Prevalence of human respiratory syncytial virus in Iran

(1)

Prevalence of human respiratory syncytial virus in Iran: a systematic review and

meta-analysis

Masoud Dadashi

¹

, Hossein Goudarzi

¹

, Parviz Owlia

²

& Ebrahim Faghihloo*

^,1

1Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2Molecular Microbiology Research Center, Shahed University, Tehran, Iran

* Author for correspondence: Tel.: +98 21 2387 2556; Fax: +98 21 2387 6472; [email protected]

Aim:

We sought to determine the prevalence of human respiratory syncytial virus (HRSV) in people in Iran between the year 1996 and 2016.

Methods:

Prevalence of HRSV in Iran was determined from 1996 to 2016 using data from PubMed, Web of Science, EMBASE, Cochrane Library, Google Scholar and Iranian databases. Analysis was performed by Comprehensive Meta-Analysis software.

Result:

The prevalence of HRSV infections was 18.0% (95% CI: 14.6–22.0) in people in different regions of Iran. Additionally, the incidence of HRSV in north, center, west and south of Iran were 16.4% (95% CI: 11.8–22.4), 20.0% (95% CI:

15.5–25.5), 16.8% (95% CI: 10.0–27.0) and 10.6% (95% CI: 2.4–36.9), respectively.

Conclusion:

According to the high prevalence of HRSV infection among people with respiratory infections in Iran, HRSV screening and evaluating of co-circulate HRSV genotypes can be helpful for vaccination design in the future.

First draft submitted: 4 May 2017; Accepted for publication: 18 September 2017; Published online:

17 January 2018

Keywords:HRSV•Iran•meta-analysis

Human respiratory syncytial virus (HRSV) is one of the main causes of infections in the lower respiratory tract among children worldwide

^[1–3]

. The pathogen contains a lipid-envelope and helical nucleocapsid and belongs to the Pneumovirus genus, which is a member of the Paramyxoviridae family

^[4]

. The 15.2 kb genome of HRSV is a nonsegmented RNA containing 10 genes that all together encode for 11 proteins

[3

,

5]

. There are two significant glycoproteins, F and G, in the envelope of HRSV which play a key role in virus adherence and entrance into the host cell

^[6

,

^7]

. According to genetic and antigenic variation, HRSV can be categorized into two distinct serotypes:

type A and type B

^[8]

. The G glycoprotein intercedes adsorption into the cell by interacting with receptors on the host cell

^[9]

, and F glycoprotein mediated the merging of host cell membranes and virus

^[4]

. Although infection with HRSV often occurs in childhood and in younger children

^[10

,

^11]

, it should be noted that infection with this virus also occurs among vulnerable groups such as the elderly and patients with an immunocompromised immune system

^[12

,

^13]

. Based on many epidemiological studies, HRSV displays an obvious schema of seasonality, and epidemics are common in the winter and during the tropical regions in monsoon season, with a top incidence between November and January in most countries

^[8

,

¹⁴

,

^15]

. In tropical areas, HRSV prevalence occurs in the wet seasons

^[16]

. As HRSV contributes to a vast number of respiratory diseases and may be related to asthma in later life

^[17

,

^18]

, a rise in HRSV outbreaks is a great concern. Since there are different climates, highly populated areas and less densely populated areas in Iran, we decided to conduct a systematic review and meta-analyze the published studies providing data around the distribution of HRSV in different areas of Iran.

Methods Literature search

An information collection was established for prevalence of HRSV in Iran from 1996 to 2016 using Medline

(via PubMed), Web of Science, EMBASE, Cochrane Library, Google Scholar, Scientific Information and Iranian

databases. The search was restricted to original research articles published in English and Persian that present

the prevalence or incidence of HRSV in healthcare settings of Iran. The following keywords were used to search

(2)

Medical Subject Headings, titles and abstracts with the help of Boolean operators (and, or): respiratory syncytial virus, HRSV, Prevalence, Incidence and Iran. We also searched bibliographies of retrieved articles for additional articles.

Inclusion & exclusion criteria

All original research articles presenting cross-sectional studies on the prevalence of HRSV in Iran were considered.

The selection of articles for review was completed based on three factors: titles, abstracts and full texts. In safety evaluation, we further included studies only if they were conducted with more than 100 subjects. Articles excluded from the analysis were discounted for the following reasons: they considered only subpopulations such as H1N1 cases or they studied other types of respiratory pathogens; they were review articles; reported in languages other than English or Persian; meta-analyses or systematic reviews; and duplicate publication of the same study. Articles available only in abstract form were also excluded.

Data extraction & definitions

From the included studies, the following variables were extracted: author’s name, study time, publication year, settings, patient sample size, number of HRSV isolates, source of isolates and prevalence of HRSV. Two investigators extracted data from all of the included studies independently. Inconsistencies between the reviewers were discussed to obtain consensus.

