Ethical Approval

This report is based exclusively on publicly available information and aggregate event descriptions. The clinical and treatment data are from peer-reviewed literature. No individual-level data were used. This manuscript does not meet criteria for institutional review board evaluation.

Epidemiological Characteristics of Orthohantavirus

In humans, pathogenic rodent-borne orthohantaviruses cause two major severe syndromes depending broadly on viral phylogeography: (1) hemorrhagic fever with renal syndrome (HFRS), caused mainly by Eurasian species and characterized by capillary leak and acute kidney injury (AKI); and (2) HCPS, caused by American species and characterized by rapidly progressive noncardiogenic pulmonary edema, respiratory failure, and often, cardiogenic shock (Table 2 and Figure 2). ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7,Reference Saavedra, Díaz, Retamal-Díaz and Kalergis13}

Figure 2.

Timeline of Clinical Phases of ANDV.

Note: A description of the clinical phases of ANDV with selected symptoms and laboratory values.

Abbreviation: ANDV, Andes Virus; GI, Gastrointestinal; LDH, Lactate Dehydrogenase; aPTT, Activated Partial Thromboplastin Time; CFR, Case Fatality Rate; AV-ECMO, Veno-Arterial Extracorporeal Membrane Oxygenation.

The primary reservoir for ANDV is the long-tailed pygmy rice rat (Oligoryzomys longicaudatus). ^{Reference Juan, Levis, Pini, Polop, Steinmann and Provensal14} Spillovers to humans result from inhalation of aerosolized dried viral particles from contaminated rodent urine, feces, or saliva. ^{Reference Padula, Figueroa and Navarrete15}

Andes Virus has a reproductive number (R₀) of 2.12 – meaning, prior to outbreak containment measures, each infected person, on average, spreads the virus to more than two susceptible others, and so on, which can lead to an exponential rise in the epidemiologic curve. ^{Reference Martínez, Di Paola and Alonso5} Effective public health measures can reduce the R₀ to below 1.00, thereby halting the outbreak and preventing a global pandemic.

Once there is an established outbreak of a hantavirus with cardiopulmonary syndrome, it is necessary for WHO Emergency Medical Teams, ¹⁶ prehospital, ^{Reference Koenig, Beÿ and Monkeypox17} and other health workers world-wide to have an available Identify-Isolate-Inform ^{Reference Koenig18,Reference Marty, Beÿ and Koenig19} (3I) tool and be trained in its application. Physicians and other health care professionals must be sufficiently knowledgeable to identify potential cases and reassure a frequently misinformed public when a different cause of symptoms is detected.

Patients with ANDV have high viral loads in body fluids, which explains its unique ability among Orthohantavirus for documented person-to-person spread. Among Old World Orthohantavirus, Puumala Virus (PUUV) provides the clearest evidence of salivary shedding in humans; however, despite detectable viral RNA in saliva and salivary-gland tissue, epidemiologic evidence confirming person-to-person transmission is lacking. ^{Reference Pettersson, Klingström, Hardestam, Lundkvist, Ahlm and Evander20,Reference Pettersson, Rasmuson, Andersson, Ahlm and Evander21}

Scientific findings to date suggest that human-to-human transmission of ANDV requires close human contact, such as sharing utensils or food, deep kissing, sexual intimacy, and breastfeeding ^{Reference Ferrés, Martínez-Valdebenito and Angulo22} during the symptomatic prodromal phase. ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7} However, additional routes of transmission are plausible since ANDV can be aerosolized during severe coughing. Therefore, proper infection precautions and setting-appropriate personal protective equipment (PPE) are advised.

