Etiological and Epidemiological Characteristics of Lethality from Acute Viral Hepatitis, Kyrgyzstan, 2009−2018

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Introduction

The morbidity caused by hepatitis B virus (HBV) causes great damage to the socio-economic condition of the country, regardless of the level of development [1-3]. World experience shows that despite the successful implementation of vaccination programs against HBV infection, a certain part of children and adults remain unreached by this preventive measure. The consequence of this is the presence of the incidence of acute viral hepatitis B (AHB) in the population [4-7]. This situation is also typical for the Kyrgyz Republic, where the average cumulative incidence of AHB in the population within the period of 2009-2018 was 8 cases per 100,000 population, including people over 15 years old — 10.7⁰/₀₀₀₀, and children — 1.3⁰/₀₀₀₀ [8]. It should be emphasized that in the country, at the state level, vaccination is supported only for children who have been immunized within the National Vaccination Calendar (NVC) since 1999 [9]. According to WHO experts, more than 100,000 people suffer from chronic viral hepatitis C in Kyrgyzstan [10]. The presence of a cyclical increase in the incidence of viral hepatitis A every 3-4 years up to 250-409 people per 100,000 population emphasizes the particular relevance of this pathology to the Republic [11]. At the same time, vaccination against Hepatitis A is not included in the NVC; it is carried out in rare cases and on a paid basis. The high incidence of OHA indicates a low coverage of preventive vaccinations, especially for children, which is completely dependent on the awareness, consciousness and activity of citizens. The presence of mortality from acute liver damage defines this problem as one of the diseases with a high burden of disease both on the regional and global scales [12-14]. Unfortunately, in our country, the epidemiological surveillance system continues to detect lethal cases of AVH, which occur even among pregnant women [15-17].

The purpose of this study was to determine the etiological structure of lethality from acute hepatitis and its comparison with morbidity and mortality for the period of 2009-2018.

Materials and methods

To study the etiological structure, dynamics of mortality and lethality from acute viral hepatitis, the data of the State Reporting Form No. 1 “Report on Infectious, Parasitic and Non-Infectious Diseases” of the Department of Disease Prevention and State Sanitary and Epidemiological Supervision of the Ministry of Health of the Kyrgyz Republic (DDP and SSES of the Ministry of Health of the Kyrgyz Republic) for the period of 2009-2018 were analyzed. The Report records lethal cases among adults and children “0-14 years”, which in turn are grouped into 0-12 months, 1-2 years, 3-4 years and 5-14 years and are cumulated in the E-health Center (EHC) of the Ministry of Health of the Kyrgyz Republic [8]. The population size by age is based on the database of the National Statistical Committee of the Kyrgyz Republic [18]. The material was processed using the Microsoft Office Excel statistical package software. Morbidity and mortality were calculated per 100,000 population and lethality per 10,000 cases. The extensive indicator the share of the studied features was calculated as a percentage. Calculating the standard error of proportion was made by the following formula:

$\sqrt{p\frac{\left(1-p\right)}{n}}$

since p was expressed as a percentage, (1 p) was replaced by (100 p) [19].

The 95% confidence interval for the proportion was estimated using the formula:

Results

Over the past 10 years (2009-2018), in the Kyrgyz Republic, a total of 138,612 cases of AVH were detected, of which 109 patients died. The distribution of deceased patients by etiological structure is presented in Figure 1.

 

 

According to the routine epidemiological surveillance system, over the analyzed 10 years (2009-2018), the dominant share in the overall structure of fatal cases was constituted by patients with AHV (n = 40, 36.7%) and AHB (n = 39, 35.7%) that occurred with approximately the same frequency. The etiology of AVH was not identified in every fifth patient who died from hepatitis, and therefore they were diagnosed as “unverified acute viral hepatitis” (22.9%, 25/109). C virus (HCV) was the cause of death in 4 patients (3%), and hepatitis delta virus (HDV) in 1 patient. Among the deceased, there were no cases of hepatitis E virus (HEV).