Quality assessment

Included studies were appraised for quality, using a quality assessment checklist, which was designed by the Joanna Briggs Institute

^[19]

.

Meta-analysis

Analysis was performed using Comprehensive Meta-Analysis (V2.2, Bio stat) software. Generally, fixed or random effect models were used but this was dependent on statistical heterogeneity between studies to calculate summary estimates. Statistical heterogeneity was quantified by the I

²

statistic. In order to remove possible publication bias, Egger weighted regression methods were deployed. The value of p < 0.05 was considered indicative of statistically significant publication bias.

Results

Characteristics of included studies

Initially, a total of 265 articles were collected. In secondary screening, 211 of them were excluded on the basis of the title and abstract evaluation (Figure 1). In the next step, 27 of the remaining 54 studies were excluded upon a full text search. A total of 27 eligible studies were chosen for final analysis. Characteristics of the included articles are summarized in Table 1. Geographic location of studies covered east, west, north, south and center of Iran, and majority (n [%]) of the studies were from center of Iran. Unfortunately, no studies reporting data from the east of Iran met the criteria to be included in our meta-analysis. Diagnostic methods for HRSV mainly included molecular and nonmolecular methods. Additionally, HRSV species were isolated from nasopharyngeal swabs, nasopharyngeal aspirate, throat swabs, respiratory specimens and serum samples.

The prevalence of human respiratory syncytial virus strains

The pooled prevalence of HRSV infections among molecular testing-positive cases of HRSV was 18.0 (95% CI:

14.6–22.0) (Table 2). The heterogeneity test indicated that there were heterogeneities between studies (I

²

= 91.0;

p < 0.001). As it is shown in Table 2, Figure 2 shows the forest plot of meta-analysis of HRSV prevalence. Based on data in Table 2 & Figure 3, no evidence of publication bias was observed (p > 0.05 for Egger weighted regression analysis). As presented in Table 2, the outbreak of the HRSV in post-2009 studies is more than the previous reports. Table 3 shows the stratified analyses according to the geographic areas of included studies. The prevalence of the virus in the center, west, north and south of Iran was reported as 20, 16.8, 16.4 and 10.6%, respectively.

Unfortunately, none of the studies in the east of Iran met the criteria to be included in our meta-analysis. Also in this study, the prevalence of HRSV in Iran was evaluated based on the detection method of HRSV (Tables 4

& 5). As shown in Table 4, detection of HRSV by molecular and nonmolecular methods was reported 19.4 and

16.2%, respectively. Figure 4 shows the used method for HRSV detection, and distribution of HRSV infections

(3)

265 PubMed, Web of science, Embase, Cochrane library, Scopus and Iranian databases

81 abstracts reviewed

184 articles excluded title not relevant

27 articles excluded

Studies on non human samples; n = 5 Review articles; n = 8

Not reported RSV data; n = 14

27 articles excluded

Not reported RSV data; n = 12 Non standard method for RSV Detection; n = 15

54 full-text articles reviewed

27 studies included in the Meta-analysis

Figure 1. Flow diagram of literature search and study selection.

in different parts of Iran has been shown in Figure 5. Also, most of HRSV genotypes among patients with HRSV infection were GA1 and GA2, respectively (Figure 6).

Discussion

The current systematic review and meta-analysis reports the prevalence of HRSV infections in Iran. Our analyses showed that the prevalence of HRSV infections was 18.0% (95% CI: 14.6–22.0) among patients with respiratory infections in different parts of Iran (Table 2). According to the results of our study, the HRSV incidence rate was higher in the center of Iran (20.0% [95% CI: 15.5–25.5]) than other parts of this country. This high prevalence of HRSV in the center of Iran could be due to several reasons, including high population and research centers. Another reason could be that the samples examined and reported in Tehran, capital of Iran, were taken and transferred from other cities of Iran. Also, these results showed an increase in HRSV infection between 2009 and 2013 (22.3%

[95% CI: 17.2–28.5]) in comparison with other studies before the year 2009. This could be explained by the use

of more sensitive molecular detection tools, HRSV identification methods and increased knowledge about HRSV

detection

^[20]

.

(4)

Table 1. Characteristics of studies included in the meta-analysis.

Study name Time of study Published year Province Total number

(inpatients, outpatients)

Number of HRSV cases

Types of samples

Diagnostics Ref.

