EMAIL TESTIMONY of

EMAIL TESTIMONY of

John David Brown to

THE SUB-COMMITTEE ON NATIONAL SECURITY, EMERGING THREATS, AND INTERNATIONAL RELATIONS chaired by Representative Christopher Shays

COMMITTEE ON GOVERNMENT REFORM

HOUSE OF REPRESENTATIVES OF THE UNITED STATES OF AMERICA

SUBJECT: Examining the Department of Veterans’ Affairs’ implementation of the Persian Gulf War Veterans Act of 1998

VENUE: Room #2154 Rayburn House

DATE: November 15th 2005

_________________________________________________

01. John Brown is a British citizen who contracted onchocerciasis in Saudi Arabia. He has an American friend with similar symptoms but a different diagnosis. The American is diagnosed with Gulf War syndrome (GWS). The sole purpose of his testimony is to alert Congress to a specific shortcoming in the screening of 1991 Gulf War veterans (GWVs) in the hope that government intervention will ensure that Americans with onchocerciasis are screened for onchocerciasis and treated for onchocerciasis and not left to rot. John Brown has no other agenda.

02. Between 1983 and 1986, Brown was employed at Dhahran by the General Directorate of Military Works of the Saudi Ministry of Defence and Aviation. He had previously worked on the construction of the Al-Khobar power and desalination plant a few miles to the east on the Persian Gulf coast.

03. In autumn 1983 he fell acutely ill. The illness was never properly investigated but has been retrospectively diagnosed as probable fascioliasis contracted eating contaminated salad vegetables from the local market (refer section 13). Following concomitant infection with Onchocerca volvulus, he remains ill to this day and has been too sick to work since 1991, the year of Operation Desert Storm.

04. In 1997, and quite by chance, he presented with frank signs of onchocerciasis. On acquiring a rare suntan (he is white) he discovered that his shins were depigmented and his shoulders covered in ‘leopard skin’. Onchocerciasis is the only disease known to localise depigmentation to the shins and this presentation is unique to longstanding chronic disease. His legs looked absurd yet doctors could not diagnose the cause. One specialist could only think it must be sunburn.

05. Depigmentation cannot be seen on white skin, although his shins itched and twitched at night in bed; a condition known as restless legs or Ekbom’s syndrome. His itching and twitching resolved with onchocerciasis treatment.

06. Psychiatrists like to diagnose Ekbom’s as delusional parasitosis. The evidence herein testifies to the fact that the only delusional aspect of delusional parasitosis is that it is delusional. Concomitant with the hypopigmentation and hyperpigmentation, Brown suffered from the full range of multiple symptoms known as GWS but he never had an inflammatory rash.

07. An inflammatory rash that comes and goes is one of the multiple manifestations of his American friend’s illness. Brown provided this friend with information to take to his VA clinic supporting a request to be investigated by Mazzotti Test. This reveals onchocerciasis within a matter of hours.

08. His friend’s specialist looked up onchocerciasis in a textbook and suggested first trying treatment for another condition. As always, this treatment was ineffective.

09. Within the last few weeks the American returned to the clinic to report the failure of the treatment and again requested to be investigated for onchocerciasis by the Mazzotti test. Once again his request was ignored.

010. It looks unlikely that any GWVs will receive the diagnostics and treatment they need without intervening government directives.

SOURCES AND QUALITY OF EVIDENCE

011. Firstly Brown draws on some five years work experience in the Eastern Province of Saudi Arabia.

012. Secondly he draws on his personal experience with specialists in infectious diseases whose knowledge of onchocerciasis he has found to be deficient.

013. Thirdly he submits medical evidence gleaned since 1997 when he realised that he had been infected with onchocerciasis for a dozen or more years.

014. The integrity of the medical evidence has secured Brown a clinical diagnosis and treatment on the grounds that he inevitably contracted onchocerciasis in Saudi Arabia. It therefore follows that some GWVs also contracted onchocerciasis in Saudi Arabia and probably elsewhere in the Gulf War theatre.

015. Unfortunately Brown has failed to persuade doctors to publish a letter or paper advocating the investigation and treatment of others with Gulf related illnesses. His view is that, in the medical profession, dog prefers not to eat dog. He senses a determined reluctance, by doctors, to stand up and be seen to be the individual that blows the whistle on the GWS debacle. Accordingly, the impetus to secure medical interventions for his sick friend and others will have to come from outside of the medical profession; from congressmen for instance.

016. All but two of the medical references cited herein are available from the National Library of Medicine, Maryland. The critical references by Chumbley and Woodruff should be available from other sources but if not, I will supply copies upon request.

CONTENTS

1. Synopsis

2. Introduction to worms and flukes

3. Symptoms of the ultimate multi-symptom disease

4. Onchocerciasis immune deficiency

5. Autoimmunity

6. Doxycycline is anthelminthic

7. Recommended treatment

8. Blue skin disease and the hide-and-seek history of filariasis in Arabia

9. Impediments to the detection and recognition of onchocerciasis in different ethnic groups and in new Arabian endemic regions

10. Exposure to onchocerciasis

11. Variations in presentations occurring in natives of endemic zones compared to lightly infected expatriates like the GWVs

12. Problems with laboratory findings for GWVs

13. Fascioliasis

14. The French

15. Conclusion

16. References

1.0 SYNOPSIS

1.1 In 1980, heavily infected cases of onchocerciasis presenting as river blindness were reported by Chumbley[1] from the military hospital on the Gulf War, Stealth bomber base at Khamis Mushayt[2].

1.2 In the late 1970s the zoologist, Buttiker, observed the presence of the blackfly vectors in the region and alerted Chumbley to the possibility of onchocerciasis in the area. Buttiker then published Chumbley’s report in a volume of obscure Swiss tomes on the flora and fauna of Saudi Arabia, thereby eluding inclusion in the Index Medicus, and skipping the attention of Gulf War syndrome investigators[3,4]. Navigation to Chumbley is provided by Connor and co-workers in their 1983 study of sowda in North Yemen[5] so a conscientious search of the medical literature would have inevitably led GWS researchers to Chumbley.

1.3 Additional heavily infected cases presenting as sowda were reported from Riyadh in 1991[6]. From the medical literature, therefore, it is predictable that virtually everyone at Khamis Mushayt and Riyadh are, at least to some small extent, infected[7]. Yet not a single American[3] or British[4] veteran has been screened for this disease.

