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Lviv clinical bulletin 2017, 4(20): 60-74

https://doi.org/10.25040/lkv2017.04.060

Herpesviruses in Patients With Systemic Lupus Erythematosus (Literature Review and Clinical Cases Description)

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U. Abrahamovych, O. Abrahamovych, S. Guta

Danylo Halytsky Lviv National Medical University

Introduction. Systemic Lupus Erythematosus (SLE) – is an autoimmune illness, which causes polyclonal antibodies effect. The frequency of this illness sets 6-35 new incidents in 100 000 populations per year. It usually predominates for reproductive age women (90,0 % incidents) [82, 37, 97]. It often brings about disability and three times more than in the general population – to death [14, 59].

Etiology and SLE pathogenesis are still insufficiently researched [55, 63, 95]. There is an investigation of ultraviolet radiation, medicines and chemicals, also the impact of smoking, vaccination and other environmental factors, apart from various infectious agents in the emergence of SLE aggravation [7, 37, 38, 74, 89, 95, 117].

According to The World Health Organization (WHO), there is a great amount of population, which is contaminated with one or more serovariate herpesviruses [13]. Over 90,0 % of SLE patients are infected with cytomegalovirus [33,83], over 99,5 % with M. E. Epshtein – I. Barr (EBV) [39, 54]. That is why all scholars are trying to make the clarification of the role in the occurance of pathogenesis, the ability to influence on clinically laboratory features, course and illness consequences.

The aim of the research is to make a source review about herpesviruses role in systemic lupus erythematosus patients and describe clinical cases for infected patients from our own practice.

Materials and methods. We have been using content analysis, system and comparative analysis, bibliosenatic method of actual research methods studing in relation to the genus of herpesvirus for SLE patients. The research for the source was carried out in science medical information bases: PubMed-NCBI, Medline, ResearchGate with key words “herpesviruses”, “systemic lupus erythematosus”, “herpes simplex”, “herpes zoster”, “cytomigalovirus”, “Epstein-Barr virus”, “herpesvirus type 6”, “herpesvirus type 7”, “herpesvirus type 8”. 118 English and Ukrainian sources were analyzed. Sources with herpesviruses for SLE patiens were selected. Exclusion criteria were publications in other foreign languages, animal studies.

The result of the research and description of clinical cases. Sources reviews. It is known that herpesviruse infections are the most common for humans. [6, 11]. According to the clinical manifestations of the disease spectrum caused by viruses, they are not inferior to any other disease and consistently hold the second place in the structure of mortality from infectious diseases, which defines not only medical but also their social significance [11]. Herpesviruses can damage partically all organs and systems in the human body. It is distinguished acute (primary infection) and chronic forms of herpesvirus infection, which is divided into latent (the presence of the Genome virus in the tissues of the body without the elements formation of the virus), persistent (in the infected cell there are normal metabolic processes and at the same time sustaining the reproduction of the pathogen), and reactive the virus (replication of viral deoxyribonucleic acid (DNA) and the intensive formation of new virions after latent or persistent forms) [10,62]. The group of herpes viruses includes about 100 representatives, which only 8 are pathogenic to humans [6, 11, 13]. There are three subfamilies: α-herpesviruses (1 and 2 type herpes simplex virus (HSV), herpes zoster virus (HZV)), β-herpesviruses (CBM or herpesvirus of type 5, herpesvirus of type 6 and herpesvirus of type 7), gamma-herpesviruses (lymphotronic – EBV and herpesvirus type 8) [13, 62].

The herpes infection viruses are about 90,0% of the population and has no tendency to decrease [5, 6]. The herpesviruses role in the onset of human disease began to be studied in the first quarter of this century. In 1912, W. Grutter has found for the first time viral inclusion in the fluid herpes vesicles. Thus, proving the herpesvirus nature of keratitis [2, 12]. In 1920, the first HSV culture was obtained in vitro. At least, 8 antigenetic serotypes have been discovered in the etiology of more than 40 human diseases [12].

HSV is one the DNA-containing representatives of the herpesvirus family. There are two serotypes: HSV type 1 and HSV type 2. The transmission of the virus is possible both from a person without clinical HSV infection manifestations, which spreads viruses from the mucous membranes. The incubation period is from 1 to 26 days. After the virus enters the mucous membranes or damaged skin, it penetrates the cells of the epidermis and the dermis, initiating viral replication in them, which usually runs subclinically. The virus then enters sensitive or autonomic nerve endings, spreading in neuronal cells and subsequently in autonomous nerve ganglia. For HSV type 1 most often characterized by lesion of the ganglion of the three-neck nerve, as well as the spread on the upper and lower cervical ganglia. HSV type 2 most often affects the sacral nerve ganglion (S2-S5). Infection may occur repeatedly throughout the year.

It is also known that both virus serotypes can cause orally-facial and genital oral and facial infections, but HSV type 1 more often causes real-file form, and HSV type 2 – genital.  The most common clinical manifestations of oro-facial form of infection are fever, myaliosis, inability to eat through the formation of ulcers, cervical lymphadenopathy, rhinoststomaty pharyngitis, lips ulceration, herpes eczema. Genital form of weakness turns out to be fever, headache, myalgias general lymphadenopathy, dysuria eruptions or genitalian ulcers [12, 62]. Other variants of infection, tenner forms of herpetic infection may also arise due to the inoculation of the virus through the damaged skin, which is accompanied by swelling, redness, painful vesicular or pustular lesion, lymphadenopathy); encephalitis [5, 18] (acute fever, focal neurological symptoms), herpes meningitis [5]; visceral lesion, in particular, esophagitis, pneumonitis [114, 88] interstitial pneumonia: monoarticular arthritis, idiopathic thrombocytopenia etc. [62].

