Zasady postępowania w przypadku infekcji wirusem Herpes przebiegającej z zajęciem ośrodkowego układu nerwowego obowiązujące na Ukrainie

Pavel Dyachenko1, Anatoly Dyachenko2, Olha Smiianova2, Victoria Kurhanskaya2, Ruslan Efremin2

1Center of Infectious Disorders of the Nervous System, si “l.v. gROMASHEVSKY iNSTITUTE OF EPIDEMIOLOGY AND INFECTION DISEASES OF nams of UKRAINE”, Kyiv, Ukraine

2SUMY STATE UNIVERSITY, SUMY, UKRAINE

 

Abstract

Introduction: Herpesviruses (HVs) are ubiquitous pathogens that infect humans usually during childhood, followed by a life-long persistence in a latent state in many sites of a body including the nerve cells. After reactivation HVs can affect the Central Nervous System (CNS) becoming a major cause of morbidity and mortality worldwide as well as long-term neurological sequelae. Despite being an important public health problem very few population-based studies were conducted so far in the world and none in Ukraine.

The aim: to explore the clinical features and etiology of herpesvirus encephalitis (HVE) in a prospective single center study from January 2014 to January 2017.

Materials and methods: 107 adult patients with confirmed herpesvirus infection and symptoms of possible encephalitis (CNS lesion) were analyzed in the study. CSF and blood contents, antibody for HVs M and G classes, and MRI scans have been studied, but the crucial diagnostic sign was the presence of specific viral DNA in the CSF or blood.

Results: 74 (69.3%) out of 107 patients were females, the male to female ratio was 1:2.2. The median age of patients was 36.9 years (range 20-65 years). Most common clinical features were fever, meningism (stiff neck), and focal neurological signs. The genome of HVs was detected in CSF samples obtained from all patients as follows: Herpes simplex virus 1 and 2 – 13 (12.1 %), Varicella zoster virus – 2 (1.8), Cytomegalovirus – 14 (13 %), Epstein Barr virus – 22 (20.5 %), Human herpesvirus 6 – 5 (4.7 %), Human herpesvirus 7 – 13 (12.1 %). Co-infection (≥ 2 HVs) was observed in 38 patients (35.5 %). CSF of 27 patients contained two viral DNA, and 11 – three one in various combination. Human herpesvirus 8 was not found.

Conclusions: The most frequently diagnosed infections in hospital based study were Human herpesvirus 5 (EBV), followed by HSV-1/2, CMV, and HHV-7. Significant part of patients (35.5 %) were co-infected with two or three HVs. Predisposing factor for Ukrainian population is sex.

 

Wiad Lek 2018, 71, 7, -1294

 

INTRODUCTION

Human herpesviruses (HVs) are ubiquitous infectious agents belonging to the herpesvirus family (Herpesviridae). Primary herpesvirus infection usually occurs during childhood and may cause several benign self-limited clinical manifestations, followed by a life-long persistence in a latent state with possible reactivation in case of immunodeficiency. Serious health problems, including CNS lesions can occur as a result of HVs reactivation. One of them, encephalitis, is a serious polyetiologic inflammatory process of the brain. At present not all the causes of the disease are established. It is well known only that they can be infectious and non-infectious. The viral agents of encephalitis vary greatly between countries, with herpesviruses (HVs) being the major etiology in many countries both developed and industrialized. Herpesvirus encephalitis (HVE) accounts for up to 40% of all viral encephalitis, and are major causes of mortality and long-term neurological sequelae throughout the world even when using antiviral drugs. Since surveillance and recording of herpesvirus infections (HVI) are not common practice, it is difficult to establish exact figures for the prevalence of both HVI and HVE. It is considered to be approximately 0.8 per 100 000 populations [1-3]. Despite being an important public health problem, very few population-based studies have been carried out so far in the world and none in Ukraine. We present the clinical and etiological data obtained in prospective single center population study with 107 enrolled adult patients in Ukraine.

THE AIM

The aim of this study was to better define the clinical profiles and etiologic priorities of HVE in Ukraine through a prospective hospital-based study from January 2014 to January 2015.

