Trained enumerators interviewed participants face to face for approximately 20–30 minutes and administered a structured checklist covering 25 possible daily health complaints. The total score ranged from zero to 25 and was divided into three domains: sensory function or pain, body-system function, and activity participation. Participants were eligible if they were at least 15 years old, had diagnosed diabetes and reported a previous COVID-19 infection. Vaccination status was verified using electronic records from Indonesia’s SatuSehat platform and physical vaccination cards. Missing data were addressed through K-nearest-neighbours imputation with k = 5, producing an analytic sample of 420 participants. The count outcomes were modelled with negative binomial regression adjusted for sociodemographic and clinical variables.

The participants had a median age of 60 years, and 70.2% were female. A total of 36.2% had received a COVID-19 vaccine before their infection. Joint or muscle pain was the most prevalent complaint, reported by 46.0% of participants, followed by visual impairment at 43.1% and fatigue at 24.3%. The multivariable results also identified associations between demographic or clinical characteristics and particular complaint domains. Female participants had a higher rate of total daily complaints than male participants, with an incidence rate ratio of 1.25 and a 95% confidence interval of 1.02–1.53. Participants with secondary education had a lower rate of body-system dysfunction, with an incidence rate ratio of 0.66, while the absence of other comorbidities was associated with a lower rate of sensory or pain complaints, with an incidence rate ratio of 0.84. The supplied abstract did not provide confidence intervals for these two domain-specific estimates.

Vaccination after the index COVID-19 infection was not significantly associated with a lower rate of complaints related to that infection. The estimated incidence rate ratio was 1.06, with a 95% confidence interval of 0.90–1.26, which includes no difference. This estimate does not show that vaccination after infection reduced complaints, but it also does not establish that vaccination before infection was superior to vaccination after infection. The significant pre-infection estimate and the non-significant post-infection estimate came from separate comparisons, and the reported confidence interval for the post-infection association includes both lower and higher values than one. The clearest finding was therefore the observed association between pre-infection vaccination status and the overall rate of daily complaints, rather than a demonstrated advantage of one vaccination timing over the other.

The study offers a primary-care view of health burdens reported by people with diabetes after COVID-19, a population for which evidence from low- and middle-income settings was described as limited. The authors proposed that vaccination promotion could be integrated into routine chronic-disease management in these settings, while calling for prospective confirmation of the association. Several features constrain that conclusion. The cross-sectional design assessed vaccination and infection histories retrospectively and collected the other data at a single time point, allowing the analysis to estimate rates but not establish temporal or causal relationships. The sample was drawn from one Indonesian province and included only people with self-reported prior infection, with no uninfected control group. Unmeasured differences between vaccinated and never-vaccinated participants could therefore contribute to the observed pattern, and the findings may not generalize to other populations or primary-care systems. Within these limitations, the study linked pre-infection vaccination with a lower overall burden of daily complaints among 420 Indonesian primary-care patients with diabetes after COVID-19.

Subject of Research: Association of pre-infection COVID-19 vaccination with daily health complaints among Indonesian primary-care patients with diabetes.

Article Title: Beyond the pandemic declaration: daily health complaints in diabetic COVID-19 survivors and the association with prior vaccination in Indonesian primary care

Article References: Machmud, P. B., Khatimah, H., Mahkota, R., Veronica, J., & Wijayanto, A. W. (2026). Beyond the pandemic declaration: daily health complaints in diabetic COVID-19 survivors and the association with prior vaccination in Indonesian primary care. BMC Public Health. https://doi.org/10.1186/s12889-026-30043-2

Image Credits: AI Generated

DOI: 10.1186/s12889-026-30043-2

Keywords: COVID-19 vaccination, diabetes mellitus, daily health complaints, post-COVID symptoms, cross-sectional study, primary care, Indonesia, long COVID, negative binomial regression, Beyond, pandemic, declaration

The research team, led by pulmonologist Homer L. Twigg III, took advantage of a unique resource: a CLIA-approved clinical bronchoalveolar lavage laboratory that serves clinicians across central Indiana. Bronchoalveolar lavage, or BAL, involves threading a bronchoscope into the airways and instilling saline to wash out cells and soluble proteins from the alveolar spaces, the site where gas exchange occurs. Since October 2020, the laboratory had been receiving BAL fluid from patients undergoing bronchoscopy as part of their clinical work-up for persistent pulmonary symptoms after COVID-19. The only requirement for inclusion in the study cohort was a documented positive SARS-CoV-2 PCR test at some point before the lavage was performed.

By May 2022, the investigators had collected 37 BAL samples from 37 different patients. Five of these were obtained less than 28 days after a positive test and were classified as acute infections, while the remaining 32 were collected between 28 and 730 days after diagnosis, with a median of 178 days. The samples were processed by cytocentrifugation to generate cell differentials, and specimens contaminated with more than 15 percent buccal mucosal or airway epithelial cells were excluded. Two control groups were used for comparison: five healthy volunteers undergoing research bronchoscopy, and seven patients whose clinical BAL samples predated the pandemic entirely.

The cellular analysis revealed that suspected post-COVID-19 lung disease splits into three distinct inflammatory phenotypes. The first was essentially a normal BAL cell differential, with no increase in lymphocytes and minimal neutrophil accumulation. The second was a neutrophilic predominant pattern, defined by neutrophils making up at least 10 percent of the total nucleated cell population and exceeding the lymphocyte fraction. The third was a lymphocytic predominant pattern, in which lymphocytes accounted for at least 15 percent of cells and outnumbered neutrophils. Among the 12 patients with elevated lymphocytes, 8 had markedly inverted CD4-to-CD8 ratios, a finding classically associated with hypersensitivity pneumonitis, nonspecific interstitial pneumonia, chronic viral infections, and cryptogenic organizing pneumonia. The two patients with elevated rather than inverted ratios had underlying conditions, sarcoidosis in one case and mycobacterial antigen-associated hypersensitivity pneumonitis in the other, both known to drive CD4-predominant alveolitis.

Perhaps the most striking result came from the search for viral remnants. Using a commercial ELISA with a sensitivity of 0.256 picograms per milliliter, the team measured SARS-CoV-2 spike protein in acellular BAL fluid. Spike protein was readily detected in unconcentrated lavage fluid from the post-COVID patients compared with controls, and the difference remained significant even after correcting for dilution by expressing concentrations as picograms per milliliter of epithelial lining fluid, calculated using the urea method developed by Rennard and colleagues. Remarkably, spike protein was detected up to 627 days after the initial diagnostic test, supporting the hypothesis that residual viral proteins persist in the lung long after acute infection has cleared. The authors note that expanded data on persistent spike and nucleocapsid proteins, as well as viral nucleic acids, in this same cohort are described in a separate submitted manuscript.

To probe the pulmonary antibody response, the investigators turned to the PepSeq platform, a highly multiplexed serological technique that uses libraries of thousands of DNA-barcoded peptides with next-generation sequencing readout. For these experiments, a human virome-wide assay comprising 15,000 peptides was employed, with samples sequenced to a depth of more than 50 reads per peptide and replicate samples showing a median Z-score concordance of 0.94. Of the first 23 post-COVID subjects tested, 14, or 61 percent, had anti-SARS-CoV-2 antibodies in their BAL fluid, including many with polyclonal responses targeting epitopes on both spike and nucleocapsid proteins. Because the unstructured 30-mer peptides used in PepSeq cannot generally detect antibodies against conformational epitopes, the team also measured neutralizing activity with the cPass assay, which tests the ability of a sample to block binding between spike protein and the ACE2 receptor. Eleven of the 37 BAL samples, or 30 percent, exceeded the assay’s 30 percent inhibition cutoff, while no control sample exceeded 18 percent, and there was complete concordance between neutralizing antibody detection and PepSeq positivity.

The clinical correlations, however, proved more elusive. All subjects underwent chest CT scanning before bronchoscopy, and the scans were reviewed blindly by a NIOSH B Reader radiologist and grouped into predominantly ground glass opacities, predominantly fibrotic or interstitial changes, an equal mixture of both, or other patterns. No clear association emerged between radiographic appearance and the type of inflammatory milieu found in the lung. Long-term outcomes, tracked through chart review as of January 1, 2026, included vital status, need for lung transplant, and need for supplemental oxygen. The BAL inflammatory pattern was unable to predict long-term outcome in this underpowered analysis, although an intriguing signal appeared: no early adverse outcomes were observed among subjects with a normal BAL differential. In unadjusted logistic regression, the odds of a good outcome relative to the neutrophilic pattern were 2.13 for the normal group and 2.24 for the lymphocytic group, with confidence intervals that crossed one.

