CAPITULO II Caracterización del Territorio
2. El origen de las formas en México
C om p arison s w e e k s 0-12: s e e text
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K w a Z u lu 1 9 9 8 6 H R Z E 60 O F S 1 9 8 0 S H T E / S H R P E .A f r ic a 1 9 7 5 6 S H R 40 E A fr ic a 1 9 7 5 2 S H T / 1 6 H T S .I n d ia 1 9 7 0 1 2 S H WeekThe differences between locations are in part due to varying chemotherapy regimes but considering the data from other M vaccae studies it seems that sub-Saharan African tuberculosis behaves differently to South India, and that KwaZulu TB may operate distinctly from elsewhere in sub-Saharan and South Africa. It is possible that faster sputum culture conversion is found in studies with high proportions of milder cases of disease. It may be
that the quality of laboratory facilities vary, in South Africa’s favour.
Weight gain
Using the data available the analysis in chapter 7 demonstrated the patterns of weight gain analysed from start to end of treatment, during the first two months and from two months to the end of chemotherapy. Statistically significant gain was identified in M. vaccae patients; that this was due to the weight changes of the first eight weeks. The centres have been compared showing Mseleni had a larger difference between active and placebo cases, whilst Manguzi patients gained more weight in both treatment arms. These patterns were enhanced amongst positive weight gainers. The influence of M vaccae is confirmed when chemotherapy-immunotherapy interval is checked for weight gain; intervals o f 0-7 days, 8-14 days, 15-21 days, 22-28 days match the weekly weight gains described. Differences in weight change have also been shown amongst cures, relapses and lost cases above.
Other studies report weight differences between the start and end o f treatment but do not take into account the time difference of the measurements. The effect o f weight change between gender and various body builds is complex to analyse. In general men are heavier than women and the expected weight gain of two people starting at 40 kg and 70 kg will very different. A 30% gain in the former may a comparable improvement in health to 10% in the latter. This criterion of weight change according to body size merits further study. Starting weights are given in chapter 7 showing that both treatment arms started with similar mean weights. One way o f estimating weight change across a spectrum of disease is to analyse different stages o f disease at the start. This analysis is shown in Table 8.4 indicating a particular advantage for overall weight gain o fM vaccae in more severe cases.
Table 8.4: Study B - Weight gain (kg/week) by stage of disease and treatment group
Treatment n mean S.D. t df P mean diff. 95% conf. interval lower upper Mild A P 16 0.825 0.794 1.250 29 0.221 0.340 -0.216 0.894 15 0.485 0.711 Moderate A P 33 0.562 0.940 0.023 62 0.982 0.004 -0.375 0.384 31 0.558 0.496 Severe A P 19 1.194 1.418 1.710 38 0.095 0.568 -0.105 1.242 21 0.625 0.535
The set o f patients with positive weight change warrant further analysis to search for characteristics that may shed additional light on their success. In terms of outcome there are proportionately fewer deaths as 4.9% died from TB compared with the overall results, whilst 2.4% died from other causes compared with 4.3% overall. In addition there are increased radiology cures (39.8% versus 33.5%) and increased clinical assessment cures (48.8% versus 42.1%). More had converted sputum cultures at week 8 (40.7% versus 34.1% overall). These are all trends without statistical significance and there is no noticeable change in the active/placebo ratios. Thus as a group these patients tended to become healthier by various parameters but no further M vaccae influence is clear. Looking at baseline parameters finds a slight change in trend stage of disease only: Table 7.25 shows almost equal proportions of disease stage for active and placebo patients. In positive weight changers there are 1.6% fewer severe cases in the active group and 0.8% more mild and moderate cases in the placebo group; thus there is a slender deviation towards a healthier set o f patients in the active group. Anova regression analysis again shows the BCG effect. No noticeable difference is seen in age, chemotherapy/injection intervals or erythema induration at 48 hours.
