Emerging Diseases & Zoonoses — Questions

A complete answer confirms the outbreak briefly, then concentrates on practical, RSV-appropriate infection prevention and control, because that is what stops transmission.

a. Confirm the outbreak and define cases. Confirm RSV by polymerase chain reaction, confirm that the number exceeds the expected background, and set a working case definition (a neonate on the unit with a compatible illness and laboratory-confirmed RSV in the period). Use rapid point-of-care testing to identify cases quickly, since prompt detection drives cohorting.

b. Establish the extent. Actively screen all neonates and staff for compatible illness, compile a line listing, and plot cases by onset and cot location to see how far transmission has reached. Keep this brief: it orients control but must not delay it.

c. Institute infection prevention and control (the priority). RSV spreads by respiratory droplets and by contact with secretions on hands, surfaces and shared equipment, so control targets those routes:

• Hand hygiene is the single most effective measure: alcohol-based hand rub before and after every contact, reinforced for staff, parents and visitors.
• Contact and droplet precautions for all cases and contacts: gloves and gowns for hands-on care, surgical mask and eye protection for close or aerosol-generating contact.
• Cohort infected neonates in one area and cohort the nursing staff, so dedicated staff care for infected or for uninfected babies but do not cross between them.
• Exclude symptomatic staff from work and restrict visitors with respiratory symptoms; limit non-essential entry to the unit.
• Environmental cleaning and equipment decontamination: disinfect surfaces and shared items, and dedicate equipment (stethoscopes, monitors, saturation probes) to each cohort.
• Relieve overcrowding and understaffing and ensure adequate spacing between cots, both established risk factors for nosocomial RSV.
• Close the unit to new admissions if transmission continues despite the above.
• Consider RSV monoclonal antibody prophylaxis (palivizumab or nirsevimab) for high-risk exposed neonates per local policy, recognising its role in outbreak control is adjunctive and the evidence limited.

d. Surveillance, communication and closure. Notify the infection prevention and control team and unit management, maintain active surveillance for new cases, educate staff, and declare the outbreak over once no new cases occur for two incubation periods (RSV incubation is about two to eight days).

A complete answer defines the term and names two distinct mechanisms.

Definition. An emerging viral infection is one newly recognised in a host or population, or a known infection expanding into a new geographical area or host species, often with a change in pathogenicity.

Mechanisms (any two):

• Zoonotic spillover from an animal reservoir, the dominant route, which introduces genuinely new genetic material into the human population.
• Genetic change in an existing virus: reassortment (as in influenza A), recombination, or mutation and selection that extends host range or virulence.
• Ecological or behavioural change that brings an endemic virus into new contact with people, or a breakdown of control (falling vaccine coverage) that allows re-emergence.

Antigenic drift is the gradual accumulation of point mutations in the surface proteins, selected because they evade existing antibody. The change is small and incremental, drives seasonal epidemics, and is why the influenza vaccine is reformulated each year.

Antigenic shift is the abrupt acquisition of a new surface protein by reassortment when two strains co-infect one host. The change is large, produces a subtype the population has little immunity to, and can cause a pandemic.

Notifiable Medical Condition (NMC) reporting is the statutory surveillance system that requires designated conditions to be reported to the public-health authority.

• Legal basis. Reporting is mandatory under national health legislation (in South Africa, the National Health Act), placing a duty on both clinicians and laboratories.
• Categories by urgency. Conditions are graded by how fast they must be reported: the most serious, such as the viral haemorrhagic fevers, measles and acute flaccid paralysis, require immediate notification within 24 hours, while others allow a few days.
• Who reports and how. The attending clinician and the diagnostic laboratory both notify, increasingly through an electronic system that improves completeness and timeliness.
• Purpose. Notification triggers the public-health response (contact tracing, prophylaxis, outbreak control) and feeds national and global surveillance.

Surveillance is often hardest where it is most needed, at the sites where emerging viruses first appear.

• Weak laboratory infrastructure. Limited testing capacity and unreliable supply chains delay or prevent confirmation, and reference testing may be far away.
• Incomplete vital registration. Many deaths go unregistered or uncertified, so mortality data are poor; verbal autopsy is sometimes the only tool.
• Under-reporting. Passive systems capture only a fraction of cases where access to care is low and reporting is not resourced.
• Workforce and funding gaps. Too few trained field epidemiologists and competing priorities limit timely analysis and response.
• Mitigations. Sentinel sites, community-based surveillance, mobile-phone reporting, simple tools and field-epidemiology training programmes extend reach at lower cost.

Crimean-Congo haemorrhagic fever virus infects mononuclear phagocytes (monocytes and macrophages), dendritic cells, endothelial cells and hepatocytes.

Infection of macrophages and dendritic cells triggers release of pro-inflammatory cytokines which, with direct infection of endothelium, increases vascular permeability and activates coagulation, producing capillary leak and disseminated intravascular coagulation. Infection of hepatocytes causes hepatic necrosis. Together these drive the multi-organ failure of severe disease.

Surveillance is the ongoing, systematic collection, analysis, interpretation and dissemination of health data, linked to action: “information for action”.

• Systematic and continuous. Data are gathered routinely against a standard case definition, not ad hoc.
• The surveillance cycle. Collection feeds analysis and interpretation, then dissemination, then public-health action, with feedback to the providers of the data; a weak link degrades the whole.
• Fit for purpose. Systems are chosen and judged against attributes that trade off, chiefly sensitivity, timeliness, representativeness and predictive value.
• A clinical trigger plus laboratory confirmation. Effective viral surveillance pairs a syndromic or clinical signal (influenza-like illness, acute flaccid paralysis) with laboratory confirmation and, increasingly, genomic and environmental data.

Human behaviour and movement repeatedly turn a contained reservoir virus into a human problem.

• Travel. Air travel disperses a virus globally within days, as the spread of SARS-CoV-2 from China to dozens of countries showed; the journeys an index case makes can decide whether an outbreak is containable.
• Trade and food systems. The wildlife trade and live-animal markets place reservoir species in contact with people, and intensive farming creates amplifying hosts.
• Encroachment. Deforestation and movement into wild habitat expose people to novel viruses and remove the predators that limit reservoir populations.
• Behaviour. Changes in sexual behaviour, injecting drug use and new medical procedures alter the transmission of endemic viruses such as the human immunodeficiency virus (HIV) and hepatitis B.
• Displacement and conflict. War and the collapse of public-health programmes allow re-emergence, as poliovirus did in Gaza in 2024.

• Heavy rainfall: prolonged rains, often in an El Nino year, flood shallow depressions (dambos).
• Mosquito hatching: flooding hatches Aedes eggs already carrying the virus through transovarial transmission.
• Livestock amplification: the virus amplifies in sheep, cattle and goats, producing abortion storms that act as a sentinel.
• Secondary vectors: Culex and other mosquitoes amplify transmission further.
• Human spillover: people are infected by mosquito bites and by contact with infected animal tissues at slaughter, veterinary work or nursing sick animals.

Because viruses evolve fast enough to differ over short periods, their sequences carry information about how they are related and how they have spread.

• Reconstructing transmission. Genetically near-identical viruses from different patients suggest a recent common source or transmission chain, while greater genetic distance argues against a direct link; this is used to investigate nosocomial outbreaks and to map an epidemic’s spread.
• Dating and origin. Tip-dated phylogenies, using each sequence’s sampling date, estimate when the most recent common ancestor existed and where a lineage arose.
• Reading the tree. Branch support such as bootstrap values indicates how reliable a grouping is, and trees that disagree across the genome flag recombination.
• Tracking change. The same methods follow the emergence and spread of drug-resistance and immune-escape variants.

Zoonotic spillover is the transmission of a virus from its animal reservoir into people. Most emerging viruses are zoonotic, and spillover is the event that introduces new viral genetic material into the human population.

For a spillover to lead anywhere, several barriers must be crossed: the virus must reach a susceptible person, attach to and enter human cells (usually requiring receptor compatibility), then replicate and shed efficiently enough to pass to the next host. Many zoonotic viruses cannot transmit between people, so their human basic reproduction number (R0) is near zero and every case needs fresh exposure to the reservoir. Spillover is more likely between closely related host species, which share similar cell receptors and habitat.

A case definition is the agreed set of criteria for counting someone as a case, applied consistently throughout an investigation.

• Comparability. A standard definition lets cases be counted the same way across person, place and time, so a rise is real and not an artefact of differing clinical judgement.
• Sensitivity then specificity. Early, suspected definitions are deliberately broad so true cases are not missed; they are tightened to probable and confirmed for the analytic study to reduce misclassification.
• Avoiding bias. When testing an unknown source, the definition must not include the exposure under investigation, or the association becomes circular.
• Triage. Layered definitions also guide who is isolated, treated and tested when capacity is limited.

The laboratory turns clinical suspicion into confirmed fact and links cases that clinical features alone cannot.

• Confirming the agent. Identifying, or excluding, the causative virus verifies that an outbreak is real and establishes what it is.
• Linking cases. Molecular typing and genomic sequencing show whether separate cases share a strain, defining the outbreak’s extent and its transmission chains.
• Early signal. Laboratory-based reporting and reference-laboratory networks often detect an unusual cluster before clinical notification does.
• Guiding response. Strain characterisation informs antiviral susceptibility, vaccine matching and the choice of control measures.

Roughly one third of emerging and re-emerging infections are caused by ribonucleic acid (RNA) viruses, out of proportion to their share of known viruses. The reason is their capacity for rapid evolution.

• High mutation rates. The RNA-dependent RNA polymerase lacks proofreading, generating about one mutation per genome per replication and a diverse variant population from which host-adapted mutants are selected.
• Large populations and short generation times mean advantageous variants arise and are selected quickly.
• Recombination and, in segmented genomes, reassortment produce sudden, large genetic change, including new host-range or virulence determinants.

Together these let an RNA virus adapt to a new host over days to weeks, against the years to millennia over which the host evolves its defences.

The primary vector is the Hyalomma tick (notably Hyalomma marginatum and H. rufipes).

• Long mouthparts: a long hypostome and palps, longer than in most other hard ticks.
• Banded legs: pale and dark striping along the legs.
• Eyes on the scutum: distinct eyes at the margins of the shield, on a relatively large red-brown body.

• Hyalomma tick exposure: the Hyalomma tick is both reservoir and vector, and farming and outdoor work in the drier interior bring people into contact with infected ticks.
• Livestock contact at slaughter: viraemic cattle, sheep and goats transmit through blood and tissues during slaughter, dehorning and castration, so abattoir and farm workers are at risk.
• Nosocomial and contact spread: a viraemic patient’s blood and body fluids transmit to carers and health workers, extending outbreaks beyond the animal exposure.

Acute flaccid paralysis (AFP) surveillance is the backbone of polio eradication: every case of sudden floppy weakness is investigated to prove or exclude poliovirus.

