Post by fritolay66 on Jul 8, 2008 15:10:14 GMT -5
I looked in the forum archives and didn't see any reference to this in any previous threads/posts. If it is a repeat, then I apologize. I thought it was interesting and thought perhaps some of you might find it interesting as well.
members.aol.com/SynergyHN/roundworm
Click here to return to: CISRA--SynergyHN Home Page
A Parasitic Roundworm Linked to Chronic Fatigue Syndrome
by J. C. Waterhouse, Ph.D.
(Disclaimer: This material is intended for information only and is not medical advice. Neither CISRA nor the editor receive funding from any doctor, lab or manufacturer of any medication or associated products.)
Abstract
This article reports on the work of Lawrence Klapow, Ph.D., who has found evidence of a new roundworm species, provisionally named Cryptostrongylus pulmoni, in patients with chronic fatigue syndrome (CFS). In a blinded, controlled study (1, 2), the roundworm adults and larvae were found in sputum of almost half of the CFS patients and none of the controls. This association with CFS was found to be highly statistically significant (P~0.001). Currently, commercial laboratory tests and drug treatment trials await the results of recent efforts to characterize the roundworm's DNA. It is thought that the parasite reproduces in the lungs, giving rise to larvae which migrate to the intestinal tract. Some roundworm larvae burrow through the intestinal walls into tissue and migrate back to the lungs to develop into adults, which then produce larvae to continue the cycle. Only 3 patients have attempted treatment with anti-roundworm drugs so far, and although symptom improvement appears promising, it appears that this proposed new roundworm may be difficult to completely eradicate. The most promising drugs based on this very limited anecdotal evidence appear to be ivermectin and inhaled low dose thiabendazole (now, it would have to be replaced by albendazole). Oral thiabendazole was too toxic and should not be used. The usefulness of oral albendazole remains to be further evaluated along with other drugs. The use of ivermectin was accompanied by itching and/or diarrhea, perhaps indicating a roundworm die-off reaction. Unlike many other helminthic parasites, this species does not appear to produce elevated eosinophils or IgE when the illness becomes chronic. Instead, it is thought to use strategies that certain other roundworm species have been found to use that elevate the TH1 immune response and inhibit a more effective anti-parasitic TH2 response. Klapow also proposes ways in which infection by this species may be able to explain a number of common CFS characteristics, like initial respiratory infection, low cortisol, frequent gastrointestinal complaints, leaky gut, low blood pressure and neurological symptoms. This author concludes with some speculations on alternative treatment and diagnostic possibilities.
Editorial Note (Added in 2006 and updated in April, 2008): For an update on my views of roundworm treatment at present and treatment of chronic fatigue syndrome in general, see the transcript of a talk I gave in 2005. I give an overview of what has helped me most, with an emphasis on a new approach, called the Marshall Protocol (MP). For many, the MP seems to be able to reverse the immune dysregulation that may account for susceptibility to multiple chronic infections. My own view is that there needs to be more research on treatment of this roundworm before I would recommend attempting it. Careful and thorough attention to identifying and controlling food sensitivities (see Food Allergy/Sensitivity Testing), followed by the use of the Marshall Protocol appears to be a good alternative approach at this time, while awaiting future research on this proposed new roundworm species.
Introduction
Chronic fatigue syndrome (CFS) is a disease characterized by substantial fatigue of greater than 6 months duration, muscle aches and cognitive problems and frequently involves sore throat, tender lymph nodes and unrefreshing sleep. Currently no established cause has been found, but there are many proposed causes, some infectious and some not. Some have proposed there may be subgroups of CFS patients with different causes. One hypothesis is that many cases of CFS are caused by a new species of roundworm, provisionally named Cryptostrongylus pulmoni (C. pulmoni). An invertebrate zoologist, Lawrence Klapow, Ph.D. has found evidence for this roundworm during years of research, and his findings have been further supported by the results of a blinded controlled study (1). This article will first discuss Klapow’s hypothesis that a chronic infection caused by C. pulmoni is the source of many of the prominent symptoms of CFS and then explore possibilities for treatment.
Historical and Scientific Background
Klapow’s discovery began through a discussion with an immunologist regarding a CFS patient. The patient was thought to possibly have a roundworm infection, due to a slightly elevated level of eosinophils in the patient’s blood and some unusual rashes (1, 3). A series of culture and stool tests for the known type of roundworm suspected to be the cause (a threadworm, Strongyloides stercoralis) came up negative. However, since Klapow was aware of chronic parasites that migrate between the digestive and respiratory tracts, he decided to do microscopic investigations of the sputum coughed up by the patient. He found what he believed to be a previously unknown roundworm and gave it a provisional name, Cryptostrongylus pulmoni, which means “hidden lung worm.”
Roundworms (also called nematodes or helminthes) cause a variety of acute and chronic infections around the world, some serious and some mild and self limited (1, 4). There is a history of roundworms being introduced into Western countries following Asian wars, when soldiers and immigrants traveled between Europe and Asia (1). In the case of the proposed new roundworm, C. pulmoni, Klapow’s study of the anatomy of C. pulmoni suggests it may be related to the trichostrongylid genus Nycteridostrongylus (1, 5, 6). This type of roundworm infects small mammal’s intestines in Southeast Asian and Northern Australian rain forests. This resemblance, if confirmed, together with the increase in CFS cases in the 1980’s (7) suggests that soldiers and immigrants from the East Asian Tropics might have introduced the disease into the U.S. and Europe following the French and American involvements in East Asia. The tendency to latency and slow development of symptoms would make it hard to clearly identify causal patterns. There is some support among data on soldiers returning from Southeast Asia developing CFS-like symptoms (8), but clearly much more research needs to be done on this. Taking a longer term historical view, in the Victorian era, there may have been a similar situation in which soldiers returning from Indochina brought a roundworm infection back to France (1). Many American women traveling to France in that era could then have brought back roundworm infections that had originated in Asia. This could possibly account for the “neurasthenia” observed in that era ( some have compared neurasthenia to CFS). Whether C. pulmoni was a source of infection at that time is unknown. For another example, in 1974, chronic cases of Strongyloides stercoralis, another roundworm, were diagnosed in some British soldiers who had been POWs in Southeast Asia in WWII (9).
Evidence From a Blinded, Controlled Study
Evidence for the presence of this new roundworm has been reported in a blinded, controlled study, for which several prominent CFS researchers referred patients (e.g., Dr. Anthony Komaroff, Dr. David Bell and Dr. Roger Mazlen) (1, 2). In the first part of the study, 5 of the 11 CFS patients (45%) and none of the 6 controls were found to have the C. pulmoni larvae in a 3-day sputum sample (2). In the second larger blinded study that included additional CDC-defined CFS patients and controls, the same pattern was obtained. A total of 14 out of 30 (47%) of the CFS patients tested positive, while none of the 21 controls tested positive for the roundworm (1). The association between C. pulmoni infection and CFS was highly significant. It is extremely unlikely that the results could have been due to chance. The actual percentage who have the roundworm infection is likely to be somewhat higher, since the larvae are rare and hard to detect, requiring somewhat specialized techniques and considerable time at the microscope in distinguishing the adults and larvae from debris. However, despite difficulties, Klapow has succeeded in photographing C. pulmoni and distinguishing its anatomical characteristics (10).
In the larger study of the roundworm in CFS (1), questionnaires were filled out by the participants to see if any relationship could be found between the types of patients, their symptoms and whether or not their sputum tested positive for C. pulmoni. The data reveal no significant differences in symptoms between those patients who tested positive and those patients who tested negative. There was not a higher incidence of coughs (30-40%) or travel outside the U.S between C. pulmoni positive and negative patients. Patients showed highly statistically significant differences from controls in reported allergies, spotted rashes and bowel symptoms, as well as in the incidence of C. pulmoni (significance levels ranged from P-0.001 to P<0.001). The relatively low occurrence of significant coughing in C. pulmoni positive patients might relate to the lack of a very effective immune reaction to the roundworm, as discussed below.
Why Might a New Roundworm Species Be So Elusive and Chronically Debilitating?
There are a number of factor that might explain why this new roundworm has not been identified before. Among the reasons may be its rarity, small size, lack of an esophageal bulb (which makes it harder to identify) and its likely period of latency. There are also some very interesting characteristics of roundworm infections that have been discovered in other roundworm species that could contribute to a delay in discovery. For instance, C. pulmoni may be like other roundworms that have been found to have ways of manipulating the mammalian immune system to keep it from responding effectively to eliminate it (1). One consequence of these evasive tactics is the lack of much increase of the typical indicators of a TH2 anti-parasitic immune response in the blood of patients chronically infected with roundworms (e.g., elevated eosinophils and IgE). This may be explained by the fact that some roundworm species have been reported to produce a substance similar to interferon-gamma which might stimulate the TH1 anti-viral pathway (1, 11). The stimulation of the anti-viral pathway then suppresses the anti-parasitic pathway, thus suppressing IgE and eosinophils. This has been found to occur through soluble CD23, an IgE binding protein which reduces serum IgE (12). The consequence of these tactics is a picture fairly similar to what is observed in CFS. There is an activation of the anti-viral pathway (13), fairly low levels of increased eosinophils sometimes observed early in the illness, and an actual decrease in IgE relative to the normal population as the illness becomes chronic (14). The IgE levels are often reported as normal, however Klapow argues that they may really reflect a decline in IgE. A history of allergies is often reported by patients (1), which should raise IgE above normal. However the actual data indicate that IgE is lower than normal in most studies, according to Klapow, which suggests active IgE suppression.
