Correlation of Laboratory Profile and Clinical Features in Dengue Viral Illness in the Pediatric Population: A Retrospective Analysis
Corresponding Author: Keyur D Mahajan, Department of Paediatrics, Deenanath Mangeshkar Hospital & Research Center, Pune, Maharashtra, India, Phone: +91 9850175069, e-mail: firstname.lastname@example.org
Received on: 12 May 2023; Accepted on: 03 July 2023; Published on: 29 September 2023
Objective: To study the correlation between laboratory profile and clinical features in dengue viral illness in the pediatric population.
Materials and methods: A retrospective study was conducted on pediatric patients, ranging from 0 to 16 years old, diagnosed with dengue viral illness and admitted to the pediatric care unit between January and December of 2022. The outcome of interest measured was the correlation between laboratory profile and clinical features of dengue patients. Depending on data distribution, appropriate tests were applied for analysis. Data were collected from hospital software records according to the set pro forma. The medical notes and the Laboratory Information System were evaluated using a tool for standard assessment.
Conclusion: The presentation of dengue viral illness can vary, and it is crucial to diagnose it early for effective patient management. Upon admission, common clinical presentations include fever, nausea, vomiting, abdominal pain, body ache, leg pains, and retro-orbital pain. However, there was no association between presenting complaints and progression to severe illness. Although all five patients who died from the disease were females, it is inconclusive if sex is a significant risk factor for severe disease. Likewise, the patient’s age has no association with the progression to severe disease. Platelet count, serum (Sr) albumin, Sr glutamic-oxaloacetic transaminase (SGOT)/Sr glutamic pyruvic transaminase (SGPT), prothrombin time (PT) international normalized ratio (INR), and Sr ferritin levels are all excellent predictors of prognosis for severe dengue. Peak Sr ferritin levels indicating the highest immune response were seen on day 5 of illness and were not affected by the age or sex of the patient.
How to cite this article: Mahajan KD, Joshi R. Correlation of Laboratory Profile and Clinical Features in Dengue Viral Illness in the Pediatric Population: A Retrospective Analysis. Pediatr Inf Dis 2023;5(3):71–78.
Source of support: Nil
Conflict of interest: None
Keywords: Clinical features in pediatric dengue, Dengue fever, Laboratory profile in pediatric dengue, Serum ferritin in dengue
Dengue virus (DENV) is an arbovirus (arthropod-transmitted virus) from the Flavivirus family and is one of the leading causes of mosquito-borne diseases worldwide.1 It is a single-stranded, enveloped ribonucleic acid (RNA) virus transmitted to humans commonly through the bite of Aedes aegypti and sometimes Aedes albopictus mosquitoes.2 There are four serotypes for the DENV, DENV-1, DENV-2, DENV-3, and DENV-4.
Dengue fever is common across tropical regions, with fluctuations in the level of danger affected by factors such as precipitation, temperature, and unplanned, fast urban growth. The prevalence of dengue fever has significantly increased globally in the past few years. However, the exact figures related to the number of cases are not accurately reported, and some cases are incorrectly categorized. According to recent estimates, there are roughly 390 million cases of dengue infections worldwide every year, with a credible range of 284–528 million. Out of these cases, 96 million individuals experience clinical symptoms of varying severity.3 Additionally, another study found that approximately 3.9 billion people living in 128 different countries are at risk of contracting DENVs.4 The incidence of dengue fever is increasing worldwide, particularly in tropical nations, which creates a significant public health challenge for developing nations. According to World Health Organization (WHO) estimates, in 2019, dengue cases reached a new global high with widespread impact across all regions. Additionally, Afghanistan documented its initial instance of dengue transmission. But amidst the coronavirus disease of 2019 pandemic, it was reported that in 22 countries where dengue fever is prevalent, there was a reduction of around 16% in its occurrence, according to data, and we might see an upsurge in cases postpandemic.5
