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Clinical application of a dot blot test for diagnosis of enteric fever due to Salmonella enterica serovar typhi in patients with typhoid fever from Colombia and Peru.

Clinical application of a dot blot test to detect immunoglobulin G (IgG) (88% sensitivity and specificity) and IgM (12.1% sensitivity and 97% specificity) against flagellar antigen from Salmonella enterica serovar Typhi was performed in Peruvian and Colombian patients with typhoid fever. This test can be used as a good predictor of serovar Typhi infection in regions lacking laboratory facilities and in field studies.

Adolescent↗

DNA sequence analysis of glycoprotein G gene of bovine ephemeral fever virus and development of a double oil emulsion vaccine against bovine ephemeral fever.

The surface glycoprotein G is considered as the major neutralizing and protective antigen of bovine ephemeral fever virus (BEFV). Comparison of the deduced amino acid sequence of G protein of BEFV isolates during the period 1984-2004 outbreaks in Taiwan showed amino acid substitutions in the neutralizing epitopes. All the isolates differ markedly in the neutralizing epitope at the same amino acid positions compared to the currently available killed vaccine strain (Tn73). Tn88128 strain isolated in 1999 showed the maximum variability of 12 amino acids, 5 amino acid in the neutralization epitope and 7 apart from, respectively. Combinations of both Tn88128 (1999) and commercially available vaccine strain (Tn73) were developed and its safety was evaluated in mice, guinea pigs, calves, and pregnant cows. None of the animals showed any adverse effect or clinical signs. Calves were immunized with commercial vaccine (Tn73) and, combined vaccine (Tn73 and Tn88128), respectively, with adjuvants such as Al-gel and water-in-oil-in-water (w/o/w) oil and PBS alone and challenged with Tn88128 strains. Except PBS administered animals, all the vaccinated animals showed protective immune response. However, animals immunized with combined vaccine plus w/o/w adjuvant elicited stronger neutralization antibodies and long lasting immunity compared to other vaccines.

Amino Acid Sequence↗

Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax-DEN2) vaccine: Phase I clinical trial for safety and immunogenicity: effect of yellow fever pre-immunity in induction of cross neutralizing antibody responses to all 4 dengue serotypes.

A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax-DEN2) in comparison to that of YF vaccine (YF-VAX). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log10 PFU of ChimeriVax-DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naïve subjects inoculated with either ChimeriVax-DEN2 or YF-VAX. In contrast, 100% of YF immune subjects inoculated with ChimeriVax-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax-DEN2 vaccine is consistent with that of YF-VAX, and (2) preimmunity to YF virus does not interfere with ChimeriVax-DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.

Adolescent↗

Fever, jaundice, and multiple organ system failure associated with 17D-derived yellow fever vaccination, 1996-2001.

At the June 2001 meeting of the Advisory Committee for Immunization Practices (ACIP), seven cases of multiple organ system failure (MOSF) in recipients of 17D-derived yellow fever (YF) vaccine were presented. In response, an ACIP working group was formed to review the cases, assess the risk for serious adverse events following YF vaccination, and consider revision of the 1990 YF vaccination recommendations. This notice summarizes these cases and describes an enhanced surveillance program designed to refine risk estimates and improve histopathologic documentation of MOSF potentially associated with YF vaccination.

Fever↗

An epidemic of Rift Valley fever in Egypt. 1. Diagnosis of Rift Valley fever in man.

Rift Valley fever (RVF) virus was isolated from 53 of 56 sera collected from patients with a clinical picture of dengue-like illness during the peak of the epidemic of RVF in Egypt in the autumn of 1977. RVF virus was also isolated from the throat washings of two patients and the faeces of four, all of whom were positive for virus isolation from the serum. All the isolates were identified by the complement fixation (CF) test. Serological diagnosis of RVF, using paired sera from 16 patients, was made by both the haemagglutination-inhibition (HI) and CF tests. HI antibodies were demonstrated in all the acute sera, whereas CF antibodies, which seem to appear later, were detected in only seven acute and twelve convalescent sera. A longer period than the 12 days in this study must be allowed to elapse between the taking of the paired sera for a definite serological diagnosis to be obtained, especially when CF antibodies are taken into account.

