Demam Dengue & Demam Berdarah Dengue

Hardjono Soeparto

Pendahuluan

Dengue :infeksi disebabkan virus,ditularkan oleh nyamuk Aedes Aegyptie. Infeksi menimbulkan sakit seperti flu, kadang2 berpotensi komplikasi fatal pada dengue berat.Incidence dengue secara global meningkat dramatis pada dekade sekarang..Kurang lebih setengah penduduk dunia berisiko terserang penyakit ini.Dengue diketemukan diseluruh dunia yang beriklim tropis dan subtropis, terbanyak di daerah urban dan semi-urban..

Dengue berat sebagai penyebab utama penyakit yang serius dan kematian diantara anak2 dibeberapa negara Asia dan Amerika Latin.Tidak ada terapi yang spesifik untuk dengue /dengue berat, tapi deteksi dini dan pelayanan medis yang tepat dan cepatakan menurunkan fatality rates dibawah 1%. (WHO, 2012).Pencegahan dan pengendalian dengue hanya tergantung pada usaha2 pengendalian vektor yang efektif.

Epidemiologi

Dengue saat ini merupakan penyakit virus yang ditularkan oleh arthropoda yang paling penting.Virus dengue mempunyai 4 serotipe yang saling berhubungan, tapi berbeda antigenisitasnya yaitu DENV-1, DENV- 2, DENV-3 and DENV-4,dari famili Flaviviridae , ditransmisikan ke manusia oleh nyamuk Aedes aegypti.

Infeksi Dengue dapat -asimptomatik atau-menyebabkan suatu spektrum penyakit, yangberlangsung dari yang ringan sampai berat yangberpotensi fatal. Endemis pada pada beberapa wilayah didunia,terutama Asia Tenggara, Pasifik Barat dan Amerika, dengan kurng lebih 2.5 billion orang berisiko terkena dengue.

Epidemi dengue, tercatat pertama kali tahun 1950 di negara2 Asia Tenggara, dan epidemi terjadi tiap 3 sampai 5 tahun, kemudian menyebar ke India, Sri Lanka, Maldives dan China pada tahun 1980 an, dansebagai penyebab utama masuk rumah sakit dan kematian diantara anak2 di Asia.

Patofisiologi dan Patogenesis

PatofisiologiMekanismeBila seekor nyamuk pembawa virus dengue menggigit seseorang, virus masuk kulit bersama saliva nyamuk.Virus terikat dan masuk sel darah putih dan diberkembang biak dalam sel kemudian beredar keseluruh tubuh.

Sel darah putih menanggapi dengan produksi sejumlah protein sinyal, seperti interferon, yang bertanggung jawab atas timbulnya banyak simptom,seperti demam,simptom seperti flu dan nyeri yang sangat.

Pada infeksi yang berat, produksi virus dalam tubuhsangat meningkat dan lebih banyak organ (seperti hati dan sumsum tulang) dapat terkena, dan cairan dari aliran darah bocor melalui dinding pembuluh darah kecil ke rongga tubuh.

Sebagai hasilnya, darah yang beredar dalam pembuluh darah kurang, dan tekanan darah menjadi begitu rendah sehingga tidak dapat memasok cukup darah pada organ2 vital.Lebih lanjut, disfungsi sumsum tulang akan mengurangi banyaknya trombosit, yang berguna untuk penjendalan darah yang efektif ; ini meningkatkan risiko perdarahan.

Reproduksi VirusSekali berada dalam kulit, virus dengue terikat pada sel2 Langerhans (suatu populasi dari sel2 dendritic dalam kulit yang mengidentifikasi patogens)..Virus masuk kedalam sel2 melalui ikatan antara protein virus danProtein membran pada sel Langerhans, lebih spesifik -C-type lectins disebut DC-SIGN, -mannose receptor dan -CLEC5A. DC-SIGN, suatu reseptor non-spesifik untuk material asing pada sel dendritic, Rupanya menjadi titik utama untuk masuk. Sel2 dendritic berpindah ke kelenjar limfe yang lebih dekat.

Sementara itu genome dari virus melakukan replikasi pada vesikel yang terikat membran pada endoplasmic reticulum dari sel, dimana aparatus untuk sintesis protein dari sel memproduksi protein viral yang baru, dan RNA dari virus yang di copy.Partikel virus Imatur ditransport ke Golgi apparatus, bagian sel dimana beberapa protein menerima rantai gula yang perlu (glycoproteins).

Virus baru yang matur bersemi pada permukaansel yang mengalami infeksi ,yang dilepaskan secara exocytosis. Mereka kemudian dapat masuk sel darah putih yang lain, seperti monocytes dan macrophages.

Reaksi awal dari sel yang terinfeksi adalah memproduksi interferon, suatu cytokine yang dapat memunculkan sejumlah pertahanan terhadap infeksi virus melalui innate immune system dengan memperbesar produksi sejumlah besar grup protein yang dmediasi oleh JAK-STAT pathway. Beberapa serotipe dari virus dengue virus tampak mempunyai mekanisme memperlambat proses ini.

Interferon juga mengaktifkan adaptive immune system, yang menunjukkan pada generasi dari antibodi terhadap virus juga T cells yang langsung menyerang setiap sel yang terinfeksi virus.Berbagai macam antibodi dibangkitkan ; beberapa berikatan dekat dengan protein virus dan target mereka untuk phagocytosis (dimakan oleh specialized cells dan dirusak), tetapi beberapa terikat pada virus kurang baik dan tampil mengantarkan virus ke bagian dari fagosit tapi tidak dirusak tapi mampu untuk replikasi lebih lanjut.