1.4 Tens of thousands of Arabian expatriates, of all ethnicities, must have contracted onchocerciasis over the years, yet no expatriate case has ever been reported in the medical literature; an anomaly first noticed 40 years ago[8]. The expatriate presentations have gone unrecognised. Expatriate disease does not present as river blindness or sowda, so it is unknown how the disease presents in expatriates from America, Europe, India and South East Asia working in Arabia.

1.5 Multiple cycles of long courses of doxycycline, prescribed to GWVs for mycoplasmal infections[9], also kill endosymbiotic bacteria essential for the homeostasis of adult Onchocerca, interrupting embryogenesis and accelerating their degeneration and death[10]. That is, the antibiotic treatment regimens recommended by Garth Nicolson for mycoplasma infections also resolve onchocerciasis, albeit not very efficiently.

1.6 Large numbers of American servicemen fighting in the Pacific during World War II were infested by other genera of filarial parasites with pathogeneses that were different and more acute than presentations occurring amongst the endemic population with heavier parasite loads[11]. History repeats itself. Will we never learn?

1.7 Regardless of the obscurity of Chumbley’s report from Khamis Mushayt, the evidence submitted herein testifies to the enormity of the medical negligence and incompetence that resulted in the avoidable misery and morbidity known as Gulf War syndrome.

2.0 INTRODUCTION TO WORMS AND FLUKES (known as HELMINTHS)

2.1 Medical laymen may benefit from this summary on the fundamental differences between the infestations of worms and flukes on the one hand and the infections of replicating microbes on the other.

2.2 There are some 300 genera/species of helminths that infest humans. Unlike other infectious agents such as bacteria, viruses, mycoplasmas and other parasites, helminths typically do not multiply in number within their mammalian host.

2.3 Hence, and virtually without exception, a single infectious larva or egg matures into a single adult worm or fluke. It does not replicate like bacteria or viruses and develop into ten, or a hundred, or a thousand worms or flukes. If helminths did replicate like other pathogens, infestations would be easy to detect but unfortunately the opposite is the case. Once mature, helminths can produce many offspring/eggs for up to 40 years in some cases. These offspring/eggs are then taken up by secondary hosts such as insects or snails, before morphosing to the stage where they are once again infectious to mammals.

2.4 In the case of the 1991 Gulf War veterans (GWVs), it will be demonstrated herein that their multisymptom illness is caused by the parasitic filarial worm, Onchocerca volvulus, the secondary insect vectors of which are blackfly species of the genus, Simulium. The disease is called onchocerciasis and the longer the time spent in an endemic zone, the greater the build up of the parasite load, which in turn may cause more patently recognisable disease manifestations.

2.5 Consequently, the parasite loads of briefly exposed GWVs, are very much lower than those of the long term residents of Arabia, and GWVs’ minimal parasite loads will frequently be undetectable by laboratory screening, whereas the higher parasite loads and frank disease manifestations of long term residents are typically detectable and have been reported in medical journals. Protocols for determining the cut-off between positive and negative serology in natives of endemic zones compared to minimally infected GWVs should, therefore, vary to accommodate differences in parasite loads and duration of exposure but variations have not been allowed for by doctors who have little or no experience of lightly infected cases.

2.6 The GWVs’ Onchocerca parasite loads were therefore 'fixed' when they returned home from the Gulf War theatre. Indeed, since arriving home their parasite loads have gradually decreased as the worms have died off naturally. This has rendered their infection progressively more difficult to isolate while symptoms due to chronicity have been getting progressively more serious and severe. Consensus of opinion estimates the life of adult O. volvulus to be nominally 15 to 20 years so there is no time to lose investigating the GWVs for onchocerciasis.

2.7 In very lightly infected cases, few if any symptoms may be directly attributable to the parasite per se. Filarial worms are known to be immunosuppressive (refer section 4). They suppress inflammatory immune responses which accounts for the paucity of non-specific serological evidence in GWVs. Consequently, most symptoms may occur as a consequence of the affects of secondary pathogenic processes caused by opportunistic infectious agents, toxic exposures and vaccines, that have already been implicated in the GWVs’ pathology. In both South-East Asia and Africa, non-white natives of endemic regions are known to tolerate quite heavy parasite loads, but there are reports in the medical literature of Europeans falling seriously ill upon minimal exposure.

2.8 It is fair to say that minimal helminth infections are the most difficult of diagnoses for doctors to make. This is particularly so in cases infected with more than one genera of worm or fluke and therefore presenting with confusing overlapping symptoms. Some GWVs may have contracted two or three different types of worms or flukes during their time in the Gulf region. Possible concomitant obstructive fascioliasis is addressed in section 13.

3.0 SYMPTOMS OF THE ULTIMATE MULTISYMPTOM DISEASE

3.1 Onchocerciasis is universally known by the misleading tag, ‘river blindness’. Puyuelo and Holstein[12] reported blindness from Upper Volta where there is a proverb, “Nearness to streams eats the eyes” whereas Hughes and Sarkies[13] reported that eye lesions are absent in eyes streaming with microfilariae in Lower Volta. Suffice to say that onchocerciasis may or may not cause ocular disease ranging in severity from blurred vision to blindness. Other common manifestations of onchocerciasis are less well known, but as with river blindness and GWS, the epidemiology is random.

3.2 In 1965 Woodruff provided an internal report to the WHO Expert Committee on Onchocerciasis, on the disabling non-opthalmological effects of the disease[14]. It listed the following symptoms; pruritis; erysipelas de la costa (dermatitis) – This is the nearest documented presentation to that of my American colleague; lymphoedema; atrophy of the skin (premature wrinkling); leonine facies (folds in facial skin); mal morado (violet coloured dermatitis like lichen planus) - I have met a British veteran with this presenting on his legs; hyper/hypopigmentation (leopard skin and depigmented shins) - I presented with this manifestation – the hypopigmentation cannot be seen on white skin and the hyperpigmentation is a freckle rash; lymphadenopathy (enlarged and sclerosed lymph nodes sometimes known as ‘hanging groins’); calcinosis; subcutaneous nodules; and nakalanga syndrome (retarded growth and development associated with epilepsy).