Milani 1998 2003 Tehran 365 70 NPA Cell culture and

DIF

[34]

Maleknejad 1999 2001 Tehran 145 56 NPA DIF [35]

Noorbakhsh 2001 2001 Tehran 83 20 NPS IIF [36]

Seyfi 2002 2002 West Azerbaijan 252 62 Not stated DIF [37]

Arabzadeh 2006 2006 Kerman 168 63 NPS RT-PCR [38]

Barati 2007 2009 Tehran 160 9 NPS IMC [39]

Kahbazi 2008 2011 Markazi 300 18 NPS RT-PCR [40]

Faghihloo1 2009 2011 Tehran 107 24 TS RT-PCR [30]

PourakbarI 2012 2014 Tehran 232 40 NPA RT-PCR [41]

Abshirini 2013 2015 Khouzestan 76 15 NPA, NPS RT-PCR [42]

Gilani 1996–1998 2001 Tehran 268 33 NPS Cell culture and

DIF

[43]

Farshad 2001–2002 2008 Mazandaran 202 26 NPS IIF [44]

Naghipoor 2003–2004 2007 Guilan 261 39 NPA, NPS RT-PCR [45]

Hamkar 2005–2006 2007 Tehran 212 34 NPS DIF [46]

Alborzi 2006–2007 2009 Fars 255 5 NPA Cell culture and

DIF

[47]

Karimi 2007–2008 2010 Chahar

mahal-Bakhtiari

300 26 SS ELISA [48]

Khalilzadeh 2007–2008 2010 Tehran 50 7 NPS RT-PCR ,Rt-PCR [49]

Faghihloo2 2007–2009 2010 Tehran 179 38 NPA, NPS RT-PCR [50]

Faghihloo3 2007–2013 2014 Tehran 485 94 NPS Nested RT-PCR [29]

Nikfar 2008–2009 2013 Khouzestan 100 9 TS RT-PCR [51]

Malekshahi 2008–2009 2010 Tehran 202 34 RS RT-PCR [52]

Sawadkohi 2008–2010 2012 Mazandaran 180 40 TS ELISA [53]

Alavi 2009–2010 2013 Khouzestan 100 29 TS Nested PCR [54]

Chavoshzadeh 2009–2010 2013 Tehran 96 44 TS PCR [55]

Shahrabadi 2009–2011 2011 Tehran 132 53 NPS DIF [56]

Parsania 2010–2013 2016 Tehran 158 49 NPS, NPA Rt-PCR [57]

Moattari 2011–2013 2015 Fars 280 30 NPS, TS RT-PCR [58]

DIF: Direct immunofluorescence; ELISA: Enzyme-linked immunosorbent assay; HRSV: Human respiratory syncytial virus; IIF: Indirect immunofluorescence; IMC: Immonochromatography;

NPA: Nasopharyngeal aspirate; NPS: Nasopharyngeal swab; RS: Respiratory specimen; Rt-PCR: Real-time polymerase chain reaction; RT-PCR: Reverse transcription polymerase chain reaction; SS: Serum samples; TS: Throat swab.

Table 2. Meta-analysis of prevalence of human respiratory syncytial virus infections in Iran.

Subgroups Number of

studies

Prevalence of HRSV (95% CI)

n/N Heterogeneity

test, I2 (%)

Heterogeneity test, p-value

Egger’s test, t Egger’s test, p-value

Overall effects 27 18.0 (14.6–22.0) 967/5348 91.253 ⬍.001 2.144 0.041

Researches before 2005 7 19.9 (14.4–26.7) 306/1576 88.798 ⬍.001 0.38 0.71

Researches between 2005 and 2008

8 10.9 (5.8–19.5) 200/1624 94.345 ⬍.001 2.53 0.04

Researches between 2009 and 2013

12 22.3 (17.2–28.5) 461/2148 88.905 ⬍.001 0.13 0.89

HRSV: Human respiratory syncytial virus.

The epidemiology of HRSV has gradually changed since its emergence was reported

^[21

,

^22]

. Initially there were

occasional reports, but now it has become one of the established causes of community acquired pneumonia

^[23]

. The

high prevalence of HRSV (18.0%) among viral respiratory infection may be due to several factors

[24

,

25]

. First and

above all is the lack of efficient vaccine control and prevention of HRSV infection

^[26]

. Clinical aspects of HRSV

(5)

Miani Maleknejad Noorbakhsh Seyfi Arabzadeh Barati Kahbazi Faghinioo1 Pourakbari Abshirini Glani Farshad Naghipoor Hamkar Aloorzi Karimi Khalilzadeh Faghinioo2 Faghinioo3 Nikfar Malekshahi Sawadoohi Alavi

Chavoshzadeh Shahrabad Parsania Moattari

0.192 0.385 0.241 0.246 0.375 0.056 0.060 0.224 0.172 0.197 0.123 0.129 0.149 0.160 0.020 0.087 0.140 0.212 0.194 0.090 0.168 0.222 0.290 0.458 0.402 0.310 0.107 0.180 Study name

Event rate

Lower limit

Upper

limit Z-value p-value

Event rate and 95% CI Statistics for each study

-1.00 -0.50 0.00 0.50 1.00

Meta analysis

0.155 0.311 0.161 0.197 0.305 0.030 0.038 0.155 0.129 0.123 0.089 0.089 0.111 0.117 0.008 0.060 0.068 0.159 0.161 0.047 0.123 0.167 0.210 0.362 0.321 0.243 0.076 0.146

