Dengue fever: A personal perspective

Dengue fever: A personal perspective

ANTIMICROBICS AND INFECTIOUS DISEASES NEWSLETTER Editor-in-Chief Charles W. Stratton, MD Vanderbilt University School of Medicine Nashville, Tennesse...

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Editor-in-Chief Charles W. Stratton, MD Vanderbilt University School of Medicine Nashville, Tennessee Full editorial board appears on back cover

Volume 17, Number 3 March 1998

Dengue Fever: A Personal Perspective Piero Garzaro, MD Department of Medicine Wright State University School of Medicine Dayton, OH 45409

Introduction Dengue fever is one of the most important viral diseases in the world, yet one with which many Americans are not very familiar. When I say Americans, I ' m referring to North Americans since almost all citizens of Latin American countries know the disease. Dengue is an endemic viral disease of the tropical and subtropical regions of the world with 2.5 billion people at risk for this infection. Dengue is the most important tropical infectious disease in the world after malaria. The incidence and geographical distribution of both the viruses and the mosquito vector of dengue have greatly increased in recent years, and the clinical illness appears to be worsening with severe forms that can threaten the patient's life, primarily through increased vascular permeability and shock. An estimated 100 million people per year are infected by the arthropodborne virus (arbovirus) of the Flavivirus family group. In fact, dengue fever is now considered an emerging infectious disease because its incidence is increasing in Central America and Mexico due to the failure to control its mosquito vector. Of significance to the expanding geographical distribution is that recently an outbreak of dengue occurred in Texas. Dengue fever is characterized by a variety of clinical manifestations, including fever with chills, headache, retroocular pain, general malaise, myalgia, and arthralgia, and often an exanthem. The author is quite familiar with

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the symptoms of dengue since he personally experienced them while in medical school, long before he had heard the call of infectious diseases as a career. History The fwst recorded epidemic of a denguelike illness is from China in 992 AD and the next from the French West Indies in 1635. The first clinical report of dengue in the Americas was in 1780 and is attributed to Benjamin Rush, a colonial physician and signer of the Declaration of Independence. Dengue thus has been recognized as a clinical entity for at least two centuries. It took over one century before mosquito transmission and the viral etiology of the disease was demonstrated by studies in human volunteers in 1905 to 1906. The virus itself was not isolated until 1944. Four antigenically distinct viruses (types 1-4) were subsequently established as the cause of dengue. In 1954, a "new" syndrome, dengue hemorrhagic fever (DHF), was associated with dengue infection in the Philippines. DHF causes a disseminated intravascular coagulopathy (DIC)-like syndrome; deaths are associated with hemorrhages in the lungs and the cerebrum. It is estimated that several hundred thousand cases of DHF occur yearly; the case fatality rate for DHF averages about 5%, but has been reported as high as 44% in some studies. Another aspect of dengue that may be seen with DHF (or, less commonly, alone) is dengue shock syndrome (DSS), which is thought to be due to increased permeability of blood vessels. Etiology The etiologic agents of dengue fever are

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four serologically related RNA viruses that belong to the arbovirus classification; the majority of them are classified within the Togaviridae, Bunyaviridae, or Flaviviridae families. Dengue viruses belong to the family Flaviviridae, genus Flavivirus, species dengue fever types 1 through 4. It has a genome of 10 to 11 kilobases or single-stranded positive polarity RNA contained in the enveloped icosahedral nucleocapsids with a diameter of 45 to 55/am. The cellular receptor utilized by the dengue virus envelope protein to bind to target cells is known to be a highly sulfated type of heparan sulfate. This binding is a critical determinant of infectivity and allows the virus to enter the host cell. Within the host cell, the life cycle is entirely intracytoplasmic. Virions accumulate in the endoplasmic reticulum and are released by exocytosis or cell lysis without budding from the plasma membrane. Flavi-

In T h i s Issue

Dengue Fever: A Personal Perspective . . . . . . . . . . . . . . . . . . .


