To describe clinical characteristics and hs-CRP, procalcitonin, interleukinee-6 of severe viral pneumonia and co-infection with other viruses or/and bacteria among children under 5 years old at National Hospital of Pediatrics from January, 2015 to March, 2017.
Journal of military pharmaco-medicine no8-2019 RESEARCH ON CLINICAL CHARACTERISTICS AND hs-CRP, PROCALCITONIN, INTERLEUKINE-6 IN CHILDREN UNDER YEARS OLD WITH SEVERE VIRAL PNEUMONIA AND CO-INFECTION Nguyen Thi Ngoc Tran1; Do Quyet2; Dao Minh Tuan1 SUMMARY Objectives: To describe clinical characteristics and hs-CRP, procalcitonin, interleukinee-6 of severe viral pneumonia and co-infection with other viruses or/and bacteria among children under years old at National Hospital of Pediatrics from January, 2015 to March, 2017 Subjects and methods: Descriptive, cross-sectional study on 53 children under years old were diagnosed with severe viral pneumonia co-infection with other viruses or/and bacteria Results: Pneumonia caused by syncytial respiratory virus in 14 patients (26.4%), influenza A in 13 patients (24.5%), Adenovirus in 12 patients (22.6%), Rhinovirus in 10 patients (18.9%) and influenza B in patients (7.6%) Children could be co-infected with other viruses or/and bacteria Haemophilus influenza co-infection rate was the highest (19 patients = 45.2%), followed by Klebsiella pneumoniae and Pseudomonas aeruginosa (19.1%) The lowest rate of bacterial co-infection was Burkholderia cepacia and Staphylococcus aureus (1 case = 2.4%) In the bacterial co-infection group, rate of cyanosis was the lowest (20.6%); the highest rate of cyanosis was in the group of viral-bacterial co-infections (100.0%) The difference between three groups was significant (p < 0.05) There was no difference in other clinical characteristics and hs-CRP, procalcitonin, interleukine-6 among three groups (p > 0.05) Conclusion: The incidence of children with pneumonia had co-infection in syncytial respiratory virus group was the highest Children could be co-infected with other viruses or/and bacteria Haemophilus influenza co-infection rate was the highest The difference of cyanosis between three groups was significant There was no difference in other clinical characteristics and hs-CPR, procalcitonin, interleukine-6 among three groups * Keywords: Pneumonia; Co-infection; Children INTRODUCTION In Vietnam, on average, children get acute respiratory infections from - times every year, including - times of pneumonia [1] The number of children with pneumonia accounts for 30 - 40% of cases of examination and treatment in hospitals Death rate of pneumonia accounts for 75% of death cases from respiratory diseases and 30 - 35% of death cases National Hospital of Pediatrics Vietnam Military Medical University Corresponding author: Nguyen Thi Ngoc Tran (dr.ngoctran259@yahoo.com.vn) Date received: 04/09/2019 Date accepted: 11/10/2019 173 Journal of military pharmaco-medicine no8-2019 among children [1] The incidence of viral pneumonia is quite high, accounting for 60 - 70% [1] Common viruses that cause pneumonia are syncytial respiratory virus (RSV), influenza, Rhinovirus, Adenovirus [5] More than one-third of cases of viral and bacterial co-infection aggravate the disease [6, 7] Currently, the viral diagnostic method has many advantages to help identify the cause quickly and accurately such as fast antigen detection test, real-time PCR and multi-primed PCR with high sensitivity and specificity The study of factors evaluating severe conditions such as CRP (as well as hs-CRP), procalcitonin (PCT) and cytokines (such as interleukine-1 (IL-1), IL-6, IL-8, IL-10 and HMGB-1) will facilitate diagnosis, differential diagnosis (viral and bacterial infections), prognosis and appropriate treatment, avoiding misuse of antibiotic use Especially, IL-6 exhibits very specify for acute inflammation Up to