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Amyloidosis in cystic fibrosis
Paediatric Respiratory Reviews 31 (2019) 32–34
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
The 2018 Royal Society Of Medicine Cystic Fibrosis Symposium
Amyloidosis in cystic fibrosis Thomas Simpson, Caroline Elston, Patricia Macedo, Felicity Perrin ⇑ Adult Cystic Fibrosis Service, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom
a r t i c l e
i n f o
Keywords: Cystic fibrosis Nephrotic syndrome Amyloidosis
a b s t r a c t As the life expectancy of patients with cystic fibrosis has increased, greater attention has been paid towards the diagnosis and management of the longer term consequences of the condition. A recognised but rare complication of the disease is the development of secondary amyloidosis. Whilst deposition of amyloid protein has been reported in a high proportion of patients with cystic fibrosis at post-mortem [1] and Serum Amyloid A protein has been shown to correlate with disease activity and response to antibiotics [2], the manifestation of clinical disease remains extremely uncommon. The prognosis for patients with amyloid secondary to cystic fibrosis in published reports has been historically bleak [3–6], however there may be novel approaches in the era of biological therapies. The theoretical potential for an increase in the incidence of secondary amyloid amongst the population of cystic fibrosis patients who are experiencing much longer lifespans means that it is worthwhile to consider the condition and its possible treatments in more detail. We report a case and a review of the literature. Ó 2019 Elsevier Ltd. All rights reserved.
CASE REPORT A female patient was diagnosed with cystic fibrosis at birth following her presentation with meconium ileus. Her cystic fibrosis genotype was Phe508del/ptrp1282X. She was born and raised in Lithuania and a review of the available medical records showed frequent respiratory tract infections and extremely poor weight gain. She had reported positive sputum cultures for both Pseudomonas spp. and Burkholderia spp. by the age of 9 years. She moved to the United Kingdom at 14 years of age. Her first NHS assessment highlighted severe lung disease and extremely poor nutritional state, with a Forced Expiratory Volume in 1 second (FEV1) of 68% predicted and body mass index (BMI) of 13.9. Over the next 6 years she went on to be diagnosed with exocrine pancreatic insufficiency, CF liver disease with heterogenous parenchyma, osteoporosis and mild hearing impairment. She was chronically colonised as an adult with Staphylococcus aureus and Aspergillus, with no evidence of Burkholderia spp. infection. She was treated with long-term nebulised anti-Pseudomonal antibiotics. Her maintenance therapy included long-term flucloxacillin, alternating month nebulised tobramycin and promixin, as well as mucolytics and nutritional support. Her management included insertion of a gastrostomy for overnight feeding, and she also had a ‘‘portacath” inserted as she continued to require regular ⇑ Corresponding author. E-mail addresses: [email protected] (T. Simpson), felicity.perrin@nhs. net (F. Perrin). https://doi.org/10.1016/j.prrv.2019.04.007 1526-0542/Ó 2019 Elsevier Ltd. All rights reserved.
