Clinical and epidemiological features of measles in children hospitalized during two outbreaks (2005–2006 and 2017–2018) in Ukraine

Results. In 2017–2018, the majority of hospitalized children with measles (62.9 %) were school age children. Compared to 2006, the mean age of patients has increased significantly, the proportion of children in the first year of life has significantly decreased and the percentage of children of primary school age (6 to 11 years old) has increased. Compared to 2005–2006, an increase in the duration of fever (from 6.60 to 7.26), shortening of prodromal period (from 3.68 to 2.96) and prolongation of rash period (from 4.97 to 5.88) are characteristic of the course of measles in 2017–2018. Leukopenia was observed in almost every fifth patient. In 14.3 % of patients in 2017–2018, the course of the disease was complicated (the vast majority was associated with respiratory tract organs). Compared to 2005-2006, the structure of patients with measles in 2017–2018 had the proportion of vaccinated patients decreased and, respectively, the percentage of unvaccinated individuals increased: the proportion of unvaccinated patients was 72.1 %; unknown vaccination status – 2.9 %. Approximately 10.0 % of children had only one administration of a measles vaccine.

Measles is a highly contagious disease of viral nature. Before the use of the measles vaccine in 1963 in the United States and the introduction of a large-scale vaccination, epidemic outbreaks were observed every 2-3 years, and the number of deaths from this infection reached approximately 2.6 million people annually. However, even despite the availability of a safe and effective vaccine, this disease remains one of the main causes of death among children throughout the world. In 2016, approximately 89.780 people died as a result of the measles, mostly children under 5 years old [1]. In Ukraine, several epidemic outbreaks of measles infection occurred over the past few years (Fig. 1).
The most powerful outbreak in the last two decades in Ukraine was recorded in 2006, during which 42.724 cases of this disease were registered (Source, date and content of request Consulted experts WHO Regional Office for Europe-Alert and Response Operations Main conclusions and recommendations). According to the Center for Public Health of the Ministry of Health of Ukraine (PHC), more than 41.000 children and adults were affected by measles in the European Region in 6 months of 2018. In seven countries of the European Region (Greece, Georgia, Italy, Russian Federation, Serbia, Ukraine and France), more than 1000 cases of measles in children and adults in each of these countries were recorded. In Ukraine, on the 41st week since the beginning of the year, measles was diagnosed in 33.165 people, including 13.184 adults and 19.981 children (PHC).
The outbreak of measles of 2006 in Ukraine was caused mainly by the measles virus genotype D6 [2]. However, during the last outbreak, which is still ongoing, the circulation of other variants of measles virus including genotypes B3, D8 and D9 is observed on the territory of Ukraine.
We suggested that the emergence of new varieties of measles virus could lead to certain changes in the clinical picture of the disease.

Aim
The purpose of this study was to find out the clinical and epidemiological features of measles in children during the outbreak of 2017-2018. Mean values (M) and standard deviations (SD) were calculated for data presentation. The difference between the quantitative indicators was determined using the oneway or multivariate ANOVA. In the case of non-compliance with normal distribution and / or insignificant number of variants, the Mann-Whitney test was used; categorical values were analyzed using the odd ratio (OR) and the Xisquare test (Хi 2 ). Statistically significant difference was considered at P < 0.05.