now, no much studies about viral pneumonia co-infection and other inflammation factors in pneumonia due to co-infection with bacteria and other viruses in Vietnamese children have been carried out Therefore, we have conducted the project with aims: To describe the clinical characteristics and hs-CRP, PCT, IL-6 of severe viral pneumonia and co-infection with bacteria and/or other viruses in under years old children at National Hospital of Pediatrics from January, 2015 to March, 2017 174 SUBJECTS AND METHODS Subjects 53 patients under years old, who were diagnosed with severe viral pneumonia due to co-infection with bacteria and/or other viruses, were treated at National Hospital of Pediatrics from January, 2015 to March, 2017 * Exclusion criteria: - Patients were under month of age and older than years old - Patients had non-viral pneumonia (pneumonia after drowning, chemical pneumonia, aspiration pneumonia) - Patients had chronic, associated congenital diseases (airway malformation, congenital lung disease, liver failure, kidney failure ) - Patients were eligible to participate in the study but the parents or guardian did not agree to participate Methods - Study design: Descriptive, crosssectional study - Sample size: 53 patients * Diagnosis of severe viral pneumonia with co-infection: - Diagnosis of pneumonia: Patients were diagnosed with pneumonia according to WHO (2013) criteria: Cough or having difficulty in breathing, rapid breathing, intercostal muscle external retraction, cracker, crepitation, X-ray image of infiltrated parenchyma [4] - Diagnosis of severe pneumonia: A child with cough or having difficulty in breathing, plus at least one of the following main symptoms: Cyanosis or Journal of military pharmaco-medicine no8-2019 SpO2 < 90%, severe respiratory failure (wheezing and severe chest retraction) Signs of pneumonia with severe general signs such as not drinking or giving up or vomitting everything, coma or unconsciousness, seizures - Diagnosis of viral pneumonia with co-infection: Patients with two or more of the following tests are positive: Rapid test of influenza A, B, RSV, RT-PCR of influenza A, B, RSV, Adenovirus, Rhinovirus and bacterial culture are positive in nasopharyngeal fluid test * Study techniques: retraction, nasal flaring, head-bobbing with each breath, intercostal muscle contraction, rales in the lungs +.Other symptoms: Skin rash, conjunctivitis, hepatomegaly, vomiting, diarrhea - Subclinical: + Index: hs-CRP, PCT, IL-6, PaO2 + Rapid test for influenza A, B, RSV; RT-PCR for Adenovirus, Rhinovirus + Bacterial culture * Criteria of evaluation applied in the study: - hs-CRP: Normal: ≤ 0.5 mg/dL - Clinical symptoms: + Systemic symptoms: Temperature, breathing rate, heart rate, weight, SpO2 - PCT: Increase: > 0.05 ng/mL; normal: ≤ 0.05 ng/mL + Functional symptoms: Cough, wheezing, runny nose, vomiting, convulsions - IL-6: Unit pg/mL (study) + Examination of respiratory entity symptoms: Difficulty in breathing, chest - Microbiological test: Negative or positive - PaO2: Normal 70 - 99 mmHg * Data analysis: By STATA 14.0 software RESULTS During the study period from January, 2015 to March, 2017, there were 53 patients with viral pneumonia co-infected with bacteria and/or viruses Table 1: Characteristics of microbiology (n = 53) baterium bacteria bacteria virus baterium + virus bacterium + viruses n n n n n n RSV (n = 14) 2 Influenza A (n = 13) 0 Adenovirus (n = 12) Rhinovirus (n = 10) 0 Influenza B (n = 4) 0 0 Virus Among 14 children with RSV co-infection, cases infected only bacterium In 13 children with influenza A infection, children infected with virus In the groups of children with Adenovirus, Rhinovirus and influenza B, the majority number of children were infected with only bacterium 175 Journal of military pharmaco-medicine no8-2019 Table 2: Charateristics of bacterial