccine protects the people it targets. Using the Person Level Integrated Data Asset managed by the Australian Bureau of Statistics, the investigators linked records from the Australian Immunisation Register, the Pharmaceutical Benefits Scheme, the Medicare Benefits Schedule and death registrations, with data available through 30 June 2025. Because zoster diagnoses are not captured directly in these registries, the team used dispensed prescriptions for antiviral drugs specifically indicated for zoster treatment, including aciclovir, valaciclovir and famciclovir, as a surrogate marker of disease.

The ecological arm of the study tracked quarterly antiviral prescription rates across the adult population from January 2014 to June 2025, spanning the entire history of Australia’s national zoster vaccination effort. That effort began in November 2016 with a single dose of the live-attenuated zoster vaccine, known by the brand name Zostavax, offered to people aged 70 with catch-up for those aged 71 to 79. The live vaccine was never an option for immunocompromised people because it contains a weakened but living virus. In June 2021 the adjuvanted recombinant zoster vaccine, Shingrix, became available in Australia, and in November 2023 it replaced the live vaccine on the National Immunisation Program, with free eligibility extended to everyone aged 65 and over and to adults aged 18 to 64 taking selected immunocompromising medications.

The prescription data told a striking temporal story. Rates of zoster antiviral dispensing among 70 to 79 year olds fell from 3.84 per 1000 population in the final quarter of 2016 to 2.61 per 1000 by early 2018, coinciding with the introduction of the live vaccine. After the recombinant vaccine joined the national program in late 2023, declines appeared in every eligible age group: rates in 65 to 69 year olds fell from 3.16 to 2.32 per 1000, in 70 to 79 year olds from 3.07 to 2.30 per 1000, and in those aged 80 and over from 3.79 to 2.81 per 1000 by mid-2025. Crucially, prescription rates among adults aged 18 to 64 remained essentially stable across the entire eleven-year observation window, a pattern consistent with the declines being driven by vaccination of the targeted older groups rather than by some population-wide shift.

Not every trend mapped neatly onto program milestones. Between late 2021 and mid-2023, prescription rates declined across all age groups, a period that corresponds to no change in zoster vaccination policy and to only limited private uptake of the newly available recombinant vaccine. The authors suggest the COVID-19 pandemic and reduced healthcare-seeking behaviour during that period as a plausible explanation. Rates in younger adults returned to pre-2021 levels by late 2023, while rates in those aged 65 and over continued downward, a divergence that aligns with the expanded recombinant vaccine eligibility. The data also carry a reassuring message about childhood chickenpox vaccination: despite hypotheses that reduced natural boosting with wild-type varicella might raise adult zoster risk, prescription rates among 18 to 49 year olds stayed low and stable throughout the study period.

To measure vaccine effectiveness directly, the team constructed two cohorts. The first comprised 4,488,937 adults aged 65 and over on 1 November 2023, the day the recombinant vaccine entered the national program. Most, 64.6 percent, had no record of zoster vaccination at baseline, while a third had received the older live vaccine, mostly those aged 70 and above who had been eligible under the earlier program. During a median follow-up of 607 days, 71,985 individuals, or 1.6 percent of the cohort, had a record of zoster antiviral treatment. Uptake of the new vaccine was substantial but incomplete: among those without prior recombinant vaccination, 42 percent received at least one dose during follow-up, and 35 percent completed the two-dose series by 30 June 2025, with a median interval of 98 days between doses.

The effectiveness estimates in this older cohort were solid. The incidence rate of zoster was 12.84 per 1000 person-years among unvaccinated individuals, compared with 4.94 per 1000 person-years among those who had received two doses of the recombinant vaccine. After adjustment for age, gender, general practitioner visit frequency, comorbidities, prior zoster treatment and immunocompromising medication use, two-dose effectiveness against treated zoster was 63 percent, with a single dose providing 54 percent. The older live vaccine performed considerably worse: 37 percent when given within the previous five years and only 20 percent when given more than five years earlier, a waning pattern that mirrors international evidence and underpins the global phase-out of the live vaccine. Effectiveness of the recombinant vaccine was consistent across the 65 to 69, 70 to 79 and 80-plus age strata, and rose slightly to 69 percent in a subgroup analysis restricted to people with no prior zoster diagnosis.