• Sensitivity. Detect at least the expected background of non-polio AFP, a target of around 1 to 2 cases per 100,000 children under 15 years, which shows the system finds cases even where polio is absent.
• Completeness and timeliness. Report and investigate every case promptly, with immediate case investigation.
• Adequate stool specimens. Collect two stool samples 24 to 48 hours apart, within 14 days of onset, transported in a cold chain to an accredited laboratory.
• Laboratory confirmation. Test within the WHO-accredited poliovirus laboratory network, with genomic characterisation to distinguish wild, vaccine (Sabin) and vaccine-derived strains.

SA case definition

The NICD aligns with the WHO clinical case definition, with four tiers under the Notifiable Medical Condition (NMC) framework:

• Suspected case — fever + generalised maculopapular (non-vesicular) rash + at least one of cough, coryza, or conjunctivitis. Or any case a clinician considers compatible with measles.
• Laboratory-confirmed — a suspected case with positive measles IgM, measles RNA by RT-PCR, or a 4-fold rise in measles IgG between paired sera; and no measles-containing vaccine within ~6 weeks (which can cause false-positive IgM).
• Epidemiologically linked — a suspected case with documented exposure to a lab-confirmed case (acceptable in an established outbreak).
• Discarded — investigated and lab-negative.

Context of use

Measles is a Category 1 NMC — suspected cases must be reported to NICD immediately (within 24 hours). The definition drives:

• the public-health response — contact tracing, PEP for susceptible contacts, exclusion of cases and unvaccinated contacts;
• elimination surveillance — SA, as part of the WHO African Region, is measured against indicators including the discarded non-measles-case rate and the proportion of suspected cases with adequate specimens;
• early outbreak detection — a single lab-confirmed case in a previously elimination-status area triggers an outbreak response.

Role of the laboratory

In a suspected case — confirm or exclude with measles IgM serology (routine) and RT-PCR on respiratory/urine/oral-fluid specimens (more sensitive in early disease and in the immunocompromised). Test relevant differentials, particularly rubella IgM (also reportable, same elimination programme), and parvovirus B19, dengue or chikungunya as clinical features dictate. Notify NICD on any positive result.

In a confirmed case — genotype at the NICD reference laboratory (450-nt N-gene C-terminal region, sometimes the H gene) to assign one of the 8 clades / 24 genotypes. Genotyping supports source attribution (imported vs endemic), transmission-chain mapping, vaccine-strain identification (when a vaccinee presents IgM-positive), and submission to the WHO MeaNS database — required for elimination certification (continuous interruption of endemic genotype for ≥12 months).

The laboratory is therefore both a clinical service (confirming the case in front of the registrar) and a public-health instrument (elimination surveillance and outbreak attribution).

A complete answer describes the clinical association, the biological mechanism and the determinants of risk.

The association

The 2015 to 2016 American epidemic was accompanied by a marked rise in infants born with microcephaly, first recognised in north-east Brazil, which drew the link between maternal Zika infection and congenital brain injury and prompted a WHO public health emergency in 2016.

Congenital Zika syndrome

Microcephaly is the hallmark of a broader congenital Zika syndrome that also includes intracranial calcification, ventriculomegaly, ocular lesions such as macular scarring, congenital contractures and sensorineural hearing loss, with later neurodevelopmental impairment; infection can also cause miscarriage and stillbirth.

Mechanism

Zika virus has a tropism for fetal neural progenitor cells, in which it impairs proliferation and causes cell death, interrupting cortical development; the placenta and fetal tissues sustain the infection that seeds the fetal brain.

Determinants of risk

The risk is greatest with infection in the first trimester, though injury can follow later infection. Because about 80% of maternal infections are asymptomatic, exposure is often unrecognised, which is why maternal serology and fetal ultrasound surveillance are central to management.

A complete answer covers the incubation and onset, the characteristic rash and arthritis, the usual course and recovery, the chronic joint sequela, and brief epidemiological framing.

Incubation and onset. After an incubation of about two to eight days, the illness begins abruptly, with fever, rash and joint pain arising together over a short period during a brief viraemia.

Rash. A maculopapular, often intensely itchy rash spreads over the trunk and limbs and may involve the palms and soles; individual lesions can develop a central vesicle, and the rash is occasionally haemorrhagic.

Arthritis. Arthralgia and arthritis favour the larger joints, the ankles, knees, wrists and elbows, and may be severe enough to limit movement, accompanied by myalgia and malaise.

Course and recovery. The illness is self-limited, settling in most people within about two weeks, and the great majority recover completely; severe or fatal disease is rare, and infection confers lasting immunity.

Chronic sequela. In about a third of patients, arthralgia and joint stiffness persist for months and sometimes years after the acute illness, the principal long-term morbidity.

Epidemiological framing. The disease is a seasonal late-summer illness of northern Europe (where it is called Pogosta fever, Ockelbo disease and Karelian fever) and of southern Africa, arising as a spillover from a wild-bird and mosquito cycle.

A complete answer marshals the epidemiological, virological and biological lines of evidence that together establish causation rather than mere association.

Epidemiological evidence

The temporal and geographic coincidence of the microcephaly surge with the wave of Zika transmission, the sharp rise above expected baseline rates, and the reproduction of the association across affected regions and in later outbreaks support a causal link. The greatest risk with first-trimester infection provides a biological gradient consistent with a teratogen.

Direct virological evidence

Zika viral RNA and antigen have been detected in the amniotic fluid, fetal brain tissue and placenta of affected pregnancies, and virus has been recovered from the brains of infants with microcephaly, placing the virus at the site of injury.

Biological plausibility

Zika virus infects and kills neural progenitor cells in cell and animal models, and infection of pregnant animals reproduces fetal brain injury, providing an experimental mechanism.

Judgement

Applying causal criteria of strength, consistency, temporality, biological gradient, plausibility and experimental support, the evidence is judged sufficient to conclude that Zika virus infection causes congenital microcephaly and the wider congenital Zika syndrome.

Emergence is driven by viral, host, and ecological factors acting together.

Viral factors. Error-prone replication generates a quasispecies from which variants with new properties are selected; reassortment (as in influenza A) and recombination can produce sudden, large genetic change. A virus long adapted to its natural host is often of low virulence there, but the same virus on jumping to a new host species, with which it has no evolutionary history, may cause severe disease. Acquisition of a new receptor usage or a virulence determinant, such as a polybasic haemagglutinin cleavage site, can extend host range or pathogenicity.

Host and ecological factors. Most emerging viruses are zoonotic, crossing from an animal reservoir at points of contact widened by deforestation, agricultural intensification, the wildlife trade, and urbanisation. Expanding vector ranges, human population growth, displacement and travel, and growing numbers of immunocompromised hosts all increase spillover and onward spread. Breakdown of control measures, including falling vaccine coverage, allows re-emergence of agents once suppressed.

Examples. SARS-CoV-2 (a coronavirus spillover causing a pandemic), pandemic and highly pathogenic avian influenza (reassortment and host-range change), Zika and Ebola viruses (expansion from limited foci into large outbreaks), and mpox (spread beyond its previous range). Re-emergence is seen where measles or poliovirus return as vaccination coverage falls. The unifying theme is a virus meeting a new or newly susceptible host population.

A complete answer separates the sources of new variation from the forces that shape it.

Sources of genetic variation

• Mutation. Error-prone polymerases, lacking proofreading in RNA viruses, generate about one mutation per genome per replication, the ultimate source of all variation.
• Recombination. Co-infection lets RNA-virus polymerases switch templates (copy-choice), combining changes from two genomes in a single step; it is frequent in retroviruses and coronaviruses.
• Reassortment. Segmented viruses such as influenza A exchange whole segments, producing abrupt change (the basis of antigenic shift).

Forces that shape variation

• Natural selection. Purifying selection removes the many deleterious mutations; positive selection fixes the few advantageous ones (immune escape, drug resistance, host adaptation), measurable as dN/dS.
• Genetic drift and bottlenecks. Within a host, vast populations make selection efficient; at transmission a severe bottleneck, sometimes a single particle, lets chance dominate.
• Constraints. The mutation rate is capped by an error threshold that limits genome size, and compact genomes with overlapping functions tolerate little change.

Consequences

The product is a fast-moving, diverse population (sometimes modelled as a quasispecies) that pre-contains immune-escape and resistance variants, evolves on a measurable molecular clock, and can adapt to new hosts. Evolution is therefore the engine of antigenic variation, drug resistance and emergence.

A complete answer links why displaced populations are at higher viral risk to the public-health response that risk demands.

Why displaced populations are at higher risk

• Overcrowding and poor sanitation in camps and informal settlements favour faecal-oral and respiratory spread (measles, hepatitis A and E, poliovirus).
• Collapsed services and vaccination gaps leave susceptible cohorts, allowing re-emergence of vaccine-preventable viruses, as with measles outbreaks and the return of poliovirus in conflict zones such as Gaza in 2024.
• Movement across boundaries carries viruses into new areas and exposes migrants to agents to which they have no immunity.
• Interrupted treatment for chronic viral infection (HIV, hepatitis B) worsens both individual outcomes and onward transmission.

The public-health response

• Catch-up and mass vaccination (measles, polio) on arrival.
• Surveillance with adapted case definitions, using syndromic surveillance where laboratory capacity is limited.
• Water, sanitation and shelter to interrupt transmission.
• Continuity of care for chronic infections, and integration of migrant health into national systems rather than parallel provision.

The unifying theme is that displacement removes the social and programmatic barriers that normally hold viruses in check, so the response must rebuild those barriers quickly.

Expanded dengue syndrome describes organ-specific disease, such as hepatitis, myocarditis or encephalopathy, beyond the classical plasma-leakage picture.

Dengue is not chronic, the term is not a vaccine effect, and it is neither limited to pregnancy nor a description of Zika co-infection.

The Far-Eastern subtype has a predilection for the anterior horn cells of the cervical cord, producing a poliomyelitis-like flaccid paralysis of the shoulder girdle and arms.

Retinitis, a purely sensory neuropathy, a hepatic haemorrhagic fever and isolated facial palsy are not the characteristic pattern.

Leptospirosis can reproduce the fever, jaundice, bleeding and renal impairment of severe yellow fever and is treatable, so it must be excluded; severe malaria, viral hepatitis and other viral haemorrhagic fevers also enter the differential.

The remaining options do not cause this jaundice-plus-haemorrhage-plus-renal picture.

Because hantavirus species cross-react serologically, a positive screen is confirmed with a species-specific or neutralisation assay.

The screen alone cannot identify the species, and culture, marrow biopsy and simply repeating the screen do not resolve it.

Hepatitis B virus is digested in the mosquito gut and never replicates in or migrates through the insect, so it is not an arbovirus even though it circulates in blood.

Yellow fever, dengue, West Nile and Rift Valley fever viruses all replicate in their vectors and are true arboviruses.

By day 10 the viraemia has usually cleared and antibody has risen, so IgM and IgG serology is the diagnostic approach.

