Introduction

Hemorrhagic Fevers This diverse group of illnesses results from infection with one of several single-stranded RNA viruses (members of the families Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae). Flaviviruses, such as the West Nile pathogen, are discussed above under arboviruses; dengue and yellow fever, both with occasional hemorrhagic complications, are discussed in the following sections alongside the immunologic responses to them. The clinical symptoms in the early phase of a viral hemorrhagic fever are very similar, irrespective of the causative virus, and resemble a flu-like illness or gastroenteritis. Headache, myalgia, gastrointestinal symptoms, and symptoms of upper respiratory tract infection dominate the clinical picture and hepatitis is common. Laboratory features usually include thrombocytopenia, leukopenia, (although with Lassa fever leukocytosis is noted), anemia, and often elevated liver function tests as well as findings consistent with disseminated intravascular coagulation (except in Lassa fever). The late phase is more specific and is characterized by organ failure, persistent leukopenia, altered mental status, and hemorrhage. The case-fatality rate ranges from 5% to 30% and may be as high as 90% in Ebola fever. There is no evidence of chronic infection among survivors. Modes of transmission are similarly diverse. Dengue and yellow fever are due to flaviviruses transmitted by mosquitoes, while Omsk hemorrhagic fever and Kyasanur Forest disease are due to tick-borne flaviviruses. Lassa fever is rodent associated, as are Junin hemorrhagic fever and other diseases due to New World Arenaviridae. Ebola fever and Marburg fever are due to filoviruses with unknown vectors. The bunyaviruses include the tick-borne Crimean-Congo hemorrhagic fever and the mosquito-borne Rift Valley fever (a major outbreak in Saudi Arabia in 20002001 involved over 800 persons), while infections due to the hantaviruses (discussed separately below) are associated with rodent exposure. The Nipah virus in Malaysia is a zoonotic paramyxovirus that does not cause hemorrhagic fever but instead causes a primarily encephalitic infection. Most cases are associated with a history of contact with pigs. Flying foxes appear to be the natural host. Persons with symptoms compatible with those of any hemorrhagic fever and who have traveled from a possible endemic area should be isolated for diagnosis and symptomatic treatment. Diagnosis may be made by growing the virus from blood obtained early in the disease, by reverse transcriptase PCR, or by demonstration of a significant specific fourfold or greater rise in

antibody titer. These tests are generally available only through the Centers for Disease Control and Prevention. Isolation is particularly important because diseases due to some of these agents, such as Ebola virus, are highly transmissible and carry a mortality rate of 5090%. The pathophysiology of these infections includes infection of a wide variety of cell types, but in particular lymphoid tissues, tissues involved in the coagulation cascade, and the immune system. Many of the symptoms are due to the effect of inflammatory mediators such as cytokines and chemokines. Adrenal dysfunction is a common sequela and a cause for the development of the late-stage shock associated with viral hemorrhagic fevers. Through the Ebola epidemics in Zaire, Gabon and Uganda, the Marburg virus outbreak in the Republic of Congo in recent years and the imported Yellow Fever and Lassa cases to Europe we all became aware that dangerous infections could enter Europe in a very short time. Travel is a potent factor in the emergence of infections and the current volume, speed and distance of travel are unprecedented a problem which has been addressed by the WHO (1, 2). This has increased the risk that persons infected with a number of diseases, including VHF, may occur in Europe. The following guidelines have been drawn up to help the European healthcare systems in there preparing to deal with a suspected case.While many VHFs were initially considered to be highly communication between humans,this concept has not been substantiated. Although nosocomial transmission has occurred in areas with endemic disease, accumulated evidence suggests that transmission of these viruses does not commonly occur through casual or remote contact. Several importations to non-endemic countries have occurred without subsequent disease outbreaks. While secondary cases of Marburg, Ebola, Lassa and CCHF have been documented, only few secondary cases following an importation episode have been identified : Lassa fever (Ivory Coast Germany ;3, 4), Marburg (Zimbabwe S. Africa;, Ebola (Gabon S. Africa;)Body secretions and excretions, blood, semen and tissue specimens from infected patients contain infectious material. It is evident that the risk of infection increases with the clinical progression of the disease. Persons at highest risk of secondary infection are those who are in closest contact with an infected person or her/his body fluids during the period of incubation and acute illness. Such persons include those with close contact with patients, providing direct medical and nursing care, and laboratory workers handling blood, tissues or other specimens