Penyakit berat Tidak jelas , mengapa infeksi sekunder dengan strain yang berbeda dari virus dengue menempatkan seseorang berisiko menderita DBD dan DSS.Hipotesis yang paling banyak diterima adalah dari antibody-dependent enhancement (ADE)

Mekanisme yang pasti dibelakang ADE adalah tidak jelas.Mungkin disebabkan oleh ikatan yang kurang dari non-neutralizing antibodies dan diantarkan ke compartment yang salah dari sel darah putih yang memakan virus untuk dihancurkan.

Kecurigaan bahwa ADE bukan satu2nyamekanisme yang melatar belakangi komplikasi yang berhubungan dengan dengue yang berat, dan berbagai jalur penelitian mengimplikasikan suatu peranan untuk T cells dan soluble factors seperti cytokines dan complement system.

Penyakit berat ditandai oleh dua masalah :-disfungsi dari endothelium dan -gangguan pembekuan darah Disfungsi endothelial menunjukkan kebocoran cairan dari pembuluh darah ke rongga dada dan perut, sedangkan gangguan koagulasi bertanggung jawab untuk timbulnya komplikasi perdarahan..

Patogenesis Patogenesis belum diketahui pastiHipotesis: “The secondary heterologous infection / the sequential infection” : DBD setelah terinfeksi virus dengue ke 2 serotipe lain dalam jarak waktu 6 bulan – 5 tahun (IDAI, 2010).

“The Immunological Enhancement Hypothesis”: Antibodi(IgG)hambat replikasi virus dalam monosit: *enhancing - antibody *neutralizing- antibody -AB monoklonal reaktif non-neutralisasi : neutralisasi (-); memicu replikasi virus (+).-Kelompok AB neutralisasi: neutralisasi (+); replikasi (-).

AB non-neutralisasi(pada infeksi primer) kompleks imun (pada infeksi sekunder)memacu replikasi virus.Infeksi sekunder virus dengue, serotipe bedamanifestasi berat: ↑ reaksi imunologis(“the immunological enhancement hypothesis”)

“The immunological enhancement hypothesis”:(a) Sel fagosit mononuklear(monosit, makrofag, histiosit,sel Kupffer):tempat infeksi virus Dengue primer.(b) Sebagai reseptor spesifik:non neutralizing AB melekatnya virus dengue mekanisme aferen.(c) Virus denguereplikasi dalam sel fagosit mononuklear yang telah terinfeksi.

(d) Sel monosit telah mengandung kompleks imun usus, hati,limpa, sumsum tulang mekanisme eferen (DBD -/+ rejatan jumlah sel yang terkena infeksi).(e) Sel monosit teraktifasi + sistim humoral+ sis komplemen dilepaskan mediator permeabilitas kapiler& aktivasi sistim koagulasi: mekanisme efektor

Pada manusia, awal perjalanan dari infeksi dengue sekunder, level dari viremia langsung memprediksikan severitas penyakit.Pada tahap akut dini dari infeksi dengue sekunder, terjadi*Aktivasi sangat cepat dari sistim complement*Dekat sebelum atau selama shock, -level darah dari soluble tumor necrosis factor receptor, interferon-γ, and interleukin 2 meningkat. -C1q, C3, C4, C5–C8, dan C3 proactivators tertekan, -C3 catabolic rates meningkat. .

Faktor2 ini dapat berinteraksi pada sel endotelial untuk memproduksi peningkatan permeabilitas vaskuler melalui nitric oxide final pathway. Darah menjendal dan sistim fibrinolytic systems diaktivasi,Levels dari factor XII (Hageman factor) mengalami depresi. Mekanisme dari perdarahan pada demam berdarah dengue tidak diketahui, tapi suatu tingkat ringan dari disseminatedintravascular coagulation, kerusakan hati, danthrombocytopenia dapat bekerja secara sinergis.

Kerusakan kapiler memungkinkan kebocoran ke ruangan ekstravaskuler dari -cairan, -elektrolit, -protein2 kecil, dan, pada beberapa keadaan -sel2darah merah . Redistribusi internal dari cairan, bersama dengan defisit disebabkan oleh puasa, haus, dan muntah menghasilkan- hemokonsentrasi, hipovolemia, meningkatkan kerja - jantung, hipoksia jaringan, asidosis metabolik, dan - hyponatremia

Spektrum DBD

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 days) while viral replication takes place in target dendritic cells.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells,

result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• Dengue viral infections frequently are not apparent. In most cases, especially in children younger than 15 years, the patient is asymptomatic or has a mild undifferentiated febrile illness lasting 5-7 days.

• Classic dengue fever primarily occurs in nonimmune, nonindigenous adults and children and is typically self-limiting. Recovery is usually complete by 7-10 days.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Dengue hemorrhagic fever and dengue shock syndrome usually occur around the third to seventh day of illness during a second dengue infection in persons with preexisting actively or passively (maternally) acquired immunity to a heterologous dengue virus serotype

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• Dengue fever• Dengue presents in a nonspecific manner

similarly to that of many other viral and bacterial illnesses. Fever typically begins on the third day of illness and persists 5-7 days, abating with the cessation of viremia.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Fever may reach 41C°. Occasionally, and more frequently in children, the fever abates for a day and recurs, a pattern that is termed a saddleback fever; however, this pattern is more commonly seen in dengue hemorrhagic fever.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Leukopenia, lymphopenia near the end of the febrile phase, and thrombocytopenia are common findings in dengue fever and are believed to be caused by direct destructive actions of the virus on bone marrow precursor cells. The resulting active viral replication and cellular destruction in the bone marrow are believed to cause the bone pain.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Approximately one third of patients with dengue fever may have mild hemorrhagic symptoms, including petechiae, gingival bleeding, and a positive tourniquet test (>20 petechiae in an area of 2.5 X 2.5 cm). Dengue fever is rarely fatal