NS1 antigen, RT-PCR and culture detect the virus directly and are reliable only in the first few days, while the patient is viraemic.

Infection gives durable protection against the infecting serotype but only short-lived cross-protection against the other three, which is why a later heterologous infection is possible and dangerous.

Immunity is neither lifelong across all serotypes nor absent, and it is not limited to a single other serotype or sterilising for the genus.

Zika IgM cross-reacts strongly with dengue and other flaviviruses, so a reactive result needs confirmation by plaque-reduction neutralisation, and interpretation is harder in people with prior flavivirus exposure or vaccination.

Neutralisation measures antibody rather than RNA, is more not less laborious, and the timing statements are incorrect.

Qdenga can be given without screening a recipient’s dengue serostatus first, and is WHO-recommended for children in high-transmission settings.

It still needs a cold chain and two doses, protects only against dengue, and does not replace vector control.

The WHO Director-General declares a PHEIC, on the advice of an Emergency Committee, under the International Health Regulations (2005). It marks an extraordinary event that risks international spread and may need a coordinated response, and triggers temporary recommendations to member states.

Vaccine-associated viscerotropic disease resembles severe wild-type yellow fever, has a case-fatality near 50%, occurs in first-time recipients and increases markedly with age, which is why elderly travellers are vaccinated only when exposure risk is genuine.

Vaccine-associated neurotropic disease is the separate encephalitic reaction; the other options are not the recognised viscerotropic syndrome.

dN/dS above one signals positive selection, where amino-acid-changing mutations are favoured, as in the antibody-targeted surface proteins. A ratio below one indicates purifying selection, the usual state of compact RNA-virus genomes.

About a third of patients have arthralgia and joint stiffness that persist for months and sometimes years after the acute illness, the main long-term morbidity.

The other outcomes are not features of Sindbis infection.

When the human R0 is near zero the virus cannot sustain human chains, so every case depends on fresh spillover from the reservoir, the pattern seen with Lassa fever in West Africa. Only once R0 approaches and passes one can sustained human transmission occur.

West Nile virus is transmitted by Culex mosquitoes from a bird reservoir, not by Aedes aegypti.

Dengue, Zika, chikungunya and, in its urban cycle, yellow fever are all spread by Aedes aegypti, one vector serving three virus families.

The incubation period is about 7 to 14 days after a tick bite, and tends to be shorter after milk-borne infection.

The other intervals are too short or too long for tick-borne encephalitis.

The virus is taken up by clathrin-mediated endocytosis, and the acid endosome triggers E1 to form fusion trimers that merge the membranes.

Fusion is low-pH dependent rather than neutral-pH, is driven by E1 rather than the capsid or 6K, and alphaviruses do not inject their genome.

A point-source outbreak follows a single brief common exposure, so all cases appear within one incubation period, giving a sharp rise and fall. The exposure time can be estimated by counting one mean incubation period back from the peak.

An outbreak, used interchangeably with epidemic, is the occurrence of more cases than expected for a given population, place and time, or a single case of something new or of major significance. The steady background level is endemic disease.

An epizootic is an outbreak in an animal population, the animal equivalent of an epidemic, whereas enzootic transmission is the steady background maintenance of a virus in its reservoir. An epizootic frequently precedes human cases, as with West Nile virus in birds.

Non-neutralising antibody from a prior serotype binds a new serotype and carries it more efficiently into Fc-receptor-bearing macrophages, raising viral load and the inflammatory response.

Complement lysis, molecular mimicry and direct cytotoxicity are not the mechanism, and antibody does not durably cross-neutralise the four serotypes.

The World Health Organization estimates that more than 60% of emerging infectious diseases reported globally come from animals, and the share is higher still among genuinely new agents. This zoonotic dominance is why emergence is framed as a problem of the human-animal-environment interface.

The lower options understate the animal contribution; ~90% overstates it.

Only about 1% to 2% of infections progress to severe disease; the great majority are a self-limiting febrile illness.

Severe disease is uncommon, but the scale of epizootics still yields many such cases.

About 80% of Zika infections cause no symptoms, so transmission is largely silent and outbreaks can be extensive before recognition; symptomatic disease is usually mild and lasts up to a week.

The lower figures understate the high asymptomatic fraction.

Transmission imposes a severe bottleneck, and a new HIV or influenza infection is frequently established by just one virus particle. This sharply reduces diversity and lets chance, not only fitness, decide which variants are passed on.

A molecular clock lets the timing of a most recent common ancestor be estimated and outbreaks be dated and traced, because sequences sampled even weeks apart already differ. RNA viruses are therefore called measurably evolving populations.

Tick-borne encephalitis can be acquired by drinking unpasteurised milk or dairy from an infected goat, sheep or cow, which sheds virus during its viraemia.

Sexual, respiratory, rodent-excreta and waterborne routes are not features of the virus.

West Nile virus is transmitted by blood transfusion and organ transplantation, and rarely through breast milk and in pregnancy. Organ transmission is especially dangerous because it can come from donors without detectable viraemia into immunosuppressed recipients, which is why blood services screen donations during transmission seasons.

The other routes are not recognised means of West Nile transmission.

CCHFV is the most widely distributed tick-borne virus, endemic across Africa, the Balkans, the Middle East, Central Asia and the Indian subcontinent, following the range of Hyalomma ticks.

It is an Old World, tick-borne virus, not mosquito-borne, rodent-borne or geographically confined.

Most chikungunya infections are symptomatic, unlike dengue and Zika, though up to a quarter are subclinical or asymptomatic.

It is not silent in most people, is not restricted to children or to reinfection, and only a minority develop chronic arthritis.

Despite profound capillary leak, true haemorrhage is uncommon in cardiopulmonary syndrome, which is dominated instead by pulmonary oedema and shock.

It does not spare the lungs, its case-fatality (~35 to 40%) is higher than most HFRS, and ribavirin has no proven benefit in it.

First-trimester infection carries the highest risk, and microcephaly is the hallmark, accompanied by intracranial calcification, ventriculomegaly, ocular lesions, contractures and hearing loss; infection can also cause miscarriage and stillbirth.

The other combinations misstate the timing or the pattern of injury.

A proofreading exoribonuclease lowers the coronavirus error rate, lifting the usual ceiling on RNA-virus genome size. It is the exception to the rule that RNA polymerases lack proofreading, and it shapes how this emerging-virus family evolves.

A successful jump is more likely between closely related hosts, which share less-divergent cell receptors and often the same habitat, giving both compatibility and exposure. Receptor compatibility is the key molecular barrier to host range.

Ribavirin has been used for decades and may help when started early, but recent meta-analyses question its benefit and several investigators have called for randomised trials.

It is still given in many endemic settings, particularly when CCHF cannot be distinguished from other haemorrhagic fevers, so it is neither proven nor contraindicated.

Since 2013 the WHO has held that a single dose of 17D gives lifelong protection, and the International Health Regulations were amended in 2016 so that a valid vaccination certificate no longer expires.

The former recommendation was a ten-year booster; the other schedules do not apply to this live-attenuated vaccine.

Infection near delivery can cause neonatal dengue and raises the risk of preterm birth, low birth weight and peripartum haemorrhage.

There is a real perinatal risk, and the congenital defects listed belong to rubella and varicella, not dengue.

Host furin cleaves prM in the trans-Golgi network as the particle exits, priming it for infectivity; incomplete cleavage leaves a mixture of mature and immature virions.

NS3 processes the polyprotein, not prM at maturation, and neuraminidase, caspases and host RNA polymerase have no role here.

Dengue is a positive-sense RNA flavivirus (genus Orthoflavivirus) with four serotypes, DENV-1 to DENV-4.

It is not segmented or negative-sense, not a DNA virus or retrovirus, and not an alphavirus (the arthritogenic Togaviridae).

Because IgM does not cross the blood-brain barrier, its presence in cerebrospinal fluid signals infection within the central nervous system. In serum, West Nile IgM can persist for more than a year and cross-reacts with other flaviviruses, so paired sera and neutralisation may be needed.

The other statements misstate the specificity and timing of the assay.

At low prevalence the positive predictive value falls, so a larger share of positive results are false. Predictive value depends on prevalence, not only on a test’s sensitivity and specificity, which is why surveillance signals are confirmed before action.

The coagulopathy of severe yellow fever makes liver biopsy dangerous, and it has caused fatal haemorrhage. The definitive tissue diagnosis is instead made post-mortem by immunostaining or PCR for viral antigen in the liver.

The other complications are not the reason biopsy is contraindicated in acute yellow fever.

The plaque-reduction neutralisation test measures type-specific neutralising antibody and is the confirmatory gold standard when flavivirus serology cross-reacts.

Capture and antigen ELISAs and haemagglutination inhibition are prone to the same cross-reactivity that created the problem.

Humans reach a viraemia high enough to infect feeding mosquitoes with dengue, so they are the amplifying host in the urban human-to-mosquito-to-human cycle.

For West Nile, Japanese encephalitis, Eastern equine encephalitis and Sindbis viruses, humans are dead-end hosts that do not sustain transmission.

RVFV shows only about 4% to 5% nucleotide diversity among strains since the 1970s and behaves as a single antigenic type, so one well-matched vaccine can protect broadly.

It does not undergo antigenic shift or drift into escape serotypes.

The virus infects endothelium without killing it, and disease follows from an immune-mediated rise in capillary permeability, so recovery leaves no vascular scarring.

It is not directly cytopathic, does not act through thrombosis or a toxin, and antibody-dependent enhancement is a dengue mechanism.

Like other members of the order Bunyavirales, hantaviruses prime their messenger RNA by cap-snatching, stealing capped fragments from host transcripts, entirely in the cytoplasm.

They do not use a poly-A primer, reverse transcription, ribozymes or nuclear splicing.

Error-prone reverse transcription, combined with an enormous replicative output (on the order of ten billion virions a day), generates a quasispecies, a swarm of related variants within each host.

This standing diversity is the raw material for immune escape and for the rapid selection of drug resistance, so the distractors (uniformity, reduced mutation, or loss of core functions) are the opposite of what high error rates produce.

Hantaviruses are acquired by inhaling aerosols of infected rodent urine, droppings and saliva, typically when disturbing contaminated dust indoors.

They are not arthropod-borne, so tick and mosquito bites are irrelevant, and water and sexual transmission are not significant routes (person-to-person spread is confined to Andes virus).

Diagnosis rests on serology, with virus-specific IgM in serum and cerebrospinal fluid and a rising IgG on paired sera, because the viraemia is usually past by the time encephalitis appears; reverse-transcription PCR helps early, especially in Venezuelan infection.

Agar culture, urinary antigen, electroencephalography alone and skin biopsy are not the approach.

After E2-mediated attachment, the virus enters by clathrin-mediated endocytosis, and the acid endosome triggers E1 to fuse the membranes, releasing the nucleocapsid into the cytoplasm.

