Clinical and molecular characterization of children and adults with respiratory bocavirus infection in Mexico: a cross-sectional nested study within the ILI002 prospective observational study.

Background: Human Bocaviruses (HBoV) can cause acute respiratory tract infections. High coinfection rates cloud its pathogenicity. This study sought to describe the clinical features of HBoV1 disease in children and adults with Influenza-like illness (ILI), exploring associations between viral load, clinical features, and seasonality. Methods: Patients who tested positive for HBoV1 by polymerase chain reaction, enrolled from April 2010 to March 2014 in the ILI002 prospective observational cohort study were included in this cross-sectional nested study. Participants were included in ILI002 if they presented with signs and/or symptoms suggestive of influenza-like illness. Samples were tested for viral load, and NP1 and VP1/VP2 phylogenetic analyses, except for the samples lacking suitable and viable clinical material for genotyping. Findings: We identified HBoV1 in 157 (2.8%) of participants. Prevalence was 4.5% in children and 1.8% in adults. Single HBoV1 detection occurred in 41.1% and 46.3% of children and adults, respectively. Children commonly experienced fever (83.3%), cough with sputum (74.4%), and shortness of breath (72.2%). In the multivariate analysis of children, significant positive associations were detected between viral loads and age (0.20 [95% CI: 0.07, 0.33]), and the presence of fever (2.64 [95% CI: 1.35, 3.94]), nasal congestion (1.03 [95% CI: 0.07, 1.99]), dry cough (1.32 [95% CI: 0.42, 2.22]), chest congestion (1.57 [95% CI: 0.33, 2.80]), red eyes (1.25 [95% CI: 0.35, 2.14]), cough with sputum (1.79 [95% CI: 0.80, 2.78]), and other signs and symptoms such as chills, dizziness, and diaphoresis (1.73 [95% CI: 0.19, 3.27]). In contrast, significant negative associations were found between viral loads and percent neutrophils on the blood count (-0.04 [95% CI: -0.06, -0.02]), fatigue (-1.60 [95% CI: -2.46, -0.74]) and the presence of other symptoms or signs, including adenopathy and rash (-1.26 [95% CI: -2.31, -0.21]). Adults commonly experienced sore throat (73.1%), fatigue (77.4%), and headache (73.1%). In the multivariate analysis of adults, significant positive associations were detected between viral load and body mass index (0.13 [95% CI: 0.04, 0.21]), and the presence of confusion (1.54 [95% CI: 0.55, 2.53]), and sore throat (1.03 [95% CI: 0.20, 1.85]), and significant negative associations were detected between viral load and chest congestion (-1.16 [95% CI: -2.07, -0.24]). HBoV1 was detected throughout the year irrespective of season, temperature, and humidity. Interpretation: This study demonstrated the importance of detecting HBoV1 in patients with influenza-like illness either as single infection or co-infection, in both adults and children, and improves the characterization of HBoV1 seasonality, clinical features, and viral load. Phylogenetic analyses show a high conservation. Funding: The Mexican Emerging Infectious Diseases Clinical Research Network (LaRed), CONACYT (Fondo Sectorial SSA/IMSS/ISSSTE, Projects No. 71260 and No. 127088), Fondos federales no. HIM/2015/006, NIAID, NIH through a contract with Westat, Inc. (HHSN2722009000031, HHSN27200002), NCI, NIH (75N91019D00024, 75N91019F00130). Additional information at the end of the manuscript.

Etiology, clinical characteristics, and risk factors associated with severe influenza-like illnesses in Mexican adults.

