• View in gallery

    Country-stratified proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia. Columns and error bars refer to proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia, with their 95% confidence interval (CI).

  • View in gallery

    Country- and age-stratified proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia. Columns and error bars refer to proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia with their 95% confidence interval (CI).

  • 1.

    Nair H 2011. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 378: 19171930.

    • Search Google Scholar
    • Export Citation
  • 2.

    Mina MJ, Klugman KP, 2014. The role of influenza in the severity and transmission of respiratory bacterial disease. Lancet Respir Med 2: 750763.

    • Search Google Scholar
    • Export Citation
  • 3.

    Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O’Brien KL, Campbell H, Black RE, 2013. Global burden of childhood pneumonia and diarrhoea. Lancet 381: 14051416.

    • Search Google Scholar
    • Export Citation
  • 4.

    Rello J, Pop-Vicas A, 2009. Clinical review: primary influenza viral pneumonia. Crit Care 13: 235.

  • 5.

    Fischer WA 2nd, Gong M, Bhagwanjee S, Sevransky J, 2014. Global burden of influenza as a cause of cardiopulmonary morbidity and mortality. Glob Heart 9: 325336.

    • Search Google Scholar
    • Export Citation
  • 6.

    Komurian-Pradel F 2013. Enhancing research capacities in infectious diseases: the GABRIEL network, a joint approach to major local health issues in developing countries. Clin Epidemiol Glob Health 1: 4043.

    • Search Google Scholar
    • Export Citation
  • 7.

    Picot VS Pneumonia GABRIEL Network, 2014. Multicenter case-control study protocol of pneumonia etiology in children: global approach to biological research, infectious diseases and epidemics in low-income countries (GABRIEL network). BMC Infect Dis 14: 635.

    • Search Google Scholar
    • Export Citation
  • 8.

    Bénet T for the GABRIEL Network, 2017. Severity of pneumonia in under 5-year-old children from developing countries: a multicenter, prospective, observational study. Am J Trop Med Hyg 97: 6876.

    • Search Google Scholar
    • Export Citation
  • 9.

    Bénet T Global Approach to Biological Research, Infectious Diseases and Epidemics in Low-Income Countries (GABRIEL) Network, 2017. Microorganisms associated with pneumonia in children < 5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective, case-control study. Clin Infect Dis 65: 604612.

    • Search Google Scholar
    • Export Citation
  • 10.

    Cherian T 2005. Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ 83: 353359.

    • Search Google Scholar
    • Export Citation
  • 11.

    Albrich WC 2014. Pneumococcal colonisation density: a new marker for disease severity in HIV-infected adults with pneumonia. BMJ Open 4: e005953.

    • Search Google Scholar
    • Export Citation
  • 12.

    Albrich WC, Madhi SA, Adrian PV, Telles JN, Paranhos-Baccalà G, Klugman KP, 2014. Genomic load from sputum samples and nasopharyngeal swabs for diagnosis of pneumococcal pneumonia in HIV-infected adults. J Clin Microbiol 52: 42244229.

    • Search Google Scholar
    • Export Citation
  • 13.

    Ali A, Khowaja AR, Bashir MZ, Aziz F, Mustafa S, Zaidi A, 2013. Role of human metapneumovirus, influenza A virus and respiratory syncytial virus in causing WHO-defined severe pneumonia in children in a developing country. PLoS One 8: e74756.

    • Search Google Scholar
    • Export Citation
  • 14.

    Ruuskanen O, Lahti E, Jennings LC, Murdoch DR, 2011. Viral pneumonia. Lancet 377: 12641275.

  • 15.

    Chiu SS, Tse CY, Lau YL, Peiris M, 2001. Influenza A infection is an important cause of febrile seizures. Pediatrics 108: E63.

  • 16.

    Izadnegahdar R, Cohen AL, Klugman KP, Qazi SA, 2013. Childhood pneumonia in developing countries. Lancet Respir Med 1: 574584.

  • 17.

    Gordon A, Saborío S, Videa E, López R, Kuan G, Balmaseda A, Harris E, 2010. Clinical attack rate and presentation of pandemic H1N1 influenza versus seasonal influenza A and B in a pediatric cohort in Nicaragua. Clin Infect Dis 50: 14621467.

    • Search Google Scholar
    • Export Citation
  • 18.

    Tenenbaum T, Franz A, Neuhausen N, Willems R, Brade J, Schweitzer-Krantz S, Adams O, Schroten H, Henrich B, 2012. Clinical characteristics of children with lower respiratory tract infections are dependent on the carriage of specific pathogens in the nasopharynx. Eur J Clin Microbiol Infect Dis 31: 31733182.

    • Search Google Scholar
    • Export Citation
  • 19.

