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Consensus and Guideline

Guidelines for the Diagnosis and Treatment of Dengue in China

Zhang, Fuchun1; He, Jianfeng2; Peng, Jie3; Tang, Xiaoping1,∗; Qin, Chengfeng4; Lu, Hongzhou5; Li, Xingwang6; Liu, Qingquan7; Zhao, Hong8; Sheng, Jifang9; Wang, Guiqiang8,∗

Editor(s): Zhao, Wei; Wang, Haijuan

Author Information
Infectious Diseases & Immunity: October 2021 - Volume 1 - Issue 3 - p 144-152
doi: 10.1097/ID9.0000000000000026

Abstract

Introduction

Dengue is an acute infectious disease caused by the dengue virus (DENV), which is one of the most widely spread mosquito-borne infectious diseases worldwide. Dengue causes flu-like symptoms and can be lethal and kill up to 20% of those with severe dengue, and has been a growing threat for decades. The World Health Organization (WHO) listed dengue as a potential threat among ten diseases in 2019.[1] In recent years, the dengue fever epidemic in China has gradually spread from southeastern coastal areas to all parts of the country.[2] The clinical and laboratory characteristics of dengue fever in China differ greatly from those reported in endemic areas. The vast majority of patients are adults, and most severe cases involve elderly adults with underlying diseases, and clinicians have insufficient experience in the early diagnosis and treatment of severe dengue. To standardize the diagnosis, treatment, and prevention of dengue fever, the Society of Infectious Diseases and the Society of Tropical Diseases and Parasitology of the Chinese Medical Association, and the Society of Emergency Medicine of the China Association of Chinese Medicine organized relevant experts in China to formulate the “Guidelines for the diagnosis and treatment of dengue in China” (hereinafter referred to as the Guidelines) in 2018, according to the latest domestic and international evidence of evidence-based medicine and 2009 WHO “Dengue: guidelines for diagnosis, treatment, prevention and control: new edition”,[3] the 2014 “guidelines for diagnosis and treatment of dengue” issued by the National Health and Family Planning Commission of the People's Republic of China,[4] and the professional standard of the People's Republic of China “diagnosis for dengue fever (WS216-2018)”.[5]

This guideline is intended to help clinicians make rational decisions in the diagnosis and treatment of dengue fever; however, this is not a mandatory standard and cannot encompass or address all issues in the diagnosis, treatment, and management of dengue fever. Therefore, clinicians should develop reasonable treatment plans based on their professional knowledge, clinical experience, and available medical resources and treat each patient on a case-by-case basis.

The levels of evidence in this guideline are divided into three levels: A, B, and C. The levels of recommendation are divided into two levels, 1 and 2 (revised according to the Grading of Recommendations Assessment and Development and Evaluation [GRADE] grading), as shown in Table 1.

Table 1 - Level of evidence and recommendation for recommendations
Level Detailed description
Level of evidence
 A High quality. Further research is very unlikely to change our confidence in the estimate of the effect.
 B Moderate quality. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
 C Low quality. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Level of recommendation
 1 Strong recommendation, which takes full account of the quality of the evidence, the likely prognosis of the patient, and the cost of treatment to reach a final recommendation.
 2 Weak recommendation, where the value of the evidence is mixed, where there is uncertainty in the recommendation, or where the recommended treatment opinion may have a higher cost to efficacy ratio, etc, are preferred to lower grades of recommendation.

Terms

Dengue virus (DENV): It is the causative agent of dengue fever and is classified into four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4).

Non-structural protein 1 (NS1 protein): The NS1 protein, encoded by the DENV genome, is secreted in large quantities in the serum of patients in the early stages of infection and can be used as a specific indicator for early diagnosis.

Antibody-dependent enhancement (ADE): Secondary infection with a heterozygous DENV can lead to ADE, which is one of the mechanisms of severe disease.

Imported cases and indigenous cases: Imported case includes both an abroad imported case and a domestic imported case. An abroad imported case is that who has traveled to a dengue-endemic country or region within 14 days before the onset of the disease. Domestic imported case is case that has left the prefecture (current address) and traveled to a dengue-endemic area outside the prefecture within 14 days before the onset of the disease. An indigenous case refers to a case that has not left the county (current address) within 14 days before the onset of the disease.[6]

Endemic: Areas where dengue is endemic, the DENV continues to circulate between the population and the vector Aedes mosquito, with outbreaks occurring year after year; most adults are already infected and most new cases are in children; multiple DENV serotypes may be circulating.

Warning signs: Clinical and laboratory warning signs of possible serious illness in dengue.

Severe dengue: It is a severe type of dengue fever with clinical manifestations such as severe bleeding, shock, and severe organ damage.