courses of antibiotics. She had intermittent episodes of haemoptysis and had been assessed as appropriate for bronchial artery embolisation, which she had declined. Her best FEV1 in the last year was 1.8 litres (58% predicted) and her BMI had improved to 19.2. At the age of 20 years, she was noted to have proteinuria with normal renal function and was referred to the renal team for assessment. She was booked for a renal biopsy but this was delayed as she was out of the country. She re-presented 3 months later on her return, with generalised swelling, initially only in the lower limbs but progressively affecting her abdomen and face as well. Her renal function tests remained normal but she had significant proteinuria, with a urine protein:creatinine ratio of 284, and a serum albumin of 11grams/litre, confirming nephrotic syndrome and she was admitted under the renal team for investigation. A biopsy demonstrated positive staining with Congo Red and Amyloid immunostain and she was diagnosed with amyloidosis. She was referred to a specialist amyloid clinic, commenced on diuretics and an ACE inhibitor and anti-coagulated with a direct oral anti-coagulant. She remained in hospital for several weeks, with the aim of optimising her sputum and infection load with antibiotics, nebulisers and physiotherapy. However, she developed a very low mood, largely as a result of generalised oedema and its impact on her self-image, leading to disengagement with many therapies. During the course of her admission her FEV1 was persistently low, between 1 and 1.2 litres (c. 30% predicted). She also suffered a number of complications, including an acute kidney injury, requiring temporary withholding of her diuretics and ACE
T. Simpson et al. / Paediatric Respiratory Reviews 31 (2019) 32–34
inhibitor, and severe epistaxis leading to cessation of her anticoagulation. She went on to have a review by the Ear Nose and Throat team as well as bronchial artery embolisation prior to commencement of warfarin. Serology for connective tissue disease was unremarkable. Her assessment at the amyloid centre, including a Serum Amyloid P scan, revealed deposition in the spleen, adrenals and kidneys, with sparing of the myocardium. The opinion of the amyloid specialist was that this represented almost certain AA amyloid and a diagnosis of amyloidosis secondary to cystic fibrosis was confirmed. She had regular blood tests for inflammatory markers including C-reactive protein, with plans for contemporaneous Serum Amyloid A protein (SAA) levels, to assess the degree to which the acute burden of infection and inflammation as a result of her cystic fibrosis was correlated with levels of SAA in the blood and the likely speed of disease progression. No disease specific treatments for her amyloidosis had yet been trialled. She remained under close monitoring of her fluid balance and electrolyte levels. She received regular infusions of human albumin solution. Her lung function remained poor despite intensive intravenous antibiotic therapy to suppress infection and inflammation levels, although no specific infectious agents were identified during this time. She had further episodes of haemoptysis and repeated bronchial artery embolisation. Four months after her diagnosis, she developed severe intractable diarrhoea; there was no infectious cause identified, and although not confirmed by biopsy, it was assumed this was due to amyloid affecting her bowel. She became very dehydrated and significantly lost weight and was admitted to hospital. Whilst in hospital she developed chest pain and a chest radiograph revealed a left-sided pneumothorax. A drain was sited with some reinflation of the lung. However, despite active therapy she became terminally unwell and she was kept comfortable. She died less than 6 months after the initial diagnosis was made.
AMYLOIDOSIS IN CYSTIC FIBROSIS In patients with chronic infections or inflammatory disorders, abnormal accumulation of SAA, an acute-phase protein, is seen, typically depositing in the abdominal organs. It usually presents with proteinuria, organomegaly or goitre. It is a recognised but rare complication of cystic fibrosis. Whilst multi-organ amyloid deposits are reported in 33% of patients with cystic fibrosis in a study of post-mortem investigations, only 1 of those patients had clinical manifestations of the disease [1]. A retrospective survey of the French CF network identified 9 cases of histologically confirmed cases of AA amyloidosis complicating cystic fibrosis in a country with a prevalence of more than 7000 patients in 2016 [3]. There are now more than 50 published cases of this condition worldwide. It has been proposed that the increasing life-expectancy of cystic fibrosis patients should lead to a rise in incidence of secondary amyloidosis as a natural consequence of prolonged survival in a chronic inflammatory state [4]. This predicted increase has yet to manifest however. The aetiology of this condition remains unclear. One small study showed that in a population of CF patients screened for renal complications, patients who were Phe508del homozygotes had a higher risk of proteinuria, however there were only 2 cases of amyloidosis within that group [7]. Some authors suggest that the development of secondary amyloidosis in cystic fibrosis is dependent on poor control of infection and thus inflammation in childhood [5]. This has been a feature of reported cases, including ours. It may be that the continued rarity of this condition is due to earlier diagnosis and significant