    Madhi SA, Klugman KP; Vaccine Trialist Group, 2004. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 10: 811813.

    • Search Google Scholar
    • Export Citation
  • 20.

    Klein EY, Monteforte B, Gupta A, Jiang W, May L, Hsieh YH, Dugas A, 2016. The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza Other Respir Viruses 10: 394403.

    • Search Google Scholar
    • Export Citation
  • 21.

    Qi L 2016. Epidemiological and virological characteristics of influenza in Chongqing, China, 2011–2015. PLoS One 11: e0167866.

  • 22.

    Simmerman JM 2009. Incidence, seasonality and mortality associated with influenza pneumonia in Thailand: 2005–2008. PLoS One 4: e7776.

  • 23.

    Tarnagda Z 2014. Sentinel surveillance of influenza in Burkina Faso: identification of circulating strains during 2010–2012. Influenza Other Respir Viruses 8: 524529.

    • Search Google Scholar
    • Export Citation
  • 24.

    Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H, 2008. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ 86: 408416.

    • Search Google Scholar
    • Export Citation
  • 25.

    Domínguez A Cases and Controls in Pandemic Influenza Working Group Spain (CIBERESP), 2013. Benefit of conjugate pneumococcal vaccination in preventing influenza hospitalization in children: a case-control study. Pediatr Infect Dis J 32: 330334.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Burden of Influenza in Less Than 5-Year-Old Children Admitted to Hospital with Pneumonia in Developing and Emerging Countries: A Descriptive, Multicenter Study

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  • 1 Emerging Pathogens Laboratory, Fondation Mérieux, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Lyon, France;
  • 2 Infection Control and Epidemiology Department, Hospices Civils de Lyon, Lyon, France;
  • 3 Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia;
  • 4 MOH Key Laboratory of the Systems Biology of Pathogens and Dr. Christophe Mérieux Laboratory, Fondation Mérieux, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;
  • 5 Centres GHESKIO (Groupe Haïtien d’Etude du Sarcome de Kaposi et des Infections Opportunistes), Port-au-Prince, Haiti;
  • 6 Chatrapati Shahu Ji Maharaj Medical University, Lucknow, India;
  • 7 KEM Hospital Research Center, Pune, India;
  • 8 Fondation Mérieux, Centre d’Infectiologie Charles Mérieux, Antananarivo, Madagascar;
  • 9 Gabriel Touré Hospital, Bamako, Mali;
  • 10 Mongolian Academy of Medical Sciences, Ulaanbaatar, Mongolia;
  • 11 Research Institute of Health, Asunción, Paraguay;
  • 12 Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands

This descriptive 4-year study reports the proportion of detection of influenza viruses in less than 5-year-old children hospitalized for pneumonia in eight developing and emerging countries and describes clinical and microbiological characteristics of influenza-related pneumonia cases. Hospitalized children presenting radiologically confirmed pneumonia aged 2–60 months were prospectively enrolled in this observational standardized study. Mean proportion of isolated influenza virus was 9.7% (95% confidence interval: 7.9–11.8%) among 888 pneumonia children analyzed, with moderate heterogeneity between countries—ranging from 6.2% in Cambodia to 18.8% in Haiti. The clinical characteristics of children with influenza-related pneumonia were not substantially different from those of other pneumonia cases. Influenza A H1N1-related pneumonia cases appeared as more severe than pneumonia cases related to other strains of influenza. Streptococcus pneumoniae was detected more often in blood samples from influenza-related cases than in those without detected influenza viruses (19.7% versus 9.5%, P = 0.018). Influenza-related pneumonia is frequent among children less than 5 years old with pneumonia, living in developing and emerging countries. Influenza might be a frequent etiologic agent responsible for pneumonia or a predisposing status factor for pneumococcal-related pneumonia in this population.

INTRODUCTION

Influenza is a major cause of mortality and morbidity in young children worldwide. According to a meta-analysis published in 2011,1 a total of one million severe, acute, lower respiratory infections and between 28,000 and 111,500 deaths may be attributable annually to influenza-associated infections in children younger than 5 years, with 99% of these deaths occurring in developing countries. Influenza viruses are recognized as risk factors for secondary bacterial infections or co-colonizations2 or as etiological agents of viral pneumonia.3 Therefore, detection of influenza viruses in upper respiratory samples from children with pneumonia might be related to one of these phenomena or both.

The burden of influenza has been determined in industrialized countries, with attack rates reaching between 10% and 20% during seasonal outbreaks or higher during pandemics,4 but data from developing and emerging nations remain scarce.5 We conducted a descriptive study of less than 5-year-old children hospitalized because of pneumonia in developing and emerging countries. The main objective was to estimate the age- and country-stratified proportion of influenza-related pneumonia in this population. Secondary objectives were the description of clinical and microbiological characteristics of—particularly bacterial coinfections in—influenza-related pneumonia cases.

