THE DENGUE SYNDROME Dengue viruses are arboviruses capable of infecting humans, and causing disease. These infections may be asymptomatic or may lead to (a) "classical" dengue fever, or (b) dengue haemorrhagic fever without shock, or (c) dengue haemorrhagic fever with shock. The manifestations of the dengue syndrome are as shown in Fig. 1. Dengue fever is a self-limiting disease and represents the majority of cases of dengue infection. A prevalence of Aedes294 EPIDEMIOLOGY OF COMMUNICABLE OSCASES oegypti and Aedes albopictus together with the circulation of dengue virus of more than one type in any particular area tends to be associated with outbreaks of DHF/DSS (1) deficient water management including imprope storage practices in urban, peri-urban and mone leading to proliferation of mosquito breeding disease has a seasonal pattern le the cases Dis monsoon, and it is not uniformly distributed thro year. However, in the southern states and G transmission is perennial (4) Problem statement Dengue fever (DF) and its severe forms dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) have become major international public health concerns. Over the past three decades, there has been dramatic global increase in the frequency of dengue fever, DHF and DSS and their epidemics. It is found in tropical and subtropical regions around the world, predominantly in urban and semi-urban areas, and are now spreading to rural areas About 3.9 billion people in 129 countries are at risk of Infection with dengue viruses. A recent estimate indicates 390 million dengue infections per year, of which 96 million manifest clinically with any severity of disease. The number of reported cases have increased from over 2.4 million in 2010 to the highest number of cases, l.e. 6.5 million cases and more than 7,300 deaths recorded in the year 2023 (2). Not only the number of cases are increasing as disease is spreading to new areas, but explosive outbreaks are occurring. The year 2016 was characterized by large dengue outbreaks worldwide. In 2015, Delhi, recorded its worst outbreak since 2006 with over 15,000 cases. Worldwide, annually about 500,000 people with DHF require hospitalization. Approximately 90 per cent of them are children aged less than than f five years, and about 2.5 per cent of those affected die. During epidemics, Infection rate among those who have not been previously exposed to the virus are often 40 to 50 per cent, but can also reach 80 to 90 per cent (3). Co-circulation of multiple serotypes/genotypes is evident. Dengue and DHF is endemic in more than 100 countries in the WHO regions of Africa, the Americas, Eastern Mediterranean, South-East Asia and Western Pacific. The South-East Asia and Western Pacific regions are most seriously affected. The regions of Americas reported 4.5 million cases with 2,300 deaths. A high number of cases were also reported in Asia - Bangladesh (321,000), Malaysia (111,400), Thalland (150,000) and Viet Nam (369,000) (2). Detection of all four serotypes has now rendered the countries hyperendemic. The countries of South-East Asia region are divided into 3 categories (3). Category A (Bangladesh, India, Indonesia, Maldives, Myanmar, Sri Lanka, Thailand and Timor-Leste) a. Major public health problem; b. Leading cause of hospitalization and death among children; c. Hyperendemicity with all 4 serotypes circulating in urban areas; and d. Spreading to rural areas. Category B (Bhutan, Nepal) a. Endemicity uncertain: b. Bhutan reported first outbreak in 2004, and c. Nepal reported first indigenous case in 2004. Category C (DPR Korea) No evidence of endemicity. INDIA In India, the risk of dengue has shown an increase in recent years due to rapid urbanization, lifestyle changes anddeficient water management including improper storage practices in urban, peri-urban and rural leading to proliferation of mosquito breeding sites disease has a seasonal pattern i.e. the cases pe monsoon, and it is not uniformly distributed through year. However, in the southern states and Gujar transmission is perennial (4). Dengue is endemic in 35 states/UTs. During 2022 166,718 cases were reported with 243 deaths. All the four serotypes i.e. dengue 1, 2, 3 and 4 have isolated in India but at present DENV-1 and DE serotypes are widespread (6).Epidemiological determinants Agent factors are (a) AGENT The dengue virus forms a distinct complex within the genus flautuirus based on antigenic and biological tharacteristics. There are four virus serotypes which are designated as DENV-1, DENV-2, DENV-3 and DENV-4 Infection with any one serotype confers lifelong immunity to that virus serotype (7) Although all four serotypes antigenically similar, they are different enough to elicit cross-prolection for only a few months after infection by any one of them. Secondary infection with dengue serotype 2 or multiple infection with different serotypes lead to severe form dengue DHF/DSS (3). The first infection probably sensitizes the patient, while the second infection with different serotype appears to produce immunological catastrophy. The pathogenesis of severe syndrome involves pre-existing dengue antibody. It is postulated that virus antibodies are formed within a few days of the second dengue infection and that the non-neutralizing enhancing antibodies promote infection of higher numbers of mononuclear cells, followed by the release of cytokines, vasoactive mediators, and procoagulants, leading to the disseminated intravascular coagulation seen in the haemorrhagic fever syndrome (8). All four serotypes have been associated with epidemics of dengue fever (with or without DHF) with varying degree of severity. (b) VECTOR: Aedes aegypti and Aedes albopictus are the two most important vectors of dengue. They both carry high vectorial competency for dengue virus, i.e., high susceptibility to infecting virus, ability to replicate the virus and ability to transmit the virus to another host. Aedes degypti is a highly domesticated, strongly anthropophilic, nervous feeder (i.e., it bites more than one host to complete one blood meal) and is a discordant species (i.e., it needs more than one feed for the completion of the gonotropic cycle). This habit results in the generation of multiple cases and the clustering of dengue cases in the cities. On the contrary, Ae. albopictus partly invades peripheral areas of urban cities. It is an aggressive feeder and concordant species, i.e., the species can complete its blood meal in one go on one person and also does not require a second blood meal for the completion of the gonotropic cycle. Transmission of disease The Aedes mosquito becomes infective by feeding on a patient from the