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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 5  |  Page : 243-248

Secondary bacterial infection in dengue fever and associated risk factors – An observational study in children


1 Department of Paediatrics, Velammal Medical College Hospital and Research Institute, Madurai, Tamil Nadu, India
2 Department of Anaesthesia and Critical Care Medicine, Velammal Medical College Hospital and Research Institute, Madurai, Tamil Nadu, India
3 Department of Microbiology, Velammal Medical College Hospital and Research Institute, Madurai, Tamil Nadu, India

Date of Submission08-Apr-2020
Date of Decision23-May-2020
Date of Acceptance17-Jun-2020
Date of Web Publication14-Sep-2020

Correspondence Address:
Dr. Sridhurga Udayasankar
Department of Paediatrics, Velammal Medical College Hospital and Research Institute, Madurai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPCC.JPCC_48_20

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  Abstract 


Background: Dengue fever remains one of the leading causes of hospitalization among children in endemic areas. Clinical manifestations of dengue fever are highly variable. There are only a few pediatric dengue fever cases reported with secondary bacterial infection. Knowledge of prevalence, risk factors, and predictors of bacterial infection among children with dengue fever is essential to initiate antibiotics.
Objective: The objective of this study was to assess the prevalence of bacterial infection, analysis of risk factors, and predictors of bacterial infection among dengue fever patients with prolonged or recurrent fever after critical phase of illness.
Design: This was a retrospective observational study.
Setting: This study was conducted in the pediatric department of a tertiary hospital.
Patients: Children with dengue fever who present with persistent or prolonged fever even after critical phase were included in the study.
Results: Eighty-three children with dengue fever who had persistent fever for more than 5 days or recurrent fever were included in our study. Twenty-nine patients (34.9%) had definite secondary bacterial infection confirmed by positive culture and seven patients had probable secondary bacterial infection. The risk of secondary bacterial infection was higher in infants (P = 0.054), children who had fever >5 days on admission (P = 0.020), and children who had severe dengue (P = 0.016). The duration of hospital stay increased significantly in those with secondary bacterial infection (P = 0.041). No mortality was reported in culture-positive group.
Conclusion: Our study highlights the increased risk of multidrug-resistant secondary bacterial infection among infants and in children who presented with fever >5 days and severe dengue fever. Hence, a low threshold to work up for secondary bacterial infections and early initiation of empirical antibiotics is warranted in these patients.

Keywords: Dengue fever, immune paralysis, infants, secondary bacterial infection


How to cite this article:
Udayasankar S, Sivakumar V, Sundaramurthy R. Secondary bacterial infection in dengue fever and associated risk factors – An observational study in children. J Pediatr Crit Care 2020;7:243-8

How to cite this URL:
Udayasankar S, Sivakumar V, Sundaramurthy R. Secondary bacterial infection in dengue fever and associated risk factors – An observational study in children. J Pediatr Crit Care [serial online] 2020 [cited 2020 Sep 23];7:243-8. Available from: http://www.jpcc.org.in/text.asp?2020/7/5/243/295021




  Introduction Top


Dengue fever is the most widespread mosquito-borne arboviral infection in tropical and subtropical regions.[1] The estimated prevalence of dengue fever is 390 million infections annually, with 96 million of these infections being clinically apparent, threatening more than 40% of the world's population.[2],[3] Clinical manifestations of dengue fever are highly variable, ranging from mild flu-like illness to severe life-threatening disease – dengue hemorrhagic fever or shock syndrome.[4],[5]

Dengue fever is characterized by three phases – febrile, critical, and recovery. During the critical phase, there is an increase in vascular permeability due to endothelial cell dysfunction resulting in capillary leakage followed by coagulopathy, hemorrhage, and multi-organ dysfunction.[6] Although there is no specific treatment for dengue fever, early detection and supportive management is the key in reducing mortality as per the new clinical management guidelines for dengue (dengue with/without warning signs and severe dengue) by the World Health Organization (WHO).[7]

A majority of dengue fever patients recover with supportive management, but a few develop either cytokine storm manifesting as secondary hemophagocytic lymphohistiocytosis[8] or sepsis, due to over activation of compensatory anti-inflammatory response causing immune paralysis.[9] Many other hypotheses such as endothelial cell disintegration by antibodies against dengue nonstructural protein 1 and capillary leak leading to transgut migration of microbes are postulated for bacterial infections in dengue fever patients. The outcome of dengue fever with bacterial infection is worse than the severe dengue illness itself.[10],[11]

Although there are many hypotheses, the exact prevalence of bacterial infections occurring either as concurrent or superadded infection among dengue patients is lacking in our setup.[1],[12] Most of the studies are also carried out in adult population which may not be applicable to pediatric population. Dengue clinical management guidelines do not recommend the use of antibiotics during any of the stages of dengue due to sparse evidence of secondary bacterial infections in severe dengue patients.[7]

Hence, our present study is aimed to assess the prevalence of bacterial infection, analysis of risk factors, and predictors of bacterial infection among dengue fever children with prolonged or recurrent fever.