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• Dengue hemorrhagic fever• Dengue hemorrhagic fever occurs less frequently

than dengue fever but has a more dramatic clinical presentation. In most of Asia, where it first was described, dengue hemorrhagic fever is primarily a disease of children. However, in the Americas, and more recently reported in Taiwan, dengue hemorrhagic fever has an equal distribution in all ages.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Dengue hemorrhagic fever typically begins with the initial manifestations of dengue fever. The acute febrile illness (temperatures ≤40°C), like that of dengue fever, lasts approximately 2-7 days. However, in persons with dengue hemorrhagic fever, the fever reappears, giving a biphasic or saddleback fever curve.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• Along with biphasic fever, patients with dengue hemorrhagic fever have progressive thrombocytopenia, increasing hematocrit (20% absolute rise from baseline) and low albumin (signs of hemoconcentration preceding shock), more obvious hemorrhagic manifestations (>50% of patients have a positive tourniquet test), and progressive effusions (pleural or peritoneal).

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Lymphocytosis, often with atypical lymphocytes, commonly develops before defervescence or the onset of shock. Transaminase levels may be mildly elevated or present in the several thousands associated with hepatomegaly in those patients with acute hepatitis. Low fibrinogen and elevated fibrin split products are signs of disseminated intravascular coagulation. Severe metabolic acidosis and circulatory failure can occur.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• The critical feature of dengue hemorrhagic fever is plasma leakage. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• Liver damage manifests as increases in levels of alanine aminotransferase and aspartate aminotransferase, low albumin levels, and deranged coagulation parameters (prothrombin time, partial thromboplastin time).

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–alpha, interleukin [IL]–2). This is similar to that seen with fatal yellow fever and Ebola infections.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• As the term implies, dengue shock syndrome is essentially dengue hemorrhagic fever with progression into circulatory failure, with ensuing hypotension, narrow pulse pressure (< 20 mm Hg), and, ultimately, shock and death if left untreated. Death may occur 8-24 hours after onset of signs of circulatory failure. The most common clinical findings in impending shock include hypothermia, abdominal pain, vomiting, and restlessness

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

• Secondary infection• The immunopathology of dengue hemorrhagic

fever/dengue shock syndrome remains incompletely understood. Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior infection with one or more dengue serotypes.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

When an individual is infected with another serotype (ie, secondary infection) and produces low levels of nonneutralizing antibodies, these antibodies, directed against 1 of 2 surface proteins (precursor membrane protein and envelope protein), when bound by, have beemacrophage and monocyte Fc receptorsn proposed to fail to neutralize virus and instead form an antigen-antibody complex.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

This results in increased viral entry into macrophages bearing IgG receptors, allowing unchecked viral replication with higher viral titers and increased cytokine production and complement activation, a phenomenon called antibody-dependent enhancement.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

The affected macrophages release vasoactive mediators that increase vascular permeability, leading to vascular leakage, hypovolemia, and shock. This mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis. Infants born to mothers who have had dengue, as maternally derived dengue neutralizing IgGs wane, are also thought to be at risk for enhanced disease.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Some researchers suggest that T-cell immunopathology may play a role, with increased T-cell activation and apoptosis. Increased concentrations of interferon have been recorded 1-2 days following fever onset during symptomatic secondary dengue infections.[26] The activation of cytokines, including TNF-alpha, TNF receptors, soluble CD8, and soluble IL-2 receptors, has been correlated with disease severity.

Suzanne Moore Shepherd,(2013), Dengue Medscape Updated: Jul 18, 2013

Cuban studies have shown that stored serum sample analysis demonstrated progressive loss of cross-reactive neutralizing antibodies to DENV-2 as the interval since DENV-1 infection increased.

In addition, certain dengue strains, particularly those of DENV-2, have been proposed to be more virulent, in part because more epidemics of dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes.

Klasifikasi

Klasifikasi WHO 2009 membagi Demam Dengue dalam 2 grup:

1.Tanpa komplikasi2.BeratKlasifikasi WHO 1997 , membagi Dengue :1.Demam yang tak dapat dideferensiasi,2.Demam Dengue, dan 3.Demam Berdarah Dengue.

Demam Berdarah Dengue dibagi grade I – IV. Grade I : demam, mudah memar atau test tourniquet positive Grade II : perdarahan spontan di kulit dan dimana saja Grade III : bukti klinis dari shock, Grade IV : shock berat, tekanan darah dan nadi tak dapat dideteksi. Grades III and IV disebut sebagai “sindrom shock dengue”

WHO ( 1975 ) membagi 4 derajat penyakit DBD:*1.Demam + gejala tak khas, satu2-nya manifestasi perdarahan: uji tourniquet positif*2.Derajat 1 +perdarahan spontan di kulit dan/ atau perdarahan lain.*3.Tanda kegagalan sirkulasi: N cepat & lembut tekanan nadi ↓ ≤ 20 mmHg, hipotensi + kulit dingin,lembab, gelisah.*4.Syok berat, N tak teraba, Tek. darah tak terukur.

Jayaratne S D, Atukorale V, Gomes L,ChangT, Wijesinghe T, Fernando S, Ogg G S , Malavige G N, (2012)

There was much criticism regarding the WHO 1997 dengue classification guidelines, in particular that it underestimated many patients who developed shock and severe dengue. In addition, many pointed out the need to standardize the dengue diagnostic criteria in order to implement better patient management guidelines. Therefore, following the observations of a large multi-centre study, which was conducted in South East Asia and Latin America, the WHO revised their guidelines in 2009.

