Dengue Fever in Pediatrics

Abstract

Dengue continues to be a health problem in the world, according to data from the PAHO. In recent years, dengue cases have been reported from 505,430 cases in the year 2000 to 5.2 million in the year 2019; among the most affected groups are those under 15 years of age. Dengue is a viral disease caused by a virus of the Flaviviridae family, of the Flavivirus genus. It is a disease that requires the bite of the female Aedes aegypti mosquito; the incubation period varies from 8 to 12 days. The pathophysiology of dengue is due to the alterations suffered by the endothelium when caused by the viral particle. Three phases have been identified: 1. the febrile phase; 2. the critical phase, in which patients develop systemic symptoms with a greater inflammatory response, with a risk of bleeding; and 3. the recovery phase. The main symptoms are fever, headache, retro-ocular pain, arthralgia, myalgia, and within the laboratory alterations are elevated hematocrit (hemoconcentration), leukopenia, and thrombocytopenia, among the complications, are pleural and pericardial effusion and ascites, as well like crash and death.

1. Introduction

Dengue continues to be a severe health problem in the world. According to data from the PAHO, despite the measures to try to contain the number of dengue cases, it continues to be a problem of public health in at least 100 countries. In recent years, dengue cases have increased, probably associated with the increase in urbanization of some areas. This situation conditioned an increase in cases from 505,430 cases in the year 2000 to 5.2 million in the year 2019, and of these 28,000 cases were serious, with a report of 1534 deaths. During the year 2020, of the reported cases of dengue fever, 66% of the deaths correspond to the group of patients under 15 years of age. By the year 2021, 1,324,108 cases of arbovirus were reported, and of these, 89% (1,173,674) of the cases corresponded to dengue fever, the highest incidence of cases is concentrated in the regions of Africa, America, the Eastern Mediterranean, Southeast Asia, and the Western Pacific. During the pandemic, although there was a decrease in infectious diseases, there was also an apparent decrease in dengue cases between 2020 and 2021. This decrease was attributed to an underreporting of cases during the COVID-19 pandemic. However, this decrease in the incidence of infectious diseases did not occur in all countries, since in some countries, such as Pakistan and Thailand, they observed an increase in infectious diseases that were already controlled, such as typhoid fever, measles, and dengue fever, after the confinement [1, 2, 3, 4].

Dengue is a viral disease produced by a virus of the Flaviviridae family, of the Flavivirus genus, and there are four serotypes, DENV1, DENV2, DENV3, and DENV4. It is a disease that requires a vector for its transmission. The transmission of dengue fever is carried out by the bite of the female Aedes aegypti mosquito. The incubation period varies from 8 to 12 days, the onset of symptoms is related to the initial viral concentration, cases of dengue hemorrhagic fever have been reported more frequently in patients under 15 years of age, so review this topic as part of the diseases of the pediatric age. In some parts of the world, such as Asian countries, dengue fever has been considered a pediatric health problem. In Latin America, it was considered an entity with a higher incidence in the adult population; however, in recent decades, there has been an increase in the cases in the pediatric population, although not only the cases in the pediatric age have increased, but also the presentation of complications in this age group. Another problem that has been observed in some dengue-endemic cities has been co-infections, con-infections with typhus have been found in India, and during the COVID-19 pandemic, cases of dengue with co-infections with the SARS-COV2 virus were documented in dengue-endemic countries, so in these places, particular interest should be paid to the symptoms of these patients in whom dengue fever is suspected [5, 6, 7, 8].

Although it is true that this problem occurs in tropical places and with certain geographical characteristics, we must not forget that it can also be a traveler’s disease and that symptoms develop once the patient has returned to their place of origin, so that if a patient presents a fever that is difficult to control, accompanied by headache, joint pain, rash and/or signs of bleeding after traveling to a tropical area, the diagnostic possibility of dengue fever or dengue hemorrhagic fever should be investigated, as the case may be. The cases have been increasing in countries like Brazil, which entails, in addition to being a health problem, an increase in the economic requirements to handle this increase in cases [9, 10].

The diagnosis of dengue fever is established by identifying those tested for the virus from the sixth day by the Enzyme-Linked ImmunoSorbent Assay ELISA technique or by PCR). These tests will be carried out after the fifth or sixth day. Return day for greater diagnostic certainty [9].

