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071201 prophylaxis with single-dose doxycycline for the prevention
C o p y r ig ht 2 0 0 1 by t he Ma s s ac h u s e t t s Me d ic a l S o c ie t y
V O L U M E 3 4 5 PROPHYLAXIS WITH SINGLE-DOSE DOXYCYCLINE FOR THE PREVENTION OF LYME DISEASE AFTER AN IXODES SCAPULARIS TICK BITE
ROBERT B. NADELMAN, M.D., JOHN NOWAKOWSKI, M.D., DURLAND FISH, PH.D., RICHARD C. FALCO, PH.D.,
KATHERINE FREEMAN, DR.P.H., DONNA MCKENNA, R.N., PETER WELCH, M.D., ROBERT MARCUS, M.D.,
MARIA E. AGÜERO-ROSENFELD, M.D., DAVID T. DENNIS, M.D., AND GARY P. WORMSER, M.D.,
ABSTRACT
YME disease is transmitted by the bite of an
Background Ixodes scapularis tick and is the most com-
treatment after an Ixodes scapularis tick bite will pre-
States.1 This infection may be prevented by
Methods
vaccination.2,3 However, the vaccine’s general accept-
ease is hyperendemic, we conducted a randomized,
ance is likely to be limited by its cost (a cost to the
double-blind, placebo-controlled trial of treatment
pharmacist of $61.25 per dose) and the need for
with a single 200-mg dose of doxycycline in 482 sub-
multiple doses to achieve and maintain protection.2,3
jects who had removed attached I. scapularis ticks
In addition, the vaccine is less than 100 percent ef-
from their bodies within the previous 72 hours. At base
fective and is currently approved only for persons 15
line, three weeks, and six weeks, subjects were inter-
viewed and examined, and serum antibody tests were
Antimicrobial prophylaxis for persons with I. scap-
performed, along with blood cultures for Borreliaburgdorferi.ularis tick bites may be a way to prevent Lyme dis-
Results
ease. However, it is not known whether antimicrobial
of the tick bite in a significantly smaller proportion of
agents can effectively cure incubating Borrelia burg-
the subjects in the doxycycline group than of those
dorferi infection. In an animal model of another tick-
in the placebo group (1 of 235 subjects [0.4 percent]
borne disease, Rocky Mountain spotted fever, anti-
vs. 8 of 247 subjects [3.2 percent], P<0.04). The effi-
biotic prophylaxis appeared to delay but not prevent
cacy of treatment was 87 percent (95 percent confi-
infection.4 Antimicrobial therapy for the prevention
dence interval, 25 to 98 percent). Objective extracuta-
of Lyme disease after I. scapularis tick bites has not
neous signs of Lyme disease did not develop in any
been shown to be effective in controlled treatment
subject, and there were no asymptomatic serocon-
trials.5-9 In these studies, as well as in a model of cost
versions. Treatment with doxycycline was associated
effectiveness,10 the drug regimens consisted of cours-
with more frequent adverse effects (in 30.1 percentof subjects, as compared with 11.1 percent of those
es of antibiotics lasting 10 to 14 days, similar to those
assigned to placebo; P<0.001), primarily nausea (15.4
typically recommended for the treatment of clinical-
percent vs. 2.6 percent) and vomiting (5.8 percent vs. 1.3 percent). Erythema migrans developed more fre-
From the Department of Medicine, Division of Infectious Diseases
quently after untreated bites from nymphal ticks than
(R.B.N., J.N., R.C.F., D.M., G.P.W.), and the Department of Pathology
after bites from adult female ticks (8 of 142 bites [5.6
(M.E.A.-R.), New York Medical College; and the Lyme Disease DiagnosticCenter, Westchester Medical Center (R.B.N., J.N., D.M., G.P.W.) — both in
percent] vs. 0 of 97 bites [0 percent], P=0.02).
Valhalla, N.Y.; the Department of Epidemiology and Public Health, Yale
Conclusions
University School of Medicine, New Haven, Conn. (D.F.); the Vector Ecol-
given within 72 hours after an I. scapularis tick bite
ogy Laboratory, Louis Calder Center, Fordham University, Armonk, N.Y.
can prevent the development of Lyme disease. (N Engl
(R.C.F.); the Department of Epidemiology and Social Medicine, Albert Ein-stein College of Medicine, Bronx, N.Y. (K.F.); Northern Westchester Hospi-
tal Center, Mt. Kisco, N.Y. (P.W., R.M.); and the Division of Vector-Borne
Copyright 2001 Massachusetts Medical Society.
