Sunday, April 21, 2013


IS IDIOPATHIC PULMONARY FIBROSIS (IPF) A DUST MITE ALLERGEN-INDUCED DISEASE?

INTRODUCTION
In spite of a substantial progress in medical sciences during the 20th century the pathogenesis of numerous diseases remains unknown and their therapy non-existent. Some of these diseases are terminal and their diagnosis is equivalent to the death sentence. Idiopathic pulmonary fibrosis (IPF) is one of the diseases with unknown etiology, poor prognosis, and prevalence rates of 4.6-16.3 cases per 100,000 individuals. In this manuscript we propose the hypothesis that continuing exposure toward house dust mite allergen(s) could cause a lung fibrosis resembling the IPF. A timely identification of factors capable of inducing IPF could lead to the cure of the disease or control of its progression.

IDIOPATHIC PULMONARY FIBROSIS (IPF)
Pulmonary fibrosis is a pathological process, usually affecting both lungs, and characterized by excessive deposition of fibrous connective tissue and collagen in pulmonary interstitial spaces (1). It is a common feature of various interstitial pneumonias.   Correct identification of the cause of fibrosis determines the prognosis.  The causes have been identified in asbestosis, silicosis, psittacosis or farmer’s lung. The prognosis of these fibrotic diseases is usually favorable, providing patients are no longer exposed to the environmental factors that may have contributed to the disease. The prognosis is poor and the disease is considered terminal if the cause remains unknown as in the case of IPF.  The life expectancy of patients diagnosed with IPF has been estimated as 2 to 5 years, although some of the patients are surviving for more than 10 years after diagnosis (2). The existence of slow and rapidly progressing, as well as familiar and sporadic forms of the disease, suggests that IPF may not be a single disease. No drugs fo0r the treatment of IPF have been approved by Food and Drug Administration (FDA) in the United States of America, although corticosteroids and immunosuppressants are used off-label, mostly with little or no beneficial effect. Pirfenidone has been approved in Japan and European Community for the treatment of IPF and various potential antifibrotic drugs are in preclinical development or clinical trials (3). It is conceivable that the progressive nature of IPF is due to continuous exposure of patients to toxins or allergens that may have caused the disease. Misdiagnosis of IPF is not uncommon. Patients with hypersensitivity pneumonitis, scleroderma, drug toxicity or other pulmonary diseases have been often referred to pulmonary clinics for the treatment of IPF (K.C. Meyer, 2012, Personal Communication). Currently IPF is viewed as a result of interplay of largely unknown genetic and environmental factors. The genetic factors were identified only in a small minority of patients (estimated as 2 to 20% of all IPF patients). For instance genetic defects in surfactant protein A2 have been associated with IPF (4). In some patients with familial IPF mutations in genes encoding RNA components of telomerase have been found (5).

HOUSE DUST MITES AND THEIR ANTIGENS
House dust mites (HDM) are arachnids, related to ticks and spiders. They are 0.5 mm in length and 0.25 mm in width; they can be barely seen with naked eyes, but can be identified using 100 x or higher magnification.  There are at least 30 different species of HDM:  the most abundant species is Dermatophagoides (D.) pteronyssinus.   HDM are present in most homes probably for centuries, although their existence has not been recognized until 1964. It has been estimated that up to 500 HDM can be found in one gram of house dust. Their major source of food is decomposed human or animal skin cells, so that they thrive near humans in mattresses, carpets, pillows and soft furniture. Since the discovery of HDM many articles on all aspects of their taxonomy, physiology and pathology have been published. The most complete source of information on HDM is the book by M.J. Colloff (6).  HDM have been implicated in the pathogenesis of several, mostly allergic diseases, including asthma, rhinitis, keratoconjuctivitis and atopic eczema. The role of HDM in asthma was a subject of International Workshop in 1987 (7). Twenty-one groups of allergens (2-10 in each group) are known to be produced by HDM and many of them can be found in their fecal pellets. Most common allergens, Der p 1 and Der f 1, belong to the Group 1 and are produced by D. pteronyssinus and D. farina, respectively. Der p 1 was purified and characterized in 1980. It is a cysteine proteinase that in addition to its allergenic properties, has been found to disrupt epithelial tight junctions in human pulmonary epithelial cells in vitro and, therefore, promote crossing of epithelial barrier by allergens (8).
The levels of specific IgG for Der p 1 have been found to be higher in serum of individuals known to be exposed to HDM than in non-exposed subjects (9).