MATERIALS AND METHODS

This descriptive investigation was based on pneumonia cases provided by a large, multicenter, prospective case–control study carried out between the end of 2009 and the beginning of 2014 in nine settings from eight developing and emerging countries: Cambodia, China, Haiti, India (two settings), Madagascar, Mali, Mongolia, and Paraguay. The participating sites were members of the Global Approach to Biological Research, Infectious Diseases and Epidemics in Low-income Countries network established by Fondation Mérieux.6 The protocol, sites, and initial results of the prospective study have been reported in detail elsewhere.7 This study is an ancillary analysis of the previously collected data.8,9 Briefly, incident cases of 2- to 60-month-old children hospitalized with a suspected pneumonia were identified by study clinicians at each participating site and assessed for eligibility. Pneumonia cases were defined by the following criteria:

  • Cough and/or dyspnea;
  • tachypnea, as delineated by the WHO (breathing rate ≥ 50 cycles per minute in children 2–12 months of age and ≥ 40 cycles per minute in children 12–59 months of age)9;
  • first symptoms appearing within the last 14 days; and
  • radiological confirmation of pneumonia, as per WHO guidelines, including primary end-point pneumonia or other infiltrates.10

Patients who met the inclusion criteria and from whom signed informed consent was obtained from their parents or legal guardians were included in the study.

Demographic characteristics, medical history, vital signs, clinical symptoms, and biological parameters at admission were recorded prospectively for each patient on a standardized data collection form. Data quality was monitored and evaluated by each site and by the same scientists of the Emerging Pathogens Laboratory (Lyon, France).

Specimens (nasal swabs/aspirates and blood) were collected in the first 48 hours of patient hospitalization. Biological samples were taken before in-hospital administration of antibiotics. Whole blood allowed complete blood count and culture, and a standard semiquantitative real-time multiplex polymerase chain reaction (RT-PCR) assay was performed for the identification of Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae type B.11,12 C-reactive protein and procalcitonin were quantified in serum. Respiratory specimens were tested for the detection of viruses and bacteria by another RT-PCR assay with a panel of 19 viruses and five bacteria (fast-track diagnostics respiratory pathogens 21 plus; Fast-track Diagnostic, Esch-sur-Alzette, Luxembourg). A centralized, blinded polymer chain reaction (PCR) respiratory quality control panel was provided to all sites to ensure procedure validation on-site before the specimens were processed locally.

Continuous variables were reported as median and interquartile range (IQR) with comparisons by the Mann–Whitney U test. Categorical variables were computed as number of individuals and percentage, with χ2 or Fisher’s exact test as appropriate for comparison. Calculated proportion rates of influenza-related pneumonia represented mean occurrence over the study period. They were reported per 100 patients with their 95% confidence interval (CI). Statistical analysis was undertaken with Stata version 13.0 (StataCorp., College Station, TX).

RESULTS

Overall, 86 influenza-related pneumonia cases were observed among 888 pneumonia children analyzed. Mean influenza proportion in less than 5-year-old children with pneumonia was 9.7% (95% CI: 7.9–11.8%). Country-stratified influenza proportion rates ranged from 6.2% (95% CI: 3.3–10.6%) in Cambodia and 6.2% (95% CI: 2.3–13.3%) in Madagascar to 18.8% (95% CI: 12.1–27.3%) in Haiti, as shown in Figure 1. No substantial seasonality was retrieved, neither on overall data nor after stratification by geographical area (Supplemental Figure 1A–E).

Figure 1.
Figure 1.

Country-stratified proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia. Columns and error bars refer to proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia, with their 95% confidence interval (CI).

Citation: The American Journal of Tropical Medicine and Hygiene 98, 6; 10.4269/ajtmh.17-0494

Influenza proportion in children with pneumonia was homogeneous in different age strata (9.7% in children aged 2–11 months, 9.7% in children aged 12–23 months, and 9.6% in children aged 24–60 months; P = 0.99). Figure 2 reports country- and age-stratified proportions of influenza-related pneumonia. In the 2- to 11-month-old group, influenza proportions ranged from 4.0% (95% CI: 0.7–12.6%) in Mali to 25.7% (95% CI: 12.4–16.3%) in Haiti. It ranged from 0% (95% CI: 0–10.1%) in Madagascar to 23.7% (95% CI: 2.2–39.0%) in India in the 12- to 23-month-old group and between 3.5% (95% CI: 0.2–15.8%) in Paraguay and 21.9% (95% CI: 10.1–38.5%) in Haiti in the 24- to 60-month-old group.

Figure 2.
Figure 2.

