Cognitive impairment and infectious burden in the elderly.

Infectious agents have been suspected as contributing factors to dementia, especially in Alzheimer disease. We intended to test whether viral or bacterial seropositivity is associated with cognitive impairment among home-dwelling elderly. Viral burden (seropositivity for herpes simplex type 1 (HSVI), type 2 (HSV2), or cytomegalovirus (CMV), and bacterial burden (Chlamydia pneumoniae and Mycoplasma pneumoniae) were tested among 383 home-dwelling individuals with vascular disease (mainly coronary heart disease) in the ongoing DEBATE study (mean age 80 years). Mini-mental state examination (MMSE) and its changes were used to define cognitive impairment. At baseline, 0-1, 2, and 3 positive titers toward viruses were found in 48 (12.5 %), 229 (59.8 %), and 106 (27.7 %) individuals,respectively. MMSE points decreased with increasing viral burden (p = 0.03). At baseline,58 individuals (15.1 %) had cognitive impairment (MMSE < 24 points) which after adjustments was significantly associated with seropositivity for 3 viruses (risk ratio 2.5, 95%confidence interval 1.3 to 4.7). MMSE score decreased in 150 cases (43%) during 12-month follow-up. After adjustment for MMSE score at baseline and with 0-1 seropositivities as reference (1.0), the risk ratios were 1.8 (95 % confidence interval 0.9 to 3.6) and 2.3 (95% confidence interval 1.1 to 5.0) for 2 and 3 seropositivities, respectively. No significant associations were observed between bacterial burden and cognition. Viral burden of herpes virus and cytomegalovirus was associated with cognitive impairment in home-dwelling elderly. The association may offer a preventable cause of cognitive decline.

CMV infection is usually associated with concurrent HHV-6 and HHV-7 antigenemia in liver transplant patients.

Human herpesvirus 6 and 7 (HHV-6, HHV-7) have been recently reported in liver transplant patients. HHV-6 may cause fever, neurological disorders and hepatitis. The clinical significance of HHV-7 is less clear. HHV-6 and -7 are closely related to cytomegalovirus (CMV), and interactions between the viruses have also been suggested. In this study, we investigated the post transplant HHV-6 and -7 antigenemia was in relation to symptomatic CMV disease after liver transplantation. Consecutive 34 adult liver allograft recipients transplanted during 1999-2000 were included in the study. CMV infections were diagnosed by the frequent monitoring of pp65-antigenemia and by viral cultures. HHV-6 and -7 were demonstrated, by using immunoperoxidase staining and monoclonal antibodies against the virus specific antigens, in the mononuclear cells from the same blood specimens which were obtained for CMV pp65 monitoring. Altogether 322 blood specimens were analyzed. CMV disease was diagnosed in 12 (35%) patients during the first 3 months (first pp65 positive specimen mean 25 days, range 8-61 days) after transplantation. Concurrent HHV-6 antigenemia was detected in 10/12 (mean 14 days, range 6-22 days) and HHV-7 antigenemia in 9/12 patients (mean 25 days, range 10-89 days) after transplantation. HHV-6 usually appeared slightly before CMV. All CMV infections were successfully treated with ganciclovir and the CMV-antigenemia subsided. HHV-6 and -7 antigenemia also responded to the antiviral treatment, but more slowly than CMV. In conclusion, CMV infection was usually associated with HHV-6 and -7 antigenemia in liver transplant patients. The results support the suggestion that CMV, HHV-6 and -7 may have interactions. The clinical symptoms of CMV infection, may also be linked with HHV-6 or -7.

Infections of the central nervous system of suspected viral origin: a collaborative study from Finland.

We studied 3231 patients with acute central nervous system (CNS) symptoms of suspected viral origin to elucidate the current etiologic spectrum. In 46% of the cases, a viral finding was observed. Varicella-zoster virus (VZV) was the main agent associated with encephalitis, as well as meningitis and myelitis. VZV comprised 29% of all confirmed or probable etiologic agents. Herpes simplex virus (HSV) and enteroviruses accounted 11% each, and influenza A virus 7%. VZV seems to have achieved a major role in viral infections of CNS. In encephalitis in our population, VZV is clearly more commonly associated with these neurological diseases than HSV. The increase in VZV findings may in part be a pseudophenomenon due to improved diagnostic methods, however, a true increase may have occurred and the pathogenetic mechanisms behind this should be elucidated.

Seroetiology of acute lower respiratory infections among hospitalized children in Beijing.