Dengue can manifest in various ways, ranging from a mild febrile illness to a severe, potentially fatal disease. According to panels of experts in various locations, including Havana, Cuba in 2007, Kuala Lumpur, Malaysia in 2007, and at WHO headquarters in Geneva, Switzerland in 2008, it is widely agreed upon that dengue is a single disease that can present with a variety of clinical manifestations and often exhibits unpredictable progression and results.6 Although a majority of patients recuperate from a nonthreatening illness on their own, there is a small proportion that may experience a severe condition characterized by plasma leakage, sometimes accompanied by bleeding. Treating these severe cases with intravenous rehydration has been shown to decrease the risk of dying to <1%. Identifying patients that could progress to a more harmful stage is not always straightforward, but it is crucial since treating them properly could prevent more serious complications.6
The organization WHO proposed a revised severity classification for dengue in 2009 to aid clinicians in determining appropriate patient triage, observation, and treatment levels with greater practical relevance. The following image, taken from the WHO’s dengue guidelines, illustrates how we can distinguish between a child with dengue viral illness who is experiencing a severe form of the disease and one who is not. The criteria classify dengue patients into two categories: nonsevere dengue (with or without warning signs) and severe dengue (if the child exhibits any of the three criteria—severe plasma leakage, severe hemorrhage, or any severe organ involvement)6 (Fig. 1).
The classification mentioned serves as a guide for clinicians to determine the appropriate observation or treatment setting for patients with varying degrees of dengue fever. Typically, patients without warning signs are observed at home, those exhibiting warning signs are admitted to a ward, and patients with severe dengue require pediatric intensive care unit (ICU) monitoring. However, this classification may not always accurately predict a patient’s clinical course, as it can be unpredictable. Even a well and stable child may suddenly deteriorate and require ICU care. To address this issue, researchers have attempted to identify various risk factors and create scoring systems to predict the likelihood of a child progressing to severe dengue disease. In accordance with the WHO guidelines set in 2009, Sangkaew et al. discovered that severe illness was linked to clinical symptoms such as vomiting, abdominal pain and tenderness, spontaneous and mucosal bleeding, and clinical fluid accumulation.7 Another study by Srisuphanunt et al. attempted to create a rating system where the total scores ranged from 0 to 38.6, and the threshold score for predicting dengue severity was over 14.8 In recent times, researchers have shown a growing interest in using inflammatory markers such as serum (Sr) ferritin levels to predict the occurrence of severe dengue.9,10
MATERIALS AND METHODS
A medical record review was conducted on pediatric patients, ranging from 0 to 16 years old, who tested positive for dengue NS1, immunoglobulin (Ig) M or both and were admitted to the pediatric care unit between January and December of 2022.
The dengue NS1 test was utilized to identify the NS1 nonstructural protein of the DENV, which is discharged into the bloodstream during dengue infection. The presence of NS1 can be detected in the initial phase of DENV infections and show a comparable level of sensitivity to molecular tests within the first 0–7 days of symptoms. NS1 testing should not be done after day 7. A positive NS1 test result points to a dengue infection but cannot confirm the serotype. It is worth noting that a negative NS1 test result cannot completely rule out an infection, and we performed additional tests such as dengue IgM antibody to confirm recent dengue exposure.11
It is essential to quickly diagnose and provide early treatment for patients with dengue, as delayed diagnosis can lead to severe outcomes. Although the WHO suggests real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) for diagnosis, these methods may not be practical in developing nations due to financial constraints, limited availability, and longer result times. Instead, our laboratory employs a rapid diagnostic method called Immunofluorescence assay. As per the WHO paper on the evaluation of commercially available anti-DENV IgM tests, the rapid diagnostic tests (RDTs) showed lower agreement with the reference standard assays for both sensitivity and specificity than ELISA-based tests, but there are studies which have also shown that detecting NS1 and IgM through Immunofluorescence assay yielded comparable results to serology or RT-PCR.12,13
All pediatric patients diagnosed with dengue viral infection between the age-group 0 and 16 years and admitted to our hospital between the 1st of January and the 31st of December 2022.
Possible alternative diagnosis present.
