v21n13

DEPARTMENT OF PATHOLOGY
The Johns Hopkins Medical Institutions

Vol. 21, No. 13
THE JOHNS HOPKINS MICROBIOLOGY NEWSLETTER
Tuesday, April 9, 2002

Provided by Karen Fujii, Division of Outbreak Investigation, Maryland Department of Health and Mental Hygiene.

8 outbreaks were reported to DHMH during MMWR Week 14 (March 31 - April 6):

5 GE-type illness outbreaks
1 Shigellosis outbreak at a daycare in Baltimore City
4 foodborne gastroenteritis outbreaks associated with food service facilities
(1 in Charles Co., 1 in Washington Co.,
1 in Anne Arundel Co., 1 in Prince George's Co.)
1 respiratory illness outbreak
1 influenza-like illness outbreak at a nursing home in Baltimore Co.
2 miscellaneous outbreaks
1 outbreak of vancomycin-resistant enterococci (VRE) at a nursing home in Talbot Co. (3 urine culture positive)
1 outbreak of sepsis among newborns at a hospital in Baltimore Co.
(5 culture-positive for Staphylococcus epidermidis, 1 culture-positive for Streptococcus viridans, 1 culture-positive for E. coli)

The Johns Hopkins Hospital, Department of Pathology, Information provided by, Jeffrey L. Seibel, MD, PhD, Department of Pathology

Patient Clinical Information: A 34 year-old African American female is 6 months status-post cadaveric renal transplantation for familial glomerulonephritis. She presents with malaise, fever and a dry cough. Pertinent laboratory values included a therapeutic FK506 level, white blood cells 1260 per cu mm, hemoglobin 8.3 g/dL, platelets 140,000 per cu mm, serum creatinine 1.4 mg/dL. Chest CT scan showed a nonspecific infiltrate in the base of the left lung. Sputum cultures were negative for bacteria and fungi. Blood submitted for CMV culture and antigenemia testing was negative. Parvovirus B19 PCR testing of blood was negative. The possibility of a human herpesvirus 6 infection was considered and the microbiology laboratory was consulted for information on HHV-6 testing.

Organism: HHV-6 was first described in 1986. It is a typical human herpesvirus with an envelope and a linear double-stranded DNA genome. However, it shares less than 5% sequence homology with other members of the group. There are A and B subtypes with 75-97% sequence homology, but which appear to differ in clinical patterns. The B subtype is more prevalent in primary infection and is the subtype most commonly found in saliva and peripheral blood mononuclear cells. The A subtype is more commonly identified in CSF, suggesting a more neurotropic tendency. HHV-6 grows in T lymphocytes, monocytes/macrophages and neuroglial cells. HHV-6 can replicate and produce mature virions within lymphocytes, in contrast to EBV which remains latent in lymphocytes.

Epidemiology and Clinical Manifestations: HHV-6 is associated with several specific diseases. Common infections of infants and children include Exanthem subitum (Sixth disease), infantile fever (without rash) and febrile seizures. Indeed, by the age of 2 years greater than 95% of children are seropositive for HHV-6. Transmission is likely through saliva, although maternal-fetal transmission may also occur. HHV-6 has also been implicated in lymphoproliferative disorders, meningoencephalitis, hepatitis and idiopathic thrombocytopenic purpura. It has been studied as a possible etiologic agent in multiple sclerosis and progressive multifocal leukoencephalopathy. Much attention has been focused recently on HHV-6 in immunocompromised individuals. In HIV-infected patients HHV-6 may reactivate, however it is uncertain whether active infections actually result. In bone marrow transplant patients HHV-6 infection has been correlated with pneumonitis, graft-versus host disease and rash. It has been suggested that HHV-6 may also cause adverse outcomes in solid organ transplants. The connection has been difficult to study due to the limitations of available HHV-6 laboratory tests.

Diagnosis: Due to its high seroprevalence, detection of anti-HHV-6 IgG is only useful in seeking seroconversion in an initially HHV-6 seronegative patient. Anti-HHV-6 IgM is not optimal either, since 5% of healthy adults can be positive and in children there are culture-proven cases in which an IgM response was not detected. HHV-6 subtypes cannot be distinguished serologically and in some assays there is cross-reaction with HHV-7. HHV-6 culture from peripheral mononuclear cells is theoretically useful, since latent virus should not grow in culture and healthy individuals do not harbor actively replicating virus. However, the culture involves in vitro manipulations of the patient's cells that may in some cases reactivate latent virus, leading to false positives. In addition, viral reactivation and reinfection does indeed occur in immunodeficient patients. However, it is unclear whether this actually correlates with clinical disease. Many PCR-based assays have been developed to detect the HHV-6 genome in serum, CSF and even tissue. Qualitative PCR assays, however, have low sensitivity and can falsely amplify latent viral DNA from degrading cells within the specimen. Attempts to circumvent these problems include using quantitative PCR methods and separately measuring viral load in the liquid and cellular fractions of the specimen. Despite the analytical sensitivity and specificity of these assays, it is thus far difficult to assess their utility without a clinical "gold standard" for clinically significant HHV-6 infection. Unfortunately, this problem also exists for other highly prevalent microorganisms for which PCR assays have been developed, e.g. CMV.

Treatment: HHV-6 in vitro sensitivity to antivirals has been tested, but no sizeable clinical studies have been performed. While foscarnet inhibits the virus, acyclovir does not. Ganciclovir effectiveness is variable.

Follow-up: The serum specimen was sent to an outside laboratory for HHV-6 PCR analysis. No HHV-6 virus was detected. The patient was treated empirically for bacterial pneumonia and improved clinically.

References:
1. Koneman et al. Color Atlas and Textbook of Diagnostic Microbiology, 5^thEdition, Lippincott-Raven, Philadelphia, 1997.

2. Brown KE. Principles and Practice of Infectious Diseases, 5^th Edition. Edited by GL Mandell, JE Bennett, and R Dolan. Churchill Livingstone, Inc., Philadelphia, 2000.

3. Locatelli G et al. Real-time Quantitative PCR for human herpesvirus 6 DNA. J Clin Microbiol (2000);38:4042-4048.

4. Yoshikawa T et al. A prospective study of human herpesvirus-6 infection in renal transplantation. Transplantation (1992);54:879-883.

5. Herbein G et al. Longitudinal study of human herpesvirus 6 infection in organ transplant recipients. Clin Infect Dis (1996);22:171-173.

6. Wade AW et al. Human herpes virus-6 or Epstein-Barr virus infection and acute allograft rejection in pediatric kidney transplant recipients: greater risk for immunologically naïve recipients. Transpl proc (1998);30:2091-2093.

7. Hall CB et al. Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. J Infect Dis (1998);26:132-137.