Antiviral agents.

In recent years, the antiviral armamentarium has expanded considerably. Currently available agents are virustatic, inhibiting specific steps in the process of viral replication. No agent is active against nonreplicating or latent viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex encephalitis, mucocutaneous herpetic infection, varicella infection in the immunosuppressed host, and herpes zoster infection in the normal and the immunosuppressed host. It can also be used for prevention of herpesvirus infection in immunocompromised patients. Ganciclovir is indicated for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS) and is effective in the management of organ-specific cytomegalovirus infection in other immunocompromised patients. Chronic hepatitis C and condyloma acuminatum due to human papillomavirus respond to therapy with interferon alfa-2b. Patients with human immunodeficiency virus infection and CD4 lymphocyte counts of less than 500 cells/mm3 should be treated with zidovudine. Amantadine is useful in a therapeutic and prophylactic role in the management of influenza A virus infection. With the expanded use of and indications for antiviral therapy, clinically significant resistance to these agents has been encountered with increasing frequency.     

Antiviral drugs in the immunocompetent host: part I. Treatment of hepatitis,cytomegalovirus, and herpes infections

Since the release of amantadine in 1966, other agents designed to fight a diverse range of viral infections have been released. Part I of this two-part article focuses on agents used to manage hepatitis, cytomegalovirus, and herpes infections. In patients with chronic hepatitis B, interferon alfa-2b or lamivudine is the treatment of choice. Pegylated interferon alfa-2a or -2b, along with ribavirin, is standard treatment for patients with chronic hepatitis C. Although treatment of cytomegalovirus infections generally is supportive, there have been reports of severely ill patients who improved after receiving ganciclovir or foscarnet. Oral antiviral agents for initial and recurrent herpes simplex virus infections have been shown to shorten the duration of lesions. Treatment of herpes zoster infections with antiviral drugs shortens the course of infection and decreases symptoms. Studies have shown that antiviral treatment can prevent prolonged post-herpetic neuralgia, although this use remains controversial.     

Antiviral agents

Only a few agents with antiviral activity are available for routine clinical use. Amantadine hydrochloride is effective in the prophylaxis of influenza A. In addition, accumulated evidence shows that amantadine has some therapeutic effect when used early in the course of an influenza A infection. Idoxuridine and adenine arabinoside have found application as topical agents in the treatment of herpes simplex keratitis. Adenine arabinoside has also been approved for the treatment of disseminated infections due to herpes zoster and herpes simplex. Acyclovir sodium has been approved as a topical agent in the treatment of limited mucocutaneous herpes simplex viral infections in immunosuppressed patients and of initial episodes of genital herpes simplex infections in patients with normal immunity. Ribavirin, an experimental agent with a wide spectrum of activity in vitro, has not fulfilled expectations in clinical trials. Because of the eradication of smallpox, methisazone has become obsolete as a prophylactic agent in smallpox.     

Dermatologic manifestations of infectious diseases in pregnancy

Several pathogens that have been identified as teratogenic or fetotoxic have associated dermatologic changes when active infection is present. Viral and bacterial teratogenic pathogens include herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, cytomegalovirus, human papilloma virus, human parvovirus B19, rubella, viral hepatitis, syphilis, and gonorrhea. This article focuses on the characteristic dermatologic manifestation of these diseases in pregnancy; diagnostic strategies; interpretation of maternal and fetal laboratory test results; treatment of the pregnant woman, fetus, and newborn; and congenital outcomes of treated and untreated infection. Emphasis is placed on vaccination and prevention of transmission of infection to pregnant women.     

Cellular and Humoral Immunity in the Pathogenesis of Recurrent Herpes Viral Infections in Patients with Lymphoma

86 patients with lymphoma were evaluated prospectively for clinical and laboratory evidence of recurrent varicella-zoster, herpes simplex, and cytomegalovirus infections during the first 16 mo of treatment. Cellular immunity to the viral antigens was measured by in vitro lymphocyte transformation and interferon production. Antibody titers and nonspecific measures of cellular immunity, including T-cell quantitation and transformation to phytohemagglutinin, were also assessed. The patients treated with radiation and chemotherapy had the highest incidence of reactivation of each of the viruses (15-19%). Greater susceptibility to herpes viral reactivation in these patients correlated with suppression of cell-mediated immunity to the specific virus. In individual patients, suppression of cellular immunity to the specific herpes viral antigen preceded each episode of reactivation, but recurrent infection did not occur in all patients with diminished specific lymphocyte transformation. Absence of the response appears to be a necessary but not a sufficient condition for the recrudescence of latent infection. Better preservation of cellular immunity to herpes simplex antigen during treatment was associated with infrequent reactivation of herpes simplex. In 25 patients with acute herpes zoster, uncomplicated recovery from the infection was accompanied by the development of lymphocyte transformation and interferon production to varicella-zoster antigen. Quantitation of T-cell numbers and phytohemagglutinin transformation did not correlate with the presence of viral cellular immunity in treated patients. Responses returned while T-cell numbers were low, and the recovery of phytohemagglutinin transformation often preceded recovery of the responses to viral antigens. Although some patients had deficiencies in viral cellular immunity at diagnosis, the duration of the suppression of specific antiviral responses resulting from treatment appears to be the most important factor predisposing to the recurrence of herpes infections in lymphoma patients.     

