Herpes simplex (HS) in adults: clinical guidelines

List of Abbreviations

Ag – antigen

ALT – alanine aminotransferase

AST – aspartate aminotransferase

Abs – antibodies

IM – intramuscular

HIV – human immunodeficiency virus

WHO – World Health Organization

HSV – herpes simplex virus

HSV-1 – herpes simplex virus type 1

HSV-2 – herpes simplex virus type 2

EBV – Epstein-Barr virus

GH – genital herpes

HI – herpesvirus infection

HS – herpetic stomatitis

DNA – deoxyribonucleic acid

GI – gastrointestinal tract

STI – sexually transmitted infections

EIA – enzyme immunoassay

CT – computed tomography

mg – milligram

mL – millilitre

Ministry of Health of the Russian Federation – Ministry of Health of the Russian Federation

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

MRI – magnetic resonance imaging

NASID – Pokrovsky National Association of Infectious Diseases

AHS – acute herpetic stomatitis

AVT – antiviral therapy

HSV – herpes simplex

PCR – polymerase chain reaction

RAS – Russian Academy of Sciences

RCT – randomized controlled trial

RF – Russian Federation

CSF – cerebrospinal fluid is a biological fluid that constantly circulates in the cerebral ventricles, cerebrospinal fluid pathways, and the subarachnoid space of the brain and spinal cord

LCE – level of confidence of evidence

US – ultrasound examination

GRS – grade of recommendation strength

FZ – federal law

CIC – circulating immune complexes

CMV — cytomegalovirus

CNS – central nervous system

ALP – alkaline phosphatase

Class A immunoglobulins (IgA)

IgM – immunoglobulin class M

IgG – class G immunoglobulins

Terms and Definitions

Autoinoculation – the mechanical transfer of an infectious agent from one part of the body to other parts.

Abortive form – a course of the disease in which not all clinical symptoms manifest or clinical symptoms of the infection are minimal.

Herpetic co-infection – simultaneous infection with multiple types of herpesviruses.

Disease outcomes – the medical and biological consequences of a disease.

Latent herpesvirus infection – an inactive stage of infection in which the virus is not detected in biological materials but persists as a DNA-protein complex in nerve ganglia.

Manifest herpesvirus infection – an active stage of infection characterized by clinical symptoms.

Nosological entity – a set of clinical, laboratory, and instrumental diagnostic signs that allow a disease (poisoning, trauma, physiological state) to be identified and classified into a group of conditions sharing a common etiology, pathogenesis, and clinical manifestations.

Complication of a disease – the addition to a disease of a syndrome of physiological process impairment; - violation of the integrity of an organ or its wall; - hemorrhage; - developed acute or chronic failure of an organ or organ system function.

Primary disease – a disease that, by itself or due to complications, necessitates priority medical care due to the greatest threat to working capacity, life, and health, or leads to disability, or causes death.

Pantropism the ability of viruses to affect various systems and organs.

Persistence the ability of a virus to continuously or cyclically multiply (replicate) in infected cells of tropic tissues, creating a constant threat of developing an infectious process.

Primary infection develops after infection of a previously uninfected person with a virus. The infection is accompanied by the appearance of antiviral antibodies (seroconversion) and a 4-fold increase in the concentration of class G immunoglobulins.

Primary (first) episode of herpes – newly identified clinical manifestations of herpesvirus infection.

Preventive antiviral therapy – administration of systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors, to prevent the development of various complications.

Herpes simplex – a widespread viral infection caused by herpes simplex virus types 1 and 2, characterized by diverse manifestations: from asymptomatic course or skin and mucous membrane lesions of various localization to severe generalized forms involving internal organs and the central nervous system.

Herpes recurrence – repeatedly recorded clinical manifestations of herpesvirus infection.

Widespread form of herpes simplex – two or more lesions.

Superinfection (subclinical and clinical); the layering of one infection onto another – for example, sexual transmission of HSV-2 to a person suffering from herpetic stomatitis caused by HSV-1.

Suppressive therapy – long-term, sometimes multi-year, continuous administration of low doses of systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors, during periods free from disease recurrence.

Concomitant disease – a disease that has no causal relationship with the underlying disease, is inferior to it in terms of the need for medical care, impact on working capacity, danger to life and health, and is not the cause of death.

Severity of a disease or condition – a criterion defining the degree of damage to the organs and/or systems of the human body or impairment of their functions caused by the disease or condition or their complication.

Episodic therapy – administration of systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors, at the time of recurrence in therapeutic doses while observing the frequency and duration of treatment.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Herpes simplex (HS) – a widespread viral infection caused by herpes simplex virus (HSV) types 1 and 2, characterized by diverse manifestations: from an asymptomatic course or lesions of the skin and mucous membranes of various localizations to severe generalized forms involving the central nervous system (CNS), internal organs, and eyes [1,2,3].

Clinical guidelines for herpetiform eczema, anogenital herpetic viral infection, neonatal herpes, and herpetic eye diseases are set out in separate documents and are not covered in these guidelines.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causative agent of the disease is the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) (Simplexvirus humanalpha 1, Simplexvirus humanalpha 2, HSV 1, HSV 2), belonging to the family Orthoherpesviridae, subfamily Alphaherpesvirinae [1,4]. The viral genome is represented by linear double-stranded deoxyribonucleic acid (DNA) [1,4].

The biological properties of HSV-1/-2 are: pantropism, capacity for lifelong persistence and latency in the infected human organism [1,2,4,5,6].

Main components of HSV pathogenesis [2,3,4,5,6,7]:

• tropism of HSV for epithelial and nerve cells, determining the polymorphism of clinical manifestations of the disease [2,4,5];

• infection of sensory ganglia of the autonomic nervous system;

• lifelong persistence;

• ability to reactivate under the influence of trigger factors, which can be both infectious and non-infectious factors [2,3,4,5,6,7].

HSV enters the human body through mucous membranes and skin (the risk of HSV infection increases with trauma to the mucous membranes and skin), in some cases with infected donor material [1,2,3,5,7].

The first stage of the pathogenesis of acquired herpesvirus infection is the adsorption and replication of the virus at the site of inoculation (at the portal of entry): on the mucous membranes of the oral cavity, the vermilion border of the lips, upper respiratory tract, conjunctiva, and genitals [2,3,4,5]. Replication of the pathogen in epithelial cells leads to their death with the formation of necrosis foci and vesicles [4,6]. Via the lymph and blood stream, the virus is carried to the lymph nodes [2,3,4,5,7]. Viral replication in regional lymph nodes leads to the development of lymphadenitis, intracellular and extracellular viremia, and subsequent hematogenous dissemination of the virus to internal organs, the brain, and distant lymph nodes [2,3,5].

The second stage is the neurogenic penetration of HSV into sensory (sympathetic) regional nerve ganglia, where it persists throughout life with periodic reactivation [1,2,3,5,7,8,9,10,11]. HSV-1, which predominantly causes lesions of the oral mucosa, nasopharynx, and lips, persists in the sensory ganglia of the trigeminal nerve (Gasserian ganglion) and other cranial nerves. Dissemination of HSV-1 is possible via the optic nerve in ophthalmoherpes (keratitis, keratoiridocyclitis, uveitis, etc.), the olfactory nerve in nasopharyngeal involvement with subsequent penetration into the central nervous system (CNS), and less commonly by the hematogenous route [1,2,3,5,7]. HSV-2, which predominantly causes lesions of the genitals, perineum, anal region, lower extremities, and buttocks, persists in the lumbosacral spinal ganglia [2,5]. Hematogenous dissemination of the virus and its transport to distant nerve ganglia, in particular the sacral and lumbar nerves, determine the possibility of developing genital herpes infections via non-sexual transmission through the oral mucosa [2,3,4,5]. The centrifugal spread of HSV during recurrence determines the anatomical constancy of lesions during HSV recurrences [2,4,5].

In nerve ganglia, the virus is inaccessible to humoral and cellular immunity factors – virus-neutralizing antibodies and T-killers [2,4,5]. The virus has the ability to spread from an infected cell to a neighboring uninfected cell via intercellular bridges and contacts, bypassing the intercellular space and avoiding contact with neutralizing antiviral antibodies that do not penetrate the cell. These very features account for the phenomenon of HSV "immune evasion" [2,4,5,7,8].

Persistence of HSV in skin epidermocytes and mucous membrane epithelium is also observed [1,2,4,5,7].

A distinctive feature of the biological affinity (cytotropism) of the virus is its ability to infect cells of the mononuclear phagocyte system, polymorphonuclear neutrophils, and lymphocytes [2,4,5,7]. HSV replication in neutrophils and lymphocytes is accompanied by the destruction of the latter. As for macrophages, these cells are considered as a micromodel of the macroorganism's resistance or susceptibility to herpetic infection [2,4,5,9]. Macrophage permissiveness to HSV and active viral reproduction in these cells are among the pathogenetic mechanisms determining the macroorganism's susceptibility to herpetic infection and the development of clinical manifestations [2,4,5,9]. Macrophage nonpermissiveness and the development of abortive herpetic infection contribute to the development of subclinical forms of the disease [2,9].

HSV is accompanied by the development of specific humoral and cellular immunity [2,4,5,7,8,10,11]. Features of anti-herpetic immunity include: non-sterile (the virus is not eliminated from the body), type-specific (predominantly against the corresponding virus type), and partially cross-reactive [2,4,5,7,10,11]. The inefficiency of anti-herpetic immunity is due to the fact that the virus persists in ganglia not as intact particles, but in the form of subviral structures—a DNA-protein complex [2,4,5]. The inefficiency of humoral immunity is evidenced by relapses of HSV against the background of high anti-herpetic antibody titers [2,4,5,7,8,10,11]. Antiviral antibodies do not protect against infection with the same virus at another site (autoinoculation), or with a serologically related virus strain at the same site (superinfection) [2,4,7]. Following a herpes relapse, a non-significant increase in anti-HSV antibody titers is recorded, while in a minority of patients, antibody titers do not change. At the same time, a high level of antibodies can provide fetal protection against intrauterine infection [2,3,5,12].

Cellular immunity mediated by T-killers, natural killers, and macrophages plays an important role in preventing disease relapse [2,4,5,11]. At the same time, cases of monthly HSV relapses are known in individuals without any significant changes in immunological parameters [2,3,5,7,9,10,11]. Viral reproduction in lymphocytes, neutrophils, and monocytes-macrophages underlies T-cell type immunodeficiency [2,4,5,10,13]. The mechanisms of the immunosuppressive action are caused by the suppression of chemotaxis and a decrease in the phagocytosis process activity, inhibition of natural killer function, and the lymphocyte blast transformation reaction [2,4,5,9,10,11].

Interferon deficiency plays a significant role in the pathogenesis of the disease [2,4,5,7,9,14,15,16,17,18]. Suppression of the leukocyte interferon response, their ability to synthesize in vitro alpha-interferon (IFN) when treated (stimulated) with interferon inducers—interferonogens; a decrease in the ability of lymphocytes to synthesize gamma-interferon, and fibroblasts to synthesize beta-interferon are recorded [2,4,5,14]. The levels of alpha-, beta-, and gamma-interferons in patients with recurrent HSV are reduced by 10 to 20 times compared to the control group [2,4,5,7,14,18]. Local suppression of IFN production in the foci of herpetic lesions is also registered [2,5,7,15].

The clinical course of acute and recurrent forms of HSV is determined both by the biological characteristics of the HSV that caused the disease and by the individual characteristics of the infected person's immune response to viral antigens [2,3,5,7,8,9].

Exacerbation of HSV is triggered by various factors, for example, decreased immunoreactivity (general and local), acute infections (influenza, ARVI), endocrine disorders, administration of antibiotics, systemic corticosteroids, antineoplastic drugs, hyperinsolation, hypothermia, psychoemotional stress, surgical and cosmetological interventions, etc. [1,2,3,4,5,7,8,19,20,21].

An important pathogenetic component of HSV is the sensitization of the macroorganism to the HSV antigen [2,4,5,7,19,20]. A delayed-type hypersensitivity reaction develops with the infiltration of cellular elements at the site of the forming rashes, which is clinically manifested as redness, swelling, and itching in the focus of the herpetic lesion. A more severe clinical course of HSV is observed in allergic patients [2,3,5,20].

1.3 Epidemiology of the Disease or Condition

HSV-1 and HSV-2 (pathogens of HSV) are ubiquitous [1,2,19,20,22,23,24,25]. According to the World Health Organization (WHO), worldwide approximately 3.7 billion people under the age of 50 (67% of the population) are infected with HSV-1, and about 417 million people aged 15 to 49 (11% of the population) are infected with HSV-2 [1,22]. The infection rate of the population increases with age and depends on the socio-economic standard of living and domestic traditions of various ethnic groups [1,22,23,26]. In the Russian Federation, only anogenital herpetic infection caused by HSV-1/-2 is registered [2,27]. In 2020, the incidence of anogenital herpetic infection was 8.7 cases per 100,000 population [27]. It should be noted that official statistics do not fully reflect the real picture of HSV incidence due to frequent subclinical and atypical forms of the disease [2,3,19,20,22,23,28]. In HSV, manifest clinical forms of the disease are registered in 10 – 15% of cases, mild forms—in 10% of cases [2,4,5,19,20,23]. Individuals without a history of herpes episodes account for 70% [1,2,4,19,20,23].