33
improvements in the management of cystic fibrosis in childhood, the very same factors contributing to prolonged life-expectancy. In this model, the incidence of amyloidosis will continue to remain very low as the very interventions which are predicted to increase the potential pool of incident cases may also be those which reduce the likelihood of disease development. Treatment of secondary amyloidosis relies principally on immaculate control of the chronic inflammatory state. In cystic fibrosis this is challenging as there is a need to balance the benefits of prolonged intensive therapy including antibiotics, with the risks of both development of antibiotic resistant pathogens, but also the impact on quality of life for patients already burdened with daily regimens of physiotherapy and nebulised therapies. Also, there are further challenges in maintaining an appropriate fluid balance to support effective sputum clearance in the context of nephrotic syndrome, as well as difficult decisions regarding anti-coagulation in a population who are at risk of both lifethreatening thrombosis and haemorrhage. Some case reports have indicated a benefit in using colchicine therapy, which has proven benefit in the management of AA amyloid as a result of familial Mediterranean fever [8,9]. However, the largest published case series reported no effect in the context of cystic fibrosis [3]. Novel approaches may be possible but remain untested, with the development of monoclonal antibodies against both interleukin-1 and interleukin-17, which are implicated in the development of inflammation in cystic fibrosis. The prognosis for patients with cystic fibrosis developing secondary amyloidosis is very poor. The literature suggests a median duration from diagnosis of proteinuria to death of 8 months, with a majority of reported patients dead within a year of diagnosis [3]. Published cases of transplantation in the context of secondary amyloidosis are extremely rare with mixed outcomes. CONCLUSION Amyloidosis secondary to cystic fibrosis remains a very rare condition despite significant improvements in life-expectancy, possibly due to earlier diagnosis and improved management of cystic fibrosis in childhood. Proteinuria could form a part of routine annual reviews and further testing performed rapidly where appropriate, particularly in the context of poor childhood control of cystic fibrosis. Morbidity and mortality from this condition remain very high, with a poor prognosis and no proven disease-specific interventions. Transplantation of these patients needs careful consideration on a case-by-case basis. An international registry of these patients may be an appropriate next step to develop greater understanding of the condition, given the extremely low incidence. Acknowledgements Thank you to the Adult Cystic Fibrosis Service at King’s College Hospital NHS Foundation trust for their assistance in preparing this report, and to the family for consenting to the publication of the included case. References [1] McGlennen RC, Burke BA, Dehner LP. Systemic amyloidosis complicating cystic fibrosis. A retrospective pathologic study. Arch Pathol Lab Med 1986;110 (10):879–84. [2] Marhaug G, Permin H, Husby G. Amyloid-related serum protein (SAA) as an indicator of lung infection in cystic fibrosis. Acta Pædiatrica 1983;72(6):861–6. [3] Stankovic Stojanovic K, Hubert D, Leroy S, Dominique S, Grenet D, Colombat M, et al. Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network. Amyloid 2014;21(4):231–7. [4] Gaffney K, Gibbons D, Keogh B, FitzGerald MX. Amyloidosis complicating cystic fibrosis. Thorax 1993;48(9):949–50.
34
T. Simpson et al. / Paediatric Respiratory Reviews 31 (2019) 32–34
[5] Melzi ML, Costantini D, Giani M, Appiani AC, Giunta AM. Severe nephropathy in three adolescents with cystic fibrosis. Arch Dis Child 1991;66(12):1444–7. [6] Mc Laughlin AM, Crotty TB, Egan JJ, Watson AJ, Gallagher CG. Amyloidosis in cystic fibrosis: a case series. J Cyst Fibros 2006;5(1):59–61. [7] Santoro D, Postorino A, Lucanto C, Costa S, Cristadoro S, Pellegrino S, et al. Cystic fibrosis: a risk condition for renal disease. J Renal Nutr 2017;27(6):470–3.
