Chronic meningoencephalitis caused by Echo virus 6 in a patient with common variable immunodeficiency : Successful treatment with pleconaril.

Chronic enteroviral meningoencephalitis, most commonly caused by echoviruses, can particularly be seen in agammaglobulinemic patients. In spite of the fact that no specific treatment for enteroviral infections exists, pleconaril is an antiviral drug reported to be efficient against enteroviral infections in infants and adults. We present a case of a 42-year-old male, previously diagnosed with common variable immunodeficiency, who presented with severe chronic meningoencephalitis caused by Echo virus 6 and was successfully treated with pleconaril. Enteroviruses usually cause mild symptoms, but some strains can cause life-threatening conditions especially in immunocompromised patients. Although pleconaril production is unprofitable due to the rarity of severe disease, our effective treatment should encourage further availability of pleconaril.

Genetic diversity of a Korean echovirus 5 isolate and response of the strain to five antiviral drugs.

An outbreak of echovirus 5 (ECV 5) occurred in Korea in 2006, marking the first time this virus had been identified in the country since enterovirus surveillance began in 1993. Using a sample isolated from a young male patient with aseptic meningitis, we performed sequencing of the Korean ECV 5 strain and compared it with a prototype strain (Noyce). At the nucleotide level, the P1 region (85.3%) had the highest identity value; at the amino acid level, the P3 region (98.0%) had the highest identity value. The two strains shared all cleavage sites, with the exception of the VP1/2A site, which was TY/GA in the Noyce strain but TR/GA in the Korean ECV 5 isolate. In Vero cells infected with the Korean ECV 5 isolate, no cytotoxicity was observed in the presence of azidothymidine, acyclovir, amantadine, lamivudine, or ribavirin, when the drugs were administered at a CC50 value >100 µg/mL. Of the five drugs, only amantadine (IC50: 1 ± 0.42 µg/mL, TI: 100) and ribavirin (IC50: 22 ± 1.36 µg/mL, TI: 4.55) had any antiviral activity against the Korean ECV 5 isolate.

[Acute myocarditis caused by ECHO virus].

Enteroviral infection is characterized by clinical polymorphism. One of its clinical manifestation is myocarditis, which is usually caused by Coxsackie virus. ECHO viruses cause the disease mostly in childhood. The article presents a case of enteroviral (ECHO) infection complicated by pneumonia and focal myocarditis in a 41-year-old patient, hospitalized during a season of influenza and acute respiratory infections. Acute myocarditis was moderate and the patient recovered by day 23.

Current status of anti-picornavirus therapies.

Picornaviruses are important human pathogens causing severe morbidity and some mortality with the potential to cause worldwide crippling disease. Currently, there are few treatments for many of the viruses in the Picornaviridae, For rhinoviruses, there are no approved treatments, although ruprintrivir looks promising in clinical trials and pyridazinyl oxime ethers may prove useful. Poliovirus treatments are needed to supplement the World Health Organization's polio eradication plan in order to treat infections caused by reversion of the attenuated vaccine virus and to supplement vaccine coverage control in polio endemic areas. However, no promising compounds for treatment of poliovirus have been developed due to the efficacy of the vaccines in use. Broad-spectrum inhibitors developed for other picornavirus may be useful for poliovirus infections. Coxsackievirus infections in children and in infants are being treated with pleconaril with some efficacy in reducing mortality and improving recovery, albeit the treatment is often on a compassionate use basis. There are no therapies for echovirus infections. Very little drug discovery research is being done to develop inhibitors for echovirus infections, probably due to the broad-spectrum inhibition exhibited by capsid binding agents and protease inhibitors discovered for treatment of other picornaviruses. For example, pyridazinyl oxime ethers are inhibitory to most echoviruses. Treatments for enterovirus infections are also limited, although in a small clinical trial, milrinone seemed to reduce mortality and improve recovery from EV71-induced pulmonary edema. Thus, these results strongly emphasize the need for the development of potent and nontoxic compounds for the treatment of picornavirus infections.