Infectious Diseases, National Center for Infectious Diseases, Centers for Dis-ease Control and Prevention, Fort Collins, Colo. (D.T.D.). Address reprintrequests to Dr. Nadelman at the Division of Infectious Diseases, WestchesterMedical Center, Macy Pavilion 209 Southeast, Valhalla, NY 10595.
*Other investigators in the Tick Bite Study Group are listed in the Ap-
Because of its potential importance in the treatment of Lyme disease,
this article was published at www.nejm.org on June 12, 2001.
N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · 79
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Copyright 2001 Massachusetts Medical Society. All rights reserved.
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
ly evident early Lyme disease. On the basis of the ex-
(FIAX, Whittaker Bioproducts, Walkersville, Md.) from 1987
perience with syphilis11 and leptospirosis,12 it might be
through 1990, and by polyvalent enzyme-linked immunosorbent
anticipated, however, that a much shorter course of
assay (ELISA) (WhittakerStat, Whittaker Bioproducts) after 1990. Specimens with equivocal or positive assay results were retested by
antimicrobial therapy would be effective in treating
separate immunoblot assays for IgM and IgG antibodies to B. burg-
an incubating (but inapparent) spirochetal infection. dorferi (MarDx Diagnostics, Carlsbad, Calif.). All tests were per-
We studied the efficacy and safety of a single 200-mg
formed and interpreted according to the manufacturers’ instruc-
dose of doxycycline in preventing Lyme disease after
tions. Assays on specimens from the same patient were run inparallel. Heparinized whole blood (0.3 ml) or, in some cases, serum
(0.3 ml) was cultured for B. burgdorferi in modified Barbour–Stoenner–Kelly medium by means of previously described tech-
Subjects Primary End Point
Between May 1987 and December 1996, we recruited subjects
The primary end point was the development of erythema mi-
who had removed an attached I. scapularis tick from their bodies
grans at the site of the tick bite. Erythema migrans occurring at
within the preceding 72 hours and had been bitten in Westches-
a different site from that of the identified tick bite and laboratory
ter County, New York, where Lyme disease is hyperendemic.13 El-
evidence of B. burgdorferi infection in the absence of erythema
igible subjects 12 years old or older were enrolled after they had
migrans were analyzed as secondary end points. Seroconversion was
given written informed consent. Parental consent was obtained for
defined as a change from a negative result on ELISA to an equiv-
those who were younger than 18 years old. Subjects were excluded
ocal or positive result in association with the presence of IgM bands
if they had clinical signs of Lyme disease (e.g., erythema migrans)
on immunoblotting that met the recommended criteria for sero-
at the time of enrollment, were taking or had just completed a
course of antibiotics effective against B. burgdorferi, were pregnantor lactating, had been vaccinated against Lyme disease, or did not
Sample Size
submit to study personnel the tick that bit them. Enrolled subjectswhose ticks were later identified as something other than I. scap-
The frequency of Lyme disease (characterized by erythema mi-
ularis were included only in the analysis of safety. Subjects were
grans) among untreated subjects who had been bitten by an I. scap-
evaluated at Westchester Medical Center, a university medical cen-
ularis tick in Westchester County was initially estimated to be ap-
ter (461 of the 506 subjects [91.1 percent]), or at a nearby com-
proximately 5 percent. The smallest clinically important reduction in
munity hospital (45 subjects [8.9 percent]).
this rate was considered to be a reduction from 5 percent to 1 per-cent. Since it was expected that doxycycline would be at least as
effective as placebo in preventing the occurrence of disease, the hy-pothesis was considered one-tailed. Because the frequency (inci-
The species, sex, and stage of the ticks were determined by a
dence) in each group was expected to be quite small, an arc-sine
medical entomologist. Ticks were initially classified as unfed (flat)
transformation was performed in conjunction with the binomial
or partly fed (partially engorged) on the basis of a visual inspection.
