Diagnosis of Psoriasis in Hard-To-Treat Body Locations

Introduction
Inflammatory pathology represented by psoriasis vulgaris is much more than a simple skin condition and is a global health problem. Psoriasis for many patients results in a marked functional, psychological and social morbidity. The concept of psoriasis severity refers to many different aspects of psoriasis, including the extent of the disease, the location of the lesions, the degree of inflammation, the ability to respond to treatment and the impact on quality of life. Thus, patients with any type of psoriasis require an assessment of the severity of the disease, the impact of the disease on physical, psychological and social condition, diagnosis of the existence of psoriatic arthritis or other comorbidities. Overall assessment of the patient, assessment of the affected body surface, nail damage, affected areas with high impact and difficult to treat, or any systemic disorder such as fever, malaise, which are common in unstable forms of psoriasis such as erythroderma or generalized pustular psoriasis [1].

Psoriasis is a chronic, multisystemic disease with many comorbidities, which is often difficult to treat, and some cases may be refractory to treatment. Total eradication of plaques is difficult to achieve, and the remission time is short. Recurrence is inevitable and is often preceded by poor adherence to topical therapy. Forms of gouttate psoriasis may resolve spontaneously or may progress to chronic plaque psoriasis. Erythrodermic psoriasis and generalized pustular psoriasis can be life-threatening if left untreated and recurrences are common [2]. The clinical form of psoriasis in plaques refers to the form of well-defined erythematoussquamous plaques, “salmon-pink” to bright red, covered with thick, multilayered, non-adherent silvery white or gray-white scales. Brocq’s methodical maneuver highlights the whitening and fragmentation of the scale, and the detachment of the last layer of scales can objectify a punctiform bleeding (Auspitz sign) due to the phenomenon of papillomatosis. The annular or arched appearance may appear through the central resolution of the plaques and the confluence of the small plaques may determine the appearance of a geographical map.

The common locations are represented by the extension areas of the limbs (knees, elbows), the lumbosacral area, the scalp or the umbilical region. Clinically form of gouttate psoriasis presents multiple, round, small lesions (0.5-1 cm in diameter) (Figures 1a-1f), particularly on the trunk and upper limbs, with rapid extension, being a common form in children and young adults. Inverted (flexural) psoriasis has erythematous plaque lesions, with fine scales, in the major genito-crural, axillary and submammary folds [3]. Healthcare professionals and patients using the term psoriasis usually refer to plaque psoriasis and unless otherwise stated. The term “difficult-to-treat areas” usually refers to the face region, flexion areas, genitals (affected in 45% of cases), scalp, palmoplantar region and are so named because psoriasis in these places can have a significant impact and can lead to functional impairment and require carefully selected topical therapy, which may be resistant to treatment [4].

Figure 1: Clinical aspects of psoriasis vulgaris: erythematous-squamous plaques located on the extension areas of the ulnar region (a), knee (b), forearm (c), scalp (d) and psoriatic onychopathy with leuconiquia, distal onycholysis and longitudinal ridges (e), with the appearance of “oil stains” index and middle accompanied by skin lesions on the dorsal faces of the hands (f).

The scalp is one of the most common sites for psoriasis, usually with well-defined individual erythematous-squamous plaques, which often which usually extend about 1 cm beyond the hairline and advance to the cervical, retroauricular and facial regions, accompanied by pruritus and discomfort. Scalp psoriasis does not usually induce alopecia and the most common differential diagnosis of scalp psoriasis includes seborrheic dermatitis, tinea capitis and lichen planopilaris [5]. In addition, dermatomyositis involving the scalp may have lesions similar to psoriasis [2]. Flexural or inverse psoriasis is characterized by erythematous, shiny, smooth, well-defined plaques, the scales are not clearly visible due to the characteristic moisture in the folds and common topographic areas include the axillary area, sub mammary folds, groin and intergluteal fold. Inverse psoriasis is less common than plaque psoriasis and is estimated to affect 3-36% of patients [6]. In infants, it can often occur in the diaper area, with a typical damage to the groin folds, also known as napkin psoriasis. Common differential diagnoses include bacterial or Candidiasis intertrigo, tinea cruris, contact dermatitis, fold eczema and Hailey-Hailey disease [1].

Genital psoriasis affects up to 60% of patients throughout life [7] and can have a significant impact on patients’ psycho-social function due to physical symptoms such as itching and local pain, with a negative impact on sexual health [1]. As with inverse psoriasis, the scales are discrete or absent, and painful fissures in the intergluteal fissure and intense erythema can be a diagnostic argument. Vulvar psoriasis requires differential diagnosis with atopic dermatitis, contact dermatitis, sclero-atrophic lichen, lichen planus and premalignant lesions [8]. In men, irritative balanitis, Zoon balanitis, Queyrat erythroplasia or extramammary Paget’s disease can mimic genital psoriasis [8]. When nail changes or typical erythematous-squamous lesions of psoriasis are missing elsewhere in the body, skin biopsy may be helpful in establishing a certain diagnosis. The motivation of the study is given the importance of the need to outline the epidemiological profile of psoriasis which affects the quality of life through psycho-emotional impact and hard to treat body locations.

Materials & Methods

We performed a retrospective epidemiological study of 527 hospitalized patients diagnosed with psoriasis vulgaris in the Dermatological Clinic of the Emergency County Clinical Hospital “Saint Spiridon”, Iasi in order to establish the frequency of major forms of psoriasis and describe the characteristics demographics such as gender distribution, age group and hard to treat body locations in psoriasis. The collection of information from the observation sheets complied with both the type of information collected for each patient and the time intervals at which they were obtained. Criteria for inclusion in the group of patients with inflammatory pathology included patients with main clinical and/ or histological diagnosis with psoriasis vulgaris hospitalized in the Dermatology Clinic within the County Emergency Hospital “Saint” Spiridon in Iasi, during 1.01.2016-31.12.2019 for 4 years, patients whose observation sheets or electronic files contained sufficient information to make them relevant to the study. Exclusion criteria were represented by patients whose observation sheets or electronic files did not contain sufficient information to make their inclusion in the study possible.

After applying the selection criteria, a series of 527 patients was created that met all the specified conditions. The information was collected from computer databases and patient observation sheets and included a number of variables relevant to the research. Variables analyzed in the group with psoriasis vulgaris were represented by gender (female or male), age, clinical form of psoriasis (plaque psoriasis, gouttate psoriasis, palmoplantar pustular psoriasis, generalized pustular psoriasis, erythrodermic psoriasis, inverse psoriasis, plaque and gouttate psoriasis, pustular psoriasis, inverse and gouttate psoriasis, psoriasis vulgaris in plaques, gouttate and inverse psoriasis, pustular and inverse psoriasis vulgaris, gouttate psoriasis and pustular psoriasis). Similarly, hard to treat locations distribution such as scalp, palmoplantar area, nails, genital region, large folds, face were analyzed. Quality of life was assessed using standardized Daily Life Quality Index (DLQI) severity score through questionnaire which revealed following values: 0-1 = no effect on the patient’s quality of life; 2-5 = low effect on the patient’s quality of life; 6-10 = moderate effect on the patient’s quality of life; 11- 20 = important effect on the patient’s quality of life; 21-30 = very important effect on the patient’s quality of life.

