Nghiên cứu đặc điểm lâm sàng, cận lâm sàng và HS CRP, procalcitonin, interleukin 6 trong viêm phổi nặng do vi rút ở trẻ em dưới 5 tuổi tt tiếng anh

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RATIONALE
1. The necessary of thesis
According to a World Health Organization (WHO) report, in 1997,
3.9 million people worldwide died from acute lower respiratory
infections and 394 million new cases. In Vietnam, on average, each child
can contract acute respiratory infections 3 to 5 times, pneumonia
accounts for 30-34% of cases. The cause of pneumonia accounts for
75% of deaths from respiratory diseases and 30-35% of deaths among
children. The prevalence of pneumonia virus in children is quite high,
accounting for 60-70%. More than one-third of cases of co-infection
with viruses and bacteria will worsen the condition.
Advanced virus diagnostic techniques is able to find out the causes
quickly and to identify virus types accurately such as rapid test for virus
antigen, Real-time. PCR, multi-primer PCR.
Quantifying a number of factors such as hs-CRP, Procalcitonin and
Interleukin-6 helps to assess the severity of the disease, diagnosis,
prognosis and appropriate treatment in order to avoid the spread of
antibiotic use.
In Vietnam, there have been separate studies on pneumonia caused by
each virus as well as some factors reflecting inflammation in viral
pneumonia. However, there has not been a full review of the severe or
co-bacterial viral pneumonia and the association between viral
pneumonia and a number of factors that reflect childhood inflammation.
Therefore, we conducted the topic "Research clinical, subclinical
characteristics and hs-CRP, Procalcitonin, Interleukin 6 in severe
viral pneumonia in children under 5 years old" with two objectives:
1. Research clinical and subclinical characteristics of severe viral
pneumonia in children under 5 years old from 2/2015 to 2/2017.
2. Assess the relationship between hs-CRP, Procalcitonin,
Interleukin-6 and clinical, subclinical, treatment results, viral etiology

in severe viral pneumonia in children under 5 years old.
2. Practical significance and new contributions of the thesis
Bronchitis is a common disease in children, a leading cause of
morbidity and mortality, especially in children under 5. The cause of
viral pneumonia accounts for 60-70%. With the development of science,


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there are many methods such as Real-time PCR, multi-primed PCR with
high sensitivity and specificity to accurately diagnose viral pneumonia,
and markers such as hs-CRP, Procalcitonin, Interleukin-6 to assess the
condtion of patient for better treatment and prognosis.
The study identifies the viral etiology model in both single and
multiple infections with 73.8% of children infected with a single virus,
including RSV infection (36.1%), influenza A (24.3%), Adenovirus
(19.8%), influenza B (6.9%) and 53 children (26.2%) were co-infected
with bacteria and / or viruses. The thesis stated the correlation between
hs-CRP, PCT, IL-6 inflammation index and the difference of some
clinical and subclinical signs with these inflammatory markers. The
research is believed to be reliable because of being conducted at the
largest pediatric center in Vietnam. Therefore the thesis is very practical,
thesisal and scientific.
3. The thesis structure
The thesis is presented in 124 pages including: Introduction (2
pages), overview (38 pages), subjects and methods (16 pages), results
(39 pages), discussion (26 pages), conclusions (2 pages) and
recommendations (1 page). The thesis consists of 47 tables, 6 charts, 4
illustrative figures. The thesis has 135 references, including 38
Vietnamese, 97 English.
Chapter 1

OVERVIEW

1.1. Definition
1.1.1. Definition of Pneumonia
According to WHO: Pneumonia is a disease usually caused by
viruses or bacteria. Pneumonia is divided into two types: pneumonia
severe and not severe depending on the clinical. Antibiotics are often
used in pneumonia and severe pneumonia. Severe pneumonia requires
special care such as oxygen breathing and hospitalization.
1.1.2. Definition of viral pneumonia
- Viral pneumonia: is a pneumonia caused by a viral infection in the
lower respiratory tract. The disease usually occurs in the winter and
spring. The invasive virus causes irritation, swelling, epithelial
desquamation and airway obstruction. The typical lesions in pneumonia


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are alveoli and small air passages filled with fluid, mucus or pus
reducing or lose gas exchange function that results in respiratory failure.
1.1.3. The definition of hs-CRP, PCT and IL-6
1.3.1.1. Reactive C protein (CRP)
CRP is known as a marker of inflammation, the sensitivity of hsCRP has higher than that of CRP, especially in low concentration
samples, so it has better diagnostic value of inflammation.
1.3.1.2. Procalcitonin (PCT)
PCT is a specific marker for bacterial and septicemia. PCT helps
distinguish between infected and non-bacterial infection, thereby
shortening the time of diagnosis, distinguishing bacterial or viral
infections.
1.3.1.3. Interleukin 6
Interleukin 6 (IL-6) is an interleukin that acts as an important

