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Indian J Pediatr DOI 10.1007/s12098-017-2514-y

Indian J Pediatr DOI 10.1007/s12098-017-2514-y ORIGINAL ARTICLE Etiology and Risk Factors Determining Poor Outcome of

ORIGINAL ARTICLE

ORIGINAL ARTICLE

Etiology and Risk Factors Determining Poor Outcome of Severe Pneumonia in UnderFive Children

Suresh Kumar Jakhar 1 & Mukul Pandey 1 & Dheeraj Shah 1 & V. G. Ramachandran 2 & Rumpa Saha 2 & Natasha Gupta 3 & Piyush Gupta 1

Received: 5 March 2017 /Accepted: 21 September 2017 # Dr. K C Chaudhuri Foundation 2017

Abstract Objectives To determine the etiology of severe pneumonia (pneumonia with chest indrawing) in under-five children, and to study the risk factors for poor outcomes viz., treatment failure, need for change in antibiotics, prolonged hospital stay, need for mechanical ventilationand mortality.Methods Children (age 2 mo to 5 y) with pneumonia and chest drawing were enrolled prosp ectively from October 2012 through September 2013. Clinical history was recorded, and examination, anthropometry and investigations (including chest X-ray, blood culture and nasopharyngeal swab culture) were performed. Children were managed as per standard guide- lines, and recovery outcomes were recorded in form of treat- ment failure(defined as persistence of features of severe pneu- monia after 72 h or worsening of clinical condition before 72 h), need for change of antibiotics and prolonged (>5 d) hospital stay. The associations between the clinical, anthropometric and diagnostic risk factors and the recovery outcomes were evaluat- ed by univariate and multivariate logistic regression analysis. Results Out of 120 children enrolled in the study, 36 (42%) were culture positive (nasopharyngeal/blood); most common bacteria isolated were Streptococcal pneumoniae and Staphylococcal aureus, respectively. Treatment failure was seen in 15 (12.5%), 34 (28.3%) needed change of antibiotics, and 50

* Dheeraj Shah shahdheeraj@hotmail.com

1 Department of Pediatrics, University College of Medical Sciences & GTB Hospital, Dilshad Garden, Delhi 110095, India

2 Department of Microbiology, University College of Medical Sciences & GTB Hospital, Dilshad Garden, Delhi, India

3 Department of Radiology, University College of Medical Sciences & GTB Hospital, Dilshad Garden, Delhi, India

Sciences & GTB Hospital, Dilshad Garden, Delhi, India (41.6%) children required prolonged hospitalization. Low

(41.6%) children required prolonged hospitalization. Low birth weight, overcrowding, general danger signs (lethargy/unable to drink), clinical rickets, crepitation, leukocytosis and positive blood culture were significant risk factors for treatment failure, prolonged hospital stay and antibiotics change. On multivariate logistic regression analysis, respiratory rate of >70/min (OR 19.94, 95%CI 1.42280.29), lethargy/unconsciousness (OR 114.2, 95%CI 3.144147.92), and positive blood culture (OR 15.24, 95%CI 2.5391.67) had more chances of treatment fail- ure. Duration of hospital stay was prolonged in those who had inability to drink (OR 3.89, CI 1.3710.99) or abnormal chest X-ray (OR 8.45, CI 3.5620.04). Children with rickets (OR 3.69, CI 1.1411.96), and those with abnormal chest X-ray (OR 9.66, CI 2.6235.53) had a higher odds of change in anti- biotics. Presence of wheeze was a protective factor for treatment failure (OR 0.03, CI 0.000.37) and change of antibiotics (OR 0.24, CI 0.070.74). Conclusions Staphylococcus aureus and Streptococcus pneumoniae are the predominant organisms causing severe pneumonia in our setting. Children with risk factors such as respiratory rate >70/min, rickets, lethargy/unconsciousness, not able to drink, abnormal chest X-ray or positive blood culture are likely to have a delayed recovery or need of change of antibiotics, whereas those with wheeze are likely to recover faster with less chances of treatment failure.