3.3 Of importance to GWVs who claim to have reproductive problems was his observation that microfilariae in the investing membranes of the testes may be associated with the serious depopulation that occurs in highly endemic regions. Interestingly Gasparini[15] observed the ‘obliteration’ of the saphenous veins and its different branches at the cural ring (groin). I have this manifestation.

3.4 Woodruff’s report contained a single case history to illustrate debility which he regarded as an affect of great importance. He wrote:

“Personal experience of some 1500 patients with onchocerciasis studied in East and West Africa, Central America and in London has led to the unmistakable conclusion that the disease may be associated with significant degrees of debility and loss of energy. The importance of this symptom was first made clear by the case of a vigorous and active person much given to mountaineering whose presenting symptom was lack of energy which had caused him to forego mountaineering expeditions to which he had been greatly looking forward. His debility led to him being investigated and eventually to a definitive diagnosis of onchocerciasis being made in the absence of any other cause for his symptoms. Following treatment his vigour has been restored and he has undertaken the various climbs that he had earlier foregone.”

3.5 This is, so far as I am aware, the only reference in existence to a case of chronic fatigue syndrome (CFS) being diagnosed as onchocerciasis, that is, CFS is an onchocerciasis-like illness and since Gulf War syndrome has been described as a CFS-like illness, it too is by definition an onchocerciasis-like illness.

3.6 Woodruff's observations, like those of McCarthy[16] and Pryce[17] demonstrate the remarkable variations between lightly infected cases, who may have detectable microfilariae yet be asymptomatic, or who may have no detectable signs of disease, like the mountaineer, but who are ill and debilitated. There are no hard and fast rules as to whom or when to treat. Woodruff’s final summarising sentence also nutshells Gulf War syndrome. He wrote:

“Though many of the symptoms of onchocerciasis taken individually are not serious, in summation they may cause a state of great human misery, and almost certain economic incapacity.”

3.7 These days the mountaineer's onchocerciasis could be detected by Recombinant Antigen Panel (RAP) serology or Polymerase Chain Reaction (PCR) skin probe but doctors are not investigating cases with these assays. Today the mountaineer would be wrongly diagnosed with CFS or Gulf related multisymptom illness, as I was and as thousands of my fellow invalids have been. And like us, he might be given unhelpful and inappropriate cognitive behaviour and graded exercise therapy (CBT/GET) to help him cope with his ailment; or he might be diagnosed as hyperventilating and treated with sessions of breathing in and out of a paper bag; or he might be given some other useless and stupid treatment, but he would definitely not be diagnosed with, and treated for, onchocerciasis. In the light of such incompetence is it any surprise that Woodruff’s observation was that cases may resort to alcohol abuse. In lieu of treatment it seems to me as good a means of coping as any other.

3.8 The myriad of presentations described by Woodruff is not exhaustive. There is increasing evidence of an association between onchocerciasis and epilepsy[18], with claims that onchocerciasis control programmes in endemic areas have eliminated seizures completely[19] or reduced their incidence and severity[20]. Microfilariae have been found in cerebrospinal fluid[21] and the optic nerve[22], suggesting the potential to cause serious neurological disease.

3.9 This is particularly relevant in the light of Robert Haley’s findings of damage to basal ganglia in GWVs[23,24] and the US Department of Veterans’ Affairs’ announcement that GWVs are twice as likely to develop the neuromuscular disease, amyotrophic lateral sclerosis, as personnel not deployed in the 1991 Gulf War. There are also recent claims by GWVs that they are more likely to develop Parkinson’s disease. I submit that onchocerciasis is, variously or in part, involved in this neurological pathology.

3.10 Other observations relevant to GWVs’ illness have come from rheumatologists working in Africa. Parasitic rheumatism due to Dracunculus medinensis, the guinea worm[25,26], and to Strongyloides stercoralis[27] have been reported, but onchocerciasis may be the largest single cause of rheumatism in the tropics[28].

3.11 In Cameroon one study indicated onchocerciasis to be the biggest cause of morbidity with 87% infected and accounting for 20% of all working days lost. Occular disease only presented in 5% of these cases and there was no permanent blindness[29]. As long ago as 1965, arthralgia was reported in 54% of cases in Tanzania[30] and in 1967 backache and musculoskeletal pain were reported in 64% of cases in Nigeria[31].

3.12 In Nigeria, cases of musculoskeletal pain were investigated for onchocerciasis with a single skin snip from the iliac crest region. This revealed that 70% of all onchocerciasis cases were presenting with musculoskeletal pain, half of them with backache. If only the textbook symptoms of cutaneous or ocular manifestations had prompted suspicion of the disease, the diagnosis would have been missed in nearly 3/4 of the total cases presenting. The commonest presentation of onchocerciasis was found to be the middle aged farmer with backache[32,33]. Another seldom recognized, but very common symptom was found to be insomnia[34].

3.13 In a letter[28] to the British Journal of Rheumatology in 1988, CA Pearson, a former Chief Medical Officer in Nigeria, wrote:

“Overseas workers do return after many years in endemic areas, and if our index of suspicion is not high when dealing with such travellers who present with backache or other musculoskeletal pains, we might miss the opportunity of achieving a most satisfying therapeutic success. Should we not rethink our approach to third world rheumatism? Their problem may become our problem. As rheumatoid arthritis is relatively rare in the tropics would it not be helpful to tag onchocerciasis, not only with the well-established name of 'river blindness', but also with the name of 'tropical rheumatism' or 'tropical backache'? This would remind physicians and general practitioners in endemic areas, and those who serve patients who have lived temporarily in those areas, of the importance of rheumatic symptoms in this disease.”

3.14 I submit that, in respect of onchocerciasis, the Gulf War syndrome debacle has demonstrated that Pearson’s 'index of suspicion' of onchocerciasis by doctors in the USA and UK is absolute zero. Worse still, American[3] and British[4] investigators found that Gulf War syndrome was not unique to the veterans, but occurred in personnel not deployed in the 1991 Gulf War. In consequence, it is likely that there are few physicians in North America and Europe who, at some point in their career, have not missed the diagnosis with dire, and sometimes fatal, consequences for their patients. Thus we have, in all probability, the biggest goof-up in medical history.