Tourniquet test: Also known as the capillary fragility test. A circle of 5 cm in diameter is drawn 4 cm below the bend of the elbow on the flexed side of the forearm and a sphygmomanometer cuff is placed on the upper arm of that side. The blood pressure is first measured and then kept between systolic and diastolic for 8 minutes before being released. When the skin color returns to normal, count the number of new bleeding spots on the skin within the circle; more than 10 new bleeding spots are considered positive for the arm restraint test.

Hematocrit (HCT): It is also known as erythrocyte pressure volume, refers to the ratio of the volume of red blood cells in the blood.

Fluid overload: In patients with severe dengue, excessive or rapid intravenous rehydration or inappropriate types of rehydration can lead to respiratory distress or acute pulmonary edema, large pleural effusions, and tense ascites.

Epidemiology and prevention

Epidemiology

Patients with dengue fever, latent infections, and non-human primates carrying the virus are the main sources of dengue transmission. Dengue is mainly transmitted through the bite of the vector Aedes mosquito, which sucks blood. In China, the main vectors are Aedes albopictus and Aedes aegypti. The population is generally susceptible, and some people become ill after infection.[7,8] After infection with DENV, the body develops lasting immunity to the same type of virus but does not provide effective protection against different types of viral infections. Re-infection with a different type of DENV triggers an increase in non-neutralizing cross-reactive antibodies, causing ADE, which is an important mechanism in the development of severe dengue and is one of the major barriers to the development of a dengue vaccine.[9]

Dengue is the most widespread arboviral disease in the world and is endemic in tropical and subtropical regions worldwide, particularly in more than 100 countries and territories in Southeast Asia, the Pacific Islands, and the Caribbean.[10] The incidence of dengue fever has increased 30-fold in the last 50 years. The WHO estimates that approximately 2.5 billion people worldwide are at risk of dengue infection, with up to 3.2 million cases reported annually in WHO member countries, making it a serious public health problem and a major disease burden worldwide.[11,12]

There is no evidence of endemic areas of dengue fever in China. Imported cases can be introduced into China year-round and can lead to local outbreaks and epidemics during the summer and autumn seasons when the density of Aedes mosquitoes is high, south of northern China. There are two forms of epidemics in China: imported cases and local infections, with imported cases existing all year round and the main sources of cases being Myanmar, Laos, Philippines, Thailand, and other Southeast Asian countries and regions.[13] Since the outbreak of dengue fever in Foshan City, Guangdong Province in 1978, epidemics and outbreaks have occurred in Guangdong, Yunnan, Hainan, Fujian, Guangxi, and Zhejiang provinces.[13,14] In 1989, China included dengue fever in the epidemic management of category B infectious diseases. In 2013, the first outbreak of severe dengue fever occurred in the border areas of Yunnan Province[15]; in 2014, a large-scale outbreak of dengue fever occurred in Guangdong Province, with more than 45,000 reported cases and a high number of severe cases, with a fatality rate of 1.3/10,000, and a trend of endemic in some areas of Guangdong Province.[16,17] In recent years, China's dengue fever epidemic has tended to spread from the tropical and subtropical southeastern coast to the temperate northern inland areas, with epidemics of local cases occurring in Henan Province in 2013 and Shandong Province in 2017.[14,18]

Dengue is endemic in Southeast Asia and other countries where it is prevalent year-round. Children and adolescents comprise the majority of the population affected, while older people are more resistant to dengue because they have been infected several times. The incidence of the disease is more frequent in men than in women.[19] However, dengue is found in all age groups in China, mainly in the 20 to 50 age group, with no significant difference in gender distribution, and the occupations of the cases are mainly domestic, commercial, and non-working.[20]

Prevention[21]

The main preventive measures for dengue fever are mosquito prevention and control; cutting off the transmission route, such as killing adult mosquitoes; removing breeding sites for Aedes; personal protection, wearing long-sleeved clothing and trousers; using mosquito repellents, etc. It is also important to diagnose patients early (especially those within 5 days of the onset of the disease) and to isolate them from mosquitoes. The vaccine is the most effective preventive measure.[22]

Recommendation 1: There is no vaccine available for this disease in China, and early detection is of great importance for the prevention and control; hence, it is important to ask about the epidemiological history of the case (B1).

Recommendation 2: Patients should be treated with anti-mosquito isolation within 5 days of onset, while adult mosquitoes should be immediately killed around hospital admission wards, medical staff should wear long-sleeved clothing and trousers, and screen doors and windows should be installed in duty rooms to prevent mosquito bites (C1).