Keywords Severe pneumonia . Risk factors . Treatment failure

Introduction

Pneumonia accounts for nearly one-fifth of childhood deaths worldwide [1]. India contributed 14.9% of deaths of children under 5 y of age in the year 2015 [2]. In view of high mortality

Indian J Pediatr

from severe pneumonia in developing countries, it is neces- sary to understand the factors determining poor outcome of pneumonia. Studies from different regions have identified some risk factors for mortality viz., young age of the child, acute malnutrition, lack of breastfeeding, and presence of ra- diological abnormality. However, most studies are from African or South American regions, and have focused on mortality without assessing other important outcomes such as treatment failure, need for change of antibiotics, and dura- tion of hospitalization. There is a paucity of prospectively collected data on etiology or risk factors determining poor outcome of severe pneumonia from developing country set- ting. The authors conducted this descriptive study to deter- mine the etiology and various risk factors in predicting poor outcome of severe pneumonia in under-five children in India.

Material and Methods

This was a hospital-based, descriptive, cohort study, conducted between October 2012 to September 2013 in the Departments of Pediatrics and Microbiology at a medical college affiliated hos- pital mainly catering to the urban poor population of East Delhi and Western Uttar Pradesh, India. Children aged between 2 mo to 5 y with diagnosis of severe pneumonia (on the day of pre- sentation to the hospital) were included after obtaining written informed consent from parents. Severe pneumonia was defined as presence of lower chest indrawing (definite inward movement of lower chest during quiet breathing) and/or with general danger signs (not able to drink, persistent vomiting, convulsions, lethar- gy or unconscious, stridor in calm child or severe malnutrition), in children presenting with cough or difficult breathing [3]. Children with non-respiratory (e.g., congestive cardiac failure, metabolic acidosis, neurogeni c hyperventilation), non- infectious (e.g., foreign body aspiration, hydrocarbon ingestion) causes of respiratory distress, and those with two or more epi- sodes of wheezing illness in past were excluded. Children who had received parenteral antibiotics before presenting to the hos- pital were also excluded. The study was approved by the Institutional Ethical Committee of University College of Medical Sciences, New Delhi. History was obtained pertaining to symptomatology, diet (in- cluding details of breastfeeding and complementary feeding), birth weight and immunization status, and home environment. Socioeconomic status was determined by using modified Kuppuswamy scale [ 4 ]. Physical examination included recoding of vital signs (temperature, heart rate, and respiratory rate); and assessment of fast breathing, chest indrawing (definite inward movement of lower chest during quiet breathing), signs of hypoxia (head nodding, grunting, and cyanosis), clinical signs of rickets; and chest auscultation for crepitation/wheezing. Anthropometry, including weight, length/height and mid-upper arm circumference (MUAC), was recorded using standard

