Handbook For Clinical Management Of Dengue PDF (World Health Organization, 2012)

HANDBOOK FOR CLINICAL MANAGEMENT OF DENGUE WHO Library Cataloguing-in-Publication Data Handbook for clinical management of dengue. 1.Dengue – therapy. 2.Dengue – diagnosis. 3.Clinical medicine. 4.Handbooks. I.World Health Organization. ISBN 978 92 4 150471 3 (NLM classification: WC 528) © World Health Organization 2012 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www. who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Cover photographs were provided by Dr Thomas Scott and Dr Raman Velayudhan. Handbook for clinical management of dengue Contents Foreword.............................................................................................................................. v! Methodology........................................................................................................................ vi! Acknowledgements............................................................................................................. vi! Abbreviations...................................................................................................................... vii! 1.! Overview, differential diagnosis and dengue diagnostics............................................. 1! 1.1! Overview and course of dengue illness................................................................. 1! 1.1.1! Febrile phase.................................................................................................. 2! 1.1.2! Critical phase.................................................................................................. 2! 1.1.3! Recovery phase.............................................................................................. 3! 1.1.4! Severe dengue............................................................................................... 4! 1.1.5! References..................................................................................................... 6! 1.2! Dengue case classification.................................................................................... 7! 1.2.1! Development of the revised dengue case classification................................. 7! 1.2.2! References..................................................................................................... 9! 1.2.3 Differential diagnoses of dengue....................................................................... 10! 1.2.4 References......................................................................................................... 13! 1.3! Dengue diagnostics for clinicians........................................................................ 15! 1.3.1! References................................................................................................... 20! 2.! Recommendations for clinical management............................................................... 22! 2.1! A stepwise approach to the management of dengue.......................................... 22! 2.1.1! Step I – Overall assessment......................................................................... 22! 2.1.2! Step II – Diagnosis, assessment of disease phase and severity................. 23! 2.1.3! Step III – Disease notification and management decision (Groups A–C).... 23! 2.2! Treatment according to Groups A–C (1).............................................................. 25! 2.2.1! Group A........................................................................................................ 25! 2.2.2! Group B........................................................................................................ 26! 2.2.3! Group C........................................................................................................ 27! 2.2.4! References................................................................................................... 38! 2.3! Complications and intensive care management.................................................. 39! 2.3.1! Acute respiratory distress and failure........................................................... 43! ii 2.3.2! Fluid overload............................................................................................... 44! 2.3.3! Co-infections and nosocomial infections...................................................... 49! 2.3.4! Haemophagocytic syndrome........................................................................ 49! 2.3.5! Supportive care and adjuvant therapy.......................................................... 49! 2.3.6! References................................................................................................... 51! 2.4! Treatment of dengue in specific risk groups........................................................ 52! 2.4.1! Dengue in adults – some specific issues..................................................... 52! 2.4.2! Dengue in the elderly.................................................................................... 53! 2.4.3! Dengue in cases with co-morbidities............................................................ 54! 2.4.4! References................................................................................................... 58! 2.4.5! Dengue in pregnancy................................................................................... 59! 2.4.6! References................................................................................................... 62! 2.4.7! Dengue in paediatric cases.......................................................................... 63! 2.4.8! References................................................................................................... 67! 3.! Pitfalls in the management of dengue and solutions.................................................. 69! 3.1! Frontline physicians............................................................................................. 69! 3.2! At the emergency department............................................................................. 73! 3.3! Shock and its many manifestations..................................................................... 73! 3.4! Parenteral fluid therapy........................................................................................ 75! 3.5! Urine output......................................................................................................... 77! 3.6! Blood transfusions for severe bleeding............................................................... 79! 3.7! References.......................................................................................................... 82! 4.! Case studies............................................................................................................... 83! 4.1! Case study one.................................................................................................... 83! 4.2! Case study two.................................................................................................... 87! 4.3! Case study three.................................................................................................. 93! 4.4! Case study four.................................................................................................... 98! 5.! Annex........................................................................................................................ 102! 5.1! Textbox A: Good and bad clinical practice........................................................ 102! 5.2! Textbox B: Differential diagnosis of dengue fever............................................. 103! 5.3! Textbox C: Warning signs.................................................................................. 104! iii 5.4! Textbox D: Haemodynamic assessment: continuum of haemodynamic changes.............................................................. 104! 5.5! Textbox E: Admission criteria............................................................................ 105! 5.6! Textbox F: Discharge criteria............................................................................. 105! 5.7! Textbox G: Home-care card for dengue (for patient or adult caregiver)............ 106! 5.8! Textbox H: Calculations for normal maintenance of intravenous fluid infusion. 107! 5.9! Textbox I: Hourly maintenance fluid regime based on ideal body weight.......... 107! 5.10! Textbox J: Estimated ideal body weight for overweight or obese adults........... 108! 5.11! Textbox K: Example of a monitoring chart for dengue: Vital signs and hourly fluid monitoring of dengue patients................................ 109! 5.12! Textbox L: Choice of intravenous fluids for resuscitation.................................. 111! iv Foreword Since publication of the new edition of Dengue: Guidelines for diagnosis, treatment, prevention and control by the World Health Organization (WHO) in 20091, the need to provide more training to health-care workers in this area has become increasingly evident. Existing training materials need to include more detail to help clinicians recognize the evolution of the course of dengue disease in its various forms of severity, and to enable them to apply the knowledge and principles of management accordingly. With this aim in mind and following previous successful collaborations, the WHO Department of Control of Neglected Tropical Diseases (WHO/NTD) and the Special Programme for Research and Training in Tropical Diseases (WHO/TDR), set out to develop new training materials. This handbook has been produced to be made widely available to health-care practitioners at all levels. Aspects of managing severe cases of dengue are also described for practitioners at higher levels of health care. Additional and more specific guidance on the various areas related to clinical management of dengue (from other sources in WHO and elsewhere) are cited in the reference sections. Contributions and reviews, by many experts both within and outside WHO, have facilitated the preparation of this publication through consultative and peer review processes. We are most grateful to all contributors who are listed in the acknowledgements section. This handbook is not intended to replace national treatment training materials and guidelines but it aims to assist in the development of such materials produced at a local, national or regional level. All information is up-to-date at the time of writing, to the best knowledge of the authors. 