MATERIALS AND METHODS

Study design, patients and site. This prospective study examining the correct HVs that cause encephalitis, took place from January 2014 until the end of December 2016 at The Center of Infectious Disorders of the Nervous System (Kyiv, Ukraine). CIDNS is an adult tertiary referral, infectious diseases hospital covering Kyiv and the central regions. It has 20 beds with approximately 200-250 admissions annually. Patients are admitted to CIDNS if they have clinical evidence of a CNS infection: fever >38 °C, or febrile episode reported within the previous month; cerebrospinal fluid (CSF) abnormalities (>four white blood cells per mm3 or CSF proteins >0.4 g/L); at least one of the neurological signs (confusion, altered mental status, seizures, focal deficiency).

Exclusion criteria included noninfectious CNS disease (cerebral tumor, cerebral abscess, and neurosurgery within the previous two-four months) and meningitis without clinical manifestation of brain involvement. Patients below 18 years were not included in the study, since children with CNS infections are managed in other specialized centers. Basic demographic information was collected from all patients using case report forms. Patients were managed by hospital doctors following routine clinical practice i.e. history, physical examination, haematology, biochemistry, blood and CSF culture, and lumbar punctures (LP), and radiology. The CSF and serum samples were collected from all patients at admission and immediately sent to lab for analysis.

Vaccine status. According to the Order of the Ministry of Health of Ukraine No. 276 of October 31, 2000, mandatory preventive vaccinations are conducted against the following infections: Hepatitis B, Tuberculosis, Diphtheria, Pertussis (Whooping cough), Tetanus, Poliomyelitis, Measles, Rubella, epidemic Parotitis. No regular antiherpetic vaccines are currently used in Ukraine.

Serology. ELISA test (Euroimmun AG, Germany) was used for serological survey. The diagnostic algorithm included testing for antibodies of class M to HSV1/2, CMV, EBV, VZV, and class G to HHV1-6, and autoantibodies to the main protein of myelin, S-100, neurospecific enolase (NSE), the general human brain antigen. All patients were tested for the above markers.

Intrathecal antibody (ITAB) synthesis to any HVs, one of the inclusion criteria of this study, was determined by the standard method used at our laboratory [4,5]. Briefly, we calculated the serum/CSF sample ratio by measuring the IgG titers of the specific virus by ELISA, where after this ratio was compared with the ratio of corresponding IgG titers against a reference virus (for example, measles, or another antigen). In addition, the CSF/serum albumin ratio and IgG index, (CSF/serum IgG ratio)/(CSF/serum albumin ratio), were calculated to estimate blood-brain barrier damage and intrathecal antibody production [6].

Real-Time PCR analysis. The qualitative and quantitative content of viral DNA in CSF and blood samples was determined in the commercial laboratory “DNA lab” (Kiev) using kits for detection and quantification of Human Herpesvirus DNA by Real-Time PCR from ABAnalitika, and ABI 7500 Fast Dx cycler. The limit of the analytical sensitivity for the kit (p = 0.05) with ABI 7500 system is 0.4 – 2 viral genome copies (gc) / µL DNA extract (depending on specific virus), the linear range is 2.5 to 107 gc / reaction. Thus, the results were available in digital form as an exact DNA concentration in 1 ml of the sample. Electrophoresis of rt-PCR products according to the reaction procedure was not provided.

Clinical diagnosis and final decision. The final conclusion for the etiology of infection and recruiting the patient into the study was mainly based on the detection of viral DNA in CSF or blood, however neuroimaging data and characteristic clinical signs also were taken into account. The diagnosis was considered to be Confirmed when the DNA of any pathogen was found by PCR in the CSF (or blood) samples; Highly probable – when intrathecal IgG antibody synthesis against a specific virus and/or IgM AB in blood were detected; Suspected – when only IgG antibodies were found in the blood [7]. Patients of the first two group were enrolled into the study. Written inform consent was obtained from all patients or from close relatives.

Statistical analysis. For statistical analysis continuous data were compared with Mann-Whitney U test. Proportions were analyzed by Fisher’s exact test. A p value of ≤0.05 was considered statistically significant.

RESULTS

Demography. Altogether 196 patients meeting the initial criteria of CNS infectious disorders were enrolled between January 2014 and January 2017. The majority of patients admitted to CIDNS were transferred from another hospital. 89 patients were excluded from further analysis because the diseases were caused by bacteria or non-infectious in nature. The remaining 107 adult patients with confirmed herpesvirus infection and symptoms of possible encephalitis (CNS lesion) were analyzed in the study. 33 (30.8%) patients were males, and 74 (69.3%) – females, the male to female ratio was 1:2.2. The median age of patients was 36.9 years (range 20-65 years). The demographic and clinical characteristics of the participants are outlined in Table I.