test for two independent samples to derive the required sample siz-
When possible, the duration of the tick’s attachment to the sub-
es. On the basis of an alpha level of 0.05 and a power of 80 per-
ject was estimated on the basis of a measurement of the tick scutal
cent, the planned sample size was 129 subjects in each treatment
index. This determination (the ratio of tick body length to scutal
group. At the time the projected number of subjects had been en-
width) was calculated as reported previously.14
rolled, it appeared that the risk of erythema migrans was limited
Clinical Evaluation
to subjects who had been bitten by nymphal I. scapularis ticks. Thus, it became important to continue to enroll subjects until suf-
At enrollment, at three weeks, and at six weeks, participants
ficient statistical power could be achieved in the subgroup of sub-
were examined and interviewed with the use of a written question-
naire. During the course of the study, specific questions regardingadverse effects of the study medication were added to the ques-
Statistical Analysis
tionnaire. The analysis of adverse events was therefore restricted tothe 309 subjects for whom this information was available. Subjects
Categorical variables were compared by means of the two-tailed
were encouraged to contact study personnel if clinical symptoms
Fisher’s exact test or the two-tailed chi-square test. The final analy-
occurred between the scheduled visits or in the period immediately
sis for the primary end point was also two-tailed, in order to be
after the final visit. They were also counseled on ways to prevent
more conservative. Student’s t-test was used for continuous vari-
tick bites. Blood was collected at each visit for antibody testing and
ables. Statistical analyses were performed with the use of SAS soft-
ware (version 6.12, SAS Institute, Cary, N.C.). Because an interimanalysis was performed in September 1992, the determination of the
Study Medication
alpha level was based on the O’Brien–Fleming criteria.17 A P valueof 0.0475 or lower was considered to indicate statistical signifi-
After clinical evaluation and phlebotomy, subjects were given
cance in the final analysis. The efficacy of prophylaxis was calcu-
two pills from a vial that contained either two 100-mg capsules of
lated as follows: (1¡[the risk of infection among the doxycycline-
doxycycline or two identical-appearing placebo pills containing
treated subjects÷the risk among subjects receiving placebo])¬100
lactose. Capsules were prepared by the hospital pharmacy and dis-
percent.8 A 95 percent confidence interval was computed around
tributed according to a randomization list that maintained a 1:1
the efficacy rate with the use of the test-based method.18
ratio between subjects in the doxycycline group and those in the pla-cebo group. Both subjects and study personnel were unaware of
the contents of the vials. Subjects swallowed the pills under directobservation by study personnel.
A total of 506 subjects were randomly assigned to
receive either doxycycline or placebo; this total in-
Laboratory Tests
cluded 6 persons who were enrolled twice in different
Urine pregnancy tests (Clearview HCG II, Wampole Laborato-
years. The primary (intention-to-treat) analysis was
ries, Cranbury, N.J.) were performed at the initial encounter forall women of childbearing potential. Serum antibodies to B. burg-
restricted to the 482 subjects who had removed iden-
dorferi were measured by polyvalent fluorescence immunoassay
tifiable I. scapularis ticks from their bodies (Table 1). 80 · N Engl J Med, Vol. 345, No. 2 · July 12, 2001
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P R O P H Y L A X I S W I T H S I N G L E - D O S E D OX YCYC L I N E F O R P R EV E N T I O N O F LY M E D I S E AS E A F T E R A T I C K B I T E
subgroup of subjects who had removed only nymphal
TABLE 1. CHARACTERISTICS OF 482 SUBJECTS WHO HAD
ticks.) The demographic characteristics of the 235 sub-
REMOVED IXODES SCAPULARIS TICKS FROM THEIR BODIES
jects in the doxycycline group were similar to those
of the 247 subjects in the placebo group (Table 1). A total of 431 subjects (89.4 percent) completed all
DOXYCYCLINE
three visits (enrollment, three weeks, and six weeks). CHARACTERISTIC
Erythema migrans occurred at the site of the tick
bite in 8 of the 247 subjects in the placebo group
Subjects
(3.2 percent), as compared with 1 of the 235 subjects
in the doxycycline group (0.4 percent, P<0.04). Sev-
en of these nine subjects also had laboratory evidence
of Lyme disease, including skin cultures positive for
Multiple tick bites at enrollment — no. (%)
B. burgdorferi in all four subjects who underwent a
skin biopsy. Seroconversion determined by ELISA oc-
curred in seven subjects. An additional subject (in
the doxycycline group) who remained seronegative by
ELISA was positive for IgM antibody on immuno-
blotting. The last of the nine subjects with erythema
migrans had an equivocal result on ELISA and neg-
ative results for IgM and IgG antibodies on immuno-
blotting and did not return for serologic testing dur-
Erythema migrans developed at the site of the tick
bite a median of 12 days (range, 4 to 17) after the re-
moval of nymphal I. scapularis ticks that showed vis-
ual evidence of partial engorgement with blood (Ta-
ble 2). In untreated subjects, bites from nymphal ticks
were significantly more likely than bites from adult
ticks to be associated with erythema migrans (8 of
142 [5.6 percent] vs. 0 of 97 [0 percent], P=0.02).
