| disease | Yellow Fever |
| alias | Yellow Fever |
Yellow Rebing (yellow fever) is an acute pestilence disease caused by the yellow Rebing virus, transmitted by Aedes mosquitoes, and is mainly prevalent in Africa and Central and South America. Clinical features include fever, severe headache, jaundice, bleeding, and proteinuria.
bubble_chart Epidemiology
Yellow Rebing is mainly prevalent in tropical regions such as South America, Central America, and Africa, with more cases occurring in March and April. Although Asian regions, including our country, have similar geographical, climatic, mosquito, and monkey conditions to the aforementioned areas, there have been no reports of epidemic or confirmed cases of this disease so far. Since World War II, due to widespread vaccination and mosquito control measures in Central and South American countries, the disease has largely disappeared in urban areas. However, in recent years, due to factors such as population migration to forested areas, the re-emergence of Aedes aegypti mosquitoes, the development of resistance to killing worms agents, and the relaxation of preventive measures, the incidence of this disease has shown a resurgence trend in the past 5 to 6 years. Between 1987 and 1991, Yellow Rebing was prevalent in Nigeria, infecting hundreds of thousands of people. The epidemic of Yellow Rebing in rural areas, especially in various parts of Africa, has never ceased. Yellow Rebing can be divided into urban and jungle types.
(1) Source of pestilence The main source of pestilence for the urban type is patients and asymptomatic carriers, especially those within 4 days of onset. The main source of pestilence for the jungle type is monkeys and other primates, from which the virus can be isolated in the blood of infected animals.
(2) Transmission route The transmission vector is mosquitoes. The urban type is solely transmitted by Aedes aegypti mosquitoes, spreading in a human-Aedes aegypti-human cycle. The jungle type involves more complex mosquito species, including Aedes africanus, Aedes simpsoni, Hemagogus, and Sabethes, circulating in a monkey-Aedes africanus or Hemagogus-monkey cycle. Humans become infected by entering the jungle for work. Mosquitoes become pestilent 9 to 12 days after sucking the blood of patients or infected monkeys and can carry the virus for life.(3) Susceptible population In the urban type, all ages and genders are susceptible, but most adults have acquired immunity, so patients are mostly children. In the jungle type, patients are mostly adult males. Infection confers lasting immunity, and no cases of reinfection have been found.
Mild and asymptomatic cases of Yellow Rebing are far more common than severe cases, as evidenced by the presence of specific neutralizing antibodies in the former. These cases play a crucial role in the spread of the disease, and outbreaks can occur when large numbers of non-immune people enter the area.
The pathogen is the yellow Rebing virus (yellow fever virus), which belongs to the genus Flavivirus of the family Flaviviridae (formerly group B arbovirus), and has cross-immune reactions with other viruses in the same genus such as dengue Rebing virus. The virus particles are spherical, with a diameter of 37-50nm, and are enveloped by a lipoprotein membrane with spikes on the surface. The viral genome is a single-stranded positive-sense RNA, with a molecular weight of approximately 3.8×106 and a length of about 11kb, containing only one long open reading frame, with about 96% of the nucleotides within this frame. The flavivirus genome is divided into two segments: the 5' end 1/4 encodes three structural proteins of the virus, namely the C protein (capsid protein), M protein (membrane protein), and E protein (envelope protein); the 3' end 3/4 encodes seven non-structural proteins. Both the 5' and 3' ends of the genome have a non-coding region.
The E protein is the main envelope glycoprotein, containing viral hemagglutinin and neutralizing antigenic determinants, and may be a ligand for certain host cell surface receptors. When it binds to the receptor, it can infect the cell. The E protein may be a membrane fusion protein, inducing the fusion of the viral envelope with the cell membrane, facilitating the entry of the virus particle into the cell and causing infection. The M protein can increase the infectivity of the virus and form the surface structure of the virus particle. The role of non-structural proteins is not fully understood, but they may play an important role in the viral immune response.The yellow Rebing virus has a tropism for visceral organs such as the liver, kidney, and heart (in humans and primates) and for the nervous system (in mice). After multiple passages in chicken embryos, attenuated strains can be obtained for use as vaccines. The virus is rapidly inactivated by heat, common disinfectants, ether, and sodium deoxycholate, but can survive for several months in 50% glycerol solution and maintain viability for many years when freeze-dried. Mice and rhesus monkeys are commonly used susceptible experimental animals.