Etiology and pathogenesis

Etiology

DENV is a pathogen of dengue fever and is classified into four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) depending on antigenicity, each of which can cause dengue and severe dengue.[3] DENV belongs to the Flavivirus genus of the Flaviviridae family. Members of the genus Flavivirus also include important human pathogens such as yellow fever virus, West Nile virus, Zika virus, encephalitis B virus, tick-borne encephalitis virus, and St. Louis encephalitis virus. The DENV genome is a single-stranded positive-stranded RNA of approximately 11 kb in length with non-coding regions at both ends and a single internal open reading frame encoding three structural proteins (C, prM/M, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). DENV is spherical particles with an internal nucleocapsid consisting of capsid protein C and genomic RNA and an external lipid bilayer embedded with viral structural proteins prM and E, with a diameter of 45 to 55 nm.[23] The NS1 protein is an important non-structural protein encoded by the DENV and can exist in three forms: intracellular, membrane-bound, and extracellularly secreted. Clinical studies have found that the presence of large amounts of NS1 protein in the serum of patients with DENV infection in the acute phase can be used as a specific indicator for early laboratory diagnosis.[24]

DENV is sensitive to heat, ultrasound, ultraviolet, 0.05% formaldehyde solution, lactic acid, potassium permanganate, gentian violet, and others can inactivate the virus, which is most stable in an environment of pH 7 to 9, and can survive for a long time at −70°C or via freeze-drying.

Pathogenesis

After the DENV enters the body through the bite of the Aedes aegypti mosquito, it proliferates in the monocyte-phagocyte system and enters the circulation, causing the first viremia, which then colonizes the reticuloendothelial system and lymphoid tissue, replicates to a certain extent in peripheral blood mononuclear cells, macrophages in tissues, and Kupffer cells in the liver, and enters the circulation again, causing a second viremia. The DENV binds to specific antibodies produced by the body to form immune complexes that activate the complement and coagulation systems, leading to increased vascular permeability, vasodilation, congestion, extravasation of plasma proteins, and tangible blood components, causing pathophysiological changes such as hemoconcentration, hemorrhage, and shock. Recent studies have shown that the cellular immune effect of DENV infection and the various cytokines produced mediate the immune response and affect the progression of the disease and its outcome. The virus also inhibits leukocyte and platelet production in the bone marrow, leading to leukopenia and thrombocytopenia. The mechanism of hemorrhage may be thrombocytopenia and its dysfunction and depletion of coagulation factors.[8–21,23]

The pathogenesis of severe dengue has not yet been fully elucidated because of the lack of ideal animal models. All four serotypes of the DENV are capable of causing severe dengue. Host and viral factors, such as ADE, cytokine storm, and viral virulence variation due to secondary DENV infection play an essential role in the pathogenesis of severe dengue.[25–29]

The pathophysiological changes in severe dengue mainly include increased vascular permeability and plasma extravasation, with no significant capillary endothelial cell damage. Plasma extravasation is the main clinical manifestation of severe dengue fever. Around time of defervescence, plasma enters the cavity in large quantities, blood volume is reduced, hemoconcentration occurs, erythrocyte specific volume increases and blood pressure falls, eventually leading to shock. Shock is hypovolemic shock caused by plasma extravasation resulting in reduced blood volume, terminal vasoconstriction resulting in cold extremities, high diastolic blood pressure, and reduced pulse pressure difference, and to maintain myocardial perfusion during the compensatory phase of shock when diastolic blood pressure is elevated.[8–21,23]

Clinical features[3,4,30]

The incubation period for dengue fever is usually 1 to 14 days, most commonly at 5 to 9 days.

Dengue fever is a systemic disease with a complex and varied clinical presentation. The typical course of dengue fever is divided into three phases: the febrile phase, the critical phase, and the recovery phase. Depending on the severity of the disease, there are two clinical types of dengue fever: dengue and severe dengue. Most patients present with dengue fever, which may be characterized by a febrile and recovery phase only, while only a minority of patients develop severe dengue.

Course and clinical manifestations

The febrile phase: The patient usually has an acute onset. The first symptom is a sudden onset of high fever, which may be accompanied by chills, and the body temperature can reach 40°C within 24 hours. In addition to fever, patients may also experience headache, orbital pain, generalized muscle, bone and joint pain, fatigue, nausea, vomiting, poor appetite, abdominal pain, diarrhea, and other gastrointestinal symptoms. The febrile phase usually lasts 3 to 7 days. A congestive rash or punctate hemorrhagic rash appears on the face and extremities on the third to the sixth day of the disease, typically consisting of pinpoint hemorrhagic spots on the extremities or a fused erythematous rash with small patches of normal skin scattered throughout, like islands in a red ocean, referred to as “skin islands.” Varying degrees of bleeding, such as subcutaneous or mucosal bleeding, bruising at the injection site, gingival bleeding, epistaxis, and a positive beam arm test may occur.