The findings carry significant implications for how post-COVID-19 lung disease is studied and treated. Because the NASEM definition of long COVID adopted by the NIH RECOVER initiative is purely clinical, relying on symptoms and radiographic findings after documented infection, patients grouped together under that umbrella may in fact harbor fundamentally different processes. The authors suggest that patients with a CD8-predominant lymphocytic pattern may have cryptogenic organizing pneumonia and could respond to corticosteroids, while those with neutrophilic inflammation may have the usual interstitial pneumonia pattern described in surgical lung biopsies of post-COVID patients. Patients with normal lavage fluid, who underwent bronchoscopy because of persistent CT abnormalities, likely have stable scar tissue from their acute infection, which could explain why some post-COVID fibrotic changes fail to progress and may even resolve, echoing the experience after SARS-CoV-1.

The persistence of spike protein also fits into a broader picture of chronic viral antigen stimulation. Prior work has documented residual viral proteins long after other infections, including HIV Nef protein in the lungs of aviremic patients and residual antigen presentation following influenza. Autopsy studies performed a median of 39 days after infection found persistent viral genomic RNA in nearly all patients, and a systematic review detected SARS-CoV-2 RNA in various tissues in 5 to 59 percent of subjects up to six months after acute infection. Persistent antigen can sustain chronic inflammation through multiple mechanisms, including ongoing B and T cell responses, T cell exhaustion and immunosenescence, direct stimulation of macrophages through TLR2, and activation of the complement system, which could plausibly drive the neutrophilic inflammation seen in a third of the patients. Notably, some form of immunosuppression was prevalent in the cohort, affecting 28 of 37 subjects, which the authors suggest may contribute to failure to clear the virus.

The investigators are careful to acknowledge the limitations of their work. The cohort is small and underpowered for linking inflammatory patterns to outcomes, the samples were collected relatively early in the pandemic before widespread vaccination and when more virulent strains circulated, and the cPass 30 percent cutoff was developed for plasma rather than BAL fluid, making the neutralization findings exploratory. There is also no comparison cohort of previously infected patients without chronic lung disease. Still, the study demonstrates that post-COVID-19 lung disease exists in several immunologically distinct forms, that viral proteins can linger in the lung for up to two years, and that clinical presentation alone may be an unreliable guide to the biology underneath. Whether residual SARS-CoV-2 components drive these phenotypes, and whether SARS-CoV-2-specific immune responses can ameliorate the disease, is currently under study.

Subject of Research: Inflammatory and immunologic profiling of bronchoalveolar lavage fluid in patients with post-COVID-19 lung disease

Article Title: Inflammatory and immunologic analysis of bronchoalveolar lavage from patients with post-COVID-19 lung disease

Article References: Twigg, H. L., III, Wilson, R., Yu, A. Q., Li, W., Altin, J. A., Tarver, R. D., Knight, I., Smith, P. A., Fraser, M. E., Castelluccio, P., & Rie, J. (2026). Inflammatory and immunologic analysis of bronchoalveolar lavage from patients with post-COVID-19 lung disease. Frontiers in Microbiology, 17, Article 1923299. https://doi.org/10.3389/fmicb.2026.1923299

Image Credits: AI Generated

DOI: 10.3389/fmicb.2026.1923299

Keywords: long COVID, post-COVID-19 lung disease, bronchoalveolar lavage, SARS-CoV-2, spike protein, viral persistence, neutralizing antibodies, PepSeq, pulmonary inflammation, interstitial lung disease, alveolar macrophages, immunosenescence

Senior author Dr. Chadi Saad-Roy, an assistant professor in UBC’s Department of Mathematics and Department of Microbiology and Immunology, said the models indicate that even modest post-infection costs can tip the scales and make the case for vaccine-driven elimination. The central insight of the work is that most existing frameworks for evaluating infectious disease management strategies focus almost exclusively on the acute phase of infection, quantifying hospitalizations, deaths, and transmission during the active illness while treating recovery as the end of the story. When a substantial fraction of recovered individuals go on to experience lingering sequelae, that accounting error can fundamentally distort the cost-benefit calculus that determines how aggressively a population should be vaccinated.

To address this gap, the team developed a system of mathematical equations designed to examine the interactions between interventions and post-infection effects. From the perspective of society, Dr. Saad-Roy explained, there is some cost to producing vaccines, and there is a large benefit to reducing infections and their downstream consequences, so the essential question is where the optimum lies. For a genuinely benign virus, it may not be worth vaccinating at all. For other infections, it may be best to vaccinate enough people to eliminate the disease entirely. In many realistic cases, the ideal point falls somewhere between those extremes, and the new modelling framework is intended to help answer precisely those questions in a principled way.

The researchers began with an epidemiological model of the classic susceptible-infectious-recovered type, which tracks the fraction of a population in each disease state over time. This compartmental structure allowed them to evaluate non-pharmaceutical interventions that reduce transmission, such as masking, social distancing, and air filtration, as complements to vaccination rather than substitutes for it. On long timescales, the team found that these non-pharmaceutical measures substantially decreased the portion of people who became infected and then recovered, and who were therefore vulnerable to post-infection effects. That result suggests that transmission-reducing measures can meaningfully reduce the long-term disease burden even when their most visible impact is on acute case counts.

The next step was to couple the epidemiological model to an economic one, allowing the researchers to assess how the costs associated with post-recovery syndromes alter the optimal level of vaccine coverage. To build a tool capable of pinpointing that sweet spot, they wrote equations that account for the societal cost of both acute and long-term infection, including expenses such as hospitalization and the loss of labor force productivity, alongside the cost of vaccination in terms of development, production, distribution, and recruitment. This dual accounting makes explicit what has often been implicit in immunization policy debates: the true price of an infection extends well beyond the acute episode, and the true cost of a vaccine campaign depends on how easily coverage can be expanded.

A key innovation of the study lies in how it treats vaccine costs. The team examined three different scenarios describing how the marginal cost of vaccination changes as the number of doses administered increases. In the accelerating scenario, there is a first wave of easy-to-reach vaccine adopters, and it becomes progressively harder to vaccinate additional people because of hesitancy or logistical barriers. In the decelerating scenario, initial resistance to vaccination gives way to peer influence that makes each additional individual easier to reach. The third scenario alternates between acceleration and deceleration, capturing settings where uptake dynamics shift back and forth as campaigns mature.

Across all three cost scenarios, the researchers found that the ideal amount of vaccine coverage was highly sensitive to post-acute effects. Even small post-infection costs were sufficient to shift the optimal coverage to higher rates, and in some cases to push the optimum all the way to elimination levels. This sensitivity means that diseases once considered marginal candidates for elimination campaigns, on the basis of acute severity alone, may become clear candidates once the cumulative burden of post-infection morbidity is factored in. Conversely, the result underscores how fragile optimal policy can be when the long-term consequences of infection are dismissed or left unmeasured.

Dr. Saad-Roy emphasized that the phenomenon needs to be tackled rigorously rather than dismissing individuals’ experiences as anecdotal. To more systematically monitor and document post-infection effects, he suggested that researchers conduct large, long-term cohort studies that survey participants on a broad constellation of symptoms. Such studies would supply the empirical cost estimates that models like these require, replacing scattered clinical impressions with population-level data on incidence, duration, and severity of post-acute conditions. Because these interventions reduce acute infection, he noted, they in turn mitigate post-acute burden and ultimately lead to a healthier world.

The practical implications extend to how vaccination campaigns are designed and communicated. It is critical, the authors argue, to understand which vaccine cost scenario, accelerating or decelerating, is actually at play in a specific setting in order to determine the optimal coverage level. That determination will require socioeconomic studies exploring vaccine decision-making dynamics in a given time and place, which may themselves be shaped by outreach efforts. Prakhar Jaiswal, a graduate student in the UBC Department of Mathematics and first author of the study, observed that educating people about the benefits of vaccination and reducing hesitancy can lower the cost of vaccination and tip the balance in favor of vaccinating to eliminate the disease. In other words, public engagement is not merely a soft complement to immunization programs but a direct lever on the economics that determine whether elimination is the rational target.

