key: cord-0797341-coytxm83
authors: Gregianini, Tatiana Schäffer; Seadi, Claudete Farina; Zavarize Neto, Luiz Domingos; Martins, Letícia Garay; Muller, Guilherme Cerutti; Straliotto, Selir Maria; da Veiga, Ana Beatriz Gorini
title: A 28‐year study of human parainfluenza in Rio Grande do Sul, Southern Brazil
date: 2019-03-28
journal: J Med Virol
DOI: 10.1002/jmv.25459
sha: 53b8d0b9c0472feda728b084ce1e405ee0c834b2
doc_id: 797341
cord_uid: coytxm83

PROBLEM: Human parainfluenza virus (hPIV) is an important pathogen in respiratory infections, however the health burden of hPIV is underestimated. This study describes the infections by hPIV1‐3 in Rio Grande do Sul, Brazil, from 1990 to 2017, providing data of the frequency and seasonality of cases and associated clinical symptoms. METHOD OF STUDY: Nasopharyngeal samples of patients with respiratory infection were collected, clinical data were analyzed, and immunofluorescence was used to detect hPIV. RESULTS: Respiratory viruses were detected in 33.63% of respiratory infections. In a total of 11 606 cases of viral respiratory infection, 781 were positive for hPIV; hPIV prevalence ranged from 2.14% to 27% of viral respiratory infections. hPIV1 circulates mainly during fall; hPIV3 circulation, in turn, starts in fall and peaks during spring; and cases of hPIV2 are reported along the year, with peaks in fall and early spring. The most affected age group was children, with hPIV prevalence of 74.23% in patients for less than 1 year. A higher proportion of girls were infected than boys, however, no difference by sex was observed considering all age groups. The most frequent type was hPIV3, especially in hospitalized patients. Both hPIV1 and 3 were associated with dyspnea, while hPIV2 caused mild symptoms mainly in nonhospitalized patients. Nineteen fatalities occurred, 89.5% of them associated with risk factors (prematurity; chronic diseases; age, <1 or >60 years). CONCLUSION: hPIV causes a high number of respiratory infections, leading to hospitalization especially in children; epidemiological and surveillance studies are important for the control and management of respiratory infections.

Human parainfluenza viruses (hPIVs) infect the upper and lower respiratory tract of humans causing symptoms ranging from mild acute respiratory infection (ARI) to severe acute respiratory infection (SARI); severe cases might lead to death. hPIVs were discovered in the late 1950s; they belong to the family Paramyxoviridae and are divided into four types-hPIV1, 2, 3, and 4, the latter subdivided in subtypes hPIV4a and hPIV4b-which belong to two different genera:

Respirovirus (hPIV1 and 3) and Rubulavirus (hPIV2 and 4). 1 The clinical profile of patients infected by hPIV may vary according to viral type: hPIV1 is known to cause laryngotracheobronchitis (croup) 2 ; hPIV2 is associated to hospitalizations, however, little is known about its epidemiology 2 ; hPIV3, which is the most prevalent type, is one of the main causes of pneumonia and bronchiolitis in children and newborns 2 ; and hPIV4 is associated with mild upper respiratory tract infections in children and adults. 2, 3 Respiratory infections associated with hPIV are observed yearround, and trends in viral type circulation can be observed in some regions. Usually, during fall the main hPIV types are hPIV1 and 2, and during spring hPIV3 becomes dominant. 2, 4 The factors that contribute to specific regional viral circulation are not well understood and do not necessarily depend on the climate; for example, a study reports high hPIV3 prevalence during summer and beginning of fall in the United Kingdom, and during winter in Norway and Denmark 5 ; in other geographic regions, this virus is more frequent from spring to summer. 6 In Brazil, respiratory infections are the leading cause of hospitalization in children, 7 especially in the southern region, which includes the state of Rio Grande do Sul (RS). An increase in the prevalence of respiratory viruses is usually observed in RS from May to August; nonetheless, respiratory virus outbreaks are also registered during the summer. 4, 8, 9 Because of this, state health authorities in RS Epidemiological surveillance is the basis for the control and prevention of viral respiratory infections, however regional efforts regarding surveillance of respiratory viruses are directed mainly to influenza A virus (IAV) and human respiratory syncytial virus (hRSV), therefore little is known about other viral pathogens associated to ARI and SARI in RS. The present study describes the prevalence of hPIVs in RS from 1990 to 2017, providing important data and contributing to public health strategies regarding respiratory infections in South America.

This study includes 34 038 patients with respiratory infection symptoms in RS from June 1990 to December 2017. All patients that sought medical assistance at health units due to symptoms of respiratory infection and that were diagnosed with ARI or SARI were included in this study. Clinical symptoms considered to define SARI were dyspnea (oxygen saturation below 95%), fever, myalgia, lethargy, cough, and sore throat. 9, 10 For ARI definition, clinical symptoms were fever (above 37.5°C ), accompanied by cough or sore throat, and at least one of these symptoms: headache, myalgia, and arthralgia. 9 2.1 | Virus detection Nasopharyngeal secretion, including nasopharyngeal aspirates and swabs, was collected for laboratory analyses. Samples were processed at LACEN-RS, a reference laboratory that belongs to the Brazilian network of Influenza and Other Respiratory Virus Surveillance and performs analyses of respiratory infections in RS.