Entry is not neutral-pH fusion, genome injection, receptor-independent, or nuclear.

The CCHFV L and M segments are markedly larger than in other bunyavirals, the oversized L protein carrying a cap-snatching endonuclease and an OTU deubiquitinase domain in addition to the polymerase.

The genome is negative-sense, tripartite RNA; an ambisense S segment is a phlebovirus feature, seen in Rift Valley fever virus, not CCHFV.

The L polymerase cleaves short capped fragments from host messenger RNAs and uses them to prime transcription (cap-snatching), a strategy shared across the bunyavirals and carried out entirely in the cytoplasm.

Protein-primed and self-priming mechanisms belong to other virus groups.

The tick is both vector and reservoir: it passes CCHFV transstadially across its moults and transovarially into its eggs, so the enzootic cycle persists without the vertebrate host being permanently infected.

Humans are dead-end hosts, and mosquitoes play no part in the cycle.

Diagnosis is usually serological, with virus-specific IgM detectable in the acute illness and a rising IgG on paired sera; reverse-transcription PCR and isolation are possible early, when the patient still has viraemia.

Bacterial culture, cerebrospinal fluid microscopy, biopsy alone and stool antigen are not the approach.

The 5’ two-thirds of the positive-sense genome is translated directly into the nonstructural polyprotein (nsP1 to nsP4); the structural proteins come from a separate subgenomic messenger RNA.

The genome is non-segmented and positive-sense, so there is no virion polymerase and no one-protein-per-segment arrangement.

Humans and horses can be infected and can fall ill, but their viraemia is too low and brief to infect feeding mosquitoes, so they cannot sustain the transmission cycle. The bird-mosquito cycle maintains the virus.

They are bitten and are fully susceptible; transfusion is a rare additional route, not the reason they are dead-end hosts.

The large majority of random mutations are deleterious or lethal (around 40% lethal in vesicular stomatitis virus), with only ~4% beneficial. This is why purifying selection is the dominant force on these genomes.

Specific IgM and IgG appear around days five to seven only in those who survive; fatal cases usually die before they seroconvert.

Molecular detection, not serology, is therefore decisive in severe disease, and a negative antibody result never excludes CCHF in a severely ill patient.

Viral loads above roughly 10⁸ genome copies per millilitre predict a fatal course, whereas lower loads accompany milder disease.

Viral load, platelet count and clotting times are combined in severity scores; a high load signals worse, not milder, disease.

The critical phase begins around defervescence, typically days 4 to 6, which is why a settling fever can dangerously masquerade as improvement.

Leakage is not a feature of the first febrile day, the incubation period or the recovery phase, and it does not wait three weeks.

The kidney bears the brunt in HFRS, giving the oliguric phase of acute kidney injury that is the usual time of death.

The lung is the target in the New World cardiopulmonary syndrome; the liver, heart and brain are not the primary organs, though overlap between the syndromes occurs.

A vigorous cytotoxic CD8 T-cell response is closely associated with severe disease, its intensity tracking the degree of capillary leak, which is why the disease is largely immunopathological.

Conversely, a high early neutralising-antibody titre predicts a better outcome; low cytokines, rapid clearance and an absent response are not markers of severity.

With a very high ratio of subclinical to clinical infection (on the order of 250 to 1), most people in endemic areas are infected and immune by adulthood, so clinical disease falls mainly on children.

The other groups are not the predominant affected population in highly endemic settings.

Memory T cells raised against the first serotype respond poorly to the second and release a disproportionate cytokine burst, a T-cell “original antigenic sin” that helps drive the vascular leak.

They do not clear the virus faster, make sterilising antibody, prevent viraemia or block Fc receptors.

Most South African cases are imported by travellers, but Aedes aegypti is present in parts of the country, so a viraemic case could seed local transmission.

It is not endemic like the local alphavirus Sindbis, is not tick-borne, is not excluded by a lack of vector, and is an arthritic rather than encephalitic illness.

West Nile virus is a category 3 notifiable medical condition in South Africa, reported through the routine notification system rather than the immediate emergency pathway reserved for the viral haemorrhagic fevers.

It is notifiable in humans and is not confined to International Health Regulations reporting.

Rift Valley fever and Crimean-Congo haemorrhagic fever are Category 1 notifiable medical conditions and must be notified within 24 hours, reflecting their haemorrhagic-fever severity.

All other arboviral infections, whether endemic or imported, are Category 3 and reported through routine channels.

The period of intoxication follows a brief remission and brings jaundice, acute kidney injury and a haemorrhagic diathesis, by which time viraemia has usually cleared; death, when it occurs, is around the seventh to tenth day.

The period of infection is the initial viraemic febrile phase, the period of remission is a short symptom-free interval where many recover, and the incubation period precedes symptoms.

During the early viraemic days, reverse-transcriptase PCR (and NS1 antigen detection) on blood is the test of choice; IgM-capture ELISA becomes useful from about day four.

Plaque-reduction neutralisation resolves cross-reactivity but is confirmatory rather than an early frontline test, liver biopsy is contraindicated in acute illness, and convalescent serology is too slow to guide acute management.

Reverse-transcription PCR on blood detects viral RNA during the high-titre viraemia of the first week; IgM becomes useful from about day five.

IgG marks past infection, culture from joint fluid is usually negative, and there is no routine urinary antigen test.

Fruit bats are the Nipah reservoir, but pigs acted as the amplifying host in Malaysia, multiplying the virus and bridging it to farmers. (In the Bangladesh outbreaks transmission was direct, via date-palm sap.) Horses are the amplifying host for the related Hendra virus.

Humans and horses develop too little viraemia to infect feeding mosquitoes, so they are dead-end hosts; birds are the amplifying reservoir and Culex mosquitoes the vector. A dead-end host is infected but does not pass the virus onward.

Clinical Sindbis disease in northern Europe clusters in middle-aged adults, women more than men, in the late-summer season of peak mosquito activity.

It is not primarily a disease of children, infants, the elderly or travellers.

The sylvatic cycle circulates between non-human primates and forest canopy mosquitoes, with humans infected incidentally when they enter the forest; this is why young men clearing land are most exposed.

Pigs amplify Japanese encephalitis, wild birds amplify West Nile and Japanese encephalitis, and rodents maintain hantaviruses and arenaviruses.

The urban cycle is driven by Aedes aegypti, a domestic container-breeding mosquito, with humans as the sole amplifying host. This is the cycle responsible for explosive city epidemics.

Anopheles transmits malaria, Culex tritaeniorhynchus transmits Japanese encephalitis, Haemagogus drives the sylvatic (jungle) cycle in the Americas, and Culex quinquefasciatus is a West Nile vector.

Western equine encephalitis is generally mild in adults but can be severe in infants, with seizures and a substantial risk of permanent brain damage in survivors.

The other groups are at lower risk.

Sindbis is an Old World arthritogenic alphavirus, causing fever, rash and arthritis, and sits in the Western equine encephalitis antigenic complex despite its non-encephalitic disease.

The other groupings are separate genera or the encephalitic New World clade.

Japanese encephalitis virus is the prototype of the Japanese encephalitis serocomplex, which also contains West Nile, St Louis encephalitis and Murray Valley encephalitis viruses, and shares their neurotropism.

Dengue, Spondweni (which holds Zika), tick-borne encephalitis and yellow fever form separate serogroups.

Kunjin virus is the Australian subtype of West Nile virus, classified within lineage 1b, and generally causes milder disease.

It is not a separate virus, a tick-borne agent, the African lineage 2 strain, or a vaccine strain.

Because viraemia is high in the acute phase, reverse-transcription polymerase chain reaction (RT-PCR) and immunoglobulin M (IgM) capture ELISA on blood are the mainstays, supported by virus isolation and paired serology.

RVF is mosquito-borne, so there is no tick to identify.

Madariaga virus is the species into which the South American strains formerly called Eastern equine encephalitis virus were reclassified, and it is generally much less virulent in people.

It is not a vaccine strain, not tick-borne, not the most virulent member, and not Western virus.

Measles probably evolved from rinderpest, a virus of cattle, once human populations grew large enough to sustain transmission without an animal reservoir, the birth of a crowd disease. Smallpox, by contrast, is most closely related to camelpox.

Although mosquitoes drive the animal epizootic, most people are infected by direct contact with the blood or tissues of infected livestock, during slaughter, birthing and the handling of aborted material.

Mosquito bite is a lesser route, and there is no person-to-person spread.

Wet years, driven by the El Nino Southern Oscillation, boost rodent food and numbers, raising human contact and hantavirus cardiopulmonary cases.

Cold dry conditions reduce rodent numbers, and ticks, birds and indoor gatherings are irrelevant to a rodent-borne, non-arthropod virus.

New World hantaviruses, such as Sin Nombre and Andes, classically cause hantavirus cardiopulmonary syndrome, dominated by non-cardiogenic pulmonary oedema and shock.

Haemorrhagic fever with renal syndrome is the Old World counterpart; encephalitis, polyarthritis and hepatitis are not hantavirus syndromes.

Although viruses mutate constantly, pure mutation in human-adapted strains is an uncommon route to a new disease; most newly emerging viruses draw their new genetic material from infection of non-human species, that is, from zoonosis.

The other routes occur but do not account for the bulk of emergence.

In the first few days the virus is detected directly, so NS1 antigen and RT-PCR are the tests of choice; RT-PCR also gives the serotype.

Serology is unreliable this early, blood culture does not grow the virus, and the tourniquet test supports assessment but does not confirm the diagnosis.

Gn and Gc are arranged as an ordered icosahedral lattice on the lipid envelope, a more regular surface than the pleomorphic nairoviruses, and there is no matrix protein.

The genome exists as a ribonucleoprotein, not an icosahedral capsid.

Pathogenic hantaviruses use beta-3 integrins, receptors that also regulate vascular permeability and platelet function, linking entry to disease; non-pathogenic species use beta-1 integrins.

CD4 and CCR5 are HIV receptors, ACE2 is used by SARS-CoV-2, and sialic acid is an influenza receptor.

Chronic joint symptoms, affecting on the order of 40% of adults, are predicted by older age, female sex, severe acute illness and high acute viral load.

Young age, mild disease and vaccination all make persistent arthralgia less likely.

When different parts of a genome have different evolutionary histories, the trees disagree across the breakpoint, the signature of recombination. Comparing a virus tree with its host tree, by contrast, distinguishes codivergence from cross-species host jumping.

These northern European names, from Finland, Sweden and Russia, all denote Sindbis virus disease.

Chikungunya and Ross River are other arthritogenic alphaviruses, and West Nile and tick-borne encephalitis are encephalitic flaviviruses.

Pushing the virus past its error threshold, so that fit genomes can no longer be regenerated, collapses the population: lethal mutagenesis, also called error catastrophe. The experimental agents are 5-fluorouracil and ribavirin, and the principle underlies modern mutagenic antivirals.

