MANAGEMENT OF DENGUE Fever latest guidelines

Management of dengue fever latest guidelines

1. MANAGEMENT OF DENGUE Presenters: Dr. Suguna Kari, Dr. Muskan Chandak Moderators: Dr.(Prof). Rajnish Singh Dr. Garyll Ryan(SR)

2. HISTORICAL BACKGROUND Derived from a Swahili phrase “Ka- Dinga pepo” which means cramp like seizure caused by an evil spirit First case ever recorded was in jin dynasty between 265-420 AD when it was referred to as water poison associated with flying insects. The first dengue-like illness reported in India in Chennai in 1780, and first time isolated in 1944 in Kolkata. First epidemic ever recorded was in 1780s(Breakbone fever) Massive movement of troops during WW II to the remote regions of southeast asia and pacific islands facilitated the spread of dengue dramatically all over the globe.

3. EPIDEMIOLOGY One of the most important viral diseases which has emerged as an endemic in more than 100 countries in all continents except Europe Asia represents ~70% of the disease burden. 3.9 billion people(half of the world’s population) live in dengue endemic countries

4. Each year

5. AGENT Dengue virus: single stranded RNA virus of genus Flaviviridae Four virus serotypes: DEN-1, DEN-2, DEN-3, DEN-4 DEN-2 > DEN-1 are most prevalent in India Antigenically similar but different enough to offer cross protection for only a few months for the other serotypes. Reservoirs: Man, Mosquito Transovarian transmission is observed in mosquito which made control more complicated.

6. VECTOR Transmitted by the bite of Aedes mosquito A. aegypti is the most potential vector Other species: A. albopictus, A. polynesiensis , A. niveus India: A. aegypti is prevalent in urban areas while A. albopictus in rural areas The aedes usually become infected with dengue virus when it takes blood meal from infected person, when viremia is in sufficient titre. It usually occurs 1-2 days before and lasts 4-5 days after the onset of fever. Then after an extrinsic incubation period of 8-10 days, the mosquito becomes infective. The life cycle of aedes aegypti mosquito is around 30-45 days.

7. ENVIRONMENTAL FACTORS Population of A. aegypti fluctuates with rainfall and water storage Survives best between 16-30ºC and a relative humidity of 60-80%, thrives during warmer months and cannot survive during winter. Breeds in domestic man made receptacles Examples: water coolers, storage pots, unused tyres, open overhead tanks, construction sites, sub urban slums.

8. HOST FACTORS All ages and both the sexes are equally susceptible Travel to dengue endemic area is an important risk factor Persons from non-endemic areas who travel to endemic areas and get infected will introduce the disease in the non endemic area.

9. PATHOPHYSIOLOGY Primary or first infection in non immune persons usually causes dengue fever Secondary infection with a different serotype causes more severe illness like DHF/DSS

10. PRIMARY VS SECONDARY INFECTION PRIMARY SECONDARY Viremia Lower viremia Comparatively longer lasting viremia Higher viremia Short-lasting viremia NS1Antigen High titre May remain elevated until day 9 of illness Low titre Rarely found beyond 5-7 days of illness IgM/IgG ratio >1.2 <1.2 DHF and other complications Less More

11. Antibody dependent enhancement(ADE) of infection has been hypothesized as a mechanism to explain severe dengue in course of secondary infection . Here the non-neutralizing, cross-reactive antibodies raised during a primary infection, bind to epitopes of heterologous virus and facilitates its entry into cells. Increased number of infected cells results in a higher viral burden and thus more robust immune response, resulting in more tissue damage. Sequence of DENV infection Risk of DHF/DSS(as compared to primary infection) DENV 1 followed by DENV 2 500 fold DENV 3 followed by DENV 2 150fold DENV 4 followed by DENV 2 50 fold

12. CLINICAL MANIFESTATIONS Intrinsic Incubation period is 4-7 days (range=3-14 days) Infected person might be symptomatic or asymptomatic and symptoms can range from simple undifferentiated fever to life threatening hemorrhage and shock.

