Since its discovery in 1976, Ebola virus has caused more than 40 confirmed outbreaks across sub-Saharan Africa, sixteen of them in the Democratic Republic of Congo (DRC). Health systems in the region have developed protocols, trained responders, and, since 2019, relied on a licensed vaccine to reduce transmission among those most at risk. That vaccine, rVSV-ZEBOV (Ervebo), has been a critical tool. It works against the Zaire strain, which has driven virtually every major DRC outbreak. But the 2026 outbreak is different.

On 15 May 2026, the DRC Ministry of Health declared an Ebola outbreak in Ituri Province in the north-eastern part of the country. The causative agent is Bundibugyo virus (BDBV), a rare Ebola species for which there is no approved vaccine and no approved treatment. Within 24 hours, cases had crossed the border into Uganda. Within 48 hours, a confirmed case was identified in Kinshasa, the DRC’s capital, some 1,700 kilometres from the epicentre. On 17 May 2026, the World Health Organisation (WHO) declared the outbreak a Public Health Emergency of International Concern (PHEIC).

As of 16 May, there were 246 suspected cases and 80 suspected deaths across at least three health zones in Ituri, alongside three laboratory-confirmed cases in Uganda and Kinshasa. These numbers almost certainly understate the true incidence. A high positivity rate in initial testing, eight confirmed positives from just thirteen samples, points to a much larger undetected outbreak.

What is Bundibugyo virus?

The genus Orthoebolavirus contains six recognised species. Four are known to cause disease in humans: Zaire, Sudan, Tai Forest, and Bundibugyo. Zaire has been responsible for the most catastrophic outbreaks, including the 2013–2016 West African epidemic that infected nearly 30,000 people and killed over 11,000. Sudan has caused nine outbreaks since 1976, most recently in Uganda in January 2025. Tai Forest has infected only a single confirmed human case, in 1994.

Bundibugyo virus was first characterised as a distinct species in 2007–2008, when an outbreak struck Bundibugyo District in western Uganda, a region that borders the DRC. That outbreak produced 131 reported cases and 42 deaths. A second outbreak occurred in 2012, in Province Orientale in the DRC, resulting in 38 laboratory-confirmed cases and 13 deaths. Molecular analysis of the 2012 outbreak suggested the possibility of multiple independent spillover events from an animal reservoir, rather than a single introduction with subsequent human-to-human spread.

The 2026 outbreak is therefore only the third documented Bundibugyo event in human history and, by a considerable margin, the largest. It has already surpassed both previous outbreaks combined in suspected case count, and has demonstrated rapid cross-border spread within weeks of its presumed index case.

In clinical presentation, Bundibugyo infection closely resembles Ebola Zaire. Onset is typically sudden, with fever, fatigue, muscle pain, headache, and sore throat - flu-like symptoms - in the early phase, progressing to vomiting, diarrhoea, rash, and haemorrhagic features - internal and external bleeding - in severe disease. The incubation period runs from 2 to 21 days, averaging 8–10 days. One notable difference: the case fatality rate (CFR) for Bundibugyo is estimated at 30–40%, somewhat lower than the 70–90% seen in untreated Zaire outbreaks.

The diagnostic blind spot: how the outbreak grew unseen

A notable feature of this outbreak is how long the virus spread before anyone knew what it was. The earliest known case is a nurse who developed symptoms on 24 April 2026 and died at the Evangelical Medical Centre in Bunia, Ituri’s provincial capital. Yet the outbreak was not declared until 15 May - three weeks later.

The reason lies in a critical diagnostic gap. Field testing for Ebola in the DRC relies heavily on the GeneXpert platform, which is designed to detect Ebola Zaire, the strain responsible for almost all previous DRC outbreaks. When samples from the affected health zones were tested in Bunia, they returned negative. It was only when samples were sent to the National Institute of Biomedical Research (INRB) in Kinshasa, where multi-species Ebola assays are available, that the Bundibugyo strain was identified.

Decades of Zaire-centric outbreaks have shaped surveillance infrastructure, diagnostic capacity, and response protocols around a single viral species. When a different species arrives, with identical clinical features but a different genome, diagnosis can be missed. The result is unchecked community transmission during the period when containment is most achievable.

The head of epidemiology and global health at INRB, Placide Mbala, has been explicit: a rapid field-deployable test capable of detecting Bundibugyo virus is urgently needed. This is an immediate requirement for which no solution is currently available.

