Articles in English
Specific Features of the Individual Immunity Response as a Risk Factor in the Children's' Post-Bronchiolitic Recurrent Wheezing.
Ioan Anghelescu M.D.,PhDrd,Doina Popescu Plesca MD,PhD
1.1. The Immunological Maturation
The nature of the immunological response during the foetal development favours a Th2 phenotype (preferential secretion of IL-4, IL-5).
This Th2 polarization is a physiological adaptation process that protects the foeto-placental unit against the toxic effects of the gamma interferon and of the Th1 maternal immunity (A Labbe and G Dutau 1998). After the birth, the immunitary system will slowly direct itself towards a Th1 phenotype. The protective effect against atopy exerted by the viral infections might be the consequence of the activation of the dendritic cells containing antigens with the stimulation of the defence mediated by the gamma interferon followed by maturation towards Th1.
Recent research shows, on the contrary, that in the RPBW course there is a predominantly Th2 response. This immunitary depression on the account of the T CD4 lymphocytes will be more severe on the Th1 sub-population than for the Th2. This effect will favour a Th2 umoral response, which could explain the inflammatory response, the deficiencies in the production of the T lymphocytes, the limited protection against the subsequent infectious aggressions and the specific and non-specific response IgE anti-RSV(respiratory syncytial virus). We may conclude saying that the number of the maturative phenomena explains the apparent fragility of the infant against the pulmonary aggressions. The frequency of the broncho-obstructive pathology with the infants and the babies is the consequence of certain immunological and physiological special features. Undoubtedly, at such an early age begin the inflammatory phenomena that will finally lead to alterations of the pulmonary function with the child and the adult.
As far as bacterial infections are concerned, it has been demonstrated (D Dragomir 1999) that if they are precociously produced in the infant's life, they have a protective effect against the development of atopy with these children. The mechanism would consist in that these bacterial infections augment the Th1 subset of the lymphocytes T-CD4+ and produce a suppression of the Th2 subset.
It has been demonstrated that the CD14 synthesis is genetically codified on the long side of the 5 chromosome and that, when the polymorphism of that particular genetic region is of TT (thymine-thymine) type in the position 15q of the gene, it will produce more CD 14, and as a consequence of the Th1 stimulation and of the Th2 inhibition in the serum there will be lesser quantities of IgE.
As a consequence of the APC stimulation by the bacterial LPZ at the CD14 level, these antigene presenting cells produce more IL-12 which will promote precursory Th, predominant towards the Th1 subtype and not towards Th2 with a specific part in the atopy development. Therefore, the bacterial infection protects against the development of the atopy.
1.2. RPBW(recurrent post-bronchiolitic wheezing) and the Immunity
During the past years, using momentary techniques, several authors have shown an increase of the IgE anti RSV and proinflammatory mediants production during bronchiolitis and the RPBW episodes.
During a number of successive studies, Welliver and the collaborators (quoted by A Labbe and G Dutau 1998) by means of ELISA techniques have objectivised IgE specifically anti RSV in the nasopharyngeal secretions of the RPBW affected infants.
These features are decelable with the beginning of the affection but they progressively increase to attain a maximum within a couple of weeks (recurrent wheezing). They are significantly more abundant with the RPBW infants as compared with those who had an ORL infection with the same virus. In a four years longitudinal study the same authors have established a close correlation between the initially high levels of the IgE and the frequency of the subsequent recurrences. For this reason it is considered that an increased value of the IgE during the inaugurative episode constitutes a good predictive of the RPBW.
The Caswell study (quoted by A Labbe and G Dutau 1998) confirms the results obtained by Welliver, with the specification that they noted a latent sensitization against the A2 antigen of the RSV (which is going to be discussed later on to a greater extent) as well as the histaminic emission from the basophilic polynuclearies.
1.2.1. The Recurrent Post-Bronchiolitic Wheezing and the Inflammation Mediants
220.127.116.11. Volovitz and his collaborators have found the LEUCOTRINES LCT4 in the nasal secretions as much as 83 % from the RPBW RSV+ cases studied.
18.104.22.168. The cationic-eosinofilic protein measured in the nasopharyngeal secretion of the RPBW infants is a marker of the eosinofile degranulation. In the study of Garofalo (quoted by A Labbe & G Dutau 1998) it is four times higher than with the children which had an ORL type RSV infection. The research of Ingram (quoted by Labbe and Dutau 1998) confirms those of Garofalo: the number of infants with values over 200 Ng/ml is of 41 % against the 6 % test witness.
22.214.171.124. Triptase and the Severe Bronchiolitis
During his study, Everard (quoted by Labbe & Dutau 1998) has dosed IgE total, triptase and the ARNm in the bronchoalveolar washing fluid for the infants intubated for severe RSV bronchiolitis. The results are in favour of the mastocitary degranulation.