Clinical features. Preadmission illnesses lasted a median of 52 days, range 11 to 188. Clinical profiles observed among the patients with herpesvirus in CSF are characterized by extreme diversity and a combination of several CNS symptoms and syndromes. The symptoms of the patients on admission are presented by frequency in Table 1. Overall, headache 93 (86.9 %) and cochlea-vestibular impairments 88 (82.2 %) were the most commonly recorded symptoms. Vegetative dysfunction 45 (42 %), fever 9 (8.4 %), sleep disorders 8 (7.5 %), mental confusion 13 (12.1 %), pyramidal insufficiencies 38 (35.5 %), convulsions 32 (29.9 %), scattered neurological symptoms 29 (27.1 %), pelvic disorders 6 (5.6 %), reduced hearing 6 (5.6 %) were reported less frequently. A minority of patients had neurological signs e.g. nerve palsies/paresis 8 (7.4 %). Profound hearing loss was not detected.

CSF and blood profile. The majority of patients 103 (96.2 %) had LPs done either on admission (n=88, 82.2 %) or by the next day. White cell count (WCC) in 71% of CSF samples was < 10 cells/mm3. In the remaining samples, moderate cytosis was observed. Lymphocyte prevailed. The protein content of CSF was normal in 89 (83.2 %) patients, and slightly increased (up to 0.99 g / l) in 18 patients. Normal level of WBC, or a small leukopenia was recorded in the blood. The genome of HVs was detected in CSF samples obtained from all patients as follows: Herpes simplex virus 1 and 2 – 13 (12.1 %), Varicella zoster virus – 2 (1.8), Cytomegalovirus – 14 (13 %), Epstein Barr virus – 22 (20.5 %), Human herpesvirus 6 – 5 (4.7 %), Human herpesvirus 7 – 13 (12.1 %). Co-infection (≥ 2 HVs) was observed in 38 patients (35.5 %). CSF of 27 patients contained two viral DNA, and 11 – three one in various combination. Human herpesvirus 8 was not found.

Imaging. An important diagnostic and prognostic value has also neurovascular changes in the structure of the brain (table II, fig.1-4). As can be seen from the table focal changes in the brain are observed much more often – in 61 (57 %) cases against 35 (32.7 %) for diffuse disorders. In 11 patients (10.3 %) no changes in MRI were detected. Findings include focal and diffuse changes of the limbic system around bilateral, temporal, occipital, and frontal areas. Signs develop gradually, but they are somewhat delayed as compared to the clinical symptoms. Encephalitis often involves the cortex, hippocampal, and extrahippocampal structures involving the amygdala, tentorial cortex, thalamus, hypothalamus and deep forebrain structures, cerebellum, and brain stem (fig.1-4). Edema, necrosis, and sclerosis are frequently found. These typical findings are subsequently resolved and brain atrophy is observed in the convalescent period. Taking into account the localization of CNS lesions, the following clinical diagnoses were established: arachnoencephalitis, encephalitis, and meningoencephalitis – 46 (43 %), arachnoiditis – 34 (31.8 %), disseminated encephalomyelitis – 16 (15 %).

Treatment. Patients with approved neurological symptoms received Acyclovir (20 mg/kg), which was administered intravenous daily during 2-3 weeks to all patients with HSV-1/2 and VZV infections), or Ganciclovir (10 mg/kg, per day intravenous for 2-3 weeks to patients with EBV, CMV, HHV-6, and HHV-7 infections). Interferon α2b 3000000 IU per day for 2 weeks, or human immunoglobulin intravenous (0.2 g/kg per day for 5 day) and managed supportively with ademetionine, 400 mg, and citicoline, 1000 mg both intravenous daily.

Outcome. The mean duration of hospital stay was 19.7 ± 15.3 days (range: 7-69). As a result of treatment, 55 patients had a good outcome and after discharge they returned home. The condition of 49 patients improved significantly (a decrease of some neurologic symptoms, but with preservation of some manifestations of cerebrosthenic, vestibulo-atactic syndromes, pyramidal insufficiency). These patients were transferred to a convalescence facility. 3 patients, which condition worsened against the background of the therapy (dysfunction of the stem and cortical structures increased), were moved to an intensive care unit for further treatment. No patient died.

discussion

This prospective study has documented the range of herpesviruses causing CNS infections in patients admitted to a referral hospital in Kyiv. The data described here highlight the main clinical characteristics of herpesvirus associated encephalitis and other lesions of CNS. Should first emphasize the unnatural gender ratio of patients with a large prevalence of women. Of course, there is a sex balance in the general population, but this really reflects the gender composition of patients on hospital treatment. For example, in our center, seven out of eight hospital wards are reserved for women.

