Varicella zoster virus (VZV) is an exclusively human alphaherpesvirus that infects >90% of the global population. Primary infection typically causes varicella (chickenpox), after which VZV establishes lifelong latency in ganglionic neurons along the entire neuroaxis. Virus reactivation, typically triggered by age-associated immune dysfunction or immune suppressive conditions, produces herpes zoster (shingles) that can be complicated by post-herpetic neuralgia. In limited instances, VZV reactivation (and rarely primary infection) also produces multisystem disease including vasculopathy, cranial neuropathies, myelopathy and cardiovascular or gastrointestinal complications; these complications can occur without, or temporally dissociated from, rash. Diagnosis of varicella or herpes zoster relies on clinical presentation of a disseminated or dermatomal-distribution rash, respectively; diagnosis of VZV infection (owing to replicating virus) is more challenging when cases are atypical and/or occur without rash. Prevention strategies include administration of live attenuated varicella vaccine and recombinant zoster vaccine. VZV infection is treated with antiviral drugs including oral valacyclovir (drug of choice), famciclovir, acyclovir or amenamevir; for severe or disseminated disease, intravenous acyclovir or foscarnet (when other drugs fail) are used. Critical challenges remain in recognizing and diagnosing atypical presentations, developing novel therapeutics, establishing the causal role of VZV in vascular and neurodegenerative disease, and achieving broader vaccine implementation worldwide.
Cancer pain is a persistent and multifaceted global health problem that profoundly impairs quality of life, function and prognosis. Cancer pain occurs across all cancer types and stages, including in long-term survivors, with prevalence and severity influenced by tumour location, treatment modality, metastatic burden, sex, age and comorbidities. Mechanistically, cancer pain is not a single entity but arises from diverse processes including peripheral nociception, central sensitization and maladaptive neuroplasticity. Growing evidence highlights a key contribution of non-neuronal cells, such as immune cells, Schwann cells and central glia, in regulating cancer-related nociceptive signalling. Sex differences and effects of sex hormones further modulate pain perception, susceptibility to treatment-related toxicities and response to analgesic therapies. Comprehensive assessment integrates quantitative sensory testing with psychosocial screening to capture biological and psychosocial determinants of pain. Effective management requires individualized, multimodal strategies combining non-opioid and opioid analgesics, adjuvant agents and emerging targeted therapies with non-pharmacological approaches such as interventional and neuromodulatory procedures, psychological therapies and palliative care. Improving patient-reported outcomes remains central, particularly in cancer survivors with chronic pain. Precision medicine approaches, including mechanistic phenotyping and biomarker-driven and pharmacogenomic strategies, hold promise for tailoring cancer pain management to individual clinical, psychosocial and molecular profiles, ultimately enhancing treatment efficacy and long-term outcomes.
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of antimicrobial-resistant infection worldwide. The spectrum of diseases caused by MRSA range from uncomplicated skin and soft-tissue infections to life-threatening invasive infections such as bacteraemia, pneumonia, osteomyelitis and endocarditis. MRSA commonly colonizes the skin and mucosal surfaces as an asymptomatic commensal but can transition to an invasive pathogen when host barriers are disrupted or immune defences are compromised. The shift from commensal to pathogen is facilitated by a broad repertoire of virulence factors that promote adhesion, immune evasion, tissue invasion and persistence within host tissues. Despite the development of several new antibiotics with activity against MRSA, clinical outcomes during invasive infections are poor, with many patients experiencing persistent or recurrent infection. Strategies to prevent MRSA infection include infection control measures, screening and targeted decolonization approaches; however, the effectiveness of these interventions varies and often depends on local MRSA prevalence and epidemiological context. Understanding the epidemiology, pathogenesis and clinical management of MRSA remains essential to guide effective prevention and treatment strategies.