day before onset to the 5th day (viraemia) stage) of illness. After an extrinsic incubation period of 8 to 10 days, the mosquito becomes infective, and is able to transmit the infection. Once the mosquito becomes infective. It remains so for life. The genital tract of the mosquito gets infected and transovarian transmission of dengue virus occurs when virus enters fully developed eggs at the time of oviposition. Environmental factors The population of Aedes aegypti fluctuates with rainfall and water storage. Its life span is influenced by temperature and humidity, survives best between 16°C-30°C and a relative humidity of 60-80 per cent. It breeds in the Containers in and around the houses. Being a domestic breeder, it is a endophagic and endophilic. However, even with a 2°C inerende ih temperature the extrinsic incubation THE DENGUL SYNDROM 295 period of DENV will be shortened and more infected mosquitoes are available for a longer duration. Besitles that the mosquitoes will bite more frequently because of dehydration and thus increase man-mosquito contact (3, 6) The failure of urban authorities to provide civil amenities and poor public health infrastructure raises the potential for the vector to breed at high level and makes the environment transmission conducive. The rural spread of the vector is relatively recent occurrence associated with the development of rural water supply schemes, improved transport systems, scarcity of water and lifestyle changes (6) Dengue in the community (3) A number of factors that contribute to initiation and maintenance of an epidemic include: (i) the strain of the virus, which may influence the magnitude and duration o the viraemia in humans; (ii) the density, behaviour anc vectorial capacity of the vector population; (iii) the susceptibility of the human population (both genetic factor and pre-existing immune profile); and (iv) the introduction of the virus into a receptive community. DF/DHF syndrome DF/DHF is characterized by the iceberg or pyramis phenomenon. At the base of the pyramid, most of the case are symptomless, followed by DF, DHF and DSS. Clusters c cases have been reported in particular households c neighbourhoods due to the feeding behaviour of the vector Affected population The population affected varies from one outbreak another. Actual estimates can be made by obtaining clinica subclinical ratios during epidemics. In a well-define epidemic study in North Queensland, Australia, wi primary infection, 20% to 50% of the population was four affected. Severity of the disease The serotype that produces the secondary infection ar in particular, the serotype sequence are important ascertain the severity of the disease. All the four serotyp are able to produce DHF cases. However, during sequent infections, only 2% to 4% of individuals develop seve disease. Studies in Thailand have revealed that the DENV DENV-2 sequence of infection was associated with 500 fold risk of DHF compared with primary infection. the DENV-3/DENV-2 sequence the risk was 150-fold, an DENV-4/DENV-2 sequence had a 50-fold risk of DHF Th is no time-limit to sensitization after a primary infection. 1997 Santiago de Cuba epidemic clearly demonstrated t with the introduction of DENV-2, DHF had occurred 16-years after the primary infection with DENV-1 High-risk patients (3) The following host factors contribute to more se disease and its complications 1 infants and elderly: 2 obesity: 3 pregnancy: 4. peptic ulcer disease, 5 women who are in menstruation or have abno bleeding:296 EPIDEMIOLOGY OF COMMUNICABLE DISEASES 6 haemolytic disease such as G-6PD, thalassaemia and other haemoglobinopathies 7. congenital heart disease chronic diseases such as diabetes mellitus, hypertension, asthma, ischaemic heart disease, chronic renal failure, liver cirrhosis, and patients on steroid or NSAID treatment. Clinical mainfestations Dengue virus infection may be asymptomatic or may cause undifferientiated febrile illness (viral syndrome), dengue fever(DF), or dengue haemorrhagic fever (DHF) including dengue shock syndrome (DSS) as shown in Fig.1 1. Undifferentiated fever Infants, children and adults who have been infected with denuge virus, especially for the first time (Le primary dengue infection), may develop a simple fever indistinguishable from other viral infection. Maculopapular may accompany the fever or may appear during defervescence. Upper respiratory and gastrointestinal symptoms are common. rashes may 2. Classical dengue fever All ages and both sexes are susceptible to dengue fever. Children usually have a milder disease than adults. The illness is characterized by an incubation period of 3 to 10 days (commonly 5-6 days). The onset is sudden, with chills and high fever, Intense headache, muscle and joint pains, which prevent all movement. Within 24 hours retroorbital pain, particularly on eye movements or eye pressure and photophobia develops. Other common symptoms include extreme weakness, anorexia, constipation, altered taste sensation, colicky pain and abdominal tenderness, dragging pain in inguinal region, sore throat and general depression. Fever is usually between 39°C and 40°C. Fever is typically but not inevitably followed by a remission of a few hours to 2 days (biphasic curve). The skin eruptions appear in 80 per cent of cases during the remission or during second febrile phase, which lasts for 1-2 days. The rash is accompanied by similar but milder symptoms. The rash may be diffuse flushing, mottling or fleeting pin-point eruptions on the face, neck and chest during the first half of the febrile period and a conspicuous rash, that may be maculopapular of scarlatiniform on 3rd or 4th day. It starts on the us trunk and may spread to the extremities and tanly face. It may be accompanied by itching and typeтмен The tash lasts for 2 hours to several days and followed by desquamation 111 Fever lasts for about rarely more than 7 days after which recovery complete although convalescence may be protracte The case fatality is exceedingly low 3. Dengue haemorrhagic fever Dengue haemorrhagic fever (DHF) is a severs foms dengue fever. The course of dengue illness can be into three phases-febrile phase, critical phase and phase, as shown in Fig. 2 (9). Days of illness Temperature Dehydration Shock bleeding Rest fuid me Potential clinical issues Organ impairment Platelet Laboratory changes Haematocrit Serology and virology Viraemia Febrile FIG.2 Critical Course of dengue illness Recovery pham Source: (10) 1. Febrile phase 40 123456789 The course of dengue illness Following an incubation period of four to six days, de illness commonly begins abruptly with high leve DENGUE VIRUS