REVIEW ARTICLE JIACM 2004; 5(3): 247-58 Dengue Fever A Dangerous Foe Ashish Goel*, Dharmeshkumar N Patel**, Krishna K Lakhani***, SB Agarwal****, Abhishek Agarwal*, Sunil Singla*, Ruchika Agarwal* Abstract Dengue fever is the most common arthropod-borne self-limiting viral disease with clinical spectrum ranging from asymptomatic infection to life threatening shock, so called dengue shock syndrome. Haemoconcentration and thrombocytopenia are the distinctive features of dengue hemorrhagic fever. Supportive fluid replacement therapy and vigilant monitoring is the cornerstone for the successful management of the condition. Vector control measures are the most important preventive methods. Keywords: Dengue haemorrhagic fever, Dengue shock syndrome. Introduction Dengue fever (DF) is the most common arthropod-borne viral disease and is one of the most important emerging infectious diseases of urban and peri-urban areas of tropical regions. Since the 18th century, dengue has caused repeated epidemics worldwide. H. Graham in 1903 implicated Aedes aegypti as the vector for the disease and the virus was isolated in 1944 by Albert Sabin et al 1. Dengue haemorrhagic fever gained nosologic status in 1954 and subsequently became endemic in many areas of tropical Asia. India belongs to category B, where dengue is an emerging disease with cyclical epidemics becoming more frequent 2. There have been repeated epidemics with the latest outbreak in the capital city of Delhi and various other states of India. Aetiology (a) Causative agent: Four dengue viruses (types 1-4) within the genus flavivirus and family flaviviridae, are the causative agents. All four subtypes are found in India. Dengue virions are small particles with lipoprotein envelope and nucleocapsid of single stranded RNA genome with positive polarity. There is a close antigenic similarity between the four serotypes but the cross protection in humans is at best partial and transient 1. (b) Transmission: Reservoir of infection is both man and mosquito. The transmission cycle is Man-Mosquito-Man. Aedes aegypti is the principal vector, the other less important vectors being Aedes albopictus, Aedes polynesiensis, and several species of Aedes scutellaris complex 1, 2. The extrinsic incubation period is 8-11 days, with mosquitoes remaining infected for life. Aedes aegypti also called the tiger mosquito is a daybiter with limited flight range, and breeds in fresh water collected indoors and peri-domestically in tropical areas. The outbreaks coincide with the monsoon 3. The epidemiologic significance of transovarian mosquito cycle and jungle transmission cycle is unknown 1. Epidemiology Dengue affects more than 100 countries all over the world except Europe. In India, the first recorded outbreak of dengue fever was in 1812 and serological survey was conducted in 1952 4. In 1996, an outbreak involving 10,000 cases occurred in New Delhi; 400 deaths were reported in the outbreak 2. Contd. on page 250 * Resident, ** Assistant Professor, *** Associate Professor and Head of Unit, Department of Medicine, BJ Medical College and New Civil Hospital, Ahmedabad-16 (Gujarat). **** Professor and Head, Department of Medicine, CU Shah Medical College, Surendranagar, Gujarat.