After invading the human body, the virus spreads to local lymph nodes and replicates within them. A few days later, it enters the bloodstream, causing viremia, which primarily affects the liver, spleen, kidneys, lymph nodes, bone marrow, and striated muscles. Subsequently, the virus disappears from the blood, but it can still be detected in the spleen, bone marrow, lymph nodes, and other locations. Highly virulent strains of the virus often predominantly attack the liver, leading to severe pathological changes.
bubble_chart Pathological ChangesThe pathological changes of yellow Rebing are caused by the aggregation of the virus in various organ tissues and its replication and proliferation within them. Liver lesions are mainly seen in the midzonal area of the lobules, with hepatocytes showing cloudy swelling, spotty coagulative necrosis, and eosinophilic hyaline degeneration, forming the characteristic Councilman bodies; severe liver lesions can lead to deep jaundice, bleeding in various parts, hypoglycemia, etc. Kidney lesions vary in severity; they are seen in the proximal convoluted tubules, with tubular epithelial cells showing cloudy swelling, shedding, or necrosis, and the lumen filled with granular debris; decreased renal function and uremia are caused by reduced blood volume, tubular necrosis, etc. The myocardium shows extensive degenerative changes and fatty infiltration, with occasional focal hemorrhages, and the lesions often involve the sinoatrial node and the bundle of His; clinically, this can manifest as bradycardia, arrhythmia, hypotension, heart failure, etc. The brain occasionally shows edema and focal hemorrhages, which are secondary to metabolic changes such as hypoxia and lactic acidosis in the brain tissue, rather than direct viral invasion. There is no inflammatory cell infiltration in the tissues of various organs, which is one of the characteristics of this disease. The tendency to bleed is related to thrombocytopenia, abnormal platelet function, and reduced coagulation factors.
bubble_chart Clinical Manifestations
After infection with yellow Rebing fever, 5-20% develop clinical illness, while the rest experience latent infection. The incubation period is 3-7 days. Mild cases may only present with fever, headache, grade I proteinuria, etc., without jaundice or bleeding, and recover after a few days. Severe cases can generally be divided into three stages: the infection stage, the toxic stage, and the stage of convalescence.
(1) Infection stage: The onset is abrupt, accompanied by shivering, followed by rapidly rising high fever, severe headache, body pain, significant lack of strength, nausea, vomiting, constipation, etc. Initially, the vomit consists of stomach contents, later resembling gall fel. Patients experience dysphoria and anxiety, flushed face, congested conjunctiva, red and crimson tongue, and dry skin. The heart rate initially increases in parallel with the fever, then gradually shifts to a relatively moderate pulse. This stage lasts about 3 days, with grade I jaundice and proteinuria appearing by the end.
(2) Toxic stage: Generally begins on the 4th day of the illness. Some cases may have a brief (a few hours to 1 day) stage of remission, with a slight drop and then a rise in temperature, forming a saddle shape. This stage still features high fever and a slowed heart rate, with deepening jaundice, hence the name yellow Rebing fever. Patients appear apathetic, with a grayish complexion and frequent vomiting. Proteinuria becomes more pronounced, accompanied by oliguria. The prominent symptoms of this stage are bleeding phenomena such as gum bleeding, epistaxis, skin petechiae and ecchymoses, gastrointestinal, urinary tract, and uterus bleeding, etc. The vomit consists of black altered blood. The heart is often enlarged, heart sounds become weaker, and blood pressure is low. Severe patients may experience delirium, unconsciousness, persistent hiccups, anuria, etc., accompanied by large amounts of black vomit. This stage lasts 3-4 days, with most deaths occurring during this period.