[8] Santoro D, Postorino A, Costa S, Cristadoro S, Buemi M, Magazzù G. Renal amyloidosis in cystic fibrosis: role of colchicine therapy. Clin Kidney J 2013;7 (1):81–2. [9] Kuwertz-Bröking E, Koch HG, Everding AS, Bulla M, Dworinczak B, Helmchen U, et al. Colchicine for secondary nephropathic amyloidosis in cystic fibrosis. Lancet 1995;345(8958):1178–9.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
The 2018 Royal Society Of Medicine Cystic Fibrosis Symposium
Amyloidosis in cystic fibrosis Thomas Simpson, Caroline Elston, Patricia Macedo, Felicity Perrin ⇑ Adult Cystic Fibrosis Service, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, United Kingdom
a r t i c l e
i n f o
Keywords: Cystic fibrosis Nephrotic syndrome Amyloidosis
a b s t r a c t As the life expectancy of patients with cystic fibrosis has increased, greater attention has been paid towards the diagnosis and management of the longer term consequences of the condition. A recognised but rare complication of the disease is the development of secondary amyloidosis. Whilst deposition of amyloid protein has been reported in a high proportion of patients with cystic fibrosis at post-mortem [1] and Serum Amyloid A protein has been shown to correlate with disease activity and response to antibiotics [2], the manifestation of clinical disease remains extremely uncommon. The prognosis for patients with amyloid secondary to cystic fibrosis in published reports has been historically bleak [3–6], however there may be novel approaches in the era of biological therapies. The theoretical potential for an increase in the incidence of secondary amyloid amongst the population of cystic fibrosis patients who are experiencing much longer lifespans means that it is worthwhile to consider the condition and its possible treatments in more detail. We report a case and a review of the literature. Ó 2019 Elsevier Ltd. All rights reserved.
CASE REPORT A female patient was diagnosed with cystic fibrosis at birth following her presentation with meconium ileus. Her cystic fibrosis genotype was Phe508del/ptrp1282X. She was born and raised in Lithuania and a review of the available medical records showed frequent respiratory tract infections and extremely poor weight gain. She had reported positive sputum cultures for both Pseudomonas spp. and Burkholderia spp. by the age of 9 years. She moved to the United Kingdom at 14 years of age. Her first NHS assessment highlighted severe lung disease and extremely poor nutritional state, with a Forced Expiratory Volume in 1 second (FEV1) of 68% predicted and body mass index (BMI) of 13.9. Over the next 6 years she went on to be diagnosed with exocrine pancreatic insufficiency, CF liver disease with heterogenous parenchyma, osteoporosis and mild hearing impairment. She was chronically colonised as an adult with Staphylococcus aureus and Aspergillus, with no evidence of Burkholderia spp. infection. She was treated with long-term nebulised anti-Pseudomonal antibiotics. Her maintenance therapy included long-term flucloxacillin, alternating month nebulised tobramycin and promixin, as well as mucolytics and nutritional support. Her management included insertion of a gastrostomy for overnight feeding, and she also had a ‘‘portacath” inserted as she continued to require regular ⇑ Corresponding author. E-mail addresses: [email protected] (T. Simpson), felicity.perrin@nhs. net (F. Perrin). https://doi.org/10.1016/j.prrv.2019.04.007 1526-0542/Ó 2019 Elsevier Ltd. All rights reserved.