126.96.36.199. Citokines and Adhesion Molecules in RPBW
During the study of Smith (quoted by Labbe & Dutau 1998), 94 infants received at the beginning of the acute episode and during the convalescence seric level of IL-4, the soluble receptor of IL-2 (CS-25), the intercellular adhesion molecule 1 (ICAM-1), the eosinofilic cationic protein (ECP) and the mielo-peroxidase (MPO). The authors observed signs of lymphocytic activation (CD-25 increase during the acute phase and ICAM-1 increase on the duration of the acute phase and the convalescence) as well as an eosinofilic increase (ECP), while the activity of the mononuclearies seems not to have been affected.
1.2.3. The differences in cell immunitary responsivenes towards the RSV infection have been correlated with an enhancement of the air ways response and lately, the signs of cell immunity activation signs with the increase of citokines Th-2 are considered to connect the illness with the asthma but not with the atopy which is compulsory in asthma.
On basis of these findings, Renzi and his collaborators (1997) begin a research on the possibility of the enhancement of the Th2:IL-4 citokines, or possible effects IL-5 (on the eosinofiles) with the RPBW children.
The results show an increase of the number of eosinofiles and lymphocytes CD4+, CD25+ and CD23+ after five months from the bronchiolitis and compared with the sound similar age pacients (p<0.05). The IL-4 plasma levels, initially identical with those of the sound subjects, suffered too a significant increase. After five months from the bronchiolitis, the lymphocytes of the RPBW children are producing more IL-4 as compared with the D Farinae antigens sound subjects. Between the number of RPBW>20 days and the value of the eosinofily and basefily in the peripheral blood have been found a positive correlation. During the bronchiolitis, the lymphocytes of these children were producing less g-interferon when stimulated with IL-2.
The results then lead to the conclusion that the cell immunity is affected five months after the maiden episode, but the reason for the presence of the cell immunity activation signs five months after bronchiolitis remains unknown.
It might be due to the want of suppression of the inflammation by the macrophagocytes, to the recurrent infection or, as it has been demonstrated on guinea pigs, to the persistency of the virus and the immunitary responsivenes directed towards it. The persistency of the infection and the chronical inflammation could be accounted to the Th2 immunological response, but also to the immunosuppressing treatment. That is why the immunomodulatory treatment with LUIVAC seems logical, all the more so - as it will be shown - this treatment is followed by an amelioration of the inflammatory phenomena objectified by the amelioration of the PEF, VSH and of the number of eosinofiles.
The activation of the Th (T helper) lymphocytes leads to a citokine release. It demonstrates the production of IL-4 (produced by the Th-2) and the diminution of the g-interferon (produced by the Th-1); the same phenomenon is implied in the production of IgE in atopy (similar to the asthma situation, except the fact that with the RPBW subjects, being unatopical, the illness does not last for life as in asthma). The same significant differences have been found with the RPBW children, no matter if they were RSV+ or RSV-.
1.3. The Umoral Immunity
188.8.131.52. The dosage of the anti-RSV antibodies presents a reduced interest with the infant, who produces low quantities of antibodies, is not a rapid method because it is executed on two serums drawn within a 20 days' time interval.
More interesting seems to be:
184.108.40.206. The search of the anti RSV antibodies IgM CLASS in immunofluorescency or ELISA, which can be performed in a few hours. During the acute phase of the infection, in 60-70% of the cases, an IgM response is to be found with the less than six months infants are. These antibodies appear during the first week of infection and persist as far as three months after that. Because of the very low quantities of triturates obtained, the results are hard to interpret.
220.127.116.11. A specific IgA dosage may allow the diagnosis in the absence of the IgM anti-RSV. The IgA antibody response to respiratory syncytial virus (RSV) was determined in nasopharyngeal secretions (NPS) of 22 infants and children infected with RSV group A strains, employing an ELISA. The antibody activity observed during the convalescent phase against whole virus, fusion glycoprotein (F) and large glycoprotein (G) was examined in young infants (under 6 months) and compared with that of older individuals (6 to 16 months). Both groups showed similar degrees of IgA antibody activity to whole virus in NPS; however, older individuals showed a significantly higher activity of IgA F antibody than that of IgA G antibody in the NPS. On the other hand, in the NPS of young infants, IgA F antibody was somewhat suppressed and IgA G antibody activity predominated over that of IgA F. Pre-existing (maternal) serum IgG anti-RSV F antibody activity was higher than that of antibody to G. A significant reverse correlation was observed between the activity of pre-existing serum IgG F antibody and NPS IgA F antibody in the convalescent phase after primary infection with RSV. These observations suggest that maternally derived RSV IgG antibody, which contains abundant anti-F activity, may suppress the development of IgA F antibody response at infection sites in the respiratory tract in young infants during primary RSV infection. These changes may be related to the severity of acute infection and longer convalescence often observed in young infants during RSV infection (Yamazaki H 1994).
