Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study

Background: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018. Methods: We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries. Findings: In 2018, among children under 5 years globally, there were an estimated 109·5 million influenza virus episodes (uncertainty range [UR] 63·1–190·6), 10·1 million influenza-virus-associated ALRI cases (6·8–15·1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000–1 415 000), 15 300 in-hospital deaths (5800–43 800), and up to 34 800 (13 200–97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries. Interpretation: A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries. Funding: WHO; Bill & Melinda Gates Foundation.Fil: Wang, Xin. University of Edinburgh; Reino UnidoFil: Li, You. University of Edinburgh; Reino UnidoFil: O'Brien, Katherine L.. University Johns Hopkins; Estados UnidosFil: Madhi, Shabir A.. University of the Witwatersrand; SudáfricaFil: Widdowson, Marc Alain. Centers for Disease Control and Prevention; Estados UnidosFil: Byass, Peter. Umea University; SueciaFil: Omer, Saad B.. Yale School Of Public Health; Estados UnidosFil: Abbas, Qalab. Aga Khan University; PakistánFil: Ali, Asad. Aga Khan University; PakistánFil: Amu, Alberta. Dodowa Health Research Centre; GhanaFil: Azziz-Baumgartner, Eduardo. Centers for Disease Control and Prevention; Estados UnidosFil: Bassat, Quique. University Of Barcelona; EspañaFil: Abdullah Brooks, W.. University Johns Hopkins; Estados UnidosFil: Chaves, Sandra S.. Centers for Disease Control and Prevention; Estados UnidosFil: Chung, Alexandria. University of Edinburgh; Reino UnidoFil: Cohen, Cheryl. National Institute For Communicable Diseases; SudáfricaFil: Echavarría, Marcela Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Fasce, Rodrigo A.. Public Health Institute; ChileFil: Gentile, Angela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Gordon, Aubree. University of Michigan; Estados UnidosFil: Groome, Michelle. University of the Witwatersrand; SudáfricaFil: Heikkinen, Terho. University Of Turku; FinlandiaFil: Hirve, Siddhivinayak. Kem Hospital Research Centre; IndiaFil: Jara, Jorge H.. Universidad del Valle de Guatemala; GuatemalaFil: Katz, Mark A.. Clalit Research Institute; IsraelFil: Khuri Bulos, Najwa. University Of Jordan School Of Medicine; JordaniaFil: Krishnan, Anand. All India Institute Of Medical Sciences; IndiaFil: de Leon, Oscar. Universidad del Valle de Guatemala; GuatemalaFil: Lucero, Marilla G.. Research Institute For Tropical Medicine; FilipinasFil: McCracken, John P.. Universidad del Valle de Guatemala; GuatemalaFil: Mira-Iglesias, Ainara. Fundación Para El Fomento de la Investigación Sanitaria; EspañaFil: Moïsi, Jennifer C.. Agence de Médecine Préventive; FranciaFil: Munywoki, Patrick K.. No especifíca;Fil: Ourohiré, Millogo. No especifíca;Fil: Polack, Fernando Pedro. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Rahi, Manveer. University of Edinburgh; Reino UnidoFil: Rasmussen, Zeba A.. National Institutes Of Health; Estados UnidosFil: Rath, Barbara A.. Vienna Vaccine Safety Initiative; AlemaniaFil: Saha, Samir K.. Child Health Research Foundation; BangladeshFil: Simões, Eric A.F.. University of Colorado; Estados UnidosFil: Sotomayor, Viviana. Ministerio de Salud de Santiago de Chile; ChileFil: Thamthitiwat, Somsak. Thailand Ministry Of Public Health; TailandiaFil: Treurnicht, Florette K.. University of the Witwatersrand; SudáfricaFil: Wamukoya, Marylene. African Population & Health Research Center; KeniaFil: Lay-Myint, Yoshida. Nagasaki University; JapónFil: Zar, Heather J.. University of Cape Town; SudáfricaFil: Campbell, Harry. University of Edinburgh; Reino UnidoFil: Nair, Harish. University of Edinburgh; Reino Unid

Burden of laboratory-confirmed shigellosis infections in Guatemala 2007-2012: results from a population-based surveillance system