Contd. from page 247 Pathogenesis After the bite by an infected mosquito, the virus replicates in the regional lymph nodes of the affected individual and is disseminated via the lymph and blood to the other tissues. Majority of the infections are self-limiting and only a small proportion leads to severe illness, dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS), which are characterised by abnormally increased capillary permeability and disordered haemostasis 1. The DHF/DSS are primarily seen in the young (age < 12 yrs) and mostly in secondary infection, i.e., infection from a different serotype after recovery from the previous infection. This is explained by the non-neutralising antibody dependent enhancement of the infected cells leading to cytokine release 5. Pathology 1 The pathologic findings include: Depression of all haemopoietic cells including megakaryocytic in bone marrow. Active proliferation and lymphocytolysis in germinal centers in lymph nodes and spleen. Focal mid-zonal necrosis and fatty changes in liver, and Occasionally glomerulonephritis (due to immunecomplex deposition). Clinical spectrum 2,6 The spectrum of clinical manifestations is shown in Fig.1. Majority of the infections that occur in children are asymptomatic, while they are mostly symptomatic in adults. The various manifestations of dengue infection can be graded according to Table I. Besides helping to assess the overall prognosis, the grading has therapeutic implications also. 1-4, 6-9 Clinical features (A) Classic dengue ( Break-bone fever ): The incubation period is usually 4-6 days (range 3-14 days) followed by abrupt onset of fever, chills, headache, retro-orbital pain, and lumbosacral aching. The fever is typically of 39-40 C and is occasionally followed by remission lasting few hours to 2 days followed by a second febrile phase for 1 to 2 days (biphasic curve). Fever lasts for 5-7 days. A transient generalised erythematous flush like rash may be present during the first 24-48 hrs. The typical morbilliform rash appearing on the trunk and spreading centripetally to face and extremities usually occur during the second febrile phase. It may be accompanied by itching and hyperaesthesia, lasts for several days and can be followed by desquamation. Generalised myalgia, arthralgia, and constitutional symptoms like anorexia, nausea, vomiting, and dysgeusia can also be present. The physical examination may reveal relative bradycardia and generalised lymphadenopathy. Marked leucopenia and neutropenia are typical, and thrombocytopenia may occur on 3rd to 8th day. In some epidemics dengue fever may be associated with haemorrhagic phenomena, particularly petechial haemorrhages and epistaxis, G.I. bleed, haematuria, hypermenorrhoea; but in the absence of signs of plasma leakage, a diagnosis of DHF is unwarranted. Convalescence may be accompanied by asthenia and bradycardia. The case definition of dengue fever is summarised in Table II. (B) Dengue haemorrhagic fever (DHF) : DHF is a severe form of dengue fever. 90% of DHF cases occur during secondary infections, which can be explained by the generation of non-neutralising antibodies that bind to the heterologous dengue virus. This virus antibody complex enhances the virus entry into Fc receptor bearing lymphoid cells, a mechanism known as antibody-dependent enhancement. Macrophage infection is central to the pathogenesis of dengue fever and origin of DHF/DSS. The infected macrophages release various cytokines leading to increased vascular permeability and shock. Dengue serotype 2 is apparently more dangerous as compared to others. 250 Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004
Table I : Grading of severity of dengue fever 7. DF/DHF Grade* Symptoms Laboratory DF Fever with two or more of be following: Leucopenia, occasionally 1. Headache thrombocytopenia may be present, 2. Retro-orbital pain no e/o plasma loss 3. Myalgia 4. Arthralgia DHF I Above signs + positive tourniquet test Thrombocytopenia < 100,000, Hct rise 20% DHF II Above signs + spontaneous bleeding - do - DHF III Above signs + circulatory failure - do - (weak pulse, hypotension, restlessness) DHF IV Profound shock with undetectable BP and Pulse - do - *DHF Grade III and IV are also called as DSS. Table II : Case definition of dengue fever 3. Suspect case Acute onset High fever of < 7 days duration Severe headache, backache Joint and muscle pain, and retro-orbital pain With or without rash Probable case Suspect case of DF High vector density Presence of confirmed case in the area Confirmed case Isolation of virus from blood in early phase. Serological test for IgM antibody in single serum or a four-fold rise of antibodies in paired serum samples. Following an incubation period of 4-6 days, the illness commonly begins abruptly with high fever accompanied by facial flushing and headache. During