courses of antibiotics. She had intermittent episodes of haemoptysis and had been assessed as appropriate for bronchial artery embolisation, which she had declined. Her best FEV1 in the last year was 1.8 litres (58% predicted) and her BMI had improved to 19.2. At the age of 20 years, she was noted to have proteinuria with normal renal function and was referred to the renal team for assessment. She was booked for a renal biopsy but this was delayed as she was out of the country. She re-presented 3 months later on her return, with generalised swelling, initially only in the lower limbs but progressively affecting her abdomen and face as well. Her renal function tests remained normal but she had significant proteinuria, with a urine protein:creatinine ratio of 284, and a serum albumin of 11grams/litre, confirming nephrotic syndrome and she was admitted under the renal team for investigation. A biopsy demonstrated positive staining with Congo Red and Amyloid immunostain and she was diagnosed with amyloidosis. She was referred to a specialist amyloid clinic, commenced on diuretics and an ACE inhibitor and anti-coagulated with a direct oral anti-coagulant. She remained in hospital for several weeks, with the aim of optimising her sputum and infection load with antibiotics, nebulisers and physiotherapy. However, she developed a very low mood, largely as a result of generalised oedema and its impact on her self-image, leading to disengagement with many therapies. During the course of her admission her FEV1 was persistently low, between 1 and 1.2 litres (c. 30% predicted). She also suffered a number of complications, including an acute kidney injury, requiring temporary withholding of her diuretics and ACE
T. Simpson et al. / Paediatric Respiratory Reviews 31 (2019) 32–34
inhibitor, and severe epistaxis leading to cessation of her anticoagulation. She went on to have a review by the Ear Nose and Throat team as well as bronchial artery embolisation prior to commencement of warfarin. Serology for connective tissue disease was unremarkable. Her assessment at the amyloid centre, including a Serum Amyloid P scan, revealed deposition in the spleen, adrenals and kidneys, with sparing of the myocardium. The opinion of the amyloid specialist was that this represented almost certain AA amyloid and a diagnosis of amyloidosis secondary to cystic fibrosis was confirmed. She had regular blood tests for inflammatory markers including C-reactive protein, with plans for contemporaneous Serum Amyloid A protein (SAA) levels, to assess the degree to which the acute burden of infection and inflammation as a result of her cystic fibrosis was correlated with levels of SAA in the blood and the likely speed of disease progression. No disease specific treatments for her amyloidosis had yet been trialled. She remained under close monitoring of her fluid balance and electrolyte levels. She received regular infusions of human albumin solution. Her lung function remained poor despite intensive intravenous antibiotic therapy to suppress infection and inflammation levels, although no specific infectious agents were identified during this time. She had further episodes of haemoptysis and repeated bronchial artery embolisation. Four months after her diagnosis, she developed severe intractable diarrhoea; there was no infectious cause identified, and although not confirmed by biopsy, it was assumed this was due to amyloid affecting her bowel. She became very dehydrated and significantly lost weight and was admitted to hospital. Whilst in hospital she developed chest pain and a chest radiograph revealed a left-sided pneumothorax. A drain was sited with some reinflation of the lung. However, despite active therapy she became terminally unwell and she was kept comfortable. She died less than 6 months after the initial diagnosis was made.
AMYLOIDOSIS IN CYSTIC FIBROSIS In patients with chronic infections or inflammatory disorders, abnormal accumulation of SAA, an acute-phase protein, is seen, typically depositing in the abdominal organs. It usually presents with proteinuria, organomegaly or goitre. It is a recognised but rare complication of cystic fibrosis. Whilst multi-organ amyloid deposits are reported in 33% of patients with cystic fibrosis in a study of post-mortem investigations, only 1 of those patients had clinical manifestations of the disease [1]. A retrospective survey of the French CF network identified 9 cases of histologically confirmed cases of AA amyloidosis complicating cystic fibrosis in a country with a prevalence of more than 7000 patients in 2016 [3]. There are now more than 50 published cases of this condition worldwide. It has been proposed that the increasing life-expectancy of cystic fibrosis patients should lead to a rise in incidence of secondary amyloidosis as a natural consequence of prolonged survival in a chronic inflammatory state [4]. This predicted increase has yet to manifest however. The aetiology of this condition remains unclear. One small study showed that in a population of CF patients screened for renal complications, patients who were Phe508del homozygotes had a higher risk of proteinuria, however there were only 2 cases of amyloidosis within that group [7]. Some authors suggest that the development of secondary amyloidosis in cystic fibrosis is dependent on poor control of infection and thus inflammation in childhood [5]. This has been a feature of reported cases, including ours. It may be that the continued rarity of this condition is due to earlier diagnosis and significant
