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The patients were two American boys, seven and nine years old, living in Thailand, who almost simultaneously developed irritated eyes and slightly runny noses, progressing to fever, headache, and severe muscle pain. It hurt them to move their eyes, and they refused to walk because of pain in their legs.The symptoms subsided after a couple of days, only to recur at lesser intensity. No treatment was given, and they were completely back to normal within a week.Their illness was diagnosed as dengue (pronounced DEN-gay), also known as "breakbone fever."

1. What causes dengue and where does it occur?

2. Why is dengue important?

3. What is known about the pathogenesis of dengue?

4. What can be done to prevent dengue?

Discussion

1. Dengue is caused by any of four closely related flaviviruses, dengue 1,2,3, and 4.The disease occurs in large areas of the tropics and subtropics around the world. In the Americas, the disease is transmitted mainly by Aedes aegypti mosquitoes, which have staged a comeback after being almost eradicated in the 1960s.This vector now occurs year-

round along the Gulf of Mexico. Serious dengue epidemics occurred in Brazil and Cuba in 2002.

2. The two individuals presented here had a mild form of the disease that characteristically involves newcomers to an area where the disease commonly occurs. In endemic areas, the disease is characterized by fever, headache, muscle aches, rash, nausea, and vomiting. In a small percentage of cases, however, the effects of dengue infection are much more serious, resulting in dengue hemorrhagic fever.This form of the disease is characterized by bleeding and leakage of fluid from the capillaries. An important result is that the blood pressure drops, and the blood thickens.With expert treatment, the mortality is about 1% to 2%. Dengue shock syndrome is another potential development. It is characterized by profound shock and disseminated intravascular coagulation (DIC) and has a mortality above 40%.

3. About 90% of the cases of hemorrhagic fever or shock occur in subjects who have previously been infected by a dengue virus and have antibody to it.The remaining cases occur largely in infants who still have transplacentally acquired maternal antibody against dengue viruses.These antibodies, whether from earlier infection or from the mother, attach to the infecting dengue virus strain and thereby promote its uptake by macrophages.The virus, instead of being killed, reproduces in the macrophage.This results in the death of the macrophage and release of chemicals that cause leaky capillaries and shock.T lymphocytes may also play a role in this process in older children and adults. Evidence also exists that the virus causes a depression of the bone marrow, accounting for the very low white blood cell and platelet counts seen in dengue.

4. Scientists at Mahidol University in Bangkok and other research centers around the world are working on vaccines designed to bring dengue under control. At present, control efforts are largely directed at killing mosquitoes and their larvae and eliminating water containers around houses where the mosquitoes breed. Scientists at Colorado State University have successfully genetically engineered mosquitoes to render their cells incapable of reproducing dengue virus.This was accomplished by using another virus to introduce an antisense segment of the dengue genome into the mosquito cells.This was a dramatic accomplishment, but years of work remain before it can play a role in the control of dengue. ■ antisense technology, p. 176

Symptoms

Typically, symptoms of infectious mononucleosis appear after a long incubation period, usually 30 to 60 days. They consist of fever, a sore throat covered with pus, marked fatigue, and enlargement of the spleen and lymph nodes. In most cases, the fever and sore throat are gone in about 2 weeks, the enlarged lymph nodes in 3. Persons can usually return to school or work within 4 weeks, but some suffer severe exhaustion and difficulty concentrating that prohibits return to normal activities for months.

Causative Agent

Infectious mononucleosis is caused by the Epstein-Barr (EB) virus named after its discoverers, M. A. Epstein and Y. M. Barr. It is a double-stranded DNA virus of the herpesvirus family, and although identical in appearance, it is not closely related to any of the other known herpesviruses that cause human disease. This interesting virus was unknown until the early 1960s when it was isolated from Burkitt's lymphoma, a malignant tumor derived from B lymphocytes, common in parts of Africa. Subsequent studies showed that EB virus is the cause of infectious mononucleosis. ■ B lymphocytes, pp. 394,404

Pathogenesis

Primary infection with EB virus is analogous to throat infections with the herpes simplex virus in that both viruses initially infect the mouth and throat and then become latent in another cell type. The probable sequence of events is shown in figure 28.8.

Following replication in epithelium of the mouth, saliva-producing glands, and throat, the Epstein-Barr virus is carried by the lymphatics to the lymph nodes. There it infects B lymphocytes, which have specific surface receptors for the virus. During the illness, up to 20% of the circulating B lymphocytes are infected with the virus. The B-cell infection can be (1) productive, in which the virus replicates and kills the B cell, or (2) non-productive, in which the virus establishes a latent infection, existing as either extrachromosomal circular DNA, or integrated into the host cell chromosome at random sites. For most of these cells, the infection is non-productive, but profound changes in the cells result from the infection. The virus activates the B cells, causing multiple clones of B lymphocytes to proliferate and produce immunoglobulin. The infected cells are also "immortal," meaning that they can reproduce indefinitely in laboratory cultures.

The T lymphocytes respond actively to the infection and destroy any B cells with productive infections since these B cells display viral antigens on their surfaces. The abnormal-appearing lymphocytes characteristically seen in smears of the patient's blood are activated helper T cells (figure 28.9).

