"Super-Spreaders" and Person-to-Person Transmission of Andes Virus in Argentina

An important known risk factor for person-to-person transmission of ANDV is prolonged or close contact with symptomatic persons.

“An important known risk factor for person-to-person transmission of ANDV is prolonged or close contact with symptomatic persons.17,18,21”

• cites [17] 17. Ferrés M, Vial P, Marco C, et al. Pro- spective evaluation of household contacts of persons with hantavirus cardiopulmo- The New England Journal of Medicine Downloaded from nejm.org on August 29, 2023. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. n engl j med 383;23 nejm.org December 3, 2020 nary syndrome in Chile. J Infect Dis 2007; 195: 1563-71. sourceSupported
• cites [18] 18. Lázaro ME, Cantoni GE, Calanni LM, et al. Clusters of hantavirus infection, southern Argentina. Emerg Infect Dis 2007; 13: 104-10. sourcePartly supported

  The Discussion says close and prolonged contact may be necessary for person-to-person transmission of Andes virus, particularly during the early phase of illness. That supports the importance of contact with an infected person, but the claim presents a tentative, combined condition as an established risk factor involving either close or prolonged contact. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [21] 21. World Health Organization. Hanta- virus pulmonary syndrome -Argentine Republic. 2019 (https://www . who . int/ csr/ don/ 23 -January -2019 -hantavirus -argentina/ en/ ).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The ANDV Epuyén/18-19 strain shows a facility (R>2) for sustaining continuous chains of transmission if no control measures are enforced.

“The super-spreading capability of the ANDV Epuyén/18-19 strain shows a facility (R>2) for sustaining continuous chains of transmission if no control measures are enforced.39”

• cites [39] 39. Geoghegan JL, Holmes EC. Predicting virus emergence amid evolutionary noise. Open Biol 2017; 7: 170189. sourceCould not verify

  The nature of virus emergence section discusses sustained transmission in other viruses, while the population-genetic framework section discusses transmission in general; neither addresses the ANDV Epuyén/18-19 strain. Searches for ANDV, Epuyén, R>2, and transmission without control measures found no passage supporting the strain-specific claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Clinical investigations involving patients with ANDV hantavirus pulmonary syndrome in this outbreak revealed that patients with a high viral load and liver injury were more likely than other patients to spread infection.

“Clinical investigations involving patients with ANDV hantavirus pulmonary syndrome in this outbreak revealed that patients with a high viral load and liver injury were more likely than other patients to spread infection.”

RNA belonging to the S segment of the viral genome of ANDV was detected by RT-qPCR in all blood specimens.

“RNA belonging to the S segment of the viral genome of ANDV was detected by RT-qPCR in all blood specimens (Table 1 and Supplementary Appendix 2).”

Incubation periods ranged from 9 to 40 days.

“Incubation periods ranged from 9 to 40 days.”

No significant differences or associations were found between disease severity and Z value (P>0.05).

“No significant differences or associations were found between disease severity and Z value (P>0.05)(Supplementary Appendix 3).”

An additional 10 persons who attended the wake and were in close contact with Patient 9 became ill between 14 and 40 days after the wake for Patient 2.

“An additional 10 persons who attended the wake and were in close contact with Patient 9 became ill between 14 and 40 days after the wake for Patient 2.”

Approximately 82 health care workers were exposed to symptomatic patients with confirmed ANDV infection at Hospital Esquel Zonal from December 2 to December 13, 2018.

“Approximately 82 health care workers were exposed to symptomatic patients with confirmed ANDV infection at Hospital Esquel Zonal from December 2 to December 13, 2018.”

The posterior median R value across the entire outbreak was 1.19 (95% credible interval, 0.82 to 1.56).

“The posterior median R value across the entire outbreak was 1.19 (95% credible interval, 0.82 to 1.56)”

The remaining 12 patients were each in contact with at least one previously symptomatic patient.

“The remaining 12 patients were each in contact with at least one previously symptomatic patient.”

Around December 31, 2018, after the 18th case of ANDV hantavirus pulmonary syndrome was confirmed, public health authorities ordered isolation measures for symptomatic patients and self-quarantine for high-risk case contacts.

“Around December 31, 2018, after the 18th case of ANDV hantavirus pulmonary syndrome was confirmed, public health authorities ordered isolation measures for symptomatic patients and self-quarantine for high-risk case contacts (Supplementary Appendix 1).”

The phylogenetic analysis confirmed that the outbreak was caused by a single spillover event.

“The phylogenetic analysis confirmed that the outbreak was caused by a single spillover event (Fig. 1A).”

Sequences shared 99.8 to 100.0% identity with the other ANDV sequences involved in the outbreak.

“Sequences shared 99.8 to 100.0% identity with the other ANDV sequences involved in the outbreak (Table S5).”