3.15 In summary, the above reports from the medical literature indicate that onchocerciasis is an extraordinarily ‘multi’ symptom illness that may present with any combination of the following symptoms: fatigue; debility; rheumatic musculoskeletal pain; ocular disease that may cause blindness; vascular disease; lymphatic disease; many presentations of dermatitis, pruritis; neurological disease; insomnia; and disease of the reproductive organs. And when it presents with these predictable symptoms, as it has in the Gulf War veterans, the diagnosis is serially and universally missed. I find this mind-boggling.

4.0 ONCHOCERCIASIS IMMUNE DEFICIENCY

4.1 There is a Th1/Th2 (Th = T-helper cell) cytokine response imbalance occurring in GWS cases described by Roberto Montero, Nancy Klimas, and Mary Ann Fletcher (University of Miami School of Medicine) in the Journal of Chronic Fatigue Syndrome[1] from which I quote, "affected individuals are biased toward a T-helper-2-type, or humoral (antibody producing) immunity-oriented cytokine expression pattern, over a Th1-type, or cellular mediated (natural killer cell and macrophage activating) immunity orientated one."

4.2 In simple English this means that while our antibody producing immunological mechanisms are over-performing, our inflammatory (think red and sore) mechanisms are suppressed and under-performing. This informative paper discusses the effectiveness of various convoluted interventions to correct this imbalance, and from which GWVs variously seemed to benefit.

4.3 Various stimuli will manipulate either humoral or cellular responses separately, in the manner described by the Miami researchers. For instance, vaccines, amongst other things, enhance humoral cytokine responses, and boozing, amongst other things, suppresses cellular cytokine responses, but very few stimuli will simultaneously do both, leaving little room for manoeuvre.

4.4 I spent many weeks conscientiously trawling the medical electronic databases, every-which-way, for any pathogens that are known to simultaneously affect cytokine responses in this manner. The only papers to be trawled up identified tissue-invasive helminths, specifically filaria and schistosomes, and that was my lot. I submit that it is significant that not one of the pathogens often hypothesised as being the aetiological basis of GWS were picked up by my search. I submit that this effectively excludes them as possible underlying aetiological agents of GWS, but not as secondary pathogens.

4.5 The immunological aberration described in the Montero/Klimas/Fletcher paper is identical to that described in a paper on onchocerciasis by Stewart and co-workers, published in 1999[36]. This paper demonstrates that Onchocerca volvulus suppresses Th1-type responses to both parasite and non-parasite antigens with a corresponding enhancement of Th2-type responses. The relevance of this finding, when applied to GWS, is that when microbe infections are concomitant with onchocerciasis, they do not necessarily provoke the all-important, telltale non-specific inflammatory responses that they would otherwise provoke.

4.6 Microbes (bacteria, viruses, mycoplasmas, fungi etc) and, by the way, cancer cells provoke an inflammatory immune response that is a product of cellular (Th1) immunity. As a physician's rule of thumb, but no more, infectious disease causes inflammation, so their attitude is that no inflammation equates to no infection.

4.7 It is the detection of components of non-specific inflammation; rheumatoid factor, antinuclear factor, extractable nuclear antigen, reactive protein and, most commonly, ESR that doctors rely on to determine whether a patient is genuinely sick, albeit on account of microbes or cancer, or whether they are mad or malingering. When these telltale haematological signs of inflammation are absent, the patient may be wrongly diagnosed as mad or malingering.

4.8 In this event, the correct finding is that the patient may indeed be mad or malingering, UNLESS they are infested with tissue-invasive helminths that are suppressing their inflammatory responses. Further investigation is then required, with exquisitely sensitive pathogen-specific tests (section 9.0 and para 12.1), for the differential diagnosis to be correctly determined.

4.9 Published research into GWS reveals that this has not been happening in the USA[3] or UK[4], possibly because the assays are not commercially available. Under these circumstances, I submit that the only legitimate means of determining such a patient's state of health is by their response to empirical treatment with anthelmintic therapy that may need to be prolonged.

4.10 An obstacle that GWVs must overcome is doctors’ assumption that tissue-invasive helminths are not causing disease in their patients. Doctors assume, through no fault of their own, but shortcomings in their training, that microbes are the only likely causes of disabling chronic infection; re-education is required.

Immunology driven by adults and embryos

4.11 With onchocerciasis, the suppression of cellular immunity is directly related to the microfilarial load as demonstrated by the reversal of hyporesponsiveness after chemotherapy[37-40]. This post treatment increase in cellular responsiveness is transient lasting for around six months and is only maintained with ongoing treatment, that is; continuous cycles of chemotherapy are required to clear microfilariae and maintain the correction of the immune imbalance.

4.12 The enhancement of humoral responses is thought not to be directly related to the microfilarial load, but to the age of the patient (maturation of the immune system and duration of exposure to the parasite) and inversely to the microfilarial load[36]. In lymphatic filariasis, however, it has been demonstrated that the adult female worms of Brugia malayi are the driving force of type-2 polarisation in mouse infections[41]. Whether this is also the case in onchocerciasis is unclear, because the Th1/Th2 imbalance is corrected with ivermectin (drug of choice) treatment that clears microfilariae but not macrofilariae. Thus, the question as to whether all adult worms must be killed to fully resolve the complex immune imbalance remains unanswered by research to date.

5.0 AUTOIMMUNITY

5.1 Onchocerca volvulus is a large pathogen with a complex cell structure that shares many antigens with human tissues and is therefore capable of causing autoimmune disease. For instance, a worm antigen is cross-reactive with a component of the retinal pigment epithelium[42] and another antigen is shared with keratin[43]. Antibodies against autoantigens of nerve fibre, ganglion cell and Muller cell have also been found in cases, which may implicate autoimmune mechanisms in the development of river blindness[44]. Auto-antibodies as well as parasite specific antibodies are reduced, however, following treatment with ivermectin so microfilariae are certainly involved in part, if not entirely. But this still does not exclude adult worms as a significant factor in the immune imbalance.

5.2 The question as to the importance of autoimmunity is complicated. Gallin and co-workers[45] demonstrated that the enhanced immune activity resulting in the Arabian hyperreactive presentation of sowda was due to the development of autoantibodies to defensin, whereas in generalised African onchocerciasis, parasite antigens are tolerated and there is no reactivity to defensins. It is therefore conceivable that there may be autoimmune variations in the Caucasian presentations of GWS between, say, blondes, brunettes and redheads.

