Pathology of Chikungunya Virus Infection: Emergence and Clinical Insights

Use of Repellents & Treatment Issues

Recommendations concerning the use of topical insect repellents in children and pregnant women vary widely from country to country. Rational repellent prescription for a child must take into account age, active substance concentration, topical substance tolerance, nature and surface of the skin to protect, number of daily applications and the length of use in a risk–benefit ratio assessment perspective. Generally, topical repellents should not be used under the age of 2 months. Owing to the severity of neonatal infection and atypical forms of CHIKV infection in very young infants, parental training about prevention of mosquito bites during the perinatal period and distribution of impregnated mosquito nets should be carried out during outbreaks. DEET (N,N-diethyl-m-toluamide, now called N,N-diethyl-3-methylbenzamide) is considered the most effective insect repellent for personal protection but is not recommended for young children, pregnant or lactating women due to its potential neurotoxic effects.^[85] Novel formulations of natural repellents may be of use for this group [Selambarom J, Unpublished Data].

The elaboration of animal models in mice and macaques has recently significantly increased the scope for new antiviral therapies as aforementioned, and these models were invaluable to test the efficacy of the polyvalent anti-CHIKV immunoglobulins. Viremic mothers in labor and neonates born to viremic mothers, patients with severe neurological presentation of the disease, small infants with rapidly extensive skin blistering or adults with severe underlying comorbidities could benefit from this passive immunization technique. The in cellulo antiviral action of chloroquine was reported long ago.^[86] In the particular case of alphaviruses that include CHIKV, chloroquine inhibited the replication of Sindbis and Semliki forest viruses in cellulo, although a mouse model suggested that chloroquine may enhance the viral replication of Semliki forest virus in vivo.^[87]

During the La Réunion outbreak, the efficacy of chloroquine in the treatment of acute CHIK infections was discussed following positive in vitro studies. A double-blind randomized placebo-controlled trial was conducted and suggested that there is no justification for the use of chloroquine to treat acute CHIK infections.^[88] In the trial, 27 patients received chloroquine (600 mg on day 1, 600 mg on days 2 and 3, and 300 mg on days 4 and 5), and 27 patients received a placebo treatment. No significant difference between the groups could be identified regarding the duration of febrile arthralgia or the decrease of viremia between days 1 and 3. Moreover, at day 200, patients who received chloroquine complained more frequently of arthralgia than those who received placebo. Quinine, another antimalarial molecule, is currently being studied in cellulo, with variable results. Although ribavirin inhibits a wide range of RNA viruses in cellulo, there is no evidence supporting the clinical efficacy of ribavirin in vivo for the treatment of CHIK infection. The efficacy of interferon and of the combination of IFN-α and ribavirin remains to be ascertained.^[88] IFN-α has been tested in a mouse model of CHIKV and was shown to be protective only when injected prior to infection.^[89]

Work is currently being pursued to identify specific inhibitors of viral enzymes such as CHIKV polymerase-capping enzymes, proteases and helicases, as recently demonstrated for the nonstructural protein nsP3.^[90] Some of these proteins are now available as active soluble compounds. RNA interference targeting the nsP3 and E1 of CHIKV was recently shown to be an active route against viral replication, but failed to induce long-term inhibition, possibly due to the rapid replicating nature of alphaviruses.^[91]

According to de Lamballerie et al.,^[88] the treatment of CHIKV infection using antiviral drugs is likely to be difficult given the extremely high and short-lived virus load. Therefore, an antiviral treatment may only be useful for preventing the infection in individuals such as the elderly and for the management of severe cases, as well as cases where the virus may be persisting in tissue sanctuaries.^[57]