Table 2: Agents of Viral Haemorrhagic Fevers

Mosquito bome Arenaviridae Lassa fever (LHF) ArgentineHF(Junin) BolivianHF(Machupo) Brazilian HF(Sabia) Venezuelan(Guanarito)

Tick bome

Rodent bome

Person to person

BSL

o o o o o

4 4 4 4 4

Bunyaviridae CrimeanCongoHF(CCHF Hantaan* Rift Valley fever (RVF) o o n 4 3 3

Filoviridae Ebola (EHF) Marburg (MHF) f f 4 4

Flaviviridae Dengue, Type 1-4 Yellow Fever (YF) Kyasanur Forest fever OmskHaemorrhagic fever n n o o (3) 3 3 3

Togaviridae Chikungunya (CHF) n 3

Poxviridae Monkeypox f 4

* Person-to-person spread : n= none; o = occasional; f = frequent =Biosafety level = Squirrel monkey = Domestic animals =Unknown reservoir and source =Does not classify as VHF

Each of these families share a number of common features: With the exception of Monkeypox (dsDNA) they are all RNA viruses with a lipid envelope,their survival is dependent on an animal or insect host and they are geographically restricted to the areas where their host species live. Humans are not the natural reservoir for any of these viruses and human cases occur sporadically. They can cause severe life-threatening diseases with high mortality. Most of these viruses are endemic in a number of parts of the world: most notably Africa,parts of South America and some rural parts of the Middle East and Eastern Europe. Moreover, environmental conditions for the maintenance of these pathogens may be present in parts of Europe. Since cases of VHF are occasionally imported into Europe, there is a risk of secondary infection, particularly among hospital and laboratory staff. Accidental inoculation may result from needle sticks or contamination of broken skin or mucous membranes by infected blood or body fluids. Strict infection control precautions are required to protect those who may be exposed.

In addition there is the constant albeit very low risk of import of the reservoir and vector, and particularly for mosquito-borne diseases (Dengue, Yellow fewer, Rift Valley fever, West Nile fever, malaria) to European countries, which could cause occasional outbreaks. It should be noted that parts of Europe are already endemic for hantavirus infections, Crimean-Congo HF, and West Nile virus which qualify as VHF pathogens. Consideration should be given to the possibility of importation of both reservoir animals and vectors of other VHF viruses.

Viral haemorrhagic fever viruses

Ebola fever Ebola was first recognized in 1976 in the Democratic Republic of Congo. It is a severe, often fatal disease in humans and non-human primates. Ebola typically appears in sporadic outbreaks usually within a health-care setting. The exact location, origin and natural reservoir, and the endemic region of Ebola remain unknown as well as is the exact mode of transmission to humans but researchers believe that the virus is zoonotic, native to the African continent. EbolaReston however is originated in the Philippines. Confirmed cases of Ebola have been reported in the Democratic Republic of the Congo, Gabon, Sudan, Uganda and the Ivory Coast. In 1976 a laboratory worker in the UK became ill as a result of a needle stick injury. Mortality is high. The mortality rate in outbreaks in Africa ranges from 40% up to 80 % depending on the strain involved and other factors.