HSV-induced viral encephalitis is the most frequently diagnosed viral encephalitis in developed countries. Encephalitis incidence rates vary depending on the region of the world, the studied population, and the diagnostic methods used, averaging 1 in 250,000 – 500,000 people [2,53].

HSV is an anthroponotic disease [1,2,3]. In most cases, infection occurs in childhood [1,2,3,5]. The main transmission routes are airborne droplet and contact-domestical; autoinoculation is possible in the presence of infection [1,2,3,4,5]. The port of entry for the virus is the skin of the lips, the oral mucosa, less frequently the nasopharynx, and the eye conjunctiva [1,2,3,4,5,8]. Patients with rashes present the greatest danger. The risk of HSV infection increases with trauma to the skin and mucous membranes.

Horizontal transmission routes include iatrogenic ones: blood transfusion, transplantation (during organ and tissue, bone marrow, cornea transplantation, etc.) [2,3,5,8,9,11,21,22,29,30].

The vertical mechanism of transmission includes intrauterine infection of the fetus via maternal blood, as well as via the ascending route [2,12,31,32,33,34]. Fetal HSV infection frequently occurs during childbirth when the fetus passes through the infected birth canal [12,25,31,32,33,34]. The risk of fetal infection can reach 50% in the event of primary genital herpes in a pregnant woman 6 weeks prior to delivery; in recurrent genital herpes, the risk of fetal infection is estimated at 3 – 5% [2,25,31,32,33,34].

1.4 Features of Coding the Disease or Condition

International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)

B00.1 Herpesviral vesicular dermatitis

B00.2 Herpesviral gingivostomatitis and pharyngotonsillitis

B00.3+ Herpesviral meningitis (G02.0*)

B00.4+ Herpesviral encephalitis (G05.1*)

B00.7 Disseminated herpesviral disease

B00.8 Other forms of herpesviral infections

B00.9 Herpesviral infection, unspecified

B34.9 Viral infection, unspecified

K12.1 Other forms of stomatitis

1.5 Classification of the disease or condition

1.5.1 By mechanism of infection:

• acquired:

✔ primary;

✔ recurrent;

• congenital.

1.5.2 By form of the infectious process:

• latent;

• localized;

• widespread;

• generalized.

1.5.3 By duration of virus persistence in the body:

• acute;

• chronic;

• slow.

1.5.4 By clinical manifestations and localization:

• typical forms:

✔ lesion of the gastrointestinal mucosa: stomatitis, gingivitis, esophagitis, etc. [2,35];

✔ skin lesions: herpes labialis, herpes of the alae nasi, face, hands, buttocks, etc. [1,2,3,5];

✔ lesions of the genitals and urogenital tract: lesions of the mucous membranes of the penis, vulva (vulvitis), vagina (vaginitis), cervical canal (cervicitis), urethra (urethritis), urinary bladder, etc. [2,5,36,37];

✔ eye lesions (ophthalmoherpes): conjunctivitis, keratitis, iridocyclitis, optic neuritis, neuromyelitis optica, etc. [8];

✔ lesions of the nervous system: meningitis, encephalitis, meningoencephalitis, neuritis, meningoencephaloradiculitis, bulbar nerve lesions, etc. [2,38,39,40];

✔ visceral lesions: tracheobronchitis, pneumonia, hepatitis, pancreatitis, etc. [2,3,5];

✔ generalized HSV: visceral form (pneumonia, hepatitis, esophagitis, etc.) and disseminated form (sepsis) [2,3,5].

✔ atypical forms [2,3,5]:

✔ abortive;

✔ edematous;

✔ zosteriform herpes simplex;

✔ herpetiform eczema (Kaposi's varicelliform eruption);

✔ ulcerative-necrotic;

✔ hemorrhagic;

✔ erosive-ulcerative;

✔ disseminated;

✔ rupioid;

✔ migratory.

1.5.5 By presence of complications:

• uncomplicated;

• complicated.

1.5.6 By period of the disease:

• prodromal period;

• catarrhal period;

• rash period;

• regression period.

1.5.7 By degree of severity:

• mild (1-3 relapses per year);

• moderate (4-6 relapses per year);

• severe (6 or more recrudescences per year).

1.5.8 By stage:

• active:

✔ with clinical manifestations (relapse);

✔ asymptomatic;

• inactive.

1.5.9 By form of infection:

• primary infection:

✔ primary manifest infection;

✔ primary subclinical infection;

✔ primary infection with a single site of viral entry;

• primary infection with multiple portals of entry of the infection;

• autoinoculation;

• latent infection;

• first episode of herpes;

• herpes relapse;

• co-infection;

• superinfection.

1.6 Clinical presentation of the disease or condition

Clinical manifestations of HSV depend on the infection mechanism, localization of the pathological process and its extent, and the patient's immune status [2,3,5,7,19,20].

In clinical practice, a distinction is made between the primary clinical episode (primary HSV) and recurrent manifestations of the infection (HSV relapse). The frequency of relapses directly depends on the degree of immune system depression, primarily the degree of reduced endogenous interferon production [2,5,13,14]. Depending on the severity of the disease course, the risk of systemic HSV complications increases. In pronounced immunodeficiencies, a permanent course of HSV may be observed (relapses follow one another without intervals) [2,4,5,7,8,15,19,36].

Primary herpes simplex (primary HSV) occurs after the first contact with HSV [1,2,3,5,7,19,20]. This most commonly happens in childhood. In seronegative liver, kidney, and other organ transplant recipients, a primary infection from the allograft (donor-derived infection) is possible at any age [2,3,5,8,9,11,21,22,29,30,31].

The primary episode is characterized by pronounced clinical symptoms and may be accompanied by a prodromal stage.

Subjective symptoms:

Complaints of burning, tingling, pain in the area of rashes of varying severity; fatigue, malaise, weakness, debility, decreased performance, headache, photophobia, irritability, sleep disturbances, paresthesias; elevated body temperature, tenderness/enlargement of regional lymph nodes.

Objective symptoms:

Manifest (typical) form of genital herpes:

- hyperemia and edema of the skin and mucous membranes in the affected area;

- single or multiple, tendency to group, polycyclic scalloped vesicles with clear contents;

- superficial, possibly coated, scalloped erosions 2–4 mm in size formed after vesicle rupture, crusts. When secondary infection joins, purulent exudate.

Atypical forms of herpes simplex:

- abortive: erythema and edema without the development of rash elements;

- erythematous: erythematous pruritic spot of various sizes, with blurred margins, irregular outlines;

- erosive-ulcerative: ulcers formed from vesicles, after healing of which atrophic scars are formed;

- edematous: pronounced edema of the subcutaneous adipose tissue without vesicle formation; - fissure form: fissures of the skin and mucous membrane accompanied by itching, hemorrhagic: single or multiple vesicular elements with hemorrhagic contents;

- ulcerative-necrotic: long-healing ulcers transforming from erosions formed after vesicle rupture;

- bullous form is represented by a single multilocular blister [2,5].

The duration of the primary HSV episode is 10–14 days or more, while that of a relapse averages 5–6 days (in immunocompromised patients, e.g., patients in late stages of HIV infection, HSV relapses are more prolonged, characterized by a high risk of process dissemination, extensive, long-standing mucocutaneous lesions, and enlargement of regional lymph nodes). Primary HSV caused by HSV-1 and/or HSV-2 proceeds similarly [1,2,3,5,7,19,20,36].

Recurrent herpes simplex is distinguished by a lower intensity and duration of clinical manifestations [2,3,4,5,7,8,19,20,35,36].

The frequency of HSV relapses can vary from 1–3 exacerbations per year to 6–12 or more exacerbations per year. In some patients, the process takes on a "monotonous", continuous character, in which new rashes appear while other rashes have not yet resolved. The risk of developing systemic complications is also determined by the severity of the HSV course and the severity of immune disorders [2,3,5,19,20,30,36].

The localization of rashes in recurrent HSV is usually fixed at the site of viral entry into the skin or mucous membrane ("locus minoris") [2,3,5,8,19,20,36]. Relapses of the disease are preceded by prodromal phenomena: burning, tingling, itching. Grouped vesicles 1.5–2 mm in size appear against the background of erythema, their clear contents become turbid, sometimes they can become hemorrhagic [2,3,5,20,36]. Rashes are most often represented by a single lesion consisting of 3–5 grouped vesicles, after the rupture of which painful erosions are formed with scalloped outlines, a soft, hyperemic base, and a smooth, moist surface. Upon secondary infection or trauma, the erosion turns into a superficial ulcer with slight peripheral edema. Regional lymphadenitis occurs, and the lymph nodes are moderately tender. After epithelialization of the erosions, slowly resolving hyperpigmentation may remain.

When the process is localized on the skin, the contents of the vesicles may dry into crusts.

Recurrent HSV may be accompanied by systemic manifestations such as esophagitis, gastritis, bronchitis, pneumonia, thyroid gland involvement, etc. The coincidence in time of rashes and systemic complaints may indicate systemic involvement [2,3,5,19,20,36].

Recurrent HSV in immunocompetent and immunocompromised individuals can cause severe isolated and disseminated neurological disorders with various topographical localizations of the lesion (often in the manner of polyradiculopathy, ganglionitis, in some cases in the form of meningoencephalitis, transverse myelitis, or recurrent lymphocytic meningitis - Mollaret's meningitis), and skin manifestations may be absent entirely [2,3,38,39,40,41,42].

Recurrent HSV (regardless of its localization area) significantly reduces the quality of life of patients, bringing physical suffering (itching, pain), psychological and mental problems [2,3,5,7,19,20,36,43].

Features of clinical forms of Herpes Simplex

Herpetic stomatitis (HS) – a clinical form of HSV characterized by involvement of the oral mucosa with the appearance of vesicular rashes and erosions in the area of the tongue, inner surface of the lips, gums, cheeks, hard and soft palate, elevated body temperature, headache [2,3,5,35,44,45,46,47]. The incubation period of the disease is 1–8 days. The severity of symptoms depends on the degree of severity of the process [2,3,5,35,44,45,46]. The clinical picture is represented by edema, hyperemia, grouped vesicles, after the rupture of which painful polycyclic erosions are formed with remnants of exfoliated epithelium, hyperemia, pain and bleeding of the gums (gingivitis), profuse salivation, with increased saliva viscosity [45,46,47]. Vesicles, erosions, and crusts on a hyperemic edematous base may also be noted on the skin of the perioral zone [2,5,35,44,45,46,47]. Regional submandibular lymph nodes are enlarged and tender. In moderate and severe clinical forms of HS, bilateral inflammation of the submandibular and cervical lymph nodes is observed. Lymphadenitis may precede the appearance of vesicles (erosions) in the mouth and persist on average for 7–10 days after complete epithelialization of the elements. Patients complain of soreness, discomfort when eating, bad breath [2,5,35,44,45,46]. HS is a self-limiting disease [2,35,45]. The duration of the process depends on the patient's immune status, the presence of carious and broken teeth, concomitant diseases, and the timeliness of therapy administration [2,3,5,35,45,47].

Herpetic vesicular dermatitis (HVD) – a chronic recurrent herpetic lesion of any area of the skin and mucous membranes outside the genital localization [1,2,3,5,19,20,45,47]. Clinically, HVD is characterized by the presence of small, grouped vesicles on a hyperemic edematous base, upon rupture of which erosions with polycyclic edges are formed, sometimes merging into a larger lesion [2,5,47]. The appearance of rashes may be accompanied by itching, burning, and pain [2,3,5,19,20]. In a number of patients, an increase in body temperature and enlargement of regional lymph nodes are noted.

Visceral form of HSV. Internal organs can be affected in HSV [2,3,5,12,19,20,30,31,32,48,49,50,51]: lungs (bronchitis, tracheobronchitis, pneumonia, pneumonitis) [49,50,51], esophagus (esophagitis), liver (hepatitis accompanied by an increase in liver enzymes, which is reversible) [2,48], heart (myocarditis), etc.; coagulopathies also occur [2,3,31]. Fever, leukopenia, and hepatitis are common signs of disseminated disease [2,48]. Pneumonitis has been described in recipients of all organ types [2,29,30,49,38,39,49], but is most frequently encountered in heart and lung transplant recipients [2,51].

Herpetic encephalitis. HSV-1/-2 cause meningitis, encephalitis, meningoencephalitis, meningoencephaloradiculitis, neuritis, cranial nerve palsies, and various peripheral nervous system syndromes [2,3,5,31,32,38,39,40,41,42,52,53,54,55,56]. It has been established that HSV-2 most frequently causes meningitis in adults (especially recurrent), as well as meningoencephalitis in immunocompromised individuals [53].