The proliferating lymphocytes are responsible for the large numbers of mononuclear cells that give the disease its name. Their numbers and appearance sometimes mistakenly suggest the diagnosis of leukemia, which is disproved when the patient spontaneously recovers. In many cases, a consequence of B-cell infection is the appearance of an IgM antibody that will react with an antigen on the red blood cells of certain animal species,

728 Chapter 28 Blood and Lymphatic Infections EB virus

" Epithelium

Activated lymphocyte i

Productively infected B cell

728 Chapter 28 Blood and Lymphatic Infections EB virus

" Epithelium

Productively infected B cell

Virus Infected

EB virus attaches to and infects epithelium of the throat, where it replicates and causes pharyngitis.

Lymphatic vessel

Blood vessel

Virions enter the lymphatic vessels and are carried to the lymph nodes. Some virions escape the lymph node trap and are carried to the bloodstream.

Virions attach specifically to B lymphocytes and infect them, producing either latent or productive infections.

Viral genome

Figure 28.8 Pathogenesis of Infectious Mononucleosis

EB virus attaches to and infects epithelium of the throat, where it replicates and causes pharyngitis.

Lymphatic vessel

Blood vessel

Virions enter the lymphatic vessels and are carried to the lymph nodes. Some virions escape the lymph node trap and are carried to the bloodstream.

Virions attach specifically to B lymphocytes and infect them, producing either latent or productive infections.

Activated lymphocyte

The infected B lymphocytes actively replicate and differentiate into cells producing random immunoglobulins, including heterophile antibody.

Plasma cells

Heterophile antibody

Productively infected B cell

Heterophile antibody

T cells respond to infection and destroy the lymphocytes replicating EB virus.

Lysed B cell

Activated T cell

The infected B lymphocytes actively replicate and differentiate into cells producing random immunoglobulins, including heterophile antibody.

Plasma cells

T cells respond to infection and destroy the lymphocytes replicating EB virus.

Viral genome

Latently infected B cell

Activated T cell

Latently infected B cell m mwm

Lysed B cell

Latently infected B lymphocytes become immortal. They are not attacked by T cells.

Figure 28.8 Pathogenesis of Infectious Mononucleosis notably sheep, horse, and ox. This kind of antibody arising against antigens of another animal is called a heterophile antibody. It generally has no pathologic significance, but its presence helps in diagnosing infectious mononucleosis. The antibody does not react specifically with EB virus. Enlargement of the lymph nodes and spleen reflects the active replication of lymphocytes. Hemorrhage from rupture of the enlarged spleen is the chief cause of the rare deaths due to infectious mononucleosis. It is most likely to occur within 3 to 4 weeks of the onset of illness. Patients are instructed to avoid exertion and contact sports, but almost half of the cases of splenic rupture occur in the absence of trauma.

The possibility that EB virus could play a role in causing certain malignant tumors has been intensely investigated. The malignancies most closely related to EB virus infection—Burkitt's lymphoma and nasopharyngeal carcinoma—cluster dramatically in certain populations. This suggests that factors other than simple EB viral infection must be present for these malignancies to develop. EB virus-associated Burkitt's lymphoma cases occur mainly in children in East Africa and New Guinea, whereas nasopharyngeal carcinoma is common in Southeast China. The EB virus genome is detectable in 90% to 100% of these two malignancies. Infectious mononucleosis has not been shown to increase risk of malignant tumors in otherwise healthy American college students. Evidence suggests that EB virus may be a fac tor, however, in some malignancies in patients with immunodeficiency from AIDS or organ transplantation.

Epidemiology

The EB virus is distributed worldwide and infects individuals in crowded, economically disadvantaged groups at an early age without producing significant illness. In such populations, the characteristic infectious mononucleosis syndrome is quite rare. More affluent populations such as students entering college in the United States often have escaped past infection with the agent and lack immunity to EB virus. In any year, an estimated 1.5 million college students will either have had the disease or will get it during the college year. Infectious mononucleosis occurs almost exclusively in adolescents and adults who lack antibody to the virus. Even in the age group of 15 to 24 years, however, only about half of the EB virus infections produce infectious mononucleosis; the remainder develop few or no symptoms.

EB virus is present in the saliva for up to 18 months after infectious mononucleosis, and thereafter it occurs intermittently for life. Continuous salivary shedding of virus is common in people with AIDS or other immunodeficiencies. Mouth-to-mouth kissing is an important mode of transmission of infectious mononucleosis in young adults, giving rise to the name "kissing disease." The donor of the virus is usually asymptomatic

Reactive Lymphocytes
(a)
Case Report Infectious Mononucleosis

Figure 28.9 Normal and Infectious Mononucleosis Blood Smears

Photomicrographs of (a) a normal blood smear showing two polymorphonuclear neutrophils (PMNs), a lymphocyte and a monocyte and (b) an infectious mononucleosis blood smear showing an abnormal lymphocyte.

Figure 28.9 Normal and Infectious Mononucleosis Blood Smears

Photomicrographs of (a) a normal blood smear showing two polymorphonuclear neutrophils (PMNs), a lymphocyte and a monocyte and (b) an infectious mononucleosis blood smear showing an abnormal lymphocyte.

and may have been infected in the past without developing symptoms of infectious mononucleosis. By middle age, most people have demonstrable antibody to the virus, indicating past infection. There is no animal reservoir.

Prevention and Treatment

Prevention is aided by avoiding the saliva of another person, as well as objects such as toothbrushes or drinking glasses possibly contaminated with another's saliva. No vaccine for infectious mononucleosis is available. The antiviral medication acyclovir inhibits productive infection by the virus and is of value in rare serious cases; however, it has no activity against the latent infection.

Table 28.6 gives the main features of infectious mononu-cleosis.

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