If a case presented in Europe, nosocomial transmission is most likely to occur through either direct or indirect contact with the blood and/or secretions of an infected patient. The Reston strain appears not to be pathogenic, and airborne transmission appears not to occur during outbreaks of the human pathogen strains Zaire and Sudan. Conjunctivitis, petechiae and in the case of filovirus infections (Marburg and Ebola) amorbilliform skin rash appear later and are suggestive of VHF. These symptoms do not occur until the second week of infection by which time a reasonable suspicion of VHF should exist in the presence of a compatible travel history, the absence of a history strongly suggestive of other illnesses and at least two negative blood smears for malaria. Marburg fever Marburg virus was first recognised in 1967 when outbreaks of haemorrhagic fever occurred simultaneously in Marburg and Frankfurt in Germany and in Belgrade in the former Yugoslavia. The virus had arrived with imported monkeys from Uganda. The next case did not occur until 1975 in Johannesburg and the patient had most likely been exposed while travelling in Zimbabwe. A travelling companion and a nurse were subsequently infected. In 1980 there were two further cases, one in Western Kenya and the secondary in Nairobi. In 1987 another case was reported in an individual who had travelled extensively in Kenya. A total of 39 people were infected by contact to imported African green monkeys or secondary infection. Marburg virus is endemic in Durba region part of DR of Congo and also appears in parts of Uganda, Western Kenya and perhaps Zimbabwe. As with Ebola the animal reservoirs for Marburg virus remain unknown. Also the route of transmission from animals to humans is unknown. If a case were to occur in Europe those most at risk would be hospital staff and also family members or other individuals who had cared for the patient prior to their diagnosis. While the case fatality rate was initially thought to be significantly lower than that of Ebola, analysis of recent outbreaks in the Democratic Republic of Congo have shown that this is also greater than 70%. Recovery from Marburg can be long and known sequelae include orchitis, recurrent hepatitis, transverse myelitis and uveitis.

Lassa fever Lassa Fever is an acute viral illness that occurs in West Africa. The illness was first reported in 1969 when two missionary nurses died in Nigeria. Lassa Fever is endemic in parts of West Africa including

Guinea, Liberia, Sierra Leone and Nigeria. The reservoir of Lassa virus is the multimammate rat. Humans can be infected in several ways. Rats shed the virus in urine and droppings and therefore primary transmission is likely to be through direct contact with these materials. Infection can also occur following airborne transmission. Secondary transmission can also occur through person to person contact. In Europe such secondary transmission is most likely to occur in a healthcare setting by either contact with the virus in blood, tissue or secretions of a case or by breathing in airborne particles which the patient can produce by coughing. It is the potential transmission by aerosol that makes Lassa particularly dangerous. Approximately 15-20% of patients hospitalised for Lassa fever die. The death rates are particularly high for women in the third trimester of pregnancy and for foetuses, about 95% of which die in the uterus of infected expectant mothers. Following recovery the most common complication is deafness which occurs in approximately 33% of cases.

Crimean-Congo haemorrhagic fever Crimean-Congo Haemorrhagic Fever (CCHF) was first described in the Crimea in 1944. In 1969 it was recognised that the virus causing Crimean haemorrhagic fever was the same as that responsible for an illness identified in 1956 in the Congo, hence the linkage of the two names. CCHF is transmitted by tick bite and caused by a virus which is widespread in East and West Africa, Central Asia and the former USSR. More recently, CCHF or antibody to it, has been detected in Dubai, Iraq, South Africa, Pakistan, Greece, Turkey, Albania, Afghanistan, and India. CCHF is a severe illness in humans with a high mortality but fortunately human illness occurs infrequently. Animal infection is more common. Animals become infected with CCHF from the bite of infected ticks. Humans who become infected usually do so from direct contact with blood or other tissues from infected animals or directly from a tick bite. The majority of cases have occurred in those involved with the livestock industry such as agricultural workers, slaughterhouse workers and vets. Dengue Essentials of Diagnosis

Exposure 710 days before onset. Sudden onset of high fever, chills, severe myalgias, headache, sore throat, prostration, and depression.

Biphasic fever curve: initial phase, 37 days; remission, few hours to 2 days; second phase, 12 days.

Biphasic rash: evanescent, then maculopapular, scarlatiniform, morbilliform, or petechial changes from extremities to torso.

Leukopenia and thrombocytopenia in the hemorrhagic form.