Influenza A and B viruses are considerable public health threats. Annual seasonal epidemics are driven by antigenic drift and cause an estimated 3-5 million severe cases and 290,000-650,000 deaths annually. The clinical presentation of seasonal influenza is typically an abrupt, uncomplicated acute respiratory illness with full recovery; however, it can lead to severe, life-threatening complications in individuals at high risk. Antigenic shift caused by reassortment of a seasonal influenza A virus with avian and/or swine influenza A viruses has led to unpredictable pandemics. The successful cross-species transmission of influenza A viruses requires key viral adaptations, including changes in receptor specificity and compatibility with host factors such as ANP32A. Host defence involves a layered innate response, which is antagonized by proteins, such as non-structural protein 1, and a robust adaptive immunity comprising cytotoxic CD8+ T cells targeting conserved internal proteins and B cells producing neutralizing antibodies. Diagnosis primarily depends on highly sensitive PCR-based methods and multiplexed rapid antigen tests. Prevention involves annually updated seasonal vaccines (including inactivated, live attenuated and protein-based vaccines), while treatment relies on early use of neuraminidase and polymerase acidic protein inhibitors. Research priorities include the development of improved vaccines and a better understanding of influenza virus transmission from animals to humans.
Eosinophilic gastrointestinal diseases (EGID) are characterized by abnormal and prominent eosinophilic inflammation of the gastrointestinal mucosa, associated with symptoms related to the segment involved, in the absence of secondary causes of eosinophilia. EGID may affect different parts of the gastrointestinal tract, causing eosinophilic oesophagitis (EoE), eosinophilic gastritis, eosinophilic enteritis and eosinophilic colitis either individually or in combination. Secondary causes of eosinophilic infiltration of the gastrointestinal tract include parasitic infections, the use of certain medications, vasculitis, allergic syndromes, haematological conditions and other inflammatory diseases. The incidence of EGID is increasing globally. EoE is the most reported form, with a prevalence of ~1 in 700 individuals. Several pathogenetic mechanisms are being investigated, in particular, the crosstalk between aeroallergens and mucosal inflammatory cell activation, which leads to a T helper 2 cell inflammatory response and disruption of epithelial barrier integrity. EGID is frequently associated with other T helper 2 cell-driven disorders, such as atopic dermatitis, allergic rhinitis and asthma. EGID is diagnosed through histological assessment, with biopsy samples of affected areas typically showing increased eosinophils, after excluding secondary causes of eosinophilia. For EoE, new treatments, including biologic therapies, are now available, whereas therapeutic options for non-EoE EGID remain limited. Patients' quality of life may be impaired owing to social and functional limitations from symptoms, such as dysphagia and food impaction in EoE, or diarrhoea and abdominal pain in eosinophilic colitis.
Accidental hypothermia is an unintentional drop in core body temperature below 35 °C. It can occur at any time of year and in any climate, and can affect all age groups. The epidemiology of accidental hypothermia reflects the interaction between biological susceptibility, social conditions and exposure to environmental factors. As core temperature falls and thermoregulation mechanisms become insufficient, the metabolism slows, consciousness deteriorates and the hypothermic myocardium becomes increasingly prone to arrhythmias and cardiac arrest. The prognosis is variable, and treatment outcomes are dependent on multiple factors, with cardiac arrest being the decisive determinant, carrying an in-hospital mortality rate of up to 50%. Diagnosis relies on accurate core temperature measurement whenever possible, together with clinical staging when measurement is unavailable. The management of accidental hypothermia should follow the hypothermic chain of survival: prevent further cooling, handle the patient gently, provide airway, breathing and circulatory support, choose the correct destination hospital, and rewarm the patient using passive, active external, active internal or extracorporeal techniques according to severity. Extracorporeal life support is crucial for patients with hypothermic cardiac arrest. Most survivors of hypothermic cardiac arrest have excellent neurological outcomes. Effective prevention and education, together with well-organized regional pathways of care and personalized strategies to prevent cardiac arrest, are needed to improve outcomes.
Primary aldosteronism (PA) results from excessive aldosterone production by one or both adrenal glands and is an important cause of hypertension, leading to increased cardiovascular and renal morbidities. PA is primarily caused by a spectrum of somatic or germline mutations in aldosterone-driver genes and superimposed aberrant adrenal expression of various G-protein-coupled receptors and their ligands, leading to dysregulated aldosterone production. PA remains underdiagnosed, and simplified testing by measuring renin and aldosterone is recommended in all people with hypertension to maximize the diagnosis of PA. Some individuals with PA may also have co-secretion of cortisol, which contributes to cardiometabolic morbidities. Adrenal vein sampling, emerging functional imaging and novel biomarkers can identify whether a unilateral source of PA can be treated with surgical adrenalectomy. However, the majority of patients with PA have bilateral disease, warranting medical therapy with dietary sodium restriction and mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors in the near future. Medical therapy objectives are to normalize blood pressure and serum potassium; a rise in renin can serve as a biomarker of adequate therapy and reduced risk for adverse cardio-renal outcomes. Patients with PA should be monitored longitudinally for disease progression or recurrence, to manage potential adverse effects of treatment, and to optimize therapy of cardiovascular and other co-morbidities.
