Interpretation for Diagnosis and Treatment of Dengue Fever J Int Transl Med, 2014, 2(4):498-502; doi: 10.11910/2227-6394.2014.02.04.15 Open Access
Commentary
Interpretation of Guideline for Diagnosis and Treatment of Dengue Fever YE Zhen-hua, DU Fu-rong, YANG Xue, WU Yin-ping, YI Zi, CHEN Chong Editorial Board of Journal of International Translational Medicine
Key words: Dengue Fever; Etiology; Epidemiology; Diagnosis; Treatment; Modern medicine; Traditional Chinese medicine
Introduction
Etiology
Dengue Fever (DF), an acute infectious disease caused by
DENV was first separated by Siban in 1944, and then obtained
Dengue virus (DENV) and widely prevalent in tropical and
from patients with hemorrhagic fever and Aedes aegypti in
subtropical regions, is an insect-borne viral disease with the
Philippines, Thailand, Vietnam, Singapore etc. in 1956 [5].
most wide spread, highest incidence and greater harm. With the
DENV, which belongs to F1aviviridae, F1avivirus, has the
substantial increase in the incidence of DF in recent decades,
shape of sphere, diameter of 45 ～ 55 nm and 4 serotypes,
statistical data from WHO shows that over 40% of world
namely DENV-1, DENV-2, DENV-3 and DENV-4[6]. All of the
population (about 2.5 billion) are facing the risk of infecting
4 serotypes can infect human beings, primarily transmitted by
DF and Dengue hemorrhagic fever (DHF, namely Severe DF)
Aedes aegypti and Aedes albopictus, while the severe case and
[1]
in 2007, with 50 ～ 100 million new cases every year . Global
mortality rates of DENV-2 are higher than other types.
DF cases are estimated to reach up to 9.6 million in 2013, increased by 3 times compared with the year of 2012. DF has
DENV is sensitive to heat. It can be inactivated in 30 min at
been intermittently epidemic in China and the scope of case
56℃ , while its infectivity maintains for several weeks at 4℃ and
distribution has been expanded since its outbreak in Foshan,
long-term surviving at -70℃ or in freeze drying circumstances.
Guangdong in 1978[2]. Therefore, the monitoring and prevention
Moreover, DENV can also be inactivated ultrasound,
of DF has become a major concern of international public
ultraviolet, 0.05% formaldehyde solution, lactic acid, potassium
health. To further enhance the medical treatment of DF patients
permanganate, gentian violet and so on.
and protect people’s health and life safety, National Health and Family Planning Commission of the People’s Republic of
Epidemiology
China formulates Guideline for Diagnosis and Treatment of
DF is prevalent in tropical and subtropical regions, especially
Dengue Fever (Edition 2, 2014) on the basis of recent DF cases
in more than 100 countries and regions in Southeast Asia,
and Dengue Guidelines for Diagnosis, Treatment, Prevention
the Pacific islands and the Caribbean Sea. All provinces in
and Control[3] World Health Organization (WHO) formulated
China have infected case reports, widely prevalent in Southern
[4]
provinces like Guangdong, Yunnan, Fujian, Zhejiang, Hainan
(Hereinafter referred to as Guideline), and the following is the
and so on and mainly in summer and autumn [7]. The main
interpretation of the Guideline.
infection sources of DF are DF patients, inapparent infestors and
in 2009, with the latest version being Version 2 in 2014
498
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J Int Transl Med, 2014, 2(4):498-502 nonhuman primates infected with DENV and infected media,
indications such as sharp abdominal pain, persistent vomiting
Aedes. The main route of transmission is bites of Aedes, and
etc.. Some patients may appear with continuous and unremitting
the transmitting vectors mainly are Aedes aegypti and Aedes
high fever, worsen condition after defervesce or obvious plasma
albopictus. People are generally susceptible but with partial
leakage caused by increased capillary permeability, and severe
onsets after infection. Human body can produce long-lasting
patients with shock and damage of other vital organs. Patients
immunity to the same type of virus but the virus can’t be shaped
often manifested with progressive leucopenia and rapid low
to form an effective protection after DENV infection. The
platelet count before the occurrence of plasma leakage, and
body immune response of may occur if being re-infecting with
the degrees vary significantly in different patients such as
heterotypes or a plurality of different serotypes, leading to severe
chemosis, hydropericardium, hydrothorax, ascites and so on.
