Silent Infection Research Articles

Human babesiosis: Recent discoveries

Babesiosis is caused by intraerythrocytic parasites of the genus Babesia, which is a common animal infection worldwide. This protozoa requires both a competent vertebrate and a nonvertebrate host (Ixodes sp. etc.) to maintain the transmission cycle. Human babesiosis is predominantly caused by Babesia microti (rodent-borne piroplasm, an emerging zoonosis in humans in North America) and by Babesia divergens (bovine pathogen, in Europe). Occasionally, infection in America is caused also by a newly recognized species, so-called WA1 piroplasm. The spectrum of human babesiosis in the USA is broad, and ranges from an apparently silent infection to a fulminant. In Europe, babesiosis is considerably rarer, but more lethal (42% mortality rate in Europe and 5% in the USA, for clinically apparent infections) and mostly in splenectomized patients. Various determinants are involved in the severity of infection, such as age, immunocompetence and coinfection with other pathogens (Borrelia burgdorferi). B. microti antigens can trigger specific activation of T-cells and the infection can be effectively controlled by a Th1-dominant CD4+ T-cell response. The diagnosis of babesiosis should include examination of blood smears stained by Giemsa, as well as serologic evaluation with indirect immunofluorescent antibody tests and possibly PCR. The treatment of babesiosis depends on severity of cases; if it is mild it resolves spontaneously, whereas very severe cases with B. divergens require prompt treatment that includes erythrocyte exchange transfuision along with intravenous clindamycin and oral quinine to arrest hemolysis and prevent renalfailure. This paper offers an overview of recent developments in the investigation of Babesia sp. and babesiosis.

Improved detection of HCV Infection in hemodialysis patients using a new HCV RNA qualitative assay: experience of a transplant center

Hepatitis C virus (HCV) is frequently a silent infection in hemodialysis (HD) patients with a prevalence of 8-10%. Improving HCV detection in this population prior to transplantation is critical both for infection control and optimal patient care. To assess the current HCV testing practice of the National Institute for Transplantation (PCR testing of enzyme immunoassay (EIA) positive HD patients) by evaluating a subset of EIA positive and EIA negative samples with the VERSANT HCV RNA Qualitative Assay based on transcription mediated amplification (HCV Qual (TMA)) (sensitivity < or = 9.6 IU/ml) and in-house PCR (HCV Qual (PCR)) (sensitivity approximately 149 IU/ml). 2321 HD patients were screened by Abbott HCV EIA 2.0. A subset of 80/169 E IA positive samples and 100/2152 EIA negative samples were tested by both assays. TMA/PCR discordant samples were genotyped. PCR and TMA gave concordant results in 67/80 (83.8%) of EIA positive samples. 11/80 (14.7%) were reactive by HCV Qual (TMA), but not by HCV Qual (PCR); 2/80 (2.7%) were reactive by HCV Qual (PCR), but not by HCV Qual (TMA). 2/100 (2%) EIA negative samples were reactive and 95/100 (95%) were non-reactive by both assays. Three (3%) were only HCV Qual (TMA) reactive. 11/14 TMA+/PCR-samples with sufficient volume were genotyped. HCV Qual (TMA) identified active HCV infection in more EIA positive and EIA negative patients than HCV Qual (PCR) and should be part of our testing algorithm.

Dendritic cells harbor infectious porcine circovirus type 2 in the absence of apparent cell modulation or replication of the virus.