Hematologic abnormalities, including thrombocytopenia, lymphopenia, leukocytosis, and neutrophilia, were observed in the majority of cases.

“Hematologic abnormalities, including thrombocytopenia, lymphopenia, leukocytosis, and neutrophilia, were also observed in the majority of cases.”

Of the 45 persons who worked in the intensive care unit and emergency department, only a small number used any form of personal protective equipment while they were in direct contact with an infected patient.

“Of the 45 persons who worked in the intensive care unit and emergency department, only a small number used any form of personal protective equipment (including N95 respirators [N100 respirators for intubations and cleaning], goggles, and disposable laboratory coats) while they were in direct contact with an infected patient.”

The mean (±SD) serial interval (the time from symptom onset in a primary case to symptom onset in an epidemiologically linked secondary case) was approximately 23±7 days.

“The mean (±SD) serial interval (the time from symptom onset in a primary case to symptom onset in an epidemiologically linked secondary case) was approximately 23±7 days (Fig. S4).”

Four patients (Patients 10, 29, 33, and 34) may have been infected by more than one person.

“Four patients (Patients 10, 29, 33, and 34) may have been infected by more than one person.”

Fatal cases were characterized by severe compromise in hemodynamic function, as evidenced by marked hypotension.

“Fatal cases were characterized by severe compromise in hemodynamic function, as evidenced by marked hypotension.”

The first person-to-person transmission event was traced to a birthday party with approximately 100 guests.

“Our findings traced the first person-to-person transmission event to a birthday party with approximately 100 guests.”

Patients with a less pronounced elevation of stem cell growth factor β were more likely to be spreaders than nonspreaders (odds ratio, 0.27; 95% CI, 0.09 to 0.73).

“Patients with higher levels of interleukin-1β (odds ratio, 2.4; 95% CI, 1.3 to 5.5) or a less pronounced elevation of stem cell growth factor β (odds ratio, 0.27; 95% CI, 0.09 to 0.73) were more likely to be spreaders than nonspreaders.”

The median R value for the entire 15-week period was 1.19.

“The median R value for the entire 15-week period was 1.19.”

Stem cell growth factor β and the Z value in patients with the Epuyén/18-19 strain of ANDV were negatively correlated (r = -0.41; 95% CI, -0.61 to -0.15).

“Notably, stem cell growth factor β and the Z value in patients with the Epuyén/18-19 strain of ANDV were negatively correlated (r = -0.41;95% CI, -0.61 to -0.15).”

Next-generation sequencing yielded complete or nearly complete ANDV genomic sequences (from the S, M, and L segments), with more than 98% coverage, from 27 of 28 available specimens.

“Next-generation sequencing yielded complete or nearly complete ANDV genomic sequences (from the S, M, and L segments), with more than 98% coverage, from 27 of 28 available specimens (Table S3).”

The transmission and exposure events for all 33 secondary cases and four waves of human infection were reconstructed on the basis of the known and probable epidemiologic relationships among cases.

“The transmission and exposure events for all 33 secondary cases and four waves of human infection were reconstructed on the basis of the known and probable epidemiologic relationships among cases (Fig. 1B).”

• AssumptionRests on an assumption: The known and probable epidemiologic relationships among cases are accurate enough to reconstruct person-to-person transmission events.

Among the first 18 patients with confirmed infection (who had not yet been isolated), those with higher viral loads were more likely to spread infection to another person (odds ratio for elevated viral load, 1.7; 95% CI, 1.2 to 3.6).

“Among the first 18 patients with confirmed infection (who had not yet been isolated), those with higher viral loads were more likely to spread infection to another person (odds ratio for elevated viral load, 1.7; 95% CI, 1.2 to 3.6).”

Z values were positively correlated with LDH levels in patients before they were isolated (r = 0.54; 95% CI, 0.09 to 0.80).

“positive correlations were found between Z values and LDH (r = 0.54; 95% CI, 0.09 to 0.80), AST (r = 0.56; 95% CI, 0.10 to 0.82), and ALT levels (r = 0.63; 95% CI, 0.21 to 0.85) in patients before they were isolated.”

The Z value was correlated with decreasing prothrombin index.

“The Z value was correlated with increasing ALT levels in the blood, longer prothrombin response times, and decreasing prothrombin index.”

Z values were positively correlated with AST levels in patients before they were isolated (r = 0.56; 95% CI, 0.10 to 0.82).

“positive correlations were found between Z values and LDH (r = 0.54; 95% CI, 0.09 to 0.80), AST (r = 0.56; 95% CI, 0.10 to 0.82), and ALT levels (r = 0.63; 95% CI, 0.21 to 0.85) in patients before they were isolated.”

Patients with higher levels of interleukin-1β were more likely to be spreaders than nonspreaders (odds ratio, 2.4; 95% CI, 1.3 to 5.5).

