Table of Contents

Sarcoidosis

Sarcoidosis or sarc is a multisystem disorder characterized by granuloma, ball-like encapsulations of phagocytic cells driven by microbes. Sarcoidosis is often called the “great masquerader” as there may be several atypical or nonspecific presentations – including not just the lungs but the brain, lymph glands, spleen, liver, skin and heart among others.1

An infectious etiology of sarcoidosis has long been suspected. Today scientific evidence provides a strong, if not conclusive, link between infectious agents and sarcoidosis.2

Sarcoidosis was the first disease treated by the Marshall Protocol.3 The FDA's Office of Orphan Products Development has conferred orphan drug status on several MP medications.

Evidence of infectious cause

Today scientific evidence provides a strong, if not conclusive, link between infectious agents and sarcoidosis.4

History of conflicting results

Related articles: Detecting bacteria, Koch's postulates

An infectious etiology of sarcoidosis has long been suspected and investigated, sometimes with inconsistent results. For example, the histologic similarity of sarcoidosis to Mycobacterium tuberculosis (see discussion of granuloma below) infection led to the “extensive” evaluation of this organism as a possible etiologic factor.5 The findings have been mixed with some investigators finding evidence of M. tuberculosis6 7 and some failing to confirm this work.8 9 10 11 12 In their 1996 review of mycobacteria's possible role in sarcoidosis, Zumla and James list 15 studies evaluating a mycobacterial cause of sarcoidosis, only three of which were negative.13

There appear to several reasons why researchers have failed to definitively link microbes to sarcoidosis in all cases. For one, even today researchers adhere to the antiquated model of disease set forth by Koch's postulates namely that a pathogen must be: found in all cases of the disease examined, prepared and maintained in a pure culture, capable of producing the original infection, even after several generations in culture, and retrievable from an inoculated animal and cultured again. For all their lingering influence, Koch's postulates never anticipated the era of the human metagenome in which thousands of difficult or impossible-to-culture species of bacteria – rather than just one – contribute to a single disease state. Indeed, the notion of a single causative agent is not in keeping with the worldwide distribution of sarcoidosis.14 Koch's century-old ideas have held science back from understanding how chronic disease occurs because they make no provision for these facts.

Communities of microbes found in patients

The following types and species of bacteria have been found in patients with sarcoidosis, especially the granuloma:

Mycobacterial and propionibacterial DNA have been found in the lymph nodes of Japanese and European patients with sarcoidosis.35

Granuloma without necrosis in a lymph node of a person with sarcoidosis.

Granuloma

A granuloma is a ball of immune cells associated with various disease states including sarcoidosis, Crohn's, and tuberculosis. (Hence, the term “granulomatous diseases.”) The presence of noncaseating (no tissue death) granuloma of the lungs is the hallmark of sarcoidosis. In sarcoidosis, granuloma are most commonly found in the alveolar septa, the walls of bronchi, and the pulmonary arteries and veins.

At their core, granuloma contain cells from the innate immune system: macrophages and monocytes. Lymphocytes, which are a part of the adaptive or acquired immune system, tend to exist on the periphery or in latter stages of development.36 37

Granulomas may represent an extreme form of innate immune dysfunction.38 The macrophages and monocytes in granuloma are infected by intracellular pathogens such as Mycobacteria. When infected, the internal chemistry of innate immune cells is altered such that these cells no longer undergo apoptosis (programmed cell death).39 Significant differences in the expression of apoptosis-related genes were found in peripheral blood of patients with acute onset sarcoidosis.40

Also, they cease to move towards chemical signals driving an immune response, instead aggregating in clumps. One other side effect of infected macrophages is the dysregulation of the Vitamin D Receptor, leading to the high levels of 1,25-D characteristic of chronic inflammatory diseases.

In a number of diseases such as tuberculosis, leprosy, histoplasmosis, cryptococcosis, blastomycosis, coccidioidomycosis and syphilis, the formation of a granuloma is widely considered to be an indication of infection.41 Even so, many researchers continue to assume that certain chronic diseases such as sarcoidosis and Crohn's disease are not caused by infection even though they present with granuloma which are similar to those found in diseases known to be infectious.

In fact, the presence of granuloma are entirely consistent with an infectious disease. For example, a Japanese team showed that one could use Propionibacterium acnes in mice to induce lung granuloma mimicking sarcoidosis.42 The distinction between infectious and “non-infectious” granulomatous diseases, may be further complicated by reports such as those by Warrier who reported a case of cutaneous sarcoidosis, the histology of which showed tuberculoid granuloma.43

Some researchers have argued that, rather than be a host-protective structures formed to contain infection,44 granuloma may be exploited to expand and disseminate an infection. A Cell paper explains how Mycobacteria implicated in tuberculosis may recruit new macrophages to, nascent granulomas.45

Other evidence

If anything, patients with autoimmune disease are immunocompromised. A study of the prevalence of the key antimicrobial peptide showed that patients with sarcoidosis expressed it less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all. Source: Kanchwala et al.

Autoimmune vs. immunosuppressed

Patients with autoimmune disease often show inconsistent signs of autoimmune reactivity.

Kanchwala et al. showed that patients with sarcoidosis expressed the antimicrobial peptide cathelicidin less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all.60 Wiken et al. showed that there was a reduced TLR2 mRNA expression in patients with Lofgren's syndrome (a type of acute sarcoidosis).61 Note that TLR2 (which the Marshall Pathogenesis theorizes is downregulated in autoimmune disease states) is expressed by the VDR.