1 Available from: http://whqlibdoc.who.int/publications/2009/9789241547871_eng.pdf, last accessed July 2012. v Methodology This handbook was developed as outlined below: Writing team Each chapter was allocated to one lead writer who received a small fee for their work. Declarations of interest were obtained from all lead writers and no conflicting interests were declared as a result. The lead writers were chosen because of their expertise in the field and their willingness to undertake the work. Peer review All the chapters were submitted for peer review. The group of peer reviewers was determined by the coordinator and lead writers in consensus, not excluding any potential peer reviewer for a particular view. The peer reviewers were not paid for their work. Declarations of interest were obtained from all peer reviewers and no conflicting interests were declared. For each chapter, resolution of disputed issues arising from the comments of the peer reviewers was achieved by electronic mail discussion within the group of lead writers. Acknowledgements Dr Lucy Chai See Lum of the University of Malaya, Kuala Lumpur, Malaysia was the contract holder for the development of the handbook. Funds were made available by the World Health Organization’s Department of Control of Neglected Tropical Diseases (WHO/NTD). Dr Lum was responsible for coordinating the lead authors of all chapters. Dr Silvia Runge-Ranzinger coordinated the finalization of the handbook with the help of Dr Olaf Horstick (WHO/TDR) and Dr Raman Velayudhan (WHO/NTD). Lead writers for chapters were: Dr Lucy Chai See Lum; Dr Maria Guadalupe Guzmán; Dr Eric Martinéz; Dr Lian Huat Tan; Dr Nguyen Thanh Hung. The handbook was peer reviewed by the following individuals: Dr Naeema A Akbar; Dr Douangdao Souk Aloun; Dr Christopher Gregory; Dr Axel Kroeger; Dr Ida Safitri Laksono; Dr Jose Martinez; Dr Laurent Thomas; Dr Rivaldo Venancio; Dr Martin Weber; Dr Bridget Wills. The following individuals reviewed and edited the comments of peer reviewers: Dr Lucy Chai See Lum; Dr Lian Huat Tan; Dr Silvia Runge-Ranzinger. vi Abbreviations ALT Alanine aminotransferase ARDS Acute respiratory distress syndrome AST Aspartate aminotransferase BP BP °C Degree Celsius CBC Complete blood count CNS Central nervous system CPAP Continuous positive airway pressure CRF Chronic renal failure CRT Capillary refill time CT Computer tomography CVP Central venous pressure CVVH Continuous veno-venous haemodialysis DEN Dengue DEN-1 Dengue virus serotype 1 DEN-2 Dengue virus serotype 2 DEN-3 Dengue virus serotype 3 DEN-4 Dengue virus serotype 4 DF Dengue fever DHF Dengue haemorrhagic fever DIVC Disseminated intravascular coagulopathy DSS Dengue shock syndrome DPG Diphosphoglycerate ECG Electrocardiogram ED Emergency department ELISA Enzyme-linked immunosorbent assay FBC Full blood count FFP Fresh frozen plasma FWB Fresh whole blood G6PD Glucose-6-phosphate dehydrogenase GCS Glasgow Coma Scale GP General practitioner Hb Haemoglobulin HCO3 Bicarbonate HCT Haematocrit HF Haemorrhagic fever HELLP Haemolysis, elevated liver enzymes and low platelet count HI Haemagglutinin inhibition test HIA Haemagglutination inhibition assay HIV Human immunodeficiency virus HPS Hantavirus pulmonary syndrome HR Heart rate IBW Ideal body weight ICU Intensive care unit IgM Immunoglobulin M IgG Immunoglobulin G IHA Indirect haemagglutination IMCI Integrated management of childhood illness INR International normalized ratio JVP Jugular venous pressure vii LVEDD Left ventricular end-diastolic diameters MAP Mean arterial pressure NS1 Ag Non-structural protein 1 antigen NSAID Non-steroidal anti-inflammatory agent NT Neutralization test ORS Oral rehydration solution PaCO2 Partial pressure of carbon dioxide PCR Polymerase chain reaction PEEP Positive end-expiratory pressure PICU Paediatric intensive care unit PLT Platelets PR Pulse rate PT Prothrombin time PTT Partial thromboplastin time RA Ringer’s acetate RBC Red blood cell RL Ringer’s lactate RR Respiratory rate RT-PCR Reverse transcriptase polymerase chain reaction SARS Severe acute respiratory syndrome SD Standard deviation SpO2 Oxygen saturation TWBC Total white blood count URTI Upper respiratory tract infection WBC White blood cell WHO World Health Organization WHO/TDR Special Programme for Research and Training in Tropical Diseases WHO/NTD Department of Control of Neglected Tropical Diseases YF Yellow fever viii 1. Overview, differential diagnosis and dengue diagnostics 1.1 Overview and course of dengue illness Dengue viruses cause symptomatic infections or asymptomatic seroconversion. Symptomatic dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum that includes both severe and non-severe clinical manifestations (1). After the incubation period, the illness begins abruptly and, in patients with moderate to severe disease, is followed by three phases − febrile, critical and recovery (Figure 1). Due to its dynamic nature, the severity of the disease will usually only be apparent around defervescence i.e. during the transition of the febrile to the afebrile phase, which often coincides with the onset of the critical phase. For a disease that is complex in its manifestations, management is relatively simple, inexpensive and very effective in saving lives, so long as correct and timely interventions are instituted. The key to a good clinical outcome is understanding and being alert to the clinical problems that arise during the different phases of the disease, leading to a rational approach in case management. An overview of good and bad clinical practices is given in Textbox A. Activities (triage and management decisions) at the primary and secondary care levels (where patients are first seen and evaluated) are critical in determining the clinical outcome of dengue. A well-managed front-line response not only reduces the number of unnecessary hospital admissions but also saves the lives of dengue patients. Early notification of dengue cases seen in primary and secondary care is crucial for identifying outbreaks and initiating an early response. Differential diagnosis needs to be considered (Textbox B). Fig. 1. The course of dengue illness IgM = immunoglobulin M; IgG = immunoglobulin G. Temperature is given in degrees Celsius (°C) Source: adapted from Yip, 1980 (2) by authors. 1 1.1.1 Febrile phase Patients typically develop a high-grade fever suddenly. This acute febrile phase usually lasts 2−7 days and is often accompanied by facial flushing, skin erythema, generalized body ache, myalgia, arthralgia, retro-orbital eye pain, photophobia, rubeliform exanthema and headache (1). Some patients may have a sore throat, an injected pharynx, and conjunctival injection. Anorexia, nausea and vomiting are common. It can be difficult to distinguish dengue clinically from non-dengue febrile diseases in the early febrile phase. A positive tourniquet test in this phase indicates an increased probability of dengue (3, 4). However, these clinical features do not predict the severity of disease. Therefore it is crucial to monitor for warning signs and other clinical parameters (Textbox C) in order to recognize progression to the critical phase. Mild haemorrhagic manifestations such as petechiae and mucosal membrane bleeding (e.g. of the nose and gums) may be seen (3, 5). Easy bruising and bleeding at venepuncture sites is present in some cases. Massive vaginal bleeding (in women of childbearing age) and gastrointestinal bleeding may occur during this phase although this is not common (5). The liver may be enlarged and tender after a few days of fever (3). The earliest abnormality in the full blood count is a progressive decrease in total white cell count, which should alert the physician to a high probability of dengue (3). In addition to these somatic symptoms, with the onset of fever patients may suffer an acute and progressive loss in their ability to perform their daily functions such as schooling, work and interpersonal relations (6). 1.1.2 Critical phase During the transition from the febrile to afebrile phase, patients without an increase in capillary permeability will improve without going through the critical phase. Instead of improving with the subsidence of high fever; patients with increased capillary permeability may manifest with the warning signs, mostly as a result of plasma leakage. The warning signs (summarized in Textbox C) mark the beginning of the critical phase. These patients become worse around the time of defervescence, when the temperature drops to 37.5−38°C or less and remains below this level, usually on days 3–8 of illness. Progressive leukopenia (3) followed by a rapid decrease in platelet count usually precedes plasma leakage. An increasing haematocrit above the baseline may be one of the earliest additional signs (7, 8). The period of clinically significant plasma leakage usually lasts 24−48 hours. The degree of plasma leakage varies. A rising haematocrit precedes changes in blood pressure (BP) and pulse volume. The degree of haemoconcentration above the baseline haematocrit reflects the severity of plasma leakage; however, this may be reduced by early intravenous fluid therapy. Hence, frequent haematocrit determinations are essential because they signal the need for possible adjustments to intravenous fluid therapy. Pleural effusion and ascites are usually only clinically detectable after intravenous fluid therapy, unless plasma leakage is significant. A right lateral decubitus chest radiograph, ultrasound detection of free fluid in the chest or abdomen, or gall bladder wall oedema may precede clinical detection. In addition to the plasma leakage, haemorrhagic manifestations such as easy bruising and bleeding at venepuncture sites occur frequently. 