Severe echovirus 30 infection in twin neonates.

Although enteroviruses can cause overwhelming and fatal systemic infections in neonates, such severe neonatal infections remain uncommon and rarely involve both of twin neonates at the same time. We report the cases of twin neonates who developed fever initially, and then progressed to disseminated systemic disease with marked thrombocytopenia, coagulopathy, and hepatic failure. One of the neonates died and the other survived. Both neonates were treated with intravenous immunoglobulin and maternal fresh frozen plasma was also given to the neonate who survived. Virus cultures from the nasopharynx, rectum and cerebral spinal fluid of both neonates yielded enterovirus, later typed as echovirus 30. The surviving neonate had normal development without obvious sequelae during a follow-up period of 1 year. The major determinant of the survival from severe neonatal enterovirus infection might have been the pre-existing severity of the disease before treatment, and complete recovery could be expected if the infant survived the acute stage of illness.

A season of aseptic meningitis in Germany: epidemiologic, clinical and diagnostic aspects.

OBJECTIVE: We assessed epidemiologic, clinical and laboratory features of aseptic meningitis during one season of multiserotype enteroviral meningitis in East Germany in 70 consecutive patients with aseptic meningitis admitted to the Children's University Hospital Leipzig. RESULTS: Patients, age 1 to 16 years, typically presented with headache, emesis and fever, whereas signs of meningeal irritation were only moderately expressed in one-half of the patients. The median number of leukocytes in the CSF was 151 cells/mm(3) (range, 2 to 1,820) with a high percentage of polymorphonuclear cells (PMNs). Initial blood counts showed mild leukocytosis and pronounced PMN predominance (78.9 +/- 1.3%). The percentage of PMNs in the peripheral blood decreased in favor of mononuclear cells after 3 days to a pattern more compatible with viral infection as opposed to that suggestive for bacteria in the beginning. Mean cerebrospinal fluid values of protein, glucose and lactate and the C-reactive protein were mildly elevated or normal. Nonpolio enteroviruses were detected in 30 of 70 patients. Subsequent serotyping revealed echovirus type 13 (13 patients), type 6 (2), type 30 (1) and coxsackie B virus type 5 (2). There were no differences in demographic or clinical data between enterovirus positive and negative patients. CONCLUSIONS: Even though individual laboratory values do not solely allow discrimination between viral and bacterial meningitis, the combined epidemiologic, clinical and laboratory data facilitate the diagnosis of aseptic meningitis in most cases. Viral diagnostics, identifying echovirus type 13 that thus far has not been associated with epidemics of meningitis, adds important epidemiologic information.

Acute flaccid paralysis syndrome associated with echovirus 19, managed with pleconaril and intravenous immunoglobulin.

We describe a 39-year-old woman who had undergone bilateral lung and renal transplantation and who was admitted to the hospital with acute onset of flaccid paralysis of the left leg due to echovirus 19 infection. The patient was treated with pleconaril and intravenous immunoglobulin, which correlated with clinical and laboratory evidence of improvement.

Bone marrow failure with concurrent enteroviral infection in a newborn.

A newborn baby, with transient pancytopenia concurrent to Echovirus type 11 infection, was hospitalized for fever, diarrhea, rash, generalized petechiae and hepatosplenomegaly. Subsequent investigation showed bone marrow failure. To our knowledge this is the first reported case of bone marrow failure with concomitant enteroviral infection.

Severe neonatal enteroviral hepatitis treated with pleconaril.

Neonatal enteroviral hepatitis carries high morbidity and mortality. We treated three full term neonates with severe enteroviral hepatitis with pleconaril on an open label compassionate use protocol. Each mother had history of a viral-like syndrome within 1 week before delivery. The neonates presented at 4 to 5 days of age with fulminant hepatic failure with severe coagulopathy, and each yielded an echovirus. All were treated with pleconaril (VP63843) at 5 mg/kg every 8 h by nasogastric tube. Two of the three neonates with life-threatening enteroviral hepatitis recovered fully. Further experience with pleconaril for neonatal enteroviral hepatitis is warranted.