Country- and age-stratified proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia. Columns and error bars refer to proportions of influenza-related pneumonia among less than 5-year-old children with pneumonia with their 95% confidence interval (CI).

Citation: The American Journal of Tropical Medicine and Hygiene 98, 6; 10.4269/ajtmh.17-0494

Table 1 enumerates the characteristics of influenza-related pneumonia cases in comparison to pneumonia cases without identified influenza viruses. No statistically significant differences in demographics, vital signs, and clinical symptoms were observed between the two groups. White blood cell (WBC) and neutrophil counts were significantly lower in influenza-related pneumonia cases (P < 0.001 and P = 0.002, respectively).

Table 1

Demographics at hospital admission, medical history, vital signs, clinical symptoms, and biological parameters of influenza-related pneumonia cases compared with pneumonia cases without detected influenza viruses

CharacteristicsInfluenza positive among pneumonia cases (N = 86)Influenza negative among pneumonia cases (N = 802)P
Demographics at admission*
 Male gender53 (61.6)474 (59.1)0.65
 Country0.024
  Cambodia11 (12.8)165 (20.6)
  China3 (3.5)36 (4.5)
  Haiti19 (22.1)82 (10.2)
  Lucknow, India13 (15.1)83 (10.4)
  Vadu, India4 (4.7)67 (8.4)
  Madagascar5 (5.8)75 (9.4)
  Mali11 (12.8)107 (13.3)
  Mongolia13 (15.1)95 (11.9)
  Paraguay7 (8.1)92 (11.5)
 Age, months, median (IQR)36 (25–48)34 (27–45)0.50
 Weight, kg, median (IQR)9 (7.2–10.5)9 (7–11)0.86
 Height, cm, median (IQR)80 (73–87)77 (66.3–88)0.074
 Body mass index, median (IQR)14.9 (13.5–15.8)15.1 (13.6–17.0)0.20
 Mid-upper arm circumference, median (IQR)14 (13–15.5)14 (12–16)0.72
 Weight-for-height Z-score ≤ 2 SD16/55 (29.1)127/517 (24.6)0.46
 Weight-for-height Z-score ≤ 3 SD8/55 (14.6)61/517 (11.8)0.55
Medical history*
 Heart condition2/85 (2.4)37/801 (4.2)0.57
 Lung disease12/75 (16.0)93/629 (14.8)0.73
 Tuberculosis1/85 (1.2)5/788 (0.6)0.46
 Asthma0/85 (0.0)17/789 (2.2)0.40
 Pneumonia23/69 (33.3)182/555 (32.8)1.00
 Other lung disease0/74 (0.0)24/620 (3.9)0.10
 HIV positive0/76 (0.0)9/682 (1.3)0.61
 Contact since 2009 with other persons affected by tuberculosis1/71 (1.4)13/581 (2.2)1.00
 Contracted a cold or pharyngitis during prior 2 weeks13/72 (18.1)151/621 (24.3)0.31
 Contracted influenza during prior 2 weeks8/71 (11.3)82/600 (16.7)0.71
 Prior treatment of fever56/86 (65.1)573/791 (72.4)0.17
 Prior antibiotics treatment45/73 (61.6)398/628 (63.4)0.77
 Referred from another health-care center12/74 (16.2)90/615 (14.6)0.73
 Time period between symptoms and hospitalization, days, median (IQR)5 (4–8)5 (3–7)0.21
Vital signs at admission
 Temperature, °C, median (IQR)38.5 (37.6–38.9)38.3 (37.7–38.8)0.74
 Breathing rate, cycles/minute, median (IQR)55 (48–60)54 (46–60)0.81
 Cardiac rate, beats/minute, median (IQR)136 (120–152)136 (121–152)0.60
 Systolic blood pressure, mm of Hg, median (IQR)90 (84–93)90 (84–98)0.24
 Diastolic blood pressure, mm of Hg, median (IQR)60 (57–68)60 (55–68)0.99
 Arterial oxygen saturation, %, median (IQR)95 (92–97)95 (92–97)0.82
Clinical symptoms at enrollment*
 Dyspnea83/86 (96.5)754/799 (94.4)0.40
 Cough85/86 (98.8)793/800 (99.1)0.79
 Cyanosis8/85 (9.4)77/799 (9.6)0.95
 Lower chest indrawing
 Dullness to percussion24/84 (28.6)205/795 (25.8)0.58
 Pulmonary crackles61/85 (71.8)546/799 (68.3)0.52
 Wheezing23/86 (26.7)258/796 (32.4)0.28
 Rhonchi25/79 (31.7)267/705 (37.9)0.28
 Diminished breathing sounds16/79 (20.3)207/704 (29.4)0.088
 Prostration or lethargy23/74 (31.1)155/632 (24.5)0.22
 Convulsions6/75 (8.0)24/634 (3.8)0.086
 Rhinopharyngitis17/75 (22.8)141/632 (22.3)0.94
 Otitis1/75 (1.3)9/634 (1.4)0.95
 Conjunctivitis0/86 (0.0)15/799 (1.9)0.20
 Skin rash3/75 (4.0)18/636 (2.8)0.57
 Inability to drink13/86 (15.1)99/797 (12.4)0.48
 Vomiting17/86 (19.8)153/798 (19.2)0.89
 Diarrhea14/86 (16.3)113/800 (14.1)0.59
 H1N1 vaccination in 20093/52 (5.8)17/480 (3.5)0.42
 PCV13 vaccination3/68 (4.4)18/546 (3.3)0.63
 Oxygen therapy33/74 (44.6)294/627 (46.9)0.71
Evolution during hospitalization
 Duration of hospitalization, day, median (IQR)6 (3–10)6 (2–10)0.73
 Duration of fever, day, median (IQR)4.5 (3–7)4 (3–6)0.15
 Duration of oxygen requirements, day, median (IQR)2.5 (1.5–3)2 (1–4)0.85
 Death3/80 (3.8)18/770 (2.3)0.44
Biological parameters
 Procalcitonin, ng/mL, median (IQR)0.43 (0.10–2.20)0.47 (0.09–3.50)0.49
 C-reactive protein, mg/L, median (IQR)30.0 (8.0–96.0)26.0 (7.2–88.0)0.62
 White blood cell count, mm3, median (IQR)11,300 (7,600–16,200)15,400 (10,200–23,300)< 0.001
 Neutrophil count, mm3, median (IQR)3,775 (2,204–7,507)6,383 (3,274–11,400)0.002