Infection by zoonotic ANDV has a highly variable incubation period with symptoms manifesting as early as seven days after infection, though most publications report a range of 14 to 49 days. Symptoms develop around a median of 18 days. ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7} Severe disease appears to result largely from endothelial cell barrier dysfunction and dysregulated host inflammatory responses, rather than from direct lytic cytopathic effects of the virus. ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7,Reference Saavedra, Díaz, Retamal-Díaz and Kalergis13,Reference Morzunov, Khaiboullina, St Jeor, Rizvanov and Lombardi23} Andes Virus RNA is detectable in blood before symptom onset. During acute illness, viral RNA is present in multiple body fluids, supporting biologic plausibility for transmission beginning before or very early in symptomatic disease (Figure 2). ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7,Reference Vial, Martínez-Valdebenito, Ríos, Martínez, Vial and Valdivieso24}

Clinical Manifestations

The prodromal phase lasts two-to-seven days. ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7} Symptoms include fever, headache, myalgias, gastrointestinal (GI) disturbances, and, occasionally, petechiae. High systemic viremia is present with viral negative-sense, single-stranded RNA detectable by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in blood, nasopharyngeal secretions, saliva, and gingival crevicular fluid. Infectious virus particles remain viable in these fluids. Furthermore, the non-specific viral symptoms of the prodromal phase can mimic many other diseases. ^{Reference Ferrés, Martínez-Valdebenito and Henriquez6,Reference Harris, Sinchi, Lawler and Frank25}

Symptoms of the cardiopulmonary phase include abrupt onset of cough, dyspnea, tachycardia, hypotension, and rapid progression to non-cardiogenic pulmonary edema which progresses to cardiogenic shock, myocardial depression, and respiratory failure in more than one-half of cases. ^{Reference Llah, Mir, Sharif, Khan and Mir26} This report showed a case fatality rate (CFR) of 23% (three deaths out of 13 cases), ¹ which is consistent with prior published CFR data that range from 21% to 50%. ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7} Death frequently results within 24 hours of hospitalization. ^{Reference Vial, Martínez-Valdebenito, Ríos, Martínez, Vial and Valdivieso24}

Viral shedding time for ANDV is extremely prolonged at 16 days, meaning isolation must continue for at least that length of time. Remarkably, ANDV has been detected in semen 278 days ^{Reference Ferrés, Martínez-Valdebenito and Henriquez6} and 71 months ^{Reference Züst, Ackermann-Gäumann and Liechti27} after recovery.

Clinicians must maintain a high index of suspicion for ANDV, especially in patients with compatible symptoms and exposure history related to endemic areas or contact with confirmed cases as defined by WHO. ²⁸ For suspected cases, rigorous infection control, including appropriate PPE, is mandatory due to risk of human-to-human transmission.

Patient Management

Acute Treatment—As demonstrated by recent outbreaks in Argentina and Chile with a 32% CFR, ^{Reference Durante-Mangoni, Cafarella, Mercadante and Scarpulla29} overall mortality rate with basic care alone is 25%-30%. Conversely, investigators reported a 20% mortality rate (80% survival rate) with extracorporeal membrane oxygenation (ECMO). ^{Reference Dietl, Wernly and Pett30} The mainstay of treatment is meticulous hemodynamic and respiratory management to prevent fluid overload and pulmonary edema. Importantly, AV-ECMO (veno-arterial ECMO) is life-saving in severe cases and should be initiated promptly before shock manifests. ^{Reference López, Pérez-Araos and Salazar31}

Infectious disease specialists can provide guidance on potential experimental or off-label therapies, especially after high-risk exposures. These treatments include:

• • Post-Exposure Prophylaxis: Favipiravir demonstrated promising results in preclinical trials if administered pre-viremia, though clinical data are limited. ^{Reference Safronetz, Falzarano, Scott, Furuta, Feldmann and Gowen32}

• • Convalescent Plasma and Monoclonal Antibodies: A clinical trial showed mortality reduced to 14% compared with standard care (32%). ^{Reference Garrido, Prescott and Calvo33}

• • Ribavirin: While useful for one of the HFRS viruses (Hantaan), it has not significantly improved survival in human HCPS trials. ^{Reference Mertz, Miedzinski and Goade34}

• • Immunomodulation: Experimental immunotherapy therapies for HCPS exist (Table 3 ^{Reference Antonen, Leppänen and Tenhunen35–Reference Vial, Valdivieso and Ferres38} ).

  Table 3.