co-infection (n* = 42) Patients with each type of bacteria (n = 48) Percentage of co-infected patients (%) Percentage of all patients (%) Haemophilus influenza 19 45.2 9.4 Klebsiella pneumoniae 19.1 4.0 Pseudomonas aeruginosa 19.1 4.0 Streptococcus pneumoniae 16.7 3.5 Acinetobacter baumannii 9.5 2.0 Burkholderia cepacia 2.4 0.5 Staphylococcus aureus 2.4 0.5 Bacterial co-infection (*n: Number of patients with severe viral pneumonia co-infection) The highest incidence was Haemophilus influenza co-infection (45.2%), followed by Klebsiella pneumoniae and Pseudomonas aeruginosa (19.1%) The lowest incidences were Burkholderia cepacia and Staphylococcus aureus (1 case = 2.4%) Table 3: Clinical characteristics of patients with co-infected pneumonia (n = 53) Co-infection Bacteria (n = 34) Symptoms Systemic Respiratory Others Bacteria + virus (n = 8) p n % n % n % Fever 30 88.2 10 90.9 75.0 0.51** Tachycardia 20 58.8 10 90.9 50.0 0.10** Runny nose 14 41.2 36.4 12.5 0.38* Wheezing 29 85.3 81.8 75.0 0.76* Grunting 2.9 18.2 25.0 0.06* Poor feeding 23 67.6 10 90.9 100.0 0.08* Not feeding 5.9 9.1 12.5 0.78* Not drinking 5.9 9.1 12.5 0.78* Irritating and crying 11 32.4 9.1 50.0 0.17* Convulsions 0.0 9.1 12.5 0.12* Cyanosis 20.6 45.5 100.0 < 0.01* Diarrhea 11 32.3 9.1 12.5 0.33* Hepato-splenomegaly 11.8 27.3 37.5 0.15* Skin rash 2.9 18.2 12.5 0.13* (*: Fisher’s exact test) 176 Virus (n = 11) Journal of military pharmaco-medicine no8-2019 Among the co-infection groups, the cyanosis rate was the lowest with 20.6% The highest incidence was found in the co-infection with bacteria and viruses (100.0%) The difference between three groups was significant (p < 0.05) There was no difference in other characteristics among three groups (p > 0.05) Table 4: Characteristics of respiratory failure in co-infected pneumonia patients (n = 53) Co-infection Bacteria (n = 34) Characteristics SpO2 PaO2 Virus (n = 11) Bacteria + virus (n = 8) n % n % n % Grade (SpO2 90 - 95%) 22 64.7 45.5 37.5 Grade (SpO2 85 - 90%) 26.5 27.3 25.0 Grade (SpO2 < 85%) 8.8 27.3 37.5 Normal 11 32.4 27.3 50.0 Mild respiratory failure 14 41.2 27.3 37.5 Moderate respiratory failure 17.6 18.2 0.0 Severe respiratory failure 8.8 27.3 12.5 p 0.23* 0.61* (*: Fisher’s exact test) There was no difference in respiratory failure groups among three groups (p > 0.05) Table 5: Subclinical characteristics in co-infected pneumonia patients (n = 53) Co-infection Index Bacteria (n = 34) th Median 25 - 75 hs-CRP (mg/dL) 12.7 PCT (ng/mL) IL-6 (pg/mL) Virus (n = 11) th th Median 25 - 75 2.4; 50.2 4.1 2.3 0.2; 5.4 3.4; 16.3 Bacteria + virus (n = 8) th th p th Median 25 - 75 0.3; 8.2 4.0 2.1;17.9 0.13* 0.4 0.2; 1.0 0.4; 3.6 0.19* 10.6 5.2; 21.1 24.8 7.7; 91.1 0.39* (*: Kruska-Wallis test) hs-CRP had the fastest increase in the co-infection group (median = 12.7), followed by the co-infection with virus group (median = 4.1), co-infection with viruses and bacteria (median = 4.0) Similarly, PCT had the highest increase in the co-infection group only (median = 2.3), followed by the co-infection with viruses and bacteria (median = 1.0), the lowest one was in the co-infection group with virus only (median = 0.4) IL-6 had the highest one in the co-infection group with both virus and bacteria (median = 24.8), followed by the co-infection group with virus only (median = 10.6), the lowest increase was in the co-infection group with bacteria (median = 5.4) However, all differences were not significant (p > 0.05) 177 Journal of military pharmaco-medicine no8-2019 DISCUSSION Characteristics of viral-bacterial infection co-infected Childhood viral pneumonia is a common illness, with an incidence of 36 - 40 episodes/1,000 children/year in those < years old The concomitant viral-bacterial infection can cause the severe pneumonia in children O'Brien K.L (2000) determined that preceding influenza