Drugs Therapy of Stress On Upper Respiratory Tract Infections Easiness in Downs: Survey On One-Year and Two-Year Results

Renato Cocchi M.D., Ph.D. (Sociology) Italian Journal of Intellective Impairment 11 (2): 161-171 (1998 Dec)

Reprinted with the permission of Renato Cocchi Via A. Rabbeno, 3 42100 Reggio Emilia, Italy +39 0522 320 716 Mobile +39 348 5145 520 URL: http://www.stress-cocchi.net

This is a retrospective study of a series of 185 home-reared Down Ss. All they had therapies for one year, 145 of them for two years, because presenting various degrees of easiness to Upper Respiratory Tract infections (URTI). 185 Ss sample data: 96 M and 79 F, M/F ratio = 121.52, chromosomal diagnosis, standard Trisomy 21 = 90.81%; mosaicisms = 3.24%; translocations = 5.41%; only clinical diagnosis.- 0.54%; Average age at first consultation: 56.83 ± 49.35 months, average therapy length: 60.99 ± 42.18 months. 145 Ss sample data: 79 M and 66 F, MIF ratio = 119. 70,- chromosomal diagnosis. standard Trisomy 21 = 90.34%; mosaicisms = 3.45%; translocations = 5.52%; only clinical diagnosis: 0.68%. Average age at first consultation. 55.50 ± 49.70 months,- average therapy length: 73.42 ± 3.9.41 months.
The reduction of URTI easiness after l-year or 2-years drug therapy was highly significant (0009 for both samples). The disappearance of it took place in 20.53% after one-year therapy and 41.38% after two-year therapy. As seen in children up to nine years old 155 Ss) and up to eight years (116 Ss) at 1st consultation, the age growing favoring effect was considered as negligible.
The paper reports the list of drugs prescribed at 1st consultation - mainly , pyridoxine and a low dose benzodiazepine -, with their daily doses. The same for the percent of any drug used and the rationale for their use.

Key words: Downs syndrome; Upper Respiratory Tract Infections; Easiness; One-year drug therapy, Two-year drug therapy.

Materials and methods
The current survey deals with the clinical records related to all subjects who took the prescribed drug therapy and had one-year or two-years-checkups after the first visit. This makes a casual consecutive series of Downs that has its selective criterion on those Down Ss having come back for checkups at least for this minimum time. As home-reared and home-living Downs they came from all parts of Italy to outpatients' consultations, between January 1979 and April 1997.
During their 1st consultation all these Ss had their easiness to URTI evaluated and recorded by severity, along with other signs and symptoms. The scoring of that easiness had its reference to the past 12 months (or, in children aged less than one year, to past therapy months) by recording according to a severity scale as follows: (0) = as in a healthy child; = nasal catarrh usually present; = 1 + susceptibility to cough and cold with few feverish episodes; (3) = 1 + 2 + easiness to tonsillitis, pharyngitis, bronchitis with moderate fever and limited need of antibiotics (up to four regimens per year); (4) = 1 + 2 + 3 + high temperatures, occasional otitis- and bronchial pneumonia, and frequent use of antibiotics (more than four regimens per year). l used the same scoring way during following checkups.
The records about autistic or PDDs Ss were discarded because we saw that this second heavier pathology can modify the URTI easiness (Cocchi and Bonaduce, 1988).
From the remaining records I collected: sex, chromosomal diagnosis; age at 1st consultation; scoring of URTI easiness at 1st consultation; the same at on-year or two-years checkups; follow-up; drugs prescribed at the first checkup and their daily doses.
I processed data by means and URTI easiness graduation and I applied Wilcoxon's Signed Ranks Test or Chi Square Test when suitable.

Results
Only 185 cards for the one-year survey, and only 145 cards for the two-year survey out of 510,fitted those criteria. They refer to home reared Downs coming from all Italy.
Tables 1-2 and 12 summarize epidemiological data of the samples, table 3 shows drugs prescribed at first consultation. Then Tables 4-11 and 13-15 present the URTI easiness scoring according to one-year or two-year survey.
In graphics 1-4 1 showed the variation of URTI easiness according to each grade of seventy, both for the 185 Ss sample and the 145 Ss sample. The same I did for the samples of 155 and 116 Ss, where the favoring age growing variable got out.