HYPOTHESIS
HDM allergens cause in sensitive individuals immediate-type hypersensitivity reaction with production of IgE and activation of mast cells. We are proposing that in some individuals long-term exposure to HDM allergens can lead to chronic hypersensitivity pneumonitis that is often misdiagnosed as IPF. We visualize that long term exposure to HDM allergens may cause chronic inflammation and fibrosis while immediate-type hypersensitivity reaction could be suppressed. Our hypothesis is supported by the fact that dust mites particles smaller that 5µm could reach alveoli (10). Local inflammation favors the formation of pro-fibrogenic growth factors and cytokines (TGFβ, IL-1β, IL-4, IL-5, IL-13, IL-25). Our hypothesis is supported by findings that basophiles, exposed to Der p 1, are known to produce large amounts of cytokines, such as IL-4, IL-5 and IL-13 (11). Furthermore, Der p 1 disrupts tight junctions in lung epithelial cells in vitro (8), as well as barrier function of such human surfactant molecules as SP-A and SP-D (12), effects that can facilitate fibrogenesis and proteolysis of lung epithelial cells. Der p 1 is also likely to activate fibroblasts and promote formation of contractile myofibroblasts directly through its specific protease activating receptors (13), or indirectly through pro-fibrogenic cytokines.

CONCLUSIONS
The progressive nature of IPF, as compared to pulmonary fibrosis of known etiology, is likely due to chronic exposure of patients to HDM allergens that caused the disease originally. The patients develop chronic allergic response leading eventually to massive irreversible fibrosis and death.
The acceptance of our hypothesis should lead to a drastic change in the approach to the treatment of patients with pulmonary diseases of unknown etiology. The patients with idiopathic non-productive cough and/or suspicion of interstitial pneumonia should be advised by their primary healthcare providers to consult an allergist to determine  (using skin prick test or  blood levels of IgG specific for Der p 1) whether they are allergic to HDM extract. In case of a positive finding the patients should be advised to minimize their exposure to the HDM allergens by modifying their environment. This should include encasing mattresses, box springs and pillows into allergen-impermeable covers, removal of carpeting, upholstered furniture, drapes and stuffed toys from their houses, use of only washable bed sheets and covers, lowering humidity and use of air filters. If these changes will not lead to a cure or a substantial improvement in patients’ condition, allergen immunotherapy can be considered (14).
Our hypothesis also points out additional therapeutic targets for the development of novel drugs for patients with pulmonary diseases associated with an allergy to HDM extracts. Antibodies to Der p 1 and/or other HDM allergens as well as Der p 1 – antagonists may be useful in the treatment of IPF.

SUMMARY
The prognosis of pulmonary fibrosis is highly dependent on the identification of its cause by health care providers as well as on patients’ environment and lifestyle. If the cause of the disease is not identified, patients are diagnosed as having IPF, a terminal disease with short life expectancy. The pathology of IPF cannot always be clearly differentiated from that of some of the other lung diseases, including chronic hypersensitivity pneumonitis. Clinical course of IPF can also differ substantially in various patients. We are proposing that some patients, currently diagnosed with IPF, actually suffer from chronic hypersensitivity to dust mite allergens and that in hypersensitive individuals dust mite allergens can induce the release of pro-fibrinogenic cytokines, epithelial damage and eventually fibrosis. This hypothesis leads to new targets and approaches to the therapy of fibrosis, including avoidance of excessive exposure to dust mite allergens, therapeutic use of dust mite allergens antibodies and chemical blockade of dust mite allergens-induced cytokine release.