Results
The diagnosis was based on clinical and epidemiological data (contact with measles patients, a typical clinical aspect), confirmed by PCR studies and the determination of specific IgM antibodies.
Patients were divided into two groups: one group included 90 children hospitalized during 2005-2006; and 140 children during 2017-2018. Age and gender characteristics of patients are presented in Table 1.
In 2017-2018, the majority of hospitalized children with measles (62.9 %) were school age children. Compared to 2006, the mean age of patients has increased significantly, the proportion of children in the first year of life has significantly decreased and the percentage of children of primary school age (6 to 11 years old) has increased (P < 0.0001). The gender structure did not change significantly (P > 0.05).
In 2017-2018, the proportion of patients unvaccinated against measles was 72.1 % and vaccination status was unknown in 4 (2.9 %) ( Table 2 Table 2). The duration of inpatient treatment did not significantly depend on the age of patients: it was 5.57 ± 2.10 days (2 to 12 days) in children in the first year of life, 5.63 ± 3.97 days (1 to 19 days) in 1-2-year-old children, 6.07 ± 1.96 days (2 to 11 days) in 2-5-year-old children, 6.02 ± 2.39 days (1 to 16 days) in 6-11-year-old children, 6.26 ± 2.88 days (1 to 16 days) in children over 12 years old. Among children vaccinated against measles (at least 1 dose of the vaccine), the duration of stay in the hospital was 6.03 ± 2.44 days (1 to 14 days), among non-vaccinated -5.94 ± 2.75days (1 to 19 days) (P > 0.05). The duration of stay in a hospital was significantly longer in patients with the complicated course of measles -8.10 ± 2.93 days compared to patients without complications -5.53 ± 2.35 days (P = 0.00001).
Classic triad -conjunctivitis, cough and runny nosewas present in 79.1 % of patient. Conjunctivitis was observed in 85.7 % of patients, cough -in 96.1%, runny nose -in 87.8 %. Another known symptom of measles infection, the Koplik's spots, was documented in 90.0% of patients.
Fever was observed in all patients. There was no significant difference in the level of fever between different age groups (P > 0.05). In children vaccinated with at least one dose of measles vaccine, the body temperature was 39.3 ± 0.6 °C (37.5 to 40.0°C), the duration of the fever was 6.6 ± 1.74 days (1 to 10 days). In unvaccinated patients, respectively, the body temperature was 39.3 ± 0.55 °С (38.0 to 40.5 °С), duration was 7.5 ± 1.92 days (4 to 13 days)significantly longer (P = 0.018). Compared to 2005-2006, the mean duration of fever significantly increased in children undergoing treatment in 2017-2018 ( Table 2).
The average duration of the prodromal period in patients with measles in 2017-2018 was significantly shorter compared to 2005-2006 data ( Table 2). We observed a decrease in the duration of this period in all age groups. Moreover, we did not find a significant relationship between the duration of the prodromal period and age: among all patients   and was significantly longer than that in patients vaccinated with minimum one single administration of measles vaccine: 2.4 ± 1.31 days (1 to 6 days) (P = 0.004). Rush was present in all patients. In all cases, the rush was maculopapular with a tendency to fuse. In 97.0 % of patients, there was a progression of rash with characteristic distribution from the head to the distal parts of limbs. In all patients, the spread of rash lasted 2-3 days. The rash was present on the skin for an average of 5.55 days (3 to 12 days). In comparison with 2005-2006, the duration of rash was significantly longer in 2017-2018. The duration of rash did not significantly depend on the vaccination status and was 5.63 ± 1.73 days (3 to 12 days) in unvaccinated patients and 5.30 ± 1.30 days (3 to 10 days) in vaccinated patients (at least one vaccine) (P > 0.05). At the same time, according to the results of our observation, the duration of rash depended on the child's age. In children in the first year of life, the duration of rash was 4.96 ± 1.29 days, in 1-2 year-old patients: 6.09 ± 2.11 days, in 2-5 year-old patients: 5.60 ± 1.29 days, in 6-11 year-old patients: 6.02 ± 1.78 days, in patients over 12 years old: 5.13 ± 1.44 days (P = 0.0058).
The count of peripheral blood leukocytes in patients in 2017-2018 ranged from 2.1 to 32.2 G/L. In 96.3 % of patients in the first study, there was a shift of neutrophils towards their young forms. The percentage of stab neutrophils in the first study on the first day of hospitalization ranged from 1 to 37 % (15.2 ± 7.42 %). Leukocyte count depending on the day of examination is shown in Fig. 2. A decrease in the number of leukocytes was observed predominantly during days 4-6 of the disease. An elevated leukocytes count (more than 9 G/L) was typical in the interval from days 6 to 13 from the onset of the disease.
Leukopenia, one of the most common laboratory symptoms of measles, was observed in almost every fifth  Table 2). The incidence among children in the first year of life was 16.7 %, in the age group from 1 to 2 years old: 23.1 %, in 2-5-year old patients: 17.8 %, in 6-11-year old patients: 11.3 %, in patients over 12 years old: 21.3 % (frequency depending on age was not significant). The incidence of complications was 18.1 % among unvaccinated patients and 15.7 % among vaccinated ones (at least 1 vaccine), OD = 1.09 (0.51-2.34). Table 3 presents the spectrum and frequency of individual complications.
Bronchitis was observed in 8 children, of whom 3 patients were of the first year of life, 2 patients of 2 to 5 years old, 2 patients of 6 to 11 years old and 1 patient over 12 years old.