Since the Luivac increases the circulating SigA and IgA, it seems a logical remedy for this immunological perturbation. A response in IgA anti RSV is observed only with the older than 6 months infants (Kaul 1981), suggesting a practice of repeated immunisations within the risk groups.
Studies of the IgA and IgG class antibodies kinetics during the period after the inaugural bronchiolitis show differentiations between the small infant and the 8 - 17 months baby. Immunological studies made by Tsutsumi and his collaborators in 1995 on cell cultures suggest that the healing of recurrences be rather connected to the IgA synthesis than to the IgG. With the older child, the subsequent infections (RPBW) will determinate a prompt answer on all the three-immunoglobulin lines.
High IgG, IgA and IgM specific anti RSV, are detected within 5 - 7 days from the re-infection, explaining the shorter and lighter duration of the recurrents.
On basis of the considerations above, the treatment of this affection should follow the modulation of the cell and umoral immunity response, as well as the diminution of the susceptibility towards the bacterial infections induced by the chronical peri-bronchic inflammation induced by the viral infection plus the distorted immunologic response.
The answer to these desiderata seems to be offered by the bacterial lisate Luivac.
In the following, we shall try to demonstrate why this medicine is an immuno-therapeutical agent and not a mere immuno-stimulant.
2. The Immuno-modulator LUIVAC.
2.1. The Mucosa Immunitary System
In order to understand the way LUIVAC acts, we should recall a few things about the lymphoid system. It has:
Primary lymphoid organs
the bone marrow
2. Secondary lymphoid organs
the lymphoid ganglions
the GALT (gut associated lymphoid tissue)
the BALT (bronchic associated tissue)
The tasks of the primary lymphoid tissue are:
to produce immune cells in the bone marrow
to train these cells in becoming efectors
in the thymus (without antigenic contact).
The tasks of the secondary lymphoid tissue are:
* to fight the antibodies
* to maintain the immune response
* The intercommunication between the lymphocytes
* to spread the lymphocytes in circulation (with or without previous antibody contact)
The MALT (mucosa associated lymphoid tissue) avails of all the defence mechanism of the respiratory tracts.
2.2. Something about Embryology
In order to understand how the LUIVAC works, we should remember that the following organs developed themselves as evaginations of the intestinal tracts: the pharynx, the stomach, the bronchic tree, the urinary and the genital tracts.
Despite their subsequent evolution and the different functions of these organs, their mucosa remains connected with the intestinal mucosa by means of a common immunitary system. The practical consequence is that, if a micro organism penetrates the gastro-intestinal tract, the information is transmitted further and the defence mechanism is primed at the level of all the other mucosa which have a common ontogenetic development. The digestive tract is characterised by a high ability of absorption and a large number of immuno-competent cells.
The oral absorption is followed by the taking over of the antigen by the specialised epithelial cells M (microfold) and passed to the intra-epithelial lymphocytes which migrate towards the Peyer plates. At the Peyer plates level, the B immature cells are sensitised. Transported through the efferent lymphoid vessels, these immature sensitised P-cells reach the general circulation, from where they will migrate only in the mucosa tissue (MALT = mucosa associated lymphoid tissue), thus achieving that what the immunologists speak of as “homing”. They are differentiated in IgA producing cells. The union of two IgA molecules and the formation of the secretory piece will lead to the apparition of the secretory IgA (SigA) which will be posed on the mucosa surface.
2.3. Should the LUIVAC be considered as a means of immuno-modulation and immunity stimulation in the RPBW?
The LUIVAC is a bacterial lisate produced in the `90-ies and which, as compared with the similar preparations produces by that time, retained its antigen qualities, in the practice proved to have immuno-modulating qualities superior to other products of the same type.
In 1993, in the “International Immunology” has been demonstrated for the first time that the bacterial lisate LUIVAC produces a specific migration of the primary lymphocytes from the place of inoculation on the digestive mucosa to the respiratory tract mucosa.
2.3.1. As an oral immuno-therapeutic agent, LUIVAC is a bacterial lisate containing at least 1x109 bacterial organisms out of the following types:
These are considered as being the most frequent causes of the recurrent respiratory infections.
As we shall further elaborate, the experience demonstrates that the product activates specific and non-specific factors of the Immunitary System.
Placebo controlled double-blind studies, proofed as being in accordance with the GCP (good clinical practice = a set of rules concerning the clinical research applicable within the European Community), have shown that LUIVAC reduces the duration, the severity and the number of recurrences with the respiratory recurrent infection patients, no matter whether these infections were viral (minor) or bacterial (major).