2 If shock occurs when a critical volume of plasma is lost through leakage, it is often preceded by warning signs. The body temperature may be subnormal when shock occurs. With profound and/or prolonged shock, hypoperfusion results in metabolic acidosis, progressive organ impairment, and disseminated intravascular coagulation. This in turn can lead to severe haemorrhage causing the haematocrit to decrease in severe shock. Instead of the leukopenia usually seen during this phase of dengue, the total white cell count may increase as a stress response in patients with severe bleeding. In addition, severe organ involvement may develop such as severe hepatitis, encephalitis, myocarditis, and/or severe bleeding, without obvious plasma leakage or shock (9). Some patients progress to the critical phase of plasma leakage and shock before defervescence; in these patients a rising haematocrit and rapid onset of thrombocytopenia or the warning signs, indicate the onset of plasma leakage. Cases of dengue with warning signs will usually recover with intravenous rehydration. Some cases will deteriorate to severe dengue (see Section 1.1.4). Warning signs of dengue Warning signs usually precede the manifestations of shock and appear towards the end of the febrile phase, usually between days 3–7 of illness. Persistent vomiting and severe abdominal pain are early indications of plasma leakage and become increasingly worse as the patient progresses to the shock state. The patient becomes increasingly lethargic but usually remains mentally alert. These symptoms may persist into the shock stage. Weakness, dizziness or postural hypotension occur during the shock state. Spontaneous mucosal bleeding or bleeding at previous venepuncture sites are important haemorrhagic manifestations. Increasing liver size and a tender liver is frequently observed. However, clinical fluid accumulation may only be detected if plasma loss is significant or after treatment with intravenous fluids. A rapid and progressive decrease in platelet count to about 100 000 cells/mm3 and a rising haematocrit above the baseline may be the earliest sign of plasma leakage. This is usually preceded by leukopenia (≤ 5000 cells/mm3) (4). human's rash 1.1.3 Recovery phase -Electrocardiographic changes - Bradycardia - As the patient survives the 24−48 hour 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 is -Herman stabilizes, and diuresis ensues. Some patients have a confluent erythematous or petechial rash with small areas of normal skin, described as “isles of white in the sea of red” (10). Some may experience generalized pruritus. Bradycardia and electrocardiographic changes are common during this stage. The haematocrit stabilizes or may be lower due to the dilutional effect of reabsorbed fluid. The white blood cell count usually starts to rise soon after defervescence but the recovery of the platelet count is typically later than that of the white blood cell count. Respiratory distress from massive pleural effusion and ascites, pulmonary oedema or congestive heart failure will occur during the critical and/or recovery phases if excessive intravenous fluids have been administered. Clinical problems during the different phases of dengue are summarized in Table 1. 3 Table 1. Medical complications seen in the febrile, critical and recovery phases of dengue 1 Febrile phase Dehydration: high fever may cause neurological disturbances and febrile seizures in young children 2 Critical phase Shock from plasma leakage: severe haemorrhage; organ impairment 3 Recovery phase Hypervolaemia (only if intravenous fluid therapy has been excessive and/or has extended into this period) and acute pulmonary oedema 1.1.4 Severe dengue A case of severe dengue is defined as a suspected dengue patient with one or more of the following (see Section 1.2, Figure 2): & (i) severe plasma leakage that leads to shock (dengue shock) and/or fluid accumulation with respiratory distress; (ii) severe bleeding; (iii) severe organ impairment. 1.1.4.1 Severe plasma leakage and dengue shock Dengue shock syndrome (DSS) is a form of hypovolaemic shock and results from continued vascular permeability and plasma leakage. This usually takes place around - defervescence, i.e. on days 4−5 of illness (range of days 3−8), and is often preceded by warning signs. From this point onwards, patients who do not receive prompt intravenous fluid therapy progress rapidly to a state of shock. Dengue shock presents as a physiologic continuum, progressing from asymptomatic capillary leakage to compensated shock to hypotensive shock and ultimately to cardiac arrest (Textbox D). Tachycardia (without fever during defervescence), is an early cardiac response to hypovolaemia. It is important to note that some patients, particularly adolescents and adults do not develop tachycardia even when in shock. During the initial stage of shock, the compensatory mechanism that maintains a normal systolic BP produces tachycardia, quiet tachypnoea (tachypnoea without increased effort) (11), and peripheral vasoconstriction with reduced skin perfusion (manifested as cold extremities and delayed capillary refill time of > 2 seconds and weak volume peripheral pulses). As peripheral vascular resistance increases, the diastolic pressure rises towards the systolic pressure and the pulse pressure (the difference between the systolic and diastolic pressures) narrows. The patient is considered to have compensated shock if the systolic pressure is maintained at the normal or slightly above normal range but the pulse pressure is ≤ 20 mmHg in children (e.g. 100/85 mmHg) or if they have signs of poor capillary perfusion (cold extremities, delayed capillary refill, or tachycardia). In adults, a pulse pressure of ≤ 20 mmHg may indicate more severe shock. Compensated metabolic acidosis is observed when the pH is normal with low carbon dioxide tension and a low bicarbonate level. 4 Patients who have dengue and are in compensated shock often remain conscious and lucid. The inexperienced physician may measure a normal systolic pressure and a normal pulse oximetry (SpO2 95–100%) in a conscious patient and underestimate the critical state of the patient. Worsening hypovolaemic shock manifests as increasing tachycardia and peripheral vasoconstriction. Not only are the extremities cold and cyanosed but the limbs become mottled, cold and clammy. By this stage the breathing becomes more rapid and increases in depth − a compensation for the metabolic acidosis (Kussmaul’s breathing). Finally, there is decompensation, both systolic and diastolic BPs disappear suddenly and dramatically, and the patient is said to have hypotensive or decompensated shock. At this time the peripheral pulses disappear while the central pulse (femoral) will be weak. Hypotension develops when physiologic attempts to maintain systolic BP and perfusion are no longer effective. One key clinical sign of this deterioration is a change in mental state as brain perfusion declines. The patient becomes restless, confused and extremely lethargic. Seizures may occur and agitation may alternate with lethargy. On the other hand, children and young adults have been known to have a clear mental status even in profound shock. Adults have been known to be able to work until the stage of profound shock is reached. The failure of infants and children to recognize, focus or make eye contact with parents may be an early ominous sign of cortical hypoperfusion, as is the failure to respond to painful stimuli such as venepuncture. Parents may be the first to recognize these signs − but they may be unable to describe them, other than to say something is wrong. Listen to parents! Hypotension is a late finding and signals an imminent total cardiorespiratory collapse. Prolonged hypotensive shock and hypoxia lead to severe metabolic acidosis, multiple organ failure and an extremely difficult clinical course (12) (Textbox D). It may take a few hours for patients to progress from warning signs to compensated shock and another few hours for compensated shock to progress to hypotensive shock, but only minutes for hypotensive shock to progress to cardiorespiratory collapse and cardiac arrest. Hypotension is associated with prolonged shock which is often complicated by major bleeding (12). Patients with severe dengue have varying degrees of coagulation abnormalities, but these are usually not sufficient to cause major bleeding (13). 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 corticosteroids have been taken. Bleeding may occur in patients with previous peptic or duodenal ulcers (14, 15). Acute liver and renal failure and encephalopathy may be present in severe shock; these have been described even in the absence of severe plasma leakage or shock (16–21). Cardiomyopathy and encephalitis have also been reported in a few dengue case series (22–25). However, most deaths from dengue occur in patients with profound and prolonged shock resulting from plasma leakage and complicated by bleeding and/or fluid overload. Patients with severe plasma leakage may not have shock if prompt fluid replacement has been carried out. Instead, they manifest with respiratory distress due to massive pleural effusion and ascites, which can also be exacerbated by unguided intravenous fluid therapy. 5 1.1.5 References 1. Rigau-Pérez JG et al., Dengue and dengue haemorrhagic fever. Lancet, 1998, 352:971–977. 2. Yip WCL. Dengue haemorrhagic fever: current approaches to management. Medical Progress, 1980, 7:13. 