Tests and diagnosis

No definitive laboratory test diagnostic of sarcoidosis has been identified. For example, sarcoidosis is not diagnosed by the presence of certain antibodies as there usually are none.62

In the absence of a single agreed upon etiologic agent, sarcoidosis often remains a diagnosis of exclusion, although a typical presentation may strongly suggest the diagnosis. The diagnosis of sarcoidosis is established when a compatible clinical and radiographic picture is supported by histologic evidence of noncaseating granulomas in affected tissues and exclusion of other granulomatous diseases (e.g. Crohn's) capable of producing a similar histologic or clinical picture. Note that sarcoidosis is sometimes confused with benign or malignant cancerous tumors.63 Patients should make their doctors aware of any previous sarcoidosis diagnosis (even if only suspected) so sarcoidosis can be investigated as a possible cause of any lumps or tumors.

The MP medication olmesartan blocks formation of fibrotic tissue. However, given that the MP works through generating immunopathology, it would be expected that some sarcoidosis patients on the MP experience a temporary increase in signs of their disease. This would include temporary increases in the appearance of fibrotic tissue and size of lymph nodes a visible on an x-ray. Earlier in the course of therapy, patients are likely to see the most change in the gas transfer coefficient, the DLco, which most doctors don't measure because it can't be done with the simple office spirometer.

Spontaneous remission

Its reputation for spontaneous remission not withstanding, chronic inflammatory diseases such as sarcoidosis never go away on their own. It’s not that patients with sarcoidosis don't experience periods where they might feel better. Unfortunately, these intervals are usually a sign that the immune system has become severely compromised. In sarcoidosis, symptom resolution tends to be temporary as evidence by the epidemiological research.

Management and treatment

The Marshall Protocol is a treatment for sarcoidosis. Other treatments (some of which are contraindicated) include the following.

Immunosuppressive medications

For many physicians, immunosuppressive medications are a first-line treatment for sarcoidosis. These drugs suppress the innate immune response, which provides some patients with temporary symptom palliation, because they reduce immunopathology, the bacterial die-off reaction.

Lung transplantation

In the face of end-stage pulmonary sarcoidosis, many pulmonologists advise patients to consider lung transplantation. While a number of patients with advanced forms of sarcoidosis (including many who need supplemental oxygen) have done well on the MP, lung transplantation for sarcoidosis is problematic for several reasons.

A lung transplant fails to address the underlying cause, and, as a result, disease reoccurrence is not uncommon. A Danish study showed that lungs implanted in sarcoid patients are reinfected with granulomas five months later (reinfection was determined to come from the recipient patient)70 while another study showed recurrent sarcoidosis occurred as late as 56 months after the procedure.71

According to several observational studies, the median survival time of sarcoidosis patients after they receive a transplant has been reported to be about 4.7 years72 – about half that of other major transplanted organ recipients.

Finally, any quality of life during time following transplant is limit. To ward off tissue rejection and survive several years, patients must take a cocktail of anti-rejection and immunosuppressive drugs, classes of drugs which entale a number of side effects.

There are at least several patients who have chosen to do MP rather than be on a Transplant List.

If I had to choose between a lung transplant or the MP, I would choose the MP because it relies on carefully selected, simple low-cost, low risk antibiotics to treat the chronic infection caused by pleomorphic bacteria, along with Benicar and lifestyle changes to control the runaway 1,25-D. I was able to get off oxygen (I was using 2 liters) and avoided what the pulmonologist believed was the impending collapse of my right middle lobe using the MP. Fibrosis and bronchiectasis were still visible on my last lung imaging, but I now walk six miles a day without dyspnea.

You really need to think carefully about what you are willing to do/endure and how you are willing to live your life at this point. You have to realize that you get the final vote about your medical care; nothing goes without your approval, and you have a significant say in choice of treatment. I would only consider having a lung transplant after I had given the MP my all - like my life depended on it.

Staying out of the sun and taking antibiotics and Benicar for a few years is a comparatively low-risk therapy for a disease that can be fatal. I had to fire my specialist and let my treating doctor know that I was “willing to risk dying from sarcoidosis” before I would accept the risks of the conventional treatment offered to me. If you have your mind made up, you should be able to get a physician to help you implement the MP.

Belinda Fenter, MarshallProtocol.com

Other treatments

Vitamin D metabolism

Main article: Metabolism of vitamin D and the Vitamin D Receptor

Under most normal conditions, serum levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-D), are constant throughout the year (no variability due to sun exposure),73 but there is no such tight biochemical regulation in at least some chronic inflammatory diseases such as sarcoidosis. Patients with sarcoidosis tend to have high levels of 1,25-D. As the article Metabolism of vitamin D and the Vitamin D Receptor explains, these high levels may be a direct outcome of microbes' effect on slowing activity of the VDR. It is also an indication of innate immune dysfunction.

It is sometimes thought that the liver and kidney are the only sites for conversion of 25-D into 1,25-D, but this process happens outside those organs – not coincidentally, at the very sites where patients report symptoms of chronic disease. High levels of 1,25-D and the enzyme which leads to the production of 1,25-D, 1 α-hydroxylase, have been found at various locations where the human body needs a strong host defense.74 Zehnder et al found increased expression of the enzyme 1 α-hydroxylase – the enzyme which converts 25-D into 1,25-D – in the skin cells of sarcoidosis patients where sarcoidosis patients tend to have disease symptoms.75 They write:

In particular, the expression of 1α-OHase [1 α-hydroxylase] by activated macrophages and epidermal keratinocytes [skin cells] suggests a role for 1,25(OH)2D3 [1,25-D] as an immunomodulatory and/or antiproliferative hormone.