HIV = human immunodeficiency virus; IQR = interquartile range; PCV = pneumococcal conjugate vaccine; SD = standard deviation.

Reported as number/number with available data (%).

For the current illness.

Supplemental Table 1 lists age-stratified characteristics of influenza-related pneumonia cases compared with pneumonia cases without identified influenza viruses. In the 2- to 11-month-old and 12- to 23-month-old age groups, few significant differences in characteristics were observed. In the 24- to 60-month-old age group, wheezing, diminished breathing sounds, and rhonchi were identified less frequently in influenza-related pneumonia cases compared with pneumonia cases without identified influenza viruses (P = 0.044, P = 0.038, and P = 0.01, respectively); in addition, convulsions occurred more often (P = 0.03) and WBC and neutrophil counts were lower (P < 0.001 and P = 0.002, respectively).

Overall, influenza A virus was found in nasal swabs and aspirates in 60/86 patients (69.8%) and 24/86 patients (27.9%) were found with H1N1 influenza A virus. Influenza B virus was detected in 26/86 patients (30.2%). Influenza A (including A H1N1) and B virus proportions were not different by age groups (P = 0.58, 0.53, and 0.40, respectively). By country, proportions of influenza A virus among detected influenza viruses ranged from 33.3% in China to 100% in Mali (P = 0.004). Influenza A H1N1–related pneumonia cases seemed to be more severe than pneumonia cases related to other strains of influenza. For these patients, a decrease in breathing sounds was observed (P = 0.03), the median breathing rate was higher (57.5 versus 52 cycles/minutes, P = 0.02) and arterial oxygen saturation was lower (93.5% versus 96%, P = 0.005), but median delay between symptoms and hospitalization was higher for influenza A H1N1–related cases (7 versus 5 days, P = 0.023) (Supplemental Table 2).

Table 2 depicts the microorganisms detected from blood and respiratory samples. Viral coinfections were observed in 46/86 (53.5%) of the influenza-related pneumonia group and viral–bacterial coinfection/co-colonizations in 61/86 (70.9%). Blood RT-PCR assay was frequently more positive for S. pneumoniae in the influenza-related pneumonia group (13/66 [19.7%] versus 61/645 [9.5%], P = 0.018), whereas association was negative for other viral infections (respiratory syncytial virus and rhinovirus).

Table 2

Microorganisms detected in blood and respiratory samples from influenza-related pneumonia children compared with pneumonia children without identified influenza viruses