The interdisciplinary team behind the study includes co-authors Daniel Coombs of UBC Mathematics, Caroline Wagner of McGill Bioengineering, and Troy Day of Queen’s Mathematics and Statistics. The research was supported by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. As health systems worldwide continue to grapple with the legacy of long COVID and prepare for future viral threats, the study offers a quantitative argument that the era of evaluating vaccines by acute outcomes alone is drawing to a close, and that the arithmetic of elimination looks far more favorable once the full lifetime cost of infection is on the table.

Subject of Research: Mathematical modelling of how post-infection morbidity costs influence optimal vaccine coverage levels

Article Title: Even modest post-infection complications can make expanded vaccine coverage cost effective: New modelling

Article References: Even modest post-infection complications can make expanded vaccine coverage cost effective: New modelling. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: vaccine coverage, post-infection complications, long COVID, mathematical modelling, cost-effectiveness, epidemiology, non-pharmaceutical interventions, vaccine hesitancy, disease elimination, public health, University of British Columbia, PNAS

The authors ground their analysis in the historical legacy of hysteria, a diagnosis popularised in the early twentieth century that attributed physical symptoms to emotional distress primarily among women. They argue that this diagnostic framework provides essential context for contemporary patterns of dismissal and pathologisation, particularly towards marginalised populations. The term medical gaslighting itself did not appear in the academic literature until 2020, emerging in an account of a woman with long COVID who reported repeated dismissal prior to diagnosis. Since then, the concept has gained recognition in literature on chronic or contested illnesses, yet it still lacks a clear, consistent, and theoretically grounded definition that could guide research, clinical practice, and public understanding.

To construct their definition, the researchers draw on the origins of gaslighting in Patrick Hamilton’s 1938 play Gas Light, which depicts a husband manipulating his wife into doubting her sanity by dimming the gaslights in their home. The term entered academic literature through case studies of involuntary hospitalisation as psychological abuse and has since come to describe a form of psychological abuse in which an individual is manipulated into questioning their own perception of reality. The authors highlight sociologist Paige Sweet’s interviews with forty-three survivors of domestic violence, which demonstrated that gaslighting becomes especially abusive when embedded within social inequities and power dynamics, particularly those related to gender. Sweet conceptualises gaslighting as repeated efforts to construct a surreal environment in which victims are made to feel or appear crazy, thereby undermining their sense of reality, identity, autonomy, and mobility.

Building on this foundation, the researchers examine how medical gaslighting operates within Western medicine’s structural constraints. They cite a qualitative analysis of 334 online survey responses in which respondents with long COVID used the language of medical gaslighting to make sense of their experiences seeking care. Participants described repeated dismissal by medical professionals who were unable or reluctant to recognise their symptoms as real, with physicians invoking biomedical objectivity, including negative diagnostic test results, to discount patients’ subjective symptoms. The authors of that study suggest that medical gaslighting can be understood as a rhetoric of ontological politics, echoing Annemarie Mol’s argument that what counts as real in medicine is inherently political. This framing positions medical gaslighting not merely as an interpersonal failure but as a systemic condition embedded within the epistemology of Western medicine itself.

The researchers emphasise that Western medicine has historically been constructed around a normative body: wealthy, White, able-bodied, heterosexual, cisgender, and endosex male. Although medical gaslighting is not exclusive to marginalised communities, this structural bias systemically disadvantages those outside the norm. They cite interviews with twelve gynaecologists and general practitioners in which women with endometriosis were characterised as hysterical and labelled crazy when they failed to respond to diagnosis or treatment as expected. Miranda Fricker’s concept of epistemic injustice, which describes harm done to someone in their capacity as a knower due to prejudice or limited interpretive resources, provides a useful framework for understanding how implicit biases and power dynamics produce such harm. The authors also highlight the role of intersectionality, noting that while Black women may experience compounded marginalisation within healthcare, White women benefit from racial privilege while still experiencing gender-based disadvantage.

The perspective piece engages critically with alternative framings that have emerged in recent medical literature. Emergency physician Robert Jedick has argued that the term medical gaslighting overlooks physicians’ perspectives and frames patient-provider relationships in conflict, proposing miscommunication as an alternative that better acknowledges the organisational pressures facing medical professionals. The Australian researchers counter that characterising such encounters as miscommunication risks reframing structurally embedded power dynamics as interpersonal misunderstandings, shifting responsibility towards patients seeking recognition of their symptoms. They argue that this reframing may invalidate the lived experiences of those harmed by medical gaslighting, and that the language of medical gaslighting can function as a form of self-advocacy, enabling patients to make sense of their experiences within a medical system that has failed to recognise their legitimacy.

The researchers also address the question of intent, which has divided scholars in the field. Some have distinguished manipulative gaslighting from epistemic gaslighting on the basis of intent, while others have proposed medical invalidation to describe gaslighting-like behaviours that occur without manipulative intent, including those arising from well-meaning clinical practice. The authors argue that patients cannot reasonably be expected to discern the intent of medical professionals, and that introducing additional terminology is unlikely to resolve underlying epistemic tensions when the meaning of the existing term remains contested. They contend that the outcomes of both manipulative and unintentional dismissal are often similar, leading individuals to question or doubt the legitimacy of their concerns, and that a definition of medical gaslighting must recognise that it occurs regardless of intent.

Having surveyed the conceptual landscape, the researchers advance their own definition, which they present as a framework for empirical and clinical inquiry. They define medical gaslighting as a complex phenomenon, understood through psychological and sociological frameworks, in which individuals experience the repeated dismissal and invalidation of their health concerns by medical professionals, healthcare organisations, or the broader medical system, an experience that leads them to question or doubt the legitimacy of their concerns. Influenced by systemic inequities and power dynamics, it occurs regardless of intent and often in the absence of evidence-based care. The authors stress that this definition should continue to evolve as the field progresses, and that it establishes a foundation for academics and medical professionals to identify and address systemic inequities within Western medicine while reinforcing accountability within the medical system.

The researchers argue that such accountability can inform training that prioritises patient-centred care and transparent communication in clinical decision-making, strengthening patient-provider relationships, particularly in the management of chronic or contested illnesses within internal medicine. They distinguish their framing from legal claims of medical negligence, which typically focus on isolated incidents or individual providers, noting that medical gaslighting is more accurately understood as a psychological and institutional process that normalises the devaluation of individuals lacking testimonial power within the medical system. Over time, repeated encounters may generate a documented history of misdiagnoses and ineffective treatments, leading to patients being labelled as psychosomatic or manipulative, with clinical records potentially reflecting the implicit biases of previous providers and leaving patients with limited authority to challenge such assumptions.

Ultimately, the authors call for Western medicine to turn its diagnostic gaze towards medical gaslighting and work to extinguish the systemic inequities that sustain it. They contend that sensationalisation of the term has limited meaningful engagement, leaving insufficient empirical and clinical work to guide practice, and that there is an urgent need to identify and address medical gaslighting within Western medicine to prevent further dismissal and invalidation. By advancing a clear, theoretically grounded definition that affirms the lived experiences of those harmed while establishing a framework for research and clinical inquiry, the researchers aim to ensure that the phenomenon is consistently understood across public, academic, and clinical contexts, transforming a viral term into a rigorous instrument for structural change.

Subject of Research: Medical Gaslighting

Article Title: Defining Medical Gaslighting—To Extinguish It

Article References: Janiszewski, C. M. S., Mosterd, D., Emerson, C., Mikocka-Walus, A., & Grech, L. B. (2026). Defining Medical Gaslighting—To Extinguish It. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10787-8

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10787-8

Keywords: medical gaslighting, patient dismissal, chronic illness, epistemic injustice, healthcare inequities, long COVID, patient-provider communication, systemic bias, internal medicine, medical sociology, Defining, Medical

The review begins with a striking observation about the structure of long COVID itself. Rather than arising from a single defect, the condition appears to involve a self-reinforcing triad of persistent low-grade inflammation, autonomic nervous system imbalance, and metabolic dysfunction. Patients commonly show sustained elevation of inflammatory cytokines such as IL-6, TNF-α, and IL-1β, driven in part by lingering viral antigens, tissue injury, and macrophages locked in a pro-inflammatory state. At the same time, heart rate variability studies reveal a shift toward sympathetic dominance and reduced parasympathetic tone, while immune cells undergo a metabolic switch from efficient oxidative phosphorylation to aerobic glycolysis, depleting ATP, accumulating lactate, and damaging mitochondria through excess reactive oxygen species. Each abnormality amplifies the others, creating a vicious cycle that the authors describe as an inflammation–autonomic–metabolic pathological triad.