In order to carry out retrospective studies subsequently, we coded this information in order to be able to enter it in a database with parametric and non-parametric data that we analyzed statistically. The statistical analysis of the data was performed with the software STATISTICA ver. 7.0. Depending on the needs of the statistical analysis, the data were used either in the original version or were grouped according to some classification criteria imposed by methodologies, or established according to the type and particularities of the variables included in the analyzes. We analyzed the differences between the mean values according to the grouping variables, using the t test for independent samples according to the grouping variables sex and environment of origin, appreciating as significant the differences located at a significance threshold p <0.05. The significance of the differences between the frequencies was evaluated with the help of the χ2 test, appreciating as significant the differences when the calculated value of the χ2 test will be higher than the critical value corresponding to the significance threshold p = 0.05. If percentages were compared, the significance of the differences was assessed using the Z test, assessing as significant the differences located at a significance threshold p <0.05.

The present study was carried out in accordance with the 1964 Helsinki Declaration and subsequent amendments and was approved by the Ethics Commission of the University of Medicine and Pharmacy “Grigore T. Popa” Iasi and by the Ethics Commission of the Emergency County Clinical Hospital “Saint Spiridon”, Iași, through the ethics opinion in accordance with the Research Law no. 206 of 27 May 2004 on good conduct in scientific research, technological development and innovation, as well as with the European legislation in force (European Regulation 679) on the processing of personal data. The rights to integrity and confidentiality of the subjects included in the study were respected.

Results

Frequency of Cases with Special Impairment, Depending on Age Groups

To compare the frequency of cases by age groups by sex, the Z test was used to compare the percentages of two different populations (in our case men and women), at the minimum significance threshold p <0.05. The study included a number of 527 patients diagnosed with psoriasis vulgaris, with a distribution by age groups showing 229 women and 298 men, with 49.15% of the total number of the group , respectively 288 patients with urban background. After comparing the frequency with which special impairments occurred by age groups, the following (Tables 1 & 2) significant differences were obtained:

Table 1: Frequency of cases with special impairment, depending on age groups.

Table 2: Differences of frequency of cases with special impairment, depending on age groups.

a) The frequency of scalp psoriasis was significantly higher in patients aged ≤18 years (51.61% compared to 32.73% aged 19-49 years, Z = 2.01, p = 0.02; compared to 31 , 66% aged between 50-69 years, Z = 2.22, p = 0.01; compared to 29.17% aged ≥ 70 years, Z = 2.18, p = 0.01);

b) The frequency of palmar involvement was significantly higher in patients aged 50-69 years (30.5% compared to 16.13% aged ≤18 years, Z = 1.67, p = 0.047; compared to 15.76 % aged 19- 49 years, Z = 3.43, p = 0.0003; compared to 18.06% aged ≥ 70 years, Z = 2.08, p = 0.019);

c) The frequency of plantar involvement was significantly higher in patients aged 50-69 years (30.5% compared to 16.13% aged ≤18 years, Z = 1.67, p = 0.047; compared to 15.76 % aged 19- 49 years, Z = 3.43, p = 0.0003, compared to 16.67% aged ≥ 70 years, Z = 2.32, p = 0.01);

d) The frequency of nail psoriasis was significantly higher in patients aged 50-69 years (42.08% compared to 29.7% aged 19-49 years, Z = 2.57, p = 0.005 and compared to 20 , 83% aged ≥ 70 years, Z = 3.30, p = 0.0005);

e) The frequency of facial extension was significantly higher in patients aged ≤18 years (12.9% compared to 4.24% aged 19- 49 years, Z = 1.92, p = 0.027, compared to 1.16 % aged between 19-49 years, Z = 4.02, p <0.00001 and compared to 1.39% aged ≥ 70 years, Z = 2.49, p = 0.006); it was found that the frequency in patients aged 19-49 years was significantly higher than that of patients aged 50-69 years (4.24% compared to 1.16%, Z = 2.04, p = 0.02). 3.2. The relationship between the clinical form of psoriasis and the special condition:

To see if a particular clinical form of psoriasis is significantly associated with a particular special condition, it was necessary to compare the frequencies of each special condition with all the others in each clinical form of psoriasis. In order to be able to make those comparisons, it was necessary to convert the gross frequencies of each special affectation into percentage frequencies by relating them to the total cases of each corresponding special impairment, the result of which was then multiplied by 100. The differences between the percentages were tested with Z test, being considered significant those differences that were located at a significance threshold p <0.05.

Comparison of the incidence of special conditions in patients with plaque psoriasis (Table 3, Figure 2) showed that:

a) Facial psoriasis (100% of cases) was significantly more common compared to: 73.17% in the palmar area, Z = 2.3, p = 0.01; 72.13% in plantar area, Z = 2.36, p = 0.009 and 82.29% in large folds, Z = 1.77, p = 0.038;

b) Scalp involvement (93.64% of cases) was significantly more common compared to: 73.17% in the palms, Z = 4.88, p <0.00001; 72.13% in plants, Z = 5.06, p <0.00001; 87.91% for nails, Z = 1.86, p = 0.03 and 82.29% for large folds, Z = 2.92, p = 0.0017;

c) Nail psoriasis (87.91% of cases), was significantly higher than: 73.17% in palms, Z = 3.28, p = 0.0005 and 72.13% in plants, Z = 3, 48, p = 0.00025;

d) The involvement in the area of large folds (82.29% of cases) was significantly higher than 72.13% in plants, Z = 1.76, p = 0.04.

Table 3: Percentage frequency of clinical forms of psoriasis and special condition.

Figure 2: Glucose levels behavior.

In patients with inverse psoriasis it was also observed that the frequency of cases with psoriasis of genital area was significantly higher, 38.1%, compared to 20.49% with plantar area, Z = 1.77, p = 0.038. 3.3. Comparison of the frequency of cases with DLQI scores <10, between 10-20 and higher than 20 (Tables 4 & 5): In the four age groups, the results highlighted the following significant differences:

a) The frequency of cases with DLQI scores <10, was significantly higher in patients aged 50-69 years (38.22% compared to 22.58% of those aged ≤18 years, Z = 1.71, p = 0.04 and compared to 29.09% of those aged 19-59 years, Z = 2.10, p = 0.017) and those aged ≥ 70 years (44.44% compared to 22.58% of those aged ≤18 years, Z = 1.93, p = 0.027 and compared to 29.09% of those aged 19-49 years, Z = 2.3, p = 0.01); the frequency of cases with DLQI scores between 10-20, did not differ significantly depending on the age groups;

b) The frequency of cases with DLQI scores> 20, was significantly lower in patients aged ≤18 years (6.45% compared to 30.03% of those aged 19-49 years, Z = 2.76, p = 0.0028, compared to 25.48% of those aged 50-69 years, Z = 2.36, p = 0.009, compared to 36.11% of those aged ≥ 70 years, Z = 3.10, p = 0.001); the frequency of cases with DLQI scores> 20 was significantly higher in patients aged ≥ 70 years compared to those aged 50-69 years (36.11% compared to 25.48%, Z = 1.78, p = 0.037 ).

Table 4: Frequency of cases after DLQI score, depending on age groups.

Table 5: Differences by DLQI score depending on age groups.

