Dengue.pptx

Dengue is a viral disease. describes about its cause and treatment in detail.

1. Dengue Dr. P K Maharana.

2. Introduction Dengue is a viral infection caused by the dengue virus (DENV), transmitted to humans through the bite of infected mosquitoes. About half of the world's population is now at risk of dengue with an estimated 100–400 million infections occurring each year. Dengue is found in tropical and sub-tropical climates worldwide, mostly in urban and semi-urban areas. While many DENV infections are asymptomatic or produce only mild illness, DENV can occasionally cause more severe cases, and even death.

3. Epidemiology Dengue is a vector-borne viral disease caused by the flavivirus dengue virus (DENV), they are of 4 sero types, infection with one type gives life long immunity to the specific type, dose not protect against other sub-types rather the severity increases. Caused due to mosquito bite, female , Aedes aegypti & Aedes albopictus . Estimated that almost 400 million cases of dengue fever ( DF) and half a million cases of dengue hemorrhagic fever (DHF) occur worldwide, affecting half of the world’s population in 112 countries. Countries most affected USA, Africa, Australia, South East Asia including India. Average case fatality rate is around 5% (22000). Up to 90% of patients with DHF are children less than 15 years , especially in South East and South Asia .

4. History . The first dengue outbreak was reported in 1779 from Jakarta, (Indonesia) and Cairo,( Egypt). In 1780 a report of outbreak was from North America, the Philadelphia outbreak. ( Rush 1951 ) The first two outbreak of Dengue Hemorrhagic fever ( DHF) was from Manila in Philippines in 1953 & 1956, respectively. By 1975, dengue infections became a frequent cause of morbidity and mortality particularly among the children in countries of South East Asia. In recent time, the largest outbreak of dengue, was in the year 2016, in the USA , with more than 2.38 million cases reported. In this outbreak, the highest contribution was from Brazil, with 1.5 million cases. In the last decade, epidemics caused by multiple serotypes (hyperendemicity) have become increasingly frequent. Dengue has become one of the most important mosquito born viral disease in the world. Apart from public health impacts it affects the economy to a very large extent.

5. World prevalence of Dengue

6. Dengue in India The Indian subcontinent, owing to its suitable environment, has several reports of dengue outbreaks involving all serotypes. ( Dar et al. 2006 ;  Mustafa et al. 2015 ).  A recent dengue epidemic was recorded in the year 2017, where 1 88 401 infections and 325 deaths reported(NVBDCP).

7. Mode of transmission Transmission from human to human through mosquito bite.( When a female Aedes Aegypti feeds on an infected individual, along with blood it socks the virus, the virus multiplies inside the mosquito and subsequently when the mosquito bites a healthy individual the virus passes to the human being present in the saliva) 1. Vector born – ( Commonest) Bite of an infected female Aedes Aegypti mosquito. 2 . Blood Born : ( Rarely) From infected pregnant mother to foetus. Blood Transfusion or organ transplantation . Needle Stick Injury .

8. Incubation Period Period of infectivity : An individual remains infective during the period of viraemia, normally it co-inside with period of fever, 2days before and 2 days after, usually 7 days. Extrinsic incubation period : It is the time when the mosquito receives the virus through feed till it secrets virus through saliva. It is roughly ( 8-12) days. Intrinsic Incubation Period : ( 3-14 days), The period from the entry of virus to clinical manifestation.

9. Transmission from Mosquito to Human Transmission from mosquito to human beings : through the bites of infected female mosquitoes , primarily the  Aedes aegypti  mosquito . Other species within the Aedes genus can also act as vectors. After feeding on a DENV-infected person, the virus replicates in the mosquito midgut before disseminating to secondary tissues, including the salivary glands. Transmission occurs from saliva to the biting site on skin. The time it takes from ingesting the virus to actual transmission to a new host is termed the extrinsic incubation period (EIP). The EIP takes about 8–12 days when the ambient temperature is between 25–28°C. Once infectious, the  mosquito can transmit the virus for the rest of its life . Human-to-mosquito transmission : U p to 2 days before someone shows symptoms of the illness, and up to 2 days after the fever has resolved .