5.3 In post HIV/AIDS times one might imagine that emphasis would be placed on immune deficiency diseases in doctors’ training but this is not the case. Duke addresses onchocerciasis immune deficiency in the Oxford Textbook of Medicine under the subheading, 'Generalized signs and symptoms'[46(p915)]. He writes, "Extreme wasting, dwarfism with delayed sexual development, epilepsy, AND A FAILURE TO REACT IMMUNOLOGICALLY TO ANTIGENIC, STIMULI (my emphasis) have all been associated with heavy O. volvulus infection." That's the lot; just nine words, the limit of our primary care doctors’ training on this serious immune deficiency.

Symptomatic secondary cofactors

5.4 Researchers in the field of GWS have allowed themselves to be distracted from the underlying immunological aberration described above, by the possible affects of vaccinations and battlefield toxins to which GWVs were exposed. Of CFS Ramsey wrote:

"It is not so much the aetiological agents, as the immunological state of the patient which determines the development of the disease. This was suggested to me several years ago when two friends on holiday contracted the same respiratory virus infection: one recovered uneventfully, the other (a doctor) developed ME (CFS) and has become a chronic sufferer."[47]

It is therefore the case with onchocerciasis that Ramsay's 'immunological state of the patient' is temporarily corrected by treatment with ivermectin.

6.0 DOXYCYCLINE IS ANTHELMINTHIC

6.1 Ivermectin is microfilaricidal but not macrofilaricidal, although repeated doses degenerate and accelerate the death of adult worms[46]. The adult worms, however, have an Achilles' heel in that they harbour essential symbiotic bacteria that are sensitive to antibiotics which, in turn, renders the parasite vulnerable to antibiotic therapy.

6.2 In 2000, Hoerauf and co-workers published a paper[48] documenting novel therapy from which I quote:

"Endosymbiotic bacteria living in plasmodia or worm parasites are required for the homeostasis of their host. We show that targeting of Walbachia spp bacteria (order Rickettsiales) in Onchocerca volvulus filariae by doxycycline leads to a sterility of adult worms to an extent not seen with drugs used against onchocerciasis. Present chemotherapy, such as ivermectin (drug of first choice) is mainly targeted against mature microfilariae, and not at adult worms or early embryos, leading to a reappearance of skin microfilariae several months after treatment. There is therefore a pressing need for new antifilarial drugs that have macrofilaricidal efficacy or that show total or long-lasting suppression of embryo production, to complement microfilaricides such as ivermectin."

6.3 Hoerauf and co-researchers treated a group of Ghanaian onchocerciasis cases, presenting with nodules, with 100mg/day Vibramycin (doxycycline) for 6 weeks. Four months after the end of treatment, which was well tolerated in all cases, onchocercoma (nodules containing 1 to 6 female worms) were excised and examined for wolbachia, adult worm degeneration, and disturbance of embryogenesis. Only 5 of 90 worms were positive for bacteria showing only a few organisms. No worms had intact embryogenesis, and only 9 showed any embryos, all of which were degenerated. The researchers commented that there was a clear trend to the more frequent degeneration or death of adult worms.

6.4 A modest course of doxycycline was thus demonstrated to cause disabling damage to the majority of adult worms. Unfortunately, the regimen of doxycycline required to kill the worms is not yet known. It is surely significant that, for around a decade, Garth Nicolson has been resolving GWS and CFS with multiple 6-week courses of doxycycline that would be predicted to eventually kill adult Onchocerca.

6.5 Following the controversy in the early 1990s over whether or not Gulf War Syndrome was a non-disease and all-in-the-mind, Garth Nicolson successfully treated sick USAF veterans in Texas with repeat 6-week courses of doxycycline. He detected DNA sequences of an invasive mycoplasma species [M. fermentans (incognitus strain)], the isolation and culture of which is beyond the capacity of most laboratories. Accordingly he wrote a letter to JAMA[49] urging physicians to treat the veterans empirically.

6.6 It is particularly significant that most of Nicolson's GWS patients were airforce personnel, some of whom would have been stationed far from combat zones at remote airbases, such as the Stealth bomber base at Khamis Mushayt. He has identified DNA sequences of 4 mycoplasma species (M. fermentans, M. pneumoniae, M. hominis, M. penetrans) in the blood of CFS, fibromyalgia[50] and rheumatoid arthritis[51] cases, but he has not cultured any, so far. His assertion is that leukocytes are infected, precluding proof by culture with today's technology. Encouragingly he reports that all of these cases have either resolved or responded, with varying degrees of success, to antibiotic therapy and particularly to doxycycline.

6.7 Nicolson nutshelled his case for treatment thus:

"87 GWI patients that tested positive for mycoplasmal infections were treated with antibiotics. All patients relapsed after the first six-week cycle of therapy, but after up to six cycles of therapy 69 OF THE 87 PATIENTS RECOVERED AND RETURNED TO ACTIVE DUTY (my emphasis). The clinical responses that are seen are not due to placebo effects, because administration of some antibiotics, such as penicillins, resulted in patients becoming more, and not less, symptomatic, and they are not due to immunosuppressive effects that can occur with some of the recommended antibiotics. INTERESTINGLY, CFS, FMS AND GWS PATIENTS THAT SLOWLY RECOVER AFTER SEVERAL CYCLES OF ANTIBIOTICS ARE GENERALLY LESS ENVIRONMENTALLY SENSITIVE, SUGGESTING THAT THEIR IMMUNE SYSTEMS MAY BE RETURNING TO PRE-ILLNESS STATES (my emphasis). If such patients had illnesses that were caused by psychological or psychiatric problems, or solely by chemical exposures they should not respond to the recommended antibiotics and slowly recover. In addition, if such treatments were just reducing autoimmune responses, then patients should relapse after the treatments are discontinued."[52]

6.8 It is important to take cognizance of Nicolson's observation that cases become less environmentally sensitive as they recover, since this is consistent with the down-regulation of a predominant Th2 response, typically associated with atopy and autoimmunity. Most helminthologists concur that the life span of microfilariae in the human body is up to 2 years, although I have not seen where they get this figure from. Correspondingly, it is the case that Nicolson's Gulf War onchocerciasis patients achieve a permanent resolution of their infection after up to 24 months of therapy when their microfilarial load has been greatly or completely reduced through natural causes, that is; when the Th1/Th2 cytokine response imbalance has been corrected and full competence restored to the patient's inflammatory responses.

