Lung transplantation in an intensive care patient with pulmonary alveolar microlithiasis - a case report

Introduction: Pulmonary alveolar microlithiasis (PAM) is an autosomal recessive disease characterized by the deposition of phosphate and calcium in the alveoli. The disease progresses asymptomatically until later stages. When it becomes symptomatic, lung transplantations performed before the onset of right heart failure may improve life expectancy and quality. Here we present a case report concerning the very first Turkish PAM patient to have undergone lung transplantation surgery. Patient information: A 52 year-old female, Caucasian patient, already diagnosed with PAM in infancy, was admitted to the intensive care unit, diagnosed with pneumonia and hospitalized for 20 days. We decided to refer the patient to a specialized center for lung transplantation. Bilateral lung transplantation was performed in Vienna 14 months later and no recurrence was observed during the first postoperative year. Conclusion: Bilateral lung transplantation may improve both the life expectancy and the quality of life of PAM diagnosed patients with severe respiratory failure who do not suffer from right heart failure. The risk of recurrence should not be considered as a justifying reason to avoid transplantation as a treatment method.


Introduction
Pulmonary alveolar microlithiasis (PAM) was first described by Harbitz in 1918 1 . This rare disease which progresses with calcium and phosphate deposition in the alveolar space is an autosomal recessive disorder caused by the SLC34A2 gene mutation 2,3 . Radiological images reveal typically bilateral, diffuse and symmetrical sandstorm-like widespread radiopaque micronodules 4 . Turkey is the country with the highest PAM prevalence (16.3%), followed by Italy and USA 5,6 . The only known treatment is lung transplantation performed before the onset of right heart failure. No recurrence has been reported after transplantation 7,8 . Here we present the case report of the first Turkish patient followed-up in the intensive care unit (ICU) with the diagnosis of PAM, who needed ventilator support at the time of discharge from the ICU and received lung transplantation in Austria.

Patient information
A 52 year-old female patient, with a family history of PAM, was diagnosed with the same disease when she was 10 years old and received no treatment or intervention until 2012. The patient affected by PAM presented with tachypnea, exertional dyspnea and fatigue to the Emergency Department and she was admitted to the ICU in 2012 with suspicion of pneumonia. At the time of ICU admission, she was conscious, cooperative and the initial vital signs were SpO 2 : 57% (spontaneous respiration under 5lt/min mask O 2 support), pulse rate: 127/mn: blood pressure: 126/65mmHg, body temperature: 37°C, C-reactive protein (CRP): 10.83 and leucocyte: 9600/mm 3 . The arterial blood gas values (10lt/min mask O 2 ) were detected as pH:7.45 PaO 2 : 53.5mmHg PaCO 2 : 34mmHg SaO 2 : 86.5% HCO 3 : 24.9 mmol/L base excess: 0.3 mmol/L Na: 133 mmol/L K: 4.8 mmol/L Cl: 106 mmol/L Ca: 1.09 mmol/L lactate: 1.3 mmol/L. The patient was given non-invasive mechanical ventilation (NIMV) support with positive end-expiratory pressure (PEEP): 10cmH 2 O and inspiratory pressure (IP): 22cmH 2 O FiO 2 : 60%. The chest X-ray and thoracic computed tomography (CT) taken at the ICU admission revealed bilateral, diffuse involvement (sandstorm) and decreased aeration areas of both lungs ( Figure 1, Figure 2). The infection markers (body temperature, leucocyte, CRP) of the patient receiving NIMV support  during the 20 days of ICU hospitalization improved after the 15 th day. The daily respiratory parameters (respiratory rate, PaO 2 , PaO 2 :FiO 2 ratio, SpO 2 ), infection markers and the administered medications are shown in Figure 3 and Figure 4. Since the patient still had the consistent need of NIMV support despite the improvement of the laboratory values, and no changes were detected in the radiological images, she was evaluated together with Pulmonary Diseases and Cardiology departments. Following thoracic CT, echocardiography (mild pulmonary hypertension, EF 60%) and respiratory function tests (Forced Expiratory Volume in 1 second, FEV 1 :0.51L Forced Vital Capacity, FVC:0.54L FEV 1 /FVC:0.94), the patient was discharged from the ICU on the 20 th day and referred to a specialized lung transplantation center. No extrapulmonary involvement was observed by Positron Emission Tomography (PET). The patient underwent bilateral lung transplantation in Vienna 14 months after initial admission (she was under oxygen and NIMV support during these 14 months). She was followed-up during the first seven postoperative days in the ICU and discharged on the 21 st day from the hospital. On the postoperative 6 th month, the values of the patient, having no need for oxygen or NIMV support, were FEV 1 :2.21 FVC:2.26 FEV 1 /FVC:98%. The results of chest X-rays taken on the postoperative 1 st month and 1 st year, the thoracic CT scans taken on the postoperative 6 th month and 1 st year and the arterial blood gas under room air on the postoperative 6 th month of the patient administered mycophenolic acid 760mg/day, tacrolimus 0.5mg/day, and prednisolone 5mg/day medication are demonstrated in Figure 1, Figure 2 and Figure 3 respectively.