Table 1: epidemiological and clinical data of the sample related to the one-year survey (185 Ss) No. of Ss 185 100.00% M 96 57.30% F 79 42.70% M/F 121.52 Chromosomal diagnosis Standard Trisomy 21 168 90.81% Mosaicisms 6 3.24% translocations 10 5.41% Unknown, only clinical diagnosis 1 0.54% Age at 1st consultation, range in months 4 - 280 Average ± SD 56.83 ± Follow-up, range in months 12 - 169 Average ± SD 60.99 ±

As we can see in Table 1 the M/F ratio does not fully overlap what we know for live born Italian infants. The distribution of the chromosomal diagnoses stays within the variance limits for Italian and International samples.
Although the slight reduction of the male prevalence, we can assume the sample here surveyed as a representative sample at least of the Italian population of Downs.

Table 2: Epidemiological and clinical data of the sample related to the two-years survey (145 Ss) No. of Ss 145 100.00% M 79 54.48% F 66 45.52% M/F 119.70 Chromosomal diagnosis Standard Trisomy 21 131 90.34% Mosaicisms 5 3.45% translocations 8 5.52% Unknown, only clinical diagnosis 1 0.68% Age at 1st consultation, range in months 4 - 280 Average ± SD 55.50 ± Follow-up, range in months 24 - 169 Average ± SD 73.42 ±

As we can see in Table 2 the M/F ratio does not fully overlap what we know for live from Italian infants. The distribution of the chromosomal diagnoses stays within the variance for talon and international samples. Although the slight reduction of the male prevalence, we can assume this sample as representative for at least the Italian population of Downs.

Table 3: Drugs prescribed at first consultation and their daily doses. Drug in use mg/die No. of Ss % Pyridoxine (*) 75-150 185 100.00 L-glutamine 125-250 159 85.94 L-glutamine + pemoline (**) 45+5 - 90+10 26 14.06 Diazepam 1-2.5 163 88.11 Bromazepam 0.5-1.5 16 8.11 Oxazepam 7.5-15 7 3.77 Folates (*) 7.5 31 16.76 Total 586
(*)In many cases the drug was prescribed every second day by alternating pyridoxine and folates, so the daily dose reports it as if it was prescribed every day.
(**) No more marketed in Italy

The average prescription summed up 3.16 drugs per person. Glutamine, alone or in combination with pemoline, pyridoxine and a low dose benzodiazepine was the basic regimen.

Tab. 4: Comparison of the results in the whole sample (185 Ss) URTI easiness' graduation Initial scores Final scores No. of Ss % No. of Ss % Not present (O) 0 0.00 117 63.24 Present, mild (1) 31 16.76 29 15.67 moderate (2) 39 21.08 18 9.73 severe (3) 79 42.70 16 8.65 Profound (4) 36 19.46 5 2.70 Totals 185 100.00 185 100.00 Average severity ± SD 2.65 ± 0.98 0.72 ± 1.11

Wilcoxon's Signed Ranks Test: z = 10.786 and p < .0009

As a global survey, at final scoring only about 37% of the sample went along to present URTI easiness. On the other hand, increased severity (grades 3-4) went down from about 62% to less than 12%. Tab. 5: Comparison between initial scores and scores after one-year drug therapy in the whole sample (185 Ss) URTI easiness' graduation Initial scores After 1-year therapy No. of Ss % No. of Ss % Not present (O) 0 0.00 38 20.53 Present, mild (1) 31 16.76 35 18.92 Moderate (2) 39 21.08 51 27.57 Severe (3) 79 42.70 47 25.40 Profound (4) 36 19.46 14 7.58 Totals 185 100.00 185 100.00 Average severity ± SD 2.65 ± 0.98 1.80 ± 1.24 Wilcoxon's Signed Ranks Test: z = 8.919 and p < .0009

After one-year of drug therapy more than 20% of the subjects lost their URTI easiness and severe forms (grades 3-4) decreased from about 62% to about 33%.