  Experimental Immunotherapy for Hantavirus Cardiopulmonary Syndrome (HCPS)

  

  Table 3. Long description

  A table comparing experimental immunotherapy treatments for Hantavirus Cardiopulmonary Syndrome (HCPS). The table has 8 rows and 4 columns. Column headers are Treatment, Mechanism of Action, Current Data, and Potential value for Andes HCPS. Row 1: Treatment: Icatibant (Subcutaneous Injection); Mechanism of Action: Immunomodulator, Bradykinin B2 receptor antagonist; Current Data: Antagonizes vascular leakage, At least one PUUV case showed improved outcome, Helped several patients with severe HFRS; Potential value for Andes HCPS: Under consideration for severe cases. Row 2: Treatment: Dasatinib (Oral); Mechanism of Action: Src kinase inhibitor; Current Data: Blocks Src kinase activation that drives hantavirus-induced VE-cadherin dissociation, Landmark 2011 study showing dasatinib dramatically inhibited Andes virus-induced endothelial cell permeability with an IC50 of just 1 nanomolar, 90% blockade of VE-cadherin dissociation from adherens junctions in ANDV-infected endothelial cells; Potential value for Andes HCPS: Significant promise for HCPS treatment, but no clinical trials or animal studies have specifically evaluated dasatinib in HCPS, Early administration needed to block irreversible endothelial data, Future investigation for pre-exposure prophylaxis. Row 3: Treatment: Vandetanib (Oral); Mechanism of Action: Vascular endothelial growth factor 2 (VEGFR2) inhibitor; Current Data: Reduction of the ANDV-induced increased endovascular permeability, Increased survival in ANDV hamster model (if given 5 days before infection), Does not provide protection after viremia onset; Potential value for Andes HCPS: Preclinical state, Very limited promise for HCPS, Animal studies with disappointing results, Significant safety concerns in critically ill HCPS patients. Row 4: Treatment: Pazopanib (Oral); Mechanism of Action: Multi-tyrosine kinase inhibitor (including VEGFR inhibitor); Current Data: Multi-tyrosine kinase inhibitor specifically targeting VEGFR-1, -2, and -3, PDGFR- and -, FGFR-1 and -3, Kit, Itk, Lck, and c-Fms, Provides comprehensive coverage of angiogenic pathways relevant to hantavirus pathophysiology, Superior efficacy in blocking hantavirus-induced permeability in vitro, Specifically designed to impair angiogenesis by abrogating VEGFR-2 function; Potential value for Andes HCPS: Hypothetical value, more potent and focused VEGFR2 inhibition, Optimized pharmacokinetic profile, Achieves therapeutic concentrations that exceed the IC50 needed for endothelial protection, 31-hour half-life and once-daily dosing would be particularly advantageous in HCPS where consistent VEGFR2 blockade is critical for preventing progressive vascular leak. Row 5: Treatment: Vilobelimab (Intravenous); Mechanism of Action: Anti-Complement factor C5a antibody; Current Data: Pathophysiology of HCPS involves complement activation and C5a-mediated inflammation, Directly relevant to vilobelimabs mechanism of action (blocks C5a), countering a powerful chemoattractant for neutrophils, Reduced mortality rates in other severe, viral-induced acute respiratory distress syndrome (ARDS); Potential value for Andes HCPS: Hypothetical value, No clinical trials on HCPS, Ideally given within the first 24-48 hours of cardiopulmonary phase, before irreversible organ damage. Row 6: Treatment: Tocilizumab (Intravenous or Subcutaneous Injection); Mechanism of Action: Anti-IL-6 receptor antibody; Current Data: Mixed theoretical support, Potentially blocks life-threatening cytokine storm driven by IL-6, Mixed data on IL-6 levels in ANDV patients, Robust Th1-type immune response and cytokine storm in HCPS may require broader immunomodulation; Potential value for Andes HCPS: Hypothetical value, Needed early in disease course during prodromal phase or early cardiopulmonary phase before irreversible endothelial damage. Row 7: Treatment: FX-06 (Intravenous); Mechanism of Action: Natural peptide (B15-42) targeting VE-cadherin, Reseals endothelial barrier; Current Data: Potentially antagonizes vascular leakage, Potentially reseals the endothelial barrier to directly halt vascular leak and pulmonary edema, Andes virus nucleocapsid protein specifically binds to rho GDI (Rho GDP dissociation inhibitor), releasing and activating RhoA, which leads to stress fiber formation and increased permeability, Endothelial barrier resealing mechanism could directly counteract the primary pathophysiologic mechanism; Potential value for Andes HCPS: Hypothetical value, No clinical trials on HCPS, but efficacy in Dengue shock syndrome, LPS-induced edema, COVID-19 cytokine storm, and systemic capillary leak syndrome. Row 8: Treatment: Methyl-Prednisolone (Intravenous); Mechanism of Action: Immunomodulator; Current Data: High dose methylprednisolone tested in a clinical trial with high dose for HCPS hantavirus severe infections in Chile had no effect; Potential value for Andes HCPS: No evidence for low- dose administration.