A number of studies have demonstrated that the level of the hormone 1,25-D rises in patients with certain chronic diseases. Kavathia et al. found that in patients with sarcoidosis, those with high serum levels of 1,25-D have more pronounced chronic treatment needs.76

Calcium metabolism

Hypercalcemia (excess levels of calcium in the blood) and hypercalciuria (excessive urinary calcium excretion) are frequently associated with the granulomatous diseases. Prevalence data suggests that 30 to 50 percent of patients with sarcoidosis have hypercalciuria and 10 to 20 percent have hypercalcemia.77 78 Until recently, some researchers suggested that these processes were caused by high levels of 1,25-D.(Manolagas SC Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21:115-37. )) 79 As a result, patients with granulomatous disease are widely cautioned to limit sunlight exposure and vitamin D ingestion – recommendations that are generally not offered to patients with other chronic inflammatory diseases. Even pro-vitamin D advocates such as Michael Holick, M.D. have issued such cautions for high-dose supplementation of vitamin D in granulomatous diseases.80

However, according to the Marshall Pathogenesis, any essential discrepancy in calcium/VDR metabolism between the granulomatous and non-granulomatous diseases is limited. The prevalence data suggests as much. Not everyone who has sarcoidosis gets hypercalcemia, and a large number of patients with other diseases such as breast and lung cancers are at risk for the condition.81 Further, in many diseases for which hypercalcemia is not suspected, the condition tends to go underdiagnosed.

Consistent with its classically understood role in maintaining bone health, the Vitamin D Receptor does appear to play at least some direct role in calcium regulation: a 2010 paper showed that the VDR signals stem cells responsible for osteoblast (bone-building) activity.82 But, researchers have since emphasized the role of estrogens and the estrogen receptor in maintaining bone health.83 In a 2007 study in Cell, Nakamura and colleagues showed that, in a female mouse model, removing estrogen receptor alpha in osteoblasts demonstrated that estrogen directly induces osteoclast apoptosis.84 The loss of estrogen among women at menopause may play some role in this process, but it is too soon to say this relationship is causal. Nakamura's work was done in otherwise healthy mouse cells rather than in human cells – which may be infected by pathogens. If such cells were infected, supplementation with estrogen would not address the underlying disease process.

Incidence and prevalence

An analysis of the 2001 ACCESS study challenged the widely held stereotype that the American patients most often affected by sarcoidosis are African-Americans and under 40.85

Commonly involved organs

Sarcoidosis can affect any organ, initially presenting with one or more of the following abnormalities (in order of frequency according to the 2001 ACCESS study, which used data collected by pulmonologists).86

Lung (pulmonary)

One estimation of percentage of overt organ involvement in sarcoidosis. Occult involvement is in parentheses.91

Managing respiratory symptoms

Main article: Managing respiratory symptoms

Patients at risk for respiratory problems should ask their physicians for a prescription for supplemental oxygen.

A variety of strategies that do not involve medication are available for patients who have uncomfortable respiratory symptoms including breathing exercises, getting more fluids, rest, and others. Also, patients have reported relief taking guaifenesin, using bronchodilator inhalers (steroid inhalers are contraindicated), and nebulizers. Supplemental oxygen may be useful or necessary in some cases even though it may be needed only for a few hours a day for a few months.

While it is certainly possible to contract an acute respiratory infection while on the Marshall Protocol, many symptoms of immunopathology mimic those of an acute respiratory infection. Early recognition and effective management of immunopathology are very important when a patient has respiratory symptoms. Any symptom that correlates with MP therapy may be due to immunopathology.

Emergency medical personnel should know that a patient is on the MP. The article Notice for health care providers provides information that emergency medical personnel need to know.

A cough can develop at any time in sarcoidosis. It can be related to anything from upper respiratory involvement and post-nasal drip to chest involvement or even triggered by exposure to dust, fungus, odors or fumes.

Belinda, MarshallProtocol.com

Skin (cutaneous sarcoidosis)

Cutaneous manifestations of sarcoidosis are common and varied, and one patient can have different types of sarcoid skin lesions at the same time. Because of its diverse skin manifestations, sarcoidosis is most frequently diagnosed by a dermatologist. When a patient with sarcoidosis presents with skin problems, physicians should be alert to sarcoidosis as likely the source of these problems.

Lupus pernio

Lupus pernio is not another disease, nor is it related to lupus. Lupus pernio is a chronic plaquelike hardening of the face, usually appearing with violet discoloration of the cheeks, lips, nose, and ears. It can erode into cartilage or bone. Lupus pernio lesions can be permanently disfiguring and cause a patient to feel embarrassed, particularly since they may be noticeable on facial areas so visible to the public.

Sometimes lupus pernio lesions will have an appearance of small “beads” along their edge, especially if the sore is on the rim of the nose. Like some other cutaneous sarcoidosis lesions, lupus pernio can appear at sites of old scars or trauma92 as well as in the upper respiratory tract93 – both sites of which can be quite resistant to the standard immunosuppressive therapies. These lesions can occur when the nose, face or hands are exposed to cold or wind, so it's a good idea for patients with sacroidosis to keep these areas protected from wind and cold. Avoiding exposure to bright lights is also an important preventative measure. Lupus pernio is said to be the skin lesion most characteristic (a diagnostic indicator) of sarcoidosis94, but not all sarcoidosis patients have these skin lesions.

My experience with lupus pernio is that it flares with exposure to light plus cold and wind. I suspect you have still been having a good bit of cool wind and weather in your part of the world. You may need to keep your nose better protected. I know that's hard to do, so if nothing else, you can stay indoors during daytime as much as possible and wrap a scarf around your nose if it is cool or windy.

Warning of the risk of scarring, whether on the skin or in the lungs, is a common tactic to pressure patients to use the treatment a physician prefers. Lupus pernio has a reputation for being difficult to treat. In reality, the doctor has no way to know whether you will scar. Certainly I sustained no scars from my winter bouts with lupus pernio.

Within a month, you will probably have this lupus pernio flare behind you and you can deal more assertively with your doctor to reassure him you are on the correct treatment, MP.

Continuing to take Benicar allows your immune system to work more efficiently and provides protection of organs. Prednisone injections will have a systemic effect, but less than if you took an oral dose.