Encephalitis may develop as a result of a primary infection, but more often due to the activation of a latent virus [2,3,38,39,40,41,42]. Herpes encephalitis during pregnancy is rare, occurring more frequently in the late second and early third trimesters of pregnancy [2,48]. In 95% of cases, the causative agent of encephalitis is HSV-1 [2,3,39,40,41,52,53]. In 1/3 of cases involving the central nervous system, cutaneous herpetic manifestations are absent [2,38,42,51,52,53,54]. The course of encephalitis comprises 4 periods: 1) infectious manifestations before the onset of neurological disorders (from 1 to 30 days), 2) neurological disorders (from 1 to 50 days), 3) reconvalescence (from 1 to 12 months), 4) residual effects [2,3,38,54]. In most patients, the disease begins acutely with fever and general infectious manifestations, accompanied by weakness, headache, nausea/vomiting, and respiratory symptoms [2,38,39,40,41,42,54]. The temperature in most patients is high (38–39°C and above); the duration of the febrile period averages 12 days. The increase in neurological symptoms occurs against the background of high fever, accompanied by increased intoxication and severity of the disease. Impaired consciousness of the confusional, lethargic, or disoriented type (in place and time) is detected in the majority of patients. In 12% of patients, severe consciousness disorders up to coma are observed [2,38,40,41,42,48]. Epileptic seizures with tonic and clonic convulsions in the acute period are observed in more than 50% of patients. In 1/3 of patients, encephalitis begins with a seizure syndrome. Mental disorders are registered in 80% of patients [38,39,53,54]. In 20% of patients, the disease begins with psychiatric disorders, against the background of which neurological symptoms subsequently develop. Some patients experience hallucinations (most often visual). Patients are disoriented in place and time and commit unmotivated acts. Impairment of higher mental functions often manifests as aphasias. One-third of patients experience motor disorders in the form of central paralysis and paresis [3,38,39,53]. Cranial nerve involvement (oculomotor and facial nerves) is frequently noted in patients. Pronounced meningeal syndrome in the form of hyperesthesia, photophobia, nuchal rigidity, Kernig's, and Brudzinski's signs is observed in 1/3 of patients. The severity of meningeal syndrome does not always correlate with the severity of inflammatory changes in the cerebrospinal fluid, which are noted in 90% of patients (in the form of an increase in cells ranging from 6 to 1,600 cells per µL, and protein ranging from 0.4 to 9.9 g/L) [2,3,38,52,53]. Some patients may exhibit delayed CSF clearance, which may indicate the chronic nature of the infectious process [2,38,52,53]. In untreated patients, herpes encephalitis rapidly progresses with cerebral edema and destruction of brainstem areas, leading to death within 7-14 days [38,40,53,54].

Case fatality rate in patients without timely, specific antiviral treatment can reach >50% [53].

In 2/3 of surviving patients, neuropsychiatric complications and various long-term sequelae are observed [2,3,5,38,39,42,48,52,53,55].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria

Criteria for establishing the diagnosis of the disease/condition

The diagnosis of herpes simplex (HS) in adults is established based on complaints, medical history, physical examination findings, laboratory results, and, in some cases, special diagnostic examinations [2,3,5,7,8,19,20,37,38,45,48,51,54,55,56,61,62,64].

Diagnosis of HS in adults aims to determine the nosology, clinical form, severity of the condition, and to identify complications and indications for treatment [2,3,5,7,8,19,20,37,38,45,48,51,54,55,56,61,62,64].

2.1 Complaints and Anamnesis

Complaints depend on the clinical form of HS and the localization of the process. Complaints and medical history are described in Section 1.6 – "Clinical Presentation".

Comments: Such factors may include drug hypersensitivity; inadequate psychoemotional state of the patient prior to treatment [43]; refusal of treatment.

Comments: risk factors for a severe and complicated course of herpes simplex may include life-threatening acute conditions/diseases or exacerbations of chronic diseases requiring the involvement of specialist physicians in the relevant field [2,3,29,30,39,41,45,48,53,60,61,62,63].

2.2 Physical Examination

Comments: using a spatula (probe), the condition of the epiglottis is determined, the texture and density of the surface are evaluated, and attention is paid to the presence of spots and the nature of mucosal defects in the oral cavity [2,3,5,35,45,46,47,51]. During the examination, attention is paid to the localization, size, and depth of pathological changes (vesicles, aphthae), tenderness or lack of sensitivity upon examination, and the intensity of salivation. Examination of the skin reveals rashes in the form of foci consisting of grouped, less commonly coalescing vesicles with clear contents, erosive-ulcerative elements, as well as their number, localization, typical features, tenderness, etc. [2,3,5,8,19,20,31,32,35,37,56]. Involvement of the eye mucosa is possible, presenting with eye redness, tearing, photophobia, decreased visual acuity, and rashes [2,3,8].

Comments: examination of the lymph nodes is performed bimanually and bilaterally, comparing the right and left sides. Inspection of the lymph nodes provides information on the presence of inflammatory or infectious processes.

Comments: physical examination will reveal potential central or peripheral nervous system pathology against the background of a current or recent febrile illness (behavioral or personality changes with cognitive decline, altered consciousness – confusion, disorientation, psychomotor agitation, stupor, coma; numbness, paresthesia, pain, limb paresis and paralysis, brainstem dysfunction, pelvic sphincter disturbances, generalized seizures, mental disorders, etc.) [2,53,66,68,69]. The severity of cerebral injury correlates with the Glasgow Coma Scale score. Glasgow Coma Scale (GCS) is an internationally recognized tool for the objective assessment of the level of consciousness in patients with CNS infections. Scale scores allow tracking the dynamics of the patient's condition and making decisions regarding the need for intubation, neuroimaging, or transfer to the ICU [3,53,66,68,69]. Although the signs of HSV encephalitis are nonspecific, individuals with suspected HSV encephalitis may exhibit moderate pyrexia (fever), speech disturbances (dysphasia and aphasia), and behavioral changes that can be mistakenly attributed to mental illness or the toxic effects of alcohol, etc. [53].

2.3 Laboratory Diagnostics

2.3.1 Non-specific laboratory diagnostics

Comments: viral infections are typically characterized in the complete blood count by leukopenia or normocytosis, and an increased percentage of lymphocytes and monocytes relative to other leukocyte forms. However, changes similar to those seen in bacterial infections may occur (leukocytosis, left shift of the leukocyte formula, elevated ESR). High leukocyte counts and a left shift of the leukocyte formula indicate a high risk of complications and require therapy adjustment (including antibacterial therapy).

In CBC, depending on the severity of herpetic stomatitis, leukopenia, an increased number of band neutrophils, and elevated ESR may be observed [2,35].

In UA for uncomplicated herpes simplex, there are no pathological changes; in cases of pronounced fever and intoxication syndrome, there is an increase in urine specific gravity, transient mild leukocyturia, proteinuria, and cylindruria, which disappear upon normalization of body temperature and relief of infectious intoxication manifestations. In severe herpetic stomatitis, UA shows albuminuria, cylindruria, and microhematuria. In biochemical blood tests for uncomplicated herpes simplex, there are no pathological changes; in the case of herpesvirus-induced hepatitis, an increase in total bilirubin due to the direct fraction, and elevated activity of ALT, AST, and ALP are observed [2,3,5,48]. In severe forms of herpetic stomatitis, elevated creatinine and urea levels are observed in biochemical blood tests.

2.3.2 Specific laboratory diagnostics

- qualitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in blood by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- quantitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in blood by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- qualitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in vesicular fluid and scrapings from rashes on mucous membranes and skin by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- quantitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in vesicular fluid and scrapings from rashes on mucous membranes and skin by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- qualitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in saliva by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- quantitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in saliva by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- qualitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in urine by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- quantitative determination of Herpes simplex virus types 1, 2 (Herpes simplex virus types 1, 2) DNA in urine by polymerase chain reaction (PCR) [2,3,5,24,25,32,33,34,36,39,48,50,52,56,72,73,74,75,76,77,78,79,80].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments: biological material (e.g., vesicle contents and/or scrapings from mucous membranes and skin, and/or biological fluids and body secretions (blood, saliva, urine, etc.)) is subject to examination depending on the clinical presentation and anamnesis data; when obtaining biological material, potential multi-site infection should be taken into account [2,5,72,73,74,75,76,77,78,79].

Detection of HSV-1/-2 DNA (Herpes simplex virus types 1, 2) in scrapings from the oral mucosa, vesicular rash discharge, and erosive-ulcerative skin lesions using polymerase chain reaction (PCR) is the method of choice [2,74,75,78,80]. Real-time quantitative PCR determination of HSV-1/-2 (Herpes simplex virus types 1, 2) DNA is undoubtedly valuable; the test results can be used both for diagnostic purposes, for identifying indications for suppressive antiviral therapy, and for assessing treatment efficacy [2,3,5,19,20,29,32,33,48,49,50,70,72,73].

The PCR diagnostic method is of particular importance: in primary infection during the "serological window" stage prior to antibody synthesis, when the detection of HSV-1/-2 (Herpes simplex virus types 1, 2) DNA in the blood is the sole marker of active viral replication; in asymptomatic herpes, when the disease lacks a clear clinical picture but pathological processes are present, and patients, shedding the virus during contacts, infect partners [2,3,5,28,37,72,77,78,79,80]. PCR testing can also be used for the differential diagnosis of HSV-1 and HSV-2 (Herpes simplex virus type 1, type 2) [2,22,26,41,78,79].

In HS patients with a history of low antiviral therapy (AVT) efficacy episodes, examination of biological material (vesicle contents and/or scrapings from mucous membranes and skin, and/or biological fluids and body secretions depending on the clinical picture) using molecular genetic methods is indicated to detect specific HSV-1 and/or HSV-2 (Herpes simplex virus types 1, 2) DNA fragments and determine viral load (quantitative PCR test), in order to exclude drug resistance mutations of the virus to systemic antiviral drugs from the group: nucleosides and nucleotides, excluding reverse transcriptase inhibitors (ATC code: J05AB) [2,3,4,5,29,49,50].

Various inhibitory factors can affect test sensitivity; therefore, strict requirements are imposed on clinical material collection, storage/transportation conditions, and laboratory organization and operation mode to prevent clinical material contamination [2,3,4,5,72,78].

In some cases, to confirm the etiology of the disease and determine the sensitivity of the virus to systemic antiviral drugs, a virological method may be used, based on isolating the virus (Herpes simplex virus type 1, type 2) from biological material (e.g., vesicle contents, scrapings from mucous membranes and skin, blood, CSF, etc.) on susceptible cell cultures, followed by its identification and determination of sensitivity to systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors [2,4,5,78,79,80].

- determination of class M (IgM) and/or class G (IgG) antibodies (Abs) to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) by enzyme-linked immunosorbent assay (ELISA) [2,3,5,25,28,29,34,36,39,48,50,52,53,61,62,74,76,81,82,83,84,85]:

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

- determination of class M (IgM) antibodies to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1,2) in blood [2,3,5,25,28,29,34,36,39,48,50,52,53,61,62,74,76,81,82,83,84,85].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

- determination of class G (IgG) antibodies to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1,2) in blood [2,3,5,25,28,29,34,36,39,48,50,52,53,61,62,74,76,81,82,83,84,85].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

- determination of class G (IgG) antibodies to herpes simplex virus type 1 (Herpes simplex virus types 1) in blood [2,3,5,25,28,29,34,36,39,48,50,52,53,61,62,74,76,81,82,83,84,85].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

- determination of class G (IgG) antibodies to herpes simplex virus type 2 (Herpes simplex virus types 1) in blood [2,3,5,25,28,29,34,36,39,48,50,52,53,61,62,74,76,81,82,83,84,85].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: detection of class M (IgM) antibodies to HSV-1/-2 (Herpes simplex virus types 1, 2) has the greatest diagnostic value as an indicator of active disease process—their presence indicates an acute infection, reinfection, superinfection, or reactivation [2,3,4,5,7,19,20,21,28,77,81]. However, in clinically pronounced cases, including typical presentations of herpes simplex, specific IgM antibodies to HSV are rarely detected (in 3–6% of cases). The laboratory criterion confirming the clinical diagnosis of herpes simplex is a 4-fold or greater rise in the titer of specific IgG antibodies to HSV over 10–14 days (paired sera method) [2,3,4,5,7].

Serological testing is also indicated when examining sexual partners of patients, where one partner is HSV-seronegative. If discordant serological results are obtained between sexual partners, counseling should be provided regarding options for monitoring and reducing the risk of virus transmission [1,2,3,4,5,32,33,34,37].

In organ and tissue recipients, serostatus should be determined by testing for class G (IgG) antibodies to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) prior to transplantation for appropriate post-transplant risk stratification [2,3,29,49,50].

