Tropical Manifestations of Common Viral Infections

Epidemiology

In 1964, EBV was first identified by Epstein, Achong, and Barr from a cultured African Burkitt's lymphoma using electron microscopy. More than 90% of adults in the world have been infected with EBV and carry the virus as a lifelong persistent infection. This population has latent infection of B lymphocytes and virus production in saliva. In the majority of cases, primary infection occurs subclinically during childhood, and is often spread between family members via salivary contact.

In low socioeconomic groups, EBV seroconversion occurs early in non-industrialized countries (i.e., in the tropics). In Thailand, the seroprevalence of anti-EBV immunoglobulin G (IgG) antibody in previously healthy hospitalized children aged 6 months to 15 years was 68.4%. Children who were reared at home had lower seroprevalence rates, further suggesting that EBV is more easily spread in crowded conditions.

A seroepidemiologic study in Bangladesh on 502 patients between 15 days and 90 years demonstrated an 81.3% prevalence of EBV infection. By the age of 1 year, 42.4% of infants had antibodies to EBV. In Turkey, a seroepidemiologic study of 540 subjects found seropositivity to be 99.4%.

In affluent industrialized nations, seroconversion may be delayed until adolescence, when infectious mononucleosis (IM) occurs in 50–74% of cases. Transplantation of organs with EBV infection into a previously seronegative recipient can cause infection, which is a risk factor for post-transplant lymphoproliferative disease (PTLD). The blood of healthy donors with latent EBV infection is another potential route of transmission.

Pathogenesis

EBV enters through the oropharyngeal passage and infects resting B cells and / or epithelial cells. In the productive primary phase, virus is released to infect B cells circulating in the oropharynx, resulting in a latent infection. The infected B cells induce an enormous expansion of virus-specific and non-specific T cells that cause the symptoms of IM. This antiviral T-cell response results in the regression of the infected B cells, which evade the immune system by limiting viral antigen expression of latent membrane protein 2 (LMP-2) and EBV-encoded RNA (EBERs). EBV then persists for the lifetime of the individual, periodically reactivating to shed virions and spreading the virus to new hosts.

There are two kinds of EBV (1 and 2 or A and B) circulating in the world, based on the polymorphism within the gene loci expressing Epstein–Barr nuclear antigen (EBNA) 2, 3A, 3B, and 3C proteins. The main difference is the reduced transformation capacity and thus the lower clinical aggressiveness of the type 2 virus. There is no specific disease association, but type 1 is more prevalent in the west, and types 1 and 2 are equally prevalent in Africa and Papua New Guinea.

Like others in the herpesvirus family, EBV can establish either a lytic or a latent infection in host cells. The EBV-infected tumor cells contain one of the three types of latent EBV infection, and expression of the latent EBV gene products is adequate for immortalization of B cells in vitro. The latent virus is replicated once per cell cycle as an episome using the host cell DNA polymerase, the viral oriP replication origin, and the viral EBNA-1 protein.

The role of EBV in oncology is thought to correlate with different types of viral latency and associated histology. Type I latency occurs when viral gene expression is limited to the EBNA-1 protein and BARF0. Burkitt's lymphoma typically exhibits type I latency. In type II latency, the cells express EBNA-1, LMP-1, LMP-2, and BARF0 (which is transcribed but possibly not translated). Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC) are the characteristic cancers associated with type II latency. Type III latency is associated with expression of all latency-associated proteins (EBNA-1, 2A, 2B, 3A, 3B, 3C, LP, BARF0) and the two viral membrane proteins LMP-1 and LMP-2. Post-transplant-type lymphomas, lymphoproliferative disease in immunocompromised, and lymphoblastoid B-cell lines typify type III latency.

Infectious Mononucleosis

In industrialized nations, IM, or glandular fever, is one of the common causes of prolonged illness in adolescents and young adults. The incubation period may last between 4 and 7 weeks, after which the patient may experience fever, sore throat, lymphadenopathy, splenomegaly, and hepatocellular dysfunction with possible jaundice. A rash, such as macular erythema, petechiae, and urticaria, occurs in only about 3% of cases, but concomitant administration of ampicillin or related anti­biotics results in rash in about 90% of cases. Hypersomnia, prolonged fatigue, and short-term depressive disorders are common after IM.

Serologic testing is the most common method of diagnosis confirmation. Although often absent in young children, heterophile antibody is present in 85% of adolescents and adults with IM. The Monospot is a quick slide test for the detection of heterophile antibodies, but false positives may occur with other viral infections, autoimmune disease, and lymphomas. A more sensitive and specific test is IgM to the Epstein–Barr viral capsid antigen (VCA), which may persist for 1–2 months. IgG to early antigens in the acute phase or EBNAs, which are associated with convalescence, may be useful in some cases.