2. Clinical manifestations

The pathophysiology of dengue is derived from the alterations suffered by the endothelium when infected by viral particles and the inflammatory response secondary to the infection. During the inflammatory response, the non-structural protein 1 (NS1) of the virus adheres to the vascular endothelium, altering the vascular permeability of molecules and liquids, the coagulation pathways will also suffer alterations, vascular fibrinolysis events will be triggered, and secondarily alteration of platelet adhesion, which generates a problem of thrombosis. These alterations would explain the presence of complications in dengue hemorrhagic fever, the vascular damage will initially cause alterations in the permeability of the endothelium, which, if they persist, can cause lysis of the endothelial cells, once irreversible damage to the endothelium is established. This allows proteins and fluids to leak into the third space, this leak of extravascular fluid will result in hemoconcentration and elevated hematocrit, loss of intravascular fluid that translates as arterial hypotension, which if perpetuated can condition the shock phase, and the presence of complications that lead the patient to death [11, 12, 13, 14].

As part of the study of the inflammatory response, some studies have been carried out in which various cytokines have been identified. The type of cytokines that have been identified seem to be related to the infecting serotype in such a way that it has been found that in infections by In DENV2 serotype, the cytokines IL12p70, IL6, and TNF-α are found to be higher than in DENV1 infections; however, interleukin 8 levels are similar in infections by both serotypes. In patients with dengue fever, a greater number of Interferon IF-Ύ than in patients with dengue hemorrhagic fever, the fact that the DENV2 serotype is associated with a higher concentration of cytokines also makes it associated with infections with a greater inflammatory response, and therefore with a greater number of hospitalizations [12].

In a study carried out in Mexico, higher concentrations of IL-12p70, TNF-α, and IL-6 were reported in patients with hemorrhagic dengue fever with the DENV2 serotype than in patients with the DENV1 serotype. However, the levels of TNF-α, IL -12p70, and IL-6 were higher in patients with dengue fever than in patients with dengue hemorrhagic fever infected with the DENV1 serotive. Higher concentrations of interferon (IFN)-γ and IL-12p70 were observed in patients with dengue hemorrhagic fever. If we remember that these cytokines are proinflammatory, it is understood why they are found in higher concentrations in patients with dengue hemorrhagic fever, and why the increase in endothelial permeability results in hemodynamic and coagulation alterations in these patients. Cytokines related to the endothelial inflammatory process, such as IL-12p70, IFN-γ, TNF-α, and IL-6, were higher in patients with dengue hemorrhagic fever. If we remember that these cytokines are pro-inflammatory, it is understood why it is found in older patients. Concentration in patients with dengue hemorrhagic fever and the reason for the increase in endothelial permeability, which allows capillary leakage of fluids, would explain the hemoconcentration, decreased intravascular flow, hypotension, and a greater risk of presenting a state of shock and complications, such as pleural and pericardial effusion and/or ascites [11, 12, 14].

It is evident that the inflammatory response of the patient will depend on the infecting serotype. It must not be forgotten that the different serotypes may be circulating in the same region, it will also influence the response if it is a primary infection or reinfection, either by the same serotype or a different serotype will also affect this response if the patient has other comorbidities, such as arterial hypertension, some immune deficiency or any history that affects the patient’s immune response [12, 14].

The clinical symptoms of dengue in pediatrics are variable and sometimes milder than in adults. However, three stages have been described: the febrile stage, the critical stage, and the recovery phase.

In the febrile phase, it occurs between the second and seventh day, there is a fever of up to 40°C, which is mediated by the response of IL1, IL6, and TNF and in this phase, the viremia is recorded by the viral particle that circulates or is associated with lymphocytes, macrophages or platelets. This febrile phase can be accompanied by headache, which is holocranial with retro-ocular pain, myalgia, and arthralgia, predominantly in the long bones, lower back, and lower limbs. A rash that appears between the 3rd and 4th day; some patients show improvement during this phase; patients with a history of a previous infection may present a shorter febrile period and improve or advance to the severe phase [8, 12, 15].

It is in the critical phase that the inflammatory response will cause alterations in the endothelium, which together with hypoalbuminemia will condition the leakage of capillary fluid, favoring the presence of pleural effusion, ascites, and edema in the extremities. At this stage, bleeding data, such as epistaxis, hemorrhages in the skin (petechiae) and mucous membranes, digestive tract can be presented; liver failure may also occur. It is in this phase that hypovolemic shock, due to hemoconcentration, can occur neurological problems, such as encephalitis, that can be caused by liver failure, should not be ruled out. Dengue shock must be managed in an intensive care area since that if not handled properly can cause the death of the patient. During the follow-up of a patient with a diagnosis of dengue fever, one should be aware of some symptoms that have been described as alarm data that could precede the state of shock, such as abdominal pain, vomiting, drowsiness, and hepatomegaly [13, 14].