techniques. Severe acute malnutrition (SAM) was defined as weight for height Z score < 3 standard deviation (SD) or MUAC <11.5 cm [5]. Respiratory rate was measured for a full minute and if it was fast (RR >50/min for age 2 mo1 y and >40/min for 15 y), it was measured again and the average of two readings was noted. The count was done at a time when the child was quiet. Baseline oxygen saturation was measured using a pulse oximeter with a probe on a finger or toe, in room air. Hypoxia was defined as oxygen saturation < 92% in room air [3]. A blood sample was obtained for hemoglobin, total leuco- cyte count, serum electrolytes, serum 25(OH)D levels and blood culture at the time of hospitalization. Chest X-ray was obtained in all children and interpreted by a radiologist blinded to the clinical details. Nasopharyngeal swabs were obtained for iden- tification of Haemophilus influenzae and Streptococcus pneumoniae within 24 h of enrolment. A sterile swab was in- troduced into the nasopharynx, parallel to palate and kept there for 30 s. Then the swab was rotated, removed and plated imme- diately on blood agar along with staphylococcal streak, and on chocolate agar. Plates were incubated for 1824 h at 37 °C in 510% CO 2 , and bacteria were identified by colony morphology, gram stain and their biochemical reactions [6]. Patients were treated with antibiotics for severe pneumonia as per guidelines of Indian Academy of Pediatrics [7]. Children were monitored for respiratory rate, chest indrawing, oxygen saturation, auscultatory findings, fever, feeding, cyanosis and mental status every 8 hourly. Intravenous antibiotics were switched to oral antibiotics after 4872 h, if the lower chest indrawing disappeared by that time. The child was discharged only when the child was afebrile (temperature < 100.4 °F) and there was no fast breathing for at least 24 h. The main outcomes of interest were to study the bacterial etiology and outcome as treatment failure, defined as persis- tence of features of severe pneumonia after 72 h or worsening of clinical condition before 72 h [8]. The secondary outcomes in- cluded need for change of antibiotics (as per treating clinicians perception of non-improvement), need for mechanical ventila- tion (if airway and breathing was compromised) [3], prolonged (more than five days) hospitalization and death. The risk factors assessed were socio-demographic and clinical parameters (breastfeeding, smoking member in family, overcrowding, so- cioeconomic status, cooking fuel other than LPG), nutritional status of the child (presence of wasting, severe wasting, stunting, MUAC <11.5 cm), immunization status, presence of anemia (defined as hemoglobin <11 g/dl) [3], rickets, auscultation find- ing of wheezing, presence of general danger signs, and investi- gations (presence of anemia, hypovitaminosis D [9], chest X-ray abnormalities and positive blood culture). The data were entered in Microsoft Excel worksheet and analyzed with SPSS Version 17.0. Chi-square test or Fischer Exact test (as applicable) was used to study the associations between the categorical risk factors and the outcome. Continuous parameters were compared by using unpaired

Indian J Pediatr

Student t-test. To find out the independent contribution of each factor towards the outcome, multivariate logistic regression analysis was used. The authors calculated odds ratio and 95% confidence interval for the parameters, which were found to be significant in univariate analysis. A P value of less than 0.05 was considered statistically significant.

Results

A total of 120 children (74 boys and 46 girls) aged between 2 mo to 5 y with diagnosis of severe pneumonia were enrolled. Out of these 79 (66%) were aged less than one year. Baseline anthropometry, immunization status, clinical and laboratory profile is shown in Table 1. Streptococcus pneumoniae was isolated in 22 (26%) chil- dren from nasopharyngeal swabs. In blood culture, methicillin-sensitive and meth icillin-resistant (sensitive to vancomycin and linezolid) Staphylococcal aureus was isolat- ed in 14 and 2 children respectively. Klebsiella spp. was iso- lated from blood culture in 2 patients, E.coli in 1 patient and Acinetobacter spp. in 1 patient. Thirty-six (42%) children with severe pneumonia had an organism isolated from either

Table 1 Baseline anthropometric, im munization, clinical, and laboratory profile of study children (N = 120)

Parameter

Value Mean ± SD; Median (Range)

Age (months) Anthropometry Weight (kg) Length / height (cm) Weight for age Z-score (WAZ)

11.9 ± 11.5; 8 (2, 60)

7.15 ± 2.25; 7 (2.5, 15) 69.3 ± 10.9; 68 (48, 116) 1.97 ± 1.36; 1.71 (6.29, 1.14)

Length / height for age Z-score (HAZ) 1.43 ± 1.61; 1.28 (6.49, 2.71)

Weight for height Z-score (WHZ) MUAC # (cm)

1.47 ± 1.54; 1.47 (5.08, 3.32) 13.14 ± 0.62; 13.05 (11.5, 14)

Immunization status * ; N (%) Completely immunized

71 (59)

Partially immunized

40 (33)

Unimmunized

9 (7.5)

Clinical features; N (%) Not able to drink

85 (71)

Lethargy or unconscious

7 (6)

Anemia

37 (31)

Rickets

30 (25)

Crepitations

37 (31)

Wheeze

23 (19)

Crepitations + Wheeze

58 (48)

Laboratory Vitamin D[25(OH) D3] $ level

12.73 ± 7.3; 11.03 (2.02, 37.32)

Radiological features; N (%) Infiltrates

43 (36)

Consolidation

7 (6)

Pyo-pneumothorax

2 (2)