Discussion

Psoriasis is a major global health problem with an increased prevalence with values ranging from 0.09% [9] to 11.4% [10] with a significant impact on patients’ quality of life. Clinical examination and evaluation through several tools that quantify the quality of life, such as the Dermatology Life Quality Index (DLQI). Cutaneous involvement of the scalp, face, palms, soles, nails and mucosal involvement such as genitals can be particularly debilitating [11]. Few available research on patients with psoriasis in hard-to-treat locations were based on large study populations with psoriasis. The main objective of this study was to describe patients’ clinical and demographic characteristics, disease severity, and quality of life impacts in patients with hard-to-treat body locations of psoriasis. We investigated the prevalence of hard-to-treat body locations of psoriasis, and similarly we described patients’ clinical and demographic characteristics. In the current retrospective study, the analysis of the total number of hospitalizations (527) in relation to the distribution by sex showed that each year the percentage was higher in men, the percentage frequency differences between the sexes being due to the higher number of men (298) compared with that of women (229).

Gender differences in the characteristics of skin conditions can be influenced by complex interactive mechanisms involving the effect of anatomy, physiology, immunity, genetics, epigenetics, sex hormones, ethnic background, as well as geographical, sociocultural and environmental factors. Epidemiological data reported in the literature show that psoriasis is considered equally prevalent in both sexes [12]. However, of all the studies that reported prevalence by sex, some indicated that psoriasis is more common in men [13], but the values quoted are not statistically significant, and others indicate that psoriasis appears to be less common or more widespread among women than among men [14], so further studies and investigations are needed to differentiate genetic and behavioral factors. The age distribution of the clinical forms of psoriasis vulgaris in the group of patients analyzed showed that the frequency of gouty psoriasis associated or not with erythematoussquamous plaque lesions appeared significantly higher in patients aged 18 years or less, aspects confirmed in the literature as well [15].

Psoriasis was subclassified according to the age of onset and thus psoriasis with early onset (also called type I) can occur before the age of 40, with maximum onset at the age of 16-22. Late-onset psoriasis, also called type II psoriasis, has onset at or after the age of 40, with a maximum age of onset between 57 and 60 years [16]. Other epidemiological studies indicating that the average age in patients with pustular psoriasis is reported between 48 and 50 years [17]. Another significant difference was found in patients aged ≥ 70 years in whom the frequency of reversed psoriasis appeared significantly higher with vulgaris and pustular psoriasis (98.61% compared to 92.28% in those aged 50-69 years). There is a relationship between plaque and pustular psoriasis, as some people may have episodes of plaque psoriasis that precede or follow pustular lesions, the most common trigger factors being viral or bacterial infections or improper use of corticosteroid therapy. This higher frequency may also be due to the fact that as the population of people over the age of 65 in the world continues to grow, the incidence of older people suffering from psoriasis will also increase proportionately.

Patients with the clinical form of plaque psoriasis had as the most common special location to the scalp (93.64% of cases) compared to the palmo-plantar, nail or flexural region. Psoriasis located in areas difficult to treat has a negative impact on quality of life. Thus, studies show that up to 80% of psoriasis patients develop scalp psoriasis and up to 97% of affected individuals reported that the disease affects their daily lives [18]. The frequency of facial and scalp damage was significantly higher in patients younger than 18 years and aged 19-49 years than in patients aged 50-69 years. Scalp is one of the most common sites for psoriasis and facial damage occurs at one time in about half of those affected by psoriasis. Thus, in young, active patients, the damage to these special areas by the unsightly presence of erythematous-squamous lesions on very visible areas often causes psychosocial problems. Common chronic conditions such as psoriasis may be associated with increased psychological distress [19]. Psoriasis is associated with low selfesteem, anxiety (30%) and depressive disorders (60%) [20].

The treatment of psoriasis can promote the relief of depression both due to decreased psychodynamic problems and the production of tumor necrosis factor alpha (TNF-alpha), aspects that need to be considered during therapeutic decision-making [21]. In the presence of these multiple possible comorbidities, the optimal management of the patient with psoriasis vulgaris consists in the holistic approach and the interdisciplinary approach [22]. After comparing the frequency with which special impairments occurred by age groups, it was obtained that the frequency of palmoplantar involvement was significantly higher in patients aged 50-69 years. Although palmoplantar psoriasis is a disabling variant of psoriasis and therapeutically challenging condition its epidemiology is poorly defined [23,24]. Palmoplantar psoriasis can occur at any age. Statistically analyzed data are according to available data from a systematic review and meta-analysis [25] which included a total of 2083 patients with palmoplantar psoriasis (1072 men and 841 women) and the ages of the patients ranged from 8 to 87 years, while the mean age ranged from 37.4 years to 58.5 years. With the exception of two studies, all studies reported a clinical type of palmoplantar psoriasis with hyperkeratosis, pustular or mixed plaques, and the most common was the type of hyperkeratosis plaque [25].

Also in this age group between 50-69 years the frequency of nail damage was significantly higher than those aged 19-49 years (42.08% compared to 29.7%). Literature review shows that men and women are equally affected by nail psoriasis, and its prevalence increases with the age of the study population [26]. Results from a Danish skin cohort with a total of 4016 adults with psoriasis showed that the most frequently affected hard-to-treat area was the scalp (43.0%), followed by the face (29.9%), nails (24.5%), soles (15.6%), genitals (14.1%), and palms (13.7%) [27]. Similarly to our study results, higher prevalence was generally seen with increasing psoriasis severity and patients with involvement of certain hard-totreat areas such as hands, feet, and genitals had clinically relevant DLQI impairments. Psoriasis is no longer considered just a skin disease, but rather a chronic systemic inflammatory disease that presents a substantial risk in increasing the rate of comorbidities [28]. Nail damage is an important problem in dermatological practice, and nail psoriasis may be present alone or may be associated with other skin lesions.

The nail involvement (87.91% of cases) was significantly higher than the palmoplantar area, and the damage in the area of large folds (82.29% of cases) was significantly higher than 72.13 % of the plantar area. Nail psoriasis has been reported in 10-80% of patients with psoriasis, with nails psoriasis on the upper limbs being more often affected than those on the lower limbs. Moreover psoriasis is a common cause of disturbance of the nail morphology and may be associated with all clinical forms of disease [29]. The importance of nail psoriasis was studied, and in a survey in the Netherlands, 79% of patients reported nail involvement, 52% suffering from associated pain and 14% having major restrictions in daily life due to changes in the nail apparatus [2]. Currently, the association of an inflammation of the nail bed has a prevalence between 10-80% recorded in patients with psoriasis [2]. The anatomical connection between the last phalanx and the nail unit determines the correlation between arthropathic psoriasis and nail changes [30].

Some manifestations of psoriasis are associated with an increased risk of developing other manifestations, for example, psoriatic arthropathy in patients with psoriasis with manifestations on the scalp and nails [31]. Psoriatic arthritis is a chronic systemic inflammatory disorder characterized by joint inflammation with a prevalence of 0.05% - 0.25% of the population and 6% to 41% of patients with psoriasis [32]. Although nail psoriasis is usually investigated by clinical examination, the diagnosis of incipient form of disease is needed. Patients with nail damage appear to have an increased incidence of psoriatic arthritis [33]. In the present study, out of the 527 patients with psoriasis, 98 patients presented different clinical forms of onychopathy (18.6%), a result that falls within the range reported in the literature. In our study the frequency of cases with psoriasis of genital area was significantly higher, 38.1% in patients with flexural psoriasis compared to 20.49% with plantar area, Z = 1.77, p = 0.038. Similarly, Kelly, et al. [34] reported that psoriasis involving the genital area occurs in up to two-thirds of psoriasis patients but is often overlooked by physicians.