Belinda Fenter, MarshallProtocol.com

Erythema nodosum (subcutaneous nodules)

Erythema nodosum are raised red, tender nodular lesions, generally but not exclusively on the anterior surface of the lower part of the leg. These lesions do not represent granulomatous involvement of the skin. Rather, the histopathology is primarily that of a panniculitis (inflammation of the fatty layer under the skin), with cellular inflammation and edema of the deep dermis and subcutaneous tissue. The presence of erythema nodosum is commonly observed in other infectious diseases such as tuberculosis.95

Eye (ocular sarcoidosis)

The reported frequency of ocular manifestations for sarcoidosis varies according to the source and group studied, but may be as high as 70%.96 In the eye, the common sites of involvement are the skin of eyelid, conjunctiva, uveal tract, retina, optic nerve and lacrimal gland.97 Common symptoms of ocular sarcoidosis include:

Some asymptomatic patients still have active inflammation. Initially asymptomatic patients with ocular sarcoidosis can eventually develop blindness. Therefore, it is recommended that all patients with sarcoidosis receive a dedicated ophthalmologic examination.

Columbia University researcher Emil Wirotsko identified cell wall deficient bacteria – which he described as “mollicute-like organisms” – in the vitreous fluid of sarcoidal eyes.99 He further showed that the introduction of these microbes into mouse model effectively reproduced the chronic inflammatory process and granuloma that are the hallmark of sarcoidosis.

Lymph nodes

A lymph node, also called a gland, is a small ball-shaped organ of the immune system, distributed widely throughout the body and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as filters or traps for foreign particles.

Lymph nodes play a vital role in the body's ability to fight off microbes. During an infection, the lymph nodes can expand due to intense B-cell proliferation in the germinal centers, a condition commonly referred to as “swollen glands.” Lymphadenopathy refers to “disease of the lymph nodes.” It is, however, almost synonymously used with “swollen or enlarged lymph nodes.” Lymphadenopathy can occur anywhere there are lymph node, but especially the neck, armpits, groin, or chest. Enlarged or tender glands can often be detected by low-tech means: visually or by palpation. Lymph nodes deep in the groin or beneath the ribs in the chest can be monitored with imaging such as chest x-ray, CT or PET scan.

Like any sarcoidosis symptom, lymphadenopathy may flare with immunopathology, resulting in enlarged and/or tender lymph nodes. The increase in the size of lymph nodes is consistent with an immunostimulatory therapy such as the Marshall Protocol. However, in later stages of sarcoidosis the lymph nodes shrink as their functionality decreases. This may be because they become too damaged to function. It is not unusual for lymph nodes to be calcified in sarcoidosis patients.100

While it is true that chest pain can be due to cardiac involvement, it may simply be due to other problems brought on by sarcoidosis such as enlarged lymph nodes which can cause pressure, crowding and pain in the chest. Enlarged lymph noses can also result in bronchial obstructions.

Management

Related article: Massage and other manipulation therapies

Massage can increase lymphatic flow101 as can osteopathic manipulation.102 Patients seeking this kind of therapy should look for therapists competent in techniques to help the lymphatic system and familiar with the needs of patients with chronic illness.

Liver

Sarcoidosis of the liver is not uncommon.103 According to Richard W Goodgame, MD, “The prevalence of hepatic granulomas in sarcoidosis is 65%. In a study of 100 patients with hepatic sarcoidosis, the majority of patients were asymptomatic and had normal abdominal examinations.”

The angtiotensin receptor blocker olmesartan has been shown to reduce liver fibrosis104 and aid liver healing.105 Some patients with sarcoidosis of the liver are mistakenly told they have “fatty liver disease” or cirrhosis.

Spleen

The reported frequency of splenomegaly, enlargement or inflammation of the spleen, in sarcoidosis has ranged from 1% to 40%.106

Neurologic (neurosarcoidosis)

Neurosarcoidosis (sometimes shortened to neurosarcoid) refers to sarcoidosis involving the central nervous system (brain and spinal cord). It can have many manifestations, but abnormalities of the cranial nerves (a group of twelve nerves supplying the head and neck area) are the most common. It may develop acutely, subacutely, and chronically. Approximately 5-10% of people with sarcoidosis of other organs develop central nervous system involvement. Only 1% of people with sarcoidosis will have neurosarcoidosis alone without involvement of any other organs. Diagnosis can be difficult, with no test apart from biopsy being completely reliable.

Psychiatric problems occur in 20% of cases; many different disorders have been reported, e.g. depression and psychosis. Peripheral neuropathy has been reported in up to 15% of cases of neurosarcoidosis.107

Managing neurological symptoms

Main article: Managing neurological symptoms

Cardiac

According to a 2003 study of Dutch patients, 30% of people with sarcoidosis suffer from chest pain.108 A similar proportion of sarcoidosis patients were found to have cardiac involvement upon autopsy.109 A third paper found that perhaps 50% of sarcoidosis patients have cardiac involvement that is not diagnosed110.

While it is true that chest pain can be due to cardiac involvement,111 it may simply be due to other problems brought on by sarcoidosis such as enlarged lymph nodes which can cause pressure, crowding and pain in the chest.

All sarcoidosis patients are cautioned to assume they may have unrecognized cardiac involvement and to control their level of immunopathology accordingly.

Managing cardiac symptoms

Main article: Managing cardiac symptoms

While a severe cardiac immunopathological reaction is rare, it has the potential to be life-threatening. Therefore, health care providers are cautioned to be on the alert for cardiac symptoms in all their patients. Also, patients with risk factors or legitimate cause for concern should know when seek medical attention.

Other

Patient interviews

Gene Johnson

sarcoidosis, bladder cancer

Read the interview

Chris Eastlund

diabetes, sarcoidosis, irritable bowel syndrome

Read the interview

Freddie Ash

sarcoidosis of the heart, coronary artery disease, atrial fibrillation

Read the interview

Sherry Cook

sarcoidosis, cat scratch fever, restless leg syndrome

Read the interview

Mirek Wozga

sarcoidosis

Read the interview

Guss Wilkinson

sarcoidosis, psoriasis, insomnia, kidney stones

Read the interview

Roy P.

sarcoidosis, rheumatoid arthritis

Read the interview

Leesa Shanahan

sarcoidosis (Heerfordt's Syndrome), uveitis

Read the interview

Shirley J. (Saj)

sarcoidosis

Read the interview

Carole Morgan

sarcoidosis, fibromyalgia, chronic fatigue syndrome (CFS)

Read the interview

JST

neurosarcoidosis, systemic sarcoidosis; spasticity, myasthenia, CNS dysfunction, joint pain, pulmonary, splenic and cardiac involvement

Read the interview

<br clear=“left” />

</div> </html>

Interviews of patients with other diseases are also available.