The critical phase: The critical phase usually occurs between 3 and 8 days of the disease. During this period, some patients may experience significant plasma leakage due to increased capillary permeability, which may result in severe abdominal pain, persistent vomiting, bulbar conjunctival edema, signs of leakage from the extremities, pleural effusion, and ascites. Severe symptoms may cause shock, with manifestations such as hypothermia, tachycardia, wet and cold extremities, weak pulse, reduced pulse pressure, or failure to measure blood pressure. As the shock worsens and persists, metabolic acidosis, multi-organ dysfunction, and diffuse intravascular coagulation may occur. Laboratory tests may show progressive leukopenia, a rapid decrease in platelet count, elevated HCT, and a decrease in albumin levels. In a small number of patients, there is no significant plasma leakage, but severe bleeding (eg, subcutaneous hematoma, gastrointestinal bleeding, vaginal bleeding, intracranial bleeding, hemoptysis, carnivorous hematuria, etc) may still occur. In severe cases, chest tightness, palpitations, arrhythmia, orthopnea, shortness of breath, dyspnea, drowsiness, irritability, delirium, convulsions, coma, abnormal behavior, stiff-neck, lumbar pain, oliguria or anuria, profound jaundice, and other severe organ damage signs may also manifest. Death in patients with severe dengue usually occurs 24 to 48 hours after the start of the critical phase.

The recovery phase: 2 to 3 days after the critical phase, the patient improves, gastrointestinal symptoms decrease, white blood cell and platelet counts rebound, and the patient enters the recovery phase. Some patients may see pinpoint bleeding spots and may have skin pruritus.

The high-risk population of severe dengue[4,5,30]

Elderly, infant, and pregnant women; people with comorbidities such as diabetes, hypertension, coronary heart disease, peptic ulcer, asthma, chronic kidney disease, and chronic liver disease; and people with immunodeficiency states.

Early warning signs for recognition of severe case[4,5,30]

Early warning signs for severe cases include as follows: (1) deterioration after fever reduction or persistent high fever for 1 week, (2) severe abdominal pain, (3) persistent vomiting, (4) chest tightness and palpitations, (5) lethargy or irritability, (6) marked bleeding tendency (mucosal bleeding, dermal ecchymosis, etc), (7) oliguria, (8) rapid decline in platelets early in the course of the illness; (9) decreased serum albumin; (10) elevated HCT; (11) arrhythmias; (12) pleural effusion, ascites, or thickening of the gallbladder wall.

Diagnosis[3–5,30]

Laboratory diagnosis

Routine blood tests: Decreased white blood cell and platelet counts. The decrease in platelet count is proportional to the severity of the disease; increased HCT indicates hemoconcentration.[31]

Blood biochemical test: More than half of the patients showed mild to moderate elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), with a more pronounced increase in AST than ALT. Some patients have elevated B-type natriuretic peptide, cardiac enzyme profile, troponin, and serum creatinine.[31]

Pathogenic and serological tests: DENV nucleic acid, NS1 antigen, or IgM/IgG antibody test should be performed early in the course of the disease, and virus typing and virus isolation can be performed when available.[32,33] The specific tests and their significance are as follows:

  • (1) IgM antibody capture enzyme-linked immunosorbent assay (Mac-ELISA) to detect IgM antibodies to DENV. A positive IgM antibody indicates that the patient is newly infected with DENV, which is suitable for the early diagnosis of dengue fever.
  • (2) Direct enzyme-linked immunosorbent assay (ELISA) to detect IgM antibodies to DENV. A positive test indicated that the patient was newly infected with DENV, which is suitable for the early diagnosis of dengue fever.
  • (3) Enzyme immunoassay for the detection of the DENV NS1 antigen. A positive result indicates that the patient has a recent DENV infection, which is suitable for the early diagnosis of dengue fever.
  • (4) Immunofluorescence method (FA/IFA) to detect DENV IgG antibody. A positive result only indicates the possible presence of DENV infection, but a serum antibody potency of 1:80 or higher is diagnostic. A four-fold or higher increase in the potency of the recovering serum antibody compared to the acute serum antibody can confirm the recent infection of DENV.
  • (5) TaqMan probe real-time quantitative polymerase chain reaction for the detection of DENV RNA. This is a sensitive, specific, rapid, and low contamination method for the detection of DENV RNA in the early sera of patients with dengue fever, either qualitatively or quantitatively.
  • (6) Reverse transcription polymerase chain reaction (PCR) technique for DENV RNA detection and typing identification. This method allows the detection and typing of DENV in early cases, and the gene amplification products can be further acutely sequenced and analyzed.
  • (7) C6/36 Aedes albopictus cell isolation for the DENV. Isolation of DENV from blood, tissue, or adult mosquitoes of patients confirms the presence of DENV infection, and the virus type can be determined by identification.

The collection, storage, and transport of clinical specimens are important aspects of the accuracy of laboratory results and are particularly important for virus isolation and viral nucleic acid testing. Try to collect double copies of serum from patients in the acute and recovery phases. Venous blood of about 2 to 5 mL should be collected in sterile non-anticoagulated tubes, stored at 4°C, and sent to the laboratory for serum isolation within 24 hours. The specimen was tested as soon as possible after receipt by the laboratory. Sera that cannot be tested for pathogenicity in time can be stored frozen at −70°C, and repeated freezing and thawing should be avoided as much as possible; specimens for serological studies should be stored at −20°C.