The study of the dynamics of the etiological structure of AVH for the analyzed period showed that hepatitis A was the cause of death in 45-54% of patients from 2010 to 2013. In 2014, the proportion of deaths from AHA decreased to 18%, but in subsequent years there was an increase in lethality, and in 2017 it reached the previous level again (50%). As for AHB infection, in 2009, 2014, 2017-2018, it was the cause of death of every second patient, and in the periods 2010-2012 and 2015-2016 every third patient who died. Hepatitis C virus as the cause of death in 4 patients with AVH was established in 2010, 2014, and 2015. The proportion of unsverified hepatitis among patients with unfavorable outcome reached 30% in 2009, n = 13, 2013, n = 11, 2016, n = 14, and 2018, n = 11.

The analysis of the age composition of the deceased patients showed the presence of children with AHA, AHB, AHC and “unverified acute hepatitis” among them. For the analyzed period, the epidemiological surveillance system detected 5 fatal cases of children with AHB and an average cumulative morbidity was 1.2⁰/₀₀₀₀. Given the small number of this group, it was decided to present the age distribution in absolute numbers: 0-12 months of life — 2 children (2009 and 2015), 1-2 years — 1 (in 2009), and 5-14 years — 2 children (2011 and 2012). 1 child who was in the “5-14 years old” age group died from acute hepatitis C (AHC). 9 of the 25 patients who died with the diagnosis of “unspecified acute hepatitis” were children under 14 years (under12 months—1, 3-4 years—2and5-14— 6 children).

For a more detailed study of the epidemic situation in terms of AVH mortality, a comparative analysis of mortality (per 100,000 population, ⁰/₀₀₀₀), lethality (per 10,000 cases, ⁰/₀₀₀₀) was carried out and correlated to morbidity (Figure 2). The chart shows that the average cumulative incidence of AVH was 240.9⁰/₀₀₀₀ with a 1.6-time decrease over 10 years (2009-2018). At the same time, a rise in the incidence was observed in the period 2011-2013, with a peak in 2012 (400.3⁰/₀₀₀₀), mainly due to hepatitis A. Subsequently, the incidence curve had a wave-like aspect, with a decrease in the intensity of the process in 2015 almost 2 times (190.9⁰/₀₀₀₀), with an increase in 2016 by 50⁰/₀₀₀₀ — 1.3 times (242.8⁰/₀₀₀₀), and in 2017 there was recorded a decrease of almost 100⁰/₀₀₀₀, which was the minimum indicator (145.5⁰/₀₀₀₀) for the entire analyzed period.

 

 

The AVH lethality curve for the same period of time had an inverse dependence on the incidence, that is, there was a decrease in the lethality rate in the years of increased incidence (4.5, 5,4, and 4.9⁰/₀₀₀₀, 2011, 2013, and 2012, respectively) and an increase in the years of relative epidemic well-being (12.4, 9.6, and 9.0⁰/₀₀₀₀, 2015, 2016, and 2017, res pectively). At the sam e time, the average cumulative lethality rate was 8 people per 10,000 (⁰/₀₀₀) cases with u trend to in-crease (by 13.2 %) for 2009-2018. The mortality indicator averaged 2 cases per 1,000,000 population and decreased by 25% over the analyzed period. The direction of the curve repeated the lethality dynamics: at the peak of the rise in morbidity, this indicator decreased (0.11⁰/₀₀₀₀, 2011) androse to 2.4⁰/₀₀₀₀ 1n 2015, when the lowest level of morbidity was observed for the entire analyzed period.

It should be noted that despite the fact that children have been vaccinated against hepatitis B since 1999 as part of the National Vaccination Calendar in the country, there 1 e still cases of deaths of children from AHB.Therefore, it wasdecided to conduct a comparative analysis of morbidity, mortality and lethality from acute hepatitis B (Figure 3).