Patients experiences

From: Sue Lyons Date: 2011-12-14 13:50:45 Reply: http://marshallprotocol.com/reply.php?topic_id=7078

I just returned from a wonderful family vacation in Disney World. I was so excited that I was able to walk and keep up with my family… mostly, anyway and didn't need a wheelchair! When we booked our trip 10 months ago, I was planning to reserve a wheelchair to access the monorail and keep up with my family. As the summer progressed and I was feeling better I was confident that I was able to walk up ramps, etc. and did! The other wonderful news I have is that I was able to fly round trip from Alaska to Florida keeping my oxygen saturation above 90% without supplemental oxygen! I had my approved POC with Doctor's prescription etc. if needed, but my saturation was good as was my heart rate between 55 bpm and 75 bpm! I am thrilled!

Sue Lyons, MarshallProtocol.com

Read more

Keywords:

Notes and comments

smoking reduces risk

Am J Respir Crit Care Med. 2004 Apr 15;169(8):893-5.

Is smoking beneficial for granulomatous lung diseases?

Maier LA. Comment in: Am J Respir Crit Care Med. 2004 Jul 15;170(2):199-200; author reply 200. Am J Respir Crit Care Med. 2004 Oct 1;170(7):821; author reply 821. Comment on: Am J Respir Crit Care Med. 2004 Apr 15;169(8):903-9.

PMID: 15072982

The Etiologic Agent of SarcoidosisWhat If There Isn’t One?