In the two groups combined, nymphal ticks were
nearly twice as likely as adult ticks to be partially en-
*Data are based on an intention-to-treat analysis. An additional 24 sub-
gorged (159 of 266 ticks [59.8 percent] vs. 64 of 197
jects underwent randomization (12 to each treatment group) but were ex-cluded from this analysis because they had been bitten by ticks other than
ticks [32.5 percent], P<0.001). The estimated median
I. scapularis, including dermacentor species (4 subjects), amblyomma spe-
duration of attachment, based on the tick scutal index
cies (7 subjects), I. cookei (1 subject), and ticks of unknown species or no
for the 115 nymphal ticks that were measured, was 30
identifiable tick (12 subjects). The classification of engorgement status wasbased on the tick’s macroscopic appearance. The estimation of the duration
hours (range, 4 to 125), as compared with 10 hours
of attachment was based on the scutal index obtained for 115 nymphal
(range, 0 to 148) for 76 adult ticks (P<0.001). Un-
ticks (55 from the doxycycline group and 60 from the placebo group) and76 adult ticks (37 from the doxycycline group and 39 from the placebo
treated bites from nymphal ticks that had been at-
tached to subjects for an estimated 72 hours or longer
†It was unknown whether 2 of the 247 subjects in the placebo group
were more likely to result in erythema migrans than
were untreated bites from nymphal ticks that had been
‡Seropositivity was determined by fluorescence immunoassay or enzyme-
feeding for less than 72 hours (3 of 12 bites [25 per-
linked immunosorbent assay. An additional 21 subjects had equivocal titers(10 in the doxycycline group and 11 in the placebo group). Base-line se-
cent; 95 percent confidence interval, 7 to 57 percent]
rologic testing was not performed in three subjects in the doxycycline
group and two subjects in the placebo group.
Objective extracutaneous manifestations of Lyme
§The subgroup with bites from nymphal ticks includes three subjects
disease (e.g., facial-nerve palsy, meningitis, heart block,
who removed both a nymphal and a larval tick and two subjects who re-moved both an adult and a nymphal tick.
and oligoarthritis) were not observed during the studyperiod, nor was asymptomatic seroconversion (thedevelopment of antibody to B. burgdorferi). Howev-er, in addition to the nine subjects in whom erythe-
Of those subjects, 28 had removed multiple ticks at
ma migrans developed at the identified site of the
the time of the bite that led to enrollment, including
tick bite, solitary erythema migrans lesions developed
23 who had removed at least two ticks of the same
in two subjects (one in each group) at other sites. In
stage, 3 who had removed both a nymphal and a lar-
three other subjects (one in the doxycycline group
val I. scapularis tick, and 2 who had removed both
and two in the placebo group), transient viral-like ill-
a nymphal and an adult I. scapularis tick. (For certain
nesses developed, with laboratory evidence of B. burg-
analyses, the latter five subjects were included in the
N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · 81
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
TABLE 2. ERYTHEMA MIGRANS AT THE SITE TABLE 3. OTHER CLINICAL EVENTS AFTER A BITE
OF AN IXODES SCAPULARIS TICK BITE IN 482 SUBJECTS.
FROM AN IXODES SCAPULARIS TICK. DOXYCYCLINE DOXYCYCLINE TICK STAGE AND ENGORGEMENT STATUS
*P values were derived by the two-tailed Fisher’s exact test.
†These subjects also had laboratory evidence of Borrelia burgdorferi in-
*P values were derived by the two-tailed Fisher’s exact test.