 

 

The average cumulative incidence over the observed 10 years was 7.7⁰/₀₀₀₀, with a progressive 2.1-time decrease (by 52.3%) over the study period (10.9 and 5.2⁰/₀₀₀₀, 2009 and 2018, respectively). At the same time, during the first five years of the analyzed period, the lethality rate decreased 4.7 times (by 78.8%) (103.3 and 21.9⁰/₀₀₀, 2009 and 2013, respectively), and since 2014, there has been a sharp rise in lethality – 6.2 times (21.9 and 137.0⁰/₀₀₀, 2013 and 2014, respectively). This trend continued in the subsequent years: 137.0 and 153.8⁰/₀₀₀, 2014 and 2018, respectively. The average cumulative indicator was 89.8⁰/₀₀₀. The mortality rate decreased similarly to lethality during the first five year of the period under study (0.11 and 0.02⁰/₀₀₀₀, 2009 and 2013, respectively) and increased 5 times in 2014 (0.02 and 0.10⁰/₀₀₀₀, 2013 and 2014, respectively). In the period 2014−2018, despite the increasing trend in the lethality rate, the mortality rate remained stable at the level of 0.07−0.08⁰/₀₀₀₀. 

Thus, the analytis of 5nmula0ive indicator ratio over the 10-year period showed that the incidence of AHB was 31.3 times lower than AVH (240,9 and 7.7⁰/₀₀₀₀, AVHrnd AHB, respe8tiveiy), the mortality was 2.7 times lower (0.19 and 0.07⁰/₀₀₀₀, AVH and AHB, respectively), but the lethality was 11.4 times higher (7,9 and 89,8⁰/₀₀₀₀, AVH and AHB, respectively). The results of the study of dynamic indicators in 2009-2018 show a decrease in the incidence of both AVH in general (1.6 times) and AHB (2.1 times), while the rate of decrease of the latter was higher. The dynamics of mortality decrease at these pathologies was the same (1.3 times and 1.4 times, AVH and AHB, respectively), and the lethality rate increased 1.2 times in terms of AVH and 1.5 times in terms of AHB.

The results of the analysis of the above indicators in deceased children with AHB are presented in Figure 4.

 

 

As shown in the diagram, the incidence of AHB in children decreased 15.5 times in the dynamics (3.1 and 0.2⁰/₀₀₀₀, 2009 and 2018, respectively). The average lethality rate was 166 people per 10,000 cases in children, with a minimum of 256.4⁰/₀₀₀ in 2009, and a maximum of 1428.6⁰/₀₀₀ in 2015. The mortality rate varied from 5 to 12 cases per 10,000,000 children.

Comparison of morbidity, mortality and lethality in children from AHB with similar indicators in the general population of patients revealed that, for the period of 2009-2018, the average cumulative incidence of AHB in children was 6.4 times lower compared to the general population of patients with this pathology (7.7 and 1.2⁰/₀₀₀₀, total and children, respectively), the mortality was also 2.3 times lower (0.07 and 0.03⁰/₀₀₀₀, total and children, respectively); but the lethality was 1.8 times higher (89.8 and 165.9⁰/₀₀₀₀, total and children, respectively).

Discussion

The analysis of the etiological structure of mortality from AVH for the period of 2009-2018 showed that the fatal outcome was recorded at all forms of acute viral liver disease (AHB, AHA, AHC, AHD) detected in the country with the exception of AHE.

Despite the fact that AHB vaccination has been carried out in the country for the last 20 years, the proportion of deaths from AHB remains quite high (36.7%). The presence of morbidity and mortality from AHB in children indicates insufficient HBV vaccination coverage of them, even within the NVC. The unfavorable situation with hepatitis B among adults can be explained by the fact that the expenses on immunization against AHB for people over 15 years are borne by the population that, against the background of weak information and educational support, does not pay enough serious attention to this issue. The above requires the study of the causes of morbidity and mortality of children and adults from AHB infection against the background of vaccination of children in the framework of NVC in order to develop preventive and anti-epidemic measures in response.

The frequent occurrence of lethal cases (35.7%) in AHA patients is undoubtedly related to the long-term unfavorable epidemic situation in the country. As many scientists and health care organizers of the country point out, despite the fact that AHA is an enterovirus and improving the provision of drinking water to the population along with compliance with sanitary and hygienic measures should have led to a decrease in the spread of infection, the hepatitis A incidence in the Kyrgyz Republic has been remaining at a high level for several decades [11]. The existence of mortality from it, against the background of high morbidity (154.3⁰/₀₀₀₀, 2018), requires decision on the inclusion of vaccination against AHA in the National Vaccination Calendar, against the background of constant social mobilization of the population to fight AHA.