Dendritic cells (DCs) play crucial roles in innate and adaptive immune responses, rendering them critical targets for virus infections. Porcine circovirus type 2 (PCV2) is associated with the development of postweaning multisystemic wasting syndrome (PMWS) in piglets. We demonstrate here that 80 to 90% of monocyte-derived and bone marrow-derived DCs interact with PCV2 similar to the early stages of an infection. There was no evidence for virus replication, but the virus did persist in DCs without loss of infectivity nor the induction of cell death. This could reflect an abortive infection, but there was no evidence of virus uncoating-the infectivity remained intact for at least 5 days. Alternatively, the results may reflect DC endocytosis of antigenic material. However, there was no modulation of DC surface major histocompatibility complex class I and class II, CD80/86, CD25, CD16, or CD14. Furthermore, infected DC did not transmit virus to syngeneic T lymphocytes, even when the latter were activated. Such coculture did not induce PCV2 replication or death of the lymphocytes or DCs. These results demonstrate that PCV2 can persist in DCs in the absence of virus replication or degradation. Such a silent virus infection presents a novel mechanism of not only immune evasion but also escaping the DC degradation pathway. Because of their migratory capacity, infection of DCs thus provides a potent vehicle for transport of the virus throughout the host without the need for replication. In addition, the lymphopenia seen in PMWS is not a direct effect of the virus on lymphocytes but would require additional events, as proposed by others.

Determinación de células peroxidasa positivas en líquido seminal: ¿es un parámetro confiable para el diagnóstico de infección genital asintomática?

The presence of leukocytes, detected by peroxidase test in semen, can be a good indicator of infections in the male genital tract. Peroxidase positive cells have been positively correlated with elevated values of elastase, one of the major proteases liberated by granulocytes at the inflammation place. However, seminal granulocytes may not be adequately detected by the peroxidase test in comparison with immunological methods. To correlate the determination of peroxidase positive cells with the elastase level in the seminal plasma. Seminal plasma from 64 patients with a high number of round cells (> 106/ml) in semen, was studied. Correlation analysis was done using the Pearson correlation coefficient. No correlation between the level of granulocyte elastase and the number of peroxidase positive cells (r = 0.2237, p > 0.05), or even the number of round cells (r = 0.03934, p > 0.05) was observed. Our results suggest that the determination of peroxidase positive cells is not a reliable indicator of leukocytes in the seminal plasma and their absence do not discard a silent genital tract infection.

What we have learned from an antibiotic trial in fetal fibronectin positive women

Clinically silent upper genital tract microbial infections have been strongly associated with spontaneous preterm delivery, especially prior to 32 weeks gestational age. This condition represents a potentially preventable or reversible cause of preterm birth using safe, readily available, and inexpensive antibiotics. Fetal fibronectin detected in cervical and vaginal secretions between 22 to 24 weeks’ gestation is a powerful predictor of subsequent risk for spontaneous preterm delivery. Evidence indicates that the detection of fetal fibronectin in cervical/vaginal secretions could represent a marker for clinically silent upper genital tract microbial infection. Thus, the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (NICHD MFMU) Network performed a randomized clinical trial to determine if antibiotic treatment (metronidazole plus erythromycin) of asymptomatic women with a positive cervical or vaginal fetal fibronectin test in early pregnancy will reduce the risk of spontaneous preterm delivery. No significant difference was observed between the antibiotic- and placebo-treated groups for spontaneous preterm delivery before 37 week’s gestation (relative risk 1.17, 95% confidence interval 0.80-1.70). Therefore, use of the fetal fibronectin test to identify women for antibiotic treatment in an effort to prevent preterm birth should be discouraged, and current clinical use of the fetal fibronectin test should be limited to its negative predictive value.

Herpes Simplex Virus-Specific Memory CD8 + T Cells Are Selectively Activated and Retained in Latently Infected Sensory Ganglia

This study challenges the concept that herpes simplex virus type 1 (HSV-1) latency represents a silent infection that is ignored by the host immune system, and suggests antigen-directed retention of memory CD8 + T cells. CD8 + T cells specific for the immunodominant gB 498-505 HSV-1 epitope are selectively retained in the ophthalmic branch of the latently infected trigeminal ganglion, where they acquire and maintain an activation phenotype and the capacity to produce IFN-γ. Some CD8 + T cells showed TCR polarization to junctions with neurons. A gB 498-505 peptide-specific CD8 + T cell clone can block HSV-1 reactivation from latency in ex vivo trigeminal ganglion cultures. We conclude that CD8 + T cells provide active surveillance of HSV-1 gene expression in latently infected sensory neurons.