the first few days the illness usually resembles the classical DF, but maculopapular rash is less common. Anorexia, vomiting, epigastric discomfort, tenderness at the right costal margin, and generalised abdominal pain are common. The critical stage is reached after 2-7 days when fever subsides, and features of circulatory disturbances start appearing which may culminate in DSS and death within 24-48 hrs. This phase of DHF is accompanied by ascites, pleural effusion (usually right sided), and petechiae, ecchymoses and other spontaneous haemorrhages including GI haemorrhage, metromenorrhagia, and epistaxis. Liver is usually palpable varying from just palpable to 2-4 cms. Poor prognostic indicators, although rare, include metabolic acidosis, encephalopathy, intracerebral haemorrhage and hepatic failure. Criteria for diagnosis of DHF 2, 3 : (a) Clinical features 1. Pyrexia Sudden onset, high grade, lasting 2-7 days. 2. Haemorrhagic manifestations in the form of at least one of the following: - Petechiae, purpura, echymoses. - Epistaxis, gum bleeding, bleeding from mucosa, GIT, or injection site - Hematemesis and/or malena - A positive tourniquet test: In this test a sphygmomanometer cuff is inflated on the arm to point midway between systolic and diastolic pressures for 5 minutes. A positive test is declared when > 20 petechiae appear in a 2.5 cm square (or 3 cm diameter circle) Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004 251
Fig. 1 : Clinical spectrum of dengue fever 6. on the skin surface on the forearm. In patients in shock, the test usually becomes positive if it is performed after recovery from shock. The test may be negative or only mildly positive (> 10 petechiae/2.5 sq cm) during the phase of profound shock. 3. Hepatomegaly. (b) Laboratory criteria 4. Thrombocytopenia ( 100,000/cmm) 5. Evidence of plasma leakage manifested by at least one of the following: A rise in haematocrit ³ 20% above average for age, sex, and population. Signs of plasma leakage such as pleural effusion. (C) Dengue shock syndrome (DSS): Some patients of DHF manifest signs of restlessness, abdominal pain, and shock (rapid and weak pulse, cold clammy extremities, diaphoresis, circumoral cyanosis, irritability, or change in mental status). These cases known as DSS, are characterised by narrowing of the pulse pressure to 20 mm Hg or hypotension and in severe cases (DHF Gr IV) undetectable BP and pulse. Thus, diagnosis of DSS is based on all the criteria of DHF plus manifestations of shock. The duration of shock is very short and the patient may die within 12-24 hours or recovers rapidly following appropriate fluid replacement therapy during this period. Uncorrected shock may give rise to complicated course with metabolic acidosis, severe bleeding from G.I. and other organs, DIC, and overall poor prognosis. Unusual manifestation/complication of DHF: 1. Hepatic encephalopathy due to acute hepatic failure. 2. CNS manifestations 10 convulsions and/or coma due to encephalopathy or occasionally encephalitis; intracranial haemorrhage or thrombosis due to DIC. 3. Renal failure. 4. Haemolytic-uraemic syndrome. 5. Dual infections with other endemic diseases, e.g., leptospirosis, viral hepatitis B, typhoid, etc. 6. Superinfection with other microbes e.g., UTI, pneumonia, septicaemia, etc. 252 Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004
7. Fluid overload If fluids are continued beyond critical phase when reabsorption occurs. Disease course DF and DHF have an unpredictable course which is illustrated in Fig. 2: Differential diagnosis 6 Early in febrile illness, the differential diagnosis includes a wide spectrum of viral and bacterial infections (e.g., malaria, leptospirosis, yellow fever, Hantavirus, typhoid, chikungunya fever, meningococcaemia, etc.). The presence of marked thrombocytopenia with concurrent haemoconcentration differentiates DHF/DSS from the other diseases. Laboratory investigations 1, 4 (A) Virus isolation: The virus should be sought from serum obtained during febrile phase of illness. (B) Serology: fixation, or neutralising antibody titers in appropriately timed paired sera drawn 7-14 days apart. Samples are to be collected as follows: S1 (acute serum) As soon as possible after hospital admission. S2 (convalescent serum) Shortly before discharge from hospital (gap of 10-14 days). S3 (late convalescent serum) If possible, 14-21 days after disease onset. Haemagglutination inhibition assays It is the WHO recommended reference test for dengue virus infections. The interpretation is shown in Table III. The disadvantages of these tests are: ELISA Time consuming Cannot identify specific serotypes Cross-reaction with other related flaviviruses, e.g., Yellow fever, West Nile fever, Japanese encephalitis, etc. Serologic diagnosis is achieved by demonstrating a rise in haemagglutination inhibition, complement (i) The IgM antibody Capture ELISA (MAC-ELISA) is especially useful in diagnosis of recent infection. By Fig. 2 : Disease course of dengue fever. Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004 253