Objective: The aim of this study was to determine the risk factors associated with severe influenza-like illness (ILI) in Mexican adults that could be useful to clinicians when assessing patients with ILI. Methods: Data from adult patients enrolled from 2010 through 2014 in ILI002 - a prospective hospital-based observational cohort study - were analyzed. Etiology and clinical characteristics were compared between cases of severe ILI (defined as hospitalization and/or death) and cases of non-severe ILI. Results: Overall, 1428 (39.0%) out of a total 3664 cases of ILI were classified as severe. Adjusted analyses showed a higher risk of severe ILI associated with signs and symptoms related to lower tract infection, i.e. cough with sputum (odds ratio (OR) 2.037, 95% confidence interval (CI) 1.206-3.477; P = 0.008), dyspnea (OR 5.044, 95% CI 2.99-8.631; and shortness of breath (OR 5.24, 95% CI 3.0839.124; P < 0.001), and with increases in lactate dehydrogenase (OR 4.426, 95% CI 2.321-8.881; P < 0.001) and C-reactive protein (OR 3.618, 95% CI 2.5955.196; P < 0.001). Further, there was an increased risk of severe ILI with a longer time between symptom onset and inclusion (OR 1.108, 95% CI 1.049-1.172; P < 0.001) and with chronic steroid use (OR 14.324, 95% CI 8.059-26.216; P < 0.001). Conclusions: Respiratory viruses can cause severe ILI. The results of this study highlight the importance of evaluating data compatible with lower tract involvement and previous use of immunosuppressants at baseline, because patients meeting these conditions may develop severe illness.

Different Clinical Presentations of Human Rhinovirus Species Infection in Children and Adults in Mexico.

Background: Human rhinoviruses (HRVs) are a common cause of influenza-like illness, with the ability to infect the upper and lower respiratory tracts. In this study we aim to describe the clinical and molecular features of HRV infection in Mexican children and adults. Methods: We performed a hospital-based, 4-year multicenter prospective observational cohort study of patients with influenza-like illness. Participants who tested positive for HRV were included. We described demographic, clinical, and laboratory characteristics and the association between HRV types, illness severity, and clinical outcomes. Results: Of the 5662 subjects recruited, 1473 (26%) had HRV; of those, 988 (67.1%) were adults (≥18 years) and 485 (32.9%) were children. One hundred sixty-seven (11.33%) samples were sequenced; 101 (60.5%) were rhinovirus species A (HRV-A), 22 (13.2%) were rhinovirus species B (HRV-B), and 44 (26.3%) were rhinovirus species C (HRV-C). Among children and adults, 30.5% and 23.5%, respectively, were hospitalized (non-intensive care unit [ICU]). The odds of HRV-C are higher than HRV-A for participants in the ICU (compared to outpatient) and when platelets, lymphocytes, white blood cells, and lactate dehydrogenase are increased. The odds of HRV-C are higher than HRV-A and HRV-B with shortness of breath. The odds of HRV-A are higher than HRV-B, and the odds of HRV-B are higher than HRV-C, when mild symptoms like muscle ache and headache occur. Conclusions: Rhinoviruses are a common cause of influenza-like illness. It is necessary to improve the surveillance, testing, and species identification for these viruses to understand different clinical presentations and risk factors associated with worse outcomes. Clinical Trials Registration. NCT01418287.

Comparison of Rates of Hospitalization Between Single and Dual Virus Detection in a Mexican Cohort of Children and Adults With Influenza-Like Illness.

BACKGROUND: Molecular detection methods allow for the simultaneous detection of several infectious agents. This study assesses whether co-infection with 2 viruses as compared with 1 is associated with increased hospitalization in those with acute respiratory infections. METHODS: We prospectively enrolled a cohort of pediatric and adult participants with influenza-like illness during 2010-2014 in Mexico. Clinical information and respiratory samples were collected at enrollment. Respiratory viruses were detected with multiplex polymerase chain reaction (PCR) and influenza-specific reverse transcription PCR assays. Participants were followed for 14 and 28 days after inclusion. Severity of disease, as measured by hospitalization with acute respiratory infections, was compared between single and dual viral infections. RESULTS: Among 5662 participants in the study, either 1 (n = 3285) or 2 (n = 641) viruses were detected in 3926 participants. Rhinovirus (n = 1433), influenza (n = 888), and coronaviruses (n = 703) were the most frequently detected viruses (either alone or in co-infection). Bocavirus, respiratory syncytial virus (RSV), metapneumovirus, and rhinovirus cases were hospitalized more often than other viruses. Bocavirus+rhinovirus cases were hospitalized more often than those with rhinovirus alone (but not bocavirus alone). RSV cases were more likely to be hospitalized than cases with co-infections of RSV and parainfluenza virus or coronavirus. Metapneumovirus cases were hospitalized more often than those co-infected with metapneumovirus+coronavirus. CONCLUSIONS: In this study, detection of 2 viruses did not significantly increase hospitalizations compared with single virus infections. Larger studies will allow for distinguishing between sequential and simultaneous infection and for a better understanding of the role of each virus during the evolution of acute respiratory episodes.