Recommendation 3: Suspected cases or clinically diagnosed cases with DENV nucleic acid and NS1 antigen detected in blood within 1 to 5 days of onset, or isolation of DENV, or recovery period with more than a four-fold increase in serum specific IgG antibody titer compared to the acute period or conversion to positive can be diagnosed as confirmed cases (A1).[3–5]

Recommendation 4: Detection of IgM early in the course of the disease suggests acute infection (B1).[32]

Recommendation 5: Detection of IgG within 1 week of onset suggests secondary infection (B1).[34]

Imaging diagnosis

  • 1 Computed tomography (CT) examination of the chest and abdomen may reveal pleural effusion, pericardial effusion, ascites, and, in a few cases, subcutaneous hematoma or exudates; Chest X-ray examination may reveal an enlarged heart.
  • 2 Abdominal ultrasound may reveal thickening of the gallbladder wall, ascites, and enlargement of the liver and spleen. Ultrasound of the heart may reveal a weakened heartbeat or, in severe cases, an enlarged heart with a reduced left ventricular ejection fraction.
  • 3 Head CT and magnetic resonance imaging (MRI) can detect cerebral edema and intracranial hemorrhage.

Recommendation 6: Pleural effusion, ascites, and pericardial effusion on CT or ultrasound of the chest and abdomen are suggestive of plasma leakage (A1).

Electrocardiogram examination

Various arrhythmias, conduction blocks, non-specific ST-segment elevation, and T-wave inversions can be detected.

Clinical classification and diagnosis[3–5,30,35]

Based on the epidemiological data, clinical manifestations, etiology, serology, laboratory, and imaging findings of the patients, dengue fever can be classified into two clinical types: dengue and severe dengue.

Dengue: Recent travel to a dengue-endemic area, residence, or workplace with a case of dengue fever; clinical signs of fever with body malaise, anorexia, nausea, headache, muscle and bone and joint pain, rash, and bleeding tendencies; leukopenia and/or thrombocytopenia; and positive for DENV IgM antibody, NS1 antigen, or DENV nucleic acid.

Severe dengue: One of the following severe manifestations in addition to the diagnostic criteria for dengue fever: (1) severe bleeding: subcutaneous hematoma, hematuria, hemoptysis, gastrointestinal bleeding, vaginal bleeding, and intracranial bleeding; (2) shock: tachycardia, cold extremities, prolonged capillary filling time >3 seconds, weak or undetectable pulse, reduced pulse pressure difference, decreased blood pressure (<90/60 mmHg [1 mmHg=0.133 kPa], or 20% decrease from basal blood pressure) or blood pressure cannot be measured; (3) severe organ damage: acute respiratory distress syndrome (ARDS) or respiratory failure, acute myocarditis or acute heart failure, acute liver injury (ALT or AST >1000 U/L), acute renal insufficiency, encephalopathy or encephalitis, and other important organ damage.

Recommendation 7: The diagnosis of dengue fever is based on a recent epidemiological history of dengue fever; clinical manifestations such as fever with feebleness, muscle and bone joint pain, rash and bleeding tendency, or leukocytopenia and/or thrombocytopenia; positive for DENV IgM antibody, NS1 antigen or DENV nucleic acid, or a fourfold or more increase in serum-specific IgG antibody titer in the recovery phase compared to the acute phase or a negative to positive (A1).

Recommendation 8: The diagnosis of severe dengue is based on the presence of one of the following severe manifestations on top of the diagnostic criteria for dengue fever: severe hemorrhage; severe plasma leakage; and severe organ damage including ARDS or respiratory failure, acute myocarditis or acute heart failure, acute liver damage (ALT and/or AST > 1000 IU/L), acute renal insufficiency, encephalopathy or encephalitis, etc (A1).

Treatment[3,4,21,30,35,36]

The principles of treatment are early detection, early diagnosis, early mosquito prevention and isolation, and early treatment.

There is no specific antiviral treatment for dengue fever, and the main measures are symptomatic support treatment, general management, and preventive treatment. Figure S1, https://links.lww.com/IDI/A6 presents a summary of management decisions.

General management

General management includes (1) bed rest and light semi-liquid diet; (2) anti-mosquito isolation until the fever subsides and symptoms resolve; (3) monitoring of consciousness, vital signs, fluid intake and output, urine volume, blood count, liver and kidney function, cardiac enzymes, and warning signs of severe dengue.

