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Pertussis (whooping cough) is a highly contagious, respiratory disease caused by Bordetella pertussis (B. pertussis). The clinical symptoms of pertussis change with age, previous exposure to B. pertussis and immunization status. In newborns clinical manifestations may be severe. Most infants have a typical paroxysmal cough which can last more than two months.
Pertussis is a major cause of morbidity worldwide and of mortality in infants in developing countries. Pertussis continues as a public health concern threat given its re-emergence despite high vaccination coverage. Epidemic cycles reoccur every 2 to 5 years and 2015 has witnessed the worst outbreak in the past 70 years.
Although ample evidence confirms coinfections between B. pertussis and other pathogens, especially viruses, the role of coinfections remains debated [4–6]. Most mixed infections probably arise accidentally and whether they cause more severe disease than B. pertussis alone remains unclear [7–14]. Extending current knowledge on virus coinfections would make it easier to care for infants with pertussis.
We designed this study to compare clinical disease severity in infants with B. pertussis infection alone and those with B. pertussis and viral coinfections hospitalized in two Italian centers over two years. We also analyzed how respiratory infections and pertussis cases were distributed during the two years study. As primary outcome measures we assigned each infant a clinical severity score and assessed length of hospitalization. As an experimental approach to provide reliable data on lower respiratory virus infections we used an extended respiratory virus panel that can detect 14 respiratory viral targets with real-time reverse-transcriptase-polymerase chain reaction (RT-PCR) assay.
Pertussis is a major public health problem, affecting adolescents and adults as well as children. Despite a widespread vaccination program, over the past fifteen years was seen a return of pertussis worldwide. Pertussis resurgence in Europe has been attributed to an incomplete immunization program or to genetic changes in Bordetella pertussis (B. pertussis). The currently used acellular pertussis vaccine contains the pertactin gene variant prn1 and the pertussis toxin-B S1 subunit. Molecular changes in these two genes over the past years suggest that the antigenic divergence may make pertussis vaccination less effective than before.
In some countries pertussis immunization is not mandatory and in others vaccination schedules suggest the first dose to be given at the age of 3 months. Hence, some infants remain unimmunized or incompletely immunized. In those who are incompletely immunized pertussis may develop in an atypical clinical form and be difficult to diagnose. Pertussis can be especially difficult to diagnose in children under 1 year of age during winter season, when other pathogens, such as respiratory syncytial virus (RSV), circulate. In these difficult cases, pertussis acute respiratory symptoms can overlap with those of bronchiolitis. A study conducted in a group of infants hospitalized for RSV bronchiolitis showed that almost 2% of the patients were co-infected with B. pertussis[7,8]. Since B. pertussis-RSV co-infection is infrequent in young infants, physicians should keep the possibility of co-infections in mind as to diagnose it early and prevent bronchiolitis from becoming more severe.
Although the standard diagnostic criterion for identifying B. pertussis is culture obtained from nasal swabs or nasopharyngeal aspirates, confirmatory information comes nowdays from molecular techniques such as real time-polymerase chain reaction (RT-PCR). Usually, in clinical practice the diagnosis is generally reached without microbiological confirmation. What we conspicuously lack is the clinician’s awareness of the clinical and laboratory data needed to reach a suspected B. pertussis diagnosis in order to start treatment early.
The main purposes in our retrospective, single-center study were to describe and compare clinical and laboratory features in infants with pertussis infection to infants hospitalized for RSV bronchiolitis, and to analyze the genetic characteristics of B. pertussis.
Despite a widespread vaccination program, pertussis continues to be a common worldwide infection in pediatric and adult populations. In the past decade, there has been a resurgence of this disease in United States and European countries, peaking every 2 to 5 years [1–7]. The last peak reported in Europe was in 2012.
In contrast to what is reported in other countries, in Italy after the introduction of acellular vaccine in 1995 incidence has continued to decrease and pertussis has not reemerged yet [9, 10]. Therefore epidemic cycles have been clearly less identifiable due to the low incidence. In our country, vaccination schedule provides a pertussis vaccine dose at 3, 5 and 12 months and a booster is recommended in the preschool period and in adolescents. Vaccination coverage during the analyzed period was around 95 %.
Since other countries with high immunization coverage over a long period of time experienced a resurgence of pertussis [3, 5], we hypothesized that the epidemiology of this disease in Italy may be affected by the lack of recognition by clinicians with the consequence of limiting the use of laboratory confirmation. In clinical practice the diagnosis of pertussis is generally reached without microbiological confirmation leading to a possible lack of clinical awareness to start early treatment and prevent complications.
Infants are known to acquire pertussis from adolescents’ and adults’ contacts that return susceptible to the disease because of waning immunity as well as from unvaccinated children [12–14]. Clinical manifestations may be different depending on age. Severe symptoms are common in young unvaccinated infants and pertussis continues to be a major cause of vaccine-preventable death in this age group. However, cases with atypical clinical presentations do occur and may be often unrecognized, especially during the winter season, when other respiratory viruses circulate and the minimum incidence of pertussis is usually observed. The annual seasonality in the Italian pertussis incidence peaked between March and August while the minimum incidence has been observed between September and February.
We therefore systematically studied a series of infants ≤3 months of age hospitalized with respiratory symptoms to detect how frequently physicians suspected pertussis on a clinical basis and the actual frequency of laboratory confirmed cases. We compared patients with pertussis infections and patients with other respiratory infections to identify clinical and laboratory predictors of pertussis.
B. pertussis DNA was extracted with QIAamp DNA minikit (QiaGEM, Hilden, Germania) and amplified with the “Bordetella Real-Time PCR” kit (Diagenode Diagnostics, Liège, Belgio). The assay gave binary results. For RT-PCR the SYBR Green Detection assay we used the LightCycler 2.0 system (Roche Diagnostic). Data were analyzed with LightCycler software (version 4.0, Roche Diagnostic). Only the positive samples for B. pertussis were cultured on charcoal agar plates (Oxoid England) containing defibrinated sheep blood at 10% and incubated at 35 °C up to 7 days and inspected daily, as previously described.