“Patients with higher levels of interleukin-1β (odds ratio, 2.4; 95% CI, 1.3 to 5.5) or a less pronounced elevation of stem cell growth factor β (odds ratio, 0.27; 95% CI, 0.09 to 0.73) were more likely to be spreaders than nonspreaders.”

The R value after control measures were implemented was 0.96.

“The blue dashed line indicates the median R value before control measures were implemented (R = 2.12) by the Ministry of Health, and the red dashed line indicates the R value after control measures were implemented (R = 0.96); these values are shown for each 1-week period, where possible.”

During the prodromal phase, patients with secondary cases of infection with the Epuyén/18-19 strain of ANDV presented with the typical clinical symptoms associated with ANDV hantavirus pulmonary syndrome.

“During the prodromal phase, patients with secondary cases of infection with the Epuyén/18-19 strain of ANDV presented with the typical clinical symptoms associated with ANDV hantavirus pulmonary syndrome (Table 2).”

A median-joining haplotype network showed that the infections in 78% of patients (21 of 27 patients) shared a single viral haplotype that formed a central node from which six additional haplotypes spread out.

“A medianjoining haplotype network showed that the infections in 78% of patients (21 of 27 patients) shared a single viral haplotype that formed a central node from which six additional haplotypes spread out (Fig. 1C).”

Few genomic mutations were identified among the strains involved in the outbreak transmitted person-to-person, despite Epuyén/18-19 and Epilink/96 being sampled 22 years apart.

“Although the Epuyén/18-19 and Epilink/96 sequences were sampled 22 years apart, few genomic mutations were identified among the strains involved in the outbreak that were transmitted from person to person.”

Two additional nosocomial transmission events occurred at the smaller Epuyén Rural Hospital, for which information on the use of standard personal protective equipment was not available.

“Two additional nosocomial transmission events occurred at the smaller Epuyén Rural Hospital, for which information on the use of standard personal protective equipment was not available.”

The Epuyén/18-19 sequences are most closely related to those recovered from an unrelated case of ANDV hantavirus pulmonary syndrome that occurred in 2018 (the NRC-6/18 strain) in a patient from a neighboring town and to the Epilink/96 strain.

“The Epuyén/18-19 sequences are most closely related to those recovered from an unrelated case of ANDV hantavirus pulmonary syndrome that occurred in 2018 (the NRC-6/18 strain) in a patient from a neighboring town and to the Epilink/96 strain.”

Bivariate analyses revealed differences in the levels of interleukin-1β, interleukin-18, interleukin-13, stem cell factor, and stem cell growth factor β between all spreaders and nonspreaders.

“Bivariate analyses revealed differences in the levels of interleukin-1β, interleukin-18, interleukin-13, stem cell factor, and stem cell growth factor β between all spreaders and nonspreaders (Table 3).”

Except for Patient 5, all person-to-person spreaders of ANDV presented with compromised respiratory function.

“Except for Patient 5, all person-to-person spreaders of ANDV presented with compromised respiratory function.”

Phylogenetic analysis confirmed that the Epuyén/18-19 strain belongs to the ANDV variant.

“Phylogenetic analysis confirmed that the Epuyén/18-19 strain belongs to the ANDV variant (Fig. 1A, Fig. S1, and Table S4).”

The Z value was correlated with longer prothrombin response times.

“The Z value was correlated with increasing ALT levels in the blood, longer prothrombin response times, and decreasing prothrombin index.”

The most common clinical feature after the prodromal phase was the rapid onset of acute respiratory distress, marking the onset of the cardiopulmonary phase, which was evidenced by different degrees of compromise of respiratory function in 25 of 33 patients (76%).

“The most common clinical feature after the prodromal phase was the rapid onset of acute respiratory distress, marking the onset of the cardiopulmonary phase, which was evidenced by different degrees of compromise of respiratory function (in 25 of 33 patients [76%]).”

The viral load in patients before isolation was positively correlated with patient age (r = 0.46; 95% CI, 0.14 to 0.70).

“The viral load in patients before isolation was also positively correlated with patient age (r = 0.46; 95% CI, 0.14 to 0.70).”

Except for the haplotype of the specimen obtained from Patient 22, all the variant haplotypes were in terminal nodes (i.e., they were not transmitted to secondary cases).

“Except for the haplotype of the specimen obtained from Patient 22, all the variant haplotypes were in terminal nodes (i.e., they were not transmitted to secondary cases).”

Z values were positively correlated with ALT levels in patients before they were isolated (r = 0.63; 95% CI, 0.21 to 0.85).

“positive correlations were found between Z values and LDH (r = 0.54; 95% CI, 0.09 to 0.80), AST (r = 0.56; 95% CI, 0.10 to 0.82), and ALT levels (r = 0.63; 95% CI, 0.21 to 0.85) in patients before they were isolated.”