Piero Garzaro, MD

Disseminated Cornynebacterium Propinquum (CDC group ANF-3) Infection in a Patient with Reactivated Tuberculosis . . . . . . . .


A case report

News Brief . . . . . . . . . . . . . . . . . . . .


Society Notice . . . . . . . . . . . . . . . . .


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virus infection generally does not affect host cell macromolecular synthesis dramatically until late in infection, when cytopathic effects become evident. In contrast to retrovirus, they have no intermediate DNA form.

Vector Dengue fever is transmitted exclusively from human to human by the bite of infected mosquitoes of the Aedes family, although there has been a reported case of nosocomial transmission of dengue from a needlestick injury. In the Caribbean, the mosquito vector is A. aegypti, which is present in almost all the territories. Other vectors include A. albopticus and A. triseriatus, which are distributed widely in the eastern part of the United States up to the Great Lakes. In Asia and Oceania, A. scutellaris and A. polynesiensis are commonly encountered agents of transmission. Humans are the only known reservoir of the disease. Among insects, sexual or vertical transmission of all serotypes of the dengue fever virus by A. albopticus has been documented. Apparently, females do not transmit the infection to the male, which support the hypothesis that male mosquitoes acquire the infection vertically. Vertical transmission of dengue has also been documented in other members of the Aedes family. A. aegypti is a peridomestic mosquito with a short flight range that breeds almost exclusively in artificial habitats such as water storage vessels, old tires and other items that collect water. Ecological changes are thought to be important in the increasing incidence of dengue. Irrigation and other developmental projects, urbanization, and deforestation have all resulted in vector population densities that appear to enable the emergence of dengue. Combined with this is greater human travel that can spread the virus into areas in which they had been hitherto



Table 1. Clinical manifestations

absent. The male feeds mainly on flowers while the female feeds mainly on human blood, therefore becoming the principal transmitter of the disease. The mosquito acquires the infection from the blood of a viremic host, then the virus rapidly infects almost all the tissues of the mosquito, finally multiplying in the salivary glands. The time from the initial blood meal until the virus is produced in the salivary glands is called the extrinsic incubation period and it usually lasts 8 to 14 days. During this time, the mosquito cannot transmit the infection; however, the mosquito will remain infectious for the remainder of its life, usually several weeks. During this time, infected female mosquitoes are able to transmit virus vertically to new generations without pathology. The mosquito passes through four life cycles: egg, larvae, pupa, and adult. The eggs are capable of resisting long periods of dehydration, up to one year. This is one of the principal obstacles for the control of mosquitoes since the eggs can be transported long distances in dry recipients. Summer is the principal period of activity of arbovirus in the temperate regions, but in the tropical areas, the disease may occur endemically throughout the year, particularly with increased activity in the rainy season when mosquito numbers are increased.

First Phase (first day) Abrupt onset fever lasting two to seven days with temperature of 39 to 41°C Back pain Frontal headache or retroocular pain Transitory macular eruption (disappears upon pressure) Slow pulse in relation to fever Myalgia/arthralgia Second Phase (second to sixth day) Nausea Vomiting Diarrhea Generalized adenopathy Anorexia Taste aberrations Hyperesthesia Hyperalgesia Third Phase (after one to two days) Defervescense Fourth Phase (biphasic fever) Temperature rises again Generalized morbilliform rash Skin desquamation Fifth Phase (convalescence) Prolongued asthesia Mental depression Bradycardia/ventricular extrasystole

Clinical Symptoms The four serotypes of dengue virus produce a similar clinical picture that may vary in severity from a subclinical infection to the worst manifestations of DHF including death. Classic dengue fever develops after an incubation period of 3 to 15 days and is characterized by an abrupt onset of fever, chills, headache, and general malaise. Another common symptom is retroocular pain accentuated by eye movements (the author remembers this very well). Anorexia, nausea,



vomiting, and back pain may be clinical complaints. Arthralgias may be severe, which is why dengue fever is also known as breakbone fever (Table 1). Meningismus, encephalitis, clinical myocarditis, and fulminant hepatitis with renal impairment have also been reported infrequently. The fever traditionally lasts three to seven days and may be biphasic. The patient may defervesce after approxi-


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@ 1999 Elsevier Science Inc.