inflammatory cytokine during the acute inflammatory phase.
1.2. Reasons
1.2.1. Causes of pneumonia
1.2.2. Causes of viral pneumonia
- Pneumonia-causing viruses: influenza virus, sub-influenza virus,
respiratory syncytial virus, Adenovirus.
- Virus rarely causes pneumonia: Rhinovirus, Coronavirus.
- The virus causes systemic illness, pneumonia complications:
Herpes, chicken pox, measles, Cytomegalovirus…
1.3. Mechanism of pathogenesis of viral pneumonia
1.3.1. Infiltration of virus at airway
1.3.2. Cell destruction and inflammatory response
1.3.3. Recovery after viral infection
1.4. Symptoms of viral pneumonia
1.4.1. Epidemiological factors
- Living in an infected area
- Contact with other children or adults infected with the virus
1.4.2. Clinical symptoms
+ Fever: high fever fluctuates or reduces body temperature in young
children, fatigue, crying, dry lips (66.9 - 87%)
+ Cough: dry cough or cough with a lot of mucus secretion (71.967.7%)
+ Wheezing (41.1%)
+ Runny nose (61.6%)


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+ Rapid breathing with age (92%)
+ Dyspnea, thoracic recess (73%), nasal fluttering, head nodding
with breathing, intercostal muscle contraction, receding concave
(53.1%)

+ Breathing Oxygen support (56.12%)
+ Ventilator support (3.06%)
+ Vomiting (24.2-22.6%)
+ Diarrhea (15.7 - 4.3%)
+ Skin rash (4.3%)
+ Other symptoms: Fatigue, poor appetite, sweating, muscle and
joint aches (57.1%).
+ The most common bacterial pneumonia is Streptococcus
pneumonia.
1.4.3. Subclinical symptoms
- Blood formula: when being infected pneumonia, the number of
white blood cells <10 G/L, usually the cause of virus.
- Hs-CRP: usually <6 mg/l, there are studies that take hs-CRP
values <20 mg/l. If a secondary bacterial infection occurs, hs-CRP
increases.
- PCT: suggest viral pneumonia when PCT <0.1 µg/L.
- X-ray: often shows interstitial lesions on both sides of the lung.
1.5. Diagnoses
1.5.1. Diagnoses of pneumonia
1.5.2. Diagnoses of severe viral pneumonia
A Children have a cough or difficulty in breathing accompanied by
at least one of the following main symptoms:
- Cyanosis or SpO2 <90%.
- Severe respiratory distress
- Signs of pneumonia with severe general signs:
+ Unable to drink or breastfeed.
+ Coma or not awake.
+ Convulsions.
- Some or all other signs of pneumonia.
- Inflammation of the upper respiratory tract syndrome.

- Symptoms in the lungs: wheezing, rapid breathing, shortness of
breath. Lungs have moist rales, snoring rashes.
- X-ray: image of pneumonia
- Finding the virus in nasal fluid, dysentery, phlegm


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1.6. Treatment of severe viral pneumonia
1.6.1. Anti-respiratory depression
1.6.2. Symptomatic treatment and support
1.6.3. Anti-bacterial infection
1.6.4. Treatment of the cause
1.7. Pneumonia due to some common viruses in children
1.7.1. Influenza virus
1.7.2. Respiratory syncytial virus
1.7.3. Adenovirus
1.7.4. Rhinovirus
1.8. Co-infected pneumonia.
1.8.1. Pneumonia is co-infected with viruses and bacteria.
1.8.2. Mechanism of co-infection, secondary infection
1.9. Inflammatory markers
1.9.1. Hs-CRP
1.9.2. Procalcitonin
1.9.3. Interleukin 6
1.9.4. Roles and mechanisms of some biological markers
1.10. Research situation of viral pneumonia and
inflammatory markers in children
1.10.1. Researches in the world.
In 1986, Mullis K. and et al. proposed the basic method for running
PCR, a process in which DNA can be artificially multiplied by multiple

replications by DNA polymerase. In 2011, Ruuskanen O. and et al.
published a reasearch on viral pneumonia by PCR that showed the coinfection with viruses and bacteria in one third of cases. Huijskens E.G.
and et al. has studied and evaluated the diagnoses of viral pneumonia in
children by real-time PCR. In the 1990s, the number of drugs used to
treat viral infections increased, especially antiretroviral drugs.
Amantadine, the first systemic antiviral drug, was used in 1966.
Ribavirin, Aerosol (1985), Alfa Interferon (1986), Foscarnet (1991),
Rimantadine (1993) and Fomivirsen (1998). Researches and
understanding of the physiological and pathophysiological role of
cytokine have gained significant achievements. Cytokine is involved in
many biological processes in the body such as embryogenesis,
reproduction, hematopoiesis, immune response, inflammation.
1.10.2. Researches in Vietnam.