Pneumonia complicated the course of measles in seven patients. In all cases, this was a secondary bacterial complication. The durations of pneumonia were within 4-6 days (median -6 days). In all cases, pneumonia was confirmed radiologically. One patient had pneumonia complicated by pleuritis. Three children had pneumonia accompanied by respiratory insufficiency and the use of supportive oxygen therapy was required. Bacterial complications from ENT organs occurred in 11 patients. Among them, there were six cases of sinusitis and five cases of otitis media. All cases were registered among children over 6  In 2018, we observed two patients with CNS damage. Among them, a girl of 5.5 years old, unvaccinated against measles, whose disease started suddenly with a temperature rise to febrile values, the appearance of catarrhal phenomena. On the 3rd day of the disease, a maculopapular rash appeared on the face that spread throughout the body during the next 24 hours. On the 5th day, the general condition of the child worsened, she became sleepy, refused to eat, could not rise from the bed without help, pain in the legs and back appeared, while the rash on the skin at that time disappeared. On the 6th day of the disease, during the examination, an impairment of consciousness was recorded (score 13 based on the Glasgow Coma Scale, E4V4M5); the physical examination showed positive meningeal symptoms (rigor of the occipital muscles, Kernig's and Brudzinski's signs), symptoms of spinal nerve roots tension (Neri's sign). The child was not accessible for the productive contact. The face was symmetrical. The bulbar group of the cranial nerves was not impaired. Pupils D = S, moderately expanded, photoreaction was preserved, conjugate. General muscular hypotonia. Abdominal reflexes were absent. There were no seizures and vomit. Body temperature was 36.4-36.6. Microcirculation was not affected. Breathing was spontaneous, effective, biomechanics was not impaired, with the support of humidified oxygen through a face mask. Heart rate was 58-86/min, blood pressure was 103/41-83/48 mmHg. Peristalsis was preserved. There was no self-defecation. Diuresis was sufficient at 3 ml/kg/hr. During the next 3 days, the state of consciousness deteriorated. At day 8 of the disease, a result of measles-specific IgM study was obtained. On the day 9 of the disease, the level of consciousness was 9 based on the Glasgow Coma Scale (E4V1M4), bradycardia increased to 44/min, there was a decrease in blood pressure to 65/40 mmHg. Cerebrospinal fluid analysis revealed slight lymphocytic pleocytosis, while a MRI study showed scattered focal changes. From the 10 th day of the disease, there was a gradual improvement of the child's condition. Restoration of consciousness was observed on day 12. During discharge from the hospital on the 18 th day of the disease, the child had minor manifestations persisted in the form of a decrease in muscular strength in the limbs, increased fatigue.
Another child, an 11-year-old girl, was hospitalized to the KCCH with an impairment of consciousness (score 9 according to the Glasgow Coma Scale, E4V1M4). No impairments of the cranial nerves were observed. Abdominal reflexes were not activated. Muscle tone was lowered. Breathing was spontaneous, effective. Hemodynamics was stable. The disease history showed that the child suffered from measles at the age of 9 months old. 1.5 years ago, the girl suddenly began having her motor function impaired in the form of spontaneous tremor of hands, inclination of her head to the right, episodes of involuntary falls up to 30 times a day. Subsequently, there were periods of deterioration and improvement of her neurological status. Four days before hospitalization in our clinic, the child became sleepier, the intensity of myoclonus and hallucinatory reactions increased. On the day of hospitalization, the child had consciousness impaired to the level of a sopor (score 9 according to the Glasgow Coma Scale, E4V1M4), and lymphocytic pleocytosis was detected in the cerebrospinal fluid. MRI of the brain showed signs of periventricular leukoaraiosis. The results of the cerebrospinal fluid test for the markers of toxoplasmosis, CMV, EBV, VZV, HSV1/2, HHV 6-7 (PCR) were negative, but a high titer of IgG antibody to measles virus was detected. The child received empirical antiviral therapy (acyclovir), immunomodulatory therapy (corticosteroids, intravenous immunoglobulin), supportive and symptomatic agents. However, despite the treatment, the condition of the child progressively deteriorated with the gradual development of multiple organ failure. On the day 18 of inpatient treatment, the patient had a cardiac arrest associated with increased cardiac insufficiency and the development of DIC-syndrome, and death of the patient was recorded.
Manifestations of liver damage were observed in two patients in 2017-2018. They showed an increase in transaminases, including an increase in ALT of more than two normal values. There were no clinical manifestations of hepatic dysfunction in these patients. In both cases, a spontaneous normalization of the ALT level was observed, the duration of hypertransferasemia did not exceed 10 days.
Concomitant pathology in patients with measles was found to be practically identical in 2006 and 2018 ( Table  2). We took into account both the premorbid condition and the cases of acute diseases that developed during the stay of patients with measles in the hospital and were not associated with the underlying disease by causative relationships. Concomitant pathology was represented by a broad spectrum of chronic and acute diseases, among which allergic dermatitis was most common (5 cases), congenital heart disease (3 cases), chicken pox (3 cases), deficiency anemia (3 cases), ascariasis (2 cases), bronchial asthma (2 cases). Among other rare cases, patients with HIV infection, epilepsy, hemophilia, diabetes mellitus, rheumatoid arthritis, and urinary tract infections should be noted. We found that the presence of concomitant pathology was associated with a higher frequency of complications. On the background of concomitant pathology, the incidence of complications was 34.4 %, and in children without concomitant pathology -15.7 % (P = 0.006, Хі 2 test). complication in patients with measles varies according to some data but can be very serious [12][13][14][15]. We observed the manifestations of gastroenteritis in four patients who belonged to the category of early age children. All these cases were recorded among patients during the epidemic breakout of [2005][2006]. No diarrhea was observed among patients in 2017-2018.

Conclusions
1. During the current outbreak, school age children and adolescents prevail in the age structure of ill children hospitalized with measles.
2. Compared to [2005][2006], an increase in the duration of fever, shortening of prodromal period and prolongation of rash period are characteristic of the course of measles in 2017-2018.
3. Changes in the clinical and epidemiological features of the disease may be associated with changes in the spectrum of circulating strains of measles virus.