3. Kalayanarooj S et al., Early clinical and laboratory indicators of acute dengue illness. Journal of Infectious Diseases, 1997, 176:313–321. 4. Cao XT et al., Evaluation of the World Health Organization standard tourniquet test in the diagnosis of dengue infection in Vietnam. Tropical Medicine and International Health, 2002, 7:125–132. 5. Balmaseda A et al., Assessment of the World Health Organization scheme for classification of dengue severity in Nicaragua. American Journal of Tropical Medicine and Hygiene, 2005, 73:1059–1062. 6. Lum LCS et al., Quality of life of dengue patients. American Journal of Tropical Medicine and Hygiene, 2008, 78(6):862–867. 7. Srikiatkhachorn A et al., Natural history of plasma leakage in dengue hemorrhagic fever: a serial ultrasonic study. The Pediatric Infectious Disease Journal, 2007, 26(4):283−290. 8. Nimmannitya S et al., Dengue and chikungunya virus infection in man in Thailand, 1962−64. Observations on hospitalized patients with haemorrhagic fever. American Journal of Tropical Medicine and Hygiene, 1969, 18(6):954−971. 9. Martinez-Torres E, Polanco-Anaya AC, Pleites-Sandoval EB. Why and how children with dengue die? Revista cubana de medicina tropical, 2008, 60(1):40−47. 10. Nimmannitya S. Clinical spectrum and management of dengue haemorrhagic fever. Southeast Asian Journal of Tropical Medicine and Public Health, 1987, 18(3):392−397. 11. Pediatric Advanced Life Support (PALS) Provider Manual, Dallas, American Heart Association, 2006. 12. Lum LCS et al., Risk factors for hemorrhage in severe dengue infection. Journal of Pediatrics, 2002, 140:629–631. 13. Wills BA et al., Coagulation abnormalities in dengue hemorrhagic fever: Serial investigations in 167 Vietnamese children with dengue shock syndrome. Clinical Infectious Diseases, 2002, 35:277–285. 14. Tsai CJ et al., Upper gastrointestinal bleeding in dengue fever. American Journal of Gastroenterolgy, 1991, 86(1):33–35. 15. Chiu YC et al., Endoscopic findings and management of dengue patients with upper gastrointestinal bleeding. American Journal of Tropical Medicine and Hygiene, 2005, 73(2):441–444. 16. Lum LC et al., Fulminant hepatitis in dengue infection. Southeast Asian Journal of Tropical Medicine and Public Health, 1993, 24(3):467–471. 17. Nguyen TL, Nguyen TH, Tieu NT. The impact of dengue haemorrhagic fever on liver function. Research in Virology, 1997, 148(4):273–277. 18. Poovorawan Y et al., Dengue virus infection: a major cause of acute hepatic failure in Thai children. Annals of Tropical Paediatrics, 2006, 26(1):17–23. 19. Ooi ET et al., Gastrointestinal manifestations of dengue infection in adults. Medical Journal of Malaysia, 2008, 63(5):401–405. 20. Kumar R et al., Prevalence of dengue infection in north Indian children with acute hepatic failure. Annals of Hepatology. 2008, 7(1):59–62. 21. Trung DT et al., Liver involvement associated with dengue infection in adults in Vietnam. American Journal of Tropical Medicine and Hygiene. 2010, 83(4):774–780. 22. Lum LCS et al., Dengue encephalitis: a true entity? American Journal of Tropical Medicine and Hygiene, 1995, 54(3):256–923. 23. Miagostovich MP, Ramos RG, Nicol AF. Retrospective study on dengue fatal cases. Clinical Neuropathology, 1997, 16:204–208. 24. Solomon T et al., Neurological manifestations of dengue infection. Lancet, 2000, 355:1053–1059. 25. Pancharoen C, Thisyakorn U. Neurological manifestations in dengue patients. Southeast Asian Journal of Tropical Medicine and Public Health, 2001, 32(2):341–345. 6 1.2 Dengue case classification Changes in the epidemiology of dengue, especially with an increasing number of cases in adults (with and without co-morbidities) and the expansion of dengue into other regions of the world, has led to problems with the use of the existing WHO classification. This clinical guide uses three categories for case management (A, B, C), based on the model of case classification that follows (Figure 2) after a patient has fulfilled the criteria for probable dengue. Fig. 2. Dengue case classification by severity Dengue case classification by severity Dengue ± warning signs Severe dengue with 1.Severe plasma leakage Without warning signs 2.Severe haemorrhage 3.Severe organ impairment Criteria for dengue ± warning signs Criteria for severe dengue Probable dengue Warning signs* 1. Severe plasma leakage Live in/travel to dengue Abdominal pain or leading to: endemic area. Fever and 2 tenderness Shock (DSS) of the following criteria: Persistent vomiting Fluid accumulation with Nausea, vomiting Clinical fluid accumulation respiratory distress Rash Mucosal bleed Aches and pains Lethargy; restlessness 2. Severe bleeding Tourniquet test positive Liver enlargement >2cm as evaluated by clinician Leucopenia Laboratory: Increase in HCT 3. Severe organ involvement Any warning sign concurrent with rapid Liver: AST or ALT>=1000 Laboratory confirmed decrease in platelet count CNS: Impaired WHO/TDR 2009 dengue (important when no sign of plasma * Requiring strict observation consciousness leakage) and medical intervention Heart and other organs ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system; DSS = dengue shock syndrome; HCT = haematocrit 1.2.1 Development of the revised dengue case classification The development of the revised dengue case classification into dengue (with or without warning signs), and severe dengue, is based on several different steps and studies: 1. There have been many reports of difficulties in the use of the previous classification (1–3), which were summarized in a systematic literature review (4). Difficulties in applying the criteria for dengue haemorrhagic fever in the clinical situation, together with the increase in clinically severe dengue cases which did not fulfil the strict criteria, led to the request for the classification to be reconsidered. 2. A further set of studies (5), comparing existing national, regional and international guidelines for dengue prevention and control, concluded that the dengue case 7 classification existing at the time was being used inconsistently. Many countries report dengue according to locally-adapted case classification schemes and there was a perceived need to revise the case classification into levels of severity. 3. A prospective clinical multicentre study across dengue-endemic regions was set up to collect evidence about criteria for classifying dengue into levels of severity. This was supported by WHO/TDR and funded by the European Union. The study findings confirmed that by using a set of clinical and/or laboratory parameters, one sees a clear-cut difference between patients with severe and non-severe dengue. However, for practical reasons it was desirable to split the large group of patients with non-severe dengue into two subgroups – patients with warning signs and those without. The criteria for diagnosing dengue are presented in Figure 2. It must be kept in mind that even dengue patients without warning signs may develop severe dengue. 4. Expert consensus groups meeting in Latin America (Havana, Cuba, 2007), South- East Asia (Kuala Lumpur, Malaysia, 2007) and at WHO headquarters (Geneva, Switzerland, 2008) agreed that “dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome”. 5. The updated model for classifying dengue has been suggested by the Geneva- based expert group and a set of studies has been initiated comparing this model to the previous case classification in terms of applicability and user-friendliness. 6. Based on current experience it can be concluded that classification into levels of severity is highly likely to be of practical use. First, to aid the clinicians’ decisions about where, and how intensively, the patient should be observed and treated (i.e. for triage, which is particularly useful in outbreaks). Second, for more consistent reporting in national and international surveillance systems, and as an end-point measure in dengue vaccine and drug trials. 7. Since many countries have started to use the newly suggested model, this handbook adopts the distinction between dengue and severe dengue. 8 1.2.2 References 1. Guha-Sapir D, Schimmer B. Dengue fever: new paradigms for a changing epidemiology. Emerging Themes in Epidemiology, 2005, 2:1. 2. Deen JL et al., The WHO dengue classification and case definitions: time for a reassessment. Lancet, 2006, 368:170–173. 3. Rigau-Perez J. Severe dengue: the need for new case definitions. Lancet Infectious Diseases, 2006, 6:297– 302. 4. Bandyopadhyay S, Lum LC, Kroeger A. Classifying dengue: a review of the difficulties in using the WHO case classification for dengue haemorrhagic fever. Tropical Medicine and International Health, 2006, 11(8):1238–1255. 5. Santamaria R et al., Comparison and critical appraisal of dengue clinical guidelines and their use in Asia and Latin America. International Health, 2009, 1:133–140. 6. Dengue. Guidelines for diagnosis, treatment prevention and control, Geneva, World Health Organization, 2009, WHO/HTM/NTD/DEN/2009. 