There are also a number of characteristics of certain chronic roundworm infections that would result in fairly large effects from relatively low levels of organisms (1). And most of these effects correspond fairly closely with the situation in CFS. For instance, C. pulmoni might be like other roundworms that have been shown to secrete substances that could have quite negative effects on infected humans. The secreted substances include one that mimics the limbic system neuropeptide HCNP (hippocampal cholinergic neurostimulatory polypeptide), which is thought to be involved in the immune system and memory (1, 16, 17, 18). Other potentially harmful substances include ones that are similar to the IgE inhibitor CD23 (19), acetylcholinesterase (20), VIP (vasoactive intestinal polypeptide) (1, 21), and some that are inducers of autoimmunity (22).
Substances secreted by the roundworms could act in a number of ways to affect the immune system, for instance, they could induce their host to have immune reactions to a wide variety of mostly harmless antigens (1, 23) or cause autoimmune reactions (1, 24). The VIP-like substances can cause MAST cells to become unstable and overreact to antigens (25). This might be involved in the food and chemical sensitivities reported in CFS patients. A VIP-like substance secreted by the roundworm might also influence autonomic cardiovascular reflexes and result in symptoms like those experienced in CFS involving abnormal regulation of blood pressure (orthostatic intolerance or POTS and related conditions). A sort of poisoning of cholinergic neurotransmission might occur through the roundworm’s secretion of antigenic forms of acetylcholinesterase, and this might increase sensitivity to inhaled chemical irritants (1).
The probable life cycle characteristics of the roundworm also may be important in yielding clues to the nature of CFS. It is thought to enter the body through ingestion of food contaminated with feces containing C. pulmoni (1, 10). Then, the larvae pass through the intestinal tract, from which they burrow through the intestinal walls into tissue. Apparently, some larvae make it to the lungs to develop into adults and then produce another generation to continue the cycle. In the process of burrowing through tissue, the larvae create tiny holes in the gut, which could allow other infectious viruses, bacteria and fungi to enter the tissue more easily. Roundworms themselves can also serve as reservoirs for other microbes, such as viruses (1). This phenomenon, combined with the immunosuppressive effects already discussed, could help allow other infectious microbes, including opportunistic ones, to gain entry to the tissues, take hold and become more serious. This could help to explain the wide variety of infectious agents that have been identified in various subsets of CFS patients (26).
Further Possible Connections of Roundworms With CFS and Other Illnesses
It has been found that eosinophils are physiologically activated in CFS (1, 27). However, they are not much increased in number, being only marginally elevated in only about 20% of patients. This would be consistent with an immune suppressing roundworm infection.
CFS patients have considerable cognitive difficulties and these might be due primarily to cytokines or substances secreted by the proposed roundworm. But it should be noted that in other species, chronic disseminated roundworm infections can lead to roundworms infecting the brain (4). Although the postulated life cycle of C. pulmoni involves an ability to reproduce only in the lungs, there is also evidence of a migratory larval stage which could invade many different tissues, including the brain.
There is also an interesting way in which roundworms might interact with emotions and stress responses that some research has linked with CFS, as well as a variety of other illnesses. Klapow states that it “is known that roundworm infections can produce emotional symptoms, likely due to their cytokine and neurotransmitter secretions” (1, 18), and this may be due to secretion of HCNP (see above). In addition, elevated cortisol is known to potentially worsen roundworm infections (hyperinfection) (1, 4). Thus, a stressful event that produced a period of elevated cortisol might have seemed to initiate the CFS because it might have worsened an existing latent roundworm infection to the point where symptoms became obvious. In those with CFS, who have, by definition, been sick for more than six months, many patients have moved into another phase of illness where they have lower serum cortisol. This may be an attempt by the body to fight the roundworm infection, since it is known that animals with chronic roundworm infections have low cortisol (1, 28, 29). This low cortisol is thought to be an attempt by the body to eliminate the parasite by countering the strategies used by the roundworm. In other words, high cortisol lowers the anti-parasitic immune response, so the low cortisol of the animal would increase the anti-parasitic response. According to this theory, long term use of cortisone in CFS, even at fairly low levels, might be counterproductive (1).
Whether or not C. pulmoni can account for CFS, roundworms of this sort might be a useful area for research in a variety of illnesses, especially given the recent increases in knowledge of their potential for evading and manipulating the immune system. Also, recent increases in international travel/immigration and the past history of introductions of roundworms into Western countries support the view that more research on helminthes is needed. The lower prevalence of the more obvious helminthic infections in wealthier countries might explain the slowness in research on these disease agents. There may well be other unknown roundworms that play roles in diseases that are not yet suspected.
Potentials for Treatment
Only 3 patients are currently known to have attempted treatment of C. pulmoni with anti-roundworm drugs. Improvement through drug treatment appears promising, however long term treatment in one patient indicates that the roundworm may be difficult to completely eradicate (5). The most promising drugs based on this very limited anecdotal evidence appear to be oral ivermectin and the inhalation of an amount of dissolved thiabendazole equal to approximately 5% to 7% of the oral dose. Now, thiabendazole would have to be replaced by the less toxic albendazole or another more soluble drug (inhaled forms of anti-parasitic drugs are not commercially available at present). Oral thiabendazole was too toxic and should not be used. Oral albendazole, while having significant side effects, might prove to be useful in combination with other drugs. Inhaled low dose thiabendazole in one patient seemed to have a delayed effect resulting in marked improvement after weekly use for 4 to 5 months. The delay in improvement could be due to the long life cycle of the roundworm, which means that larvae in the rest of the body can still cause symptoms. for a long time even if those in the lungs are killed. The use of oral ivermectin (brand name, Stromectol) was accompanied by itching and/or diarrhea, perhaps indicating a reaction to the die-off of the roundworm larvae. It might be that a combination of drugs used for a long time might be needed to eradicate the roundworm. However, based on the experience of two of the patients, it may be that treatment with ivermectin alone might reduce the severity of the illness significantly in only a few weeks or months.
There is not yet sufficient information to know what approach is best. Perhaps a weekly dose of oral ivermectin at the amount adjusted for weight (e.g., 6-21 mg) or perhaps several days in a row of ivermectin repeated every few weeks. Future research will have to determine what is most effective. The fairly low reproductive rate of the roundworm would probably mean that it would take intensive treatment for a fairly long time (perhaps a year or more) before drug resistance would be likely to develop. Two of the patients did take enough of the anti-roundworm drugs to feel they improved significantly (some improvement in one patient in a few weeks and in the other in a few months). One patient used several drugs and the other used only ivermectin. But, of course, this is only anecdotal information and must be interpreted very cautiously. Ivermectin has some potential side effects, but they are not as severe as some other drugs taken by CFS patients on an experimental basis. Inhalation of drugs other than thiabendazole might also have potential, however, one patient’s trial of inhaled ivermectin did not seem to be very successful (30).
Characterizing the Roundworm’s DNA and the Development of a Commercial Test
The development of a commercially available test and a complete characterization of the DNA of C. pulmoni has been slowed during the first few years following Klapow's discovery by the poor quality of most of the specimens, which were often partial or decayed, and the long hours needed to find each specimen (sometimes as many as 200 hours per patient). Only very recently, Klapow was able to find several fresh C. pulmoni specimens, which lead to greater interest among roundworm specialists in academia. Now, specialized techniques can be employed to characterize specimens by DNA and electron microscope imaging. However, the availability of a commercial test for the roundworm may still be a year or more in the future. Those researchers interested in trying to find C. pulmoni in sputum might go to the web site (members.tripod.com/lak123), where there are diagrams of male and female C. pulmoni and detailed instructions on the techniques that might be used to process and examine samples from patients. Unfortunately, due to the many hours needed to use the microscope to find specimens and the time needed for his current research, Dr. Klapow can not test patients for C. pulmoni at the present time. When a test is available, the above web site will announce it. (Note: Doctors and researchers who would like to reach Dr. Klapow can do so through the author of this article at jcwat101@aol.com).
Some Speculations on Diagnosis and Treatment
So far, I have been summarizing the work of Dr. Klapow and the research on other roundworms that he describes. The current lack of a diagnostic test and the scarcity of information on the best treatment approach is disappointing for CFS patients. I have a number of speculative ideas for what doctors and patients might do if they want to try to diagnose, treat and help in research in this very experimental area. I am not advocating or recommending any treatment approaches, just sharing my own speculations on possibilities for what might be done while awaiting definitive answers.