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After the application of real-time PCR and real-time PCR, there
have been many researrches on viruses causing respiratory diseases in
children in recent years. However, rsearsches go into each virus such as
Adenovirus, respiratory syncytial virus, H1N1 flu causing bronchitis in
children. Tran Anh Tuan's study (2012) on the role of viruses in acute
bronchiolitis in children.
Research on application of xTAG multi-PCR technique to diagnose
the causes of respiratory infections in children at National Children’s
Hospital in 2012-2013 to identify the infection status of 18 common
viruses, and it also shows co-infection between viruses and bacteria.
Vietnam has conducted a number of marker tests that reflect the
condition of inflammation. In 2007, author Bui Binh Bao Son and et al.
published a research on blood PCT concentration in 50 children from 2
months to 5 years old suffering pneumnia. In addition, there are also

other researches related to PCT such as research on PCT characteristics
in the diagnosis of neonatal sepsis by Tran Thi Lam and et al. research
on the role of PCT in diagnosing the differences between pus
meningitis and encephalitis aseptic in children published by author Tran
Kiem Hao and et al. in 2014. Research on prognostic value of TNF-α,
IL-β, IL-6 and IL-10 in septic shock in 74 children by Phung The
Nguyen and et al. at Children's Hospital 1. Research on IL-concentration
6, TNF-α in serum of 30 pediatric patients with autoimmune arthritis in
polyarthritis in National Children’s Hospital by Le Quynh Chi .
Chapter 2
SUBJECTS AND METHODS
2.1. Research subjects
Patients, from 1 month to under 5 years old, have been diagnosed
with severe viral pneumonia according to WHO-2013 standards and
treated at National Children’s Hospital from February 2015 to February
2017.
2.1.1. Criteria for selecting research subjects
2.1.1.1. Diagnosis of pneumonia
2.1.1.2. Diagnosis of severe viral pneumonia
The Children have a cough or difficulty in breathing accompanied
by at least one of the following main symptoms:
- Cyanosis or SpO2 <90%.
- Severe respiratory distress (moaning and heavy chest recession ...)


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- Signs of pneumonia with severe general signs:
+ Unable to drink or breastfeed.
+ Coma or not awake.
+ Convulsions.

- Some or all other signs of pneumonia.
- Inflammation of the upper respiratory tract syndrome.
- Symptoms in the lungs: wheezing, rapid breathing, shortness of
breath. Lungs have moist or moist rales, snoring rashes.
- X-ray: image of pneumonia
- Finding the virus in nasal fluid, dysentery, phlegm
2.1.2. Exclusion criteria
- Children under 1 month of age and older than 5 years.
- Patients with non-viral pneumonia (eg pneumonia after drowning,
choking oil, pneumonia ...).
- Patients with pneumonia do not have severe signs.
-Patients with chronic, congenital diseases (such as: airway
malformation, congenital lung disease, liver failure, kidney failure ...).
- Patients are eligible to participate in the study but the family does
not agree to participate.
2.2. Research methods
2.2.1. Research design
Described cross section research
2.2.2. Research sample size:
- Formula to calculate study sample size
Where:
n: Sample size
p: The incidence of viral pneumonia (p = 0.597).
Z21-α/2: 1.96 with 95% confidence
Δ: Accuracy, Δ = 0.05.
- According to calculations, the number of samples needed is n>192
patients.
- In this research, a sample size of 202 children was selected
- Methods to choose convenient samples.
2.2.3. Research parameters

2.2.3.1. General characteristics of the research subjects
- Age, gender


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- History: obstetrics, nourishment, immunization, disease,
treatment.
2.2.3.2. Clinical:
- Check and find signs of the whole body: temperature, breathing
rate, heart rate, weight, SpO2 ...
- Examination of functional symptoms: cough, wheezing, runny
nose
- Physical examination of respiratory symptoms
+ Difficulty breathing, chest shrinkage, fluttering nose, nodding
head with breathing, intercostal muscle pull, receding concave: yes or no
+ Listen to lung rales: yes or no
- Subclinical: Blood counts, hs-CRP, PCT, IL-6, Blood gases
+ Chest X-ray
- Microbiological tests:
+ Adenovirus, Rhinovirus: performed by real-time PCR
+ Influenza A, B, RSV: implemented by rapid test method or RT-PCR
+ Transplanting count, classify bacteria and make antibiotics.
2.2.4. Criteria for evaluating research parameters
2.2.4.1. Evaluating clinical symptoms
2.2.4.2. Evaluating subclinical results
- Radiographs of the heart and lungs:
+ The fuzzy image has localized system in 1-2 lung lobes.
+ The watermark does not have a scattered system in the area of the
lungs and around the navel, asymmetry.
+ Sometimes the image is grid or nodular lesions, sometimes the

blur is very small, not more than one lung segment, less dense, gathering
like butterfly wings in pulmonary edema.
+ In children, there may be enlarged swollen umbilical lympho
nodes.
- Virus test:
2.2.4.3. Treatment results:
* Discharge:
- No respiratory depression
- Children eat well, are overall good condition
- Blood test, chest X-ray examination is stabel
- Children may take medicine or have completed a course of
injections of antibiotics