VBB causes two clinical forms of the disease: chickenpox and herpes zoster. Chickenpox is a highly contagious disease, usually occurring in childhood (about 50,0% of the incidents at the age of 6-9 years old) and accompanied by a dark vesicular rash on the skin, rarely – on the mucous membranes of the pharynx and vagina.

Possible complications: secondary bacterial superinfection, post herpetic neuralgia, aseptic meningitis, encephalitis, syndrome J. Guinea — J. A. Barre, pneumonia [23, 25, 50, 62].

Herpes is symptomatic reactivation of BBV, often acquired in childhood infection [26, 62, 70]. Virus is a latent stage in the spinal ganglia or a long time: more than 90,0% of the adult population over 60 years old have serological features of the previous infection with the BBB. Latent virus control in the ganglia provides humoral and cellular mechanisms; its reactivation is preceded be a change in the balance of the immune system [16].

Herpes is a skin vesiculiar rash on the nerves course [30, 62, 70]. Herpes zoster complications are visceral dissemination with damage to the central nervous system (CNS), acute jade herpetic neuralgia and also often gamage to the lungs and liver [62, 114]. The most important risk factors for herpes zoster are age of the patient and use of immunosuppressants [30, 102].

CNS belongs to the β-viruses of the herpesviruses family [36]. Biurus can infect epithelial cells, endothelial cells, fibroblasts, mononuclear cells of the peripheral blood, as well as nerve cells [29, 96].  According to various information, the CNS prevalence infection is 30,0 – 100,0% [18, 29, 36, 40, 100], it affects mainly patients with attenuated immunity [36, 43]. CNS detects saliva, breast milk, feces, urine [24, 62].

Herpes can also be transmitted sexually, during blood transfusion (0,14-10,0%). Primary infection CNS leads a significant T-lymphocytic response and may be accompanied by a mononucleosis syndrome, which is similar to that often accompanied by mononucleosis syndrome that is similar to mononucleosis in the case of EBV infection. Polyclonal activation of CNS β-cells leads to the appearance of rheumatoid factor and other antibodies in the case of mononucleosis in the case of EBV infection. [62]. Possible various clinical manifestations of CBNS infection: fever, general malaise, headache, pneumonia and alveolar hemorrhage, skin ulceration, proteinuria and renal insufficiency, thrombocytopenia, pancytopenia, hepatitis, vasculitis, retinitis, encephalitis [62]. V. I. Moroz in his study described hearing impairment in CNS-ibfection patients [13].

Herpes of type 6 was first isolated in 1986 from leukocytes of peripheral blood of persons with various lympho-proliferative disease [62]. Primary infections usually occur in a child’s age (up to 2-3 years old). In Europe, viruses are detected in almost 90,0% of people [15]. Persistance after the primary infection occurs in the blood, urine and other physiological secrets with the subsequent formation of non-sterile lifetime immunity [9, 11].

Virus is transmitted trough saliva and, probably, genital organs secrets [9, 62]. Babies and children can be rashed, had fever, hole.  Rarely convulsion [11]. People over the age of 16, the virus may in some cases cause a mononucleosis syndrome, fever, encephalitis, pneumonitis, rheumatocholecular hepatitis cytotoxicity, chronic encephalomyelitis syndrome0, histiocytic necrotic lymphadenitis [6, 11, 15, 62].

Herpes virus type 7 discovered in 1990 from T-lymphocytes [62]. Most of the population (about 75.0%) is infected by the virus in childhood [11]. The highest concentration of the virus is found in saliva, less frequently in breast milk. Viremia can be a manifestation of primary infection or reactivation of infection [62]. This virus can be a cofactor in the appearance of herpes type 6 associated pathological states, as well as other immunodeficiencies [9, 11].

Possible clinical manifestations of the infection are fever or convulsions, meningoencephalitis, respiratory or gastric disorder symptoms, chronic fatigue syndrome [9, 11, 62].

EBV, also known as Herpes Virus Type 4 (LHG4-HHV4), consists of a linear bicuspiric deoxyribonucleic (DNA) genome in the body of an icosahedral capsid [38, 62]. EBV is a common infectious agent, latent infection is about 90.0-95.0% of the world’s population [3, 62, 108]. The virus is passed through saliva and reproduced first on the surface of the mucous membrane in the epithelial cells of the oropharynx and nasopharynx [3, 38]. Then the virus penetrates adjacent tissues, as well as infects B-cells [47, 76]. The central place in understanding the biology of an EBV disease is the ability of the virus to transition from the active lithic cycle to the latent state from which the virus reacts [3, 38, 107]. Primary EBV infection in childhood is often minor or asymptomatic, but infection in adolescence causes infectious mononucleosis (IM) in 30.0-70.0% of cases where the virus infects up to 20.0% of organism’s B cells [38, 64, 106]. The incubation period is about 4-6 weeks. The virus spreads through contact with infected person’s saliva (90.0% of infections), rarely – due to blood transfusion or bone marrow transplantation [62].

The most common symptoms and clinical manifestations of IM are skin rash, sore throat, palatine exanthema, arthralgia, kidney damage, anemia, granulocytopenia, thrombocytopenia, atypical lymphocytosis; pharyngitis, lymphadenopathy, hepatosplenomegaly, liver dysfunction (more than 90.0% of cases), fatigue, muscle pain, fever, loss of appetite, headache and general weakness [3, 8, 62, 65]. In addition, a possible central nervous system lesion, including the appearance of encephalitis or meningitis, has also been discovered association with some tumors [1, 6, 8, 62].