General Considerations Dengue is due to a flavivirus transmitted by the bite of the Aedes mosquito. It may be caused by one of four serotypes widely distributed between the tropics of Capricorn and Cancer. An estimated 50100 million cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever occur each year. The incubation period is 315 days (usually 710 days). When the virus is introduced into susceptible populations, usually by viremic travelers, epidemic attack rates range from 50% to 70%. Transmission occurred in the United States in southern Texas and nearby Mexican border towns in 1986 and 1999. In 2001, a large outbreak in Hawaii was traced to a traveler returning from French Polynesia. Severe epidemics of dengue hemorrhagic fever (serotype 3) occurred over the past 20 years in East Africa, Sri Lanka, and Latin America. Symptoms and Signs Dengue fever is usually a nonspecific, self-limited biphasic febrile illness, but its presentation may range from asymptomatic to severe hemorrhagic fever and fatal shock (dengue shock syndrome). Infection is asymptomatic in 80% of infants and children. The illness is more severe and begins more suddenly in adults. After an incubation period of 45 days, there is a sudden onset of high fever, chills, and "break bone" aching of the head, back, and extremities accompanied by sore throat, prostration, and malaise. There may be conjunctival redness and flushing or blotching of the skin. Initially, the skin appears flushed, but 34 days after the lysis of the fever, a maculopapular rash, which spares palms and soles, appears in over 50% of cases. As the rash fades, localized clusters of petechiae on the extensor surface of the limbs become apparent. Hepatitis frequently complicates dengue fever. Dengue hemorrhagic fever usually affects children living in endemic areas and is most likely to occur in secondary infections with serotype 2. A few days into the illness, signs of hemorrhage such as ecchymoses, gastrointestinal bleeding, and epistaxis appear. Symptoms found more often among the hemorrhagic fever subset of patients include restlessness, epistaxis, and abdominal pain. Some dengue virus envelope glycoproteins are homologous with segments of clotting factors, including

plasminogen, and thus the hemorrhagic fever may represent an autoimmune reaction. A subset of patients progresses to dengue shock syndrome in which acute fever, hemorrhagic manifestations, and marked capillary leak are prominent, the latter manifesting as pleural effusions, ascites, and a tendency to develop shock. Before the rash of dengue appears, the infection is difficult to distinguish from malaria, yellow fever, or influenza; the rash makes dengue far more likely. Continuous abdominal pain with vomiting, a decrease in the level of consciousness, and hypothermia should raise concern about dengue shock syndrome.

Complications Usual complications include depression, chronic fatigue, pneumonia, bone marrow failure, hepatitis, iritis, orchitis, and oophoritis. Neurologic complications such as encephalitis and transverse myelitis are less often reported. Dengue hemorrhagic fever or shock with concomitant bacterial infection is associated with advanced age, higher fever, gastrointestinal bleeding, renal impairment, and altered consciousness.

Prevention Available prophylactic measures include control of mosquitoes by screening and insect repellents, particularly during early morning and late afternoon exposures. A screening program at an airport for persons with fever facilitated the diagnosis of dengue and the implementation of public health measures in Taipei, Taiwan. A variety of vaccines, involving attenuated or genetically modified virus, are under study including combinations of attenuated dengue strains.

Hantaviruses Hantaviruses are rodent-borne enveloped RNA bunyaviruses with several distinct serotypes. These differ in rodent hosts, geographic distribution, and degree of pathogenicity for humans. They cause two major clinical syndromes: hemorrhagic fever (discussed above) and the hantavirus pulmonary syndrome. Aerosols of virus-contaminated rodent urine and perhaps feces are thought to be the main vehicle for transmission to humans. The ubiquity of hantaviruses is becoming recognized, with descriptions of infections from North and South America and additional infections from Europe and Asia. The Hantaan serotype viruses cause severe hemorrhagic fever with renal syndrome and are found