At the center of this cycle, the review places the vagus nerve and its cholinergic anti-inflammatory pathway, often abbreviated CAP. The vagus nerve, the tenth cranial nerve, maintains a constant dialogue between the brain and the visceral organs, with roughly 80 percent of its fibers carrying sensory information upward and the remainder delivering regulatory commands downward. When inflammatory signals reach the brainstem’s nucleus tractus solitarius, a reflex arc triggers efferent vagal output that releases acetylcholine onto immune cells in organs such as the spleen and liver. Acetylcholine binds to α7 nicotinic acetylcholine receptors on macrophages, activating a JAK2–STAT3 signaling cascade that suppresses NF-κB, inhibits assembly of the NLRP3 inflammasome, and thereby curtails production of TNF-α, IL-6, and IL-1β. In parallel, the same receptor signaling promotes Nrf2-dependent antioxidant defenses, inducing enzymes such as heme oxygenase-1 and superoxide dismutase.

Crucially, the review argues that the CAP is more than an anti-inflammatory reflex. Cholinergic signaling cross-talks with the AMPK–SIRT1–PGC-1α axis, a trio of metabolic regulators that governs mitochondrial biogenesis, antioxidant capacity, and energy homeostasis. Acetylcholine can enhance AMPK phosphorylation through calcium-dependent mechanisms, while SIRT1 activates PGC-1α by deacetylation, boosting the production of new mitochondria and improving oxidative metabolism. This coupling means that a single neural pathway could, in principle, simultaneously dampen inflammation and rebuild cellular energy supply—precisely the two functions that appear deranged in long COVID. The authors describe the CAP as a regulatory hub where neural, immune, and metabolic control converge, rather than a one-dimensional brake on cytokines.

Building on this anatomy, the review proposes that many long COVID patients may exhibit what it calls CAP hyporesponsiveness—a provisional research descriptor, not a diagnosis—characterized by reduced vagal tone, diminished acetylcholine availability, downregulated α7nAChR expression, and consequently weakened anti-inflammatory feedback. The authors are explicit that heart rate variability reduction alone cannot establish this pattern, since HRV is an indirect and non-specific marker. Instead, they outline candidate mechanistic domains spanning autonomic regulation, cholinergic signaling, inflammatory pathway activation, systemic inflammatory burden, and metabolic-mitochondrial stress, all of which would need to be measured together in prospective studies before the concept could be validated or translated into clinical subtyping.

The strongest evidence that electroacupuncture can engage this pathway comes from animal studies, and the review grades that evidence carefully. In mouse models of sepsis-related lung injury, postoperative ileus, and acute pancreatitis, stimulation at the Zusanli acupoint (ST36) on the lower leg restored α7nAChR expression, inhibited NF-κB signaling, and reduced inflammatory cytokines—and, critically, these protective effects were abolished when researchers cut the vagus nerve or blocked the α7nAChR receptor with antagonists such as methyllycaconitine. Such pathway-disruption experiments provide direct evidence that the vagal–cholinergic axis mediates at least some of electroacupuncture’s anti-inflammatory effects. Other animal work, including studies in diabetic rats, shows that electroacupuncture increases AMPK, PGC-1α, and GLUT4 expression and raises skeletal muscle ATP, supporting the metabolic arm of the proposed framework, though these findings do not by themselves prove CAP involvement.

Human evidence is more indirect but broadly consistent. Clinical studies in healthy volunteers and patients with inflammatory conditions report that electroacupuncture alters heart rate variability in a frequency-dependent manner, increases high-frequency vagal components, reduces sympathetic stress indices, and lowers circulating TNF-α and IL-1β in conditions such as knee osteoarthritis. Functional neuroimaging shows that stimulation at ST36 modulates brain regions involved in somatosensory, limbic, and autonomic processing, and small clinical reports in long COVID patients describe improvements in fatigue, dyspnea, abnormal heart rate, and inflammatory markers alongside enhanced HRV. Because no human study has directly tested CAP dependence through pathway disruption, the authors classify all clinical findings as supportive rather than conclusive, a distinction they maintain throughout the review.

To organize these heterogeneous results, the authors propose an integrated EA–CAP–AMPK–SIRT1–PGC-1α model, in which electroacupuncture stimulation enhances vagal afferent input, activates central autonomic integration in the brainstem, releases acetylcholine onto α7nAChR-expressing immune cells, and thereby suppresses NF-κB and NLRP3 signaling while simultaneously supporting mitochondrial function through the metabolic axis. They supplement this with a Neural Resonance Modulation hypothesis, suggesting that frequency-specific somatosensory input may synchronize rhythmic activity within brainstem–hypothalamic circuits, and with a neuro–immune–metabolic loop framework describing how anti-inflammatory, metabolic, and central integrative processes reinforce one another. The model explicitly distinguishes directly supported links from inferred connections and clinical extrapolations, marking the proposed convergence between CAP signaling and metabolic recovery as biologically plausible but not yet experimentally confirmed.

Looking toward translation, the review outlines phenotype-oriented strategies for future trials, proposing candidate long COVID subgroups—an autonomic-dominant type defined by abnormal HRV and orthostatic intolerance, an inflammatory-immune type marked by elevated CRP and cytokines, a metabolic-mitochondrial type dominated by fatigue and exercise intolerance, and a mixed type—each with tailored acupoints, stimulation frequencies, and outcome measures. Low-frequency stimulation of two to fifteen hertz for twenty to thirty minutes, two to three times weekly, remains the most commonly used protocol. A randomized, sham-controlled trial protocol recently designed to test electroacupuncture for long COVID neuropsychiatric symptoms in 150 patients over 16 weeks may provide the first rigorous test, though results remain pending.

The authors acknowledge substantial obstacles: stimulation parameters and acupoint combinations vary widely across studies, indirect markers such as HRV lack specificity, and mechanistic research has typically examined single pathways rather than the multi-layered coupling their framework proposes. Progress, they argue, will require CAP-centered assessment systems that combine heart rate variability, immunomics, metabolomics, and functional neuroimaging, together with phenotype-stratified randomized trials and, eventually, AI-assisted closed-loop devices that adjust stimulation in real time based on physiological feedback. Whether electroacupuncture ultimately proves effective for long COVID remains an open question, but the review offers something the field has lacked: a structured, evidence-graded map of how a peripheral nerve intervention might plausibly reach the neural, immune, and metabolic networks that this perplexing disease disrupts.

Subject of Research: Electroacupuncture modulation of vagal cholinergic anti-inflammatory and neuro-immune-metabolic pathways in long COVID

Article Title: Integrative perspectives on electroacupuncture modulation of vagal–cholinergic and neuro–immune–metabolic regulation in long COVID

Article References: Wang, L., Hu, X., & Yan, D. (2026). Integrative perspectives on electroacupuncture modulation of vagal–cholinergic and neuro–immune–metabolic regulation in long COVID. Frontiers in Integrative Neuroscience, 20, Article 1775007. https://doi.org/10.3389/fnint.2026.1775007

Image Credits: AI Generated

DOI: 10.3389/fnint.2026.1775007

Keywords: long COVID, electroacupuncture, vagus nerve, cholinergic anti-inflammatory pathway, alpha7 nicotinic acetylcholine receptor, NF-kB, NLRP3 inflammasome, AMPK, SIRT1, PGC-1alpha, mitochondrial dysfunction, autonomic dysfunction

The research team, led by investigators at Brigham and Women’s Hospital and Harvard Medical School including M. Elizabeth Moss and Bruce Levy, applied a technique known as lipid mediator metabololipidomics, using liquid chromatography coupled with tandem mass spectrometry, to profile hundreds of fat-derived signaling molecules in blood plasma. Their subjects came from two cohorts totaling 106 participants with recent SARS-CoV-2 infection. Sixty-four went on to meet clinical criteria for Long COVID, defined by the National Academies as an infection-associated chronic condition persisting at least three months, while 42 fully recovered. By comparing lipid profiles between these groups at different time points, the researchers could ask whether the chemistry of inflammation resolution differs in people who develop the syndrome.

