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This week’s blog features another of the fantastic entries we received to our 2018 Student Voice essay competition. Here, Anna-Lucia Koerling from the University of Cambridge compares the diagnosis and delivery of treatments for Idiopathic Pulmonary Fibrosis between multiple countries.

Rare disease patients are an underserved population. Their diseases often receive little public notice, and many face long delays before a diagnosis is made. Paucity of availability of diagnostic techniques means that conditions such as idiopathic pulmonary fibrosis (IPF), the subject of this essay, are underreported. These issues are often particularly acute in less economically developed countries, and even in emerging economies such as the BRIC nations (Brazil, Russia, India, and China). The huge populations of the BRIC nations may therefore represent a valuable opportunity to progress towards effective treatment for IPF and other rare diseases (1). An obvious comparison, as the nearest wealthy nation in size, is the USA, which will herein be compared to China.

IPF is one of the more prevalent rare diseases, affecting approximately 3 million people worldwide (2). It presents with breathlessness on exertion, increasing cough, and fine inspiratory crackles. It is invariably fatal, but there are various patterns of survival, depending on whether the disease is slowly or rapidly progressive, and on the presence of acute exacerbations (3). There is no current curative treatment, and there are few drug therapies available. Lung transplantation confers some benefit, however there are few donor lungs available, and many IPF patients do not fulfil transplant criteria. IPF is a nonneoplastic, non-inflammatory disease, characterised by the formation of granulation tissue within the lungs. IPF is usually rapidly fatal, with one study finding that median survival time was 2.8 years from diagnosis (11). Its histological counterpart is known as usual interstitial pneumonia (UIP), and is characterised by alveolar septal thickening, with sheets of collagen replacing normal interstitial tissue (12).

The disease has an incidence of approximately 11 per 100,000 men and 7 per 100,000 women worldwide (4), although these data are likely to be inaccurate, as epidemiological data is extremely limited. Unfortunately, estimating incidence and prevalence is difficult, as diagnostic criteria vary between countries, and making an accurate diagnosis is difficult. Variability in the diagnostic criteria used is responsible for inconsistencies in estimation – for example, the annual IPF incidence in Europe ranges between 0.22 and 7.4/100,000 population in different studies (5).

The epidemiology of IPF in China remains unclear. There have been no specific epidemiological studies, and whilst it is possible to extrapolate the reported incidence from developed nations, higher rates of smoking and occupational exposure to chemicals in China means that these estimations are likely to be too low (6). An epidemiological study of IPF in China would be of great utility in identifying risk factors and patterns of disease, as well as helping a novel population of sufferers. Such studies will hopefully become easier in future, as the first official list of rare diseases was released by the Chinese government in 2018, and included IPF (7).

Incidence of IPF in the USA has been better documented. Studies estimate that incidence is between 5 and 8 per 100,000 (using narrow criteria). Prevalence estimates vary between 14 and 27.9 cases per 100,000 population using the same criteria (89). The similarity of the incidence and prevalence figures is a stark reminder of the short lifespan of IPF patients after diagnosis.

Mean age of presentation is 66, and IPF incidence increases with age, with over 65% of cases in one study presenting in patients over 60 (13). Though the name of the disease suggests no known cause, an environmental aetiology is supported by the pattern of disease. Unfortunately, as with many rare diseases, the small sample size makes establishing a causative factor difficult. IPF is strongly linked to smoking, with an odds ratio of 2.3 reported for those with a 20-40 pack year history, and studies have also linked it to other environmental factors, including exposure to silica and livestock (14). China has the world’s largest population of smokers, with 54% of men and 3.4% of women making up a population of 318 million current smokers (15).