The frequency of the viral or bacterial infections with the patients suffering of chronical broncho-obstructive affections has been observed in longitudinal studies over a period of eight years (quoted by Ochsenhirt in1997) on lots of patients with and without a chronical broncho-obstructive illness. The main result was that, while the incidence of the viral infections was almost the same for both the groups, for the WR group, the incidence of bacterial infections had been three times higher than that of the normal subjects. The most common pathogen agents incriminated were Haemophilus Influenzae and Streptococcus Pneumoniae.
Besides the immunological perturbations produced by the viral infection per se over an organism with a certain immunity response predisposition (Th2), a number of medicines largely used in the Recurrent Wheezing (corticoids) cause immuno-suppression thus bringing the patient to the state of a subject for the LUIVAC administration. Among these we name: the ionising radiations (repeated radiographs), the corticoids, the non-steroid anti-inflammatories (aspirin, ibuprofen, etc.), the antibiotics. Moreover, the same author stresses the importance of the psychosocial stress (disorganized families, social problems) on the increase of the infection risk due to the induction of the immuno-suppression. During the last years, the connection stress-respiratory tract infections have been recognized. For the LUIVAC to be active is needed an active and sound immunitary system; it can prove efficient only in the presence of the immunity system factors able to respond to LUIVAC charge.
The way of administration requires each dose to contain at least 109 bacteria out of each strain of bacterial lisate.
As in all the other vaccine there is no relationship dose-response in the classical meaning. The dose is administrated in the morning on empty stomach for 28 days in a row, followed by a break of again 28 days and another 28 days' LUIVAC revaccination (booster). 28 days are needed for administration because this is the duration needed by the immunitary cells to differentiate and to reach maturity. Unlike other immuno-stimulant treatments this one can be administrated even during a recurrence or within the interval between the recurrences.
The following dogma are mentioned in the literature:
90% out of the acute bronchic infections (especially WR) are viral-caused.
The illness has a gentle evolution and does not last long.
Thence - there is no antibiotic therapy indication.
The viral infection alteration of the bronchial mucosa might lead to bacterial complications. The most frequently implied micro organisms are Haemophilus influenzae, Streptococcus Pneumoniae and Branhamella Catarrhalis. The frequency and clinical signification of the supra-infections with the infant is still unclear, as for instance the colonisation of the air tracts with the normal child.
Recent evidence (quoted by Ochesnhirt 1997) may lead to the modification of these dogmas:
A microbiological investigation presented at the European Rhinology Society convention in Rome (5-6 oct.'92) showed that only 28% out of the so-called viral infections are of pure viral etyology.
A Czech longitudinal study with a span of eleven years (Ochsenhirt 1997) on the incidence and the etyology of the acute respiratory infections, indicates a percentage of only 37,4 % out of the annual media.
A Finnish study (again Ochsenhirt 1997) showed that, with the under five children infected with adeno-viruses, the bacterial supra-infection is the rule in as much as 45% of the cases.
In another eight years longitudinal study made in the Netherlands and quoted by the same, was shown that for the WR children the bacterial infection is three - four times more frequent than the viral infection as far as recurrences are concerned. The bacterial infection has been found mostly with the risk groups: diabetics, immuno-suppressed, dystrophics, ricketsics, and anaemics.
2.4. The LUIVAC Produced Immuno-Activation
In the experimental results shown in the chart above, LUIVAC produces an activation of both the specific and non-specific defences. We shall further on to elaborate on these charts in detail.
2.4.1. The Immuno-Activation
The effect of LUIVAC is based on the specific immuno-stimulation, as in the active immunisations, but increasing in the same time the non-specific immunity response.
According to Baenkler (1991) this increase of an inadequate immunity response may best be called “immuno-activation”.
2.4.2. Experimental Studies
18.104.22.168. The LUIVAC Action
The complexity of the interactions within the Immunity System makes impossible for the practice to indicate all the effects LUIVAC has on the specific and non-specific mechanisms. That is why the studies have been focused on the research of the effects on the principal immunity mechanisms.
22.214.171.124.1. The LUIVAC activates the cell immunity
The enhancement of the phagocyte activity at the level of neutrophiles
Neutrophiles destroy a large quantity of pathogens releasing high quantities of oxidants (“oxidative-burst”). The production of hydrogen peroxide usually takes place at a low level in order to avoid the alteration of the cells by themselves. In the case of the pathogenic organisms invasion, this restriction is abandoned. LUIVAC increases significantly the activity of the neutrophile granulocytes.
If the mucociliary clearance and the coughing reflex are the principal defence mechanisms for the superior bronchic tract, the activity of the alveolar macrophages is crucial for the sterilisation of the inferior (alveolar) region.
The BAL( broncho-alveolar washing liquid) contains 93% alveolar macrophages.
The alveolar macrophages cause a series of mediators and intervene in the presentation of the antigen.