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- Parents understand the signs of pneumonia, risk factors and when
is to return to the hospital.
* Support, reduction: patients with stable condition , can be treated
at home.
* Department transfer, hospital transfer: Patients who get rid of
severe pneumonia, suffer other diseass must be transferred to other
department or hospital.
* Death: the patients die at the hospital or request to die.
2.2.5. How to conduct
2.2.5.1. Clinical
- Built up medical sample that is appropriate for the research
subjects . Develop research consent form.
- Patients are closely monitored for changes in daily clinical
symptoms and early detection of possible complications.
- Each patient has a separate record with all information related to

the thesis.
2.2.5.2. Subclinical
- Quantification of hs-CRP was determined by turbidity
measurement using Olympus AU 2700.
- PCT quantification was determined by luminescent immunization
method, running on ADVIA Centaur machine of Siemens.
- Quantifying IL-6 when patients are hospitalized with BioRad's
Bio-Plex Protein Array System.
- Test for finding the primary causes: Quick Test or RT-PCR for
Influenza A, B, RSV, Adenovirus, Rhinovirus
2.3. Methods of data analyzing and processing
Data were processed by STATA 14.0 software
The statistical algorithms are used in this thesis as follows:
- Avergae sample calculation (), standard deviation (SD), median,
T-student test, Multiple average comparision, test ꭓ2, Fisher, two
median comparision, calculating sensitivity, specificity, cut-point by
analyzing ROC curve, evaluating correlation coefficient
2.4. Medical ethics:
- The management board of the National Hospital of Pediatrics and
Department of Respiratory granted permission for post-graduate student
to carried out this research.


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- Patient's parents are informed of the purpose and content of the
research, in order to ensure the commitment and acceptance of the
patient's family.
- Patients are guaranteed the rights of comprehensive examination
and evaluation. Their personal information is maintained safely.
- Special tests IL-6 are self-funded by post-graduate student.

2.5. Research process flowchart


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Chapter 3
RESEARCH RESULTS
From February 2015 to February 2017, the research was conducted
in 202 patients with severe viral pneumonia who were treated in the
National Children’s Hospital.
3.1. Research clinical and subclinical characteristics of severe viral
pneumonia in children under 5 years old.
3.1.1. Some common characteristics of pediatric patients
3.1.1.1. Age and gender
- 124 male and 78 female. Male/female ratio = 1.59/1
- Patients are mostly under 12 months of age (76.7%). The average
age is 8.4 months, the lowest is 1 month and the highest is 48.7 months
3.1.1.2. Time of illness: mainly from February to April (46.0%).
3.1.1.3. Obstetric history: The proportion of children who are
underweight at birth (<2500g) is 19.8%. There are 19.8% of premature.
3.1.1.4. History of nutrition and vaccination: 33.7% of children were
malnourished, only 74.3% of children were vaccinated according to the
schedule.
3.1.1.5. History of illness: 25.7% of children have respiratory illness.
3.1.1.6. History: The average number of days of being ill before having
treatment in hospital is 6.89 days, There are 71.8% of children with
number of day of being ill ≤ 7 days, 41.1% are inpatient and 26.2% are
outpatient before being treated in the hospital.
3.1.2. Clinical and subclinical characteristics
3.1.2.1. Clinical characteristics:

- 71.8% of children have fever symptoms
- The rate of children having cough is 100%, runny nose is 39.6%;
wheezing is 83.7%.
- Physical symptoms, the most common ones are tachypnea,
thoracic receding, moist lung in 100%;


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NUMBE R OF PAT IE NT S

3.1.2.2. Subclinical characteristics:
- The average concentration of IL-6 in the researched group is 28.2
± 81.7 (pg / ml), the lowest value is 0, the highest value is 500.
- The average concentration of PCT is 1.7 ± 4.2 (ng / ml), the
lowest value is 0.01, the highest value is 44.0.
- Average hs-CRP value in theresearched group is 15.6 ± 31.5 (mg /
dl), median is 4.2, the minimum value is 0.1, the highest value is 273.

5.00%
21.30%
Interstitial
lesions

73.70%
Blurred
lesions

Other lesions

Figure 3.3. Lung X-ray damage (n = 202)
Comment: 149 patients with fuzzy lesions, 43 patients with
interstitial lung lesions, 10 patients with other injuries
- hs-CRP concentration > 6 mg/l is 43.1%; PCT concentration >0.5
ng/ml is 50.0%.
- 19.3% had moderate respiratory failure and 8.9% had severe
respiratory failure.
3.1.2.3. Virus and bacterial characteristics
The majority of children has RSV (36.1%), followed by Influenza A
(24.3%) and Adenovirus (19.8%). The percentage of children suffered
Influenza B is thelowest at 6.9%. There are 149 children infected with
the virus, 53 children (26.2%) are infected with bacteria or/and viruses.
Table 3.13. Co-infection characteristics (n = 53)
1
1
Gran
1
1
BC
BC
d
2 BC 3 BC
BC
VR
1
2
Total
Virus
VR
VR

Total Total Total Total Total Total Total
RSV
8
2
1
2
1
0
14
Influenza A 5
0
0
6
0
2
13
Adenovirus 6
0
1
3
2
0
12


