C ase Report Respiration 1992;59:250-252
Pediatric Chest Diseases Department. Haccttepe Childrens’ Hospital, Pediatrics Unit, Turkish Health and Therapy Foundation, and Pediatric Surgery Department, Hacettepe Childrens’ Hospital, Ankara, Turkey
Treatment of Pulmonary Alveolar Microlithiasis with a Diphosphonate Preliminary Results of a Case
Key W ords
Abstract
Diphosphonate Pulmonary alveolar microlithiasis Children
A diphosphonate, disodium etidronate, a compound known to inhibit microcrystal growth of hydroxyapatite was given to a 3.5-year-old girl with pulmonary alveolar microlithiasis (PAM) that was symptomatic. The drug was used for ap proximately 36 months in a single daily dose of 15 mg/kg. No significant side ef fects were encountered with somewhat clearing of lung bases in chest radio grams and subjective improvement in general condition. These findings sug gest a role of diphosphonates in the treatment of PAM.
Pulmonary alveolar microlithiasis (PAM) is a rare dis ease of unknown etiology in which calcium phosphate microliths are deposited throughout the lung parenchyma. These deposits characteristically give the sandstorm ap pearance to the pulmonary radiograms. Cases from the neonatal period to 80 years of age are reported without any sex predilection [1], About half of the cases have a family pattern [2, 3], The disease has a variable spectrum of severity ranging from cases of heavy respiratory failure to cases diagnosed in screening. No specific treatment is available for the present time. A new drug, disodium etidronate has been used with encouraging preliminary results in a toddler girl in this case report.
Case A 3.5-year-old girl was referred because of consistent radiologic findings despite various therapies. History included fatigue and non productive cough which developed gradually about I year ago. She had been given treatment for miliary tuberculosis in a district hospi
Received: M ay 5 .1992 Accepted: July 8,1992
tal because of radiologic findings in chest x-ray (fig. 1). She was the second child of the parents with an unconsangineous marriage. Fam ily history was unremarkable for tuberculosis and Mantoux test was negative. Her mother, father and brother had all normal pulmonary radiograms. Physical examination revealed an undernutritioned child (weight in 10th percentile) with slight exertional dyspnea. The rest of the examination was normal. Complete blood count, urinaly sis. electrolytes, calcium, phosphate, alkaline phosphatase, total pro tein and immunoglobulin values were all within normal limits and sweat test was normal at presentation. Initial pulmonary function tests were, unfortunately, unsuccessful due to lack of patient compli ance. Open lung biopsy was performed and PAM was diagnosed. Af ter a detailed discussion with and information given to the parents, written parental consent was obtained for therapy with disodium eti dronate (Didronel®, Procter and Gamble). Didronel was started at 2(X) mg/day (15 mg/kg) orally in a single dose at the age of 4 years. Blood chemistry, clinical and radiological signs were checked every month in the first year and every 3 months thereafter. At age 4.5 years pulmonary function tests were available and revealed a slightly ob structive pattern which resumed in the follow-up (table I). The dose was increased to 400 mg/day after the first year. However, hyperphos phatemia (p = 6.9 mg/dl) developed in 1 month and urinary calcium/ creatinine excretion ratio was 0.6. Abdominal x-ray was negative for urinary calculi. After tapering of the dose to 200 mg again blood and urine chemistry resumed to normal. Blood urea nitrogen, calcium
Dr. M.F.Toppare Ciflcvlcr Sok No 3/9 06690 A. Ayranci. Ankara (Turkey)
© l992S.K argcr AG.Basct 0025-7931/924)594-0250 S 2.75«
Downloaded by: King's College London 137.73.144.138 - 12/2/2017 4:39:09 AM
Ayhan Gocmen3 Mete F. Toppare0 Nural Kiper* Nebil Buyukpumukcu0
Fig. 1. At 4 years, before treatment.
Fig. 3. At 7 years, resolution most prominent in left lower lobe.
Table 1. Pulmo nary function tests
"*®st
VC FEV, FEV,/FEV MMEFR PFR
Age, years_____________ 4.5
6.0
7.0
98 94 76 64 86
100 114 92 97 102
109 102 87 81 100
Values are in percent of standard for age. VC = Vital capacity; FEV, = forced vi tal capacity first second; MMEFR = maxi mal mid-expiratory flow rate; PFR = peak flow rate.
D iscussion
and alkaline phosphatase values and creatinine clearance were all within normal limitis. The patient used the drug regularly for approx imately 36 months. At present, the pulmonary function tests are within normal limits and slight resolution is visible in chest x-ray (fig. 2, 3). The parents expressed marked subjective improvement in general condition with less fatigue and decreased episodes of respira tory symptoms. Her weight achieved 25 percentile and there was no exertional dyspnea anymore.