two days following defervescence, patients with primary or secondary infections have detectable IgM antibodies. These antibodies wane rapidly, so that by 2-3 months the majority of patients are seronegative; thus tests on a single serum sample may indicate recent infection. IgM antibodies are relatively specific for dengue, but do not distinguish between the various serotypes. Rising titer of IgM antibodies is much more specific. towards the end of febrile phase. A relative lymphocytosis with more than 15% atypical lymphocytes is common at the end of febrile phase (critical stage) and at early shock stage. Hypoproteinaemia. Mildly elevated AST and BUN. Evidence for DIC (prolonged PT and aptt with decreased serum fibrinogen and increased FDP). (ii) IgG ELISA has results and interpretatation comparable to haemaggglutination inhibition assay. Thrombocytopenia. Rising haematocrit. Table III : Interpretation of haemagglutination inhibition test 4,6. S1 S2 Interpretation < 1:20 < 1:1280 Primary dengue > 1:20 > 1:1280 Secondary dengue > 1:1280 Presumptive e/o secondary dengue Commercial dengue blot assay: Metabolic acidosis. It is rapid diagnostic test, which is as sensitive as haemagglutination inhibition assay in diagnosing a secondary dengue infection but not so in case of primary infection. Newer diagnostic techniques: (1) Reverse transcriptase polymerase chain reaction (RT- PCR): Very sensitive and specific for detection of viral RNA. (2) Hybridisation probe: Identification of viral nucleic acids with the help of hybridisation probes. (3) Immuno-cytochemical methods: Use of enzyme conjugates, such as peroxidases and phosphatases in conjugation with either polyclonal or monoclonal antibodies to detect dengue virus antigen. Other associated laboratory findings are: WBC count WBC count may be normal but leucopenia is common. Neutrophils decrease Urine mild albuminuria. Management It can be decided according to clinical manifestations and grading as mentioned in Table I. (A) Dengue fever: Treatment of dengue fever is symptomatic, e.g., sponging, acetaminophen (not more than 4 tablets/ day), bed rest, and oral rehydration therapy. Patient can be managed at home if no signs of dehydration or bleeding are present and only after proper education, which should include: (1) Avoid aspirin/nsaids. (2) Contact doctor if danger signs like abdominal pain, malena, bleeding, and cold skin develops. (B) Dengue haemorrhagic fever (Grade I and II): The management of the febrile phase is same as the classic dengue even though the patients are usually hospitalised. The volume replacement during critical phase is 254 Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004
illustrated in Fig. 3. Careful and repeated estimation of volume status is the cornerstone in the fluid management. This should include measuring vital signs, urine output, haematocrit, and serum protein concentration. To avoid fluid overload, the fluid therapy is stopped when haematocrit drops to approximately 40% and clinical signs and urine output improves. (C) Dengue shock syndrome (DHF Grade III / IV): The fluid replacement therapy required in DSS is much more aggressive with careful monitoring of the above mentioned parameters. The volume replacement therapy is illustrated in Fig. 4. Platelet rich blood components are replaced if profound thrombocytopenia (Platelet count < 10,000/ cmm) is present. Points to remember: (1) Hospitalisation may be necessary when Fig. 3 : Volume replacement in DHF I and II 7. Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004 255
Fig. 4 : Volume replacement in DSS 7. significant dehydration (>10% of normal body weight) has occurred. Other signs of significant dehydration are highlighted in Table IV. (2) Avoid NSAIDs/aspirin. (3) Avoid blood transfusion/iv fluids unless indicated. (4) Avoid steroids. (5) Do not use antibiotics. (6) Avoid rapid changes in rate of fluid infusion. (7) Insertion of nasogastric tube to determine concealed bleeding or for lavage to stop bleeding is not recommended and is actually hazardous. (8) Correct acidosis if present. Signs of recovery: Stable pulse, blood pressure, and respiratory rate. Normal temperature. No evident external/internal bleeding. Return of appetite. No vomiting. Good urine output. Stable haematocrit. Convalescent confluent petechial rash. Criteria for discharging patients: Absence of fever for atleast 24 hrs without use of 256 Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004