*As per Delhi Government Schedule

# Mid upper arm circumference available in 88 children

$ Done in 100 children

nasopharyngeal or blood culture. Children with wheeze had lesser frequency of bacterial infection in comparison to those without wheeze (17.2% vs. 52.6%; P < 0.001). Treatment failure occurred in 15 (12.5%); 34 (28.3%) needed change of antibiotics, and 50 p atients (41.6%) required prolonged hospitalization. No patient needed mechanical venti- lation and no one died. Risk factors for poor outcome (treatment failure, prolonged hospital stay and antibiotics change) are de- tailed in Table 2. On univariate analysis, low birth weight, over- crowding, general danger signs (lethargy/unable to drink), clin- ical rickets, crepitation, total leukocyte counts and positive blood culture were statistically significant risk factors for treat- ment failure, prolonged hospital stay and antibiotics change. Children who were never breastfed, smoking in family, mean oxygen saturation, anemia and mean vitamin D levels were not significantly associated with any of the poor outcome. On multivariate logistic regression analysis (Table 3), re- spiratory rate of >70/min, lethargy/unconsciousness and pos- itive blood culture had more chances of treatment failure. Duration of hospital stay was prolonged in those who had inability to drink or abnormal chest X-ray. Children with rick- ets, and those with abnormal chest X-ray had a higher odds of change in antibiotics. Presence of wheeze was a protective factor for treatment failure and change of antibiotic.

Discussion

The authors studied the etiology and various socio-demo- graphic, clinical and laboratory parameters associated with poor outcomes in 120 under-five children hospitalized with WHO-defined severe pneumonia. Streptococcus pneumoniae (nasopharyngeal swab) and Staphylococcal aureus (blood) were the predominant organisms isolated in children with pneumonia. Children having lethargy/unconsciousness, not able to drink, clinical rickets, positive blood culture or abnor- mal chest X-ray had significantly poor outcomes in term of treatment failure, prolonged hospital stay or antibiotics change; whereas presence of wheeze predicted lesser chance of treatment failure or antibiotic change. Major limitation of index study was evaluation of etiological organism by nasopharyngeal aspirate and lack of investigations for viruses, chlamydiae or mycoplasmae. Isolation of bacteria from only nasopharynx may not necessarily mean that these are responsible for pneumonia. The authors only excluded children who received parenteral antibiotics before presenting to the hos- pital. Few patients could have received oral antibiotics before being referred to the hospital, and this could have affected yield of organisms from cultures. In authorsset-up, most patients are not given prescriptions for oral drugs received in the unorga- nized set-up, and it is often difficult to obtain a history of receipt/ non-receipt of oral antibiotics. The authors could not identify risk factors for mortality and requirement of mechanical

Indian J Pediatr

Table 2 Association of various factors with treatment failure, prolonged hospital stay and change in antibiotics

Parameters

Treatment failure (n = 15)

P value

Prolonged hospital stay (n = 50)

P value

Antibiotics changed (n = 34)

P value

Age (months) Mean ± SD Sex (Male) Birth weight (kg) Mean ± SD Unimmunized Never breast fed Smoking in family member Overcrowding Lower Socioeconomic status* Cooking fuel other than LPG SAM Lethargy or unconscious Not able to drink Sign of rickets Respiratory rate (Mean ± SD) SPO 2 (Mean ± SD) Crepitations Hemoglobin (g/dL) Mean ± SD High TLC count (/cumm) Mean ± SD Vitamin D level (ng/mL) Mean ± SD Abnormal Chest X- ray Positive Nasopharyngeal aspirate culture Positive Blood culture

7.26 ± 6.35 9 (60%) 2.13 ± 0.37 4 (27%) 2 (13.3%) 4 (27%) 14 (93%) 14 (93%) 6 (40%) 5 (33%) 4 (27%) 15 (100%) 7 (47%) 68 ± 7 95 ± 2 13 (87%) 9.40 ± 1.96 24,126 ± 15,390 10.42 ± 7.32 15 (100%) 8 (53%) 10 (68%)