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic haematopoietic cell transplantation. cGVHD has a heterogeneous biology and morbid manifestations, affecting 30-70% of recipients and substantially impairing quality of life and is the leading cause of non-relapse mortality in allo-HCT recipients. This immune-mediated condition arises from complex immune dysregulation involving B cell and T cell activation, regulatory T cell dysfunction, and fibrosis driven by macrophages and fibroblasts. Glucocorticoids remain the first-line treatment; however, similar to 50% of patients develop steroid-refractory or steroid-dependent cGVHD, necessitating prolonged immunosuppression causing considerable toxicity. Four second-line treatments have been approved by the FDA - ibrutinib, ruxolitinib, belumosudil and axatilimab - targeting B cell signalling, JAK-STAT, ROCK2 and CSF1R pathways, respectively, and emerging therapies such as rovadicitinib show promise. However, substantial challenges persist in cGVHD treatment, including the heterogeneous biology and morbid manifestations (that is, lung and skin sclerosis), drug resistance and suboptimal supportive care. Biomarkers for early diagnosis and personalized treatment remain under investigation. Multidisciplinary care, infection control and psychosocial support are critical to improving quality of life in patients with cGVHD. Future research should prioritize mechanistic insights, antifibrotic therapies and integrating organ-specific interventions to enhance outcomes in patients with cGVHD.
Atopic dermatitis (AD) is the most common inflammatory skin disease and carries the highest disability-adjusted life-years burden, ranking 15th among all non-fatal diseases globally. It is characterized by intensely itchy skin and is associated with multiple comorbidities, such as food allergy, asthma, allergic rhinitis and eosinophilic oesophagitis, which are mainly driven by type 2 immune responses. Other comorbidities include mental health disorders, disordered bone health, and cutaneous and extracutaneous infections. AD is also associated with other immune-mediated inflammatory diseases, including alopecia areata, vitiligo and inflammatory bowel disease. AD most often starts in the first 2 years of life but can occur at any life stage and onset at >60 years of age is increasingly common. The twenty-first century has brought greater insights into disease pathology, with an understanding of the complex interplay between the skin barrier, cutaneous and systemic immune pathways, cutaneous microbiome and neural networks. This improved mechanistic understanding has enabled rational drug design and a shift from non-specific broad immunomodulation to targeted biologic therapies and small molecules for severe disease and from topical corticosteroids to next-generation therapies for mild and moderate disease. Yet, considerable global inequity remains in access to these novel therapeutics.
Osteomyelitis, defined as inflammation of bone, is a highly morbid disease that is most commonly caused by bacterial infection. Infectious osteomyelitis occurs across a spectrum of ages and affects previously healthy individuals as well as individuals with medical comorbidities. Establishment of osteomyelitis typically occurs following one of three general pathological mechanisms, including haematogenous seeding of healthy or injured bone, extension of a contiguous soft tissue infection, or direct inoculation of microorganisms into the bone following trauma. A wide spectrum of microbial pathogens can cause osteomyelitis in these settings. The most common aetiologies share common pathogenic traits such as the propensity to form biofilms, the elaboration of immunoevasive toxins and virulence factors, and the ability to adhere to and invade bone tissue. Challenges in diagnosing, prognosing and treating osteomyelitis remain owing to limitations of conventional cultures, absence of faithful biomarkers, inability to delineate acute versus chronic infection, and therapeutic recalcitrance. Despite prolonged antimicrobial therapy, many individuals with osteomyelitis fail treatment and go on to develop highly morbid complications. Improvements in the management of osteomyelitis will require an ongoing commitment to multidisciplinary clinical care, basic and translational research to uncover pathophysiological mechanisms of disease, and sustained investments in new approaches for the diagnosis, treatment and mitigation of complications.
Wearables have the potential to address one of medicine’s major blind spots: the under-representation of women. They could help to close this gap by advancing measurement and monitoring into clinically meaningful insights of personalized data. However, realizing this potential requires validation, equity and clinical rigour to avoid reinforcing existing inequities.