Jayaratne S D, Atukorale V, Gomes L,ChangT, Wijesinghe T, Fernando S, Ogg G S , Malavige G N, (2012)

Accordingly the WHO changed their clinical classification of acute dengue as probable dengue, dengue with warning signs and severe dengue, which were thought to be more simple and easier to understand. Furthermore, the revised guidelines have been shown to be more sensitive and specific in detecting patients with severe dengue than the traditional guidelines. The warning signs were devised in order to help health care professionals to decide who needs hospital admission and more intensive monitoring during epidemics of dengue infection, without the need for extensive laboratory investigations.

Penampilan klinis Infeksi Virus Dengue

Penampilan klinis Infeksi Virus Dengue dapat sebagai -Asymptomatic,-Undifferentiated Fever, -Dengue Fever atau Dengue Hemorrhagic Fever yang disertai dengan plasma leakage (kebocoran plasma) dengan akibat dapat timbul shock (Dengue Shock Syndrome).

Atau dapat dibuat diagram sbb :AsymptomaticSymptomatic Undifferentiated Fever Dengue Fever

Tanpa PerdarahanDengan Perdarahan

Dengue Hemorrhagic FeverTanpa shockDengan shock :Dengue Shock Syndrome

Bagaimana mengenali Dengue Fever / Dengue Hemorrhagic Fever Dengue FeverAdalah penyakit akut yang ditandai oleh panas 2 – 7 hari, disertai 2atau lebih gejala klinik dibawah. Gejala yang dimaksud adalah :Sakit kepalaNyeri retro orbitalMyalgia / ArthralgiaRuam

Manifestasi perdarahan, tourniquet test dan petechiaeLeukopeniaPada anak, Dengue Fever biasanya tampil klinis ringan, sedang pada orang dewasa dapat disertai nyeri tulang dan pada saat confalescence melalui periode prolong fatique, bahkan kadang disertai depresi.

Demam Berdarah DengueAdalah Infeksi o.k virus dengue, dengan gejala seperti demam dengue yang disertai manifestasi perdarahan yang lebih prominen :*Test Tourniquet positif.*Petechiae, echimosis atau purpura.*Perdarahan mukosa (epistaksis, perdarahan gusi).

*Trombositopenia ( 100.000 / cu mm ).*Plasma leakage / kebocoran plasma yang disebabkan oleh meningkatnya permeabilitas kapiler, dengan ditandai oleh : -Meningkatnya PCV 20 %. -Gangguan sirkulasi -Efusi pleura, ascites.

Patokan diagnosis DBD (WHO,1975) (Klinis/Lab)

Klinis:Demam tinggi mendadak dan terus menerus 2-7 hari1. Manifestasi perdarahan, minimal uji tourniquet positif & salah satu perdarahan yang lain ( petekia,purpura,ekimosis,epistaksis, perdarahan gusi hematemesis dan atau melena.

2. Pembesaran hati3. Syok, ditandai:-nadi lemah & cepat tekanan darah ↓(tek sistolik≤ 80 mmHg), kulit dingin & lembab (ujung hidung, jari kaki tangan, gelisah, sianosis sirkum oral.

Laboratorium*Trombositopenia ( ≤ 100.000/ul ) &*Hemokonsentrasi (HCT ≥ 20% dari sebelum sakit).Diagnosa Klinis DBD:Ditemukan:-2 atau 3 patokan klinis +-Trombositopenia + Hemokonsentrasi

Definisi kasus DHF menurut WHO

Pasien dengan 4 kriteria sbb:• 1. Panas mendadak tinggi, akut selama 2–7 hari.• 2. Manifestasi Hemoragik dengan positif tourniquet test.• 3. Jumlah Trombosit < 100 X 10⁹ /l.• 4. Hemokonsentrasi (peningkatan PCV > 20%) atau adanya bukti kebocoran plasma – sebagai contoh:ascites, effusi pleural, serum protein/ albumin rendah. (Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004):

Grading (Tingkatan) dari DHF

• N Grade I: no shock: only positive tourniquet test.

• N Grade II: no shock; has spontaneous bleeding other than a positive tourniquet test.

• N Grade III: shock.• N Grade IV: profound shock with

unmeasurable blood pressure or/and pulse. (Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

• Dengue Shock Syndrome ( DSS )• Adalah penampilan klinis Dengue

Hemorrhagic Fever yang disertai tanda-tanda kegagalan sirkulasi berupa :

• Penyempitan pulse pressure ( 20 mm Hg ).• Nadi cepat dan kecil.• Hipotensi.• Akral dingin.

Perjalanan Klinis

Simptom karakteristik dari dengue:*onset demam mendadak ,*sakit kepala (tipik lokasi belakang mata),*nyeri otot dan sendi, *rash..

Nama alternative untuk dengue, "break-bone fever“, berasal dari nyeri otot dan sendi.Perjalanan infeksinya dibagi 3 fase -febrile, -critical, dan-recovery

Fase febrile :*Demam tinggi., sering > 40 °C (104 °F), *Disertai nyeri seluruh tubuh dan sakit kepala; berlangsung 2 -7 hari. *Pada tahap ini terjadi rash,pada hari 1 atau 2 sebagai flushed skin, atau akhir perjalanan penyakit (hari 4–7), sebagai measles-like rash.

Beberapa petechiae (bintik merah kecil yang tidak menghilang bila kulit ditekan, disebabkankerusakan kapiler) dapat muncul. Juga terjadi beberapa perdarahan ringan pada mucous membranes mulut dan hidung.Demam itu sendiri biphasic , berhenti dan kemudian kembali dalam satu atau dua hari.