Adult↗

Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa.

OBJECTIVE: To describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A low-penetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). METHODS: The MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured. RESULTS: Mutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Her IgD values varied between normal and slightly increased, and the MK activity was in the low-normal range, while urinary mevalonate concentrations were always normal. CONCLUSION: The genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS.

Adolescent↗

["Emerging infectious diseases". Dengue-fever, West-Nile-fever, SARS, avian influenza, HIV].

Some emerging infectious diseases have recently become endemic in Germany. Others remain confined to specific regions in the world. Physicians notice them only when travelers after infection in endemic areas present themselves with symptoms. Several of these emerging infections will be explained. HIV is an example for an imported pathogen which has become endemic in Germany. SARS and avian influenza are zoonoses with the potential to spread from person to person. Avian influenza in humans provides a possibility for the reassortment of a potential new pandemic strain. Outbreaks of dengue fever in endemic areas are reflected in increased infections in travelers returning from these areas. Currently, West-Nile-virus infections are only imported into Germany. The timely implementation of diagnostic, therapeutic and infection control measures requires physicians to include these diseases in their differential diagnosis. To achieve this goal, good cooperation between physicians, laboratories and the public health service is essential.

Animals↗

Use of the yellow fever virus vaccine strain 17D for the study of strategies for the treatment of yellow fever virus infections.

We have employed the attenuated vaccine strain 17D of yellow fever virus (YFV) to evaluate the inhibitory effect of a selected series of compounds on YFV in Vero cells. Use of the vaccine strain does not require high-level microbiological containment facilities and should allow extensive screening. In addition, YFV may serve as a model for other flaviviruses including hepatitis C virus (HCV), and thus strategies for the treatment of YFV infections may apply to flavivirus infections in general. In the present study, several compounds belonging to different classes of nucleoside analogues and polyanions were evaluated for their inhibitory effect on the replication of YFV. Compounds that are targeted at: (i) IMP dehydrogenase (ribavirin, EICAR, tiazofurin, selenazofurin and mycophenolic acid), (ii) OMP decarboxylase (pyrazofurin and 6-azauridine), (iii) CTP synthetase (carbodine and cyclopentenyl cytosine), (iv) dihydrofolate reductase (methotrexate) and the (v) sulfated polymers (dextran sulfate and PAVAS) proved inhibitory to the replication of YFV. Mycophenolic acid (EC50: 0.08 microgram/ml). EICAR (EC50: 0.8 microgram/ml) and methotrexate (EC50: 0.07 microgram/ml) were the most effective. The findings that EICAR and mycophenolic acid, despite their potent anti-YFV activity, had little or no effect on the replication of the bunyavirus Punta Toro or herpes simplex virus in Vero cells, indicates that their anti-YFV activity is rather specific and does not merely result from cytotoxicity. Inhibitors of S-adenosylhomocysteine hydrolase (SAH hydrolase) and thymidylate synthase were found to be devoid of anti-YFV activity.

Animals↗

Comparison of the nucleotide and deduced amino acid sequences of the structural protein genes of the yellow fever 17DD vaccine strain from Senegal with those of other yellow fever vaccine viruses.

The nucleic acid and deduced amino acid sequences of the structural proteins of the 17DD vaccine strain of yellow fever (YF) virus originating from Senegal are compared with those published for other vaccine strains of YF virus. Even though the 17D-204 and 17DD substrains of 17D diverged at passage 195 of 17D, they show a very high degree of nucleotide (99.5%) and amino acid (99.5%) homology over this region. The sequences are discussed with respect to monoclonal antibodies that can distinguish between 17DD and 17D-204 substrains of YF vaccines.

