Volume 24, Number 9—September 2018
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Maripa Virus RNA Load and Antibody Response in Hantavirus Pulmonary Syndrome, French Guiana
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Séverine Matheus https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#comment" rel="nofollow"> ,
Hatem Kallel, Alexandre Roux, Laetitia Bremand, Bhety Labeau, David
Moua, Dominique Rousset, Damien Donato, Vincent Lacoste, Stéphanie
Houcke, Claire Mayence, Benoît de Thoisy, Didier Hommel, and Anne
Lavergne
Author affiliations: Institut
Pasteur de la Guyane, Cayenne, French Guiana (S. Matheus, L. Bremand,
B. Labeau, D. Moua, D. Rousset, D. Donato, V. Lacoste, B. de Thoisy, A.
Lavergne); Centre Hospitalier de Cayenne, Cayenne (H. Kallel, A. Roux, S. Houcke, C. Mayence, D. Hommel)
https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#suggestedcitation" rel="nofollow - Suggested citation for this article
Abstract
We report viral RNA loads and antibody responses in 6
severe human cases of Maripa virus infection (2 favorable outcomes) and
monitored both measures during the 6-week course of disease in 1
nonfatal case. Further research is needed to determine prevalence of
this virus and its effect on other hantaviruses.
Hantaviruses are members of the genus Orthohantavirus (family Hantaviridae)
and are carried by various rodent species, depending on the strain.
Humans can be infected by inhalation of aerosolized viruses excreted in
the urine or feces of infected rodents. New World hantaviruses in the
Americas cause hantavirus pulmonary syndrome (HPS) in humans,
characterized by fever, headache, cough, myalgia, and nausea, evolving
rapidly to pulmonary edema ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r1" rel="nofollow - 1 , https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r2" rel="nofollow - 2 ). This respiratory insufficiency is associated with death in 26%–39% of cases, depending on the New World hantavirus species ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r3" rel="nofollow - 3 , https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r4" rel="nofollow - 4 ).
Following the identification of Sin Nombre virus (SNV) as the
etiologic agent of HPS in the United States in 1993, many other
hantaviruses have been identified in the Americas ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r3" rel="nofollow - 3 – https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r6" rel="nofollow - 6 ).
In French Guiana, a laboratory-confirmed case of hantavirus infection
was reported in a hospitalized patient in 2008; the complete sequence
analysis showed that this was a novel hantavirus closely related to the
Rio Mamore species called Maripa virus ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r7" rel="nofollow - 7 , https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r8" rel="nofollow - 8 ).
We describe antibody responses to Maripa hantavirus infection and
viral RNA loads in the 6 laboratory-confirmed human cases in French
Guiana, measured at admission to the hospital. We also report how these 2
markers evolved during the course of the disease in the most recent
hospitalized case-patient, who had a favorable clinical outcome.
From the time hantavirus diagnostic tools were set up at French
Guiana’s Institut Pasteur in 2008, a total of 6 severe human cases of
infection by native hantavirus have been reported. All the patients were
male; the mean age was 54.6 years (range 38–71 years). The mean time
from onset of the disease until admission to the hospital was 4.6 days
(range 2–7 days). The clinical outcome was favorable for 2 of the
patients; 4 died ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t1" rel="nofollow - Table 1 ). The clinical and biologic parameters of the first 5 confirmed hantavirus cases were reported previously ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r9" rel="nofollow - 9 ).
The sixth patient was a 47-year-old man who complained of fever, cough,
myalgia, and sweating that had been developing over 6 days. He was
admitted to the Andrée Rosemon General Hospital in Cayenne, French
Guiana, on August 31, 2017. He experienced respiratory failure,
requiring rapid transfer to the intensive care unit for intubation and
mechanical ventilation. Thoracic radiography revealed bilateral diffuse
alveolar pulmonary infiltrates. The patient remained under mechanical
ventilation for 18 days and was discharged from hospital after 23 days
with complete clinical recovery. The clinical symptoms of the patient,
and his outdoor activities making the contact with rodents possible, led
to suspicion of acute hantavirus infection, which was confirmed by
molecular and serologic tests. The complete RNA coding sequence of the S
RNA segment (GenBank accession no. MG785209) was also generated and
compared with those of the other 5 previous hantavirus cases, showing
that it corresponded to a Maripa virus infection ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r9" rel="nofollow - 9 ).
We tested serum samples from the 6 HPS case-patients that were
collected on admission at the intensive care unit and the other 7
sequential serum samples provided from case-patient 6 (6 samples during
the hospitalization and 1 after discharge). We performed serologic IgM
and IgG tests and assayed them for viral RNA quantification ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t1" rel="nofollow - Tables 1 , https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t2" rel="nofollow - 2 ). We obtained informed consent from the patients, their representatives, or both at admission and before discharge.
We assayed all serum samples by IgM capture and IgG ELISA using the protocol described by Ksiazek et al. ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r10" rel="nofollow - 10 ).
We tested samples against SNV antigen and control antigen using 4-fold
dilutions, from 1:100 to 1:6,400. Because of antibody
cross-reactivities, positive ELISA findings with SNV antigens indicated
infections with New World hantaviruses. The positive criteria were
similar to those described by MacNeil et al. ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r11" rel="nofollow - 11 ).