INFECTION Asymptomatic Undifferentiated fever (viral syndrome) Without haemorrhage Dengue fever (DF) With unusual haemorrhage DHF non-shock Symptomatic Dengue haemorrhagic fever (DHF) (with plasma leakage) DHF with shock Dengue shock syndrome (DSS) Expanded dengue syndrome Isolated organopathy (unusual manifestation! mirce (3) FIG. 1 Manifestations of the dengue virus infectionnied by facial flushing and headache Anorexia. pigashic discomfort, tenderness at the right costal and generalized abdominal pain are common. During the but few dave the illness usually resembles classical DF Radeonpular rash usually rubelliform type, is less It may appear early or late in the course of the м. Скалноnally, the temperature may be 40°C to 41°C and febrile convulsions may occur particularly in infants (11 The major pathophysiologic changes that determine the of disease in DHF and differentiate it from DF are ma leakage and abnormal haemostasis, as manifested Testepenia. These two clinical laboratory changes ranghaematocrit value and moderate to marked axinctive and constant findings A positive fournicate test is the most common Memorrhagic phenomenon. The test is performed by anga blood pressure cuff to a mid point between systolic and diastolic pressure for 5 minutes. The test is considered Tinch squarel are observed in DHE the test usually gives a sove when 10 or more petechiae per 25x25cm Sedinte positive with 20 petechiae or more (6) 1. Crical phase (10) Around the time of defervescence, when the temperature ps to 37.5-38°C or less, and remains below this level, semeability in parallel with increasing haematocrit levels ally on days 3-7 of illness, an increase in capillary may occur. This marks the beginning of the critical phase. The period of clinically significant plasma leakage usually 24-48 hours. Progressive leukopenia followed by a rapid decrease in platelet count usually precedes plasma leakage. At this point atents without an increase in capillary permeability will prove, while those with increased capillary permeability say become worse as a result of lost plasma volume. The dagve of plasma leakage varies. Pleural effusion mostly on ght side and ascites may be clinically detectable depending on the degree of plasma leakage and the volume of fluid herapy, Gall bladder oedema has been found to precede plasma leakage. Hence chest X-ray and abdominal chasound can be useful tools for diagnosis. The degree of norase above the baseline haematocrit often reflects the severity of plasma leakage. Shock occurs when a critical volume of plasma is lost trough leakage. It is often preceded by warning signs of abdominal pain or tenderness, persistent vomiting, clinical Bud accumulation, mucosal bleeding, lethargy, restlessness. her enlargement more than 2 cm. and oliguria. The body emperature may be subnormal when shock occurs. With Prolonged shock, the consequent organ hypoperfusion s in progressive organ impairment, metabolic acidosis end disseminated intravascular coagulation. This in turn as to severe haemorrhage causing the haematocrit to decrease in severe shock. Instead of the leukopenia usually wm during this phase of dengue, the total white cell count ay increase in patients with severe bleeding. In addition. Mine organ impairment such as severe hepatits, morphalitis or myocarditis and/or severe bleeding may also trelop without obvious plasma leakage or shock. Those who improve after defervescence are said to have severe denque Some patients progress to the critical shof plasma leakage without defervescence and in these sales, changes in the full blood count should be used to ide the onset of the critical phase and plasma leakage. Those who deteriorate will manifest with warning signs This THE DENGUE SYNDROME 297 is called dengue with warning signs Cases of dengue with warning signs will probably recover with early intravenous rehydration ion. Some cases will deteriorate to severe dengue 3. Recovery phase patients may have a rash of "isles of white in the sea of red" If the patient survives the 24-48 hours critical phase, a gradual reabsorption of extravascular compartment fluid takes place in the following 48-72 hours General well-being Improves, appetite returns, gastrointestinal symptoms abate haemodynamic status stabilizes and diuresis ensues Some Some may experience generalized pruritos Bradycardia and electrocardiographic changes are common during this stage OL phase aye De The haematocrit stabilizes or may be lower due to the dilutional effect of reabsorbed fluid. White blood cell count usually starts to rise soon after defervescence but the recovery of platelet count is typically later than that of white blood cell count Respiratory distress from massive pleural effusion and ascites will occur at any time if excessive intravenous fluids have been administered. During the critical and or recovery phases, excessive fluid therapy is associated with pulmonary oedema or congestive heart failure 4. Severe dengue Severe dengue is defined by one or more of the following (1) plasma leakage that may lead to shock (dengue shock) and/or fluid accumulation, with or without respiratory distress, and/or (ii) severe bleeding, and/or (iii) severe organ impairment. As dengue vascular permeability progresses, hypovolaemia worsens and results in shock. It usually takes place around defervescence, usually on day 4 or 5 (range days 3-7) of illness, preceded by the warning signs. During the initial stage of shock, the compensatory mechanism which maintains a normal systolic blood pressure also produces tachycardia and peripheral vasoconstriction with reduced skin perfusion, resulting in cold extremities and delayed capillary refill time. Uniquely, the diastolic pressure rises towards the systolic pressure and the pulse pressure narrows as the peripheral vascular resistance increases. Patients in dengue shock often remain conscious and lucid. The inexperienced physician may measure a normal systolic pressure and misjudge the critical state of the patient. Finally, there is decompensation and both pressures disappear abruptly Prolonged hypotensive shock and hypoxia may lead to multi-organ failure and an extremely difficult clinical course The patient is considered to have shock if the pulse pressure is $20 mm Hg in children or heishe has signs of poor capillary perfusion (cold extremities, delayed capillary refill, or rapid pulse rate) In adults, the pulse pressure of $20 mm Hg may indicate a more severe shock. Hypotension is usually associated with prolonged shock which is often complicated by major bleeding. Patients with severe dengue may have coagulation abnormalities, but these are usually not sufficient