antipyretics. Return of appetite. Visible clinical improvement. Good urine output. Minimum of three days after recovery from shock. No respiratory distress from pleural effusion and no ascites. Platelet count of > 50,000/cmm. Table IV : Signs of significant dehydration 6. 1. > 10% decrease in normal body weight 2. Tachycardia 3. Increased capillary refill time (> 2 seconds) 4. Cool, mottled, pale skin 5. Diminished peripheral pulses 6. Changes in mental status 7. Oliguria 8. Sudden rise in haematocrit or continuously elevated haematocrit despite administration of fluids 9. Narrowing of pulse pressure (< 20 mm Hg.) 10. Hypotension (a late finding representing uncorrected shock) Prognosis The case-fatality rate reported varies greatly with case ascertainment and the quality of treatment; however, most DHF/DSS patients respond well to supportive therapy, and overall mortality in an experienced center is as low as 1% 5. Other factors affecting prognosis are mentioned in Table V. Prevention and control: Factors increasing the risk of DF/DHF outbreaks are: 1. Increasing urbanisation 2. Expanding mosquito breeding due to : Shortage of water supply Traditional water storage Poor garbage collection 3. Changing lifestyle, (e.g., use of water-coolers) 4. Rapid transportation Prevention of dengue outbreaks can be achieved by reducing vector populations through diminution of breeding sites and use of larvicidal agents. The measures of prevention and control of outbreak are delineated in Table VI. Long term measures include the recommended steps for vector control under National Anti-Malaria Programme (NAMP). Table V : Factors affecting prognosis of dengue fever 5. 1. Presence of enhancing and non-neutralising antibodies increases the severity. 2. Age: Susceptibility of DHF/DSS drops considerably after 12 years of age. 3. Sex: Females are more often affected than males. 4. Race : Caucasians are more often affected then blacks. 5. Nutritional status : Malnutrition is protective. 6. Sequence of infection: Serotype 1 followed by serotype 2 seems to be more dangerous than serotype 4 followed by serotype 2. 7. Infecting serotype: Type 2 is apparently more dangerous than the other serotypes. Table VI : Measures for prevention and control of DHF outbreak 3. 1. Initiate vector surveillance and control measures, (e.g., residual spraying). 2. Ensure community participation. 3. Assess facilities for case management of patients with haemorrhagic shock. 4. Alert health personnel to report increase/clustering of cases. 5. Measures for prevention of mosquito bites to be conveyed to general population: i. Wear clothes that cover arms and legs. ii. Use of mosquito nets/repellants. iii. Keep patients protected from mosquito bite in acute phase. 6. Elimination of mosquito breeding places: i. Empty water tanks once a week. ii. Cover and seal septic tanks and soak away pits. iii. iv. Removal of rubbish. Remove water from coolers and other places where water has remained stagnant. Immunisation Tetravalent vaccines are in advanced stage of development in Thailand and will be available in the near future 1. Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004 257
Conclusion Though dengue fever is usually a self-limiting disease, lack of proper monitoring and adequate volume replacement may lead to fatal outcome. In view of emerging outbreaks of dengue fever in various states of India, it becomes imperative for primary care physicians to have an updated knowledge about early diagnosis and recent management guidelines. References 1. Vaughn DW, Greene S. Dengue and Dengue Hemorrhagic Fever. In: Strickland GJ (ed). Hunter s Tropical Medicine and Emerging Infectious Diseases. 8th ed. Philadelphia: W.B. Saunders and Co., 2000; 240-45. 2. Park K. Dengue Syndrome. In: Park s Textbook of Preventive and Social Medicine. 16th ed. Jabalpur: M/s. Banarsidas Bhanot. 2000; 186-89. 3. National Insitute of Communicable Diseases. Investigation and Control of Outbreaks: Dengue and Dengue hemorrhagic fever, July 1997. 4. Chugh SK, Yadava SK. Dengue hemorrhagic fever. In: Panja M (ed). Medicine Update Proceedings of Scientific Sessions, APICON 2001. Association of Physicians of India 315-19. 5. Peters CJ. Infections caused by arthropod - and rodent borne viruses. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL(eds). Harrison s Principles of Internal Medicine. 15th ed. New York: McGraw Hill 2001; 1152-66. 6. WHO. Dengue Hemorrhagic Fever: Diagnosis, treatment, prevention and control. 2nd ed.: Geneva 1997. 7. WHO/SEARO. Guidelines for treatment of dengue fever/ dengue hemorrhagic fever in small hospitals, New Delhi. 1999. 8. Chincholika SV, Kulkarni AT. Problems and prospects of dengue hemorrhagic fever. Indian Medical Gazette 2003; CXXXVII (2): 56-8. 9. Pazare AR. Dengue fever. The Indian Practitioner 2000; 56 (8): 549-53. 10. Koley TK, Jain S, Sharma H et al. Dengue encephalitis. JAPI 2003; 51: 424. 258 Journal, Indian Academy of Clinical Medicine Vol. 5, No. 3 July-September, 2004