‡Seroconversion was documented in this subject by enzyme-linked im-
munosorbent assay (ELISA) but not by IgM blotting.
§One subject had a change from negative to equivocal results on ELISA
and from negative to reactive results on IgM blotting; the other subjecthad a negative serologic test but a positive blood culture for B. burgdorferi.
Nine additional subjects (five in the doxycycline
¶These subjects did not have erythema migrans or laboratory evidence
group and four in the placebo group) reported fe-
ʈInformation was available for 161 subjects in the doxycycline group and
brile episodes after removing I. scapularis ticks dur-
ing the six-week study period but had no laboratoryevidence of B. burgdorferi infection. A total of 59 ofthe 325 subjects questioned (18.2 percent) recognizedadditional tick bites after enrollment but during thesix-week study period. TABLE 4. ADVERSE EVENTS.*
Adverse events (primarily nausea and vomiting)
were more frequent in the doxycycline group than in
DOXYCYCLINE
the placebo group (P<0.001) (Table 4). However,
these events were not serious and were self-limited. No
subject reported photosensitivity or a rash attribut-
DISCUSSION
This randomized, controlled trial shows that anti-
microbial prophylaxis with a single 200-mg dose of
doxycycline, given after a recognized bite from an
I. scapularis tick, is highly effective in preventing the
development of Lyme disease. Prophylaxis with dox-
*Data are from 309 subjects with recorded answers to spe-
ycycline had an efficacy of 87 percent, which compares
cific questions about adverse events; some subjects had more
favorably with the 95 percent efficacy rate of doxy-
cycline given once weekly to prevent leptospirosis.12
†P values were derived by the two-tailed Fisher’s exact test
The efficacy rate found in our study should be inter-
‡Other adverse events included headache (in 2 subjects),
preted cautiously, however, because of the relatively
stiff neck (1), fatigue (1), weakness (1), decreased appetite
small number of subjects in whom Lyme disease de-
(1), feeling “feverish” (1), and having “flushes” (1).
veloped and the resultant wide 95 percent confidenceinterval (25 to 98 percent).
Our results contrast with those of previous stud-
ies,6-8 which showed no clear protection attributable
study demonstrated the efficacy of antimicrobial pro-
to antimicrobial prophylaxis given after a tick bite. We
phylaxis is probably related to its size (482 subjects,
observed a beneficial effect of prophylactic doxycy-
as compared with 56 subjects,6 184 subjects,7 and 387
cline despite a fairly low infection rate in the placebo
subjects8 in the other randomized studies), which
group (3.2 percent) — a rate similar to that in other
provided the study with greater statistical power to
studies (range, 1.1 to 3.4 percent). The fact that our
82 · N Engl J Med, Vol. 345, No. 2 · July 12, 2001
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Copyright 2001 Massachusetts Medical Society. All rights reserved.
P R O P H Y L A X I S W I T H S I N G L E - D O S E D OX YCYC L I N E F O R P R EV E N T I O N O F LY M E D I S E AS E A F T E R A T I C K B I T E
Our use of a restrictive primary end point (erythe-
ticks (which are considerably larger than nymphal
ma migrans at the site of the tick bite) could have
ticks) are detected and removed earlier in the feed-
resulted in underestimation of the actual incidence
ing process than nymphal ticks; in our study, the es-
of B. burgdorferi infection attributable to the bite of
timated median duration of attachment for adult ticks
an identified I. scapularis tick. However, this end point
in both groups (10 hours) was one third as long as
was chosen deliberately. Erythema migrans at the site
of the bite is the most common clinical manifesta-
Although no serious adverse events were noted,
tion associated with B. burgdorferi infection and is the
30.1 percent of those who received doxycycline had
only reliable marker of infection caused by that spe-
medication-related problems, as compared with 11.1
cific bite. As shown in our study, subsequent tick bites
percent with placebo. The events reported were pri-
are common (reported by 59 of the 325 subjects we
marily nausea (15.4 percent with doxycycline vs. 2.6
questioned [18.2 percent]), even over a period as short
percent with placebo, P<0.001) and vomiting (5.8
as six weeks. Indeed, solitary erythema migrans de-
percent vs. 1.3 percent, P=0.06). Taking doxycycline