Symptomatic treatment

  • 1. Reduce fever: Physical cooling is the mainstay, and warm baths can be used; acetaminophen can be administered to patients with high fever if they cannot tolerate it. Acetylsalicylic acid (aspirin), ibuprofen, and other non-steroidal anti-inflammatory drugs (NSAIDs) are used with caution to avoid aggravating gastritis or bleeding.
  • 2. Rehydration: In cases of heavy sweating or diarrhea, rehydration is given according to the patient's level of dehydration, with oral rehydration as the mainstay. Patients with nausea and anorexia can be rehydrated by administering small amounts of oral rehydration fluid. Oral rehydration salts, soups, and juices can prevent electrolyte imbalance. Carbonated drinks should be used with caution to avoid causing physiological stress-related hyperglycemia. Patients with frequent vomiting, difficulty in eating, or low blood pressure should be promptly administered intravenous fluids, which can be given as isotonic solutions such as 0.9% saline.
  • 3. Sedation and pain relief: Symptomatic treatment such as Valium may be given.
  • 4. The elderly, pregnant women and those with underlying illnesses should be hospitalized promptly and given close observation and rehydration treatment.
  • 5. Traditional Chinese medicine dialectical treatment according to the patient's wishes.

Recommendation 9: Monitor temperature, white blood cells, platelets, HCT, blood glucose, urine output, liquid intake and output volume, and liver and kidney function dynamically (A1).

Recommendation 10: Prompt hospitalization is recommended for the elderly, pregnant women, and those with serious underlying health conditions (B1).

Recommendation 11: The use of existing antiviral drugs is not recommended (B2).

Recommendation 12: Enhanced supportive symptomatic treatment may improve the prognosis (A1).

Recommendation 13: Oral rehydration solution is the mainstay (A2).

Recommendation 14: Prompt rehydration therapy for those with warning signs can prevent progression (B1).

Recommendation 15: Platelet transfusion is not recommended for dengue fever with significantly reduced platelets (A1).

Recommendation 16: Dialectical treatment with traditional Chinese medicine is recommended(B2).

Treatment of severe dengue[3,4,30,35,37–39]

Patients with severe dengue need to be hospitalized, with close monitoring for consciousness, urine output, vital signs, and blood lactate levels when available. Critically ill patients need to be transferred to the intensive care unit (ICU) for treatment. Patients with severe plasma leakage, shock, ARDS, severe bleeding, or other critical organ dysfunction should be treated actively.

Principles of rehydration

The principle of rehydration in severe dengue is to maintain good tissue and organ perfusion. The type and quantity of rehydration fluids should also be adjusted at any time according to the patient's HCT, platelets, electrolytes, urine output, and hemodynamic situation. The amount of intravenous rehydration should be controlled provided that good tissue and organ perfusion is maintained and urine output reaches approximately 0.5 mL·kg−1·h−1. The amount of intravenous rehydration should be gradually reduced as the plasma leakage rate decreases and the course of the disease nears the end of the critical phase.

Anti-shock treatment

Fluid resuscitation should be administered as soon as possible when a shock occurs. Initial fluid resuscitation is based on isotonic crystalloids (eg, saline), and colloidal solutions may be added for the shock that is refractory to initial fluid resuscitation or for more severe shock. In addition, actively correct the acid-base imbalance. If blood pressure cannot be maintained with fluid resuscitation, vasoactive drugs should be used; in severe bleeding-induced shock, prompt transfusion of red blood cells or whole blood should be administered. Hemodynamic monitoring can be performed to guide treatment, if available.

Rehydration therapy is vital in people at high risk of severe dengue. Early intravenous rehydration may reduce the severity of the disease if the patient has early warning signs of severe dengue or shows signs of plasma leakage, and reasonable rehydration may reduce the incidence of shock.

In cases of severe plasma extravasation, especially in the presence of hypoproteinemia, human albumin can be administered promptly to prevent the onset or progression of shock.

Lactate should be monitored in severe dengue, and improvement in dynamic lactate values as a monitoring indicator is important for fluid resuscitation and vasoactive drug use strategies.

Prevention and treatment of hemorrhage

(1) Local hemostasis is given for explicit sites of bleeding, for example, severe epistaxis. Administer acid-inhibition medicine if gastrointestinal bleeding occurs. Avoid invasive diagnostics and treatment, such as gastric or urinary catheter insertion. (2) For severe bleeding with hemoglobin below 70 g/L, red blood cells were transfused accordingly. (3) For severe bleeding with platelet count <30 × 109/L, fresh platelets were transfused. For dengue fever with a significant drop in platelets but with no clear signs of bleeding, platelet transfusion cannot prevent bleeding and improve prognosis.

Treatment of severe organ damage

  • (1) Acute myocarditis and acute heart failure: bed rest, continuous low to medium flow oxygenation, keeping the stool soft, and limiting intravenous fluids and the rate of infusion. Antiarrhythmic drugs are administered depending on the patient's condition in the presence of frequent atrial or ventricular premature beats. In the event of heart failure, diuretic treatment should be administered first, maintaining a negative fluid balance of 500 to 800 mL per day and avoiding blood pressure below 90/60 mmHg. There is a risk of exacerbation of myocardial ischemia and arrhythmia with repeated oral or intravenous digoxin.
  • (2) Encephalopathy and encephalitis: lower temperature, oxygen administration, and control of the amount and rate of intravenous infusion. Mannitol or diuretics are administered intravenously to reduce cerebral edema according to the condition. In the presence of central respiratory failure, assisted ventilatory support should be provided promptly.
  • (3) Acute renal failure: staging can be performed with reference to the criteria for acute renal impairment and prompt hemodialysis.
  • (4) Liver failure: Severe liver injury may occur in some patients, and if liver failure occurs, routine management is needed.