"Differential risk of hospitalization among single virus infections causing influenza-like illnesses".

BACKGROUND: Acute respiratory infections are a major cause of morbidity in children and are often caused by viruses. However, the relative severity of illness associated with different viruses is unclear. The objective of this study was to evaluate the risk of hospitalization from different viruses in children presenting with an influenza-like illness (ILI). METHODS: Data from children 5 years old or younger participating in an ILI natural history study from April 2010 to March 2014 was analyzed. The adjusted odds ratio for hospitalization was estimated in children with infections caused by respiratory syncytial virus (RSV), metapneumovirus, bocavirus, parainfluenza viruses, rhinovirus/enterovirus, coronavirus, adenovirus, and influenza. RESULTS: A total of 1486 children (408 outpatients and 1078 inpatients) were included in this analysis. At least one virus was detected in 1227 (82.6%) patients. The most frequent viruses detected as single pathogens were RSV (n = 286), rhinovirus/enterovirus (n = 251), parainfluenza viruses (n = 104), and influenza A or B (n = 99). After controlling for potential confounders (age, sex, recruitment site, days from symptom onset to enrollment, and underlying illnesses), children with RSV and metapneumovirus infections showed a greater likelihood of hospitalization than those infected by parainfluenza viruses (OR 2.7 and 1.9, respectively), rhinovirus/enterovirus (OR 3.1 and 2.1, respectively), coronaviruses (OR 4.9 and 3.4, respectively), adenovirus (OR 4.6 and 3.2, respectively), and influenza (OR 6.3 and 4.4, respectively). CONCLUSIONS: Children presenting with ILI caused by RSV and metapneumovirus were at greatest risk for hospitalization, while children with rhinovirus/enterovirus, parainfluenza, coronavirus, adenovirus, and influenza were at lower risk of hospitalization.

Underweight, overweight, and obesity as independent risk factors for hospitalization in adults and children from influenza and other respiratory viruses.

BACKGROUND: The relationship between obesity and risk of complications described during the 2009 influenza pandemic is poorly defined for seasonal influenza and other viral causes of influenza-like illness (ILI). METHODS: An observational cohort of hospitalized and outpatient participants with ILI was conducted in six hospitals in Mexico. Nasopharyngeal swabs were tested for influenza and other common respiratory pathogens. RESULTS: A total of 4778 participants were enrolled in this study and had complete data. A total of 2053 (43.0%) had severe ILI. Seven hundred and seventy-eight (16.3%) were positive for influenza, 2636 (55.2%) were positive for other viral respiratory pathogens, and 1364 (28.5%) had no respiratory virus isolated. Adults with influenza were more likely to be hospitalized if they were underweight (OR: 5.20), obese (OR: 3.18), or morbidly obese (OR: 18.40) compared to normal-weight adults. Obese adults with H1N1 had a sixfold increase in odds of hospitalization over H3N2 and B (obese OR: 8.96 vs 1.35, morbidly obese OR: 35.13 vs 5.58, respectively) compared to normal-weight adults. In adults with coronavirus, metapneumovirus, parainfluenza, and rhinovirus, participants that were underweight (OR: 4.07) and morbidly obese (OR: 2.78) were more likely to be hospitalized as compared to normal-weight adults. All-cause influenza-like illness had a similar but less pronounced association between underweight or morbidly obesity and hospitalization. CONCLUSIONS: There is an increased risk of being hospitalized in adult participants that are underweight or morbidly obese, regardless of their viral pathogen status. Having influenza, however, significantly increases the odds of hospitalization in those who are underweight or morbidly obese.