  Abbreviations: HCPS, Hantavirus Cardiopulmonary Syndrome; PUUV, Puumala Virus; HFRS, Hemorrhagic Fever with Renal Syndrome; ANDV, Andes Virus; VEGFR2, Vascular Endothelial Growth Factor 2; PDGFR, Platelet-Derived Growth Factor Receptor; FGFR, Fibroblast Growth Factor Receptor; ARDS, Acute Respiratory Distress Syndrome; GDI, Gestational Diabetes Insipidus; GDP; LPS, Lipopolysaccharide.

Long-Term Neurologic and Endocrine Manifestations—The ten survivors of the 2026 MV Hondius ANDV outbreak warrant systematic long-term neurological and endocrinological surveillance. ^{Reference Van den Berg, UKHSA ANDV and Severi39} A comprehensive JAMA review authored by Nath highlights possible neurological complications of hantavirus infection, including post-infectious encephalomyelitis, seizures, Guillain-Barré syndrome, transverse myelitis, and pituitary apoplexy. Though uncommon, they can be severe. Pituitary damage may cause hormonal dysfunction (fatigue, adrenal insufficiency, hypothyroidism, diabetes insipidus, sexual dysfunction, and amenorrhea) manifesting in 18% of survivors after weeks to months (median of two years post-infection). ^{Reference Nath40} Pathogenic mechanisms (endothelial dysfunction, thrombocytopenia-related hemorrhage, and hypotension-induced ischemia) are shared across hantavirus syndromes. ^{Reference Stojanovic, Pekic and Cvijovic41,Reference Bhoelan, Langerak and Noack42} While data on long-term sequelae specific to ANDV-HCPS remain insufficient, there are reports of retinal hemorrhage, optic neuritis, sensorineural hearing loss, and chronic renal and pulmonary dysfunction. ^{Reference Vial, Ferrés, Vial, Klingström, Ahlm and López7} Nath emphasizes that data from case reports and small series are biased toward severe manifestations and calls for prospective natural history studies with long-term follow-up to fully characterize the breadth of nervous system involvement.

Given these data, the ten survivors described in this report should undergo baseline and serial endocrine evaluations (including pituitary hormone panels) at four-to-eight weeks and then annually, along with neurological assessment for delayed post-infectious complications, for a minimum of two years post-infection. ^{Reference Van den Berg, UKHSA ANDV and Severi39,Reference Nath40}

Identify-Isolate-Inform (3I) Tool

Originally conceived during the 2014 Ebola outbreak, ^{Reference Koenig18,Reference Koenig, Majestic and Burns43} the 3I concept has been widely applied to multiple diseases in the form of a decision-making tool for frontline clinicians. Persons under investigation for a transmissible disease are identified based on exposure or epidemiologic risk factor coupled with signs and symptoms. When there is concern for disease transmission, they are immediately isolated. The final step is to inform relevant infection control and public health entities.

While no specific ANDV 3I tool has been developed, the concepts can be applied, just as they have been for other infectious diseases. ^{Reference Koenig, Beÿ and McDonald44,Reference Koenig, Beÿ and Monkeypox45} In anticipation of the next ANDV outbreak, the baseline 3I framework can be populated and tailored with virus-specific data to create an ANDV tool to guide the localized response. A dedicated ANDV tool for frontline clinicians at prehospital and health care facility levels during a known outbreak would facilitate recognition, treatment, and outbreak containment.