0.235 0.468 0.344 0.303 0.451 0.105 0.093 0.313 0.227 0.302 0.168 0.182 0.198 0.216 0.046 0.124 0.266 0.278 0.231 0.164 0.226 0.289 0.386 0.558 0.487 0.386 0.149 0.220

-10.820 -2.716 -4.471 -7.657 -3.205 -8.219 -11.318 -5.354 -9.025 -4.868 -10.560 -9.102 -10.017 -8.845 -8.661 -11.476 -4.454 -7.174 -12.409 -6.621 -8.495 -6.988 -4.063 -0.816 -2.248 -4.649 -10.973 -11.914

0.000 0.007 0.000 0.000 0.001 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.415 0.025 0.000 0.000 0.000

Figure 2. Forest plot of the meta-analysis of prevalence of human respiratory syncytial virus infections.

infections highlight four different goal societies or aim populations for vaccines: the HRSV infant, the HRSV child ≥6 months of age, pregnant women and the elderly. Due to different immunity features in each group, goal societies may need various vaccination strategies to prevent HRSV infection. Another factor is the high variation of nucleic acid sequence of the G glycoprotein. As previously mentioned, it is the G glycoprotein that mediates HRSV adsorption through the host-cell surface; in conclusion, polymorphism in the G glycoprotein gene is the key hurdle in the development of an HRSV vaccine. Third, as infants age, maternity immunity decreases and due to their naive immune system, this leaves infants vulnerable to HRSV infections. Hospital acquired infection in high population societies such as Iran can be regarded as the fourth factor. Moreover, the presence of diverse infectious strains associated with HRSV has added to the problem

^[27]

.

Many studies have indicated that A and B isolates co-circulate during epidemics, with group A generally

overcoming group B

^[28]

. This is probably due to several factors. It has been considered that infection with

(6)

Standard error

Funnel plot of standard error by logit event rate

Logit event rate

-4 -3 -2 -1 0 1 2 3 4

0.5 0.4 0.3 0.2 0.1 0.0

Figure 3. Funnel plot of the meta-analysis of prevalence of human respiratory syncytial virus infections.

Table 3. Meta-analysis of prevalence of human respiratory syncytial virus infections in different points of Iran.

Number of studies

test, I2 (%)

Overall effects 27 18.0 (14.6–22.0) 967/5348 91.253 ⬍0.001 2.144 0.041

North of Iran (Guilan, Mazandaran)

3 16.4 (11.8–22.4) 105/643 69.673 ⬍0.001 0.60 0.65

Center of Iran (Tehran, Markazi)

16 20.0 (15.5–25.5) 623/3174 91.159 ⬍0.001 0.84 0.41

West of Iran (Khouzestan, Tabriz, Shahre Kord)

5 16.8 (10.0–27.0) 283/616 89.190 ⬍0.001 0.83 0.46

South of Iran (Fars, Kerman)

3 10.6 (2.4–36.9) 141/828 97.361 ⬍0.001 1.44 0.38

Table 4. Meta-analysis of prevalence of human respiratory syncytial virus infections based on molecular and nonmolecular methods.

test, I2 (%)

Overall effects 27 18.0 (14.6–22.0) 967/5348 91.253 ⬍0.001 2.144 0.041

Molecular methods 15 19.4 (14.9–24.9) 533/2794 90.186 ⬍0.001 0.860 0.405

Nonmolecular methods 12 16.2 (11.4–22.7) 434/2554 73.437 ⬍0.001 0.206 0.870

serogroup B results in a lower intensity disease, therefore probably identified less often. The next hypothesis is that

infection with serogroup B can generate long-lasting serogroup-particular immunity. Furthermore, serogroup B

glycoprotein G could elicit a better antibody response than serogroup A glycoprotein G. It seems determination of

HRSV genotypes is very important to the design of infection control, due to the lack of prevalence data, we do not

know exactly which serogroups each HRSV isolate belonged to. It was only in the few studies that were performed

in recent years that this information was available. These studies show that group A genotypes were isolated during

2007–2013, while group B viruses were isolated during 2009–2013. Phylogenetic analysis showed that all HRSV

(7)

Table 5. Meta-analysis of prevalence of human respiratory syncytial virus infections based on different detection methods.

test, I2 (%)

Overall effects 27 18.0 (14.6–22.0) 967/5348 91.253 ⬍0.001 2.144 0.041

RT-PCR 12 16.5 (12.6–21.3) 411/2440 87.283 ⬍0.001 1321 0.215

Real-time and nested PCR 3 34.9 (25.8–45.3) 122/354 73.437 ⬍0.001 0.206 0.870

ELISA and IMC 3 10.8 (4.6–23.4) 75/640 92.033 ⬍0.001 1.154 0.454

IF 3 9.4 (3.0–26.1) 51/540 92.960 ⬍0.001 1.092 0.471

DIF 6 23.6 (16.2–33.2) 308/1374 92.323 ⬍0.001 0.073 0.945

DIF: Direct immunofluorescence; ELISA: Enzyme-linked immunosorbent assay; HRSV: Human respiratory syncytial virus; IF: Immunofluorescence; IMC: Immonochromatography;

PCR: Polymerase chain reaction; RT-PCR: Reverse transcription polymerase chain reaction.