Amimicrobics and Infectious Diseases Newsletter 17(3) 1998

mately 48 hours but not to normal temperature, and will exhibit fever again one or more days later. The cutaneous eruption and erythema may appear shortly before the onset of fever or 24 to 48 hours after the fever is manifested. The rash starts on the trunk and spreads centrifugally to the face, neck, and extremities. Flushing of the skin may disappear after one to two days or may blend into an erythematous maculopapular rash that develops on the second to sixth day of illness coinciding with the time of defervescence. In the cases of dengue accompanied by visual disturbances, the chief complaints include blurred vision, central scotoma, floaters, and photophobia. Fundoscopic exam may demonstrate retinal hemorrhage, Roth spots, diffuse retinal edema, and blurring of the optic disk. Neurologic manifestations are not associated with any particular serotype, but sometimes these signs are undistinguishable from encephalitis. Guillan-Barre and Reye's syndromes have also been reported. Studies suggest that the virus does not cross the blood-brain barrier. Laboratory findings include early neutropenia with subsequent lymphocytosis, often marked by atypical lymphocytes. Thrombocytopenia may also be seen. Mild proteinuria and elevation of liver enzymes may be demonstrated. Patients generally recover completely within one week with classic dengue fever, but the infection has a more severe form, DHE DHF is a distinctive disease. Characterized by an increase in vascular permeability, hypovolemia, hemoconcentration (hematocrit increase in 20% or more), thrombocytopenia (< 100,000), evidence of vascular collapse, coagulopathy, and hemorrhagic manifestations such as positive tourniquet test, skin hemorrhages, epistaxis, and gum bleeding. The WHO classified DHF into four levels, from grade I which is characterized by fever and non-specific constitutional symptoms, to grade IV which is profound shock. The presence of thrombocytopenia with concurrent hemoconcentration differentiates grade I and II DHF from classic dengue fever. DHF usually occurs more frequently in children less than 15 years old; however, it can also occur in adults and can lead to death in both. The patient with DHF can have a

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fever for two to seven days with various non- specific symptoms but can suddenly deteriorate. When the fever begins to fall, the patient can become restless, irritable, and lethargic. Hemorrhagic manifestations such as petechiae, purpura, ecchymosis, epistaxis, and gum bleeding may appear. The patient may even develop gastrointestinal bleeding. Hepatomegaly with or without jaundice also may be present. The vast majority of patients develop thrombocytopenia and hemoconcentration as a result of plasma leakage from the intravascular compartment secondary to increased vascular permeability. A frequent finding in patients with DHF is a right-sided pleural effusion associated with tachypnea and dyspnea. Ascites and pericardial effusion have also been described.

The most significant criterion for the diagnosis of dengue fever is the clinical picture. Moreover, it is important to realize that laboratory tests do not confirm or rule out the clinical diagnosis of dengue fever. Laboratory findings often documented are thrombocytopenia and hemoconcentration. Signs of consumption coagulopathy are found with slightly elevated fibrin split products, fall in serum complement, decrease in several coagulation factors such as factor VIII, prolonged PTI-, and decreased activities of antothrombin III and alpha2-antiplasmin. However, despite all these findings, frank DIC is rarely observed. There is also a decrease in total protein, which is correlated with disease severity. Most patients (77%) have a normal erythrocyte sedimentation rate, while 15% and 8% have slightly and moderately elevated ESR, respectively. Mortality has been reported between 10 to 30% in patients with DHF, and death usually occurs on the fourth or fifth day of illness.