Amino Acid Sequence↗

Goats, germs, and fever: Are the pyrin mutations responsible for familial Mediterranean fever protective against Brucellosis?

Mutations in the MEFV gene are highly prevalent in the Middle East and Mediterranean basin, with carrier rates of up to 1:3 in some populations. More than 50 mutations in the MEFV gene have been described. The high prevalence, multiple mutations, and geographic localization to the Middle East suggest a positive selection advantage for the abnormal gene operating in this area over the last several thousand years. To date, no satisfactory explanation of this phenomenon has been made. Rather, many harmful effects of these mutations have been described. MEFV gene mutations cause familial Mediterranean fever in homozygotes, a disease associated with recurrent febrile inflammatory episodes, and death from renal failure and amyloidosis. Heterozygotes with MEFV mutations are predisposed to premature coronary disease, and rheumatologic conditions such as Behçet's disease. MEFV mutations do not appear to protect against tuberculosis. Brucellosis is still highly endemic in the Middle East because of the traditional reliance for meat and dairy production on goats and sheep, the major vectors for this zoonosis. Brucellosis causes a prolonged febrile illness lasting for months and even years, and it may have exacted a major toll among Bronze Age peasant populations in the Middle East. The gene product for MEFV, pyrin, normally inhibits interleukin-1beta production. Mutations in MEFV result in a pro-inflammatory state, with a Th1 polarization and high levels of interferon-gamma. This may actually be protective against intracellular pathogens such as brucellosis. The possible heterozygote advantage of MEFV mutations against brucellosis may therefore be a balanced polymorphism, analogous to the protective effect against malaria that maintains high levels of sickle cell trait in sub-Saharan Africa.

Animals↗

Vaccination with a single dose of a recombinant porcine adenovirus expressing the classical swine fever virus gp55 (E2) gene protects pigs against classical swine fever.

A recombinant porcine adenovirus (rPAV) with the gp55 (E2) gene from the classical swine fever virus (CSFV) 'Weybridge' strain inserted into the right hand end of the PAV serotype 3 (PAV3) genome was constructed. Expression of gp55 was directed by the major late promoter and tri-partite leader sequences located and cloned from PAV3. No compensatory deletions of PAV DNA sequences were made. Vaccination of outbred pigs with a single dose of the recombinant virus (rPAV-gp55) resulted in complete protection from lethal challenge with CSFV. No adverse clinical signs were observed in vaccinated animals following administration of rPAV-gp55 and following challenge, no clinical signs of CSF were observed prior to, or at, post mortem. The insert made into the rPAV increased the genome length to 106.8% of wild type and therefore exceeded the expected maximum insert size for a stable recombinant by almost 2%. Thus rPAV-gp55 contains the largest stable insertion made into a non-deleted Mastadeno virus recombinant so far reported.

Adenoviridae↗

Expression of the yellow fever virus envelope protein using hybrid SV40/yellow fever viruses.

The cDNA coding for the yellow fever virus (YFV) envelope protein (E) was inserted into an SV40 vector under the control of the late promoter in place of the VP1 gene. The recombinant virus expressed a 52-Kd polypeptide which was detected by immunoprecipitation with a monoclonal antibody raised against the E protein. Surprisingly, this protein was visualized in the nucleus of the infected cells. The possible presence of a sequence involved in nuclear migration of the E protein and naturally ignored during virus infection is discussed. The sequence coding for the mature E protein is directly preceded in the YFV genome by a sequence of 45 nucleotides coding for a 15-amino-acid long hydrophobic oligopeptide. The sequence of this oligopeptide was inserted into the SV40 recombinant virus between the ATG codon and the first codon for the E protein. The E protein expressed by this new SV40 recombinant virus was found to be localized in the cytoplasm of the infected cells in association with intracellular membranes. These results strongly suggest that the 15-amino-acid long hydrophobic region naturally plays a role as a signal peptide for the E protein.

Animals↗

Yellow fever virus/dengue-2 virus and yellow fever virus/dengue-4 virus chimeras: biological characterization, immunogenicity, and protection against dengue encephalitis in the mouse model.