The effect of the bacterial lisate on the alveolar macrophage has been observed in studies that have used the cAMP cell level as a parameter of the macrophage activities. If at the end of the treatment the activity has been significantly inferior with the immunised subjects than with the witnesses, after five days from the infection debut the activity (the cAMP level) has been significantly superior.
After the stimulation with PGE2 the cAMP concentration diminished, this means a reduction of the phagocyte activity.
The diminution of the pulmonary inflammatory reaction after the infection - PMN Elastase.
The study of Van Daal et al. (1991) calls the attention on the diminution of the alveolar inflammation by means of the PMN-elastase reduction (the elastase has a pro-inflammatory activity causing alterations of the conjunctive tissue).
126.96.36.199.2. LUIVAC activates the umoral immunity
The enhancement of the g-interferon in the rat BAL
In the Van Daal 1992 study, the g-interferon levels have been measured in the broncho-alveolar wash liquid after two different LUIVAC doses and a lethal dose of Streptococcus Pneumoniae. The g-interferon level found after the two doses has been significantly higher than that with the witness lot, where the levels were under the detectable limit.
The IgA and SigA enhancement after LUIVAC administration
In the Fruhwirt (Fruhwirt et al. 1990 quoted by Ochsenhirt) study is noted an enhancement of the IgA immunity response in the serum and at the level of the Peyer plates. The microscopic examination of the Peyer plates have shown an increase of the number of IgA generating cells with the LUIVAC stimulated animal as against the witness.
The SigA enhancement with the voluntary subjects
In the 1989 Fruhwirt study, the LUIVAC administration effect shows a significant SigA increase one months after the administration.
The SigA enhancement with the patients
In the Reidel-Seifert 1991 study (quoted by Ochsenhirt) effected within a period of three months on 65 children with recurrent respiratory infections, the salivary SigA have been definitely increased with the group of patients that had been received LUIVAC, as against the witness lot (double-blind study, randomised, placebo controlled).
The anti-Klebsiela antibodies IgG and IgM class
, according to the Van Dijke 1991 study (quoted by Ochsenhirt), were found definitely higher with the experiment animal after the LUIVAC administration.
The protection against lethal infections
Van Daal and his collaborators have experimentally tested in 1990 the protection conferred by the LUIVAC against the administration on rats of lethal doses of Streptococcus Pneumoniae, Klebsiella Pneumoniae and Influenza A virus. The survival rate with the rats immunised against S.Pneumoniae depended on the dose (between 18 and 30 %) and was statistically significantly higher with the lot of immunised rats as against the witness lot (p<0.05). For Klebsiella the survival enhancement at 6 days was significant (p<0.001) as against the witness lot (Van Dijke at al. 1991)
The LUIVAC immunised rats survived significantly more (15 - 70 % depending on dose) when loaded with a lethal dose of Influenza A virus, as against the witness (Van Daal et al. 1991).
All the toxicity studies have been performed in accordance with the GLP(good laboratory practice) norms. Doses equivalent to the administration of 900 tb/day with humans (Ochsenhirt - LUIVAC Monograph), when given to animals proofed be completely inoffensive. There was no possibility to determine a dose of maximal tolerability because doses of over 1,620 mg/kg/day have been very well tolerated without histologycal or biochemical changes.
The Mutagenity and Teratogenity of the preparation had been tested in accordance with the GLP norms of good laboratory practice, and the LUIVAC proved inoffensive / innocuous.
3. Material ant Method
3.1. The Object of this research is the study of the individual response after the immuno-modulation with LUIVAC.
The criteria of selection for the study were monthly recurrences during the last year or the presence of at least two severe recurrences that required intensive therapy (oxigenotherapy and PEV).
The principal study criteria have been the tolerability of the preparation, the gravity of the recurrences, their number and duration.
The secondary study criteria have been the detection of the other RPBW risk factors and their identification, the treatment with Ketotifen and inhalator topic corticoid.
Proceeding from the above described considerations concerning the RPBW risk immunologic factors and the LUIVAC immuno-modulator, between 1997 and 1989 I have studied 81 children aged 0 to 10 all suffering from recurrent postbronchiolitic wheezing. The children were studied by means of questionnaires filled in with the occasion of the clinical examinations.
The following parameters have been followed: name and forename, the environment, the age, the number of the questionnaire or from the examination rooster, the age when the first episode occurred, the recurrence frequency and their duration, the presence of the risk factors (community or others children in the family), community, air pollutants, tobacco influence (ante- or postpartum, mixed), artificial nutrition, anemia, rickets, the presence of neonatal pathology (pre-maturity, the hyaline membranes illness, severe pneumonia), bronchiolitis in antecedents, the presence of certain allergies in the heredo-colateral antecedents (asthma, allergic rhynite, chronic rashes).