BACKGROUND: Little is known of the etiology of childhood acute lower respiratory infections in China, where the use of antimicrobials is indiscriminate. Trials to change such a policy require etiologic data, especially on the bacteria most relevant to these common diseases. METHODS: One hundred consecutive infants and children from 3 months to 14 years of age with symptoms and signs compatible with acute lower respiratory infections were studied prospectively in the largest pediatric hospital in Beijing from February to May, 1997. Blood culture, thorax radiography and paired sera for 20 microbiologic assays were taken, and the course of illness was monitored uniformly. Disease severity was graded. RESULTS: In 24 cases there was evidence only of bacterial etiology, and in 5 solely viral agents were found; 3 children probably had a mixed bacterial-viral infection. Surprisingly no pneumococcal infection was detected, Mycoplasma pneumoniae (n = 21), Haemophilus influenzae type b (n = 8) and Chlamydia pneumoniae (n = 7) being the dominant bacteria. All children recovered. CONCLUSIONS: Routine use of antimicrobials for these patients seems unjustified. Serologic evidence for the H. influenzae type b etiology is encouraging in terms of vaccination, but confirmatory studies are needed.

A major role of viruses in convulsive status epilepticus in children: a prospective study of 22 children.

UNLABELLED: A group of 22 previously healthy children with their first convulsive status epilepticus (SE), treated at Kuopio University Hospital, Finland, were prospectively studied. Eleven children had febrile and 11 afebrile SE. Polymerase chain reaction was used to detect specific DNA from CSF, enzyme immunoassays and immunofluorescence assays to detect specific antibodies in serum and CSF, viral cultures were obtained from CSF, throat and stool and antigen detection from throat specimens. Viral infection was identified in 10 of 11 children with febrile SE (91%) and in 7 of 11 with afebrile SE (64%). Human herpes virus 6 infection was identified in 12 children (55%), and in at least six of them the infection was primary. Single cases of human herpes virus 7, parainfluenza 3, adenovirus 1, echovirus 22, rota, influenza A and Mycoplasma pneumoniae infection were diagnosed. CONCLUSION: Viruses, human herpes virus 6 in particular, seem to be major associated factors in convulsive status epilepticus, both febrile and afebrile. Human herpes virus 7 and Mycoplasma pneumoniae are novel agents associated with status epilepticus.

HHV-6 reactivation is often associated with CMV infection in liver transplant patients.

Human herpesvirus 6 (HHV-6) infection has been recently reported in liver transplant patients. HHV-6 is closely related to cytomegalo-virus (CMV), and some interaction between the viruses has been suggested. In this study, the post-transplant HHV-6 antigenemia was investigated in relation to symptomatic CMV infections in adult liver transplant patients. CMV infections were diagnosed by the pp65 antigenemia test and by viral cultures. HHV-6 infections were demonstrated by the HHV-6 antigenemia test and by serology. Significant symptomatic CMV infection was diagnosed in 42 of 75 patients during the first 6 months after transplantation. All CMV infections were successfully treated with ganciclovir. Concurrent HHV-6 antigenemia was detected in 21 (50%) of 42 patients with CMV infection. All HHV-6 infections were reactivations. HHV-6 also responded to the antiviral treatment, but with less clear effect. In conclusion, HHV-6 reactivation is often associated with CMV infection in liver transplant patients. The results support the suggestion that CMV and HHV-6 may have interactions.

Human herpesvirus-6 antigenemia after liver transplantation.

BACKGROUND: Human herpesvirus (HHV)-6 has recently been reported in liver transplant patients. It infects and causes dysfunction in hepatic transplants, which provides serious differential diagnostic problems between allograft rejection and viral infection. The diagnosis of posttransplantation HHV-6 infection is usually based on serology or on polymerase chain reaction detection of viral DNA in peripheral blood specimens. However, serology does not tell the exact time of the infection, and detection of viral DNA by polymerase chain reaction may also indicate a latent infection in seropositive patients. Here we report the diagnostic use of frequent monitoring of HHV-6 antigenemia after liver transplantation. METHODS: Altogether 622 blood specimens from 51 consecutive adult liver transplant patients were analyzed. The diagnosis was based on demonstration of HHV-6-specific antigens in peripheral blood mononuclear cells using immunoperoxidase staining and monoclonal antibodies and on serology. RESULTS: During the first year (7-280 days) after transplantation, HHV-6 infection was diagnosed in 11 (22%) of 51 patients. HHV-6 early antigens, as well as HHV-6 variant B antigens, were detected in all 11 patients. HHV-6 diagnosis was confirmed by serology. The episode of HHV-6 antigenemia usually lasted for several weeks together with mild, if any, clinical signs of the infection. A significant graft dysfunction was associated with HHV-6 antigenemia in 8 of 11 patients, and viral antigens were also detected in the liver biopsy specimens of 3 of these patients. CONCLUSIONS: An active HHV-6 infection can be diagnosed from peripheral blood by detection of virus-specific antigens in mononuclear cells. HHV-6 antigenemia correlated with seroresponse.

