Drug Therapy of Upper Respiratory Tract Infections Easiness in Downs: A Survey on 328 Persons

Renato Cocchi M.D., Ph.D. (Sociology) Italian Journal of Intellective Impairment 11 (1): 9-17 (1998 Jun)

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

Key words: Down's syndrome; Upper Respiratory Tract Infections; Easiness; Drug therapy.

In my previous research (Cocchi, 1997) I investigated the time-course of easiness to Upper Respiratory Tract Infections (URTI) in 510 non drug treated Downs, as reported at first consultation. Part of them followed drug therapies for different time length, so I can evaluate global therapy results on URTI easiness. The time-course of that easiness will have the comparison with non treated subjects.

Materials and methods
This second survey deals with the clinical records related to all subjects who took the prescribed drug therapy and had at least one checkup after the first visit. This makes a casual consecutive series of Downs that has its selection criterion on the fact that those Downs came back for checkups. 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. This easiness was appraised with reference to the past 12 months (or, in children aged less than one year, with reference to past months) by recording according to a severity scale as follows:
(0) = as in a healthy child;
(1) = nasal catarrh usually present;
(2) = 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).
I used the same scoring's way during the first checkup or following checkups. From these checkups I collected the scores recorded during the last ones, but some cases came back only once for checkup.
The records about autistic or PDD DS 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; age at last consultation; length of the drug therapy; scoring of URTI easiness at 1st consultation; the same at last checkup; drugs in use at the last checkup and their daily doses. I processed data by age intervals' statistics and I applied Chi Square Test, when suitable.

Results
Only 328 cards out of 510 fitted the criteria of this survey. They refer to home reared Downs coming from all Italy. Table 1 summarizes epidemiological data of these subjects, table 2 shows drugs in use at last checkups, and tables 3-11 present the URTI easiness scoring according to age intervals.
In graphics 1-5 I showed the time-course of URTI easiness and of each grade of severity, as recorded during the 1st consultation and the last checkup.

Table 1: Epidemiological and clinical data of the sample

No. of Ss	328	100.00%
M	188	57.31%
F	140	42.31%
M/F ratio	134.29
Chromosomal diagnosis
Standard trisomy 21	298	90.85%
Mosaicisms	12	3.66%
Translocations	12	3.66%
Unknown, only clinical diag.	6	1.83%
Age at 1st consult.: range (months)	4-410
Average ± SD	67.70 ±61.64
Age at last checkup: range	7-417
Average ± SD	116.60 ±67.88
Length of drug therapy: range	2-169
Average ± SD	48.04 ±43.58

As we can see in Table 1 the M/F ratio closely overlaps what we know for live born Italian infants. The distribution of the chromosomal diagnoses stays within the variance limits for Italian and International samples. For that we can maintain the sample here surveyed as a representative sample at least of the Italian population of Downs.

Table 2: Drugs in use at the last checkup

Drug in use			mg/die (*)	no. of Ss	%
Pyridoxine			75-150	267	81.40
Diazepam			1-2.5	237	72.26
S-adenosil-l-methionine			100	190	72.26
A polyvitaminc compound (BEROCCA)TM			1 cp x sett	189	57.93
L-glutamine			125-250	187	45.12
Folates			7.5	143	43.60
Pyritinol			50-100	139	42.38
Alpha-tocopherole			50	74	22.56
Vit. B1+B6+B12	125+125+500mcg
Bromazepam			0.5-1.5	59	17.99
Biotin			2.5-5	59	17.99
5-hydroxytriptofan			25-50	43	13.11
Arginine pidolas			250	42	12.80
L-glutamine + pemoline		45+5 - 90+10		41	12.50
Glycine(in BIOTASSINA)™			200	34	10.37
Carnitine			500	34	10.37
Viloxazine			50-100	22	6.71
Delorazepam			0.5	18	5.59
Alpha-ketoglutarato of pyridoxine			300	18	4.00
Deanol			320	10	3.05
Oxazepam			7.5-15	9	2.74
Piracetam			800	7	2.13
Pantotenate			150	7	2.13
Amitriptyline+ perphenazine			10 + 2	6	1.83
Acetyl-carnitine			250	5	1.52
Clobazam			10	5	1.52
Taurine			500	3	0.91
Total				1802

(*) In many cases the drug was prescribed every second day, so the daily dose reports it as it was prescribed every day. The average prescription summed up 5.49 drugs per person. Pyridoxine, alone or in combination with thiamine and cyanocobalamine, and a low dose benzodiazepine were always in it.

Tab. 3: Global comparison between initial and final scores

URTI easiness graduation	initial scores	final scores
	No.of Ss	%	No. of Ss	%
Not present (0)	99	30.19	221	67.37
Present, mild (1)	37	11.28	35	10.67
moderatea (2)	49	14.94	30	9.15
severe (3)	97	29.57	32	9.76
profound (4)	46	14.02	10	3.05
Totals	328	100.00	328	100.00

Chi Square = 107.032 with 4 df and p < .0009. As a global survey, 69% of the sample presented URTI easiness at 1st consultation, with increased severity (grades 3-4) in 40% of them. At final scoring only about 33% of the same sample went along to present URTI easiness, but increased severity went down to less than 13% of them.