Although high-dose acyclovir reduces virus production in the throat, it does not significantly alter the duration of symptoms. The symptoms of IM are due to secretion of cytokines by the large numbers of activated cytotoxic (CD8) T lymphocytes rather than to virus infection of B cells, which explains the lack of efficacy of acyclovir.

Chronic Active EPSTEIN–BARR VIRUS Infection

Chronic active Epstein–Barr virus (CAEBV) infection is a rare but serious condition that occurs in a previously healthy person after documented primary EBV infection. The peripheral blood has a significant increase of EBV load with infection of T and / or natural killer cells. The acute IM antibody pattern remains, including failure to produce antibodies to EBNA-1, high IgG, anti-VCA and early antigen, and sometimes persistence of anti-VCA IgM. Vital organ involvement often occurs, such as bone marrow hypoplasia, hepatitis, interstitial pneumonia, and splenomegaly. CAEBV has a high morbidity and mortality rate owing to hemophagocytic syndrome, hepatic failure, lymphoma, or sepsis. This condition is hard to treat, but adoptive immunotherapy or bone marrow transplantation has been reported to be useful.

Oral Hairy Leukoplakia

First reported in 1984, oral hairy leukoplakia was described in young male homosexuals who were immunosuppressed. It is now well documented to occur in all risk groups for HIV, including HIV-2, as well as in transplant patients and drug-induced immunosuppression. The prevalence has been estimated as between 7.5% and 25% of AIDS patients.

It is characterized by bilateral, elevated white patches with a verrucous or filiform, irregular surface that cannot be scraped off on the lateral borders and dorsum of the tongue ( Fig. 16-1 ). These asymptomatic, non-malignant lesions have also been found on the ventral surfaces of the tongue, buccal mucosa, floor of the mouth, palatal mucosa, and oropharynx. The presence of koilocytes in the superficial epithelial layers is the histologic pathognomonic sign. Other unique histopathologic features include a lack of a notable inflammatory infiltrate in the associated submucosa and profound acanthosis, often with koilocytic changes.

Oral hairy leukoplakia is the only EBV-related chronic disease where the virus replicates profusely. The amount of viral replication is directly proportional to the degree of keratinocyte differentiation. Further, in permissive herpesvirus infections where abundant virus production results in cell lysis, the epithelial cells housing this replicative activity remain intact.

Although its frequent association with HIV usually motivates the search for immunosuppression, oral hairy leukoplakia and its link with HIV in direct lesion development have not been determined. It has been related to a high HIV viral load and a low CD4 count. Oral hairy leukoplakia may develop secondary to EBV reactivation. The presence of EBV DNA in basal and parabasal lingual cells suggests that oral hairy leukoplakia in HIV patients might represent a reactivation of latent lingual infection. However, hematogenous superinfection of the tongue with EBV of HIV-positive individuals may precede or lead to the development of oral hairy leukoplakia. Recent studies have demonstrated that EBV-infected monocytes, macrophages, and Langerhans cells migrate and infect the differentiated cells of the spinous layer of the tongue and trigger extensive viral replication and spread. EBV strains replicating in the oral hairy leukoplakia lesion are different from those shed into the oral cavity, which had been hematogenously carried to the lingual epidermis.

Since the prevalence of HIV in Africa is so high, several studies have attempted to determine whether the prevalence of oral hairy leukoplakia is also elevated. Many studies have demonstated that the prevalence of oral hairy leukoplakia found in Africa is similar to the prevalence found in the USA. In other parts of the world, the prevalence of oral hairy leukoplakia in HIV-positive patients varies between India (3%), Singapore (5%), Hong Kong (11%), Thailand (7–26%), Cambodia (35.6%), and Australia (45.2%).

Since it is a benign lesion with low morbidity, oral hairy leukoplakia does not require specific treatment. However, the patient may wish to reduce symptoms such as discomfort, mild pain, and paresthesiae, or to treat the lesion for cosmetic reasons. To be effective, acyclovir has to be prescribed at a higher dose (800 mg five times a day). However, treatment failures with acyclovir occur commonly, especially in the immuno­compromised patient. One study showed that valacyclovir appears to be a safe and effective treatment in HIV-positive patients.

Cancers

EBV is one of the most diversely oncogenic viruses known. We will describe some of the cancers most commonly associated with EBV.