First, in the area of diagnosis, those doctors and researchers with the abilities and supplies needed, might try to identify C. pulmoni microscopically according to the instructions at: www.members.tripod.com/lak123. In addition, the level of suspicion of a roundworm infection in a patient might be increased by a number of symptoms and signs. Although none of these signs and symptoms might prove to be necessary, and there is not yet sufficient data to prove they increase the likelihood, nevertheless, on theoretical grounds, they might increase the chances of a roundworm infection in a CFS patient. They include travel to, or direct or indirect contact with Southeast Asia or Northern Australia or their immigrants, spotted rashes, low grade eosinophilia at some point in the illness, pre-CFS IgE allergies that later developed into lower IgE levels, extensive non-IgE food and/or chemical sensitivities, gastrointestinal symptoms such as irritable bowel syndrome, a respiratory infection coinciding with the beginning of CFS symptoms, the role of high levels of stress in the beginning of the illness, or a persistent cough. Also, some of the substances that might be secreted by C. pulmoni might be investigated. This is particularly experimental, but a doctor might look for elevated CD23 lymphocyte markers. Or qualified researchers might look for substances that are similar in structure to HCNP, VIP or some of the other substances secreted by roundworms, as discussed above.
Another possibility for both diagnosis and treatment is the empirical therapeutic/diagnostic probe. If a doctor feels it is warranted in a particular CFS patient, he/she could prescribe a dose of ivermectin. If the patient has itching or diarrhea, or some other symptom that suggests a die-off reaction, soon after the ivermectin is given, then this might be evidence of a roundworm infection. The patients who have tried this drug indicate that no benefit is achieved by only one dose. If ivermectin was repeated on a number of occasions, and the die-off reaction became gradually less and/or the patient improved, this might support the role of a roundworm. For those using ivermectin intensively, it would probably be advisable to do periodic blood tests, in case side effects develop. For other diseases, ivermectin is typically used at a rather low frequency and so there is not much data on more intensive use in humans, although use in animals has been fairly extensive.
There is also a way in which one could test the effect of herbal and other potential anti-roundworm agents that might have less side effects than ivermectin. If one gave ivemectin on 2 or 3 occasions and found a consistent die-off response, then one could give the alternative substance, and then by comparison with the effect of the ivermectin, one might attempt to judge whether the alternative substance had anti-roundworm effects. There is some research in the animal literature suggesting some herbs have an effect on roundworms (31). For instance, some dewormers used include some species of Artemesia (wormwood), as well as the herb, Chenopodium ambrosiodes (goosefoot). But of course, to establish the safety and efficacy of alternative agents against potential C. pulmoni infections in humans, much research would be needed.
It also may be that some dietary components of Asian food might have anti-roundworm effects. For instances marsala, a spice used in Southeast Asian cooking, contains catechin a condensed tannin (CT) also found in green tea. CT's have been reported to reduce nematode survival and reproduction (30). There is also some suggestive evidence that the alcohol extract of Pau D'arco may produce lowered body itching and might have a beneficial anti-roundworm effect (30). However, it may be difficult for some patients to tolerate herbs due to the tendency for food sensitivities in CFS (discussed below). For those interested in researching antihelminthic alternatives, further searching in the veterinary and herbal literature would probably be helpful.
Another potentially beneficial approach would be to focus on reducing the negative effects of immune overactivation that might be caused by the roundworm, which might be responsible for a large part of the symptoms experienced. This could be done by focusing on only consuming foods with the least potential for provoking sensitivity reactions, as well as avoiding exposure to chemical irritants. Most CFS patients do not have seem to have many IgE-mediated allergies, but they tend to have more non-IgE sensitivities that utilize Type II, Type III and Type IV immune reactions, sometimes called delayed-type hypersensitivities. The approach of minimizing these immune hypersensitivities has been helpful to many with CFS and a wide array of conditions (32, 33). It is likely that most CFS patients have more food and chemical sensitivities than they realize due to “masking” effects and could benefit greatly from going further in identifying their optimal diet and reducing chemical exposure (33, 34). A great deal can be done by the patient at home to reduce immune sensitivity reactions, by using the pulse test and other methods, in addition to laboratory and clinical methods (33).
For example, one CFS patient who tested positive for C. pulmoni has improved greatly over many years of reducing food and chemical immune hypersensitivities (this patient is still very far from well and must be on a very restrictive diet). It is also interesting that whenever a period of minimal food sensitivity exposure is achieved in this patient, with less anxiety, diarrhea and insomnia, there is a corresponding increase in sinus symptoms, such as congestion, sneezing and coughing. Thus, there is a tendency to alternate between types of symptoms. This occurs in the absence of any change in inhalant allergy exposure and in an environment in which inhalant exposures have been minimized with a good air filter (though admittedly, the environment is not as pure as a few chemically sensitive patients have attained). This type of alternation of symptom types has been described as alternating between symptom states defined by Randolph and Moss as alternating between +1 or +2 and -1 or -2 (34).
There may be other explanations for these alternating states, but it might be that in some patients, the alternation could be due to a C. pulmoni infection. The non-IgE food sensitivity reactions might be increasing both cortisol and TH1 immune reactions (with symptoms of anxiety, diarrhea and insomnia), which temporarily suppresses the TH2, anti-parasitic response. When the food sensitivity reactions and associated TH1 immune reactions are reduced, the TH2, anti-parasitic response can then increase and produce the sinus symptoms as part of the immune system’s attempt to eradicate the roundworm. The extreme difficulty this patient has experienced in completely eliminating the food sensitivities could be due to fighting an uphill battle in the context of the multiple effects on immune function of the roundworm infection (see above). The roundworm’s proposed manipulation of the patient’s immune system, as well as its burrowing through the gut wall making it truly a “leaky gut,” may have made any fight to eliminate the sensitivities much harder and perhaps impossible with food/chemical sensitivity reduction techniques alone. One might speculate that some patients with milder or shorter-term C. pulmoni infection and few or no coinfections, perhaps could get well using the allergy/sensitivity reduction alone.
Possible Relationship to a New Treatment Approach For TH1 Dominant Diseases
Now, I will briefly mention my own view on how research on this roundworm might relate to some recent research on autoimmune disease, Lyme disease, fibromyalgia and CFS that emphasizes treating the cause of excessive TH1 inflammation. This approach proposes the causative role of intracellular cell wall deficient (CWD) forms of bacteria that seem to use an excessive TH1 inflammatory response to hide from the immune system (35, 36). I would suggest the hypothesis that perhaps half of the CFS patients, possibly the sickest ones, may have a symbiotic situation in which the roundworm and CWD bacteria are able to benefit from each other's activities by promoting an excessive TH1 response The roundworm might directly cause a TH1 response through secreting substances that stimulate IFN gamma (11) or through other substances that stimulate autoimmunity and overreactions to antigens in general (23, 24). Indirectly, they may promote a TH1 response by burrowing through the intestinal wall, allowing other microbial pathogens (including CWD capable bacteria) and food and chemical antigens easier access to the bloodstream and tissues and thus provide even more antigens to stimulate and overactivate the immune system. By contributing to TH1 inflammation, C. pulmoni might be promoting the proliferation of CWD forms of bacteria, while itself benefiting from the TH1 response’s suppression of the anti-parasitic TH2 response.
The research of Marshall et al (35, 36) has led to the development of the Marshall Protocol (MP) for diseases of excessive TH1 inflammation. The Marshall Protocol involves the use of immune modulation to reduce the excessive TH1 response, combined with a series of low dose antibiotics, introduced very gradually. After having good success in treating the autoimmune disease sarcoidosis, it has only recently begun to be used in CFS and Lyme patients and has shown some positive initial results. It is possible that integrating anti-roundworm treatment into the Marshall Protocol in some way might be worth considering at some point. Perhaps some of the sickest CFS patients might benefit from anti-roundworm treatment and/or reducing the food and chemical sensitivities it may be fostering, before trying the MP. The MP is quite difficult for some patients at the beginning and some patients have had to stop it and then try again later. The very sickest of the CFS population are, for the most part, probably not those who are currently trying the MP, as they are typically too ill to study it and participate in the free Internet discussion groups (marshallprotocol.com or sarcinfo.com).
The idea that some patients have both the proposed roundworm infection and CWD infection is not purely theoretical. A number of CFS patients that Klapow has found to be positive for C. pulmoni have also tested positive for Lyme disease (30). The Lyme disease spirochete is known to also exist in CWD forms, the form of bacteria that the Marshall Protocol was designed to treat. As is widely known from experience with HIV-AIDS, there are certain immune suppressing organisms that make it more likely for one to have multiple infections and it may be that this is a role that chronic infection with C. pulmoni plays in CFS. Whether it is involved in other diseases is an open possibility, as the only patients tested for this roundworm so far are CFS patients.
The way in which the MP is currently being used fits in some ways with the state of the roundworm diagnosis situation. This is because with the MP, the Jarisch-Herxheimer reaction (bacterial die-off reaction) in response to antibiotics is used as an indicator that a particular antibiotic is killing CWD bacteria. The use of ivermectin as a diagnostic/therapeutic probe (see above) to see if a die-off reaction occurs is somewhat similar. At present, it is unknown how ivermectin might interact with the immune modulation of the MP and it should not be combined with the MP until more is known. Caution is warranted because the MP intensifies the action and die-off reactions of certain antibiotics (thus requiring the use of quite low initial antibiotic dosages). However, prior treatment for those CFS patients who are too ill to begin the MP might be an option to consider. Or if it were found that a CFS patient was not progressing well, the patient might stop the MP temporarily and try an anti-roundworm therapeutic probe or treatment trial, and then resume the MP.