Herpesvirus type 8 was first discovered in 1994-1995 from the tissue of M. Kaposi’s sarcoma and other lymphomas of people with acquired human immunodeficiency syndrome (AIDS). The virus attacks B-lymphocytes, macrophages, endothelial and epithelial cells and is found in patients with lymphomas, M. Kaposi’s sarcoma in the case of human immunodeficiency virus (HIV) infection, lymphoproliferative diseases of the immune system B-cell line. Transmitted through saliva, sexual contacts, organ transplantation [6, 9, 86]. Possible clinical manifestations are M. Kaposi’s sarcoma, fever, splenomegaly, encephalitis, pharyngitis, lymphoid hyperplasia, pancytopenia [6, 9, 62].

In recent decades, the researchers’ efforts have been focused on clarifying the role of viral infection in patients with SLE, namely the creation of the so-called viral hypothesis [80, 81], in which they are attempting to give answers to fundamentally important clinical questions [17, 44, 85, 115].

Some authors argue that viral infections can provoke the appearance of a disease in a genetically predisposed person [82, 94, 109, 116].

M. Ramos-Casals and colleagues [80] suggested that viruses may play a pathogenic role in the development of SLE, to be a trigger factor, or to contribute to the aggravation of the disease.

The relationship between the altered immune function and the infection in the case of SLE is extremely complicated, since infectious agents can interact with the immune system in several ways, and the immune system itself works as a complex mechanism [16]. According to many researchers, molecular mimicry can play an important role, that is, the similarity of antigen viruses with antigens on the surface of their own cells, which can trigger an autoimmune reaction cascade [46, 44, 85].

It is also known that patients with SLE have defects in the humoral and cellular parts of the immune system. Some of these defects can provoke the inadequacy of immune defense against pathogenic microorganisms [16, 62, 85].

An important factor in the immune system, which plays an important role in protecting organism from pathogens, is the complement system. The authors [16, 79] argue that in patients with higher risk of being infected there are partial defects in the complement system, which in turn often is found in patients with SLE. It is believed that the genetic defects of the early components of the classical pathway of the complement system activation, in particular C1q deficiency, are the main risk factors for the occurrence of SLE, since C1q plays an important role in complement activation through the recognition and clearance of apoptotic material, antibodies and structural proteins on bacteria and viruses. At the same time, the use of the complement system components by immune complexes limits the number of available components for use in the event of penetration of pathogenic microorganisms. It is proved [16] that the lectin pathway for activating the complement system is involved in the pathogenesis of SLE and is likely to increase the susceptibility to infections.

Researchers believe that one of the most common quantitative blood disorders in patients with SLE is T-cell lymphopenia, which correlates with exacerbations of the disease and response to immunosuppressive treatment. It is believed that this is one of the factors that increases the predisposition of such patients to infections. T-cells also exhibit an important functional deficit. The disadvantages of T-cell cytolytic activity are largely attributable to a decrease in interleukin-2 and gamma-interferon production [16].

It has been known for a long time that it is common for herpesviruses to have a lifetime persistence of the virus in cells of the nerve ganglia, which causes the course of periods of exacerbation and remission. In recent years, there are reports in the literature that herpesviruses persist not only in nerve cells, but also in cells of the immune system, which can lead to death or decrease in the functional activity of the immune system cells and the appearance of secondary immunodeficient conditions that support long-term persistence virus [12]. Periods alternation of exacerbation and remission of SLE is also important, which may resemble periods of acute and latent herpesvirus infection [20, 58].

In patients with SLE there are described cases of such more severe forms of HSV, as pneumonitis, pneumonia, bronchiolitis, and the appearance of pulmonary hypertension [80, 88].

Researchers believe that SLE patients more often have shingles herpes in comparison with healthy individuals [28, 90]. According to other researchers [45], lymphopenia and immunosuppressive drugs are important factors in the occurrence of shingles herpes in patients with SLE in the beginning of the disease. It has also been found that in patients with SLE, shingles herpes is in severe form [16, 23, 25], they more often have eye lesions [75], lupus nephritis, and increase the antibody content to Smith-antigen [61].

According to many authors [29, 42, 44, 46, 98] deserves attention also studying the role of CMV in patients with SLE. It is known that CMV can affect various organs and systems of the human organism and systematic infection by them, as well as by individual organs, may be manifested by signs similar to the manifestations of SLE.

Today, researchers are working to find out the main features of the connection between CMV infection and SLE [92, 93]: a) Whether CMV is just an opportunistic infection in patients with SLE, which is much more common in such patients who use glucocorticosteroids or other immunosuppressive drugs; b) whether the occurrence of SLE caused by CMV; c) Whether the CMV infection is a “trigger” of SLE; d) Whether CMV is one of the pathogenetic mechanisms of SLE. Thus, in patients with initial symptoms of SLE, [51, 73] anti-CMV IgM or CMV-DNA was detected, which, according to the authors, hypothetically suggests CMV as a cause of SLE. S. Yamazaki and others [115] believe that CMV-infection can be a trigger for SLE. Canadian researchers [87] argue that the majority of pediatric patients with SLE, infected CMV, have fever, nephrotic syndrome, hepatomegaly, pneumonitis, anemia, significant lymphopenia compared with non-SLE patients who are not infected with CMV. In the study of J. Chen and others [29], it was described that the incidence of IgG and Ig M in CMV was not significantly different between adult SLE patients and control subjects, but the IgG and Ig M antibody content for SLE patients was significantly higher than in healthy people. In addition, in patients with Ig M antibodies to CMV, which indicate an acute infection or a chronic exacerbation, a higher level of SLEDAI activity was detected in comparison with patients with SLE with a negative result. There is also described a reliably often increase in the titre of antibodies Ig M to CMV [19, 20, 103], positive Ig G to CMV [68, 17], as well as the presence of CMV-DNA and the number of copies of the virus’s genome [52] in patients with SLE in comparison with healthy ones of the control group.