During the study period, we enrolled 215 patients. The admission diagnosis of those patients is reported in Table 1.
Out of 215 patients tested, 53 had a positive RT-PCR for BP (24.7 %). Of the 162 patients resulted negative for BP, 119 were positive for RV infections (55.3 %): RSV was diagnosed in 48 (40.3 %), Rhinovirus in 37 (31.1 %), Parainfluenzae Virus in 9 (7.6 %), Adenovirus in 4 (3.4 %), Metapneumovirus in 4 (3.4 %), Influenzae Virus in 3 (2.5 %), Coronavirus in 3 (2.5 %), Rhinovirus + Adenovirus in 4 (3.4 %), Rhinovirus + Coronavirus in 2 (1.7 %), RSV + Adenovirus in 2 (1.7 %), Parainfluenzae virus + Metapmeumovirus in 2 (1.7 %), RSV + Coronavirus in 1 (0.8 %).
No etiological agent was identified on nasopharyngeal aspirate of 43 patients (20 %). Those patients were discharged with the following diagnoses: apnea (ICD-9 code 78609) (21), bronchiolitis (13), laryngitis/laryngomalacia (3), unexplained fever in infants (2), sepsis (1), pneumonia (1), intraventricular septal defect (1), HHV6 encephalitis (1).
At admission, pertussis was clinical suspected in 22 patients only on the basis of the WHO definition. Sixteen of them had a positive RT-PCR for BP, while the 6 patients resulted negative to BP were discharged with diagnosis of bronchiolitis in 5 cases (2 RSV, 2 Rhinovirus and 1 Parainfluenzae Virus) and apnea in 1 case (negative nasopharyngeal aspirate). On the other hand, among the remaining 193 patients who had a different diagnosis at admission, 37 were RT-PCR positive for BP. Thus the sensitivity of clinical diagnosis at admission was 30.2 % (19.52–43.54) and the specificity 96.3 % (92.16–98.29).
The clinical and laboratory characteristics on admission were compared between BP+ patients, RV+ patients and BP-RV- patients (Table 2). Cough, paroxysmal cough, whoop, apnea, fever, rhinorrhea, white blood count, lymphocytes count, length of symptoms before admission and length of hospital stay were statistically different among the three groups.
When we applied the logistic regression model to explore predictive clinical manifestations and/or laboratory test for pertussis, data showed that paroxysmal cough, absence of fever, absolute lymphocyte count >10.000 n/mm3 and duration of symptoms before admission ≥5 days were significantly associated with pertussis compared with other diagnoses (Table 3).
Notably, when we analyzed the length of symptoms before admission of patients with BP+ we found that 20 patients (37.7 %) reported symptoms for less than 7 days; 20 patients (37.7 %) reported symptoms for 7- < 14 days and 13 of them (24.5 %) reported symptoms for more than 14 days.
Therefore, our data showed that apnea is not predictive for pertussis, but it’s a frequent clinical manifestation (30/53); among BP+ patients, 22 (41.5 %) reported apnea associated with cough and cyanosis, while 8 of them (15.1 %) reported apnea alone not associated with other symptoms.
Complications (oxygen requirement and pneumonia) were not statistically different in the three groups. No deaths were reported (Table 2).
Regarding ongoing antibiotic therapy, 34 of our patients (9 BP+, 21 VR+, 4 BP-/VR-) had already started antibiotics before admission; particularly, 19 patients (7 BP+, 10 VR+, 2 BP-/VR-) had already started macrolide therapy when specimens were collected.
When we analyzed the seasonal trend of our BP+ patients, we found that the maximum incidence was between June and September, but we had cases even in winter with a peak in February (Fig. 1).
With regard to coinfection, of the 53 pertussis cases, 18 (34 %) had a positive RV result in addition to BP: 8 patients had PCR positive for Rhinovirus, 4 for Coronavirus, 1 for RSV, 1 for Metapneumovirus, 1 for Parainfluenza Virus, 1 for Influenza + Coronavirus, 2 for Rhinovirus + Parainfluenza. We didn’t find any significant differences between patients with pertussis as monoinfection and patients with pertussis plus RV infection.
Influenza A virus (IAV) is a major animal and public health concern given the zoonotic nature of IAV (1–3). As a natural host to IAV, research on IAV in swine has relevance to both human and animal medicine. IAV is a segmented, negative-sense, single-stranded RNA virus. The surface glycoproteins, hemaggluttinin (HA) and neuraminidase (NA), are used to type IAV, and currently H1N1, H1N2, and H3N2 viruses circulate in pigs in the United States (4, 5). There are a large number of IAV H1 and H3 genetic and antigenic variants co-circulating, and continued antigenic drift and shift of circulating viruses has made control of IAV in swine very difficult (5). Live-attenuated influenza virus (LAIV) vaccination in swine has been shown to provide cross-protection against heterologous IAV of the same subtype, and partial protection against different subtypes [reviewed in Sandbulte et al. (6)]. LAIV is licensed for use in humans and was recently approved for use in swine, with numerous experimental studies documenting improved efficacy of LAIV over inactivated vaccines (7, 8). Several LAIV vaccines for use in swine have been developed; each with a different attenuation mechanism (9–11). Similar to humans, intranasal LAIV vaccination in pigs induces the production of IAV-specific mucosal IgA, but little peripheral IAV-specific IgG (8). The induction of immunity in the respiratory tract has been shown to be the mechanism by which LAIV vaccines provide significant cross-protection against heterologous strains of IAV, limiting viral replication throughout the respiratory tract [reviewed in Rose et al. (12)].
