Influenza related pneumonia in children under five years old in Indonesia : An analysis of the risk factors

Background : Pneumonia is more commonly among children under five years old and caused by several risk factors. Pneumonia causes 1.9 – 2.2 million children death worldwide every year, in which 1.3 million (81%) generally occurs in first 2 years of life. Seventy two percent of pneumonia occurs in children under five years old in 15 countries. Indonesia was the 7th highest in the world. The prevalence of pneumonia in Indonesia was 18.5/1000 population and only 1.6/1000 received treatment. Objective of the study is to elaborate the risk factors of the influenza related pneumonia in children under five years old. Method : The pneumonia control program in Ministry of Health focuses on early detection and treatment for bacterial pneumonia in community. Severe acute respiratory infection (SARI) can develop fatal pneumonia. We collected data from the pneumonia surveillance database in the Acute Respiratory Infection sub directorate. Results : Influenza related pneumonia was 13% of acute lower respiratory infection in pediatric. The number of children under five years old death estimation was 28,000-115,000 and 99% happened in developing countries. Conclusion : In Indonesia, proportion of influenza from SARI surveillance was 12% and mainly in children under five years old (36%). Pneumonia was 18% of SARI cases with positive influenza. The effect of Influenza become pneumonia remain unclear.


INTRODUCTION
Severe acute respiratory infection (SARI) can develop progressive pneumonia in few hours and cause fatal pneumonia in children under five years old.Pneumonia remains the most cause of death in children under five years old worldwide.Of 5.9 million children death globally, pneumonia was 16%.72% of pneumonia has happened in 15 countries.Indonesia was in 7th rank. 1 World Health Organization (WHO) estimated 1.9-2.2millions children death from acute respiratory infection (ARI) every year. 2,3neumonia as cause of death in 1.3 million children under five years old and 81% death occurred in two years of first life. 4According to Demography Health Survey 2012, infant mortality rate in Indonesia was 32/1000 live births and under five years old mortality rate was 40/1000 live births.Proportion of pneumonia death was 9.4%.Basic Health Survey (2013) got periods prevalence of pneumonia under five years old 18.5/1000 population and the children who got treatment only 1.6/1000. 5,68][9] One of SARI caused is influenza virus as important pathogen in public health.Influenza is also zoonotic infection such as Avian Influenza that circulates endemic in poultry, sometimes evoke an outbreak in human and can result pandemic.The most common prevalence of Influenza in school age children but the severe disease can happen in infant, elderly people, and high risk person with comorbid. 10,11Seasonal influenza was second common caused in children with pneumonia and substantial contribute to hospital admission and cause of death in children under five years old. 4,12Experience from influenza pandemic H1N1 2009 lead many countries including Indonesia, to raise pandemic awareness through Influenza Like Illness/ ILI and SARI surveillance.SARI was clinical syndrome of acute respiratory infection that caused by influenza virus or other pathogens. 10n high risk people such as children, elderly people, and chronic disease, influenza can be severe and fatal.There were about 3-5 million severe cases and 250-500 thousand of death every year. 13nfluenza outbreak can reached more than 49,000 of death and 200,000 people need hospital admission every year, only in USA.11WHO estimated 20% of hospitalized children under five years old with SARI and 90% of SARI was pneumonia.][15] Countries with four seasons like Europe and America have more clearly influenza data and the peak of Influenza was in winter.But the information was limited in tropical and subtropical developing countries.In WHO South East Asian Region (SEAR), influenza with severe pneumonia episode 273 thousand (78-1094 thousand) and proportion of severe cases was 5%, while death was about 49 thousand and proportion was 11.1%. 4In Indonesia, Influenza were identified 20.1% of ILI cases and 21.7% of SARI cases in 2003-2007. 16In 2011, influenza positive were confirmed 6% of SARI cases. 17In 2013-2015, influenza positive were confirmed 11.8% of SARI cases from six hospital sentinel site and 15% were pneumonia.40% of influenza positive were in age group 1-4 years. 18,19This proportion was high enough but still influenza related pneumonia was unrecognized and underreporting as well.Objective of the study is to elaborate the risk factors of the influenza related pneumonia in children under five years old.