The logic behind the approach rests on a well-established but underappreciated branch of immunology. Essential polyunsaturated fatty acids such as arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid are not merely fuel; they are raw materials for an entire pharmacopeia of signaling molecules. Lipoxygenase enzymes convert these fats into specialized pro-resolving mediators, including lipoxins, resolvins, protectins, and maresins, which actively coordinate the return of tissues to homeostasis after injury or infection. In a self-limited inflammatory response, the body performs a metabolic class switch, pivoting from pro-inflammatory prostaglandins and leukotrienes to these pro-resolving mediators. If that switch fails, inflammation can smolder indefinitely.

The first major finding came from the acute phase. In samples drawn within 30 days of a positive test, participants who would later develop Long COVID showed significantly elevated levels of three products of the 12-lipoxygenase enzyme: 12-hydroxyeicosatetraenoic acid from arachidonic acid, 14-hydroxydocosahexaenoic acid from DHA, and 12-hydroxyeicosapentaenoic acid from EPA. This association held even after the researchers statistically controlled for the severity of the initial infection, gender, and self-reported race. A composite score aggregating all 12-lipoxygenase products was likewise a significant predictor of later Long COVID, as were aggregate measures of arachidonic acid and EPA metabolism. Notably, the pattern was not simply a byproduct of generalized platelet activation, since thromboxane products of platelet cyclooxygenase were not elevated.

The 12-lipoxygenase signal is intriguing because the enzyme is highly expressed in platelets and sits at the crossroads of clotting and inflammation. Acute SARS-CoV-2 infection is known to trigger endothelial inflammation, angiogenesis, platelet activation, and microthrombi, and the new data suggest that selective 12-lipoxygenase activation, which can occur through thrombin receptors, collagen signaling, or immune complexes independently of the cyclooxygenase pathway, may link these processes to the later development of persistent symptoms. The researchers also observed that reduced levels of interleukin-22 and of resolvin D1, a DHA-derived pro-resolving mediator, in the acute phase predicted Long COVID risk, hinting that a deficit in resolution chemistry may accompany the excess lipoxygenase activity.

After the first month, the picture shifted. In cross-sectional samples collected more than a month post-infection, the correlation structure of the lipidome itself had changed. In recovered participants, intermediates derived from the same parent fatty acid tended to rise and fall together, indicating that metabolism was organized around the available fats. In Long COVID participants, this within-family correlation was lost for the DHA and EPA families, while a strong signature of 5-lipoxygenase activation emerged across fatty acid families. The authors interpret this as an uncoupling of PUFA metabolism in Long COVID, in which enzyme activity, rather than substrate availability, drives the lipid profile, consistent with disrupted lipid mediator class switching.

Longitudinal sampling over the first year after infection sharpened the temporal picture. Levels of 15-HETE, an arachidonic acid product, remained significantly higher in Long COVID participants, while resolvin D1 was consistently lower; indeed, resolvin D1 was undetectable in 14.3 percent of Long COVID samples but in none of the recovered samples. Several metabolites, including 17-HDoHE, 14-HDoHE, and lipoxin A4, showed significant interactions with time, diverging between the groups in the three-to-nine-month window after infection. These trajectories suggest that lipoxygenase activity remains elevated for months in Long COVID even as production of key pro-resolving mediators stays depressed, a combination that could sustain defective resolution of inflammation.

The study also intersected with another leading hypothesis about Long COVID: persistence of viral proteins. Using ultra-sensitive single molecule array assays, the researchers detected SARS-CoV-2 spike protein in a subset of both Long COVID and recovered participants long after acute infection, and unsupervised clustering of the multidimensional data separated samples largely by the presence or absence of spike. Within Long COVID samples, plasma levels of 17-HDoHE correlated significantly with spike protein abundance, a relationship absent in recovered participants. When the team clustered Long COVID samples using lipid mediators alone, four distinct biochemical subtypes emerged, one enriched in 17-HDoHE and another almost entirely lacking resolvin D1, hinting that Long COVID may encompass several metabolically distinct endotypes rather than a single disease process.

The authors are careful to note limitations. The cohorts were modest in size, particularly the recovered group in the longitudinal arm, and clinical status was determined by chart review rather than validated survey instruments. Medication use, especially aspirin, which can suppress 12-lipoxygenase activity, and dietary intake of omega-3 fatty acids were not captured, and parent fatty acid levels were not quantified. Many bioactive mediators fell below detection limits in plasma, prompting the authors to call for serum-based analyses that could better distinguish deficient substrate from dysregulated enzymatic machinery.

Even so, the findings open concrete paths forward. Elevated 12-lipoxygenase products in the first month of infection could serve as an early biomarker identifying patients at risk of Long COVID before symptoms become chronic, and the results dovetail with an ongoing randomized controlled trial, ARACOV-02, testing whether supplementation with pro-resolving mediator precursors such as 17-HDoHE, 14-HDoHE, and 18-HEPE, combined with telerehabilitation, can improve outcomes in established disease. More broadly, the work reframes Long COVID as a disorder of failed inflammatory resolution, a concept that may ultimately connect viral persistence, platelet biology, and fat metabolism into a single mechanistic story, and offers researchers a biochemical handle on one of the pandemic’s most stubborn legacies.

Subject of Research: Lipoxygenase-catalyzed metabolism of essential polyunsaturated fatty acids in Long COVID

Article Title: Long COVID is associated with lipoxygenase-catalyzed metabolism of essential polyunsaturated fatty acids

Article References: Moss, M. E., Pons, S., Tavares, L. P., Tang, Y., Alter, G., Karlson, E., Baden, L., Walt, D. R., & Levy, B. D. (2026). Long COVID is associated with lipoxygenase-catalyzed metabolism of essential polyunsaturated fatty acids. iScience, 29(11), Article 117581. https://doi.org/10.1016/j.isci.2026.117581

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117581

Keywords: Long COVID, SARS-CoV-2, lipoxygenase, polyunsaturated fatty acids, specialized pro-resolving mediators, lipidomics, inflammation resolution, resolvin D1, platelets, spike protein, 12-HETE, iScience

The trial recruited patients from the Long COVID Outpatient Clinic at IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico between November 2022 and November 2023. Of 347 individuals screened, 53 met the strict inclusion criteria: documented SARS-CoV-2 infection, persistent symptoms lasting at least three months, and clinically relevant fatigue defined by a Chalder Fatigue Scale (CFS) score of at least 4 out of 11. After excluding five participants with low adherence, 48 patients completed the study, 25 in the placebo arm and 23 in the VSL#3 arm. The cohort was evenly split between sexes, with a median age of 54 years and a median symptom duration of 30 months, underscoring how entrenched these symptoms had become.

VSL#3 is no ordinary probiotic. Each sachet delivers 450 billion colony-forming units of eight live freeze-dried bacterial strains, including four Bifidobacterium and four Lactobacillus species along with Streptococcus thermophilus. Participants took two sachets daily for 28 days, with placebo sachets identical in appearance, smell, and taste. The choice of formulation was deliberate: several of its constituent genera, particularly Bifidobacterium and Lactobacillus, have been repeatedly reported as depleted in patients with COVID-19 and long COVID, and their loss has been linked to persistent inflammation and symptom burden.

The primary endpoint was unambiguous. Patients receiving VSL#3 experienced a 24.24 percent median reduction in CFS score, compared with just 6.06 percent in the placebo group, a difference that reached statistical significance at p = 0.037. The responder rate told an even clearer story: 68 percent of VSL#3-treated patients improved meaningfully, versus 35.7 percent of those on placebo (p = 0.019). Crucially, the clinical benefit was maintained at the four-week follow-up visit after treatment discontinuation, arguing against a purely transient effect of the supplementation period.

Beyond fatigue, the trial captured improvements across selected patient-reported outcomes. Quality-of-life measures from the SF-36 survey showed gains in physical functioning and role limitation due to emotional problems in the VSL#3 group, and gastrointestinal symptom scores improved as well, with notable reductions in epigastric pain. These parallel improvements align with the trial’s underlying hypothesis: that the gut, far from being a bystander in long COVID, may be an active participant in the disease process.

To probe the biological mechanisms, the researchers layered clinical outcomes with an ambitious multi-omic workup. Fecal samples underwent 16S rRNA gene sequencing to profile gut microbiota composition, while targeted metabolomics quantified short-chain fatty acids and neuromodulators such as dopamine and serotonin in both fecal and serum samples. Blood analyses included immune cell phenotyping by multiparametric flow cytometry and serum cytokine profiling using a 45-plex Luminex panel. The integration of these datasets allowed the team to look for coordinated patterns linking microbial changes, immune signaling, and clinical response.