  Methods Top


This retrospective observational study was carried out in the pediatric department of a large tertiary care medical college hospital in South India after the institute ethical committee approval (IEC No: VMCIEC/18/2018). Children <16 years of age admitted between July and December 2017 were included in the study. Dengue fever was diagnosed in children with compatible clinical features (probable dengue as defined by the WHO progressing to develop either warning signs or shock) and laboratory findings (hemoconcentration, thrombocytopenia, leukopenia, or radiological signs of plasma leakage). This was confirmed either by positive NS1 antigen and/or immunoglobulin M (IgM) antibodies by enzyme-linked immunosorbent assay (ELISA) against dengue (Panbio Dengue NS1, IgM, IgG ELISA-Standard Diagnostics, Gyeonggi, Republic of Korea). Isolated IgG ELISA-positive patients with no other clinical signs were excluded from the study.

Out of these dengue-positive cases, we included children who had persistent or recurrent fever even after the critical phase. Critical phase was defined as per the WHO criteria and classified as warning signs and severe dengue. Children were considered to have recovered once the warning signs subsided or hemodynamic instability improved with a decrease in hematocrit and improving platelet count. Children who continued to have fever through critical phase into recovery phase (fever >5 days) were defined as persistent fever, and children who became afebrile during the course and then developed fever during recovery phase were defined as recurrent fever. These children were started on antibiotics as per hospital antibiotic policy (BL/BLI – injection Pip–Taz). These children were investigated for bacterial infections. These children were investigated for bacterial infections with complete hemogram, C - Reactive Protein (CRP), Chest Xray (In children with respiratory symptoms), blood culture, urine culture, cerebrospinal fluid analysis (in children with seizures, altered sensorium), serology for bacterial infection (Widal, Scrub antibody). Those who had any one positive culture were considered as definite secondary bacterial infection following dengue fever. Based on these, participants were divided into two groups: one with definite secondary bacterial infection and the other group whose cultures were negative. Among those with culture negative, probable secondary bacterial infection was considered if CRP was positive (>6 mg/L) or leukocytosis (>15,000/cu mm).

The demographic, clinical, and laboratory data were retrieved from case records. These parameters were compared between children who had secondary bacterial infection (definite and probable) and those who did not have any evidence of secondary bacterial infection.

Statistic analysis

Categorical variables were presented by frequency distribution and analyzed using univariate analysis (Chi-square test). Risk factors for bacteremia were further assessed using multivariate analysis. Any P < 0.05 was considered statistically significant.


  Results Top


During our study period, 423 children were admitted in our pediatric department with a diagnosis of dengue fever. Eighty-three children with persistent or recurrent fever were included in the study. Twenty-nine children (34.9%) had any one culture positive which was labeled as definite secondary bacterial infection, and 54 children had culture negative. Among 54 children who had culture negative, 7 had sepsis screen positive (positive CRP or leukocytosis) and labeled as probable secondary bacterial infection. Six children had elevated serum ferritin and the rest 41 were inconclusive. Those six children who had high ferritin were worked up for hemophagocytic lymphohistiocytosis and were excluded from further analysis. The number of children who had probable secondary bacterial infection was too less; hence, both groups – culture-positive sepsis and probable sepsis – are combined together for further analysis. The prevalence of secondary bacterial infection in our study population was 8.5% (36/423). On analyzing the 29 children with secondary bacterial infection, 6 had bacteremia, 20 had urinary tract infection (UTI), 2 had UTI with bacteremia, and 1 had bacteremia with CSF culture positive. Organisms and their resistance patterns are depicted in [Table 1].
Table 1: Secondary bacterial culture isolate and resistance pattern of organisms

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Analysis of demographic details of the study participants revealed 35 males and 42 females. The baseline characteristics of the study population are given in [Table 2]. Sixteen males and 20 females had secondary bacterial infection, and there was no significant difference between them. While analyzing the age group, secondary bacterial infection was highest among infants (7/10) (P = 0.054). Characteristics of fever analysis showed that secondary bacterial infection was higher in children (13/19) with longer fever duration (>5 days), with P = 0.020. Of those 36 children, 27 had persistent fever and 9 had recurrent fever. Seven out of eight children with severe dengue developed secondary bacterial infection (P = 0.016). Length of hospital stay was longer among children with secondary bacterial infection compared to children who recovered without bacterial infection (P = 0.041). A comparison of the hematological parameters did not show any significant difference between both the groups.
Table 2: Baseline characters of study population (n=77)

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The demographic, clinical and hematological parameters of both groups are compared in [Table 3] and 4. [Table 4] shows the risk associated with the independent variables sex, age groups, fever days, severity of illness, length of hospital stay, and hematological parameters and the dependent variable on multivariate analysis.
Table 3: Comparison of demographic, clinical, and hematological parameters