Diagnosis and management of viral infections

With the introduction of new diagnostic techniques and the expanding choices of antiviral agents, clinical virology is rapidly becoming an important field in infectious diseases. While effective therapy for several respiratory viruses, cytomegalovirus, hepatitis B virus, and Epstein-Barr virus is not currently available, herpes simplex, varicella zoster, and influenza A associated diseases can be adequately treated in many cases at the present time. New agents such as interferon, other nucleoside analogues, and immunomodulators are being investigated for their role in the treatment of viral illnesses, and many such illnesses with high morbidity and mortality may soon have effective therapy.     

Current concepts and challenges in the prevention and treatment of viral infections in immunocompromised cancer patients

 Patients with acute leukemia treated with intensive chemotherapy and recipients of bone marrow or peripheral blood stem cell transplants are at high risk of serious viral disease. Recent progress in diagnostic methods and in antiviral drug treatment has permitted the development of efficient management strategies particularly for infections due to herpes simplex virus, varicella-zoster virus, and cytomegalovirus in these patients. By contrast, specific treatment of other virus infections in immunocompromised cancer patients remains an unresolved issue. The emergence of herpesvirus resistance to antiviral drugs is a matter of concern, and its clinical importance among patients with malignancy needs to be elucidated. Future investigations may furthermore help to clarify the role of novel antiviral agents, such as cidofovir, lobucavir, and compound 1263W94, and of the adoptive immunotherapy with virus-specific CTL clones in severely immunodeficient cancer patients.     

Antiviral drugs 1983

A number of antiviral compounds are currently available, and several others are of great interest. Trifluridine, idoxuridine, and vidarabine are effective topically in herpes simplex virus keratoconjunctivitis infection. Vidarabine (and presumably acyclovir) is effective in herpes simplex virus encephalitis and in herpes zoster infections in the immunocompromised host. Acyclovir is effective topically, orally, and intravenously in primary herpes genitalis, and the oral and intravenous forms are effective in recurrent herpes genitalis as well. Amantadine and rimantadine are effective prophylactically and therapeutically in influenza A infections. Ribavirin and interferon, although not licensed, are of great interest. Ribavirin may be useful in respiratory syncytial virus infections, and interferon may be of benefit in common colds and related disorders.     

Viral pneumonias. A diagnostic and therapeutic challenge

Viral pneumonias are both a diagnostic and a therapeutic challenge for primary care physicians. The illness should be suspected when an upper respiratory tract infection progresses to include dyspnea and cyanosis. Rapid diagnostic tests are now available to detect most of the viruses that cause pneumonias. Fortunately, viral pneumonias usually resolve without specific antiviral therapy; however, ribavirin is indicated for respiratory syncytial virus pneumonia in children and ganciclovir sodium (Cytovene) for cytomegalovirus pneumonia in immunocompromised patients. Acyclovir (Zovirax) is indicated for pneumonias due to herpes simplex virus and varicella-zoster virus infections. A high index of suspicion for bacterial superinfections is essential to reduce the risk of death from this complication.     

Viral Infections in the Neonate

Maternal to child transmission of viral infections can have devastating outcomes on the developing fetus and the neonate. Effective prevention and screening programs for women of childbearing age are key factors in influencing the outcomes for the neonate. Furthermore, early identification of viral infections in neonates is critical to the success of the treatment plan. This article describes the mechanism of maternal to child transmission of viral infections and examines the general approach to the neonate with suspected viral infection. The diagnosis, treatment, and prevention of neonatal cytomegalovirus, herpes simplex virus, and human immunodeficiency virus infections are presented. Lastly, current challenges and controversies related to the management of viral infections in the neonate are discussed.     