Bordetella bronchiseptica can colonize the respiratory tract of a large number of mammals, including mice, rabbits, dogs and pigs, among others. Respiratory disease associated with B. bronchiseptica covers a wide spectrum, including kennel cough in dogs and atrophic rhinitis in pigs (13, 14). In humans, B. pertussis infection can lead to whooping cough, though colonization without clinical presentation has been documented (15, 16). Similarly, B. bronchiseptica exposure to pigs can result in chronic, asymptomatic colonization of the respiratory tract and it is believed to be ubiquitous in swine production systems. Co-infection with IAV or coronavirus and B. bronchiseptica in pigs causes exacerbated pulmonary disease, indicating the negative impact of B. bronchiseptica colonization with viral infection (17, 18). Bordetella species encode for a number of virulence factors, including tracheal cytotoxin, dermonecrotic toxin, lipopolysaccharide, and a type III secretion system (19). While the gene locus controlling expression of many virulence factors, including the type III secretion system, has been highly investigated, factors that alter expression of virulence genes in vivo are not completely understood (20, 21).
In the past decade, the complex interaction between mucosal surfaces and colonizing microbiota has been recognized as important in modulating both health and disease states [reviewed in Esposito and principi (22)]. The commensal microbiota of the upper respiratory tract includes bacterial species in which colonization alone does not lead to clinical disease, but upon a stressful event (i.e., viral infection, immunosuppression) these bacteria play a major role in disease pathogenesis, often referred to as pathobionts. Administration of LAIV vaccine induces changes in the nasal microbiota and gene expression in nasal epithelium. In addition, LAIV administration alters colonization dynamics of important bacterial pathogens (23). Given the ubiquitous nature of B. bronchiseptica in swine and the documented increase in disease following B. bronchiseptica with IAV co-infection, we performed a study to determine if B. bronchiseptica colonization prior to LAIV vaccination altered LAIV immunogenicity and efficacy against heterologous IAV challenge, or the dynamics of B. bronchiseptica colonization.
Nasopharyngeal cultures, polymerase chain reaction (PCR) testing and serologic studies are available to confirm an infection with Bordetella pertussis, the causative organism.11 However, these tests offer varying levels of sensitivity and may not be obtainable in a timely fashion to confirm cases in the acute setting. Furthermore, other laboratory studies, such as a complete blood count (CBC), may be helpful in distinguishing causes for cough, but only in certain age groups (see “Differential Diagnosis” section). Imaging studies also provide limited information, as patients often do not demonstrate significant findings on chest radiograph. However, chest imaging may be helpful in assessing for superinfection.
Pertussis is a highly contagious respiratory tract infection, caused mainly by Bordetella pertussis and less frequently by Bordetella parapertussis. In the pre-vaccination era, infants and children contracted pertussis in their first years of life, with a clinical course characterized by uncontrollable coughing attacks, often accompanied by paroxysms, post-tussive vomiting, and inspiratory whooping. Consistently high vaccination coverage has substantially decreased pertussis in the population [2, 3], but newborns too young to be vaccinated remain at high risk for severe complications including apnea, cyanosis, pneumonia, encephalopathy or even death. This risk is increasing due to the worldwide pertussis reemergence in the 1990s, even in areas of high vaccination coverage in all age groups, with transmission of disease from household members to newborns. Today, high pertussis incidences in infants are observed, with incidence peaking every two to three years [3, 5, 6]. Worldwide in 2014, an estimated 24 million cases and 160,000 deaths from pertussis occurred in children younger than 5 years, with the African region contributing the greatest share. In the Netherlands, each year approximately 150–180 children <2y are hospitalized and one infant, in general too young to be vaccinated, dies due to pertussis. For this reason, many countries are discussing prenatal pertussis vaccination of mothers to protect newborns, and a growing number of countries now recommend it. This measure is effective in preventing pertussis in the first months of life and has decreased the pertussis disease burden in young infants [10, 11]. In the Netherlands, the Health Council advised that 3rd trimester maternal pertussis vaccination be offered. This is overall very effective in prevention of pertussis in early infancy, but preterms may benefit less due to a smaller time-window for mother-to-child transfer of antibodies before delivery [12, 13]. However, vaccine effectiveness (VE) is reportedly lower after 2nd trimester pertussis vaccination. Given the introduction of a maternal vaccination strategy against pertussis in The Netherlands, we sought to gain more insight into the current pertussis burden among hospitalized infants, with special attention to preterms.
Severe and sometimes fatal pertussis-related complications can occur in certain groups. These include infants <12 months of age, particularly those
The study was conducted in the PICU of Children’s Hospital Béchir Hamza of Tunis. The PICU is in a university-affiliated children’s hospital and provides intensive care services to a national pediatric population of 850 000 children less than 15 years old. The hospital has 360 beds, and the PICU has 16 beds (500 admissions/year).