Analysis of the 21 negative or unchanged weight gain cases does not reveal any predicting effect from baseline features, except for more severe TB stages in the M vaccae group (1/6 active and 5/6 placebos mild; 6/7 active and 1/7 placebos moderate; 4/5 active and 1/5 placebos severe; p=0.019). There is no noteable deviation in chemotherapy/injection interval or erythema at 48 hours from overall results or positive weight gainers. Three of the seven overall HIV-positive cases are in this subgroup. Outcome measures show that at post treatment analysis there is a trend fo rM vaccae patients to be faring worse than placebo (4/5 active and 1/5 placebos relapse; 1/5 active and 4/5 placebos well; 6/8 active and 2/8 placebos lost; 1 placebo death from TB; p=0.062). These results reflect the outcome o f the pattern of TB stage at onset above. At three to four year follow-up there is no difference between treatment arms (1/2 active and 1/2 placebos relapse; 3/6 active and 3/6 placebos well; 5/7 active and 2/7 placebos lost; 0/2 active and 2/2 placebo TB deaths; 2/3 active and
1/3 placebo other deaths).
The KwaZulu relapses have missed the M. vaccae increased weight gain effect; as in other studies not all cases improve with immunotherapy. Unless a chance effect it is likely there is another key step in the understanding of immunopathology beyond the TH2-TH1 switch.
BCG
In this KwaZulu data BCG status was a confounder for the greater weight gain seen in active cases. Corrah's Gambia (1994) data provides BCG status and found no deaths for BCG+ve cases in either active or placebo groups and a reduction in deaths for the immunotherapy group for those BCG-ve 167/204 (81.8%) of patients had scar status identified; of these 91/167 (54.5%) were BCG+ve and 75/167 (44.9%) were BCG-ve, with 1/167 equivocal. These compare with 47.7% BCG+ve and 52.3% BCG-ve cases in 669 students at Mseleni school (unpublished data, 1983); an age effect was seen where BCG+ve cases were 53.2% in children up to 11 years and 44.4% in those over 11 years of age.
The BCG+ve percentage has increased fi'om the 1974 KwaZulu tuberculosis survey, as expected with increasing vaccine uptake (Arabin, Gartig et al. 1979). The Gambia data includes 5615 children studied with an overall 35% BCG+ve rate and showed increasing scar status with age. Longitudinal studies are required to fiirther investigate the effect of scar loss seen with ageing in Malawi children (Fine, Ponnighaus et al. 1989) as well as BCG efficacy in general.
Some benefit is suggested by its contribution to weight gain in the Study B M vaccae group. Searching further analysis in Studies A and B data reveals trends in favour of having BCG in that more BCG+ve cases were new PTB patients - 59/154 (38.8%) compared with 46/154 (30.0%) BCG-ve cases, more had mild or moderate disease, more had chest X-rays with mild pathology, and fewer died from TB at three to four year follow-up (7/91 or 7.7% BCG+ve TB deaths versus 9/75 or 12.0% BCG-ve TB deaths). No statistical significant results exist for baseline criteria, measures or outcomes for BCG status.
Baseline criteria
Regarding gender, previous disease within two years occurred more often in males (18/23), moderate and severe disease occurred more in males (75/116, p = 0.083), males tended to have more severe initial chest X-rays and males had proportionately more malnutrition and alcoholism. Men presented with an average age o f four years older than women. Possible explanations for males having more severe later presentations include cultural factors and over-crowding in hostels causing increased exposure to M tuberculosis, or greater susceptibility for some reason (Sutherland 1976).
In common with studies in other developing countries who experience a high annual risk of infection the average age in this study is well below 50 years.
Other studies have not classified initial severity o f disease except the Nigerian paper which reported all patients as having severe TB The Gambian study found some patients were clinically wasted (35% active, 45% placebo) and had very bad chest X-ray on first examination (27% active, 39% placebo). These percentages would compare with moderate and severe cases in this study.
Differences between centres
Baseline features from the tables in chapter 7 show Mseleni had fewer new cases of TB (69.1% compared with 86.9% at Manguzi) with a corresponding higher chronic relapse group. The 17/55 cases concerned had a lower rate of sputum culture conversion at week
8 of 6/17 (35.3%); 4/6 were active cases with 2/6 placebo cases. The 13/99 Manguzi relapses converted 6/13 (46.2%) by week 8, 3/6 in each treatment arm. 49.1% o f Mseleni cases had BCG scars compared with 57.6% of Manguzi cases. Mseleni had a fewer proportion of severe stages of disease (16.7%) contrasted with Manguzi (38.6%). Mseleni cases included five non-PTB patients (Manguzi 100% PTB). Manguzi had twice the proportion of malnutrition as coexisting disease. The chemotherapy drugs were the same at both hospitals, but the doses and schedules differed. The chemotherapy/immunotherapy interval was on average 4 days earlier at Mseleni than at Manguzi.