6.9 It is during the initial period of treatment when Nicolson's cases relapse if therapy is abandoned. This coincides with the period when the mature microfilarial load is high, that is; when the Th1/Th2 cytokine response imbalance is still intact, and inflammatory reactions remain suppressed.

6.10 Nicolson's antibiotic therapies are not microfilaricidal, but only prevent the microfilarial load from increasing. I submit that this is why Donta’s study[ ] indicated that 12 months treatment with doxycycline was of no benfit to GWVs. Onchocerciasis cases could not be expected to feel the benefit of treatment with doxycycline alone for roughly 2 years or more.

7.0 RECOMMENDED TREATMENT

7.1 There is no clinical experience of combined antibiotic and anthelminthic drug therapy. Accordingly, I submit the following regimen for consideration. Six-week courses of 200mg/day doxycycline with six-weeks interval between courses. A single 12mg dose of ivermectin to be taken at the end of each course. That is, at 3 month intervals which is the recommended expatriate dose. A three weeks course of 12mg/kg/body weight diethylcarbamazine to be commenced 3 weeks after taking ivermectin (to ensure absence of microfilariae in the eyes), i.e. the completion of diethylcarbamazine course is immediately prior to commencement of successive courses of doxycycline. The treatment should be continued until the illness resolves.

8.0 BLUE SKIN DISEASE AND THE HIDE-AND-SEEK HISTORY OF FILARIASIS IN ARABIA

8.1 A strange dermatitis of unknown aetiology was recorded by Petrie and Seal[53] in Yemen in 1939/40. They gave it the curious name of Blue Skin Disease.

8.2 This dermatitis was known to the local Yemenis as, ‘sowda’, the feminine form of the Arabic, ‘aswad’ meaning black, because of the dark colour of the affected skin. It typically occurs on a single limb, usually a leg starting low down and spreading upwards. It also appears to be self-curing within a period of 2 to 5 years which is not consistent with other reports of onchocerciasis. The native people believe the source of their dermatitis to be the local lymph nodes that enlarge, become solid and rubbery without adhesions so they can be moved about.

8.3 Petrie and Seal reported that:

“An outstanding feature is the enlargement of the groin glands. Arab sufferers usually insist that these glands are the main seat of the disease and come asking that this, ‘umm’ (Arabic for mother or origin) be removed. The Bedouin treatment for the condition is to bite these glands through the skin so that they are broken into small masses.”

8.4 The aetiology remained a mystery until Alan Woodruff (Professor of Clinical Tropical Medicine at the London Hospital for Tropical Diseases) visited Aden in 1955 and suggested it might be onchocerciasis. At that time onchocerciasis had not been reported outside of Africa, Central America and South America. Attempts were made to isolate microfilariae from skin snips but were unsuccessful.

8.5 In Fawdry’s article of 1957 confirming the involvement of onchocerciasis in blue skin disease[54] he recounted previously dismissing this possibility since text books that he had consulted misinformed him that subcutaneous tumours were the presenting feature of onchocerciasis. These were not what patients in the Yemen complained of.

8.6 This indicates the importance of physicians recognising the presentations of helminthiases and being trained to have a high ‘index of suspicion’ of these diseases. Fawdry recollected seeing ‘insignificant’ single lumps resembling fibromata in one or two previous cases, and in due course a typical case of sowda arrived at his hospital asking for lumps in his groins to be removed. He was found to have a half inch diameter subcutaneous tumour on the inner aspect of the mid-thigh that caused him no discomfort. Fawdry excised this tumour and found a bundle of filarial worms inside. Buckly at the London Hospital for Tropical Diseases identified these as Onchocerca volvulus and the patient’s reaction to chemotherapy: swelling, increased itching and eruptions in the affected limb only, confirmed the filarial origin of the disease. Fawdry was, however, unable to follow up the case and could not comment on whether this chemotherapy resolved it.

8.7 Fawdry also reported the excision of the inguinal and femoral glands of a patient who insisted on the removal of their ‘umm’ despite Fawdry’s assurances that this was unnecessary. This patient developed a solid oedema of the thigh but retained an unswollen but still itching lower leg. No comment was made as to whether this surgery was ultimately successful on follow up.

8.8 Sowda was unlike any of the many other presentations of onchocerciasis known at that time, so to recognise it as onchocerciasis in a region from which the disease had not previously been reported evidences Woodruff’s genius. It is therefore puzzling that he did not mention it in his WHO Report of 1965 (section 3) despite reporting extensively on pruritis and dermatitis. The evidence suggests that, by 1965, Woodruff was undecided whether secondary agents like environmental toxic agents or opportunistic infectious agents were determining the multiple symptoms and presentations of onchocerciasis. This followed three publications in 1964 by Giuseppe Gasparini[8,15,55], Senior Surgeon and Director of Dermatological Services of the Republic Hospital of Tiaz (Italian Technical Assistance to Yemen).

8.9 In his medical survey of the Tiaz-Mokha region, Gasparini identified schistosomiasis and malaria as the main health problems followed by treponematosis (endemic syphilis) and sowda. He was suspicious that sowda could not be straight forward onchocerciasis per se. In all three publications he reports that over a period of 5 years he had treated patients with suramin and hetrazan without resolving the condition. Gasparini’s experience was that the only efficacious treatment was the removal of the inguinal and femural lymph nodes. He reported pruritis subsiding 2 or 3 days after the operation and the gradual recovery of the leg. But there is no question that Fawdry demonstrated the involvement of filaria and unlike Gasparini, had not been able to resolve the disease by the removal of lymph glands from the groin but it is not known if Fawdry’s case (para 8.7) would have gone on to recover eventually.

8.10 In 1964, Gasparini also told a conference that he frequently encountered cases of sowda complicated by other infections. He reported that the dark lesions of sowda are often mixed with papillomata and skin gummata or bone involvement typical of endemic syphilis. Indeed, he found that papules on the legs dried and fell off with antibacterial treatment indicating that they were not onchocercomas but secondary bacterial manifestations.