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Pathogenesis and Pathology Classic dengue fever Dengue virus infection causes a systemic infection with two important components. Following an infected mosquito bite fever, viremia develops with as many as 10 5 human infectious doses per milliliter and three to four days later a maculopapular rash develops. The main pathologic findings are endothelial cell swelling in the small vessels of the papillary dermis, diapedesis of neutrophils, extravasation of erythrocytes, perivascular edema, and mononuclear cell infiltrates. There is also a degeneration of endothelial cells and neutrophils. The pathogenesis of this cutaneous eruption is not yet known.

Dengue Hemorrhagic Fever There are at present two hypothesis of the pathogenesis of DHF. The first one states that the infecting virus determines the severity of disease, with the virulence varying among different strains (antigenic variation). There is no clear evidence to support this concept since studies done in Asia demonstrated that hemorrhagic disease can occur with strains of any serotype. The second hypothesis, which is the most widely accepted, suggests an immunologicallymediated pathogenesis in which antibodymediated enhancement of the viral infection causes D H E The immunological status of the host is critical; antibodies already present before the current infection, whether acquired from an earlier dengue infection or transplacentally, interact with the present infecting virus, producing an enhanced or potentiated illness, and subsequently, a more severe disease. This may not be the only factor involved, however. During a Cuban outbreak of DHF in 1981, many persons who suffered a secondary infection did not present with a severe clinical picture. At present, DHF is only described in persons suffering a second, but not a third or fourth dengue infection. It is hypothesized that low levels of neutralizing antibodies against dengue may result in an increased number of infected cells, and these cells release mediators that cause increased plasma leakage and eventually shock. A unique cytokine, human cytotoxic factor, has been shown to occur in the sera of patients with DHE This cytokine has been found

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only in CD4+ T cells. Moreover, the level of immunoreactive circulating and cell-generated tumor necrosis factor alpha (TNFct) is elevated in dengueinfected patients. Soluble TNF receptor (TNFR) levels also have been shown to be elevated with a consistent positive relationship with disease severity. It is thought that large-scale release of soluble TNFR may be an early and specific marker of the endothelial changes that cause DSS. The mechanism for DSS is not clearly understood. There appears to be no evidence of injury to the vasculature during infection. The short-lived nature of the plasma leakage in DSS suggests that altered permeability of the blood vessels is most likely due to a soluble mediator. Dengue virus replication in humans seems to be somewhat restricted to cells of the mononuclear phagocyte lineage, with the greater the number of phagocytes infected, the more severe the disease. However, in vitro studies using endothelial cells from human umbilical cord vein have noted replication of dengue viruses (types 1, 2, 3, and 4). Infection of endothelial cells may cause apoptosis. Type 4 (DEN-4) is the only serotype shown to infect hematopoietic cells as well as hematopoietic cell lines. This infection is not cytotoxic but slows cell proliferation. Studies done in patients with DHF show that during the thrombocytopenic phase of the disease (occurring from the third through eighth day), the levels of thrombopoietin did not increase, despite low platelet counts. However, beginning at the sixth to seventh day, a rapid increase in thrombopoietin was observed, with a concomitant increase in platelet counts. By the ninth to eleventh day, all patients were in the phase of convalescence. Morphologic studies of the bone marrow confirm these findings.

Diagnosis The most significant criterion for diagnosis is the clinical picture. If the illness goes beyond a mild febrile illness and there is a positive tourniquet test and/or thrombocytopenia with hemoconcentradon, criteria for DHF exist. These characteristic features of DHF typically occur simultaneously with defervescence, while the early clinical features of DHF are indistinguishable from classic dengue fever. A clinical definition by the WHO


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is based on the presence of high continuous fever, hemorrhagic manifestations (including at least a positive tourniquet test), hepatomegaly, thrombocytopenia (<100K), and hemoconcentration (hematocrit increased by >20% above baseline value). A study to identify early indicators of acute dengue virus infection was conducted among Thai children. At enrollment in the study, children with dengue fever were more likely than children with other febrile illness to report anorexia, nausea and vomiting, and to have a positive tourniquet test. Children with dengue fever also had lower total WBC counts, including absolute neutrophil and absolute monocyte counts, and a higher ALT and AST than children with other febrile illnesses. Of note is that AST levels were higher in children who eventually developed DHF than in those with classic dengue fever.