Two yellow fever virus (YFV)/dengue virus chimeras which encode the prM and E proteins of either dengue virus serotype 2 (dengue-2 virus) or dengue-4 virus within the genome of the YFV 17D strain (YF5.2iv infectious clone) were constructed and characterized for their properties in cell culture and as experimental vaccines in mice. The prM and E proteins appeared to be properly processed and glycosylated, and in plaque reduction neutralization tests and other assays of antigenic specificity, the E proteins exhibited profiles which resembled those of the homologous dengue virus serotypes. Both chimeric viruses replicated in cell lines of vertebrate and mosquito origin to levels comparable to those of homologous dengue viruses but less efficiently than the YF5.2iv parent. YFV/dengue-4 virus, but not YFV/dengue-2 virus, was neurovirulent for 3-week-old mice by intracerebral inoculation; however, both viruses were attenuated when administered by the intraperitoneal route in mice of that age. Single-dose inoculation of either chimeric virus at a dose of 10(5) PFU by the intraperitoneal route induced detectable levels of neutralizing antibodies against the homologous dengue virus strains. Mice which had been immunized in this manner were fully protected from challenge with homologous neurovirulent dengue viruses by intracerebral inoculation compared to unimmunized mice. Protection was associated with significant increases in geometric mean titers of neutralizing antibody compared to those for unimmunized mice. These data indicate that YFV/dengue virus chimeras elicit antibodies which represent protective memory responses in the mouse model of dengue encephalitis. The levels of neurovirulence and immunogenicity of the chimeric viruses in mice correlate with the degree of adaptation of the dengue virus strain to mice. This study supports ongoing investigations concerning the use of this technology for development of a live attenuated viral vaccine against dengue viruses.

Amino Acid Sequence↗

Genetic relationships and evolution of genotypes of yellow fever virus and other members of the yellow fever virus group within the Flavivirus genus based on the 3' noncoding region.

Genetic relationships among flaviviruses within the yellow fever (YF) virus genetic group were investigated by comparing nucleotide sequences of the 3' noncoding region (3'NCR). Size heterogeneity was observed between members and even among strains of the same viral species. Size variation between YF strains was due to duplications and/or deletions of repeated nucleotide sequence elements (RYF). West African genotypes had three copies of the RYF (RYF1, RYF2, and RYF3); the Angola and the East and Central African genotypes had two copies (RYF1 and RYF3); and South American genotypes had only a single copy (RYF3). Nucleotide sequence analyses suggest a deletion within the 3'NCR of South American genotypes, including RYF1 and RYF2. Based on studies with the French neurotropic vaccine strain, passage of a YF virus strain in cell culture can result in deletion of RYF1 and RYF2. Taken together, these observations suggest that South American genotypes of YF virus evolved from West African genotypes and that the South American genotypes lost RYF1 and RYF2, possibly in a single event. Repeated sequence elements were found within the 3'NCR of other members of the YF virus genetic group, suggesting that it is probably characteristic for members of the YF virus genetic group. A core sequence of 15 nucleotides, containing two stem-loops, was found within the 3'NCR of all members of the YF genetic group and may represent the progenitor repeat sequence. Secondary structure predictions of the 3'NCR showed very similar structures for viruses that were closely related phylogenetically.

Africa, Western↗

[Study of the epidemiology of Far Eastern scarlatina-like fever in the Maritime Territory. I. Contamination of vegetables, root crops and pickled foods with the pseudotuberculosis microbe (Yersinia pseudotuberculosis) in foci of the scarlatina-like fever].

There was revealed high incidence of contamination with Yersinia pseudotuberculosis of vegetables, roots and pickled products (less frequently) in the vegetable store-houses of the majority of the far Eastern scarlatina-like fever foci in Primorie. Contamination of the mentioned food products increased by the spring-beginning of summer seasons; vegetables and roots which are often used raw--onion, carrots, cabbage--displayed the greastest contamination.