9 1.2.3 Differential diagnoses of dengue A number of infectious and non infectious diseases mimic dengue and severe dengue. It is thus necessary for clinicians to be familiar with the epidemiological characteristics of febrile diseases in the locality. Clinical manifestations associated with fever, epidemiological information and virological tests (if available) are particularly useful in patients with acute undifferentiated fever (1, 2). Conditions that present with an influenza-like syndrome, such as influenza itself, measles, chikungunya, infectious mononucleosis and human immunodeficiency virus (HIV) seroconversion illness, may mimic the febrile phase of dengue (Textbox B). Upper respiratory symptoms such as rhinitis and cough are always present in influenza, in addition to fever, headache and body pains which are also commonly seen in dengue. Patients with dengue usually have gastrointestinal symptoms (i.e. abdominal discomfort, vomiting and sometimes diarrhoea) during the febrile phase. Coinfections with both dengue and influenza viruses make the differential diagnosis more difficult. Only rhinitis and/or nasal congestion are frankly prominent in influenza cases (3). Infection with adenoviruses may cause fever associated with rash, abdominal pain, leukopenia, lymphopenia and organ impairment (liver, heart). Bleeding can occur, but is not frequent. Rhinitis or pharyngitis, cough and other respiratory symptoms are present, associated with cervical adenopathies in most patients (4). The diagnosis of severe acute respiratory syndrome (SARS) is difficult early in the illness. When large SARS outbreaks occurred in dengue-endemic countries, laboratory features that were highly predictive of dengue diagnosis were leukopenia and low platelet count (5). ↳ While fever, arthralgia, rash, malaise and leukopenia are common in both chikungunya and dengue, symmetric arthritis of small joints is pathognomonic of the former. A bleeding tendency and pronounced thrombocytopenia are more frequent in dengue (6, 7). Primary infection with HIV may mimic dengue with high fever, malaise, rash and generalized adenopathies (8). Splenomegaly and prolonged fever should prompt the consideration of malaria and typhoid in the differential diagnoses. Fever, malaise, vomiting, liver enlargement and elevated liver enzymes may be misdiagnosed as infectious hepatitis, and vice-versa (9). Evidence of plasma leakage during defervescence and thrombocytopenia are more in keeping with dengue. The rash associated with measles and rubella has a particular distribution from the head to the trunk and extremities, but in dengue the rash usually first appears on the trunk and later extends to the face and extremities (10). Although both diseases may have common signs and symptoms, including myalgia and arthralgia, measles patients always have a cough, rhinitis and conjunctivitis. Fever, rash and adenopathies may be seen in dengue, rubella, erythema infectiosum caused by parvovirus B19 (11), and herpes virus type 6 (12). Other exanthems such as enteroviruses, infectious mononucleosis, scarlet fever and Kawasaki disease are associated with particular characteristics. Sepsis and meningococcal disease should be considered in shock patients because of the need for urgent treatment with specific antibiotics. Common symptoms and signs with dengue cases are fever, rash, petechiae, bleedings and shock associated with leukopenia (particularly in severe gram-negative sepsis and poor prognosis meningococcaemia) and thrombocytopenia (13). In septic shock, the temperature is usually high, although it could be subnormal in the late stages. Bounding pulses with warm extremities are present in 10 early septic shock. In dengue patients, shock usually occurs after defervescence; hence the temperature is often subnormal or normal, pulse volume is small, and pulse pressure is narrowed with the patient having cold extremities. Clinical and radiographic signs of plasma leakage and progressive haemoconcentration in severe dengue cases are useful distinguishing features. Another helpful tool to differentiate dengue from these other diseases is to determine the sequence of signs and symptoms, including warning signs during defervescence that frequently announce severe dengue. Clinical distinction between leptospirosis and dengue may be challenging, particularly when both epidemics are concurrent (14). Delayed antibiotic therapy is associated with mortality in leptospirosis. Jaundice is more often associated with leptospirosis, but ocular pain, arthralgia and diarrhoea could be present as well (15). Leptospirosis is frequently associated with professional activity (e.g. working with garbage or in agriculture) or with a history of certain pastimes (e.g. trekking to waterfalls or playing water sports). Pulmonary haemorrhage is a particular form of leptospirosis without jaundice that has some common signs and symptoms with severe dengue; these include fever, thrombocytopenia, shock and massive bleeding in the lungs (16). Pulmonary haemorrhage is uncommon in dengue; evidence of plasma leak such as pleural effusion or ascites would suggest the diagnosis of dengue. Leukopenia and thrombocytopenia, with or without bleeding, may be clinical manifestations of infectious diseases such as malaria, leptospirosis, typhoid, typhus, bacterial sepsis and acute HIV-seroconversion illness. Leukopenia and thrombocytopenia may be present in non-infectious diseases such as systemic lupus and other systemic auto-immune diseases; acute leukaemia (17) and other haematological disorders such as Henoch-Schönlein purpura and thrombocytopenic purpuric syndromes, mainly thrombotic thrombocytopenic purpura and immunological thrombocytopenic purpura. During the critical phase of dengue, patients with plasma leakage or shock may present with severe abdominal pain when the fever subsides. The severe abdominal pain may mimic an acute abdominal condition such as in acute appendicitis. Ultrasound studies in these patients have shown fluid collection around the appendix. Other abdominal signs such as right iliac fossa tenderness and rebound tenderness disappear after a few days of conservative management (18). Another misdiagnosis is acute (alithiasis) cholecystitis, with the abdominal ultrasonograph showing thickening/oedema of the wall of the gallbladder. This is associated with pain in the subhepatic region, mainly during defervescence. Plasma leakage, not inflammation, is responsible for these clinical features. Patients who underwent surgery as a result of misdiagnosis with an acute surgical abdominal condition have been found to have life- threatening bleedings; some went on to die. Failure to recognize severe abdominal pain as a warning sign that heralds severe dengue has led to the misdiagnosis of renal lithiasis and delayed intravenous fluid treatment for dengue shock. A differentiating feature of an acute surgical abdomen and the severe abdominal pain of dengue shock is that the abdomen in dengue shock is soft and the pain subsides with fluid resuscitation. Other medical emergencies presenting with intense and continuous abdominal pain include diabetic ketoacidosis, renal failure and lactic acidosis. Again, evidence of plasma leakage (especially after intravenous fluid therapy), thrombocytopenia and bleeding tendencies help to distinguish dengue from other medical or surgical conditions. 11 The group of viral haemorrhagic fever diseases have bleeding, thrombocytopenia and shock in common. All have the monocyte/macrophage as the target cell (19). These diseases are present in different geographic areas, have different vectors (Table 2), have causative agents that belong to different viral families (20–22), and have different means of transmission. The main pathogenic difference is that the severity of dengue disease is mediated by an immunological disorder that enhances viral infection, causing patients to have complications after the viraemic (febrile) phase, during defervescence or 24 hours later. An analysis of the particular clinical, epidemiological and vectoral information will lead to the respective diagnosis. Yellow fever (YF) is now considered a re-emergent disease in Africa and the Americas. Aedes aegypti is the common vector of YF and dengue and some clinical features are common to both diseases. The classic description of YF covers two phases: the febrile phase and the toxic phase. During the toxic phase, liver damage causing jaundice, renal insufficiency and central nervous system impairment are life-threatening characteristics. The disease in adults has been associated with high mortality, a relatively short duration, symptoms such as headache, back pain, fever, vomiting and nausea, jaundice, haemorrhages and unconsciousness (23). Severe dengue with noncardiogenic pulmonary oedema (fluid overload) and pulmonary distress has clinical signs common to the Hantavirus pulmonary syndrome (HPS). In severe dengue, and not in HPS, the pulmonary oedema is usually preceded by prolonged or recurrent shock, associated with bleedings in the lung and other sites, together with signs of plasma leakage and fluid overload. The initial picture of HPS is very similar to that of influenza, with fever, myalgia, vomiting and cough associated with dyspnoea at the end of the first week, and leukocytosis, neutrophilia, thrombocytopenia and elevated haematocrits (24). Children with HPS may have severe abdominal pain and liver enlargement, but bleeding is not frequent and they do not present with pulmonary haemorrhage, but with interstitial and alveolar oedema (25). Table 2. Viral haemorrhagic fevers Disease Virus (family) Geographic area Vector Argentinian HF Junin (Arenaviridae) Argentina Rodents Bolivian HF Machupo (Arenaviridae) Plurinational state of Rodents Bolivia Lassa fever Lassa (Arenaviridae) Africa Rodents Dengue Dengue (Flaviviridae) America/Africa/Asia Mosquitoes Yellow fever Yellow Fever (Flaviviridae) South America/Asia Mosquito Haemorrhagic fever with Hantaan and related Europe/Asia/America and Rodents renal syndrome (Bunyaviridae) Africa Rift valley fever Rift Valley fever (Bunyaviridae) Africa Mosquito Crimean-Congo Crimean/Congo haemorrhagic Africa/Europe/Asia Ticks haemorrhagic fever fever virus (Crimea Bunyaviridae) Ebola fever Ebola (Filoviridae) Africa Unknown Marburg fever Marburg (Filoviridae) Africa Unknown Kyasanur forest fever Kyasanur HF (Flaviviridae) India Ticks Omsk haemorrhagic fever Omsk HF (Flaviviridae) Russia-Romania Ticks Venezuelan haemorrhagic Guanarito (Arenaviridae) Venezuela (state of Rodents fever Portuguesa) HF = haemorrhagic fever 12 1.2.4 References 1. Phuong HL et al., Acute undifferentiated fever in Binh Thuan province, Vietnam: imprecise clinical diagnosis and irrational pharmaco-therapy. Tropical Medicine and International Health, 2006, 11(6): 869–879. 