http://chestjournal.chestpubs.org/content/124/1/6.full

References

1. Bottaro L, Calderan L, Dibilio D, Mosconi E, Maffessanti M Pulmonary sarcoidosis: atypical HRTC features and differential diagnostic problems. Radiol Med. 2004;107:273-85.
2. , 4. , 13. , 14. Ezzie ME, Crouser ED Considering an infectious etiology of sarcoidosis. Clin Dermatol. 2007;25:259-66.
3. Marshall TG, Marshall FE Sarcoidosis succumbs to antibiotics--implications for autoimmune disease. Autoimmun Rev. 2004;3:295-300.
5. Mangiapan G, Hance AJ Mycobacteria and sarcoidosis: an overview and summary of recent molecular biological data. Sarcoidosis. 1995;12:20-37.
6. Mitchell IC, Turk JL, Mitchell DN Detection of mycobacterial rRNA in sarcoidosis with liquid-phase hybridisation. Lancet. 1992;339:1015-7.
7. Saboor SA, Johnson NM, McFadden J Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction. Lancet. 1992;339:1012-5.
8. Bocart D, Lecossier D, De Lassence A, Valeyre D, Battesti JP, Hance AJ A search for mycobacterial DNA in granulomatous tissues from patients with sarcoidosis using the polymerase chain reaction. Am Rev Respir Dis. 1992;145:1142-8.
9. Richter E, Greinert U, Kirsten D, Rüsch-Gerdes S, Schlüter C, Duchrow M, Galle J, Magnussen H, Schlaak M, Flad HD, Gerdes J Assessment of mycobacterial DNA in cells and tissues of mycobacterial and sarcoid lesions. Am J Respir Crit Care Med. 1996;153:375-80.
10. Vokurka M, Lecossier D, du Bois RM, Wallaert B, Kambouchner M, Tazi A, Hance AJ Absence of DNA from mycobacteria of the M. tuberculosis complex in sarcoidosis. Am J Respir Crit Care Med. 1997;156:1000-3.
11. Wilsher ML, Menzies RE, Croxson MC Mycobacterium tuberculosis DNA in tissues affected by sarcoidosis. Thorax. 1998;53:871-4.
12. Ishige I, Usui Y, Takemura T, Eishi Y Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of Japanese patients with sarcoidosis. Lancet. 1999;354:120-3.
15. Almenoff PL, Johnson A, Lesser M, Mattman LH Growth of acid fast L forms from the blood of patients with sarcoidosis. Thorax. 1996;51:530-3.
16. Cantwell AR Jr Histologic observations of variably acid-fast pleomorphic bacteria in systemic sarcoidosis: a report of 3 cases. Growth. 1982;46:113-25.
17. Mitchell DN The nature and physical characteristics of a transmissible agent from human sarcoid tissue. Ann N Y Acad Sci. 1976;278:233-48.
18. Johnson LA, Edsall JR, Austin JH, Ellis K Pulmonary sarcoidosis: could mycoplasma-like organisms be a cause? Sarcoidosis Vasc Diffuse Lung Dis. 1996;13:38-42.
19. Hua B, Li QD, Wang FM [Borrelia burgdorferi may be the causal agent of sarcoidosis] Zhonghua Nei Ke Za Zhi. 1992;30:631-3, 659.
20. Liu HG [Spirochetes in the cheilits granulomatosa and sarcoidosis] Zhonghua Yi Xue Za Zhi. 1993;73:142-4, 189-90.
21. Xu Z, Ma D, Luo W [Detection of Borrelia burgdorferi DNA in granulomatous tissues from patients with sarcoidosis using polymerase chain reaction in situ technique] Zhonghua Jie He He Hu Xi Za Zhi. 1996;19:279-81.
22. Ishihara M, Ohno S, Ono H, Isogai E, Kimura K, Isogai H, Aoki K, Ishida T, Suzuki K, Kotake S, Hiraga Y Seroprevalence of anti-Borrelia antibodies among patients with confirmed sarcoidosis in a region of Japan where Lyme borreliosis is endemic. Graefes Arch Clin Exp Ophthalmol. 1998;236:280-4.
23. , 35. Eishi Y, Suga M, Ishige I, Kobayashi D, Yamada T, Takemura T, Takizawa T, Koike M, Kudoh S, Costabel U, Guzman J, Rizzato G, Gambacorta M, du Bois R, Nicholson AG, Sharma OP, Ando M Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204.
24. Li N, Bajoghli A, Kubba A, Bhawan J Identification of mycobacterial DNA in cutaneous lesions of sarcoidosis. J Cutan Pathol. 1999;26:271-8.
25. Drake WP, Pei Z, Pride DT, Collins RD, Cover TL, Blaser MJ Molecular analysis of sarcoidosis tissues for mycobacterium species DNA. Emerg Infect Dis. 2002;8:1334-41.
26. el-Zaatari FA, Naser SA, Markesich DC, Kalter DC, Engstand L, Graham DY Identification of Mycobacterium avium complex in sarcoidosis. J Clin Microbiol. 1996;34:2240-5.
27. Drake WP, Dhason MS, Nadaf M, Shepherd BE, Vadivelu S, Hajizadeh R, Newman LS, Kalams SA Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. Infect Immun. 2007;75:527-30.
28. Drake WP, Newman LS Mycobacterial antigens may be important in sarcoidosis pathogenesis. Curr Opin Pulm Med. 2006;12:359-63.
29. Fité E, Fernández-Figueras MT, Prats R, Vaquero M, Morera J High prevalence of Mycobacterium tuberculosis DNA in biopsies from sarcoidosis patients from Catalonia, Spain. Respiration. 2006;73:20-6.
30. Klemen H, Husain AN, Cagle PT, Garrity ER, Popper HH Mycobacterial DNA in recurrent sarcoidosis in the transplanted lung--a PCR-based study on four cases. Virchows Arch. 2000;436:365-9.
31. Grosser M, Luther T, Müller J, Schuppler M, Bickhardt J, Matthiessen W, Müller M Detection of M. tuberculosis DNA in sarcoidosis: correlation with T-cell response. Lab Invest. 1999;79:775-84.
32. Arai T, Inoue Y, Eishi Y, Yamamoto S, Sakatani M Propionibacterium acnes in granulomas of a patient with necrotising sarcoid granulomatosis. Thorax. 2008;63:90-1.
33. Yasuhara T, Tada R, Nakano Y, Tei M, Mochida C, Kamei M, Kinoshita S The presence of Propionibacterium spp. in the vitreous fluid of uveitis patients with sarcoidosis. Acta Ophthalmol Scand. 2005;83:364-9.
34. Nilsson K, Påhlson C, Lukinius A, Eriksson L, Nilsson L, Lindquist O Presence of Rickettsia helvetica in granulomatous tissue from patients with sarcoidosis. J Infect Dis. 2002;185:1128-38.
36. van Maarsseven AC, Mullink H, Alons CL, Stam J Distribution of T-lymphocyte subsets in different portions of sarcoid granulomas: immunohistologic analysis with monoclonal antibodies. Hum Pathol. 1986;17:493-500.
37. , 38. Turner OC, Basaraba RJ, Orme IM Immunopathogenesis of pulmonary granulomas in the guinea pig after infection with Mycobacterium tuberculosis. Infect Immun. 2003;71:864-71.
39. Häcker G, Kirschnek S, Fischer SF Apoptosis in infectious disease: how bacteria interfere with the apoptotic apparatus. Med Microbiol Immunol. 2006;195:11-9.