From the perspective of a hypothesized C. pulmoni infection, combining the MP with anti-roundworm treatment might get around the potential problem of anti-roundworm drug resistance or difficulty of complete eradication. These difficulties have been observed in animals with other chronic roundworm infections. Also, there is some indication that in the one patient who has attempted long term treatment of C. pulmoni with several anti-roundworm drugs, some drug resistance may have developed. It might be that the immune modulation of the MP and its reduction of the CWD bacteria, might help a promote a better immune response to the roundworm parasite that would aid the anti-roundworm drugs sufficiently to completely eradicate the roundworms.
The above sections have discussed a type of symbiotic relationship between CWD bacteria and C. pulmoni in which they each affect the human immune system in a way that helps themselves and each other. Another possibility in CFS is a sort of symbiotic relationship between certain viruses and roundworm infections. For example, there is evidence of a significant association between the roundworm infection strongylosis and HTLV1 viral infections (37).
Conclusions
In conclusion, for most patients, it would probably be wise to wait until DNA analysis is able to confirm the work on C. pulmoni done so far and a commercial test for it is available. Then, research trials will be done to try to determine what drug or combinations of drugs are most effective for treatment. But for those doctors, researchers and patients who want to contribute to research in this area and do not want to wait for several years, some speculations have been presented as a starting point. It is hoped that these research ideas will lead to information that will help in the process of determining what lab tests and anti-microbial agents would be most useful, as well as gain further evidence regarding the role of this “hidden lung worm” in chronic fatigue syndrome.
(Note: Any doctors, researchers or patients who would like to share any experiences they may have related to the above diagnostic and treatment possibilities are encouraged to send accounts to me at: jcwat101@aol.com), and if they seem significant, I may compile them for a future article for the purpose of advancing research in this area. All personal information will be kept confidential.)
References
(1) Klapow LA: A suspected new chronic roundworm parasite, Cryptostrongylus pulmoni (provisional), associated with chronic fatigue syndrome in blinded trials. Poster Presentation. Proceedings of the 2001 ME/CFS AHMF Conference in Sydney Australia
(2) Klapow LA: Roundworm-like specimens in the sputum of chronic fatigue syndrome patients and controls in open and blinded analysis. Journal of Chronic Fatigue Syndrome 1999;5 (3/4):247-8.
(3) Von Kuster LC, Genta RM. Cutaneous manifestations of strongyloidiasis. vArch Dermatol 1988 Dec;124(12):1826-30
(4) Fauci, Anthony S., and others, editors. 1997. Harrison’s Principles of Internal Medicine. McGraw Hill.
(5) Klapow LA: Evidence for a new chronic parasite in CFS: The finding and the challenge. Presentation for the Carousel Network for Chronic Neuroimmune Diseases of Sonoma County. May 2004. Santa Rosa, CA.
(6) Durette-Desset MC, Chaubaud AG, 1981. Sur Molineinae Parasites De Mammiferes. Annales de Parasitology (Paris), 1981; 56(5):489-502. French [English abstract]
(7) Klonoff DC. Chronic Fatigue Syndrome. Clin Infect Dis 1992 Nov;15(5):812-23
(8) De Vries M, Soetekouw PM, Van Der Meer JW, Bleijenberg G. Natural course of symptoms in Cambodia veterans: a follow-up study. Psychol Med 2001 Feb;31(2):331-8.
(9) Pelletier LL Jr. Chronic strongyloidiasis in World War II Far East ex-prisoners of war. Am J Trop Med Hyg 1984 Jan;33(1):55-61.
(10) Klapow, LA: Amphids and other defining roundworm structures in the larvae of Cryptostongylus pulmoni from patients with chronic fatigue syndrome. Poster Presentation. AACFS Seventh International Conference on Chronic Fatigue Syndrome, Fibromyalgia, and other Related Illnesses Conference, Oct. 8-10, 2004, Madison, WI.
(11) Grencis RK, Entwistle GM. Production of an interferon-gamma homologue by an intestinal nematode: Functionally significant or interesting artefact? Parasitology 1997;115 Suppl:S101-6
(12) Pritchard DI, Kumar S, Edmonds P: Soluble (s)CD23 levels in a parasitized population from Papua New Guinea. Parasite Immunol 1993 Apr;15(4):205.
(13) Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Muller WE, Schroder HC, Carter WA, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis 1994 Jan;18 Suppl 1:S96-104.
(14) Baraniuk JN, Clauw D, Carneiro ALM et al. IgE Concentrations in Chronic Fatigue Syndrome. J Chronic Fatigue Syndrome 1998;4(1):13-21.
(15) Mawle A, Nisenbaum R, Dobbins J et al. Immune Responses associated with Chronic Fatigue Syndrome: A Case-Controlled Study. J Infect Diseases, 1997:175;316-41.
(16) Gems D, Ferguson CJ, Robertson BD, Nieves R, Page AP, Blaxter ML, Maizels RM: An abundant, trans-spliced mRNA from Toxocara canis infective larvae encodes a 26-kDa protein with homology to phosphatidylethanolamine-binding proteins. J Biol Chem 1995 Aug 4;270(31):18517-22
(17) Klapow, LA (unpublished). BLAST analysis of the 26-kDa secretion of Toxacara canis resembles the limbic system neuropeptide HCNP.
(18) Marmor M, Glickman L, Shofer F, Faich LA, RosenbergC, Cornblatt B, Friedman S: Toxocara canis infection of children: epidemiologic and neuropsychologic findings. Am J Public Health 1987 May;77(5):554-9.
(19) Loukas A, Doedens A, Hintz M, Maizels RM. Identification of a new C-type lectin, TES-70, secreted by infective larvae of Toxocara canis, which binds to host ligands. Parasitology 2000 Nov;121 Pt 5:545-54.
(20) McKeand JB, Knox DP, Duncan JL, Kennedy MW. The immunogenicity of the acetylcholinesterases of the cattle lungworm Dictyocaulus viviparus. Int J Parasitol 1994 Jul;24(4):501-10.
(21) Foster N, Lee DL. Vasoactive intestinal polypeptide-like and peptide histidine isoleucine-like proteins excreted/secreted by Nippostrongylus brasiliensis, Nematodirus battus and Ascaridia galli. Parasitology 1996 Sep;113 ( Pt 3):287-92.
(22) Chandrashekar R, Curtis KC, Weil GJ. Molecular characterization of a parasite antigen in sera from onchocerciasis patients that is immunologically cross-reactive with human keratin. J Infect Dis 1995 Jun;171(6):1586-92.
(23) Pritchard DI. Immunity to helminths: is too much IgE parasite--rather than host-protective? Parasite Immunol Jan 1993:15;5-9.
(24) von Mikecz A, Konstantinov K, Buchwald DS, Gerace L, Tan EM: High frequency of autoantibodies to insoluble cellular antigens in patients with chronic fatigue syndrome. Arthritis Rheum 1997 Feb;40(2):295-305.
(25) Stewart MJ, Emery DL, McClure SJ, Bendixsen: The effects of four neuropeptides on the degranulation of mucosal mast cells from sheep. Immunol Cell Biol 1996 Jun;74(3):255-7.
(26) John JF Jr, Friedman, K: Infections in CFIDS. The CFIDS Chronicle. Spring 2002;15(2). The Chronic Fatigue and Immune Dysfunction Syndrome Association of America, Charlotte, NC. Adapted from “A Consensus Manual for the Primary Care and Management of Chronic Fatigue Syndrome,” 2001. Acad of Med of New Jersey, U of Med & Dent NJ and NJ Dept of Health and Senior Services.
(27) Schacterle RS, Conti F, Laura Magrini L, Komaroff AL, Valesini G. Increased Eosinophil Protein X Levels in Chronic Fatigue Syndrome. J of Chronic Fatigue Syndrome, 2001:9 (1/2);21-30.
(28) Bailenger J, Faraggi G: Mechanism of hypocorticosteronemia action of Strongyloides ratti in the rat] : Ann Parasitol Hum Comp 1975 Mar-Apr;50(2):187-97. [English abstract]
(29) Bailenger J, Carcenac F, Faraggi G, Cabannes A: Role of hypocorticosteronemy in the self cure mechanism in rats with Strongyloides ratti parasites (author's transl)] Ann Parasitol Hum Comp 1976 Nov-Dec;51(6):653-65. [English abstract]
(30) Klapow, LA: personal communication.
(31) Duval, J: The control of internal parasites in ruminants. (http://www.eap.mcgill.ca/AgroBio/ab370-04e.htm)
(32) Waterhouse, JC: Innovative Approaches to Fibromyalgia. CISRA’s Synergy Health Newsletter 1996;1:1-5, Chronic Illness Support and Research Association, Pasadena, CA.
(33) Waterhouse, JC: Food Allergy/Sensitivity: The Pulse Test and Other Strategies. CISRA’s Synergy Health Newsletter 1999;5:1-11. Chronic Illness Support and Research Association, Pasadena, CA.
(34) Randolph TG, Moss, R.W. An Alternative Approach to Allergies. Harper & Row, 1980.
(35) Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3).
(36) Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics-implications for autoimmune disease. Autoimmun Rev 2004;Jun;3(4):295-300.
(37) Porto AF, Neva FA, Bittencourt H, Lisboa W, Thompson R, Alcantara L, Carvalho EM: HTLV-1 decreases Th2 type of immune response in patients with strongyloidiasis. Parasite Immunol 2001 Sep;23(9):503-7.
