Management Of Viral Infections Research Articles

Viral infections in the elderly

PREVIEWViral diseases are an important cause of morbidity and mortality in elderly patients, whether they live in the community or in long-term care facilities. Management of viral infections in older adults is complicated by factors that include the infrequency or absence of common signs and symptoms of infection and adverse drug reactions. In this article, Drs Bader and McKinsey discuss the clinical features and treatment of herpes zoster and the respiratory diseases caused by influenza and respiratory syncytial virus (RSV).

Calibration Curves for Real-Time PCR

Despite the increasing use of real-time PCR in the diagnosis and management of viral infections, there are no published studies adequately addressing the optimum number of calibrators, the number of replicates of each calibrator, and the frequency with which calibration needs to be repeated. This study was designed to address these issues. Cycle threshold data (ABI 7700) was collected from >50 consecutive real-time PCR runs for hepatitis B and Epstein-Barr viruses. Our routine calibration curve made from serial 10-fold dilutions run in duplicate was compared with alternative options, including duplicate 100-fold dilutions, inclusion of a low-copy calibrator, and omission of the duplicate determination. Control data were used to examine the use of an average calibration curve made from multiple runs. Use of duplicate serial 10-fold dilutions led to the least imprecision, duplicate 100-fold dilutions had slightly higher imprecision, and calibration curves obtained with singlet measurements showed the greatest imprecision. For patient data, the duplicate 100-fold dilution calibration curve produced results that best matched those from the routine calibration curve. Use of singlet dilutions or inclusion of a low-copy calibrator produced poorer agreement. Variability in controls was lower with a daily calibration curve than with an average calibration curve. Duplicate 100-fold dilution calibration curves produced equivalent results and the same imprecision as curves with more calibrators, and thus are a valid alternative. Laboratories should carefully evaluate the variability resulting from the use of average calibration curves before adopting this approach.

Effects of Growth Hormone-Releasing Hormone on Bone Turnover in Human Immunodeficiency Virus-Infected Men with Fat Accumulation

GHRH is a potentially appealing strategy to simultaneously improve fat distribution and increase bone turnover in HIV-infected patients. We investigated the effects of GHRH (1 mg sc twice a day over 12 wk) in 31 HIV-infected men with abdominal fat accumulation (age 46 +/- 1 yr, body mass index 26.2 +/- 0.6 kg/m2) in a randomized, double-blind, placebo-controlled study. We previously reported significant effects of GHRH on IGF-I and truncal fat. In this study, we assessed whether GHRH increased markers of bone turnover. At baseline, 32% of our subjects (n = 10) demonstrated a bone density Z score less than -1.0 sd and greater than or equal to -2.5 sd, and 3% (n = 1) demonstrated a Z score of less than -2.5 sd. IGF-I correlated with N-terminal telopeptide (NTx) (r = 0.49, P = 0.005) and tended to correlate with C-terminal telopeptide (CTx) (r = 0.35, P = 0.06) at baseline. Of the bone resorption markers, CTx increased significantly (0.16 +/- 0.07 vs. -0.03 +/- 0.03 ng/ml, GHRH vs. placebo, P = 0.02), and NTx tended to increase in response to GHRH (2.8 +/- 1.4 vs. -0.5 +/- 1.0 nm bone collagen equivalent, GHRH vs. placebo, P = 0.07). Of the bone formation markers, N-terminal propeptide of type 1 procollagen increased (14.6 +/- 9 vs. -6.8 +/- 3.1 microg/liter, GHRH vs. placebo, P = 0.03) and osteocalcin tended to increase (8.4 +/- 3.0 vs. 2.0 +/- 1.6 ng/ml, GHRH vs. placebo, P = 0.06) in response to GHRH. The calciotropic hormones, calcium and phosphorus, did not change significantly. The change in IGF-I correlated with the change in NTx (r = 0.45, P = 0.02), CTx (r = 0.38, P = 0.05), and osteocalcin (r = 0.55, P = 0.002). GHRH improves fat distribution and bone metabolism in men with HIV-related fat accumulation. Long-term studies are needed to determine whether the stimulatory effects of GHRH on bone turnover will translate into increased bone density in this population.