40. Rutherford RM, Kehren J, Staedtler F, Chibout SD, Egan JJ, Tamm M, Gilmartin JJ, Brutsche MH Functional genomics in sarcoidosis--reduced or increased apoptosis? Swiss Med Wkly. 2001;131:459-70.
41. , 44. Cosma CL, Sherman DR, Ramakrishnan L The secret lives of the pathogenic mycobacteria. Annu Rev Microbiol. 2003;57:641-76.
42. Iio K, Iio TU, Okui Y, Ichikawa H, Tanimoto Y, Miyahara N, Kanehiro A, Tanimoto M, Nakata Y, Kataoka M Experimental pulmonary granuloma mimicking sarcoidosis induced by Propionibacterium acnes in mice. Acta Med Okayama. 2010;64:75-83.
43. Warrier S, Muhammed Fassaludeen AS, Safia B Cutaneous sarcoidosis with tuberculoid granuloma. Indian J Dermatol Venereol Leprol. 2002;68:300-1.
45. Davis JM, Ramakrishnan L The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell. 2009;136:37-49.
46. Selim A, Ehrsam E, Atassi MB, Khachemoune A Scar sarcoidosis: a case report and brief review. Cutis. 2006;78:418-22.
47. de Almeida HL, Fiss RC Scar sarcoidosis with a 50-year interval between an accident and onset of lesions. Dermatol Online J. 2008;14:18.
48. Sorabjee JS, Garje R Reactivation of old scars: inevitably sarcoid. Postgrad Med J. 2005;81:60-1.
49. Corazza M, Bacilieri S, Strumìa R Post-herpes zoster scar sarcoidosis. Acta Derm Venereol. 1999;79:95.
50. Alabi GO, George AO Cutaneous sarcoidosis and tribal scarifications in West Africa. Int J Dermatol. 1989;28:29-31.
51. Healsmith MF, Hutchinson PE The development of scar sarcoidosis at the site of desensitization injections. Clin Exp Dermatol. 1992;17:369-70.
52. Padilla ML, Schilero GJ, Teirstein AS Donor-acquired sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:18-24.
53. Heyll A, Meckenstock G, Aul C, Söhngen D, Borchard F, Hadding U, Mödder U, Leschke M, Schneider W Possible transmission of sarcoidosis via allogeneic bone marrow transplantation. Bone Marrow Transplant. 1994;14:161-4.
54. Sundar KM, Carveth HJ, Gosselin MV, Beatty PG, Colby TV, Hoidal JR Granulomatous pneumonitis following bone marrow transplantation. Bone Marrow Transplant. 2001;28:627-30.
55. Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J, Tata LJ Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax. 2006;61:980-5.
56. Kern DG, Neill MA, Wrenn DS, Varone JC Investigation of a unique time-space cluster of sarcoidosis in firefighters. Am Rev Respir Dis. 1993;148:974-80.
57. Rossman MD, Kreider ME Lesson learned from ACCESS (A Case Controlled Etiologic Study of Sarcoidosis). Proc Am Thorac Soc. 2007;4:453-6.
58. , 86. Rybicki BA, Iannuzzi MC, Frederick MM, Thompson BW, Rossman MD, Bresnitz EA, Terrin ML, Moller DR, Barnard J, Baughman RP, DePalo L, Hunninghake G, Johns C, Judson MA, Knatterud GL, McLennan G, Newman LS, Rabin DL, Rose C, Teirstein AS, Weinberger SE, Yeager H, Cherniack R Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001;164:2085-91.
59. Moller DR Potential etiologic agents in sarcoidosis. Proc Am Thorac Soc. 2007;4:465-8.
60. Kanchwala, A., B. Barna, et al. (2009). Deficiencies of cathelicidin and vitamin D accompany disease severity in sarcoidosis.
61. Wikén M, Idali F, Al Hayja MA, Grunewald J, Eklund A, Wahlström J No evidence of altered alveolar macrophage polarization, but reduced expression of TLR2, in bronchoalveolar lavage cells in sarcoidosis. Respir Res. 2010;11:121.
62. , 78. Sharma OP Vitamin D, calcium, and sarcoidosis. Chest. 1996;109:535-9.
63. Powell JL, Cunill ES, Gajewski WH, Novotny DB Sarcoidosis mimicking recurrent endometrial cancer. Gynecol Oncol. 2005;99:770-3.
64. Grutters JC, van den Bosch JM Corticosteroid treatment in sarcoidosis. Eur Respir J. 2006;28:627-36.
65. Judson MA, Baughman RP, Thompson BW, Teirstein AS, Terrin ML, Rossman MD, Yeager H Jr, McLennan G, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki BA, Weinberger SE, Knatterud GL, Cherniak R Two year prognosis of sarcoidosis: the ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20:204-11.
66. Aggarwal BB, Shishodia S, Takada Y, Jackson-Bernitsas D, Ahn KS, Sethi G, Ichikawa H TNF blockade: an inflammatory issue. Ernst Schering Res Found Workshop. 2006;:161-86.
67. Grattendick KJ, Nakashima JM, Feng L, Giri SN, Margolin SB Effects of three anti-TNF-alpha drugs: etanercept, infliximab and pirfenidone on release of TNF-alpha in medium and TNF-alpha associated with the cell in vitro. Int Immunopharmacol. 2008;8:679-87.
68. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275-85.
69. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55.
70. Milman N, Andersen CB, Burton CM, Iversen M Recurrent sarcoid granulomas in a transplanted lung derive from recipient immune cells. Eur Respir J. 2005;26:549-52.
71. Walker S, Mikhail G, Banner N, Partridge J, Khaghani A, Burke M, Yacoub M Medium term results of lung transplantation for end stage pulmonary sarcoidosis. Thorax. 1998;53:281-4.
72. Lingaraju R, Pochettino A, Blumenthal NP, Mendez J, Lee J, Christie JD, Kotloff RM, Ahya VN, Hadjiliadis D Lung transplant outcomes in white and African American recipients: special focus on acute and chronic rejection. J Heart Lung Transplant. 2009;28:8-13.
73. Moan J, Lagunova Z, Lindberg FA, Porojnicu AC Seasonal variation of 1,25-dihydroxyvitamin D and its association with body mass index and age. J Steroid Biochem Mol Biol. 2009;113:217-21.
74. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol. 2008;181:7090-9.
75. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86:888-94.
76. Kavathia D, Buckley JD, Rao D, Rybicki B, Burke R Elevated 1, 25-dihydroxyvitamin D levels are associated with protracted treatment in sarcoidosis. Respir Med. 2010;:.
77. Adams JS Vitamin D metabolite-mediated hypercalcemia. Endocrinol Metab Clin North Am. 1989;18:765-78.
79. Brot C, Jørgensen N, Madsen OR, Jensen LB, Sørensen OH Relationships between bone mineral density, serum vitamin D metabolites and calcium:phosphorus intake in healthy perimenopausal women. J Intern Med. 1999;245:509-16.