Abstract Background We describe the epidemiology and antimicrobial susceptibility patterns of culture-confirmed Shigella infections in facility-based surveillance sites in Guatemala. Current studies using quantitative molecular diagnostics suggest Shigella may contribute most to the global diarrheal disease burden. Since identification of Shigella requires culturing techniques using stool specimens and few laboratories in Guatemala routinely culture for this pathogen, little is known about the true burden of Shigella in Guatemala or, importantly, the antimicrobial resistance patterns. Methods Clinical, epidemiological, and laboratory data were collected on 5399 patients with acute diarrhea (≥3 loose stools in 24 h) from June 2007–August 2012. Multidrug resistance (MDR) was defined as resistance to ampicillin and trimethoprim/sulfamethoxazole. Results Five percent (261) of stool specimens yielded Shigella spp. The annual incidence of laboratory-confirmed infections ranged from 5.0 to 24.1 per 100,000 persons in Santa Rosa and 0.3 to 6.2 per 100,000 in Quetzaltenango; 58% of cases occurred in children < 5 years of age. Thirty patients were hospitalized; one patient died. Oral rehydration or intravenous solution was used to treat 72% of hospitalized and 15% of ambulatory cases. Fifty-nine percent of cases were S. flexneri and 51% of cases were MDR. Conclusions Shigella is an important cause of bacterial diarrhea in children and prevalence of MDR highlights the importance of appropriate treatment regimens. This study demonstrates that strengthening laboratory capacity in Guatemala can help determine causes which can lead to prevention of diarrheal diseases, particularly in children. Such capacity building is also critical for rapid detection and control of public health threats at their source and therefore for global health security

Incidence of Hospitalized Pneumococcal Pneumonia among Adults in Guatemala, 2008-2012.

Streptococcus pneumoniae is a leading cause of pneumonia worldwide. However, the burden of pneumococcal pneumonia among adults in low- and middle-income countries is not well described.Data from 2008-2012 was analyzed from two surveillance sites in Guatemala to describe the incidence of pneumococcal pneumonia in adults. A case of hospitalized pneumococcal pneumonia was defined as a positive pneumococcal urinary antigen test or blood culture in persons aged ≥ 18 years hospitalized with an acute respiratory infection (ARI).Among 1595 adults admitted with ARI, 1363 (82%) had either urine testing (n = 1286) or blood culture (n = 338) performed. Of these, 188 (14%) had pneumococcal pneumonia, including 173 detected by urine only, 8 by blood culture only, and 7 by both methods. Incidence rates increased with age, with the lowest rate among 18-24 year-olds (2.75/100,000) and the highest among ≥65 year-olds (31.3/100,000). The adjusted incidence of hospitalized pneumococcal pneumonia was 18.6/100,000 overall, with in-hospital mortality of 5%.An important burden of hospitalized pneumococcal pneumonia in adults was described, particularly for the elderly. However, even adjusted rates likely underestimate the true burden of pneumococcal pneumonia in the community. These data provide a baseline against which to measure the indirect effects of the 2013 introduction of the pneumococcal conjugate vaccine in children in Guatemala

Surveillance for hospitalized acute respiratory infection in Guatemala.

Acute respiratory infections (ARI) are an important cause of illness and death worldwide, yet data on the etiology of ARI and the population-level burden in developing countries are limited. Surveillance for ARI was conducted at two hospitals in Guatemala. Patients admitted with at least one sign of acute infection and one sign or symptom of respiratory illness met the criteria for a case of hospitalized ARI. Nasopharyngeal/oropharyngeal swabs were collected and tested by polymerase chain reaction for adenovirus, parainfluenza virus types 1,2 and 3, respiratory syncytial virus, influenza A and B viruses, human metapneumovirus, Chlamydia pneumioniae, and Mycoplasma pneumoniae. Urine specimens were tested for Streptococcus pneumoniae antigen. Blood culture and chest radiograph were done at the discretion of the treating physician. Between November 2007 and December 2011, 3,964 case-patients were enrolled. While cases occurred among all age groups, 2,396 (60.4%) cases occurred in children <5 years old and 463 (11.7%) among adults ≥65 years old. Viruses were found in 52.6% of all case-patients and 71.8% of those aged <1 year old; the most frequently detected was respiratory syncytial virus, affecting 26.4% of case-patients. Urine antigen testing for Streptococcus pneumoniae performed for case-patients ≥15 years old was positive in 15.1% of those tested. Among 2,364 (59.6%) of case-patients with a radiograph, 907 (40.0%) had findings suggestive of bacterial pneumonia. Overall, 230 (5.9%) case-patients died during the hospitalization. Using population denominators, the observed hospitalized ARI incidence was 128 cases per 100,000, with the highest rates seen among children <1 year old (1,703 per 100,000), followed by adults ≥65 years old (292 per 100,000). These data, which demonstrate a substantial burden of hospitalized ARI in Guatemala due to a variety of pathogens, can help guide public health policies aimed at reducing the burden of illness and death due to respiratory infections