Pada beberapa orang, penyakitnya berjalan menjadi suatu fase kritis, mengikuti resolusi demam tinggi yang berlangsung dalam satu sampai dua hari. Selama fase ini terjadi akumulasi cairan yangbermakna dalam dada dan rongga perut karena kenaikan permeabilitas kapiler dan kebocoran, deplesi cairan dari sirkulasi dan pengurangan pasokan darah pada organ vital .

Selama fase ini, dapat terjadi disfungsi organ danperdarahan hebat, dari traktus gastrointestinal. Shock (dengue shock syndrome) dan perdarahan(dengue hemorrhagic fever) terjadi pada < 5% darisemua kasus dengue,tetapi risikonya meningkat pada mereka yang sebelumnya telah mengalami infeksi dengan serotype virus dengue yang lain("secondary infection").

Fase recovery terjadi kemudian, dengan resorpsi cairan yang bocor ke aliran darah, biasanya berlangsung dalam 2-3 hari. Perbaikan biasanya berlangsung cepat, tapi dapat terjadi gatal2 yang hebat dan kecepatanjantung yang lambat. Selama tahap ini, dapat terjadi overload cairan; dan bila mengenai otak, dapat menyebabkan pengurangan level kesadaran atau kejang2.

Respon antibodi terhadap virus dengue (Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

Antibody dependent enhancement berperan dalam patogenesis dari infeksi dengue yang berat. Selama infeksi sekunder dengue, antibodi sudah ada dalam pasienmembentuk komplek dengan virus dengue.Bagian Fc dari antibodi ini dapat mengikat pada FccRI dan FccRII bearing cells dan menghasilkan kenaikan jumlah sel yang terinfeksi oleh virus dengue.Antibody dependent enhancement ditemukan hanya terjadi pada konsentrasi subneutralising dari antibodi dengue.DEN-1 immune sera pada pengenceran 1:250 (subneutralising titre), tapi tidak pada pengenceran 1:10 , meningkatkan infeksi DEN-2 dari lekosit mononuclear, sebaliknya berakibat pada kenaikan proliferasi limfosit dan penurunan produksi interferon-c (IFN-c).

(Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

After primary dengue infection, antibodies form against bothstructural and non structural viral proteins. Although, the precise role of these different antibodies are not known, antibodies against viral NS1 have been shown to induce endothelial cell apoptosis in a caspase dependent manner.After binding with antigen, different IgG subclasses vary in their capacity to activate the classical complement pathway;IgG1 being very effective whereas IgG2 being less so.

(Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

Higher levels of dengue virus specific IgG1 and IgG4 and lower levels of IgG2 are seen in patients with DHF and dengue shock syndrome compared with those with dengue fever.Since complement activation could contribute to increased vascular permeability and abnormalities in coagulation the predominating dengue specific IgG subclass may be important in the pathogenesis of severe disease.

(Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

There is recent interest in the role of IgE antibodies in disease pathogenesis. Total and dengue specific IgE antibody levels are higher in patients with DHF anddengue shock syndrome compared with those withdengue fever.Moreover, total IgE levels are significantly higher in thosepreviously exposed to dengue infections.During severe dengue infection some studies suggest there are suppressed Th1 responses whereas others report predominant Th2 responses.

(Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

Varying degrees of thrombocytopenia are common in DHF.Some of the mechanisms responsible for this include: IgM type of antiplatelet antibodies, dengue viral specific antibodies, bone marrow hypocellularity (leading to increases in defective megakaryocytes), or destruction of platelets in the liver and spleen. Antiplatelet antibodies cause lysis of platelets in the presence of complement. They are found in higher concentrations in patients withDHF/dengue shock syndrome compared with dengue fever, which probably accounts for the greater degree of thrombocytopenia seenin DHF. The DEN-2 serotype binds to human platelets only in the presence of virus specific antibody, supporting a role for immune mediated clearance of platelets.

(Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

Dengue infections are characterised by an increased of atypical lymphocytes. In addition, an increase innumbers of B-cells and a decrease in numbers of T-cells(most likely due to serum anti-T-cell antibodies) has beenreported in DHF. These changes are most pronounced onthe day of subsistence of fever or development of shock. Anti-Bcell antibodies are also found in patients with DHF. These could potentially modulate humoral immune responses during infection

Cytokine responses in dengue infections

• Dengue virus infected monocytes, B-lymphocytes, and mast cells produce different cytokines. At present there is disagreement about the predominant cytokines produced during dengue fever and DHF.

• According to Chaturvedi et al serum concentrations of tumour necrosis factor-a (TNF-a), interleukin (IL)-2, IL-6, and IFN-c are highest in the first three days of illness whereas IL-10, IL-5, and IL-4 tend to appear later.

• IL-2 and ,IFN-c are Th1 and IL-5 and IL-4 Th2 type cytokines.

• Thus, it has been suggested that Th1 responses are seen during the first 3 days and Th2 responses occur later. Increased levels of IL-13 and IL-18 have also been reported during severe dengue infections, with highest levels seen in patients with grade IV DHF. Serum IL-12 levels are highest in patients with dengue fever, but undetectable in patients with grade III and IV DHF. Levels of transformimg growth factor-b (an inhibitor of Th1 and enhancer of Th2 type cytokines) correlate with severity of disease and show an inverse relationship with IL-12 levels.