Tab. 6: Comparison between one-year therapy scores and final scores in the whole sample (185 Ss) URTI easiness' graduation After 1-year therapy Final scores No. of Ss % No. of Ss % Not present (O) 38 20.53 117 63.24 Present, mild (1) 35 18.92 29 15.67 Moderate (2) 51 27.57 18 9.73 Severe (3) 47 25.40 16 8.65 Profound (4) 14 7.58 5 2.70 Totals 185 100.00 185 100.00 Average severity ± SD 1.80 ± 1.24 0.72 ± 1.11 Wilcoxon's Signed Ranks Test: z = 9.163 and p < .0009 As we can see in Table 6, the good result after one-year of drug therapy is only a step towards a better one that needs a longer treatment. Of course, as l have found in my previous paper (Cocchi, 1998), there is also a favorable effect due to becoming older. Tab. 7: Global comparison between initial and final scores in the two-year therapy sample (145 Ss) URTI easiness' graduation Initial scores Final scores No. of Ss % No. of Ss % Not present (O) 0 0.00 93 64.14 Present, mild (1) 24 16.55 19 13.10 Moderate (2) 28 19.31 18 12.41 Severe (3) 62 42.76 11 7.59 Profound (4) 31 21.38 4 2.76 Totals 145 100.00 145 100.00 Average severity ± SD 2.69 ± 0.99 0.72 ± 1.11 Wilcoxon's Signed Ranks Test: z = 9.264 and p < .0009 As a survey on the two-years therapy sample, at final scoring only about 36% of the same sample went along to present URTI easiness, but increased seventy (grades 3-4) went down from about 64% to less than 11 %. Tab. 8: Comparison of the results after one-year drug therapy (145 Ss) URTI easiness' graduation Initial scores After 1-year therapy No. of Ss % No. of Ss % Not present (O) 0 0.00 27 64.14 Present, mild (1) 24 16.55 20 13.10 Moderate (2) 28 19.31 43 12.41 Severe (3) 62 42.76 42 7.59 Profound (4) 31 21.38 13 2.76 Totals 145 100.00 145 100.00 Average severity ± SD 2.69 ± 0.99 1.96 ± 1.24 Wilcoxon's Signed Ranks Test: z = 9.264 and p < .0009 After one-year of drug therapy more than 18% of the subjects lost their URTI easiness and severe forms (grades 3-4) decreased from about 64% to about 38%. Tab. 9: Results after two-year drug therapy URTI easiness' graduation Initial scores After 2-years therapy No. of Ss % No. of Ss % Not present (O) 0 0.00 60 41.38 Present, mild (1) 24 16.55 43 29.65 Moderate (2) 28 19.31 23 18.86 Severe (3) 62 42.76 14 9.65 Profound (4) 31 21.38 5 3.45 Totals 145 100.00 145 100.00 Average severity ± SD 2.69 ± 0.99 1.14 ± 1.13 Wilcoxon's Signed Ranks Test: z = 9.290 and p < .0009 Tab. 10: Comparison between two-year and final scores of the reduced sample (145 Ss) URTI easiness' graduation After 2-years therapy Final scores No. of Ss % No. of Ss % Not present (O) 60 41.38 93 64.14 Present, mild (1) 43 29.65 19 13.10 Moderate (2) 23 18.86 18 12.41 Severe (3) 14 9.65 11 7.59 Profound (4) 5 3.43 4 2.76 Totals 145 100.00 145 100.00 Average severity ± SD 1.04 ± 1.13 0.72 ± 1.11 Wilcoxon's Signed Ranks Test: z = 5.488 and p < .0009 As we can see in Table 9-10 the improved result after two-years of drug therapy is only a second step towards a better result that needs a longer treatment. Of course, as l have found in my previous paper (Cocchi, 1998), there is also a favorable effect on the decrease of URTI easiness due to the becoming older. Tab. 11: Comparison between l-year and 2-years therapy scores (145 Ss) URTI easiness' graduation After 1-year therapy After 2-years therapy No. of Ss % No. of Ss % Not present (O) 27 18.62 60 41.38 Present, mild (1) 20 13.79 43 29.65 Moderate (2) 43 29.66 23 18.86 Severe (3) 42 28.97 14 9.65 Profound (4) 13 8.96 5 3.45 Totals 145 100.00 145 100.00 Average severity ± SD 1.96 ± 1.24 1.14 ± 1.13 Wilcoxon's Signed Ranks Test: z = 7.999 and p < .0009 Graphics 1-2. The graphic 1-2 show that l-years drug treated Ss are healthier not treated than they were non-treated, but final scores are decidedly better. Graphics 3-4: The graphics 3-4 show that 2-years drug treated subjects are healthier than they had only one-year treatment, but their final scores are again better. To avoid any age bias, according to Cocchi, 1998, in the next Tables I checked the results in children with less than 1 0 at one-year or two-year therapy scoring. Table 12: epidemiological and clinical data of the samples of children aged up to 9 or 8 at 1st consultation, related to the one-year or two-years survey (155 or 116 Ss) Up to 9 yrs Ss % Up to 8 yrs Ss No. of Ss 155 100.00 116 100.00 M 84 53.19 60 51.73 F 71 45.81 56 48.27 M/F 118.39 107.14 Chromosomal diagnosis Standard Trisomy 21 143 92.26 106 91.38 Mosaicisms 4 2.58 4 3.45 translocations 8 5.16 6 5.17 Age at 1st consult, range 4-108 months 4-96 months Average ± SD 39.46 ± 27.91 35.10 ± 23.10 While the distribution of the chromosomal diagnoses falls within the normal range, the M/F ratio does not do it because of increasing cut down of the male prevalence. Tab. 13: Comparison after 1 -year in the children up to 9 at 1st consultation (155 Ss) URTI easiness' graduation Initial score After 1-year therapy No. of Ss % No. of Ss % Not present (O) 0 0.00 32 20.65 Present, mild (1) 27 17.42 27 17.42 Moderate (2) 28 18.06 45 29.03 Severe (3) 67 43.23 40 25.80 Profound (4) 33 21.29 11 7.10 Totals 145 100.00 145 100.00 Average severity ± SD 2.69 ± 0.99 1.82 ± 1.29 Wilcoxon's Signed Ranks Test: z = 8.346 and p < .0009 After one-year drug therapy the positive results on URTI easiness are highly significant and they cannot be due to the favoring effect of age. Tab. 14: Comparison after 2-years in the children up to 8 at 1st consultation (116 Ss) URTI easiness' graduation After 1-year therapy After 2-years therapy No. of Ss % No. of Ss % Not present (O) 0 18.62 48 41.38 Present, mild (1) 19 13.79 32 29.65 Moderate (2) 19 29.66 20 18.86 Severe (3) 51 28.97 11 9.65 Profound (4) 27 8.96 5 3.45 Totals 116 100.00 116 100.00 Average severity ± SD 2.74 ± 0.99 1.07 ± 1.16 Wilcoxon's Signed Ranks Test: z = 8.312 and p < .0009 In children treated by two-year drug therapy before they were more than 10 years old the positive results are highly significant and in this survey too we can refuse the favoring effect of age growing. Tab 15: arisen of 'scores after one-year and two-year therapy between first two samples and age growing effect reduced samples. URTI easiness' graduation After 1-year therapy After 2-years therapy Sample 1 Sample 3 Sample 2 Sample 4 Not present (O) 38 32 60 48 Present, mild (1) 35 27 43 32 Moderate (2) 51 45 23 20 Severe (3) 47 40 14 11 Profound (4) 14 11 5 5 Totals 185 155 145 116 Chi Square after one-year therapy: 0.199 with 4 df and p = .995 Chi Square after two-years therapy: 0.297 with 4 df and p = .990 As we can see there is 1% or less of the probability that both pairs of samples own a significantly different member of the couple. This Jet us to esteem the growing age favorable effect as negligible. Graphic 5-6