IMC 4%

DIF 22%

IIF 11%

ELISA

7% Nested

PCR 7%

RT-PCR 45%

Rt-PCR 4%

Percentage of used HRSV detection methods in studies

Figure 4. Overview of methods used in studies included in this review.

DIF: Direct immunofluorescence; ELISA: Enzyme-linked immunosorbent assay; IIF: Indirect

immunofluorescence; IMC: Immunochromatography; PCR: Polymerase chain reaction; Rt-PCR: Real-time polymerase chain reaction; RT-PCR: Reverse transcription polymerase chain reaction.

group A viruses belonged to three genotypes: GA1, GA2 and GA5, and the group B viruses were in the BA genotype (Figure 6)

[29–31]

.

Additional to epidemiological properties, remarkable molecular mutations in circulating isolates can account

for different virulence and pathogenicity to HRSV infection. The nucleotide changes in the glycoprotein G gene

results in amino acid changes that could affect the pattern of N- and O-glycosylation sites. Two N-glycosylation

sites at amino acid positions 251 and 294, and three motifs at position 238 were detected among group A viruses

circulating in Iran. However in group B viruses, only one N-glycosylation site at amino acid position 310 and

one O-glycosylation site at position 234 were identified

[29]

. Different patterns of N- and O-glycosylation sites

between HRSV-A and -B are important differences for virus antigenicity and can result in an increased pathogenesis

(8)

Khuzestan Lorestan

Khorramabad

Arak Kashan Qom

Semnan Shahrud

IRAQ

KUWAIT

Bushehr

KINGDOM of BAHRAIN

STATE of QATAR

PERSIAN GULF Bandar-e

Kangan

Bandar-e Langeh Fars

10–14%

14–18%

18–22%

Shiraz Ahvaz

Boyer Ahmadi Esfahan Ilam

Kermanshah Sanandaj Mahabad

AZERBAIJAN

TURKEY

ARMENIA

Ardabil Khvoy

Orumiyeh Marand

Tabriz

Azarbayjan-E -Gharbi

Azarbayjan-E Khavari

Zanjan Kordestan

Hamadan Hamadan

Markazi Gilan

Kara Qazvin

Mazandaran Badab

TEHRAN

DezfulShahr-e Kord

Chaharmahal va-Bakhtiyari

Yasuj Kohgiluyeh Va

Zamin Sharv

YazdBafq Gorgan

Bojnurd Golestan

Gonabad Khorasan

Birjand Kavir-e Namak

Mashhad

Hormozgan Sirjan

Kerman

Bam

Strait of Hormuz

Jask Chabahar Bandar

Abbas

GULF OF OMAN Zahedan

Sistan Va Baluchestan

Iranshahr

PAKISTAN AFGHANISTAN Taybad

TURKMENISTAN

Zabol Safakha CASPIAN

SEA

N

ISLAMIC REPUBLIC OF IRAN

Figure 5. Distribution of human respiratory syncytial virus infections in Iran based on percentage of incidence.

and an enhanced duplication rate in the lower region of respiratory tract

^[32

,

^33]

. As shown in the results of this meta-analysis, the prevalence of HRSV determined in studies using molecular methods are more accurate than studies using nonmolecular methods such as enzyme-linked immunosorbent assay, indirect immunofluorescence, immunochromatography and direct immunofluorescence. It can be said that molecular methods are the gold standard for HRSV detection. Although to confirm this claim would require further studies.

There were some limitations to this study which should be discussed. First of all, only published studies were

accepted in the present review and meta-analysis. Thus, as with any systematic review, the existence of potential

publication bias should be considered. Second, heterogeneity was detected among the included studies. Third, it

cannot fully represent the prevalence of HRSV in Iran because the extent of HRSV has not yet been examined in

(9)

2007 2008 2009 2010 2011 2012 2013 0

10 20 30

HRSV genotypes

Year

GA1 GA2 GA5 BA

Figure 6. Distribution of human respiratory syncytial virus genotypes among patients with human respiratory syncytial virus infection during 2007–2013.

many regions of Iran. Also, some articles lacked detailed information such as age of the patients studied and the various sections in which the patients were admitted. Fourth, being a prevalence survey, we are unable to determine risk factors for HRSV colonization or infection.