From the clinical point of view we followed: the existence of the pulmonary hyperinflation syndrome, pulmonary hypersonority, the presence of sibilants, or sub-crepitants rales, the prolonged expire, wheezing.
Radiological there were followed the existence of the basal pulmonary hyper transparency, the lowered bases, emphysema, the accentuation of the peribronchic vasculary pattern, the presence of atelectases and of the tracheo-bronchic adhenopathy.
The laboratory analyses were focused on hemograms, the value of eosinophily, VSH, and the standard immunogram. The analyses have been performed before and after the treatment. With a number of patients we measured also the dynamic PEF. We were not able to do this with all the patients because of the small number of pick flow metres and because of the lack of compliance manifested by most patients towards the repeated PEF measurements in the Hospital or in the cabinet. Also, in order to determine the atopy participation the prick test was observed. All the patients were subjected to inhalator corticoid treatment and with Ketitofen. Beginning with November 1997, a number of 58 patients random selected from the mass received each one LUIVAC pill a day (since the preparation dissolves well in water, the infants were given a pill dissolved in their tea). The pill was administrated in the morning, on empty stomach, for 28 days in a row. Then followed a 28 days' pause and another booster cure of 28 days. At the end of the first and second treatment periods we measured the immunogram, the hemogram, the tolerability, the duration of the crises before and after the treatments, the presence of adverse effects, the number and duration of the recurrences, the association with antibiotics and the evolution of the recurrences.
The cases under study were compared with 200 cases interned during the same period (November 1997 - November 1999) in the Hospital (Spitalul Judetean Ploiesti), chosen at random from the interned cases corresponding to the same study selection criteria (monthly crises of wheezing recurrent postbronchiolitis) and on which the same parameters have been followed as for the cases which received the mentioned treatment.
Were eliminated from the study the children with certified asthma and those who - at the moment of examination - were suffering from another illness imitating the recurrent wheezing (see the differential diagnosis). However, we maintained within the study a case of Fallot Tetralogy because it fulfilled all the study admission criteria. Moreover, it could be very well followed in time, because of the cardiac affection.
Out of the 58 children, we had 37 from the urban environment, while the remaining 22 were from rural environment. This corroborates the data from the previous report (outdoors risk factors in RPBW) where a positive correlation between the air pollution value in the city of Ploiesti and the RPBW was demonstrated.
The debut age is presented in the chart below.
In the witness lot, the debut age was of 21 % under six months infants, 17 % 6 - 12 months infants and 17 % children of 1 to 3 years of age.
The males have been affected in a proportion of 56,8 % (33 cases) in the experiment lot and of 78 % in the witness lot.
From the studied children, 30 had at least another brother or sister; 25 were under the influence of a community (crèche or common nursery); 37 were identified with industrial air pollution areas; with 17 we found maternal tobacco ante-partum influence and with another 17 also postpartum. In three of the cases we found conditions of neonate pathology (pre-maturity and pneumonia).
With those children (15) with whom it possible to measure the PEF, it was of 50 - 70 before the treatment, and of 70 - 80 % out of the predicted after treatment.
The atopy terrain was present only with 11 % of the cases within the experimental lot, and of 8,6% with the witness.
The children in both the experimental lot and the witness lot, have had monthly recurrences (at least 10 per year = the study selection criteria). It was precisely this high incidence of the recurrences with the risk groups the reason for this doctorate.
With 18 children we found rhino adenoiditis, with 17 rickets and with 11 anemia. 21 of them had antecedents of grave pneumonia and with another 21 we could detect inaugural bronchiolitis.
All the children that received LUIVAC showed a good tolerance for the preparation. No child complained of adverse effects, or we could detect none.
The number of RPBW recurrences before and after the treatment varied as shown in the chart below:
If when selected for the study the majority of t he children had permanent wheezing or monthly crises (the admission criteria had been of 10 per annum), the duration of the crises varied from 12 cases with less than 7 days, 43 cases with 7 to 10 days and only one with more than 10 days. With the witness lot, the medium internment duration has been of 6,8 days.
The children that received treatment combined with Ketotifen + topic inhalator corticoid (32 children = 55,1 %), the duration of the episode has been of 1 - 3 days indifferent of their being under LUIVAC treatment or not.
I observed the same in the witness lot with the children that received injectable corticoid (132 children = 66 %): the episode duration has been reduced to 1 - 3 days as compared with those who - at the same gravity - had received only oxygen, perfusion and Miofilin. Again, no amelioration of the internment duration or of the severity of the episode has been observed with the children who received inhalator Salbutamol. In some of the cases (3 infants under 3 months) I noted an aggravation of the base symptomatology probably due to the vascular effects of the b2-agonist and the redistribution in the pulmonary circulation.