veloped in two of the study subjects at a site other
with food may improve its tolerability, with only a
than that of the initial tick bite, suggesting the oc-
currence of an additional, unrecognized bite. The fol-
The ticks in our study were identified by medical
low-up was limited to six weeks in order to reduce
entomologists. Patients and clinicians may have dif-
confounding associated with illnesses that might re-
ficulty in distinguishing I. scapularis from other ticks
and arthropods, and even from scabs or debris.22 Fur-
A theoretical risk associated with prophylactic an-
thermore, the efficacy of doxycycline in the preven-
timicrobial treatment is that it might alter the dis-
tion of other infections transmitted by I. scapularis
ease presentation so that the characteristic erythema
ticks (e.g., babesiosis and human granulocytic ehrlich-
migrans rash might not be manifested in treated sub-
iosis) is unknown and should not be assumed. Nor can
jects, in whom a more subtle, nonspecific illness might
it be assumed that other antimicrobial agents that
develop or asymptomatic seroconversion might oc-
are effective for the treatment of Lyme disease (e.g.,
cur. In such circumstances, an unrecognized latent
amoxicillin) or even other regimens of doxycycline
infection might eventually result in arthritis or neu-
(e.g., 100 mg twice daily) would have similar efficacy
rologic disease. We believe that this is unlikely for
when used for short-term prophylaxis.
several reasons. First, nonspecific febrile illnesses werenot disproportionately common in the doxycycline
Supported in part by grants from the Tick-Borne Diseases Institute of the
group. Furthermore, there was no asymptomatic sero-
New York State Department of Health (C-003836, C-008372, C-011001,and C-015088) and the Centers for Disease Control and Prevention
conversion (suggesting the occurrence of subclinical
(U50/CCU 210280 and U50/CCU 210286). The contents of this report
infection) in subjects in the doxycycline group (or in
are solely the responsibility of the authors and do not necessarily represent
the placebo group). In addition, there was no de-
the official views of the New York State Department of Health or the Cen-ters for Disease Control and Prevention.
layed onset of erythema migrans at the original site ofthe tick bite in any subject during the six weeks of
We are indebted to Kathleen O’Keefe, R.N., Harold Horowitz,
observation — a period four times the average incu-
M.D., Marisa Montecalvo, M.D., Dominick Corbi, Dionysios Liver-
bation period for this rash.19 Finally, objective extra-
is, Ph.D., Thomas Daniels, Ph.D., Rhonda Corda, Jane Rainaldi,R.N., Richard Ginther, David Labowitz, Carol Carbonaro, Ph.D.,
cutaneous manifestations of Lyme disease did not
Theresa Boccia, Erin McHugh, Paul Visintainer, Ph.D., and Daniel
develop in any of the subjects in our study or in the
Byrne, M.S., for their assistance.
three other prospective trials of antimicrobial prophy-laxis (with follow-up lasting between six months and
APPENDIX
Other investigators in the Tick Bite Study Group are as follows: Susan
Our finding that only ticks that are partially en-
Bittker, Denise Cooper, Diane Holmgren, and Charles Pavia, from the De-partment of Medicine, Division of Infectious Diseases, and Ira Schwartz,
gorged with blood are associated with the develop-
from the Department of Biochemistry and Molecular Biology, New York
ment of erythema migrans at the site of the bite is
consistent with studies in animals, which have dem-
REFERENCES
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Our results also confirm those of Sood et al.,21 who
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PARTICIPANTS OF SACOSAN IV 4-7 APRIL 2011 1. VIPs Invited Minister for Rural Development Panchayati Raj, Ministry of Physical Planning & Work, Nepal Minister of Rural Rehabilitation and Development , Islamic Republic of Afghanistan Minister of Housing and Environment, Republic of Minister of Water Supply and Drainage in Sri Lanka Director General, Center for Science and Environment
“Alles is economie” Relaties tussen ziekten en industriële belangen Genezen medicijnen en chemicaliën of veroorzaken ze ziekten? De chemische landbouw leidt tot verminderde vitaminen en mineralen in landbouwproducten. Minder vitaminen en mineralen, minus 80% in 100 jaar, leiden tot een verzwakt immuunsysteem. Een verzwakt immuunsysteem leidt tot ziekte. Ziekte leidt tot medicati