Pathogenesis and current approaches to control of varicella-zoster virus infections

Abstract

Varicella-zoster virus (VZV) was once thought to be a fairly innocuous pathogen. That view is no longer tenable. The morbidity and mortality due to the primary and secondary diseases that VZV causes, varicella and herpes zoster (HZ), are significant. Fortunately, modern advances, including an available vaccine to prevent varicella, a therapeutic vaccine to diminish the incidence and ameliorate sequelae of HZ, effective antiviral drugs, a better understanding of VZV pathogenesis, and advances in diagnostic virology have made it possible to control VZV in the United States. Occult forms of VZV-induced disease have been recognized, including zoster sine herpete and enteric zoster, which have expanded the field. Future progress should include development of more effective vaccines to prevent HZ and a more complete understanding of the consequences of VZV latency in the enteric nervous system.

Fig 1

The clinical spectra of VZV infection. (A) An otherwise healthy 2-year-old child with typical varicella (primary infection). (B) A child with underlying malignant disease receiving chemotherapy who died from disseminated varicella with pneumonia. (C) Salivary VZV DNA was demonstrated in a 72-year-old patient with severe unilateral neuropathic pain, which cleared on valacyclovir. There was no rash; VZV DNA was not detected in his saliva following recovery from pain. The diagnosis was zoster sine herpete. (D) Skin of wrist of a 71-year-old otherwise healthy woman with 7 tiny vesicles that caused severe itch but no pain. This was the extent of the rash, which resembled bites from a small insect. VZV DNA was demonstrated by PCR in skin vesicles and transiently in saliva. The diagnosis was mild HZ in an elderly woman. (E) Severe, disseminated HZ in a 35-year-old man with lymphoma on anticancer therapy, with severe pain, despite antiviral therapy.

Fig 2

Potential routes taken by VZV during its life cycle. Dorsal (sensory) and ventral (motor) roots carrying axons leave the spinal cord and fuse to form a mixed spinal nerve. A dorsal root ganglion (DRG) is present within the dorsal root. The DRG contains pseudounipolar sensory neurons (red) that extend a central process in the dorsal root to the posterior spinal cord and a peripheral process that reaches its targets of innervation via the spinal nerve. The skin is one such target, and sensory nerve fibers (red) ramify within the epidermis. Visceral sensory neurons also within the DRG send their peripheral process to the gut and terminate within the ganglia of the enteric nervous system (ENS) (submucosal and myenteric) or within other layers of the bowel wall. There is evidence that rare DRG neurons extend peripheral processes both to the skin and to the gut (indicated in the diagram). During varicella, retrograde transport from the skin can enable VZV to reach sensory neurons in the DRG and, from there, the neurons of the ENS (green arrows). Following the reactivation of VZV in a sensory DRG neuron, VZV can travel via anterograde transport in spinal nerve fibers to return to the skin and infect the epidermis in a restricted dermatomal distribution. Reactivation of VZV within neurons of the ENS affects the targets that these cells innervate and gives rise to local enteric disease, such as gastric ulceration (not illustrated) (see the text).

Fig 3

A case-control study shows that two doses of varicella vaccine provide better protection than a single dose (based on data from reference 143). Between July 2006 and January 2010, 71 case subjects (children with PCR-verified varicella) and 140 matched healthy controls were enrolled in a study of vaccine efficacy. None of the cases (0%) but 22 controls (15.7%) were found to be children who received 2 doses of varicella vaccine. Sixty-six cases (93.0%) but 117 controls (83.6%) were found to be children who received 1 dose. Five cases (7.0%) but 1 control (0.7%) were found to be children who did not receive varicella vaccine (P < 0.001). The effectiveness of 2 doses of the vaccine was calculated to be 98.3% (P < 0.001). The matched odds ratio for 2 doses against a single dose of the vaccine was 0.053 (P < 0.001). The effectiveness of 2 doses of varicella vaccine is thus excellent. The odds of acquiring varicella appear to be 95% lower in children who received 2 doses of varicella vaccine than in children who received only a single dose.