13
Rhinovirus 7
0
0
0

3
0
10
Influenza B 4
0
0
0
0
0
4
Comment: Among 14 children with RSV co-infection, 8 out of 14
cases infecte withonly 1 bacteria. 6 In 13 children who suffers Influenza
A co-infection the number of children co-infected with 1 virus, 6 out of
13, the highest rate..
- The highest incidence of H. influenza co-infection (45.2%),
followed by K. pneumoniae and P. aeruginosa (with 19.1%). The lowest
are B. cepacia and S. aureus (with 2.4% equals 1 case).
3.2. Evaluating the relationship between hs-CRP, PCT, IL-6 and
clinical, subclinical, treatment results, viral etiology in viral
pneumonia in children under 5 years old.
3.2.1. Relationship between clinical, subclinical characteristics and
etiology.
- 100% of children had cough, fever, runny nose had statistically
significant differences between virus groups with p <0.01. The
percentage of children with Influenza B and Influenza A group has the
highest fever, respectively, 100.0% and 94.4%; lowest in RSV group
with 39%. The rate of children with runny nose in Influenza A and B
group are highest with 80.6% and 70.0% respectively, the lowest in the
Adenovirus group with 17.9%.
+ 100% of children have rapid breathing, chest concave, moist lung

in the lungs.
- Symptoms of tachycardia with statistically significant differences
between virus groups with p = 0.02.
- X-ray images showed that the percentage of children in RSV
group, Rhinovirus with interstitial lesions accounted for the highest with
47.5% and 37.5%, the lowest was in the Adenovirus group (21.4%).
Meanwhile, blurred lesions were found in Adenovirus group (75.0%),
Influenza A (66.7%) and Influenza B (70.0%), Rhinovirus group
(43.7%). The differences between these groups are statistically
significant (p<0.05). Apnea is seen in 1 child with Adenovirus and 2
children with Rhinovirus.
Characteristics of the test index by mere virus groups


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- The Adenovirus group has the highest leukocyte index (median =
12.4 G/L). There was a statistically significant difference between
leukocytes, lymphocytes and viral groups with p = 0.04
- Influenza B group has the highest neutrophil index, the lowest is
Rhinovirus group. Differences between Influenza A group and RSV
group; between Influenza A group and Rhinovirus group; between RSV
group and Adenovirus group; and between Adenovirus and Rhinovirus
group were statistically significant (p <0.01).
The highest rate of children with hs-CRP> 6-10 mg/l in the
Influenza B group is 80.0%; the lowest in Rhinovirus group with 12.5%.
The difference between the two groups is statistically significant (p
<0.05). The percentage of children with PCT> 0.5 ng / ml in the
Influenza B group was also highest with 90.0%; lowest in Rhinovirus
group with 31.3%. The difference between the two groups is statistically
significant (p <0.05).

3.2.2. Clinical and subclinical characteristics in pediatric patients
with severe viral co-infection
- 100% of patients have symptoms of cough, tachypnea, chest
concave, moist lung in the lungs
The co-infection group only had a higher number of white blood
cells than the co-infection group. The co-infection group of bacteria and
viruses has a higher number of white blood cells than the co-infected
group. The difference was statistically significant (p <0.05).
Hs-CRP was highest in the co-infection group only, followed by the
virus co-infection group, and lowest in the co-virus and bacterial coinfection group. PCT increased the highest in the co-infection group
only, followed by virus and bacterial co-infection group, the lowest
group was only co-infected with virus. IL-6 has the highest increase in
the co-infection group with both virus and bacteria.
- The co-infection group has a higher rate of children with fever,
cyanosis than the non-co-infected group, with statistical significance (p
<0.05
- There was no difference in lung X-ray lesion between the virusinfected group alone and the co-infected group (p>0.05).
- In the group of pediatric pneumonia patients, the number of
leukocytes, neutrophils, hs-CRP and PCT was statistically significantly


15

0 .0 0

0 .2 5

S e n s itiv ity
0 .5 0 0 .7 5

1 .0 0

higher (p<0.05) compared to the group of patients infected with virus
alone. .
- The percentage of pediatric patients in the co-infection group with
the number of white blood cells (28.3%) and the proportion of
neutrophils (35.8%) was higher than the simple group (p<0.05).
- The proportion of pediatric patients in hs-CRP co-infection
group> 6-10 mg/l was 54.7%, higher than in the simple group of 38.9%
(p<0.05). Meanwhile, in the co-infection group, PCT concentrations >
0.5 ng / ml were found in 66.0% of pediatric patients compared to
44.3% in the simple group (p<0.05).

0.00

0.25

0.50
1-Specificity

crp ROC area: 0.6114
Reference

0.75

1.00

pct ROC area: 0.6582

Figure 3.3: ROC curve of hs-CRP and PCT values in distinguishing

between purely viral pneumonia and viral pneumonia co-infection
Children with fever symptoms had significantly higher neutrophils,
hs-CRP, PCT and IL-6, which were statistically higher than those
without fever (p<0.05). Meanwhile, in the group of children with
symptoms of runny nose, IL-6 is higher than the group without
symptoms, the value is statistically significant with p<0.05.
* Using Spearman correlation coefficient for quantitative variables
distributed non-standard, the results show that:
- There is a negative correlation between hs-CRP and Hb, and a
positive correlation between hs-CRP and the number of white blood
cells and neutrophils.
- There is a positive correlation between PCT and the number of
white blood cells, neutrophils, mono leukocytes and hs-CRP.
- There is a negative correlation between IL-6 and lymphocytes, and
there is a positive correlation between IL-6 and neutrophils, hs-CRP and
PCT.