After the LUIVAC treatment, 2 children had recurrences in the next 6 months, 15 in the period between 6 and 9 months after the treatment, 8 cases at 9 - 12 months after the treatment, while 10 did not come to further controls and we may assume the were healed, and with 9 children we had both clinical and Para clinic healing confirmation.
The duration of recurrences is figured below and varied as follows: less than 7 days before the treatment with 12 cases, between 7 and 10 days with 43 cases and more than 10 days only one.
After the treatment, the duration of recurrences has been of under 7 days with 49 cases, 8 cases between 7 and 10 days and 3 cases more than 10 days.
3.2.1. Laboratory Data
The hemogram showed the presence of light and medium forms of carential hipochrome anaemia with 11 children. The leucocytosis has been normal or slightly increased in 70 % of the lymfocytosis cases. Eosinofilia (within normal limits with 70 % cases) varied between 1 and 14 % and in all cases returned to normal after the treatment. The VSH and CRP were high with 38% out of the cases, indicating a mixed infection (the bacterial mixage probably intervened on a terrain rendered more fragile by the viral infection).
The standard immunogram performed on a randomised lot of 29 cases out of the experimental lot, as shown in the chart, indicates after the treatment a distinct enhancement of the IgA and IgG values. (In the chart, IgA1 and IgG1 are the values recorded before the treatment, while IgA2 and IgG2 are those recorded after.)
The present study demonstrates that RPBW, an illness considered not long ago as being specific only to infants, in the area of the city of Ploiesti is mowing its weight towards the age of the small child. Along with other factors, to this are added the particular type of immunologic response (Th2), the umoral immunity (IgA and SigA) depressed or suppressed by the maternal antibodies (IgG maternal anti-F, fraction of the RSV, suppresses with the infant the IgA production anti-G fraction of the RSV), or as a consequence of the antibiotic, anti-inflammatory and/or cortico-therapy treatments.
As an illness viral in 60 - 80 % of the cases, RPBW can mix bacterially in almost half of the cases, as suggested by the present study values of VSH and CRP (93 % sensibility) both in the experimental and the witness lot.
Keeping in mind these considerations, our object has been to observe the immune individual response of the RPBW children at the treatment with LUIVAC as immuno-stimulatory agent who stimulates not only the specific defence mechanisms, but mostly those of the non-specific defence.
I considered that precisely on this realm of the non-specific defence this immuno-modulator can regulate a number of deficiencies observed with the RPBW child, as for instance the diminution of the g-interferon, the eosinophil production, the IgE hyper production or the inhibition of IgA and SigA which are corrected by the LUIVAC. From all this, our study shows a distinct increase of the standard immunogram fractions, especially IgA and IgG.
The results obtained under this study are super-posable over the experimental results in the consulted literature.
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CONGENITAL NEOPLASMS: ACUTE MEGACARYIOCITIC
LEUKEMIA IN NEW BORN
Dr.Ingrid Miron*, Dr.Lelia Maimescu*, Dr.Cristina Gavrilovici*,
Prof.Dr.O.Brumariu*, Dr.Doina Georgescu**, Dr.C.Bujoreanu***,
Dr. Irina Giusca*, Dr. Maria Stamatin****,
Prof. Dr. I.Tansanu*
*4th pediatric Department , “St. Maria” Iasi Children's Hospital **Haematology Department “St. Maria” Iasi Children's Hospital
*** Congenital malformations Department, Umiversity of medicie and Pharmacy, Iasi
**** Neonatology Department, “Cuza Voda” Maternity, Iasi
Congenital and neonatal leukemia occur rarely, yet carry high mortality rates and pose special problems for the perinatologist and hematologist. Although the etiology is unknown, the presence of leukemia at birth suggests genetic abnormalities and possibly intrauterine exposures to drugs or other toxins as contributing factors. Specific chromosomal rearrangements that are common in congenital leukemia have recently been identified and promise to enhance our understanding of these enigmatic diseases. Congenital leukemias may be of various lineages, although historically, monocytic and myelomonocytic congenital leukemias appear to be the most prevalent.
Here is presented a rare form of acute myeloblastic congenital leukemia. A male neonate, age 10 days, presented in our division with a large abdominal mass, trombocitopenia and severe anemia and diagnosed with megacariocytic leukemia. The patient didn't achieve complete remission despite chemotherapy and intensive care support. He died 10 days later because of a severe hemorragic event.
CONSIDERAÞII ASUPRA UNUI CAZ DE DISTROFIE
MUSCULARÃ PROGRESIVÃ DUCHENNE
Conf. Univ. Dr. EVA NEMES, Asist. Univ. Dr. ILEANA PETRESCU, Dr. DELIA PICIU
(Clinica II Pediatrie, Spitalul Clinic nr. 1 Craiova, UMF Craiova)
The progressive muscular dystrophys are the most frequently humans genetics disease.