C3 in seminal plasma has no additional informative value in the diagnosis of infection/inflammation of the male genital tract

The objective of this study was to determine the clinical significance of complement fraction C3 (C3c) in seminal plasma. Therefore 120 samples from randomly chosen subfertile males without signs of genital tract infection were screened for C3 and for seminal leucocytes as markers for subclinical infection/inflammation. A comprehensive semen evaluation included sperm analysis, sperm migration testing, immunocytochemical round cell differentiation to determine seminal leucocyte counts and the leucocyte ratio and semen cultures, in aliquots of the same ejaculates. C3 concentrations were significantly correlated with leucocyte counts per ml (P < 0.002) and per ejaculate (P < 0.001), and with the leucocyte ratio (P < 0.001). No association of C3 concentrations with semen quality or with the bacterial colonization of semen samples was found. The significant association with seminal leucocytes suggests that C3 might be used as an additional marker for silent male genital tract infection. In comparison with semen leucocytes, C3 screening does not reveal any further information about semen quality or infection/inflammation pathogenesis of the male genital tract.

Tomorrow's challenges for herpesvirus management: potential applications of valacyclovir.

Controlled trials suggest that acyclovir/valacyclovir can provide significant clinical benefits when used for prophylaxis in the immunocompromised host. These findings implicate herpesvirus(es) in the pathogenesis of complex medical conditions, including graft rejection and death. However, it is not known which of the 8 herpesviruses are important under particular circumstances. Prime candidates for triggering adverse outcomes are cytomegalovirus (CMV) in solid organ transplant recipients (causing rejection), CMV and human herpesvirus type 6 (HHV-6) in bone marrow transplant patients (causing marrow suppression), and herpes simplex virus, HHV-6, and CMV in AIDS patients (accelerating the rate of human immunodeficiency virus disease progression and death). Other diseases that may have a herpesvirus component or trigger susceptible antiviral agents include atherosclerosis and multiple sclerosis. In the future, clinicians should be alert to novel findings of randomized trials that may provide insight into the pathogenesis of these diseases and the contributions made by clinically silent herpesvirus infections.