infection (H1N1) was directly associated with pneumococcal illness in children [8] Juven had shown that more than one-half of all community-acquired pneumonia were infected with bacteria and viruses [9] In this study, in 14 patients with RSV infection, patients had co-infection with bacterium In 13 children with influenza A infection, children were infected with virus In the groups infected with Adenovirus, Rhinovirus and influenza B, the majority number of children had only bacterial co-infection The results also showed that the incidence of Haemophilus influenza was the highest (45.2%), Klebsiella pneumoniae and Pseudomonas aeruginosa 19.1% The lowest incidences were in Burkholderia cepacia and Staphylococcus aureus (1 case) In addition, in the RSV infective group, there were cases of co-infection with two or more bacteria and case of co-infection with one type of virus and one type of bacteria Meanwhile, in Adenovirus infective group, the number of infected children were and cases, respectively Comparing with the Andrew’s study (2001), it was found that, in 58 patients 178 who identified the cause of pneumonia, 65% of patients infected with virus, 35% were co-infected [10] In a recent study by Nascimento et al (2013) on 25 children with pneumonia having pleural effusion showed that 22% of cases of co-infection with bacteria and virus, of which co-infection with parainfluenza 1/3 and influenza A, RSV and influenza A were common [11] Juven (2000) found evidence of viral-bacterial infection in 30% of the children with pneumonia, a result which was in agreement with previous studies [9] According to study by Olli Ruuskanen, 49% of pneumonia cases in the study group were viral infected, of which the number of children infected with Rhinovirus was the highest at 18%, RSV was 16%, influenza A was %, influenza B and Adenovirus were 8% [6] Li Li et al (2016) studied 1,702 children with lower respiratory tract infection, the co-infection rate among Rhinovirus-type C group was 61% [12] Research by Dao Minh Tuan and Nguyen Thi Ngoc Tran on 56 children with Adenovirus pneumonia showed that patients could be co-infected with virus and other bacteria (16/56 children with Rhinovirus, 14 with CMV, with RSV), infected with influenza A, influenza B, 10 infected with bacteria, infected with Mycoplasma) [2] Children with broncho-pneumonia infected with Adenovirus had a high rate of co-infection Rhinovirus was the highest co-infection, the second was CMV co-infection, the third was bacterial co-infection This showed the importance Journal of military pharmaco-medicine no8-2019 of isolating children, not only avoiding the spread of Adenovirus to other children but also helping them to avoid new infections [2] Tran Thi Thuy's study showed that Adenovirus pneumonia patients had 9.0% of bacterial co-infection: cases of pneumococcal infection, cases of Haemophilus influenza infection, case of Moracela catarhalis infection There were 28.0% of cases with virus co-infection: mainly Rhinovirus (25.0%), RSV (4.0%) and influenza A/B (2.0%) [3] In general, the incidence of co-infection with bacteria and/or virus was the highest in the RSV group, the lowest in the influenza B group and the Rhinovirus group Clinical characteristics and subclinical This study showed that the majority of clinical and subclinical symptoms appeared to be non-specificed among co-infection groups (including bacterial co-infection, viral co-infection and co-infection with bacteria and viruses) While symptoms such as fever, tachycardia and runny nose were different between groups of infants infected with the virus alone, these symptoms did not differ between co-infected groups except cyanosis Among the co-infection groups, the lowest cyanosis rate was 20.6%; the highest rate was found in the group of bacteria and virus infections (100.0%) The difference between