13. WHO 1997 CLASSIFICATION

14. REVISED 2009 CLASSIFICATION

15. NATURAL COURSE OF THE DISEASE 3 phases Febrile Critical Convalescent or recovery phase

16. FEBRILE PHASE The onset of dengue fever is usually with sudden rise in temperature which may be biphasic, lasting 2-7 days and commonly associated with headache, flushing and rash. There may be pain in retro-orbital area, muscles, joint or bone. Rash in dengue fever is a maculopapular or macular confluent rash over the face, thorax and flexor surfaces with islands of skin sparing. It begins on day 3 and persists for 2-3 days A second rash may appear within 1-2 days of defervescence lasting for 1-5 days which is morbilliform spares the palms and soles and occasionally desquamates.

17. CRITICAL PHASE DF patients usually go to critical phase after 3 to 4 days of onset of fever. During this critical phase plasma leakage and high hemoconcentration are documented and patients may develop hypotension. Abnormal hemostasis and leakage of plasma leads to shock, bleeding, accumulation of fluid in pleural and abdominal cavity. High morbidity and mortality in severe dengue are commonly associated with various organ involvements and metabolic derangement. The period of plasma leakage usually persists for 36-48 hrs.

18. CONVALESCENT OR RECOVERY PHASE During the recovery phase the extracellular fluid which was lost due to capillary leakage returns to the circulatory system and signs and symptoms improve. This phase usually after 6-7 days of fever and last for 2-3 days. Longer convalescence may be expected in some of the patients with severe shock, organ involvement and other complications which may require specific treatment. Patient may develop pulmonary oedema due to fluid overload if the fluid replacement is not optimized carefully.

19. TORNIQUET TEST The tourniquet test is performed by inflating a blood pressure cuff to a midpoint between the systolic and diastolic pressure and maintain for five minutes. The test is considered positive when 10 or more petechiae per one square inch area over forearm are observed. In DHF, the test usually gives a definite positive test with 20 petechiae or more. The test may be negative or only mildly positive during the phase of profound shock (DSS).

20. HIGH RISK GROUP FOR SEVERE DENGUE Pregnancy Infants and Elderly Obesity Peptic ulcer diseases G6PD deficiency Thalassemia Coronary Artery Disease Chronic diseases: diabetes, COPD, bronchial asthma, hypertension Patients on steroids, antiplatelet, anticoagulant drugs HIV infected persons/ Immuno-compromised persons

21. EXPANDED DENGUE SYNDROME

22. Differentials Malaria Enteric fever Influenza Leptospirosis Meningococcal infection Chikungunya fever Epidemic typhus/ scrub typhus Crimean-Congo haemorrhagic fever Ebola haemorrhagic fever

23. MANAGEMENT Investigations Treatment

24. INVESTIGATIONS Abnormal routine investigations that suggest dengue Hematocrit: crude estimate: Hb×3 In a patient of acute febrile illness, increase in hematocrit by ≥20% during 5-7 th day of illness which coincides with the critical phase. When baseline is not available >45% Leucopenia Thrombocytopenia

25. Other derangements: Increase in urea, creatinine Mild increase in AST, ALT upto 200-250( >1000 is suggestive of hepatic involvement and severe dengue) Hyponatremia Hypoalbuminemia Mild albuminuria Increase in PT and aPTT Increase in CPK and LDH

26. TESTS FOR CONFIRMATION Isolation of the dengue virus from serum, plasma or leucocytes Demonstration of dengue virus antigen in serum or CSF samples by immunohistochemistry, immunofluorescence or ELISA Detection of dengue virus genomic sequences in serum or cerebrospinal fluid samples by polymerase chain reaction (PCR). Demonstration of IgM antibody seroconversion or a fourfold or greater change in IgG antibody titres to one or more dengue virus antigens in paired serum samples

27. NS1Ag( ELISA BASED) Dengue NS1 antigen is abundant in the serum of patients during the early stages of DENV infection. It has been found to be useful as a tool for the diagnosis of acute dengue infections. i.e. in the viremic stage, which has epidemiological significance for containing the transmission. Overall Sensitivity: 66%, Specificity: 97.9% Sensitivity in primary infection : 88% Sensitivity in secondary infection: 60.8%

28. IgM-ELISA The anti-dengue IgM antibody develops a little faster than IgG and it usually starts appearing by day 5 of the illness. In some primary infections, detectable IgM may persist for more than 90 days, but in most patients it wanes to an undetectable level by 60 days. It is especially useful for hospitalized patients, who are generally admitted late in the illness after detectable IgM is already present in the blood. MAC-ELISA has a sensitivity and specificity of approximately 90% and 98%, respectively but only when used five or more days after onset of fever.