• These reports suggest that predominant Th2 responses occur in DHF/dengue shock syndrome, whereas Th1 responses seem to protect against severe infections

DHF patients have higher levels of TNF-a, IL-6, IL-13, IL- 18, and cytotoxic factor compared with DF patients. These cytokines have been implicated in causing increased vascularpermeability and shock during dengue infections.Moreover, cytotoxic factor, produced by CD4+ T-cells, inducesmacrophages to produce the proinflammatory cytokines IL- 1a, TNF-a, and IL-8. Levels of cytotoxic factor correlate with disease severity (being highest in patients with grade IV DHF). In addition, cytotoxic factor autoantibodies protect against severe disease; highest levels being detected in patients with mild disease.

Serum IL-6 concentrations are higher in patients with DHF and dengueshock syndrome. IL-6 is produced mainly by mast cells and endothelialcells. It is an endogenous pyrogen that also increases endothelial cell permeability.Endothelial cells also produced IL-8, having potent proinflammatoryand chemoattractant activity. Levels of IL-8 are higher during severedengue infections and highest in those who died. Activated neutrophils release proteinases such as elastase, which may facilitate neutrophil mediated endothelial injury, and activate thecomplement, coagulation, and fibrinolytic systems. Since increasedserum IL-8 and elastase are found in patients with severe infections, they may have an important role in pathogenesis of dengue infections.

Dengue virus infected lymphocytes produce both IFN-aand IFN-c; levels of the former being higher than the latter.IFN-a inhibits infection of monocytes by the dengue virusand hence is important in controlling primary dengueInfections. Although levels of IFN-a are higher in DHFthan dengue fever, no differences in levels are seen amongthe different grades of DHF. No differences in levels of IFNcare seen between dengue fever or DHF patients. IFN-c isproduced early in the course of infection. Peak levels occur on or before the day of deferverscence and coincide withdisappearance of viraemia.

Dengue virus infected dendritic cells produce high levels ofTNF-a and IFN-a, but low levels of IL-12. Low IL-12 levels inDHF are probably due to failure of its induction by IFN-c.Reports suggest that IFN-c up-regulates Fc gamma

receptorson monocytes and hence augment dengue viral infection.TNF-a prolongs dendritic cell survival by up-regulatingantiapoptotic factors within it. Prolonged survival of denguevirus infected dendritic cells may contribute towardsproducing severe dengue infections.

• Serum concentrations of serum TNF-a, IFN-c, IL-10, and soluble TNF receptor (sTNF-R p75) are significantly higher in patients compared with normal controls. Increased levels of TNF-a and IL-10 correlate with haemorrhagic manifestations and platelet decay respectively. IL-10 may also down-regulate platelet function and thus contribute to platelet defects associated with dengue infections

Cellular immune responses in dengue infections

Recently, there has been greater focus on studyingaspects of cell mediated immune responses in the pathogenesis of DHF.The dengue virus can infect both CD4+ and CD8+ T-cells.Following primary infection, both serotype specific and serotype cross reactive memory T-cells are formed. Serotype cross reactive responses against DEN-2 tend to be stronger than towards other serotypes.

On secondary exposure to the virus, most serotype cross reactive CD4+

and CD8+ T cells augment infection by producing various cytokines.Immunisation studies have been done on healthy volunteers using monovalent vaccines of all four serotypes. After immunisation with one serotype, CD8+ T-cell responses are directed against a variety of viral proteins, with all donors recognising either the NS3 or NS1.2a protein. Since viral NS3 has multiple epitopes, most T-cells show

cross reactivity to these epitopes.

In response to dengue viral antigens, CD4+ T-cells produce IFN-c, TNFa, and TNF-b which may contribute to the pathogenesis of secondary dengue infections.Moreover, CD4+ T-cells from patients with previous primary dengueinfections proliferate and produce IFN-c after stimulation with a dengue antigen. As mentioned earlier, IFN-c augments dengue virus infection of human monocytes by up-regulating Fc gamma receptors on them. Liver injury during dengue infections could also be due to T-cell immune responses as studies suggest that CD4+ T-cell clones arecapable of destroying non-antigen presenting target cells such as Hepatocytes.

Dengue infections are associated with decreased numbersof CD4+ T-cells, CD8+ T-cells, and natural killer cells. Theselevels are lowest on the day of subsidence of fever ordevelopment of shock, and tend to increase thereafter. B-cellnumbers tend not to be affected. Generalised bone marrowsuppression known to occur in dengue infections may alsocontribute to the absolute lymphopenia. Reversal of CD4:CD8 ratios tends to occur around the sixth to 10th day afterthe onset of fever, being seen more frequently in patientswith DHF.

• DHF patients have increased serum concentrations of IFN-c, soluble CD4, and soluble IL-2R during the period of viraemia, followed later by an increase in soluble CD8.

• Levels of IFN-c and sIL-2R decline thereafter. This suggests that activation of T-cells may be important in controlling acute dengue virus infections.

• Studies also suggest that suppression of T-cell responses can occur in dengue fever and DHF. This could persist for at least two weeks after the onset of fever.

In one study, respiratory tract infections or diarrhoeawere seen in 6% of patients after dengue infections. This suppression has been suggested to be due to a primary defect within antigen presenting cells. IL-10,whose levels are increased in DHF, is known to downregulate antigen presenting cell responses and induceunresponsiveness in T-cells. Similar patterns ofsuppression are known to follow many viral infectionssuch as measles and infectious mononucleosis, with itsattendant increased risk of secondary infections.

Risk factors for the development of DHF

• Several risk factors have been proposed for development of DHF. These include: serotype and virulence of the infecting dengue virus, age, sex, immune status, and genetic background of the host.

• Case fatality and hospitalisation rates due to DHF/dengue shock syndrome are highest in infants and the elderly. For instance, following a secondary DEN-2

• Malavige, Fernando, Fernando, et al www.postgradmedj.com infection, the risk of death in children is nearly 15-fold higher than that in an adult.