10. Aedes aegypti Aedes aegypti  are endophilic , occurring largely indoors, container-breeder. (i.e., breeding in water-filled containers), A day-biting mosquitoes that feed preferentially on human blood under field conditions and are found in tropical and subtropical areas, with their geographic range spanning almost all continents ( Thavara et al. 2001 ).  Aedes albopictus , a more aggressive day-time biter, is exophilic under natural field conditions, commonly living outdoors, but still feeds almost exclusively on humans ( Ponlawat and Harrington 2005 ;  Delatte et al. 2010 ). The transmission of all four DENV serotypes is maintained in two cycles: sylvatic ( transmission in wild animals) and human ( Chen and Vasilakis 2011 ) The sylvatic cycle is ecologically and evolutionarily distinct from the human transmission cycle. This is maintained by non-human primates or by a monkey- Aedes -monkey cycle in the sylvatic environments of Southeast Asia, West Africa, peninsular Malaysia, and eastern Senegal ( Rudnick 1986 ).

11. Dengue Virus Virus belonging to the genus Flavivirus. • Consists of four closely related serotypes ( DEN 1- 4 ) classified according to biological and immunological criteria. • The mature dengue virion consists of a single-stranded RNA genome surrounded by an icosahedral or isometric nucleocapsid. • This nucleocapsid is covered by a lipid envelope .

12. Virus Morphology A complete virion is about 50 nm in diameter and the viral genome is approximately 11 kb in length. A well-organized outer protein layer on the surface of a lipid bilayer, and an inner nucleocapsid core.   DENV contains three structural proteins , namely, the capsid (C), membrane (M) (having a membrane precursor or PrM), e nvelope (E) , and seven non-structural proteins ( NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 ) . Envelope proteins carries out biological functions of the virus- --- 1.)-Transport of the viral genome into the host cell. 2.)- Haemagglutination of erythrocytes 3.)-Induction of neutralizing antibodies 4)-Protective immune responses.

13. Electron Microscopic Structure

14. Pathogenesis Most important changes : ↑ Vascular permeability, ↑ Thrombocytopaenia , ↑C oagulopathy . Complement activation & Hepatomegaly

15. Antibody-dependent enhancement After a primary infection with a DENV serotype, the immune system produces antibodies that bind and neutralize secondary infection with the same serotype, however, a secondary heterotypic infection may lead to enhance severity . The antibodies produced from the primary infection have the ability to bind to the  virus  but lack the ability to neutralize. These cross-reactive antibodies form infectious virus-antibody complexes are able to bind and enter in cells that present the Fc γ -receptors such as,  monocytes , macrophages, and dendritic cells, therefore, enhancing viral production leading to higher  viral loads .

16. Antibody Dependant Reaction

17. Cytokine dysregulation In the development of DHF, DENV antibodies may be unable to neutralizing and alternatively promote the entrance of a second serotype of DENV into Fcγ -expressing cells, which results in amplified activation of complements and rapidly produces cytokine. (especially pro-inflammatory type 1 cytokines, such as TNF-α and IFN-γ ). These cytokines may have a direct effect on  vascular endothelial cells  leading plasma leakage.

18. Causes of thrombocytopenia Destruction of Platelets ( Circulating Platelet antibodies ). Bone marrow suppression. DIC Peripheral sequestration of platelets.

19. Dengue Fever DF: is an acute infectious disease symptom, characterized by biphasic fever, myalgia, headache, joint pain, retro-orbital pain , body rash ,, lymphadenopathy , thrombocytopenia and leukopenia. Dengue fever has three distinct phases: febrile , critical , and convalescent . The febrile phase is characterized by a sudden high-grade fever and dehydration that can last for 2–7 days. The convalescence period is the recovery phase, when rash , itching , and increased appetite are observed .

20. Symptoms If symptoms occur, they usually begin 4–10 days after infection and last for 2–7 days. Symptoms may include: high fever (40°C/104°F) severe headache pain behind the eyes muscle and joint pains nausea vomiting swollen glands rash. 

21. Dengue Fever Cycle. Fever 2-3 days Critical period 4-5-6 day Recovery 7 th day onwards.

22. Life cycle of Dengue Fever

23. Severe Dengue Severe dengue symptoms often come after the fever has gone away: S evere abdominal pain P ersistent vomiting R apid breathing B leeding gums or nose  F atigue R estlessness B lood in vomit or stool B eing very thirsty P ale and cold skin F eeling weak.