29. IgG-ELISA An IgG-ELISA test can be used to differentiate primary and secondary dengue infections. Primary Dengue: negative IgG in the acute phase and a positive IgG in the convalescent phase of the infection Secondary Dengue: positive IgG in the acute phase and a 4 fold rise in IgG titer in the convalescent phase Requires paired sera with at least 7 day interval between the 2 samples

30. RAPID DIAGNOSTIC TESTS A number of commercial RDT kits for anti-dengue IgM/IgG antibodies and NS1 antigen are commercially available, which give the results within 15 to 25 minutes. However, the accuracy of most of these tests is not known since they have not yet been properly validated. According to WHO guidelines, these kits should not be used in clinical settings to guide management of severe dengue cases

31. ISOLATION OF VIRUS Isolation of most strains of dengue virus from clinical specimens can be accomplished in the majority of cases, provided that the sample is taken in the first five days of illness and processed without delay. Specimens that may be suitable for virus isolation include acute phase serum, plasma or washed buffy coat from the patient, autopsy tissues from fatal cases, especially liver, spleen, lymph nodes and thymus and mosquitoes collected in nature. Suitable only for research and academic purposes not for patient care.

32. POLYMERASE CHAIN REACTION(PCR) Molecular diagnosis based on reverse transcription polymerase chain reaction (RT-PCR), such as one-step or nested RT-PCR, nucleic acid sequence-based amplification (NASBA) or real-time RT-PCR has gradually replaced the virus isolation method as the new standard for the detection of dengue virus in acute-phase serum samples

33. NVBDCP-recommended tests for laboratory diagnosis For confirmation of dengue infection, Government of India ( GoI ) recommends use of ELISA-based antigen detection test (NS1) for diagnosing the cases from the first day onwards and antibody detection test IgM capture ELISA (MAC-ELISA) for diagnosing the cases after the fifth day of onset of disease

34. RECOMMENDED TESTS AS PER DURATION OF ILLNESS: DURATION OF ILLNESS DIAGNOSTIC METHOD OF CHOICE 0 to 5 th day of illness Virus isolation- Gold standard Nucleic acid detection- used for serotyping and genotyping NS1Ag detection- less expensive, used as point of care test From 5 th day onwards Antibody detection- less expensive and differentiates between primary and secondary infections IgM & IgG

35. INTERPRETATION DURATION TYPE OF ASSAY INTERPRETATION Day 1-7 NS1Ag Acute dengue infection RT-PCR Acute dengue infection Virus isolation Acute dengue infection IgM antibodies Recent dengue infection Day 5 to 3 months IgM antibodies Single positive test may indicate recent infection and seroconversion indicates acute infection IgG antibodies Single positive test may indicate recent or past infection and seroconversion or rising titre indicates acute infection

36. TREATMENT DISEASE NOTIFICATION: In endemic countries all suspected, probable and confirmed cases should be notified as soon as possible The later the notification, the more difficult it is to prevent the disease transmission In non-endemic countries usually only confirmed cases will be notified.

37. Treatment of dengue depends on the severity of patient’s symptoms and clinical status Patients can be divided into 3 groups and managed accordingly Mild dengue(Group A) Moderate dengue(Group B) Severe dengue(Group C)