Acute respiratory infections (ARIs) are the leading cause of mortality in children worldwide, particularly in developing countries. It represents an important public health problem in early development, with high mortality and morbidity among children under five years of age.1 ARIs are classified as upper respiratory tract infections or lower respiratory tract infections (LRTIs) depending on the airways predominately involved.2
Although ARIs can be caused by bacteria or fungi, viral infections are responsible for most of them. Several viruses have been consistently identified during ARIs: influenza virus, human parainfluenza virus (HPIV), human rhinovirus (HRV), adenovirus (ADV), coronavirus (HCoV), enterovirus, human metapneumovirus (HMPV), and respiratory syncytial virus (RSV).3
Moreover, viral infections are one of the many risk factors associated with wheezing illnesses and exacerbation of respiratory diseases in children of all ages.4 HRV has been associated with these exacerbations, including cough, wheezing, shortness of breath, oxygen use, and length of hospital stay.5,6 In addition, asthma inception and exacerbation had been associated with HRV7–9 and HMPV infection,10 with some reports estimating that approximately 60% of cases are associated with HRV infection.11
Human rhinovirus have been classified into two genetic species: HRV-A (including 76 serotypes) and HRV-B (including 25 serotypes). However, recently, HRV-C has been included. HRV-A and HRV-B are associated with the common cold, whereas the role of HRV-C is relatively unknown, but recent reports suggest that HRV-Cs may be more pathogenic than other HRVs.12–14
Virus identification and molecular characterization is fundamental for epidemiological surveillance and control, but also for diagnostic purposes that may lead to specific therapy and an adequate response to treatment because clinical manifestations of virus and bacteria associated with ARI overlap considerably except in epidemic situations.15
The aim of this study was to determine the association of each type of respiratory viruses with acute hypoxemic respiratory disease mainly asthma acute exacerbation or pneumonia in children admitted to a reference respiratory center in Mexico City during three different seasons.
Pertussis is an acute respiratory illness caused by Bordetella pertussis (B. pertussis). Critical pertussis (CP) is defined as pertussis disease that results in pediatric intensive care unit (PICU) admission or death. It is characterized by severe respiratory failure, important leukocytosis, pulmonary hypertension, septic shock and encephalopathy. Despite intensive care management, it causes substantial morbidity and mortality for children especially among young infants. Resurgence of pertussis in the last 20 years is evident from the Centers for Disease Control (CDC).1 Several reasons for this resurgence have been proposed, including genetic changes in Bordetella pertussis, lessened potency of pertussis vaccines, waning of vaccine-induced immunity, greater awareness of pertussis, and the general availability of better laboratory tests.2 A new resurgence was seen in 2013 in Tunisia even in the presence on a high (98%) coverage of childhood vaccination.3 The purpose of this study was to describe the institutional experience in the management of infants with CP admitted in year 2013 at Children’s hospital Bechir Hamza of Tunis, reporting the relationship between method of presentation, therapies and outcome in order to identify factors associated with death.
Respiratory syncytial virus (RSV) is the major infectious cause of lower respiratory tract illness in infants and young children around the world.1, 2 It has also been recognized as an important etiologic agent of pneumonia and other respiratory tract infections in adults and elderly patients.3, 4 The clinical presentation of this infection varies widely, from mild upper respiratory tract disease to bronchiolitis and pneumonia.5 This virus is responsible for the majority of bronchiolitis cases and causes approximately 50% of pneumonia cases during the first years of life.6 In children, host factors such as young age, prematurity, and chronic cardiopulmonary diseases have been associated with severe disease. In addition, other factors such as lower socioeconomic status, exposure to cigarette smoke, air pollution, crowded households, and the lack of breastfeeding have also been associated with severe disease.7 Viral factors associated with virulence leading to severe disease are not sufficiently understood.8
Human RSV is a member of the Paramyxoviridae family. Outbreaks of RSV infections occur between fall and spring in temperate climates and tend to last up to 5 months.9, 10 RSV isolates can be divided into two groups: group A and group B based on antigenic and genetic characteristics.8 These two groups cocirculate in the human population, with group A being more prevalent. Several studies have compared the severity of disease between infants infected with RSV group A and group B with mixed results. Most studies have not found significant clinical differences between both subtypes.8 However, a possible effect of different viral strains on disease severity remains an open question.
Despite the recognized importance of RSV as a cause of respiratory illness, the information regarding the epidemiology of this virus in Latin America, particularly among adults, is limited.11 In the present study, 570 cases of RSV infection identified during four epidemic years in Mexico were evaluated to clarify the epidemiology of this infection and to assess the possible variations in demographic and clinical characteristics according to viral groups.
Viral respiratory tract infections (VRTIs) are very common in children and their presentations vary from simple colds to life-threatening infections.1–5 The detection of a respiratory virus does not necessarily infer that the child has only a viral infection,6 since outbreaks of VRTIs are being linked to increased incidence of bacterial coinfections.7 The human body is usually capable of eliminating respiratory viral infections with no sequelae; however, in some cases, viruses bypass the immune response of the airways, causing conceivable severe respiratory diseases.8 Robust mechanical and immunosuppressive processes protect the lungs against external infections, but a single respiratory tract infection might change immunity and pathology.9
Health care providers often face a dilemma when encountering a febrile infant or child with respiratory tract infection. The reason expressed by many clinicians is the challenge to confirm whether the fever is caused by a virus or bacterium.10 Acute otitis media (AOM) is a usual bacterial coinfection that occurs in 20%–60% of cases of VRTIs.11–14 In addition, almost 60% of children with VRTI have changes in the maxillary, ethmoidal, and frontal sinuses.11,12 Moreover, in the year 1918, it was estimated that 40–50 million individuals died from the influenza pandemic, many of which were due to secondary bacterial pneumonia with Streptococcus pneumoniae.15
Acute respiratory infections (ARIs) are a leading cause of morbidity, hospitalization, and mortality among children [1–3]. According to World Health Organization (WHO), acute respiratory infections are responsible for 1.9 million annual deaths in children, mainly affecting patients under 5 years old, with a higher incidence in those from low-income countries [1, 4].
ARIs are mainly caused by a wide range of viruses and bacteria [5, 6]. Viruses are isolated in up to 80% of cases, the most common pathogens are the respiratory syncytial virus (RSV) A and B, influenza (Flu) A, B and C, parainfluenza (PIV) types 1, 2, 3 and 4, coronavirus and rhinovirus [7, 8]. Classically, S. pneumoniae and H. influenzae type b are the most commonly isolated bacteria in both throat and nasopharyngeal specimens from patients with ARIs [9, 10]. However, in resource-limited countries, atypical bacteria such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Bordetella pertussis can play an important role in ARIs and can be detected in more than 40% of patients [2, 11–14].