to cause major bleeding When major bleeding does occur it is almost always associated with profound shock since this in combination with thrombocytopenia, hypoxia and acidosis. can lead to multiple organ failure and advanced disseminated intravascular coagulation: Massive bleeding may occur without prolonged shock in instances when acetylsalicylic acid (aspirin), Ibuprofen or certicosteriods have been taken.298 SPIORMIGILOGY OF COMMUNICABLE DISEASES Unusual manifestations, including acute liver failure and encephalopathy, may be present, even in the absence of severe plasma leakage or shock Cardiomyopathy and encephalitis are also reported in a few dengue cases However, most deaths from dengue occur in patients with profound shock, particularly if the situation is complicated by fluid overload CRITERIA FOR CLINICAL DIAGNOSIS (3, 6, 11, 12) A summary of clinical diagnosis of DF and DHF is as follows Dengue fever Probable diagnosis Acute febrile illness with two or more of the following: headache, retro-orbital pain, myalgia, arthralgia/bone pain, rash, haemorrhagic manifestations, leucopenia (wbc ≤ 5000 cells/mm³), thrombocytopenia (platelet count <150,000 cells/mm²), rising haematocrit (5-10%); OR Non-ELISA based NS 1 antigen/IgM Positive (A positive test by RDT will be considered as probable due to poor sensitivity and specificity of currently available RDTs) Confirmed dengue fever (12): A case compatible with the clinical description (see above) of Dengue Fever with at least one of the following: Isolation of dengue virus (Virus culture +VE) from serum, plasma, leucocytes Demonstration of IgM antibody titre by ELISA positive in single serum sample Demonstration of dengue virus antigen in serum sample by NS1-ELISA IgG seroconversion in paired sera after 2 weeks of four-fold increase of IgG titre Detection of viral nucleic acid by polymerase chain reaction (PCR) Dengue haemorrhagic fever All of following: E acute onset of fever of two to seven days duration. haemorrhagic manifestations, shown by any of the following; positive tourniquet test, petechiae, ecchymoses or purpura, or bleeding from mucosa, gastrointestinal tract, injection sites, or other locations. platelet count ≤ 100,000 cells/mm² objective evidence of plasma leakage due to increased vascular permeability shown by any of the following ≥20% Rising haematocrit/haemoconcentration from baseline or evidence of plasma leakage such as pleural effusion, ascites or hypoproteinaemia/albuminaemia. illne the infec who IgM ISOL deng majo Dengue shock syndrome Criteria for dengue haemorrhagic fever as above with of shock including d h d e fo fe E an m the in dia hic en wh tra CO ser for spe IGN AS the any der the soli the will add The is u rap pati four IgM infe day: by E had thre for notSES and ce of and cases with cated 12. is as 9: mm³), sitive poor Ts) (see ing: from ositive serum eks of chain On of the echiae, ucosa. ations. creased wing ≥20% e such aemia e with tachycardia, cool extremities, delayed capillary weak pulse, lethargy or restlessness, which may sign of reduced brain perfusion. pulse pressure ≤ 20 mmHg with increased dia pressure, e.g. 100/80 mmHg. hypotension by age, defined as systolic p <80 mmHg for those aged <5 years, or 90mmHg for older children and adults Laboratory diagnosis (3, 6, 12) Rapid and accurate dengue diagnosis is of a para importance for: (1) clinical management; (2) epidemiolo placed the virus iso surveillance: (3) research; and (4) vaccine the the detection of dengu Epidemiological surveillance requires early determination health action towards control, as well as at sentinel sites detection of circulating serotypes/genotypes during the ine dengue virus infection during the outbreak for urgent epidemic period for use in forecasting possible outbreak The following laboratory tests are available to diagnose denga fever and DHF: ELISA BASED NS1 ANTIGEN TESTS: Dengue NS antigen, a highly conserv conserved glycoprotein, produced in bos membrane-associated and secretory forms, is abundant the serum of patients during the early stages of dengue infection and has been found to be useful as a tool for the diagnosis of acute dengue infections. It is a simple test that s highly specific and shows high sensitivity. NS1 antigen enables early detection of cases i.e., in the viremic stage which has epidemiological significance for containing the transmission. The dengue virus NS1 ELISA antigen assay a commercially available. This assay has been evaluated for sensitivity and specificity. The NS1 assay may also be usehi for differential diagnosis between flaviviruses because of the specificity of the assay. IGM-CAPTURE ENZYME-LINKED IMMUNOSORBENT ASSAY (MAC-ELISA): MAC-ELISA has been widely used in the past few years.It is a simple test which does not require any sophisticated equipment. It is based on detecting the dengue-specific IgM antibodies in the test serum by capturing them using anti-human IgM that was previously bound to the solid phase. This is followed by addition of dengue antigen,//the IgM antibody from the patient's serum is anti-Dengue, it will bind to the Dengue antigen. An enzyme-substrate is added to give a color reaction for easy detection. The anti-dengue IgM antibody develop faster than IgG and is usually detectable by day 5 of the illness. However, the rapidity with which IgM develops varies considerably among patients. Some patients have detectable IgM on days two to four after the onset of illness, while others may not develop IgM for seven to eight days after the onset In some primary infections, detectable IgM may persist for more than 90 days, but in most patients, it wanes off to undetectable levels by 60 days. It is reasonably certain, however that the person had a dengue infection sometime in the previous two D three months. MAC-ELISA has become an Invaluable tool for surveillance of dengue fever. In areas where denque is not endemic, it can be used in clinical surveillance for viral illness or for random population-based sero-surveys, with the certainty that any positives detected are recer ons. It is especially useful for hospitalized patients who are generally admitted late in the illness after detectable infections. IgM is already present in the blood dengue virus from clinical specimens can be accomplished ISOLATION OF DENGUE VIRUS Isolation of most straine of majority of cases provided the sample is taken in the fou days of illness and proc may be suitable for virus plasma or washed buffy tom fatal cases, espec thymus and mosquitoes takes 7-10 days, hence management of patien PCR (POLYMERASE diagnosis based on re one-step or nested R amplification (NASBA IgG-ELISA: An Ig compares