METHOD
The pneumonia control program in Ministry of Health focuses on early detection and treatment for bacterial pneumonia in community.Severe acute respiratory infection (SARI) can develop fatal pneumonia.We collected data from the pneumonia surveillance database in the Acute Respiratory Infection sub directorate.

Etiology
The most common bacteria were Streptococcus pneumoniae (30-50%) and Haemophilus influenzae (10-30%) and both of them can be prevented by vaccine.In some severe cases caused by Staphylococcus aureus and Klebsiella pneumoniae. 9,21,22The most common virus were Respiratory Syncytial virus/ RSV in 15-40% hospitalized pneumonia in developing countries, followed by Influenza A and B, parainfluenza, Human metapnemovirus and adenovirus. 9,21sk Factors Definite risk factors were age less than two years, asplenia or hyposplenia, diabetes, Influenza, HIV, humoral immune defect, malnutrition, low birth weight, inadequate breast feeding, no measles vaccine, indoor air pollution and crowding.The likely risk factors were chronic diseases (asthma, neurologic disorder, tuberculosis), zinc deficiency, concomitant diseases, poverty, mother experience, mother age.3][24][25][26]

Symptoms
Mostly, people with mild Influenza has mild symptom and recovery in two weeks.Some will develop to severe outcome and need hospitalization.The highest severity was in infant and who have comorbid diseases.Acute symptoms and fever often persist for 7 to 10 days.Weakness and fatigue may linger for weeks.Influenza usually occurs in winter outbreaks or epidemics (in temperate climates).Fulminant fatal influenza viral pneumonia occasionally occurs; dyspnea, cyanosis, hemoptysis, pulmonary edema, and death may proceed in as little as 48 hours after the onset of symptoms. 24