• DHF is also reported to be more severe among females.

• Generally malnutrition predisposes to many infectious diseases (for example, measles or tuberculosis) and tends to correlate positively with severity of disease. However, malnutrition appears to be significantly uncommon among patients with DHF, compared with patients with other infectious diseases or healthy children.

• DHF tends to be commoner among patients suffering from other chronic illnesses (for example, diabetes mellitus or bronchial asthma).

• The DEN-2 virus is capable of replicating better within peripheral blood mononuclear cells from asthmatics than non-asthmatics.

• Further investigation of these different factors should help us better understand the pathogenesis of DHF and may in turn allow us to identify possible therapeutic options.

Diagnosis

Diagnosis dengue berdasarkan gambaran klinis berdasar simptom yang dilaporkan dan pemeriksaan fisik, diterapkan terutama pada daerah endemis.Bagaimanapun juga penyakit dini dapat sukar untuk dideferensiasi dari infeksi virus yang lain.

Diagnosis kemungkinan berdasar pada penemuan adanya demam dan dua dari sebagai berikut:*Mual dan muntah*Rash, *Nyeri menyeluruh,*Jumlah darah putih rendah, *Test tourniquet positif atau setiap tanda2 peringatan pada seseorang yang tinggal didaerah endemis

Tanda2 peringatan terjadi sebelum onset dari Dengue yang berat.Test tourniquet terutama berguna dalam keadaan dimana investigasi laboratorium tidak tersedia. Dengan menggunakan cuff, dilakukan tekanan darah selama 5 menit diikuti penghitungan setiap petechiae. Jumlah yang tinggi menentukan diagnosis dengue. Sukar membedakan demam dengue dan chikungunya, yang sama2infeksi virus . Seringkali investigasi dilakukan untuk menyingkirkan kondisi yang lain yang memberikan simptom yang serupa seperti padamalaria, leptospirosis, demam typhoid , dan meningococcal disease.

Perubahan yang paling dini yang dapat dideteksipada investigasi laboratorik adalah jumlah seldarah putih yang rendah, yang kemudian dapatdiikuti dengan trombosit yang rendah dan asidosis metabolik.

Pada penyakit yang berat, kebocoran plasma berakibat pada hemokonsentrasi ( seperti ditunjukkan oleh meningkatnya hematokrit) dan hypoalbuminemia, leural effusions atau ascites dapat dideteksi dengan pemeriksaan fisik l, tapi demonstrasi dari cairan pada ultrasound dapat membantu dalam identifikasi dini dengue shock syndrome..

Manifestasi Klinis DHF

General- High fever, intermittent.- Severe headache (especially retro-orbital).- Flushing.- Myalgia and arthralgia.- Vomiting.- Anorexia.- Acute abdominal pain.

- Bleeding manifestations - Epistaxis. - Bleeding from gums. - Petechiae and eccymoses. - Haematemesis and maelena. - Spotting or menorrhagia in females.- Features of plasma leakage- Circulatory disturbances (low blood pressure, tachycardia,narrow pulse pressure, and poor capillary refill time).- Periserositis (pleural effusions, ascites sometimes pericarditis). (Malavige GN, Fernando S, Fernando DJ, Seneviratne SL,2004)

LABORATORY DIAGNOSIS OF DENGUEINFECTIONS

• Methods used for diagnosis of dengue infections include:

• virus isolation, serology, and molecular techniques such as reverse transcriptase-polymerase chain reaction (RT-PCR)

• However, clinicians tend to treat patients suspected of having DHF before the results from these tests are available

Pemeriksaan Laboratorium pada DHF

Haematological investigations- Jumlah Trombosit rendah < 100 x 10⁹ /l.- Leukopenia pada awal penyakit.- Limfositosis atipik ( > 15%).- Profil koagulasi abnormal ( prolonged activated partial thromboplastin time, prothrombin time, peningkatan fibrinogen degradation products).- Reduced serum complement levels.- Biochemical investigations -Low albumin levels. -Electrolyte disturbances. -Elevated liver enzymes. -Acidosis.

Test Laboratorium

Demam Dengue dapat didiagnosis dengan Test Laboratorium Mikrobiologis, dilakukan dengan*Isolasi virus dalam kultur sel, *deteksi asam nukleat dengan PCR, *deteksi antigen virus atau antibodi spesifik (serologi). Isolasi virus dan deteksi asam nukleat lebih akurat dari pada deteksi antigen. Tapi test ini tidak tersedialuas karena beaya yang mahal.

Semua test mungkin negative pada tahap awal penyakit.Test2 laboratorium ini mempunyai nilai diagnostik selama fase akut dari penyakit kecuali serologi.Test2 untuk antibodi yang spesifik virus, tipe IgG dan IgM, dapat berguna untuk konfirmasi diagnosis pada tahap kemudian dari infeksi. Baik IgG dan IgM diproduksi setelah 5–7 hari. .

Level yang tertinggi (titer) dari IgM ideteksimengikuti suatu infeksi primer, tapi IgM juga diproduksi pada infeksi sekunder dan tersier. IgM menjadi tak terdeteksi 30–90 harisetelahinfeksi primer,tapilebih awal mengikuti re-infeksi. .

IgG dapat dideteksi untuk lebih dari 60 tahun dan pada tidak adanya simptom, sebagai indikator yang bergunauntuk infeksi yang telah lalu.Setelah suatu infeksi primer, IgG mencapai level puncakdalam darah setelah 14–21 hari. Pada re-infeksi subsequent, levels puncak lebih awal

dan titernya lebih tinggi.