In patients with herpes simplex presenting with neurological symptoms, alongside the determination of class M and G antibodies (IgM, IgG) to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) in blood serum, serial determinations of class M and G antibodies (IgM, IgG) to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) in cerebrospinal fluid should be performed concurrently (in 5% of patients, herpetic encephalitis is caused by HSV-2 infection) [53,61,62,64,66].

Determination of class G (IgG) antibody avidity to herpes simplex virus types 1 and 2 (Herpes simplex virus type 1, 2) has low diagnostic utility: reactivation in clinically overt cases is accompanied by the presence of high-avidity antibodies [2,4,5].

Comments: to establish the etiology of the disease during the acute stage, cerebrospinal fluid (CSF) sampling is required (if intracranial pressure permits (!) and there are no other clinical contraindications), followed by clinical and biochemical CSF analysis and cell counting in a counting chamber (determination of pleocytosis) [53].

CSF analysis allows for the determination of: total protein level (CSF protein assay), glucose (CSF glucose level assay), chlorides (CSF chloride level assay), and pleocytosis (microscopic examination of cerebrospinal fluid, cell counting in a counting chamber [determination of pleocytosis]).

In individuals with suspected HSV encephalitis, CSF findings may include elevated protein levels, lymphocytic or mixed pleocytosis, xanthochromia, and erythrocyte admixture. In approximately 5–10% of adults with confirmed HSV encephalitis, baseline CSF parameters may be normal without pleocytosis [53]. HSV encephalitis can be hemorrhagic, with elevated red blood cell counts in the CSF in approximately 50% of cases [53].

• perform qualitative detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in cerebrospinal fluid by polymerase chain reaction (PCR) and/or quantitative detection of herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) DNA in cerebrospinal fluid by polymerase chain reaction (PCR) [2,3,39,41,42,48,53,54,61,62,64,65,66,67,68,86].

Level CLevel 3Level of recommendation evidence C (reliability level of evidence – 3).

Comments: CSF testing by PCR is the gold standard for diagnosing HSV encephalitis, meningitis, or meningoencephalitis, with a sensitivity of 98% and a specificity of 100% [53,86]. In 5–10% of adults with confirmed HSV encephalitis, initial PCR testing of CSF for HSV may be negative during the first few days of illness [53]. In patients with suspected HSV encephalitis, repeat PCR testing of CSF for HSV is recommended in 3–7 days in undiagnosed cases presenting with clinical or neuroimaging signs of the disease [39,52,53,57,65,66,68,86]. In patients with herpes simplex and neurological symptoms, PCR results may remain positive for at least 5 days after the initiation of aciclovir therapy** [39,52,53,57,65,66,68,86].

• perform serological testing of cerebrospinal fluid with determination of class M and G antibodies (IgM, IgG) to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1, 2) by enzyme-linked immunosorbent assay (ELISA) [39,52,53,57,65,66,68]:

- determination of class M (IgM) antibodies to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1,2) in cerebrospinal fluid by ELISA: qualitative determination [39,52,53,57,65,66,68];

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

and/or

- determination of class M (IgM) antibodies to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1,2) in cerebrospinal fluid by ELISA: quantitative determination [39,52,53,57,65,66,68];

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- determination of class G (IgG) antibodies to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1,2) in cerebrospinal fluid by ELISA: qualitative determination [39,52,53,57,65,66,68];

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

- determination of class G (IgG) antibodies to herpes simplex virus types 1 and 2 (Herpes simplex virus types 1,2) in cerebrospinal fluid by ELISA: quantitative determination [39,52,53,57,65,66,68].

Comments: antibodies to HSV-1/-2 are detected by ELISA in cerebrospinal fluid several days later than in blood. The test results also make it possible to determine the CSF HSV antibody index (the level of specific intrathecal humoral immune response to the virus) relative to the serum HSV antibody titer. In herpetic encephalitis, an antibody specificity index of ≥1.5 is typically achieved 7–10 days after the onset of symptoms [38,39,52,53,57,65,66,68,86].

Further CSF examinations (by ELISA and/or PCR), when indicated, may aim to identify other bacterial and viral pathogens of central nervous system infections based on epidemiological factors (age, occupation, geography and recent travel history, season of the year, potential animal or insect exposure, sexual history, vaccination) and clinical data (rash, lymphadenopathy, hepatitis, respiratory tract infections, neurological syndrome, etc.) for differential diagnosis purposes [39,52,53,57,65,66,68,86].

Due to the fact that herpes simplex (HS) is a chronic process characterized by the absence of viral clearance, monitoring for cure is not advisable.

2.4 Instrumental Diagnostics

Comments: diagnostic lumbar puncture is an important test in the management of patients with suspected encephalitis, both to confirm the diagnosis and to exclude other causes. Lumbar puncture in patients with HS is performed when brain involvement is suspected (altered mental state, unconsciousness, drowsiness or difficulty waking up, and intermittent or constant convulsions (seizures), confusion, severe weakness or paralysis, etc.), or in the presence of meningeal or focal symptoms. Contraindications to lumbar puncture include: progressive cerebral edema, herniation syndrome, hemorrhagic syndrome (or a high risk of its development) [2,3,5,38,39,52,53,57,65,66,68]. Since immediate lumbar puncture is impossible (!) in patients with elevated intracranial pressure, such patients may be started on acyclovir therapy prior to the procedure and CSF testing [2,3,39,52,53,57,65,66,68,69,70]. CSF examination is described in section 2.3.2 "Specific Laboratory Diagnostics".

i

• computed tomography (CT) of the brain and/or magnetic resonance imaging (MRI) of the brain to determine the extent of brain damage and determine treatment tactics [3,39,52,53,55,57,62,63,65,66,68,69,70,87].

GCR CLEL 4Grade of Recommendations C (Level of Evidence – 4).

Comments: differential diagnosis, including in the absence of vesicular rashes, but in the presence of intoxication symptoms, fever, meningoencephalitis symptoms, brain tumors, vascular changes, etc. Presence of necrosis foci in the brain, more often in the frontotemporal region (from the 5th–7th day of the disease) [53,55]. In herpetic encephalitis, a decrease in tissue density in the temporal lobes, ventricular dilation, and displacement of central brain structures towards the greater lesion are registered. Neurodiagnostic studies (brain CT and MRI) are important for evaluating patients with HS and signs of CNS involvement, but are not sufficient to establish an etiological diagnosis [41,42,53,55,62,87].

Comments: there are no specific findings on electrocardiography.

and/or

• chest X-ray (lung radiography, targeted chest X-ray) [2,3,5,29,51,62].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

and/or

• ultrasound examination (ultrasound) of the abdominal cavity (complex) and retroperitoneal space to monitor the state of internal organs involved in the infectious process. If herpetic esophagitis is suspected, esophagogastroduodenoscopy is recommended [2,3,5,31,48,63].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: ultrasound of the abdominal cavity (complex ultrasound examination of the abdominal organs) and retroperitoneal space is performed when organ lesions caused by HSV are suspected, to diagnose enlargement and structural changes of the liver, spleen, kidneys, and lymph nodes, and to rule out concomitant gastrointestinal pathology, which in some cases can be crucial in determining treatment tactics.

Esophagogastroduodenoscopy is performed to diagnose esophagitis of herpesviral etiology, allows visualization of esophageal mucosal erosions typical of HS, and rules out concomitant GI pathology, which in some cases may also be crucial in determining treatment tactics.

2.5 Other Procedures

Comments: diagnostic difficulties arise in the prodromal period of HS, when vesicular rashes are absent, but symptoms of intoxication, fever, etc. are present; in severe and complicated forms of HS with internal organ or nervous system involvement in the absence of characteristic rashes, and in atypical forms of the disease [2,3]. In such cases, early manifestations of HS should be differentiated from stroke, angina pectoris, myocardial infarction, pleurisy, cholecystitis, pancreatitis, etc. These conditions require consultation with other specialist physicians and instrumental diagnostic examinations (see section 2.4).

Comments: herpes simplex is considered an AIDS-defining condition. Since 1988, HS has been included in the expanded case definition for AIDS surveillance.

In patients with suspected encephalitis, the presence of HIV should be considered for three reasons [3,53]. First, the most common neurological manifestation of primary HIV-1 infection is acute self-limiting meningoencephalitis [3,53]. Second, patients with undiagnosed progressive HIV disease may have CNS infections caused by less common pathogens such as Toxoplasma gondii, human cytomegalovirus (Cytomegalovirus), Pneumocystis jirovecii, and others. Third, some of the most common CNS pathogens, such as HSV (especially HSV-2), are frequently found in HIV patients and cause unusual manifestations such as chronic encephalitis.

The examination is carried out on the basis of voluntary consent of the individual or the consent of their legal representative (Sanitary and Epidemiological Rules SanPiN 3.3686-21, Section 6 Prevention of HIV Infection).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The indication for treatment is a verified diagnosis of "simple herpes" [2,3,5,7,8,20,25,29,32,33,52,53,56,68,70,83,88]. When formulating the diagnosis of "simple herpes", the specific features of the clinical course of the disease (nosological form, clinical form, severity, period of the disease) are taken into account and justified. If there are complications and concomitant diseases, they should be recorded on a separate line:

• Complication:

• Concomitant disease:

When justifying the diagnosis, one should indicate the clinical, laboratory, and instrumental data as well as the results of special research methods that substantiate the diagnosis of "Simple herpes".

The principles of treatment for patients with simple herpes involve the following tasks [2,3,5,7,8,20,25,29,32,33,53,56,70,88]:

• preventing the further development of the pathological process caused by the disease,

• achieving stable remission,

• preventing potential complications of the disease,

• preventing recurrences of the disease.

Treatment for simple herpes should be comprehensive, aimed at inhibiting HSV replication, enhancing the body's immunoreactivity, and reducing the frequency of recurrences [2,3,5,7,20,22,29,33,42,48,61].

The choice of treatment tactics is influenced by the following factors: the period of the disease (primary episode or recurrence); severity of the disease; clinical form of the disease; leading clinical manifestations and features of the disease course taking into account signs of immunodeficiency (exhaustion, severe concomitant pathology, advanced age, pregnancy); age of the patient; presence and nature of complications; availability and feasibility of providing treatment in accordance with the required type of medical care [1,2,3,4,5,7,8,19,20,21,29,39,53,64].

3.1 Conservative Treatment

3.1.1 Etiotropic (antiviral therapy)

Treatment goals [2,3,5,7,8,20,25,29,32,33,53,56,70,88]:

• suppression of viral replication;

• reduction of the severity and duration of the disease;

• prevention of complications.

Approaches to antiviral therapy [2,3,5,7,8,20,25,28,29,32,33,53,56,70,88]:

• treatment of the primary episode;

• episodic therapy;

• preventive therapy to prevent the development of various complications;

• suppressive therapy;

• treatment during remission.

Patients with a primary episode or recurrence of simple herpes require systemic antiviral therapy (ATC code: J05) to minimize complications, shorten the duration of the disease/recurrence, and reduce future recurrences [2,3,5,7,8,20,25,29,32,33,53,56,61,70,71,76,83,88,89,90,91,92].

Comments: antiviral therapy using systemic antiviral drugs (ATC code: J05) should be initiated early in the course of the disease before obtaining the results of virological testing and should be empirical, taking into account individual clinical manifestations [2,37,88,89]. The appropriateness of prescribing a specific systemic antiviral drug is determined by the physician individually for each patient [2,3,7,20,88,89].

Comments: therapy using systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors (ATC code: J05AB), is recommended to be initiated at the first signs of skin and mucous membrane involvement (itching, burning, redness). When treating recurrent herpes, it is advisable to start treatment during the prodromal period or at the very onset of recurrence signs. Empirical prescription of systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors (ATC code: J05AB), is possible when simple herpes is suspected, prior to laboratory confirmation of the diagnosis [2,4,22,37,56,88].

Comments: Aciclovir** (a systemic antiviral drug from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors, ATC code: J05AB) is included in the List of Vital and Essential Drugs for medical use for 2024 (approved by the Order of the Government of the Russian Federation No. 3781-r dated December 23, 2023, effective January 1, 2024).

or

valaciclovir 500 mg twice daily for 7–10 days [2,99,107].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

or

#famciclovir 250 mg 3 times daily for 7–10 days [95,99,105,107].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

aciclovir** 200 mg 5 times daily for 5 days [2,7,20,37,71,88,90,94,95,99,107].

GPR ALEL 2Grade of Recommendation A (Level of Evidence – 2) or

valaciclovir 500 mg twice daily for 5 days [95,99,107].

GPR CLEL 5Grade of Recommendation C (Level of Evidence – 5) or

famciclovir 250 mg 3 times daily for 5 days [99,104,105].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: to prepare the infusion solution, the contents of a vial of aciclovir** (250 mg) are diluted in 10 ml of sodium chloride** injection solution (0.9%) or a special solvent to obtain a solution containing 25 mg of aciclovir** per 1 ml. The solution is administered as a slow intravenous infusion over 1 hour.