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50
40
30
20
10
0

0

f(x) = 0.01x + 1.6
50

100

150

200

250

300

0 .0 0

0 .2 5

S e n s it iv it y
0 .5 0
0 .7 5

1 .0 0

Figure 3.4. The linear regression equation shows the relationship
between hs-CRP and PCT
Explain the regression equation: "When the hs-CRP concentration
increased by 1 mg/l, the PCT concentration increased by 0.0296 ng/ml"
with the average correlation coefficient r = 0.3530.
- Differences in treatment time between influenza A and RSV
groups, Adenovirus, Rhinovirus; between influenza B and RSV,
Adenovirus and Rhinovirus; between RSV and Adenovirus group; and
between Adenovirus and Rhinovirus group were statistically significant

(p <0.05).
- The rate of children recovered from influenza B is the highest at
85.7%; The lowest is influenza A group with 67.3%. There was no
difference in treatment results between groups (p <0.05).
- Increased IL-6 levels are associated with an increased risk of
death in pediatric patients. Significant relationship with p <0.05
(according to the Mann-Whitney test).

0.00

0.25

0.50
1 - Specificity

0.75

1.00

Area under ROC curve = 0.6993

Figure 3.5. ROC curve of IL-6 value in distinguishing between
mortality and non-mortality rate


17
- At the cut-off value of 2.4 ng/ml, the difference between mortality
and non-mortality of IL-6 has a sensitivity of 57.14% (95% CI) and
specificity 88.24% (95% CI).
- The area under the curve (AUC) of IL-6 is 0.6993 with a 95%

confidence interval of 0.456 - 0.942.
CHAPTER 4
DISCUSSION
4.1. Research clinical and subclinical characteristics of severe viral
pneumonia in children under 5 years old.
4.1.1. Some common characteristics of pediatric patients
4.1.1.1. Age and gender
Our research results show that pneumonia is common in children
under 12 months old. The disease is more prevalent in boys than in girls,
similar to the researched that is carried out by Quach Ngoc Ngan and et
al. in children from 2 months to 5 years old at Can Tho Children
Hospital in 196 children with 48% under 12 months old; the
male/female ratio is 1.9/1
4.1.1.2. Time of illness
Research results show that the disease occurs in all months of the
year, the peaked time is spring (from February to April). Research of
Prel J.B et al. shows that Adenovirus pneumonia tends to increase as
temperature rises.
4.1.1.3. History of obstetrics
Malnutrition is a major cause of immunodeficiency. Micronutrient
deficiency causes poor growth, intellectual impairment, and increased
mortality and susceptibility to infections, leading to pneumonia.
4.1.1.4. History of illness
According to Smyth A., a number of comorbidities increase the
risk of viral pneumonia: congenital heart disease, respiratory
malformation. This study showed that 65.4% of children without
common illness, while 25.7% of children often have respiratory disease.
4.1.1.5. History features
Average number of days of being hospitalized is higher in patients

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with co-infection.
4.1.2. Clinical and subclinical characteristics
4.1.2.1. Clinical characteristics of the disease
46.4-64.4% of children with acute lower respiratory tract infection
shows fever symptoms majority of which have fever ≤ 38 0C in all
groups of viruses, symptom of cough is found in 100% of patients; over
66.7% of patients shows signs of wheezing and at least 75.3% of
patients shows signs of upper respiratory tract inflammation.
4.1.2.2. Subclinical characteristics
- X-ray characteristics
Huijskens E.G. and et al. showed lung damage in 23.8% of cases
and often manifested interstitial lesions on both sides of the lung.
Respiratory X-ray images showed that children with mostly blind
lesions were 61.4%. 35.6% had interstitial lung damage.
- Subclinical laboratorial characteristics
- Laboratory features
+ Hemoglobin and leukocytes
According to Ruuskanen O. and et al., showing that the white blood
cell count <10G/L is often suggestive of viral cause. An increased white
blood cell count indicates that the child has a bacterial infection but
75.6% of the children do not have an increased number of white blood
cells but still have the infection. Even 9.0% of children with
neutropenia.
+ hs-CRP
The proportion of pediatric patients with hs-CRP levels> 6 mg / l is
43.1%. This result is consistent with the study of Dao Minh Tuan and et
al. with the highest hs-CRP <6 mg / dl ratio with 43.75%.
+ PCT

Many studies also show that PCT can shorten diagnosis time,
distinguish bacterial or viral infections, monitor response to antibiotic
treatment and control foci better than other markers such as hs-CRP.
+ IL-6
Endeman H. and et al. Showed that in acute pneumonia Interleukin
(IL-1, IL-6, IL-8 and IL-10) acted as an acute stage protein. Cytokine
levels were significantly higher in patients with acute pneumococcal
pneumonia.