Other authors argue [101] that CMV infection is related to “vascular” manifestations of SLE, in particular, that infected patients with SLE often show signs of A. M. M. Reynot’s syndrome and, more rarely – typical kidney defects.

The similarity of clinical manifestations of SLE and CMV infection makes it difficult to determine if there is only an infection that is primary or chronic in the phase of exacerbation and is clinically similar to SLE, or the clinical symptoms in patients with SLE are caused by acute infection of the CMV, an aggravation of chronic infection, or exacerbation SLE because CMV can lead to systemic infection that resembles SLE [34, 80, 105]. CMV antigens that imitate autoantigens may be responsible for immunologic disorders in patients with CMV [29, 31]. Moreover, CMV infection can suppress the production of erythropoietin and induce or exacerbate anemia [23, 41]. However, it is not clear whether these immunologic disorders, hematologic abnormalities and renal manifestations due to CMV infection itself or as a result of exacerbation of CMV-induced CMV infection, which needs further elucidation [29].

In our time, the role of herpesviruses of the 6th and 7th types in the onset of human diseases [11] is being studied, but their role in patients with SLE is not clear enough [82]. The communication between the EBV and the SLE is widely described in the medical literature [37, 38, 55, 65, 84, 85, 116]. Some studies have shown that the spreading of EBV in young SLE patients is 99.0% compared with 70.0% in the control group of healthy individuals [53]. A study conducted in 2001 [54] found that all 192 patients with SLE, except one, were infected with EBV, which became the reason to consider EBV as the cause of SLE. Several researchers of the sarcas [20, 39, 82] describe the significantly higher Ig G values ​​for EBV in patients with SLE compared to healthy individuals. The inverse correlation with the content of antibodies to early antigen (RA / EA) to EBV and the level of lymphocytes in patients with SLE has also been revealed [82].

I. Kang and colleagues [60] described an increase in the viral load of EBV in peripheral blood monocytes, probably due to the inadequate response of CD8 + T-cells (T-killers) to EBV, as well as a 40-fold increase in EBV-load compared with healthy individuals of the control group.

At the same time, UY Moon and colleagues [69] found that the EBV-viral load in the peripheral blood monocytes in patients with SLE is 15 times higher than that of healthy people in the control group.

G. Zandman-Goddard and colleagues [116] have found a reliable correlation between the increased titre of antibodies to EBV with skin and articular manifestations in patients with SLE.

Italian scientists [35], while examining patients with increased levels of antinuclear antibodies, noticed significantly higher levels of Ig G antibodies to capsid antigen (CA / VCA) and RA / EA compared with healthy subjects. Ig M antibodies to CA / VCA are more likely to be detected in patients with increased levels of antinuclear antibodies. Scientists suggest that active EBV infection or its reactivation may be involved in the formation of antinuclear antibodies.

A group of American researchers [49] found more frequent infection with EBV in patients with SLE compared with healthy individuals, as well as bigger number of infected cells compared to patients with other autoimmune diseases. They also suggest that a large number of EBV-infected cells in patients with SLE is associated with an exacerbation of the disease.

JY Lu with his colleagues [67] reported an increased content of EBV DNA in blood serum of 41.9% examined patients with SLE compared to only 3.2% of healthy control group individuals. This suggests that patients with SLE are 13.1 times more often infected with EBV with signs of replication. In addition, it was assumed that EBV-infected B-cells can also secrete virus-encoded anti-apoptotic molecules, thus becoming resistant to apoptosis [44, 48]. Several groups of researchers [44, 60, 117] shared the opinion that an increase in the production of interferons by T-cells, mediated by the EBV, is another mechanism that participates in the pathogenesis of autoimmune processes.Various EBV antigens may reveal structural, molecular, or functional mimicries with SLE-antigens or other immune-regulatory components [44]. Repetition or reactivation of EBV infection, which leads to an increase in the content of EBV IgA and Ig G serum, may be related to SLE [78]. Other researchers believe that EBV and its reactivation may be the cause of SLE [57, 111]. However, mechanisms that are associated with a viral infection, which lead to abnormal autoimmune reactions, are not well understood [80]. It is believed [76] that the interaction between EBV and SLE is difficult – EBV can cause autoimmune processes that lead to the occurrence of SLE, but patients with SLE also have dysregulation of response to EBV and abnormal viral latent period.

Recent studies have found out the role of the 8th type of herpesvirus and its importance in patients with SLE, in which a high incidence of the virus was detected and assumptions about the significance of the virus were expressed [104, 110].

Diagnosis of SLE for the patients infected with viruses, in particular herpes group, is complicated. Often an understanding of the cause of such nonspecific clinical manifestations of SLE like fever, lymphadenopathy, pulmonary infiltrates, rash on the skin and mucous membranes, violation of blood clotting, thrombocyte leukocytopenia, hemolytic anemia, including aplasia of red blood cells, is a problem for clinicians [34]. The conducted analysis of modern literature shows a variety of clinical situations of combination of viral infections and SLE. In particular, in patients with acute viral infections that meet the criteria for classification of SLE in 1997, the following options are possible:

1) there is an acute viral infection, that imitates SLE (the disappearance of SLE symptoms and normalization of immunologic markers after treatment);

2) there is a SLE that is caused by acute viral infections (active clinical or laboratory abnormalities and / or the need for daily corticosteroid therapy for symptom control). Patients with a diagnosis of SLE and acute viral infections are likely to have: 1) mimicry of SLE exacerbation: in patients clinical and / or laboratory changes that resemble exacerbations of SLE in the absence of an altered immunological profile (low complement levels and high levels of antibodies to biphasic DNA) , which is eliminated without changing the basic treatment of SLE; 2) organ-specific acute viral infections; 3) systemic acute viral infections [80].