well to the gecondary dengue in SEROLOGICAL TES perform but not co indicates past infectio ELISA, there are fe diagnosis of deng Inhibition (HI), comp test (NT) which are technical problems. This test can also b RAPID DIAGNOST Rapid Diagnostic Te Dengue with warning signs (A) A-1 Without risk factors A-1 Fever Normal platele Without compli No evidence of Aofess and processed without delay Specimens that table for virus isolation include acute phase serum or washed buffy coat from the patient, autope fases fal cases, expecially liver, spleen, lymph nodes and and mosquitoes collected in nature. Isolation of virus 1-10 days, hence may not be very useful for starting the gment of patient with dengue fever. POLYMERASE CHAIN REACTION) Molecular es based on reverse transcription (RT-PCR), such as step or nested RT-PCR, nucleic acid sequence-based ation (NASBA), or real-time RT-PCR, has gradually aced the virus isolation method as the new standard for detection of dengue virus in acute phase serum samples. ELISA An IgG-ELISA has been developed that mpares well to the Hemagglutination-Inhibition (HI) test test can also be used to differentiate primary and ondary dengue infections. The test is simple and easy to form but not considered as a diagnostic test as it dicates past infections only ROLOGICAL TESTS Besides, MAC ELISA and IgG-LISA, there are few serological tests available for the agnosis of dengue Infection like hemagglutination-hibition (HI), complement fixation (CF) and neutralization (NT) which are not commonly used due to various chnical problems. CAPID DIAGNOSTIC TESTS: A number of commercial Rapid Diagnostic Test (RDT) kits for anti-dengue IgM/IgG THE SANGER SISCRIM 299 antibodies and N51 antigen are commercially available at present which gether wit1525nutes However, the since they have not yet been property validated Some of the RDTe have bee showed a high rate of false positive compared to standard teste, while others have agreed closely with standard seats The sensitivity and specificity of some REITs were also found to vary from batch to batch. Hence, currently, the program does not recommend the use of RDTs for diagnosia and guiding the management of Dengue lever cases CLINICAL MANAGEMENT Grading of the severity of dengue infection To decide where to treat the patient, it is important to classify the severity of dengue infection. The presence of thrombocytopenia with concurrent haemoconcentration and depending on the clinical manifestations, presence of warning signs and other high-risk factors, patients may be classified as following Mild dengue (A): May be managed on OPD basis Moderate dengue (B) Observation or admission for in hospital management Severe dengue (C) Require emergency treatment and urgent referral Fig. 3 summarizes the clinical case classification of dengue (12). Dengue viral infection Symptomatic Asymptomatic Dengue without warning signs (Mild) (A) A-1 Without risk factors A1 Fever A-2 With risk factors Normal platelet count Without complications No evidence of capillary leakage A-2: A1 with co-morbidities Home or OPD management/follow up/observation Source: (12) B-1 Dengue with warning signs & co-morbidity (Moderate) (B) Dengue with warning signs and symptoms Persistent vomiting Abdominal pain/tenderness Lethargy/restlessness Bleeding manifestations Syncope or giddiness Clinical fluid accumulation (ascites and pleural effusion) Enlarged liver (>2cm) Progressive increase in haematocrit/decrease in platelet count B2 B1 plus co-morbidity and high risk Infants Old age Diabetes Hypertension Pregnancy CAD Haemogolobinopathies Immunocompromized patient Patient on steroids, ariticoagulants or Immunosuppressants. Close monitoring and possibly hospitalization/observation FIG.3 Clinical case classification of dengue Severe dengue (C) C1, C2, C3 severe C-1 Shock C-2 Bleeding C-3 Organ involvement (Acidosis, dyseletrolytemia) Tertiary level care management300 GUIDELINES FOR TREATMENT Ad of the patient should be done at the Aamin the early felirile phase the patients oun baseline haematocrit A rapidly deceating platelet count in parallel with a rising Karmanici compared to the baseline is suggestive of press to the plasma leakage critical phase of the disease In the absence of the patients baseline, age specific population haematocrit levels could be used as a surrogate during the critical phase 1. Management of mild dengue fever (Group A) These are patients who are able to tolerate adequate volumes of oral fluide and pass urine at least once every six hours, and do not have any of of the warning signs, particularly when fever subsides Those with stable haematocrit can be sent home after being advised to return to the hospital Immediately if they develop any of the warning signs, and to adhere to the following action plan (1) Encourage intake of oral rehydration solution (ORS). fruit juice and other fluids containing electrolytes and sugar to replace losses from fever and vomiting. Adequate oral fluid intake may be able to reduce the number of hospitalizations. (Caution fluids containing sugar glucose may exacerbate hyperglycaemia of physiological stress from dengue and diabetes mellitus.) (2) Give paracetamol for high fever if the patient is uncomfortable. The interval of paracetamol dosing should not be less than six hours. Tepid sponge if the patient still has high fever. Do not give acetylsalicylic acid (aspirin), ibuprofen or other non-steroidal anti-inflammatory agents (NSAIDs) as these drugs may aggravate gastritis or bleeding. Acetylsalicylic acid (aspirin) may be associated with Reye's Syndrome. (3) Instruct the care-givers that the patient should be brought to hospital immediately if any of the following occur, no clinical improvement, deterioration around the time of delervescence, severe abdominal pain, persistent vomiting, cold and clammy extremities, lethargy or irritability/restlessness, bleeding (eg. black stools or coffee-ground vomiting), not passing urine for more than 4-6 hours. Patients who are sent home should be monitored dally by health care providers for temperature pattern, volume of fluid intake and losses, urine output (volume and frequency), warning signs, signs of plasma leakage and bleeding, haematocrit, and white blood cell and platelet counts re 2. Management of moderate and severe dengue (Group B and C) (6, 11, 12) The management of febrile phase is similar to that of DF Paracetamol is recommended to keep the temperature below 39°C Copious amount of fluid should be given orally, to the extent the patient tolerates, oral rehydration solution (ORS), such as those used for the treatment of diarrhoeal disesases and/or fruit juices are