Reassortment is the exchange of whole genome segments when two strains co-infect a cell, so it requires a segmented genome, as in influenza A. It is the molecular basis of antigenic shift.

South Africa has no documented local human hantavirus disease, and the realistic risk is an imported Andes virus case in a traveller returning from South America.

Local rodents carry only mild native African hantaviruses, not the New World cardiopulmonary strains; hantavirus is a Category 1 notifiable condition; and it is rodent-borne, not tick-borne.

Ribavirin helps HFRS when started early in the course of illness.

It has shown no benefit in the New World cardiopulmonary syndrome, and it is not used for all infections, as prophylaxis, or only in children.

Retinitis typically develops one to three weeks after the initial symptoms, sometimes after the fever has settled, and where it involves the macula it can cause permanent visual loss.

RVFV is a phlebovirus in the family Phenuiviridae, order Bunyavirales.

Nairoviridae (Crimean-Congo haemorrhagic fever) and Hantaviridae are the other bunyavirus families of note; filoviruses and flaviviruses are unrelated.

Daubney and Hudson described the disease from an outbreak of abortions and lamb deaths on a farm in Kenya’s Rift Valley, naming it enzootic hepatitis.

The Egyptian, Congo and Crimean events belong to other viruses or to much later outbreaks.

In copy-choice recombination the polymerase switches from one template to another mid-synthesis, producing a hybrid genome, the dominant mechanism in RNA viruses. The other options describe segmented-genome or DNA-virus mechanisms.

RVFV is highly infectious by aerosol, which caused many laboratory-acquired infections before modern biosafety practice, and is one reason it is handled under enhanced containment.

It does not spread from patient to patient by droplets.

Sindbis is the prototype alphavirus, isolated in 1952 near the village of Sindbis in the Nile Delta of Egypt, and became the reference virus for alphavirus structure and replication.

It is an Old World arthritogenic virus, not encephalitic, New World or tick-borne, and its outbreaks are modest rather than the largest recorded.

A propagated curve reflects person-to-person, or vector, transmission, each wave infecting the next about one incubation period later. It contrasts with the single sharp peak of a point source.

The course runs through incubation, a prehaemorrhagic phase, a haemorrhagic phase and convalescence.

The febrile-hypotensive-oliguric-diuretic sequence describes hantavirus haemorrhagic fever with renal syndrome, and a latent-reactivation pattern belongs to the herpesviruses.

An El Nino-driven drought-then-rainfall sequence produced a boom in deer-mouse numbers, raising human exposure to Sin Nombre virus and causing the outbreak. It illustrates how climate cycles drive reservoir population dynamics and spillover.

On Reunion the epidemic infected roughly a third of the population and selected the E1-A226V mutation that adapted the virus to Aedes albopictus.

It spread well beyond mainland Africa to India and Southeast Asia, remained mosquito-borne, and left substantial chronic arthralgia.

Severe CCHF bleeding reflects a dysregulated pro-inflammatory cytokine response, with high tumour necrosis factor alpha, interleukin-6 and interleukin-8, causing endothelial dysfunction and disseminated intravascular coagulation.

Direct lysis of all endothelium, autoantibodies and vitamin K deficiency are not the principal mechanism.

Incubation is shortest after a tick bite, usually about one to three days. After exposure to infected blood or tissue it is longer, around five to seven days and occasionally up to thirteen.

All the blood- and tissue-contact routes give a longer interval than the tick bite.

The OTU domain is a deubiquitinase and deISGylase: it removes regulatory ubiquitin and ISG15 tags from innate-immune signalling proteins, damping the type I interferon response.

Glycoprotein cleavage, capping, integration and translational shut-off are unrelated to this domain.

Mxra8 is used by the arthritogenic Old World alphaviruses, chikungunya, o’nyong-nyong, Ross River and Mayaro viruses, a molecular correlate of the rash-and-arthritis clade.

It has no role for the encephalitic New World alphaviruses, and the flaviviruses and phleboviruses use unrelated entry factors.

Chikungunya presents with high fever, severe symmetrical polyarthralgia and a maculopapular rash in around 80% of patients.

Jaundice and bleeding suggest a haemorrhagic fever, encephalitis and paralysis suggest an encephalitic arbovirus, and the other pictures point elsewhere.

The European and Siberian subtypes classically run a biphasic course: a grippe-like first phase, a symptom-free remission, then in a minority a neurological second phase. The Far-Eastern subtype is usually monophasic, progressing straight into severe disease.

The course is not confined to laboratory-acquired or milk-borne cases.

HFRS runs through febrile, hypotensive, oliguric, diuretic and convalescent phases, with the greatest danger in the hypotensive and oliguric stages.

The other sequences are invented or belong to other diseases.

There is no licensed human RVF vaccine; the most advanced candidate, ChAdOx1 RVF, was safe and immunogenic after a single dose in a phase 1 trial and is designed for both livestock and people.

Older inactivated preparations have protected only small numbers of laboratory and veterinary workers.

Inactivated vaccines against Hantaan and Seoul viruses are used in parts of Asia, but none is widely licensed elsewhere, so prevention rests on avoiding rodent contact.

There is no worldwide live-attenuated, mRNA or universal childhood hantavirus vaccine, and vaccines against the New World species do not exist.

NS1 is secreted from infected cells and circulates in the blood, giving an early antigen test in the first few days of illness; it also contributes to the endothelial leak.

The envelope protein is the neutralising target, the capsid protein forms the capsid, NS5 is the polymerase, and the envelope protein mediates receptor binding.

Dengvaxia is restricted to people with confirmed prior dengue infection, because in dengue-naive recipients it behaves like a first infection and primes for severe disease.

It is therefore not for the dengue-naive, and age and pregnancy are not the defining restriction.

Quarantine separates people who may be incubating an infection but are not yet ill, while isolation separates those who are already infectious. Quarantine loses value once a disease can travel internationally faster than its incubation period.

E1-A226V improved viral fitness in Aedes albopictus, a hardier and more temperate mosquito, extending the virus’s potential range.

It did not alter antiviral susceptibility, attenuate the virus, remove the vector requirement, or enable tick transmission.

Eastern equine encephalitis virus cycles between passerine birds and the mosquito Culiseta melanura in freshwater hardwood swamps of eastern North America, with less host-specific bridge vectors carrying it to people and horses.

The rodent cycle belongs to Venezuelan virus, and the other pairings are wrong.

Councilman bodies are apoptotic hepatocytes, the dominant mechanism of liver injury in yellow fever, seen with midzonal coagulative necrosis and strikingly little inflammation; intranuclear Torres bodies also occur.

Negri bodies are seen in rabies, Guarnieri bodies in poxvirus infection, Cowdry type A inclusions in herpesvirus infection, and Downey cells are the atypical lymphocytes of Epstein-Barr virus.

In 2000 RVFV appeared in Saudi Arabia and Yemen, its first confirmed spread beyond Africa, probably carried across the Red Sea in infected livestock.

Egypt and Madagascar are within Africa, and the Indian and European events did not occur.

The genus is named after the Hantaan River in South Korea, near where Ho-Wang Lee isolated Hantaan virus from the striped field mouse in the 1970s.

It is not named for a scientist, a rodent, a Greek root or a patient.

The haemorrhagic-hepatic form is the most lethal, with a case fatality of up to around 65%.

The milder febrile illness that most patients experience has a very low mortality.

Hantaviruses carry three negative-sense RNA segments, large, medium and small, encoding the polymerase, the glycoproteins and the nucleocapsid respectively.

The genome is not a single positive-sense strand, DNA of any kind, or an eight-segment genome (that is influenza).

The M segment encodes a precursor cleaved into the Gn and Gc envelope glycoproteins, which mediate receptor binding and fusion.

The S segment encodes the nucleocapsid, the L segment the polymerase; hantaviruses have no matrix protein and no reverse transcriptase.

The incubation period is short, usually 2 to 6 days, after which most people have a brief self-limiting fever.

The longer intervals describe other infections.

The incubation period is about two to eight days, after which fever, rash and arthralgia begin together.

The other intervals are far too short or too long.

The incubation period is about two to ten days, varying by virus, followed by a febrile prodrome that may progress to encephalitis.

The other intervals are far too short or too long.

Each HIV-1 group arose from a separate spillover of simian immunodeficiency virus (SIV) from chimpanzees or gorillas, after which human-to-human transmission established the pandemic. The multiple groups are the signature of repeated independent cross-species transfers.

Guillain-Barré syndrome, a post-infectious ascending flaccid paralysis, is the principal adult neurological complication and was the first severe outcome linked to Zika during the French Polynesian outbreak.

Anterior-horn paralysis is characteristic of West Nile virus, subacute sclerosing panencephalitis of measles, and parkinsonism of Japanese encephalitis.

Serology is the mainstay, and IgM is usually detectable at symptom onset because patients present after the short viraemic phase.

Culture is impractical, there is no antigen skin test, the blood film is not diagnostic, and rodent trapping is an environmental, not a clinical, tool.

Diagnosis rests on serology, chiefly IgM-capture ELISA on serum and cerebrospinal fluid, with a fourfold titre rise in paired sera confirming; serum IgM can persist for several months.

Virus is rarely isolated once neurological disease has begun, and the other options are not diagnostic tests for the virus.

There is no specific antiviral and no licensed vaccine, so care is supportive and prevention rests on avoiding mosquito bites in the wetland and woodland settings where the vectors are active.

The other measures do not apply to Sindbis virus.

The name is a Makonde word for the contorted, stooped posture that severe joint pain forces, from the 1952 epidemic on the Makonde Plateau of what is now Tanzania.

The other options describe real features of the illness but none is the origin of the name.

In 1969 Jordi Casals showed that the agent of Crimean haemorrhagic fever was identical to the Congo virus isolated in the Belgian Congo in 1956, and the two names were joined.

The virus was described in the Crimea in 1944 but not isolated until 1967; it was not co-discovered, and it causes one disease across its range.

West Nile virus cycles between birds, which develop a prolonged high-titre viraemia and act as amplifying hosts, and Culex mosquitoes. Humans and horses are incidental hosts.

Pigs amplify Japanese encephalitis, non-human primates maintain sylvatic yellow fever and Zika, rodents and Ixodes ticks maintain tick-borne encephalitis, and Aedes aegypti drives urban yellow fever and dengue.

Sindbis is maintained between wild passerine birds and ornithophilic Culex and Culiseta mosquitoes, with migratory birds dispersing it over long distances.

Humans are incidental hosts, and the other host and vector pairings belong to different arboviruses.

Platelets are consumed at the damaged, activated endothelium rather than failing to be produced, and the fall is an early diagnostic clue.

Marrow production is preserved, and sequestration, vitamin deficiency and anti-megakaryocyte autoantibodies are not the mechanism.

Japanese encephalitis virus has a predilection for the deep grey matter, especially the substantia nigra and basal ganglia, producing extrapyramidal features and a Parkinson-like syndrome that often appears in convalescence.