33
improvements in the management of cystic fibrosis in childhood, the very same factors contributing to prolonged life-expectancy. In this model, the incidence of amyloidosis will continue to remain very low as the very interventions which are predicted to increase the potential pool of incident cases may also be those which reduce the likelihood of disease development. Treatment of secondary amyloidosis relies principally on immaculate control of the chronic inflammatory state. In cystic fibrosis this is challenging as there is a need to balance the benefits of prolonged intensive therapy including antibiotics, with the risks of both development of antibiotic resistant pathogens, but also the impact on quality of life for patients already burdened with daily regimens of physiotherapy and nebulised therapies. Also, there are further challenges in maintaining an appropriate fluid balance to support effective sputum clearance in the context of nephrotic syndrome, as well as difficult decisions regarding anti-coagulation in a population who are at risk of both lifethreatening thrombosis and haemorrhage. Some case reports have indicated a benefit in using colchicine therapy, which has proven benefit in the management of AA amyloid as a result of familial Mediterranean fever [8,9]. However, the largest published case series reported no effect in the context of cystic fibrosis [3]. Novel approaches may be possible but remain untested, with the development of monoclonal antibodies against both interleukin-1 and interleukin-17, which are implicated in the development of inflammation in cystic fibrosis. The prognosis for patients with cystic fibrosis developing secondary amyloidosis is very poor. The literature suggests a median duration from diagnosis of proteinuria to death of 8 months, with a majority of reported patients dead within a year of diagnosis [3]. Published cases of transplantation in the context of secondary amyloidosis are extremely rare with mixed outcomes. CONCLUSION Amyloidosis secondary to cystic fibrosis remains a very rare condition despite significant improvements in life-expectancy, possibly due to earlier diagnosis and improved management of cystic fibrosis in childhood. Proteinuria could form a part of routine annual reviews and further testing performed rapidly where appropriate, particularly in the context of poor childhood control of cystic fibrosis. Morbidity and mortality from this condition remain very high, with a poor prognosis and no proven disease-specific interventions. Transplantation of these patients needs careful consideration on a case-by-case basis. An international registry of these patients may be an appropriate next step to develop greater understanding of the condition, given the extremely low incidence. Acknowledgements Thank you to the Adult Cystic Fibrosis Service at King’s College Hospital NHS Foundation trust for their assistance in preparing this report, and to the family for consenting to the publication of the included case. References [1] McGlennen RC, Burke BA, Dehner LP. Systemic amyloidosis complicating cystic fibrosis. A retrospective pathologic study. Arch Pathol Lab Med 1986;110 (10):879–84. [2] Marhaug G, Permin H, Husby G. Amyloid-related serum protein (SAA) as an indicator of lung infection in cystic fibrosis. Acta Pædiatrica 1983;72(6):861–6. [3] Stankovic Stojanovic K, Hubert D, Leroy S, Dominique S, Grenet D, Colombat M, et al. Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network. Amyloid 2014;21(4):231–7. [4] Gaffney K, Gibbons D, Keogh B, FitzGerald MX. Amyloidosis complicating cystic fibrosis. Thorax 1993;48(9):949–50.
34
T. Simpson et al. / Paediatric Respiratory Reviews 31 (2019) 32–34
[5] Melzi ML, Costantini D, Giani M, Appiani AC, Giunta AM. Severe nephropathy in three adolescents with cystic fibrosis. Arch Dis Child 1991;66(12):1444–7. [6] Mc Laughlin AM, Crotty TB, Egan JJ, Watson AJ, Gallagher CG. Amyloidosis in cystic fibrosis: a case series. J Cyst Fibros 2006;5(1):59–61. [7] Santoro D, Postorino A, Lucanto C, Costa S, Cristadoro S, Pellegrino S, et al. Cystic fibrosis: a risk condition for renal disease. J Renal Nutr 2017;27(6):470–3.
[8] Santoro D, Postorino A, Costa S, Cristadoro S, Buemi M, Magazzù G. Renal amyloidosis in cystic fibrosis: role of colchicine therapy. Clin Kidney J 2013;7 (1):81–2. [9] Kuwertz-Bröking E, Koch HG, Everding AS, Bulla M, Dworinczak B, Helmchen U, et al. Colchicine for secondary nephropathic amyloidosis in cystic fibrosis. Lancet 1995;345(8958):1178–9.