Exploring the Effect of Structure-Based Scaffold Hopping on the Inhibition of Coxsackievirus A24v Transduction by Pentavalent N-Acetylneuraminic Acid Conjugates.

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.

[Enteroviruses responsible for acute hemorrhagic conjunctivitis]. / Les Enterovirus responsables de conjonctivite aiguë hémorragique.

Acute hemorrhagic conjunctivitis (AHC) is an epidemic form of highly contagious conjunctivitis, characterized by conjunctival hemorrhages. The first AHC outbreak was described in 1969 in Ghana, West Africa, and was called Apollo disease, from the Apollo landing on the moon. This outbreak was caused by Enterovirus 70 (EV70) together with a Coxsackievirus A24 (CVA24v) variant, which are the major etiological agents involved in AHC outbreaks worldwide. AHC is known to be directly transmitted by close person-to-person contact or indirectly through soiled ophthalmological materials or unsafe recreational water. Recently, a possible airborne virus spread was suggested which could explain the high transmission rate of the disease. In the absence of a specific antiviral therapy, a rapid diagnosis of the causative agent is required to distinguish AHC due to enteroviruses from other ocular infectious diseases, for there are active drugs, or to quickly implement proper public health measures to limit the extension of the outbreak. However, virus identification remains difficult and time-consuming. Moreover, virological diagnosis is difficult to implement in developing countries where AHC has recently become a major problem for public health.

Management of subconjunctival haematoma by tissue plasminogen activator.

A patient with subconjunctival haematoma related to enterovirus 70 who was treated with tissue plasminogen activator (tPA) is reported. A 46-year-old man developed a severe subconjunctival haematoma and discharge in the left eye. Investigations, including coagulation tests, showed no abnormalities apart from a high-serum antibody titre for enterovirus 70. The polymerase chain reaction demonstrated enterovirus 70 DNA in resected conjunctival tissue, leading to a diagnosis of acute haemorrhagic conjunctivitis. The left eye was treated with a single subconjunctival injection of tPA (16 000 IU) and the subconjunctival haematoma resolved completely after 3 days. Severe subconjunctival haematoma can occur in patients with acute haemorrhagic conjunctivitis due to enterovirus 70. Subconjunctival injection of tPA may be useful for the treatment of severe subconjunctival haematoma.

Corneal superinfection in acute hemorrhagic conjunctivitis.

PURPOSE: This study aimed to evaluate the clinical profile, microbial spectrum, management modalities, and visual outcome in cases of corneal superinfection that occurred after an epidemic of acute hemorrhagic conjunctivitis. METHOD: A retrospective analysis of 14 eyes of 13 patients who were referred to a tertiary eye-care center with corneal ulceration after an episode of acute hemorrhagic conjunctivitis was undertaken. The parameters analyzed were age, sex, prior use of topical medications, predisposing factors, ulcer characteristics, organisms isolated, success of medical therapy and surgery, and visual outcome. RESULTS: A definite history of topical corticosteroid use to treat acute hemorrhagic conjunctivitis was elicited in 12 (86%) eyes. Cultures were positive in 86% (12/14) eyes. Organisms isolated were Pseudomonas aeruginosa (three eyes, 25%), Fusarium species (three eyes, 25%), Aspergillus species (two eyes, 16%), and Staphylococcus aureus (two eyes, 16%). Mixed infection occurred in two patients. After discontinuation of topical corticosteroids, all patients received antimicrobial therapy. The keratitis resolved in seven eyes. Therapeutic penetrating keratoplasty was required in five eyes. Two patients were lost to follow-up. CONCLUSIONS: Corneal superinfection may occur after acute hemorrhagic conjunctivitis. Use of topical corticosteroids to treat acute hemorrhagic conjunctivitis may predispose an already compromised cornea to develop microbial keratitis and such a practice should be discouraged.

Topical piroxicam and conjunctivitis.

The study of comparison of the clinical responses of acute hemorrhagic conjunctivitis to antibiotic eye drops alone and combined with topical piroxicam was analyzed. Seventy-five patients (146 eyes) with viral conjunctivitis were randomly assigned to receive topical antibiotic (35 cases) or antibiotic combined with piroxicam eye drops (40 cases). The patients were examined under slit lamp biomicroscope every other day for the first week, then twice a week until recovery. There was no statistically significant difference between groups in mean age, sex, bilaterality, history of contact, systemic involvement, mean incubation period, mean onset and mean follow-up time. Mean recovery time in the piroxicam group (4.9 days) was less than for the control group (P = 0.003). Foreign body sensation, pain and tearing in the piroxicam group recovered significantly faster than in the control group. Complete recovery of all symptoms and signs in piroxicam treated eyes (61%) was significantly more common than with antibiotic only (29%) in spite of more drug induced burning. Piroxicam eye drops may have beneficial effects for acute hemorrhagic conjunctivitis to relieve discomfort, pain, and accelerate recovery.

Inhibition of the enteroviruses that cause acute hemorrhagic conjunctivitis (AHC) by benzimidazoles; enviroxime (LY 122772) and enviradone (LY 127123).

Enviradone (EvirD, (E)-1-[(1-methylethyl) sulfonyl]-6-(1-phenyl-1-propenyl)-1 H- benzimidazole-2-amine) and Enviroxime (EvirX, 2-amino-1-(isopropyl-sulfonyl)-6-benzimidazole phenyl ketone oxime) inhibited enterovirus 70 (EV70) and coxsackievirus A24 variant (CA24v) infection of conjunctival and laryngeal cells. On average, the continuous presence of 1-3 micrograms of EvirD or EvirX/ml in cell cultures acutely infected with EV70 or CA24v inhibited virus production (> 2 log10 reduction) and 100% of the viral cytopathogenic effect (CPE). The 50% CPE inhibitory dose (ID50) for EvirD and EvirX against 11 EV70 and 15 CA24v isolates ranged from 0.01 to 0.3 microgram and 0.01-0.65 microgram/ml, respectively. The mean ID50 for EvirD and EvirX against the 26 AHC viruses was 0.17 +/- 0.12 microgram and 0.13 +/- 0.14 microgram/ml, respectively. Pretreatment for 15 min with 3 micrograms EvirX/ml or for 1-2 h with 3 micrograms EvirD/ml protected conjunctival cells against viral CPE. The cells were resistant to infection for 1-2 h at 33 and 37 degrees C after removal of EvirD and EvirX. The addition of 10 micrograms EvirD/ml up to 6 h or 10 micrograms EvirX/ml 1-2 h after low multiplicity infection inhibited viral CPE. Ten-fold less EvirD inhibited EV70 when added to glioma cells 2 h before infection than when added 2 h after infection. Our results indicate that EvirX and EvirD inhibit AHC viruses in vitro at concentrations that are not cytotoxic and suggest that EvirX or EvirD may be prove useful against AHC.

[Acute epidemic hemorrhagic conjunctivitis (AEHC) in Madagascar 1991]. / Conjonctivite épidémique hémorragique aigue (C.E.H.A.) à Madagascar 11991.

An epidemic of A.E.H.C. was broken out everywhere in Madagascar during hot season from September 1990 to May 1991 with an important acuteness in February and March. Clinical symptoms are those of A.E.H.C. to enterovirus with some particularities. Virological study shows cytopathogenic effect of enterovirus and microbiology shows the existence of several bacterial germs particularly staphylococcus epidermidis. The discovery of two cases of streptococcus pneumonia and the absence of chlamydia trachomatis make the originality of our cases. The efficacy of the association antibiotic and steroids is spectacular.