Hospitalization and death among patients with influenza, Guatemala, 2008–2012

Abstract Background Influenza is a major cause of respiratory illness resulting in 3–5 million severe cases and 291,243-645,832 deaths annually. Substantial health and financial burden may be averted by annual influenza vaccine application, especially for high risk groups. Methods We used an active facility-based surveillance platform for acute respiratory diseases in three hospitals in Guatemala, Central America, to estimate the incidence of laboratory-confirmed hospitalized influenza cases and identify risk factors associated with severe disease (defined as admission to the intensive care unit (ICU) or death). We enrolled patients presenting with signs and symptoms of acute respiratory infection (ARI) and obtained naso- and oropharyngeal samples for real-time reverse transcriptase polymerase chain reaction (RT-PCR). We used multivariable logistic regression to identify risk factors for ICU admission or death, adjusted for age and sex. Results From May 2008 to July 2012, among 6326 hospitalized ARI cases, 446 (7%) were positive for influenza: of those, 362 (81%) had influenza A and 84 (18%) had influenza B. Fifty nine percent of patients were aged ≤ 5 years, and 10% were aged ≥ 65 years. The median length of hospitalization was 5 days (interquartile range: 5). Eighty of 446 (18%) were admitted to the ICU and 28 (6%) died. Among the 28 deaths, 7% were aged ≤ 6 months, 39% 7–60 months, 21% 5–50 years, and 32% ≥ 50 years. Children aged ≤ 6 months comprised 19% of cases and 22% of ICU admissions. Women of child-bearing age comprised 6% of cases (2 admitted to ICU; 1 death). In multivariable analyses, Santa Rosa site (adjusted odds ratio [aOR] = 10, 95% confidence interval [CI] = 2–50), indigenous ethnicity (aOR = 4, 95% CI = 2–13, and radiologically-confirmed pneumonia (aOR = 5, 95% CI = 3–11) were independently associated with severe disease. Adjusted for hospital utilization rate, annual incidence of hospitalized laboratory-confirmed influenza was 24/100,000 overall, 93/100,000 for children aged < 5 years and 50/100,000 for those ≥ 65 years. Conclusions Influenza is a major contributor of hospitalization and death due to respiratory diseases in Guatemala. Further application of proven influenza prevention and treatment strategies is warranted

Factors associated with fatal cases of acute respiratory infection (ARI) among hospitalized patients in Guatemala

Abstract Background Acute respiratory infection (ARI) is an important cause of mortality in children and adults. However, studies assessing risk factors for ARI-related deaths in low- and middle-income settings are limited. We describe ARI-related death and associated factors among children aged < 2 years and adults aged ≥18 years hospitalized with ARI in Guatemala. Methods We used respiratory illness surveillance data in Guatemala from 2007 to 2013. ARI was defined as evidence of acute infection and ≥ 1 sign/symptom of respiratory disease in hospitalized patients. Clinical, sociodemographic, and follow-up data were gathered. Nasopharyngeal/oropharyngeal swabs were collected from patients with ARI and tested for 6 respiratory viruses; urine was collected only from adults with ARI and tested for pneumococcal antigen. Blood cultures and chest radiographs were performed at the physician’s discretion. Radiographs were interpreted per World Health Organization guidelines to classify endpoint pneumonia (i.e. suggestive of bacterial pneumonia). Multivariable logistic regression was used to compare characteristics of patients with fatal cases, including those who died in-hospital or were discharged in a moribund state, with those of patients with non-fatal cases. Results Among 4109 ARI cases identified in hospitalized children < 2 years old, 174 (4%) were fatal. Median age at admission was 4 and 6 months for children with fatal and non-fatal cases, respectively. Factors associated with fatality included low weight-for-age, low family income, heart disease, and endpoint pneumonia; breastfeeding and respiratory syncytial virus (RSV) detection were negatively associated with fatality. Among 1517 ARI cases identified in hospitalized adults ≥18 years, 181 (12%) episodes were fatal. Median age at admission was 57 years for adults with fatal and non-fatal cases. Low body mass index, male sex, kidney disease, and endpoint pneumonia were significantly more common among patients with fatal versus non-fatal cases. Conclusions Our findings highlight some of the factors that must be addressed in order to reduce ARI-related mortality, including promotion of good nutrition, breastfeeding, management and prevention of chronic comorbidities, and poverty reduction. Although no specific pathogen increased risk for death, endpoint pneumonia was significantly associated with fatality, suggesting that the pneumococcal conjugate vaccine could contribute to future reductions in ARI-related mortality