Tinnitus is the perception of sound without a corresponding external sound source. This condition affects approximately 14% of adults, with approximately 2% experiencing severe symptoms. Underlying mechanisms of tinnitus suggest involvement of both peripheral and central processes, in which cochlear injury and deafferentation may trigger maladaptive plasticity, increased central gain, and thalamocortical dysrhythmia, modulated by limbic and salience networks. Neuroinflammation, somatosensory-auditory coupling and other factors, such as stress, may contribute to chronicity. Clinical expression is heterogeneous. Tinnitus is often comorbid with hearing loss, hyperacusis, migraine, anxiety, depression, mild cognitive impairment, insomnia and temporomandibular disorders, influencing assessment and care. Diagnosis comprises distinguishing objective (including pulsatile) from subjective tinnitus, recognizing red flags (for example, pulse-synchronous tinnitus requiring vascular imaging), quantifying hearing with audiometry and screening for modulating somatic factors. Multimodal management can reduce the effect of tinnitus: tinnitus-focused counselling and cognitive behavioural therapy are first-line treatments, and hearing rehabilitation and targeted treatment of somatosensory contributors are valuable adjuncts. Moreover, emerging neuromodulation, including bimodal stimulation, benefits selected subgroups. New areas of research include biomarkers, deciphering tinnitus genetic architecture, inner ear regeneration, closed-loop neuromodulation and digital therapeutics.
Insomnia disorder (ID) causes both night-time and daytime symptoms. Night-time symptoms include subjective difficulties initiating and maintaining sleep and early morning awakenings, whereas fatigue, perceived impairments in cognitive functioning, and mood disturbances are common daytime symptoms. The prevalence of ID in adults is high (10-16%) and the condition represents a substantial burden for both patients and society. ID is also an independent risk factor for other mental disorders and physical diseases. Diagnosis relies on self-report, as a biomarker for the disorder has not yet been established. The aetiological and pathophysiological understanding of ID spans from epigenetic and genetic research to cognitive behavioural and psychophysiological approaches. Clinical guidelines recommend cognitive behavioural therapy for insomnia (CBT-I) as the first-line treatment. However, CBT-I still requires widespread implementation, with digital CBT-I offering a scalable solution to improve treatment accessibility. Most available hypnotic agents are recommended solely for short-term use, owing to their limited efficacy and potential adverse effects. Given the considerable proportion of patients who respond insufficiently to medications and the need for further research on CBT-I, the development of novel interventions and the refinement of existing treatments is urgently required.
Lyme borreliosis is the most common tick-borne disease in the northern hemisphere. It is a zoonosis caused by several species of Borrelia burgdorferi sensu lato and transmitted by the bite of infected ticks of the Ixodes ricinus complex. Lyme borreliosis in North America and Europe differs in certain respects, likely reflecting the different Borrelia species that cause human disease in these locations. The earliest manifestation of Lyme borreliosis is the skin lesion erythema migrans, which develops at the tick bite site, typically 7-14 days after the bite. Some untreated patients will then (within the first few weeks or months after onset of the infection) develop additional erythema migrans skin lesions or other clinical manifestations such as borrelial lymphocytoma, nervous system involvement or carditis. Several months or even years after infection onset, Lyme arthritis or acrodermatitis chronica atrophicans may develop. The diagnosis of typical erythema migrans is clinical, whereas for all other manifestations the diagnosis is supported via serological testing. Treatment with an appropriate antibiotic will result in resolution of clinical symptoms in most patients; however, some patients experience prolonged subjective symptoms, which usually improve over time. Repeated courses of antimicrobials are not beneficial except in rare cases when there is objective evidence of treatment failure.
Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease driven by a complex interplay of genetic, biological, behavioural and social factors. The epidemiology of T2DM has shifted considerably, largely attributable to increasing obesity rates. Furthermore, T2DM prevalence is increasing in younger people (diagnosis <40 years of age; early-onset T2DM), which is associated with more aggressive disease progression, higher risk factor burden, earlier and more severe complications, and greater lifetime morbidity than later-onset T2DM. T2DM is traditionally associated with a high risk of microvascular and macrovascular complications, although rates of cardiovascular complications have reduced in some high-income countries. Currently, emerging and non-traditional diabetes complications, such as those related to mental health and cognitive function, are being recognized, and people with T2DM increasingly experience multimorbidity and reduced quality of life. Additionally, a growing prevalence of obesity has resulted in high rates of obesity-related complications. Novel therapies and technologies may offer considerable benefit, although socioeconomic disparities may exacerbate barriers to effective prevention and equitable access. The complex nature of T2DM and its comorbidities underscores the urgent need for a person-centred, holistic approach that integrates glucose and weight management with broader attention to comorbidities, 24-h physical behaviours, psychosocial well-being and social determinants of health.
Intervertebral disc (IVD) degeneration is a naturally occurring process that is a consequence of biological ageing and exposure to normal physiological loading over a lifetime and is characterized by loss of IVD tissue structural integrity. The nucleus pulposus changes with loss of pressurization, decreased collagen concentration and loss of distinction from annulus fibrosus. The annulus fibrosus and cartilaginous endplate suffer delamination, tears, fractures and clefts of their respective extracellular matrix at both microscopic and macroscopic scales. This loss of structural integrity generally follows a predictable pattern of degeneration, and it predisposes the IVD to pathological states. As the disc degenerates, the likelihood of functional failure to protect the neural elements and/or to provide stable spine motion and support increases. Functional failure takes the degenerated IVD to a state of disc pathology that has various phenotypes: the most common forms are disc herniation, mechanical instability, spinal stenosis, degenerative spondylolisthesis and degenerative scoliosis. IVD pathology is commonly self-limited and non-operative treatment remains the mainstay of treatment in most patients. For patients with refractory disease, surgical intervention focuses on neural decompression and, when indicated, motion segment stabilization. Future therapies for prevention of disc degeneration, targeted disc regeneration and biological modification of the degenerative cascade might prevent or reverse pathological changes across all spinal regions.
Charcot–Marie–Tooth disease (CMT) subsumes many different inherited neuropathies. CMT and related neuropathies are among the most common inherited neurological disorders, affecting ~1 in 2,500 people globally and including both sexes. Mutations in genes that cause demyelinating forms of CMT often affect the proteins of the myelin sheath, the unfolded protein response, endosomal signalling and recycling, or key transcription factors. Mutations in genes that cause axonal forms often affect mitochondrial biology, aminoacyl-tRNA synthetases, molecular chaperones or the axonal cytoskeleton. All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits. Compared with the general population, children and adults with CMT have reduced quality of life across physical, emotional and social domains, with the physical domain being the most disabling. Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications. The investigation of genetically authentic cellular, organoid and animal models will enable the development of rational therapies. Natural history studies and biomarkers will enable potential therapies to be critically evaluated. This Primer summarizes the epidemiology, diagnosis, pathophysiology and treatment of Charcot–Marie–Tooth disease and other related peripheral neuropathies.
Cytokine storm describes a spectrum of clinical manifestations that feature increased cytokine levels in circulation owing to overactivated immune responses. These increased concentrations of cytokines can cause tissue and organ damage, potentially leading to lethality. Cytokine storm can be induced by a variety of underlying clinical conditions, including infection, auto-inflammatory and autoimmune conditions, monogenic causes, or therapeutic intervention, which often makes diagnosis and treatment difficult. However, studies have identified conserved molecular mechanisms that inform therapeutic strategies. Cytokine storm is initiated by cytokine production and exacerbated by a self-amplifying positive feedback loop between cytokines and inflammatory cell death (PANoptosis). The process begins when cells detect triggers and undergo inflammatory signalling to produce and release cytokines via canonical secretion pathways or through lytic cell death such as pyroptosis and PANoptosis. This release of inflammatory cytokines, and potentially of other damage-associated molecules, can then drive inflammation and cell death in neighbouring cells through paracrine PANoptosis, resulting in further cytokine release and the amplification of the cycle. Improved understanding of the molecular and cellular mechanisms driving cytokine storm is critical for developing effective therapeutic strategies and improving clinical outcomes. Cytokine storm represents a severe, often life-threatening systemic inflammatory syndrome characterized by elevated levels of cytokines that lead to organ damage. In this Primer, Kanneganti and colleagues describe the epidemiology and pathophysiology of cytokine storm as well as the importance of prompt diagnosis and treatment, and highlight areas of future research to improve clinical outcomes.