Why containment is especially difficult

Ebola outbreaks are always hard to contain. This one more so.

Firstly, there is no vaccine. The rVSV-ZEBOV vaccine, deployed with considerable success in the 2018–2020 DRC outbreak, is specific to Ebola Zaire. It offers no protection against Bundibugyo virus. A ring vaccination strategy, the primary tool that helped control the last major DRC outbreak, is simply not available here. The absence of both vaccine and licensed drug therapy means the entire response burden falls on isolation, contact tracing, infection prevention and control (IPC), and safe burial practices.

Ring vaccination, sometimes called reactive or targeted vaccination, is a strategy in which, rather than vaccinating entire populations, you rapidly identify and vaccinate the social and geographic ‘ring’ of people most at risk around each confirmed case: household contacts, close community contacts, and the healthcare workers who treated them. The logic is to build a protective barrier around the virus before it can reach the wider population, cutting off transmission chains at source.

This strategy, deployed with rVSV-ZEBOV, proved effective during the 2018–2020 North Kivu and Ituri epidemic, which, despite lasting nearly two years in a conflict zone, was ultimately contained without becoming a global catastrophe. By the end of that outbreak, more than 303,000 doses had been administered. Clinical evidence from Guinea’s 2015 Ebola Ça Suffit! trial demonstrated that rVSV-ZEBOV achieved approximately 100% efficacy in vaccinated contacts, giving responders a genuinely powerful and precisely targeted tool.

None of that is available now. With no licensed vaccine for Bundibugyo virus, outbreak control reverts entirely to the pre-vaccine toolkit: early detection, isolation of cases, exhaustive contact tracing, rigorous infection prevention and control (IPC) in health facilities, and safe and dignified burial practices to prevent transmission from deceased individuals. Each of these interventions is demanding under ideal circumstances; in a conflict-affected, resource-constrained setting with a three-week diagnostic delay already embedded, the challenge is huge.

Secondly, the outbreak is occurring in a highly insecure environment. Ituri Province has been the scene of sustained inter-communal violence and militia activity for years. Armed groups, including those affiliated with the Islamic State, operate in and around the affected health zones.

This directly impedes response efforts: it restricts the movement of health workers, disrupts community engagement, damages trust in health authorities, and can render entire areas inaccessible. The 2018–2020 DRC Ebola outbreak in North Kivu and Ituri - also complicated by conflict - ultimately lasted nearly two years and became the second-largest Ebola outbreak in history.

Thirdly, population mobility in the region is high. Ituri shares porous borders with Uganda and South Sudan. Mining activity in Mongwalu creates significant cross-border movement of workers. Urban centres such as Bunia serve as transit hubs. These are precisely the conditions under which outbreaks amplify geographically. Confirmed cases in Kampala, Uganda’s capital, and in Kinshasa demonstrate that the virus is already using established mobility networks to spread.

Fourth, healthcare-associated transmission appears to be occurring. At least four of the eight laboratory-confirmed cases in DRC are healthcare workers, suggesting nosocomial spread. At least four healthcare worker deaths compatible with viral haemorrhagic fever have been reported from affected areas. This pattern, seen repeatedly in Ebola outbreaks, reflects the extreme IPC demands of managing viral haemorrhagic fever patients and the catastrophic consequences of inadequate protective equipment or training.

The WHO declaration and the global response

On 17 May 2026, WHO Director-General Tedros Adhanom Ghebreyesus declared the outbreak a Public Health Emergency of International Concern under the International Health Regulations (2005). The PHEIC designation, the WHO’s highest alert level, indicates that the event is extraordinary, constitutes a public health risk through international spread, and requires coordinated global action.

WHO explicitly noted that the outbreak does not meet the criteria for a ‘pandemic emergency’ but that countries sharing land borders with the DRC are at high risk of further spread. States have been advised to activate national emergency management mechanisms, strengthen cross-border surveillance, implement screening at major transit points, and prepare health facility IPC capacity.

Africa CDC convened an urgent high-level regional coordination meeting on 15–16 May, bringing together health authorities from DRC, Uganda, and South Sudan alongside WHO, UNICEF, Médecins Sans Frontières (MSF), the Gates Foundation, the Wellcome Trust, pharmaceutical partners including Gilead Sciences, Merck, Regeneron, BioNTech, and Moderna, and multilateral funders including the World Bank and the African Development Bank. MSF has announced preparations for a large-scale operational response in Ituri.