Tab. 4: Comparison between initial and final scores of age interval up to 24 months (Average length of therapy: 5.94 months.)

URTI easiness graduation	initial scores	final scores
	No. of Ss	%	No. of Ss	%
Not present (0)	24	24.49	10	58.83
Present, mild (1)	14	14.28	2	11.76
moderate (2)	17	17.35	1	5.88
severe (3)	26	26.53	1	5.88
profound (4)	17	17.35	3	17.65
Totals	98	100.00	17	100.00

Chi Square = 9.690 with 4 df and p < .047 The results on infants up to 24 months with average 6-month therapy, although significant, need caution. Nearly all of them went back to checkups nearly before one-year of therapy.

Tab. 5: Comparison between initial and final scores of age interval from 25 to 48 months (Average length of therapy: 16.70 months.)

URTI easiness graduation	initial scores	final scores
	No.of Ss	%	No.of Ss	%
Not present (0)	9	14.75	18	40.92
Present, mild (1)	5	8.20	6	13.63
moderate (2)	8	13.11	5	11.36
severe(3)	24	39.35	12	27.27
profound (4)	15	24.59	3	6.82
Totals	61	100.00	44	100.00

Chi Square = 13.302 with 4 df and p < .011 In this age interval no URTI easiness turned out from 15% to nearly 41% and increased severity went down from about 64% to a while more than 34%.

Tab. 6: Comparison between initial and final scores of age interval from 49 to 72 months (Average length of therapy: 28.86 months.)

URTI easiness graduation	initial scores	final scores
	No. of Ss	%	No.of Ss	%
Not present (0)	8	16.33	18	48.65
Present, mild (1)	7	14.28	4	10.81
moderate (2)	4	8.16	9	24.32
severe (3)	21	42.86	9	24.32
profound (4)	9	18.37	3	6.11
Totals	49	100.00	37	100.00

Chi Square = 21.838 with 4 df and p < .0009 In this age interval no URTI easiness turned out from about 16% to nearly 49%, while increased severity went down from about 61% to about 14%.

Tab. 7: Comparison between initial and final scores of age interval from 73 to 96 months (Average length of therapy: 35.90 months.)

URTI esasiness graduation	initial scores	final scores
	No. of Ss	%	No. of Ss	%
Not present (0)	10	38.45	30	71.43
Present, mild (1)	4	15.38	7	16.67
moderate (2)	3	11.54	3	7.14
severe (3)	8	30.76	1	2.38
profound (4)	1	3.85	1	2.38
Totals	26	100.00	42	100.00

Chi Square = 13.230 with 4 df and p < .011 In these children no URTI easiness turned out from about 38% to more than 71%, while more severe forms decreased from nearly 35% to less than 5%.

Tab. 8: Comparison between initial and final scores of age interval from 97 to 120 months (Average length of therapy: 47.69 months.)

URTI easiness graduation	initial scores	final scores
	No. of Ss	%	No. of Ss	%
Not present (0)	16	43.25	28	71.80
Present, mild (1)	1	2.70	4	10.25
moderate (2)	8	21.62	4	10.25
severe (3)	9	24.32	3	7.70
profound (4)	2	5.41	0	0.00
Totals	26	100.00	42	100.00

Chi Square = 11.304 with 4 df and p < .024. No URTI easiness got up from 43% to nearly 72%. More severe forms went down from 30% to less than 8%.

Tab. 9: Comparison between initial and final scores of age interval from 121 to 144 months (Average length of therapy: 58.6 months.)

URTI easiness graduation	initial scores	final scores
	No. of Ss	%	No.of Ss	%
Not present (0)	16	55.18	29	72.50
Present, mild (1)	3	10.34	6	15.00
moderate (2)	6	20.69	2	5.00
severe (3)	3	10.34	3	7.50
profound (4)	1	3.45	0	0.00
Totals	29	100.00	40	100.00

Chi Square = 6.158 with 4 ds and p < .189 NS. No URTI easiness increases from about 55% to 72.5%, while its grades 3-4 decrease from 14% to 7.5%. The variable of age starts having its weight so Chi Square does not reach the minimal significant level.

Tab. 10: Comparison between initial and final scores of age interval from 145 to 168 months (Average length of therapy: 76.55 months.)

URTI easiness graduation	initial scores			final scores
		No.of Ss	%		No.of Ss	%
Not present (0)		4	57.16		35	79.55
Present, mild (1)		1	14.28		3	6.82
moderate (2)		1	14.28		1	2.27
severe (3)		0	0.00		5	11.36
profound (4)		1	14.28		0	0.00
Totals		7	100.00		44	100.00

Chi Square = 10.129 with 4 df and p < .039. No URTI easiness goes from about 57% to nearly 80%, while its grades 3-4 go down from about 14% to 11.36%

Tab. 11: Comparison between initial and final scores of age interval from 169 to 192 months (Average length of therapy: 79.81 months.)