(3) Stage of convalescence: The temperature drops to normal by the 7th-8th day of the illness, and symptoms and proteinuria gradually disappear, but lack of strength may persist for 1-2 weeks or even months. During this stage, close attention to the heart condition is still necessary. Generally, there are no sequelae.
bubble_chart Auxiliary Examination
(1) General routine and generation and transformation tests: Early reduction in neutrophil count, normal or slightly reduced platelet count. Elevated serum bilirubin, ALT, AST, etc. Urine protein may increase to 3-5g/L by days 4-5 of the disease course. Stool occult blood is often positive. Cerebrospinal fluid pressure is often elevated, with normal cell count. ECG may show ST-T wave abnormalities, PR and QT interval changes, etc. Prolonged clotting time, prothrombin time, and partial thromboplastin time are seen in cases of jaundice disease.
(2) Virus isolation: Inject patient blood from within 4 days of illness into suckling mouse brain or passaged Vero cells to isolate the virus, which is then identified using serological immunology.
(3) Serological immunological tests: Use acute phase and convalescent phase sera (2-4 weeks after onset) for IgM antibody capture ELISA, hemagglutination inhibition test, complement fixation test, or neutralization test. IgM antibodies, hemagglutination inhibition antibodies, and neutralizing antibodies appear within 5-7 days of onset; CF antibodies appear 7-14 days after illness. A fourfold or greater increase in antibody titer in convalescent phase serum confirms the disease. Since IgM and CF antibodies exist for a relatively short time, a rise in titer indicates recent infection. If specific IgG antibodies are present in the serum without dynamic changes in titer, it suggests past infection.
Using ELISA to detect viral antigens in early-stage serum aids in early diagnosis. This method is specific, highly sensitive, yields results within hours, and can be adopted by general laboratories.
(4) Detection of viral nucleic acid: Reverse transcription (RT)-PCR for flavivirus RNA is highly specific and sensitive, with reports both domestically and internationally, providing a reliable method for early and rapid diagnosis. However, this test requires certain technical expertise and conditions, making it difficult to popularize in general laboratories.
(5) Liver biopsy: Liver biopsy is not recommended for patients due to the risk of severe consequences such as bleeding. For fatal cases, a small piece of liver tissue can be excised using a visceral biopsy knife for pathological examination, mouse inoculation, and enzyme immunoassay (using monoclonal antibodies or human polyclonal IgM antibodies).
The diagnosis of severe cases is generally not difficult, with epidemiological data and some specific clinical symptoms such as significant facial congestion, obvious relative moderate pulse, large amounts of black vomit, massive proteinuria, jaundice, etc., all having important reference value. Mild and latent infections are not easy to diagnose, often requiring reliance on serological immunological tests including monoclonal antibodies, ELISA, and other techniques to reach a conclusion. PCR testing of blood samples for viral RNA can also be used, and when necessary, intracerebral inoculation of blood into suckling mice to isolate the virus. If the patient has not previously been infected with a virus of the same genus, positive results from hemagglutination inhibition tests, neutralization tests, complement fixation tests, etc., can be used to make a diagnosis. If no specific antibodies appear in the second serum sample, the possibility of yellow Rebing can be ruled out.
bubble_chart Treatment Measures
There is no specific treatment for this disease. Interferon inducers such as poly I:C and ribavirin have been tried in early experimental infections in rhesus monkeys, but no significant effect was observed.
(1) General treatment: Bed rest is required until complete recovery, even for mild cases, to prevent sudden changes in the cardiovascular system. Physical activity should be gradually increased. A liquid or semi-liquid diet is recommended. In cases of frequent vomiting, fasting is necessary, and appropriate intravenous rehydration with 5-10% glucose saline or plasma should be administered, paying attention to the balance of water, electrolytes, and acid-base.
(2) Symptomatic treatment: For high fever, alcohol sponge baths or other physical cooling measures can be used. For severe headache, small doses of antipyretic analgesics can be used, but aspirin and indomethacin, which may cause bleeding, should be avoided. For vomiting, metoclopramide 5-10mg can be administered orally or intramuscularly. For severe hiccups, Ritalin 10-20mg can be administered intramuscularly or intravenously. Adrenal corticosteroids can be tried for those with myocardial damage, along with oxygen inhalation. Appropriate antibacterial or antimalarial drugs should be given for secondary bacterial infections or concurrent malaria. The management of shock, DIC, uremia, and heart failure is discussed in the relevant sections.