The relatively high level of “unverified hepatitis” (22.9%) allows us to think about the possibility of liver damage by cytomegalovirus and/or herpes simplex virus, etc. The course of occult hepatitis B or acute toxic hepatitis is also not excluded. To confirm/exclude these hypotheses, it is necessary to conduct in-depth testing for HBsAg, other hepatotropic viruses using more sensitive methods and toxicological examination of patients with negative markers for viral hepatitis. Also, to avoid laboratory errors, it is necessary to use tests with high sensitivity and specificity.

Despite the generally accepted opinion about the relatively mild course of AHC, it caused deaths in 3% of patients. Taking into account the etiological and epidemiological features of AHC infection, it is necessary to pay attention to strengthening of prevention measures when providing medical services and safety of behavior among key groups.

Absolutely low incidence of AHD (1 case out of 109) is most likely due to the pathogenetic features of the disease. Late production of antibodies to AHD, class IgM, on week 3-4 of the disease, causes negative results of the examination at the beginning of the icteric period. Therefore, the etiological confirmation of acute hepatitis B with delta agent is delayed and patients, who died from this infection, are diagnosed as AHB.

Despite the fact that, over the analyzed 10 years, the population of the country was exposed to AHB 31.3 times less than AVH in general, the mortality rate from AHB was only 2.7 times lower. The fact that patients with AHB, in comparison with other AVH, had a greater risk of death, confirms the more severe course of hepatitis B (often with delta antigen), as well as the lethality rate, which was 11.4 times higher (8 and 90 per 10,000 patients, AVH and AHB, respectively).

A 6.4-time decrease in the incidence of AHB in children, a 2.3-time decrease in mortality, and a 1.9-time increase in lethality compared to general population indicators mean that the level of fatal cases has not decreased against the background of a sharp decline in recording AHB cases among children. The presence of single cases of AHB among children, including infants and young children, is explained by the fact that 1-6% of children remain unvaccinated because of parental refusals or medical counterindications. There is an urgent need to increase the coverage of children with immunoprophylaxis by conducting explanatory work to reduce the anti-vaccination mood of parents and limiting medical counterindications for the administration of vaccine.

Conclusion

Thus, the existence of morbidity and mortality of adults and children (including infants and young children) from acute hepatitis indicates that this pathology remains a high social burden for the country. Given the high lethal potential of AVH, it is necessary to improve the quality of immunization of children and expand coverage of adults with HBV vaccination. The tenfold increase in lethality from this disease requires public health representatives to enhance preventive and anti-epidemic measures, and clinicians to provide patients having this pathology with high-quality and timely medical care in order to avoid the unfavorable outcome.

About the authors

К. A. Nogoibaeva

S.B. Danyarov Kyrgyz State Medical Institute for Retraining and Advanced Training$
I.K. Akhunbaev Kyrgyz State Medical Academy

Author for correspondence.
Email: k.nogoibaeva2014@gmail.com
ORCID iD: 0000-0003-0673-872X

Kalys A. Nogoibaeva — Cand. Sci. (Med.), Assoc. Prof., Department of infectious diseases, S.B. Danyarov Kyrgyz State Medical Institute for Retraining and Advanced Training; lecturer, Department of general and clinical epidemiology, I.K. Akhunbaev Kyrgyz State Medical Academy

Bishkek 720040, 

Bishkek 720020

Kyrgyzstan

S. T. Tobokalova

S.B. Danyarov Kyrgyz State Medical Institute for Retraining and Advanced Training

Email: stobokalova@mail.ru
ORCID iD: 0000-0003-0650-1159

Saparbu T. Tobokalova — Doct. Sci. (Med.), Prof., Head of the course of infectious diseases

Bishkek 720040

Kyrgyzstan

References

Supplementary files