Herpes simplex virus type 1 (HSV-1) is the more common type of Herpes simplex virus. Some 3.7 billion people around the world are infected with HSV-1, with the majority of them being unaware of their carrier status because most infections are asymptomatic. Patients who do develop symptoms typically suffer from recurrent orolabial herpes. More severe, potentially life-threatening manifestations of HSV-1 infections may be observed in neonates and immunodeficient patients. While virostatics may alleviate symptoms and reduce morbidity and mortality, no drugs are currently available that would eliminate latent Herpes simplex virus 1 infection.
HSV-1 is the main trigger of orolabial herpes, which is commonly referred to as "cold sores". Gingivostomatitis is the clinical hallmark of the disease, and it consists in recurring ulcerative blisters on the mucosal surfaces of the lips and oral cavity. Vesicles are typically grouped and impose on an inflammatory, erythematous base [1]. Episodes are of acute onset, and a general trend towards a lessening severity of symptoms can be observed in the majority of patients. Indeed, first episodes may be associated with constitutional symptoms like fever, headache, bilateral cervical lymphadenopathy, and myalgia [2], while recurrences may be limited to some hours of prodromal symptoms like tenderness, pain, burning or itching sensations at the site of reactivation. In the immunocompetent host, bouts of orolabial herpes are generally self-limiting, and symptoms tend to subside after 10-14 days, if they do progress beyond the prodromal stage. Months or even years may pass until the next episode [1]. More severe and persistent lesions are observed in the immunocompromised and neonates [3].
Affected neonates may have acquired HSV-1 in utero, during delivery, or postnatally. The earlier the infection is established, the more detrimental consequences are to be expected. Congenital herpes simplex may cause abortion, stillbirth or perinatal death. In case of survival, growth retardation and developmental delays become apparent soon after birth. Microcephaly, encephalomalacia and intracranial calcifications are characteristic features of congenital herpes simplex and may be detected during the first days of life. The patients may suffer from fever, lethargy, and seizures, and present eye and skin lesions. Microphthalmia, cataract, chorioretinitis, and optic atrophy are common findings, and neonates often have a vesicular rash [2]. Pathogen dissemination is possible and may entail multiple organ failure and death [4].
Beyond that, immunodeficiency augments the risk of disseminated herpes simplex. HSV-1 may reach the central nervous system, lungs, liver, and other organ systems, thereby inducing life-threatening HSV-1 encephalitis, pneumonia, or hepatitis, among others. These complications may result in the following clinical pictures:
Further manifestations of HSV-1 infections comprise herpetic whitlow and ocular infections. The latter may result in blepharitis, conjunctivitis, epithelial or stromal keratitis, iridocyclitis or retinitis [8]. Herpetic whitlow is also referred to as herpetic paronychia and is characterized by an acute, often painful vesicular eruption on the fingers [1].
In the majority of cases, a tentative diagnosis of Herpes simplex infection may be made based on the patient's medical history and clinical findings. A more extensive workup may be required to determine the involvement of HSV-1 in atypical disease or infections of the immunocompromised.
In general, the intermittent course of the disease and the development of mucosal blisters are highly suspicious of a latent infection with HSV-1 or HSV-2 but don't allow for the differentiation of Herpes simplex virus types. Serological tests assessing the presence of specific IgG antibodies may shed light on this issue. Alternatively, molecular biological assays may be carried out to confirm the suspicion [9] [10]. Polymerase chain reaction for HSV-1 is considered a highly sensitive method and does not depend on the presence of viable HSV-1 or appropriately infected cells - while the conventional isolation of HSV-1 in tissue cultures does. In those cultures, characteristic cytopathic effects are typically observed after 24-48 hours. Cytological changes may also be seen during the histological examination of specimens obtained with cotton swabs or blunt scalpel blades. Syncytial giant cells, ballooning cytoplasm, and Cowdry type A intranuclear inclusions may be detected [1].
Virostatics employed in the management of HSV-1 infections inhibit peripheral virus replication and lytic cycles. They are not generally administered with curative intent, but to alleviate complaints and to shorten symptomatic episodes, and thus, they are hardly used in asymptomatic individuals. Acyclovir is the best-known representative of this type of drugs, which may be applied topically or systemically. Besides acyclovir, there is a broad spectrum of nucleoside analogues (e.g., valaciclovir, famciclovir, and penciclovir) available for the management of HSV-1 infections. Foscarnet constitutes another alternative, and additional active substances are currently on trial. The decision in favor of or against the use of determined pharmaceuticals should consider the site and severity of infection, the pharmacokinetic properties of the drug, and possible antiviral drug resistance [11].
As implied above, dormant HSV-1 in the trigeminal ganglia and other sensory neurons are not affected by acyclovir and related compounds. They don't prevent recurrence and neither resolve the latent infection. To date, there is no cure for HSV-1 infections [12].
Large parts of the global population are infected with HSV-1. Yet, up to 90% of primary HSV-1 infections - which are usually more severe than recurrences - are either asymptomatic or so mild that the patients do not notice the illness [1]. Therefore, the average reduction in the life quality of affected individuals is low. But the general lack of awareness also contributes to the spread of HSV-1 infections, for which we do not yet have a cure. Eventually, immunocompromised or otherwise more vulnerable patients may be infected: In the absence of therapy, mortality due to congenital herpes simplex exceeds 80% [2]. Similarly, HSV-1 encephalitis, pneumonia, and hepatitis are associated with high morbidity and mortality, while herpetic lymphadenitis may be self-limiting [1]. Even in immunocompetent individuals, HSV-1 keratitis may result in blindness [13].