Although numerous pathogens are associated with ARIs, their clinical manifestations are very similar, regardless of the causative agent. Thus, laboratory identification of the etiological agent is key in order to give a proper treatment and avoid the overuse of antibiotics. Moreover, ARIs due to atypical bacterial infections have become a global concern especially after their reemergence in low-income countries [11, 16].
Simultaneous infections with virus and bacteria species have become an obstacle for clinicians, their prevalence has significantly increased, with studies discovering co-infections in more than 45% of cases [11, 17–19]. Additionally, these coinfections have been associated with longer hospitalization periods, worse clinical outcomes and increased mortality, again highlighting the importance of molecular etiological confirmation [17, 19, 20].
Bordetella pertussis represents a persistent cause of morbidity and mortality in children. Accounting for an estimated 16 million cases and 195,000 deaths worldwide. In a previous study we conducted on children under 1-year-old with a probable diagnosis of Pertussis from 5 Peruvian hospitals, we reported a prevalence of 39.54% pertussis cases. With more than 60% of cases without an identified pathogen, hence a more comprehensive etiological analysis was required.
The main objective of this study was to detect the presence of 8 respiratory viruses (Influenza-A, Influenza-B, RSV-A, RSV-B, Adenovirus, Parainfluenza-1, Parainfluenza-2 and Parainfluenza-3) and atypical bacteria (Mycoplasma pneumoniae, Chlamydia pneumonia), via Polymerase Chain Reaction in samples from Peruvian children under 5 years-old previously analyzed for B. Pertussis.
Coronaviruses (CoVs), a genus of the Coronaviridae family, are positive-stranded RNA viruses. The first human coronavirus (HCoV) appeared in reports in the mid-1960s and was isolated from persons with common cold. Two species were first detected: HCoV-229E and subsequently HCoV-OC43 [1, 2]. Since then, more species were described [3–5].
The HCoV-229E strain was associated with common cold symptoms. Younger children and the elderly were considered more vulnerable to lower respiratory tract infections. Severe lower respiratory tract infection so far has only been described in immunocompromised patients [7, 8]. To our knowledge, there is no report describing life-threatening conditions in immunocompetent adults attributed to HCoV-229E. We report a case of acute respiratory distress syndrome developed in a healthy adult with no comorbidities and HCoV-229E strain identified as the only causative agent.
The human myxovirus resistance protein 1 (MxA) is an important intermediary of the IFN-induced antiviral response against a variety of viruses. MxA expression is firmly modified by type I and type III IFNs, which also requires signal transducer and activator of transcription 1 signaling. Additionally, MxA has many characteristics similar to the superfamily of large guanosine triphosphatases.78 MxA analysis could be beneficial to differentiate between bacterial and viral infections. Engelmann et al79 conducted a prospective, multicenter cohort study in different pediatric emergency departments in France on the role of MxA in the diagnosis of viral infections. MxA blood values were calculated in infants and children with verified bacterial or viral infections, uninfected controls, and infections of unknown origin. A receiver operating characteristic analysis was used to verify the diagnostic performance of MxA. The study, which included 553 children, showed that MxA was significantly higher in children with viral versus bacterial infections and uninfected controls (P<0.0001). Additionally, MxA levels were significantly higher in children with clinically diagnosed viral infections than in those with clinically diagnosed bacterial infections (P<0.001).79 Other authors have also reported the usefulness of blood MxA testing in patients with viral infections.80,81 The use MxA in diagnosing viral infection is very promising, especially in patients who are at risk of infectious complications. Two separate studies have shown that blood MxA is beneficial in differentiating between viral illness and acute graft-versus-host disease after allogenic stem cell transplantation.82,83
We compared individuals with a demonstrated single viral infection in the absence of bacterial infection with those with no viral infection detected by logistic regression models, searching for an association between viral infections and clinical symptoms. As shown in Table3, HRV infections were significantly associated with wheezing (P = 0·00 003; OR: 3·58 [95% CI: 1·9–6·7]), supraesternal retraction (P = 0·019; OR: 1·97 [95% CI: 1·11–3·49]), xiphoid retraction (P = 0·029; OR: 2·87 [95% CI: 1·14–7·2]), and with the absence of fever (P = 0·0001; OR: 0·36 [95% CI: 0·21–0·61]) and crackles (P = 0·036; OR: 0·57 [95% CI: 0·34–0·97]). Other viruses such as RSV were mostly related with the presence of crackles (P = 0·009; OR: 2·27 [95% CI: 1·21–4·25]), hyporexia (P = 0·036; OR: 2·02 [95% CI: 1·04–3·93]), and diarrhea (P = 0·002; OR: 4·63 [95% CI: 1·8–11·7]), while influenza A infection presented more malaise (P = 0·003; OR: 3·22 [95% CI: 1·45–7·15]) and postnasal drip (P = 0·008; OR: 3·38 [95% CI: 1·4–8·07]; Table3).
As shown in Table3, wheezing disorders and asthma were common in those with HRV infection (P = 0·000 003; OR: 3·65 [95% CI: 2·09–6·36]) and less likely in those with RSV (P = 0·005; OR: 0·40 [95% CI: 0·21–0·77]) and HMPV infection (P = 0·018; OR: 0·19 [95% CI: 0·04–0·87]), whereas pneumonia was likely in RSV infection (P = 0·003; OR: 2·64 [95% CI: 1·38–5·05]) and more uncommon in HRV infection (P = 0·000 009; OR: 0·29 [95% CI: 0·17–0·51]).