Copyright 2004, J.C. Waterhouse, Ph.D.
Click here to return home: CISRA--SynergyHN Home Page
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
members.aol.com/SynergyHN/roundworm
Click here to return to: CISRA--SynergyHN Home Page
A Parasitic Roundworm Linked to Chronic Fatigue Syndrome
by J. C. Waterhouse, Ph.D.
(Disclaimer: This material is intended for information only and is not medical advice. Neither CISRA nor the editor receive funding from any doctor, lab or manufacturer of any medication or associated products.)
Abstract
This article reports on the work of Lawrence Klapow, Ph.D., who has found evidence of a new roundworm species, provisionally named Cryptostrongylus pulmoni, in patients with chronic fatigue syndrome (CFS). In a blinded, controlled study (1, 2), the roundworm adults and larvae were found in sputum of almost half of the CFS patients and none of the controls. This association with CFS was found to be highly statistically significant (P~0.001). Currently, commercial laboratory tests and drug treatment trials await the results of recent efforts to characterize the roundworm's DNA. It is thought that the parasite reproduces in the lungs, giving rise to larvae which migrate to the intestinal tract. Some roundworm larvae burrow through the intestinal walls into tissue and migrate back to the lungs to develop into adults, which then produce larvae to continue the cycle. Only 3 patients have attempted treatment with anti-roundworm drugs so far, and although symptom improvement appears promising, it appears that this proposed new roundworm may be difficult to completely eradicate. The most promising drugs based on this very limited anecdotal evidence appear to be ivermectin and inhaled low dose thiabendazole (now, it would have to be replaced by albendazole). Oral thiabendazole was too toxic and should not be used. The usefulness of oral albendazole remains to be further evaluated along with other drugs. The use of ivermectin was accompanied by itching and/or diarrhea, perhaps indicating a roundworm die-off reaction. Unlike many other helminthic parasites, this species does not appear to produce elevated eosinophils or IgE when the illness becomes chronic. Instead, it is thought to use strategies that certain other roundworm species have been found to use that elevate the TH1 immune response and inhibit a more effective anti-parasitic TH2 response. Klapow also proposes ways in which infection by this species may be able to explain a number of common CFS characteristics, like initial respiratory infection, low cortisol, frequent gastrointestinal complaints, leaky gut, low blood pressure and neurological symptoms. This author concludes with some speculations on alternative treatment and diagnostic possibilities.
Editorial Note (Added in 2006 and updated in April, 2008): For an update on my views of roundworm treatment at present and treatment of chronic fatigue syndrome in general, see the transcript of a talk I gave in 2005. I give an overview of what has helped me most, with an emphasis on a new approach, called the Marshall Protocol (MP). For many, the MP seems to be able to reverse the immune dysregulation that may account for susceptibility to multiple chronic infections. My own view is that there needs to be more research on treatment of this roundworm before I would recommend attempting it. Careful and thorough attention to identifying and controlling food sensitivities (see Food Allergy/Sensitivity Testing), followed by the use of the Marshall Protocol appears to be a good alternative approach at this time, while awaiting future research on this proposed new roundworm species.
Introduction
Chronic fatigue syndrome (CFS) is a disease characterized by substantial fatigue of greater than 6 months duration, muscle aches and cognitive problems and frequently involves sore throat, tender lymph nodes and unrefreshing sleep. Currently no established cause has been found, but there are many proposed causes, some infectious and some not. Some have proposed there may be subgroups of CFS patients with different causes. One hypothesis is that many cases of CFS are caused by a new species of roundworm, provisionally named Cryptostrongylus pulmoni (C. pulmoni). An invertebrate zoologist, Lawrence Klapow, Ph.D. has found evidence for this roundworm during years of research, and his findings have been further supported by the results of a blinded controlled study (1). This article will first discuss Klapow’s hypothesis that a chronic infection caused by C. pulmoni is the source of many of the prominent symptoms of CFS and then explore possibilities for treatment.
Historical and Scientific Background
Klapow’s discovery began through a discussion with an immunologist regarding a CFS patient. The patient was thought to possibly have a roundworm infection, due to a slightly elevated level of eosinophils in the patient’s blood and some unusual rashes (1, 3). A series of culture and stool tests for the known type of roundworm suspected to be the cause (a threadworm, Strongyloides stercoralis) came up negative. However, since Klapow was aware of chronic parasites that migrate between the digestive and respiratory tracts, he decided to do microscopic investigations of the sputum coughed up by the patient. He found what he believed to be a previously unknown roundworm and gave it a provisional name, Cryptostrongylus pulmoni, which means “hidden lung worm.”
Roundworms (also called nematodes or helminthes) cause a variety of acute and chronic infections around the world, some serious and some mild and self limited (1, 4). There is a history of roundworms being introduced into Western countries following Asian wars, when soldiers and immigrants traveled between Europe and Asia (1). In the case of the proposed new roundworm, C. pulmoni, Klapow’s study of the anatomy of C. pulmoni suggests it may be related to the trichostrongylid genus Nycteridostrongylus (1, 5, 6). This type of roundworm infects small mammal’s intestines in Southeast Asian and Northern Australian rain forests. This resemblance, if confirmed, together with the increase in CFS cases in the 1980’s (7) suggests that soldiers and immigrants from the East Asian Tropics might have introduced the disease into the U.S. and Europe following the French and American involvements in East Asia. The tendency to latency and slow development of symptoms would make it hard to clearly identify causal patterns. There is some support among data on soldiers returning from Southeast Asia developing CFS-like symptoms (8), but clearly much more research needs to be done on this. Taking a longer term historical view, in the Victorian era, there may have been a similar situation in which soldiers returning from Indochina brought a roundworm infection back to France (1). Many American women traveling to France in that era could then have brought back roundworm infections that had originated in Asia. This could possibly account for the “neurasthenia” observed in that era ( some have compared neurasthenia to CFS). Whether C. pulmoni was a source of infection at that time is unknown. For another example, in 1974, chronic cases of Strongyloides stercoralis, another roundworm, were diagnosed in some British soldiers who had been POWs in Southeast Asia in WWII (9).
Evidence From a Blinded, Controlled Study
Evidence for the presence of this new roundworm has been reported in a blinded, controlled study, for which several prominent CFS researchers referred patients (e.g., Dr. Anthony Komaroff, Dr. David Bell and Dr. Roger Mazlen) (1, 2). In the first part of the study, 5 of the 11 CFS patients (45%) and none of the 6 controls were found to have the C. pulmoni larvae in a 3-day sputum sample (2). In the second larger blinded study that included additional CDC-defined CFS patients and controls, the same pattern was obtained. A total of 14 out of 30 (47%) of the CFS patients tested positive, while none of the 21 controls tested positive for the roundworm (1). The association between C. pulmoni infection and CFS was highly significant. It is extremely unlikely that the results could have been due to chance. The actual percentage who have the roundworm infection is likely to be somewhat higher, since the larvae are rare and hard to detect, requiring somewhat specialized techniques and considerable time at the microscope in distinguishing the adults and larvae from debris. However, despite difficulties, Klapow has succeeded in photographing C. pulmoni and distinguishing its anatomical characteristics (10).
In the larger study of the roundworm in CFS (1), questionnaires were filled out by the participants to see if any relationship could be found between the types of patients, their symptoms and whether or not their sputum tested positive for C. pulmoni. The data reveal no significant differences in symptoms between those patients who tested positive and those patients who tested negative. There was not a higher incidence of coughs (30-40%) or travel outside the U.S between C. pulmoni positive and negative patients. Patients showed highly statistically significant differences from controls in reported allergies, spotted rashes and bowel symptoms, as well as in the incidence of C. pulmoni (significance levels ranged from P-0.001 to P<0.001). The relatively low occurrence of significant coughing in C. pulmoni positive patients might relate to the lack of a very effective immune reaction to the roundworm, as discussed below.
Why Might a New Roundworm Species Be So Elusive and Chronically Debilitating?
There are a number of factor that might explain why this new roundworm has not been identified before. Among the reasons may be its rarity, small size, lack of an esophageal bulb (which makes it harder to identify) and its likely period of latency. There are also some very interesting characteristics of roundworm infections that have been discovered in other roundworm species that could contribute to a delay in discovery. For instance, C. pulmoni may be like other roundworms that have been found to have ways of manipulating the mammalian immune system to keep it from responding effectively to eliminate it (1). One consequence of these evasive tactics is the lack of much increase of the typical indicators of a TH2 anti-parasitic immune response in the blood of patients chronically infected with roundworms (e.g., elevated eosinophils and IgE). This may be explained by the fact that some roundworm species have been reported to produce a substance similar to interferon-gamma which might stimulate the TH1 anti-viral pathway (1, 11). The stimulation of the anti-viral pathway then suppresses the anti-parasitic pathway, thus suppressing IgE and eosinophils. This has been found to occur through soluble CD23, an IgE binding protein which reduces serum IgE (12). The consequence of these tactics is a picture fairly similar to what is observed in CFS. There is an activation of the anti-viral pathway (13), fairly low levels of increased eosinophils sometimes observed early in the illness, and an actual decrease in IgE relative to the normal population as the illness becomes chronic (14). The IgE levels are often reported as normal, however Klapow argues that they may really reflect a decline in IgE. A history of allergies is often reported by patients (1), which should raise IgE above normal. However the actual data indicate that IgE is lower than normal in most studies, according to Klapow, which suggests active IgE suppression.