Muscular dystrophy Duchenne are the severely form of progressive muscular dystrophys and she is the most common on child occurs in 2 out of 10.000 people.
Absent producing from dystrophyn determinated progressive muscle weakness and the first manifestation appear on approximately 3 to 5 years with immobilization by age 11 to 13.The pozitive diagnose to be make by the tests including serum CPK and electromyography a muscle biopsy confirms the diagnosis. Respiratory disorders are common during the later stages, beside heart disorders and determinated death by age 15.
It is presented the case one child by 14 age with disease Duchenne who was examinated from relapse disorders respiratory.
Key words: Duchenne disease, clinical symptoms, paraclinical tests.
SINDROMUL LANDAU KLEFNER
Dr Toma Rodica , medic primar neuro-psihiatrie infantilã, ºef Laborator Sãnãtate Mintalã Spitalul Judeþean Ploieºti
The acquired “Aphasia Syndrome Landau and Kleffner 1957 called “Syndrome of acquired Aphasia with convulsive disorder in children.
After apparently normal acquisition of speech and language, developed Aphasia for periods ramging from days to Months or Longer,
Temporary Aphasia is known to occur in association with certatypes of Epilepsy, particulary temporal lobe Epilepsy.
The onset of the disorder has been reported as occuring gradual the age of 7 years at one boy ne has partial Epilepsy from 2 years of old year.
The crucial element was the loss of compremesion of spoken language and was followed by loss of the ability to execute speech his intelligence is unimpaired.
This syndrom differentiation from de afness is important, because these children do best in special school dealing with aphasic children.
The treatment was anti convulsivant drog UPA 600 mg/day and Corticotherapy - Synathen 1 mg 1 f/7 days from 3 days to 7 days interval during 8 months.
The evolution was good he recovered completely.
AFECÞIUNI ALE NERVILOR PERIFERICI
Dr. Doina Pleºca, prof. dr. Dimitrie Dragomir
Clinica de Pediatrie, Spitalul Clinic de Copii " Dr. Victor Gomoiu", Bucureºti
Diseases of the peripheral nerves
The authors present the most important diseases due to the peripheral nerves that are encountered in pediatric practice. Most of them are genetically determined and become clinically apparent earlz in infancy. They are clinically characteriyed bz hipotonia.
Recent genetic studies localized the abnormal genes that are responsabile of many of the peripheral nerves dysfunction and led to new criteria of classification of the diseases and to more accurate diagnosis.
Key words: Diseases of the peripheral nerves, hypotonia, child
Dificultãþi de diagnostic într-un caz de sindrom plurimalformativ
Dr. Doina Pleºca*, dr. Liliana Creþu*, dr. Felicia Buruianã*, prof. dr. Dimitrie Dragomir*, dr. Luminiþa Neagu**
* Clinica de Pediatrie, Spitalul Clinic de Copii “Dr. Victor Gomoiu”, Bucureºti
** Departamentul de geneticã, IOMC, Bucureºti
The authors present an 18 months old infant presenting with a plurimalfprmative syndrome suggestive for trisomy 18. The clinical characteristics, imaging studies and results of genetic studies definers this syndrome are presented. We revise the most recent theoretic data availableconcerning the etiology, pathology, cclinical characteristics and evolution on trisomy 18
Key words: trisomy 18, genetic syndromes, child
TULBURÃRI DE MIGRARE NEURONALÃ
Dr. Doina Pleºca*, dr. Raluca Teleanu**, prof. dr. Dimitrie Dragomir*
*Clinica de Pediatrie, Spitalul Clinic de Copii „ Dr. Victor Gomoiu”, Bucureºti
** Rezident de neurologie pediatricã, Clinica de Neuropsihiatrie infantilã, Spitalul Clinic „Obregia”, Bucureºti
The authors of this article deal with a most interesting subject from the field of pediatric neurology. Neuronal migration defects are most interesting from the etiologic, pathologic and clinical standpoint and represent the cause of a whole array of neurologic abnormalities (seizures, mental retardation, various dysmorphisms). The cause of these abnormalities is difficult to trace without proper neuroimaging. The continuous progresses of imaging techniques (CAT scan, MRI, PET, SPECT) have opened new possibilities for the study of abnormalities in the development, differentiation and migration of neurons.
The article reviews the most recent date found in the literature, concerning the classification, pathology and etiology of neuronal migration abnormalities. We review the most representative neurologic syndromes associated with neuronal migration abnormalities.
SISTEMIC LUPUS ERRYTHEMATOSUS
The authors report a case of SLE with late onest after a 4 years long follow-up for chronic thrombocytopenic purpura.
The association of life-threatening malformative syndrome septal ventricular defect, with pulmonary hypertension , renal agenezy which contributed to the severe evolution of the SLE.