Were deaths recorded in Brazil due to cystic fibrosis or pulmonary fibrosis? A data-based analysis

Cystic fibrosis (CF, OMIM n° 219700) is a genetic condition associated with the presence of pathogenic variants in the CFTR (Cystic Fibrosis Transmembrane Regulator) gene (Marson et al., 2016; Marson, 2018; da Silva Filho et al., 2021). Historically, the illness clinical phenotype was associated with the presence of salty sweat which resulted in the use of chloride ion quantification in the sweat as a diagnosis criterion (Ong and Ramsey, 2023). In Brazil, although its higher prevalence is ascribed to individuals of Caucasian origin, it has also been observed in other ethnic and racial groups (de Azevedo et al., 2023). In the last few years, due to advancements in its treatment, the patients’ survival rate has increased (Burgel et al., 2023; Kerem et al., 2024). Therefore, individuals that would probably die at birth or in the first few years of life were seen to live up to adolescence, and more recently, to adulthood (Anton-Păduraru et al., 2024). However, there are still discrepancies regarding the life span among different populations of patients with CF and among those in the same population. For this reason, greater importance has been given to the patients’ genetic profile as well as their access to health care, diagnosis, and treatments using precision and personalized medicine (Marson et al., 2017; Kmit et al., 2019; Guo et al., 2024). Taking that into consideration, we sought to evaluate the death rate of patients with CF and determine the most affected age groups in Brazil. To achieve the study aim, we evaluated data stored in the Brazilian death register referring to patients with CF [International Classification of Diseases (ICD): E84], which resulted in 3937 deaths in a period of 26 years. Curiously, unlike the literature reports (Coriati et al., 2023; Ong and Ramsey, 2023; Singh et al., 2023) most deaths were recorded among adult or old individuals (Supplementary Table 1, Figure 1a). This fact does not characterize the epidemiological data as recorded in the Brazilian Cystic Fibrosis Registry (REBRAFC, from Portuguese Registro Brasileiro de Fibrose Cística, 2022) (Supplementary Table 2, Figure 1b). In that record, in 2021, the CF patients’ population was predominantly young and 74.4% of the individuals were under 18 years old. Also, in 2021, 50 deaths resulting from CF were reported in a population whose mean age was 21.59.9 years. This value contrasts that found in the Open-Data-SUS record of deaths, whose Death Information System registered 272 deaths only that year, out of which 51 cases reported individuals over 80 years old (Brazilian Death Information System – SIM, from Portuguese Sistema de Informações sobre Mortalidade, Open-Data-SUS). Considering the Open-Data-SUS relevance as a source of information about the health of the Brazilian population and the evidence of errors found in death registers by this research, in which CF was possibly confused with idiopathic pulmonary fibrosis as causa mortis, we concluded that this is an urgent issue, thus a critical reflection upon it promoting the discussion of this matter has become an unavoidable ethical commitment.The Brazilian Cystic Fibrosis Registry, which stores information provided by the Referral Centers, is the main source of information about the CF Brazilian population. The register efficiently monitors patients with this disease aiming to promote better access to diagnosis and treatment and, in the context exposed, is used as reference for the knowledge of this disease in the population. Considering the excellence of their register of the number of cases and patients’ follow-up, the contrasting data observed is alarming. Analyzing such contrast, there might be some factors associated with the data tabulation, which include: a) typing mistakes when entering information in the Open-Data-SUS System and b) poor data management and incorrect ICD record due to phonetic similarity, as for example ICD: J84.1 associated with interstitial pulmonary diseases including, mainly, idiopathic pulmonary fibrosis, which mainly affects the elderly (Supplementary Table 3, Figure 1a). Such semantic confusion might result from a lack of technical knowledge about CF mainly by medical doctors that give assistance to adults, including pneumologists since not long ago it was quite rare to see adults affected by this disease in the country. Such illness was essentially associated with the pediatric age range. In addition, pulmonary diseases that develop with fibrosis in addition to tomographic signals possibly found in fibrosing pulmonary diseases, which might include the presence of fibrosis and cysts (Shah et al., 2024).CF disease: A brief reviewCF is one of the most common genetic diseases. It is an autosomal recessive inheritance illness which affects