The 115 samples positive to HRV infection were typified, and 49·4% of the samples were classified as HRV-C. To determine the influence of comorbidities and other factors such as age, bacterial, and viral coinfections, multivariate logistic regression was realized. Remarkably, the relationship between HRV-C and asthma is maintained (P = 0·02; OR=2·53 [95% CI: 1·14–5·59]). The rest of types and subtypes of respiratory viruses and comorbidities such as gastroesophageal reflux were not associated with asthma either in the univariate analysis or in the adjusted analysis (data not shown).
Individuals with HMPV infection had prolonged hospital stays in days [7 (5–16·5); P = 0·015], and those with HRV infection had the shortest hospital stays [5 (4–6); P = 0·006].
Influenza like-illness (ILI) or acute respiratory infections can be caused by several types of respiratory viruses or bacteria in humans. Influenza viruses, Respiratory Syncytial viruses (RSV) and Parainfluenza viruses are identified as major viruses mostly responsible for ILI and pneumonia in several studies. However practitioners cannot diagnose the infection without a biological test confirmation. Unfortunately, these infections causes are identified in less than 50%.
Réunion Island, a French overseas territory with 850,000 inhabitants, is located in the southern hemisphere between Madagascar and Mauritius in the Indian Ocean (Latitude: 21°05.2920 S Longitude: 55°36.4380 E.). The island benefits from a healthcare system similar to mainland France and epidemiological surveillance has been developed by the regional office of the French Institute for Public Health Surveillance (Cire OI), based on the surveillance system of mainland France. Influenza activity generally increases during austral winter, corresponding to summer in Europe. Since 2011, influenza vaccination campaign in Reunion Island starts in April and the vaccine used corresponds to World Health Organization recommendations for the southern hemisphere.
Since 1996, clinical and biological influenza surveillance has been based on a sentinel practitioner’s network. In 2014, this network was composed of 58 general practitioners (GPs) spread over the island and represented around 7% of all Réunion Island GPs. Nasal swabs are randomly collected all along the year and are tested by RT-PCR for influenza viruses. Among these surveillance samples, 40 to 50% are tested positive for influenza A virus, A(H1N1)pdm09 or B virus by the virological laboratory of the University Hospital Center of Réunion. Thus ILI samples tested negative for influenza are of unknown etiology.
Several biological tools allow identifying respiratory pathogens from nasal swab. In recent years, multiplex reverse transcriptase polymerase chain reaction (RT-PCR) has been developed to identify several viruses simultaneously [7–10]. We therefore used this new method to set up a retrospective study using swabs collected by sentinel GPs from 2011 to 2012.
The main objective of our study was to characterize respiratory pathogens responsible for ILI consultations in sentinel GPs in 2011 and 2012. Secondary objectives were to highlight seasonal trends on respiratory pathogens circulation and to describe occurrence of co-infections, especially during the flu season.
Data on age (Table 2) and gender were available for all 413 patients seen for ILI in both hospitals.
Overall, 124 of the 413 patients (30.0%) were less than 15 years old (4 in SLS and 120 in TRS) and 281 patients (68.0%) were under 40 years of age (68 in SLS and 213 in TRS). In SLS, the median population age was 41 (Interquartile range [IQR]: 28–56) with 49.7% being males, whereas in TRS, the median population age was 17 ([IQR = 3–34]) with 51.1% being males.
In both institutions, 85.5% (106/124) children younger than 15 years of age were infected by at least one respiratory pathogen (Table 2). H1N1v infected patients were not significantly younger than H1N1v non infected patients (27 years old vs. 25 years old, p = 0.80) (Figure 4). However, 70.6% (48/68) of H1N1v cases were identified in patients under 40 years old (22 in SLS and 26 in TRS) and no case was observed in patients older than 65 years (Table 2). PIV infection occurred in very young patients (median age = 4 vs. 29 for patients without PIV, p<10−4) (Figure 4). The same observation was made for ADV infection (median age = 2.5 vs. 25 for patients without ADV, p = 0.006) (Figure 4). Consequently, PIV and ADV were more frequently detected in the younger population of TRS versus SLS (p<10−4 and p<10−3 respectively). In contrast, although individuals with RHV infection were slightly younger than individuals without (median age = 24 vs. 29 for patients without RHV, p = 0.05) (Figure 4), influenza-like illness associated with RHV was more frequent in SLS than in TRS (p = 0.012). Finally, patients with viral multiple infection were significantly younger than those with single infection (median, IDR: 4, 2–18.5 vs. 25, 6–43) and rates of mixed infection were significantly higher in patients under 15 years as compared to older ones (19.4% vs. 4.1%, p<0.0001).
At the time of medical attention, 383 (92.7%) standardized clinical questionnaires were collected out of 413 patients. Four of them could not be exploited because they were too incomplete. A review of the 379 workable questionnaires showed that 90.8% (344/379) of the patients included in this study fulfilled the criteria of ILI as defined above, and 52.5% had either a severe clinical presentation or an underlying risk factor of complications (45.9%, 174/379), or were in a suspected cluster of grouped cases (6.6%, 25/379).
Overall, most patients have fever (93.9%) and cough (86.1%) (Table 3). Other classical clinical signs associated with ILI such as asthenia, myalgia, shivers, headache, rhinitis or pharyngitis were less frequent. A sudden onset was also described in 59.2% of cases. Only 32.5% of the patients had a temperature above 39°C; the age of these patients ranged from zero to 86 years, with a median age of 32 years and a mean age of 34 years (data not shown).
In H1N1v infected patients (including single and multiple infections), the main symptoms were also fever (98.2%) and cough (89.5%) (Table 3). Similar median temperature was reported in H1N1v positive and in H1N1v negative patients (39 [IQR = 35.5–41] vs. 38.8 [IQR = 37.8–40.4], p = 0.68). The proportion of patients with a temperature above 39°C was not different (H1N1v positive: 34.3% vs. H1N1v negative: 32.3%, p = 0.84) (data not shown).