Preexisting illness, which can affect laboratory values.
Our study was a retrospective observational study with no intervention. The outcome of interest measured was the correlation between laboratory profile and clinical features of dengue patients. Depending on data distribution, appropriate tests were applied for analysis.
Data were collected from hospital software records according to the set pro forma. The medical notes and the Laboratory Information System were evaluated using a tool for standard assessment.
We utilized descriptive statistics to depict the data in a clear and concise manner. To explain numerical data, mean, median, and standard deviation (SD) were presented, whereas categorical data was explained using frequency and percentage. The χ2-test was performed to identify any connection between two categorical variables. To compare two independent numeric groups, the Mann–Whitney U test was executed, while for comparing more than two independent numeric groups, Kruskal–Wallis test was employed. All these analyses were conducted using Statistical Package for the Social Sciences version 25, with statistical significance considered as a p-value <0.05.
Between January and December 2022, a total of 85 patients diagnosed with dengue fever were admitted to our unit. Of these, five patients had cofactors mentioned in our exclusion criteria and were therefore not included in our study. The remaining 80 patients were diagnosed with dengue fever based on laboratory parameters of either or both dengue NS1 antigen and IgM antibody testing, as well as their clinical presentation.
Of the 80 patients, 37 (46%) were male, and 43 (54%) were female. There was no statistical difference in the distribution of cases based on sex. We further classified the patients according to their illness’s severity based on WHO guidelines.6
Among the cases, 42 were categorized as nonsevere dengue fever. Of these, 12 showed no warning signs, while 30 showed at least one warning sign (as discussed in Fig. 1). The remaining 38 cases were classified as severe dengue fever as they displayed one or more clinical features or laboratory parameters indicating severe plasma leakage, severe hemorrhage, or severe organ involvement.
There was no significant difference in the distribution of dengue cases based on sex and severity, indicating that sex does not play a role in the progression toward severe disease. However, there were five deaths among females in the pediatric ICU this year (Table 1).
We also plotted the number of patients according to different age-groups, but there was no significant association between age and progression to severe dengue (Table 2).
|Age group||Total no. of patients||No. of severe dengue patients||p-value|
The most common presenting complaint was fever, followed by nausea/vomiting, abdominal pain and ache/pain like body aches, and retro-orbital pain. The erythematous rash was also a presenting complaint in a few patients. A comparison of complaints on admission for nonsevere and severe dengue cases found no significant difference. This suggests that admission complaints alone cannot predict the progression toward severe disease (Table 3).
|Complaints on admission||Nonsevere (n= 42)||Severe (n= 38)||Total (n= 80)||p-value|
|Bleeding from any site||2||1||3||0.616|
Various clinical features were also analyzed to identify dengue warning signs and severe dengue, but no significant difference based on sex was found except for severe bleeding (p = 0.032), where all patients were females and died. This limited sample size indicates that female sex can be a contributing factor towards severe bleeding, but a larger sample size is necessary to confirm this finding (Table 4).
|Clinical signs (warning + severe)||Male (n= 37)||Female (n= 43)||Total (n= 80)||p-value|
|Clinical fluid accumulation||3||6||9||0.409|
|Liver enlargement >2 cm||4||5||9||0.908|
|Increasing HCT/ decreasing platelet count||21||29||50||0.655|
|E/o plasma leakage||11||17||28||0.359|
|Severe organ involvement||3||5||8||0.601|
In addition, we conducted an analysis of various significant laboratory parameters for distinguishing between nonsevere and severe dengue. Our findings revealed that there were notable differences in the distribution of certain laboratory values, including the lowest platelet count (p = 0.020), Sr albumin level (p ≤ 0.001), Sr ferritin level (p = 0.010), liver enzymes such as Sr glutamic-oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) (p = 0.005) and Sr glutamic pyruvic transaminase (SGPT)/alanine transaminase (ALT) (p = 0.014), and prothrombin time (PT) international normalized ratio (INR) (p = 0.046). These findings imply that these laboratory values can serve as reliable indicators for tracking patients with early warning signs and detecting the progression to severe dengue (Table 5).