Outbreak of echovirus 30 meningitis in Switzerland.

This study includes 80 patients (38 children and 42 adults) who contracted aseptic meningitis in the summer of 1996 in Fribourg, Switzerland. Virological studies revealed an enteroviral infection in 65 out of 70 (93%) investigated patients. In 47 out of the 53 cases (89%) where a precise virus could be identified, the causative agent was an Echovirus 30. More than 50 patients lived in an area within a 5-km radius. The patients presented with the classic symptoms and signs of aseptic meningitis. In contrast, polymorphonuclear leukocytes predominated in the cerebrospinal fluid in the first 24 h and 32% of the cases had a left shift in their peripheral blood smear. The patients' age did not influence white blood cell count, the proportion of polymorphonuclear leukocytes or protein concentration in the cerebrospinal fluid. Thirty-three patients (41%) received antibiotic treatment, and 38 patients (48%) left the hospital within 24 h. Only 2 neuroradiological procedures and 1 electroencephalographic recording were performed. The outcome was favourable in all patients.

Serial MRI findings of benign poliomyelitis.

A 14-year-old boy presented with incomplete transverse myelopathic symptoms associated with mild encephalitis. Magnetic resonance imaging (MRI) revealed involvement of the central portion of spinal cord extending from the C1 to T5 level on T2-weighted images with expansion of the cervical spinal cord. The boy made a full clinical recovery in a few weeks. Cultures of the pharyngeal exudate were positive for ECHO virus type 11. The lesion on MRI disappeared completely in a few months.

In vivo efficacy of SDZ 35-682, a new picornavirus capsid-binding agent.

SDZ 35-682 is a potent and selective inhibitor of the replication of members of the picornavirus group. It belongs to the group of uncoating inhibitors binding to the hydrophobic pocket in the capsid of the virion. In cell culture it inhibits several rhinovirus serotypes and echovirus 9 at concentrations as low as 0.1 micrograms/ml. In the echovirus 9 animal model the protective effect of SDZ 35-682 was found to be dependent on both, dose of drug and duration of treatment. Significant protection of newborn mice from paralysis and death could be achieved by either a high dose (126 mg/kg) given only twice, at days 0 and 1 relative to echovirus 9 inoculation, or by a lower dose administered for 4 or 6 days. This finding might be explained by assuming a long half-life for SDZ 35-682. Though clinical usefulness of SDZ 35-682 may be limited by its relatively narrow antiviral spectrum it represents a novel potent and selective inhibitor of rhinovirus and echovirus 9 replication in cell culture and in the organism.

Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review.

Chronic enteroviral meningoencephalitis is a well-recognized complication in patients with X-linked agammaglobulinemia (XLA). The majority of published cases refers to its occurrence in patients on no replacement therapy or on only intramuscular immunoglobulin. The advent of intravenous immunoglobulin (IVIg) in the early 1980s and its widespread use in XLA was thought to have virtually eradicated enteroviral meningoencephalitis in these patients. We describe the development of echovirus meningoencephalitis in an 11-year-old boy on regular IVIg replacement whose serum IgG levels were maintained at between 6 and 8 g/L (NR 6-13 g/L). Treatment with daily high-dose IVIg was commenced, with significant clinical improvement being noted within a few weeks in association with a reduction in blood-brain barrier permeability. The persistence of live virus, however, necessitated the use of intraventricular immunoglobulin. The virus proved resistant to two courses of specific intraventricular immunoglobulin and a 6-week course of oral ribavirin and eventually proved fatal 5 months after presentation. In view of the therapeutic uncertainties we have reviewed the use of immunoglobulin in the treatment of enteroviral meningoencephalitis over the past 6 years.

Influence of polyions on the early steps of enterovirus infection.