Aciclovir**, lyophilisate for solution for infusion, is the drug of choice for the treatment of severe or disseminated forms of simple herpes or CNS diseases caused by HSV type 1 and/or 2. The use of aciclovir** should not be delayed until the diagnosis is established, but should be reviewed based on the laboratory test results obtained.

The dosage regimen for aciclovir**, lyophilisate for solution for infusion, is selected depending on the diagnosis, severity and form of the disease, age, and body weight of the patient. The dose of aciclovir** should be reduced in patients with pre-existing renal impairment or in obese patients, particularly the elderly [53]. Patients with HSV infection (other than herpes encephalitis) are prescribed aciclovir**, lyophilisate for solution for infusion, at a dose of 5 mg/kg of body weight every 8 hours, provided renal function is normal.

The course of treatment with aciclovir**, lyophilisate for solution for infusion, is usually 5 days, but may vary depending on the localization of the infection, the patient's condition, and response to therapy.

In cases of severe infections caused by HSV types 1 and 2, aciclovir**, lyophilisate for solution for infusion, may be initially prescribed at a dose of 5–10 mg/kg every 8 hours until the resolution of the disease or for up to 14–21 days, followed by a switch to oral therapy [2,3,107].

Patients with herpes encephalitis are prescribed aciclovir**, lyophilisate for solution for infusion, at a dose of 10 mg/kg of body weight every 8 hours, provided renal function is normal. Studies have shown that aciclovir** (10 mg/kg or more every 8 hours) improves outcomes in adults with HSV encephalitis, reducing mortality by at least 20–30%, whereas in patients not receiving antiviral drugs, mortality exceeds 70% [53].

Standard treatment of herpes encephalitis with aciclovir**, lyophilisate for solution for infusion, may be supplemented with supportive therapy to reduce and prevent brain edema.

The duration of treatment for herpes encephalitis in adults with aciclovir** (lyophilizate for solution for infusion) in initial randomized trials of the drug was 10 days. However, subsequent reports have been published on clinical relapse of the disease after completion of a 10-day course of treatment. In patients with proven HSV encephalitis, intravenous administration of aciclovir** should be continued for 14 days, and in some cases, the course of therapy may be extended up to 21 days. The course of therapy with aciclovir** should be extended if a repeat cerebrospinal fluid (CSF) examination reveals the continued presence of HSV DNA [44,48,49,50,51,52,53,54,55]. Discontinuation of aciclovir** therapy for herpetic encephalitis should only be considered after a definitive alternative diagnosis is established or until negative results of CSF PCR testing are obtained.

In solid organ transplant recipients, HSV reactivation leads to oral or genital mucosal lesions in approximately one-third of cases in the absence of prophylaxis. Although usually mild, some patients may develop severe ulcerative lesions complicated by esophageal involvement and bacterial superinfection. In exceptional cases, reactivation or primary HSV infection can cause pneumonitis, hepatitis, tracheobronchitis, or disseminated disease. Transplant recipients with suspected visceral spread of HSV (encephalitis or pneumonitis) should receive aciclovir** as a slow intravenous infusion over 1 hour at a dose of 10 mg/kg every 8 h [53]. The duration of prophylactic use of aciclovir**, lyophilizate for solution for infusion, is determined by the duration of the period at risk for infection (on average from 5 days before transplantation to 30 days after transplantation) [89,108,109,110].

Adequate hydration status should be maintained in patients receiving intravenous or high-dose oral aciclovir [2,3,51,53,89].

#aciclovir** 400 mg twice daily [95,97,99,103,107].

GPR CLEL 5Grade of Recommendation C (Level of Evidence – 5) or

valaciclovir 500 mg once daily [2,95,99,100,101,102,107].

GPR CLEL 5Grade of Recommendation C (Level of Evidence – 5) or

valaciclovir 500 mg twice daily [95,99].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

or

valaciclovir 1 g daily (for a recurrence frequency of 10 or more per year) [2,95,99,100].

GPR CLEL 5Grade of Recommendation C (Level of Evidence – 5) or

famciclovir 250 mg twice daily [95,99,107].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: prior to preventive and/or suppressive antiviral therapy, PCR confirmation of HSV infection is required. For the efficacy of suppressive antiviral therapy, the patient's capabilities and willingness to undergo treatment according to the prescribed regimen should be considered. After completing a course of preventive/suppressive antiviral therapy, a break should be taken to assess the pattern of the infectious process. The efficacy of suppressive antiviral therapy is evaluated based on at least two recurrences.

Preventive antiviral therapy using systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors (ATX code: J05AB) – aciclovir**, valaciclovir – is also indicated for immunocompromised patients undergoing chemotherapy, organ and tissue transplantation [108,109,110,111] in order to prevent the development of active HSV infection (see clause 7).

#Aciclovir** 200 mg 5 times daily for 10 days [2,94,112,115].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

or

Valaciclovir 500 mg once daily for 10 days [95,97,99,113,114,115].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

or

Famciclovir 250 mg twice daily for 10 days [99,116].

Leveled Clinical Recommendations C Level of Evidence 5 Level of recommendation validity C (level of evidence reliability – 5).

Comments: various routes of administration of interferon preparations (ATX code: L03AB) are possible – intramuscular, rectal, vaginal, and topical in accordance with the instructions.

Interferon preparations (ATX code: L03AB, group L03 immunostimulants):

• Interferon alfa** (ATX Code L03AB):

⮚ #Interferon alfa** (Interferon alfa-2b: Interferon alfa-2b + alpha-tocopherol acetate + ascorbic acid** – rectal suppositories (R N000017/01) [2,3,5,124,125,127,128,129, 130,131,132,133, 134,135].

Rectal suppositories (interferon content 1,000,000 IU). Use 1 suppository twice a day every 12 hours daily for 10 days or more in recurrent herpes simplex [2,3,127,129,130]. Therapy may be continued based on clinical indications. In pregnant women, the use of the drug (500,000 IU) is permitted starting from the 2nd trimester of pregnancy [2,128,129,130,131,132,133,134,135].

Interferon alfa** (#Interferon alfa-2b** – gel for local and external use (R N001142/02) – interferon content 36,000 IU). Apply 0.5 cm of gel using a spatula or cotton swab/cotton bud to the affected surface 3–5 times a day for 5–6 days; if necessary, the course duration is increased until clinical manifestations disappear. The drug is used in the combination therapy of herpes simplex [2,3,127,129];

or

• Interferon alfa-2b: #interferon alfa-2b + sodium hyaluronate (INN R N003293/01) [2,5,136]. Vaginal and rectal suppositories. Suppositories for rectal use (interferon content 50,000 IU per suppository). Use 1 suppository twice a day every 12 hours daily for 10 days or more in recurrent herpes simplex; therapy may be continued based on clinical indications. Hyaluronic acid, being a major structural element of human connective tissue, ensures uniform and prolonged delivery of interferon into the blood and enhances the antiviral activity of the drug. The drug is used in the combination therapy of herpes simplex.

Comments: Solanum tuberosum (potato) shoot polysaccharide sum (derived from the plant Solanum tuberosum) — pharmacotherapeutic group: other antivirals (ATX code: J05AX), exhibits antiviral activity against DNA and RNA genomic viruses, including HSV-1/-2 (herpes simplex virus types 1 and 2), as well as immunomodulatory, anti-inflammatory, and analgesic properties [2,137,138,139,140,141,142]. It increases the body's non-specific resistance to various infections and promotes the induction of interferon synthesis [2,137,138,139,140,141,142]. For the treatment of herpesvirus infections of various localizations and immunodeficiency states associated with infectious diseases, the drug is used as a 0.04 mg/ml intravenous solution, administered slowly as an intravenous bolus of 5.0 ml (the contents of one ampoule or vial); the treatment course consists of 2–3 injections at intervals of 48 or 24 hours. If necessary, the course is repeated after 1 month (the total course dose depends on the nature and severity of the disease) [137,138,139,140,141,142]. For infectious and inflammatory diseases of the skin and/or mucous membranes caused by HSV-1/-2 (herpes simplex virus types 1 and 2), the drug may be used as 200 mcg rectal suppositories: 1 suppository at night 3 times during the 1st week with a 48-hour interval, and 2 times during the 2nd week with a 72-hour interval, as well as in the form of a gel for local and outdoor application.

or

Sodium oxodihydroacridinylacetate — pharmacotherapeutic group: other immunostimulants (L03AX). Intramuscular injection solution — Reg. No.: R N003311/01 dated 05.11.09, rev. dated 13.11.23. Numerous studies have proven the following effects: antiviral (against DNA and RNA genomic viruses), immunomodulatory, antitumor, antiprotozoal, and antibacterial [2,138,143,144,145,146,147,148,149]. The drug is administered intramuscularly at 250 mg (4–6 mg/kg); the treatment course consists of 5–7 injections over 9–13 days with a 48-hour interval; if necessary, a single dose of up to 500 mg may be used with an 18–36-hour interval (the course dose depends on the nature of the disease) [2,138,143,144,145,146,147,148,149].

or

Meglumine acridone acetate** — pharmacotherapeutic group: other immunostimulants (L03AX). It is a low-molecular-weight inducer of interferons-α and -γ, belonging to the class of acridones. It exhibits antiviral activity against RNA- and DNA-containing viruses, including herpes simplex virus types 1 and 2, as well as immunomodulatory and anti-inflammatory properties [2,138,149,150,151,152,153,154,155,156,157,158]. It increases the body's non-specific resistance to various infections. The drug rapidly penetrates the bloodstream and crosses the blood-brain barrier. It is compatible and combines well with systemic antiviral drugs from the group of nucleosides and nucleotides (except reverse transcriptase inhibitors) and interferons (when used together, it enhances the effect of these drugs). It is used in complex therapy of herpes simplex: meglumine acridone acetate** as a solution for intravenous or intramuscular administration, 250 mg (1 ampoule) 1 time per day at 48-hour intervals (treatment course of 10 injections); #meglumine acridone acetate** in tablets (150 mg) — 450–600 mg (3–4 tablets) per dose 1 time per day on days 1, 2, 4, 6, 8, 11, and 14. The course of treatment varies depending on the severity of the condition and the intensity of clinical symptoms of herpes simplex [2,138,149,150,151,152,153,154,155,156,157,158].

Not included in the list of medicines recommended by international clinical guidelines for the treatment and prevention of herpes simplex.

Comments: the vaccine for the prevention of herpetic infections belongs to the ATX group: J07BX — "other viral vaccines". The purpose of vaccination is to correct and/or form an adequate immune response, maintain it long-term in order to block HSV reactivation, and prevent relapses of the disease caused by herpes simplex viruses types 1 and 2 [150,161]. The baseline method of administration is strictly during a period of sustained remission, no earlier than 10 days after the complete disappearance of clinical manifestations of the herpetic infection. The vaccine is administered intradermally into the flexor surface of the forearm using a syringe at a single dose of 0.2 ml (controlled by the formation of an "orange peel" appearance). The vaccination course for herpetic infection of the skin and mucous membranes consists of 5 injections administered once every 7 days. Revaccination (5 injections) is carried out after 6 months. In patients with complicated herpetic infection (relapses 1 or more times per month), the 2nd and subsequent injections are repeated at 10-day intervals. If herpetic rashes appear, the intervals between injections should be doubled [150,161]. Background information: the vaccine for the prevention of relapses of herpetic infections was first introduced into healthcare practice by an order of the USSR Ministry of Health in 1979; in 2010, the Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being introduced methodological recommendations for immunization with this vaccine [160]. The vaccine has undergone a series of blind, randomized, controlled trials to evaluate its efficacy in preventing relapses of various forms of chronic recurrent infection.

Not included in the list of medicines recommended by international clinical guidelines for the treatment and prevention of herpes simplex.

Management of pregnant women with herpes simplex

aciclovir** 200 mg 4 times a day for 10 days for a first episode, 5 days for a relapse [12,32,33,34,48,57,58,59,60,71];

or

valaciclovir 500 mg 2 times a day for 10 days for a first episode, 5 days for a relapse [32].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

#aciclovir** 200 mg 4 times a day for 2–3 weeks prior to delivery.

Leveled Clinical Recommendations C Level of Evidence 5 Level of recommendation validity C (level of evidence reliability – 5).

Comments: suppressive antiviral therapy with aciclovir** from 36–38 weeks of pregnancy until delivery significantly reduces the frequency of clinical manifestations and virus shedding, thereby decreasing the risk of vertical transmission of the infection [12,32,33,60].

Comments:  #normal human immunoglobulin** (ATX code: J06BA) is an immunologically active human blood gammaglobulin fraction containing predominantly Ig with reduced anticomplementary properties [179,180]. The possibility of using normal human immunoglobulins** (ATX code: J06BA) in the complex therapy of herpes simplex in pregnant women is due to the presence of antibodies to HSV-1/-2 (herpes simplex virus types 1 and 2), as well as antibodies of various classes to a number of other microorganisms [175,179]. #Normal human immunoglobulin** is administered intramuscularly into the upper outer quadrant of the gluteus muscle or the outer surface of the thigh at 3 ml every 3 days for 5 injections, or 25 ml intravenously by drip infusion in 200 ml of sodium chloride** (ATX code: B05XA) 3 times a week every other day (3 courses during pregnancy). The dose and frequency of administration depend on the indications for use.