clinical manifestations. Besides, a study showed that age, race,
The increased amplitude of hematocrit (HCT) frequently reflects
gender, climate and other factors all can affect the prevalence of
the degree of plasma leakage, and patients may appear with
DF[8].
shock if the plasma volume is severely lacked due to plasma
Clinical manifestations
leakage. Metabolic acidosis, multiple organ dysfunction and disseminated intravascular coagulation may appear to patients
The incubation period of DF is generally 3 ～ 15 d and mostly
with longstanding shock. A few patients don’t have the symptom
5 ～ 8 d. DF is a kind of systemic disease and divided into
of obvious plasma leakage, major bleeding such as subcutaneous
typical DF, DHF and Dengue shock syndrome (DSS) according
hematoma, gastrointestinal hemorrhage, colporrhagia,
to WHO standards. Typical DF, mainly manifested with
intracranial hemorrhage, hemoptysis, gross hematuria etc.
hyperpyrexia, headache, fatigue, muscle and joint pain and may
may occur. Some patients are manifested with chest distress,
be accompanied by rash, abnormal liver function, leucopenia
palpitation, dizziness, orthopnoea, shortness of breath, dyspnea,
and thrombocytopenia, transmits rapidly and may cause large-
headache, emesis, somnolence, dysphoria, delirium, convulsion,
scale epidemic but with low mortality; DHF is a more severe
coma, dystropy, stiff neck, lumbago, oliguria or anuria, jaundice
type characterized by hyperpyrexia, hemorrhage and plasma
and other symptoms of severe organ damage.
extravasation with shock and high mortality; while DSS refers to cases accompanied by shock. And Guideline divides typical
Recovery phase
course of DF into three phases, namely acute febrile phase,
The patient’s condition improved, with relieved gastrointestinal
critical phase, and recovery phase.
symptoms, and the recovery phase starts 2 ～ 3 d after critical phase. Pinpoint hemorrhagic spots most on lower limbs and
Acute febrile phase
pruritus may occur in some patients. White blood cell count
Patients often have acute onsets with the first symptom being
begins to rise, platelet count gradually restores.
fever associated with chills, and the body temperature could be up to 40℃ within 24 h. Some patients’ body temperature drops to normal 3 ～ 5 d after pyrexia and rises again 1 ～ 3 d later,
Diagnosis
known as double quotidian fever. Fever may be associated with
Laboratory examination
headache, myalgia, bone pain and arthralgia, obvious fatigue as
Blood routine: White blood cell (WBC) count reduces to
well as nausea, vomiting, abdominal pain, diarrhea and other
below 4×109/L, mainly being neutropenia, and platelet (PLT)
gastrointestinal symptoms. Acute febrile phase generally lasts for
decreases to below 100×109/L.
2 ～ 7 d. Congestive rash or dotted hemorrhage rash may appear on the face and limbs day 3 ～ 6 in the course. Bleeding of
Urine routine: A small amount of protein, erythrocyte or urinary
different degrees may appear, such as subcutaneous hemorrhage,
cast may appear.
petechia and ecchymosis at injection site, gingival bleeding, epistaxis and positive touniguer test and so on.
Blood biochemical examination: Most patients have increased alanine transaminase (ALT) and aspartate aminotransferase
Critical phase
(AST), and some have elevated lactic dehydrogenase (LDH) or
Critical phase usually appears at the 3th ～ 8th day of the
creatine phosphokinase (CK). Some patients appear with lower
disease course, which is often marked by severe warning
potassium.
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499
J Int Transl Med, 2014, 2(4):498-502 Etiological and serologic detection: Blood specimens in acute
Severe DF: One of the following situations is conformed:
febrile phase and recovery phase can be collected to be detected.
① major bleeding: subcutaneous hematoma, hematemesis,
The early diagnosis of acute febrile phase can be detected by DF
melena, vaginal bleeding, gross hematuria, intracranial
antigen (NS1) and viral nucleic acid detection, or serological
hemorrhage etc.; ② shock: tachycardia, clamminess of
typing and virus isolation. With regard to patients with primary
extremities, filling time extension of capillaries ＞ 3 sec, weak
infection, IgM antibody can be detected 3 ～ 5 d after onset,
or undetectable pulse, decreased pulse pressure or undetectable
peaks at the 2nd week and lasts for 2 ～ 3 months; IgG antibody
blood pressure; ③ severe organ damage: liver injury (ALT and/
can be detected 1 week after onset and lasts for several years or
or AST ＞ 1 000 IU/L), ARDS, acute myocarditis, acute renal
even a lifetime. High-level IgG antibody with specificity detected
failure, encephalopathy, encephalitis etc..
in the serum of patients within the first week indicates secondary infection which can also be synthetically judged by combining with
Treatment
the ratio of IgM/IgG measured by Capture ELISA.