The bacteriology data show that Manguzi achieved higher percentages of possible samples most weeks compared with Mseleni. The results reveal similar sputum culture conversion rates at week 8 between centres, but there was a trend for more M. vaccae cases to have converted at this stage at Manguzi (46.8% active, 38.0% placebo) contrasted with Mseleni (40.0% active, 41.2% placebo). The weight gain analyses have shown that Mseleni active cases gained more weekly weight over placebo cases than Manguzi during the first two months, but Manguzi patients in both treatment arms gained double the weight o f Mseleni cases by week 8. 80.0% of Manguzi follow-up chest X-rays were judged cured compared with 63.9% of Mseleni cases; clinical cures were 88.9% and 72.5% respectively. The high mortality at six months and particularly at three to four years follow-up occurred at both centres, most marked at Mseleni. Combining the Mseleni data o f Studies A and B show
55/78 (70.5%) cures, 13/78 (16.7) relapses and 9/78 (11.5%) TB deaths compared against the corresponding 51/62 (82.3%), 9/62 (14.5%) and 1/62 (1.7%) in the Manguzi data of Table 7.49c. At 3-4 years the same Mseleni rates are 56/80 (70.0%), 3/80 (3.8%) and 14/80 (17.5%) contrasted with the Manguzi rates o f 34/44 (77.3%), 2/44 (4.5%) and 5/44 (11.4%) from Table 7.50c. Fewer follow-up chest X-rays were cured at Mseleni - 39/56 (69.9%) compared to 32/40 (80.0%) in the Manguzi data of Table 7.44c. Such differences may be due to differing chemotherapy regimen efScacy or disparate immune sensitisation from environmental mycobacteria. Socio-economic status and parasite prevalence would be similar in both health wards.
HIV data
In the face o f missing data it can still be estimated that 5-10% of the study patients were HIV-positive based on the 49/58 (84.5%) of results known on the Mseleni cases of Table 7.27; 6.1% o f these cases were HIV-positive. Additional data from TB patients and the general population of the study area have been given in the text of chpater 7. The Durban GCP M. vaccae study found no difference in outcome for HIV status (personal communication). It is unlikely therefore that HIV had a major influence on the outcome of the study, but it can be speculated that this factor had an influence on the longer term mortality.
End-point criteria
Death is a definitive criterion and the challenge for trials is to discover each one, time mortality from start of treatment and aim for as long a follow-up period as possible. In this study some deaths may not be known amongst the “lost” group. Whilst it is worthwhile ascertaining cause of death, in particular from TB, this can be subjective. The 3-4 year follow-up work in this trial had to rely on community information regarding cause of death.
Cure may be judged clinically or bacteriologically; ideally with both. As outlined patients in KwaZulu were rarely able to produce sputum after two months resulting in reliance upon clinical assessments. Where possible sputum negativity should be sought as a definitive end point. It was necessary to include all medical officers in clinical examinations; though blinded to treatment arms some inter-observer bias was inevitably introduced; ideally one observer would assess all cases although intra-observer bias may remain.
Chest radiography is as subjective as clinical examination and again inter-observer bias is prevented if one reader examines films, preferably by a specialist radiologist. It was intended to follow such a course in this study but the prohibitive filing system prevented this happening.
The ESR effect is known to be variable in its reflection of disease activity and is not descriminatory as an end-point in TB studies.
Weight gain is an expected consequence of effective treatment in a wasting disease such as TB; as said earlier the difficulty is in how weight change may be represented to provide meaningful comparison between studies of differing population groups, stages of disease severity and gender differences. Using one set of scales per patient and having one assessor are essential to reduce errors. Calculating weight gain per week is more useful than crude weight gain without a recorded time interval between measurements. The pattern o f weight increase is likely to follow an exponential curve such that weekly measurements during the first two months are usefiil for inter-study comparison; this requires sufficient manpower and organisational resources.