About 40 cases under 18 years of age have been re ported in the literature [4], The typical radiogram with contrast to paucity of clinical symptoms led to the pre sumptive diagnosis of PAM in this child and lung biopsy was confirmative. Steroids, sodium versenate, chelating agents and bronchopulmonary lavage had all been used without success in the treatment in the literature. This is the first case of PAM that is treated with disodiuni etidro nate. Disodium salt of 1-hydroxyethylidene diphosphonic acid (disodium etidronate) had been used in the treatment of Paget’s disease, and myositis ossificans progressiva with satisfactory clinical results due to its inhibitory effect on Downloaded by: King's College London 137.73.144.138 - 12/2/2017 4:39:09 AM
Fig. 2. Six months later, slight resolution in the upper lobes.
hydroxyapatite microcrystal precipitation [5-7]. We hy pothesized that Didronel may act as an inhibitory agent in PAM with a similar mechanism. In a typical course of PAM, calcium phosphate crystals are deposited beginning from the base of the lungs and slowly lead to fibrosis of the pulmonary parenchyma with subsequent cardiorespira tory insufficiency and cor pulmonale with advancing age. Nephrolithiasis and pulmonary osteoarthropathy are also reported [8,9]. The disease may also have a static or very slowly progressing course with benign nature [10]. To the best of our knowledge spontaneous regression was not re ported. As there was no guidance criteria for the course of the disease in our patient, disodium etidronate treatment was tried. The improvement in the general condition of the child, stability of the radiological lesions and pulmo nary function tests and lack of important side effects are encouraging. Apart from somewhat clearing of the lung bases, overt radiological improvement is not recorded; however, therapy still continues and forthcoming devel
opments are being followed. The initial slight obstructive pattern of the pulmonary function tests could be attri buted to normal variability [11] and was not necessarily a manifestation of PAM since the expected pattern was re strictive in this disease. Hyperphosphatemia was appar ently due to increased tubular reabsorption from the kid ney and may not be an indication for lowering the drug dose. A second biopsy which would reveal the histopatho logic changes might be of great help but was not consid ered ethical. Still a second trial of 400 mg/day of Didronel may be worthwhile, and more research is needed on this drug. We hope disodium etidronate will have implications in the therapy of PAM.
Acknowledgem ents We are indebted to Prof. M. Caglar for the examination of biopsy specimen.
References
252
5 Rogers JG. Dorst JP. Geho WB: Use and com plications of high-dose disodium etidronate therapy in fibrodysplasia ossificans progres siva. J Pediatr 1977;91:1011-1014. 6 Guncaga J. Lauffenburger T, Lentner C. Dambacher MA. Haas HG: Diphosphonate treat ment of Paget’s disease of bone. Horm Metab Res 1974;6:62-69. 7 Russel RGG, Smith R. Bishop MC. Price DA: Treatment of myositis ossificans progressiva with a diphosphonate. Lancet 1972;1:10-13. 8 Pant K. Shah A. Mathur RK. Chhabra SK. Jain SK: Pulmonary alveolar microlithiasis with pleural calcification and nephrolithiasis. Chest 1990:98:245-246.
Göcmen/Toppare/Kiper/Büyükpamukcu
9 Emri S, Çôplü L. Sclçuk T, Sahin AA, Bari§ 1: Hypertrophic pulmonary osteoarthropathy in a patient with pulmonary alveolar microlithiasis. Thorax 1991;46:145-146. 10 Prakash UBS. Barham SS. Rosenow EC, Brown ML. Payne WS: Pulmonary alveolar mi crolithiasis. A review including ultrastructural and pulmonary function studies. Mayo Clin Proc 1983;58:290-300. 11 Lebowitz MD: The use of peak expiratory flow rate measurements in respiratory disease. Pe diatr Pulmonol 1991;11:166-174.
Treatment of PAM with a Diphosphonate
Downloaded by: King's College London 137.73.144.138 - 12/2/2017 4:39:09 AM
1 Caffrey PR, Altman RS: Pulmonary1 alveolar microlithiasis in premature twins. J Pediatr 1965;16:758-763. 2 Sosman MC, Dodd GD, Jones WD. Pillmore GU: The familial occurrence of pulmonary al veolar microlithiasis. Am J Roentgenol 1957; 77:947-1012. 3 O’Neill RP, Cohn JE, Pellegrino ED: Pulmo nary alveolar microlithiasis: A family study. Ann Intern Med 1967;67:957-967. 4 Voile E, Kaufmann H J: Pulmonary alveolar mi crolithiasis in pediatric patients, review of the world literature and two new observations. Pe diatr Radiol 1987:17:439-442.