The involvement of vaccine and therapeutics manufacturers at this early stage reflects both the urgency of the situation and the current void: no approved product exists for Bundibugyo virus, and there is the question of how rapidly candidate interventions might be evaluated and deployed.

An outbreak that was always going to hit hardest here

The communities bearing the burden of this outbreak, in one of the world’s poorest and most conflict-affected regions, have been rendered vulnerable by forces that long predate this virus. Decades of extractive colonialism, post-independence political instability, and ongoing conflict over the region’s mineral wealth have left Ituri’s health infrastructure chronically underfunded and repeatedly disrupted.

The informal health facilities and gaps in IPC capacity that WHO identifies as outbreak amplifiers are not accidents; they are the product of sustained underinvestment and institutional neglect.

The diagnostic blind spot described above, Zaire-centric surveillance infrastructure failing to detect a different species, is also, in part, a resource allocation story. Comprehensive multi-species diagnostic capacity requires sustained funding that has not been consistently available. The same applies to research pipelines for Bundibugyo-specific vaccines and therapeutics; because previous Bundibugyo outbreaks were small and geographically contained, they generated insufficient commercial interest to drive product development.

It is also worth noting the timing. The outbreak is unfolding against the backdrop of significant reductions in global health funding, including cuts to USAID programming, which have reduced both surveillance capacity and community health infrastructure across Central and East Africa. A global health security architecture already under financial strain is being tested at a time when the potential consequences are most severe.

What does this mean for the UK?

The direct risk to the UK from this outbreak, based on current evidence, remains low. Ebola is not airborne. It spreads through direct contact with the bodily fluids of symptomatic individuals. There is no documented sustained transmission of any Ebola species outside Africa; even during the 2013–2016 West African epidemic only a handful of cases were exported to Europe, almost all among repatriated healthcare workers.

The UK Health Security Agency (UKHSA) maintains standing protocols for viral haemorrhagic fever (VHF) in returning travellers. NHS England High Consequence Infectious Disease (HCID) units — currently designated at Royal Free London, Royal Victoria Infirmary Newcastle, and Sheffield Teaching Hospitals — are equipped and staffed to manage suspected Ebola cases under negative-pressure isolation with full barrier precautions.

However, the absence of a Bundibugyo-specific vaccine or antiviral introduces an additional dimension of clinical uncertainty. In the event of an imported case, the two licensed Ebola therapeutics, atoltivimab/maftivimab/odesivimab (Inmazeb) and ansuvimab (Ebanga) - monoclonal antibodies which target Ebola Zaire glycoprotein used to gain access to target cells, are unlikely to be effective against Bundibugyo virus. Treatment would necessarily be supportive, as in the affected DRC communities. Clinicians should be aware of this in the unlikely event that a returning traveller from eastern DRC or Uganda presents with a febrile illness and relevant exposure history.

The probability of such an event remains very low. Nonetheless, this outbreak is a reminder that the UK’s imported VHF preparedness must account not only for the most common Ebola strain, but for the full range of viral haemorrhagic fever pathogens - a lesson that was underlined, but not fully implemented, after previous Sudan virus and Marburg alerts.

Conclusion

The 2026 Bundibugyo Ebola outbreak in the DRC is the most significant Ebola event since the 2018–2020 North Kivu epidemic. It is the first WHO PHEIC for Ebola in six years, the largest documented Bundibugyo outbreak on record, and the first to demonstrate rapid multi-country spread within days of its identification. The outbreak exposes critical gaps: diagnostic infrastructure calibrated for a single strain, a vaccine availability that does not cover rare Ebola species, and a global response system under growing resource pressure.

The communities at the centre of this outbreak are once again facing the severest consequences. The international response, now formalised under PHEIC, must be sustained, well-resourced, and attentive to the structural conditions that made this crisis possible. For the global health community, this outbreak is both a test and a reckoning.