primarily in Korea, China, and eastern Russia. The Seoul viruses produce a less severe form and are found primarily in Korea and China. The Puumala and Dobrava viruses are found in Scandinavia and Europe and are associated with a milder form of the syndrome, nephropathia epidemica, which usually presents with fever, headache, gastrointestinal symptoms, and impaired renal function. The Sin Nombre (Muerto Canyon, Four Corners) virus is one of the viruses responsible for the hantavirus pulmonary syndrome, most cases of which have been seen in the southwestern United States. Approximately 300 cases have been reported from 31 states since 1993. Outbreaks are currently being reported from Central and South America. Hantavirus pulmonary syndrome begins as a nonspecific febrile illness followed by a severe increase in pulmonary vascular permeability, leading to respiratory failure and rapid progression to a shock-like state. Hematologic features include thrombocytopenia, hemoconcentration, and leukocytosis, with abnormal lymphocytes and immature myeloid cells in the peripheral smear. Clinical similarities, including a propensity toward renal involvement exist between the New World hantaviruses and their Old World counterparts. Diagnosis can be made serologically, with most patients having both IgM and IgG antibodies at the time of presentation; by immunohistochemical staining; or by PCR amplification of viral tissue DNA. Because infection is thought to occur by inhalation of rodent wastes, prevention is aimed toward eradication of rodents in houses and avoidance of exposure to rodent excreta in rural settings. No treatment has been established as definitely effective for hantavirus pulmonary syndrome. Intravenous ribavirin has been used with some success in hemorrhagic fever with renal syndrome, and studies are currently ongoing for its use in hantavirus pulmonary syndrome.

Yellow Fever Essentials of Diagnosis

Endemic area exposure (tropical South and Central America, Africa, but not Asia). Sudden onset of severe headache, aching in legs, and tachycardia. Brief (1 day) remission, followed by bradycardia, hypotension, jaundice, hemorrhagic tendency. Proteinuria, leukopenia, bilirubinemia, bilirubinuria. Rare and potentially fatal reactions to vaccination.

General Considerations Yellow fever is a zoonotic flavivirus infection transmitted by Aedes and jungle mosquitoes. It occurs in an urban and jungle cycle in Africa and in a jungle cycle in South America. Epidemics have extended

far into the temperate zone during warm seasons. The role of yellow fever in preventing economic development in tropical areas is devastating. The mosquito transmits the infection by first biting an individual having the disease and then biting a susceptible individual after the virus has multiplied within the mosquito's body. The incubation period in humans is 36 days. Adults and children are equally susceptible, though attack rates are highest among adult males because of their work habits. Between 5% and 50% of infections are asymptomatic.

Symptoms and Signs Mild form Symptoms are malaise, headache, fever, retroorbital pain, nausea, vomiting, and photophobia. Relative bradycardia, conjunctival injection, and facial flushing may be present. Severe form Severe illness develops in about 15% of those infected with yellow fever. Initial symptoms are similar to the mild form, but a brief fever remission lasting hours to a few days is followed by a "period of intoxication" manifested by fever and relative bradycardia (Faget's sign), hypotension, jaundice, hemorrhage (gastrointestinal, nasal, oral), and delirium that may progress to coma. Prevention Transmission is prevented through mosquito control. Live virus vaccine is highly effective and should be provided for immunocompetent persons over 9 months of age living in or traveling to endemic areas. Vaccine-induced reactions, including viscerotropic and hepatotropic diseases that resemble yellow fever, are reported (particularly among elderly patients). Mass campaigns with the vaccine were carried out without significant complications in Cote d'Ivoire. The safety of the vaccine in pregnant patients is not verified, and pregnant women should, if possible, defer travel to endemic areas (see Infectious Diseases: General Problems). Eradication is difficult because of the sylvatic cycle, with forest rodents serving as a reservoir. Discrete enzootic foci of transmission appear to be more important than wandering epizootic foci as formerly thought. Treatment No specific antiviral therapy is available. Treatment is directed toward symptomatic relief and management of complications. If not in an endemic area, the patient should be isolated from mosquitoes to prevent transmission, since blood in the acute phase is potentially infectious.