19
- Characteristics of virus and bacterial infection
+ The prevalence of severe pneumonia by virus groups
The viruses that cause bronchitis are common such as Influenza
virus, RSV, Adenovirus, Rhinovirus.
+ Co-infection status: Pavia A.T. and et al. research in 58 out of 58
patients identified the cause of pneumonia, 65% of patients infected on 1
virus, bacterial co-infection was 35%.
4.1.3. Clinical and subclinical characteristics according to the
virus groups in pediatric patients infected by a single virus
4.1.3.1. Demographic characteristics
4.1.3.2. Clinical characteristics
- Pneumonia caused by RSV
D’Elia C. and et al. showed that wheezing is one of the functional
symptoms with high sensitivity and specificity of 85% and 65% in
diagnosis of ARIs caused by RSV. Our research results showed that 39%
of RSV infected children had fever, 89.8% of wheezing children.
- Pneumonia caused by Adenovirus
Adenovirus bronchitis is often acute, prone to epidemics, rapid
progression, causing complications of respiratory failure and death. The

disease is often severe and persistent, the number of days of
hospitalization lasts.
- Rhinovirus pneumonia
Rhinovirus is identified in 3-45% of children with community
pneumonia. On the other hand, some studies suggest that Rhinovirus can
multiply at body temperature and infect cells of the lower respiratory
tract.
- Pneumonia caused by Influenza A and Influenza B
Pneumonia in influenza patients can be either viral or secondary to
bacterial superinfection, common to S. pneumococcus or H. influenza
4.1.3.3. Subclinical characteristics
- X-ray characteristics
According to Kern S. and et al when studying X-ray images of 108
children with upper respiratory infections due to RSV found that: normal
images were 30%, pneumonia 32%, bronchitis 26%, stasis 11%,
collapsed lung 5%.
- White blood cell characteristics


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- Hemoglobin and platelet characteristics
- Characteristics hs-CRP
According to a study by Li L. and et al, the group of severe
Adenovirus pneumonia was 2.54 mg/l. Research by Garcia-Garcia M.L.
and et al., pneumonia virus in the community showed that the average
hs-CRP value in RSV group was 32.2 ± 46.1 mg/l, Rhinovirus was 81 ±
109 mg/l
- PCT characteristics
Because of the high specificity of PCT in response to severe
systemic infections, appropriate PCT is used to guide treatment and

evaluate prognosis. PCT has the ability to effectively detect bacterial coinfection and is an important indicator to keep in mind during child care.
- IL-6 specification
IL-6 is an important indicator for assessing viral infections.
4.1.4. Clinical and subclinical characteristics in pediatric patients
who are infected with bacteria and virus
Symptoms such as fever, tachycardia, and runny nose were different
between the groups of children infected with the virus alone.
Analysis of subclinical characteristics also showed that there was
no significant difference between the three groups on lung X-ray
characteristics, subclinical indicators such as Hb, hs-CRP, PCT or IL- 6.
The co-infection group only had a higher number of white blood
cells than the co-infection group. The co-infection group of bacteria and
viruses has a higher number of white blood cells than the co-infected
group.
4.2. Evaluating the relationship between hs-CRP, PCT, IL-6 and
clinical, subclinical, treatment results, viral etiology in severe viral
pneumonia in children under 5 years old.
4.2.1. Comparing clinical, subclinical characteristics between the
pediatric patients with severe pneumonia infected with a single virus
and the bacterial and viral co-infection
Leukocyte test, hs-CRP and PCT are important indicators to help
predict the level of bacterial and viral co-infection in patients with
severe viral pneumonia.
4.2.2. Correlation between subclinical and clinical indicators


21
The results of this study are similar to the study of IL-6 and hs-CRP
concentrations in the elderly of Monika P.K. and et al. 2016, when the
study also showed a strong relationship between these two indices in the

whole study group with r = 0,502, p<0.001; in the successful aging
group with r = 0.538, p<0.001; in the group of elderly patients related to
the aging process with r = 0.50, p<0.001.
A study by Qu J. and et al. 2015 in subjects 18 to 85 years old
showed that IL-6 levels increased when patients had fever accompanied
by bacterial infection.
A study by Wussler D. and et al. 2019 found that the diagnostic
accuracy of PCT for pneumonia was only moderate (AUC 0.75). A study
of 101 patients of Muller B. and et al. found a higher diagnostic
accuracy of PCT than hs-CRP and IL-6 in sepsis.
4.2.3. Treatment results
The study by Wussler D. and et al. showed that in patients with
dyspnea, the diagnostic accuracy of PCT in pneumonia was only
moderate and lower than IL-6 or hs-CRP.
Regarding treatment results, the number of patients recovered, at
the hospital was 143 (70.8%), the patients transferred at the hospital
were 9 (4.5%), the patients died and asked to return to death at home
were 11 patients. (5.4%).
Higher IL-6 levels are associated with an increased risk of death in
pediatric patients. Significant relationship with p<0.05. In a study by
Bacci M.R. and et al. found that high IL-6 levels at the time of
admission were associated with a patient's severe condition, mechanical
ventilation, and a pro-poor rate of death.
4.2.4. Limitations of the study
- The study was conducted at National Children’s Hospital, most
children who were admitted to the hospital were treated and used
antibiotics at lower levels, so the rate of co-infection no longer reflects
the reality. Moreover, it is difficult to distinguish co-infection or multiple
infections because most hospitalized children have had time to stay in
the frontline.