Differences in the Tropism and Nitric Oxide Production by Goat Brain Cells Infected with Caprine Arthritis Encephalitis Virus

Different types of brain cells prepared from goat-kid cerebrum explant cultures were infected by direct application of Caprine Arthritis Encephalitis Virus (CAEV). Predominantly, cells of the monocyte-macrophage lineage were specifically infected by the virus as proviral DNA was detected in infected cultures by amplification of a 414 base-pair (bp) fragment of the viral gag-gene by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Nitric oxide (NO) production by infected brain cells under different treatment groups was quantified by photometric methods. Infected enriched microglia cells produced more NO than any other group of cells cultured from the goat brain cerebrum. The present study shows that microglia are targets cells infected by the CAE virus in the brain of goats. It is believed that this finding will assist in devising immuno-prophylactic and immuno-therapeutic measures to be adopted in the management of neurological dysfunctions resulting from retroviral infections. It is also possible that the present observation on the tropism of the virus with the attendant NO production may have important implications in the pathogenesis of retroviral and other viral infections of man and animals. Key Words: CAEV, RT-PCR, gag gene, microglia cells. Trop. Vet. Vol. 21: (3) 200-206 (2003)

Hepatic Cirrhosis Occurring in a Young Woodchuck (Marmota monax) Due to Vertical Transmission of Woodchuck Hepatitis Virus (WHV)

Histologic and clinicopathologic findings of a woodchuck (Marmota monax) vertically infected with woodchuck hepatitis virus (WHV) are presented. The liver exhibits marked cirrhotic changes, which is characteristic of the pre-transformation phase of WHV. At necropsy, the woodchuck exhibited ascites and the liver had a grossly nodular appearance. Microscopically, focal hepatocyte necrosis and inflammatory cells were observed in midzonal and periportal areas in the liver. In Macchiavellos stained sections, cytoplasmic inclusion bodies appeared reddish granular materials. We believe that this may represent a new suitable and cost-effective cirrhotic model for the disease processes associated with hepadnaviruses in a number of other species, most notably Hepatitis B virus infection in man.

Interferon for postresection recurrence of hepatocellular carcinoma

In a randomized, controlled trial, 30 hepatitis C virus-infected men who underwent hepatic resection for hepatocellular carcinoma (HCC) were subsequently randomized to receive either interferon (INF)-alpha (n = 15) or no interferon (n = 15). Eighty percent of patients had hepatitis C virus genotype 1b, and 20% of patients had genotype 2a. Patients in the treatment group were given IFN-alpha, 6 M IU i.m. daily for 2 wk, then three times weekly for 14 wk, and finally twice weekly for 88 wk. The investigators were blinded to the treatment assignment. The median duration of follow-up was approximately 3 and 2.5 yr for the IFN and control groups, respectively. Three patients (15%) did not complete IFN therapy as a result of side effects. In addition, four patients (20%) with recurrence of HCC had their IFN stopped before the end of the study to allow treatment of the tumor. In the IFN group, two patients had sustained viral response, and six had biochemical response. In a survival analysis that included all randomized patients, i.e., “intention to treat,” recurrent HCC was detected in five patients (30%) in the IFN-alpha group and in 12 control patients (80%) ( p = 0.037). The difference in the rate of HCC between the groups became apparent only after the first 2 yr of follow-up. The authors concluded that IFN-alpha therapy appears to decrease the recurrence of HCC after resection in patients with chronic hepatitis C infection.

Interferon for postresection recurrence of hepatocellular carcinoma.