In our clinical practice, we encountered numerous cases of patients with SLE also chronic viral infections, which in different constellations in some cases were in the phase of replication, in others – in the phase of integration.

Recommendations for the examination of patients with SLE with suspicion of infection, fever [80] are suggested. It is necessary: ​​1) to detect not only general bacterial infections (usually urinary and respiratory tract infections), but also opportunistic viral infections, especially in patients with severe SLE (with renal insufficiency, CNS damage) receiving immunosuppressive therapy; 2) to carry out a survey of suspected people with SLE in order to detect, first of all, the most common viral infections described in patients with a disease, or individuals with confirmed SLE, which are a fever without any clear indication of its exacerbation; 3) conduct a complex clinical and laboratory, and if necessary, an instrumental examination in order to exclude the infection.

Note that in the clinician’s arsenal there are no specific clinical signs of infection with SLE patients that would make it possible to confirm its presence in the patient, and in the case of the identification of an infectious agent – to find out its role.

Among the routine indicators of exacerbation of SLE, the definition of the content of complement components (C3 and C4), the titre of biphasic DNA antibodies, erythrocyte sedimentation rate (ESR), which are important for the diagnosis of disease and the efficacy of treatment, are distinguished [91]. However, even together, they do not always make it possible to distinguish manifestations of exacerbation of the disease and infection [91, 92]. According to the authors, in fact, their growth can often be weakened by immunosuppressive drugs, especially glucocorticosteroids [71]. Conversely, a consistently high titre of antibodies to bicpiral DNA or a low content of components of the complement of C3 and C4 may be found in some patients with low disease activity [21].

According to the authors [17, 34, 80], patients with SLE with suspected acute illness that do not respond to specific treatment of SLE should be carefully evaluated for virus-specific features, along with studies of the most common viruses.

The most common laboratory methods for the diagnosis of herpes viruses include serologic diagnostics – detection of antibodies to the virus (neutralization, complementing, hemagglutination, immunofluorescence, etc.). Detection of Ig M indicates the activity of the virus (primary infection, re-infection, reactivation of the virus). In the case of primary herpesvirus infection Ig M appear on the 7th-14th day after infection and are detected within 1-3 months. Specific Ig G are antibodies of the secondary immune response, they are detected in the second half of the infectious process in the case of primary infection, as well as in the presence of latent infections (immune memory), persistence or reactivation of the virus. The method of “pair serums” – a quadruple increase in titres of specific antibodies in a two-week period is used in the case of primary infection or reactivation of the virus. A rapid change in the titre of specific Ig G antibodies is possible in the case of a transition of the virus from one form to another (a significant increase in the concentration of anti-herpetic antibodies in the serum is possible in the case of reactivation of the infection after a long latent period or a slight decrease in the titre of specific IgG antibodies are detected in the event of the formation of a latent infection after a certain reactivation period). Serologic methods should be used to determine the state of antiviral humoral immunity, also to detect a virus only in the case of primary infection, when the phenomenon of seroconversion and the appearance of specific Ig M are recorded [10].

Cytological and histological studies can also be used to detect signs of infection of cells, organs or tissues. For example, the phenomenon of cytomegaly (cells are enlarged in size, the nucleus is located eccentrically and contains a central nucleic body), which is detected in the case of CMV; A. Ttsank cells in the case of infections caused by α-herpesvirus; detection of atypical mononuclear cells [10].

The following methods are also used to detect the virus: virologic (cell culture virus isolation, expensive method and results could be ready in range from 2 to 20 days); electronic microscopy (detecting viral particles from the test medium, allowing detection of morphological signs of virions, is more often used for scientific purposes); biologic probe (infection of sensitive laboratory animals, used in case of doubtful results). Polymerase chain reaction (PCR) technology plays a leading role in the diagnosis of herpesvirus infection [9, 10] (determination of DNA virus in different media using the semi-quantitative (+, ++, +++, ++++) and quantitative (number of the virus’s copies) definition methods).

Specific monoclonal antibodies are most often used to detect viral antigens (immunomorphological methods), but the sensitivity of the method is much lower than in the case of PCR use (55.0-75.0%) [10].

For the treatment of patients with herpesvirus infections, antiviral medicine, in particular, acyclic analogues of guanosine (level of evidence A), are used; interferons and immunoglobulins [6]. So, for the treatment of infections caused by α-herpesvirus, effective medicine that inhibits viral DNA. Acyclovir is most commonly used: 200.0-400.0 mg 5 times a day (in case of oropharyngeal or genital herpes); 800.0 mg 5 times a day for 5-10 days (in case of shingles herpes); 400.0 mg twice a day for more than 6 months in case of disseminated skin herpes; in the case of central nervous system, pneumonitis, hepatitis, intravenous acyclovir is recommended (5.0-10.0 mg / kg / day in the form of infusions with a 8-hour interval). In the presence of skin-mucous membranes HSV also valacyclovir is used with a dose of 1000.0 mg per day for about 7-14 days or famciclovir with a dose of 250.0 mg three times a day for 7 days. Treatment for shingles herpes suggests the use of antiviral medicine, in particular acyclovir or valacyclovir (1500 mg / day) or famciclovir (250.0-500.0 mg three times a day) for 7-14 days. For the treatment of patients infected with CMV, it is possible to use ganciclovir (5.0-7.5 mg / kg every 12 hours) or valganciclovir (900.0 mg twice daily), for a course of 14-21 days, so you can switch to supportive treatment. Also foscarnet is used (60.0 mg / kg three times a day 10-14 days) to inhibit the viral polymerase DNA. For the treatment of herpesvirus infection, new medicine is used – cidofovir and brievudyn (in the case of shingles herpes 400.0 mg per day for 7 days) [6, 62].