preferable to plain water. IV fluid may be administered, if the patient is vomiting persistently or refusing to feed Patients should be closely monitored for the initial signs of shock. The critical period is during the transition from the Jebrile to the afebrile stage and usually occurs after the third day of illness The following parameters should be monito General condition, appetite vorm other warning signs and symptomy Peripheral perfusion assessment th frequently as indicated thecatise it is shock and is easy and fast to perform Vital signe such as temperature pols 2.4 Hours in non shock patients and ever patients with shock rate and blood pressure should bure 1 Serial haematocrit should be performed four to six hours in stable cases and sho frequent in unstable patients or those bleeding. It should be noted that haematter done before fluid resuscitation te then it should be checked after the fluid during the infusion of the bolus. Urine output should be recorded at least even is hours in uncomplicated cases and on an houry patients with profound/prolonged shock or fluid overload. During this period the amour output should be about 0.5 ml/kg/h (this should on the ideal body weight). Additional laboratory investigations Adult patients and those with co-morbidities of in shock and/or those with complications should the following laboratory investigations. Random blood glucose Blood gas analysis including lactate Serum electrolytes (sodium, potassium and calcun Renal function tests (urea and creatinine) Liver function tests (AST, ALT and bilirubinį Coagulation profile Chest radiograph Blood Group Cardiac enzymes (Pro-BNP and Troponin level if indicated among high risk groups Serum amylase and ultrasound abdomen. 2A. Management of moderate dengue patients (Group B) The dengue patients with warning signs and high groups are considered to be as moderately ill. Clinical approach for the management of moder dengue patients a. Should be admitted for in-hospital management b. Baseline haematocrit (hct) test should be perl before starting fluid therapy if the investigation delayed due to unavailability of het are available immediately. Hydration should out c. All warning symptoms and signs should be call observed. d. Blood glucose level and other laboratory tests shoul done e Encourage oral fluids if not tolerated, start intra fluid therapy of 0.9% NS or RL (They can be sent home within 12 to 24 hou show rapid recovery and are not in the critical period Fia 4 shows the algorithms for hospital management moderate dengue patients with warning signsTHE DENGUE STOR 301 Systolic pressure maintained with of Yes Dengue with warning 20% Start isotonic crystal 17-10 milk for 1 hour) IMPROVEMENT BP, pulse pressure. ure Hct, urine output capillary refilling time, pulse rate ymalloid, reduce gradually nikgh for 1-2 hours 15 nikgh for 2-4 hours 2.3 milkgh for 2-4 hours As dinical improvement noted, reduce fluid accordingly Stop IV fluids at 24-48 hours IV crystalloid/colloid solution (10 (10ml ml/kg for 1 hour) IMPROVEMENT Yes Reduce IV crystalloids 7-10 ml/kg/h for 1-2 hours No Het 45% (suspect persistent capillary leakage) Hd 45% Isuspect severe overt blewdi, check Blood transfusion 110 ming whole blood) 15 ml/kg packed RBCI Refractory hypotension consider inotropes Manage as severe dengue with de-compensated shock (Group C Algorithms for hospital management of moderate dengue patients with warning signe Source: (12) FIG. 4 Monitoring of the patient Record temperature, pulse, respiratory rate, BP should be monitored until patient is out of critical phase; bUrine output record 6 hourly, HCT determination before and after fluid replacement, then 8 hourly: d. Investigation for blood glucose, renal profile, liver profile, coagulation profile, as indicated; and . Maintain fluid balance sheet. 28. Management of Severe Dengue patients (Group C) These patients are vulnerable and require urgent admission and management. Severe dengue has following characteristics: Severe plasma leakage leading to denque shock and/or fluid accumulation with respiratory distress. b. Severe haemorrhages. or c. Severe organ impairment (hepatic damage, renal Impairment, cardiomyopathy, encephalopathy encephalitis). 4. Severe metabolic abnormalities. Principles of management of severe dengue (12): All patients to be stabilised and referred for admission to hospital which has blood transfusion facilities. Judicious IV fluid resuscitation is essential and lifesaving Preder a crystalloid solution (0.95% Normal saline or Ringer lactate) sufficient to maintain an effective circulation during the period of plasma leakage (usually for 24-48 hours) and adjust fluid as per the patient status It's advised to obtain hematocrit level before starting fluid therapy, lack of haematocrit should not delay fluid management. Monitor vital signs every 5-30 min. Use IBW for overweight and obese patients while calculating fluid rates. Blood group of the patient to be investigated Blood transfusion should be given to patients with established severe bleeding, or suspected severe bleeding (fall in Hct) with unexplained hypotension. Intravenous fluid therapy during the critical period Isotonic crystalloid solutions should be used throughout the critical period except in the very young infants <6 months of age in whom 0.45% sodium chloride may be used. Hyper-oncotic colloid solutions (osmolarity of >300 mOsm/l) such as dextran 40 or starch solutions may be used in patients with massive plasma leakage, and those not responding to the maximum volume of crystalloid. Iso-oncotic colloid solutions such as plasma and hemaccel may not be as effective. The duration of intravenous fluid therapy should not exceed 24 to 48 hours for those with shock. However, for those patients who do not have shock, the duranon of intravenous fluid therapy may have to be longer but not more than 60 to 72 hours. This is because the latter group of patients has just entered the plasma leakage period while shock patients have experienced a longer302 duration of plasma leskage before intravenous therapy has begri Always check for the signs of fluid overload. It should be noted that restoring the blood pressure is critical for survival and if this cannot be achieved quickly then the prognosis is extremely grave. Inotropes may be used to support the blood pressure at this stage Management of compensated shock (12) The action plan for treating patients with compensated shock is as shown in algorithm of Fig 5. Start intravenous fluid resuscitation with isotonic crystalloid solutions at 10-20ml/kg body weight/hour over one hour Reassess the patient's condition (vital signs, capillary refill