Influenza positive among pneumonia children (N = 86)Influenza negative among pneumonia children (N = 802)P
Viruses detected in respiratory samples
 Adenovirus2/86 (2.3)66/802 (8.2)0.053
 Bocavirus5/86 (5.8)77/802 (9.6)0.33
 Coronavirus NL630/86 (0.0)10/802 (1.2)0.61
 Coronavirus 229E0/86 (0.0)7/802 (0.9)1.00
 Coronavirus OC431/86 (1.2)19/802 (2.4)0.71
 Coronavirus HKU0/86 (0.0)23/796 (2.9)0.16
 Enterovirus3/86 (3.5)39/802 (4.9)0.79
 Human metapneumovirus4/86 (4.7)72/730 (9.9)0.22
 Parainfluenzae virus 13/86 (3.5)23/802 (2.9)0.73
 Parainfluenzae virus 20/86 (0.0)4/802 (0.5)1.00
 Parainfluenzae virus 33/86 (3.5)54/802 (6.7)0.35
 Parainfluenzae virus 44/86 (4.7)17/802 (2.1)0.14
 Parechovirus0/86 (0.0)21/802 (2.6)0.25
 Respiratory syncytial virus9/86 (10.5)169/802 (21.1)0.022
 Rhinovirus5/86 (5.8)216/802 (26.8)< 0.001
 Viral coinfection/co-colonization46/86 (53.5)172/802 (21.5)< 0.001
Bacteria detected in respiratory samples
S. pneumoniae58/86 (67.4)547/801 (68.3)0.90
S. aureus10/86 (11.6)97/801 (12.1)1.00
H. influenzae4/86 (4.7)43/802 (5.4)1.00
Mycoplasma pneumoniae0/86 (0.0)13/802 (1.6)0.63
Clamydophila spp.0/86 (0.0)4/802 (0.5)1.00
 Viral–bacterial co-colonization61/86 (70.9)468/802 (58.4)0.024
Blood samples
 Blood culture positive for a pathogenic microorganism0/86 (0.0)24/802 (3.0)0.16
 RT-PCR positive for S. aureus1/66 (1.5)12/645 (1.9)1.00
 RT-PCR positive for S. pneumoniae13/66 (19.7)61/645 (9.5)0.018
 RT-PCR positive for H. influenzae1/66 (1.5)23/645 (3.6)0.72

RT-PCR = real-time multiplex polymerase chain reaction.

DISCUSSION

Our objective was to ascertain the proportion of influenza virus–related infections in upper respiratory samples from children less than 5 years of age with pneumonia in developing and emerging countries. We observed that the mean proportion was 9.7%, with moderate variations by country—ranging from 6.2% to 18.8%—potentially because of local outbreaks. These data are consistent with the findings of Walker et al.,3 who estimated that influenza viruses are detected in 4.1–17.2% of pneumonia cases. Another study carried out in Pakistan in 2010–2011 reported a proportion of 5.3% of influenza A–related pneumonia in a population of less than 2-year-old children.13

No relevant characteristics were associated with influenza-related pneumonia cases in the 2- to 11-month-old and 12- to 23-month-old age groups. In the 24- to 60-month-old age group, lower WBC and neutrophil counts might support a viral etiology of pneumonia.14 The higher proportion of seizures is known to be associated with influenza.15 The lower proportion of rhonchi or wheezing and the diminished breathing sounds observed in the influenza-related pneumonia group were not clearly retrieved in literature. Indeed, no specific symptom permits to distinguish clearly viral from bacterial pneumonia.14,16 The observed differences may be partly explained by the large number of clinical signs collected or because both influenza-related pneumonia cases and pneumonia cases without influenza detection were affected by mixed viral and bacterial infections in varying proportions. In addition, as observed elsewhere,13,17 results displayed that influenza A H1N1–related cases were more severe than pneumonia cases related to other strains of influenza. The crude mortality rate was not higher in influenza-related pneumonia cases. The role of influenza viruses in childhood mortality is not fully understood,1 but some authors, however, report that influenza results in a substantial burden on health-care services, particularly in developing countries.1 The literature shows that the clinical characteristics of children with lower respiratory tract infections are dependent on the carriage of specific pathogens in the nasopharynx.2,18 Streptococcus pneumoniae was detected more frequently in blood samples from influenza-related cases, with a high detection rate (70.9%) of viral–bacterial co-colonizations found. As previously mentioned in the literature, it suggests that influenza viruses may be considered as precursors of bacterial pneumonia or as etiological agents of pneumonia.19 These data bring additional information to the findings of Klein et al.,20 in which co-colonization rates range between 2% and 65%. Proportions of S. pneumoniae identified in respiratory samples were also higher in influenza-related pneumonia cases compared with pneumonia cases without influenza detection (67.4% versus 35%). It may be explained by the increased rate of pneumococcal colonization in the study population. Indeed, most study participants were not vaccinated with pneumococcal conjugate vaccine (PCV) at the time of its completion.

The present study had some limitations. First, there was no evidence for seasonality because the study was not designed to assess incidence by season. Cases were recruited for more than 1 year, including the dry and rainy seasons. Even if the previous study found rainy season or low humidity levels were associated with a seasonality of influenza viruses, the latter is less prevalent in tropical than in temperate countries.2123 Second, microorganisms involved in pneumonia were detected in upper respiratory samples and those detected may not be the etiological cause of the disease.24 The multicenter nature of our study and the standardization of data collection are major strengths, reinforcing internal validity. Including incident cases increased the quality of data as well.