The second cohort examined 239,002 adults aged 18 and over who were immunocompromised by virtue of taking selected immunomodulatory or immunosuppressive medications for at least two consecutive months, ranging from moderately to highly immunocompromising therapies. This group fared distinctly worse on both counts. More than 80 percent were unvaccinated at baseline, and by the end of follow-up only 22 percent had completed two recombinant vaccine doses, though the figure concealed a sharp age divide: 44 percent among those 65 and over, who were eligible for free vaccination regardless, versus just 10 percent among those aged 18 to 64, whose eligibility for the moderately immunocompromising categories only opened in September 2024. Overall zoster incidence in this cohort was 17.59 per 1000 person-years, and two-dose effectiveness was 43 percent, with one-dose effectiveness of 36 percent and the live vaccine providing a mere 16 percent.

Most striking was the age gradient within the immunocompromised cohort. Two-dose effectiveness was 48 percent among those aged 65 and over but only 22 percent, with a confidence interval approaching zero, among those aged 18 to 64. The authors offer several non-exclusive explanations. Younger immunocompromised patients may genuinely mount weaker vaccine responses because they receive more potent immunosuppressive regimens; the study found that 41 percent of immunocompromising medications dispensed to the younger group were classified as highly immunocompromising, compared with 31 percent in the older group. Alternatively, the surrogate outcome may perform differently across ages, since previous Australian research suggests general practitioners are less likely to prescribe zoster antivirals to younger patients, which could dilute the measured signal. The 43 percent estimate also sits below the roughly 60 percent efficacy reported in trials that focused on narrower immunocompromised populations such as transplant recipients and people with haematological malignancy, underscoring the value of studying a broad, heterogeneous medicated population.

The authors are candid about the limitations inherent in registry-based surveillance. Vaccination reporting to the Australian Immunisation Register only became mandatory in 2021, so some live-vaccine recipients may have been misclassified as unvaccinated, biasing effectiveness estimates downward. The antiviral prescription outcome may capture suspected as well as confirmed zoster, and milder cases that went untreated would have been missed entirely, both of which would push estimates toward the null. The ecological trends, while compelling, are not a direct measure of incidence because repeat prescriptions across different months were counted again. Even so, the convergence of two independent analytical approaches, population-level prescription declines timed to program changes and cohort-based effectiveness estimates, provides mutually reinforcing evidence that targeted zoster vaccination is working. The clear message for policy is twofold: the recombinant vaccine delivers meaningful protection to older adults, but immunocompromised people, who face the highest risks, receive weaker protection and are vaccinated at suboptimal rates, demanding greater provider awareness, stronger uptake efforts and continued monitoring of how long protection lasts in this vulnerable group.

Subject of Research: Population-based evaluation of herpes zoster vaccine impact and effectiveness in older and pharmacologically immunocompromised adults in Australia

Article Title: The epidemiological impact and effectiveness of herpes zoster vaccination among older and pharmacologically immunocompromised adults: a population-based observational study

Article References: Reekie, J., Stepien, S., Li-Kim-Moy, J., Simpson, A., Macartney, K., & Liu, B. (2026). The epidemiological impact and effectiveness of herpes zoster vaccination among older and pharmacologically immunocompromised adults: a population-based observational study. The Lancet Regional Health – Western Pacific, 74, Article 101982. https://doi.org/10.1016/j.lanwpc.2026.101982

Image Credits: AI Generated

DOI: 10.1016/j.lanwpc.2026.101982

Keywords: herpes zoster, shingles, recombinant zoster vaccine, Shingrix, vaccine effectiveness, immunocompromised, older adults, Australia, National Immunisation Program, postherpetic neuralgia, varicella zoster virus, pharmacoepidemiology