We then compared clinical characteristics between patients positive for H1N1v, patients positive for other respiratory pathogens and negative for H1N1v and patients without any detection of respiratory pathogens (as detected with RespiFinder19®) (Table 3). There was no difference between the three groups except for fever, cough, pharyngitis. However for these latter symptoms, the comparison between patients positive for H1N1v and those positive for other respiratory pathogens or between patients positive for H1N1v and those without any detection of respiratory pathogens, showed no difference except for pharyngitis, which was less frequent in patients positive for H1N1v than in patients positive for other respiratory pathogens (Table 3).
As RHV was the most frequent aetiology in ILI, we also compared clinical symptoms observed in patients with a single infection by RHV or by H1N1v (data not shown). There was no difference except that rhinitis and pharyngitis were significantly more frequent in RHV infection (62.7% vs. 34.1% [p = 0.006] and 39.0% vs. 10.0% [p = 0.001], respectively).
Viral multiple infection (including samples with H1N1v) was not associated with a different clinical presentation. Fever and cough were observed in over 90% of the patients (90.6% and 90.3%, respectively), but only 33.3% of these patients had a temperature above 39°C, which was not different from patients with single viral infection (28.6%).
In the two academic hospitals, Saint-Louis hospital (SLS) in Paris and Tours hospital (TRS), influenza-like illness (ILI) was defined as a patient suffering from at least one general symptom (fever above 38°C, asthenia, myalgia, shivers or headache) and one respiratory symptom (cough, dyspnoea, rhinitis or pharyngitis), in agreement with the guidelines from the French Institut de Veille Sanitaire (InVS), a governmental institution responsible for surveillance and alert in all domains of public health. Criteria for severe clinical presentation were temperature below 35°C or above 39°C despite antipyretic, cardiac frequency above 120/min, respiratory frequency above 30/min, respiratory distress, systolic arterial pressure below 90 mmHg or altered consciousness. Predisposing factors of critical illness were children younger than one year old, pregnant women, diabetes, chronic pre-existing disease (such as respiratory, cardiovascular, neurologic, renal, hepatic or hematologic diseases) and immunosuppression (associated with HIV infection, organ or hematopoietic stem cells transplantation, receipt of chemotherapy or corticosteroids),. A cluster of suspected influenza infections was defined as at least three possible cases in a week in a closed community (household, school,…).
In the two institutions, the prescription of H1N1v molecular testing was recommended for patients with ILI and with either a severe clinical presentation, an underlying risk factor of complications or a condition which was not improving under antiviral treatment. Investigation of grouped suspected cases was also recommended. From week 35 (last week of August) to 44 (last week of October), 413 endonasal swabs were collected in 3 ml of Universal Transport Medium (Copan Diagnostics Inc, Murrieta, CA) from adults and children seen in emergency rooms for suspected ILI (Table 1) and sent to SLS and TRS laboratories for H1N1v detection. The two microbiology laboratories participated in the reference laboratories network for the detection of pandemic influenza H1N1v.
Clinical data were collected at the time of medical attention and reported by clinicians on a national standardized questionnaire provided by InVS,. This questionnaire included the presence or absence of the main general and respiratory symptoms associated with ILI (fever, asthenia, myalgia, shivers, headache, cough, rhinitis, pharyngitis, sudden onset).
Patients ≥1 month old who presented with an ILI to any of the participating hospitals were eligible for participation in the study. ILI was defined by the presence of at least one respiratory symptom (e.g., shortness of breath, nasal congestion, and cough) and one of the two following criteria: (i) fever ≥38°C on examination, or self‐reported fever, or feverishness in the past 24 hours; (ii) one or more non‐respiratory symptoms (e.g., malaise, headache, myalgia, or chest pain). In order to rule out a nosocomial infection, patients who had been hospitalized for more than 48 hours at the time of symptom onset were excluded from the study.
Macroscopic pneumonia in the strict control group (non-infected, non-vaccinated) was minimal (0.08 ± 0.15), and macroscopic lesions were detected in only 2 of the 6 pigs inoculated with only B. bronchiseptica (Bb/NV/NCh), with a group average of 1.8% of the lung affected (Figure 2). There was not a significant increase in the percentage of gross pneumonia in the NV/Ch group when compared to the control group, though the percentage of pigs in each group presenting with lesions was different (100 vs. 25%, respectively). Also, there was not a significant difference between NV/Ch and LAIV/Ch groups (p > 0.05). The average percentage of lung affected by lesions for the NV/Ch group was 4.1 ± 2.9 compared to 2.8 ± 4.3 for the LAIV/Ch group. There was an increase in the percentage of lung affected in the Bb/NV/Ch and Bb/LAIV/Ch groups when compared to the strict control group (p < 0.05), but not between the Bb/NV/Ch and Bb/LAIV/Ch groups (p > 0.05).
Microscopic lesions were either not present or minimal (limited to mild interstitial thickening) in the strict control group (NV/NCh; Figure 3A), as well as in all but 2 of the pigs inoculated with B. bronchiseptica alone (Bb/NV/NCh). The two Bb/NV/NCh pigs with microscopic changes had lesions consistent with chronic B. bronchiseptica pneumonia characterized by moderate thickening of the alveolar septa with fibrin and collagen, type II pneumocyte hyperplasia, and alveolar spaces variably filled with macrophages (30) (Figure 3B). Pigs inoculated with IAV alone (NV/Ch) had mild lesions consistent with IAV infection characterized primarily by suppurative bronchitis and bronchiolitis with epithelial necrosis and peribronchiolar lymphocytic infiltration (31) (Figure 3C). The presence and severity of interstitial pneumonia was minimal to mild in the NV/Ch group. The IAV-associated lesions were diminished in the vaccinated group (LAIV/Ch) when compared to the non-vaccinated group (NV/Ch). In particular the suppurative bronchitis or bronchiolitis with epithelial necrosis was reduced; however, there was peribronchiolar lymphocyte infiltration and bronchus associated lymphoid tissue (BALT) hyperplasia in the majority of LAIV/Ch pigs (Figure 3D).