References

1. World Health Organization. Epidemic of Ebola Disease caused by Bundibugyo virus in the Democratic Republic of the Congo and Uganda determined a public health emergency of international concern. WHO statement, 17 May 2026.. Available at: https://www.who.int/news/item/17-05-2026-epidemic-of-ebola-disease-in-the-democratic-republic-of-the-congo-and-uganda-determined-a-public-health-emergency-of-international-concern

2. CNN. Latest Ebola outbreak an emergency of international concern, WHO declares. CNN, 17 May 2026.. Available at: https://www.cnn.com/2026/05/16/africa/congo-uganda-ebola-international-concern-intl-hnk

3. Imperial College London School of Public Health. Ebola outbreak 2026: Q&A with experts. Imperial News, 15 May 2026.. Available at: https://www.imperial.ac.uk/news/articles/2026/ebola-outbreak-2026-qa-with-experts/

4. Africa CDC. Africa CDC calls for urgent regional coordination following Ebola Virus Disease outbreak in Ituri Province, DRC, and imported Ebola Bundibugyo case reported by Uganda. Africa CDC statement, 15 May 2026.. Available at: https://africacdc.org/news-item/africa-cdc-calls-for-urgent-regional-coordination-following-ebola-virus-disease-outbreak-in-ituri-province-drc-and-imported-ebola-bundibugyo-case-reported-by-uganda/

5. Kupferschmidt K. Major outbreak of rare Ebola virus species in northern Congo alarms scientists. Science, 17 May 2026.. Available at: https://www.science.org/content/article/major-outbreak-rare-ebola-virus-species-northern-congo-alarms-scientists

6. Médecins Sans Frontières. MSF preparing large-scale response to Ebola outbreak in Ituri province. MSF, 16 May 2026.. Available at: https://www.msf.org/msf-preparing-large-scale-response-ebola-outbreak-ituri-province

7. MacNeil A, Farnon EC, Wamala J, et al. Proportion of deaths and clinical features in Bundibugyo Ebola virus infection, Uganda. Emerg Infect Dis. 2010;16(12):1969–72.. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC3294552/

8. Albariño CG, Shoemaker T, Khristova ML, et al. Molecular analysis of the 2012 Bundibugyo virus disease outbreak. PLOS Neglected Tropical Diseases, 2013.. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC8385243/

9. Centers for Disease Control and Prevention. Ebola outbreak history. CDC, 2026.. Available at: https://www.cdc.gov/ebola/outbreaks/index.html

10. Al Jazeera. Health officials raise alarm over new Ebola outbreak in DR Congo. Al Jazeera, 15 May 2026.. Available at: https://www.aljazeera.com/news/2026/5/15/health-officials-raise-alarm-over-new-ebola-outbreak-in-dr-congo

In late April 2026, passengers and crew aboard the MV Hondius, a Dutch-flagged expedition cruise ship returning from Antarctica and remote South Atlantic islands, began to fall gravely ill. Fever, pneumonia, and acute respiratory distress syndrome progressed rapidly. Three people died. Further confirmed or suspected cases of hantavirus infection were identified, with the Andes strain confirmed by PCR.

The ship, carrying 147 people from 23 countries, found itself marooned: Cape Verde lacked the capacity to manage an evacuation, and the president of the Canary Islands refused to allow the vessel to dock, citing fears of a local outbreak and the scarring memory of COVID-19. Spain’s central government eventually overruled him.

The Hondius saga is now, simultaneously, a clinical story, a public health story, and a story about how disease and inequality are inseparable — even at sea.

The leading investigative hypothesis is that the index cases, a Dutch couple, were exposed to infected rodent material during a birdwatching excursion to a landfill in Ushuaia, southern Argentina, before the voyage departed on 1 April 2026.

What is hantavirus, and why does the Andes strain matter?

Hantaviruses are a genus of single-stranded RNA viruses with a particular tropism for vascular endothelium. They are carried principally by rodents, which act as lifelong reservoirs without themselves becoming ill. Human infection is almost always acquired by inhaling aerosolised particles from infected rodent excreta. Most hantaviruses cause dead-end infections in humans: an individual gets sick, but the chain of transmission stops there. There is no person-to-person transmission.

The Andes virus, found predominantly in southern South America and carried by the long-tailed colilargo mouse (Oligoryzomys longicaudatus), is the single known exception. It is the only hantavirus strain for which human-to-human transmission has been documented. Transmission requires close, prolonged contact - household members, intimate partners, healthcare workers without adequate protection - and appears most likely during the early prodromal phase of illness.

Two principal disease syndromes result from hantavirus infection. Hantavirus Pulmonary Syndrome (HPS), the dominant pattern in the Americas, causes massive capillary leak into the pulmonary vasculature, producing non-cardiogenic pulmonary oedema and cardiogenic shock, with case fatality rates of 35–50% for the Andes strain. Haemorrhagic Fever with Renal Syndrome (HFRS), more common in Europe and Asia and caused by strains such as Puumala and Hantaan, primarily targets the kidney and carries lower but still significant mortality.

