Vol. 17, No. 23
THE JOHNS HOPKINS MICROBIOLOGY NEWSLETTER
Monday, June 8, 1998
A. Provided by Marguerite-Hawkins, Epidemiology and Disease Control Program, Division of Outbreak Investigation, Maryland Department of Health and Mental Hygiene.
From May 21, 1998 through May 27, 1998, 5 outbreaks have been reported to the Maryland Department of Health and Mental Hygiene. They are as follows: 3 food-related gastroenteritis, 1 presumed viral gastroenteritis and 1 outbreak of hemolysis in dialysis patients
B. The Johns Hopkins Hospital. Information provided by Dr. Edward Weir, Dept. of Pathology.
Patient History: The patient is a previously healthy 39 year old Asian-American female who presented with complaints of malaise, fatigue, anorexia, and a nonpruritic rash of 3 weeks duration. She reported a 22 pound weight loss in the 3 months prior to presentation. Physical examination was remarkable for generalized lymphadenopathy, hepatosplenomegaly, and a diffuse maculopapular skin rash involving the trunk and all four extremities. Initial laboratory results revealed hypercalcemia and a marked leukocytosis with increased lymphocytes, granulocytes, and eosinophils in the periphery. A peripheral blood smear showed numerous atypical lymphocytes with multilobed nuclei. CXR was notable for bilateral infiltrates. An axillary lymph node was biopsied for diagnosis. The patient is married and monogamous, and has no history of intravenous drug abuse. She has no recent travel history.
Organism: The clinical and laboratory manifestations of the above case are consistent with a diagnosis of acute adult T-cell leukemia/lymphoma (ATLL). Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent for both ATLL and a neurologic disorder known as tropical spastic paraparesis (TSP). HTLV-1 is a member of the oncovirinae subfamily of retroviruses. Previously known as RNA tumor viruses, the oncovirinae have been associated with unregulated cell proliferation resulting in the development of leukemias and lymphomas. HTLV-1 is a spherical, enveloped RNA virus with a diameter of 80 to 120 nm. The envelope contains viral glycoproteins and is formed by budding from the plasma membrane. The envelope surrounds a capsid that contains two identical copies of the positive-strand RNA genome inside an electron dense core. Like all retroviruses, the HTLV-1 genome carries three major genes (gag, pol, and env) which encode structural proteins and enzymes necessary for viral replication. At each end of the genome are long-terminal repeats (LTRs) which contain promoters, enhancers, and other gene sequences used for binding different cellular transcription factors. However, unique to the HTLV-1 genome is the trans-regulating gene tax-rex which codes for proteins involved in the regulation of viral expression. Specifically, rex codes for proteins which post-transcriptionally regulate the ratio of spliced to unspliced viral mRNAs. REX activity thus increases the expression of viral structural genes required for the production of infectious virus. TAX directs IL-2 production and the upregulation of IL-2 receptors on T cells, and thus promotes T cell proliferation. Although HTLV-1 is capable of infecting multiple types of human cells, it has a tropism for CD4+ T cells. Once inside the cell, the viral genome is insered randomly into the host cell's genome as a provirus, where it may lie dormant or begin to replicate. HTLV-1 is cell-dependent and unlike HIV, cannot transmit infection as a cell-free virus.
HTLV-1 infections are endemic in southwest Japan, the Caribbean basin, Taiwan, sub-Saharan Africa, and areas of South and Central America. In certain parts of Japan, seroprevalence is higher than 30% of the adult population and increases with age. In the U.S., HTLV-1 prevalence ranges from 0.025% in asymptomatic blood donors to 7-49% among IVDAs and prostitutes. The virus is transmitted through blood transfusions, sexual contact, intravenous drug abuse, and breast feeding. Intrauterine infection also occurs (approximately 8% of those born to infected mothers) but is less common than vertical transmission through breast milk (20%). The rate of transmission between husband and wife over a 10 year period is 60.8% from husband to wife and 0.4% from wife to husband. Seroconversion rates related to transfusion of contaminated blood products have ranged from 44 to 63%. Risk of transfusion-associated HTLV-1 infection was highest for those receiving blood products less than 1 week old. Transmission occurs via infected lymphocytes, and therefore, does not occur with transfusion of plasma or plasma-derived products.
Clinical Disease: ATLL is a distinctive mature T cell neoplasm originally described in Japanese patients in 1977. The association with HTLV-1 is based on isolation of the virus from T cells of patients with ATLL and the fact that HTLV-1 transforms normal T cells in vitro. Furthermore, more than 90% of patients with ATLL have been shown to have antibodies to HTLV-1. However, few people who develop HTLV-1 infection progress to ATLL, with estimates ranging from 1 to 4%. In most cases, the incubation period is 20-30 years. Accelerated onset of the disease has been associated with infection through blood transfusion. The clinical manifestations of ATLL vary and include lymphadenopathy, hepatosplenomegaly, marked leukocytosis with a predominance of abnormal lymphocytes characterized by "cloverleaf" morphology, skin involvement, and hypercalcemia associated with lytic bone lesions. Approximately 25% will present with lymphoma and no evidence of leukemia. Onset may be acute and result in rapid progression of disease, with a median survival of 11 months. Other patients may have a chronic or smoldering form of the disease which has been known to transform into the acute form of ATLL. In the smoldering form, low numbers (<3%) of "cloverleaf" lymphocytes are present in the circulation but the patient has no other manifestations of systemic disease. In contrast, patients with the chronic form have a substantial absolute lymphocytosis with readily identifiable (>10%) neoplastic cells. Even though these patients have evidence of organ infiltration, the clinical course is indolent and the median survival exceeds two years. Cause of death in these patients is often secondary to opportunistic infections.
Microbiology Laboratory Diagnosis: Current serologic screening tests detect antibodies to HTLV-1 by enzyme immunoassay (EIA). False negative results are not uncommon and are due to variability in antibody response to HTLV infection and low antibody levels in some patients. Confirmatory assays must be performed to rule out false positive results. Confirmatory tests include immunofluorescence staining, immunoblotting, and radioimmunoprecipitation assays. Diagnosis can also be achieved using Southern blot and PCR. Southern blot restriction mapping is the classic method for demonstrating HTLV-1 proviral sequences in lymphocytes from acute ATLL patients who have high numbers of infected cells. This technique, however, is not sufficiently sensitive to detect the low number of infected peripheral blood lymphocytes of asymptomatic HTLV-1 carriers. Better sensitivity is achieved with PCR using primers directed against a conserved region in tax-rex. The product of the tax-rex probe is 159 nucleotides. Alternatively, pol primers, which specifically bind and amplify the HTLV-1 polymerase region, may be used and probed with SK112 (polymerase I).
Treatment: A combination of AZT and interferon-alpha has been effective in some patients with ATLL. However, no particular therapy has been approved for the management of HTLV-1 infection. Measures used to limit the spread of HTLV-1 include sexual precautions, screening blood products, and increased awareness of potential risks and diseases. Unfortunately, maternal infection of children is very difficult to control. The use of routine screening procedures for HTLV would limit spread of the virus, but such measures have not been instituted.
References