80. Holick MF Vitamin D deficiency. N Engl J Med. 2007;357:266-81.
81. Rosol TJ, Capen CC Mechanisms of cancer-induced hypercalcemia. Lab Invest. 1992;67:680-702.
82. Kawamori Y, Katayama Y, Asada N, Minagawa K, Sato M, Okamura A, Shimoyama M, Nakagawa K, Okano T, Tanimoto M, Kato S, Matsui T Importance of Vitamin D receptor for neuronal control of hematopoietic stem cell niche. Blood. 2010;:.
83. Imai Y, Youn MY, Kondoh S, Nakamura T, Kouzmenko A, Matsumoto T, Takada I, Takaoka K, Kato S Estrogens maintain bone mass by regulating expression of genes controlling function and life span in mature osteoclasts. Ann N Y Acad Sci. 2009;1173 Suppl 1:E31-9.
84. Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell. 2007;130:811-23.
85. Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H Jr, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, McLennan G, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki B, Weinberger SE, Terrin ML, Knatterud GL, Cherniak R Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164:1885-9.
87. Nunes H, Humbert M, Capron F, Brauner M, Sitbon O, Battesti JP, Simonneau G, Valeyre D Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis. Thorax. 2006;61:68-74.
88. Srigley JA, Pollanen MS Sudden death with clinically undiagnosed pulmonary hypertension. J Clin Forensic Med. 2005;12:264-7.
89. Shorr AF, Helman DL, Davies DB, Nathan SD Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics. Eur Respir J. 2005;25:783-8.
90. Hennebicque AS, Nunes H, Brillet PY, Moulahi H, Valeyre D, Brauner MW CT findings in severe thoracic sarcoidosis. Eur Radiol. 2005;15:23-30.
91. Carey, W. D., & Cleveland Clinic Foundation. 2010. Current clinical medicine. Philadelphia: Saunders Elsevier.
92. Lewis FM, Harrington CI Lupus pernio following facial trauma. Clin Exp Dermatol. 1993;18:476-7.
93. Neville E, Mills RG, Jash DK, Mackinnon DM, Carstairs LS, James DG Sarcoidosis of the upper respiratory tract and its association with lupus pernio. Thorax. 1976;31:660-4.
94. Yanardag H, Pamuk ON, Pamuk GE Lupus pernio in sarcoidosis: clinical features and treatment outcomes of 14 patients. J Clin Rheumatol. 2003;9:72-6.
95. Mert A, Ozaras R, Tabak F, Pekmezci S, Demirkesen C, Ozturk R Erythema nodosum: an experience of 10 years. Scand J Infect Dis. 2004;36:424-7.
96. Nunes H, Bouvry D, Soler P, Valeyre D Sarcoidosis. Orphanet J Rare Dis. 2007;2:46.
97. Biswas J, Krishnakumar S, Raghavendran R, Mahesh L Lid swelling and diplopia as presenting features of orbital sarcoid. Indian J Ophthalmol. 2000;48:231-3.
98. Dursun D, Akova YA, Bilezikçi B Scleritis associated with sarcoidosis. Ocul Immunol Inflamm. 2004;12:143-8.
99. Wirostko E, Johnson L, Wirostko B Sarcoidosis associated uveitis. Parasitization of vitreous leucocytes by mollicute-like organisms. Acta Ophthalmol (Copenh). 1989;67:415-24.
100. Gawne-Cain ML, Hansell DM The pattern and distribution of calcified mediastinal lymph nodes in sarcoidosis and tuberculosis: a CT study. Clin Radiol. 1996;51:263-7.
101. Mortimer PS, Simmonds R, Rezvani M, Robbins M, Hopewell JW, Ryan TJ The measurement of skin lymph flow by isotope clearance--reliability, reproducibility, injection dynamics, and the effect of massage. J Invest Dermatol. 1990;95:677-82.
102. Knott EM, Tune JD, Stoll ST, Downey HF Increased lymphatic flow in the thoracic duct during manipulative intervention. J Am Osteopath Assoc. 2005;105:447-56.
103. James DG, Sherlock S Sarcoidosis of the liver. Sarcoidosis. 1994;11:2-6.
104. Oakley F, Teoh V, Ching-A-Sue G, Bataller R, Colmenero J, Jonsson JR, Eliopoulos AG, Watson MR, Manas D, Mann DA Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology. 2009;136:2334-2344.e1.
105. Kurikawa N, Suga M, Kuroda S, Yamada K, Ishikawa H An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol. 2003;139:1085-94.
106. Salazar A, Mañá J, Corbella X, Albareda JM, Pujol R Splenomegaly in sarcoidosis: a report of 16 cases. Sarcoidosis. 1995;12:131-4.
107. Joseph FG, Scolding NJ Sarcoidosis of the nervous system. Pract Neurol. 2007;7:234-44.
108. Hoitsma E, De Vries J, van Santen-Hoeufft M, Faber CG, Drent M Impact of pain in a Dutch sarcoidosis patient population. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20:33-9.
109. Zimmer R Screening for cardiac involvement in sarcoidosis? Postgrad Med. 2002;112:12.
110. Veinot JP, Johnston B Cardiac sarcoidosis--an occult cause of sudden death: a case report and literature review. J Forensic Sci. 1998;43:715-7.
111. Abrishami B, O'Connel C, Sharma O Cardiac sarcoidosis with presentation of large left atrial mass. Curr Opin Pulm Med. 2004;10:397-400.
112. Fatahzadeh M, Rinaggio J Diagnosis of systemic sarcoidosis prompted by orofacial manifestations: a review of the literature. J Am Dent Assoc. 2006;137:54-60.
113. Yates JM, Dickenson AJ Sarcoidosis presenting as an isolated facial swelling--an unexpected diagnosis? Dent Update. 2006;33:112-4.
114. Blinder D, Yahatom R, Taicher S Oral manifestations of sarcoidosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:458-61.
115. Olivier V, Lacour JP, Castanet J, Perrin C, Ortonne JP [Cheilitis granulomatosa in a child] Arch Pediatr. 2000;7:274-7.
116. Hayter JP, Robertson JM Sarcoidosis presenting as gingivitis. Br Med J (Clin Res Ed). 1988;296:1504.
117. Vasil'ev VI, Logvinenko OA, Simonova MV, Safonova TN, Radenska-Lopovok SG, Bozh'eva LA, Shornikova NS, Andrianov SG [Sicca syndrome in sarcoidosis and involvement of the salivary and lacrymal glands] Ter Arkh. 2005;77:62-7.
118. Santoro F, Sloan SB Nail dystrophy and bony involvement in chronic sarcoidosis. J Am Acad Dermatol. 2009;60:1050-2.
119. Cohen PD, Lester RS Sarcoidosis presenting as nail dystrophy. J Cutan Med Surg. 1999;3:302-5.
120. Wakelin SH, James MP Sarcoidosis: nail dystrophy without underlying bone changes. Cutis. 1995;55:344-6.
121. Turner GA, Lower EE, Corser BC, Gunther KL, Baughman RP Sleep apnea in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14:61-4.