In the USA, ‘gold standard’ diagnosis of IPF is dependent on clinical-radiological-pathological correlation. Guidelines adopted by the American thoracic society in 2000 state that the diagnosis of IPF can be considered definitive only in the presence of a surgical lung biopsy, a high resolution CT scan demonstrating a pattern of confident IPF, and abnormal pulmonary physiology with evidence of restriction. Other known causes of interstitial lung disease must also be excluded. A probable diagnosis of IPF can be established by fulfilment of a set of clinical criteria in the absence of a surgical biopsy (13). There are several issues with these criteria; – excluding known causes of interstitial lung disease is difficult, and there are no standardised guidelines on radiographic and histological recognition of IPF. In China, diagnosis of IPF may be made either pathologically or clinically, with the Chinese Society of Respiratory Diseases considering both to be valid diagnoses (16). Chinese patients and physicians are far less likely than their counterparts in the west to perform lung biopsy (fewer than 10% of cases are diagnosed pathologically), as the procedure is expensive, and has the potential to worsen the disease. However, this doesn’t seem to impair diagnosis significantly, as one study found that the American and Chinese guidelines coincided at a rate of 84.6% (6). The main hindrance to diagnosis in China is likely to be access to respiratory specialists and high resolution CT. Smoking and occupational exposure rates are highest in rural regions, which are also the areas furthest from tertiary care centres, and rural residents are unlikely to have private supplementary medical insurance (17). It is therefore likely that IPF is significantly underdiagnosed in rural China.

Treatment possibilities for IPF patients are currently limited. Pharmacological therapies have been the main focus of clinical trials, but few have been shown to be effective. Pirfenidone is an antifibrotic, and is the only drug licensed in both the USA and China (18) for IPF, and has been shown to improve progression-free survival in patients with mild to moderate disease (19). Nintedanib is licensed in the USA but not China. It slows the rate of decline in FVC, and decreases incidence of acute exacerbations (20). Several new drugs are currently in therapeutic trials, and better understanding of IPF pathogenesis has led to proposal of a number of potential pharmacological targets (21). Most current trials are US-based, but the large population of Chinese IPF sufferers could benefit from involvement in such trials, so international cooperation may prove very beneficial.

China, unlike the US, also recommends traditional Chinese medicine (TCM) in the official guidelines for IPF treatment. There have been no large-scale randomised trials on the effects of traditional Chinese medicine, so evidence is lacking. However, several studies have reported that single herb extracts used in TCM have had beneficial effects in animal models of IPF. These include turmeric and the Chinese caterpillar fungus (22). Chinese patients are far more likely to accept TCM than their western counterparts, and it provides a cost-effective alternative to expensive drug therapy.

When drug treatment fails, the last resort is lung transplantation. This confers significant survival benefits, with a 5-year survival rate of 45% and a 10-year survival rate of 22% in the USA. Significantly more transplants are performed in the USA than China. In 2016, 2,327 lung transplants were performed in the USA, of which 37% were to treat IPF (23). By contrast, only 260 transplants had ever been performed in total in China by 2011 (24), and 45% of these were diagnosed as having end stage IPF. Survival rates were lower in China, with a 5 year survival rate of 34.7%, and 0% 10 year survival (25). Whilst lung transplantation is not a miracle cure, this is clearly one area in which expansion is possible and necessary. Lack of donors and cost of procedure remain a major problem, as is also the case in the USA. One American study found that IPF patients of lower socioeconomic status, with only public health insurance, were less likely to receive a lung biopsy, lung transplant, or to be discharged to inpatient rehabilitation (26). It appears that poverty is a major barrier to diagnosis and treatment in both China and the USA.

IPF is a devastating disease, with a dismal prognosis. Patients with IPF report a high disease burden, and many suffer from depression (27). This essay compares the current epidemiology, diagnosis, and provision of treatment for IPF in two of the world’s largest nations. The USA is the site of most clinical research into IPF, and there are several patient awareness groups. Nonetheless, there are many issues remaining, including disparities in access to treatment. China is currently investing a heavily in its healthcare system, and one obvious area to focus on is the provision of care for rare diseases. IPF is a good example of this, as China is thought to have the world’s largest population of IPF sufferers. There has been significant clinician focus on the disease, however there have been no large scale epidemiological studies or clinical trials, and patient support is minimal. These case studies highlight the multifaceted problems affecting IPF patients and their doctors worldwide, and the desperate need for international cooperation in progression towards a cure.



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Dying to breathe – Comparing Idiopathic Pulmonary Fibrosis in the world’s largest economies

by Guest Contributer time to read: 9 min