time, haematocrit, urine output) If the patient's condition improves, intravenous fluids should be gradually reduced to 7-10 ml/kg body weight/ht for 1-2 hours, then to 5-7 ml/kg body weight/ht for 1-2 hours, then to 3-5 ml/kg body weight/hr for 2-4 hours, then 2-3 ml/kg body weight/hr for 2-3 hours and then further depending on haemodynamic status, which can be maintained for up to 24-48 hours. If patient is not clinically improved (i.e. shock persists), check the haematocrit after the first bolus. If the haematocrit increases or is still high (>45%), repeat a second bolus of crystalloid solution at 10ml/kg body weight/he for one hour. After this second bolus, if there is Improvement, reduce the rate to 7-10 ml/ kg body weight/hr for 1-2 hours, and then continue to reduce as above Il haematocrit decreases compared to the reference haematocrit (<40% in children lemales, <45% in adult males), this indicates and the need to cross match and transfuse blood as possible. Give whole blood transfusion at body weight or packed RBC at 5ml/kg body weigh Management of Decompensated shock (12) Patients with decompensated/hypotensive shod be managed more vigorously. The action plan for patients with hypotensive shock is as shown in the gra of Fig 6 Initiate intravenous fluid resuscitation with crystal, colloid solution (if available) at 20 ml/kg body weig a bolus given over 15 minutes. If the patient's condition improves, give a cryma colloid infusion of 10 ml/ kg body weight/hr for one Then continue with crystalloid infusion and gradu reduce to 5-7 ml/kg body weight/hr for 1-2 hours, te to 3-5 ml/kg body weight/hr for 2-4 hours, and t ml/kg body weight/hr or less, which can be mainten for up to 24-48 hours If shock persists, review the haematocrit haematocrit increases or is still high (>45%), repre second bolus of crystalloid solution at 10-20 milileg bo weight over 15-30 minutes. After this second bol there is improvement, reduce the rate to 7-10 ml body weight/hr for 1-2 hours, and then continue gradu reduction of fluid as mentioned above. Upto three rapi boluses may be given. If haematocrit decreases compared to the initial selerea Severe dengue with compensated shock Pulse pressure 220mmhg, hypotension (SBP>90mmhg), high Hct (2 20% rise from baseline) Start isotonic crystalloid solution (10-20 ml/kg for 1 hour) IMPROVEMENT Yes IV crystalloid, reduce gradually 5-7 ml/kg/h for 1-2 hours 3-5 ml/kg/h 2-3 ml/kg/h for 2-4 hours for 2-4 hours As clinical improvement is noted, reduce fluid accordingly Stop IV fluids at 24-48 hours BP, pulse pressure, Het, urine output. capillary refilling time, pulse rate Second bolus 10-20 ml/kg over I hour IMPROVEMENT Yes Reduce IV crystalloids 7-10 ml/kg/h for 1-2 hours FIG. 5 Source (12) No Het > 45% (suspect persistent capillary leakage) Het < 45% (suspect severe over bleed), check H Blood transfusion (10 ml/kg whole blood 15 ml/kg packed RBC No Refractory hypotension consider inotropes dengi Manage as ever with de-compense shock (Group C Algorithm for management of severe dengue with compensated shockSeven Gempar with decong Yes Start atomic crystal Rapil bolus 10-20 mg over 15-30 min 1500 las maximun IMPROVEMENT BP pulse роста. capillary tefilling time, риби та whucx gradually hours gh for 2-4 hours improvement accordingly Stop IV Buids 24-48 hours 2nd Rapid bolus 10-20 ml/kg over 15-30 min. (500 ml maximum) Check for Het, if no improvement, give 3rd rapid bolus IMPROVEMENT Yes Reduce IV crystalloids 10 ml/kg/h for 1-2 hours FIG. 6 No Ha4% Suspect persistent capillary leakage No 303 Hd45% truspect severe sivert blend) check Blood banafusion 110 ming whole blood) 15 ml/kg packed RBCT Determine cardiogenic shock, septic shock Evaluate metabolic cause and organ dysfunction Evaluate concomitant medical conditions and stabilize the baseline condition Evaluate persistent acidosis and risk of (hidden) hemorrhage and treal accordingly Il needed, administer additional boluses of hydrating solution (crystalloid or colloid) over the next 24 hours, the speed and volume of each bolus will depend on clinical response Manage patient, preferably in ICU dv Source (12) Algorithm for management of severe dengue with decompensated shock haematocrit (<40% in children and adult females, <45% in adult males), this indicates bleeding and the need to cross-match and transfuse blood as soon as possible. Give whole blood transfusion at 10ml/kg body weight or packed RBC at 5ml/kg body weight. If the shock is refractory Use of inotropes should be considered. Determine cardiogenic shock, septic shock Evaluate metabolic cause and organ dysfunction Evaluate concomitant medical conditions and stabilize the baseline condition Evaluate persistent acidosis and risk of (hidden) hemorrhage and treat accordingly -Il needed, administer additional boluses of hydrating solution (crystalloid or colloid) over the next 24 hours, the speed and volume of each bolus will depend on clinical response; -Manage patient, preferably in ICU. ladications of red cell transfusion 1. Loss of blood (overt blood) - 10 per cent or more of total blood volume preferably give whole blood or components to be used. and declining haematocrit. 2. Pafractory shock despite adequate fluid administration 1. Replacement volume should be 10 ml/kg body weight at time and coagulogram should be done. 4.If fluid overload is present packed cells are to be given. Indications of platelet transfusion In general there is no need to give prophylactic platelet even at < 20,000/cu.mm. 1. Prophylactic platelet transfusion may be given at level of < 10,000/cu.mm. 2. Prolonged shock; with coagulopathy and abnormal coagulogram. 3. In case of systemic massive bleeding, platelet transfusion may be needed in addition to red cell transfusion. Criteria for discharge of patients 1. Absence of fever for atleast 24 hours without the use of anti-pyretic drugs. 2. Return of appetite. 3. Visible clinical improvement. 4. Good urine output. 5. Minimum of 2-3 days after recovery from shock. 6. No respiratory distress from pleural effusion or ascites. 