Diagnosis The differential diagnosis for hemorrhagic fever includes meningococcemia or other septicemias, Rocky Mountain spotted fever, dengue, and malaria. The likelihood of acquiring hemorrhagic fevers among travelers is low. Certain arenaviruses (the Lassa pathogen, Junin virus in its viscerotropic phase, Machupo virus) and bunyaviruses (provisionally, the Congo-Crimean Hemorrhagic Fever and Rift Valley Fever pathogens) respond to ribavirin if it is started promptly: 30 mg/kg as loading dose, followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for 3 days (see Infectious Disease: Antimicrobial Therapy). The filoviruses and the flaviviruses do not respond to ribavirin. Vaccines are needed for these pathogens. The successful yellow fever vaccine is discussed below. A live attenuated Junin vaccine is undergoing trials. A formalin-inactivated vaccine against the Rift Valley Fever pathogen is in use and a live-attenuated vaccine is under development. Therapeutic interventions that target the hematologic system are either ineffective or only marginally effective. Future studies will target combining antivirals with immune mediators.

Differential Diagnosis It may be difficult to distinguish yellow fever from hepatitis, malaria, leptospirosis, louse-borne relapsing fever, dengue, and other hemorrhagic fevers on clinical evidence alone. Albuminuria is a constant feature in yellow fever patients and its presence helps differentiate yellow fever from other viral hepatitides. Serologic confirmation is often needed.

Laboratory Tests Inflammatory diarrheal illnesses are characterized by stool specimens containing large numbers of fecal leukocytes (e.g., more than three leukocytes per high-power microscopic field in four or more fields, or markers of fecal leukocytes such as lactoferrin) or the presence of occult blood. Pathogens commonly cultured from these patients include Shigella, Salmonella, Campylobacter, Aeromonas, Yersinia, noncholera Vibrio, and C. difficile. The absence of leukocytes in a stool specimen, however, does not rule out an inflammatory diarrhea. The mean sensitivity of fecal leukocytes for the prototypical inflammatory diarrheal disease agent Shigella, averages 73% (range, 49%100%). The absence of fecal WBC suggests a non-inflammatory diarrhea.

A microbiologic diagnosis of infectious diarrhea from a stool sample is made by culture of the pathogen or isolation of toxins (e.g., C. difficile) produced by the organism. Careful selection of patients in whom stool cultures are performed should maximize the cost-effectiveness of performing this test. Stool cultures are recommended for patients with one of the following: severe diarrhea; bloody stools; or stools containing leukocytes, lactoferrin, or occult blood; or an oral temperature 101.3F. Cultures are also recommended in patients with persistent diarrhea who have not been given empiric antimicrobials. Identification of parasitic causes of infectious diarrhea is made by microscopic examination of a stool specimen for ova and parasites. More sensitive tests to diagnose parasitic infections include direct immunofluorescence assay (DFA) to detect G. lamblia and Cryptosporidium, and enzyme immunoassay (EIA) to detect G. lamblia and Cryptosporidium antigen. Enteropathogens may also be isolated from extra intestinal sites such as the blood and bone marrow, or other sites to which infection has spread. Leukopenia occurs, although it may not be present at the onset. Proteinuria is present, sometimes as high as 56 g/L, and disappears completely with recovery. Abnormal liver function tests are seen, and prothrombin time may be elevated. Serologic diagnosis is primarily by measurement of IgM by a capture ELISA. Other serologic tests include hemagglutination-inhibition and neutralization. PCR protocols are becoming more widely available.

Leukopenia is characteristic and elevated transaminases are found frequently in dengue fever. Thrombocytopenia, increased fibrinolysis, and hemoconcentration occur more often in the hemorrhagic form of the disease. Liver function abnormalities are nearly universal. The nonspecific nature of the illness mandates laboratory verification for diagnosis, usually with IgM and IgG ELISAs. Virus may be recovered from the blood during the acute phase, and several PCR protocols are being developed. Immunohistochemistry for antigen detection in tissue samples can also be used.