REFERENCES

1.       Wilson MS, Wynn TA. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol. 2009;2(2):103-21. Epub 2009 Jan 7.
2.       King TE, Jr., Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011;378(9807):1949-61.
3.       Scriabine A, Rabin DU. New developments in the therapy of pulmonary fibrosis. Adv Pharmacol. 2009;57:419-64. Epub 2009 Nov 27.
4.       Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84(1):52-9. Epub 2008 Dec 18.
5.       Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317-26.
6.       Colloff M.J. Dust Mites. Springer, Netherlands, 2009, ISBN 978-90-481-2223-3
7.     Platts-Mills TAE, Weck de AI, Aalberse AC et al. Dust mite allergens and asthma: a worldwide problem. International Workshop Report. Bull World Health Org 1988, 66(6): 769-80.
8.       Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest. 1999;104(1):123-33.
9.       Sterclova M, Vasakova M, Metlicka M. Significance of specific IgG against sensitizing antigens in extrinsic allergic alveolitis: Serological metho in EAA.
Rev Port Pneumol. 2011:17(6)P:251-9
10.     De Lucca S, Sporik R, O'Meara TJ, Tovey ER. Mite allergen (Der p 1) is not
only carried on mite feces. J Allergy Clin Immunol. 1999 Jan;103(1 Pt 1):174-5.
10.     Phillips C, Coward WR, Pritchard DI, Hewitt CR. Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites. J Leukoc Biol. 2003;73(1):165-71.
11      Deb R, Shakib F, Reid K, Clark H. Major house dust mite allergens Dermatophagoides pteronyssinus 1 and Dermatophagoides farinae 1 degrade and inactivate lung surfactant proteins A and D. J Biol Chem. 2007;282(51):36808-19. Epub 2007 Sep 11.
12.     Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol. 2002;169(8):4572-8.
13.     Incorvaia C, Fuiano N, Frati F. Allergen immunotherapy: how to balance the different views from pulmonologists and allergists? Immunotherapy.;4(8):853-7. doi: 10.2217/imt.12.79.

Monday, November 22, 2010

IPF- is your diagnosis correct?

I was wrongly diagnosed with idiopathic pulmonary fibrosis (IPF) 9 years ago. According to the medical literature the average survival is only 2 to 3 years after diagnosis. After 5 years I started wondering, why am I still alive? It turns out, it was a wrong diagnosis. I have Deep Vein Thrombosis (DVT) in my left leg for at least 10 years after my fall and leg injury. My left ankle was swelling every night, but there was no pain or any other symptoms. Emboli were traveling to my lungs leading to lung damage that was wrongly diagnosed as IPF. Now I developed pulmonary embolism (PE), a thrombus in the main pulmonary arttery that can be seen on the scan. For the last 10 days I am injecting myself subcutaneously with low dose heparin and taking orally 5 mg warfarin. I am expected to stay on warfarin for at least 6 months. I am also taking prednisone 30 mg once a day orally, and will remain on prednisone probably for another month (total 3 months). In 6 to 12 months I may even recover completely.
The wrong diagnosis of IPF is apparently not uncommon. K.C. Meyer, M.D. (Director of Interstitial Lung Disease Clinic at the Univ. of Wisconsin UW) in his Update on Clinical Trials for IPF (on Internet) lists 12 alternative diagnoses made at UW in patients claimed to suffer from IPF. They are: lymphangitic carcinoma, hypersensitivity pneumonitis, polyomyositis, scleroderma, Langerhans cell histiocytosis, NSIP, DIP, RBILD, chronic aspiration, sarcoidois, congestive heart failure, drug toxicity. DVT and PE should be now added to this list!
The DVT and PE diagnosis in my case was made by Erica Herzog, M.D., PhD, Yale Pulmonary Clinic. She questioned the cause of my left leg swelling and ordered ultrasound that revealed DVT.
Keywords: Idiopathic pulmonary fibrosis; deep vein thrombosis, pulmonary embolism; warfarin, prednisone,

Monday, November 8, 2010

VARGATEF

Vargatef (BIBF-1120)is a multikinase inhibitor under development by Boehringer-Ingelheim primarily as an antiangiogenic and antineoplastic (ovarian and non-small cell lung cancer) agent. It inhibits kinase receptors that mediate the effects of vascular endothelial growth factor (VEGF), platelet derived (PDGFalpha), fibroblasts growth factor (FGF) and Src family of kinases (Lck, Lyn, and FLT-3). Cell proliferation is inhibited by vargatef at 10-80 nmol/L. Currently 18 clinical trials with Vargatef in cancer and 3 in idiopathic pulmonary fibrosis (IPF) are listed on Clinicaltrials.gov. One Phase I safety study and one Phase II study with Vagatef in patients with IPF have been completed, but the results of the phase II trial have not been posted by the sponsor. Another trial is being planned in Japan.