Lack of ‘occult’ hepatitis B virus infection in HIV-infected patients

Despite the normalization of transaminases and seroconversion after primary hepatitis B virus (HBV) infection, most adults do not eradicate the virus. HBV DNA has been detected by polymerase chain reaction (PCR) in serum and in peripheral blood mononuclear cells a long time after recovery from HBV infection [1,2]. Moreover, the reactivation of HBV infection after its apparent clearance may occur spontaneously and, more frequently, after immune suppression [3–5]. In addition, HBV DNA may persist in the liver after the loss of hepatitis B serum antigen (HBsAg) in the serum [6]. All these findings support the concept that HBV not only does not go away but somehow may remain ‘active’ after primary infection. Occult hepatitis B has been defined as the presence of low levels of serum HBV DNA, often only detected by PCR, in HBsAg-negative individuals [7]. The prevalence of this phenomenon has been claimed to depend on the level of endemicity of HBV in a region or specific population. It may be more frequent in individuals with hepatitis C virus (HCV) co-infection [8,9]. Among the underlying mechanisms that could explain the lack of other serological markers of HBV replication in individuals with positive serum HBV DNA are an interference between HBV and HCV, and the selection of HBV ‘escape variants’ caused by mutations in the S gene precluding HBsAg synthesis [10,11]. We hypothesized that states of immunosuppression, such as HIV infection, might result in a more frequent escape of HBV replication in individuals ‘cured’ after a previous episode of acute infection. Chronic states of low-level HBV replication might lead to breakthrough HBV viraemia and overt hepatitis (HBV reactivation) at some point in HIV-infected individuals. On the basis of this rationale, we searched for the presence of serum HBV DNA using a sensitive PCR assay in a cross-sectional study conducted on a large group of well-characterized HIV-positive patients with past exposure to HBV. All HIV-infected patients with negative serum HBsAg, positive anti-hepatitis B core antibodies, and not receiving lamivudine or tenofovir attending our clinic during 2000 were selected for the study. The main demographics and laboratory data from this population were recorded, including CD4 cell counts, plasma HIV-RNA and transaminase levels. A frozen sera retrieved from these individuals was tested for the presence of HBV DNA using an ultrasensitive quantitative PCR assay (HBV Monitor, Roche Diagnostics, Almere, the Netherlands), which has a lower limit of detection of 200 HBV-DNA copies/ml. A total of 85 patients (64 men and 21 women), with a median age of 37 years, were included in the study. The median (range) CD4 lymphocyte count was 506 (48–1485) cells/mm3, and the median (range) plasma HIV-RNA level was less than 50 (< 50–175 764) copies/ml. Most subjects were former intravenous drug users, and were anti-HCV positive. Median (range) transaminase levels were aspartate aminotransferase 49 IU/ml (14–328) and alanine aminotransferase 57 IU/ml (11–465). Serum HBV DNA was undetectable in all the subjects. Occult hepatitis B has been a matter of debate over the past few years [8–11], given its clinical and epidemiological implications. In HIV-infected patients, who often are co-infected with HCV, the recognition of silent HBV infections may be of particular relevance. On one hand, more severe HCV liver disease and much poorer response to interferon-based anti-HCV therapy may occur in individuals with low-level HBV replication [9,12–15]. The mechanism for the latter effect may be the downregulation of the interferon receptor gene expression in the liver by HBV [16]. On the other hand, a reactivation of HBV infection may eventually occur as a result of the immune suppression associated with HIV, as has been reported for cancer patients receiving chemotherapy [4,5,17,18]. Our results suggest that occult HBV infection is not a frequent phenomenon (if it exists at all) among HIV/HCV co-infected individuals. The population we studied included patients with a wide degree of immunosuppression, and yet a sensitive PCR failed to detect HBV DNA in any single specimen. The reasons for the discrepancy between our data and other studies, in which up to 46% of anti-hepatitis B core-positive/HBsAg-negative individuals were HBV DNA positive, are unclear [8–11]. However, an interference with HCV, known to inhibit HBV replication, does not explain the difference, given that many of those studies included HCV-infected patients [19]. Differences among the assays used might largely explain the discordance across studies. Whereas occult HBV infection with low levels of HBV replication could explain poorer responses to anti-HBC therapy and the resurgence of overt HBV hepatitis, our results suggest that this eventuality is rather rare in the setting of HIV infection.

Seminal antibodies to human 60kd heat shock protein (HSP 60) in male partners of subfertile couples.

Heat shock proteins (HSP) are essential mammalian and bacterial stress proteins. At the cellular level, they act as chaperones, have important regulatory functions, and are considered to be an essential factor for reproduction. Scarce information exists on the role of sensitization to HSP and the potential role in the aetiology of male infertility. The potential association of immunoglobulin (Ig)A antibodies (Ab) to the human 60 kDa heat shock protein (HSP 60) with several parameters of subclinical male genital tract infection/inflammation and with semen quality and sperm fertilizing capacity was analysed in a prospective study. IgA Ab to human HSP 60 were determined in seminal plasma of 202 randomly chosen male partners of subfertile couples with a median duration of infertility of 4 years (range 1-15 years), who were asymptomatic for genital tract infection. After medical history and clinical examination, a comprehensive evaluation of semen quality, in aliquots of the same ejaculates used for HSP Ab determination, included: sperm analysis; local antisperm antibody (ASA) screening; standardized sperm-cervical mucus (CM) penetration testing; immunocytochemical round cell differentiation to determine seminal leukocyte counts; evaluation of complement fraction C(3) and of some pro-inflammatory cytokines; and microbial screening. Subsequent fertility was recorded after 6 months. The presence of HSP 60 IgA Ab in seminal fluid (total positive 6.9%) was significantly associated with leukocytospermia, the presence of C(3), and also with high interleukin (IL) levels in seminal plasma. HSP 60 Ab were not related to the bacterial colonization of ejaculates. There was no association of seminal IgA Ab to human HSP 60 with semen quality, determined with microscopical semen analysis, nor with local IgG- or IgA-class ASA. There was no relationship with sperm intrinsic motility and duration of motility in the sperm CM-penetration test, nor with sperm fertilizing capacity. The combined presence of IgA Ab to human 60 kDa HSP, leukocytes and other established infection/inflammation markers in semen might suggest a potential role of the immune response to heat shock proteins (HSP) in cases of silent male genital tract infection, but the results do not indicate a marked relationship of HSP 60 Ab in seminal fluid with standard parameters of semen quality.