Pigs that were infected with B. bronchiseptica and subsequently challenged with IAV (Bb/NV/Ch) had microscopic lesions consistent with both IAV infection as well as acute and chronic B. bronchiseptica pneumonia (Figure 3E). Influenza lesions included suppurative bronchitis and bronchiolitis with epithelial necrosis and submucosal lymphohistiocytic inflammation, as well as peribronchiolar lymphocytic infiltration. However, the suppurative bronchitis and bronchiolitis tended to be more severe than that observed in pigs infected with IAV alone, and furthermore alveoli were variably filled with neutrophils and macrophages with areas of alveolar epithelial necrosis, hemorrhage, and type II pneumocyte hyperplasia, which is consistent with acute Bordetellosis. In addition, in sections from some Bb/NV/Ch pigs there were areas consistent with chronic Bordetellosis characterized by interstitial pneumonia consisting of alveolar septal thickening with mononuclear cells as well as fibrin and collagen (Figure 3E).
Finally, as noted in the LAIV/Ch group, vaccinated pigs that had been infected with Bordetella and challenged with IAV (Bb/LAIV/Ch) had diminished bronchial and bronchiolar epithelial necrosis. However, these pigs had lesions consistent with both acute and chronic Bordetella pneumonia, including acute lesions consisting of alveoli and bronchioles that were variably filled with neutrophils and/or macrophages and alveoli with areas of epithelial necrosis, hemorrhage, and type II pneumocyte hyperplasia (Figure 3F). Sections from some of the pigs in Bb/LAIV/Ch group also contained chronic lesions of interstitial pneumonia consisting of alveolar septal thickening with mononuclear cells as well as fibrin and collagen, which is consistent with chronic B. bronchiseptica infection.
In a retrospective single-center study, from a group of infants hospitalized from October 2008 to April 2010 at our Pediatric Emergency Department for acute respiratory symptoms we selected for study 19 consecutive infants aged less than 12 months (6 boys, median age 72 days, range 20-187) with Real Time-PCR confirmed pertussis. We also analyzed data for B. pertussis variants among hospitalized patients in whom B. pertussis was cultured. As a control group, we recruited 19 age- and sex-matched infants (6 boys, median age 71 days, range 20-183) from 164 infants, hospitalized during the same period with RT-PCR confirmed RSV bronchiolitis and negative for B. pertussis. The diagnosis of bronchiolitis was considered in infants less than 12 months with the first episode of acute infection of the lower respiratory tract. Infants with co-morbidity were excluded.
Detailed demographic, clinical and laboratory data were obtained from patients’ parents with a structured questionnaire and from medical files. Clinical outcome variables evaluated included gender, gestational age, birth weight, type of delivery, DTaP (diphtheria, tetanus and acellular pertussis) vaccination received, breast feeding history, age and weight at admission, number of siblings, siblings’ schooling, cough at admission (presence and duration), paroxysmal cough, presence of fever (body temperature >37.5°C), apnea and cyanosis, chest sounds, and hospitalization days. Laboratory outcome variables investigated were white blood-cell count (WBC), lymphocyte count, eosinophil count, neutrophil count, platelet count, hemoglobin (Hb), glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), gamma-glutamyl transferase (GGT) and C-reactive protein (CRP). At hospital admission, each infant was assigned a clinical severity score ranging from 0 to 8, according to respiratory rate (<45/min = 0, 45-60/min = 1, >60/min = 2), arterial oxygen saturation in room air (> 95% = 0, 95-90% = 1, < 90% = 2), retractions (none = 0, present = 1, present + nasal flare = 2), and ability to feed (normal = 0, reduced = 1, intravenous fluid replacement =2).
All infants’ parents were asked to participate in the study and gave written informed consent. The study was approved by the Policlinico Umberto I institutional review board (Reference n° 2377/09.02.2012).
Viruses and bacteria contribute to the pathogenesis and natural history of childhood asthma.1 Respiratory syncytial virus (RSV) predominates in infants and toddlers, while human rhinovirus (hRV), influenza (Flu) viruses, parainfluenza virus (PIV), adenovirus (AdV), coronavirus (CoV), and human enterovirus (hEV) are more prevalent in older children.2
It is common for children with asthma to develop respiratory symptoms, especially during winter. Many of their clinical findings, however, result from respiratory infections that require supportive care and minimizing exposure to respiratory pathogens.3,4 The prevailing practice, nevertheless, is escalating the use of short-acting β-agonists (SABAs), long-acting β-agonists (LABAs), inhaled corticosteroids (ICSs), and leukotriene receptor antagonist. These medications are expensive and may impose serious adverse events, especially in young children.5 Therefore, identifying and controlling triggers of asthma deserve further studies.
There are no studies from the United Arab Emirates (UAE) or surrounding countries that have evaluated respiratory infections or nasopharyngeal isolates in patients with asthma. However, few studies have addressed respiratory viral infections at community level. For example, in Saudi Arabia, most cases of RSV occur from November through March and some cases have been reported at other months of the year.6 In Kuwait, a study that has investigated the causative agents in >1,000 patients with lower respiratory tract infections using PCR revealed that RSV and hRV are the major isolates among hospitalized children from October to March. PIV-2 and human CoV were not detected in any of the patients’ samples.7
Regular surveillance, especially during the winter is necessary if pathogens are to be identified with a view to possible prevention. This prospective, case–control pilot study aimed to estimate the prevalence of nasopharyngeal isolates in children with asthma during winter season and identify their clinical impact on respiratory symptoms and function. Its main objective was to address the importance of controlling respiratory pathogens in the treatment of childhood asthma.