Conclusion & future perspective

The increase in the number of HRSV infections is a major public health problem in Iran and merits further attention by health authorities, physicians and microbiologists. The regular surveillance of respiratory-associated infection would provide more information regarding pathogenic HRSV types and most importantly aid toward the design of an effective vaccine. A clearer picture of HRSV prevalence would be very useful and may facilitate more accurate action for prevention and control of HRSV infections in Iran. In particular, the introduction of HRSV screening based on rapid and reliable diagnosis during inpatient admission would be indispensable.

Summary points

r Evaluation of human respiratory syncytial virus (HRSV) infection in Iranian people.

r Distribution of HRSV infections in different points of Iran.

r Evaluation of HRSV infections based on molecular and nonmolecular methods.

r Distribution of HRSV genotypes among patients with HRSV infection.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

1 Queir´oz D, Durigon E, Botosso Vet al.Immune response to respiratory syncytial virus in young Brazilian children.Braz. J. Med. Biol.

Res.35(10), 1183–1193 (2002).

(10)

2 Feng S, Hong D, Wang Bet al.Discovery of imidazopyridine derivatives as highly potent respiratory syncytial virus fusion inhibitors.

ACS Med. Chem. Lett.6(3), 359–362 (2015).

3 Tapia LI, Shaw CA, Aideyan LOet al.Gene sequence variability of the three surface proteins of human respiratory syncytial virus (HRSV) in Texas.PLoS ONE9(3), e90786 (2014).

4 Collins PLRespiratory syncytial virus and metapneumovirus. In:D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, M. A. Martin, B.

Roizman, and S. E. Straus (ed.), Fields Virology. Lippincott Williams & Wilkins, Philadelphia, PA, USA, 1601–1646 (2007). 5th 5 Tremaglio 87, 3196–3207 (2013), Noton, S. L.. Respiratory syncytial viruspolymerase can initiate transcription from position 3 of the

leader promoter.J. Virol87, 3196–3207 (2013).

6 Peret TC, Hall CB, Hammond GWet al.Circulation patterns of group A and B human respiratory syncytial virus genotypes in five communities in North America.J. Infect. Dis.181(6), 1891–1896 (2000).

7 Currier MG, Lee S, Stobart CCet al.EGFR interacts with the fusion protein of respiratory syncytial virus strain 2–20 and mediates infection and mucin expression.PLoS Pathog.12(5), e1005622 (2016).

8 Cane PA. Molecular epidemiology of respiratory syncytial virus.Rev. Med. Virol.11(2), 103–116 (2001).

9 Rodriguez R, Ramilo O. Respiratory syncytial virus: how, why and what to do.J. Infect.68, S115–S118 (2014).

10 Thompson WW, Shay DK, Weintraub Eet al.Mortality associated with influenza and respiratory syncytial virus in the United States.

JAMA289(2), 179–186 (2003).

11 Bardach A, Rey-Ares L, Cafferata MLet al.Systematic review and meta-analysis of respiratory syncytial virus infection epidemiology in Latin America.Rev. Med. Virol.24(2), 76–89 (2014).

12 Almajhdi FN, Farrag MA, Amer HM. Genetic diversity in the G protein gene of group A human respiratory syncytial viruses circulating in Riyadh, Saudi Arabia.Arch. Virol.159(1), 73–81 (2014).

13 Jain S, Self WH, Wunderink RGet al.Community-acquired pneumonia requiring hospitalization among US adults.N. Engl. J. Med.

373(5), 415–427 (2015).

14 Cane PA, Matthews DA, Pringle CR. Analysis of relatedness of subgroup A respiratory syncytial viruses isolated worldwide.Virus Res.

25(1), 15–22 (1992).

15 Roca A, Loscertales M-P, Quint´o Let al.Genetic variability among group A and B respiratory syncytial viruses in Mozambique:

identification of a new cluster of group B isolates.J. Gen. Virol.82(1), 103–111 (2001).

16 Paynter S, Ware RS, Sly PD, Weinstein P, Williams G.Respiratory syncytial virusseasonality in tropical AustraliaAustralian and New Zealand Journal of Public Health. 39(1), 8–10 (2015).

17 Voraphani N, Stern DA, Wright AL, Guerra S, Morgan WJ, Martinez FD. Risk of current asthma among adult smokers with respiratory syncytial virus illnesses in early life.Am. J. Respir. Crit. Care Med.190(4), 392–398 (2014).

18 Backman K, Piippo-Savolainen E, Ollikainen H, Koskela H, Korppi M. Adults face increased asthma risk after infant RSV bronchiolitis and reduced respiratory health-related quality of life after RSV pneumonia.Acta Paediatr.103(8), 850–855 (2014).

19 Munn Z, Moola S, Riitano D, Lisy K. The development of a critical appraisal tool for use in systematic reviews addressing questions of prevalence.Int. J. Health Policy Manag.3(3), 123 (2014).