病毒性脑炎急性期的治疗

病毒性脑炎是指病毒感染引起的脑实质的炎症。发热、头痛、意识障碍、精神症状、抽搐、神经系统定位体征是其主要临床表现。许多病毒可引起本病,常见的有单纯疱疹病毒、水痘-带状疱疹病毒、巨细胞病毒、肠道病毒70及71、麻疹病毒、风疹病毒、流行性腮腺炎病毒及黄病毒属等,单纯疱疹病毒性脑炎最常见。目前临床大多采取综合性治疗,抗病毒、脑细胞的保护、重要脏器功能的维持、并发症的预防。现对本病急性期治疗的进展作一综述。     

Herpes Virus Infections in Immunocompromised Patients: Problems and Therapeutic Interventions

Herpes virus infections are reponsible for morbidity and mortality among immuno-suppressed patients. During the last decade substantial advances have been achieved through improvement of diagnostic techniques, development of effective antiviral agents and the use of different strategies for prophylaxis and treatment. Cytomegalovirus infection and disease can today be prevented and treated effectively; however, antiviral resistance is beginning to emerge as a potential major clinical problem. Similarly, infections with herpes simplex virus and varicella-zoster virus can be effectively treated, but antiviral resistance has also emerged for these viruses. Two new herpes viruses, human herpes viruses 6 and 7, have been discovered, and it is possible that these viruses can also cause significant problems in immunosuppressed individuals. New antiviral agents will be needed during the next decade to allow further advances in the treatment of herpes virus infections.     

9-(2-Phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency disease and opportunistic herpes simplex virus infections.

The murine model of acquired immunodeficiency disease was used to evaluate both the antiretroviral and antiherpetic activities of the acyclic nucleotide analog 9-(2-phosphonylmethoxyethyl)adenine (PMEA). The antiretroviral activity of PMEA was compared with that of azidothymidine (AZT) in mice receiving the drug either immediately after infection or at late times in disease progression. Both AZT (oral, 30 mg/kg) and PMEA (parenteral, 25 and 5 mg/kg) were effective in slowing the development of disease when administered daily beginning on the day of infection. In contrast, neither drug alone was effective in modifying disease outcome when administered several weeks after viral infection. Human recombinant alpha interferon (rhuIFN alpha-B/D at 5 x 10(7) U/kg) was also ineffective when administered late in the course of disease. However, when administered in combination, both alpha interferon and PMEA (25 mg/kg) were able to suppress disease progression even when treatment was initiated as late as 3 weeks postinfection. Mice that were immunocompromised due to LP-BM5 virus infection were highly susceptible to acute (lethal) infection with herpes simplex virus type 1, whereas their immunocompetent littermates were not. PMEA was as effective as acyclovir in the treatment of opportunistic herpes simplex virus type 1 infections in LP-BM5 virus-infected mice. Thus, like AZT, PMEA was effective against retrovirus infection, and, like acyclovir, PMEA was effective against herpes simplex virus type 1 infection. This gives PMEA the unique potential of being useful in the treatment of opportunistic herpes simplex virus infections as well as the underlying retroviral disease.     

Occult herpes family viral infections are endemic in critically ill surgical patients

OBJECTIVE: Herpes family viruses have been recognized as pathogens for many years in immunosuppressed transplant or human immunodeficiency virus patients, but they have garnered little attention as potential pathogens in the nonimmunosuppressed critically ill. The objective of this study was to define the prevalence of and risk factors for development of herpes family virus infection in chronic critically ill surgical patients. DESIGN: Prospective epidemiologic study. SETTING: A 38-bed surgical intensive care unit in a major university hospital. PATIENTS: Nonimmunosuppressed intensive care unit patients in intensive care unit for >/=5 days. INTERVENTIONS: None; patients received no antiviral treatment during the study. MEASUREMENTS AND MAIN RESULTS: Weekly cultures for cytomegalovirus (CMV) and herpes simplex virus, viral serologies, and T-cell counts were performed. The prevalence (95% confidence interval) of positive respiratory cultures for herpes simplex or CMV was 35% (22-49%); 15% (5-25%) cultured positive for CMV, 23% (11-35%) cultured positive for herpes simplex virus, and one patient's respiratory secretions culturing positive for both CMV and herpes simplex virus. The prevalence of CMV viremia was only 5.8% (1-10%). CMV+ patients had longer hospital admissions, intensive care unit admissions, and periods of ventilator dependence than CMV- patients, despite having comparable severity of illness scores. CMV+ patients also had significantly higher numbers of blood transfusions, prevalence of steroid exposure, and prevalence of hepatic dysfunction, and all were immunoglobulin G positive at the beginning of the study. In contrast, herpes simplex virus-positive patients had lengths of hospital admissions, lengths of intensive care unit admissions, and periods of ventilator dependence comparable with patients without viral infections (p >.05). CONCLUSIONS: There is a significant prevalence (22-49%) of occult active herpes family viruses in chronic critically ill surgical patients. The clinical significance of these viral infections is unknown, although CMV+ patients have significantly higher morbidity rates than CMV- patients. Several factors suggest pathogenicity, but further study is needed to define causality.     