Diagnosis and management of fluid overload

If the rate or amount of rehydration is not properly controlled, fluid overload may occur, which will lead to the development of large pleural effusions and ascites, or even cerebral edema, a common cause of acute respiratory distress in patients with severe dengue. Other causes of respiratory distress include acute pulmonary edema, severe metabolic acidosis due to shock, and ARDS.

  • (1) Risk factors that may lead to fluid overload include excessive or rapid intravenous rehydration; inappropriate types of rehydration fluids, such as hypotonic fluids during plasma leakage; inappropriate administration of excessive intravenous rehydration in patients with severe bleeding; inappropriate infusion of fresh frozen plasma, platelet concentrates, and cryoprecipitate; continued intravenous rehydration after plasma leakage has resolved (24–48 hours after the fever reduction period); and underlying diseases such as congenital or ischemic heart disease, chronic lung disease, and chronic kidney disease.
  • (2) Clinical features of fluid overload include respiratory distress, dyspnea, shortness of breath, three-concave sign, wheezing, massive pleural effusion, tense ascites, elevated jugular venous pressure, acute pulmonary edema, and refractory shock.
  • (3) Diagnosis assisted by imaging: Chest X-ray may show an enlarged heart, pleural effusion, ascites leading to diaphragm elevation, varying degrees of “butterfly wings,” and Kerley B line suggesting fluid overload and pulmonary edema.
  • (4) Therapy for fluid overload: Immediately absorb oxygen; reduce or discontinue rehydration; adjust the flow and amount of intravenous rehydration according to the condition; diuretic treatment, give a small dose of tachyphylaxis 0.1 to 0.5 mg/kg, 2 to 3 times/day accordingly; monitor serum potassium and blood oxygen; and if hypokalemia or hypertension occurs, provide timely symptomatic treatment and respiratory support if necessary.

Recommendation 17: Dynamic monitoring of mental status, blood pressure, heart rate, urine output, HCT, hemoglobin, platelets, and oxygen saturation is useful in assessing the severity of the disease and guiding treatment (A1).

Recommendation 18: Severe dengue with markedly elevated lactate suggests inadequate organ perfusion and a poor prognosis (B2).

Recommendation 19: Intravenous rehydration is the mainstay for severe dengue, but it is important to prevent fluid overload (A1).

Recommendation 20: Oxygen should be administered, rehydration should be reduced or stopped, and diuretic therapy should be administered in the event of fluid overload (A1).

Recommendation 21: In severe bleeding with a significant reduction in platelets, treatment with fresh platelet transfusion may improve the prognosis (B2).

Recommendation 22: Severe bleeding and hemoglobin below 70 g/L, transfusion of red blood cells improves prognosis (B2).

Recommendation 23: Prompt infusion of human albumin or plasma in cases of significant plasma leakage with hypoproteinemia can reduce the occurrence of shock (B2).

Recommendation 24: Use invasive tests or intramuscular injections with caution in severe dengue to avoid the risk of bleeding (B1).

Recommendation 25: Use glucocorticoids with caution (B2).

Recommendation 26: Transfer to ICU for treatment should be conducted for severe organ damage such as ARDS, severe acute myocarditis, acute renal failure, multiple organ dysfunction syndrome, etc (A2).

Traditional Chinese medicine evidence-based treatment program

Dengue fever belongs to the category of ”plague“ in Chinese medicine and can be treated with reference to ”epidemic rash,” “damp-temperature,” ”summer-temperature“ and ”summer fever".[40]

The febrile period

Stagnated dampness with warm and heat, disease involving Wei-Fen and Qi-Fen.[41,42]

Clinical manifestations: Upon initial onset, fever, headache, back pain, muscle pain, chills, absence of sweating, weakness, and lethargy, mostly accompanied by nausea, dry vomiting, poor appetite, and diarrhea. A rash may be observed in some patients.

Tongue and pulse: Red or light red tongue, greasy or thick tongue coating, and slippery pulse.

Treatment: Clearing away heat, resolving dampness, removing toxins, and expelling evil.

Reference formula: Gan Lu Disinfectant Dan, Da Yuan Drink, etc, with addition and reduction. Elsholtzia, Patchouli, Pueraria mirifica, Artemisia (later on), Qiangwu, cardamom, semen, slippery rock (decoction), Radix Paeoniae Alba, Yin chen, Cao Guo, and raw licorice. How to use: Take a decoction with water, one dose daily. Add and subtract: add Comfrey if rash is seen; add Radix et Rhizoma if thirsty; add Chai Hu if fever is evident.