38. Undifferentiated fever Fever without complications like bleeding, hypotension& organ failure Without evidence of capillary leakage Infants Old age Diabetes Hypertension Pregnancy CAD Hemoglobinopathies Immunocompromised Patient on steroids, anti-coagulants or immunosuppressants DF with warning signs and symptoms Recurrent vomiting Abdominal pain or tenderness Generalized weakness/ lethargy/ Restlessness Mild pleural effusion/ Ascites Hepatomegaly Increase in Hematocrit>20% Mucosal bleeding DF with significant hemorrhage Severe plasma leakage with shock Severe organ impairment (Expanded dengue syndrome) Severe metabolic disorder MILD DENGUE DF WITH HIGH RISK OR COMORBIDITIES DF WITH WARNING SIGNS AND SYMPTOMS SEVERE DENGUE HOME MANAGEMENT CLOSE MONITORING AND POSSIBLY HOSPITALIZATION TERTIARY LEVEL CARE

39. GROUP A(MILD DENGUE) Patients who are able to tolerate adequate amounts of oral fluids and pass urine atleast once every 6 hours and do not have any warning signs Oral intake of oral rehydration solution, fruit juice and other fluids containing electrolytes should be encouraged Fluids with sugar/glucose may exacerbate hyperglycemia of physiological stress and therefore must be used with caution Paracetamol should be given for fever, interval between dosing should not be less than 6 hours. Tepid sponging should be given if the patient still has fever. NSAIDS are to be avoided.

40. Caregivers must be instructed to bring the patient to hospital immediately if any of the following occur: No clinical improvement Deterioration around the time of defervescence Severe abdominal pain Persistent vomiting Cold and clammy extremities Lethargy/irritability or restlessness Bleeding Not passing urine for more than 4-6 hours

41. GROUP B(MODERATE DENGUE) Dengue without warning signs but with comorbidities Encourage oral fluids. Start intravenous isotonic fluids if not tolerated For obese and overweight patients, use ideal body weight for calculation of fluid infusion Intravenous fluids might be needed only for 24-48 hours after which patient can be started on oral fluids again Minimum amount required to maintain good perfusion and urine output must be given. Temperature pattern, urine output, hematocrit, WBC count and platelets must be monitored.

42. Dengue with warning signs: Obtain a reference haematocrit before fluid therapy and give only isotonic solutions Start with 5-7ml/kg/hour for 1-2 hours followed by 3-5ml/kg/hr for 2-4 hours and then reduce to 2-3ml/kg/hr or less according to clinical response Reassess the clinical status and repeat the haematocrit. If it is same or rises only minimally then continue 2-3ml/kg/hr for another 2-4 hours If vitals are worsening or haematocrit is rising rapidly increase the rate to 5-10ml/kg/hr for 1-2 hrs Give minimum fluid volume to maintain good perfusion and urine output of about 0.5ml/kg/hr

43. Reduce the intravenous fluids gradually when the hematocrit is decreasing below the baseline in a stable patient Parameters to be monitored Vital signs Peripheral perfusion(1-4hrly until the patient is out of critical phase) Urine output(4-6hrly) Hematocrit(before and after fluid replacement, then 12hrly Blood glucose

44. GROUP C The goals of fluid resuscitation : Improving central and peripheral circulation(decreasing tachycardia, improving blood pressure, pulse volume, warm and pink extremities, capillary refill time< 2 seconds) Improving end organ perfusion with stable conscious level(more alert and less restless) Urine output ≥0.5ml/kg/hour Decreasing metabolic acidosis

45. Compensated vs hypotensive shock Compensated shock Hypotensive shock Fluid loss 10-15% >15-20% Mental status Clear and lucid Change of mental status Capillary refill time Prolonged(>2 sec) Very prolonged, mottled skin Extremities Cool peripheries Cold, clammy extremities Pulse volume weak and thready Feeble or absent Heart rate 100-120 >120 Blood pressure SBP is normal, DBP increases PP decreases, postural hypotension Hypotension, unrecordable blood pressure, PP<20mmHg Respiratory rate 20-30 >30

46. In adults, the volume needed for 24 hours should be calculated as twice that required for maintenance (using the Holiday and Segar formula). For an adult weighing 60 kgs, the maintenance is: 1500 + (40x20) = 2300 ml. This means that they require 4600 ml IV fluid during 24 hours .