The pathophysiology: an immune system that becomes the enemy

Hantavirus pathology is immunopathological in nature. The virus does not destroy the endothelial cells it infects. Instead, it replicates within them while suppressing the early interferon response, buying time for widespread vascular spread before adaptive immunity can respond. When the immune response does engage, it is excessive and poorly regulated. A dense infiltrate of CD8+ cytotoxic T lymphocytes accumulates in affected tissues; the vigour of this response correlates with disease severity.

The result is a dysregulated cytokine storm — high TNF-α, IL-6, and interferon-γ — which destabilises the vascular endothelium through VE-cadherin disassembly (loosening the grip between endothelial cells and threatening barrier continuity) and elevated Vascular Endothelial Growth Factor (VEGF) signalling (increases vascular permeability). Capillary leak follows, flooding the lungs in HPS and the renal interstitium in HFRS. As the subsequent pulmonary oedema is due to increased capillary permeability, attempts to treat using a diuretic will not provide any benefit and can only decrease an already compromised circulating fluid volume.

Thrombocytopenia is almost universal, driven by platelet consumption, immune-mediated destruction, and direct viral binding via β3 integrin receptors, the receptors that hantavirus binds to to gain cellular access, and the occupation of which by the virus enhances the VEGF effect and further forces capillary leaking. Compensated disseminated intravascular coagulation can also emerge, with petechiae, haematuria, and occasionally more serious haemorrhagic complications.

In HPS specifically, a distinctive haemodynamic profile with low cardiac output, high systemic vascular resistance and relative bradycardia reflects direct cytokine-mediated myocardial depression rather than distributive shock. This pattern can mislead clinicians unfamiliar with the syndrome.

Could this become the next pandemic?

The question has circulated widely since the Hondius outbreak broke in early May 2026. The WHO has assessed the global public health risk as low, and epidemiologists are not anticipating a COVID-like scenario.

SARS-CoV-2 achieved global reach because it spread efficiently in the presymptomatic and asymptomatic phases: infected individuals who felt entirely well were seeding communities for days before their illness was apparent. Hantavirus does not do this. Individuals are not infectious before symptoms appear, and symptoms are severe enough to incapacitate quickly. The virus’s lethality constrains its spread.

Even in the Hondius outbreak, a confined ship with over 150 people in sustained close contact, an almost ideal scenario for respiratory pathogen spread, transmission remained limited to individuals with the most direct exposure. The R value estimated during the 2018–2019 Epuyen outbreak in Argentina, the largest documented Andes outbreak, was 2.12 before control measures, falling to 0.96 after their implementation. These figures reflect superspreader-driven dynamics in a tightly clustered community context, not a baseline biological constant, and should not be extrapolated to general population settings.

Continued vigilance, however, is necessary because of gaps in knowledge. Hantaviruses have been comparatively under-studied compared to other viruses. The mechanism by which the Andes virus acquired human-to-human transmissibility is not fully understood. No approved vaccine exists for any Americas-affecting hantavirus strain. And rising rodent populations in endemic regions, potentially linked to climate-driven shifts in habitat and food availability, may increase the frequency of zoonotic spillover events that could, in theory, provide further opportunities for adaptive evolution - and for human-to-human transmission.

At present, there is no specific treatment for hantavirus infection though access to intensive care does improve outcomes.

Who bears the burden?

The Hondius outbreak occurred aboard a luxury expedition cruise ship carrying passengers from wealthy nations on a voyage to Antarctica, but hantavirus is fundamentally a disease of poverty and marginalisation.

In endemic regions of South America, hantavirus disproportionately affects agricultural workers, forestry workers, and those living in rural housing with inadequate rodent exclusion. In Argentina, where the Andes strain is most prevalent, cases cluster among low-income rural communities with limited access to healthcare, poor housing stock, and occupational exposures that cannot be easily avoided. The 25.7% case fatality rate recorded across the Americas in 2025 reflects, in part, the absence of ECMO infrastructure in communities where cases actually occur. Survival from severe HPS in a well-resourced intensive care unit is better than survival in a rural district hospital.