24. DHF & DSS DHF a s prescribed by the WHO are acute and continuous fever of 2–7 days, hemorrhage associated with thrombocytopenia (100 000 cells/cu. mm or less), and haemoconcentration (Haematocrit >20% from baseline of patients of the same age). DSS: Presents with shock like features (Hypo volaemic shock), multi organ failure, along with any of the above features.

25. DHF High grade fever lasting for 2-7 days( > 104 F). Any hemorrhagic manifestations . ( Positive tourniquet test, Epistaxis, bleeding gum, petechiae on skin ) Low platelet count ( < 1,00,000 mm3). Evidence of increased vascular pe rmeability ( Low BP, High low volume Pulse , breathing difficulty, altered sensation )

26. Risk Factors Previous infection with DENV increases the risk of the individual developing severe dengue. Urbanization ( especially unplanned , is associated with dengue transmission through multiple social and environmental factor s): P opulation density, human mobility, access to reliable water source, water storage practice etc. Environmental Factors: Climate Change

27. Risk Factors with DHF

28. DSS ( Dengue Shock Syndrome) Any case that meets the four criteria of DHF , and has evidence the features of circulatory failure. Rapid weak pulse, Low BP, restlessness, cold clammy skin. DSS is a severe condition if not treated properly death in 10% cases, with proper treatment mortality reduced to 1%.

29. DSS ( Dengue Shock Syndrome ) It develops mostly after 3-5 days of fever. Hypotension and multi organ dysfunction. Low Platelet count. Bleeding diathesis. Dyspnoea (Fluid in Pleural and peritoneal space). Cardiac Failure & Death. DHF are still yet fully understood. Currently proposed risk factors correlated with DHF include  virus virulence , 10  immune enhancement, 11   cytokine storm , 12  change of lipid profile, 13  autoimmune responses, 14  host  genetic factors , 15   bacteremia  caused by  Staphylococcus aureus 16 , 17  etc.  

30. Evidence of Plasma Leakage Evidence of plasma leakage due to increased vascular permeability consists of at least one of the followings. • An elevated ↑ hematocrit ≥20% above the population mean hematocrit for age and sex. • A decline in ↓hematocrit after volume-replacement treatment of ≥20% of the baseline hematocrit. • Presence of pleural effusion or ascites detected by radiography or other imaging method. • Hypoproteinemia or hypoalbuminemia as determined by laboratory test.

31. Monitoring Look for the evidence of Hemorrhage. Capillary Leak ( Ascites, pleural effusion ) Monitor: Para meters to be monitored. Pulse ( Thready low volume pulse), Blood Pressure, Urine output ( should be between 0.5 -1ml/kg/hour). Haematocrit & Platelet Count.

32. Differential Diagnosis Dengue fever can easily be confused with non-dengue illnesses, depending on the geographical origin of the patient, other etiologies – including Non-dengue flavivirus infections – should be ruled out. These include yellow fever , Japanese encephalitis , St Louis encephalitis , Zika , and West Nile , alphaviruses ( such as Sinbis and chikungunya ), Other causes of fever- such as malaria, leptospirosis, typhoid, Rickettsial diseases  

33. Differential Diagnosis Flue, Measles, Malaria, Typhoid, Scrub Typhus,

34. Laboratory Tests Presence of virus – RT-PCR ( within 24 hours to 5days) Viral Antigen - ( NS1 ) Antibody against virus- IgM & IgG ( From 6 days onwards)

35. Blood Samples Blood Samples ( Serum) . For RT-PCR ( Stored at 4C for a week, dry ice if for a longer duration) For Antibodies in a closed container ,( avoid exposure to high temperature , ice in the box )

36. Diagnosis

37. Diagnosis Examination of Blood to detect viral antigen particle or antibodies .   NS1 antigen assay , usually positive within 1 st week ( 3-9. days ). Dengue IgM / IgG serological test  ( Both Card & ELISA ), it is only positive after 5 th Day . ELISA are the tests of choice after the first five days of illness. Immunoglobulin M (IgM) or immunoglobulin G ( IgG) are detected by enzyme-linked immunosorbent assay (ELISA).

38. During Febrile Period ( Before 5 Days) 1). Virus isolation in cell culture. 2). Detection of viral RNA by nucleic acid amplification tests (NAAT). 3). Detection of viral antigens by ELISA or rapid tests.