- The study was conducted at the hospital, so the results of the study
were only conclusive for the pneumonia children treated at the National
Children’s Hospital, not extrapolated to the community.


22

CONCLUDE
1. Research clinical and subclinical characteristics of severe viral
pneumonia in children under 5 years old.
* Description of 202 patients with severe viral pneumonia indicates:
- Majority of children with severe pneumonia are under 12 months
(76.7%). Number of illness days is less than 7 days, accounts for 71.8%.
75% of cases have had treatment before having treating in the hospital
- Clinical symptoms: fever 71.8%, wheezing 83.7%, runny nose
39.6%, cyanosis 24.3%. 100% of patients have cough, tachypnea, chest
concave and physical symptoms are moist rales. Other symptoms such
as diarrhea, cyanosis, enlarged lymph nodes is 28.2%, 24.3%, 10.4%
respectively
- Test: blood leucocytes 10400 (2200-35100), neutrophils 4200
(100-2700), lymphocytes 4200 (890-14000). Hs-CRP 4.2 (0.1-273),
PCT 0.5 (0.01-44.0) and IL-6 are 5.7 (0-500).
- Chest X-ray with primary damage is 73.7%, interstitial lesion
21.3%, 5% other lesions.
- Viral etiology: RSV 36.1%, Influenza A 24.3%, Adenovirus 19.8%,
Rhinovirus 12.9% and Influenza B 6.9%.
* Description of 149 patients with severe viral pneumonia and 53
patients with viral and bacterial coinfection indicates: The achieved
results depend on the group of pathogens that have different clinical and
subclinical manifestations.

- 149 patients (73.8%) are infected with a single virus, of which
RSV is 39.6%, Influenza A was 24.2%, Adenovirus is 18.8%, Rhinovirus
is 10.7% and Influenza B was 6.7%. 53 patients with viral and batcerial
co-infected (26.2%).
- In the only viral pneumonia group: children with Rhinovirus have
low birth weight. Children with Influenza A and B have higher fever,
more runny nose. Neutrophils concentration gets the lowest index in
Influenza B group, with differences between etiologies. Hs-CRP gets the
highest index in Influenza B group, there is a difference in these indexes


23
between groups. PCT has the highest value in Influenza B group, there
are differences between groups. IL-6 has the highest value in Influenza
A group, there are differences between groups.
- In the group of severe pneumonia with co-infection: the
outstanding issues are the infected condition with high fever, cyanosis.
The subclinical examination shows a higher number of leukocytes,
neutrophils, hs-CRP, PCT have statistical significance in comparision
with he only viral infection group.
- Diffrences between only viral coinfection pneumonia and coinfected pneumonia of hs-CRP at cut-off value of 5.06 mg/ml with Se
60.38% and Sp 60.40%; of PCT at cut-off value of 2.1 ng/ml with Se
45.28% and Sp 82.55%. The AUC of hs-CRP is 0.6114 with 95% CI of
0.52 - 0.70; of PCT is 0.6582 with 95% CI is 0.57 - 0.75.
2. Evaluating the relationship between hs-CRP, PCT, IL-6 and
clinical, subclinical, treatment results, viral etiology in viral
pneumonia in children under 5 years old.
- Fever: Neutrophils and IL-6 are higher than those without fever.
- Runny nose: PCT is higher than the group without symptoms.
- Wheezing: hs-CRP, PCT are lower than the asymptomatic group.

- Hs-CRP hs has a positive correlation with the number of white
blood cells, neutrophils, PCT, IL-6
- PCT has a positive correlation with the number of white blood
cells, neutrophils, mono leukocytes, IL-6.
- IL-6 is positively correlated with neutrophils and negatively
correlated with lymphocytes.
- At the cut-off value of 2.4 ng / ml, the difference between
mortality and non-mortality of IL-6 was Se 57.14% (95% CI) and 88
88% Sp (95% CI) . The IL-6 AUC is 0.6993 with 95% confidence
intervals of 0.456 - 0.942.
- Comparison of groups of simple viral pneumonia: fever, runny
nose, neutrophils, hs-CRP, IL-6 have differences with p <0.01; PCT is
different with p = 0.03.
- Compare the group of pneumonia caused by co-infection: fever,
neutrophils, PCT with the difference with p <0.01.


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PROPOSAL
- Viral pneuminia patients who are coinfected with pneuminiaother
viruses and bacteria, account for a high proportion (26.2%). Therefore, it
is necessary to promptly evaluate the disease condition to make
indications for the appropriate use of antibiotics, to avoid overuse of
antibiotics as well as to avoid omitting patients who are coinfected or
bacterial infected. At the same time, viral pneumonia patients should be
properly isolated so that they are not infected other viruses or bacteria
as well as do not spread the virus to other patients.
- Because the research was established in 2013, the research
conditions were quite limited compared with the present condition.

Since our research was conducted on the 5 most common viruses at the
National Children’s Hospital, it is necessary to continue conducting
researches on pneumonia caused by other viruses.
- Newborn patients was not seclected for our research since it was
conducted mainly in the department of respiratory, infectious diseases
and emergency resuscitation department. Therefore, it is needed to
conduct new researches on severe viral pneumonia in newborns .