DISCUSSIONS
Seasonal influenza circulates worldwide but only influenza A and B can cause outbreak in human and have vaccine to prevent it.Influenza A is more important pathogen that cause seasonal, endemic infections and periodic, unpredictable pandemics. 13,27,28According to seasonality, common pattern of RSV and Influenza were highest in rainy season, although Influenza circulates around the year. 9,19neumonia caused by combined of risk factors that associate with host, infection and environment. 21Influenza risk factors were children under five years old particularly children less than two years old, person with comorbid such as chronic lung diseases, hearth diseases, liver disease, kidney disease, diabetes, asthma, neurological disorders, blood disorders, HIV/AIDS, immune deficiency, obesity. 13,26o-pathogenesis between influenza and superinfection bacteria was based on multifactor.Virulence factor that showed virus has specific strain effect on host that which allows bacterial infection caused pneumonia.Influenza virus cause multiple changes in lung that can caused secondary bacterial invasion.Epithelial cells damaged, surfactant disruption, cell pieces into airway become access and source of nutrition to bacteria growth.Airway physiology changes reduce oxygen exchange, airway hyper reactive and reduce bacteria cleaning mechanism.Influenza virus can facilitate bacteria from upper respiratory inhale and invasion to lower respiratory. 29Influenza A viral replication peaks approximately 48 hours after inoculation into the nasopharynx and declines slowly, with little virus shed after about six days.The virus replicates in both the upper and lower respiratory tract.Even after the infectious virus can no longer be recovered, viral antigen can be detected in cells and secretions of infected individuals for several days.Non-fatal influenza viral infection predominantly involves the upper respiratory tract and trachea, but fatal cases of influenza usually show evidence of pneumonia. 24n pneumonia, alveoli filled with pus and fluid that cause disturbed oxygen exchange and dyspnea.Lung compliance reduce and will manifest as fast breathing.If condition getting worst, lung will more rigid and chest retraction appear.Viral infection signed by mononuclear cell accumulation in sub mucous and perivascular room that produce airway partial obstruction.Alveolar type II cell damage and surfactant production reduce so that appears hyaline membrane and lung edema. 6,29,30nfluenza can be manifest as asymptomatic to serious illness with systemic symptoms.
Seasonal influenza has sudden onset of fever (38-40˚C), cough, muscle ache, joint pain, sore throat and cold.Pneumonia can develop in few hours, usually caused by secondary infection.Pneumonia symptoms were dyspnea, cyanosis, lung edema, acute respiratory distress syndrome and death can process in 48 hours after the onset.][32] In Indonesia, pneumonia diagnosis base on clinical condition such as fast breathing and chest retraction.Age divided according to Integrated Management of Childhood Illness (IMCI) age group to determine fast breathing.The classification pneumonia by fast breathing which were age <2 months: ≥60 times/ minute; age 2-<12 months: ≥50 times/ minute; age 12-<60 months: ≥40 times/minute. 6,33Chest X-ray, blood test and culture, rapid diagnostic test for pneumococcal with immunochromatography assay, reverse transcriptase polymerase chain reaction/ RT-PCR, DNA assay as supporting examination can be used if available.5][36] Ultrasonography (USG) can diagnose accurately pneumonia cases in children and adolescence and can replace Chest X-ray for diagnoses. 30The diagnostic method such as Polymerase Chain Reaction (PCR) enhance new virus detection and vaccine for pneumococcal and Haemophilus influenzae reduce bacterial pneumonia and increase virus pneumonia. 9ostly, Influenza is mild and recovery in two weeks with supportive treatment such as nutrition and liquid and home care.Grossly, the children that treat as outpatient get oral antibiotic.In randomized study, 820 mild pneumonia in children with Amoxicillin 50 mg/weight two times a day as effective as three times a day.Nutrition for severe pneumonia or respiratory distress give through nasogastric tube or intravenous line.Tight monitoring is needed to avoid overhydration. 26Intravenous antibiotic such as Ampicillin or cephalosporin give to inpatient patient depend on local resistance. 26,30Treatment for Community Acquired Pneumonia were optimum supportive and effective antibiotic as soon as possible.Supportive treatments were oxygen, ventilator, volume resuscitation, vasopressor, nutrition can save life. 20,22ccording to Ministry of Health, severe pneumonia in health care center (Puskesmas) must refer to hospital as soon as possible after give prompt treatment such as oxygen, antibiotic first dose, antipyretic and other supportive drugs if available. 6ength of stay in pneumonia with abnormality of chest X-ray longer than normal chest X-ray. 35ntiviral for influenza can be used as treatment and prophylaxis to reduce serious complication and death. 24Ideally, antiviral given in first 48 hours since the onset.There were two class of drugs.First, Matrix 2 ion channel blocker (Adamantanes) which were Amantadine and Rimantadine, but about one third patient has drug resistant.Second, Inhibitor Neuraminidase consist of Oseltamivir and Zanamivir, while Peramivir and Laninamivir only have license in several countries.Oseltamivir dose in age 0-8 months was 6 mg/kg body weight per day, divided in 2 doses; age 9-23 months: 7 mg/kg body weight per day, divided in 2 doses; ≥24 months : 4 mg/kg body weight per day, divided in 2 doses; premature baby: 2 mg/kg body weight per day, divided in 2 doses for 5 days. 34neumococcal vaccine was recommended for age 7-12 months and given twice with 2 months interval.For age >1 year, it is given one time.Both age groups need booster one times after age >1 year or two months after the last time vaccine.For age >2 year only gives one times. 24,37hildren were primary reservoir for pneumococcal colonization in human, and eliminate carrier status will reduce transmission to population. 22nfluenza vaccine was recommended for children more than 6 months.Vaccinne was give protection for several months normally, because virus mutation gradually make population immune disappear after several years.Booster vaccine are recommend for high risk people. 24The most effective influenza vaccine if similar with circulate virus.WHO is always update vaccine compositions every two years.Since 2013-2014, quadrivalent vaccine compositions has been recomended to give more protection. 13nfluenza virus changes constantly and need surveillance to monitor virus influenza in human.Influenza surveillance is important to early detection and evaluate new virus variance or subtype. 13