CONCLUSION

In conclusion, influenza viruses are frequent in respiratory samples from children with pneumonia in developing and emerging countries with moderate heterogeneity between them. The clinical characteristics of children with influenza-related pneumonia are not substantially different from those of children without identified influenza viruses, but influenza A H1N1–related pneumonia cases were more severe than pneumonia cases with other influenza virus detected in this population. Future studies should assess the utility of influenza vaccination in children from developing countries, to prevent viral and bacterial pneumonia, as demonstrated previously with PCV vaccination obviating influenza hospitalizations in children.25

Supplementary Material

REFERENCES

  • 1.

    Nair H 2011. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 378: 19171930.

    • Search Google Scholar
    • Export Citation
  • 2.

    Mina MJ, Klugman KP, 2014. The role of influenza in the severity and transmission of respiratory bacterial disease. Lancet Respir Med 2: 750763.

    • Search Google Scholar
    • Export Citation
  • 3.

    Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O’Brien KL, Campbell H, Black RE, 2013. Global burden of childhood pneumonia and diarrhoea. Lancet 381: 14051416.

    • Search Google Scholar
    • Export Citation
  • 4.

    Rello J, Pop-Vicas A, 2009. Clinical review: primary influenza viral pneumonia. Crit Care 13: 235.

  • 5.

    Fischer WA 2nd, Gong M, Bhagwanjee S, Sevransky J, 2014. Global burden of influenza as a cause of cardiopulmonary morbidity and mortality. Glob Heart 9: 325336.

    • Search Google Scholar
    • Export Citation
  • 6.

    Komurian-Pradel F 2013. Enhancing research capacities in infectious diseases: the GABRIEL network, a joint approach to major local health issues in developing countries. Clin Epidemiol Glob Health 1: 4043.

    • Search Google Scholar
    • Export Citation
  • 7.

    Picot VS Pneumonia GABRIEL Network, 2014. Multicenter case-control study protocol of pneumonia etiology in children: global approach to biological research, infectious diseases and epidemics in low-income countries (GABRIEL network). BMC Infect Dis 14: 635.

    • Search Google Scholar
    • Export Citation
  • 8.

    Bénet T for the GABRIEL Network, 2017. Severity of pneumonia in under 5-year-old children from developing countries: a multicenter, prospective, observational study. Am J Trop Med Hyg 97: 6876.

    • Search Google Scholar
    • Export Citation
  • 9.

    Bénet T Global Approach to Biological Research, Infectious Diseases and Epidemics in Low-Income Countries (GABRIEL) Network, 2017. Microorganisms associated with pneumonia in children < 5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective, case-control study. Clin Infect Dis 65: 604612.

    • Search Google Scholar
    • Export Citation
  • 10.

    Cherian T 2005. Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ 83: 353359.

    • Search Google Scholar
    • Export Citation
  • 11.

    Albrich WC 2014. Pneumococcal colonisation density: a new marker for disease severity in HIV-infected adults with pneumonia. BMJ Open 4: e005953.

    • Search Google Scholar
    • Export Citation
  • 12.

    Albrich WC, Madhi SA, Adrian PV, Telles JN, Paranhos-Baccalà G, Klugman KP, 2014. Genomic load from sputum samples and nasopharyngeal swabs for diagnosis of pneumococcal pneumonia in HIV-infected adults. J Clin Microbiol 52: 42244229.

    • Search Google Scholar
    • Export Citation
  • 13.

    Ali A, Khowaja AR, Bashir MZ, Aziz F, Mustafa S, Zaidi A, 2013. Role of human metapneumovirus, influenza A virus and respiratory syncytial virus in causing WHO-defined severe pneumonia in children in a developing country. PLoS One 8: e74756.

    • Search Google Scholar
    • Export Citation
  • 14.

    Ruuskanen O, Lahti E, Jennings LC, Murdoch DR, 2011. Viral pneumonia. Lancet 377: 12641275.

  • 15.

    Chiu SS, Tse CY, Lau YL, Peiris M, 2001. Influenza A infection is an important cause of febrile seizures. Pediatrics 108: E63.

  • 16.

    Izadnegahdar R, Cohen AL, Klugman KP, Qazi SA, 2013. Childhood pneumonia in developing countries. Lancet Respir Med 1: 574584.

  • 17.

    Gordon A, Saborío S, Videa E, López R, Kuan G, Balmaseda A, Harris E, 2010. Clinical attack rate and presentation of pandemic H1N1 influenza versus seasonal influenza A and B in a pediatric cohort in Nicaragua. Clin Infect Dis 50: 14621467.