If severe patients can be admitted to an intensive care unit, some cases may be saved.
It was previously believed that the case fatality rate of this disease exceeded 20%, which may have been an overestimation. If mild cases and subclinical infections are included, the case fatality rate should be below 5%. The case fatality rate for severe cases varies depending on the epidemic and can reach 30-90%.
The following factors often lead to fatal outcomes: ① Rapid progression to the toxic phase, with a rapid increase in serum bilirubin; ② Severe bleeding and the occurrence of DIC; ③ Decreased renal function due to renal tubular necrosis; ④ Early onset of hypotension; ⑤ Shock; ⑥ Unconsciousness and convulsions; ⑦ Persistent hiccups, etc.
One should always be vigilant for the sudden deterioration of the virus. Throughout the course of the disease, even during the stage of convalescence, there is a possibility of cardiac insufficiency leading to death.
The focus of prevention varies by region and situation. In cities across South America, the primary measures should be mosquito prevention and eradication. In Africa, where towns and villages are more dispersed, vaccination should be the priority. During an outbreak, both vaccination and mosquito control should be implemented simultaneously. Once a case or suspected case is identified, it should be immediately reported to local health and epidemic prevention institutions to take necessary measures promptly.
(1) Management of the pestilence source: Patients should be treated locally with mosquito isolation, which is particularly crucial within the first four days of the illness. Strengthen border quarantine; individuals from epidemic areas must present valid vaccination certificates and, if necessary, be kept under observation.
(2) Cutting off transmission routes: Mosquito prevention and eradication are effective measures against yellow Rebing, including identifying and eliminating breeding grounds for Unprocessed Rehmannia Root, capturing and killing adult mosquitoes, etc. For mosquito strains resistant to 223 and 666, new killing agents like malathion and fenitrothion should be used. Countries in South America, such as Brazil, have achieved significant results through mosquito control measures, with no cases reported in cities since 1942. Strict mosquito eradication measures should be applied to all vehicles from epidemic areas, including boats, cars, and airplanes.
(3) Protecting susceptible individuals: Vaccination is an effective measure to prevent outbreaks and protect individuals. During an epidemic, vaccination should be widely administered within certain populations, with a focus on susceptible children. Many countries have produced and administered the 17D live attenuated chicken embryo vaccine, with a single subcutaneous injection of 0.5ml for both adults and children. 95% of vaccinated individuals develop immunity within 7 to 9 months, lasting for 10 years or more. Those allergic to eggs should not be vaccinated or should undergo a skin test with the vaccine before deciding to vaccinate. Infants under six months should not be vaccinated; it is best to vaccinate after one year of age to avoid encephalitis. Individuals with compromised immune systems should also avoid vaccination. Personnel entering epidemic areas, military personnel, forestry workers, hunters, laboratory personnel in contact with the virus, and travelers to epidemic areas all need to be vaccinated.
In recent years, some have used the skin scarification method for vaccination, applying a drop of vaccine after making three scratches.
Major complications include shock, intestinal bleeding, heart damage, multi-organ dysfunction, as well as DIC, bacterial pneumonia, mumps, and others.
This disease must be differentiated from dengue fever, epidemic hemorrhagic fever, leptospirosis, malignant malaria, relapsing fever, viral hepatitis, drug-induced or toxic jaundice, as well as rickettsial diseases, cold-damage disease, and various other hemorrhagic fevers (Lassa fever, African hemorrhagic fever, Bolivian hemorrhagic fever, Argentine hemorrhagic fever, etc.).
Malaria may coexist with this disease, therefore, even if malaria parasites are detected in blood or bone marrow smears, this disease cannot be ruled out. Early detection of sporadic, early-stage, or mild cases of yellow Rebing is crucial, as neglect or misdiagnosis of fistula disease can often lead to outbreaks of this disease.