Furthermore, often the impact this small area of psoriasis can have on a patient is neglected. It can have a significant impact on patients’ psychosocial function due to intrusive physical symptoms such as genital itch and pain, and a detrimental impact on sexual health and impaired relationships. Analysis of the distribution of DLQI values according to age groups showed a higher quality of life impairment in patients older than 70 years.

Conclusion
Hard-to-treat areas in psoriasis are represented by the scalp, face, palms, soles, nails and genital areas. The burden of disease may be due to high frequency of hard to treat body locations such as the facial and scalp regions at early age. Inverse psoriasis has frequently genital area involvement and consequently leads to a negative impact on patiens quality of life. Author Contributions: All authors contributed to the acquisition of the data and critical revision of manuscript for important intellectual content. AIP, DTO conceived review on dermoscopy. IAH and LGS conducted the retrospective study and contributed to statistical analysis and results interpretation. LS, IAP, DV and EPA wrote and conceived the manuscripts. All authors read and approved the final version of the manuscript.

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Use of Insecticide-Treated Nets (ITN) Against Diseases Vectors and Sucking Blood Arthropods

Introduction
Sucking Arthropods and Related Families in the World are
Mosquitoes (Culicidae), Sand flies (Psychodidae), Black flies (Simuliidae), Biting Midges (Ceratopogonidae), Tabanids (Tabanidae), Stable fly (Muscidae), Tsetse fly (Glossinidae), Kissing bug (Reduviidae), Bedbug (Cimicidae), Flea (Pulicidae), Head and body louse (Pediculicidae), Crab (Phthiridae), Mite (Trombiculidae), Hard Ticks (Ixodidae), Soft ticks (Argasidae). They transmit deferent diseases to human. World Health Organization listed the main vector borne disease in the world (Table 1). Vector-borne diseases are illnesses caused by pathogens and parasites in human populations. Every year more than one billion people are infected, and more than one million people die from vector-borne diseases including malaria, dengue, schistosomiasis, leishmaniasis, Chagas disease, yellow fever, lymphatic filariasis and onchocerciasis. For many vector-borne diseases, there are no vaccines, and drug resistance is an increasing threat. Vector control plays a vital role and is often the only way to prevent disease outbreaks. Many existing interventions, such as insecticide treated bed nets and indoor spraying, are simple and proven. Insecticide-treated bed nets are one of the most. WHO therefore recommends that everyone who is at risk of malaria sleeps under a long-lasting insecticidal net every night?

Table 1: Patients with tendon and ligament injury according to age and sex.

International donors funded over 700 million bed nets to protect families against malaria in sub-Saharan Africa. Nets should be checked regularly for holes and replaced every 2-3 years (Figure 1). The use of insecticide in impregnation of bed nets against sucking arthropods is due to these creatures are attracted to contact occupied nets by the odor of the occupants. This equipment is being used as personal protection for high-risk groups. If 80% of the entire population is coverage, it has mass killing effect. At the total coverage, ITN effect on the vector density and survival.

Figure 1: Global death from vector-borne diseases.

Advantages of Mosquito Nets

Low cost, lack of need for special equipment, fewer organization and logistical problems, less insecticide needed, compatibility with local customs, suppressed on the population nuisance insects, protection against cold, dust and snake.

Disadvantages Mosquito Nets

Several factors are involved including: culture, community acceptance due to the lack of awareness, sustainability, allergic effect, Feasibility, accessibility, misuse, not compatible with vector behavior, less coverage, program of distribution, ventilation problem, house design, restrictions of the community movement, -side effect on the pregnant women and child, -shape and design of net, re-impregnation, difficult to evaluate the impact of net.

Efficacy of Impregnated Bed Nets Depend on

Bed net types (Type of bednets can be determined through KAP study), Fabrics (cotton, nylon, polyester, polypropylene, polyethylene (Figure 2). World Health Organization recommended several insecticides for impregnation of bednets (Table 2).

Different Formulations for Impregnation of Bed Nets are: (SC = aqueous suspension concentrate, EW= emulsion, oil in water, WT= water dispersible tablet, CS = capsule suspension (microencapsulated), EC = emulsifiable concentrate.

Figure 2: Types of Fabrics of bednets.

Table 2: Pesticide recommended for impregnation of bednet.

Ways of Impregnation

Soaking, spraying, colour (green, grey, brown, black, white), coding, skirting, insecticides (killing effect, deterrent effect, packaging, safety, registration, cost, social acceptances. Shape could be rectangular, conical, pyramid (Figure 3).

Figure 3: Different type and shapes of impregnated bednet nets commonly used

Current Insecticide Impregnate Bednets Against Insect Resistant to Insecticides are

Olyset® Plus (Permethrin + PBO incorporated into polyethylene, all panels) , PermaNet® 3.0 (Combination of deltamethrin coated on polyester with strengthened border (side panels), and deltamethrin + PBO incorporated into polyethylene roof)), Tsara® Boost (Deltamethrin + PBO incorporated polyethylene, all panels) , Tsara® Plus (Combination of deltamethrin coated on polyester (side panels), and deltamethrin + PBO incorporated into polyethylene (roof)) , Veeralin® (Alpha-cypermethrin + PBO incorporated into polyethylene, all panels) , Interceptor® G2 (Alpha-cypermethrin and chlorfenapyr coated on polyester) , Royal Guard® (Alphacypermethrin and pyriproxyfen incorporated into polyethylene, all panels).

Basic Information for Evaluation of Efficacy of Impregnated Bed Nets are

Ventilation, insecticide, vector susceptibility to insecticides, efficacy of insecticides, availability of insecticides, cost of insecticide, demographic data, population estimates, target groups (children, pregnant women), socioeconomic data, sleeping pattern (outside, inside), current use of nets, cultural attitudes, colors, sizes, vector bionomics, exophilicity and endophilicity, vectorial capacity, vector density, feeding pattern, species, zoophiloicity and anthropophilicity.

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Inflamyar™ Possesses Anti-Inflammatory Effect on Human Immune Cells and Cytokine Expression In Vitro

Introduction
Since virtually all organisms are constantly exposed to the influences of the living environment, the immune system has a great importance for the physical integrity of humans. It protects against threatening external influences such as infestation by microorganisms and parasites, but also against threats from the inside of the body, like e.g. necrotic and apoptotic cell material as well as functionally degenerated cells [1,2]. The human immune system is made up of several components. A distinction is made between a cellular and a humoral part. The cellular immune system comprises highly specialized immune cells that are either mobile (e.g. in the blood) or located in various tissues, e.g. Monocytes, Granulocytes, B cells, T cells, NK cells. The humoral immune system is the part of the immune system based on plasma proteins (antibodies, complement factors and cytokines) [2,3]. Upon induction of an immune response, humoral components of the immune system are initially released by the cells located in the affected tissue. By secreting these factors, other immune cells are lured to the focus of infection [2,3]. The inflammatory response in the body is important for the resolution of the cause of the inflammation but is also the cause of the symptoms of the disease [4]. The immune response is not entirely specific to its cause; even healthy tissue is always damaged [5].

