Paroxysmal cold hemoglobinuria occupies a distinctive niche in hematology because of the peculiar behavior of the antibody responsible for it. The disorder is mediated by so-called biphasic Donath-Landsteiner antibodies, which have the unusual property of attaching themselves to red blood cells only at cold temperatures, such as those found in the capillaries of the extremities, and then triggering the destruction of those cells once they return to the warmer core of the body. This two-temperature mechanism gives the antibodies their biphasic character and explains the classic clinical hallmark of the disease: the passage of dark, hemoglobin-laden urine, often after exposure to cold. The antibody typically targets the P antigen, a carbohydrate structure found on the surface of red blood cells, and once bound it recruits complement, a cascade of blood proteins that punches lethal holes in the cell membrane, causing rapid and sometimes massive destruction of circulating red cells.

In children, PCH most often presents as a transient, self-limited illness that follows a viral infection and resolves on its own or with supportive care. In adults, the disease is considerably rarer, and when it does appear it raises two distinct possibilities: a post-infectious trigger, similar to the pediatric pattern, or an underlying hematologic malignancy that has dysregulated the immune system. The distinction matters enormously for management, because the adult form can be severe, relapsing, and tied to a serious underlying condition. The new report adds an important data point to the small literature on adult PCH by documenting a severe, life-threatening episode in an older adult and by carefully dissecting the diagnostic workup that confirmed the disease.

The patient at the center of the report was a 69-year-old man who first developed shingles, the painful blistering rash caused by reactivation of latent varicella-zoster virus that has remained dormant in nerve ganglia since a childhood chickenpox infection. Shortly afterward, he was diagnosed with COVID-19, and then he developed evidence of severe hemolysis, the rapid breakdown of red blood cells. The clinical timeline placed the onset of hemolysis after both infections, raising the possibility that either one, or both acting together, could have served as the immunologic trigger that set his immune system against his own red cells. The authors are careful to note that although the timeline is compatible with varicella-zoster reactivation triggering the disease, the specific infectious trigger cannot be definitively established, and the recent COVID-19 diagnosis represents a potential alternative trigger or co-trigger.

The diagnostic workup followed the standard logic of hemolytic anemia evaluation but arrived at an answer that required specialized testing. Initial hemolysis testing demonstrated a direct antiglobulin test, also known as a Coombs test, that was positive for complement component 3 but negative for immunoglobulin G. This pattern is a crucial clue: many autoimmune hemolytic anemias, particularly the warm-antibody type, show immunoglobulin G coating the red cells, whereas the complement-only pattern points toward a cold-reactive antibody such as the Donath-Landsteiner antibody. Confirmation came from Donath-Landsteiner testing, the definitive assay for the disease, which exploits the biphasic nature of the antibody by incubating the patient’s serum with red cells at cold temperature and then warming the mixture to demonstrate complement-mediated lysis.

Two additional findings on the patient’s blood smear aided the diagnosis and illustrate the value of careful microscopic examination. The smear showed erythrophagocytosis, the phenomenon in which white blood cells engulf red blood cells or their debris, and rosetting, in which red blood cells cluster around neutrophils in a flower-like arrangement. Both findings are commonly seen in PCH and reflect the intense inflammatory and phagocytic activity that complement-coated red cells provoke. In a disorder as rare as PCH, such morphological clues can be decisive, because clinicians may not initially suspect the diagnosis and the confirmatory Donath-Landsteiner test is not available in every laboratory.

The severity of the patient’s illness underscores that adult PCH is not a benign curiosity. His hospital course lasted 38 days and was described as complicated, requiring mechanical ventilation to support his breathing, renal replacement therapy in the form of dialysis to substitute for failing kidneys, and extensive transfusions to replace the red cells his immune system was destroying. Each of these interventions reflects a downstream consequence of massive hemolysis: the release of free hemoglobin into the circulation can injure the kidneys, severe anemia can starve tissues of oxygen, and the systemic inflammatory response can precipitate multi-organ failure. The report thus serves as a reminder that a condition often taught as a mild pediatric post-viral illness can, in adults, become a critical care emergency.