The use of normal human immunoglobulin** may be considered in the treatment of pregnant women with frequent and severe exacerbations of herpes simplex infection against the background of laboratory-diagnosed immunodeficiency, as well as in pregnant women with chronic recurrent herpetic infection and antiphospholipid syndrome for the prevention of placental insufficiency and fetal loss syndrome [175,178,179]. The drug is administered via 3 intravenous drip infusions every other day at a dose of 25 ml, 3 to 6 times per pregnancy (1-2 times per trimester), depending on the severity of the herpes infection and the degree of immunosuppression. The efficacy of immunoglobulin therapy (cessation of the threat of pregnancy

loss) is due to the stimulating effect of Ig on the compensatory and adaptive capabilities of the placenta resulting from the partial neutralization of cytopathogenic viral activity [175,179].

Comments: interferon alfa-2b (500,000 IU) suppositories (R N000017/01) are used starting from the 2nd trimester of pregnancy (from the 14th week of gestation) — 1 suppository 2 times a day every 12 hours rectally for 5-10 days. The recommended number of courses is 2. The interval between courses is 5 days. Therapy may be continued based on clinical indications. Before delivery (starting from the 38th week of gestation), 1 suppository of 500,000 IU 2 times a day (every 12 hours) daily for 10 days [129,131,132,134].

3.1.2. Pathogenetic and symptomatic therapy

Symptomatic therapy

The primary objectives of symptomatic agents are: relief of inflammatory and toxic manifestations of the disease, and prevention of complications.

Comments: detoxification therapy aims to relieve intoxication syndrome, and its volume depends on the patient's severity grade. Metabolic therapy affects the body's metabolism.

Comments: from the vitamin group (ATX code: A11), the following may be used: ascorbic acid** (ATX code: A11GA), including its combinations with other agents, vitamin A** (ATX code: A11CA), B-complex vitamins** (ATX code: A11EA), and other vitamin preparations (ATX code: A11HA). Polypharmacy should be avoided when administering this therapy.

Comments: the goal of local therapy is the rapid reduction of inflammatory symptoms and pain intensity, as well as the prevention of secondary infection of the damaged mucous membrane and skin, and the prevention of complications. Local therapy cannot replace systemic antiviral therapy. Aciclovir** 5% ointment can be used as a local antiviral drug [2,5,7,187].

As Antiseptics and disinfectants (ATX code: D08), the following can be used [2,45,185,186]: chlorhexidine** 0.5%, 0.2%, 0.05%, 0.02% (ATX code: D08AC) — solution for local and external use, or # chlorhexidine** (spray for local and external use 0.05%); other antiseptics and disinfectants (ATX code: D08AX) — hydrogen peroxide** (solution for local and external use), benzyldimethyl[3-(myristoylamino)propyl]ammonium chloride monohydrate (ATX code: D08AJ, R N001926/01) as a 0.01% solution for local use, etc. When prescribing local antiseptics and disinfectants (D08A), especially antimicrobial agents and antiseptics for the topical treatment of oral cavity diseases (A01AB) in case of stomatitis, the possibility of allergic reactions and individual intolerance reactions should be taken into account [45,184,185,188].

As local proteolytic enzymes (ATX code: D03BA) in the combination therapy of herpetic stomatitis, the following may be used [188,189]: 0.1% enzyme solutions (#trypsin (ATX code: D03BA01, lyophilisate for solution for injection and local use (LP-(006647)-(RG-RU) dated 22.08.24)) or #chymotrypsin (pharmacotherapeutic group: Other hematological agents; enzymes; ATX code: D03BA, lyophilisate for solution for injection and local use LP-(006696)-(RG-RU) dated 28.08.24)) to remove necrotic tissues and cleanse the mucosa from fibrin plaque, to achieve anti-inflammatory and anti-edematous effects, stimulate regeneration processes, and enhance phagocytosis [2,35,184,185,186,188,189,190]. Proteolytic enzyme applications are performed 2 times a day for 10 minutes for 7 days.

3.2 Surgical Treatment

Not performed.

3.3 Other Treatment

Comments: propionic acid derivatives, anilides, acetic acid derivatives, and related compounds may be prescribed.

Comments: drugs from the ATX group "Other drugs for topical treatment of oral diseases", for example, lidocaine** 2% gel, can be used to relieve pain symptoms.

Comments: the prescription of systemic antihistamines in the treatment of herpes simplex infection provides systemic desensitization effects and reduces the severity of toxic-allergic reactions and systemic intoxication. Recommended regimen: chloropyramine**, 1 tablet 3-4 times a day (75-100 mg per day), course up to 5 days.

Dietary therapy is not used in the majority of patients with herpes simplex infection; the exception is patients with herpetic stomatitis.

Comments: calculation and type of nutrition in accordance with clinical guidelines for nutritional support.

Comments: rational nutrition plays an important role in the complex of therapeutic measures in patients with herpetic stomatitis [2,184,185,186,190]. The diet includes the introduction of soft, warm, non-irritating, thermally processed food into the diet. The consumption of acidic fruits and citrus fruits is not recommended as they can increase irritation of the oral mucosa. If patients with herpetic stomatitis experience pain, the oral mucosa is anesthetized before meals using local anesthetics (gel) [184,185,186].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: medical rehabilitation is carried out in accordance with Order of the Russian Ministry of Health No. 1705n dated December 29, 2012, "On approval of the procedure for organizing medical rehabilitation". The goal of rehabilitation must be specialized, quantitatively measurable, achievable, and take into account the individual requirements of the patient. When carrying out medical rehabilitation activities (medical rehabilitation services for a patient who has undergone an infectious disease B05.014.002, in accordance with Order of the Russian Ministry of Health No. 804n dated October 13, 2017, as amended on October 26, 2022), the following principles should be considered:

- medical rehabilitation measures should begin already in the peak period or in the period of early reconvalescence, should be comprehensive in nature and carried out with the participation of various specialists (in patients with CNS lesions of herpesviral etiology, including with the participation of a neurologist and a physical and rehabilitation medicine physician) and the use, as indicated, of several technologies (pharmacotherapy, physiotherapeutic methods, emotional status management, etc.), based on the predominant symptoms and syndromes in the patient [2,3,5,38,53,61,62,63,64,66,68,69];

- during medical rehabilitation, sequence, continuity, and uninterruptedness of measures at various stages of rehabilitation and dispensary follow-up should be observed; methods of exposure adequate to the adaptive and reserve capabilities of the patient should be included in the individual rehabilitation plan [2,3,5,38,53,61,62,63,64,66,68,69].

¹ The list of medical specialists is specified in clause 2.5 "Other diagnostic examinations in patients with herpes simplex depending on organ damage and developed complications".

5. Prevention and Dispensary Observation

5.1 Non-specific prophylaxis

[1,2,3,4,5,7,20,23,24,29,30,34,59,76,77,84,135,177,186].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: sanitary and educational work as part of hygienic education and sex education in schools, during work with adolescents in adolescent centers, when adolescent girls and young women visit antenatal clinics, when working with couples in family planning centers, as well as during any patient visit for medical help to an infectious disease specialist, dermatovenereologist, etc.; observance of personal hygiene, exclusion of casual sexual contacts; use of condoms and individual prevention means during sexual contacts with non-permanent partners; due to the special danger of HSV infection during pregnancy, the use of barrier contraception methods is mandatory throughout its entire term for all types of sexual relations; abstinence from sexual relations during an episode of herpes simplex recurrence if any of the sexual partners is not infected with HSV [2,23,24,30,76,77,135,175,176,178].

Comments: identification of high-risk pregnant women: a) thorough history taking to identify episodes of herpes simplex, in particular genital herpes; b) thorough clinical examination of the birth canal, perineum, and vulva during monitoring in antenatal clinics and before the onset of labor; c) virological confirmation of herpes-like genital lesions in all women planning pregnancy [2,30,31,32,33,34,59,101,112,135,174,176,177].

[1,2,3,5,7,10,11,13,14,28,29,30,31,32,33,34,35,40,44,49,51,56,59,100,101,112].

GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comments: preventive measures consist of sanitary and educational work with the population to explain the causes of disease recurrence, in the control/elimination of risk factors provoking disease recurrence, timely sanitation of infection foci and treatment of concomitant diseases, correction of deficiencies in various parts of the immune system, hormonal status, etc.

5.2 Specific prevention of recurrent herpes simplex

5.2.1 Using systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors

Comments: complete specific treatment of the primary episode of herpes simplex; an adequately treated primary episode is less prone to disease recurrence. The use of suppressive antiviral therapy using systemic antiviral drugs from the group of nucleosides and nucleotides, excluding reverse transcriptase inhibitors, with the aim of preventing herpes simplex recurrences in patients with a frequently recurrent form of the disease and reducing the risk of virus transmission to a seronegative partner. Prevention of HSV infection of a seronegative partner: #valacyclovir 500 mg once daily for 12 months with regular sexual contacts.

5.2.2 Using immunotherapy

Comments: specific immune therapy for herpes simplex is carried out using a vaccine for the prevention of herpetic infections (ATX code: J07BX – other vaccines for the prevention of viral infections), which is produced on the basis of reproductive and immunologically competent strains of HSV-1 and -2 antigenic types [160,161]. The purpose of vaccination: prevention or alleviation of the course of chronic recurrent herpetic infection caused by HSV-1, HSV-2; activation of cellular immunity, immunocorrection in the remission phase [160,161]. Basic method of vaccine administration: only in the remission stage, no earlier than 10 days after the complete disappearance of clinical manifestations of the disease. The vaccine is administered intradermally into the inner surface of the forearm using a syringe in a single dose of 0.2 ml (control – formation of a "lemon peel") [160,161]. The vaccination course for herpetic infection of the skin and mucous membranes consists of 5 injections carried out at an interval of 7 days. In patients with complicated herpetic infection (recurrences – 1 or more times a month), the 2nd and subsequent injections are repeated at an interval of 10 days. In case of herpetic rashes, the intervals between injections are doubled [160,161].

Quarantine and isolation measures regarding contact persons are not organized.

5.3 Dispensary follow-up

Dispensary follow-up is not established for individuals who have undergone mild and/or uncomplicated forms of herpes simplex [2,3,5].

• Patients who have undergone severe and/or complicated forms of herpes simplex or herpes simplex with nervous system damage, after discharge from the hospital, are subject to dispensary follow-up [2,3,5].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: approaches to dispensary follow-up are regulated by Order of the Ministry of Health of the Russian Federation No. 173n dated March 29, 2019, "On approval of the procedure for conducting dispensary follow-up of adults" and (clauses 9, 10 of Order of the Ministry of Health of the Russian Federation No. 69n dated January 31, 2012 (as amended on February 21, 2020) "On approval of the Procedure for providing medical care to adult patients with infectious diseases").

Dispenser surveillance (active dynamic outpatient monitoring) and treatment of patients who have suffered severe and/or complicated forms of herpes simplex (HS) or HS with nervous system involvement, as well as treatment of convalescent HS patients, is carried out in the infectious diseases department (office) of a medical organization providing primary health care, or its structural subdivisions, and structural subdivisions of infectious diseases hospitals providing outpatient medical care.

Dispenser surveillance of patients who have suffered HS with nervous system involvement is carried out jointly by an infectious disease specialist and a neurologist [2,3,38,53].

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Public Health Protection in the Russian Federation", is organized and delivered:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized federal executive body;

2) in accordance with the procedure for providing medical care to adult patients with infectious diseases, which is mandatory for implementation on the territory of the Russian Federation by all medical organizations (Order of the Ministry of Health of the Russian Federation No. 69n dated January 31, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases");

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized federal executive body.

Conditions for the provision of medical services

Medical care is provided in the following forms:

• emergency medical care;

• urgent medical care;

• planned medical care.

Medical care is provided in the form of:

• primary health care;

• emergency medical care, including specialized emergency medical care;

• specialized medical care, including high-tech medical care.

Medical care for adult patients with herpes simplex may be provided in the following settings:

• outpatient (in settings not providing round-the-clock medical observation and treatment);

• inpatient (in settings providing round-the-clock medical observation and treatment).

Primary paramedic-led health-care in outpatient settings is provided at feldsher-midwifery stations.

For patients with suspected HS or a confirmed diagnosis of mild HS not requiring inpatient treatment, medical care is provided in the form of primary health care in an outpatient setting by general practitioners, district general practitioners, family physicians, and medical specialists who carry out a set of diagnostic and treatment measures, including those aimed at identifying the causative agent of infectious diseases, etc.

When HS is suspected or detected in a patient, the district general practitioner, family physician, medical specialists, and mid-level medical personnel of medical organizations shall, in the established manner (in the presence of medical indications—complications of the disease and/or treatment), refer the patient for consultation to the infectious diseases department (office) of a medical organization to receive primary specialized health care. Primary specialized health care is provided by the infectious disease specialist of the medical organization providing outpatient medical care to patients.