2. Thai KT et al., Clinical, epidemiological and virological features of dengue virus infections in Vietnamese patients presenting to primary care facilities with acute undifferentiated fever. The Journal of Infection, 2010, 60(3): 229–237. 3. Morens DM. Dengue Outbreak Investigation Group. Dengue in Puerto Rico, 1977: public health response to characterize and control an epidemic of multiple serotypes. American Journal of Tropical Medicine and Hygiene, 1986, 35:197–211. 4. Fisher RG, Boyce TG. Nonstreptococcal pharyngitis. In: Moffet´s Pediatric Infectious Diseases. A problem- oriented approach, 4th ed. Philadelphia, PA, Lippincott Williams and Wilkins, 2005: 34–35. 5. Wilder-Smith A, Earnes A, Paton NI. Use of simple laboratory features to distinguish the early stage of severe acute respiratory syndrome from dengue fever. Clinical Infectious Diseases, 2004, 39(12):1818– 1823. 6. Kularatne SA et al., Concurrent outbreaks of Chikungunya and Dengue fever in Kandy, Sri Lanka, 2006-07: a comparative analysis of clinical and laboratory features. Postgraduate Medical Journal, 2009, 85(1005):342–346. 7. Yamamoto K et al., Chikungunya fever from Malaysia. Internal Medicine, 2010, 49(5):501–505. 8. Cabie A et al., Dengue or acute retroviral syndrome? Presse Med, 2000, 29(21):1173–1174. 9. Martinez E. Diagnóstico Diferencial. In: Dengue. Rio de Janeiro, FIOCRUZ, 2005: 189−195. 10. Dietz VJ et al., Diagnosis of measles by clinical case definition in dengue endemic areas: implications for measles surveillance and control. Bulletin of the World Health Organization, 1992, 70(6):745–750. 11. Oliveira MJC et al., Frequency of measles, rubella, dengue and erythema infectiosum among suspected cases of measles and rubella in the State of Pernambuco between 2001 and 2004. Revista da Sociedade Brasileira de Medicina Tropical, 2008, 41(4):338–344. 12. Oliveira SA et al., The aetiology of maculopapular rash diseases in Niteroi, state of Rio de Janeiro, Brazil: implications for measles surveillance. Epidemiology and Infection, 2001, 127(3):509–516. 13. Martinez E. Meningococcal disease: physiopathology, clinical picture and prognosis. Revista de Hospital de Niños de Buenos Aires, 1994, 36(158-159):204–214. 14. Flannery B et al., Referral pattern of leptospirosis cases during a large urban epidemic of dengue. American Journal of Medicine and Tropical Hygiene, 2001, 65(5):657–663. 15. Sanders EJ et al., Increase of leptospirosis in dengue-negative patients after a hurricane in Puerto Rico in 1996. American Journal of Tropical Medicine and Hygiene, 1999, 61(3):399–404. 16. Muñoz F et al., Outbreak of acute febrile illness and pulmonary hemorrhage-Nicaragua 1995. Journal of the American Medical Association, 1995, 274(21):1668. 17. Gawoski JM, Ooi WW. Dengue fever mimicking plasma cell leukaemia. Archives of Pathology and Laboratory Medicine, 2003, 127(8):1026–1027. 18. Premaratna R et al., Dengue fever mimicking acute appendicitis. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2007, 101(7):683-685. 19. Halstead SB. Viral hemorrhagic fevers. Journal of Infectious Diseases, 1981, 143(1):127–129. 20. Salas R et al., Venezuelan haemorrhagic fever. Lancet, 1991, 338:1033–1036. 21. Zaki A. Isolation of a flavivirus related to the tick-borne encephalitis complex from human cases in Saudi Arabia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1997, 91(2):179–181. 13 22. Madani TA. Alkhumra virus infection, a new viral hemorrhagic fever in Saudi Arabia. The Journal of Infection, 2005, 51(2):91–97. 23. Huamán JH et al., Yellow Fever: clinical, epidemiological and serologic study, 1995-1998, Pichanaki’s Rural Hospital, Peru. 2000. 9th International Congress on Infectious Diseases. Buenos Aires, Argentina, April 10-13, 2000. Abstract 85.018, p. 200. 24. Duchin JS et al., Hantavirus Pulmonary Syndrome: a clinical description of 17 patients with a newly recognized disease. New England Journal of Medicine, 1994, 330(4):949–955. 25. Soza G et al., Síndrome pulmonar por hantavirus en población infantil. Chile: regiones IX y X. 1998-2000. Revista chilena de infectología, 2000, 17(3):248–257. 14 1.3 Dengue diagnostics for clinicians The objectives of dengue laboratory diagnosis are (i) to confirm the clinical diagnosis and (ii) to provide information for epidemiological surveillance. Laboratory diagnosis is not necessary for clinical management except in atypical cases or when carrying out differential diagnosis with other infectious diseases. Laboratory diagnosis of dengue is made by detecting the virus and/or any of its components (infective virus, virus genome, dengue antigen) or by investigating the serological responses present after infection (specifically IgM and IgG levels) (Table 3) (1– 4). Table 3. Dengue diagnostics and sample characteristics Diagnostic Clinical sample Methodology Time to results method Mosquito or mosquito cell Viral isolation One week or more culture inoculation Acute serum Nucleic acid RT-PCR and real time RT- Virus (1–5 days of 1 or 2 days detection PCR detection fever) and its NS1 Ag rapid tests Minutes components and necropsy tissues Antigen detection NS1 Ag ELISA 1 day Immuno-histochemistry 2–5 days Paired sera ELISA 1–2 days (acute serum from1–5 days IgM or IgG HIA and second seroconversion serum 15–21 Neutralization Test Minimum 7 days Serological days after) response IgM detection ELISA 1 or 2 days Serum after day (recent infection) Rapid tests Minutes 5 of fever IgG ELISA 1 or 2 days IgG detection HIA ELISA = enzyme-linked immunosorbent assay; HIA = haemagglutination inhibition assay; IgG = immunoglobulin G; IgM = immunoglobulin M; NS1 Ag = non-structural protein 1 antigen; RT-PCR = reverse transcriptase polymerase chain reaction Dengue viruses are RNA viruses belonging to the family flaviviridae, genus flavivirus. The four dengue viruses (DEN-[1–4]) are serologically related but antigenically and genetically distinctive (5–7). Three main aspects should be considered for an adequate dengue diagnosis: virological and serological markers in relation to the time of dengue infection; type of diagnostic method in relation to clinical illness; characteristics of the clinical samples. 15 Virological and serological markers in relation to time of dengue infection (Figure 3) An incubation period of 4–10 days occurs after the mosquito bites, resulting in an asymptomatic or symptomatic dengue infection. During this period the virus replicates and an antibody response is developed. In general, viraemia is detectable in most dengue cases at the same time that symptoms appear, and is no longer detectable at the time of defervescence. The development of IgM antibody is coincident with the disappearance of fever and viraemia (8). Virological and serological markers differ in time evolution and titre response and according to whether the infection is primary or secondary. In a primary infection (i.e. when an individual is infected for the first time with a flavivirus), viraemia develops from 1–2 days before the onset of fever until 4–5 days after. Accordingly, anti-dengue IgM specific antibodies can be detected 3−6 days after fever onset. On average, IgM is detected in 50% of cases by days 3–5 after the onset of illness, this figure increasing to 95–98% for days 6−10. Low levels of IgM are still detectable around one to three months after fever. In addition, the primary infection is characterized by slowly increasing but low levels of dengue-specific IgG, becoming elevated at days 9−10. Low IgG levels persist for decades, an indication of a past dengue infection (1–4, 9, 10). A totally different picture is observed during a secondary infection, with a rapid and higher increase of anti-dengue specific IgG antibodies and slower and lower levels of IgM. High IgG levels remain for 30–40 days. A short-lasting but higher viraemia level characterizes the secondary infection compared to the primary infection (1–4, 9, 10). Fig. 3. Virological and serological markers of dengue infection according to time of illness IgG Viremia Viremia IgM Primary Infection Second Infection IgG = immunoglobulin G; IgM = immunoglobulin M Type of dengue diagnostic method in relation to time of clinical illness The diagnostic method to confirm an acute infection depends on the time of clinical illness: the febrile phase is coincident with the presence of viraemia, some viral components and replication products in blood; the critical and convalescent phases coincide with the development of antibodies, as summarized in Table 3. 16 Febrile phase (day 1 to days 4–5 of fever) The infective virus can be isolated in serum by inoculation in tissue culture (mosquito cell cultures) and mosquitoes. This method allows for identification of the viral serotype. Virus genome detection using reverse transcriptase polymerase chain reaction (RT-PCR) and real-time RT-PCR confirms an acute dengue infection. Both methods have a high sensitivity and allow serotype identification and quantification of genome copies (1–4, 11– 13). Some studies suggest the presence of a higher number of copies in severe dengue cases (14–16). NS1 Ag is a marker of acute dengue infection. Both enzyme-linked immunosorbent assay (ELISA) and rapid commercial tests are available for NS1 Ag detection. The sensitivity and specificity of commercial kits in different serotype infections and days of illness are being evaluated (17–19). Critical and convalescent phases (after days 4–5 of illness) Specific IgM is the best marker of a recent dengue infection. MAC-ELISA and rapid tests are the most frequent methods for IgM detection; however a recent evaluation of four rapid tests demonstrated a low sensitivity (20, 21). In addition to IgM, high levels of specific IgG in sera collected early after fever onset as detected by ELISA and haemagglutination inhibition assay (HIA) also suggest a recent dengue infection (1–4, 9). Primary infections are characterized by high levels of IgM and low levels of IgG, while low levels of IgM with high levels of IgG characterize secondary infections. A single serum sample collected after day 5 of fever onset is useful for IgM determination. Depending on the IgG level in the sample, classification into primary or secondary infection can also be determined using the IgM/IgG optical density ratio. Ratios greater than & 1.2 (using the patient’s sera at 1/100 serum dilution) or & 1.4 (using serum dilution of 1/20) suggest a primary infection (1). In addition, IgG titres higher than 1/1280 by HIA or ELISA are also suggestive of a secondary infection (1–4, 9, 10). As IgM antibodies persist for almost three months after fever onset, the detection in samples collected late after the acute phase of illness suggests a recent infection. In dengue endemic countries, acute clinical cases with a positive IgM are classified as probable dengue cases. The study of paired sera (acute and convalescent serum samples with the second sample being collected 15–21 days after the first sample), allows for serological confirmation of dengue infection. The diagnosis depends upon the demonstration of rising titres of dengue antibodies between acute and convalescent sera (1–4, 9, 22). A broad cross-reactivity of ELISA and HIA with other flaviviruses has been observed. Neutralization Test is the method of choice for determination of specific serotype (1–4, 9, 10, 23). 