Immunological markers provide very worthwhile information if they are available, allowing inter-study comparison.
Chemotherapy resistance
No case of rifampicin or MDR-TB was identified. Isoniazid resistance occurred in 5/122 (4.1%) of cases; 4/124 (3.2%) were in new cases with 1/30 (3.3%) in relapsed cases. These figures are much lower than the South African data cited by Kleeberg on page 61. Drug resistance cannot be shown to have influenced the outcomes o f this study.
Immunology
If the serum fi’ozen on each case had been retained, likely contenders for measurement would have been IL-10, TNFa, agalactosyl IgG and heat shock proteins.
Chemotherapy/immunotherapy interval
Data is available for 21 cases injected between 0 -7 days, 50 cases 8-14 days, 48 cases 15-21 days and 15 cases 22-28 days. No statistical advantage was identified for sputum conversion or other outcome; administration is easiest if given at the start of treatment.
M vaccae immunotherapy in KwaZulu
It can be argued that M vaccae immunotherapy faces strong competition for successful therapy in tuberculosis with established modem chemotherapy regimens. The relative failure of chemotherapy to achieve expected sputum culture conversion and better clinical outcomes in this study is discussed below. Yet M vaccae had the potential to exert benefit against the unexpected poor achievement o f drug therapy that was not realised. The influence on weight gain gives some evidence thatM vaccae applies clinical benefit beyond chemotherapy alone, as has been found in other studies. This weight gain has been linked to improved well-being anecdotally, but this was not allowed for in the data code. However an explanation needs to be found as to why both treatment arms suffered low culture conversion rates at week eight and high mortality after treatment and on three to four year follow-up. Possible reasons for the lack of M. vaccae potential in this study are:
1) Administrative failure such as poor quality immunotherapy provision (manufacture, carriage, storage, incorrect intra-dermal technique) is possible but there is no evidence to support this and appropriate checks of injection proficiency were undertaken. In addition data is derived from two centres.
2) It is possible that there is a geographical variability of M vaccae efficacy. Such international diversity was also seen with Koch’s tuberculins o f the late 19th century (chapter 3), and Antigen Marianum immunotherapy for leprosy being successful in Cameroon (Blanc and Frost 1955) but not in Fiji (Beckett 1958). Stanford and Rook’s work has researched this phenomenon with a number of small studies as described. They maintain that environmental immune sensitisation has an important role in determining the host response to M. tuberculosis and BCG efficacy. In addition slow growing mycobacteria tend to favour the tissue damaging TH-2 cytokine response whilst fast growers support a host-protective TH-1 cytokine pattern. Unpublished data from 669 Mseleni school children who were skin- tested for 19 new tuberculins (prepared by Stanford) are tabulated in Appendix VIII.
Figure 8.2 - Skin test data 1983 New tuberculins; Source Appendix VIII
< 3 —
S lo w g lo w e rs
M AA AB AC
F ast g ro w ers
Du R 1387 F N e Rh R 1388 V No Dh
Mycobacterial new tuberculins
The percentages o f reactors are presented in Figure 8 .2. It can be seen that responses to slow growers were considerably more common than to fast growers. The predominance o f slow gro w er reactors lends support to the hypothesis that in KwaZulu environmental mycobacterial sensitisation plays an important role in determining reduced M vaccae
efficacy with adverse disease outcom e from M. tuberculosis.
3) Information from other M vaccae immunotherapy studies point to the fact that there is not a universal favourable response that can be detected, such as weight gain. This infers th a tM vaccae is effective in certain individuals but fails in providing uniform benefit. This effect has been seen in small pilot studies o f different designs and different end-points, if a selective effect is present the challenge is in finding why, if at least to identify prospective candidates.
4) Poor socio-economic status may have been a factor. The people in the study area are impoverished by any standards, as outlined in chapter 5, however other M vaccae studies have been carried out in similar or worse conditions, and have been able to show clinical advantage in those receiving M. vaccae.