The cerebellum, occipital cortex, hippocampus and pituitary are not the characteristic targets.

West Nile virus injures the anterior horn cells (lower motor neurons) of the spinal cord, producing an asymmetric flaccid paralysis that resembles poliomyelitis and can occur without meningitis or encephalitis.

Cerebellar, sensory-nerve, posterior-column and neuromuscular-junction lesions give different clinical pictures.

Syndromic surveillance monitors symptom patterns before a diagnosis is established, so its strength is timeliness, catching a rise early. The trade-off is low specificity, so signals still need laboratory confirmation.

Zika virus is transmitted mainly by Aedes aegypti, with a sylvatic Aedes-and-monkey cycle in Africa; the same vector transmits dengue and urban yellow fever.

Culex tritaeniorhynchus transmits Japanese encephalitis, Anopheles transmits malaria, Ixodes is a tick vector of tick-borne encephalitis, and Haemagogus drives sylvatic yellow fever.

The liver is the main target and hepatic necrosis is the central lesion of severe RVF, reflected in steeply raised transaminases and, in the worst cases, jaundice and liver failure.

Renal failure occurs but is usually secondary.

Aedes aegypti, a day-biting, container-breeding mosquito adapted to human dwellings, is the principal urban vector, with Aedes albopictus secondary.

Culex transmits West Nile and Japanese encephalitis, Anopheles transmits malaria, and the ticks listed transmit tick-borne, not mosquito-borne, viruses.

Culex tritaeniorhynchus, which breeds in rice paddies and other ground pools, is the principal vector, linking the disease to irrigated rice agriculture across Asia.

Tree-hole and container-breeding Aedes transmit yellow fever, dengue and Zika, not Japanese encephalitis.

Under a very high mutation rate, a cluster of variants with moderate but robust fitness can outcompete a population built around one high-fitness variant surrounded by poor neighbours. Selection acts on the whole quasispecies, not the single best genome.

The rash is maculopapular and often intensely itchy, spread over the trunk and limbs and sometimes involving the palms and soles, occasionally with a central vesicle or a haemorrhagic quality.

It is neither dermatomal, purely petechial, nor an ulcer.

Sin Nombre virus is carried by the deer mouse (Peromyscus maniculatus), and its numbers, and human cases, rise in wet years.

The brown rat carries Seoul, the bank vole Puumala, the striped field mouse Hantaan and the yellow-necked mouse Dobrava-Belgrade.

NSs is the dominant virulence factor: it suppresses the type I interferon response, shutting down host-cell transcription and blocking interferon-beta induction.

The polymerase, glycoproteins and nucleocapsid are separate gene products.

GP38 is a secreted glycoprotein cleaved from the M-segment precursor and an important target of protective antibodies.

The same precursor also yields the structural Gn and Gc and the non-structural NSm; the nucleoprotein is an S-segment product, and NSs is a phlebovirus protein not carried by CCHFV.

A second infection with a different serotype is the single greatest risk factor for severe dengue, acting through antibody-dependent enhancement.

A first infection, malaria co-infection, prior flavivirus vaccination and sex are not the principal drivers, though infants of immune mothers are a related special case.

IgM-capture ELISA on serum and cerebrospinal fluid is the standard test, with sensitivity approaching 100% when both are tested one to two weeks after onset; cerebrospinal-fluid IgM indicates central nervous system infection. Flavivirus cross-reactivity is the main limitation.

Virus is rarely isolated, blood is cleared early, and electroencephalography and biopsy are not confirmatory.

The incubation period is about two to twelve days, most often three to seven, after which fever and arthralgia begin abruptly.

The other intervals are far too short or too long for chikungunya.

Both syndromes typically begin about two to three weeks after exposure, after which a febrile prodrome opens the illness.

An interval of days, hours, months or a year does not fit the usual incubation.

Most people with Venezuelan equine encephalitis have a self-limited influenza-like febrile illness, and only a minority, mainly children, develop encephalitis.

It is not usually fatal, arthritic, haemorrhagic, or silent in everyone.

The urban cycle is a human-to-human loop transmitted by Aedes aegypti, distinct from the sylvatic (jungle) cycle that maintains these viruses among forest animals and forest mosquitoes. Anopheles transmits malaria, and Ixodes is a tick.

Hantaviruses infect endothelium without killing it, and disease follows from an immune-mediated rise in capillary permeability, so the injury is functional and reversible.

Direct lysis, bacterial co-infection and thrombosis are not the mechanism, and antibody-dependent enhancement is a dengue phenomenon.

The Pacific and American epidemic strains descend from the Asian lineage; Zika virus sits in the Spondweni serocomplex and exists as a single serotype with African and Asian lineages.

There is no European or tick-borne Zika lineage, and Kunjin is a subtype of West Nile virus.

Ixodes ricinus transmits tick-borne encephalitis in Europe and Ixodes persulcatus in Russia and Asia; Ixodes ricinus also transmits Lyme borreliosis, so co-infection can occur.

Hyalomma ticks transmit Crimean-Congo haemorrhagic fever, and the other genera are not the vectors of tick-borne encephalitis.

The area should be ventilated and then wetted before cleaning, so the virus is not aerosolised.

Dry sweeping or vacuuming does exactly the opposite; there is no routine vaccine and no role for prophylactic ribavirin.

Most infections are an abrupt, often biphasic influenza-like illness with fever, myalgia, arthralgia and headache, sometimes with photophobia and neck stiffness that can mimic meningitis, resolving over four to seven days.

Because livestock amplify the virus and are the main source of human infection, vaccinating animals is the most effective way to protect people, the logic of One Health.

Patients are not infectious to others, and mosquito eradication is not feasible during floods.

A mother who is viraemic around the time of delivery transmits to the newborn in roughly half of cases, causing a severe neonatal encephalopathy.

Early-pregnancy infection, chronic arthralgia, pre-existing immunity and breastfeeding are not the main route of peripartum vertical transmission.

West Nile virus sits in the Japanese encephalitis serocomplex, alongside Japanese encephalitis, St Louis encephalitis and Murray Valley encephalitis viruses, which shares its neuroinvasive tendency and drives cross-reactivity in serology.

Dengue, yellow fever, tick-borne encephalitis and the Spondweni group (which contains Zika) are separate serocomplexes.

Viral RNA and antigen persist in synovial macrophages and fibroblasts, sustaining local inflammation with interleukin-6 and other mediators.

Radiographs usually show soft-tissue swelling rather than destruction, and the mechanism is not autoantibody, bacterial infection or classic immune-complex deposition.

Epidemics arise when mutation of an enzootic strain produces a variant that replicates to high titre in horses, which then amplify the virus for floodwater mosquitoes to spread.

It is not spread person-to-person, through water, by ticks, or between birds.

In the mouse, Sindbis is the classic model of age-dependent viral encephalomyelitis, but human infection spares the nervous system and produces an arthritis, driven by macrophage inflammation rather than direct cell killing.

It does not cause encephalitis in people, is not neuron-restricted in humans, and has a wild-bird reservoir.

Cardiopulmonary syndrome is managed with careful fluid restriction, inotropic support and, in the most severe cases, extracorporeal membrane oxygenation (ECMO), which improves survival in referral centres.

Aggressive fluid loading worsens the pulmonary oedema, corticosteroids and antibiotics are not effective, and dialysis belongs to the renal syndrome.

No CCHF vaccine is widely licensed; an inactivated suckling-mouse-brain preparation used in Bulgaria is the only one in human use, and its efficacy has never been rigorously characterised.

Modern inactivated, virus-like-particle, vectored, DNA and subunit candidates remain in early development.

No Zika vaccine is licensed, although several candidates have advanced into clinical trials. Development is complicated by the need to protect pregnant women and by the theoretical concern that flavivirus antibody could enhance dengue infection.

The other statements describe vaccines that do not exist for Zika.

Management is supportive, with intensive care and ventilatory support for the respiratory failure that follows bulbar or respiratory-muscle involvement. No antiviral has shown benefit in controlled study.

Ribavirin, favipiravir, corticosteroids and monoclonal antibodies remain investigational and are not standard care.

The equine encephalitis viruses are New World agents not found in South Africa, so their relevance is as an imported differential in a traveller returning from the Americas.

The locally important alphaviruses are instead Sindbis, Middelburg and Ndumu; these viruses are not endemic, tick-borne, or locally eliminated.

South Africa is one of the two principal foci of Sindbis disease, and the close genetic link between its strains and the northern European strains shows the virus is carried between them by migratory birds.

It reports regular summer cases, is not tick-borne, and has no vaccine-based elimination.

There is no specific antiviral for tick-borne encephalitis, so management is supportive, with neurological intensive care for severe encephalitis and attention to respiratory function where cervical-cord or bulbar involvement threatens breathing.

Acyclovir treats herpes simplex encephalitis and doxycycline treats the tick-borne bacterium of Lyme disease, neither of which is tick-borne encephalitis virus.

Zika viral RNA remains detectable in urine for longer than in serum, widening the diagnostic window for reverse-transcriptase PCR.

Blood PCR is validated, cross-reactivity is a serology problem rather than a PCR one, and urine does not carry more antibody.

A case-control study compares the odds of exposure in cases and controls, giving an odds ratio, and is used when there is no enumerable denominator. A cohort study, yielding a relative risk, suits a defined countable population such as everyone at a single event.

West Nile virus was first isolated in 1937 from a febrile woman in the West Nile district of Uganda. It emerged in New York in 1999, its first appearance in the Western Hemisphere, and spread across North America within a decade.

The other locations are associated with later spread or with related viruses rather than the original isolation.

Pigs are the key amplifying host, developing a high viraemia and living close to people in rural Asia, while ardeid wading birds are natural maintenance hosts; humans and horses are dead-end hosts.

Primates, rodents and bats are not the amplifying hosts for Japanese encephalitis.

Small rodents are the principal reservoir, sustaining the cycle with Ixodes ticks, including through co-feeding between infected and uninfected ticks on the same host. Large mammals maintain the tick population but rarely transmit the virus.

Pigs, birds and primates are reservoirs for other flaviviruses, not for tick-borne encephalitis.

Eastern equine encephalitis has the highest case-fatality, of the order of 30% or more, with frequent severe neurological sequelae in survivors, especially children.

The others are considerably less lethal.

Crimean-Congo haemorrhagic fever virus spreads from patient to staff through blood and body fluids and has caused documented nosocomial outbreaks, so suspected cases need barrier nursing and viral haemorrhagic fever isolation.

The mosquito-borne dengue, West Nile, Sindbis and chikungunya viruses do not spread from person to person.

West Nile neuroinvasive disease can injure the anterior horn cells, producing an asymmetric acute flaccid paralysis that resembles poliomyelitis.

Dengue and Rift Valley fever are chiefly febrile or haemorrhagic; chikungunya and Sindbis are arthritogenic.