There are also a number of characteristics of certain chronic roundworm infections that would result in fairly large effects from relatively low levels of organisms (1). And most of these effects correspond fairly closely with the situation in CFS. For instance, C. pulmoni might be like other roundworms that have been shown to secrete substances that could have quite negative effects on infected humans. The secreted substances include one that mimics the limbic system neuropeptide HCNP (hippocampal cholinergic neurostimulatory polypeptide), which is thought to be involved in the immune system and memory (1, 16, 17, 18). Other potentially harmful substances include ones that are similar to the IgE inhibitor CD23 (19), acetylcholinesterase (20), VIP (vasoactive intestinal polypeptide) (1, 21), and some that are inducers of autoimmunity (22).
Substances secreted by the roundworms could act in a number of ways to affect the immune system, for instance, they could induce their host to have immune reactions to a wide variety of mostly harmless antigens (1, 23) or cause autoimmune reactions (1, 24). The VIP-like substances can cause MAST cells to become unstable and overreact to antigens (25). This might be involved in the food and chemical sensitivities reported in CFS patients. A VIP-like substance secreted by the roundworm might also influence autonomic cardiovascular reflexes and result in symptoms like those experienced in CFS involving abnormal regulation of blood pressure (orthostatic intolerance or POTS and related conditions). A sort of poisoning of cholinergic neurotransmission might occur through the roundworm’s secretion of antigenic forms of acetylcholinesterase, and this might increase sensitivity to inhaled chemical irritants (1).
The probable life cycle characteristics of the roundworm also may be important in yielding clues to the nature of CFS. It is thought to enter the body through ingestion of food contaminated with feces containing C. pulmoni (1, 10). Then, the larvae pass through the intestinal tract, from which they burrow through the intestinal walls into tissue. Apparently, some larvae make it to the lungs to develop into adults and then produce another generation to continue the cycle. In the process of burrowing through tissue, the larvae create tiny holes in the gut, which could allow other infectious viruses, bacteria and fungi to enter the tissue more easily. Roundworms themselves can also serve as reservoirs for other microbes, such as viruses (1). This phenomenon, combined with the immunosuppressive effects already discussed, could help allow other infectious microbes, including opportunistic ones, to gain entry to the tissues, take hold and become more serious. This could help to explain the wide variety of infectious agents that have been identified in various subsets of CFS patients (26).
Further Possible Connections of Roundworms With CFS and Other Illnesses
It has been found that eosinophils are physiologically activated in CFS (1, 27). However, they are not much increased in number, being only marginally elevated in only about 20% of patients. This would be consistent with an immune suppressing roundworm infection.
CFS patients have considerable cognitive difficulties and these might be due primarily to cytokines or substances secreted by the proposed roundworm. But it should be noted that in other species, chronic disseminated roundworm infections can lead to roundworms infecting the brain (4). Although the postulated life cycle of C. pulmoni involves an ability to reproduce only in the lungs, there is also evidence of a migratory larval stage which could invade many different tissues, including the brain.
There is also an interesting way in which roundworms might interact with emotions and stress responses that some research has linked with CFS, as well as a variety of other illnesses. Klapow states that it “is known that roundworm infections can produce emotional symptoms, likely due to their cytokine and neurotransmitter secretions” (1, 18), and this may be due to secretion of HCNP (see above). In addition, elevated cortisol is known to potentially worsen roundworm infections (hyperinfection) (1, 4). Thus, a stressful event that produced a period of elevated cortisol might have seemed to initiate the CFS because it might have worsened an existing latent roundworm infection to the point where symptoms became obvious. In those with CFS, who have, by definition, been sick for more than six months, many patients have moved into another phase of illness where they have lower serum cortisol. This may be an attempt by the body to fight the roundworm infection, since it is known that animals with chronic roundworm infections have low cortisol (1, 28, 29). This low cortisol is thought to be an attempt by the body to eliminate the parasite by countering the strategies used by the roundworm. In other words, high cortisol lowers the anti-parasitic immune response, so the low cortisol of the animal would increase the anti-parasitic response. According to this theory, long term use of cortisone in CFS, even at fairly low levels, might be counterproductive (1).
Whether or not C. pulmoni can account for CFS, roundworms of this sort might be a useful area for research in a variety of illnesses, especially given the recent increases in knowledge of their potential for evading and manipulating the immune system. Also, recent increases in international travel/immigration and the past history of introductions of roundworms into Western countries support the view that more research on helminthes is needed. The lower prevalence of the more obvious helminthic infections in wealthier countries might explain the slowness in research on these disease agents. There may well be other unknown roundworms that play roles in diseases that are not yet suspected.
Potentials for Treatment
Only 3 patients are currently known to have attempted treatment of C. pulmoni with anti-roundworm drugs. Improvement through drug treatment appears promising, however long term treatment in one patient indicates that the roundworm may be difficult to completely eradicate (5). The most promising drugs based on this very limited anecdotal evidence appear to be oral ivermectin and the inhalation of an amount of dissolved thiabendazole equal to approximately 5% to 7% of the oral dose. Now, thiabendazole would have to be replaced by the less toxic albendazole or another more soluble drug (inhaled forms of anti-parasitic drugs are not commercially available at present). Oral thiabendazole was too toxic and should not be used. Oral albendazole, while having significant side effects, might prove to be useful in combination with other drugs. Inhaled low dose thiabendazole in one patient seemed to have a delayed effect resulting in marked improvement after weekly use for 4 to 5 months. The delay in improvement could be due to the long life cycle of the roundworm, which means that larvae in the rest of the body can still cause symptoms. for a long time even if those in the lungs are killed. The use of oral ivermectin (brand name, Stromectol) was accompanied by itching and/or diarrhea, perhaps indicating a reaction to the die-off of the roundworm larvae. It might be that a combination of drugs used for a long time might be needed to eradicate the roundworm. However, based on the experience of two of the patients, it may be that treatment with ivermectin alone might reduce the severity of the illness significantly in only a few weeks or months.
There is not yet sufficient information to know what approach is best. Perhaps a weekly dose of oral ivermectin at the amount adjusted for weight (e.g., 6-21 mg) or perhaps several days in a row of ivermectin repeated every few weeks. Future research will have to determine what is most effective. The fairly low reproductive rate of the roundworm would probably mean that it would take intensive treatment for a fairly long time (perhaps a year or more) before drug resistance would be likely to develop. Two of the patients did take enough of the anti-roundworm drugs to feel they improved significantly (some improvement in one patient in a few weeks and in the other in a few months). One patient used several drugs and the other used only ivermectin. But, of course, this is only anecdotal information and must be interpreted very cautiously. Ivermectin has some potential side effects, but they are not as severe as some other drugs taken by CFS patients on an experimental basis. Inhalation of drugs other than thiabendazole might also have potential, however, one patient’s trial of inhaled ivermectin did not seem to be very successful (30).
Characterizing the Roundworm’s DNA and the Development of a Commercial Test
The development of a commercially available test and a complete characterization of the DNA of C. pulmoni has been slowed during the first few years following Klapow's discovery by the poor quality of most of the specimens, which were often partial or decayed, and the long hours needed to find each specimen (sometimes as many as 200 hours per patient). Only very recently, Klapow was able to find several fresh C. pulmoni specimens, which lead to greater interest among roundworm specialists in academia. Now, specialized techniques can be employed to characterize specimens by DNA and electron microscope imaging. However, the availability of a commercial test for the roundworm may still be a year or more in the future. Those researchers interested in trying to find C. pulmoni in sputum might go to the web site (members.tripod.com/lak123), where there are diagrams of male and female C. pulmoni and detailed instructions on the techniques that might be used to process and examine samples from patients. Unfortunately, due to the many hours needed to use the microscope to find specimens and the time needed for his current research, Dr. Klapow can not test patients for C. pulmoni at the present time. When a test is available, the above web site will announce it. (Note: Doctors and researchers who would like to reach Dr. Klapow can do so through the author of this article at jcwat101@aol.com).
Some Speculations on Diagnosis and Treatment
So far, I have been summarizing the work of Dr. Klapow and the research on other roundworms that he describes. The current lack of a diagnostic test and the scarcity of information on the best treatment approach is disappointing for CFS patients. I have a number of speculative ideas for what doctors and patients might do if they want to try to diagnose, treat and help in research in this very experimental area. I am not advocating or recommending any treatment approaches, just sharing my own speculations on possibilities for what might be done while awaiting definitive answers.
First, in the area of diagnosis, those doctors and researchers with the abilities and supplies needed, might try to identify C. pulmoni microscopically according to the instructions at: www.members.tripod.com/lak123. In addition, the level of suspicion of a roundworm infection in a patient might be increased by a number of symptoms and signs. Although none of these signs and symptoms might prove to be necessary, and there is not yet sufficient data to prove they increase the likelihood, nevertheless, on theoretical grounds, they might increase the chances of a roundworm infection in a CFS patient. They include travel to, or direct or indirect contact with Southeast Asia or Northern Australia or their immigrants, spotted rashes, low grade eosinophilia at some point in the illness, pre-CFS IgE allergies that later developed into lower IgE levels, extensive non-IgE food and/or chemical sensitivities, gastrointestinal symptoms such as irritable bowel syndrome, a respiratory infection coinciding with the beginning of CFS symptoms, the role of high levels of stress in the beginning of the illness, or a persistent cough. Also, some of the substances that might be secreted by C. pulmoni might be investigated. This is particularly experimental, but a doctor might look for elevated CD23 lymphocyte markers. Or qualified researchers might look for substances that are similar in structure to HCNP, VIP or some of the other substances secreted by roundworms, as discussed above.