Treatment for dengue fever is symptomatic and supportive. Close monitoring of vital signs and hematocrit readings to evaluate plasma loss or hemorrhage with corrective action have reduced the mortality rates for dengue hemorrhagic fever from 50% to less than 1%.

nation inhibition, complement fixation, or neutralizing antibody titers provides laboratory confirmation of dengue infection. Another test that can be used for a rapid presumptive diagnosis is to detect dengue-specific IgM antibody from serum an ELISA test.

Immunity After a person has a dengue infection, it will result in long term immunity to the virus serotype that caused the infection. In addition, a short, crossed immunity to the remaining heterologous serotypes persists for approximately six months. Treatment Treatment for both classic dengue and DHF is symptomatic and supportive. Mortality rates from DHF have been reduced from 50% to less than 1% by close monitoring of vital signs and hematocrit readings to evaluate plasma loss or hemorrhage. Steroids have been used without significant improvement. A study done in Indonesia demonstrated no reduction in mortality, duration of shock, or the amounts of fluids required for resuscitation. Antibiotics are not indicated in either form of dengue infection. The main goal is prevention. Control measures include the elimination of receptacles that can accumulate water where the larva can develop, keeping door/windows open during street fumigation, using mosquito repellents while outdoors, and isolating the patient with a mosquito net at least during the first four to five days of the disease. A vaccine is still under development. And last but not least, avoid having dengue days before a pharmacology exam; it is hard to concentrate with a bone-breaking fever!

Bibliography Even with these findings, it is important to know that laboratory tests do not confirm or rule out a clinical diagnosis. Collecting an acute phase serum sample, preferably taken during the first five days from the onset of disease makes the laboratory diagnosis of dengue virus. Virus isolation is possible from acute phase serum specimens in order to establish which serotype is present. This sample is also sent for serum antibody titer to dengue fever. A second blood sample is taken two weeks apart in the convalescent phase to compare antibody titers. A fourfold rise or more in hemaggluti-

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Agarwal R et al.: 1998. Production of cytotoxic factor by peripheral blood mononuclear cells (PBMC) in patients with dengue hemorrhagic fever. Clin Exp Immunol 112:477-481. Avirutnan Pet al.: 1998. Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis. J Immunol 161:6338-6346. Bethell DB et al.: 1998. Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever. J Infect Dis 177:778-782. Chen Y, Maguire T, Hileman RE: 1997. Dengue virus infectivity depends on

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envelope protein binding to target cell heparan sulfate. Nature Med 3:866-871. Gubler DJ: 1998. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11:480-486. Gubler DJ: 1987. Dengue and dengue hemorrhagic fever in the Americas. P R Health Sci J 6:107-111. Gubler DJ, Kuno G. (eds.). Dengue and Dengue Hemorrhagic Fever. p. 1-478. CAB International, New York, 1997. Henchal EA, Putnak JR: 1990. The dengue viruses. Clin Microbiol Rev 3:376. Hober D, Nguyen TL, Shen Let al.: 1998. Tumor necrosis factor alpha levels in plasma and whole-blood culture in dengue-infected patients: relationship between virus detection and pre-existing specific antibodies. J Med Virol 54:210-218.