Are zinc levels in seminal plasma associated with seminal leukocytes and other determinants of semen quality?

Objective: To evaluate a potential association of zinc levels with seminal leukocytes, the outcome of semen cultures; and semen quality and sperm fertilizing capacity. Design: Prospective study. Setting: Outpatient infertility clinic of a university hospital. Patient(s): Two hundred fifty-six randomly chosen asymptomatic males from subfertile couples. Intervention(s): None. Main Outcome Measure(s): Determination of zinc in seminal plasma by flame atomic absorption spectroscopy. In aliquots of the same ejaculates the following tests were performed: immunocytochemical round cell differentiation to determine leukocyte counts and ratios, microbial screening, and comprehensive evaluation of semen quality (sperm analysis, biochemical parameters, antisperm antibody testing, and in vitro examination of sperm ability to penetrate cervical mucus). The patients underwent medical history, clinical examination, and postcoital testing. Subsequent fertility was determined (controlled for female infertility factors). Result(s): The concentration of zinc in seminal plasma did not correlate in a statistically significant way with leukocytes in semen, nor was it associated with bacterial colonization. There was no statistically significant relationship of zinc in seminal plasma or serum with semen quality parameters nor with local antisperm antibody testing of the IgG or IgA class. Zinc levels did not influence sperm capacity to penetrate cervical mucus in vitro or in vivo, and did not affect subsequent fertility. Conclusion(s): The zinc level in seminal fluid and serum is not associated with silent male genital tract infection (indicated by seminal leukocytes); nor is it related to semen cultures in asymptomatic individuals. The lack of association with other semen quality parameters indicates that the routine determination of zinc levels during infertility investigation is not recommended.

Nonpathogenic Lion and Puma Lentiviruses Impart Resistance to Superinfection by Virulent Feline Immunodeficiency Virus

Summary: Lion lentivirus (LLV) and puma lentivirus (PLV) exist as highly divergent virus clades among populations of indigenously infected nondomestic felidae. The feline immunodeficiency virus (FIV) is highly divergent from LLV and PLV and is pathogenic for domestic cats. When domestic cats are infected with LLV or PLV, they have immunologically and clinically silent persistent infections. We examined whether LLV or PLV infection might impart resistance to FIV superinfection in vitro by infecting domestic cat lymphoid cells with PLV and assessing resistance of these cells to FIV. We found that infection with FIV was highly restricted by prior established PLV infection. To examine whether this resistance applied in vivo, domestic cats were asymptomatically infected with either LLV or PLV and then challenged with pathogenic FIV. Although all cats became infected with FIV, prior LLV or PLV exposure blunted CD4+ cell depletion and suppressed plasma and peripheral blood mononuclear cell FIV loads relative to FIV-challenged controls not infected with LLV or PLV, despite the lack of prechallenge neutralizing antibody activity against FIV. Thus, as compared with naive controls, cats previously infected with LLV or PLV were able to more effectively control FIV infection and resist its immunologic effects, despite the substantial genetic divergence between these lentiviruses—raising the possibility that superinfection may impart resistance to lentivirus infection by heightening innate immune mechanisms.

Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load

AbstractPrimary infection with the human herpesvirus, Epstein-Barr virus (EBV), may result in subclinical seroconversion or may appear as infectious mononucleosis (IM), a lymphoproliferative disease of variable severity. Why primary infection manifests differently between patients is unknown, and, given the difficulties in identifying donors undergoing silent seroconversion, little information has been reported. However, a longstanding assumption has been held that IM represents an exaggerated form of the virologic and immunologic events of asymptomatic infection. T-cell receptor (TCR) repertoires of a unique cohort of subclinically infected patients undergoing silent infection were studied, and the results highlight a fundamental difference between the 2 forms of infection. In contrast to the massive T-cell expansions mobilized during the acute symptomatic phase of IM, asymptomatic donors largely maintain homeostatic T-cell control and peripheral blood repertoire diversity. This disparity cannot simply be linked to severity or spread of the infection because high levels of EBV DNA were found in the blood from both types of acute infection. The results suggest that large expansions of T cells within the blood during IM may not always be associated with the control of primary EBV infection and that they may represent an overreaction that exacerbates disease.