For respiratory virus detection, either molecular or immunoassays were used in routine laboratory analysis. Influenza virus A and B were detected using the reverse-transcription quantitative polymerase chain reaction (PCR), 10 

Frequency plots were used to describe: age groups; the total number of cases positive for the respiratory virus and for hPIV types in each year of the study; and monthly circulation of hPIV types. Statistical analysis was performed using SPSS Statistics 23.0 software (IBM, Armonk, NY).

The χ 2 and Fisher exact tests were used to compare hPIV prevalence between male and female, and to analyze clinical symptoms. Results were considered statistically significant when P < 0.05.

In this study, we assessed hPIV-positivity among patients with respiratory infection in southern Brazil from 1990 to 2017. Figure 1 shows the total number of viral respiratory infections throughout the period; cases positive for hPIV1-3 are also shown. hPIV positivity in each patient group (groups 1-3 as described in Section 2) is shown in Table 1 . 16.24% were hPIV1, 41.33% hPIV3, and 42.43% hPIV2 ( Figure 1 and Table 1 ). Of note, hPIV outbreaks were observed in the city of Table 1 ).

F I G U R E 1 Total number of cases positive for respiratory viruses in Rio Grande do Sul (1990-2017) and cases positive for each hPIV type. Between 1990 and 1999, only hPIV3 was tested; years from 2000 to 2017 include data for hPIV1-3. hPIV: human parainfluenza virus T A B L E 1 Cases of patients with ARI or SARI in RS (1990 RS ( -2017 Percentage in relation to the number of hPIV-positive cases in group 3. * The χ 2 and Fisher exact tests were used. Results were considered statistically significant when P < 0.05.

F I G U R E 2 Total number of hPIV-positive cases according to epidemiological weeks in Rio Grande do Sul (data accumulated monthly from 1990 to 2017); Max temp, average maximum temperature (in degrees Celsius) registered for each month during the period; Min temp, average minimum temperature (in degrees Celsius) registered for each month during the period. hPIV, human parainfluenza virus

All three hPIVs occur throughout the year, with some alternate circulation among viral types (Figures 1,2) . Accordingly, hPIV1 and 3

show alternate prevalence: hPIV1 circulate more during fall and its incidence decreases with the appearance of hPIV3 in late fall; the latter displays a gradual increase, with the highest incidence during spring (September-October). Cases of hPIV2 occur along the year, with peaks in April (fall) and September (early spring).

Pediatric patients were most of the cases in group 1, in which 84.54% were children younger than 10 years of age. In addition, according to LACEN-RS records 62.87% of hPIV-positive cases in this group were observed in children younger than 6 months (data not shown).

Interestingly, though 59.92% of all cases positive for the respiratory virus in group 1 were male and hPIV prevalence was higher in females (7.17% vs 4.7%, respectively; P = 0.026; Table 1 ). 

When patients with ARI symptoms were analyzed (group 2), results showed the occurrence of all three hPIVs in all age groups ( Figure 3A ). Of note, in patients up to 5 years of age, hPIV3 was the most prevalent type and hPIV2 was highly prevalent among adults between 20 and 49 years of age. Of all ARI cases with confirmed viral infection, 46.76% were male; the proportion of females among hPIVpositive cases was slightly higher (14.22% vs 11.57% males; P = 0.087), and no significant differences were found between sex regardless of hPIV types (hPIV1 P = 1.0, hPIV2 P = 0.383, and hPIV3 P = 0.46).

For SARI cases notified in SINAN from 2010 to 2017 (n = 416), demographic data from 410 patients were obtained (group 3).

Regardless of the virus type, 92.2% of hPIV infections occurred in children less than 5 years of age; notably, 68.29% were children younger than 1 year ( Figure 3B ). Interestingly, even though hPIV3 is more frequent than hPIV1, the latter seems to be more distributed in all age groups. In general, people between 20 and 60 years of age are less susceptible to hPIV infections. Of all positive respiratory viruses studied in LACEN-RS from 2010 to 2017, 52.12% were male; accordingly, hPIV prevalence was slightly higher in this group (5.31% vs 4.82% in female, P = 0.392), and no significant differences were found between sex regardless of hPIV types (hPIV1 P = 0.66, hPIV2 P = 0.073, and hPIV3 P = 0.219).

The most common symptoms among ARI patients infected by hPIV were fever, cough, and coryza regardless of the viral type (Table 2) .

Of note, patients infected by hPIV2 reported nasal obstruction (77.35%), myalgia (60.37%), and arthralgia (34.9%); moreover, fever was less common among hPIV2 patients than in patients infected by either hPIV1 or 3. In patients with hPIV3, fever (87.5%) and cough (89.28%) were the most common symptoms. Less common symptoms were earache, vomiting, cyanosis, muscular pain, and wheezing.