The immunologic story behind the case is also of interest to researchers studying how infections trigger autoimmunity. Varicella-zoster virus is a herpesvirus that establishes lifelong latency in sensory ganglia and can reactivate when immune surveillance wanes, as commonly happens with aging or immunosuppression. Molecular mimicry, in which antibodies generated against viral proteins cross-react with similar structures on host tissues, is one proposed mechanism linking viral infections to autoimmune blood disorders, and the P antigen on red cells has been discussed in this context. The concurrent COVID-19 diagnosis adds a further layer of complexity, since SARS-CoV-2 infection has itself been associated with a range of autoimmune hematologic complications, including autoimmune hemolytic anemia. Disentangling which infection, if either, drove the patient’s antibody production is not possible from a single case, and the authors explicitly decline to assign a definitive cause.

From a clinical practice standpoint, the case carries several lessons. First, PCH belongs on the differential diagnosis for any patient with acute hemolytic anemia and a complement-only positive direct antiglobulin test, particularly when there is a recent history of infection, and recognizing the characteristic smear findings of erythrophagocytosis and red cell rosetting can accelerate the diagnosis. Second, in adults with PCH, clinicians must search both for infectious triggers and for underlying hematologic malignancy, since the management and prognosis differ substantially between these scenarios. Third, the biphasic Donath-Landsteiner test remains the cornerstone of confirmation, and clinicians should advocate for it when the initial serologic pattern is suggestive, because misclassification as warm autoimmune hemolytic anemia could lead to ineffective treatment strategies such as corticosteroids or rituximab, which are mainstays for warm-antibody disease but have a less established role in PCH, where avoidance of cold exposure and supportive transfusion are central.

The report, published as an open-access case report and citable under DOI 10.1007/s00277-026-07310-8, was reviewed by the Thomas Jefferson University Privacy Office in accordance with institutional policy, and informed consent for publication was obtained from the patient. The authors declare no competing interests and received no funding for the manuscript. For the hematology community, the case expands the recognized spectrum of varicella-zoster-associated PCH from primary infection to viral reactivation, a distinction that matters for the growing population of older adults in whom shingles is common. For the broader medical readership, it is a vivid illustration of how a dormant virus and an unrelated pandemic-era infection can converge on a single patient’s immune system with dramatic consequences, and of how classical serologic techniques developed more than a century ago, when Donath and Landsteiner first described the antibody that bears their names, remain indispensable tools in modern diagnostic medicine.

Subject of Research: Paroxysmal cold hemoglobinuria following varicella-zoster virus reactivation and COVID-19

Article Title: An unusual trigger for a rare hemolytic anemia: paroxysmal cold hemoglobinuria after shingles and COVID-19

Article References: Mermelstein, A. G., Reilly, S. P., & Rhoades, R. (2026). An unusual trigger for a rare hemolytic anemia: paroxysmal cold hemoglobinuria after shingles and COVID-19. Annals of Hematology. https://doi.org/10.1007/s00277-026-07310-8

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07310-8

Keywords: paroxysmal cold hemoglobinuria, Donath-Landsteiner antibody, varicella-zoster virus, shingles, COVID-19, autoimmune hemolytic anemia, complement-mediated hemolysis, erythrophagocytosis, direct antiglobulin test, hematology, case report, Annals of Hematology

The clinical significance of sacral zoster lies in anatomy. The sacral nerve roots, particularly S2 through S4, carry both autonomic and somatic fibers that govern the bladder, bowel, and genital region. When the reactivated virus inflames these roots, the consequences extend well beyond skin and pain. Patients can develop urinary retention, incomplete bladder emptying, constipation, erectile dysfunction, and, in rare severe instances, sacral radiculomyelitis or Elsberg syndrome, a condition in which inflammation spreads to the conus medullaris and cauda equina. The case report, authored by Aida Farmani and colleagues at Isfahan University of Medical Sciences, documents how the virus’s predilection for dorsal root ganglia translates into dysfunction of organs that seem, on the surface, unrelated to a dermatomal rash.