multiple organs and it shows a wide spectrum of clinical manifestations, including chronic obstructive pulmonary disease, sinusitis, steatorrhea, malnutrition, sweat electrolyte loss, and obstructive azoospermia (Dickinson and Collaco, 2021; Shteinberg et al., 2021). It is progressive and shows great severity potential (Dickinson and Collaco, 2021; Shteinberg et al., 2021). The pulmonary disease is characterized by chronic and productive cough, dyspnea, and “repetition pneumonias” (exacerbations) resulting from chronic infections, which provoke bronchiectasis and other structural alterations that compromise the pulmonary function and might cause complications such as hemoptysis, pneumothorax, and respiratory failure (Dickinson and Collaco, 2021; Shteinberg et al., 2021). The earlier patients are diagnosed and treated in referral centers, the better their quality of life and survival rates are. Although currently most people have access to the diagnosis from the positive neonatal tracking, which in Brazil is obtained by means of serum immunoreactive trypsinogen dosage in the neonatal heel pricking test (Athanazio et al., 2017), some patients depend on the medical doctor’s technical ability to suspect of this diagnosis. This is more easily accomplished when CF is in the family background, but can be hampered when depending only from recognition of signs and symptoms as suspicious. Except for the meconium ileus, most of the CF initial clinical manifestations are not pathognomonic and are found in other common childhood diseases such as pneumonia, asthma, and food allergy. For this reason, it can be considered a rare disease (mean incidence of 1:10,000 in Brazil) and due to the stigma of being a severe and potentially lethal disease, the CF hypothesis is many times disregarded when it should be considered. This causes a series of irreversible damages to those affected by the disease, which increase their morbidity (GBEFC - Grupo Brasileiro de Estudos de Fibrose Cística, n.d.). The need for more complex care tends to increase proportionally to the patients’ age (Ong and Ramsey, 2023). In developed countries such as those in Europe, around 51.2% of individuals with CF are adults with a survival period of ~50 years (Bierlaagh et al., 2021). However, in developing countries, the lifespan is shorter, for example, ~21.5 years in Brazil (Bell et al., 2020).CF remains incurable, but advances in treatment have significantly extended the lifespan and improved the quality of life of many patients (Marson et al., 2015; Burgel et al., 2023; Kerem et al., 2024). Effective management requires a multidisciplinary healthcare team, including CF specialists, to initiate treatment promptly upon positive newborn screening, even before confirmation of diagnosis (Athanazio et al., 2017). Treatment strategies focus on airway clearance techniques, medications to enhance CFTR protein function, and interventions such as respiratory and nutritional support or surgery when necessary (Grasemann and Ratjen, 2023; McGlynn et al., 2023). The comprehensive CF care team typically comprises specialists in pulmonary medicine, endocrinology, gastroenterology, fertility, genetics, nursing, nutrition, palliative care, pharmacy, physical therapy, psychology, respiratory therapy, social work, and transplant care (McGlynn et al., 2023). In CF, airway clearance methods, such as oscillatory positive expiratory pressure devices and chest physical therapy, aid in mucus clearance, reduce infections, and improve respiratory function alongside bronchodilators and mucolytic agents (Grasemann and Ratjen, 2023; McGlynn et al., 2023). Medications for CF target various aspects of the disease, including antibiotics for infection management, anti-inflammatory drugs such as Ibuprofen or Corticosteroids to reduce inflammation, and CFTR modulators to enhance defective protein function based on genetic pathogenic variants (Marson et al., 2017; Grasemann and Ratjen, 2023; McGlynn et al., 2023). CFTR modulators, administered orally, require genetic testing to determine suitability and may interact with other medications and cause side effects. The approved CFTR modulators include Elexacaftor-Tezacaftor-Ivacaftor – triple combination medicine approved for adults and children aged two and older, Ivacaftor alone – approved for adults and children as young as four months old, Lumacaftor-Ivacaftor combination – approved for people who are at least one year old, and Tezacaftor-Ivacaftor combination – approved for people as young as four months old, tailored to specific pathogenic variants of the CFTR gene (Regard et al., 2022; Jia and Taylor-Cousar, 2023; Southern et al., 2023; Cystic Fibrosis - Treatment | NHLBI, NIH, 2023). Additional therapies such as oxygen therapy, pulmonary rehabilitation, ventilator support, and extracorporeal membrane oxygenation are employed for severe