The microbiota findings were selective rather than sweeping. Overall microbial diversity, measured by alpha and beta diversity indices, did not differ significantly between groups at baseline or after treatment. Yet differential abundance analysis revealed that VSL#3 supplementation enriched specific health-associated taxa, including Bifidobacterium, Lactobacillus, Streptococcus, and Barnesiella, several of which correspond to strains in the administered formulation. Notably, clinical responders showed a distinct microbial signature beyond the supplemented organisms, with enrichment of commensal genera such as Bacteroides, Ruminococcus, Coprococcus, Phascolarctobacterium, Akkermansia, and Clostridium cluster IV, taxa associated with short-chain fatty acid production and gut ecosystem balance. Functional prediction analysis also pointed to enrichment of glycine, threonine, and methionine metabolism pathways in the VSL#3 group.

On the immune front, the results were more cautious. Within the VSL#3 group, circulating levels of IL1α, IL6, IL7, IFNα, and G-CSF declined from baseline to the end of treatment, hinting at a partial attenuation of the persistent low-grade immune activation characteristic of long COVID. However, these cytokine changes did not reach statistical significance when compared directly with the placebo arm, and the authors emphasize they should be interpreted as exploratory, hypothesis-generating observations. Immune cell phenotyping did reveal remodeling of peripheral populations, with increased proportions of CD8-positive T cells and CD68-positive macrophages alongside reduced CD66b-positive granulocytes, suggesting a shift in innate and adaptive immune balance following supplementation.

Perhaps the most intriguing findings emerged from correlation analyses linking the three data layers. In responder patients, the bacterial genus Coprococcus showed positive associations with the anti-inflammatory cytokine IL10 and with IL7, while isovaleric acid correlated positively with Coprococcus and valeric acid with Ruminococcus. Conversely, in non-responders, Akkermansia showed negative correlations with IL17 and G-CSF. These coordinated microbiota-immune-metabolic patterns, the authors suggest, may reflect broader interaction networks relevant to gut-brain communication, the axis increasingly implicated in fatigue and neurocognitive symptoms across long COVID and related post-infectious conditions such as myalgic encephalomyelitis/chronic fatigue syndrome.

The study’s strengths include its randomized, double-blind, placebo-controlled design and the depth of its integrated analyses, but the authors are candid about limitations: the small cohort size, the short post-treatment follow-up, the exploratory nature of the multi-omic work, and the inability to resolve whether enriched taxa represent durable microbiota remodeling or transient detection of supplemented strains. Longer-term, strain-resolved shotgun metagenomic studies will be needed to settle that question. Still, the persistence of clinical benefit four weeks after treatment stopped, combined with the enrichment of commensal taxa not present in the formulation, offers a compelling signal. As the first randomized placebo-controlled evidence supporting microbiota-targeted intervention for long COVID fatigue, the DELong#3 trial opens a concrete path for larger trials that could finally translate gut-directed therapy from hypothesis to standard of care.

Subject of Research: A randomized placebo-controlled trial of VSL#3 probiotic supplementation for fatigue in long COVID patients, with integrated microbiota, immune, and metabolomic analyses

Article Title: VSL#3® supplementation improves fatigue in long COVID: results from the DELong#3 randomized placebo-controlled trial

Article References: Amoroso, C., Marinoni, B., Maragno, P., Rimondi, A., Bottaro, F., Ciafardini, C., Muià, M., Honcharyuk, I., Noviello, D., Caridi, B., Sommella, E. M., Bandera, A., Gori, A., Mantero, M., Blasi, F., Ferrucci, R., Priori, A., Strati, F., Vecchi, M., … Caprioli, F. (2026). VSL#3® supplementation improves fatigue in long COVID: results from the DELong#3 randomized placebo-controlled trial. British Journal of Biomedical Science, 83, Article 16993. https://doi.org/10.3389/bjbs.2026.16993

Image Credits: AI Generated

DOI: 10.3389/bjbs.2026.16993

Keywords: long COVID, VSL#3, probiotics, gut microbiota, fatigue, randomized controlled trial, immune dysregulation, microbiota-gut-brain axis, Chalder Fatigue Scale, short-chain fatty acids, Bifidobacterium, metabolomics

The clinical picture itself helps explain why progress has been so slow. Long COVID is strikingly heterogeneous, with manifestations that include debilitating fatigue, cognitive dysfunction often described as brain fog, and persistent respiratory compromise, all affecting multiple organ systems. Despite intensive research efforts, the underlying pathophysiological mechanisms remain elusive, and that gap in understanding has directly impeded the development of effective therapies. It is precisely this fragmentation that the special issue set out to address, assembling studies that approach the syndrome from complementary angles rather than competing hypotheses.

The first strand of evidence concerns the lungs, where structural damage from acute infection can linger long after the virus itself has cleared. A team led by Garg and colleagues examined survivors of severe COVID-19 acute respiratory distress syndrome and demonstrated that specific imaging patterns on computed tomography correlate with ongoing symptoms. In particular, reticulations and septal thickening, the fine net-like changes that appear when lung architecture is disrupted, were positively associated with symptomatic dyspnoea, the distressing breathlessness that many survivors report. The researchers also found that parenchymal and atelectatic bands, linear scars within the lung tissue, were associated with reduced forced vital capacity, a standard measure of how much air the lungs can hold.

What makes that study significant, the editors note, is that it moves beyond simply documenting that abnormalities persist. By linking individual CT imaging patterns to both symptomatic and functional measures, the work establishes concrete associations between what radiologists see on a scan and what patients actually feel and how well their lungs perform. That kind of correlation is a prerequisite for using imaging as a meaningful clinical tool in follow-up care, rather than as a descriptive curiosity. It also provides a framework for stratifying patients, since different patterns of lung injury may reflect different underlying processes and may therefore respond differently to future treatments.

A companion study in the same issue addresses a practical barrier to long-term lung surveillance: radiation dose. Devkota and colleagues evaluated ultra-low-dose CT, a technique that dramatically reduces radiation exposure compared with standard protocols, in patients recovering from moderate to severe acute COVID-19 pneumonia. Their results showed that ultra-low-dose CT is comparable to standard-dose CT in accurately detecting persistent lung abnormalities. The authors reported a diagnostic accuracy of 95.0 percent overall, rising to 98 percent among non-obese subjects. Those figures matter because repeated surveillance imaging is only feasible, and ethically justifiable, if the cumulative radiation burden can be kept low. A technique that preserves diagnostic performance while cutting exposure makes serial monitoring of recovering patients a far more realistic proposition for clinics and hospitals.

The special issue then widens the anatomical scope, because the abnormalities associated with Long COVID are not confined to the lungs. In a retrospective CT angiography study, Goksu and colleagues identified significantly enlarged carotid bodies in patients previously hospitalized with COVID-19 pneumonia. The carotid bodies are small paired organs at the bifurcation of the carotid arteries that sense hypoxaemia, low oxygen levels in the blood, and modulate sympathetic nervous system activity in response. Enlargement of these structures in post-COVID patients could reflect prolonged chemoreceptor stimulation resulting from the pathophysiological changes of Long COVID, suggesting that the syndrome’s reach extends well past the respiratory system into the machinery that regulates breathing and cardiovascular tone.

The carotid body finding also raises pointed mechanistic questions. These organs are rich in ACE2 receptors, the same molecular doorway that SARS-CoV-2 uses to enter cells, and they are central to chemoreception. That combination leaves open two possibilities that are not mutually exclusive: the enlargement may be the result of direct viral injury to the tissue, or of chronic hypoxic stimulation as the body adapts to persistently disturbed oxygen dynamics, or of both acting in concert. Disentangling those mechanisms will be important, because a viral injury model and a maladaptive stimulation model would point toward very different therapeutic strategies.

Moving from structure to immunology, Kawaguchi and colleagues investigated serological profiles in an effort to identify clinically useful biomarkers for Long COVID’s heterogeneous manifestations. Their study covered 275 patients with Omicron-related Long COVID, a cohort of particular interest because most of the world’s current infections involve Omicron-lineage viruses. The team found that nucleocapsid N-antibody titers were positively associated with acute disease severity and with antiviral immune responses. Conversely, lower titers of antibodies against the spike protein’s S-antigen correlated significantly with memory impairment, the brain fog that is among the most disabling of Long COVID’s neurocognitive symptoms, and with reduced quality of life.