0.096

12.36 ± 11.88 25 (50%) 2.26 ± 0.68 6 (12%) 5 (10%) 14 (34%) 37 (74%) 40 (80%) 15 (30%) 10 (20%) 5 (10%) 43 (86%) 18 (36%) 63 ± 7 96 ± 1 23 (46%) 9.5 ± 1.85 16,764 ± 11,218 14.31 ± 8.74 36 (72%) 12 (24%) 15 (30%)

0.711

12.64 ± 12.80 18 (53%) 2.18 ± 0.48 18 (53%) 5 (14.7%) 10 (29.4%) 27 (79%) 28 (82%) 1 (35%) 10 (29%) 4 (12%) 29 (85%) 15 (44%) 62 ± 7 95 ± 1 23 (68%) 9.12 ± 2.05 19,605 ± 12,233 12.72 ± 7.65 30 (88%) 10 (30%) 13 (38%)

0.655

0.887

0.026

0.216

0.039

0.005

0.006

0.025

0.266

0.383

0.471

0.655

0.62

0.390

0.608

0.301

0.012

0.058

0.048

0.112

0.285

0.242

0.083

0.103

0.014

0.039

0.121

0.007

0.005

0.127

0.099

0.004

0.002

0.028

0.054

0.019

0.002

<0.001

0.058

0.120

0.070

0.058

0.080

<0.001

<0.001

<0.001

0.230

0.025

0.016

<0.001

0.001

0.001

0.205

0.086

0.997

<0.001

<0.001

<0.001

0.001

0.175

0.049

<0.001

0.001

<0.001

LPG Liquified petroleum gas; SAM Severe acute malnutrition; SPO 2 Oxygen saturation; TLC Total leucocyte counts

*Lower SES include class IV and class V

ventilation because none of the patient died and no one required mechanical ventilation. Absence of long term follow-up for any recurrence was also a limitation. In a study by Mathew et al. [10], S. pneumoniae (79%) and Staphylococcal aureus (30%) were the predominant isolates in nasopharyngeal aspirate and blood culture, respectively; results which are matching with present study. Another study by El Seify et al. [11] showed the most common bacterial causes of

pneumonia to be Staphylococcus aureus (13.3%), followed by Streptococcus pneumoniae and Klebsiella pneumoniae (7.8% each) from nasopharyngeal swab and blood. The possible dif- ference could be due to pneumococcal vaccine being adminis- tered to children in the study area. S. aureus, as a predominant organism isolated from blood culture in children with severe pneumonia has been reported earlier from studies conducted in the South East Asia region [12].

Table 3 Risk factors for treatment failure, prolonged hospital stay and change in antibiotics as identified by multivariate logistic regression

Parameters

Treatment failure OR (95% CI) (n = 15) (%)

Prolonged hospital OR (95% CI) Antibiotics changed OR (95% CI)

stay (n = 50) (%)

(n = 34)(%)

Age < 12 mo

12 (80)

2.27 (0.608.55)

30 (60)

0.64 (0.301.38)

21 (61.8)

0.78 (0.341.78)

Sex (Male)

9 (60)

0.06 (0.000.97)

25 (50)

1.49 (0.603.72)

18 (52.9)

0.68 (0.172.60)

Never breast fed

2 (13.3)

0.51(0.0032.85)

5 (10)

1.27 (0.169.78)

5 (14.7)

0.85 (0.079.94)

Smoking in family member

4 (26.7)

0.59 (0.048.45)

14 (34)

0.63 (0.241.65)

10 (29.4%)

0.59 (0.171.97)

Overcrowding

14 (93.3)

5.81(0.24141.77)

37 (74)

0.90 (0.292.78)

27 (79.4)

0.95 (0.204.45)

Lower Socioeconomic status

14 (93.3)

3.05 (0.0996.18)

40 (80)

1.59 (0.524.95)

28 (82.4)

1.20 (0.265.55)

Cooking fuel other than LPG

6 (40)

3.63 (0.2650.50)

15

(30)

1.16

(0.334.03)

1 (35.3)

3.17 (0.9210.93)

SAM

5 (33.3)

0.66 (0.0411.59)

10 (20)

0.45 (0.121.70)

10 (29.4)

0.84 (0.193.67)

Lethargy or unconscious

4 (26.7)