17 Characteristics of the clinical sample Similar to other enveloped viruses, dengue virus is labile and readily inactivated at temperatures above 30°C, so care should be taken during transportation and storage of samples. Serum samples collected during the first 4 days of fever are useful for virus, genome and dengue antigen detection, thus confirming a dengue infection. Samples should be rapidly transported at 4°C to the laboratory and be processed as soon as possible. Sterile serum without anticoagulant is useful. If specimen delivery cannot be performed in the first 24–48 hours, freezing at –70°C is recommended. Sera for serological studies should be stored at 4°C for short time periods and at –20°C for a longer time periods. When serum collection or transportation is not possible, blood collected on filter papers represents an opportunity for IgM and IgG determination and also for RNA detection (24, 25). Tissue specimens collected from fatal cases are useful for virus, genome and antigen detection. Liver, spleen and lymph nodes are the tissues of choice (26, 27). Tissue samples should be collected immediately after death and be immediately frozen at –70°C, or rapidly transported at 4°C to the laboratory for sample processing. Fresh tissues are also suitable for virus isolation (26–29). Besides general patient information a summary of clinical and epidemiological data, such as the date of fever onset, method of sample collection and the type of sample, should accompany clinical samples (1). The usefulness of available diagnostic tests depends on the level of health care (see Table 4). At primary-care level, rapid tests for NS1 Ag detection (suggestive of an acute dengue infection) as well as rapid tests for IgM determination (suggestive of a recent infection), are useful. As patients access care independent of the period of infection suffered – some early, some late – a combination of both NS1 Ag and IgM markers is advisable. At district health centres, both antigen-based tests and serology can be performed using ELISA and rapid tests. All diagnostic methods should be available at reference centres, including virus isolation, nucleic acid detection, diagnostics for tissues samples and all serological techniques (1–4, 30). Laboratory confirmation of a dengue case A diagnosis of dengue infection is confirmed by the detection of the virus, the viral genome or NS1 Ag, or seroconversion of IgM or IgG (from negative to positive IgM/IgG or four-fold increase in the specific antibody titre) in paired sera (see Table 5). A positive IgM serology or a haemagglutinin inhibition test (HIA) antibody titre of 1280 or higher (or comparable figures by ELISA in a single specimen), are all diagnostic criteria of a probable dengue infection. Both probable and confirmed dengue cases should be notified to health authorities (1–4, 9, 30). 18 Table 4. Recommended diagnostic tool according to laboratory service level Primary health- District health Reference care centres centres centres Virus isolation Yes Genome detection Yes NS1 Ag detection Rapid tests Yes Yes Yes ELISA Yes Yes IgM detection Rapid tests Yes Yes Yes ELISA Yes Yes IgG detection ELISA Yes IHA Yes Neutralization assay Yes ELISA = enzyme-linked immunosorbent assay; IgG = immunoglobulin G; IgM = immunoglobulin M; IHA = indirect haemagglutination; NS1 Ag = non-structural protein 1 antigen #Table 5. Confirmed and probable dengue diagnosis, interpretation of results and sample characteristics Method Interpretation Sample characteristics Confirmed Viral isolation Virus isolated Serum (collected at 1–5 days of dengue fever) infection Genome Positive RT-PCR or positive real-time detection RT-PCR Necropsy tissues Antigen detection Positive NS1 Ag Positive immunohistochemical Necropsy tissues IgM From negative IgM to positive IgM in Acute serum (days 1–5) and seroconversion paired sera convalescent serum (15–21 days after first serum) IgG From negative IgG to positive IgG in seroconversion paired sera or 4-fold increase IgG levels among paired sera Probable Positive IgM Positive IgM Single serum collected after dengue High IgG levels by ELISA or HI High IgG levels day 5 infection (≥ 1280) ELISA = enzyme-linked immunosorbent assay; IgG = immunoglobulin G; IgM = immunoglobulin M; NS1 Ag = non-structural protein 1 antigen; RT-PCR = reverse transcriptase polymerase chain reaction 19 1.3.1 References 1. Dengue. Guidelines for diagnosis, treatment prevention and control. Geneva, TDR/WHO, 2009. WHO/HTM/NTD/DEN/2009. 2. Guzman MG, Rosario D, Kouri G. In: Kalitzky M and Borowski P, eds. Diagnosis of dengue virus infection. Molecular Biology of the flaviviruses. Horizon Bioscience, UK, 2009. 3. Buchy F et al., Laboratory tests for the diagnosis of dengue virus infection. Geneva, TDR/Scientific Working Group, 2006. TDR/SWG/08. 4. Guzman MG, Kouri G. Dengue diagnosis, advances and challenges. International Journal of Infectious Diseases, 2004, 8:69–80. 5. Burke DS, Monath TP. Flaviviruses. In: Knipe DM, Howley PM eds. Fields virology. London-New York-Tokyo, Lippincott Williams & Wilkins, 2001:1043 –1125. 6. Lindenbach BD, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Knipe DM, Howley PM eds. Fields virology. London-New York-Tokyo, Lippincott Williams & Wilkins, 2001: 991–1042. 7. Chambers TJ et al., Flavivirus genome organization, expression, and replication. Annual Review of Microbiology, 1990, 44: 649–688. 8. Vaughn DW et al., Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. The Journal of Infectious Diseases, 2000, 181:2–9. 9. Dengue and dengue hemorrhagic fever in the Americas: Guidelines for prevention and control. Washington DC, Pan American Health Organization, 1994: 548. 10. Vazquez S et al., Kinetics of antibodies in sera, saliva, and urine samples from adult patients with primary or secondary dengue 3 virus infections. International Journal of Infectious Diseases, 2007, 11:256–262. 11. Kumaria R, Chakravarti A. Molecular detection and serotypic characterization of dengue viruses by single- tube multiplex transcriptase-polymerase chain reaction. Diagnostic Microbiology and Infectious Disease, 2005, 52:311–316. 12. Rosario D et al., Rapid detection and typing of Dengue viruses from clinical samples using Reverse Transcriptase- Polymerase Chain Reaction. Pan American Journal of Public Health, 1998, 4:1–5. 13. Chien LJ et al., Development of real-Time reverse Transcriptase PCR assays to detect and serotype dengue viruses. Journal of Clinical Microbiology, 2006, 44:1295–1304. 14. Libraty DH et al., High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. Journal of Infectious Diseases, 2002, 186:1165–8. 15. Libraty DH et al., Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. Journal of Infectious Diseases, 2002, 185:1213–21. 16. Wang WK et al., High levels of plasma dengue viral load during defervescence in patients with dengue hemorrhagic fever: implications for pathogenesis. Virology, 2003, 305(2):330–8. 17. Dussart P et al., Evaluation of two new commercial tests for the diagnosis of acute dengue virus infection using NS1 antigen detection in human serum. PLoS Neglected Tropical Diseases, 2008, 2:e280. 18. Hang VT et al., Diagnostic accuracy of NS1 ELISA and lateral flow rapid tests for dengue sensitivity, specificity and relationship to viraemia and antibody responses. PLoS Neglected Tropical Diseases, 2009, 3:e360. 19. Kumarasamy V et al., Evaluation of a commercial dengue NS1 antigen-capture ELISA for laboratory diagnosis of acute dengue virus infection. Journal of Virological Methods, 2007, 140(1-2):75–79. 20. Blacksell SD et al., The comparative accuracy of 8 commercial rapid immunochromatographic assays for the diagnosis of acute dengue virus infection. Clinical Infectious Diseases, 2006, 42:1127–1134. 21. Hunsperger EA et al., Evaluation of commercially available anti-dengue virus immunoglobulin M tests. Emerging Infectious Diseases, 2009, 15:436–440. 20 22. Vazquez S et al., Serological markers during dengue 3 primary and secondary infections. Journal of Clinical Virology, 2005; 33:132–137. 23. Alvarez M et al., Dengue hemorrhagic fever caused by sequential dengue 1-3 virus infections over a long time interval: Havana Epidemic, 2001-2002. American Journal of Tropical Medicine and Hygiene. 2006, 75:1113–1117. 24. Vazquez S et al., Detection de IgM contra el virus del dengue en sangre entera absorbida en papel de filtro. Rev Panam Salud Publica [Pan American Journal of Public Health], 1998, 3:174–178. 