In this patient’s case, the diagnostic pathway illustrates both the challenge and the solution. Her urinalysis showed no pyuria and her urine culture remained sterile, ruling out the urinary tract infection her dysuria might otherwise have suggested. A Tzanck smear revealed herpetic cytopathic effects, including the characteristic multinucleated giant cells that signal infection with a herpesvirus. But because herpes simplex virus can produce an identical smear picture, particularly in the genital and perineal region, the team turned to polymerase chain reaction testing on a vesicular swab. PCR is considered the diagnostic gold standard, especially in atypical or site-specific presentations like sacral zoster, because it definitively distinguishes varicella-zoster virus from herpes simplex virus, a distinction with very different implications for counseling, treatment, and prognosis.

Treatment began on the day of dermatological evaluation, roughly five days after symptom onset. The patient received oral valacyclovir at 1000 milligrams three times daily for seven days, along with gabapentin titrated for neuropathic pain. No urinary catheterization was necessary because her residual urine volumes remained low and she never developed severe retention. The clinical course was favorable: urinary symptoms resolved completely within two weeks, the skin lesions crusted and epithelialized by three weeks, and at three-month follow-up she reported only mild intermittent neuropathic dysesthesia. This relatively benign trajectory, the authors note, contrasts with some previously documented cases in which bladder dysfunction persisted for months or became permanent.

The pathophysiology of urinary dysfunction in sacral zoster is multifactorial but centers on inflammatory neuritis. The S2 through S4 nerve roots provide parasympathetic innervation to the detrusor muscle, the smooth muscle responsible for contracting the bladder during emptying. Demyelination and inflammation of these fibers can produce detrusor areflexia or hypocontractility, leaving the bladder unable to generate adequate pressure. The result is urinary retention, incomplete emptying, or dysuria. In more extensive infections, the virus can ascend to involve the spinal cord itself, producing radiculomyelitis. Urodynamic studies in previously reported patients have documented hypotonic detrusor function and bladder areflexia, confirming that the neurological injury is real and measurable, not merely subjective.

One of the most treacherous features of sacral zoster is its tendency to announce itself through visceral symptoms before any rash appears. The literature reviewed by the authors includes multiple patients whose first and dominant complaint was acute urinary retention or voiding difficulty, with vesicular eruptions emerging only days later. In such presentations, patients are easily misdiagnosed with urinary tract infection, prostatitis, vulvovaginitis, or other pelvic pathology, delaying antiviral therapy precisely during the window when it is most effective. The authors urge clinicians to consider varicella-zoster virus in any patient presenting with acute urinary symptoms accompanied by dermatomal pain, paresthesia, or perineal discomfort, even when the skin appears entirely normal.

The case report includes a comprehensive table summarizing previously published cases, and the patterns are instructive. Richmond’s classic 1974 series described a 74-year-old woman with S3 zoster and urinary retention who required catheter drainage for thirteen weeks before spontaneous voiding returned. Erol and colleagues reported a 41-year-old man with S2 through S5 involvement who suffered urinary retention, erectile dysfunction, anorectal dysfunction, and even VZV meningitis, though most deficits improved within two weeks of parenteral acyclovir. Seo and colleagues documented an 80-year-old man whose urodynamic testing revealed detrusor areflexia, while Biglione and colleagues reported a 75-year-old man who, at eight-week follow-up, still showed hypotonic neurogenic bladder on urodynamics and required ongoing alpha-blocker therapy for autonomic nerve damage. Across the collected cases, S2 through S4 involvement dominated, urinary retention and voiding dysfunction were the most common urological manifestations, and constipation, dysuria, and sexual dysfunction appeared repeatedly.

Management principles emerging from the accumulated literature are relatively consistent. Early antiviral therapy is critical to limit viral replication, reduce disease severity, and potentially decrease neurological complications. Oral acyclovir or valacyclovir suffices for uncomplicated cases, while intravenous acyclovir is reserved for severe neurological involvement, suspected radiculomyelitis, or significant urinary retention. Adjunctive gabapentin is commonly needed for neuropathic pain. From the urological side, acute retention demands prompt bladder decompression to prevent overdistension injury, alpha-blockers such as tamsulosin have been used to facilitate voiding, and bowel dysfunction may require laxatives or stool softeners. Persistent urinary dysfunction warrants urological follow-up and urodynamic assessment to guide long-term management. Most cases of urinary dysfunction resolve within several weeks, but delayed diagnosis, older age, and extensive neurological involvement are associated with poorer recovery.