respiratory complications (Southern et al., 2023). Surgical interventions, including lung or liver transplants, are considered for advanced cases of CF-associated organ dysfunction (Southern et al., 2023; Sellers et al., 2024).Idiopathic pulmonary fibrosis: A brief reviewPulmonary fibrosis involves a wide group of diseases characterized by progressive healing (fibroblasts) and progressive impairment. The idiopathic pulmonary fibrosis, as the name suggests, is a disease whose etiology has not been fully elucidated. It is the most common among the fibrosing pulmonary diseases and has a debilitating character, with high physical and emotional morbidity (Wells et al., 2024). Suitable diagnosis involves the recognition of clinical data and identification of typical patterns of alteration in high resolution thorax tomography and, sometimes, in pulmonary biopsy. Morphologically, interstitial remodeling of alveolar spaces is observed, with fibroblast foci, hyperplasic skin cells, and honeycomb-like cysts (Moss et al., 2022). The main manifestations are cough and dyspnea, which tend to worsen progressively while the pulmonary fibrosis develops and the lung function impairment increases (Maher et al., 2021). The patients’ mean age ranges between 65 and 70 years and its incidence increases over time (Fernández-Fabrellas et al., 2019). It mainly affects male individuals, and environmental (smoking and metal inhaling) and genetic risk factors are better known and associated with the illness development (Harari et al., 2020). For methodological reasons, as for example, definition variations, the incidence of idiopathic pulmonary fibrosis is not well defined. The estimates range from 0.09 to 4.51 per each 10 thousand individuals, and the affected individuals’ survival depends on the progression rhythm and the degree of pulmonary impairment (Harari et al., 2020; Maher et al., 2021; Mei et al., 2021). It is very important to distinguish idiopathic pulmonary fibrosis from other specific illnesses that might develop with the pulmonary fibrosis. Some of these cases may also have a rapidly progressive clinical course, leading to death before the patient can access a specialist doctor. This is another issue that can bias the Open-Data-SUS data regarding the cause of death described as "idiopathic pulmonary fibrosis" (Rajan et al., 2023). Idiopathic pulmonary fibrosis continues to be characterized by poor survival rates (Bonella et al., 2023). First-generation antifibrotics, Pirfenidone and Nintedanib, which received approval more than a decade ago, have shown efficacy in slowing disease progression and prolonging survival in patients with idiopathic pulmonary fibrosis, as well as showing promise in other fibrotic lung disorders, such as, for example, pneumonitis with fibrotic hypersensitivity or progressive pulmonary fibrosis (Flaherty et al., 2019; Tzilas et al., 2020; Raghu et al., 2022; Bonella et al., 2023). Despite these advances, most clinical trials targeting idiopathic pulmonary fibrosis in recent years have failed to achieve their primary endpoints, highlighting an ongoing urgent need to identify new agents or treatment strategies capable of stopping disease progression (Bonella et al., 2023). Currently, several new drugs are in various stages of clinical development, predominantly in phase I and II trials, with only a limited number in phase III trials (Bonella et al., 2023).CF disease and idiopathic pulmonary fibrosis: similarities and differencesAlthough both conditions, CF and idiopathic pulmonary fibrosis, involve pulmonary fibrosis – characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response – as a consequence of disease progression, their etiologies and clinical presentations differ markedly (Zhao et al., 2022). Idiopathic pulmonary fibrosis primarily affects older adults, and its precise etiology remains elusive (Koudstaal and Wijsenbeek, 2023; Podolanczuk et al., 2023). On the contrary, CF is a genetic disorder that typically manifests early in childhood (Athanazio et al., 2017). Symptomatically, idiopathic pulmonary fibrosis manifests with progressive dyspnea and a dry cough (Koudstaal and Wijsenbeek, 2023; Podolanczuk et al., 2023), while CF is characterized by recurrent lung infections and multi-organ involvement, including the digestive system (Marson, 2018; Diab Cáceres and Zamarrón de Lucas, 2023). Treatment strategies for idiopathic pulmonary fibrosis focus on the management of symptoms and the attenuation of disease progression (Flaherty et al., 2019; Tzilas et al., 2020; Raghu et al., 2022; Bonella et al., 2023), while CF requires a comprehensive therapeutic approach targeting respiratory, digestive, and other systemic manifestations (Marson et al., 2017; Regard et al., 2022; Grasemann and Ratjen, 2023; Jia and Taylor-Cousar, 2023; McGlynn et al., 2023; Southern et al., 2023; Cystic Fibrosis - Treatment | NHLBI, NIH, 2023).Although definitive cures for these conditions remain elusive, ongoing advancements in medical research are continuously enhancing treatment modalities and improving patient quality of life. In CF disease, significant progress has been made in recent years with the development of therapies capable of modulating the expression of the CFTR protein (Regard et al., 2022; Jia and Taylor-Cousar, 2023; Southern et al., 2023; Cystic Fibrosis - Treatment | NHLBI, NIH, 2023). Furthermore, the pathogenesis of idiopathic pulmonary fibrosis involves epithelial injury and subsequent infiltration of monocytes, which differentiate into monocyte-derived alveolar macrophages, ultimately leading to fibroblasts resistant to apoptosis (Meyer, 2017; Richeldi et al., 2017; Perrot et al., 2023). In the other case, CF arises from pathogenic variants in the CFTR gene, resulting in an absent or dysfunctional CFTR protein (Ratjen, 2009). This dysfunction disrupts chloride ion transport across epithelial cell membranes, causing excessively salty sweat and thickened secretions (Ratjen, 2009). The strategic location of the CFTR protein in epithelial cells differs between various tissues of the human body (Ratjen, 2009). In the lungs, this disruption leads to dehydration of airway surface fluid critical to maintaining ciliary function and mucociliary clearance (Ratjen, 2009). Consequently, there is a detrimental cycle of mucus retention, recurrent infections, and chronic inflammation (Ratjen, 2009). Although this pathophysiological concept is widely accepted, controversies persist with respect to multiple aspects of this cascade (Ratjen, 2009).Enhancement of the scientific and medical issue: where it went wrong and how we can resolve this errorThe good clinical practices for the diagnosis and care of CF patients and those with idiopathic pulmonary fibrosis require medical abilities and competences that go beyond the theoretical knowledge about these illnesses. Another possibility regarding flaws in care and records of these diseases is the weaknesses of the professional qualification. Lack of clinical abilities or, as pointed out by Herbert L. Fred, hyposkillia is a serious problem in Brazil too, and it raises greater concern with the sharp increase in the number of medical schools in the last few years (Fred, 2005). That author used the term to describe medical doctors who cannot obtain a proper medical history, cannot perform a reliable clinical examination, cannot evaluate critically the information gathered, find it difficult to develop good clinical reasoning and plan the treatment, and also, show poor communication skills (Fred, 2005).Considering that clinical manifestations and the age group mostly affected by CF and idiopathic pulmonary fibrosis are quite different, we believe that the confusion in relation to the death data is predominantly semantic. However, the consequences of such mistake for the Brazilian public health are damaging. At least, they alter the CF lethality indicator, thus increasing the stigma of association between CF and death, they also hamper the use of such official data in health management, care, teaching, and research (de Azevedo et al., 2023; Marques et al., 2023). Likewise, the quality of the care provided to individuals affected by these conditions is of concern, and the lack of technical knowledge might delay a proper diagnosis and treatment, thus compromising the patients’ quality of life and survival rates. CF and idiopathic pulmonary fibrosis must be better discussed and clarified.In an era when more and more genetic (and other) influences have been identified in adult life illnesses and when children with rare and complex conditions present higher lifespan, it is necessary to promote a radical paradigm change in medical education, at all levels of qualification. This education must be more holistic and connective, and its object must be individuals who are born and might live up to 100 years old, their life context and environment. The common reductionism of the current education focused on diseases and, even worse, fragmented as “children’s illnesses” and “adults’ illnesses”. As pointed out by the medical doctor and biologist Siddartha Mukherjee in the book “The Song of the Cell”, knowledge in the most varied health areas has become deeper and more specific; however, there are still gaps in relation to its connections and interdependences (The Song of the Cell, 2023). We know more and more musical scores, metaphors for deep knowledge about cells, but we still do not work as an orchestra (The Song of the Cell, 2023). In this context, the results found in this research suggest the urgent need for technical qualification and continuous education of medical doctors for this diagnosis, whose confusion might compromise the information generated and cause damage to patients.