39. NSN 1 antigen NSN 1 antigen ( Viral antigen ) is a non structural viral protein secreted by the infected cells. After the onset of illness , the virus can be detected in serum, plasma, circulating blood cells and other tissues for 4–5 days. So, in early phase, detection of viral antigen is diagnostic .

40. Antibodies IgM antibodies are the first immunoglobulin isotype to appear. These antibodies are detectable i n 50% of patients by days 3-5 after onset of illness , increasing to 80% by day 5 and 99% by day 10 . IgM antibodies levels peak about two weeks after the onset of symptoms and then decline generally to undetectable levels over 2–3 months . IgG antibodies are generally detectable at low titers at the end of the first week of illness, increasing slowly thereafter, with serum IgG still detectable after several months, and probably even for life .

41. Diagnosis Direct Method: Virus Isolation , Genome detection, NS1 detection. Indirect Method : Antibody Detection (IgM & IgG ) Virus isolation and nucleic acid detection: are more labour-intensive and costly but are also more specific than antibody detection using serologic methods.

42. Different Tests Recommended Virus Isolation Nucleic Acid detection RT-PCR Detection of Antigen Serological Tests ( MAC-ELISA) Haematological Tests: ( Haematocrit, Platelet Count)

43. How to differentiate between primary & secondary infection? 1. In secondary infection IgG is strongly positive . 2. IgM may be negative or in low titer, 3. NSN 1 antigen positive . 4. IgM/IgG ratio: > 1.2 Primary < 1.2 Secondary

44. Treatment Rest Drink plenty of liquids Use acetaminophen (paracetamol) for pain Avoid non-steroidal anti-inflammatory drugs, like ibuprofen and aspirin. Watch for severe symptoms and contact your doctor as soon as possible if you notice any

45. Laboratory findings Laboratory findings in the febrile phase include the following:   Leukopenia Mild to moderate  thrombocytopenia Elevated aspartate aminotransferase (AST) Elevated alanine aminotransferase (ALT) Hyponatremia

46. Medical complications during Febrile Phase Dehydration Hyponatremia Febrile seizures in young children Neurologic disease manifestations, including  encephalitis  and aseptic meningitis.

47. Severe Dengue Patients are considered to have severe dengue if they meet any of the following three criteria. 1.  Severe plasma leakage resulting in one or both of the following : Shock   Fluid accumulation with respiratory distress    2. Severe bleeding as evaluated by clinician    3. Severe organ involvement Hepatic (involving the liver): AST or ALT level > 1000 U/L Neurologic ( involving the central nervous system ): impaired consciousness Myocardial (involving the heart) and Other organs

48. Pathogenesis of Severe Dengue Severe dengue most commonly occurs among patients with secondary DENV infections and infants with primary infections. The most widely-cited hypothesis for the pathogenesis of severe dengue is   antibody-dependent enhancement (ADE) . Although the exact mechanisms are not clear,  ADE  is the process in which DENV, complexed with nonneutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production. Antibodies typically protect humans from viruses in 3 ways neutralization (antibody blocks virus interaction with host cell) opsonization   (antibody coats virus and typically targets it for uptake by  macrophages  and neutrophils ) antibody-dependent cellular cytotoxicity (ADCC) In dengue, nonneutralizing heterotypic IgG anti-DENV antibodies produced during a person's first DENV infection (or sub-neutralizing level of antibodies in the case of infants who acquired IgG passively in utero ) can form antibody-DENV complexes in the second infection that can allow uptake of DENV by macrophages. DENV then replicates in these macrophages thereby increasing viral production.

49. Risk Factors for Severe Dengue   Not all dengue cases are severe. Approximately 10% of dengue cases progress to severe disease, independent of treatment. Physicians might be able to prevent and treat medical complications such as fluid overload. Factors have been identified that are associated with an increased risk for severe disease, but there are no tests or biomarkers to identify which patients, when presenting early in the course of disease, will develop severe disease.

50. Critical phase The critical phase typically begins around the time of defervescence but it might begin as early as the third day after fever onset in patients who are still febrile. This is the period when those who develop severe disease will become critically ill. Onset of the critical phase can also be identified by the following:  1.Rapid decline in platelet count with a rise in hematocrit (HCT) 2.The patient might develop leukopenia up to 24 hours before platelet drop is recognized. 3.Presence of warning signs for severe disease

51. Warning Signs Warning signs include the following :  1. Clinical fluid accumulation, such as  ascites ,  pleural effusion. 2. Liver enlargement > 2 cm. 3. Severe abdominal pain. 4. Persistent vomiting (at least 3 vomiting. episodes within 24 hours ). 5. Mucosal bleed. 6. Lethargy or restlessness.