During the recovery phase, it is accompanied by the normalization of laboratory abnormalities, such as thrombocytopenia and correction of coagulation times with the consequent reduction in bleeding risks. The recovery phase can appear from 2 to 3 days after the end of the critical phase, also during this phase an itchy maculopapular rash can be observed, it must be taken into account to make the differential diagnosis with Chinkungunya [10, 16, 17, 18].

Laboratory studies should be requested in those patients who observe risk factors, such as blood count, coagulation tests, transaminases, and ammonium levels. In case the patient presents disorders of the state of consciousness, with these studies, we can document hemoconcentration when finding elevated hematocrit, which would be an indication for the use of intravenous crystalloids, decreased platelet count (thrombocytopenia), if the patient has active bleeding or is at risk of bleeding, transfusions of platelet concentrates should be performed. With the determination of the coagulation times, if an alteration occurs, the administration of fresh frozen plasma or vitamin K can be indicated as required. In patients with altered state of consciousness and elevated liver transaminases, serum ammonium concentration should be determined, if elevated, antimony measures should be installed. Imaging studies such as a chest X-ray can help us document the presence of a pleural or pericardial effusion; an abdominal x-ray or an abdominal ultrasound would help us determine the presence of ascites [12, 13, 14].

In a pediatric hospital, in the state of Morelos HNM (Hospital del Niño Morelense) in Mexico, a study was carried out from 2018 to 2022 of patients diagnosed with dengue, 105 patients were obtained, finding the following results, the average age was 9 years with DS + -4.1 years; 61% of the patients only presented dengue fever in the febrile phase, while 38% presented symptoms that placed them in the critical phase, and only 1% presented shock data; 100% of the patients presented fever; headache 53.3%; asthenia and adynamia in 45.71% and alarm data, such as abdominal pain, in 38.09%; 33.3% vomited and 10.47% reported hepatomegaly, 29.52% reported bleeding in the mucous membranes, 8.57% petechiae, and 1.9% hypotension (Table 1).

Signs and symptoms, n = 105	Frequency	Percentage
Fever	105	100%
Headache	56	53.33%
Asthenia	48	45.71%
Adynamia	48	45.71%
Arthralgias	46	43.80%
Myalgias	43	40.95%
Abdominal pain	40	38.09%
Rash	39	37.14%
Vomiting	35	33.30%
Mucosal bleeding	31	29.52%
Retro-ocular pain	29	27.61%
Hepatomegaly	11	10.47%
Petexhiae	9	8.57%
Hypotensión	4	3.80%
Hypertensión	2	1.90%

Table 1.

Signs and symptoms observed in patients with dengue from 2018 to 2022 at the hospital den Niño Morelense (HNM) Mexico.

The first changes in the laboratory that can be detected in the febrile phase are leukopenia, thrombocytopenia, and increased transaminases. In the critical phase we find increased hematocrit, hypoalbuminemia, prolongation of coagulation times. In the HNM study, laboratory determinations were also performed on the patients, and thrombocytopenia was found in 59%, hemoconcentration in 31.42%, leukopenia in 48.7%, increased transaminases in 72.13%, and hypoalbuminemia in 33.3% Table 2 [13].

Laboratory Study	n	Frequency	Percentage
Thrombocytopenia	105	71	67.61%
Leukopenia	105	51	48.70%
Hemoconcentration	105	33	31.42%
Hypertransaminemia	61	44	72.13%
Hypoalbuminemia	45	15	33.33%
Coagulopathy	62	19	30.64%

Table 2.

Laboratory changes reported in HNM patients with dengue in the period 2018–2022.

Regarding complications in this series of HNM patients, pleural effusion was found in 5.71%, hemorrhage data in 4.76%, ascites in 1.9%, pneumonia in 0.95%, acute liver failure in 0.95%, and hypovolemic shock in 0.95%. No case of encephalitis was documented and 4.28% presented more than a complication.

3. Treatment

Treatment so far is symptomatic, and there is currently a dengue vaccine indicated for people with at least one primary infection, thereby reducing the risk of severe dengue.

According to the indications of PAHO, it is suggested to classify patients for treatment, as patients with ambulatory management, hospitalized patients for observation, and hospitalized patients for intensive management.

In the first group, patients present with fever, arthralgia, and myalgia live in an endemic area for dengue fever, which is why the diagnosis of dengue is suspected. If there is no evidence of dehydration or shock, fluids and fluids should be indicated. Antipyretics, if possible, should be reassessed every 48 hours; monitoring of alarm data, such as abdominal pain, vomiting, drowsiness, and bleeding data should be indicated. At this stage, paracetamol 10–15 mg/Kg/dose can be used with a maximum dose of 4 g in 24 hours, in children, remember not to use salicylates, once the patient has been identified, it is advisable 48 hours after the onset of the symptoms to take a blood count to determine the hematocrit and platelet count [4].