|Hemoglobin on admission||g/dL||13.30||12.80||2.18||13.65||13.40||2.12||0.426|
|Total leukocyte count on admission||cells/cmm||5531.62||4675.00||2892.95||6347.57||6100.00||3107.29||0.250|
|HCT on admission||%||40.45||40.15||6.08||40.73||40.60||5.62||0.757|
|Lowest platelet count||cells/cmm||86523.81||60000.00||79359.09||46833.33||34000.00||39668.99||0.020|
|Sr albumin||gm/dL||3.77||3.75||0.44||3.22||3.21||0.65||< 0.001|
An attempt was made to identify significant parameters and the day of illness when they manifested. Data visualizations were created, which mapped all the relevant parameters for each patient based on the respective day of illness they materialized, and median values were calculated. The outcomes indicate that most patients experienced severe bleeding or severe organ involvement on day 5 of illness. Additionally, the median day for dengue shock manifestation was day 3 of illness, and parameters such as lowest platelet count, highest hematocrit (HCT) value, and plasma leakage occurred concurrently on day 6 of illness (Table 6).
|Nonsevere dengue||Severe dengue||All patients combined|
|Lowest platelet count||6.0||6.0||6.0|
|Highest HCT value||6.0||5.5||6.0|
|E/O plasma leakage||–||–||6.0|
|Severe organ involvement||–||–||5|
As discussed above, Sr ferritin levels are useful in evaluating patients with warning signs for their possibility of progression to severe disease. Further analysis was carried out to investigate the relationship between Sr ferritin value, age, and sex, and no statistical variance was noted in the distribution of Sr ferritin value based on the age or sex of the patient (Tables 7 and 8).
|Sr ferritin||0–1 years||2–5 years||6–10 years||11–16 years|
Mean Sr ferritin levels were computed based on the day of testing and presented graphically in three series—series 1 for all patients, series 2 for severe dengue patients and series 3 for nonsevere patients. There is a substantial difference in Sr ferritin levels on the 5th day of illness in severe and nonsevere dengue patients, indicating maximum immunological response on day 5 of illness (Fig. 2).
Dengue is one of the commonest vectors born viral illnesses in tropical countries. Diagnosis of dengue is a challenging part, as the disease has such a diverse presentation according to the day of illness, and different diseases can mimic dengue viral fever.6
Despite many efforts, we are not able to understand the pathogenesis of dengue completely.14 In the initial days of illness, we cannot differentiate dengue based only on clinical parameters, as it presents as a flu-like illness. Other viral illnesses like influenza, chikungunya, measles and infectious mononucleosis can easily mimic the febrile phase of illness. We have not completely understood the mechanism for systemic vascular leak and why few patients do well despite bad laboratory parameters, and why someone deteriorates suddenly despite having a good laboratory profile.15 All four viral serotypes are associated with severe dengue. But subsequent infection with another serotype after primary infection is associated with more severe illness.16,17 We also know that disease severity in dengue is not associated with viral load, but it is more of an immune-mediated mechanism.18,19
In 2009, the WHO working group set out a series of guidelines for the clinical management of dengue.6 Previously, we used to divide the dengue disease spectrum into dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. But as we know, systemic leak syndrome and hemorrhagic manifestation could overlap in a single patient, which makes the old classification less useful. The new guidelines classified dengue into dengue (with or without warning signs) and severe dengue. This helped to establish uniform and simpler clinical classification for a standardized approach all over the world.
Dengue is a disease that affects the entire body and progresses in stages. Once the incubation period ends, the sickness starts suddenly and goes through three stages: febrile, critical, and recovery.