The patient’s blood counts told the first part of the story. He was severely anemic and profoundly neutropenic, with an absolute neutrophil count of just 150 cells per microliter—far below the threshold of 500 cells per microliter that clinicians regard as a major risk factor for invasive aspergillosis. Neutrophils are the body’s first line of defense against filamentous fungi, engulfing and destroying inhaled spores before they can germinate into invasive hyphae. When chemotherapy strips that defense away, ubiquitous environmental molds that most people breathe in daily without consequence can colonize and invade tissue with alarming speed. Prolonged neutropenia lasting more than 20 days is among the strongest known predisposing factors, and the cumulative risk of invasive aspergillosis climbs to roughly 70 percent after 34 days of persistent neutropenia in vulnerable patients.

What happened next is what makes this case remarkable. A chest computed tomography scan revealed a mass-like lesion along the posterior wall of the trachea, just below the suprasternal notch. Critically, the scan showed no evidence of involvement of the lung parenchyma itself—the tissue where pulmonary aspergillosis almost always announces itself. Invasive pulmonary aspergillosis, the most feared form of the disease, typically produces nodules, halos of hemorrhage, or cavitary lesions within the lung tissue, and radiologists use these patterns to guide early treatment. Here, the lungs appeared spared. The infection had instead declared itself as a solitary, obstructing lesion inside the central airway, a pattern that mimics an endobronchial tumor or an aspirated foreign body far more than a fungal infection.

Flexible bronchoscopy settled the question of what was occupying the trachea, though not before revealing how dangerous the situation had become. The scope encountered a whitish, irregular endoluminal mass with elongated, intertwined projections and a pseudomembranous appearance—classic visual features of fungal growth—situated in the mid-trachea. The lesion was obstructing enough that the bronchoscope could not be advanced beyond it, meaning the medical team could not visually assess the distal airways for further disease, mucus impaction, or more extensive tracheobronchial involvement. Notably, the visible mucosa showed no overt invasion, necrosis, or active bleeding, and biopsies were taken without complication.

Laboratory analysis of the sampled tissue provided the definitive answer. Microscopy demonstrated septate hyphae branching at acute angles of approximately 45 degrees—the morphological signature of Aspergillus species—and polymerase chain reaction testing confirmed Aspergillus fumigatus as the causative organism. That identification is hardly surprising from an epidemiological standpoint: A. fumigatus accounts for more than 90 percent of human aspergillosis cases. The fungus is found everywhere—soil, decaying vegetation, water, food, and air—and infects hosts almost exclusively through inhalation of airborne spores, which helps explain why the respiratory tract bears the brunt of disease. Research also suggests A. fumigatus adheres to airway epithelium more effectively than related species such as A. flavus or A. niger, potentially giving it a particular advantage in colonizing the tracheobronchial tree.

Treatment was initiated promptly with amphotericin B and voriconazole, the workhorse antifungals for invasive aspergillosis. It did not matter. The patient deteriorated rapidly and died of respiratory failure within 36 hours of diagnosis. The authors of the report acknowledge that the precise mechanism of this fulminant collapse remains uncertain. The obstructing tracheal lesion itself likely played a central role—endobronchial fungal proliferation can critically narrow the airway lumen and precipitate respiratory failure—but the inability to examine beyond the obstruction means distal airway spread could not be excluded. In a patient with essentially no neutrophil defense, the authors note, multiple converging factors may have driven the fatal outcome.

The rarity of this presentation underscores its diagnostic difficulty. Endobronchial aspergillosis, defined by endoluminal fungal growth within the tracheobronchial tree, is an uncommon manifestation of Aspergillus disease. A 2019 review by Ngu and colleagues identified only 28 documented cases worldwide, most occurring in Asian males with a mean age of 58 years, and a separate series described by Huang and colleagues found 17 cases with similar demographics. The condition is frequently discovered incidentally during bronchoscopy performed for other reasons, such as evaluating hemoptysis. Symptoms—fever, breathlessness, chest pain, cough, and bleeding—are nonspecific, and risk factors include any form of immunosuppression as well as underlying lung disease. In a 2011 series of ten patients reported by Ma and colleagues, all had identifiable predisposing conditions such as tuberculosis, lung cancer, or foreign body aspiration, and only two had concurrent parenchymal lung involvement, a pattern echoed by the present case.