8.11 Both Gasparini and Fawdry reported seeing elephantiasis of the Bancroftian type, sometimes concomitant with onchocerciasis but to this day it remains unclear if this is a manifestation of onchocerciasis or whether the region is also endemic for lymphatic filariasis. There has since been a report of hydrocele and mild elephantiasis of the legs in Africans with onchocerciasis[56] and reports of American and British expatriates returning from Africa with the unilateral swelling of an upper limb[57,58]. Accordingly, it is certainly possible that cases of suspected lymphatic filariasis in Arabia were cases of atypical onchocerciasis.

8.12 Of great relevance to GWS is that Gasparini reasoned that all ethnic groups in Arabia, including expatriates, would be equally exposed to onchocerciasis. If sowda was a straightforward form of onchocerciasis, therefore, it would be predicted to occur in all ethnic groups. Sowda, however, is not found in the non-Arab community and there is no record in the medical literature of it occurring except in Arabs and Liberians. In the 1960s the possibility of different presentations of onchocerciasis being modulated by different host reactions in genetically different ethnic groups was not considered. Since then, many studies have confirmed that onchocerciasis is indeed involved in the manifestation of sowda, but the role of secondary agents in this presentation remains unknown.

8.13 It appears that Gasparini’s unease about the origins of sowda was the spark that inspired Woodruff’s 1968 article on helminths being vehicles and synergists for microbial infections[59] which, I submit, lies at the heart of GWS. For instance, I submit that the involvement of mycoplasmas in GWS, identified by Garth Nicolson, is a consequence of helminthiasis.

8.14 Seventeen years before Operation Desert Storm, doctors in Arabia were concerned that infected migrant workers could establish new foci of lymphatic filariasis as happened in Sri Lanka. In 1974 Sebai and co-workers[60] reported 10 cases of Saudi nationals with disease manifestations of lymphatic filariasis without microfilaraemia, thought to have been acquired in the south-west of the country. Microfilariae were not found, however, during subsequent night blood surveys.

8.15 This is consistent with a report from Kuwait in 1988 of 4 cases of bancroftian filariasis[61], 2 of which presented without nocturnal microfilareamia. Presentations were atypical without the classic symptoms and signs of tropical pulmonary eosinophilia, and the diagnosis was through the uncommon cytological identification of microfilariae in pleural fluid.

8.16 Sebai speculated that the risk of filariasis spreading throughout Arabia was high due to favourable conditions created by rapid urbanisation and the large influx of expatriate workers from the endemic regions of South-East Asia[62].

8.17 Bearing in mind that Sebai’s original 10 suspected Saudi cases were from the same region from which Chumbley[1] was to report river blindness a few years later, it is quite possible that the reason for microfilariae not being found in their nocturnal blood was because these cases had onchocerciasis and not lymphatic filariasis.

8.18 In 1986, however, Holmes[63] optimistically considered it unlikely that filariasis would be transmitted by mosquitoes in Dubai, but 10 years later Omar[64] was so concerned about Saudi Arabia becoming a new self-sustaining lymphatic filariasis endemic region that he recommended mandatory screening of expatriate workers in their country of origin prior to employment.

8.19 Culex pipiens is the predominant mosquito in the temperate mountains of South-West Saudi Arabia, and is a known vector of Bancroftian filariasis in the Eastern Mediterranean and Egypt. But in the low-lying towns of Saudi Arabia and in the Emirates, Culex quinquefasciatus is predominant. This mosquito species is the principal vector of Bancroftian filariasis in India[65,66] and is also a known vector in the Caribbean, hence my opinion that Holmes’ prediction was optimistic.

8.20 The Arabian Peninsula nestles between the filariasis endemic zones of Africa and South-East Asia, which together account for two thirds of the world’s filariasis. It has been a melting-pot of civilisation for 5 millennia, so it is not clear why Sebai and Omar ignored the immediate threat on their doorstep of importing filariasis from Yemen, or from Africa across the Red Sea.

8.21 Historically, trade with the ancient Kingdom of Sheba (2150 BC to 427 BC), and wars have brought an assortment of peoples to Arabia; Ethiopians, Egyptians, Greeks, Romans, Persians, Turks, Jews and Indians. More recently, pilgrims performing the hadj and expatriate workers from all corners of the world have arrived to swell the Arabian populace.

8.22 Jeddah is Arabia’s gateway to Africa being the principal port on the Red Sea. It is the main trading port with Egypt, Sudan, Eritrea/Ethiopia, Djibouti and Somalia, all of which are endemic for various filariases. These places, together with Yemen, provided the peninsula with expatriate workers prior to mass-recruitment from South-East Asia, so the threat of importing filariasis from adjacent regions was ever-present. Indeed, minimal levels of transmission have probably been occurring in the wetter south-west mountains of Arabia for centuries. But the dry central and eastern regions would not have supported the life-cycle of the vectors until a few decades ago.

8.23 There are no recent authoritative studies demonstrating whether or not onchocerciasis, lymphatic filariasis or Perstans filariasis (endemic in nearby North Africa) are now endemic throughout Arabia and the Gulf States, where man has recently provided ample nourishment to nurture the vectors of these diseases. In consequence, I respectfully submit that the world will feel a safer place when a worm savvy boffin provides us with the answer.

8.24 Please excuse me for leaving the last few lines of this section of my testimony to the telltale cryptic remarks borrowed from William Blake by the thoughtful Alan Woodruff and co-workers[67] who would not have been the least bit surprised by the involvement of onchocerciasis in GWS.

‘The distribution of onchocerciasis is very incompletely known and may be much more widespread than has hitherto been recognized.......The natural history of the disease is still incomplete and it may be necessary for us to alter many of our opinions concerning it. That, however, may not be a bad thing, for “The man who never alters his opinion is like standing water, and breeds reptiles of the mind.”

9.0 IMPEDIMENTS TO THE DETECTION AND RECOGNITION OF ONCHOCERCIASIS IN DIFFERENT ETHNIC GROUPS AND IN NEW ARABIAN ENDEMIC REGIONS.

9.1 Onchocerciasis is routinely discovered to be endemic in regions where it was thought not to present a health threat. A recent example was reported by Maia-Herzog and co-workers[68] who recently identified a new endemic region, 2000 km away from the only previously known focus in Brazil. Their study employed state of the art investigative techniques that are not commercially available; namely, recombinant antigen panel (RAP) ELISA, and polymerase chain reaction (PCR) skin probe.