114.2(3.144147.92) 5 (10)

1.21 (0.159.48)

4 (11.8)

1.76 (0.2015.40)

Not able to drink

15 (100)

*

43 (86)

3.89 (1.3710.99) 29 (85.3)

2.06 (0.498.62)

Sign of rickets

7 (46.7)

1.02 (0.0519.04)

18 (36)

2.04 (0.765.44)

15 (44.1)

3.69 (1.1411.96)

Respiratory Rate >70/min

4 (26.7)

19.94 (1.42280.29) 5 (10)

0.79 (0.163.75)

4 (11.8)

0.45 (0.082.47)

Any wheeze #

2 (13.3)

0.03 (0.000.37)

25 (50)

0.83 (0.272.49)

11 (32.4)

0.24 (0.070.74)

Anemia

7 (46.7)

0.45 (0.063.44)

21 (42)

1.21 (0.423.44)

16 (47.1)

0.88 (0.233.33)

High TLC count (>11,000/mm 3 ) 13 (86.7)

5.33 (0.3776.63)

35 (70)

0.89

(0.292.74)

29

(85.3)

3.74 (0.8316.77)

Abnormal Chest X- Ray 15 (100) *

36

(72)

8.45 (3.5620.04) 30

(88.2)

9.66 (2.6235.53)

Positive Blood culture

10 (66.7)

15.24 (2.5391.67) 15 (30)

2.12 (0.597.58) 13 (38.2)

1.42 (0.326.24)

Indian J Pediatr

There are only few studies in literature on outcome mea- sures in terms of treatment failure, prolonged hospital stay or need for change of antibiotics. Tiewsoh et al. [13] studied 200 children aged between 2 mo to 5 y with severe pneumonia, and showed that 56.5% patients needed a change in antibi- otics, 51% stayed for more than 5 d in the hospital, 20.5% needed mechanical ventilation and 10.5% died. All of these outcomes were less commonly observed in present study. Better outcomes in index patients may be due to less serious patients enrolled in present study as this hospital also catered to directly reporting patients besides referred patients as com- pared to patient enrolment from a major referral hospital in the study by Tiewsoh et al. [13]. Tiewsoh et al. [13] identified lack of exclusive breastfeeding, low birth weight and abnormal chest radiograph as risk factors for change of antibiotics. In the index study, apart from abnor- mal chest X-ray, presence of clinical rickets was also associated with increased risk for change of antibiotics. Moreover, breastfeeding status was not a risk factor for the same. Few other studies have also reported abnormal chest X-ray as a risk factor for mortality in severe pneumonia [14, 15]. Few studies have showed comparable treatment failure in hospitalized vs. home treatment group in pneumonia with chest indrawing [12, 16], suggesting oral antibiotics as effective alter- natives to parenteral antibiotics. Findings from present study have the potential to further refine the criteria for oral antibiotic use in children with pneumonia and chest indrawing; apart from those having general danger signs, children with signs of rickets or abnormal chest X-ray may be treated in hospital with paren- teral antibiotics whereas those with wheeze may be managed in community. Children with wheeze may respond better in com- munity as they have more chances of having a viral etiology rather than bacterial pneumonia [17, 18]. In the index study too, children with wheeze had significantly lesser isolation of bacte- ria and faster recovery. It is concluded that Staphylococcus aureus and Streptococcus pneumoniae are the predominant organisms causing severe pneumonia in our setting. Children with risk factors such as rickets, not able to drink, abnormal chest radiograph or positive blood culture are likely to have a delayed recovery, and should therefore be managed in hospital-based settings.

Acknowledgments Dr. Rajeev, Department of Community Medicine, for statistical analyses.

Contributions DS and PG conceptualized the study and its design. SKJ, VGR, RS and NG: participated in data collection and diagnostic work-up of study participants. MP and DS analyzed and interpreted the data. MP and SKJ drafted the manuscript, which was revised after critical inputs from PG, DS, RS, VGR and NG. All authors approved the final version of the manuscript, as submitted.

Compliance with Ethical Standards

Conflict of Interest None.

Source of Funding None.

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