The stakes of missing or delaying diagnosis are stark. Among patients with severe airway aspergillosis who require mechanical ventilation, mortality reaches 94 percent, compared with 25 percent among those who do not—a difference that reflects both advanced disease at presentation and the mechanical consequences of airway obstruction. Diagnosis itself is far from straightforward. The traditional gold standard, fungal culture, is limited by the difficulty of obtaining adequate samples from hemodynamically unstable patients, by coagulopathies such as thrombocytopenia that make biopsy risky, and by false-negative results in patients already receiving antifungal therapy. Indirect methods fill some of the gap: galactomannan detection in serum or bronchoalveolar lavage fluid shows reasonable reliability in hematologic malignancy, though its sensitivity ranges widely from 44 to 90 percent, and false positives occur with certain antibiotics and with dimorphic fungal infections. Beta-D-glucan testing, meanwhile, lacks specificity for aspergillosis altogether.

Treatment of endobronchial aspergillosis remains unstandardized, with management individualized case by case. Most clinicians favor combining systemic antifungal therapy with interventional bronchoscopy to debulk obstructing lesions, and favorable outcomes have been reported with bronchoscopically guided resection combined with drug therapy. Some experts have argued for conservative approaches, noting that systemic agents may penetrate airway lesions poorly, while intolerance or resistance to azoles, or competing infections, can push clinicians toward surgical resection. The pharmacology is also evolving: liposomal amphotericin B carries less nephrotoxicity than the deoxycholate formulation, but adverse effects including renal tubular acidosis, hypomagnesemia, and hypokalemia have shifted general clinical preference toward azoles and echinocandins for pulmonary disease.

The authors are candid about the limits of their own report. Histopathological assessment was confined to the obstructing endoluminal lesion; because of the patient’s critical condition and the risk of procedure-related complications, no biopsies were taken from the tracheal wall or cartilage. That means direct evidence of mucosal, submucosal, or cartilaginous invasion was never obtained, and the lesion could not be definitively classified as invasive or necrotizing tracheobronchitis rather than more superficial endobronchial disease. The pseudomembranous bronchoscopic appearance, the profound neutropenia, and the explosively fatal course all hint at a more aggressive process, but certainty was impossible. What the case establishes beyond doubt is the clinical lesson the authors emphasize: endobronchial Aspergillus infection belongs on the differential for any immunocompromised patient with airway obstruction, even when chest imaging shows the lungs themselves are clear. In this patient, an isolated tracheal lesion—invisible to the usual radiologic playbook—was enough to kill within two days of identification, a reminder that in the profoundly neutropenic host, the absence of parenchymal disease offers no reassurance at all.

Subject of Research: A fatal case of isolated endobronchial Aspergillus fumigatus infection in a neutropenic lymphoma patient without lung parenchymal involvement

Article Title: Endobronchial Aspergillosis Presenting as an Isolated Airway Lesion in an Immunocompromised Patient

Article References: Sadeghi, M., Sadat Hosseini Khajouei, F., GhanbarAliAkhavan, H., & Soleimani, A. M. (2026). Endobronchial Aspergillosis Presenting as an Isolated Airway Lesion in an Immunocompromised Patient. Respirology Case Reports, 14(9), Article e70701. https://doi.org/10.1002/rcr2.70701

Image Credits: AI Generated

DOI: 10.1002/rcr2.70701

Keywords: aspergillosis, Aspergillus fumigatus, endobronchial aspergillosis, neutropenia, immunocompromised, bronchoscopy, tracheal obstruction, invasive fungal infection, lymphoma, chemotherapy, respiratory failure, case report