Epidemiology and clinical characteristics of respiratory syncytial virus infections among children and adults in Mexico.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading etiological agent of acute respiratory tract infections and hospitalizations in children. However, little information is available regarding RSV infections in Latin American countries, particularly among adult patients. OBJECTIVE: To describe the epidemiology of RSV infection and to analyze the factors associated with severe infections in children and adults in Mexico. METHODS: Patients ≥1 month old, who presented with an influenza-like illness (ILI) to six hospitals in Mexico, were eligible for participation in the study. Multiplex reverse-transcriptase polymerase chain reaction identified viral pathogens in nasal swabs from 5629 episodes of ILI. Patients in whom RSV was detected were included in this report. RESULTS: Respiratory syncytial virus was detected in 399 children and 171 adults. RSV A was detected in 413 cases and RSV B in 163, including six patients who had coinfection with both subtypes; 414 (72.6%) patients required hospital admission, including 96 (16.8%) patients that required admission to the intensive care unit. Coinfection with one or more respiratory pathogens other than RSV was detected in 159 cases. Young age (in children) and older age (in adults) as well as the presence of some underlying conditions were associated with more severe disease. CONCLUSIONS: This study confirms that RSV is an important respiratory pathogen in children in Mexico. In addition, a substantial number of cases in adults were also detected highlighting the relevance of this virus in all ages. It is important to identify subjects at high risk of complications who may benefit from current or future preventive interventions.

Clinical characteristics of asthmatic patients with influenza-like illness and risk of severe exacerbations in Mexico.

BACKGROUND: Patients with chronic inflammatory lung diseases, such as asthma, are at higher risk for influenza-like illness (ILI) complications. Viral infections are known to trigger asthma exacerbations, but a thorough description of the clinical characteristics of ILI-associated asthma exacerbations and the role of viruses as a risk factor for severe exacerbation (SE) in ILI has not been published yet. OBJECTIVE: To investigate risk factors for SE in patients with ILI and asthma. METHODS: Patients with ILI symptoms were recruited from 6 hospitals of Mexico (LaRed sites) during 2010 to 2014. Those with a previous asthma diagnosis and ILI symptoms and who were 5 years or older were included. Patients were assigned as cases or controls based on symptoms reported. SE was defined when participants presented with wheezing or dyspnea and required hospitalization. RESULTS: A total of 486 patients with ILI and a diagnosis of asthma were included. There were no differences in the proportion, number, or type of viral illness among those with and without SE. Those with SE were less likely to report ILI symptoms. Muscle pain and nasal drip were predictors for patients not progressing to SE. A delay in seeking medical care was associated with SE (odds ratio, 2.93; 95% CI, 1.46-5.88). CONCLUSION: The presence of a particular virus did not predict SE. ILI symptoms in asthma patients are not associated with severe exacerbation. Patients with asthma should be encouraged to seek early medical care when ILI symptoms are first noticed to prevent serious complications.

Pediatrics in disasters: evaluation of a global training program.

The findings of this evaluation document partial success for the PEDS training program to achieve its 3 aims. It will take several years for the dissemination of this program to reach a critical mass of pediatricians and other physicians in many LMICs. Obtaining stronger support from MOHs and other governmental agencies is necessary to achieve this goal. Another additional approach would be to integrate the training into medical school and residency programs.

Clinical characteristics and outcomes of influenza and other influenza-like illnesses in Mexico City.

BACKGROUND: Influenza-like illnesses (ILI) are estimated to cause millions of deaths annually. Despite this disease burden, the etiologic causes of ILI are poorly described for many geographical regions. METHODS: Beginning in April 2010, we conducted an observational cohort study at five hospitals in Mexico City, enrolling subjects who met the criteria for ILI. Evaluations were conducted at enrollment and on day 28, with the collection of clinical data and a nasopharyngeal swab (or nasal aspirate in children). Swabs were tested by multiplex PCR for 15 viral pathogens and real-time PCR for influenza. RESULTS: During the first year, 1065 subjects were enrolled in this study, 55% of whom were hospitalized; 24% of all subjects were children. One or more pathogens were detected by PCR in 64% of subjects, most commonly rhinovirus (25% of all isolates) and influenza (24% of isolates). Six percent of subjects died, and of those, 54% had no pathogen identified. Rhinovirus was the most common pathogen among those who died, although it did not have the highest case fatality rate. CONCLUSIONS: Multiple respiratory viruses beyond influenza are associated with significant morbidity and mortality among adults and children in Mexico City. Detection of these agents could be useful for the adjustment of antibiotic treatment in severe cases.