20 Zheng Y, Liu L, Wang Set al.Prevailing genotype distribution and characteristics of human respiratory syncytial virus in northeastern China.J. Med. Virol.89(2), 222–233 (2017).

21 Cui G, Zhu R, Deng Jet al.Rapid replacement of prevailing genotype of human respiratory syncytial virus by genotype ON1 in Beijing, 2012–2014.Infect. Genet. Evol.33, 163–168 (2015).

22 Pierangeli A, Trotta D, Scagnolari Cet al.Rapid spread of the novel respiratory syncytial virus A ON1 genotype, central Italy, 2011 to 2013.Euro Surveill.19(26), pii:20843 (2014).

23 Zhan Y, Yang Z, Chen R, Wang Y, Guan W, Zhao S. Respiratory virus is a real pathogen in immunocompetent community-acquired pneumonia: comparing to influenza like illness and volunteer controls.BMC Pulm. Med.14(1), 1 (2014).

24 Murray J, Bottle A, Sharland Met al.Risk factors for hospital admission with RSV bronchiolitis in England: a population-based birth cohort study.PLoS ONE9(2), e89186 (2014).

25 Leung T, Lam D, Miu Tet al.Epidemiology and risk factors for severe respiratory syncytial virus infections requiring pediatric intensive care admission in Hong Kong children.Infection42(2), 343–350 (2014).

26 Anderson L, Dormitzer P, Nokes DJ, Rappuoli R, Roca A, Graham B. Strategic priorities for respiratory syncytial virus (RSV) vaccine development.Vaccine31, B209–B215 (2013).

27 Ciencewicki JM, Wang X, Marzec Jet al.A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection.FASEB J.28(4), 1947–1956 (2014).

28 Perron M, Stray K, Kinkade Aet al.GS-5806 inhibits a broad range of respiratory syncytial virus clinical isolates by blocking the virus-cell fusion process.Antimicrob. Agents Chemother.60(3), 1264–1273 (2015).

(11)

29 Faghihloo E, Yavarian J, Jandaghi NZS, Shadab A, Azad TM. Genotype circulation pattern of human respiratory syncytial virus in Iran.

Infect. Genet. Evol.22, 130–133 (2014).

30 Faghihloo E, Salimi V, Rezaei Fet al.Genetic diversity in the G protein gene of human respiratory syncytial virus among Iranian children with acute respiratory symptoms.Iran. J. Pediatr.21(1), 58–64 (2011).

31 Oliveira DB, Durigon EL, Carvalho ACet al.Epidemiology and genetic variability of human metapneumovirus during a 4-year-long study in Southeastern Brazil.J. Med. Virol.81(5), 915–921 (2009).

32 Martinello RA, Chen MD, Weibel C, Kahn JS. Correlation between respiratory syncytial virus genotype and severity of illness.J. Infect.

Dis.186(6), 839–842 (2002).

33 Tsukagoshi H, Ishioka T, Noda M, Kozawa K, Kimura H. Molecular epidemiology of respiratory viruses in virus-induced asthma.Front.

Microbiol.4, 278 (2013).

34 Milani M. Respiratory syncytial virus infection among young children with acute respiratory infection.Acta Med. Iran.41(4), 269–272 (2003).

35 Maleknejad P EY. Prevalence of respiratory tract infec-tion due to respiratory syncytial virus in 145 children below 5 years old, from January to May 1999 in Imam Khome-ini, Markaz Tebbi and Bahrami hospitals.Tehran Univ. Med. J.6, (2001).

36 Noorbakhsh S RS. Frequency of respiratory syncytialvirus infection and its clinical manifestations in children with acute respiratory infection in Hazrat Rasoul-e-Akram hospital.J. Iran. Univ. Med. Sci.4, 1051–1056 (2001).

37 Jedari Seyfi S RNM, Jalali A, Aghazadeh A, Ebrahimpour S. A study of lower respiratory tract infection by respiratory syncytial virus in infants and young children.Med. J. Tabriz Univ. Med. Sci.55, 11–15 (2002).

38 Arabzadeh Sam DPP, Molaie Hr, Aghaee Afshara, Salari Aa. The frequency distribution of parainfluenza, adeno and respiratory syncytial virus infections in children below 2 years of age with bronchiolititis by multiplex polymerase chain reaction method, Afzalipoor hospital, Kerman, 2006.J. Kerman Univ. Med. Sci.15, 305–311 (2008).

39 Barati M NS, Tabatabaee a, Ebrahimi Taj F, Talebitaher M. Evaluation of frequency of adeno, influenza A, band respiratory syncytial viruses in pharyngeal secretion of children (3 months to 15 years old) with upper respiratory tract infection by rapid

immunochromatographic test.Razi J. Med. Sci.16, 81–88 (2009).