The clinical and etiological diversity of herpesvirus infections makes diagnosis difficult, although it is clear that the identification of an infectious agent is critically important, not only for establishing an accurate diagnosis, but also for the timely administration of specific treatment [8]. Diagnostic procedures include serological responses to specific antibodies in the blood and cerebrospinal fluid (CSF), the detection of pathogens by molecular methods in CSF and blood, and sometimes even cultivation of pathogens in culture [9]. The diagnosis is verified through epidemiological data and clinical symptoms, among which fever, headache, altered consciousness, seizures, routine CSF analyzes and neuroimaging [9]. Despite all diagnostic achievements, the etiologic cause of much of the cases remains unknown. Thus, in the California encephalitic project, in which 1570 patients took part, 63% of them had no encephalitis cause [Glaser et al., 2006]. In a similar French study, the cause of the disease remained unknown in 80% of cases [10]. The high incidence of an unidentified diagnosis is partly due to the lack of sensitivity and specificity of the diagnostic methods currently used in the clinic [8,11]. An analysis of cerebrospinal fluid (CSF) in sporadic E typically exhibits lymphocytic pleocytosis at normal levels of glucose and protein, but often normal indicators can be observed only at the onset of the disease [12]. In CSF, a small number of erythrocytes is sometimes found, which reflects the potentially hemorrhagic nature of the disease [13]. In this study the opening pressure was sometimes elevated, and a CSF cytosis was not exceed 10 cells/mm3 in over 70% of our patients. The cells were predominantly lymphocytes with a mean of 20 cells/mm3 (0.02 × 109 cells/l). CSF protein levels, and CSF/glucose ratio were both mainly normal. Increased CSF antibody to specific herpesvirus, and a reduced serum/CSF antibody ratio, might help to diagnose HVE. According to the literature data, intrathecal antibody detection in the CSF HVE is strong evidence for etiology [14]. On the contrary, systemic serological responses should not be considered for diagnosis. However, the data we have obtained indicate that their interpretation must be very cautious. So, very often antibodies for virtually all HVs were found in the CSF. Such false positive results appear most likely due to the cross reactivity of the ELISA kits used. Therefore, positive results were taken into account only in case of coincidence with PCR data.

The use of DNA analyses enhanced substantially our ability to diagnose patients. Indeed, PCR was the only diagnostic tool in our setting for viral pathogens. Timely made diagnosis allowed appropriate treatment to be given. PCR detection of pathogen DNA in CSF is sensitive and specific, and has become the diagnostic procedure of choice, although PCR results can be negative during the early stages of disease [15].

The results obtained in this study were, in general, in line with a number of previous studies, but in some details Ukrainian priorities differ from the word: the most prominent cause of HVE in our patients was EBV (20 %, p<0.05)), followed by HSV-1/2, CMV and HHV-7 (each on 12-13%). Similarly, high prevalence of HSV-1/2, and some less CMV was shown in previously published results [1-3]. In Poland, about a quarter of all CNS infections are caused by HSV-1 [16]. In Brazil, 200 patients with CNS infections were analyzed. Herpesvirus DNA was detected in 12 % of CSF, distributed as follows: 6 % CMV; 5 % HSV-1; 05 % EBV and VZV one each [17]. Italian researches found the genome of herpesvirus in 33.5 % (52/155) of patients with acute neurological disorders. VZV was detected in 30.9 % cases followed by HSV-1 (27.9 %), and coinfection (25.4 %). The last figure is very similar to our study [18]. On the other hand, the VZV is considered to become the second most common herpetic causative agent of CNS lesions in the world, which is at the end of the list in this study [19,20]. Indian group shown immusupression sharply increased the number of cases with combined infections: a single virus was detected in 20 out of 45 HIV-infected persons, 19 cases were co-infected with two viruses, and 6 cases were positive for the three viruses [21]. In the same time, some researchers indicate a decrease in clinical and laboratory manifestations of herpesvirus infections of the CNS. In their opinion, a high fever became less frequent, and the content of cells and protein in the liquor remain normal more often [22].