In the febrile phase, individuals commonly experience a sudden onset of high fever that can persist for 2–7 days. This is often accompanied by other clinical features such as erythematous skin, overall bodily discomfort, joint and muscle pain, retro-orbital pain and headache.20,21 In addition, there may be some mild hemorrhagic symptoms like nosebleeds or bleeding from the gums or mucous membranes, as well as petechiae.21
Typically, between days 3 and 7 of an illness, as the fever begins to decrease, there may be an upsurge in capillary permeability accompanied by a rise in HCT levels which signifies the initiation of the critical phase (Fig. 3). During this phase, extensive plasma leakage usually persists for a duration of 24–48 hours. Before plasma leakage occurs, leukopenia and a rapid decrease in platelet count often happen.21 Patients who do not experience an increase in capillary permeability tend to improve, whereas those with increased permeability may worsen due to a loss of plasma volume. The extent of plasma leakage is typically indicated by the degree to which there is an increase in the baseline HCT. The amount of plasma leakage can vary, and pleural effusion and ascites may or may not be detectable based on the extent of the leakage and the fluid therapy given.6,22
Warning signs (abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, liver enlargement >2 cm, increase in HCT with a rapid decrease in platelet count) will appear in those who deteriorate.6 These cases with warning signs, if treated with early intravenous rehydration, would recover. But despite adequate rehydration, some may progress to severe dengue.
In the recovery phase, once the 24–48-hour critical period has passed, the patient undergoes a gradual reabsorption of fluid in the extravascular compartment within the next 48–72 hours. This leads to an improvement in their overall well-being, return of appetite, reduction of gastrointestinal symptoms, stabilization of their hemodynamic status, as well as the onset of diuresis.
According to WHO 2009 guidelines, severe dengue is having one or more of the following:23
Severe plasma leakage leading to shock or fluid accumulation with respiratory distress.
Severe bleeding as evaluated by the clinician.
Severe organ involvement: Liver (SGOT/SGPT of ≥1000), central nervous system (impaired consciousness), heart and other organs.
When it comes to the diagnosis and laboratory parameters, various biomarkers have been used for diagnosis, like virus isolation and serotype identification by cell culture, nucleic acid detection by RT-PCR, NS1 antigen capture by ELISA or rapid tests, or detection of host immune response in the form of virus-specific immunoglobulins, IgM and IgG by ELISA or RDTs. The timing of the appearance of these biomarkers varies according to the day of illness; we should be aware of what test should be done at the presentation.
Real-time polymerase chain reaction (RT-PCR) and cell cultures are only for research value and can be done only in certain settings. PCR-based techniques offer several benefits, including the ability to detect viral RNA from the early stages of illness. Furthermore, these techniques are known for their sensitivity, specificity, speed, ease of use, and cost-effectiveness compared to virus isolation methods.24 The diagnostic test based on the viral protein NS1 has become a favorable option in today’s times due to the need for specialized equipment and trained staff for the RTPCR test, which may not be readily available in all settings.
NS1 is a protein produced by viruses that are released from infected cells. It can be detected in primary infections from the onset of symptoms up to 9 days or more. In primary infections, NS1 can be detected even before an antibody response is mounted by the body. The levels of NS1 in the body are related to the viral titers, making it a helpful indicator of viremia.25
In our study, the most common complaints on admission were fever, nausea and vomiting, abdominal pain and other aches like body aches, leg pains, and retro-orbital pain. A study conducted in Thailand also had similar observations about the clinical profile of their patients, where vomiting, rash, headache, abdominal pain, and reduced appetite were some of their common clinical complaints on admission.8 Similar observations were also noted by Pothapregada et al. in their study where they had done clinical profiling of pediatric dengue patients.26 We also observed that there was no significant difference in the clinical presentation of patients who later progressed to severe dengue, inferring that complaints on admission could not be a predictive factor for deciding who will progress to a severe form of the disease.