Outbreaks Can Be Contained: Knowledge and Preparedness Are Key

The 2018-2019 Epuyén outbreak in Argentina demonstrated that human-to-human ANDV transmission can sustain multiple secondary generations of infections through “super-spreaders.” ^{Reference Martínez, Di Paola and Alonso5} The 2026 multi-national ship outbreak involving diverse international passengers illustrated how globalized travel can rapidly disseminate ANDV, raising concerns of a wide-spread public health emergency. The unique setting of this outbreak on a remote, expeditionary vessel highlights several challenges. These include provision of care in austere, resource-limited environments; effective prevention of disease spread in confined spaces; and coordination of outbreak response with land-based resources. These factors highlight the need to proactively isolate and manage suspected cases while awaiting definitive testing to prevent further spread onboard.

Efficient outbreak suppression relies on early recognition, contact tracing, rapid reporting and communication, strict quarantine and isolation, effective PPE use, active health monitoring during the entire incubation period, prompt supportive care, appropriate patient counseling (eg, safer-sex practices indefinitely, no breastfeeding during acute illness, and need for monitoring for long-term neurological and endocrinological sequalae), as well as rodent-control in endemic areas.

In this report of an ANDV outbreak on a maritime vessel, rapid implementation of public health measures, prompt proper medical attention, quarantine, and contact tracing were key to mitigating viral spread. The outbreak led to the establishment of the globally coordinated Natural History of Andes Virus Infection research initiative (aptly abbreviated as “NAVIS” – the Latin word for “ship”), which unites researchers and institutions across 21 countries. Its goals include studying ANDV transmission, incubation, immunity, and disease severity. ⁴⁶ Future developments to the initiative should focus on making the research accessible in an actionable form for frontline clinician use. Possible applications include bundles of care for prehospital and emergency department use; patient-management tools based on the 3I framework; and other relevant standardized processes, policies, and procedures.

Preventing ANDV Outbreak Expansion: A Call to Action

The MV Hondius outbreak provides a preview of ANDV’s global transmission potential. Three immediate preparedness actions are essential:

• • First, promote collaboration across nations and relevant sectors to identify and address drivers of diseases at the human-animal-environment interface to rapidly detect and minimize the effect of any spillovers or laboratory accidents. ⁴⁷

• • Second, update clinical protocols. Clinicians should screen patients using the 3I tool framework, which includes risk-level criteria, exposure history, signs and symptoms, and epidemiologic links to confirmed cases. Current hantavirus guidelines assume zoonotic transmission and brief infectious periods. Uniquely, ANDV requires extended quarantine, isolation, and enhanced PPE for all patient contacts.

• • Third, recalibrate surveillance systems and border-screening guidance. ^{Reference Mouchtouri48} Unlike other hantaviruses, ANDV can sustain transmission chains distant from rodent reservoirs. Prehospital settings, emergency departments, clinics, and physicians’ offices must become sentinel sites for immediately identifying and isolating imported cases and preventing secondary spread by promptly informing public health authorities.

• • Fourth, research priorities must shift toward outbreak preparedness, a task addressed by NAVIS, an initiative hosted by the Fight Infections Foundation (Barcelona, Spain). ⁴⁹ Transmission dynamics must be better understood, effective communication channels implemented, and application of the scientific basis of disease applied to evidence-based clinical management of patients. The development of diagnostics for rapid detection, effective antivirals for early treatment, and post-exposure prophylaxis for disease prevention cannot wait for the next global outbreak.

Prompt implementation of public health measures coupled with frontline clinician application of the 3I model for patient evaluation are critical actions. These can bolster outbreak preparedness, prevent international spread, foster cross-sector collaboration, and strengthen existing public health infrastructure. Furthermore, these actions will increase successful containment of future outbreaks of ANDV, thereby lessening the possibility of escalation to an International Health Regulation activation.