Patients hospitalized with SARI exhibit cough, fever, and dyspnea, and these were the symptoms mostly observed in hPIV-infected patients in groups 1 and 3; however, because samples of group 1 were analyzed before implementation of the national information system for surveillance of respiratory infections, no clinical data were available for this group of patients. Symptoms more frequent for each hPIV type are shown in Table 2 and included: dyspnea, sore throat, and myalgia for hPIV1; chills for hPIV2; and dyspnea for hPIV3. Other less reported symptoms included vomiting, tachypnea, wheezing, conjunctivitis, coryza, diarrhea, and headache.

Data regarding disease outcome (cure/fatality) were available only for group 2 (outpatients with ARI, n = 271) and group 3 (hPIVpositive patients hospitalized with SARI, n = 416); fatality outcomes were found only in group 3, with a total of 19 deaths (Table 3) . Thus, in this group, the mortality rate reached 4.57%; however, if all hPIVpositive cases are taken into account (n = 781), the mortality rate in hPIV infection was approximately 2.43%. Notably, 68.4% of the fatalities were in female patients and at least one risk factor was present in 89.5% of deaths, including prematurity, children up to 2 years, and adult above 60 years and/or patients with chronic diseases (Table 3 ).

The health burden of hPIV infection is underestimated due to lack of studies about this virus; a few studies analyzed hPIV infection in pediatric patients [11] [12] [13] [14] [15] ; apart from these, secondary data on hPIV can be found in some studies about influenza and hRSV. 6, [16] [17] [18] To help in the understanding of how hPIV impacts human health, this study describes hPIV infection in patients with respiratory infections in RS, southern Brazil, where the incidence of respiratory infections is one of the highest in the country. 9 Southern Brazil is the coldest region in the country; it is known that exposure to cold can induce vasoconstriction in the respiratory tract and suppression of immune responses. 19 However, some studies describe peaks of hPIV activity in oddnumbered years, but we did not find biennial patterns of hPIV circulation along 28 years of analysis. 2, 15, 27, 32 Viral dynamics in the human population is related to host, viral and environmental determinants, whose complexity is not well understood, especially when different viruses are involved in a pathological condition. Accordingly, respiratory infections in RS can be caused by a plethora of pathogens, including IAV, IBV, hPIV, hRSV, hAdV, and metapneumovirus 9, 34 ; in this sense, our findings show that hPIV activity is high during fall and spring, just before and after influenza and hRSV season, which occur in winter (from May to August). 35 Similarly, a study analyzed the circulation of hPIV, hRSV, and IAV in Fortaleza (Northeast Brazil) and found an inverse association between hPIV, hRSV, and IAV circulation. 16 including influenza infection. 9 In England and Wales, 43 it has been estimated that three deaths occur per year due to infection by hPIV2 in children up to 1-year old. In addition, hPIV has also been associated with mortality and a greater impact in the elderly above 75 years. 44 In our study, we found a higher fatality rate among patients infected with hPIV2 (22.22%) compared to hPIV1 and 3 (8.57% and 2.74%, respectively), mainly in young infants and in the elderly hospitalized with SARI.

One of the main limitations of this study was that only hPIV3 was assessed between 1990 and 1999, therefore data about hPIV1 and 2 infections were included in the analysis only from 2000 onwards. In addition, data was lacking for some patients, mainly those reported before 2002, therefore some patients had to be excluded from the study due to incomplete epidemiological information, both related to clinical and demographic data as well as to viral type. Another limitation was a change in the way that symptoms are reported in the system, and some important symptoms, including disease outcome, were included in the notification forms only after the 2009 influenza pandemics.

Recently, molecular methods based on singleplex-and multiplex-PCR have been developed for the diagnosis of viral respiratory infection; multiplex-PCR assays employ respiratory viruses panels which include, among other viruses, hPIVs. [45] [46] [47] Though more sensitive than IFA, multiplex-PCR presents higher costs for implementation, therefore many reference laboratories in Brazil still rely on IFA for epidemiological surveillance of viral respiratory diseases.

This represented a limitation for our study, and we cannot discard the possibility of finding a higher number of hPIV-positive cases if PCR-based methods had been used in our analyses. Nevertheless, we were able to detect a significant number of hPIV-positive cases, which reinforces the need for implementing molecular diagnostics for the respiratory virus in our region. As a matter of fact, as part of the improvement of epidemiological surveillance network in Brazil, a respiratory viruses panel to be used in multiplex-PCR is being implemented in some of the reference laboratories in the country, which will include IAV, IBV, hAdV, hPIVs, RSV, human metapneumovirus, human Bocavirus, human coronavirus, and rhinovirus.

Despite the difficulties found, we were able to perform historical analysis of cases of hPIV in RS along 28 years, with data about the epidemiological and laboratory surveillance of three hPIV types-hPIV1-3. Our analysis contributes to information about hPIV seasonality in South America, prevalence among age groups and most common symptoms observed in hPIV infection both in mild and severe acute respiratory infection.

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How to cite this article: Gregianini TS

A 28-year study of human parainfluenza in Rio Grande do Sul, Southern Brazil

The authors declare that there are no conflict of interests.

http://orcid.org/0000-0002-9912-9060