This is especially important when an acute inflammation becomes a chronic inflammation that does not succeed in elimination of the trigger. For example, this may be due to the presence of debris in the tissue or frequent overload of muscles and joints. This persisting inflammation can massively damage the surrounding, primarily healthy tissue [6,7]. The damage of healthy tissue leads to severe pain reactions in both acute and chronic inflammatory reactions [5,8]. Moreover, chronic inflammation can lead to neoplasms (carcinomas or lymphomas) in many organs and in the lymphatic tissue and promote their growth and vascularization. Causes include the chronic proliferation stimulus, the growth-promoting effects of cytokines and the genomic damage caused by reactive oxygen species produced by immigrated immune cells [9-11]. In such situations, use of anti-inflammatory agents to assist and reduce the side effects of inflammation is useful [12,13]. Among the most widely used anti-inflammatory drugs include i.e., synthetic substances such as cyclooxygenase inhibitors, steroids, immunosuppressants and cytokine inhibitors [14,15]. These substances are usually proven to be extremely effective - but in part also show a wide range of unwanted side effects [16-18]. For this reason, the active ingredients from classical medicinal plants are increasingly becoming the focus of research.

In particular, secondary plant metabolites are in the interest of science since these have been in use in traditional medicine for many centuries and thus relatively safe and side effects associated with their use often relatively low [19-23]. Plant metabolites have a wide range of pharmacological effects, such as high antioxidant, antiviral, anti-inflammatory and carcinogenic activity [24-26]. Antiinflammatory ingredients such as alkaloids, phenols, flavonoids, glycosides, terpenes, quinones, catechins and carbohydrates of aqueous extracts from various traditional herbs have been described in several studies [25,27-29]. Besides of direct antiinflammatory actions, an interaction with immunological signal cascades, such as the reduction of proinflammatory mediators by inhibiting transcription factors of gene expression (Nuclear Factor κB, Inhibitor of κB), has already been demonstrated for some of these substances [30-32]. These modulatory effects of plant substances are particularly interesting for research. The individual effects of active ingredients from plant extracts are very diverse and have so far been described inadequately. For this reason further investigations are mandatory. In this study, the anti-inflammatory effect of Inflamyar™, a commercially available homeopathicspagyric product consisting of plant extracts from Arnica montana, Bryonia cretica, Guajacum, Toxicodendron quercifolium, Bellis perennis, Ledum palustre, Ruta graveolens and Viscum album was evaluated.

Materials and Methods

All experiments were conducted by NIS Labs, Klamath Falls, USA.

Test Substance

The test substance, Flamyar™, is a homeopathic spagyric natural remedy manufactured by PEKANA Naturheilmittel GmbH (Kißlegg, Germany) and distributed in the USA under the name Inflamyar™. The test substance was developed for the treatment of sports injuries, sprains, joint problems, bruises, and muscle strains. Active ingredients are Arnica montana spag. Peka Dil. D12, Bryonia cretica spa. Peka Dil. D4, Guajacum Dil. D4, Toxicodendron quercifolium Dil. D12, Bellis perennis spag. Peka Dil. D8, Ledum palustre Dil. D4, Ruta graveolens spag. Peka Dil. D6, Viscum album spag. Peka Dil. D4.

Reagents

Histopaque1077 and Histopaque1119, RPMI1640, 200mM l-glutamine, antibiotics, fetal bovine serum, BSA (bovine serum albumin), fibronectin, and PBS (phosphate buffered saline) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Sodium azide (NaN3) was acquired from LabChem, Inc. (Pittsburgh, PA, USA). CD3 (peridinin chlorophyll protein), CD25 (brilliant violet 421), CD56 (phycoerythrin) and CD69 (fluorescein isothiocyanate), antibodies as well as heparin vacutainers were ordered from BD Biosciences (Franklin Lakes, NJ, USA). The protein multiplex array (27-Plex human cytokine Bio-Plex Pro™) was obtained from Bio- Rad Laboratories Inc. (Hercules, CA, USA).

CD69 Activation Marker Expression on Human Leukocyte Subsets

Peripheral whole blood from human healthy adult donors (n=3) was obtained upon written informed consent approval by the Sky Lakes Medical Center Institutional Review Board, Federalwide Assurance 2603. Heparinized blood samples were placed on gradient solution (Lympholyte-Poly) and centrifuged at 450 × g for 35 minutes. The layer containing PBMC (peripheral blood mononuclear cells) was separated, washed twice with 10 ml PBS (without Ca / Mg) and resuspended in RPMI 1640 (containing 10% fetal calf serum, l-glutamine and antibiotics (P/S) at a cell density of 106/ml. Two parallel culture conditions were used:

a) Adding of serial dilutions of test product without any other stimuli to test the direct immune modulating effect

b) Adding of serial dilutions of test product, followed by addition of an inflammatory insult in the form of bacterial endotoxin LPS (lipopolysaccharide), to assess the ability of test product to reprogram the human immune cells to respond differently to inflammatory stimuli.

Triple cultures were established for each test condition. Negative controls (untreated cell cultures) were established with n=6. Positive control cultures (2x n=3), n=3 containing 10 ng / ml LPS and n=3 containing 100 IU / ml IL-2 for immune cell activation via two different ways.

After an incubation time of 24 hours at 37°C and 5% CO2, blood cells were isolated and stained for 15 min with fluorochromeconjugated monoclonal antibodies at suppliers recommended concentration and then analysed via Attune acoustic-focusing flow cytometer (Thermo Fisher Scientific). Data analysis was performed using electronic gating based on cell size and granularity to distinguish lymphocytes and monocytes, allowing separate analysis of CD69 expression on lymphocyte subsets opposed to monocyte/ macrophage cell subsets. The subpopulation of lymphocytes was then analysed for CD69 expression on CD3-CD56+ NK cells. Costaining with CD3 and CD56 allowed further detailed analysis of four separate lymphocyte subpopulations, namely CD3-CD56+ NK cells, CD3+ CD56- T lymphocytes, and CD3+CD56+ NKT cells. The combination also allowed us to analyze the CD3-CD56- non-T non-NK lymphocytes for activation markers. For each of these populations we examined the expression level of the CD69 activation marker.

Cytokine Production in Peripheral Blood Mononuclear Cell Cultures

Cell culture supernatants were obtained from 24-hour culture setup described above. Expression levels of the following cytokines were tested: Interleukin (IL)-1β, -1ra, -2, -4, -5, -6, -7, -8, -9, -10, -12 (p70), -13, -15, -17, eotaxin, basic Fibroblast Growth Factor (FGF), Granulocyte-Macrophage Colony Stimulating Factor (GMCSF), Granulocyte-Colony Stimulating Factor (G-CSF), Interferon γ (IFN-γ), interferon γ -Induced Protein 10 (IP-10), Monocyte Chemoattractant Protein 1 (MCP-1), Macrophage Inflammatory Protein (MIP)-1α, MIP-1β, Platelet-Derived Growth Factor (PDGF)- BB, Regulated On Activation, Normal T Cell Expressed And Secreted (RANTES), Tumor Necrosis Factor (TNF)-α, and Vascular Endothelial Growth Factor (VEGF). The assay was analysed using magnetic protein multiplex arrays (BioPlex, Bio-Rad Laboratories Inc.) and xMAP technology (Luminex, Austin, TX, USA).

