Guideline
Intractable diffuse pulmonary diseases: Manual for diagnosis and treatment

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Abstract

This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014–FY2016 Health and Labor Sciences Research Grant on Intractable Diseases.

This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities.

The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.

Introduction

Pulmonary alveolar microlithiasis an autosomal recessive disease; where microlithiasis with a characteristic tree-ring/layered pattern, composed mainly of calcium phosphate, occurs in the alveoli.

Since the first recorded case in 1868, cases were occasionally reported during the 1900s, with the first case in Japan also reported in 1954. Despite the long history, even in recent reports, the disease has a frequency of around 1000 cases worldwide, and much remains unclear regarding its clinical realities. In Japan, Tachibana et al. conducted a nationwide survey in the 1960s and reported on the epidemiological and clinical investigation of 51 cases. Despite Tachibana et al. subsequently accumulating more than 100 cases, there had been no nationwide surveys since the 1960s.

It was amid this situation that the Intractable Diffuse Pulmonary Disease Subcommittee and Intractable Respiratory Tract Disease Subcommittee were established as part of the Diffuse Pulmonary Diseases Study Group (supported by the Health and Labor Sciences Research Grant on Intractable Diseases, started in 2014; principal researcher: Sakae Homma, Homma group). Each subcommittee was appointed to start on approaches for three diseases: (1) Hermansky-Pudlak Syndrome with interstitial pneumonia (IP), (2) pulmonary alveolar proteinosis, and (3) pulmonary alveolar microlithiasis for the former; with (1) intractable diffuse panbronchiolitis, (2) bronchiolitis obliterans, and (3) immotile ciliary syndrome for the latter. The goals were to elucidate the current state of these rare diseases and to produce diagnostic criteria and severity-scale classifications to aid in the designation of these rare intractable diffuse pulmonary diseases as specified intractable diseases. According to the goals of these activities, the pulmonary alveolar microlithiasis subcommittee was formed with Yasuhiko Nishioka as chairman and with Koichi Hagiwara as vice-chairman. First, a nationwide questionnaire survey was initiated in FY2014. The actual questionnaire survey was approved by the Institutional Review Board of Tokushima University Hospital and started in December 2014, focused on Hisatsugu Goto and Yasuhiko Nishioka of the Department of Respiratory Medicine and Rheumatology at Tokushima University. It gathered information from 641 medical institutions, each of which has more than 200 beds. I would like to use this opportunity to express my gratitude again to each institution and its physicians for cooperating with the questionnaire.

Additionally, in the production of the diagnostic criteria, we received the opinions of Dr. Teruo Tachibana, who is an expert in clinical pulmonary alveolar microlithiasis, Dr. Koichi Hagiwara, who is an expert genetic analysis, and Dr. Takeshi Johkoh, who is an expert in imaging. I would also like to express my heartfelt gratitude to the physicians that presented their cases.

Through the consolidation of the sparse clinical information, the production of the diagnostic criteria was advancing steadily during summer 2016 when Group Leader Homma presented a proposal to publish the consolidated clinical information on three diseases: (1) pulmonary alveolar microlithiasis, (2) bronchiolitis obliterans, and (3) Hermansky-Pudlak Syndrome with interstitial pneumonia (IP), as a set of guidelines, leading to a sudden rush to integrate all of the information. On reconsidering this, it was clear that there existed no detailed publications for these kinds of rare, diffuse pulmonary diseases. Consequently, the manual is the result of compiling the accumulated information in the hopes of them being of some use to physicians in their daily medical treatment. There are many places that remain lacking and, while it is difficult to say by any standard that the contents are substantial, I would request the reader to excuse this in consideration of the fact that these are rare diseases.