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Table 4: Risk factors analysis of secondary bacterial infection using multivariate analysis model

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  Discussion Top


Despite the powerful existence of the National Vector Borne Disease Control Programme (NVBDCP), dengue itself remains one of the biggest concerns in India with the high disease burden and frequent outbreaks leading to 1.88 lakhs positive cases and 325 death in 2017 as per NVBDCP data.[13] Secondary bacterial infection in dengue still remains an area to be addressed, and also, it is the need of the hour to make a decision when to start the antibiotics along with routine supportive management. Our study is one of the few studies in children describing secondary bacterial infection associated with dengue and risk factors associated with it.[14],[15]

According to our study, children with dengue fever who developed secondary bacterial infection were 8.5% similar to the study results of Pothapregada et al. (7.2%) but higher compared to the results of Pancharoen and Thisyakorn (0.5%).[16],[17] Six out of 29 (20.7%) definite secondary bacterial infection children had bacteremia which was in concordance with the study results of Leo et al.,[18] who reported that 14.3% of the dengue patients had secondary bacteremia. Few other studies by Lahiri et al., Ong et al., and Lee et al. had reported a higher rate of bacteremia 44.4%, 42.9%, and 37.5%, respectively.[19],[20],[21] This difference may be attributed to the difference in the study population group as most of the studies were done in adults. None of our children who developed bacteremia had risk factors such as central line and arterial line. Only one child was ventilated for altered sensorium.

Among our bacteremia isolates, 2 (33.3%) were methicillin-resistant Staphylococcus aureus and 2 (33.3%) were  Escherichia More Details coli (E. coli) which is discordant from the other study results as many had reported Gram-negative bacteremia as the most common. Staphylococcus infections are also raising concerns in our setup.

Among these isolates extended spectrum beta lactamases producing enterobacteriaceae and carbapenem resistant enterobacteriaceae were almost equal (ESBL - 7 and CRE - 6). 2 children with Pseudomonas aeruginosa had urosepsis with positive blood culture. None of these children with confirmed urinary tract infection were catheterised during hospital stay. In children with confirmed or probable secondary bacterial infection, only 2 children were catheterised, one with probable sepsis and another child with enterobacter meningitis. The reason for this high incidence of UTI could not be explained with the present study and needs further evaluation.

On comparing the demographic details of both the groups, there was no statistically significant difference between males and females. In our study, the odds of secondary bacterial infection is high in infants and decreases with age (odds ratio [OR] – 5.5; P = 0.054). This may be explained by the immature immune system in infants making them vulnerable to secondary bacterial infection.

Children who had fever more than 5 days on admission had significantly higher secondary bacterial infection than children who had fever less than 5 days on admission (OR 4.94, P = 0.020). The odds of secondary bacterial infection was higher in children with severe dengue (OR – 22.5; P = 0.016). This can be explained by an increase in intervention and gut translocation of microbes. Although some studies have shown an association of hematological parameters and secondary bacterial infection, our study findings have not made any significant association between secondary infection and hematological parameters lowest total count, absolute neutrophil count, platelet count, and mean platelet volume observed anytime during the illness which is similar to the study results of Kumar et al.[22]

It was also noted that children with secondary bacterial infection had significantly prolonged hospital stay than children who recovered without any infection. This shows the additional health-care burden imposed by secondary infection prolonging need for antibiotic therapy and hospital stay. However, there was no mortality, though one of the patients with Enterobacter meningitis had mild neurological deficit on follow-up. One child who had urosepsis presented to PICU with septic shock.

Limitations

The limitation of our study is that it is a retrospective study, data retrieved from case sheets, which has its own limitation. A larger sample size and a prospective study is needed.


  Conclusion Top


Secondary bacterial infection in children with dengue fever was higher in infants, children with severe dengue, and children who had fever >5 days on admission. Secondary bacterial infections result in prolonged hospital stay. Hence, a low threshold to work up for secondary infection is warranted in infants and children with severe dengue, and early initiation of antibiotics needs to be considered in appropriate situation.

Acknowledgment

  • Dr. Vikram Sagar Thimma Vidyasagar, FRCP – Senior Consultant, Nephrology, Velammal Medical College Hospital and Research Institute (VMCH and RI) – who helped in revising the article
  • Dr. Pratheebau Mohanraj Saraswathi and Dr. Priyadharshini Rajendran – Junior Residents, VMCH and RI – who helped with data collection
  • Aruna Vasudevan and Ashika Chandramohan – Interns, VMCH and RI – who helped with data collection
  • Mr. Vijay Anto James – Statistician, VMCH and RI – who helped with statistical analysis
  • Mrs. Sylvia Jayakumar – Statistical Consultant, STATSHUB – who helped with statistical analysis
  • Dr. Mathevan Ganesapillai and Dr. Jhansi Charles – who permitted us to conduct study.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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