Discussion
The etiology, epidemiology, clinical findings and typical radiological images related to PAM disease have been almost completely documented. The aim here is to discuss the advantages of lung transplantation as a treatment option for PAM.
It has been described that PAM is an autosomal recessively inherited disorder related to genetic factors 2,3 . Although PAM is rarely observed in infants 9 , the clinical findings and the radiological changes advance progressively over-time; micronodular structure (sandstorm) develops due to the deposition of calcium and phosphate, aeration areas decrease, fibrosis increases and hypoxemia occurs. Patients presenting to the hospital with these clinical findings are generally over the age of 40 and no administered treatments result in full recovery. Systemic corticosteroids, calcium-chelating agents and bronchoalveoler lavage (BAL) are palliative solutions 10 . Ozçelik et al. have described the positive effects of the long term use of sodium etidronate which is effective by inhibiting the hydroxyapatite microcrystal formation in pediatric patients 11 . However, there are also some studies showing that the sodium etidronate treatment is ineffective 7 .
The priority for these patients admitted to the ICU should be to seek solutions for recovering hypoxemia. It is observed that patients presenting highly decreased aeration areas have already undergone many treatment methods 11 . In Figure 4 we show that the patient was administered sodium etidronate, methylprednisolone and sildenafil in the ICU. Thus, considering lung transplantation as a treatment method in PAM cases instead of medication or artificial respiratory support treatments, both of which are known to be ineffective, seems rational. In our case, we discussed the lung transplantation indication of this PAM-diagnosed patient to offer her a chance of full recovery. The differences observed between the preoperative and postoperative periods demonstrated the importance of performing bilateral lung Besides, no improvement was observed in the radiological images or respiratory parameters despite the oxygen and NIMV support and the regress in the infection markers. Even at the time of discharge from the ICU, the patient was under NIMV support, and was oxygen dependent with a peripheral saturation of 90%, PaO 2 90-95mmHg and with PaO 2 /FiO 2 ratio under 150. The patient clinically worsened with infection; after the regression of the infection, she could only return to her previous hypoxemic condition despite NIMV support.
The issue that intensivists should discuss is whether a patient with a hypoxemic condition should be discharged with the recommendation of oxygen and NIMV support or whether the transplant choice should be brought forward.
Although Turkey is the country with the highest PAM prevalence, we have not encountered any published reports on transplanted cases upon the diagnosis of PAM in Turkey. Lung transplantation is a treatment option for PAM patients and is recommended in severe cases of oxygen dependent respiratory failure before the onset of right heart failure 7,8,10 . Bonette et al. recommended bilateral lung -The risk of recurrence should not be considered as a justifying reason to avoid the transplantation option.

Consent
Written informed consent for publication of this case report and accompanying figures was obtained from the patient.
Author contributions BG was involved in the initial writing of the manuscript. AO, AÇA and BYG were primarily involved in the care of our patient. WK provided intellectual contributions to the content of the manuscript as well as editorial assistance. All authors have read and approved the final version of the manuscript.

Competing interests
The authors declare that they have no competing interest.

Grant information
The author(s) declared that no grants were involved in supporting this work. only did the radiological follow-up for one year show no recurrence; but also the patient receiving immunosuppressive treatment no longer needed oxygen or artificial respiratory support systems.

Conclusion
Bilateral lung transplantation may improve both the life expectancy and quality of PAM-diagnosed patients with severe respiratory failure who do not suffer from right heart failure. The risk of recurrence should not be considered as a valid reason to eliminate transplantation option as a treatment method.

Key messages
-All the other treatment methods in PAM are palliative except for transplantation.
-A PAM-diagnosed patient being followed-up in the ICU due to severe respiratory failure needs oxygen and NIMV support even at the time of discharge.
-Intensivists should discuss the transplantation option in cooperation with the pulmonologists, cardiologists and transplantation team; they should also have an active role in the management of the PAM-diagnosed patients after their discharge.