    • Search Google Scholar
    • Export Citation
  • 18.

    Tenenbaum T, Franz A, Neuhausen N, Willems R, Brade J, Schweitzer-Krantz S, Adams O, Schroten H, Henrich B, 2012. Clinical characteristics of children with lower respiratory tract infections are dependent on the carriage of specific pathogens in the nasopharynx. Eur J Clin Microbiol Infect Dis 31: 31733182.

    • Search Google Scholar
    • Export Citation
  • 19.

    Madhi SA, Klugman KP; Vaccine Trialist Group, 2004. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 10: 811813.

    • Search Google Scholar
    • Export Citation
  • 20.

    Klein EY, Monteforte B, Gupta A, Jiang W, May L, Hsieh YH, Dugas A, 2016. The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza Other Respir Viruses 10: 394403.

    • Search Google Scholar
    • Export Citation
  • 21.

    Qi L 2016. Epidemiological and virological characteristics of influenza in Chongqing, China, 2011–2015. PLoS One 11: e0167866.

  • 22.

    Simmerman JM 2009. Incidence, seasonality and mortality associated with influenza pneumonia in Thailand: 2005–2008. PLoS One 4: e7776.

  • 23.

    Tarnagda Z 2014. Sentinel surveillance of influenza in Burkina Faso: identification of circulating strains during 2010–2012. Influenza Other Respir Viruses 8: 524529.

    • Search Google Scholar
    • Export Citation
  • 24.

    Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H, 2008. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ 86: 408416.

    • Search Google Scholar
    • Export Citation
  • 25.

    Domínguez A Cases and Controls in Pandemic Influenza Working Group Spain (CIBERESP), 2013. Benefit of conjugate pneumococcal vaccination in preventing influenza hospitalization in children: a case-control study. Pediatr Infect Dis J 32: 330334.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Cédric Dananché, Laboratoire des Pathogènes Émergents, Fondation Mérieux, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS UMR5308, ENS de Lyon, Université Claude Bernard Lyon 1, 7-11, rue Guillaume Paradin, F-69372 Lyon Cedex 08, France. E-mail: cedric.dananche@chu-lyon.fr

Ethics statement: The study protocol, informed consent statement, clinical research form, amendments, and all other study documents were submitted to and approved by the Institutional Research Ethics Committee of each site.

Authors’ addresses: Cédric Dananché, Thomas Bénet, and Philippe Vanhems, Emerging Pathogens Laboratory, Fondation Mérieux, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Lyon, France, and Service Hygiène, Epidémiologie et Prévention, Centre Hospitalier Universitaire de Lyon, Lyon, France, E-mails: cedric.dananche@chu-lyon.fr, thomas.benet@chu-lyon.fr, and philippe.vanhems@chu-lyon.fr. Valentina Sánchez Picot, Mélina Messaoudi, and Florence Komurian-Pradel, Emerging Pathogens Laboratory, Fondation Mérieux, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Lyon, France, E-mails: valentina.picot@fondation-merieux.org, melina.messaoudi@fondation-merieux.org, and florence.pradel@fondation-merieux.org. Monidarin Chou, Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia, E-mail: cmonidarin@uhs.edu.kh. Jianwei Wang, MOH Key Laboratory of the Systems Biology of Pathogens and Dr. Christophe Mérieux Laboratory, Fondation Mérieux, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, E-mail: wangjw28@163.com. Jean-William Pape, Groupe Haïtien d’Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), Port-au-Prince, Haiti, E-mail: jwpape@gheskio.org. Shally Awasthi, Chatrapati Shahuji Maharaj University, Lucknow, India, E-mail: shally07@gmail.com. Ashish Bavdekar, KEM Hospital, Pune, India, E-mail: bavdekar@vsnl.com. Mala Rakoto-Andrianarivelo, Centre d’Infectiologie Charles Mérieux, Antananarivo, Madagascar, E-mail: mala@cicm-madagascar.com. Mariam Sylla, Gabriel Touré Hospital, Bamako, Mali, E-mail: dr_mame@yahoo.fr. Pagbajabyn Nymadawa, Mongolian Academy of Medical Sciences, Ulaanbaatar, Mongolia, E-mail: nymadawa@gyals.mn. Graciela Russomando, Molecular Biology Department, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Asunción, Paraguay, E-mail: grusso@rieder.net.py. Hubert Endtz, Fondation Mérieux, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Emerging Pathogens Laboratory, Lyon, France, and Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands, E-mail: hubert.endtz@fondation-merieux.org. Gláucia Paranhos-Baccalà, Fondation Mérieux, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, ENS de Lyon, UCBL1, Emerging Pathogens Laboratory, Lyon, France, E-mail: glaucia.baccala@fondation-merieux.org.

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