Using Standardized Interpretation of Chest Radiographs to Identify Adults with Bacterial Pneumonia--Guatemala, 2007-2012.

Bacterial pneumonia is a leading cause of illness and death worldwide, but quantifying its burden is difficult due to insensitive diagnostics. Although World Health Organization (WHO) protocol standardizes pediatric chest radiograph (CXR) interpretation for epidemiologic studies of bacterial pneumonia, its validity in adults is unknown.Patients (age ≥ 15 years) admitted with respiratory infections to two Guatemalan hospitals between November 2007 and March 2012 had urine and nasopharyngeal/oropharyngeal (NP/OP) swabs collected; blood cultures and CXR were also performed at physician clinical discretion. 'Any bacterial infection' was defined as a positive urine pneumococcal antigen test, isolation of a bacterial pneumonia pathogen from blood culture, or detection of an atypical bacterial pathogen by polymerase chain reaction (PCR) of nasopharyngeal/oropharyngeal (NP/OP) specimens. 'Viral infection' was defined as detection of viral pathogens by PCR of NP/OP specimens. CXRs were interpreted according to the WHO protocol as having 'endpoint consolidation', 'other infiltrate', or 'normal' findings. We examined associations between bacterial and viral infections and endpoint consolidation.Urine antigen and/or blood culture results were available for 721 patients with CXR interpretations; of these, 385 (53%) had endpoint consolidation and 253 (35%) had other infiltrate. Any bacterial infection was detected in 119 (17%) patients, including 106 (89%) pneumococcal infections. Any bacterial infection (Diagnostic Odds Ratio [DOR] = 2.9; 95% confidence Interval (CI): 1.3-7.9) and pneumococcal infection (DOR = 3.4; 95% CI: 1.5-10.0) were associated with 'endpoint consolidation', but not 'other infiltrate' (DOR = 1.7; 95% CI: 0.7-4.9, and 1.7; 95% CI: 0.7-4.9 respectively). Viral infection was not significantly associated with 'endpoint consolidation', 'other infiltrate,' or 'normal' findings.'Endpoint consolidation' was associated with 'any bacterial infection,' specifically pneumococcal infection. Therefore, endpoint consolidation may be a useful surrogate for studies measuring the impact of interventions, such as conjugate vaccines, against bacterial pneumonia

Ascertainment of pneumococcal pneumonia within hospital surveillance of acute respiratory infection (ARI), Guatemala, 2008–2012.

<p>Flow diagram of patients included in this analysis.</p

Hospitalized pneumococcal pneumonia incidence rates and proportion of acute respiratory infection (ARI) cases by age, Guatemala, 2008–2012.

<p>Incidence rates (bars) ranged from 2.75/100,000 (among 18–24 year-olds) to as high as 31.3 per 100,000 (among adults aged ≥65 years). Proportion of ARI positive for pneumococcus (line) was more stable than the incidence rate across age groups.</p

Characteristics of patients with pneumococcal pneumonia, n = 188.

<p>^ Includes asthma or lung disease</p><p>^^ Includes cardiovascular disease or hypertension</p><p>^† Oxygen saturation <90% in Santa Rosa and <88% in Quetzaltenango, adjusted for elevation</p><p>Characteristics of patients with pneumococcal pneumonia, n = 188.</p