Patients with any comorbidity, such as arterial hypertension, diabetes mellitus, asthma, hematological diseases, cardiovascular diseases, or some autoimmune disease, children under 5 years of age, pregnant patients, and patients at social risk (who have difficult access to hospitals) should be hospitalized for surveillance. For health services, it is important to maintain hydration, intravenous (IV) crystalloid solutions should be used in case of having a high hematocrit or if diuresis is <0.5 ml/kg/hr., insist on fluid intake and keep comorbidities under control. In these patients, hematocrit, platelet count, coagulation times (PT, PTT), DHL, and transaminases (ALT, AST) should be determined. In this phase, it is indicated to take serology to try to identify the serotype [10, 19, 20].

Patients who require shock management should start infusion of crystalloid solutions in a 20mlKg bolus to try to restore a mean arterial pressure according to their age, and management of colloid solutions should be evaluated according to the hemodynamic evolution. If a decrease in hematocrit is reported, hemorrhage should be suspected, so a transfusion of concentrated erythrocytes should be evaluated. If despite fluid management, the patient still has signs of hypotension, the use of inotropes should be evaluated. These patients, in addition to the laboratory tests that have been mentioned, tests should be taken to evaluate renal function, echocardiogram, chest, and abdominal X-rays in search of pleural effusion or presence of ascites and in case of neurological data, such as loss of state of consciousness or seizures, consider performing a head tomography, magnetic resonance imaging, and/or lumbar puncture; to evaluate his discharge he must be without fever, without data of hemodynamic alteration, normal platelet count, and normal hematocrit, as well as good tolerance to the oral route to be able to discharge him without risk of relapse [4, 9, 15].

It is a fact that after the COVID-19 pandemic, many things will change. In this case, we must not forget that both COVID-19 and dengue fever are viral diseases, or that they may share clinical characteristics, in addition to the fact that they must be to consider diagnostic possibilities when faced with a patient with fever or even not to forget that both infections can be present together. The diagnosis of dengue should be thought of as one of the traveler’s diseases, so it is important to ask the patient about trips to dengue endemic places, and in this way, we can have cases of dengue fever in places where it is not endemic. The geographical and climatic conditions are not going to favor its spread, especially in communities where dengue fever is not endemic, however, it must not be forgotten that with changes in global climate conditions, the conditions for its spread can occur. Of dengue, as well as the appearance of different serotypes in regions where it is not common to find them [20].

4. Prevention

Prevention measures include the use of mosquito nets, avoiding the accumulation of scrap, and avoiding collections of stagnant water. Some authors have correlated the increase in urbanization with the increase in dengue cases, as well as the deficiency in the disposal of garbage from the communities; the use of repellents has modified the prevalence of the different serotypes, some studies reveal that people who have suffered from dengue fever will have better practices of preventive activities to avoid contracting the disease again. After the pandemic, it was observed that in some places, they improved their hygiene habits in order to reduce the risk of contracting COVID, and that improved the health of people in dengue-endemic areas, it is suggested that in endemic areas the health authorities should send information to the inhabitants in order to improve health education in these areas [21].

It should not be forgotten that dengue fever is also related to seasonal weather variability, and it is a fact that global warming is causing changes in many regions of the world, so the spread of arbovirus infections may be modified [18].

5. Conclusions

Dengue is a health problem and children are among the vulnerable groups. The clinical picture may be mild, presenting only fever and general state attack, but it should not be ruled out that each patient diagnosed with dengue fever may present hemorrhagic dengue, shock and death. So, it is important to know the clinical picture, diagnostic methods, management and, above all, in endemic areas, continue with the prevention and eradication programs of the A. aegypti vector.

Conflict of interest

The authors declare they have no conflict of interest.

Financing

This work has no funding.

Abbreviations

PAHO	Pan American Health Organization
DENV 1	Dengue virus serotype 1
DENV 2	Dengue virus serotype 2
DENV 3	Dengue virus serotype 3
ELISA	Enzyme-Linked ImmunoSorbent Assay
PCR	Polymerase chain reaction
NS1	Non-structural protein 1
IL12p70	Interleukin 12p70
IL6	Interleukin 6
TNF-α	Tumor necrosis factor alpha
IFN-γ	Gamma interferon
TNF	Tumor necrosis factor
HNM	Molerense Children’s Hospital
PTT	Partial thromboplastin time
PT	Prothrombin time
DHL	Lactic dehydrogenase
ALT	Alanine aminotransferase
AST	Aspartate aminotransferase