In the UK context, hantavirus remains rare but is present. The predominant strains are Seoul virus (carried by brown rats) and Puumala virus (carried by bank voles). Cases are most commonly associated with occupational exposure - agricultural workers, sewer workers, laboratory staff, and increasingly, pet rat owners and hobbyist rat breeders. The UKHSA monitors cases and issues guidance on safe handling of potentially contaminated environments. Critically, rodent infestation in substandard housing represents a structural exposure risk that no amount of individual health messaging can adequately address without improvement in housing conditions.

For healthcare workers, awareness of hantavirus is important because of the importance in avoiding diagnostic delay. The prodromal syndrome is non-specific - fever, myalgia, headache, nausea, abdominal pain, very much like a flu or Covid presentation - and in the UK context, a clinician who has not considered hantavirus may pursue an extensive differential workup before the diagnosis is made. Occupational and exposure history, including contact with rodents or rodent-contaminated environments, should be routine.

Clinical and public health takeaways

• Consider the exposure history. In any febrile illness with rapid respiratory deterioration, ask about rodent contact, rural environments, or travel to South America.

• Thrombocytopenia plus haemoconcentration is a useful early marker of capillary leak syndrome; combined with an appropriate exposure history, it should prompt hantavirus testing.

• The haemodynamic profile of HPS - low output, high resistance, relative bradycardia - is distinct from septic shock and requires a different management approach.

• ECMO capability. Referral to an ECMO-capable centre for severe HPS should be considered early.

• Infection control in suspected cases should include respiratory precautions given the theoretical risk of aerosol transmission, particularly for the Andes strain.

• Housing and occupational policy are hantavirus prevention. Individual advice is necessary but insufficient without structural intervention in the conditions that drive rodent exposure.

Key references

WHO Disease Outbreak News — Hantavirus cluster linked to cruise ship travel, Multi-country (May 2026)

Superspreaders and person-to-person transmission of Andes virus in Argentina — NEJM (2020)

Person-to-person transmission of Andes virus — NCBI PMC

Human-to-human transmission of Andes virus modelled in Syrian hamsters — Emerging Infectious Diseases (2023)

WHO Hantavirus Fact Sheet

MV Hondius hantavirus outbreak — Wikipedia (live updates)

UKHSA guidance on hantavirus in the UK

As understanding of post-COVID syndromes matures, clinicians increasingly encounter neurological symptoms extending beyond fatigue and cognitive dysfunction. Visual complaints are common, but most are non-specific. Diplopia is less frequent, yet it warrants careful attention because it usually indicates disturbance of ocular alignment or ocular motor control rather than primary ocular surface disease.

The published evidence to date supports a cautious position: ocular motor palsies and diplopia have been reported following SARS-CoV-2 infection, chiefly in acute and subacute settings, and their prevalence and natural history within clearly defined Long Covid cohorts remain incompletely characterised. Early in the pandemic, Neurology reports described COVID-19 presenting with ophthalmoparesis attributable to cranial nerve palsy. Subsequent literature has continued to document oculomotor, trochlear, and abducens nerve palsies temporally associated with COVID-19 infection.

Beyond discrete cranial nerve palsies, a separate strand of evidence concerns oculomotor control in post-COVID condition (PCC). Objective eye-tracking studies in PCC, particularly among individuals with cognitive complaints, have reported alterations across saccades, pursuit, fixation, vergence, and pupillary parameters. Other cohorts have reported vision-related symptoms and measurable oculomotor findings in non-hospitalised post-COVID populations. These studies support the broader proposition that ocular motor function may be affected in some PCC patients. However, it remains premature to claim that specific syndromes such as convergence insufficiency are common without stronger prevalence data.

A small but important differential is myasthenia gravis (MG). New-onset MG has been reported after SARS-CoV-2 infection, sometimes beginning with oculo-bulbar symptoms including diplopia and ptosis. While myasthenia gravis is unlikely to explain most post-COVID visual complaints, its consequences are significant enough that fluctuating diplopia or fatigable ptosis should trigger appropriate evaluation and referral.

For generalists, the practical message remains one of measured vigilance. New-onset diplopia requires structured assessment and urgent triage where red flags are present. Where investigations are unrevealing and symptoms are stable, a post-infectious mechanism may be considered---but only after exclusion of time-critical pathology.

In summary, the evidence supports that diplopia and ocular motor dysfunction can occur after SARS-CoV-2 infection, and objective studies suggest oculomotor control changes in some PCC patients. What remains uncertain is how often diplopia forms part of Long Covid, which patients are at risk, and which interventions best help. Until better cohort data emerge, clinical curiosity should be paired with careful follow-up.