the two groups was statistically significant (p < 0.05) The results of the subclinical analysis also showed that there were no significant differences between the three groups in terms of pulmonary X-ray, subclinical indicators such as Hb, hs-CRP, PCT or IL-6 The co-infected group only had a higher number of white blood cells than the co-infected group According to Toikka, it was shown that the increase of serum PCT, CRP and IL-6 had little value in the differences of bacterial and viral pneumonia in children However, in some patients with very high serum PCT, CRP or IL-6, bacterial pneumonia was possible [13] CONCLUSION Children with pneumonia with co-infection in RSV group had the highest incidence The child may be co-infected with other viruses or bacteria Haemophilus influenza co-infection had the highest rate The differences between the three groups for cyanotic symptoms were statistically significant There were no differences in other clinical features and hs-CPR, PCT, IL-6 between the three groups REFERENCES T Quy, T.T.H Van Bronchopneumonia Respiratory, Pediatric Lectures Medical Publisher Hanoi Medical University 2013, Vol 1, pp.390-396 Nguyen Thi Ngoc Tran, Dao Minh Tuan Research on some epidemiological, clinical, subclinical and prognostic factors of mortality in Adenovirus pneumonia patients at National Hospital of Pediatrics Vietnam Journal of Medicine 2017, 461 (2), pp.120-123 Tran Thi Thuy Research on epidemiological, clinical and subclinical characteristics of Adenovirus pneumonia in children from months to under years old at National Hospital of Pediatrics Master Thesis of Medicine Haiphong University of Medicine and Pharmacy 2018 179 Journal of military pharmaco-medicine no8-2019 WHO Guidelines for the management nd of common childhood illnesses edition Cough or Difficulty in Breathing 2013 Bezerra P.G et al Viral and atypical bacterial detection in acute respiratory infection in children under five years PLoS One 2011, (4), p.e18928 Ruuskanen O et al Viral pneumonia The Lancet 2011, 377 (9773), pp.1264-1275 Pavia A.T Viral infections of the lower respiratory tract: Old viruses, new viruses, and the role of diagnosis Clin Infect Dis 2011, 52, pp.S284-S289 O'Brien K.L et al Severe pneumococcal pneumonia in previously healthy children: The role of preceding influenza infection Clin Infect Dis 2000, 30 (5), pp.784-789 Juven T et al Etiology of communityacquired pneumonia in 254 hospitalized 180 children Pediatr Infect Dis J 2000, 19 (4), pp.293-298 10 Pavia A.T Viral infections of the lower respiratory tract: Old viruses, new viruses, and the role of diagnosis Clin Infect Dis 2011, 52 (Suppl 4), pp.S284-289 11 Nascimento-Carvalho C.M et al Respiratory viral infections among children with community-acquired pneumonia and pleural effusion Scandinavian Journal of Infectious Diseases 2013, 45 (6), pp.478-483 12 Li L et al An epidemiological study on human Rhinovirus C in hospitalized children with respiratory tract infections Zhongguo Dang Dai Er Ke Za Zhi 2016, 18 (11), pp.1094-1099 13 Toikka P et al Serum procalcitonin, C-reactive protein and interleukine-6 for distinguishing bacterial and viral pneumonia in children The Pediatric Infectious Disease Journal 2000, 19 (7), pp.598-602 ... majority of clinical and subclinical symptoms appeared to be non-specificed among co-infection groups (including bacterial co-infection, viral co-infection and co-infection with bacteria and viruses)... 0 .5 Bacterial co-infection (*n: Number of patients with severe viral pneumonia co-infection) The highest incidence was Haemophilus influenza co-infection ( 45. 2%), followed by Klebsiella pneumoniae... 36. 4 12 .5 0.38* Wheezing 29 85. 3 81.8 75. 0 0. 76* Grunting 2.9 18.2 25. 0 0. 06* Poor feeding 23 67 .6 10 90.9 100.0 0.08* Not feeding 5. 9 9.1 12 .5 0.78* Not drinking 5. 9 9.1 12 .5 0.78* Irritating