In modern immunotherapy of patients with herpesvirus infections, interferons (most commonly interferon alpha doses of 1.0-6.0 million IU per day) and immunoglobulins are used which are additional but important components of etiotropic treatment (level of evidence B) and in combination with antiviral medicine increase the effectiveness of treatment and reduce its duration, in particular, in patients with SLE [6].

Difficulties in treating herpesvirus infection in patients with SLE are that classical SLE treatment regimes include the use of various drugs (most of which are immunosuppressive or immunomodulatory [59]) that clinically improve the condition of patients, but they increase the risk of infection, including opportunistic infections [26, 56, 66].               

One of the probable directions for the prevention of herpesvirus infections is vaccination [26, 92, 72]. According to the recommendations of the European League against Rheumatism / EULAR, SLE patients receiving immunosuppressive drugs are safe to prescribe “killed” or subunit vaccines and not recommended – “live” vaccines [112, 92]. The feasibility of vaccination for patients with SLE is controversial – evidence has been obtained that vaccination reduces the risk of shingles herpes and postherpetic neuralgia in patients over the age of 60 [72, 112, 113]. However, some studies have found that immunization in case of vaccination may not be sufficiently effective [50] or vaccination may be accompanied by an exacerbation of the disease [27, 99, 112].

To confirm the important role of herpesvirus in patients with SLE, we give examples of clinical cases.

Patient L., born in 1988, appealed with complaints of pain in the fibrous, elbow, knee joints, small joints of the hands, which increases in the cold and during exercise, and weakens after the use of nonsteroidal anti-inflammatory drugs locally (ointment), edema of the brushes’ periarticular tissues, cynicism of the upper extremities fingers’ skin; rash on the face of the type of “butterfly”; an increase in body temperature to 37.0-38.0 °C, a periodic sensation of tingling in the right hypochondrium, which increases during respiration; hair loss; a feeling of difficulty during swallowing and vulgarity of the voice, periodic visual impairment (fuzzy image), periodic migraine headache, weight loss of 4 kg per 1 month.

From anamnesis of the disease: she considers herself ill since the spring of 2009, when she first noticed the rash on her face and appealed to the dermatologist, who put the diagnosis of “demodicosis”; the received treatment did not bring improvement. Leukopenia (leukocytes 3.4×109 / l) was detected in the same year. In 2010, after suffering from tonsillitis, the pain in the big joints of a migratory nature began to bother, and in the spring of the same year, rash on the face, fever, joint pain appeared again. Leukopenia (leukocytes 3.1×109 / l) was detected in a medical institution at the place of residence. Due to the lack of the effect of treatment, was deposited in the rheumatologic department of the Lviv Regional Clinical Hospital (LRCH). From anamnesis of life: suffered diseases – tonsillitis, boils. Tuberculosis, sexually transmitted diseases, parasitoids in and around the family, denied by relatives. Do not smoke or misuse alcohol. Heredity: not burdened. We have not observed any medicine intolerance.

Objective examination: general condition of moderate severity. Consciousness is clear. The step is not broken. Height 165.0 cm, body weight 55.0 kg. Body structure is wrong (scoliosis of the thoracic spine). The constitution is normosthenic. The skin is pale, rash according to the type of “butterfly”, elastic, dry; reticular levodo (livedo reti.) on the lower limbs; diffuse alopecia of the hair part of the head. Mucous membranes are not changed. Swelling is absent. Lymph nodes are not enlarged, not painful. Good muscle tone. Defusions, deformation of the joints is not visualized; active and passive movements in full; the strength of hands is satisfactory. Body temperature 37.3 °C (axially). Breathing through the nose is free; frequency of respiratory movements 18 / min; chest of the correct form, during palpation, elastic, voice tremor of moderate intensity; percussion – above lungs clear lung, the limits of the lungs are normal; auscultatory – weakened breath, wheezing are absent. Heart area unchanged; apical impulse is palpated in V intercostal space by 1.0 cm in the middle of the left midclavicular line. Pulse 92 / min, satisfactory filling and stress, no pulse deficit. Blood Pressure (BP) to the left – 110/80 mm Hg. Art., right – 110/80 mm Hg. Art. The limits of relative and absolute cardiac dullness are normal. Heart tones are rhythmic, clean; heart rate (HR) – 92 / min. The tongue is wet, surrounded by white layers; teeth sown; stomach – oval, during palpation soft, not painful, percussion – tympanic sound; the lower edge of the liver is smooth, does not protrude from the hypochondrium arc; its dimensions by M. G. Kurlov 9,0-8,0-7,0 cm; spleen is not palpable. The kidney area is not changed; the kidneys are not palpated, F. I. Pasternatsky’s symptom is negative on both sides. The patient’s behavior is adequate, the orientation in time and space is correct. Palpating isthmus of the thyroid gland.

Next laboratory and instrumental examinations were performed on patient:

1) a general blood test – normochromic anemia (erythrocytes – 3.5/3.7×1012/l, hemoglobin – 101/114 g/l), leukopenia (leukocytes – 3.2/4.1×109/l), acceleration of ESR (43/36 mm/h); 2) general urine analysis – erythrositivity (4-5 in the view site); 3) coprogram – no deviations found; 4) biochemical analysis of blood – increase in the level of transaminases (aspartate aminotransferase – 97 units / liter; alanine aminotransferase – 100.0 units/liter); increase in the level of C-reactive protein (48.1 mg / l); in proteinuria – increase in gamma -globulins (27.2 %); 5) immunological analysis – increase in the levels of the median (520 units) of the small circulating immune complexes (760 units), lupus erythematodes cells, LE-cells detected singles, components of the complement (C3, C4-2) – within the norm; increase of antinuclear antibodies – 8.0 (norm less than 1.0 unit/liter), increase of antibodies to bicpiral DNA (more than 200.0 IU/ml), antiphospholipid antibodies – within norm; Infection panel: antibodies Ig M to CMV 1.0 IU/ml (norm); IgM Ig G> 80.0 (less than 9.0 AO/l), Ig G antibodies to the nucleic antigen of the EBV virus 551.0 units / ml (less than 9.0); EBV Ig M-VCA – 34.9 (up to 10.0); Ig G antibodies to the capsid antigen of the EBV virus 165.0 units / l (less than 9.0); Ig G antibodies to chlamydia <1/5 (normal); PCR virus EBV (blood) – detected; EBV (cheek scratch) – detected, EBV (saliva) – detected, PCR of CMV (urine) – not detected; EBV (mucus oropharynx membranes) – detected, PCR herpes type 6 (cheek scratch) – not detected; 6) blood test for HIV, markers of hepatitis B and C, RW – negative result.

Among the deviations in the results of instrumental research: 1) capillaroscopy – local edema, spasm of capillaries; 2) X-ray of the organs of the chest – pulmonary pattern is moderately strengthened, sclerodally altered, deformed due to moderate, interstitial pneumocosclerosis; The right arch of the diaphragm is slightly higher than the normal, relatively flattened; 3) X-ray of the brushes – moderate narrowing of articular clefts of the fibrous joints, insignificant narrowing of joints’ surfaces, moderate periarticular edema of soft tissues; 4) spirogram – a violation of the ventilation capacity of the lungs by a restrictive type of second degree, respiratory failure (RF) of the II degree; 5) esophagogastroduodenofibroscopy – surface gastritis; 6) Magneto-resonance tomography of the brain – signs of organic brain changes during the examination were not detected. On the SLEDAI scale – 14 points. The patient also received a consultation of ophthalmologist – a “dry eye” syndrome of both eyes; neuropathologist – migraine; astheno-neurotic syndrome; consequences of transmitted neuroinfection.

Taking into account the patient’s complaints, information from the anamnesis, deviations found during the objective examination, in the results of laboratory and instrumental studies, the clinical diagnosis is given: “SLE: subacute course; active phase, activity of the II degree; SLEDAI – 14 points; with skin lesions (butterfly, photosensitisation), joints (polyarthritis with predominant lesion of the fibrous, elbow, knee joints, small joints of the hands, functional joint failure of the 0-I degrees), vessels (syndrome A. G. M. Reino, reticular livedo), lungs (interstitial pneumosclerosis, RF of the second degree according to the restrictive type), the nervous system (migrainous headache, astheno-neurotic syndrome), eye (“dry eye” syndrome of both eyes), hematologic (leukopenia) and immunological (antinuclear antibodies antibodies to bicpiral DNA – positive) disorders; with triggered EBV- and CMV-chronic infection in the exacerbation phase. Anemia: Chronic Illness; light. Chronic gastritis: superficial, incomplete remission phase, inadequate digestive tract I. Scoliosis of the thoracic spine. Functional Class of Therapeutic Patient III. “

Patient, beside standard scheme of SLE treatment, were assigned antiviral drugs (valacyclovir 2.0 g/day for 10 days, isoprinosin 2.0 g/day for 7 days, prophenolozide for 16 drops per day for 1 month) with valacyclovir 2.0 mg/day and interferon (interferon α 3 million via day for 14 days).

After treatment, the patient experienced improvement, normalized body temperature, reduced pain intensity in the joints, headache disappeared. Analysis of laboratory and instrumental research: Reduced ESR to 25 mm/h; normalization of transaminases, reduction of C-reactive protein up to 8.2 mg / l; decrease of antinuclear antibodies to 3.2 (norm < 1.0); CMV Ig G – 4,0 (norm <0,4); EBV Ig M-VCA – 1.7 (ng: <8.0), herpes Ig M – not detected, PCR of CMV (urine) – not detected, PCR EBV (blood; cheek scratch) – not detected. On the SLEDAI scale – 5 points.

Here is one more clinical case:

Patient M., born in 1973, filed complaints of pain in the small joints of the brushes and feet, shoulder, knee joints, the appearance of rash on the face, in the “decollete zone”, pain in the lumbar spine; periodic sensation of palpitation, loss of hair, expressed general weakness.

From anamnesis of the disease: considers herself ill about 10 years since she first noticed the appearance of rashes on the lower limbs. Treated with dermatologists without improvement. Appeared erythematous rashes on the face, the temperature was up to 38.0-39.0 °C, joint pain, leukopenia, endocarditis, myocarditis, proteinuria. After additional examination, a biopsy of the skin muscle and kidney (lupus erythematosus) was diagnosed with SLE. Since then, she has been permanently treated ambulatory, periodically inpatient. Uses: methylprednisolone (16.0 mg/day), mofetil mycophenolate (2.0 g). Due to the scarce effect of treatment, deposited to the rheumatologic department LRCH. Anamnesis of life: suffered diseases in childhood – the patient does not remember, in adulthood – in 2013 tonsillectomy. Denies having tuberculosis, sexually transmitted diseases, viral hepatitis, parasitosis herself and as well as her relatives. Denies harmful habits. Heredity is not burdened. Intolerance to medicine – from the patient’s words, allergy to iodine. Gynecological anamnesis – burdened (III pregnancy, II delivery).