Pediatric Chest Diseases Department. Haccttepe Childrens’ Hospital, Pediatrics Unit, Turkish Health and Therapy Foundation, and Pediatric Surgery Department, Hacettepe Childrens’ Hospital, Ankara, Turkey
Treatment of Pulmonary Alveolar Microlithiasis with a Diphosphonate Preliminary Results of a Case
Key W ords
Abstract
Diphosphonate Pulmonary alveolar microlithiasis Children
A diphosphonate, disodium etidronate, a compound known to inhibit microcrystal growth of hydroxyapatite was given to a 3.5-year-old girl with pulmonary alveolar microlithiasis (PAM) that was symptomatic. The drug was used for ap proximately 36 months in a single daily dose of 15 mg/kg. No significant side ef fects were encountered with somewhat clearing of lung bases in chest radio grams and subjective improvement in general condition. These findings sug gest a role of diphosphonates in the treatment of PAM.
Pulmonary alveolar microlithiasis (PAM) is a rare dis ease of unknown etiology in which calcium phosphate microliths are deposited throughout the lung parenchyma. These deposits characteristically give the sandstorm ap pearance to the pulmonary radiograms. Cases from the neonatal period to 80 years of age are reported without any sex predilection [1], About half of the cases have a family pattern [2, 3], The disease has a variable spectrum of severity ranging from cases of heavy respiratory failure to cases diagnosed in screening. No specific treatment is available for the present time. A new drug, disodium etidronate has been used with encouraging preliminary results in a toddler girl in this case report.
Case A 3.5-year-old girl was referred because of consistent radiologic findings despite various therapies. History included fatigue and non productive cough which developed gradually about I year ago. She had been given treatment for miliary tuberculosis in a district hospi
Received: M ay 5 .1992 Accepted: July 8,1992
tal because of radiologic findings in chest x-ray (fig. 1). She was the second child of the parents with an unconsangineous marriage. Fam ily history was unremarkable for tuberculosis and Mantoux test was negative. Her mother, father and brother had all normal pulmonary radiograms. Physical examination revealed an undernutritioned child (weight in 10th percentile) with slight exertional dyspnea. The rest of the examination was normal. Complete blood count, urinaly sis. electrolytes, calcium, phosphate, alkaline phosphatase, total pro tein and immunoglobulin values were all within normal limits and sweat test was normal at presentation. Initial pulmonary function tests were, unfortunately, unsuccessful due to lack of patient compli ance. Open lung biopsy was performed and PAM was diagnosed. Af ter a detailed discussion with and information given to the parents, written parental consent was obtained for therapy with disodium eti dronate (Didronel®, Procter and Gamble). Didronel was started at 2(X) mg/day (15 mg/kg) orally in a single dose at the age of 4 years. Blood chemistry, clinical and radiological signs were checked every month in the first year and every 3 months thereafter. At age 4.5 years pulmonary function tests were available and revealed a slightly ob structive pattern which resumed in the follow-up (table I). The dose was increased to 400 mg/day after the first year. However, hyperphos phatemia (p = 6.9 mg/dl) developed in 1 month and urinary calcium/ creatinine excretion ratio was 0.6. Abdominal x-ray was negative for urinary calculi. After tapering of the dose to 200 mg again blood and urine chemistry resumed to normal. Blood urea nitrogen, calcium
Dr. M.F.Toppare Ciflcvlcr Sok No 3/9 06690 A. Ayranci. Ankara (Turkey)
© l992S.K argcr AG.Basct 0025-7931/924)594-0250 S 2.75«
Downloaded by: King's College London 137.73.144.138 - 12/2/2017 4:39:09 AM
Ayhan Gocmen3 Mete F. Toppare0 Nural Kiper* Nebil Buyukpumukcu0
Fig. 1. At 4 years, before treatment.
Fig. 3. At 7 years, resolution most prominent in left lower lobe.
Table 1. Pulmo nary function tests
"*®st
VC FEV, FEV,/FEV MMEFR PFR
Age, years_____________ 4.5
6.0
7.0
98 94 76 64 86
100 114 92 97 102
109 102 87 81 100
Values are in percent of standard for age. VC = Vital capacity; FEV, = forced vi tal capacity first second; MMEFR = maxi mal mid-expiratory flow rate; PFR = peak flow rate.
D iscussion
and alkaline phosphatase values and creatinine clearance were all within normal limitis. The patient used the drug regularly for approx imately 36 months. At present, the pulmonary function tests are within normal limits and slight resolution is visible in chest x-ray (fig. 2, 3). The parents expressed marked subjective improvement in general condition with less fatigue and decreased episodes of respira tory symptoms. Her weight achieved 25 percentile and there was no exertional dyspnea anymore.