The broader lesson of this case extends to vaccination and public health. The patient had no history of varicella or herpes zoster vaccination and no known immunosuppression, underscoring that sacral zoster can occur in otherwise healthy, middle-aged adults. As shingles vaccines reduce the overall incidence of zoster, atypical presentations like this one will become rarer but no less important to recognize, since the diagnostic delay they cause is precisely what allows complications to take root. For dermatologists, urologists, and primary care clinicians alike, the message is straightforward: unexplained acute urinary symptoms paired with unilateral sacral or perineal pain should trigger consideration of varicella-zoster reactivation, careful skin inspection of the S2 through S4 dermatomes, and a low threshold for PCR confirmation. Early recognition, the authors conclude, combined with prompt antiviral treatment and appropriate supportive care, offers the best chance of preventing the prolonged neurological complications that transform a self-limiting rash into lasting disability.

Subject of Research: Sacral herpes zoster presenting with urinary symptoms

Article Title: Isolated Sacral Herpes Zoster With Urinary Symptoms: A Case Report and a Brief Review of the Literature

Article References: Farmani, A., Seyedyousefi, S., & Saber, M. (2026). Isolated Sacral Herpes Zoster With Urinary Symptoms: A Case Report and a Brief Review of the Literature. Clinical Case Reports, 14(10), Article e73684. https://doi.org/10.1002/ccr3.73684

Image Credits: AI Generated

DOI: 10.1002/ccr3.73684

Keywords: herpes zoster, varicella-zoster virus, sacral dermatome, urinary retention, neurogenic bladder, valacyclovir, PCR diagnosis, Elsberg syndrome, detrusor areflexia, postherpetic neuralgia, shingles, case report

Postherpetic neuralgia arises when the varicella-zoster virus, the same pathogen responsible for chickenpox, reactivates years or decades later as shingles and damages sensory nerve fibers. In some patients the pain persists long after the characteristic blistering rash has healed, producing burning, stabbing, or electric shock-like sensations that can last for months or even years. While the condition is well recognized as a driver of reduced quality of life, sleep disturbance, and functional impairment, the authors of the new study note that its association with subsequent formal psychiatric diagnoses has remained underexplored, particularly in large and demographically varied populations. Their work was designed to fill that gap using real-world clinical data rather than small, single-center samples.

The methodology behind the study reflects the growing power of federated electronic health record networks. The researchers identified patients aged 18 and older who received a new diagnosis of herpes zoster between 2016 and 2023. Those diagnosed with postherpetic neuralgia within one month of the shingles diagnosis formed the exposed group, while patients who did not develop the complication formed the comparison group. Crucially, the team excluded anyone who had been diagnosed with any mental disorder before the shingles diagnosis or up to one month afterward, a design choice intended to ensure that the psychiatric outcomes being measured were genuinely new conditions rather than pre-existing ones. After propensity score matching, which balanced the two groups on demographic and clinical characteristics, each cohort contained exactly 15,454 patients.

Propensity score matching is a statistical technique widely used in observational research to mimic the conditions of a randomized trial. Because patients are not randomly assigned to develop postherpetic neuralgia, differences between the groups in age, sex, comorbidities, or healthcare utilization could otherwise confound the results. By matching patients on these covariates and checking balance with standardized mean differences, the investigators reduced the likelihood that the observed association between the pain condition and mental illness is an artifact of underlying differences between the populations. The outcome measure was the hazard ratio, a statistic that captures the relative rate at which new events occur in one group compared with another over the follow-up period.

The headline finding was a hazard ratio of 1.26 for any new mental disorder among patients with postherpetic neuralgia, with a 95 percent confidence interval of 1.12 to 1.42. In practical terms, at any point during the six months of follow-up, the PHN group developed psychiatric conditions at a rate roughly a quarter higher than the matched comparison group. When the researchers broke the results down by diagnostic category, two clusters stood out. Mood disorders, which include depression and bipolar spectrum conditions, showed a hazard ratio of 1.33, while anxiety-related conditions showed a hazard ratio of 1.26. Both confidence intervals excluded the null value of one, indicating that these elevations are unlikely to be due to chance alone.