Modern medicine has no specific antiviral therapy and the
Imageological examination Unilateral or bilateral pleural effusion can be discovered by CT or chest radiograph, and interstitial pneumonia may occur to
main measures are supportive and symptomatic treatment with therapeutic principle of early discovery, diagnosis, treatment and anti-mosquito isolation at present.
some patients. Hepatosplenomegaly may be seen by B-ultrasonic
General treatment
wave, and severe DF patients may have the symptoms of
Patients should stay in bed, and have light diet, anti-mosquito
transient thickening gall bladder wall, pericardial, celiac and
isolation till abatement of fever and symptoms relieved. Patients’
pelvic effusion. Encephaledema, intracranial hemorrhage,
consciousness, vital signs, liquor intake, urine volume, PLT,
subcutaneous tissue exudation etc. can be detected by CT and
HCT, electrolyte and so on should be monitored. Hemorrhage
Magnetic Resonance Imaging (MRI).
and hematoma should be voided when arteriopuncture and
Case classification
venipuncture are performed to patients with dramatically decreased PLT. Physical cooling should be preferred if
Diagnosis can be made according to epidemiological history,
pyretolysis is needed, alcohol sponge bath avoid being adopted
clinical manifestations and laboratory test results, or clinical
by patients with significant bleeding symptoms. Antipyretic
manifestations, auxiliary examination and laboratory test results
and analgesic drugs should be used with caution due to serious
if there’s no clear epidemiological history.
complications. Fluid infusion is mainly by oral administration, and prompt intravenous infusion should be conducted to
Suspected case: People who have the clinical manifestations
patients with frequent vomiting, difficulty in eating or low
of DF, epidemiological history (having been to the area with
blood pressure. Diazepam, rotundine etc. can be administrated if
epidemic DF within 15 days before oncome, or living in places
sedation and analgesia is required.
where there are DF cases), or leukopenia and thrombocytopenia are regarded as suspected cases.
Treatment of severe DF Electrolytical changes should also be dynamically monitored
Clinically diagnosed case: People who have the clinical
in severe DF cases besides monitoring indexes mentioned in
manifestations of DF, epidemiological history, simultaneously
general treatment. Corresponding treatment should be adopted
leukopenia and thrombocytopenia and positive reaction to IgM
actively for severe plasma leakage, shock, ARDS, major
antibody are regarded as clinically diagnosed cases.
bleeding or dysfunction of other vital organs.
Confirmed case: Suspected cases or clinically diagnosed cases
Fluid infusion: The principle of fluid infusion in severe DF is
with serum NS1 antigen or viral nucleic acid detected or DENV
maintaining good tissue perfusion, meanwhile, the amount and
separated in acute phase, or serum-specific IgG antibody titer
type should be adjusted at all times according to patient’s HCT,
increased more than 4 times in recovery phase are regarded as
PLT, electrolyte, urine volume and hemodynamics.
confirmed cases. Anti-shock: Fluid resuscitation should be carried out as soon as
500
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J Int Transl Med, 2014, 2(4):498-502 possible. Isotonic crystalloid solution is mainly used in initial
weifen and qifen, flaring heat in qifen and xuefen, excessive
fluid resuscitation, colloidal solution for more severe shock, and
heat in qifen, pathogenic qi invading pericardium, pathogenic
acid-base imbalance should be actively corrected. Vasoactive
qi having been expelled entirely, binding of static blood and
drugs should be used if fluid resuscitation is unable to maintain
poison and other syndrome types[9], and certain curative effects
blood pressure, and timely infused with erythrocytes or whole
have been achieved after being treated by Sweet Dew Toxin-
blood for shock caused by severe bleeding.