Statistical Analysis

Calculations and statistical analysis was performed using the two-tailed, independent t-test using Microsoft Excel.

Results

Immune cells harvested from human peripheral blood were used as a model for potential activities on immune activating and modulating. On the one hand, the direct activation of immune cells by the test substance, and on the other hand, the priming of immune cells to respond differently to a subsequent inflammatory insult was analyzed. Therefore, two sets of cell cultures were examined in parallel, on the one hand the highly inflammatory bacterial LPS from Escherichia coli and on the other hand the recombinant Interleukin-2 (IL-2) for activation was used as a positive control, and LPS was additionally used in one of the two cultures to induce inflammation after treating the immune cells with the test substance. As indicator for immune cell activation, the activation marker CD69 (cluster of differentiation 69) was chosen. In the case of lymphoid activation, CD69 is the earliest inducible surface glycoprotein and leads to lymphocyte proliferation and signal transmission at the cellular level [33,34]. Incubation of the cell culture with the test product (Figure 1) led to a slight increase in CD69 expression on monocytes (-6.3 to 28.8%) and lymphocytes (0.8 to 10.2%). Either no effect or else a slight increase was seen on Natural Killer (NK) cells (-4.1 to 24.7%), Natural Killer T (NKT) cells (-6 to 14.3%), non-T non-NK lymphocytes (-4.3 to 12.5%) and T cells (2.8 to 8.6%).

Figure 1: CD69 expression on immune cells in 24-hour cultures of peripheral blood mononuclear cells treated with products alone (column “product”) or pretreated with product prior to the addition of the inflammatory insult LPS (column “product + LPS”) plotted as CD69 mean fluorescence intensity. Statistical significance is indicated on the bar graph (*p<0.05, **p<0.01).

Under inflammatory conditions, treatment of cultures with the test product led to a reduced CD69 expression in monocytes of all three donors at lower concentrations of the test product (-0.4 to 14.4%). The highest concentrations of the test substance showed an induced expression of CD69 up to 5.9%. The lymphocytes possessed a reduction of CD69 expression from -2.7 to 19.19% for all three donors. A 38.6 to 42.0% reduction was seen in NK cell activation for both donor 1 and donor 3; donor 2 also showed a reduction in NK cell activation but the response was more variable (ranging from -1.1 to 12.0%). Incubation of NKT cells with the test product prior to LPS stimulation resulted in a -6.3 to 19.2% reduction of CD69 expression for all three donors. T cells possessed a slight reduction in CD69 expression for both donor 1 and donor 3 (-0.2 to 5.3%); donor 2 showed a slight increase in T cell activation (5.3%) at the highest dose tested with no change at lower concentrations of the test product. CD69 expression in non-T non-NK lymphocytes showed a 2.0 to 24.0% reduction in CD69 expression for all three donors. A dose-dependency was seen for donor 1 and donor 3 on NK cells, NKT cells and lymphocytes; on T cells only for donor 3 and for all donors in non-T non-NK cells.

To obtain an overview of the effects of the test substance on the humoral components of the immune system, the test substanceinduced cytokine expression changes were analyzed on PBMC. In this part of the study, on the one hand, the direct effect of the test substance on PBMC cultures and, on the other hand, the effect of pre-incubation of PBMCs with the test substance and subsequent inflammatory stimulus (LPS) were tested. The exposure of immune cell cultures to the test substance without a subsequent inflammatory stimulus (LPS) resulted in a reduction in the cytokine IL-6 up to 98.9% (Figure 2). For two out of three donors (donor 1 and donor 2) the exposure of immune cell cultures to the test product resulted in consistent decreases in the following proinflammatory cytokines: INF-γ (8.5 – 82.2%), IL-1β (21.6 – 97.5%), IL-8 (8.6 –98.4%), IL-12p70 (46.5 – 61.4%; except lowest doses on cells of donor 2), IL-17A (12.0 – 75.7%), Eotaxin (28.4 – 65.4%; except lowest doses on cells of donor 2), IP-10 (3.9 – 74.7%), MCP-1 (55.0 – 97.7%), MIP-1α (58.8 – 97.3%), MIP-1β (13.8 – 97.2%; except lowest doses on cells of donor 2), RANTES (9.1 – 47.6%; in donor 1 and 2) and TNFα (52.4 – 75.6% in donor 1 and 2). The exposure of PBMC cultures to the test substance resulted in a reduction in the cytokine IL-13 in cultures from one donor (29.6%, without lowest dose) and no change in cultures from the other two donors. No change was seen for the cytokine IL-5 in PBMCs exposed to the test substance.

Figure 2: Percent change in proinflammatory cytokine levels in PBMC culture supernatants of three donors treated with serial dilutions of the test product in absence (column “product”) and presence (column “product + LPS”) of a subsequent inflammatory stimulus. Samples without inflammatory stimulus are compared to untreated control cultures; samples with inflammatory stimulus are compared to LPS-control (*p<0.05; **p<0.005).

An incubation of PBMCs with the test substance resulted in a reduction of the anti-inflammatory cytokines IL-1ra (16.2 – 87.4%; except lowest doses on cells of donor 2) and IL-10 (35.8 – 52.2%; except lowest doses on cells of donor 2). The data is shown in Figure 3. Measuring cytokines with pro- and anti-inflammatory properties (Figure 4), the following reactions could be assessed: For two out of three donors (donor 1 and donor 2) the exposure of immune cell cultures to the test substance resulted in consistent decreases in IL-2 (8.6 – 51.9%), IL-4 (13.0 – 72.8%), IL-9 (85.1 – 92.5%; except lowest doses on cells of donor 2) and IL-15 (-8.0 – 16.2%) levels. The exposure of immune cell cultures to the test substance led to variable effects on IL-7 (-102.9 – 60.0%) levels. In the group of growth factors (Figure 4), for two out of three donors (donor 1 and donor 2) the exposure of PBMCs to the three highest doses of the test substance resulted in consistent decreases in PDGF-BB (26.2 – 60.3%; except lowest doses on cells of donor 2), VEGF (18.9 – 56.2%; except lowest doses on cells of donor 2) and G-CSF (18.9 – 56.2%; except lowest doses on cells of donor 2). Variable effects were detected in bFGF (-44.9 – 55.4%) and GM-CSF (-20.0 – 74.1%) levels. In total, a clear dose-dependency of cytokine expression could be seen in IL-17A, Eotaxin MCP-1, RANTES, IL-1ra, IL-4, IL- 15, bFGF, PDGF-BB, VEGF and GM-CSF in a minimum of two donors.