Long Covid and diplopia — key clinical points

Read more

Summary.

The RAAS is a critical hormonal cascade that helps maintain arterial blood pressure, extracellular fluid volume, and electrolyte balance. It co-ordinates renal, vascular, and adrenal functions and interfaces with the sympathetic nervous system, vasopressin release, natriuretic peptides and local tissue systems (notably in the heart, kidney, and brain). It is a finely tuned, multi-organ system that maintains cardiovascular and fluid homeostasis.

Dysregulation contributes to hypertension, heart failure, kidney disease, and inflammatory pathologies. The RAAS is a critical hormonal cascade that helps maintain arterial blood pressure, intravascular volume, and electrolyte balance. It co-ordinates renal, vascular, and adrenal functions and interfaces with the sympathetic nervous system, vasopressin release, and local tissue systems (notably in the heart, kidney, and brain).

Modern therapeutics target this system at multiple points — renin, ACE, AT₁ receptors, and aldosterone — to modulate its activity and prevent end-organ damage.

Pathway.

Renin is synthesised and stored in juxtaglomerular (JG) cells of the kidney afferent arteriole, and is released into the blood in response to reduced renal perfusion pressure (detected by juxtaglomerular baroreceptors) and to reduced sodium chloride delivery to the macula densa.

It is also released in response to sympathetic activation via β₁-adrenoceptors at the juxtaglomerular cells.

Renin, an aspartyl protease, cleaves angiotensinogen in plasma to the decapeptide angiotensin I (Ang I).

Angiotensinogen, itself, is a glycoprotein produced mainly by the liver. Its production is increased by oestrogen, corticosteroids, thyroid hormone, and inflammation (IL-6–mediated).

Circulating angiotensin I is inactive but is converted to the active angiotensin II by Angiotensin-Converting Enzyme (ACE) on the vascular endothelial cells - particularly in the pulmonary and renal circulations. Angiotensin-Converting Enzyme removes two amino acids from angiotensin I to form angiotensin II (Ang II). It also degrades bradykinin, a vasodilator peptide, adding to the vasoconstrictive effect .

Angiotensin II acts mainly on the angiotensin II receptors AT₁ and AT₂ (both G protein-coupled receptors).

AT₁R: Mediates vasoconstriction, aldosterone release, sympathetic activation, sodium retention, and cellular growth.

AT₂R: Counter-regulatory — promotes vasodilation, anti-proliferation, apoptosis, and NO release. Although angiotensin II binds both AT₁ and AT₂ receptors, many of the vasodilatory and anti-fibrotic effects classically attributed to AT₂ activation are mediated in parallel by the angiotensin-(1–7)/Mas receptor axis.

Aldosterone is synthesised in the zona glomerulosa of the adrenal cortex. It is released following Ang II stimulation, directly in hyperkalaemia and, to a lesser extent, in response to ACTH.

It binds mineralocorticoid receptors in the distal nephron (principal cells) to:

↑ Na⁺ reabsorption via the epithelial sodium channels (ENaC) channels.

↑ K⁺ secretion via the renal outer medullary potassium (ROMK) channels.

↑ water reabsorption (secondary to sodium retention).

Aldosterone activity results in expanded extracellular volume and elevated blood pressure.

The effects of RAAS activity are counterbalanced by ACE2 which converts Ang II to Ang (1–7). This acts via Mas receptors producing vasodilation, anti-fibrosis, and anti-inflammatory effects.

Natriuretic peptides (ANP, BNP) also oppose RAAS activity by promoting loss of sodium in the urine, vasodilation, and suppression of renin/aldosterone.

Physiological Effects.

Cardiovascular.

Angiotensin II acts directly upon AT₁ receptors in vascular smooth muscle producing vasospasm, so increasing systemic vascular resistance (SVR). If the cardiac output remains constant, this action will increase the blood pressure.

Direct cardiac effects include positive inotropy and myocardial hypertrophy. Chronic stimulation can lead to myocardial fibrosis.

Renal.

RAAS activity promotes efferent arteriolar constriction which maintains glomerular filtration pressure during hypotension.

At the renal tubules, aldosterone increases Na⁺ reabsorption and K⁺ secretion in the principal cells of the distal tubule and collecting duct via its effect upon the epithelial sodium channels (ENaC) and the renal outer medullary potassium channels (ROMK channels).

Neurohormonal.