Removing Elixir, Epidemic-Clearing Toxin-Resolving Beverage, White Tiger Decoction, Aconite Center-Regulating Decoction,
Management of bleeding: Local hemostasis can be used for
Rhinoceros Horn and Rehmannia Decoction, Lophatherum and
severe epistaxis, hydrotalcite for gastrointestinal hemorrhage
Gypsum Decoction and other formulas[10]. Guideline divides DF
but invasive diagnosis and treatment such as inserting gastric
into three phases and four types for treatment based on syndrome
tube, ureter etc. should be avoided as far as possible, prompt
differentiation.
transfusion of red cells for major bleeding accompanied by hemoglobin lower than 7 g/L, and prompt PLT transfusion for
Acute febrile phase: The pathogenesis is dampness-heat
major bleeding accompanied by PLT count lower than 30 ×
constraining leading to disease involving weifen and qifen with
9
10 /L. Transfusion related acute lung injury (TRALI), platelet
clinical manifestations of fever, aversion to cold, adiapneustia,
transfusion refractoriness and other problems should be paid
fatigue, lassitude, headache, lumbago, myalgia, thirst,
more attention to in clinical blood transfusion.
hemorrhagic rash, nausea, retching, poor appetite, diarrhea, red tongue, greasy or thick tongue coating, smooth, soft and rapid
Management of acute myocarditis and acute heart failure:
pulse in the initial stage of the disease. Therapeutic method is
Patients should stay in bed, maintain low flow oxygen uptake,
clearing heat, resolving dampness, detoxification and expelling
keep bowels open and restrict the volume and speed of
pathogenic qi, and Modified Sweet Dew Toxin-Removing
intravenous infusion. Antiarrhythmic drugs such as betaloc or
Elixir, Membrane-Source–Opening Beverage etc. (Herba
amiodarone can be used for artrial premature beat or ventricular
Moslae, Herba Agastachis, Radix Puerariae Lobatae, Herba
premature beat. Diuresis should firstly be administrated to
Artemisiae Annuae, Rhizoma et Radix Notopterygii, Fructus
patients with heart failure, maintaining daily negative fluid
Amomi Rotundus, Rhizoma Pinelliae, Talcum, Radix Paeoniae
balance being 500 ～ 800 mL, and oral administration of
Rubra, Herba Artemisiae Scopariae, Fructus Tsaoko, Radix et
isosorbide mononitrate tablets 30 mg or 60 mg be given
Rhizoma Glycyrrhizae etc.), serial preparations of Agastache Qi-
secondly.
Correcting, Reduning Injection, Tanreqing Injection, qingkailing Injection, Xuebijing Injection and so on can be adopted.
M a n a g e m e n t o f en c e p h a lo p a th y a n d en c e ph alitis : Hypothermia, oxygen uptake, control of the volume and speed
Critical phase: One pathogenesis is binding of static blood
of intravenous infusion are used for general case, intravenous
and poison disturbing yingfen and xuefen with clinical
drip of mannitol or diuretic for encephaledema, glucocorticoid
manifestations of abated or deferred fever, dysphoria, insomnia,
for encephalitis to alleviate inflammation and swelling of brain
thirst, nausea, vomiting, scarlet hemorrhagic rash, epistaxis
tissues, auxiliary ventilatory support for central respiratory
or gingival bleeding, hemoptysis, hemafecia, hematuria,
failure.
colporrhagia, red tongue, yellow tongue coating, surging pulse, or deep, thread, smooth and rapid pulse. The therapeutic method
Management of other organ damage: Acute renal failure
is detoxification, dispersing blood stasis, clearing ying heat and
may be staged according to the damage criteria and timely
cooling blood, and Modified Epidemic-Clearing Toxin-Resolving
administrated with blood purification treatment, and liver failure
Beverage (crude Gypsum Fibrosum, Radix Rehmanniae, Cornu
according to its conventional treatment.
Bubali, Flos Lonicerae Japonicae, Rhizoma Coptidis, Radix
TCM treatment based on syndrome differentiation
Scutellariae, Radix Paeoniae Rubra, Radix et Rhizoma Rubiae, Cortex Moutan, roasted Fructus Gardeniae, Herba Artemisiae Annuae, crude Radix et Rhizoma Glycyrrhizae), Reduning
Traditional Chinese Medicine (TCM) classifies DF into
Injection, Tanreqing Injection, Qingkailing Injection, Xuebijing
pestilence or febrile disease, dividing it into disease involving
Injection can be used.
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J Int Transl Med, 2014, 2(4):498-502 Another pathogenesis is summer-heat and dampness attacking yang and qi failing to control blood with clinical manifestations being abated or deferred fever, fatigue, lassitude, indistinct rash or dark ecchymosis, epistaxis or gingival bleeding, hemoptysis,
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502
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