Genital herpes simplex virus infections

There has been a dramatic increase in patient visits to physicians for evaluation and treatment of genital herpes infections. This has resulted in part from an increase in genital herpes infections, particularly severe, first-episode genital herpes infections in adults without prior HSV-1 infection. Virus culture remains the most sensitive and specific method for diagnosis, and use of viral cultures is encouraged. Type-specific antibody tests have been employed in studies documenting the role of asymptomatic shedding of HSV in transmission of genital infections, the role of genital HSV in transmission of HIV, the predominance of asymptomatic and unrecognized infections in those infected with HSV-2, and the presence of past asymptomatic or unrecognized acquisition of HSV-2 in 25% of persons presenting with first-episode genital herpes. Unfortunately, commercially available serologic tests do not reliably differentiate between antibody to HSV-1 and HSV-2. Recent studies suggest that the annual risk of transmission from a sexual partner with genital herpes is about 10% in heterosexual couples. Currently, promotion of "safe sex" is the only available approach for prevention of transmission. However, ongoing research is focused on the development of an effective vaccine. Acyclovir should be used routinely in persons with first-episode genital herpes, but careful evaluation is needed in persons with recurrent genital herpes to determine whether episodic or suppressive treatment is indicated. Acyclovir should also be used routinely for episodic or suppressive treatment of HSV infections in persons with AIDS. Additional antiviral agents are needed for more effective suppressive therapy and for treatment of ACV-resistant HSV infections in the immunocompromised host.     

Novel approaches in fighting herpes simplex virus infections

The development of novel strategies to eradicate herpes simplex virus (HSV) is a global public health priority. While acyclovir and related nucleoside analogues provide successful modalities for treatment and suppression, HSV remains highly prevalent worldwide and is a major cofactor fueling the HIV epidemic. HSV is the predominant cause of genital ulcerative disease, and neonatal and sporadic infectious encephalitis. Asymptomatic shedding, which occurs more frequently than previously appreciated, contributes to viral transmission. Acyclovir resistance may be problematic for immunocompromised patients and highlights the need for new safe and effective agents. Ideally, vaccines to prevent infection, drugs to inhibit the establishment of or reactivation from latency, or vaginal microbicides to prevent sexual and perinatal transmission are needed to control the epidemic. This review summarizes current therapeutic options and strategies in development.     

Ocular viral infections

The most important viral organisms involving the eye are the DNA viruses herpes simplex, varicella-zoster, cytomegalovirus, adenovirus, and vaccinia virus. All of these agents except CMV may cause acute epithelial infection, sterile trophic ulceration due to basement membrane damage, deep corneal stromal immune reaction, and iritis. Although there are three excellent antiviral drugs commercially available, only HSV and vaccinia virus are highly sensitive to therapy with these antimetabolites; varicella-zoster virus and CMV are equivocally responsive and adenovirus has not been shown to be susceptible to these agents. In selected situations, topical or systemic corticosteroids are useful for managing any associated immune reactions in the eyes, but patients on these drugs should be monitored carefully both for superinfections and for interference with tissue healing that might ultimately threaten the integrity of the globe.     

CMV infection and pneumonia in hematological malignancies

While infection with cytomegalovirus (CMV), a member of the herpes virus family is a major cause of morbidity and mortality in patients who are immunosuppressed because of previous allogeneic bone marrow transplant, viral infection and subsequent disease are rarely reported in haematological diseases unrelated to this condition. We report here three cases of CMV pneumonia in patients affected by nonHodgkin lymphoma (NHL) and myeloma. The role of T-cell depletion is discussed.     

Oral and pharyngeal candidiasis. Topical agents for management and prevention

About half of the general population harbors Candida species in oral flora, and oral candidal infections are common. However, in immunocompromised or immunosuppressed patients, candidiasis may progress to life-threatening systemic disease. Patients with human immunodeficiency virus (HIV), acquired immunodeficiency syndrome, HIV disease, diabetes, or leukemia are particularly prone to serious systemic infection. Chemotherapy for cancer and bone marrow and organ transplantation also provide physiologic opportunities for candidal colonization. Topical therapy has the potential to prevent and treat candidiasis with less risk of side effects and drug interactions than systemic therapy. Among the effective topical agents are polyene antifungal antibiotics and imidazole compounds. Some of these agents have been found useful in prevention of serious candidal infection in high-risk patients; however, more study is needed in this area.     

Viral infections in severely immunocompromised cancer patients

Immunocompromised cancer patients are susceptible to infection by many viral pathogens. The most serious morbidity results from active infection by members of the herpes virus family. Reactivation of latent virus occurs as a sequela of cytotoxic therapy and deficiency of cell-mediated immunity, especially cytotoxic responses, the major host protective defense. Herpes simplex virus and varicella zoster virus infections are problematic in patients with all types of cancer; cytomegalovirus infections cause life-threatening morbidity in bone marrow transplant patients. Several antiviral agents are highly active against these pathogens and different strategies of using them have resulted in reduced morbidity and mortality. Ultimately, the resolution of these infections is dependent on the control of the malignancy and the ability of the patient to mount an adequate immune response.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994