In the correct diagnosis of CNS infections neuroimaging becomes key. The instrument of neuroimaging can be computed tomography (CT), preferably with contrast, or MRI. From our point of view, MRI is better suited for the diagnosis of encephalitis due to higher resolving capacity than CT. The absence of changes in MRI does not exclude CNS lesions, especially in the early stages of the infection, so it should be repeated 4-7 days if suspicion remains [23]. Thus, in one study, in 25% of patients with clinically and biologically diagnosed HVE, no pathological changes were detected [24].

This study had some limitations; one of them was the non-inclusion of other viral agents such as enterovirus, adenovirus and arbovirus that are known to be responsible for similar neurological symptoms. Additionally, herpes simplex virus was not subtyped.

CONCLUSIONS

It was the first epidemiological surveillance of herpes encephalitis in Ukraine. The findings contribute to understand the epidemiology of encephalitis and the clinical management of patients. Furthermore, this study described the main clinical manifestations of the disease, its evolution, and the use of antiviral agents in the adult population.

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Authors’ contributions:

According to the order of the Authorship.

 

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Olha Smiianova

Sumy State University

1 Sanatorna Str., 40018, Sumy, Ukraine

tel: +380507713008

e-mail: vladlor60@ukr.net

Received: 02.06.2018

Accepted: 12.09.2018

Table I. Demographic characteristics of the study participants

Number of patients

107 (100%)

Age, Me (range)

36.9 (2065)

≤ 20 years

4 (3.73%)

21–30 years

33 (30.84%)

31–40 years

28 (27.8%)

41–50 years

25 (26.16%)

51-60 years

14 (13.1%)

  ≥ 61

3 (2.8%)

Male

33 (30.8%)

Female

74 (69.3%)

Figure 2. Encephalitis with focal lesions in the left frontal-temporal lobe, associated with HSV-1/2 + EBV co-infection.

Figure 1. HHV-7 encephalitis with cerebellar lesion.

Figure 3. Brainstem encephalitis associated with CMV + HHV-6 co-infection.

Figure 4. EBV-associated encephalitis with lesion of brainstem and cerebellum structures.

Table II. Summary of clinical features, laboratory, and radiology data

 

Patients

(n=107/100%)

Clinical signs

Fever

Meningism (stiff neck)

Decreased level of consciousness

Disorientation

Confusion

Seizures

Focal neurological sings

Speech disorders

Cranial nerve palsy

Cerebellous syndrome

Sensory disorders

Myelitis

Aggressiveness

Apathy

Agitation

Parkinsonism

Hallucination

98 / 8.4

46 / 43

2 / 1.9

8 / 7.5

81 / 75.7

17 / 15.9

92 / 86

1 / 0.9

24 / 22.4

31 / 29

12 / 11.2

17 / 15.9

2 / 1.9

86 / 80.4

15 / 14

2 / 1.9

3 / 2.8

White cell count in CSF

Normal (≤10/mm3)

10-1000 mm3)

Predominance of PMNs

Predominance of lymphocytes

76 / 71

31 / 29

7 / 6.5

100 / 93.5

CSF protein

Normal (0.15-0.35 g/L)

Elevated (>0.35 g/L)

89 / 83.2

18 / 16.8

CSF/serum glucose ratio

Normal (>0.4)

Low (≤0.4)

104 / 97.2

3 / 2.8

Typical infectious pattern

Bacterial a

Viral b

15 / 14

92 / 86

Viral DNA in CSF and/or blood

HSV-1/2

VZV

CMV

EBV

HHV-6

HHV-7

Mixed infection

13 / 12.1

2 / 1.8

14 / 13

22 / 20.5

5 / 4.7

13 / 12.1

38 / 35.5

Neuroimaging (MRI data)

Focal lesions

Diffuse lesions

W/o changes

61 / 57

35 / 32.7

11 / 10.3

Outcomes

Complete recovery

Improvement

Deterioration

Sequelae

55 / 51.4

49 / 45.8

3 / 2.8

0

Death

0

Notes:

a Typical bacterial infections pattern: WBC count >100/mm3, predominance of PMNs, mild to marked elevation of protein, normal to marked decrease of CSF/serum glucose ratio.

b Typical viral infections pattern: WBC count ≤100/mm3, predominance of lymphocytes, normal to elevated protein, normal CSF/serum glucose ratio.