Saturday, November 6, 2010

Ambroxol

Ambroxol is an old drug, It has been developed and marketed in Germany by Boehringer-Ingelheim in 1970s as a mucolytic agent. It is currenly available as a drug in 18 countries, including Germany, India and Russia, but not USA or Canada. It can be purchased in large amounts from Chinese chemical manufacturing companies and in small amounts for experimental use from Western chemical supply houses (e.g. Tocries Biosciences). There is no known safety issue with ambroxol, although one case of rhabdomyolysis has been reported in a patient who was treated with ambroxol as well as other drugs. Apparently, Boehringer-Ingelheim did not apply for registration of ambroxol in USA when the drug was still under patent. After patent expiration its marketing for the same indication did not make any commercial sense.

Over the last 30 years ambroxol was studied extensively in various laboratories. Currently (2010) Medline lists 343 references to pharmacological or clinical studies with ambroxol. Malerba and Ragnoli reviewed 40 years of publications on pharmacological and clinical findings with ambroxol (1). In a more recent review article Gupta emphazised the need for well conducted clinical studies with ambroxol in severe obstructive airway disorders (2). Ambroxol was found to increase production of lung surfactant protein, to have antiinflammatory, antioxidant, local anesthetic, analgesic activities as well as to inhibit neuronal sodium channels and reduce murine influenza virus proliferation. Ambroxol was shown to reduce production of proinflammatory cytokines, including platelet derived growth factor (PDGF), TNFalpha, IL-1, IL-10 and IL-12(3-7). In some, paticularly severly ill, patients ambroxol reduced acute exacerbations of chronic pulmonary obstructive disease (e.g. COPD)(8). The pharmacological profile of ambroxol, in particularly, its ability to reduce release of cytokines, suggests its possible usefulness not only in obstructive diseases, but also in pulmonary fibrosis. Its clinical evaluation as a sole or adjunctive therapy of idiopathic pulmonary fibrosis (IPF) is indicated.

1. Malerba M., Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update Expert Opinion on the Drug Metabolism and Toxicology. 2008:4:1119-29.
2. Gupta R.R. Ambroxol - Resurgence of an old molecule as an antiinflammatory agent
in chronic obstructive airway disease. Lung India: 2010:22:, 46-9.
3. Betz, R. Glukokortikosteroide und Ambroxol hemmen die Sekretion entzuendungsfoerdernder Zytokine in tracheobronchialen Epithelzellen; Moegliche Rolle des Transkriptionsfaktors NF-kappaB. Pneumologie, 1997:51: 491-2.
4. Gibbs, B.F., Schmutzler W., Vollrath, I.B., Brosthardt P., Braam U., Wolff, H.H.,Zwadlo-Klarwasser, G. Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells. Inflammation Research, 1999:48:86-93.
5. Alhara M., Dobashi K, Aklyama M, Naruse I, Nakazawa T, Mori M. Effect of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages. Respiration. 2000: 67:662-71.
6.Utsugi M., Dobashi K., Kogo Y., Masubuchi K., Shimizu, Y., Endou K., Nakazawa T., and Mori M. Ambroxolinhibits platelet derived growth factor production in human monocytic cells.Eur J Pharmacol 2002: 436:47-51.
7. Gaida W., Klinder K., Arndt K., Weiser T., Ambroxol, a Nav 1,8-preferring Na(+)
channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. Neuropharmacol 2005:49:1220-7

Thursday, November 4, 2010

TRANILAST IN PULMONARY FIBROSIS

Tranilast (RIZABEN) is an old antiallergic drug, it is sold in Japan by KISSEY Pharmaceutical company for the treatment of allergies and also hypertrophic scar formation. Nuon Pharmaceuticals (San Mateo,CA) is developing it for new indications, including gout, rheumatoid arthritis and MS. Considerable amount of information on its pharmacology is available. Tranilast has been found to inhibit collagen synthesis in fibroblasts, decrease production of IL-6 and IL-8, inhibit VEGF-induced proliferation and migration of vascular endothelial cells, and to bind to aryl hydrocarbon receptors. These and other findings suggest that tranilast could be useful in the treatment of pulmonary fibrosis. Unfortunately, no clinical studies
in this indication are available or even planned.