The serologic investigations showed that all samples collected at
admission had detectable amounts of hantavirus IgM: minimum IgM titers >400 for patients 1, 2, 4, 5, and 6 and a maximum titer of >16,00 for patient 3 ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t1" rel="nofollow - Table 1 ). These data were similar to those reported in previous work ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r11" rel="nofollow - 11 , https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r12" rel="nofollow - 12 ). Only patient 5, who died 24 hours after admission, had serum samples positive for hantavirus IgG (titer >6,400).
Although the time from the onset of disease and sample collection at
admission was different for each of the 6 patients, this single positive
hantavirus IgG case may be explained in part by the longer viral
incubation period, resulting in the induction of IgG before the
appearance of symptoms. A previous study reported that the presence of
hantavirus IgG during the first week of infection might be a predictor
of survival, but we found no evidence supporting this view ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r11" rel="nofollow - 11 ).
To determine the viral RNA load in each serum sample, we performed
real-time PCR. Each reaction was performed in duplicate. For absolute
quantification, we calculated the exact number of copies of the gene of
interest using a standard curve established with plasmid DNA at
dilutions from 5 to 5 × 107 copies/mL. The viral RNA loads in the samples collected on admission were 5.8–6.6 log10 copies/mL (mean 6.2 ± 0.3 log10 copies/mL) ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t1" rel="nofollow - Table 1 ).
These values were similar to those observed in patients infected by
other hantaviruses, including patients with mild or moderate symptoms ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r13" rel="nofollow - 13 – https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r15" rel="nofollow - 15 ). We also observed that the viral RNA load in the 4 fatal cases was 6.2 log10 copies/mL, whereas in the 2 nonfatal cases it was 6.1 log10
copies/mL. A correlation between hantavirus RNA loads in the serum
during the acute phase of disease and the clinical outcome has been
hypothesized ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r14" rel="nofollow - 14 , https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r15" rel="nofollow - 15 );
however, although our study includes only a small number of cases and
only severe cases, it provides no evidence supporting this possibility.
Presumably, the fatal or nonfatal outcome depends not only on the
hantavirus viral load but also on other pathogenic or host factors.
The progression of these antibody responses and viral RNA loads was
also followed during the course of disease for patient 6, from admission
to the hospital (day 7) until day 46 after the onset of disease ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t2" rel="nofollow - Table 2 ).
IgM titers were high at admission but decreased to become undetectable
by day 46. Conversely, seroconversion (IgM to IgG) was observed between
day 7 and day 12; these hantavirus IgG titers then increased to 4.4 by
day 46. Likewise, viral RNA load evaluated in these 7 sequential serum
samples showed a high value at admission (6.4 log10 copies/mL), declining by 7 days later to 4.7 log10 copies/mL ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t2" rel="nofollow - Table 2 ). Viral load then remained around 4 log10 copies/mL in samples collected on days 20, 25, and 30 and was undetectable on day 46.
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Although limited in sample size, this study found similar results for
viral load and immune response in the first 6 cases of Maripa virus
infection reported in French Guiana after laboratory-based surveillance
began in 2008. Further work is needed to determine the overall
prevalence of this hantavirus in French Guiana and also the possible
undetected mild or moderate cases induced by Maripa virus infection as
reported for other New World hantaviruses ( https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r13" rel="nofollow - 13 – https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article#r15" rel="nofollow - 15 ).
Moreover, it would be informative to determine the infectious potential
of the virus in the sequential samples to provide a better
understanding of the pathophysiology of this infection. Investigations
of the immune response to hantavirus, consequences of different viral
loads, and the pathologic characteristics of different hantavirus
strains would help identify the determinants of disease outcome.
Top
Dr. Matheus is a research assistant at the Institut Pasteur de la
Guyane, Cayenne, French Guiana. Her research interests are the diagnosis
and pathophysiology of arboviruses, with special interest in hantavirus
circulation in French Guiana.
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Acknowledgments
We thank Sandrine Fernandes-Pellerin and Nathalie Jolly for their
helpful expertise on ethics issues relevant to this study. In addition,
we acknowledge Thierry Carage for his assistance.
This study was supported in part by the Centre National de Référence
des Hantavirus Laboratoire Associé financed by the Institut Pasteur de
la Guyane and Santé Publique France (Saint-Maurice, France). This study
benefited from the RESERVOIRS program, which is supported by the
European Regional Development Fund and Fonds Européen de Developpement
Régional, and received assistance from Région Guyane and Direction
Régionale pour la Recherche et la Technologie and Investissement
d’Avenir grants managed by the Agence Nationale de la Recherche (CEBA
ANR-10-LABEX-25-01).
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Tables- https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t1" rel="nofollow - Table 1. Immune response and viral loads on admission in 6 confirmed hantavirus cases, French Guiana
- https://wwwnc.cdc.gov/eid/article/24/9/18-0223-t2" rel="nofollow - Table 2. Monitoring of hantavirus antibodies and viral RNA load in sequential serum samples from patient 6, French Guiana
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Suggested citation for this article: Matheus S, Kallel H,
Roux A, Bremand L, Labeau B, Moua D, et al. Maripa virus RNA load and
antibody response in hantavirus pulmonary syndrome, French Guiana. Emerg
Infect Dis. 2018 Sep [date cited]. https://doi.org/10.3201/eid2409.170223" rel="nofollow - https://doi.org/10.3201/eid2409.170223
DOI: 10.3201/eid2409.180223
https://wwwnc.cdc.gov/eid/articles/issue/24/9/table-of-contents" rel="nofollow - Table of Contents – Volume 24, Number 9—September 2018
Source: https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article" rel="nofollow - https://wwwnc.cdc.gov/eid/article/24/9/18-0223_article
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