Five persons (Patients 2 through 6) who had been seated close to Patient 1 reported onset of symptoms consistent with ANDV hantavirus pulmonary syndrome between 17 and 24 days after the party.

“Five persons (Patients 2 through 6) who had been seated close to Patient 1 reported onset of symptoms consistent with ANDV hantavirus pulmonary syndrome between 17 and 24 days after the party (Fig. S3).”

One secondary nosocomial transmission event occurred at Hospital Esquel Zonal.

“Nonetheless, we identified one secondary nosocomial transmission event that occurred at Hospital Esquel Zonal, which is an advanced health care facility.”

Among patients with ANDV hantavirus pulmonary syndrome, high viral titers in combination with attendance at massive social gatherings or extensive contact among persons were associated with a higher likelihood of transmission.

“Among patients with ANDV hantavirus pulmonary syndrome, high viral titers in combination with attendance at massive social gatherings or extensive contact among persons were associated with a higher likelihood of transmission.”

After a single introduction of ANDV from a rodent reservoir into the human population, transmission was driven by 3 symptomatic persons who attended crowded social events.

“After a single introduction of ANDV from a rodent reservoir into the human population, transmission was driven by 3 symptomatic persons who attended crowded social events.”

Patient 2 was the most likely source for six infections in other persons during the early prodromal phase because of his active social life.

“Patient 2 was the most likely source for six infections in other persons during the early prodromal phase because of his active social life.”

Genetic factors facilitating person-to-person transmission may have been maintained in reservoir rodent host populations before the October 2018 cross-species transmission.

“Genetic factors that facilitated person-to-person transmission may have been maintained in reservoir rodent host populations before the cross-species transmission that occurred in October 2018.”

The measures limited our ability to rule out alternative avenues of transmission in multipatient homes.

“However, this also limited our ability to rule out alternative avenues of transmission in multipatient homes.”

The absence of evidence for ANDV adaptation within or between hosts or for differences in viral diversity between spreaders and nonspreaders indicates that permissive ecology and social factors have a more substantial influence than genetic changes in sustaining person-to-person transmission in human hosts.

“The absence of evidence for ANDV adaptation within or between hosts or for differences in viral diversity between spreaders and nonspreaders indicates that permissive ecology and social factors have a more substantial influence than genetic changes in sustaining person-to-person transmission in human hosts.”

Based on epidemiologic and genomic investigations, inhalation of droplets or aerosolized virions may have been the route of infection.

“On the basis of both the epidemiologic and genomic investigations of person-to-person transmission events, it appears that inhalation of droplets or aerosolized virions may have been the routes of infection.”

Our data suggest that three events of nosocomial transmission, not involving health care personnel, occurred inside hospital facilities during the Epuyén outbreak in 2018 and 2019.

“However, our data suggest that three events of nosocomial transmission, although not involving health care personnel, occurred inside hospital facilities during the outbreak in Epuyén in 2018 and 2019.”

The substantial up-regulation of IL-18, IL-1β, IL-13, SCF, and SCGF-β shows a broad but dysregulated immune response.

“Several differences between the patterns of immune response in all spreaders and nonspreaders were also notable, but the substantial up-regulation of the cytokines interleukin-18 (proinflammatory), interleukin-1β (inflammatory response), interleukin-13 (Th2), stem cell factor (hematopoiesis), and stem cell growth factor β (hematopoiesis) show a broad but dysregulated immune response.”

The spread of the Epilink/96 strain of ANDV was estimated to have had a mean R value of 0.7 (90% confidence interval [CI], 0.2 to 1.1).

“In comparison, the spread of the Epilink/96 strain of ANDV was estimated to have had a mean R value of 0.7 (90% confidence interval [CI], 0.2 to 1.1).23”

• cites [23] 23. Stein RA. Super-spreaders in infec- tious diseases. Int J Infect Dis 2011; 15(8): e510-e513.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The 2018-2019 Epuyén outbreak of ANDV hantavirus pulmonary syndrome shows evidence of person-to-person transmission of an orthohantavirus.

“The outbreak of ANDV hantavirus pulmonary syndrome in Epuyén in 2018 and 2019 shows evidence of person-to-person transmission of an orthohantavirus.”

On the basis of evidence from five reconstructed person-to-person transmission events, the route of infection in secondary cases was possibly through inhalation of droplets or aerosolized virions.

“On the basis of evidence from five reconstructed person-to-person transmission events, the route of infection in secondary cases was possibly through inhalation of droplets or aerosolized virions (Table 1 and Table S7).”

• AssumptionRests on an assumption: The known and probable epidemiologic relationships among cases are accurate enough to reconstruct person-to-person transmission events.