Specialized medical care for patients with HS is provided in medical organizations or their structural subdivisions providing specialized medical care, including in infectious diseases departments of multidisciplinary hospitals and infectious diseases hospitals, and includes diagnostics, treatment of the disease and conditions requiring the use of special methods (complex medical technologies), as well as medical rehabilitation.

Inpatient medical care for patients with HS is provided according to medical indications in cases of severe and moderate courses of the infectious disease, inability to establish a diagnosis in an outpatient setting, the need for additional laboratory and instrumental diagnostic methods for differential diagnosis, lack of a clinical effect from ongoing outpatient therapy, etc.

Treatment of HS patients in an inpatient setting is carried out upon referral by a general practitioner, district general practitioner, family physician, ambulance physician, infectious disease specialist, or medical specialists who identified the HS.

Medical care for HS patients with life-threatening acute conditions, including infectious-toxic shock, hypovolemic shock, cerebral edema and swelling, acute renal and hepatic failure, acute cardiovascular and respiratory failure, is provided: outside a medical organization—by ambulance teams (including resuscitation teams); in an inpatient setting—in isolation wards, intensive care wards (units), and intensive care units of a multidisciplinary hospital, as well as in intensive care wards (units) and intensive care units of an infectious diseases hospital in compliance with established sanitary and anti-epidemic standards.

Medical care for patients with HS combined with diseases of other organs is provided taking into account the recommendations of relevant medical specialists (neurologists, ophthalmologists, obstetrician-gynecologists, urologists, gastroenterologists, and other medical specialists). Medical care for pregnant women with HS is provided taking into account the recommendations of an obstetrician-gynecologist.

The choice of treatment tactics is influenced by the following factors: patient age; presence and nature of comorbidities; clinical form of the disease; course pattern of the disease (dynamics of symptom progression); severity of the disease; presence and nature of complications [2,3,5,7,8,10,12,13,20,21,25,26,30,31,32,35,38,45,51,56,57,58,60,61,62,63,64,66,83,99,108,109,110,133,175,185].

In most cases, monitoring and treatment of patients with HS is carried out in an outpatient setting [1,2,3,5,8,20,35,37,44].

Comments: 1) upon the appearance of new rashes or symptoms indicating the development of a generalized form of the disease, determined visually and according to virological test data; 2) upon symptoms indicating central nervous system complications (altered mental state, unconsciousness, drowsiness or difficulty waking up and periodic or constant convulsions (seizures), confusion, severe weakness or paralysis); 3) upon confirmation of a secondary bacterial infection based on laboratory test results or clinical signs (e.g., persistence of a persistently high body temperature and other symptoms for more than 3 days);

7. Additional Information

The prognosis for HS, provided adequate treatment is given, is favorable in most cases.

Factors whose presence determines the outcome of the disease are listed below [2,3,5,7,8,10,12,13,20,21,25,26,30,31,32,35,38,45,51,56,57,58,60,61,62,63,64,66,83,99,108,109,110,133,175,185]:

• presence of primary or secondary immunodeficiency;

• presence of factors exerting a suppressive effect on the patient's immune system (HIV infection, malignant neoplasms, organ and tissue transplantation, stem cell transplantation, immunosuppressant intake, etc.);

• mixed infection with other Orthoherpesviridae viruses, human immunodeficiency virus, etc.;

• somatic pathology;

• exposure to factors causing reactivation of HSV-1 and HSV-2 (psychoemotional stress, abrupt climate change, ultraviolet radiation, hormonal shifts (pregnancy), etc.);

• development of infectious complications;

• nutritional dystrophy, unbalanced diet, alcoholism;

• refusal of therapy prescribed by a specialist depending on the severity and period of the disease;

• lack of treatment or inadequate treatment of HS is fraught with a high probability of complications, including generalized ones.

7.1 Herpes simplex in solid organ and bone marrow recipients, patients with oncohematological diseases

In patients with organ and tissue transplantation, hematological diseases during or after courses of chemotherapy for the underlying disease, activation of both endogenous and acquired herpesvirus infection is possible [2,3,5,29,30,49,50,51,108,109,110]. Factors potentially increasing the frequency of HSV-1 and HSV-2 reactivation include: age, presence of clinical and laboratory signs of

immunodeficiency (agranulocytosis and/or hypogammaglobulinemia), severity of condition requiring transfer to the intensive care unit. In the absence of prophylaxis, herpes simplex can develop in 25–70% of patients after solid organ transplantation (e.g., kidney, liver, lungs, etc.) and bone marrow transplantation, in the presence of oncohematological diseases [2,29,30,49,50,51,108,109,110]. With delayed diagnosis and inadequate treatment, herpes simplex poses a real threat to the life of such patients [2,29,30,49,50,51,108,109,110].

In patients with organ and tissue transplantation, as well as oncohematological diseases, the following are distinguished [29,30,49,50,51,108,109,110]:

• HSV infection with confirmed HSV replication without clinical symptoms (in 40% of patients);

• HSV infection with confirmed HSV replication combined with corresponding symptoms.

Patients may present with malaise, fever, leukopenia/lymphopenia without viral involvement of various organs and tissues, or a severe form of the disease with viral involvement of various organs and tissues. Clinically apparent HSV infection usually develops in the first six months (most often in the first month) after transplantation and manifests as characteristic vesicular rashes on the lips and oral mucosa [29,30,49,50,51,108,109,110]. Rash elements typically persist for more than 1–2 weeks. Anogenital lesions, viral conjunctivitis, keratitis and corneal ulcers, pneumonia, and generalized forms of the disease are less common [2,8,29,30,49,50,51,108,109,110].

There are three main variants of Herpes simplex in patients [2,8,29,30,49,50,51,108,109,110]:

√ primary infection developing in HSV-seronegative patients who received a graft from seropositive donors – D+R- (disease develops in 40–60% of patients);

√ reactivation of latent endogenous virus when the donor is HSV-seronegative and the recipient is seropositive - D-R+ (disease develops in 10–15% of patients);

√ superinfection when both donor and recipient are seropositive, and active HSV is of donor origin – D+R+ (disease develops in 20–30% of patients).

In immunocompromised patients, HSV can cause organ damage (direct effect of the virus) as well as a number of indirect effects—both general and transplant-specific [2,29,30,49,109,110]. Indirect effects of HSV can occur with a persistently low viral load not accompanied by direct effects.

Potential indirect effects of HSV in solid organ recipients:

• transplant-specific effects: acute graft rejection; chronic allograft nephropathy and/or loss of the renal graft; accelerated recurrence of viral hepatitis after liver transplantation; transplant vasculopathy after liver transplantation, etc.,

• general indirect effects of HSV (increased risk of): other viral infections; bacterial infections; fungal infections; post-transplant lymphoproliferative disorders; mortality, etc.

Risk factors for HSV infection after kidney transplantation:

• characteristics of the pre-transplant serological status of the donor and recipient.

The risk of active herpesviral infection is highest when combining a donor infected with HSV who has specific antibodies to the virus with a recipient who has no antibodies to HSV in blood serum (D+/R–). It should be noted that both the D+/R+ variant (when both donor and recipient have antibodies to HSV) and the D–/R+ variant (when only the recipient has antibodies) do not exclude the development of herpesviral infection; any increase in the intensity of immunosuppression, for example, against the background of high blood concentrations of immunosuppressants (ATX code: L04), including calcineurin inhibitors** (ATX code: L04AD): cyclosporine** (ATX code: L04AD01) or tacrolimus** (ATX code: L04AD02), the use of high doses of selective immunosuppressants (ATX code: L04AA), including mycophenolic acid**, or the use of immunosuppressants (ATX code: L04) as induction immunosuppression or treatment of a rejection crisis;

• severe comorbidities;

• marked decrease in peripheral blood leukocyte count.

The highest risk of developing active herpesviral infection is observed in the first 6 months after transplantation [2,8,29,30,49,50,51,108,109,110]. Episodes of late herpesviral infection are possible – 6 to 12 months or even several years after surgery, especially after the completion of routine anti-HSV prophylaxis, against the background of other severe infectious complications, or during treatment for graft rejection.

Before transplantation, to assess the risk of disease in the recipient during the post-transplant period, it is recommended to determine anti-HSV IgG antibodies in the donor and recipient. If the pre-transplant evaluation of the recipient yields a negative result, a repeat test is necessary during transplantation [30,49,50]. In adult patients with equivocal serological results, the donor result should be considered positive, and the potential recipient's result should be carefully interpreted to identify the group of patients at the highest risk for developing active herpesviral infection.

Interpretation of pre-transplant serological test results is challenging if donors and potential recipients have received blood transfusions within the last 6 months.

Quantitative PCR is the method of choice for diagnosing Herpes simplex before and after organ transplantation, when making decisions on preemptive therapy or prophylaxis, and in monitoring treatment response [2,29,30,49,50,108,109]. Determination of antibodies to Herpes simplex virus in the blood may have prognostic value: if specific antibody titers do not rise within 2 weeks or are not detected at all, there is a threat of generalized HSV infection [2,29,30]. Virological culture examination of biomaterial (e.g., blood, saliva, or urine) can be useful in patients with a negative PCR result [2]. Asymptomatic viral excretion does not require treatment.

In organ recipients, the primary role is played by preemptive therapy for herpesviral infection, which helps mitigate the indirect effects of HSV.

There are two strategies for preventing HSV infection [2,29,30,49,51,108,109,110]:

• preemptive (proactive) therapy and prophylaxis;

• combined (hybrid) strategy—a combination of prophylaxis followed by preemptive therapy.

The preemptive therapy strategy involves regular monitoring (once a week) of HSV DNA levels in the blood using quantitative PCR and the immediate prescription of treatment upon detecting a high viral DNA copy number [2,29].

Prophylaxis involves the administration of a systemic etiotropic antiviral drug during the first months after transplantation to all recipients at high risk of developing active herpesviral infection. Prophylactic administration of direct-acting antiviral drugs effective against HSV not only prevents disease development but also reduces the risk of other herpetic infections (including those caused by human CMV, Varicella-zoster virus, Epstein-Barr virus, and human herpesvirus type 6), bacterial and protozoan infections, as well as all-cause mortality [51]. The advantages of antiviral prophylaxis include high efficacy, impact on the indirect effects of the virus, and ease of use.

For the prophylaxis of HSV infection, intravenous acyclovir** or oral acyclovir** and valacyclovir are most frequently used [2,51,89]. Acyclovir** doses are adjusted according to the glomerular filtration rate of the individual patient. This adjustment is extremely important, especially in kidney transplant recipients, since delayed or suboptimal renal allograft function is frequently observed. The use of full doses of antiviral drugs in such patients can lead to serious adverse events. Intravenous administration of acyclovir** should be slow, as bolus administration can cause drug crystallization in the renal tubules with worsening graft function. It must also be taken into account that about 60% of the acyclovir** present in the body is removed during a hemodialysis session. The duration of systemic antiviral prophylaxis depends on the virological status of the individual patient and the type of transplantation performed [2,29,30,89].

Secondary prophylaxis of HSV infection is also necessary during the treatment of acute rejection, especially when using immunosuppressants (ATX code: L04A). The standard is intravenous administration of acyclovir** followed by a transition to oral acyclovir** or valacyclovir. The duration of HSV prophylaxis during the treatment of a rejection crisis ranges from 3 to 12 weeks [89,108,109,110].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Alimbarova L.M. – Candidate of Medical Sciences, Associate Professor of the Federal State Budgetary Institution "National Research Center for Epidemiology and Microbiology named after N.F. Gamaleya" of the Russian Ministry of Health, "D.I. Ivanovsky Institute of Virology", Associate Professor of the Department of Infectology and Virology of the Institute of Professional Education of the Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" of the Russian Ministry of Health; member of the "National Association of Infectious Disease Specialists named after Academician V.I. Pokrovsky", member of the All-Russian Scientific and Practical Society of Epidemiologists, Microbiologists and Parasitologists.

2. Gomberg M.A. – Doctor of Medical Sciences, Professor, Chief Researcher of the State Budgetary Healthcare Institution "Moscow Scientific and Practical Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department", member of the LLC "National Alliance of Dermatovenereologists and Cosmetologists", President of the "Guild of Sexually Transmitted Infection Specialists 'JUSTI RU'", member of the Royal College of Physicians (RCP), member of the American Academy of Dermatology (AAD), member of the European Academy of Dermatology and Venereology (EADV), Senior Advisor of the International Union against Sexually Transmitted Infections (IUSTI).

3. Gorelov A.V. – Academician of the Russian Academy of Sciences, Professor, Head of the Department of Infectious Diseases and Epidemiology of the Federal State Budget Educational Institution of Higher Education "A.I. Evdokimov Moscow State University of Medicine and Dentistry" of the Russian Ministry of Health, Deputy Director for Scientific Work of the Federal State Budgetary Institution of Science "Central Research Institute of Epidemiology" of Rospotrebnadzor; Chairman of the Board of the National Association of Infectious Disease Specialists named after Academician V.I. Pokrovsky.