Baik kedua IgG dan IgM memberikan imunitas protektive pada serotipe infeksi dari virus. Pada test laboratorium IgG dan antibodi IgM reaksi silang dengan flaviviruses lain, seperti pada virus yellow fever ,yang membuat interpretasi dari serologi sukar.

Deteksi hanya dari IgG saja adalah tidak dipertimbangkan sebagai diagnosis kecuali sampel darah dikoleksi 14 hari tersendiri dan sebesar 4kalilipat kenaikan dalam level dari dari IgG spesifik dideteksi pada seseorang dengan simptom, deteksi dari IgM dipertimbangkan sebagai diagnosis.

IgG dapat dideteksi untuk lebih dari 60 tahun dan pada tidak adanya simptom, sebagai indikator yang berguna untuk infeksi yang telah lalu.Setelah suatu infeksi primer, IgG mencapai level puncak dalam darah setelah 14–21 hari. Pada re-infeksi subsequent, levels puncak lebih awal

dan titernya lebih tinggi

Diagnosis Banding/ DD

Hari2 pertama demam, DBD sulit dibedakan dengan-Morbili-ITP yang disertai demamDemam hari ke 3-4:*perdarahan + hepatomegali Diagnosis DBD*Syok pada DBD, DD dengan Sepsis Ensefalopati Dengue DD Ensefalitis virus lain.

Differensial Diagnosis

Demam Dengue ( Dengue fever )• Infectious mononucleosis.• Chickengunya viral infections.• Coxsackie and other enteroviral infections.• Rickettsial infections.• Rubella.• Parvovirus B19 infections.• Leptospirosis.• Influenza (Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

Demam Berdarah Dengue (DHF)• Leptospirosis.• Chikengunya viral infections.• Kawasaki disease.• Yellow fever.• Hanta viral infections.• Other viral haemorrhagic fevers.• Meningococcal septicaemia (Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004)

Tatalaksana

Bersifat suportif atasi kehilangan cairan plasma o.k -↑ permeabilitas kapiler - perdarahan

Pasien Demam Dengue ambulatoir DBD ruang perawatan biasa DBD + komplikasi ICU

a. Demam Dengue : * fase demam-tirah baring, antipiretik, kompres hangat. -cairan & elektrolit peroral *monitor suhu, jumlah trombosit & HCT.

Laboratory diagnosis of dengueinfections

Virus isolation• Mosquito cell lines.• Mosquito inoculation technique.• Vertebral cell culture.Serological diagnosis Haemagglutination inhibition test. ELISA. Complement fixation test. Neutralisation test. Antigen capture enzyme immunosorbent assay. Molecular diagnostic methods RT-PCR.

Management of dengue infections

Dengue feverTemperature control Paracetamol (60 mg/kg/day), tepid spongingLight dietMonitor For progression to DHF by monitoring platelet count and packed cell volumeGrade I and II DHFIntravenous fluids Hartmann’s solution, 5% dextrose in normal salineElectrolytes Monitor electrolytes in those with altered level of consciousnessTemperature control Paracetamol (60 mg/kg/day), tepid spongingMonitor Vital signs, urine output, and level of consciousness, packed cell volume, and platelet counts, liver enzymesObserve Haemorrhagic manifestations: petechiae, signs of gastrointestinal tract bleedingStop fluids When patient recovers from the leakage phase

Grade III and IV DHF and dengue shock syndromeIntravenous fluids Crystalloids (Hartmann’s solution, 5% dextrose in normal saline) and colloids (dextran 40, fresh frozen plasma, or gelafundin) several intravenous boluses may be neededMonitor Vital signs, urine output, and level of consciousness, packed cell volume, and platelet counts every 10–15 minutes Give oxygen If significant bleeding occurs give platelets (depends on the amount of bleeding) Correct electrolyte and metabolic abnormalities

Tanda2 peringatan saat demam / suhu mulai ↓*Nyeri perut sangat*BAB hitam*muntah2*pembesaran hati*Perdarahan kulit & mucosa*hematocrit tinggi dengan trombosit rendah*lethargy

Demam Berdarah Dengue (DBD):Perbedaan patofisiologik Demam Dengue / DBD/DSS : ada /tidaknya kebocoran plasma(plasma leakage)*penggantian volume plasma yang hilang (cairan rumatan + 5- 8%)

Komplikasi

• Encephalopathy and encephalitis.• Liver failure.• Myocarditis.• Disseminated intravascular coagulation leading to massive bleeding (Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, 2004).

Kepustakaan

Chaturvedi U C, Agarwal R, Elbishbishi E A, Mustafa A S, (2000): Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis; MiniReview; FEMS Immunology and Medical Microbiology 28 (2000) 183-188 IDAI, (2010):Infeksi Virus Dengue; dalam Buku Ajar Infeksi & Pediatri Tropis eds Soedarmo S S et al.,ed 2;15:155-81.Jayaratne S D, Atukorale V , Gomes L,ChangT, Wijesinghe T, Fernando S, Ogg G S and Malavige G N,(2012): Evaluation of the WHO revised criteria for classification of clinical disease severity in acute adult dengue infection; BMC Res Notes. 2012; 5: 645.Malavige GN, Fernando S, Fernando DJ, Seneviratne SL, (2004): Dengue viral infections Postgrad Med J 2004;80:588–601. doi: 10.1136/pgmj.2004.019638Scott B. Halstead S B,(2007): Dengue Fever and Dengue Hemorrhagic Fever ; in Kliegman:Nelson Textbook of Pediatrics, 18th ed. Chapter 266 – Suzanne Moore Shepherd,(2013): Dengue in Medscape Updated: Jul 8, 2013WHO ,(2012): Dengue and severe dengue, Media Centre, Fact sheet N°117.January 2012.