47. CHOICE OF INTRAVENOUS FLUIDS Crystalloids: use isotonic solutions NS ( Osm = 308mOsm/L) suitable option for initial fluid resuscitation large volume infusions lead to hyperchloremic acidosis RL ( Osm = 273mOsm/L) may not be suitable for resuscitation of patients with severe hyponatremia Can be used after initial fluid resuscitation with NS avoid in liver failure and in patients taking metformin

48. Colloids : Dextran Starch Gelatin : Hemaccel Benefits: Distributed in vascular compartment Increase oncotic pressure Disadvantages: May effect coagulation ( vWF /Factor VIII) Allergic reactions May cross into the interstitium : Reverse osmosis

49. INDICATIONS OF PLATELET TRANSFUSION Platelet count less than 10000/cu.mm in absence of bleeding manifestations (Prophylactic platelet transfusion). Hemorrhage with or without thrombocytopenia. Packed cell transfusion/FFP along with platelets may be required in cases of severe bleeding with coagulopathy. Whole fresh blood transfusion doesn't have any role in managing thrombocytopenia

50. PLATELET CONCENTRATE VS APHERETIC PLATELETS PLATELET CONCENTRATE(RDP) APHERETIC PLATELETS(SDP) 5× /unit 3.5× /unit Post transfusion platelet rise: 5k-10k/ Post transfusion platelet rise: 30-60k/ Differential centrifugation from freshly drawn blood units Platelet-pheresis technique cheaper costly More exposure to TTIs Less exposure to TTIs Risk of alloimmunization is higher Risk of alloimmunization is lower PLATELET CONCENTRATE(RDP) APHERETIC PLATELETS(SDP) Differential centrifugation from freshly drawn blood units Platelet-pheresis technique cheaper costly More exposure to TTIs Less exposure to TTIs Risk of alloimmunization is higher Risk of alloimmunization is lower

51. INTERPRETATION OF HEMATOCRIT ↑ Hct + Unstable vitals : Active Plasma Leakage ↑ Hct + stable vital signs : no need for extra IV fluids ↓ Hct + stable vitals + adequate output : haemodilution and/or reabsorption ↓ Hct + unstable vitals : Continued haemorrhage

52. TREATMENT OF HEMORRHAGIC COMPLICATIONS Persistent and/or severe overt bleeding in the presence of unstable hemodynamic status, regardless of the hematocrit level; A decrease in hematocrit after fluid resuscitation together with unstable hemodynamic status; Refractory shock that fails to respond to consecutive fluid resuscitation of 40-60 ml/kg; Hypotensive shock with low/normal hematocrit before fluid resuscitation; Persistent or worsening metabolic acidosis ± a well-maintained systolic blood pressure, especially in those with severe abdominal tenderness and distension.

53. Give 5–10ml/kg of fresh-packed red cells or 10–20 ml/kg of fresh whole blood at an appropriate rate and observe the clinical response. It is important that fresh whole blood or fresh red cells are given. Consider repeating the blood transfusion if there is further blood loss or no appropriate rise in hematocrit after blood transfusion.

54. CRITERIA FOR DISCHARGE All of the following must be present: CLINICAL No fever for 48 hours Improvement in clinical status(general well-being, apetite , hemodynamic status, urine output, no respiratory distress LABORATORY Increasing trend of platelet count Stable hematocrit without intravenous fluids

55. PREVENTION AND CONTROL F light range of aedes is 400m and control meaures might be based on this Anti-larva measure Source reduction Larvicides (chemical) Biological control - larvivorous fish- Gambusia, Lebister spp. Anti-adult measures Residual sprays Space sprays Genetic control - sterile male technique Personal protection Mosquito nets Repellents

56. CO-INFECTIONS

57. DENGUE AND COVID-19 CO-INFECTION WHO in guidance statement for management of COVID-19 suggests that in areas with other endemic infections that cause fever such as malaria, dengue, TB etc , as a part of screening, febrile patients should be tested as per routine protocols ,irrespective of presence of respiratory signs and symptoms, since co-infection may co-exist in such a setting.