Abstract In a randomized, controlled trial, 30 hepatitis C virus-infected men who underwent hepatic resection for hepatocellular carcinoma (HCC) were subsequently randomized to receive either interferon (INF)-alpha (n = 15) or no interferon (n = 15). Eighty percent of patients had hepatitis C virus genotype 1b, and 20% of patients had genotype 2a. Patients in the treatment group were given IFN-alpha, 6 M IU i.m. daily for 2 wk, then three times weekly for 14 wk, and finally twice weekly for 88 wk. The investigators were blinded to the treatment assignment. The median duration of follow-up was approximately 3 and 2.5 yr for the IFN and control groups, respectively. Three patients (15%) did not complete IFN therapy as a result of side effects. In addition, four patients (20%) with recurrence of HCC had their IFN stopped before the end of the study to allow treatment of the tumor. In the IFN group, two patients had sustained viral response, and six had biochemical response. In a survival analysis that included all randomized patients, i.e., “intention to treat,” recurrent HCC was detected in five patients (30%) in the IFN-alpha group and in 12 control patients (80%) (p = 0.037). The difference in the rate of HCC between the groups became apparent only after the first 2 yr of follow-up. The authors concluded that IFN-alpha therapy appears to decrease the recurrence of HCC after resection in patients with chronic hepatitis C infection.

Management of viral infections in immunocompromised cancer patients.

Immunocompromised cancer patients are at elevated risk for serious viral disease. The introduction into clinical use of potent antiviral agents and of rapid diagnostic tests resulted in the development of efficient management strategies for infections due to herpes simplex virus, varicellazoster virus, and cytomegalovirus. The emergence of herpesvirus resistance to acyclovir, ganciclovir, cidofovir, or foscarnet represents an important challenge. The new neuraminidase inhibitors zanamivir and oseltamivir are efficacious in the treatment of influenza in otherwise healthy adults, and need to be investigated among immunodeficient patients with malignancy. Preliminary data on pleconaril, a first broad-spectrum anti-picornaviral compound, are promising.

Management of viral infections in immunocompromised cancer patients.

Immunocompromised cancer patients are at elevated risk for serious viral disease. The introduction into clinical use of potent antiviral agents and of rapid diagnostic tests resulted in the development of efficient management strategies for infections due to herpes simplex virus, varicellazoster virus, and cytomegalovirus. The emergence of herpesvirus resistance to acyclovir, ganciclovir, cidofovir, or foscarnet represents an important challenge. The new neuraminidase inhibitors zanamivir and oseltamivir are efficacious in the treatment of influenza in otherwise healthy adults, and need to be investigated among immunodeficient patients with malignancy. Preliminary data on pleconaril, a first broad-spectrum anti-picornaviral compound, are promising.

Challenges and options in the management of viral infections after stem cell transplantation.

During the period of profound combined immunodeficiency after bone marrow or peripheral blood stem cell transplantation (SCT), patients are at increased risk for serious viral disease. Recent advances in rapid diagnostic methods and the introduction of potent antiviral compounds have made it possible to establish efficient management strategies for several herpesviruses. Acyclovir, valaciclovir, and famciclovir are widely used for the treatment of herpes simplex virus or varicella zoster virus disease. Intravenous ganciclovir, foscarnet, and cidofovir are available for prevention or therapy of cytomegalovirus disease, and oral valganciclovir could become a valuable alternative to intravenous treatment if shown to be effective and safe after SCT. Preliminary data on pleconaril for therapy of picornaviral disease are promising. Future investigations may help to clarify the role of the neuraminidase inhibitors zanamivir and oseltamivir in the management of influenza in SCT recipients. The emergence of viruses resistant to antiviral drugs is of concern, and alternative treatment strategies need to be defined.

Interferon: benefit beyond hepatitis therapy?

In a randomized, controlled trial, 30 hepatitis C virus–infected men who underwent hepatic resection for hepatocellular carcinoma (HCC) were subsequently randomized to receive either interferon α (n = 15) or no interferon (n = 15). Eighty percent of patients had HCV genotype 1b and 20% had genotype 2a. Patients in the treatment group were given interferon α (6 million IU i.m.) daily for 2 wk, then three times weekly for 14 wk, and finally twice weekly for 88 wk. The investigators were blinded to the treatment assignment. The median durations of follow-up were approximately 3 and 2.5 yr for the interferon and control groups, respectively. Three patients (15%) did not complete interferon therapy as a result of side effects. In addition, four patients (20%) with recurrence of HCC had their interferon stopped before the end of the study to allow treatment of the tumor. In the interferon group, two patients had sustained viral response and six had biochemical response. In a survival analysis that included all randomized patients ( i.e., intention to treat), recurrent HCC was detected in five patients (30%) in the interferon-α group and in 12 control patients (80%) ( p = 0.037). The difference in the rate of HCC between the groups became apparent only after the first 2 yr of follow-up. The authors concluded that interferon-α therapy appears to decrease the recurrence of HCC after resection in patients with chronic hepatitis C infection.