40 Kahbazi M, Fahmizad A, Armin Set al.Aetiology of upper respiratory tract infections in children in Arak city: a community-based study.Acta Microbiol. Immunol. Hung.58(4), 289–296 (2011).

41 Pourakbari B, Mahmoudi S, Movahedi Zet al.Viral etiology of acute lower respiratory tract infections in hospitalized young children in a childrens’ referral hospital in Iran.Turk. J. Pediatr.56, 354–359 (2014).

42 Abshirini H, Makvandi M, Ashrafi MS, Hamidifard M, Saki N. Prevalence of rhinovirus and respiratory syncytial virus among patients with chronic rhinosinusitis.Jundishapur J. Microbiol.8(3), e20068 (2015).

43 Modarres Gilani S, Rahbarimanesh A. A survey of respiratory syncytial virus in children in three educational and therapeutic pediatric centers in Tehran.Med. J. Islam. Repub. Iran15(2), 79–82 (2001).

44 Farshad N, Saffar M, Khalilian A, Saffar H. Respiratory viruses in hospitalized children with acute lower respiratory tract infections, Mazandaran Province, Iran.Indian Pediatr.45(7), 590 (2008).

45 Naghipour M, Hart CA, Cuevas L. Burden of acute respiratory infections in a family cohort in Iran.Epidemiol. Infect.135(08), 1384–1388 (2007).

46 Hamkar R, Mirnourollahi M, Naseri M, Nourozbabaee Z. [Frequency of viral agents in acuterespiratory infections in Iran 2005–2006].Iran J. Infect. Dis. Trop. Med. 12(38), 27–32 (2007).

47 Alborzi A, Aelami MH, Ziyaeyan Met al.Viral etiology of acute respiratory infections among Iranian Hajj pilgrims, 2006.J. Travel Med.

16(4), 239–242 (2009).

48 Karimi A, Khoshdel A, Imani R. Seroprevalence of respiratory synsytial virus and humam parainfluenzae virus in children with respiratory problems in Shahre-Kord, Central Iran.Iranian Red Cresc. Med. J.2010(4), 504–506 (2010).

49 Khalilzadeh S, Boloorsaz MR, Nadji SaRet al.Molecular epidemiology of respiratory viral pathogens in children with asthma exacerbations admitted to Dr. Masih Daneshvari hospital.Iranian J. Pediatric Soc.2(2), 58–64 (2010).

50 Faghihloo E RF, Salimi V, Naseri Met al.Molecular epidemiology of human respiratory syncytial virus in Iran.Acta Virol.55, 81–83 (2011).

51 Nikfar R, Shamsizadeh A, Makvandi M, Khoshghalb A. Detection of respiratory syncytial virus in hospitalized children with acute lower respiratory tract infections, using RT-PCR in Ahvaz, Iran.Archiv. Pediatric Infectious Dis.1(3), 118–121 (2013).

52 Malekshahi SS, Azad TM, Yavarian J, Shahmahmoodi S, Naseri M, Rezaei F. Molecular detection of respiratory viruses in clinical specimens from children with acute respiratory disease in Iran.Pediatr. Infect. Dis. J.29(10), 931–933 (2010).

53 Sawadkohi RB, Mohammadzade I, Mohammadpour-Mir Aet al.Prevalence of acute lower respiratory tract infections due to respiratory syncytial virus in Amirkola Children’s Hospital, Northern Iran during March 2008–March 2010.Iranian Red Crescent medical journal 14(10), 680 (2012).

(12)

54 Alavi SM, Makvandi M, Fard SN, Alavi L. Human respiratory syncytial virus infection and its subgroups among the hospitalized young children with acute respiratory infection.Jundishapur J. Microbiol.6(8), e6452 (2013).

55 Chavoshzadeh Z, Abdinia B, Fahimzad A, Samakosh H, Khanbabaei G, Tabatabaei SA. Molecular study of respiratory syncytial virus, human rhinovirus and human metapneumovirus, detected in children with acute wheezing.Arch. Pediatr. Infect. Dis.1(1), 14–17 (2013).

56 Shahrabadi M A-PA. Occurrence of respiratorysyncytial virus infection in children referred to Kasra hospital diagnostic laboratory during 2009–2011.Iran J. Virol.5, 6–9 (2011).

57 Parsania M, Poopak B, Pouriayevali MH, Haghighi S, Amirkhani A, Nateghian A. Detection of human metapneumovirus and respiratory syncytial virus by real-time polymerase chain reaction among hospitalized young children in Iran.Jundishapur J. Microbiol.

9(3), e32974 (2016).

58 Moattari A, Aleyasin S, Emami A, Fyruzi M, Pirbonyeh N. The prevalence of human metapneumovirus and respiratory syncytial virus and coinfection with both in hospitalized children with acute respiratory infection in South of Iran.Arch. Pediatr. Infect. Dis.3(3), e21581 (2015).