58. WHY IS CO-INFECTION A PUBLIC HEALTH CHALLENGE Difficult to distinguish because of their overlapping clinical and laboratory parameters Both have unpredictable clinical course and require in-hospital monitoring for management. A high index of suspicion is required to diagnose dengue-COVID co-infections. Even false positivity cannot be ruled out creating a diagnostic challenge In the setting of a co-infection one might enhance the severity of other IV fluid therapy is challenging in these patients due to propensity to develop early ARDS/pulmonary edema LMWH might cause bleeding in dengue in the setting of thrombocytopenia Both the viral diseases do not have any specific anti viral drugs.

59. CASE CLASSIFICATION OF CO-INFECTION

60. Co-infected patients may have dominant dengue or dominant COVID-19 or a co-dominant infection. From the medical literature published so far, the relative incidence of codominant variety seems to be higher in symptomatic co-infected patients. For all the above categories a confirmed case will only be labelled if microbiologically proven by RTPCR/CBNAAT/RAT in case of COVID-19 and be NS1Ag or IgM(ELISA based) for dengue Among those, the cases where clinical presentation is suggestive but testing is negative will come under probable category.

61. SPECIFIC THERAPEUTIC OPTIONS FOR CO-INFECTION FLUID THERAPY: Depends on hemodynamic status and degree of severity Fluids can be given as per dengue protocol but we need to be careful as aggressive resuscitation leads to worsening of oxygenation In such scenario IVC guided fluids must be administered(where point of care facility is available) with continuous monitoring for worsening oxygenation Aggressive resuscitation must be done in patients with shock

62. LMWH: Indicated in management of patients with moderate and severe COVID, however careful monitoring is required with D-dimer estimation and when platelets fall below 1 lakh it may be withheld based on clinical condition In case of co-infection with bleeding, it should be immediately discontinued.

63. CORTICOSTEROIDS: Dexamethasone is effective in cases of severe COVID-19. Course of illness is not affected much if it is given after dengue viremic stage i.e 5/6 days of dengue illness Hence steroids can be continued as per COVID-19 management guidelines Tocilizumab, antivirals and other supportive management to be continued as per current COVID-19 guidelines .

64. OTHER PREVALENT CO-INFECTIONS Co-infections with other mosquito-borne tropical fevers like malaria and chikungunya have also been observed and reported. These three vector borne diseases share an overlapping epidemic pattern Interactions of multiple pathogens within a host may potentially result in several different outcomes. Fever with rigors and myalgias is the initial presentation at undifferentiated stage Lack of differentiating clinical features in the early stages may prove a handicap but quicker laboratory reports might help

65. In malaria and dengue co-infection it is necessary to analyze prolonged fever with thrombocytopenia, anemia, renal injury and jaundice that may be more severe and pronounced. In dengue-chikungunya co-infections diarrhea and bleeding might be severe and joont pains might predominate. In light of co-infection, cardiorespiratory status, volume status and electrolyte parameters need to be stabilized and management must be modified accordingly Inability to diagnose or mistreatment of tropical infections can be detrimental to host with adverse effect on prognosis.

66. DENGUE VACCINES Tetravalent vaccine with four immunogens giving balanced immune response which is long-lasting against all four viruses. 4 types: Live attenuated viruses Chimeric live attenuated viruses Inactivated or sub-unit vaccines Nucleic acid-based vaccines The lead candidate vaccines are: a tetravalent, live attenuated, recombinant vaccine and the tetravalent dengue subunit vaccine, DSV4. A live attenuated vaccine known as Dengvaxia , developed by Sanofi, was licensed in 2015. This vaccine, which appears to predispose dengue-naïve recipients to an increased risk of hospitalization in the future, is recommended by the World Health Organization only for adults with a history of prior dengue virus infection. 

67. ANTI-VIRAL DRUGS NS5 RNA dependent RNA polymerase inhibitors and NS3 protease inhibitors. 5 such compounds have been identified with anti-DENV replication activity without cytotoxicity

68. Pan-serotype antiviral with activity against NS4B protein NITD-688

69. TAKE HOME MESSAGE 16 states have been declared as dengue endemic, with all 4 serotypes circulating in India since 2003 Primary infection while secondary infection is more fatal Co-infection with other tropical infections must always be ruled out NS1Ag by ELISA until day 5 and serology after day 5 remain the choice of diagnostic tests Close monitoring of warning signs and timely intervention can save lives in severe cases of dengue.