Interferon: benefit beyond hepatitis therapy?

In a randomized, controlled trial, 30 hepatitis C virus–infected men who underwent hepatic resection for hepatocellular carcinoma (HCC) were subsequently randomized to receive either interferon α (n = 15) or no interferon (n = 15). Eighty percent of patients had HCV genotype 1b and 20% had genotype 2a. Patients in the treatment group were given interferon α (6 million IU i.m.) daily for 2 wk, then three times weekly for 14 wk, and finally twice weekly for 88 wk. The investigators were blinded to the treatment assignment. The median durations of follow-up were approximately 3 and 2.5 yr for the interferon and control groups, respectively. Three patients (15%) did not complete interferon therapy as a result of side effects. In addition, four patients (20%) with recurrence of HCC had their interferon stopped before the end of the study to allow treatment of the tumor. In the interferon group, two patients had sustained viral response and six had biochemical response. In a survival analysis that included all randomized patients (i.e., intention to treat), recurrent HCC was detected in five patients (30%) in the interferon-α group and in 12 control patients (80%) (p = 0.037). The difference in the rate of HCC between the groups became apparent only after the first 2 yr of follow-up. The authors concluded that interferon-α therapy appears to decrease the recurrence of HCC after resection in patients with chronic hepatitis C infection.

Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo

Oseltamivir phosphate (Tamiflu, Ro 64-0796) is the first orally administered neuraminidase (NA) inhibitor approved for use in treatment and prevention of influenza virus infection in man. Oseltamivir phosphate is the pro-drug of the active metabolite oseltamivir carboxylate (Ro 64-0802). Extensive monitoring throughout the oseltamivir development programme has identified a very low incidence of patients who have carried drug-resistant virus. The predominant mutation seen is the substitution of arginine for lysine at position 292 of the viral NA. The fitness of clinically isolated influenza virus A/Sydney/5/97 (H3N2) carrying this mutation was markedly reduced in animal models of influenza virus infection. The infectivity and replicative abilities of R292K mutant virus were reduced by at least 2 logs in a mouse model of influenza infection and by 2 and 4 logs, respectively, in the ferret model. Pathogenicity of R292K influenza virus A/Sydney/5/97 was reduced in ferrets as measured by inflammatory and febrile responses at least in parallel to the decrease in replicative ability. The data indicate that the R292K NA mutation compromises viral fitness such that virus carrying this mutation is unlikely to be of significant clinical consequence in man.

Immunomodulatory therapy in the management of viral infections in patients with HIV infection

Human immunodeficiency virus (HIV) causes disease by infecting lymphocytes and progressively destroying critical regulatory and effector cells of the immune system, leaving patients vulnerable to a number of bacterial, fungal, and viral infections. Facial herpes (herpes simplex virus-1 [HSV-1]), genital herpes (HSV-2), herpes zoster (varicella zoster virus), oral hairy leukoplakia (Epstein-Barr virus), Kaposi’s sarcoma (HHV-8), molluscum contagiosum, condyloma acuminata (human papillomavirus [HPV-6, HPV-11]), plantar warts (HPV-1), and facial warts and flat warts (HPV-5) are some of the cutaneous viral diseases most commonly seen in HIV-infected patients. Two immunomodulatory agents, imiquimod (Aldara), shown to be safe and effective in the management of genital warts, and alitretinoin gel, shown to be safe and effective in the treatment of Kaposi’s sarcoma, may offer a new therapeutic approach to treatment of cutaneous viral diseases. There is a strong scientific rationale to suggest that imiquimod and alitretinoin gel may be useful in the treatment of a variety of cutaneous viral diseases that have been shown to respond to immunomodulatory drugs. This represents a new approach in the therapeutic treatment paradigm for treatment of cutaneous viral diseases at their site of infection. (J Am Acad Dermatol 2000;43:S27-30.)

T-cell memory: lessons from Epstein-Barr virus infection in man.