Perhaps the most striking result emerged from the subgroup analyses. When the cohort was stratified by age, the association was strongest among younger adults. Patients aged 18 to 39 who developed postherpetic neuralgia had a hazard ratio of 1.82 for new mental disorders, with a confidence interval of 1.15 to 2.86, meaning their risk was nearly double that of matched peers without the pain condition. This finding challenges the common assumption that the psychiatric burden of shingles complications falls mainly on older adults, who experience the highest rates of the condition itself. Younger patients may face distinct vulnerabilities, including disruption of work, caregiving responsibilities, and social life during prime working years, as well as the psychological shock of developing a condition typically associated with aging.

Sex and race also shaped the pattern of risk. Female patients with postherpetic neuralgia showed a hazard ratio of 1.39 for new mental disorders, compared with 1.21 to 1.60 confidence bounds, suggesting a stronger association in women than in men. Across racial groups, elevated risks were observed for White patients at a hazard ratio of 1.26, Black patients at 1.44, and Asian patients at 1.97, the latter with a wide confidence interval of 1.06 to 3.67 reflecting a smaller number of events. The authors also examined herpes zoster vaccination status and the anatomical site of disease as stratification variables, underscoring their effort to identify which patient groups might benefit most from targeted psychological screening.

The biological plausibility of a link between chronic neuropathic pain and psychiatric illness is well supported by prior literature. Persistent pain activates stress-response systems, including the hypothalamic-pituitary-adrenal axis, and is associated with elevated levels of inflammatory signaling molecules such as interleukin-1, interleukin-6, and tumor necrosis factor alpha, all of which have been implicated in the pathophysiology of depression and anxiety. Chronic pain also disrupts sleep, limits physical activity, and erodes social engagement, each of which is an established risk factor for mood deterioration. In the specific case of postherpetic neuralgia, damage to sensory neurons can produce allodynia, a state in which normally painless stimuli such as clothing against the skin become excruciating, a symptom burden that patients frequently describe as among the most disabling aspects of the condition.

The study’s authors conclude that clinicians should consider early psychological evaluation and intervention for patients with postherpetic neuralgia, rather than treating the condition purely as a pain management problem. Because the elevated risk was measurable within six months of the shingles diagnosis, there is a defined window in which proactive screening for depression and anxiety could plausibly alter trajectories. The findings also add weight to public health arguments for shingles vaccination, since preventing herpes zoster and its most common chronic complication would avert the downstream psychiatric morbidity documented here. The research received support from Chung Shan Medical University Hospital, National Taichung University of Science and Technology, and Taiwan’s Ministry of Science and Technology, and was approved by the institutional review board of Chung Shan Medical University Hospital.

As with all observational studies, some caveats apply. The analysis relies on diagnostic codes recorded in electronic health records, which can vary in accuracy and completeness across institutions, and the six-month follow-up period cannot capture psychiatric outcomes that emerge later. Residual confounding is always possible in matched cohort designs, since factors such as pain intensity, medication use, and socioeconomic circumstances are imperfectly captured in claims-style data. Nevertheless, the scale of the TriNetX network, the rigorous exclusion of pre-existing mental illness, and the consistency of the signal across multiple demographic subgroups lend considerable credibility to the central conclusion: postherpetic neuralgia is not merely a sensory disorder but a condition with measurable consequences for mental health, and the youngest patients, who are least expected to suffer it, may bear the heaviest psychological toll.

Subject of Research: Association between postherpetic neuralgia and subsequent mental disorders in a large U.S. retrospective cohort

Article Title: Mental health impact of post-herpetic neuralgia: a retrospective cohort study from 15,454 patients using TriNetX network database

Article References: Yang, M.-H., Hsiao, Y.-P., Wang, Y.-H., Huang, L.-H., Du, Y.-S., & Wu, T.-J. (2026). Mental health impact of post-herpetic neuralgia: a retrospective cohort study from 15,454 patients using TriNetX network database. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08675-w

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08675-w

Keywords: postherpetic neuralgia, herpes zoster, shingles, mental disorders, depression, anxiety, mood disorders, TriNetX, retrospective cohort study, propensity score matching, neuropathic pain, varicella-zoster virus

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