Human herpesvirus-6 associated encephalitis with subsequent infantile spasms and cerebellar astrocytoma.

A 14-month-old girl presented after 3 days of fever, floppiness, and diffuse urticarial exanthem. She developed encephalitis and carditis and 1 week later, intractable seizures. Initial CT and MRI showed no changes in the brain parenchyma. On days 14 and 34 after the onset of symptoms, a human herpesvirus-6 (HHV-6) genome in cerebrospinal fluid was identified by polymerase chain reaction (PCR). Convulsions became more frequent and 11 weeks from the onset, they changed to typical infantile spasms with hypsarrhythmic electroencephalogram. She gradually lost her social contact and ability to walk and sit. Eleven months after the primary infection, a repeated MRI of the brain revealed a cystic tumour of 2 cm in diameter near the vermis. The tumour was surgically removed, and shown to be a pilocytic astrocytoma on histopathological examination. HHV-6 DNA was detected by PCR in new tumour tissue. This is the first reported case of HHV-6 encephalitis associated with carditis, infantile spasms, and a subsequent brain tumour containing the HHV-6 genome.

Etiology of measles- and rubella-like illnesses in measles, mumps, and rubella-vaccinated children.

The viral etiology of measles- or rubella-like illnesses after MMR (measles, mumps, and rubella) vaccination was studied prospectively in 993 acutely ill Finnish children with fever and rash in 1983-1995. Their sera were tested for adeno-, entero-, and parvovirus B19 antibodies. Sera of 300 children <4 years old were also tested for human herpesvirus 6 (HHV-6) antibodies. Measles and rubella had been excluded by previous antibody testing. Serologic diagnosis of adeno-, entero-, or parvovirus infection was based on EIA (IgM or IgG antibodies) and that of HHV-6 on indirect immunofluorescence. A viral etiology was verified in 368 cases, most commonly parvovirus (20%), followed by enterovirus (9%) and adenovirus (4%). Among young children, HHV-6 infection was found in 37 (12%). Thirty-eight children (4%) had double infections. This study confirms that measles- or rubella-like illnesses in MMR-vaccinated children are often caused by other viruses. Each suspected vaccine failure requires laboratory confirmation to maintain reliable surveillance and control and to establish the specific etiology of the disease.

Immunoreactivation of Epstein-Barr virus due to cytomegalovirus primary infection.

Serological diagnosis of herpes virus infections is hampered by concurrent expression of IgM for heterologous members of this virus family. To assess the frequency of such multiple diagnostic findings and to understand their etiology, we sought by using IgG, IgM, and IgG avidity test serodiagnoses for Epstein-Barr virus (EBV) among immunocompetent or immune-suppressed patients with well-documented cytomegalovirus (CMV) primary infection. Controls had primary infection by EBV or had acute septic or severe respiratory infection. Among EBV-seropositive patients with CMV primary infection, a large proportion (13/56, 23%) showed antibody profiles of EBV reactivation: seroconversion of VCA IgM and/or > or = fourfold rise of VCA IgG, together with high or intermediate avidity of VCA IgG. Most of the CMV patients with EBV serodiagnosis showed also diagnostic HHV-6 antibody rises. In contrast to the frequently occurring CMV-induced EBV immunoreactivation, EBV primary infections did not appear to induce immunoreactivations of CMV (0/22). Only one (2%) CMV patient had a significant varicella zoster virus (VZV) antibody rise. The studies show that CMV is a particularly active inducer of some, but not all, members of the herpes virus family and suggest that the in vivo interplay between CMV and EBV occurs unidirectionally. The high frequency of heterologous herpes virus immunoreactivations poses demands on laboratory diagnosis.

Human herpesvirus-6 infection after liver transplantation.

A diagnosis of posttransplantation human herpesvirus-6 (HHV-6) infection was established for eight adult recipients among a liver transplantation patient population of 121. The diagnosis was based on serology and demonstration of HHV-6 specific antigens in liver biopsy specimens with use of monoclonal antibodies and immunoperoxidase staining. A significant graft dysfunction was recorded in association with serodiagnosis. HHV-6 early antigens, as well as HHV-6 variant B antigens, were detected retrospectively in all six available liver biopsy specimens. Histologic examination of biopsy specimens demonstrated acute rejection in 5 of the 8 patients, and 3 patients had portal lymphocyte infiltration. In five cases cytomegalovirus (CMV) infection was associated with HHV-6 infection; in four cases CMV antigens were also detected in the biopsy specimens. Two patients who had pure HHV-6 infection without CMV infection or rejection had significantly impaired graft function, with a positive antigen-detection test. Thus, HHV-6 may infect the liver allograft and cause graft dysfunction and may possibly be associated with rejection and/or CMV infection.

Growth of Chlamydia pneumoniae in cultured human peripheral blood mononuclear cells and induction of a cytokine response.