While analyzing warning signs and signs for severe dengue as per WHO classification, we have observed that laboratory parameter like increasing HCT and decreasing platelet count was the most common warning sign, followed by evidence of (e/o) plasma leakage, abdominal pain, lethargy, and persistent vomiting. We have also observed that sex is also not the statistically significant predictive factor (p = 0.849) in deciding who will progress to a severe form of the disease; however, all five deaths which occurred during this study period were of the female sex. A study done in Vietnam showed that girls had a higher risk for dengue shock syndrome and death as compared to boys.27 But to conclude that the female sex is a predisposing factor for mortality in dengue based on these observations, we will need a larger multicentric trial. When we analyzed to progression to severe dengue based on age as a criterion, we found that, again, age is also not a significant risk factor for progression to severe dengue. Similar observations were also made in another study done in Thailand.28
In lab parameters, platelet count, liver function tests (Sr albumin, SGOT/SGPT, PT INR), and Sr ferritin level values are statistically significant in differentiating severe dengue. Monitoring these values will definitely help us to decide the course of action and level of monitoring required for a particular patient. Similar observations were noted by Sangkaew et al. in their systemic review, where they tried to identify the risk predictors for progression to severe dengue.7
As we know, severe dengue is a manifestation of an immune response of a body rather than a direct effect of a virus on various organs,18,19 more focus is now shifted to studying immune markers in dengue patients. We also tried to study the correlation of Sr ferritin, one of the statistically significant inflammatory markers, for its association with age and sex, and we found that there is no statistically significant variation between age and sex. Thus, this inflammatory marker can be used in all patients with severe dengue, irrespective of age and sex.
When we plotted mean Sr ferritin levels according to the day of illness on which they were done, we can see there is a peak on day 5 of illness in severe dengue patients, thus indicating the highest immune response on day 5th of illness. Similar observations were made in a study done by Sekhar in pediatric patients.29 Chaiyaratana et al. in their study concluded that sr ferritin levels ≥1200 can be used as a predictor of severe dengue.30 Thus, we can conclude that Sr ferritin can be used as a predictor for severe dengue. Similar observations were done by Soundravally and colleagues.31
Future Advances in Dengue
We feel current guidelines in the management of dengue are based mainly on managing shock and hemorrhagic manifestation. We all know the severity of dengue depends on the immunological response mounted by the patient to illness rather than viral load. In our settings, we have many times seen a child deteriorates quickly despite a diagnosis made in time. WHO algorithms for management are based mainly on two factors, first, hypotension, that is, management of shock, and second, management of hemorrhagic manifestations. We, as clinicians, think more research is needed in the immunological aspect of dengue and its management because there are still many things that we do not understand. Studies are being conducted on mouse models for the use of monoclonal antibodies in the management of dengue, and a lot of research is needed in this aspect.32,33
There are many futuristic tests under development, like advanced lyophilized loop-mediated isothermal amplification based point of care technique for the detection of DENV.34 Piezoelectric immunochip coated with thin films of bacterial cellulose nanocrystals for dengue detection.35
Significant strides have been made by researchers in creating reliable and secure vaccines against the DENV. It is expected that a safe and cost-effective vaccine for dengue may become commercially available within the next few years.36 Antiviral drugs are also under investigation to diminish the threat of severe dengue illnesses.37,38 In the event that safe antiviral treatments are developed, individuals can receive them during dengue epidemics with or without a fever to reduce the symptoms of dengue.
Limitations of the Study
Our study had some notable restrictions. For instance, OPD basis managed nonsevere dengue patients were not included. Additionally, to eliminate possible biases in our study, a larger patient pool is necessary.
The presentation of dengue viral illness can vary, and it is crucial to diagnose it early for effective patient management. Upon admission, common clinical presentations include fever, nausea, vomiting, abdominal pain, body ache, leg pains, and retro-orbital pain. However, there was no association between presenting complaints and progression to severe illness. Although all five patients who died from the disease were females, it is inconclusive if sex is a significant risk factor for severe disease. Likewise, the patient’s age has no association with progression to severe disease. The prognosis for severe dengue is well predicted by the platelet count, Sr albumin, SGOT/SGPT, PT INR, and Sr ferritin levels. Peak Sr ferritin levels, which indicate the strongest immunological response, were observed on day five of the illness and were unaffected by the patient’s age or gender.
Keyur D Mahajan https://orcid.org/0000-0001-5738-1818
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