The Bunyavirales carry a three-segment negative-sense RNA genome and bud at the Golgi, unlike the flaviviruses (endoplasmic reticulum) and alphaviruses (plasma membrane).

Flaviviridae and Togaviridae have non-segmented positive-sense genomes; Reoviridae are segmented but double-stranded; Rhabdoviridae are non-segmented negative-sense.

The live-attenuated 17D yellow fever vaccine is highly effective and is required under the International Health Regulations for travel to and from endemic countries.

No licensed vaccine exists for West Nile or Zika; dengue and chikungunya vaccines exist but are not International Health Regulations travel requirements.

Ardeid wading birds, such as herons and egrets, are the natural maintenance hosts, with pigs as the amplifying host that drives human exposure.

Poultry, songbirds and waterfowl are not the recognised maintenance hosts, and birds are integral to the cycle.

nsP4 is the RNA-dependent RNA polymerase.

nsP1 caps the RNA and anchors the replication complex, nsP2 is the protease and helicase, nsP3 is a virulence and host-range determinant, and capsid is a structural protein.

Western equine encephalitis virus arose by recombination, its genome descended from an Eastern-equine-encephalitis-like ancestor with the structural genes of a Sindbis-like virus.

The others are not recombinants.

The RVFV small (S) segment is ambisense, encoding the nucleocapsid protein in one orientation and the non-structural NSs from the opposite-sense strand.

The genome is otherwise negative-sense, tripartite RNA, not DNA, positive-sense, circular or unsegmented.

Zika virus is sexually transmitted and persists in immune-privileged sites, notably the testis, for weeks to months, prolonging the window of sexual transmissibility; it is also transmitted vertically and by transfusion.

It is mosquito-borne rather than tick-borne, readily infects humans, does not cause a hepatic haemorrhagic fever, and has no licensed vaccine.

Seoul virus is distributed worldwide because its reservoir, the brown rat, has followed shipping to every continent, making it the one HFRS agent found far beyond the Old World.

Hantaan and Puumala are regional Old World viruses, Sin Nombre and Andes are New World cardiopulmonary agents.

Andes virus is the only hantavirus with documented person-to-person transmission, which is why a suspected case needs isolation and contact tracing, as in the 2026 cruise-ship outbreak.

Every other hantavirus is acquired solely from rodent excreta, with humans a dead-end host.

A failure to mount an early type I interferon response is linked to severe and fatal disease, and those who die often fail to make RVFV-specific antibody.

A brisk innate response followed by neutralising antibody is the correlate of protection.

The vaccine is produced in embryonated chicken eggs, so severe egg allergy is a contraindication. Other contraindications are significant immunosuppression, thymus disorders and infancy under six months.

Controlled hypertension, prior dengue, splenectomy and stable ischaemic heart disease are not contraindications to 17D.

Meticulous fluid balance through the critical phase, with avoidance of non-steroidal anti-inflammatory drugs, is the core of management; paracetamol is preferred for fever.

Platelets are transfused for bleeding rather than a number alone, aspirin worsens bleeding, corticosteroids do not help, and there is no specific antiviral.

Advancing age is the dominant risk factor, with neuroinvasive disease many times commoner in older adults; immunosuppression, especially in organ-transplant recipients, also raises the risk. Susceptibility to infection is similar across ages, so age drives severity rather than acquisition.

The remaining options are not established risk factors for neuroinvasion.

Western equine encephalitis virus, isolated from horse brains in California in 1930, was the first alphavirus ever grown in culture.

The three viruses were recovered from encephalitic horses in the Americas during the 1930s, not from African birds, not after 2000, and not before 1900.

Human Western equine encephalitis has all but vanished, with no North American case for many years, for reasons that appear ecological rather than a loss of virulence.

Its vector is Culex tarsalis, not Culiseta melanura; it is a New World, mosquito-borne virus.

Transovarial transmission passes the virus from an infected female mosquito to her eggs, so drought-resistant eggs can seed the next outbreak when the rains return.

Mechanical transmission and bridge vectoring move virus between hosts, not into eggs; antigenic shift and cap-snatching are unrelated molecular processes.

LDLRAD3, a low-density lipoprotein receptor-related protein, is a key entry receptor for Venezuelan equine encephalitis virus.

MXRA8 serves the arthritogenic Old World alphaviruses, and the others are not its receptor.

Aedes aegypti and Aedes albopictus sustain the urban cycle, and human viraemia is high enough to infect them, so no animal reservoir is needed for an epidemic.

Anopheles transmit malaria, Culex and Culiseta transmit encephalitic arboviruses, and Psorophora are equine-encephalitis vectors.

Bilateral thalamic lesions are characteristic of Japanese encephalitis on CT or MRI, in keeping with its deep grey-matter tropism.

Temporal-lobe necrosis suggests herpes simplex encephalitis, and the other patterns are not typical of Japanese encephalitis.

Persistent vomiting and abdominal pain are recognised warning signs, alongside mucosal bleeding, lethargy, fluid accumulation and a rising haematocrit with falling platelets.

Fever, headache and myalgia are features of uncomplicated dengue, and an isolated loose stool is not a warning sign.

Puumala virus causes the mild HFRS historically called nephropathia epidemica, and accounts for most of the European caseload.

Hantaan and Dobrava-Belgrade cause severe HFRS, Seoul a moderate form, and Andes is a New World cardiopulmonary agent.

The Quadripartite comprises the WHO, FAO, WOAH and UNEP, which together produced the One Health Joint Plan of Action. The World Trade Organization is not part of it.

Like other bunyavirals, CCHFV has no matrix protein. Inside the envelope the three genome segments exist as ribonucleoproteins, each coated by nucleocapsid protein and bound to the L polymerase.

Gn and Gc form the surface spikes, so all four of the other proteins are present.

Faget’s sign is a pulse that is slow relative to the height of the fever, characteristic of the viraemic period of yellow fever (and also of typhoid).

Romaña’s sign is the periorbital oedema of acute Chagas disease, Koplik spots are pathognomonic of measles, Forchheimer spots occur in rubella and scarlet fever, and Pastia’s lines are seen in scarlet fever.

An arbovirus must replicate inside its arthropod vector, completing the extrinsic incubation period from gut to salivary glands. This biological transmission is the defining criterion of the group.

Carriage on the mouthparts is mechanical transmission, which excludes a virus. A DNA genome, faecal-oral spread and a human reservoir are irrelevant to the definition; most arboviruses have RNA genomes and non-human reservoirs.

Ixchiq, approved in late 2023, was the world’s first licensed chikungunya vaccine, a live-attenuated single-dose product; a virus-like particle vaccine, Vimkunya, followed.

Vaccines are not limited to inactivated designs, do not remove the need for bite avoidance and vector control, and are for adults and adolescents rather than young infants.

Viraemia is high, correlates with disease severity, and neutralising antibody to E2 mediates recovery and confers durable, probably lifelong, immunity.

Viraemia is neither low nor irrelevant, immunity is durable rather than brief, and antibody rather than cytotoxic T cells alone is the principal protective arm.

All three viruses are neurotropic, invading the brain and infecting neurons, and Eastern equine encephalitis virus is the most neurovirulent.

Susceptibility to fatal disease is highest at the extremes of age, and neuroinvasion can occur by several routes, not only along nerves.

Severe cardiopulmonary syndrome may require extracorporeal membrane oxygenation, and corticosteroids have not been shown to help; care is otherwise supportive.

HFRS often needs dialysis, ribavirin does not cure cardiopulmonary disease, and antibiotics treat a viral illness only if bacterial co-infection arises.

The human-pathogenic hantaviruses belong to the genus Orthohantavirus in the family Hantaviridae, a true taxonomic grouping.

Unlike “arbovirus”, the name reflects shared ancestry, not ecology; the wider family also infects shrews, moles, bats and lower vertebrates; and the genome is segmented negative-sense RNA, not DNA, in the order Bunyavirales rather than the Flaviviridae.

Effective inactivated (for example the Vero-cell IXIARO) and live-attenuated (SA14-14-2) vaccines drive routine childhood immunisation across endemic Asia and are recommended for at-risk travellers; because the virus is a single serotype, they protect across genotypes.

The mouse-brain vaccine is largely phased out, vaccines are not genotype-restricted, and children are the main target group.

There is no licensed human vaccine; veterinary vaccines protect horses, and Venezuelan equine encephalitis virus is highly infectious by aerosol and a recognised biothreat.

Human vaccines remain investigational, the laboratory-aerosol hazard is real, and equine vaccination is central to outbreak control.

Treatment is supportive; unlike for Crimean-Congo haemorrhagic fever, ribavirin is not recommended for RVF, having been linked to late-onset encephalitis in animal studies, and corticosteroids are not recommended either.

No antiviral is approved for the disease.

E2 is the attachment protein and the dominant target of neutralising antibody, while E1 carries the fusion peptide.

E3 chaperones the E2 precursor and is cleaved by furin; the capsid forms the internal nucleocapsid, not the surface spikes.

Despite abundant Aedes aegypti, yellow fever has never established endemic transmission in Asia, a puzzle attributed to dengue cross-protection, vector competence and historical trade patterns; about 90% of the burden falls on Africa.

South America carries the minority of cases, the virus is not eradicated from Africa, and it is a tropical rather than temperate disease.

Hantaviruses lack a matrix protein and assemble by budding at the Golgi, a shared bunyavirus feature.

They are enveloped, do not assemble at the plasma membrane, and do not integrate into host DNA.

Sindbis is an enveloped, roughly 70 nm particle with a single positive-sense RNA genome of about 11.7 kb, expressed as nonstructural and structural protein sets.

It is not non-enveloped, DNA, segmented or double-stranded, and it is E2 that attaches while E1 fuses.

Effective inactivated whole-virus vaccines based on the European subtype cross-protect against all three subtypes, with efficacy above 95%; they are given as a multi-dose primary series with periodic boosters.

There is no single-dose lifelong tick-borne encephalitis vaccine, and protection is not restricted to the European subtype.

There is no licensed human West Nile vaccine, though effective inactivated equine vaccines are widely used. Human candidates have reached early-phase trials, but the sporadic, scattered nature of human disease has made large efficacy trials impractical.

The other statements describe vaccines that do not exist for human West Nile virus.

The Far-Eastern subtype is the most severe, with a case-fatality of roughly 20% to 40%, compared with about 6% to 8% for the Siberian and 0.5% to 2% for the European subtype.

Kunjin is a subtype of West Nile virus, not of tick-borne encephalitis virus.

In active surveillance health officials take the initiative to obtain reports, giving high completeness and timeliness, but it is resource-intensive and reserved for priority diseases. Passive surveillance is cheaper and wider but under-reports.

Wild birds develop a prolonged, high-titre viraemia and are the amplifying hosts that sustain the bird-mosquito cycle. Horses and humans are dead-end hosts that do not amplify the virus.

Pigs amplify Japanese encephalitis, not West Nile virus, and cattle are not significant amplifying hosts.