In vitro infection of freshly isolated human peripheral blood mononuclear cells (HPBMC) with Chlamydia pneumoniae was found to induce a production of tumour necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interferon alpha (IFN-alpha). The secretion was dependent on the amount of infecting chlamydiae and most of it occurred during the first 12 to 24 h. Lipopolysaccharide (LPS) of Salmonella minnesota Rechemotype, used as a positive control for HPBMC activation, induced a release of TNF-alpha, IL-1 beta and IL-6, but not of IFN-alpha, similar to the effect of C. pneumoniae. Viable chlamydiae could not be recovered from HPBMCs infected immediately after their isolation, whereas HPBMCs which were cultured in vitro for 3 to 9 days before infection were able to maintain the growth of C. pneumoniae. Growth inside HPBMCs as well as induction of cytokine response may have a role in the pathogenesis of C. pneumoniae infection.

Serology versus clinical signs or symptoms and main laboratory findings in the diagnosis of exanthema subitum (roseola infantum).

Twenty-five patients with clinical exanthema subitum (roseola infantum) were enrolled into a study, where acute-phase and convalescent sera were examined for antibodies to human herpesvirus 6 (HHV-6), several other viruses, and other microbes. In addition, an acute-phase fecal specimen was examined for viruses by electron microscopy. Confirmative or suggestive serologic evidence for recent HHV-6 infection was obtained in 23 (92%) cases. Conversion to HHV-6 was found in 19 (76%), a diagnostic (greater than or equal to 4-fold) titer rise in 2, a twofold titer rise in 1, and a stable relatively high titer in 1 of the patients; only 2 (8%) individuals remained negative. The other microbial assays produced only two slight mycoplasma antibody rises and one rotavirus identification in the fecal specimen. It is concluded that if the clinical diagnosis of exanthema subitum is deemed doubtful, HHV-6 infection is verifiable in about 75% of the cases by serology.

Virus-induced interferon production in human leukocytes: a low responder to one virus can be a high responder to another virus.

We measured the amounts of interferon (IFN) induced by four wild-type strains and two attenuated vaccine strains of poliovirus, testing each virus in 12-58 separate batches of human peripheral blood leukocytes. There were big and consistent differences in the mean amounts of IFN formed by leukocytes from different donors in response to all these polioviruses. Almost invariably, the wild-type polioviruses gave rise to more IFN than the corresponding attenuated strains, but overall, the amounts induced by one strain of poliovirus were proportional to those induced by another. There were indications of similar correlations with six different influenza viruses and with three strains of herpes simplex virus. In contrast, there was no correlation between the IFN yields induced with a poliovirus, three other enteroviruses, and various other viruses. These results suggest that the leukocytes from a given individual have a capacity to form IFN in vitro that is determined both by the genetic make-up of that individual and the particular virus concerned. If the same phenomenon applies to IFN production by cells in vivo, it may have a role in pathogenesis of viral infections.

Genivir (DIP-253) 1% cream versus placebo cream in the treatment of recurrent genital herpes: a double-blind study.

A total of 100 heterosexual adults of either sex with frequent episodes of recurrent genital herpes were allocated to treatment with either Genivir (DIP-253) 1% cream or placebo cream. All patients had genital herpes previously verified by a positive viral culture. The study was carried out as a double-blind parallel group trial. Fifty patients were allocated to each of the two treatment groups. The treatment was initiated within 24 hours after the first sign of a recurrence, and at the pretreatment examination all patients had developed typical lesions with blisters and/or sores. At baseline a sample for herpes virus culture and typing was obtained. The creams were applied four times daily for five days. Follow-up examinations were carried out on days 1, 2, 4 and if needed on days 7, 10 and 14. The major factor used for assessment of efficacy was the time to complete healing of all lesions. Duration of pruritus and pain were also recorded. In the group of patients treated with Genivir cream the time to complete healing was 3.3 days and in the placebo group 6.1 days. The difference was statistically significant (P less than 0.001). The mean duration of pain was 1.3 days in the Genivir group and 2.5 days in the placebo group: this difference also reached significance (P less than 0.01). The duration of pruritus was about the same in both groups. The active agent in Genivir, DIP-253, is a heterocyclic aromatic complex with confirmed anti-herpetic activity and with evidence of a local immunomodulatory effect. It was concluded that the efficacy of topical application of DIP-253 may be due to combined antiviral and immunomodulatory activities.

Severe encephalitis associated with disseminated echovirus 22 infection.

Severe encephalitis associated with disseminated echovirus 22 infection occurred in a previously healthy 5-month-old boy. Echovirus 22 was diagnosed by a seroconversion both in serum and cerebrospinal fluid and by isolation of the virus from several stool samples. The child damaged severely and at the age of 8 1/2 months infantile spasms developed.