Chinese patent medicine: Huo Xiang Zheng Qi series of preparations, etc.

The critical phase

  • (1) Toxic and stagnant, disturbing the Ying and moving the blood[43]: Clinical manifestations include remission of fever, or prolonged fever, restlessness, thirst, bright red blood-like rash, often accompanied by epistaxis, bleeding from the gums, hemoptysis, blood in the stool, blood in the urine, and vaginal bleeding.
  • Tongue and pulse: Red tongue, yellow coating and lack of fluid, bounding pulse or sunken, and slippery pulse.
  • Treatment: Removing toxic and blood stasis, clearing the Ying-fen, and cooling the blood.
  • Reference formula: Qing Pestis and Defeat Poison Drink plus reduction. Raw gypsum, raw earth, water hyacinth, honeysuckle, yellow lily of the valley, Scutellaria, red peony, Cyperus, Dan Pi, fried gardenia, Artemisia, and raw licorice. How to use: Take a decoction with water, one dose daily. Add and subtract: Add Zixue San and Angong Niuhuang Wan for delirium and convulsions.
  • (2) Summer heat and dampness injuring Yang and Qi failing to control blood[44]: Clinical manifestations include remission of fever or prolonged fever, malaise and lethargy, vague rash, or dark bruises, often accompanied by epistaxis, bleeding from the gums, hemoptysis, blood in the stool, blood in the urine, and vaginal bleeding.
  • Tongue and pulse: Dark tongue with greasy coating and weak and feeble pulse.
  • Treatment: Warming the Yang, benefiting the Qi and intaking the blood.

Reference formula: Radix Eucommiae Lizhong Tang combined with Huang Tu Tang, plus or minus. Zao Xin Huang Tu, Gunner's Fructus Pseudostellariae, Radix Codonopsis pilosulae, Gunner's ginger, Scutellariae scutellariae, thorn bush charcoal, fried Atractylodes macrocephala, and roasted licorice. How to use: Take a decoction with water, one dose daily.

The recovery phase

Uncleared residual evil and both Qi and Yin injuries.[45] Clinical manifestations include late onset, mostly weakness and lethargy, nausea, poor appetite, thirst, irregular bowel movements, and mostly pruritic skin rashes.

Tongue and pulse: Pale red tongue, white and greasy coating, and deficient pulse.

Treatment: Clearing away heat and dampness, invigorating the spleen, and harmonizing the stomach.

Reference formula: bamboo leaf and gypsum soup combined with raw pulse drink. Bamboo leaf, southern ginseng, raw barley, raw yam, Radix Panax notoginseng, Radix Rehmanniae, Radix maitake, raw rice malt, Radix et Rhizoma gastrodiae, Radix et Rhizoma ginseng, and raw licorice. How to use: Take a decoction with water, one dose daily.

Problems to be solved[13,46–48]

  • 1. An urgent need for predictive biomarkers to predict progression to severe dengue.
  • 2. Development of neutralizing antibodies and specific antiviral drugs for dengue.
  • 3. Clinical features and management of special populations with dengue, such as the elderly, pregnant women, and those with comorbidities and immunodeficiency state.
  • 4. Clinical study of traditional Chinese medicine for the treatment of dengue with a high quality of evidence in evidence-based medicine.
  • 5. Development and promotion of effective vaccines.
  • 6. Determination method of secondary infection with another type of DENV.
  • 7. The pathogenesis of severe dengue.
  • 8. The health economics study to assess the disease burden of dengue in China and epidemiological prediction and early warning.

Acknowledgments

Jinlin Hou, Wenwu Yin, Dexin Li, Taisheng Li, Lai Wei, Hongning Zhou, Yan He, Caiyan Zhao, Yuqiang Mi, Wu Ni, Yan Huang, Weiping Cai, Zhiwei Li, Rongbing Wang, Jian Wang, and other experts made valuable comments and suggestions during the letter review and meeting review of this guideline. Wenxin Hong participated in the summary of the consultation. Zuning Ren and Lingzhai Zhao participated in the literature search. Changtai Wang assisted in developing the flow chart. Zhiyue Ou participated in the English translation work, etc.

Funding

This study was supported by National Key R&D Program of China (2020YFC1200100); National Science and Technology Major Project of China (2017ZX10305501-003); Special Program of Science and Technology of Guangdong Province (2013A020229001, 2013A020229002); The Major Program of Guangzhou Healthcare Collaborative Innovation (201508020263, 201803040006); Pilot Project of Guangzhou Clinical Medicine Research And Transformation Center (2014Y2-00550).

Conflicts of Interest

None.

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Keywords:

Dengue; Diagnosis; Treatment; Guideline

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