The exposure of PBMCs to the test substance with a subsequent inflammatory stimulus (LPS) led to consistent decreases in IL-13 (2.4 – 34.9%) and RANTES (43.8 – 85.7%). An incubation with the three lowest doses of the test substance led to consistent decreases in the following cytokines: INF-γ (0.0 – 26.3%), IL-1β (-1.4 – 41.4%), IL-17A (-9.1 – 7.8), IP-10 (-6.4 – 27.6%) and TNF-α (4.2 – 41.4; except highest doses on cells of donor 2 and 3). A consistent biphasic response, i.e. increases at higher doses and decreases at lower doses of the test substance, was seen for IL-6 (-177.4 – 19.3%) and Eotaxin (-35.2 – 12.8%). Variable effects were detected on IL-5 (-40.8 – 55.4%), IL-8 (-3356.6 – 79.8%), IL-12p70 (-97.6 - 58.8%), MCP-1 (-98.8 – 42.6%) and MIP-1α (-123.2 – 79.3 %) levels and no effects were seen on MIP-1β levels (Figure 2). Consistent decreases in IL-1ra (3.9 – 64.7%) and variable effects on IL-10 (-27-6 – 45.8%) levels were detected in PBMC cultures (Figure 3). The exposure of immune cell cultures to the three lower doses of the test substance led to consistent decreases in the following cytokines: IL-2 (12.0 – 44.5%), IL-4 (9.1 – 23.3%), IL-9 (1.8 – 10.2%) and IL-15 (2.8 – 27.9%); variable effects were found on IL-7 levels (-40.7 – 29.0%).

Under inflammatory conditions, the exposure of PBMC cultures to the test substance led to a decreased concentration of bFGF (9.3 – 24.4%; except donor 2), PDGF-BB (7.8 – 46.3%) and GM-CSF (-0.3 – 23.0%; except highest dose) in a concentration dependent manner. The growth factors VEGF (-7.5 – 58.8%) and G-CSF (-5.9 – 61.6%) showed variable results with a decrease in cytokine expression in two of three donors. According to the results from stimulation of PBMC without inflammatory stimulus, very consistent responses were seen for all three donors (Figure 4). Also in this group, a dosedependent cytokine expression was found in IFN-γ, IL-1β, IL-6, IL- 17A, Eotaxin, IP-10, MIP-1α, TNFα, IL-2, IL-4, IL-9, IL-15, PDGF-BB, GM-CSF and IL-10.

Figure 3: Percent change in anti-inflammatory cytokine levels in PBMC culture supernatants of three donors treated with serial dilutions of the test product in absence (column “product”) and presence (column “product + LPS”) of a subsequent inflammatory stimulus. Samples without inflammatory stimulus are compared to untreated control cultures; samples with inflammatory stimulus are compared to LPS-control (*p<0.05; **p<0.005).

Figure 4: Percent change in levels of cytokine with pro- and anti-inflammatory capacities and growth factors in PBMC culture supernatants of three donors treated with serial dilutions of the test product in absence (column “product”) and presence (column “product + LPS”) of a subsequent inflammatory stimulus. Samples without inflammatory stimulus are compared to untreated control cultures; samples with inflammatory stimulus are compared to LPS-control (*p<0.05; **p<0.005).

Discussion

In the present study, stimulation of immune cells with the test substance was done in the presence and absence of a subsequent inflammatory stimulus. Thereafter, CD69 expression, i.e., the activation of immune cells, was measured along with the cytokine expression. The data show no effects or only a slight induction of CD69 expression after stimulation of the immune cells with the test substance in the absence of an inflammatory stimulus. With the exception of the T cells, the immune cells showed only isolated inductions of CD69 expression compared to untreated controls. These inductions were distributed over the entire concentration spectrum of the test substance and no dose-dependency was seen. In addition, a reduced expression of proinflammatory cytokines was measured in groups without subsequent inflammatory insult. Noteworthy here is the particularly strong reduction of IL-1β, IL-6, IL-8, MIP-1α, MIP-1β and TNFα. The anti-inflammatory cytokines and growth factors also show a regulation in this context; in relation to the proinflammatory cytokines, however, this is more moderate. This suggests a shift of pro- and anti-inflammatory cytokines activity ratio towards an anti-inflammatory level. Together, the findings from CD69 and cytokine expression indicate an antiinflammatory effect of the test substance.

Upon incubation of immune cells in the presence of a subsequent inflammatory stimulus, a reduction in immune cell activation could be demonstrated for most of the samples in two out of three donors, indicating an anti-inflammatory effect of the test substance also under inflammatory conditions. Correlatively, a reduced expression of cytokines and growth factors the doses of 1.56 to 25 ml/l of test substance was measured. Interestingly, the results show an induction of cytokine expression in a concentration range of 25 to 100 ml/l of test substance, in particular of proinflammatory cytokines. This biphasic effect of the test substance (cytokine reduction at low levels and induction at high concentrations) is in contrast to the reduction of CD69 expression at this concentration. An association between reduced CD69 expression at high doses of the test substance and increased cytokine expression at the same dose, in addition to the shift in the balance between pro- and anti-inflammatory cytokines seen in the previous experiments, indicates an additional anti-inflammatory mechanism of action of the test substance. However, further investigations are needed to verify this.

Unfortunately, not all donors in this study showed an equal response to the test substance. In view of the individual variations in the immune status of the donors (e. g. genetic and epigenetic aspects, potential pre-existing conditions), high deviations in the data from primary cells of different donors are not unexpected [35- 37]. From this point of view, the results of this study are relatively consistent. The observed dose-dependent regulation of the CD69 and cytokine expression of individual groups clearly underlines the validity of the data. In addition, the data generated in this study is consistent with previously published data from other workgroups. For example, a significantly reduced in vitro LPS-induced expression of TNFα, IL-1 and IL-6 from the human whole blood culture and RAW-264.7 cells showed Mahajan et al. after incubation with different dilutions of A. montana and Bryonia species (6CH, 30CH, 200CH) [38]. Lussignoli et al. showed a significant reduction in systemic IL-6 expression in a traumatic animal model after the use of a homeopathic preparation containing A. montana and other plant extracts and minerals [39]. In another study, T. quercifolium in dilutions of 6CH, 12CH, 30CH and 200CH appeared to interfere with an histamine, prostaglandins and other inflammatory mediators driven inflammatory processes [40]. Anti-inflammatory actions due to inhibition of both lipoxygenase and cyclooxygenase metabolic pathways were also seen in homeopathic remedy containing A. montana and T. quercifolium [41]. Porozov et al. described reduced IL-1β, TNFα and IL-8 secretion without an effect on human T cell and monocyte proliferation by a homeopathic remedy containing A. montana and B. perennis [42]. In addition, various studies showed anti-inflammatory properties of various extracts out of A. montana [43-48], Bryonia species [48-50], T. quercifolium [40,51,52], B. perennis [53], L. palustre [54,55], R. graveolens [56-60] and V. album [61-65], which are also contained in the test substance of this study. In summary, the data of the present study possesses a clear antiinflammatory effect and thus a potential for the test substance for the treatment of acute or chronic inflammatory reactions.