Jimenez DR, Santana JL, Ramirez-Ronda CH: 1988. Neurological disorders associated with dengue infection. Bol Assoc Med P R 80:208. Kalayanarooj S, Vaughn Set al: 1997. Early clinical and laboratory indicators of acute dengue illness. J Inf Dis 176:4. Lai CJ, Bray M, Men R et al.: 1998. Evaluation of molecular strategies to develop a live dengue vaccine. Clin Diagn Virol 10:173-179. Lange RW, Beall B: 1992. Dengue fever: a resurgent risk for the international traveler. Amer Fam Phys 45:3. Mandell D, Bennet J, Dolin R: Principles and practice of infectious diseases. 4th Edition, p. 1465-1474. Churchill and Livingstone, New York, 1995. Mariarmeau Pet al.: 1998. Apoptotic cell death in response to dengue virus infec-

tion: the pathogenesis of dengue haemorrhagic fever revisited. Clin Diagn Virol 10:113-119. Nelson MJ: Aedes aegypti: Biology and Ecology. Pan American Health Organization, Washington, DC. 1986. Ramirez-Ronda CH, Garcia CD: 1994. Dengue in the western hemisphere. Inf Dis Clin N Am 8:1. Rigau-Perez JG, Clark GG, Gubler DJ, Reiter P, Sanders DJ, Vomdam AV: 1998. Dengue and dengue hemorrhagic fever. Lancet 352:971-977. Rodriguez-Tan RS, Weir MR: 1998. Dengue: a review. Texas Med 94:53-59. Waterman SH, Gubler DJ: 1989. Dengue fever. Clin Dermatol 7:117. Young NS: 1990. Flaviviruses and bone marrow failure. JAMA 263:3065.

Case Report

•D i s s e m i n a t e d Cornynebacterium Propinquum ( C D C group A N F - 3 ) Infection in a Patient with Reactivated Tuberculosis Suresh J. Antony, MD Texas Tech University Medical Center 7848 Gateway East El Paso, TX 79915 Delfina Dominguez, PhD University of Texas at El Paso El Paso, TX 79914 We report the first case in medical literature of disseminated Cornybacterium propinquum infection in a patient with extrapulmonary tuberculosis. The microbiology and the treatment of this unusual bacterium is reviewed. Case Report A 76-year-old white male with a remote history of pulmonary tuberculosis was admitted to the hospital with chest pain and underwent a coronary artery bypass procedure. He was admitted a few weeks later in cardiorespiratory arrest. During the resuscitation, the sternal wound opened and subsequently became infected with Staphylococcus epidermidis. The hospitalization was complicated with a right-sided pleural effusion, persistent low grade fevers, and night sweats. He was started on nafcillin to treat the sternal wound infection, but despite this, continued to become progressively ill.

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Thorocentesis done two weeks later grew Mycobacterium tuberculum sensitive to the standard antitubercular medications. The white blood cell count was 4,300 cell/cu mm with a differential of 72 segs, 17 lymphs, 6 monos, and 2 bands. Repeated blood and urine cultures were negative. Central lines were changed frequently and the catheter tips had no growth. Despite isoniazid, ethambutol, pyrazinamide and rifampin, the patient continued to have low grade fevers. A bone marrow biopsy and repeat blood cultures (two sets) were performed. After 48 h of incubation, the Gram stain of the bone marrow revealed Gram-positive pleo-

morphic bacilli which eventually grew well on 5% sheep blood and chocolate agars under aerobic conditions. The isolate was subjected to a set of conventional biochemical tests (Specialty Labs, Inc., Santa Monica, CA) including Catalse, Oxidase, Motility, Gelatin, Nitrate, Urea, Bile Esculin, TSI, Glucose, Maltose, Sucrose, Mannitol, Xylose, and Trealose. Results from these biochemical tests are shown in Table 1.The bacterium was noted to be susceptible to ciprofloxacin, cefazolin, gentamicin, vancomycin, imipenem, and cephalothin and resistant to r~orfloxacin and oxacillin. The patient was empirically placed on vancomycin before the iden-

Table 1. Biochemical characteristics of C. propinquum isolated from bone marrow and blood Catalase















Bile Esculin



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