Discussion
This second research on drug therapies for URTI easiness in Downs enlightens more information on the time course of the results as a function of the treatment's length. The graduation of the scale used for scoring URTI easiness is the same I used in previous research (Cocchi, 1987, Cocchi and Bonaduce, 1988; Cocchi, 1990, Cocchi, 1997; Cocchi 1998).
The examined samples could represent at least the Italian population of 21 trisomics, but the M/F ratio is debatable. It does not fully overlap what already found in live births of Italian Downs (Camera and Mastroiacovo, 1984). The distribution of chromosomal diagnoses too, is what usually found either in laity and foreign countries (Camera and Mastroiacovo, 1984, Hook, 1981).
The drugs prescribed at first consultation, as reported in Tab. 3, are all GABAergic drugs, folates and pemoline excluded. Since the pioneering clinical study in depressed children (1981) normal and Down children, with easiness to upper respiratory tract infections, were successfully treated by GABAergic drugs (1998).
Research showed that even psychological stress undermines host resistance to infections through neuro-endocrine mediated changes in immune competence (Boyce et al., 1995). It is the same for every kind of stress of external or internal origin or both. The adrenergic blockade improves cellular immune responses in humans, otherwise depressed by the so called mental stress as one type of internal stresses (Bachen et al., 1995).
Because the immune-suppressive action of stress via the GABA impairment (Horger and Roth, 1995) and subsequent cortisol hyper-incretion or hyper-activity (Dhabhar et al., 1996; Haessig et al., 1996; Dantzer, 1997; Friedman and Irwin, 1997), the rationale to counteract this easiness by drugs can get its explanation as it follows.
This treatment uses GABAergic drugs like l-glutamine as the precursor of GABA via l-glutamic acid (Laake et al., 1995; Shupliakov et al., 1997); pyridoxine as the cofactor of all decarboxyiases, GAD inclusive(Baxter,1976); a benzodiazepine as the sensitizer of type A GABAergic receptors (Bruni et al., 1980; Viukari, 1983; Schoch et al., 1985).
This 3-drugs prescription works in a synergistic way and can restore the glutamic-GABA pathways impaired by the stress itself. The use of a benzodiazepine aims to resensitize type A GABAergic receptors, the first metabolic point where stress applies itself.
Without doing it we can induce only the increasing of glutamate the cytotoxic effects of which are now well known. This evening use of a benzodiazepine is the best way to restore sleep (Viukari, 1983) often impaired by excess adrenergic stimulation. But it works also by avoiding side effects like daily drowsiness and muscle relaxation.
On the other hand l-glutamine is directly involved in the nucleogenesis of rapid proliferating cells (Gismondo et al., 1998). It is the donor of the N atom 3 and the N atom 9 of the purinic ring, the first step in the synthesis of nucleic acids (Stryer, 1988). And by this way it contributes to a better production of leukocytes (Heberer et al., 1996; Newsholm & Calder 1997; Yoo, et al., 1997). These cells are the basis of non-specific immunity. I always need to remind that this result, again found in Downs, is not peculiar of them. My first clinical] research on this topic dealt with 61 depressed children among which I treated my first patient with Down's syndrome (Cocchi 1981).
Now we can sum up the reasoning that prompted me to assume that Down children are in a permanent stress condition (Cocchi, 1993). If there is a frequent URTI easiness that can have relief by artistry drugs, and this easiness can refer to a stress effect, then there is a stress condition. Which kind of stress? I am maintaining that they deal with a permanent metabolic stress due to the 150% overworking of all the metabolisms the genes of which are in the chromosome 21, because of a third chromosome 21
In this investigation too the age favoring effect, which seems starting to works in many children only when they are 10-12 (Cocchi 1998), was found of poor influence. In that previous survey we found a surely "per se" positive effect of long lasting drug therapies till 10 years of age. This was confirmed by the early disappearance of more severe forms since 8-10 years, a fact noted only since 16 years in non-treated Downs (Cocchi, 1997).

Conclusions
This second retrospective study on narrowing down of URTI easiness in drugs treated Downs bears out the previous one (Cocchi, 1987). The positive results after one-year and two-years of treatment cannot depend on the favoring variable of age growing and are highly significant. When compared with last checkups of the same subjects, these results have a lesser favorable extent.
This was exactly the purpose and the point where I started the use of drug therapies in Down children. Nevertheless many other positive outcomes went out, as reported elsewhere Cocchi, 1990; Cocchi, 1991; Cocchi, 1992; Cocchi and Favuto, 1993)

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