Treatment of Patients With Infectious Diarrhea Infectious diarrhea is generally a self-limiting illness, and most patients never seek medical attention. In many cases, replacement of fluids and electrolytes is all that is required. Medical evaluation is warranted for patients with profuse watery diarrhea with dehydration, six or more unformed stools within a 24-hour period, bloody stools, temperature >101.3F, or illness of >48 hours' duration. Other persons requiring medical evaluation for a diarrheal illness include patients >50 years of age with severe abdominal pain, patients 70 years of age, and immunocompromised patients (e.g., acquired immunodeficiency syndrome [AIDS], organ transplant recipient, or patients have cancer chemotherapy). The evaluation of any diarrheal illness should also consider the possibility of a noninfectious cause for the illness, such as medications, inflammatory bowel disease, radiation colitis, or malabsorption syndromes. Treatment entails the appropriate use of volume support (with Ringer's lactate the preferred agent in moderately severe shock), blood products, and pressor agents, and acetaminophen rather than nonsteroidal anti-inflammatory drugs for analgesia. Activities are gradually restored during prolonged convalescences. Endoscopic therapy is useful in evaluating and managing gastrointestinal hemorrhage although injection therapy with sclerosing agents is not beneficial in most dengue hemorrhagic states. Monitoring platelet counts does not usefully predict clinically significant bleeding. Monitoring for hemoconcentration, however, may help in anticipating the complications of dengue hemorrhagic fever or shock syndrome.

Treatment of Viral Hemorrhagic Fever

Rehydration Therapy Depending on the degree of dehydration and ongoing losses, fluids and electrolytes may be replaced intravenously or orally. The degree of dehydration is assessed by careful physical examination and measurement of vital signs. Severe dehydration is characterized by lethargy and inadequate oral intake; very sunken and dry eyes and a very dry tongue and mouth; and a very fast, weak or non plapable pulse. Other characteristics of dehydration include poor urine output and low blood pressure. Intravenous replacement therapies are warranted for severely dehydrated persons, or persons with intestinal ileus or who are unable to drink on their own. Mild to moderate dehydration can be treated primarily with oral replacement therapies. For adults able to drink normally, beverages containing glucose (e.g., lemonades, sweet sodas, or fruit juices) or soups

rich in electrolytes are recommended. In developing countries, oral replacement therapy solutions containing optimal concentrations of glucose, sodium, potassium, chloride, and bicarbonate are responsible for the significant reduction in mortality attributed to dehydration. These oral replacement solutions are effective because sodium absorption is accelerated in the presence of glucose.

Drug Therapy Bismuth Subsalicylate Bismuth subsalicylate is an antidiarrheal agent with antibacterial properties. Adverse effects of bismuth subsalicylate include darkening of the tongue and stools, tinnitus, and encephalopathy when high doses are used. Bismuth subsalicylate can interfere with the absorption of other medications such as doxycycline used in malaria prophylaxis, and fluoroquinolones used in the management of travelers diarrhea. Loperamide and Diphenoxylate/Atropine The antimotility agents loperamide and the combination product diphenoxylate/atropine provide symptomatic relief by slowing intestinal transit time. Loperamide is preferred over diphenoxylate/atropine because of its better efficacy, lower potential for adverse effects, and availability as an over-the-counter preparation. Diphenoxylate/atropine can cause drowsiness, dizziness, dry mouth, and urinary retention. Although controversial, experts do not recommend the use of antimotility drugs in persons with fever or bloody diarrheaor when invasive pathogens are suspected, because of concerns that prolonging the clearance of pathogens from the intestinal tract could worsen the severity of illness. Probiotics Probiotics are live microbial mixtures of bacteria and yeasts used to restore the normal intestinal flora, thereby reducing intestinal colonization with pathogenic organisms. Probiotics can also produce pathogen-inhibiting substances, inhibit pathogen adhesion to the GI tract, inhibit the action of microbial toxins, and stimulate immune defense mechanisms. Interest in probiotics stems in part from their potential to decrease the use of antibiotics. Disadvantages of probiotics include the lack of both well-controlled trials supporting their efficacy and quality controls on the manufacturing of these products, and the risk for systemic infection, particularly in the immunocompromised host. Some evidence supports the use of probiotics for the treatment of rotavirus diarrhea in children and as an adjunct for the treatment of recurrent C. difficile colitis.

Bibliography
McgrawHill Access Medicine Chapter 31 : Current Medical Dx & Tx > Infectious Diseases: Viral & Rickettsial > Viral Diseases >

Applied Therapeutics: The Clinical Use Of Drugs, 9th Edition > Table of Contents > Section Fifteen - Infectious Disorders > Chapter 62 - Infectious Diarrhea