4. Dolya O.V. – Doctor of Medical Sciences, Deputy Director for Scientific Work of the State Budgetary Healthcare Institution "Moscow Scientific and Practical Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department", member of the LLC "National Alliance of Dermatovenereologists and Cosmetologists", member of the European Union against STIs (IUSTI/WHO), member of the European Academy of Dermatology and Venereology (EADV), member of the "Guild of Sexually Transmitted Infection Specialists 'JUSTI RU'".

5. Zhukova O.V. – Doctor of Medical Sciences, Professor, Chief Physician of the State Budgetary Healthcare Institution "Moscow Scientific and Practical Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department", Head of the Department of Dermatovenereology and Allergology with a Course of Immunology of the Medical Institute of the Federal State Autonomous Educational Institution of Higher Education "Peoples' Friendship University of Russia", Executive Director of the LLC "National Alliance of Dermatovenereologists and Cosmetologists", member of the European Union against STIs (IUSTI/WHO), member of the "Guild of Sexually Transmitted Infection Specialists 'JUSTI RU'", Chief freelance specialist in dermatovenereology and cosmetology of the Central Federal District of the Russian Ministry of Health.

6. Kisina V.I. – Doctor of Medical Sciences, Professor, Chief Researcher of the State Budgetary Healthcare Institution "Moscow Scientific and Practical Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department", member of the LLC "National Alliance of Dermatovenereologists and Cosmetologists", member of the European Union against STIs (IUSTI/WHO), member of the "Guild of Sexually Transmitted Infection Specialists 'JUSTI RU'", member of the Russian Interregional Society of Evidence-Based Medicine Specialists, member of the "Interdisciplinary Association of Reproductive Medicine Specialists (MARS)".

7. Novak K.E. – Candidate of Medical Sciences, Associate Professor, Associate Professor of the Department of Adult Infectious Diseases and Epidemiology of the Federal State Budget Educational Institution of Higher Education "Saint Petersburg State Pediatric Medical University" of the Russian Ministry of Health, member of the National Association of Infectious Disease Specialists named after Academician V.I. Pokrovsky.

8. Potekaev N.N. – Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Chief Freelance Specialist in Dermatovenereology and Cosmetology of the Russian Ministry of Health, Chief Freelance Specialist in Dermatovenereology and Cosmetology of the Moscow Healthcare Department, Director of the State Budgetary Healthcare Institution "Moscow Scientific and Practical Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department", Head of the Department of Skin Diseases and Cosmetology of the Faculty of Additional Professional Education of the Federal State Autonomous Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University" of the Russian Ministry of Health, President of the LLC "National Alliance of Dermatovenereologists and Cosmetologists", member of the European Union against STIs (IUSTI/WHO), Honorary President of the Euro-Asian Association of Dermatovenereologists (EAAD), member of the Board of Directors of the European Academy of Dermatology and Venereology (EADV), corresponding member of the German Dermatological Society (DDG).

9. Khaldin A.A. – Doctor of Medical Sciences, Professor, Chief Researcher of the State Budgetary Healthcare Institution "Moscow Scientific and Practical Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department", President of the Non-Profit Partnership "Russian Herpes Forum", member of the LLC "National Alliance of Dermatologists and Cosmetologists".

10. Chernova N.I. – Doctor of Medical Sciences, Head of the Department of Anogenital Dermatoses and Sexually Transmitted Infections, State Budgetary Healthcare Institution "Moscow Scientific and Practical Center for Dermatovenereology and Cosmetology of the Moscow Healthcare Department", member of the LLC "National Alliance of Dermatovenereologists and Cosmetologists", member of the Guild of Sexually Transmitted Infection Specialists "JUSTI RU", member of the International Society for the Study of Vulvovaginal Disorders (ISSVD), member of the European Academy of Dermatology and Venereology (EADV), member of the Interdisciplinary Association of Reproductive Medicine Specialists (MARS).

11. Chulanov V.P. – Doctor of Medical Sciences, Deputy Director for Scientific Work and Innovative Development of the "National Medical Research Center of Phthisiopulmonology and Infectious Diseases" of the Russian Ministry of Health; Chief Freelance Specialist in Infectious Diseases of the Russian Ministry of Health; member of the Board of the National Association of Infectious Disease Specialists named after Academician V.I. Pokrovsky.

12. Shestakova I.V. – Doctor of Medical Sciences, Professor of the Department of Infectious Diseases and Epidemiology of the Federal State Budget Educational Institution of Higher Education "A.I. Evdokimov Moscow State University of Medicine and Dentistry" of the Russian Ministry of Health.

13. Esaulenko E.V. – Doctor of Medical Sciences, Professor, Head of the Department of Adult Infectious Diseases and Epidemiology of the Federal State Budget Educational Institution of Higher Education "SPbSPMU" of the Russian Ministry of Health; Head of the Laboratory of Viral Hepatitis of the Federal State Budgetary Institution of Science "Pasteur St. Petersburg Research Institute of Epidemiology and Microbiology" of Rospotrebnadzor; member of the Board of the National Association of Infectious Disease Specialists named after Academician V.I. Pokrovsky.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Infectious disease specialist;

2. Dermatovenereologist;

3. Virologist;

4. Neurologist;

5. General practitioner (internist);

6. General practitioner (family physician);

7. Medical students, residents, postgraduate students.

Clinical guidelines can be used in the development of educational and methodological complexes for the training and professional advancement of physicians.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) rating scale for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on natural healing factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 323-FZ of November 21, 2011 (as amended on December 28, 2024) "On the Fundamentals of Healthcare Protection of Citizens in the Russian Federation" (with amendments and addenda, entering into force on March 1, 2025).

2. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Legislation in the Russian Federation' Regarding Clinical Practice Guidelines."

3. Order of the Ministry of Health and Social Development of Russia No. 69n of January 31, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases".

4. Order of the Russian Ministry of Health No. 804n of October 13, 2017 (as amended on September 24, 2020, with amendments of October 26, 2022) "On Approval of the Nomenclature of Medical Services".

5. Order of the Russian Ministry of Health No. 205n of May 2, 2023 (as amended on December 4, 2023) "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers".

6. Order of the Russian Ministry of Health No. 996N of December 9, 2019 "On the Nomenclature of Specialties of Specialists with Higher Medical and Pharmaceutical Education, approved by Order of the Ministry of Health of the Russian Federation No. 700n of October 7, 2015".

7. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of the Criteria for Assessing the Quality of Medical Care".

8. Order of the Russian Ministry of Health No. 168n of March 15, 2022 (as amended on February 28, 2024) "On Approval of the Procedure for Conducting Dispensary Observation of Adults".

9. Order of the Russian Ministry of Health No. 464n of May 18, 2021 "On Approval of the Rules for Conducting Laboratory Tests".

10. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

11. Order of the Russian Ministry of Health No. 1130n of October 20, 2020 "On Approval of the Procedure for Providing Medical Care in the Field of 'Obstetrics and Gynecology'".

12. Clinical Guidelines "Normal Pregnancy", 2020, Russian Society of Obstetricians and Gynecologists (RSOG).

13. Clinical Guidelines "Female Infertility", 2020, Russian Society of Obstetricians and Gynecologists (RSOG).

14. Clinical Guidelines "Singleton Childbirth, Delivery via Cesarean Section", 2020, Russian Society of Obstetricians and Gynecologists (RSOG).

15. Clinical Guidelines "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care" (approved by the Russian Ministry of Health).

16. Order of the Ministry of Health of Russia No. 395n dated June 21, 2013 "On Approval of Therapeutic Nutrition Norms".

17. Order of the Russian Ministry of Health No. 1008 of September 23, 2020 "On Approval of the Procedure for Supplying Patients with Therapeutic Nutrition".

18. SanPiN 3.3686-21 "Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases" approved by the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021 (as amended on May 25, 2022). Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021 (as amended on May 25, 2022) "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'."

19. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on April 16, 2024) "On Approval of the List of Vital and Essential Drugs, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care."

Appendix B. Physician Action Algorithms

Figure B2. Management algorithm for a patient with suspected herpes simplex encephalitis (HSE)

Figure B3. Algorithm for differential diagnosis of herpes simplex accompanied by nervous system involvement with other non-infectious and infectious diseases accompanied by nervous system involvement

Table B1. Algorithm for differential diagnosis of herpes simplex with other infectious and non-infectious diseases manifesting as skin and mucous membrane rashes or ulcers

Appendix C. Patient Information

Herpes simplex (HS) is one of the most common human infectious diseases. The causative agent is the herpes simplex virus (HSV). There are 2 HSV serotypes known: HSV type 1 and HSV type 2.

HS is an anthroponotic infection, the source of which is humans: patients with manifest, mild, or asymptomatic forms of the disease, and virus carriers. The virus can be contained in various biological fluids (saliva, urine, blood, seminal fluid, cervical secretion, breast milk). The virus can be transmitted by airborne droplets, sexually, by contact and household transmission, antenatally (from mother to child), and during organ and tissue transplantation. HSV infection can be either congenital or acquired.

Currently, there is a rapid increase in HSV infection rates, caused by the high susceptibility of all age groups of the population to the virus and the biological characteristics of the pathogen: ease of transmission mechanism in the population, pantropism, and a tendency toward persistence. A feature of HS is that complete elimination of the virus from the body does not occur after primary infection.

HSV is capable of causing damage to individual organs and systems as well as systemic diseases in humans. Long-term persistence of the virus in the human body can suppress the activity of various links of the immune system and contribute to the development of a secondary immunodeficiency state. Most commonly, individuals experience lesions of mucous membranes and skin integument of various localizations (upper and lower lips, nasal wings, nasal passages, chin, cheeks, oral cavity, etc.), the typical manifestation of which is the appearance of grouped vesicles with clear serous content against a background of localized edema and hyperemia. Eruptions are usually preceded by prodromal symptoms: subjective sensations of burning, itching, and pain at the site of future eruptions. Often, along with local symptoms, systemic symptoms are noted: fever, headache, weakness, myalgia, and regional lymphadenopathy.

The clinical presentation of HS can vary significantly depending on the route of transmission, the localization of the pathological process and its extent, the age of patients, and their immune status. HS can occur in acute, latent, and chronic forms, where periods of exacerbation alternate with periods of remission of varying duration. Reactivation of the latent virus occurs against the background of provoking factors individual to each patient. In 30–70% of infected individuals, the disease is subclinical or atypical.

With a decrease in the body's immunoreactivity, especially in individuals undergoing organ and tissue transplantation, oncological diseases, or HIV infection, HSV-1/-2 can lead to the development of generalized or disseminated forms of the disease with unusual clinical manifestations, and a prolonged and severe course.

HSV is also dangerous during pregnancy, especially if the virus enters the mother's body for the first time during gestation. In this case, the probability of fetal infection is very high, as the mother's body does not yet have antibodies to neutralize the virus. Infection of the child is possible at birth and after birth during breastfeeding.

Various methods are used in the treatment of HS patients (depending on the specific clinical situation). The indication for HS treatment is the presence of clinical manifestations of the disease. The presence of specific anti-herpetic antibodies in the patient's blood serum is not an indication for therapy. Medications must be prescribed by a physician; self-treatment is unacceptable. The main antiviral drugs in the treatment of HS are nucleoside and nucleotide analogues (excluding reverse transcriptase inhibitors): acyclovir, valacyclovir, famciclovir. These medications interfere with virus replication processes. One of the main conditions for the effective use of these drugs is timeliness. Treatment must be initiated at the first signs of the disease—in the prodromal period or within the first 2–3 days of relapse. It should be noted that none of the above-mentioned drugs has an advantage in efficacy on the course of the disease, does not lead to HSV eradication from the body, and does not always affect the frequency and severity of subsequent relapses. In a number of cases, treatment using these drugs does not always achieve the desired result. Interferon (IFN) group drugs are also used for HS therapy, their action aimed at activating innate immunity, the cytokine system, and phagocytosis. The use of IFN and its inducers is indicated both for shifts in the immune system as a whole and for disorders of local immunity mechanisms. For the prevention of relapses in patients with frequent HS recurrences and low efficacy of chemotherapy, specific viral infection vaccines are used, which are prescribed in the remission phase after the disappearance of signs of exacerbation. The use of the vaccine aims to correct immunity, stop viremia, and achieve specific desensitization.

In most cases, patients with herpes simplex (HS) are treated on an outpatient basis; severe disease courses and complications require inpatient care. It should be noted that recurrent HS changes a person's lifestyle and temperament. Patients with recurrent HS need to monitor their immune status, avoid hypothermia, take vitamins, exercise, play sports, and maintain a healthy lifestyle.

If you have just learned about your condition, do not hesitate to ask your attending physician about what is happening to you. Your emotional well-being is just as important as your physical health. Remember that you are not obligated to inform others that you are infected with HSV, but you should strive to prevent infecting other people.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

None.