The influence of electric charged molecules on the early phases of enterovirus infection was studied in order to select antiviral compounds able to prevent viral attachment. The effect of different polyelectrolytes on the multiplication of coxsackie virus B3, echovirus 6 and hepatitis A virus was investigated in susceptible cells by adding the drug before, during or after the viral adsorption period. Among polyanions, the polysaccharides heparin and dextran sulfate inhibited viral infectivity, dextran sulfate being the most effective mainly towards hepatitis A virus infection. DEAE-dextran and protamine sulfate, generally recognized as enhancers of infectivity of naked and enveloped viruses, exhibited an inhibitory effect towards the three picornaviruses tested. Only in the case of hepatitis A did DEAE-dextran slightly improve viral antigen synthesis. The inhibitory effect shown by compounds belonging to positive and negative polyions suggests that the electric charge is not sufficient by itself to explain the antiviral activity of these drugs.

In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug.

WIN 54954 (5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl]-3- methylisoxazole) is a new member of the class of broad-spectrum antipicornavirus compounds known to bind in a hydrophobic pocket within virion capsid protein VP1. In plaque reduction assays, WIN 54954 reduced plaque formation of 50 of 52 rhinovirus serotypes (MICs ranged from 0.007 to 2.2 micrograms/ml). A concentration of 0.28 microgram/ml was effective in inhibiting 80% of the 52 serotypes tested (EC80). WIN 54954 was also effective in inhibiting 15 commonly isolated enteroviruses, with an EC80 of 0.06 microgram/ml. Furthermore, WIN 54954 was effective in reducing the yield of two selected enteroviruses in cell culture by 90% at concentrations approximately equal to their MICs. The therapeutic efficacy of intragastrically administered WIN 54954 was assessed in suckling mice infected with coxsackievirus A-9 or echovirus type 9 (Barty) 2.5 days prior to initiation of therapy. Single daily doses of 2 and 100 mg/kg protected 50% of the mice from developing paralysis (PD50) following infection with coxsackievirus A-9 and echovirus-9, respectively. At the PD50 doses for these two viruses, levels of WIN 54954 in serum were maintained above the in vitro MICs for a significant portion of the dosing interval. The dose-dependent reduction in viral titers observed in coxsackievirus A-9-infected mice correlated well with the therapeutic dose response. The potency and spectrum of WIN 54954 make it a potentially useful compound for the treatment of human enterovirus and rhinovirus infections.

Use of WIN 51711 to prevent echovirus type 9-induced paralysis in suckling mice.

The systemic efficacy of the antipicornavirus agent WIN 51711 was assessed in suckling mice infected with echovirus type 9 (Barty strain). Single, daily intraperitoneal doses of WIN 51711 as low as 10 mg/kg significantly (P less than .01) slowed the rate of onset of echovirus-induced paralysis and reduced the number of paralyzed animals. Intraperitoneal administration beginning 2 hr before infection or 48 hr after infection was equally effective in preventing paralysis. Oral administration of WIN 51711 twice daily beginning 72 hr after infection was the most-effective dosage regimen, with doses as low as 3 mg/kg preventing paralysis in 75% of the animals. Titers of virus in asymptomatic mice on day 6 after infection were reduced by up to 4.75 log pfu in WIN 51711-medicated mice when compared with placebo. Maximal concentrations of WIN 51711 in adult mice after oral medication with a 100 mg/kg dose were 24.3, 21.5, 10.4, 9.8, 6.9, and 4.1 micrograms/g in heart, kidney, brain, liver, serum (micrograms/ml), and muscle, respectively at 0.5-1.0 hr after medication.

IgG subclass deficiencies: identifying and treating patients at risk.

IgG subclass deficiencies can increase the risk of pulmonary infections or other severe recurrent infections. Various groups of patients were studied in an attempt to learn more about (1) measuring the IgG subclass levels (particularly IgG4 levels) of possible high-risk patients; (2) identifying those patients who are at risk of developing recurrent infections, and (3) treating these patients once they have been identified. Individual cases are presented, and associations of isolated subclass deficiencies are examined with respect to infection. Replacement therapy with plasma or intravenous immunoglobulin (IVIG) to increase titers of deficient or absent subclasses is suggested.