PNEUMONIA IN THE ELDERLY

Pneumonia, including community-acquired, LTCF-acquired, and nosocomial infections, is a major cause of morbidity and mortality among the elderly. The aged with pneumonia often present with atypical features, including confusion, lethargy, and general deterioration of condition (silent infection). Further investigations, such as a chest radiograph frequently are required for diagnosis. The chest radiograph may be normal early on in the course of infection, particularly in dehydrated patients. The elderly are hospitalized more frequently for pneumonia, have a greater need for intravenous therapy, have a longer hospital stay, have a more prolonged course, have greater morbidity, and ultimately have a poorer outcome. Nevertheless, it may not be chronologic age per se that has a negative impact on the manifestations and outcome of pneumonia in the elderly, but rather the presence of underlying comorbid illness. The mainstay of therapy for pneumonia is antibiotics, and studies in the community and hospital have confirmed the important positive impact of early appropriate empiric therapy on outcome. Many relatively simple procedures, including attention to nutrition, influenza and pneumococcal vaccination, and avoidance of intubation, may help limit the occurrence of such infections.

Role of silent hepatitis B virus in chronic hepatitis B surface antigen(−) liver disease

Despite a number of studies documenting hepatitis B virus (HBV) infection in the absence of hepatitis B surface antigen (HBsAg) a causal relationship between silent HBV infection and liver disease remain difficult to establish. In particular, both the prevalence and clinical significance of this observation are poorly understood. Why is HBV replication apparently so low in these patients? A number of studies have tried to elucidate the mechanism of HBsAg negative infections, and considerable data documenting HBV infectivity or reinfection in the absence of detectable HBsAg support the hypothesis that in some of these cases, HBV is undergoing low-level replication in the liver and this, in several situations including: (1) chronic liver disease, alcoholic liver disease, hepatocellular carcinoma; (2) viral reactivation following cancer chemotherapy or immunosuppression and (3) transmission via transfusion or from human serum to chimpanzees. In a recent study including 50 patients with chronic liver disease of unknown etiology we could detect serum HBV DNA by nested polymerase chain reaction (PCR) in 15/50 patients (50% at the cirrhosis stage) in the absence of HBsAg; in the liver of the 15 patients both HBcAg and/or HBsAg can be detected at very low-level. Viral host factors allowing HBV persistence in the absence of HBsAg can depend on several mechanisms. Coinfections with HCV can explain only a proportion of HBsAg(−) HBV infections. Secondly, HBV mutations in the core promotor region leading to a minimal viral replication, or mutations in the HBsAg-encoding region might explain the absence of serological recognition. Finally, it is possible that in some cases host immune mechanisms can maintain HBV infection in a latent state until transmission to another individual who subsequently develops a more active infection especially when immunosuppressive therapy is employed. Existence of HBsAg(−) HBV infections should be taken into account by the use of sensitive PCR tests for prevention of viral transmission in the settings of blood donations and organ transplants.

Bronchoalveolar lavage macrophage and lymphocyte phenotypes in lung transplant recipients