Disease Reservoirs↗

Relationship of Tel Hashomer criteria and Mediterranean fever gene mutations in a cohort of Turkish familial Mediterranean fever patients.

OBJECTIVE: To evaluate the frequency of 5 mutations and their relationship with the Tel Hashomer criteria in 85 FMF patients. METHODS: We looked for mutations in the Mediterranean fever (MEFV) gene in 84 consecutive patients who admitted to the Department of Medical Genetics of Afyon Kocatepe University, with a variable (from high to low) clinical suspicion of FMF. By using polymerase chain reaction and Hybridization-ELISA methods, 5 mutations (M694V, M694I, V726A, M680I and E148Q) have been studied between December 2002 and January 2005. RESULTS: We detected homozygote mutations in 12 patients (25.3%) and heterozygote mutations in 23 patients (48.9%) out of 47 patients with high clinical suspicion of FMF using Tel Hashomer criteria. In 12 patients (25.3%), no mutation was detected despite the clinical diagnosis of FMF was likely according to the Tel Hashomer clinical criteria. On the other hand, we detected homozygote mutations in 2 patients (5.4%) and heterozygote mutations in 17 patients (45.9%) out of 37 patients with low clinical suspicion of FMF using Tel Hashomer criteria. In 18 out of 37 patients (48.6%) in this group no mutation was detected. CONCLUSION: In patients with high or low clinical suspicion of diagnosis of FMF according to Tel Hashomer criteria, the frequency of homozygote patients was significantly higher than the frequency of patients with no mutation, but it was not higher than the frequency of heterozygote patients.

Adolescent↗

Epidemic of fever of unknown origin in rural Thailand, caused by influenza A (H1N1) and dengue fever.

In the late summer (rainy season) of 1987, a sharp outbreak of fever of unknown origin (FUO) in rural southern Thailand was investigated by a field epidemiology team. In a random survey of households, 40 percent of the children and 20 percent of adults were reported to have had febrile illnesses within the last month. There was at least one death, possibly from Reye's syndrome. Testing 34 pairs of acute and convalescent sera showed significant HI antibody titer rises to influenza A (Taiwan/(H1N1) (9 cases) and dengue virus (12 cases). Testing 79 single sera with the antibody capture ELISA test for dengue, revealed that 23 percent had high titers in the IgM serum fraction suggesting recent infection. There were also six antibody titer rises to coxsackie B viruses, three from well controls. Dengue has previously been observed as a cause of FUO in rural areas in the tropics, but finding a combined epidemic of dengue and influenza was unexpected. With cooperative villagers, adequate personnel and laboratory support, especially the antigen capture ELISA test for dengue infections, it is feasible to successfully investigate disease outbreaks with serologic methods in remote villages.

Chikungunya virus↗

Coagulopathy in hemorrhagic fever with renal syndrome (Korean hemorrhagic fever).

The pathophysiology of bleeding manifestations in hemorrhagic fever with renal syndrome (HFRS) was elucidated by serially evaluating coagulation and fibrinolytic profiles and complement alterations in patients with HFRS. In the early stage of the disease, platelet counts, platelet survival time, and platelet aggregation in vitro decreased. Prolongation of bleeding time, prothrombin time, and activated partial thromboplastin time was noted, with decreases in coagulation factors II, V, VIII, IX, and X. Levels of fibrinogen were decreased, and those of fibrinogen-fibrin degradation products in serum and urine were increased. Concentrations of plasminogen, alpha 2-plasmin inhibitor, and antithrombin III in plasma were depressed. Procoagulant activity was present in plasma. Circulating immune complexes were found, whereas serum levels of C3 were decreased. In the early stage of HFRS, thrombocytopenia, defects in platelet function, and disseminated intravascular coagulation may play central roles in the pathogenesis of bleeding manifestations. Vasculopathy and immunologic aberrations also may play a role.

Antigen-Antibody Complex↗