Bronchiolitis obliterans is a severe complication that causes the QOL of hematopoietic stem cell transplant and lung transplant patients to decline, and it also affects long-term prognoses. However, it does not only affect transplant patients, and there are more than a few reports of idiopathic bronchiolitis obliterans and bronchiolitis obliterans as a complication to various autoimmune disorders. Diffuse Pulmonary Diseases Study Group (supported by the Health and Labor Sciences Research Grant on Intractable Diseases) conducted the first nationwide research survey into bronchiolitis obliterans in Japan during 2003 (group leader: Toshihiro Nukiwa, Nukiwa group), with the second in 2011 (group leader: Yukihiko Sugiyama, Sugiyama group). The first nationwide survey included 287 cases from before 2003 (105 cases from pathological diagnosis, with 182 cases from clinical diagnosis). The second nationwide survey included 477 cases from 2004 to 2011 (93 cases from pathological diagnosis, with 384 cases from clinical diagnosis). Based on the second nationwide research survey, the Sugiyama and Homma groups held four clinical conferences at Nippon Medical School and Nagoya University for those cases out the 93 with pathological diagnosis for which cooperation was obtained for a secondary survey. The conferences assembled specialists in internal respiratory medicine, thoracic diagnostic imaging specialists, and pathologists specialized in lung pathology, thus accumulating clinical, imaging, and pathological information.

As per the results of the previous two nationwide surveys, the disease was found to be a rare one. Diagnosis is difficult, and there exists no effective treatment method. The body of evidence for treatment is scarce, and there is no coherent collection of cases. Given this situation, the Homma group produced Intractable Diffuse Pulmonary Diseases: Manual for Diagnosis and Treatment, which included the cases that were definitively diagnosed as bronchiolitis obliterans at the clinical conferences into the second nationwide research survey Since transplantation therapies are expected to become more common in the future, the diagnosis and treatment of bronchiolitis obliterans is likely to become an even more serious challenge. I hope that this manual will be of help in daily treatment, as well as in shedding new light on bronchiolitis obliterans. I would like to give the highest regards and heartfelt gratitude to the medical institutions that cooperated with the research survey across Japan and everyone involved, including those that participated in the clinical conferences.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive congenital disease that presents with oculocutaneous albinism and bleeding tendencies that are due to reduced platelet function; however, it causes intractable interstitial pneumonia and pulmonary fibrosis in adulthood, making it a considerable problem clinically. Due to its rarity, HPS had not been researched methodically or systematically in Japan, even by epidemiological surveys. Therefore, the Diffuse Pulmonary Diseases Study Group, which started in 2014 as part of the Health and Labor Sciences Research Grant on Intractable Diseases, aimed to formulate the diagnosis and treatment of HPS with interstitial pneumonia in Japan. Incidentally, the diagnostic criteria for the oculocutaneous albinism (p. 77), which was a specified intractable disease in the Intractable Disease Health Care Act, were determined as of July 1, 2015, after the epidemiological survey. Among such criteria, HPS was specified as “a syndrome complicated with general symptoms,” and pulmonary fibrosis complications were set as a condition to meet the severity requirement for health benefits. The next step after having grasped the data from the first epidemiological survey for the disease in Japan was to pursue greater understanding of the disease's pathology. Consequently, a case report was submitted treating it as a rare disease, and it was decided that guidelines for its diagnosis and treatment should be formulated.

There are around 10 gene mutations related to the onset of HPS; however, there are cases where no mutations are found in any of the HPS-1, HPS-2, or HPS-4 genes, which are known for their close relationship with pulmonary lesions (see p.92 “Chapter 3 D Case (4)”). Even with the related genes determined, as the mutations and the mechanism of onset of interstitial pneumonia/pulmonary fibrosis are not necessarily exhibited in the lung tissues and as it is commonly accompanied with bleeding tendencies, some hold the opinion that both surgical lung biopsies and bronchoscopy should be avoided. Interstitial pneumonia, which many HPS patients develop, has no subjective symptoms upon onset. Considering that the respiratory function is also normal, it may indeed be more clinically accurate to call the disease HPS-associated interstitial pneumonia.” If the interstitial pneumonia accompanying the HPS progresses to the stage of intractable, chronic, progressive fibrosis, then it would actually be more appropriate to call it HPS associated pulmonary fibrosis.” However, as there is currently no evidence for making such a distinction, there is likely little significance in such discriminations.