Background Recent publications have demonstrated potentially pathologic changes in bronchoalveolar lavage (BAL) from clinically stable lung transplant recipients (SLTRs), but there are few available data on alveolar macrophages (AMs). We formulated the hypothesis that changes in BAL AM and lymphocyte phenotypes would be apparent even in SLTRs. Methods A cross-sectional study using a standardized 3 × 60 ml BAL, investigating lymphocyte and AM phenotypes in 19 SLTRs, 5 subjects with bronchiolitis obliterans syndrome (BOS) and 18 normal control volunteers. BAL lymphocyte and AM markers were assessed using flow cytometry. Results We confirmed a significant elevation of neutrophils in all lung transplant recipients with a more marked elevation in the BOS subjects. Flow-cytometric analysis showed increased numbers of natural killer (NK; CD56/CD16-positive) cells, increased CD11b- and CD11c-positive CD3 lymphocytes, increased CD8-positive lymphocytes and increased HLA-DR expression in CD8 cells from the lung transplant recipients, when compared with normals ( p < .005). In contrast, the expression of a number of AM surface markers, associated with a range of host defense functions against bacteria, fungi and viruses (CD11a, CD11b, CD11c, HLA-DR, CD14), was lower in both SLTRs and those with BOS ( p < .05). Conclusions These novel findings are consistent with complex lymphocyte and macrophage changes that may result from clinically silent infection, partially suppressed rejection, or both.

Is multiple sclerosis caused by a silent infection with malarial parasites? A historico-epidemiological approach: part I

Though many details are known about the epidemiology of multiple sclerosis (MS), its aetiology has remained an enigma. To find a solution to this problem, the concept of so called ‘anophelism without malaria’ was put on trial. ‘Anophelism without malaria’ is a basic assumption of the epidemiology of malaria. It means that there is no transmission of malaria in the temperate zone, although the insect vector (the different species of anopheles) can be found nearly everywhere. Starting with the results from blood tests of five patients suffering from MS which indicate an infection with plasmodia, the old hypothesis of the malarial aetiology of MS (Mannaberg 1899) is reappraised and compared with today’s pathological findings. A comparison of the old map of malaria with the later distribution of MS in the USA has been made, supporting the assumption that an infection with plasmodia in early childhood prevents a later disease, while a silent infection at the time of adolescence or later is its cause.

Is multiple sclerosis caused by a silent infection with malarial parasites? A historico-epidemiological approach: part II

The comparison between the old map of malaria and the later distribution of multiple sclerosis (MS) first carried out in the USA (Part I) is continued in Europe. The Italian ‘dilemma’ (Kurtzke), meaning the disappearance of the north–south gradient in Italy by recent surveys, can be solved when considering the dependence of malaria transmission in relation to the altitude. Further, the high prevalence of MS in earlier times in Mississippi, Louisianna and in the former province of Lucania in Italy can be explained by preceding epidemics of malaria. Brickner’s therapeutic trial with quinine in cases of MS patients is reevaluated, and by this the Jarisch-Herxheimer reaction is shown to exist in MS too. The possible significance of the old and rather forgotten provocative methods for the diagnosis of latent malaria is discussed.

Dermatological immune restoration syndrome: does it exist?

Dermatological conditions are often an early clue to HIV infection and are common. As the disease progresses patients develop a dominant Th-2 immunological response that may facilitate the development of a number of skin conditions. With antiretroviral therapy the Th-1 response is restored and some skin problems regress. But, paradoxically, some cutaneous conditions may worsen, such as herpes zoster, mucocutaneous herpes, eosinophilic folliculitis and mycobacterial infections. This may be because immune restoration of a host's immunity causes recognition of silent or latent infection and results in development of the condition.

In vitro activation of feline immunodeficiency virus in ramified microglial cells from asymptomatically infected cats.

Intravenous infection of cats with feline immunodeficiency virus was used as a model system to study activation of virus replication in brain-resident microglial cells in vitro. Virus release by ramified microglial cells isolated from subclinically infected animals was detectable in cell-free tissue culture supernatant only by reverse transcription and nested PCR of gag-specific RNA sequences and not by virion-associated reverse transcriptase activity. In contrast, cocultivation of in vivo-infected microglial cells with mitogen-activated peripheral blood mononuclear cells (PBMC) regularly allows detection of high virus yields in cell-free tissue culture fluid. Besides uptake and multiplication of microglia-derived virus in PBMC, release of virus from microglia is stimulated by cell contact with PBMC. The data suggest that T lymphocytes patrolling the central nervous system could reactivate the semilatent state of lentiviruses in microglial cells in the course of clinically silent central nervous system infection.