9.2 Maia-Herzog’s investigation was prompted by the case of a sixteen years old girl who had never been outside of the region, and who was confirmed with onchocerciasis in 1986. Since the case was autochthonous, skin biopsies from 2000 local individuals were investigated by the traditional parasitological method but none were found to be infected.

9.3 In 1999, the investigation by Maia-Herzog’s team identified very lightly infected cases from three towns in the region by both RAP/ELISA and PCR methods. The researchers considered that the route for the introduction of the parasite into the region was through the immigration of large numbers of garimpeiros (gold miners) from Brazil’s Amazonia focus between 1970 and 1980. This prompted questions regarding the geographical extent and location of unknown endemic zones in Brazil; questions that could only be answered by sampling large numbers of people throughout the whole country. In parallel, it is legitimate to hypothesise that, along side the known endemic regions, unidentified endemic zones also exist in Arabia because large numbers of the native Arab and expatriate populations have not been investigated for the disease. The GWVs are a case in point; don’t look, don’t find.

Blackflies at Dhahran, Saudi Arabia, 1983

9.4 When I arrived at Dhahran in January 1983, the installation of irrigation pipes for the landscaping around the new houses where I lived [refer attached photo] was almost complete. This landscaping was an experimental model for the landscaping on an adjacent military base the size of a large village that was then under construction. Any health problems associated with the experimental landscaping, therefore, would have been replicated many times over on the military base by the start of the Gulf War in 1991.

9.5 During the summer months the midday temperature reached 55 deg C (130 deg F). There is little, if any, shade in a sandy desert. Insects and reptiles cannot survive for more than a few seconds during daylight hours in such extreme conditions, so I never saw any of these. Prior to installing the landscaping I could sit in my garden of sand and not see a single insect all day.

9.6 Medical tracts on onchocerciasis, such as that found in the Oxford Textbook of Medicine, advise that blackflies (Simulium species) require fast flowing rivers and streams for breeding. They crawl down overhanging vegetation and lay their eggs up to 100mm below the water surface. Most importantly, the flies mate at sites of white water; waterfalls, rapids, weirs, fords, hydro-electric facilities and the like. They are attracted by the spume. Ordinarily, their diet is exclusively cellulose but, like mosquitoes, the female requires a blood meal to achieve ovulation. Hence the historical link between white water and biting flies. Blackflies’ behaviour becomes aggressive in proximity to a spray of water. This is partly how onchocerciasis acquired the tag, ‘river blindness’.

9.7 Dhahran is as dry as a bone and as flat as a pancake so there are no fast flowing watercourses or sites of white water in the entire Gulf region. There is barely a single day of rain in a year. I estimate that the nearest river or stream to Dhahran would be in Iraq or Oman, between 600km and 800km away. It is clearly the case that going back several decades, blackflies could not have survived or existed in Eastern Arabia adjacent to the Persian Gulf.

9.8 Over recent decades, however, rapid urbanisation and the provision of abundant water supplies have literally changed the colour of the Arabian landscape. From an aeroplane one sees how desert settlements are delineated by their emerald green landscaping.

9. 9 I was able to sit in my sandy garden and enjoy a barbeque free from flies for my first few months at Dhahran while the irrigation piping was installed around my house. However, within a few days of opening the irrigation valves and planting shrubs to provide shade, swarms of blackflies homed in on the sprinklers like a biblical plague. Heaven knows where they came from. Wherever there was a sprinkler there was a cloud of buzzing blackflies.

9.10 I only considered where the flies laid their eggs after leaving Arabia so this remains unknown to me. There were 2 evaporation ponds from sewage treatment plants quite nearby with well established reed beds. There was also an ozone (not chlorine) treated swimming pool approximately a kilometre away. I guess the evaporation ponds would have been the more likely egg depositories, but I cannot be sure.

9.11 Either way, man’s best endeavours to tame the Arabian desert have provided an alternative to fast flowing river environments for blackflies to flourish and facilitate the transmission of onchocerciasis in regions where Mother Nature alone precludes transmission. In parallel, increases in the incidence of lymphatic filariasis were reported from Pacific regions following the introduction of large irrigation projects. Once again history has repeated itself.

10.0 EXPOSURE TO ONCHOCERCIASIS

10.1 Human and zoonotic onchocerciasis share the same blackfly vectors, so where zoonotic disease exists it is not surprising to also find human disease. Allied health risk assessors should have been suspicious of the risk of onchocerciasis in the Gulf region because of the high incidence of the disease in local camels[69,70,71]. More than 59% are infected and camels are hardly associated with sites of white water. High rates of transmission must be occurring in proximity to human settlements, as opposed to remote desert locations where there is no water to attract and sustain the blackfly vectors. Because urbanisation and settlements facilitate transmission between camels, it should have been self-evident that transmission was probably occurring between humans, but this possibility was not, and never has been, considered up until now.

10.2 Armed services personnel are unlikely to have been exposed to blackflies away from settlements in the remote combat zones of the sandy deserts of Eastern Arabia, Kuwait and Iraq. Forces stationed on or near airbases, however, would most certainly have been exposed. Most airbases in the region share an airfield with civilian carriers, and enjoy convenient access to the facilities of the ubiquitous hotel chains associated with civilian airports.

10.3 Many bases will have had their own swimming pool, but if not, the hotels had pools that non-residents could use. These pools were always situated in pleasant landscaped gardens, sustained by irrigation sprinklers. Anybody who has been swimming in an Arabian hotel pool will testify to shooing away the tormenting flies after a dip. It is in environs such as this that armed services personnel engaging in relaxation, as opposed to fighting on the front line, would have been exposed to onchocerciasis. I submit that this is why GWS cases stationed 1000km away from combat zones, such as at Khamis Mushayt, were exposed to this disease.

10.4 This being the case, the incidence of GWS would be expected to be lowest amongst navy veterans unexposed to blackflies through serving off-shore. Indeed, research by Dr Lea Steele[72] found that the prevalence of illness amongst GWVs from Kansas, was 21% among those who served on board ship compared to 42% among those who were in Iraq and Kuwait.