Thursday, October 7, 2010

Missing drugs

Idiopathic Pulmonary Fibrosis (IPF) is one of one of many diseases for which there is no Food and Drug Administration (FDA) approved drugs in USA. This does not mean, however, that there are no drugs of possible benefit for this disease. Based on the recommendation of Thoracic Society some pulmonary physicians prescribe glucocorticoids (e.g. prednisone) with or without immunosuppressants (e.g. azathioprine) . Only occasional benefit has been reported with this approach. Without FDA approval or recommendation of a professional society physicians are understandably reluctant to prescribe drugs that can conceivably be useful in the treatment of IPF, although they have right to prescribe drugs off-label. The reasons for this reluctancy include potential lawsuits and cost of malpractice insurance. There is also no readily available information source on the off-label use of drugs approved for other indications. Neither FDA, nor textbooks or databases provide such information and pharmaceutical companies are strictly prohibited to inform physicians about potential off-label indications for their drugs. One of the drugs used off-label in IPF is N-methyl-acetylcysteine (known also as NAC), a glutathione precursor and powerful antioxidant and hepatoprotective. In USA NAC is approved and commercially available (ACETADOTE) as an antidote for acetaminophen intoxication, but not other indications. Its usefulness in the therapy of IPF in combination with glucosteroids was suggested by a clinical trial (1), that led to still more ongoing trials. Since NAC's toxicity is very low and there is an urgent need for IPF therapeutics, NAC should be made available to all IPF patients. Fortunately, it is available also as a dietary supplement from Puritan's Pride, although this company cannot provide any information on its use in IPF. Even if additional clinical trial confirm effectiveness of NAC in IPF, it will probably never become a standard IPF therapeutic, since no pharmaceutical company will be capable of covering the cost of NAC development for this new indication without use patent coverage. NAC's availability for a very low cost as a dietary supplement will also further complicate its development as an IPF drug.

Wednesday, June 23, 2010

IPF SYMPTOMATOLOGY

Since Idiopathic Pulmonary Fibrosis (IPF) may not be a single disease, it is not surprising that disease symptoms may vary among patients. Also in the same patient the symptoms may differ with the stage of the disease. A chronic postnasal drip was my first symptom. I attributed subsequent attacks of non-productive cough to throat irritation caused by nasal discharge due to sinus infection. I consulted otorhinolaryngologist who found no evidence of any sinus disease. The persistent cough attacks in the mornings led my family physician to refer me to a radiologist for a chest X-ray and subsequently to a cardiologist because of slight right heart enlargement. Cardiologist found no evidence of heart failure and referred me to a pulmonologist who made a tentative diagnosis of IPF on the basis of X-ray, catscan and pulmonary function test.
At ca 3 years after the initial diagnosis I first experienced oxygen desaturation on exercise. Now, at 8 years after diagnosis, this is my major symptom. My arterial blood oxygen levels decrease from 95% at rest to as low as 83% after a few steps around the house. Desaturation is always associated with tachycardia, my heart increases from 70 or 80 beats/min to 110 or even 120 beats/min. Oxygen inhalation reduces desaturation effect but not necessarily cardiac acceleration. Postnasal drip is now replaced by frontal nasal discharge that is enhanced by oxygen inhalation. Another symptom at the late stage of the disease is a disturbance in temperature regulation. A burning feet sensation appears to be independent of either oxygen saturation levels or of actual skin temperature. If oxygen saturation is lowered below 90% an attack of dry cough is likely to follow, but occasionally I had cough attacks even at normal blood oxygen levels. Another symptom of the disease is weight loss; I started to loose weight at ca 6 years after diagnosis and lost ca 25 pounds within the last two years.
Hypersensitivity diseases are often associated with skin eruptions. I experienced eruptions in anal region that responded to local antihistaminics or steroids. These eruptions may indicate hypersensitivity to a dietary component, cytokine or a bacterial toxin. They may conceivably help in the elucidation of the etiology of my disease.