Another possibility for both diagnosis and treatment is the empirical therapeutic/diagnostic probe. If a doctor feels it is warranted in a particular CFS patient, he/she could prescribe a dose of ivermectin. If the patient has itching or diarrhea, or some other symptom that suggests a die-off reaction, soon after the ivermectin is given, then this might be evidence of a roundworm infection. The patients who have tried this drug indicate that no benefit is achieved by only one dose. If ivermectin was repeated on a number of occasions, and the die-off reaction became gradually less and/or the patient improved, this might support the role of a roundworm. For those using ivermectin intensively, it would probably be advisable to do periodic blood tests, in case side effects develop. For other diseases, ivermectin is typically used at a rather low frequency and so there is not much data on more intensive use in humans, although use in animals has been fairly extensive.
There is also a way in which one could test the effect of herbal and other potential anti-roundworm agents that might have less side effects than ivermectin. If one gave ivemectin on 2 or 3 occasions and found a consistent die-off response, then one could give the alternative substance, and then by comparison with the effect of the ivermectin, one might attempt to judge whether the alternative substance had anti-roundworm effects. There is some research in the animal literature suggesting some herbs have an effect on roundworms (31). For instance, some dewormers used include some species of Artemesia (wormwood), as well as the herb, Chenopodium ambrosiodes (goosefoot). But of course, to establish the safety and efficacy of alternative agents against potential C. pulmoni infections in humans, much research would be needed.
It also may be that some dietary components of Asian food might have anti-roundworm effects. For instances marsala, a spice used in Southeast Asian cooking, contains catechin a condensed tannin (CT) also found in green tea. CT's have been reported to reduce nematode survival and reproduction (30). There is also some suggestive evidence that the alcohol extract of Pau D'arco may produce lowered body itching and might have a beneficial anti-roundworm effect (30). However, it may be difficult for some patients to tolerate herbs due to the tendency for food sensitivities in CFS (discussed below). For those interested in researching antihelminthic alternatives, further searching in the veterinary and herbal literature would probably be helpful.
Another potentially beneficial approach would be to focus on reducing the negative effects of immune overactivation that might be caused by the roundworm, which might be responsible for a large part of the symptoms experienced. This could be done by focusing on only consuming foods with the least potential for provoking sensitivity reactions, as well as avoiding exposure to chemical irritants. Most CFS patients do not have seem to have many IgE-mediated allergies, but they tend to have more non-IgE sensitivities that utilize Type II, Type III and Type IV immune reactions, sometimes called delayed-type hypersensitivities. The approach of minimizing these immune hypersensitivities has been helpful to many with CFS and a wide array of conditions (32, 33). It is likely that most CFS patients have more food and chemical sensitivities than they realize due to “masking” effects and could benefit greatly from going further in identifying their optimal diet and reducing chemical exposure (33, 34). A great deal can be done by the patient at home to reduce immune sensitivity reactions, by using the pulse test and other methods, in addition to laboratory and clinical methods (33).
For example, one CFS patient who tested positive for C. pulmoni has improved greatly over many years of reducing food and chemical immune hypersensitivities (this patient is still very far from well and must be on a very restrictive diet). It is also interesting that whenever a period of minimal food sensitivity exposure is achieved in this patient, with less anxiety, diarrhea and insomnia, there is a corresponding increase in sinus symptoms, such as congestion, sneezing and coughing. Thus, there is a tendency to alternate between types of symptoms. This occurs in the absence of any change in inhalant allergy exposure and in an environment in which inhalant exposures have been minimized with a good air filter (though admittedly, the environment is not as pure as a few chemically sensitive patients have attained). This type of alternation of symptom types has been described as alternating between symptom states defined by Randolph and Moss as alternating between +1 or +2 and -1 or -2 (34).
There may be other explanations for these alternating states, but it might be that in some patients, the alternation could be due to a C. pulmoni infection. The non-IgE food sensitivity reactions might be increasing both cortisol and TH1 immune reactions (with symptoms of anxiety, diarrhea and insomnia), which temporarily suppresses the TH2, anti-parasitic response. When the food sensitivity reactions and associated TH1 immune reactions are reduced, the TH2, anti-parasitic response can then increase and produce the sinus symptoms as part of the immune system’s attempt to eradicate the roundworm. The extreme difficulty this patient has experienced in completely eliminating the food sensitivities could be due to fighting an uphill battle in the context of the multiple effects on immune function of the roundworm infection (see above). The roundworm’s proposed manipulation of the patient’s immune system, as well as its burrowing through the gut wall making it truly a “leaky gut,” may have made any fight to eliminate the sensitivities much harder and perhaps impossible with food/chemical sensitivity reduction techniques alone. One might speculate that some patients with milder or shorter-term C. pulmoni infection and few or no coinfections, perhaps could get well using the allergy/sensitivity reduction alone.
Possible Relationship to a New Treatment Approach For TH1 Dominant Diseases
Now, I will briefly mention my own view on how research on this roundworm might relate to some recent research on autoimmune disease, Lyme disease, fibromyalgia and CFS that emphasizes treating the cause of excessive TH1 inflammation. This approach proposes the causative role of intracellular cell wall deficient (CWD) forms of bacteria that seem to use an excessive TH1 inflammatory response to hide from the immune system (35, 36). I would suggest the hypothesis that perhaps half of the CFS patients, possibly the sickest ones, may have a symbiotic situation in which the roundworm and CWD bacteria are able to benefit from each other's activities by promoting an excessive TH1 response The roundworm might directly cause a TH1 response through secreting substances that stimulate IFN gamma (11) or through other substances that stimulate autoimmunity and overreactions to antigens in general (23, 24). Indirectly, they may promote a TH1 response by burrowing through the intestinal wall, allowing other microbial pathogens (including CWD capable bacteria) and food and chemical antigens easier access to the bloodstream and tissues and thus provide even more antigens to stimulate and overactivate the immune system. By contributing to TH1 inflammation, C. pulmoni might be promoting the proliferation of CWD forms of bacteria, while itself benefiting from the TH1 response’s suppression of the anti-parasitic TH2 response.
The research of Marshall et al (35, 36) has led to the development of the Marshall Protocol (MP) for diseases of excessive TH1 inflammation. The Marshall Protocol involves the use of immune modulation to reduce the excessive TH1 response, combined with a series of low dose antibiotics, introduced very gradually. After having good success in treating the autoimmune disease sarcoidosis, it has only recently begun to be used in CFS and Lyme patients and has shown some positive initial results. It is possible that integrating anti-roundworm treatment into the Marshall Protocol in some way might be worth considering at some point. Perhaps some of the sickest CFS patients might benefit from anti-roundworm treatment and/or reducing the food and chemical sensitivities it may be fostering, before trying the MP. The MP is quite difficult for some patients at the beginning and some patients have had to stop it and then try again later. The very sickest of the CFS population are, for the most part, probably not those who are currently trying the MP, as they are typically too ill to study it and participate in the free Internet discussion groups (marshallprotocol.com or sarcinfo.com).
The idea that some patients have both the proposed roundworm infection and CWD infection is not purely theoretical. A number of CFS patients that Klapow has found to be positive for C. pulmoni have also tested positive for Lyme disease (30). The Lyme disease spirochete is known to also exist in CWD forms, the form of bacteria that the Marshall Protocol was designed to treat. As is widely known from experience with HIV-AIDS, there are certain immune suppressing organisms that make it more likely for one to have multiple infections and it may be that this is a role that chronic infection with C. pulmoni plays in CFS. Whether it is involved in other diseases is an open possibility, as the only patients tested for this roundworm so far are CFS patients.
The way in which the MP is currently being used fits in some ways with the state of the roundworm diagnosis situation. This is because with the MP, the Jarisch-Herxheimer reaction (bacterial die-off reaction) in response to antibiotics is used as an indicator that a particular antibiotic is killing CWD bacteria. The use of ivermectin as a diagnostic/therapeutic probe (see above) to see if a die-off reaction occurs is somewhat similar. At present, it is unknown how ivermectin might interact with the immune modulation of the MP and it should not be combined with the MP until more is known. Caution is warranted because the MP intensifies the action and die-off reactions of certain antibiotics (thus requiring the use of quite low initial antibiotic dosages). However, prior treatment for those CFS patients who are too ill to begin the MP might be an option to consider. Or if it were found that a CFS patient was not progressing well, the patient might stop the MP temporarily and try an anti-roundworm therapeutic probe or treatment trial, and then resume the MP.
From the perspective of a hypothesized C. pulmoni infection, combining the MP with anti-roundworm treatment might get around the potential problem of anti-roundworm drug resistance or difficulty of complete eradication. These difficulties have been observed in animals with other chronic roundworm infections. Also, there is some indication that in the one patient who has attempted long term treatment of C. pulmoni with several anti-roundworm drugs, some drug resistance may have developed. It might be that the immune modulation of the MP and its reduction of the CWD bacteria, might help a promote a better immune response to the roundworm parasite that would aid the anti-roundworm drugs sufficiently to completely eradicate the roundworms.