Powassan virus is a member of the tick-borne encephalitis serocomplex, which also contains Kyasanur Forest disease, Omsk haemorrhagic fever and louping ill viruses.

Japanese encephalitis and West Nile viruses form the mosquito-borne Japanese encephalitis serocomplex, and dengue and yellow fever are separate groups.

O’nyong-nyong virus causes a near-identical fever, arthralgia and rash syndrome and is chikungunya’s closest relative, separated serologically and by its prominent cervical lymphadenopathy.

Dengue and Zika share the setting but favour myalgia; Ross River is a more distant arthritogenic alphavirus; West Nile is an encephalitic flavivirus.

Lineage 2 is the endemic African lineage, first characterised on the continent, and drives South African equine and human disease; it has more recently seeded large European outbreaks.

Lineage 1a caused the 1999 New York outbreak and is the most widespread, lineage 1b is the milder Australian Kunjin virus, and the minor lineages are not major causes of southern African disease.

Human viraemia is too low to infect feeding mosquitoes, so people cannot sustain the cycle, which is maintained by pigs and wading birds; there is no human-to-human spread.

Humans are fully susceptible and are bitten in the field, so the other options are incorrect.

The RNA-dependent RNA polymerase has no proofreading or repair function, so its errors are not corrected, giving about one mutation per genome per replication. DNA viruses use higher-fidelity polymerases and so evolve far more slowly.

Necrosis is midzonal and the reticulin framework is preserved, so survivors regenerate normal architecture and heal without cirrhosis. Transaminases can remain raised for weeks, but there is no postnecrotic scarring.

The remaining options describe fibrotic or destructive processes that do not occur in yellow fever hepatitis.

The mutant cloud already contains rare drug-resistant variants before the drug is ever encountered, so a single agent simply selects them, often within days. Durable regimens therefore combine agents with independent resistance pathways.

Until dengue is excluded, paracetamol is preferred because non-steroidal anti-inflammatory drugs and aspirin carry a bleeding risk in dengue.

There is no chikungunya antiviral to interact with, these drugs do not worsen arthralgia, none clears the virus, and they become the mainstay for chikungunya arthralgia once dengue is excluded.

Chikungunya is an Old World arthritogenic alphavirus, causing fever, rash and polyarthritis.

The New World alphaviruses (eastern, western and Venezuelan equine encephalitis) are classically encephalitic, and the flaviviruses and phleboviruses are separate genera.

Yellow fever virus is the type species of the genus Orthoflavivirus (family Flaviviridae), a small enveloped positive-sense single-stranded RNA virus; the family name derives from flavus, Latin for yellow.

Alphavirus holds chikungunya, Orthonairovirus holds Crimean-Congo haemorrhagic fever virus, Phlebovirus holds Rift Valley fever virus, and Orthohantavirus holds the hantaviruses.

Zika virus was isolated in 1947 from a sentinel rhesus monkey in the Zika Forest of Uganda, and soon after from Aedes mosquitoes at the same site.

Yap Island (2007) and French Polynesia (2013 to 2014) were later outbreaks, and the Americas epidemic began in 2015; none was the site of first isolation.

a. Severe yellow fever in the period of intoxication. The biphasic pattern (febrile illness, brief remission, then jaundice, bleeding and renal impairment) in an unvaccinated traveller from an endemic forest is characteristic.

b. By this stage viraemia is waning, so serology (IgM-capture ELISA) is the mainstay, supported by reverse-transcriptase PCR or NS1 antigen if he is still within the viraemic window; plaque-reduction neutralisation resolves flavivirus cross-reactivity. Liver biopsy is contraindicated.

c. Supportive intensive care: fluid and electrolyte management, organ support including renal replacement for acute kidney injury, correction of coagulopathy with blood products, and avoidance of salicylates. There is no licensed antiviral.

d. Notify the case as a notifiable medical condition and prevent mosquito access to the viraemic patient to block onward transmission.

a. West Nile neuroinvasive disease (encephalitis with acute flaccid paralysis), supported by the season, the lymphocytic cerebrospinal fluid and the sick sentinel horses.

b. Advancing age is the dominant risk factor for neuroinvasive disease, with the risk in the elderly many times that of young adults.

c. IgM-capture ELISA on serum and cerebrospinal fluid (IgM in cerebrospinal fluid indicates central nervous system infection), with reverse-transcriptase PCR on cerebrospinal fluid or early serum; paired sera help address IgM persistence and flavivirus cross-reactivity, and samples are screened for other arboviruses.

d. Supportive care, with close attention to bulbar and respiratory function and intensive care with ventilation if respiratory failure develops; no antiviral is of proven benefit.

a. Tick-borne encephalitis in its biphasic form: a grippe-like first phase, a remission, then a neurological second phase of meningitis or meningoencephalitis, typical of the European subtype.

b. The unpasteurised goat’s milk, because tick-borne encephalitis virus can be acquired by the alimentary route from the milk of infected goats, sheep or cattle, an additional exposure to the tick bite.

c. Serology, with IgM-capture ELISA on serum and cerebrospinal fluid and a rising titre in paired sera; virus is rarely isolated once neurological disease has begun.

d. Tick-borne encephalitis vaccination before travel (with tick-bite avoidance and avoiding unpasteurised dairy as supporting measures).

a. Zika virus infection. The mild febrile illness with rash, arthralgia and non-purulent conjunctivitis after travel to an endemic region is characteristic (dengue and chikungunya are the main differentials).

b. Reverse-transcriptase PCR on blood and urine (urine has a longer detection window), with serology if presentation is later; the key pitfall is strong flavivirus cross-reactivity, so a positive IgM needs confirmation by plaque-reduction neutralisation and interpretation is harder with prior flavivirus exposure.

c. The concern is congenital Zika syndrome, particularly microcephaly, greatest after first-trimester infection; monitoring is by serial fetal ultrasound, with amniotic-fluid testing where indicated and paediatric assessment of the neonate.

d. Because Zika persists in semen and is sexually transmitted, the partner should use condoms or abstain for the recommended period to avoid re-exposing her during the pregnancy.

• Severe egg allergy, because the vaccine is grown in embryonated chicken eggs.
• Significant immunosuppression, including symptomatic HIV with a low CD4 count, and thymus disorders.
• Infancy under six months (and caution between six and nine months), given the risk of vaccine-associated neurotropic disease.
• Advanced age, a caution rather than an absolute bar, because vaccine-associated viscerotropic disease rises steeply in first-time recipients over about 60 years.

• Meningitis: an aseptic meningitis with a lymphocytic cerebrospinal-fluid pleocytosis.
• Encephalitis: altered consciousness ranging to coma, often with tremor, myoclonus and parkinsonian features.
• Acute flaccid paralysis: an asymmetric, poliomyelitis-like weakness from anterior horn cell destruction, which may occur without meningitis or encephalitis.

• Sylvatic (jungle) cycle: between non-human primates and forest canopy mosquitoes, Haemagogus and Sabethes species in the Americas and Aedes africanus in Africa; humans infected incidentally.
• Intermediate (savannah) cycle: between monkeys and humans via tree-hole Aedes, for example Aedes furcifer and Aedes luteocephalus, the commonest source of African outbreaks.
• Urban cycle: human to human via Aedes aegypti, the domestic container-breeding mosquito responsible for explosive city epidemics.

• European (Western) subtype: the mildest, with a case-fatality of about 0.5% to 2%; transmitted by Ixodes ricinus.
• Siberian subtype: intermediate severity, case-fatality about 6% to 8%, and associated with chronic progressive disease.
• Far-Eastern subtype: the most severe, case-fatality about 20% to 40%, often monophasic with prominent paralysis.

• Persistent IgM: serum IgM can remain detectable for more than a year, so a positive result may reflect past rather than current infection; correlate with the clinical picture and, where possible, demonstrate seroconversion in paired sera.
• Flavivirus cross-reactivity: antibody cross-reacts with other flaviviruses and with yellow fever or Japanese encephalitis vaccination, so paired serology is essential and plaque-reduction neutralisation is used to confirm the specific virus. Specimens are also screened for other co-circulating arboviruses.

A complete answer covers the transmission ecology, the human burden and the tiered laboratory approach with its pitfalls.

Epidemiology

West Nile virus is the most widely distributed flavivirus, maintained in an enzootic cycle between Culex mosquitoes and birds, the birds acting as amplifying hosts through a prolonged high-titre viraemia. Humans and horses are dead-end hosts. Transmission peaks in late summer and early autumn. The virus can also spread by blood transfusion, organ transplantation, breast milk and in pregnancy. Most infection is silent: about a quarter of infections are symptomatic and roughly 1 in 150 develops neuroinvasive disease, the risk rising steeply with age. Lineage 1a caused the 1999 North American emergence, while lineage 2 is endemic in southern Africa.

Laboratory diagnosis

Diagnosis is anchored on serology: IgM-capture ELISA on serum and cerebrospinal fluid, with cerebrospinal-fluid IgM indicating central nervous system infection because IgM does not cross the blood-brain barrier. Two pitfalls must be managed: IgM can persist for over a year, and antibody cross-reacts across flaviviruses and with vaccination, so paired sera and plaque-reduction neutralisation are used to confirm. Reverse-transcriptase PCR and culture on serum or cerebrospinal fluid are useful only in the brief viraemic window (roughly the first six days) and a negative result does not exclude infection; PCR is most valuable in immunocompromised patients with prolonged viraemia and blunted antibody. Specimens are also screened for other co-circulating arboviruses given the overlapping presentations.

A complete answer links the viscerotropic tropism of the virus to the triphasic clinical course and the mechanisms of organ failure.

Viral entry and dissemination

After a mosquito bite the virus replicates in local lymph nodes, seeds the reticuloendothelial system and produces a high-titre viraemia that carries it to the liver, kidney and other organs. Nonstructural proteins antagonise interferon induction and signalling, helping the virus reach the viraemia that precedes severe disease.

Hepatic and renal injury

The liver is the principal target. Necrosis is midzonal, sparing cells around the central vein and portal tracts, and hepatocytes die by apoptosis into eosinophilic Councilman bodies with minimal inflammation. Because the reticulin framework is preserved, survivors heal without cirrhosis. The kidney shows acute tubular necrosis, producing the heavy albuminuria that is a clinical hallmark.

Systemic mechanisms of severe disease

Direct cytopathic injury alone does not explain shock. A dysregulated innate response, a high circulating cytokine load, coagulopathy that may progress to disseminated intravascular coagulation, and increased vascular permeability combine to cause multi-organ failure.

Clinical course

After an incubation of about three to six days, illness runs a triphasic course: a viraemic period of infection (fever, myalgia, Faget’s sign), a brief remission, and in a minority a period of intoxication with jaundice, acute kidney injury and a haemorrhagic diathesis including the classic black vomit. Death is usually on the seventh to tenth day, and case-fatality among jaundiced cases is roughly 20% to 50%; management is supportive because no antiviral exists.