7. Platelet count > 50,000/cu.mm. Management and referral of dengue cases at Primary Health Centre (PHC) level In the PHC, the following guidelines (as shown in Fig. 7) have to be followed for management of dengue cases and for referral of severe/complicated cases to higher centre304 THOLMES GO OF COMMUNICABLE DISEASES Management of Dengue lever Stable, orally sccepting KhHet Normal Advice Plenty of oral fluid, PCM & explain warning signs/symptoms Hb/Hett BP & pulse pressure Normal IV fluid 6ml/kg/hr. for 1-2 hrs. Repeat Hct H of decompe IV fluid 10-20ml/kg over 15-30 min Improvement No Improveme IV fluid 10-20 over 1. bleeding Home management/discharge Improvement Improvement Maintenance fluids (IV) Hct: Normal No Improvement Persistent hypotento altered sensoriun bleeding, rapidly fal Tracales higher omr FIG. 7 Management and referral of dengue cases at PHC level Source (12) Patient should be advised to come for follow-up after 24h for evaluation. He should report to the nearest hospital immediately in case of the following complaints: Bleeding from any site (fresh red spots on skin, black stools, red urine, nose bleed, menorrhagia) Severe abdominal pain Refusal to take orally/poor intake Persistent vomiting, not passing urine for 12 hr. Decreased urinary output Restlessness Seizure Excessive crying (young infants). Altered sensorium and behavioral changes Severe persistent headache Cold clammy skin Sudden drop in temperature. Disease notification In dengue-endemic countries, cases of suspected, probable and confirmed dengue should be notified as soon as possible so that appropriate health measures can be initiated. CONTROL MEASURES 1. Mosquito control The vectors of DF and DHF (eg. A. aegypti) breed in and around houses and, in principle can be controlled by individual and community action, using antiadult and a measures. These measures are outlined in chapter 15 2. Vaccines (13) There are currently 2 licensed dengue vaccinen ( TDV (Dengvaxia, Sanofi); and TAK-003 (Qdenga, Tin Both are tetravalent live-attenuated vaccines but diée extent of chimerization and the genome back-bonr as in efficacy and safety. CYD-TDV vaccine CYD-TDV consists of 4 live attenuated secon viruses (representing each of the 4 DENV serotypes attenuated yellow fever 17D virus genome back-bone The vaccine schedule consists of 3 doses adminis months apart, with an indication for Individuals ord years or 9-60 years (depending on the count regulatory approvals) living in denque-endemic con areas. In clinical trials, CYD-TDV has been sho efficacious and safe in persons who have had dema infection in the past (seropositive individuals) but no the risk of severe dengue in those who experience the natural dengue infection after vaccination (sermep individuals) For countries considering vaccination their dengue control programme pre-vaccinations for past dengue infection is the recommended Using this strategy, only persons with evidence f dengue infection (based on an antibody test or doc-403 vaccine miyavailable in single dose vial or pre-filled The vertine is tetravalent, live attenuated vaccine and tele reconstituted using 0.22% saline solution. It is The vaccine must be stored at a temperature of and has a shelf life of 18 months The vaccination Are the primary series is 2 doses administered European Medicines Agency and the United Kingdom's lines and Healthcare products Regulatory Agency, in India, it is licensed for use in those aged 6-65 years. The indication for use varies between countries HH Signs of cutely with an interval of 3 months between doses or decompensie is licensed for use in individuals aged 24 years by fluid 10-20ml/kg over 15-30 min No Improvement 9 1 IV fluid: 10-20mited immunity; (3) Individuals with symptomatic HIV over 1 hr, if Hat bleeding Persistent hypotention, algus altered sensorium, active bleeding, rapidly falling He provement Transfer to higher center antiadult and antilana lined in chapter 15. ised dengue vaccines: CYD id TAK-003 (Qdenga, Takeda nuated vaccines but differ in the the genome back-bone, as well h of the 4 DENV serotypes/ with c. f 4 live attenuated recombina 7D virus genome back-bone. consists of 3 doses administered dication for individuals aged 9451. lepending on the country-specif ng in denque-endemic countries of CYD-TDV has been shown to be ersons who have had dengue virut opositive individuals), but increase n after vaccination (seronegativ in those who experience their first gramme, pre-vaccination screening s considering vaccination as part of on is the recommended strate on an antibody test, or documentel y persons with evidence of pas would be vaccinated. The manufacturer stipulates that vaccination is contra-dicted in: (1) individuals with a history of severe allergic tion to any component of the dengue vaccine or after mur administration of the dengue vaccine or a vaccine aining the same components; (2) individuals with angenital or acquired immune deficiency that impairs cell-lection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function: pregnant or breastfeeding women; and that vaccination should be postponed in individuals with moderate to severe brile or acute disease. 2. Other measures Isolation of the patient under bed-nets during the first few days, individual protection against mosquitoes. The personal prophylactic measures are wearing of full sleeves shirts and full pants; use of mosquito repellent creams, Iquids, coils, mats etc.; use of bed-nets for sleeping infants and young children during day time to prevent mosquito bite. The environmental measurements are detection and elimination of mosquito breeding places, management of roof tops, porticos and sunshades, proper covering of stored water, observation of weekly dry day. Global strategy for dengue prevention and control 2012-2020 (14) Denque is a global threat that requires a global response involving all possible partners. The global strategy promotes co-ordination and collaboration among multisectora partners on integrated vector management approach and sustained control measures at all levels. The goals are: a. to reduce dengue mortality by at least 50 per cent by 2020 b. to reduce dengue morbidity by at least 25 per cent b 2020; and to estimate the true burden of the disease bu 2015. References WHO (1993), Monograph on Dengue/Dengue Haemorrhagic Fev No 22. Compiled by Prasert Thongchroen, Regional Publication, SEAR 2. WHO (2024). Fact Sheet on Denque. 23rd April, 2024. 3. WHO (2011), Comprehensive Guidelines for Prevention and Cont edition, Regional office of SEAR. of Dengue and Dengue Haemorrhagic Fever, Revised and expand 4. Govt. of India ( DGHS. Ministry 2018). Annual Report 2017-2018. 5. Govt. of India (2023), National Health Profile 2023. DGHS, Mini 6. Health and Family Welfare. New Delhi of Health Govt. of India (2008), Guidelines for Clinical Management of Den Fever, Dengue Haemorrhagic Fever and Dengue Shock Sundro and Family Welfare. New Delhi Ministry of Health and Family Welfare. New Delhi 7 WHO (2012), Weekly Epidemiological Record, No. 8. 24th Feb 20 Explain like a professor telling n explaining with logical reasoning n from scratch to a person who has zero knowledge making them understand concept n not rote Highlight keywords

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