The RAAS can stimulate thirst through its effects upon the hypothalamus, and increase ADH (vasopressin) release which leads to water retention.

There is also sympathetic activation via brainstem nuclei, with consequent adrenergic effects upon the heart and circulation.

Cellular Mechanisms.

• AT₁ Receptor: A G-protein–coupled receptor (GPCR) activating phospholipase C leads to IP₃ + DAG, ↑ intracellular Ca²⁺ and, consequently, vasoconstriction, aldosterone synthesis, and cellular growth.

• Aldosterone mechanism: Nuclear receptor binding leads to increased transcription of ENaC and Na⁺/K⁺-ATPase subunits so facilitating increased Na⁺ re-uptake.

Clinical Relevance.

In heart failure, chronic RAAS activation leads to vasoconstriction, sodium retention and cardiac remodelling. ACE inhibitors, ARBs, MRAs (spironolactone) can be beneficial.

Hypertension is associated with over-activity of the angiotensin II/aldosterone axis. Appropriate therapeutic options include ACE inhibitors, angiotensin receptor blockers and renin inhibitors.

Glomerular hypertension and fibrosis from persistent from persistent angiotensin II stimulus is a feature of chronic kidney disease (CKD). RAAS blockade can slow CKD progression.

In COVID-19, use of ACE2 receptor by the coronavirus disrupts balance between angiotensin II and angiotensin (1-7) and AT₁R and MasR signalling - a possible link to endothelial injury and cytokine storm; also to potential therapeutic options.

Suggested Reading.

Classical RAAS physiology

• Hall JE, Guyton AC

Textbook of Medical Physiology

Elsevier (latest ed.)

Gold-standard integrative physiology reference

Chapters on renal sodium handling, RAAS, pressure–natriuresis

Especially strong on system-level control of BP

https://www.elsevier.com/books/guyton-and-hall-textbook-of-medical-physiology/hall/978-0-323-59712-8

• Atlas SA

The renin–angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition

Journal of Managed Care Pharmacy (2007)

Clear overview of classical RAAS

Good bridge between physiology and therapeutics

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673245/

DOI: https://doi.org/10.18553/jmcp.2007.13.s8-b.9

• Peach MJ

Renin–angiotensin system: biochemistry and mechanisms of action

Physiological Reviews (1977)

Older but still authoritative

Excellent mechanistic detail on Ang II signalling

https://journals.physiology.org/doi/10.1152/physrev.1977.57.2.313

ACE2, Ang-(1–7), Mas receptor (counter-regulatory RAAS)

• Donoghue M et al.

A Novel Angiotensin-Converting Enzyme–Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9

Circulation Research Volume 87, Issue 5, 1 September 2000; Pages e1-e9

Landmark paper identifying ACE2 as a functional RAAS enzyme

https://doi.org/10.1161/01.RES.87.5.e1

• Santos RAS, et al.

The ACE2/Angiotensin-(1–7)/Mas Axis of the Renin–Angiotensin System: focus on angiotensin-(1–7)

Physiological Reviews, 2018

This review highlights roles of Ang-(1–7) via the Mas receptor and describes how this axis counterbalances the “classical” RAAS (Ang II/AT$_1$) in the heart, vessels, and kidneys.

https://pubmed.ncbi.nlm.nih.gov/29351514/

DOI: https://doi.org/10.1152/physrev.00023.2016

• Patel VB, Zhong J-C, Grant MB, Oudit GY

Role of the ACE2/Ang-(1–7) Axis of the Renin-Angiotensin System in Heart Failure

Circulation Research (2016)

Clinical relevance of ACE2

Heart failure, vascular disease, remodelling

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.116.307708

DOI: https://doi.org/10.1161/CIRCRESAHA.116.307708

RAAS, ACE2, and modern disease (HFpEF, lung, endothelium)

• Imai Y, Kuba K, Rao S et al.

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Nature (2005)

Key demonstration of ACE2 as a protective enzyme

Foundational for later COVID-19 work

https://www.nature.com/articles/nature03712

DOI: https://doi.org/10.1038/nature03712

• Vaduganathan M et al.

Renin–angiotensin–aldosterone system inhibitors in patients with COVID-19

NEJM (2020)

Clinical clarification of ACEi/ARB effects on ACE2

Important for modern interpretation

https://www.nejm.org/doi/full/10.1056/NEJMsr2005760

DOI: https://doi.org/10.1056/NEJMsr2005760

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