URTI easiness graduation	initial scores			final scores
		No.of Ss	%		No.of Ss	%
Not present (0)		6	54.55		21	80.77
Present, mild (1)		1	9.09		2	7.69
moderate (2)		1	9.09		1	3.85
severe (3)		3	27.27		2	7.69
profound (4)		0	0.00		0	0.00
Totals		11	100.00		26	100.00

Chi Square = 3.333 with 3 df and p < .465 NS. No URTI easiness goes from more than 54% to about 81%, while its severe grades go down from 27% to less than 8%.

Tab. 12: Comparison between initial and final scores of age interval from 193 and more months (Average length of therapy: 69.15 months.)

URTI easines graduation	initial scores			final scores
		No.of Ss	%		No.of Ss	%
Not present (0)		6	60.00		32	82.05
Present, mild (1)		1	10.00		1	2.56
moderate (2)		1	10.00		4	10.26
severe (3)		2	20.00		2	5.13
profound (4)		0	0.00		0	0.00
Totals		10	100.00		39	100.00

Chi Square = 3.734 with 3 df and p < .394 NS
Chi Square = 3.734 with 3 df and p < .394 NS

In this age group no URTI easiness turned out from 60% to more than 82%, while more severe forms turned down from 20% to a while more than 5%.

Initial and final data as a function of age have summaries in graphic 1 (time-course of no URTI easiness) and in graphics 2-5 (time-course of each grade of severity).

As you can see, drug treated persons have always a higher rate of no URTI easiness.

The graphic 2 shows that drug treated subjects have low rates of grade 1 URTI easiness since their 12-14 years of age.
As we can see, since 8 years of age drug treated Downs have a lower rate of grade 2 URTI easiness than non treated Downs. The final peak seems only a statistical artifact.

The graphic 4 shows that drug treated Downs had always lesser grade 3 URTI easiness rate than non treated Downs. The null rate in 14 years non treated Downs comes from a statistical artifact.

From the graphic 5 it clearly appears that drug treated Downs do not catch the more severe form of URTI easiness since their 10 years. The same fact happens only since 16 years in non treated Downs.

Discussion
This research is the first one on drug therapies for URTI easiness in Down's syndrome that takes into account the age as a favourable factor. 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). The examined sample represents at least the Italian population of 21 trisomics. This is so for its extent, the coming from all Italy and the M/F ratio overlapping what already found in live births of Italian Downs (Camera and Mastroiacovo, 1984). The distribution of chromosomal diagnoses too, is not far from what usually found either in Italy and foreign countries (Camera and Mastroiacovo, 1984, Hook, 1981). Being present 6 Ss with only a clinical diagnosis, it does not spoil the distribution congruence of sample chromosomal anomalies.
The average drug therapy lasted four years. The drugs in use at last checkups, as reported in Tab. 2, have a basis on a benzodiazepine and pyridoxine as prescribed alone or together with thiamine and cyanocobalamine. I made the choice of drugs according to signs, symptoms and behaviours of each child, considering both age and the length of the therapy up to now. If I collected the therapies prescribed at first consultations, I had a lesser amount of different drugs. So the presence of l-glutamine, alone or in a compound with pemoline, should have been more significant.
The whole sample had double age stratification in two ways, both for URTI easiness at the age of 1st consultation and URTI easiness at the last checkup. Except infants' age up to 24 months, already debatable because the last checkup happened after average 6 months therapy, subjects compared into the same age interval are nearly all different. This double stratification let to cutting off the variable of the age, so pointing out the effects of the therapies.
In this survey we can already note a surely positive effect of drug therapies per se till 10 years of age. This is 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).
How the probands could get out at such a cut off, I send back to my previous papers as for a whole explanation of action mechanisms, with a wide references support (Cocchi, 1981 e 1987). By shortly summarizing, l-glutamine, pyridoxine and the benzodiazepine as antistress drugs reduce the immune suppressive action of the cortisol. On the other hand l-glutamine acts as a sole supplier of a carbon atom for the production of cells' nuclei. This is of value for the leukocytes nuclei that are the basis of the 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 Down patient (Cocchi, 1981)

Conclusions
This new retrospective study on narrowing down of URTI easiness in drug treated Downs bears out the previous one (Cocchi, 1987). The result does not depend on the favouring variable of age and it is significant, at least till 10 years of age. After this time the favouring effect of age overlaps the effect of drugs, thus avoiding a clear distinction. This comes out according the type of detection of this study, where I thought out the scoring of the last checkup. Since this is an early and quite firm effect, I have to plan a future research where scoring it at a fixed distance from first consultation. Although I reached now positive results, I think that fixed times of 1 and 2 years would offer more information.

References
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Cocchi R. Susceptibility to infective respiratory diseases in depressed children. Epidemiological survey of 126 subjects, clinical-therapeutic report of 61 cases. Acta Psychiat. Belg. 1981, 81: 350-365.
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Hook E.B.: Down syndrome: Frequency in human popolation and factors pertinent to variation in rates. In: De la Cruz F.F., Gerald P.S. (eds): Trisomy 21 (Down Syndrome) research perspectives. University Park Press, Baltimore, 1981.