Those results expand understanding of the immunological underpinnings of neurocognitive symptoms and suggest that a blood test capable of flagging patients at risk of cognitive sequelae may one day be feasible. The authors are careful, however, to flag the interpretive pitfalls. Vaccination status and the time elapsed since infection both shape antibody profiles, and any biomarker built on serology must account for those variables before it can be trusted in the clinic. The caution is a reminder that in a post-vaccine, repeatedly exposed population, the immune signature of Long COVID is layered over a complex history of immunological events.

Finally, the issue turns from diagnosis to treatment, and to an organ system that has become a focal point of Long COVID research: the gut. Amoroso and colleagues conducted a randomized, double-blind, placebo-controlled trial in which patients with Long COVID received four weeks of probiotic supplementation or placebo. The probiotic arm achieved a significantly greater reduction in clinically relevant fatigue scores than placebo, with 24.24 percent of treated patients reaching that threshold compared with 6.06 percent on placebo. Crucially, the clinical improvement was accompanied by concurrent changes in gut microbial taxa, in microbiota-associated metabolites and in immune-related pathways, offering a plausible biological mechanism rather than an unexplained statistical signal. The editors caution that the modest sample size warrants restraint, but they describe the result as an exciting indication that gut-directed therapies deserve serious consideration in the Long COVID treatment landscape.

Read as a whole, the five studies converge on a single conclusion that the editors of the issue emphasize: Long COVID is a syndrome of genuine complexity, and no single measurement, organ or discipline will capture it alone. Continued research using diverse and integrated methodologies, spanning imaging, immunological, physiological and microbiome-related measures, will be essential for improving the characterization, monitoring and treatment of the condition. Much remains unresolved in elucidating the underlying causes of Long COVID, let alone alleviating the burden it places on patients and health systems. But the trajectory on display in this collection, from structural imaging that predicts symptoms, to immune markers that track cognitive decline, to microbial interventions that measurably reduce fatigue, illustrates how multidisciplinary work can turn a bewildering syndrome into a set of tractable, testable questions. The British Journal of Biomedical Science has signalled its commitment to serving as a forum for exactly that kind of rigorous, cross-cutting research, and the field will need more of it if the legacy of the pandemic is to be met with answers rather than open questions.

Subject of Research: Multidisciplinary biomedical research on the pathophysiology, biomarkers and treatment of Long COVID

Article Title: Editorial: Long COVID in the biomedical sciences

Article References: Kunnath, A. P., Kavanagh, O., & Tan, S. C. (2026). Editorial: Long COVID in the biomedical sciences. British Journal of Biomedical Science, 83, Article 17822. https://doi.org/10.3389/bjbs.2026.17822

Image Credits: AI Generated

DOI: 10.3389/bjbs.2026.17822

Keywords: Long COVID, PASC, SARS-CoV-2, computed tomography, carotid body, serological biomarkers, brain fog, probiotics, gut microbiome, fatigue, ARDS, British Journal of Biomedical Science

The study, led by Daisuke Miyamori, Shuhei Yoshida, and Masanori Ito of the Department of General Internal Medicine at Hiroshima University Hospital, was published in BMC Public Health. The researchers harnessed the National Database of Health Insurance Claims and Specific Health Checkups of Japan, known as the NDB, an extraordinarily comprehensive repository that captures prescription activity across virtually the entire Japanese population. Because Japan maintains a universal insurance system, the database offers an unusually complete picture of who receives which medications, when, and in what clinical context, making it a powerful instrument for detecting subtle shifts in disease incidence at the population scale.

The methodological core of the investigation was a matched cohort design, one of the most rigorous observational frameworks available for questions of this kind. The team identified 778,362 individuals who had been diagnosed with COVID-19 and then constructed a comparison group of uninfected patients matched on key characteristics, ensuring that the two groups were as similar as possible apart from their infection status. Matching on factors such as age, sex, and baseline health status is critical in pharmacoepidemiology because it reduces confounding, the persistent threat that an apparent association between infection and prescription rates might actually reflect underlying differences between the groups rather than a genuine biological effect of the virus.

Once the cohorts were assembled, the researchers tracked new prescriptions for four classes of allergy-related medications: H1 antihistamines, which block the histamine receptors that drive itching, sneezing, and urticaria; leukotriene receptor antagonists, which target a different inflammatory pathway central to asthma and allergic rhinitis; ophthalmic drops for allergic eye disease; and nasal sprays for rhinitis. Crucially, the team counted only new prescriptions, meaning patients who had already been receiving these drugs before their infection or matching date were excluded from the outcome analysis. This distinction matters enormously. A rise in refills among existing allergy sufferers would tell a very different story from a rise in people who had never needed allergy medication before suddenly requiring it, and only the latter points toward genuinely new allergic disease.

Over a median follow-up of seven months, the signal was clear and statistically robust. The incidence rate ratio for new allergy drug prescriptions among the COVID-19 group, compared with controls, was 1.21, with a 95 percent confidence interval of 1.20 to 1.23. In practical terms, for every million person-months of follow-up, the infected group accumulated roughly 1,528 more new prescriptions than the uninfected group, a figure the researchers report as an incidence rate difference with a confidence interval of 1,492 to 1,564. A 21 percent relative elevation may sound modest, but applied across the hundreds of millions of infections that occurred worldwide during the pandemic, it translates into a substantial burden of newly medicated allergic disease.

Perhaps the most consequential findings emerged from the subgroup analyses, which probed whether the effect of COVID-19 was distributed evenly across the population or concentrated in particular groups. The answer was emphatic: the elevation was markedly stronger among older adults and among patients with significant pre-existing illness. For individuals aged 65 and above, the incidence rate ratio climbed to 1.33, with a confidence interval of 1.31 to 1.35, while for patients scoring 4 or higher on the Charlson Comorbidity Index, a validated composite measure that weights conditions such as diabetes, chronic kidney disease, and heart failure, the ratio reached 1.35. These are not marginal statistical artifacts; the confidence intervals sit comfortably above the null value of 1.0, indicating that the excess risk in these vulnerable subgroups is unlikely to be a chance finding.

The sensitivity analyses extended the picture into the temporal domain, addressing the question that haunts much of the long COVID literature: does the effect fade, or does it persist? When the researchers examined follow-up periods extending beyond one year, the elevated prescription rates remained detectable. Among those aged 65 and older, the incidence rate ratio was still 1.14 at more than a year post-infection, and among patients with Charlson Comorbidity Index scores of 4 or greater it remained 1.17. The attenuation relative to the overall follow-up window suggests some degree of normalization over time, but the persistence of a measurable excess a full year after infection argues against the phenomenon being a transient artifact of post-viral irritation or short-lived diagnostic attention.

The biological plausibility of these findings rests on well-characterized immunological mechanisms. SARS-CoV-2 infection is known to perturb immune regulation in ways that can outlast the acute illness. Studies have documented shifts in T cell populations, dysregulation of type 2 immune pathways that govern allergic responses, and elevations in IgE, the antibody class central to allergic sensitization, following viral infections. Viral respiratory infections in general have long been implicated in the initiation and exacerbation of allergic airway disease, with epithelial damage and barrier disruption in the nasal and bronchial mucosa creating conditions favorable to allergen penetration and chronic inflammation. A SARS-CoV-2-driven tilt of the immune system toward type 2 skewing would provide a coherent mechanistic account for increased demand for antihistamines, leukotriene modifiers, and topical anti-inflammatory preparations.

The authors are careful to frame their conclusions within the limits of an observational, claims-based design. Prescription records are a proxy for diagnosed allergic conditions, not a direct measurement of disease, and prescribing behavior can be influenced by factors other than underlying pathology, including heightened patient vigilance after a serious illness and increased contact with the health system. The median follow-up of seven months, while sufficient to detect the signal, leaves longer horizons incompletely characterized for much of the cohort. Residual confounding cannot be entirely excluded in any non-randomized comparison, however meticulous the matching. Nevertheless, the consistency of the effect across four distinct drug classes, the dose-response-like gradient across age and comorbidity strata, and the persistence in sensitivity analyses collectively strengthen the case that the association reflects a real clinical phenomenon rather than a statistical mirage.