HSV-1 is a human pathogen that belongs to the family of herpesviridae and the subfamily of alphaherpesvirinae. HSV-1 particles measure about 150 nm in diameter and consist of an episomal double-stranded DNA genome, capsid, tegument, and envelope [1].
HSV-1 is most commonly acquired through oral secretions as a mucosal infection during early childhood. Because characteristic herpes blisters form near the primary site of infection, the oral acquisition of HSV-1 usually results in orolabial herpes [13]. It shall be noted, though, that case numbers of genital herpes due to HSV-1 have been increasing worldwide [14]. In this context, HSV-1 may be acquired via the oro-genital or genital-genital routes. Then again, the presence of HSV-1 in vaginal secretions is a major risk factor for congenital herpes simplex in children born to infected mothers. The risk of transmission is highest in case of first infections during the third trimester of pregnancy, which may cause neonates to acquire the virus during delivery. The intrauterine transmission of HSV-1 is feasible but accounts for <5% of congenital cases [2].
Manifestations other than orolabial or genital herpes are relatively rare, but HSV-1 may initiate infections at other mucosal or cutaneous surfaces. In this context, direct droplet spread of the virus may result in HSV-1 keratitis and related disorders [8], while herpetic whitlow usually affects the distal phalanx of one or more fingers [1].
Finally, the possibility of autoinoculation shall be mentioned. Indeed, herpes keratitis is most frequently diagnosed in those suffering from orolabial herpes: Infectious droplets may originate from the patient's own oral secretions [1].
HSV-1 is highly prevalent all over the world. According to estimates, a total of 3.7 billion people are infected with this virus, which results in a global prevalence of 67%. Interestingly, prevalence rates of <50% have only been observed in children aged <5 years, thereby confirming the assumption of primary infections mainly occurring in infancy or early childhood [14].
HSV-1 is able to replicate within epithelial cells and neurons. Primary infections are usually established within the stratified squamous epithelium of the oral or anogenital mucosa, where first lytic cycles are completed [3]. The virus subsequently invades the local sensory nerve endings and is retrogradely transported along the axon to the neuronal cell body. Accordingly, HSV-1 is typically found in the trigeminal ganglia [2]. While the axonal ascent of HSV-1 is critical for establishing life-long infections, the virus remains latent in neurons and barely replicates. Further lytic cycles are induced upon reactivation, when the pathogen undergoes anterograde transport towards peripheral nerve endings and surrounding epithelial cells [3]. Even though HSV-1 tends to return to the primary site of infection, the virus may take alternative routes. Transport towards other parts of the trigeminal dermatome, for instance, is assumed to be a major cause of ocular infections with HSV-1 [8].
The reactivation of latent HSV-1 infections has been related to emotional stress, infectious diseases, fever, fatigue, and trauma, to immunosuppression, menstruation, and pregnancy. In most cases, though, the precise cause of the current episode cannot be identified [1].
To date, there are no vaccines against HSV-1 infections. Due to the extremely high prevalence of the pathogen, the general risk of infection is high. Nevertheless, seronegative people may adopt certain rules of conduct to reduce their individual risk of acquiring HSV-1, and such rules should be followed during periods of increased susceptibility. Pregnant women, for instance, should avoid primary infections to protect their unborn child. They should be encouraged to avoid the direct or indirect contact with people suffering from symptomatic orolabial herpes, to abstain from oral sex, and to use condoms. On the other hand, the prophylactic administration of antiviral drugs is recommended in seropositive patients undergoing immunosuppressive or chemotherapy [6].
Herpes simplex viruses belong to the family of herpesviridae. There are two types of Herpes simplex viruses, which are referred to as HSV-1 and HSV-2. Infections with either type of virus may trigger a variety of diseases. The majority of patients presents with characteristic lesions in the mouth and throat or external genitals, but systemic disease has been reported. In any case, mucocutaneous herpes simplex virus infections are most commonly attributed to HSV-1, while genital herpes is frequently caused by HSV-2 [13]. Clinical findings hardly allow for the differentiation between HSV-1 and HSV-2, which requires serological or molecular biological studies. In order to avoid duplications of content, though, this article focuses on mucocutaneous herpes and summarizes less common manifestations of infections with HSV-1. For detailed information on genital herpes, the interested reader is referred to the respective entry on Herpes simplex virus 2 infection, available on this platform.
Herpes simplex virus 1 infection is most commonly associated with orolabial herpes, i.e., the recurrent appearance of ulcerative blisters on the mucosal surfaces of the lips and oral cavity. However, there is a variety of other manifestations of infections with HSV-1, as the causative agent is commonly called:
Due to the high prevalence of the virus, the life-long prevention of an HSV-1 infection is a major challenge. Nevertheless, measures may be taken to prevent a primary infection and to avoid recurrences during periods of increased susceptibility. The individual risk of contracting HSV-1 may be reduced by avoiding the direct or indirect contact with people suffering from symptomatic orolabial herpes, abstaining from oral sex, and using condoms. Antiviral drugs may be administered to prevent symptomatic episodes, to alleviate complaints and to accelerate the healing of lesions.