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The Dilemma of Choosing a Vaccine Against SARSCoV2 in Children? /SARSCoV2 Vaccine in Children

Introduction
Vaccines for children are the basis for the prevention of serious, infectious diseases, which is why, for the last 6-7 decades, health workers have tried to keep the coverage of the population with vaccines over 90%, at least in developed countries. The rapid spread of the covid19 pandemic has posed a dilemma for us - should we vaccinate children against SARSCoV2 infection, with which vaccine (prepared by known technology or new technology), or should children be exposed to natural infection and stay unvaccinated? Pediatricians are daily exposed to pressure from certain pharmaceutical companies to vaccinate children older than 12 years with a certain vaccine, despite published and positive research on a vaccine that is applicable for children older than 3 years. Is this a simple match of pharmaceutical companies or is it a match between “new” and “old” vaccine technology or is it a fair match of scientific facts? Does the scientific and professional public, worldwide, agree that children should be vaccinated against SARSCoV2 infection, is there a safe and protective vaccine, and what age children should be included in the vaccination? Does vaccination of children against SARSCoV2 have a scientific justification after 18 months from the beginning of the COVID19 pandemic and after the arrival of new strains of SARASCoV2 against which the effectiveness of previous vaccines is partly because they don’t protect against infection but protect against a severe clinical picture? Here we consider the achievements so far on the vaccine against SARSCoV2 infection in children.

Children are often asymptomatic COVID19 i.e. Children are significant carriers of SARSCoV2 in the community. Children suffer mainly from mild to moderate clinical pictures of COVID19. According to the American Academy of Pediatrics, so far an extremely small number of children have suffered from a severe clinical picture of COVID19 (2.4% of total patients) or died of COVID19 (0.08% of total patients), and these are children with comorbidities (obesity, diabetes, neurological progressive diseases) [1]. However, children often show the long-COVID19 or post-COVID19, and these are predominantly children who were carriers of SARSCoV2 or suffered a mild clinical picture of COVID19. Long-COVID19 or post- COVID19 in children is mainly presented as a severe clinical picture in the form of the multisystem inflammatory syndrome (MISC) or similar-MISC which includes myocardial dysfunction, shock, and severe respiratory failure whose treatment is carried out in the intensive care unit.

Certainly, the prevention of COVID19 is more effective than the treatment of a child with COVID19 or long-COVID19, which is a kind of recommendation for vaccination of children against SARSCoV2. Indeed, there is an indication that children must be vaccinated against SARSCoV2 infection. We have been waiting for the results of research on adults for 18 months and accordingly, it is necessary to check the effectiveness of COVID19 vaccines in the child population, of course with the implementation of ethical principles of clinical research. A new circumstance is the poor efficacy of previous vaccines, in adults, against new strains of SARSCoV2 (delta, mu) and the fact that, in the September wave of the COVID19 pandemic, a worrying number of children became ill (25.7% of the total number of patients) compared to previous waves [1].

The basic two groups of vaccines against SARSCoV2 infection are known and apply according to the technology of vaccine preparation. A total of 13 different vaccines are used worldwide. One group of vaccines was made by the known technology of vaccine production with whole, purified, inactivated SARSCoV2 (manufacturers: Sinopharm, Sinovac Biotech, Bharat Biotech) [2,3]. The second group of vaccines was made with a new vaccine production technology using:
1. mRNA against spike protein proteins (manufacturer: Pfizer BioNTech, Modern), or
2. Recombinant adenovirus as a vector against spike protein viruses (AstraZeneca, Institute of India, Janssen/ Johnson&Johnson, Gamaleya National Center of Epidemiology and Microbiology, CanSinoBiologics), or
3. Recombinant spike protein with a new adjuvant (manufacturer: Novavax) or DNA plasmid [4,5].

The first three mentioned vaccine platforms have passed phase 3 and their effectiveness in the prevention of SARSCoV2 infection in adults has been confirmed, while research in the pediatric population is in the initial stages. Application of the fourth platform, i.e., the DNA vaccine began to be used in September 2021, in India, in adults and children older than 12 years [5], so we do not have data on its real effectiveness. We evaluate each vaccine according to its effectiveness, immunogenicity, and safety. Table 1 shows the basic characteristics of individual vaccines which are recommended for children. The efficacy of the inactivated vaccine against SARSCoV2 ranges from 50 to 83.5% [6]. The efficacy of a vaccine containing mRNA against the spike protein SARSCoV2 ranges from 94.1 to 95% [6]. The efficiency of the so-called “vector” vaccines against SARSCoV2 ranges from 65.7 to 91.6% [6]. The efficacy of a vaccine containing a recombinant spike protein with a new adjuvant is 89.7% [6]. The efficacy of the DNA vaccine, estimated in the laboratory, is 67% but is aimed at suppressing the delta strain of the SARSCoV2 virus [5,6].

To achieve high efficiency and immunogenicity of the vaccine, it is necessary to establish an efficient and known mechanism of immunization with phagocytosis using antigen-presenting or dendritic cells that activate T-lymphocytes, which will consequently activate B-lymphocytes, thus achieving cellular and humoral immune response. The second dose of the vaccine enhances and prolongs immunity against SARSCoV2 in terms of an increase in IgG antibody titer to the spike protein SARSCoV2 (S1-RBD) with neutralizing capacity, to a lesser extent to the N-protein SARSCoV2, as well as an increase in INF-gamma secretion after recognition of SARSCoV2 antigen, primarily CD4 lymphocytes and a lesser extent CD8 lymphocytes. Since the time of Pasteur, we have been considering the effectiveness of an inactivated (“dead”) vaccine, that contains the entire infectious agent and conjugate vaccine that contains parts instead of the whole live virus. For example, pertussis vaccination coverage is 86% after 3 doses of vaccine (primarily whole-cell vaccine), which provided a low rate of pertussis in children [7]. It is this efficacy of the pertussis vaccine that can be compared with the efficacy of the inactivated SARSCoV2 vaccine [2,3]. Vaccines that use mRNA or DNA provide human cells with genetic information for an important part of SARSCoV2 against which the immune response is elicited. Vector vaccines transmit genetic information, through another virus for part of SARSCoV2, to human cells that produce a viral protein and elicit an immune response. Protein subunit vaccines produce proteins from viruses so that the human immune system learns to attack them.

Immunogenicity in previous studies was estimated as the percentage of seroconversion, i.e. Increase in the titer of neutral antibodies to SARS-CoV-2 after 28 days of vaccine administration. It is still not specified which antibody titer prevents infection or why there is a quantitative but not qualitative increase in anti-SARS-CoV antibodies after vaccination nor which CD4/CD8 lymphocyte ratio protects against SARSCoV2 infection nor how long post vaccination immunity lasts? The seroconversion achieved by the inactivated SARSCoV2 vaccine found in two independent studies in children was approximately the same: 96.8-100% according to the vaccine dose (1.5 and 3.0 mcg, respectively) compared to 100% after 56 days of the first dose, regardless of whether the dose was 4 mcg or 8 mcg and regardless of age group (3-5 years, 6-12 years, 13- 17 years) [2, 3]. In school-age children, seroconversion with the inactivated vaccine against SARSCoV2 is achieved after 28 days from the first dose [2]. The mRNA produced by Pfizer is 100% effective and contributes to a robust response by producing antibodies to SARSCoV2 in children aged 12-15 years after 7 days of the second dose of the vaccine [4,8]. The vaccine safety data in terms of the number of adverse local and systemic reactions in children are shown in Table 1 [6,9,10]. Data on the efficacy of other vaccines for adults are discussed in the English Covid Vaccination Program [6]. To achieve herd immunity, it is crucial to achieving coverage of the population by vaccination of approximately 80%, which has been achieved by several countries in the world (Portugal, Spain, and Denmark). Until the achievement of collective immunity, it is necessary to implement epidemiological protection measures against the SARSCoV2 infection.

Table 1: Vaccines against SARSCoV2 applicable in children.

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