The above sections have discussed a type of symbiotic relationship between CWD bacteria and C. pulmoni in which they each affect the human immune system in a way that helps themselves and each other. Another possibility in CFS is a sort of symbiotic relationship between certain viruses and roundworm infections. For example, there is evidence of a significant association between the roundworm infection strongylosis and HTLV1 viral infections (37).
Conclusions
In conclusion, for most patients, it would probably be wise to wait until DNA analysis is able to confirm the work on C. pulmoni done so far and a commercial test for it is available. Then, research trials will be done to try to determine what drug or combinations of drugs are most effective for treatment. But for those doctors, researchers and patients who want to contribute to research in this area and do not want to wait for several years, some speculations have been presented as a starting point. It is hoped that these research ideas will lead to information that will help in the process of determining what lab tests and anti-microbial agents would be most useful, as well as gain further evidence regarding the role of this “hidden lung worm” in chronic fatigue syndrome.
(Note: Any doctors, researchers or patients who would like to share any experiences they may have related to the above diagnostic and treatment possibilities are encouraged to send accounts to me at: jcwat101@aol.com), and if they seem significant, I may compile them for a future article for the purpose of advancing research in this area. All personal information will be kept confidential.)
References
(1) Klapow LA: A suspected new chronic roundworm parasite, Cryptostrongylus pulmoni (provisional), associated with chronic fatigue syndrome in blinded trials. Poster Presentation. Proceedings of the 2001 ME/CFS AHMF Conference in Sydney Australia
(2) Klapow LA: Roundworm-like specimens in the sputum of chronic fatigue syndrome patients and controls in open and blinded analysis. Journal of Chronic Fatigue Syndrome 1999;5 (3/4):247-8.
(3) Von Kuster LC, Genta RM. Cutaneous manifestations of strongyloidiasis. vArch Dermatol 1988 Dec;124(12):1826-30
(4) Fauci, Anthony S., and others, editors. 1997. Harrison’s Principles of Internal Medicine. McGraw Hill.
(5) Klapow LA: Evidence for a new chronic parasite in CFS: The finding and the challenge. Presentation for the Carousel Network for Chronic Neuroimmune Diseases of Sonoma County. May 2004. Santa Rosa, CA.
(6) Durette-Desset MC, Chaubaud AG, 1981. Sur Molineinae Parasites De Mammiferes. Annales de Parasitology (Paris), 1981; 56(5):489-502. French [English abstract]
(7) Klonoff DC. Chronic Fatigue Syndrome. Clin Infect Dis 1992 Nov;15(5):812-23
(8) De Vries M, Soetekouw PM, Van Der Meer JW, Bleijenberg G. Natural course of symptoms in Cambodia veterans: a follow-up study. Psychol Med 2001 Feb;31(2):331-8.
(9) Pelletier LL Jr. Chronic strongyloidiasis in World War II Far East ex-prisoners of war. Am J Trop Med Hyg 1984 Jan;33(1):55-61.
(10) Klapow, LA: Amphids and other defining roundworm structures in the larvae of Cryptostongylus pulmoni from patients with chronic fatigue syndrome. Poster Presentation. AACFS Seventh International Conference on Chronic Fatigue Syndrome, Fibromyalgia, and other Related Illnesses Conference, Oct. 8-10, 2004, Madison, WI.
(11) Grencis RK, Entwistle GM. Production of an interferon-gamma homologue by an intestinal nematode: Functionally significant or interesting artefact? Parasitology 1997;115 Suppl:S101-6
(12) Pritchard DI, Kumar S, Edmonds P: Soluble (s)CD23 levels in a parasitized population from Papua New Guinea. Parasite Immunol 1993 Apr;15(4):205.
(13) Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Muller WE, Schroder HC, Carter WA, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis 1994 Jan;18 Suppl 1:S96-104.
(14) Baraniuk JN, Clauw D, Carneiro ALM et al. IgE Concentrations in Chronic Fatigue Syndrome. J Chronic Fatigue Syndrome 1998;4(1):13-21.
(15) Mawle A, Nisenbaum R, Dobbins J et al. Immune Responses associated with Chronic Fatigue Syndrome: A Case-Controlled Study. J Infect Diseases, 1997:175;316-41.
(16) Gems D, Ferguson CJ, Robertson BD, Nieves R, Page AP, Blaxter ML, Maizels RM: An abundant, trans-spliced mRNA from Toxocara canis infective larvae encodes a 26-kDa protein with homology to phosphatidylethanolamine-binding proteins. J Biol Chem 1995 Aug 4;270(31):18517-22
(17) Klapow, LA (unpublished). BLAST analysis of the 26-kDa secretion of Toxacara canis resembles the limbic system neuropeptide HCNP.
(18) Marmor M, Glickman L, Shofer F, Faich LA, RosenbergC, Cornblatt B, Friedman S: Toxocara canis infection of children: epidemiologic and neuropsychologic findings. Am J Public Health 1987 May;77(5):554-9.
(19) Loukas A, Doedens A, Hintz M, Maizels RM. Identification of a new C-type lectin, TES-70, secreted by infective larvae of Toxocara canis, which binds to host ligands. Parasitology 2000 Nov;121 Pt 5:545-54.
(20) McKeand JB, Knox DP, Duncan JL, Kennedy MW. The immunogenicity of the acetylcholinesterases of the cattle lungworm Dictyocaulus viviparus. Int J Parasitol 1994 Jul;24(4):501-10.
(21) Foster N, Lee DL. Vasoactive intestinal polypeptide-like and peptide histidine isoleucine-like proteins excreted/secreted by Nippostrongylus brasiliensis, Nematodirus battus and Ascaridia galli. Parasitology 1996 Sep;113 ( Pt 3):287-92.
(22) Chandrashekar R, Curtis KC, Weil GJ. Molecular characterization of a parasite antigen in sera from onchocerciasis patients that is immunologically cross-reactive with human keratin. J Infect Dis 1995 Jun;171(6):1586-92.
(23) Pritchard DI. Immunity to helminths: is too much IgE parasite--rather than host-protective? Parasite Immunol Jan 1993:15;5-9.
(24) von Mikecz A, Konstantinov K, Buchwald DS, Gerace L, Tan EM: High frequency of autoantibodies to insoluble cellular antigens in patients with chronic fatigue syndrome. Arthritis Rheum 1997 Feb;40(2):295-305.
(25) Stewart MJ, Emery DL, McClure SJ, Bendixsen: The effects of four neuropeptides on the degranulation of mucosal mast cells from sheep. Immunol Cell Biol 1996 Jun;74(3):255-7.
(26) John JF Jr, Friedman, K: Infections in CFIDS. The CFIDS Chronicle. Spring 2002;15(2). The Chronic Fatigue and Immune Dysfunction Syndrome Association of America, Charlotte, NC. Adapted from “A Consensus Manual for the Primary Care and Management of Chronic Fatigue Syndrome,” 2001. Acad of Med of New Jersey, U of Med & Dent NJ and NJ Dept of Health and Senior Services.
(27) Schacterle RS, Conti F, Laura Magrini L, Komaroff AL, Valesini G. Increased Eosinophil Protein X Levels in Chronic Fatigue Syndrome. J of Chronic Fatigue Syndrome, 2001:9 (1/2);21-30.
(28) Bailenger J, Faraggi G: Mechanism of hypocorticosteronemia action of Strongyloides ratti in the rat] : Ann Parasitol Hum Comp 1975 Mar-Apr;50(2):187-97. [English abstract]
(29) Bailenger J, Carcenac F, Faraggi G, Cabannes A: Role of hypocorticosteronemy in the self cure mechanism in rats with Strongyloides ratti parasites (author's transl)] Ann Parasitol Hum Comp 1976 Nov-Dec;51(6):653-65. [English abstract]
(30) Klapow, LA: personal communication.
(31) Duval, J: The control of internal parasites in ruminants. (http://www.eap.mcgill.ca/AgroBio/ab370-04e.htm)
(32) Waterhouse, JC: Innovative Approaches to Fibromyalgia. CISRA’s Synergy Health Newsletter 1996;1:1-5, Chronic Illness Support and Research Association, Pasadena, CA.
(33) Waterhouse, JC: Food Allergy/Sensitivity: The Pulse Test and Other Strategies. CISRA’s Synergy Health Newsletter 1999;5:1-11. Chronic Illness Support and Research Association, Pasadena, CA.
(34) Randolph TG, Moss, R.W. An Alternative Approach to Allergies. Harper & Row, 1980.
(35) Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3).
(36) Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics-implications for autoimmune disease. Autoimmun Rev 2004;Jun;3(4):295-300.
(37) Porto AF, Neva FA, Bittencourt H, Lisboa W, Thompson R, Alcantara L, Carvalho EM: HTLV-1 decreases Th2 type of immune response in patients with strongyloidiasis. Parasite Immunol 2001 Sep;23(9):503-7.
Copyright 2004, J.C. Waterhouse, Ph.D.
Click here to return home: CISRA--SynergyHN Home Page
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------