52. Medical complications during Critical Phase I nclude the following : Hypovolamic shock from plasma leakage End organ impairment due to prolonged shock Severe hemorrhage Encephalopathy

53. Recovery Recovery depends on the severity of the illness and any treatments prescribed in the febrile and critical phases. Onset of the recovery phase can be identified by the following:     Features of improvement . Gradual reabsorption of  extravasated  fluid (such as from plasma leakage) over 48–72 hours. Increased diuresis (patient might wet bed ).   Hemodynamic status stabilizes. Patient can temporarily become bradycardic ( but haemodynamically stable ).

54. Clinical manifestations Clinical manifestations during the recovery phase include the following:  A second rash that might be macular or erythematous with small circular islands of normal, unaffected skin . This convalescent rash can be very pruritic and desquamate. Severe fatigue. Laboratory findings in the recovery phase include the following :  HCT stabilizes or is slightly lower due to a dilutional effect of reabsorbed  plasma (hemodilution ). White blood count (WBC) begins rising soon after defervescence. Platelet count increases following WBC recovery.

55. Causes of Death Severe dengue can result in death . Causes of death from dengue include the following: Unrecognized dengue without appropriate medical management. Unrecognized or prolonged shock. Unrecognized occult hemorrhage. Fluid overload. Nosocomial infections. Liver failure.

56. The 2009 WHO guidelines emphasize the importance of detecting clinically significant plasma leakage early.

57. Close Monitoring of Vital Parameters Level of consciousness  (Use GCS.) Skin temperature, color, and moisture level (normal, dry or clammy) Peripheral pulse volume/ Capillary refill Heart rate Blood pressure Respiratory rate Urine output Early signs of shock include: Narrowing of pulse pressure (PP) with rising diastolic blood pressure (DBP) Delayed capillary refill (> 2 seconds) Tachycardia in absence of fever

58. Group A patients Rest Rehydration Paracetamol for fever. Do not  give corticosteroids to patients with dengue. Do not  give NSAIDS, for example acetyl- salicylic acid (aspirin) and ibuprofen. Do not  give antibiotics, unless there is a clinical suspicion of leptospirosis or of a dual infection.

59. Management in group B patients Group B and C patients require hospital monitoring and treatment. These patients require the following interventions: Monitoring  hemodynamic status  and tracking intake and output Use of HCT to guide interventions Use isotonic intravenous fluids (IVFs) to restore plasma volume Monitoring for signs of occult bleeding Use of blood products as needed Correction of metabolic acidosis, use of electrolytes as needed Use of  colloids  for refractory shock

60. How to calculate Hypotension in < 10yrs of age. Hypotension in patients younger than 10 years old is defined by a SBP of less than 70 + (2 times the patient age in years).

61. Dengue Cases with Plasma Leak

62. Treatment of Hemorrhage Packed red blood cells (PRBC) or whole blood (if volume is not an issue for the patient) should be given to dengue patients who have clinically significant occult or overt hemorrhage.   Give 5–10 mL/kg of PRBC or 10–20 mL/kg of whole blood at appropriate rate and observe the clinical response. Consider repeating the blood transfusion, if There is further blood loss.   There is no appropriate increase in HCT after blood transfusion. For instance, an appropriate increase is 3%–4% rise in HCT for every 10 cc/kg of PRBC given.

63. Vaccine A vaccine called Dengvaxia recommended for people who have had dengue at least once and live in places where the disease is common . So far only one vaccine (Dengvaxia) has been approved and licensed in some countries. Several additional  dengue vaccine candidates  are under evaluation. Dengue vaccine is only for people showing positive past infection and remaining dengue endemic region .

64. Prevention To lower the risk of getting dengue by protecting yourself from mosquito bites by using:   1.Clothes that cover as much of your body as possible 2.Mosquito nets if sleeping during the day, ideally nets sprayed with insect repellent. 3.Window screens. 4.Mosquito repellents ( Containing DEET, Picaridin or IR3535 )   coils and vaporizers. The mosquitoes that spread dengue are active during the day.