Perhaps because of its onset slightly earlier than idiopathic pulmonary fibrosis, during when one is in their 30s–40s, the subsequent clinical course is diverse, with some cases having a long course of around 10 years. At present, there have been no medical treatments verified as being effective and, in the current situation where control of the causative genes is difficult, it seems likely that hopes must be placed on anti-fibrosis treatments that exhibit efficacy toward idiopathic pulmonary fibrosis. In fact, some recent thinking suggests that idiopathic pulmonary fibrosis itself is a complex genetic disease. It is anticipated that efficacy will be verified for treatments for HPS with interstitial pneumonia; however, at present, it seems that the only option is the administration of anti-fibrosis drugs, the efficacy of which is currently only theoretical.

Section snippets

Background

Pulmonary alveolar microlithiasis (OMIM265100) is an autosomal recessive disease characterized by microlithiasis with a distinctive tree-ring/layered pattern, composed mainly of calcium phosphate, occurring in the alveoli. It occurs with high frequency among siblings and those whose parents were in a consanguineous marriage [1]. The microliths develop slowly and eventually cover many of the alveoli. At the same time, chronic inflammation and fibrosis occurs in the alveolar wall. Many cases are

Background

Bronchiolitis obliterans is a disease with characteristics of the pathologically narrowing or obstruction of small bronchi and membranous bronchiole due to granulation or fibrosis induced by unknown causes. The obstructive changes of bronchioles are generally irreversible. Therefore, patients with bronchiolitis obliterans often suffer from respiratory failure; as a consequence, the prognosis and quality of life (QOL) remain very poor [23,24]. Bronchiolitis obliterans has been known as one of

Mechanism of pathogenesis and onset

Pulmonary fibrosis is caused by environmental and genetic factors. It is characterized by the accumulation of pulmonary fibroblasts and retention in the extracellular matrix. Hermansky-Pudlak syndrome (HPS) is a quite-frequent genetic disease associated with pulmonary fibrosis. HPSwas first reported by Czechoslovakian physicians Dr. Frantisek Hermansky and Dr. Paulus Pudlak in 1959, who had two cases that presented with albinism of the eyes and skin, with bleeding tendencies [59]. This

Conclusions

It is important that amendments continue to be made appropriately, based upon the rapid advances in medical treatment.

I hope that this manual will be of assistance to many physicians of respiratory medicine departments, and I would like to express my deepest gratitude for the considerable efforts of the Production Committee members, the prompt literature retrieval undertaken by the staff of the Toho University Medical Media Center, and the cooperation of the staff of Nankodo Co., Ltd. regarding

Funding

The formulation of the present manual was funded exclusively with survey and research grants from the Ministry of Health, Labour and Welfare, the Study Group on Diffuse Pulmonary Disorders, Scientific Research/Research on Intractable Diseases.

Conflict of Interest

The Japanese Respiratory Society has set up a conflicts of interest (COI) committee to manage COI appropriately, based on the shared guidelines and detailed regulations regarding COI determined in coordination with the Japanese Society of Internal Medicine (the guidelines and forms regarding COI are published on the society's website).

COI information for members of the Intractable Diffuse Pulmonary Diseases: Manual for Diagnosis and Treatment Production Committee is shown below.

  • 1)

    Reception of

Acknowledgments

The authors are grateful to the following for their help in the preparation of the manuscript.

External evaluators (in the order of Japanese syllabary).

Shoji Kudo, Japan Anti-Tuberculosis Association.

Yukihiko Sugiyama, Japan Association for Development of Community Medicine, Nerima Hikarigaoka Hospital.

Toshihiro Nukiwa, Professor Emeritus, Tohoku University.

and.

Collaborators (case submissions) (in the order of Japanese syllabary).

Hiroki Ashizawa, Respirology Department, Shizuoka Shimizu Hospital.

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    This is a translated summary of a full guideline published as a book in Japanese (ISBN: 4-524-25118-6) by The Japanese Respiratory Society, Intractable Diffuse Pulmonary Diseases: Manual for Diagnosis and Treatment, 2017.

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