Epstein-Barr virus offers an ideal opportunity to follow the human T-cell response to a virus infection over time from its acute primary phase, as seen in infectious mononucleosis patients, into the memory phase that accompanies life-long virus persistence. Here we review recent evidence on the development and maturation of cytotoxic T-cell memory using this viral system.

Fasting Hyperinsulinemia in Human Immunodeficiency Virus-Infected Men: Relationship to Body Composition, Gonadal Function, and Protease Inhibitor Use

Fasting Hyperinsulinemia in Human Immunodeficiency Virus-Infected Men: Relationship to Body Composition, Gonadal Function, and Protease Inhibitor Use

Diagnosis and management of viral infections in intensive care units

The first part of this review will consider those viral infections that can result in organ failure severe enough to require a period of life support in an intensive care unit (ICU). The viruses included are those likely to be encountered, from time to time, in ICU around the UK. The laboratory diagnosis, antiviral treatment and infection control aspects will be discussed for viral lower respiratory tract infections, acute viral encephalitis and viral myocarditis. Viral hepatitis will be included in the second part, because in ICU most patients infected with these viruses will be there for reasons other than liver failure. The second part of the review will consider those blood-borne and persistent viral infections that can be transmitted to health care workers if they receive a penetrating injury while performing invasive procedures on infected patients in the ICU. The control of blood-borne viruses in the health care setting has been reviewed recently, 1 and is the subject of numerous important guideline document (the most recent is included in the references) and the details will not be presented in this review.

HIV type-1 infection of the cotton rat (Sigmodon fulviventer and S. hispidus).

Cotton rats (Sigmodon hispidus and S. fulviventer) are susceptible to many viruses that infect humans (e.g., poliovirus, respiratory syncytial virus, influenza virus, adenovirus, and parainfluenza virus) and have been influential in developing therapeutic clinical intervention strategies for many viral infections of man. This study set out to determine whether cotton rats are susceptible to infection with HIV type 1 (HIV-1). Results indicate that HIV-1 does infect the cotton rat and S. fulviventer is more susceptible than S. hispidus. The virus was passaged from animal to animal for a total of three serial passages; but HIV replicated poorly in vivo, was only detectable as proviral DNA, and never exceeded one provirus per 1.8 x 10(5) cotton rat peripheral blood mononuclear cells. Infection induced a distinct and characteristic anti-HIV antibody response that, in some animals, included neutralizing antibodies, recognized all of the major HIV-1 antigens and the antibodies lasted out to 52 wk post-infection. Neonate S. fulviventer were not more susceptible to infection than adults. In vitro culture studies produced indirect evidence of viral replication by detection of viral gag gene RNA in reverse transcriptase-PCR assays on viral culture supernatants. Collectively, these results indicate that HIV-1 can replicate in a nontransgenic rodent and that this system may have potential as an animal model for HIV-1 infection if viral replication rates can be improved in vivo.

Influenza virus resistance to neuraminidase inhibitors

The recent reports from Hong Kong of an avian influenza virus which caused the death of six people has served to remind us of the constant threat of pandemics posed by influenza. Recently, structure-based drug design has resulted in the discovery of a new class of antiviral agents which specifically target the influenza virus neuraminidase. Two neuraminidase inhibitors are currently undergoing clinical evaluation for the prevention and treatment of influenza virus infection in man. Here we review the results of in vitro and in vivo studies relating to the potential development of resistance to this new class of compounds.

Recent advances in the management of viral infections.

The immunocompromised cancer patient is vulnerable to a wide spectrum of viral pathogens (Table 1). There has been increasing recognition of viruses as clinically important pathogens in cancer patients during the past decade. In part this is attributable to improved diagnostic techniques to better recognize viral pathogens as causes of illnesses not earlier recognized to be virally caused. In part this is also due to the increasing dose intensity of cytoreductive regimens used to control cancer, the increasing use of bone marrow transplantation (BMT) in the treatment of neoplastic diseases, and improvements in supportive care that permit patients to survive bacterial and fungal infections that in the past might have led to death before viral illness became manifest. Thus, there are greater numbers of highly immunosuppressed patients with severe compromise in cell-mediated immunity, the major host defense against most viral pathogens.