The public health implications are considerable. If COVID-19 genuinely accelerates the onset of allergic disease, health systems should anticipate elevated demand for allergy care in the years following waves of infection, particularly among older adults and patients with multimorbidity, the very groups already bearing the heaviest burden of post-acute sequelae. The researchers emphasize the need for continued monitoring and for personalized post-COVID-19 support, a recommendation that aligns with a broader shift in the field toward viewing SARS-CoV-2 not merely as an acute respiratory pathogen but as a systemic insult with heterogeneous, organ-spanning, and sometimes durable consequences. For clinicians, the study suggests a lowered threshold for evaluating new allergic symptoms in post-COVID patients; for researchers, it opens a rich vein of questions about mechanism, duration, and reversibility. As the pandemic recedes from daily attention, studies of this scale and rigor serve as a reminder that its epidemiological aftermath is still being written, one prescription record at a time.

Subject of Research: The association between COVID-19 infection and subsequent new allergy medication prescriptions in Japan

Article Title: COVID-19 and subsequent new allergy drug prescriptions: a matched cohort study in Japan

Article References: Miyamori, D., Yoshida, S., & Ito, M. (2026). COVID-19 and subsequent new allergy drug prescriptions: a matched cohort study in Japan. BMC Public Health. https://doi.org/10.1186/s12889-026-29757-0

Image Credits: AI Generated

DOI: 10.1186/s12889-026-29757-0

Keywords: COVID-19, allergy, SARS-CoV-2, antihistamines, leukotriene receptor antagonists, matched cohort study, Japan, national insurance claims database, post-acute sequelae, long COVID, allergic rhinitis, public health

The letter, written by Jason D. Goldman of the University of Washington’s Division of Allergy and Infectious Diseases and Jeffrey N. Martin of the Department of Epidemiology and Biostatistics at the University of California, San Francisco, takes aim at a validation study by Azola and colleagues. That study sought to determine how well the PASC score, formally known as the RECOVER-Adult Long COVID Research Index, performs when applied to real patients. The score assigns point values to various symptoms and laboratory findings, with a threshold above which a patient is classified as having Long COVID, also called post-acute sequelae of SARS-CoV-2 infection, or PASC. Goldman and Martin do not dismiss the effort. In fact, they commend the Azola team’s willingness to consider any symptom as a potential manifestation of the disease, in line with the broad definition advanced by the National Academies of Sciences, Engineering, and Medicine. Their objection concerns how the study’s accuracy estimates were produced.

At the heart of the critique lies a problem familiar to anyone who studies diagnostic testing: spectrum bias. When researchers evaluate how sensitive a test is, meaning its ability to correctly identify people who truly have the condition, the ideal case group should be a representative sample of all people with that condition in the general population. Some will have florid, multi-symptom disease; others will have a single lingering complaint. But the Azola study drew its Long COVID cases from a specialty Long COVID clinic, a population that Goldman and Martin describe as almost certainly enriched for patients with many symptoms. Because a positive PASC score requires a sufficient accumulation of symptom points, patients with only one symptom, or with several symptoms that carry low point values, would be far less likely to clear the diagnostic threshold. Had such patients been included in the case group, the measured sensitivity would have been considerably lower. By selecting cases from a clinic that preferentially treats the most symptomatic patients, the study effectively guaranteed that the score would look better at detection than it would in the wider world.

The bias did not stop there. Goldman and Martin note that the Azola study required its Long COVID cases to have at least one neuropsychiatric symptom, and that 62 percent of the case group experienced brain fog, a symptom worth three points under the scoring system. This requirement means the researchers built part of the case definition directly into the enrollment criteria. When a portion of what the test is designed to detect is already guaranteed to be present in every case, the test’s measured sensitivity is inflated by construction. It is a subtle but consequential distinction: the study did not ask whether the PASC score can find Long COVID among all people who have it, but whether it can confirm the disease in patients pre-selected to display some of its hallmark features.

Specificity, the flip side of diagnostic accuracy, fares no better in the analysis by Goldman and Martin. A test’s specificity reflects how reliably it returns a negative result in people who do not have the condition. To measure this meaningfully for a Long COVID classifier, the authors of the letter argue, the optimal comparison group would consist of patients who present with symptoms that overlap with Long COVID but whose illness stems from something other than prior SARS-CoV-2 infection. That is precisely the challenge clinicians face in practice: a patient arrives with fatigue, cognitive difficulties, or exercise intolerance, and the doctor must determine whether the cause is Long COVID or some other condition. A classifier is only useful if it can separate these possibilities. Instead, the Azola study assembled a group described as fully recovered and healthy controls, people with no symptoms at all. It surprised no one, least of all Goldman and Martin, that not a single control participant met the PASC score threshold. The resulting specificity estimate, effectively perfect on paper, is inflated in a way that tells clinicians almost nothing about the scenario they actually confront.

The third pillar of the critique concerns predictive values, numbers that often matter most to patients and physicians. Positive predictive value indicates the probability that a person with a positive test truly has the disease; negative predictive value indicates the probability that a person with a negative test truly does not. Unlike sensitivity and specificity, predictive values depend intimately on how common the disease is in the population being tested. Case-control designs, in which researchers hand-pick a group with the disease and a group without it, cannot estimate predictive values because the chosen proportions bear no necessary relationship to real-world prevalence. Goldman and Martin point out that the Azola validation, as a case-control study, simply cannot deliver these numbers. Whatever predictive figures might be quoted would be artifacts of how many cases and controls the investigators chose to enroll, not properties of the score in any actual clinical population.

Goldman and Martin do acknowledge one strength of the original work. The Azola team examined different combinations of fewer symptoms, reported in their supplemental materials, in an effort to explore how alternative configurations of the index might perform. This flexibility matters, because a rigid threshold may behave very differently across the heterogeneous presentations of post-viral illness. But the letter writers emphasize that every symptom combination evaluated within the same case-control framework inherits the same distortions. Optimizing symptom sets within a biased design does not remove the bias; it merely produces precision around an inaccurate estimate.

The implications extend well beyond a single academic dispute. Long COVID affects millions of people worldwide, and the absence of an objective diagnostic test has complicated everything from clinical care to disability determinations to the design of treatment trials. The RECOVER index was intended, in part, to standardize research classification so that studies across institutions could enroll comparable patient groups. If validation studies overstate the score’s accuracy, researchers may adopt the threshold with unwarranted confidence, misclassifying patients in ways that blur the very scientific questions the index was built to sharpen. Conversely, an honest accounting of the score’s limitations does not render it useless; it clarifies that the tool was designed and evaluated for research classification, not as a bedside diagnostic, and that its performance in general clinical populations remains an open empirical question.

The letter distills the matter into a stark summary. What the Azola study actually measured, Goldman and Martin conclude, is the fraction of patients cared for in a specialty Long COVID clinic, all of whom had at least one neuropsychiatric symptom, who met the PASC score threshold for the condition. That is a legitimate and informative measurement, but it is not validation of the score. True validation would require sampling cases from the full spectrum of disease severity in the general population and comparing them against symptomatic individuals whose ailments arise from causes other than SARS-CoV-2 infection. Only such a design could yield unbiased estimates of sensitivity, specificity, and predictive value.

For the field of post-viral illness research, the episode serves as a methodological cautionary tale at a moment when the pressure to produce actionable diagnostics is immense. Patients want answers, clinicians want tools, and health systems want standardized criteria. But the discipline of clinical epidemiology, as articulated in the textbooks Goldman and Martin invoke, exists precisely to insist that a test’s advertised accuracy reflects the populations and circumstances in which it will actually be used. Until the PASC score faces evaluation in a truly representative case group and against genuinely symptomatic comparator groups, its published performance figures should be read as optimistic upper bounds rather than established facts. The difference between those two readings could shape how Long COVID is diagnosed, studied, and treated for years to come.

Subject of Research: Validation methods and diagnostic accuracy of the RECOVER PASC score for Long COVID classification

Article Title: RE: Putting the PASC Score to the Test: Clinical vs. Statistical Accuracy in Long COVID Diagnosis (Azola et al. JGIM)

Article References: Goldman, J. D., & Martin, J. N. (2026). RE: Putting the PASC Score to the Test: Clinical vs. Statistical Accuracy in Long COVID Diagnosis (Azola et al. JGIM). Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10852-2

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10852-2

Keywords: Long COVID, PASC score, RECOVER Initiative, diagnostic accuracy, spectrum bias, sensitivity, specificity, predictive value, Journal of General Internal Medicine, SARS-CoV-2, clinical epidemiology, validation study