25. Prado I et al., PCR detection of dengue virus using dried whole blood spotted on filter paper. Journal of Virological Methods, 2005, 125:75–81. 26. Guzman MG et al., Fatal dengue hemorrhagic fever in Cuba 1997. International Journal of Infectious Diseases, 1999, 3:130–135. 27. Rosen L et al., Detection of dengue virus RNA by reverse transcription-polymerase chain reaction in the liver and lymphoid organs but not in the brain in fatal human infection. American Journal of Tropical Medicine and Hygiene, 1999, 61(5):720–724. 28. Hall WC et al., Demonstration of yellow fever and dengue antigens in formalin-fixed paraffin-embedded human liver by immunohistochemical analysis. American Journal of Tropical Medicine and Hygiene, 1991, 45:408–417. 29. Limonta D et al., Apoptosis in tissues from fatal dengue shock syndrome. Journal of Clinical Virology, 2007, 40:50–54. 30. Vorndam V, Kuno G. Laboratory diagnosis of dengue virus infections. In: Gubler DJ, Kuno G, eds. Dengue and dengue hemorrhagic fever. New York, NY, CAB International, 1997: 313–333. 21 2. Recommendations for clinical management 2.1 A stepwise approach to the management of dengue Health-care workers at the first levels of care should apply a stepwise approach as suggested in Table 6. Table 6. A stepwise approach to the management of dengue Step I − Overall assessment I.1 History, including symptoms, past medical and family history I.2 Physical examination, including full physical and mental assessment I.3 Investigation, including routine laboratory tests and dengue-specific laboratory tests Step II − Diagnosis, assessment of disease phase and severity Step III − Management III.1 Disease notification III.2 Management decisions. Depending on the clinical manifestations and other circumstances, patients may (1): - be sent home (Group A) - be referred for in-hospital management (Group B) - require emergency treatment and urgent referral (Group C) 2.1.1 Step I – Overall assessment The history should include: date of onset of fever/illness; quantity of oral fluid intake; diarrhoea; urine output (frequency, volume and time of last voiding); assessment of warning signs (Textbox C); change in mental state/seizure/dizziness; other important relevant history, such as family or neighbourhood dengue, travel to dengue-endemic areas, co-existing conditions (e.g. infancy, pregnancy, obesity, diabetes mellitus, hypertension), jungle trekking and swimming in waterfalls (consider leptospirosis, typhus, malaria), recent unprotected sex or drug abuse (consider acute HIV-seroconversion illness). The physical examination should include: -assessment of mental state; -assessment of hydration status; ~assessment of haemodynamic status (Textbox D); ~checking for quiet tachypnoea/acidotic breathing/pleural effusion; >checking for abdominal tenderness/hepatomegaly/ascites; examination for rash and bleeding manifestations; -tourniquet test (repeat if previously negative or if there is no bleeding manifestation). 22 The investigation (refer also to Section 1.3) If facilities are available, a full blood count should be done at the first visit (it may be normal); and this should be repeated daily until the critical phase is over. The haematocrit in the early febrile phase could be used as the patient’s own baseline. Decreasing white blood cell and platelet counts make the diagnosis of dengue very likely. Leukopenia usually precedes the onset of the critical phase and has been associated with severe disease. A rapid decrease in platelet count, concomitant with a rising haematocrit compared to the baseline, is suggestive of progress to the plasma leakage/critical phase of the disease. These changes are usually preceded by leukopenia (≤ 5000 cells/mm3). In the absence of the patient’s baseline, age-specific population haematocrit levels could be used as a surrogate during the critical phase. If facilities for a full blood count are not available or if resources are limited, such as in outbreak settings, a full blood count or microhaematocrit should be done at the first visit to establish the baseline. This should be repeated after the 3rd day of illness and in those with warning signs and risk factors for severe disease. Dengue-specific laboratory tests should be performed to confirm the diagnosis. However, it is not necessary for the acute management of patients, except in cases with unusual manifestations. Additional tests should be considered in patients with co-morbidities and severe disease as indicated. These may include tests of liver function, glucose, serum electrolytes, urea and creatinine, bicarbonate or lactate, cardiac enzymes, electrocardiogram (ECG) and urine- specific gravity. 2.1.2 Step II – Diagnosis, assessment of disease phase and severity On the basis of evaluations of the history, physical examination and/or full blood count and haematocrit, clinicians should determine whether the disease is dengue, which phase it is in (febrile, critical or recovery), whether there are warning signs, the hydration and haemodynamic state of the patient, and whether the patient requires admission (Textboxes E and F). 2.1.3 Step III – Disease notification and management decision (Groups A–C) Disease notification In dengue-endemic countries, cases of suspected, probable and confirmed dengue should be notified early so that appropriate public-health measures can be initiated. Laboratory confirmation is not necessary before notification, but it should be obtained. In non-endemic countries, usually only confirmed cases will be notified. Management decisions Depending on the clinical manifestations and other circumstances, patients may either be sent home (Group A); be referred for in-hospital management (Group B); or require emergency treatment and urgent referral (Group C). Figure 4 shows a summary of management decisions. 23 Fig. 4 Dengue case management algorithm (2) Dengue Case Management Presumptive Diagnosis: Live in / travel to endemic area plus Fever and two of the following: Assessment Anorexia and nausea Rash Aches and pains Warning signs Leucopenia Warning signs: Tourniquet test positive Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleed Lab.confirmed dengue Lethargy; restlessness (important when no sign Liver enlargement >2cm Laboratory: Increase in HCT concurrent with rapid of plasma leakage) decrease of platelet count negative positive Classification Co-existing conditions positive Social circumstances negative * * * Dengue without Dengue with warning signs warning signs Severe Dengue Group A Group B Group C May be sent home Referred for in-hospital care Require emergency treatment Group criteria Group criteria OR Group criteria Patients who do not have warning signs Patients with any of the following Existing warning signs: Patients with any of the following features. AND features: o A b d o minal pain or tenderness o S e v ere plasma leakage with shock and/or fluid accumulation with who are able: o C o-existing conditions such o P ersistent vomiting respiratory distress o T o tolerate adequate volumes of oral as pregnancy, infancy, old o C l i nical fluid accumulation o S e v ere bleeding fluids age, diabetes mellitus o M u c o sal bleeding o S e v ere organ impairment o T o pass urine at least once every 6 o S o cial circumstances such as o L ethargy/ restlessness hours living alone, living far from o L i ver enlargement >2cm hospital o L a b oratory: increase in Hct Laboratory tests Laboratory tests Laboratory tests o Full blood Count (FBC) o Full blood Count (FBC) o Full blood Count (FBC) o O t h er organ function tests as o H a e matocrit (Hct ) o H a e matocrit (Hct) o H a e matocrit (Hct) indicated Treatment Treatment Treatment Treatment of compensated shock: Advice for: o E n c ouragement for oral o O btain reference Hct before fluid therapy o Start I.V. fluid resuscitation with isotonic crystalloid solutions at 5-10 o A d e quate bed rest fluids o G i v e isotonic solutions such as 0,9% ml/kg/hr over 1 hr o A d e quate fluid intake o I f not tolerated, start saline, Ringer lactate, start with 5-7 o R eassess patient’s condition, o P a r a c etamol, 4 gram max. per day in intravenous fluid therapy ml/kg/hr for 1-2 hours, then reduce to 3- If patient improves: adults and accordingly in children 0,9% saline or Ringer Lactate 5 ml/kg/hr for 2-4 hr, and then reduce to o I. V. fluids should be reduced gradually to 5-7 ml/kg/hr for 1-2 hr, then to 3- Management at maintenance rate 2-3 ml/kg/hr or less according to clinical 5 ml/kg/hr for 2-4 hr, then to 2-3 ml/kg/hr for 2-4 hr and then reduced Patients with stable Hct can be sent home * response further depending on haemodynamic status Hot is the basis Reassess clinical status and repeat Hct o I f Hct remains the same or rises only o I. V. fluids can be maintained for up to 24 - 48 hours If patient still unstable: minimally -> continue with 2-3 ml/kg/hr o C h eck Hct after first bolus for another 2-4 hours o If Hct increases/ still high (>50%), repeat a second bolus of crystalloid o I f worsening of vital signs and rapidly solution at 10-20 ml/kg/hr for 1 hr. rising Hct -> increase rate to 5-10 o I f improvement after second bolus, reduce rate to 7-10 ml/kg/hr for 1-2 hr, ml/kg/hr for 1-2 hours continue to reduce as above. Reassess clinical status, repeat Hct and o If Hct decreases, this indicates bleeding and need to cross-match and review fluid infusion rates accordingly transfuse blood as soon as possible o R e duce intravenous fluids gradually Treatment of hypotensive shock when the rate of plasma leakage o I nitiate I.V. fluid resuscitation with crystalloid or colloid solution at 20 decreases towards the end of the critical ml/kg as a bolus for 15 min phase. If patient im p r o v e s This is indicated by: o G i v e a crystalloid / colloid solution of 10 ml/kg/hr for 1 hr, then reduce

Handbook For Clinical Management Of Dengue PDF (World Health Organization, 2012)

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