About 40 cases under 18 years of age have been re ported in the literature [4], The typical radiogram with contrast to paucity of clinical symptoms led to the pre sumptive diagnosis of PAM in this child and lung biopsy was confirmative. Steroids, sodium versenate, chelating agents and bronchopulmonary lavage had all been used without success in the treatment in the literature. This is the first case of PAM that is treated with disodiuni etidro nate. Disodium salt of 1-hydroxyethylidene diphosphonic acid (disodium etidronate) had been used in the treatment of Paget’s disease, and myositis ossificans progressiva with satisfactory clinical results due to its inhibitory effect on Downloaded by: King's College London 137.73.144.138 - 12/2/2017 4:39:09 AM
Fig. 2. Six months later, slight resolution in the upper lobes.
hydroxyapatite microcrystal precipitation [5-7]. We hy pothesized that Didronel may act as an inhibitory agent in PAM with a similar mechanism. In a typical course of PAM, calcium phosphate crystals are deposited beginning from the base of the lungs and slowly lead to fibrosis of the pulmonary parenchyma with subsequent cardiorespira tory insufficiency and cor pulmonale with advancing age. Nephrolithiasis and pulmonary osteoarthropathy are also reported [8,9]. The disease may also have a static or very slowly progressing course with benign nature [10]. To the best of our knowledge spontaneous regression was not re ported. As there was no guidance criteria for the course of the disease in our patient, disodium etidronate treatment was tried. The improvement in the general condition of the child, stability of the radiological lesions and pulmo nary function tests and lack of important side effects are encouraging. Apart from somewhat clearing of the lung bases, overt radiological improvement is not recorded; however, therapy still continues and forthcoming devel
opments are being followed. The initial slight obstructive pattern of the pulmonary function tests could be attri buted to normal variability [11] and was not necessarily a manifestation of PAM since the expected pattern was re strictive in this disease. Hyperphosphatemia was appar ently due to increased tubular reabsorption from the kid ney and may not be an indication for lowering the drug dose. A second biopsy which would reveal the histopatho logic changes might be of great help but was not consid ered ethical. Still a second trial of 400 mg/day of Didronel may be worthwhile, and more research is needed on this drug. We hope disodium etidronate will have implications in the therapy of PAM.
Acknowledgem ents We are indebted to Prof. M. Caglar for the examination of biopsy specimen.
References
252
5 Rogers JG. Dorst JP. Geho WB: Use and com plications of high-dose disodium etidronate therapy in fibrodysplasia ossificans progres siva. J Pediatr 1977;91:1011-1014. 6 Guncaga J. Lauffenburger T, Lentner C. Dambacher MA. Haas HG: Diphosphonate treat ment of Paget’s disease of bone. Horm Metab Res 1974;6:62-69. 7 Russel RGG, Smith R. Bishop MC. Price DA: Treatment of myositis ossificans progressiva with a diphosphonate. Lancet 1972;1:10-13. 8 Pant K. Shah A. Mathur RK. Chhabra SK. Jain SK: Pulmonary alveolar microlithiasis with pleural calcification and nephrolithiasis. Chest 1990:98:245-246.
Göcmen/Toppare/Kiper/Büyükpamukcu
9 Emri S, Çôplü L. Sclçuk T, Sahin AA, Bari§ 1: Hypertrophic pulmonary osteoarthropathy in a patient with pulmonary alveolar microlithiasis. Thorax 1991;46:145-146. 10 Prakash UBS. Barham SS. Rosenow EC, Brown ML. Payne WS: Pulmonary alveolar mi crolithiasis. A review including ultrastructural and pulmonary function studies. Mayo Clin Proc 1983;58:290-300. 11 Lebowitz MD: The use of peak expiratory flow rate measurements in respiratory disease. Pe diatr Pulmonol 1991;11:166-174.
Treatment of PAM with a Diphosphonate
Downloaded by: King's College London 137.73.144.138 - 12/2/2017 4:39:09 AM
1 Caffrey PR, Altman RS: Pulmonary1 alveolar microlithiasis in premature twins. J Pediatr 1965;16:758-763. 2 Sosman MC, Dodd GD, Jones WD. Pillmore GU: The familial occurrence of pulmonary al veolar microlithiasis. Am J Roentgenol 1957; 77:947-1012. 3 O’Neill RP, Cohn JE, Pellegrino ED: Pulmo nary alveolar microlithiasis: A family study. Ann Intern Med 1967;67:957-967. 4 Voile E, Kaufmann H J: Pulmonary alveolar mi crolithiasis in pediatric patients, review of the world literature and two new observations. Pe diatr Radiol 1987:17:439-442.