Objectively: general condition of moderate severity. Consciousness is clear. The step is not broken. Height 170.0 cm, body weight 86.3 kg. The structure of the body is correct. Constitution is hypersthenic. The skin – erythematous rash according to the type of “butterfly”, rash in the “decolte zone”, humidity is normal; diffuse alopecia; mucous membranes, available for inspection, pink, normal humidity. Moderate edema on the lower limbs. Peripheral lymph nodes are not enlarged, not painful. Skeletal muscles: good tone. Diffusions of the brushes’ small joints; volume of movements: active and passive are somewhat limited in the painful joints; the strength of the hands is weakened. Body temperature 36.5 °C. Breathing through the nose free; frequency of respiratory movements 20/min, breathing rhythmic; type of breathing – thoracic; thorax of the correct form, palpation – elastic; voice tremor – moderate intensity; percussion above the lungs – clear lung sound; the limits of the lungs – in norm; auscultatory – vesicular breathing over the entire surface of the lungs, no signs of wheezing. Heart area unchanged; apical impulse is palpated in V intercostal space by 1.0 cm in the middle of the left midclavicular line; the heart rate rhythm – correct, the tones of the heart – rhythmic and sonorous. Pulse – 88 / min. There is no pulse deficit. Arterial pressure 130/100 mm Hg. Art. The limits of relative and absolute cardiac dullness are normal. HR – 88/min. Tongue – clean, moist; teeth are saved; oval-shaped stomach, during palpation soft, not painful, percussion-tympanic sound; the lower edge of the liver does not protrude from the lower edge of the hypochondrium arc; liver size according to M.G. Kurlov 9,0-8,0-7,0 cm; spleen is not palpable. The kidney area is not changed; The kidneys are not palpable, the symptom of F. I. Pasternatsky: on the left – positive, on the right – positive. Behavior – adequate, orientation in time and space is correct. Palpating isthmus of the thyroid gland.

Laboratory and instrumental examinations were performed on patient: in the general analysis of blood – lymphocytosis (lymphocytes – 46.0 %), acceleration of ESR to 25 mm/h; in the general analysis of urine proteinuria (protein – 0.66 g/l), in the biochemical analysis of blood – the appearance of C-reactive protein (37.3 mg/l (norm <5,0)); among immunological studies: antinuclear antibodies – more than 3.0 (norm <1,0); antibodies to bicpiral DNA – more than 200.0 IU/ml (norm < 25.0 IU/ml); Antiphospholipid antibodies Ig M – 9.6 (less than 10.0); LE-cells are found in a large number. A blood test was conducted to determine the markers of hepatitis B and C – negative result. PCR examination of HSV (blood) – not detected, PCR of CMV (urine) – not detected, PCR EBV (blood) – detected, PCR herpes virus type 6 (cheek scratch) was not detected. Among the deviations in the results of instrumental research: 1) ultrasound examination of internal organs – kidneys  parenchyma of increased etiology; 2) X-ray of the brushes – moderate, epiphyseal, osteoporosis changes, relative narrowing of the articular cracks of the interphalangeal joints; moderate, para-articular thickening of soft tissues; 3) capillaroscopy – angiodistonic changes, spasm of capillaries. On the SLEDAI scale – 4 points. The patient also received consultation of ophthalmologic – a “dry eye” syndrome of both eyes, retinal angiopathy of both eyes; cardiologist – arterial hypertension: stage II (hypertensive retinal angiopathy), I degree of risk 3 (high), heart failure (HF), stage I.

Clinical diagnosis is given: “SLE: chronic course with increasing severity; active phase, activity level II, SLEDAI 4 points; affecting skin and appendages (erythema – “butterfly”, alopecia), joints (polyarthritis with predominant lesion of small joints of the brushes and feet, shoulder, knee joints, X-ray stage 0-I, functional deficiency of joints II), vessels (syndrome A. G. M. Reino), heart (endocarditis E. Libman – B. Zaks in anamnesis, myocarditis in anamnesis); kidney (chronic kidney disease: stage I: lupus glomerulonephritis (nephrobiosis)), eyes (“dry eye” syndrome of both eyes), with immunological (antinuclear antibodies, antibodies to bicpiral DNA – positive) and hematologic disorders (anamnesis of leukopenia). Chronic EBV-infection, phase of exacerbation. Symptomatic arterial hypertension: mixed genesis (medication + renoparenchymatous), stage II (retinal angiopathy), I degree; degree of risk 3 (high); HF I stage. Condition after tonsillectomy (2013). Functional class of therapeutic patient II.”

Before treatment, the patient was given antiviral (acyclovir 400.0 mg 5 times a day for 15 days) and detoxification medicine.

After the treatment, the intensity of the rash on the face decreased, the rash disappeared in the “decolte zone”, the intensity of pain in the joints decreased; the level of lymphocytes was normalized, ESR decreased to 16 mm / h. and the content of C-reactive protein decreased to 14.2 mg/l; PCR EBV (blood) – not detected.

In the two clinical cases described above, patients with SFR have not previously been diagnosed with a viral infection that negatively affected the course of the disease, and the optimization of complex treatment with the inclusion of antiviral medicine gave a positive effect.

Conclusions An overview of modern literature and presented clinical cases from own practice give an opportunity to suggest that herpesviruses, in particular cytomegalovirus and M. E. Epstein’s – I. Barr virus, can be a factor in the risk of systemic lupus erythematosus, its cause, “trigger”, one from pathogenetic mechanisms, especially in genetically-minded individuals. The similarity of clinical manifestations of polysyndromic systemic lupus erythematosus, with lesions of various organs, and herpesvirus infections significantly complicates the determination whether there is only an infection that is primary or chronic in the phase of exacerbation and is clinically similar to systemic lupus erythematosus, or clinical symptoms already in patients with systemic red lupus caused by acute infection, exacerbation of chronic infection or exacerbation of the systemic lupus erythematosus, and this requires a deepening of knowledge about the role of herpesvirus viruses in patients with systemic lupus erythematosus, first of all, in the emergence of comorbid, isolating the syntropic, lesions of internal organs.

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