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Case PresentationA 20-year-old man presented to the pulmonology outpatient clinic with gradually progressive exertional dyspnea for 2 years. He denied history of fever, cough, wheezing, chest tightness, weight loss, or hemoptysis. He had no history of tobacco use and worked as a clerk at the airport. There was no occupational or environmental exposure. He had no medical or pulmonary or cardiac history. His family history was noncontributory. A 20-year-old man presented to the pulmonology outpatient clinic with gradually progressive exertional dyspnea for 2 years. He denied history of fever, cough, wheezing, chest tightness, weight loss, or hemoptysis. He had no history of tobacco use and worked as a clerk at the airport. There was no occupational or environmental exposure. He had no medical or pulmonary or cardiac history. His family history was noncontributory. At presentation, he looked comfortable with a pulse rate of 78 beats/min, respiratory rate of 36 breaths/min, BP of 134/86 mmHg, temperature of 37.1 °C, and oxygen saturation of 98% on room air. The upper and lower respiratory system examination did not reveal any abnormality. The rest of the systemic examination was also normal. CBC count, kidney function tests, liver function tests, and blood sugar levels were within normal limits. Chest radiograph showed bilateral fine reticulonodular opacities predominant in the lower zones. There was increased opacification of the lesions over 6 months (Fig 1). High-resolution CT (HRCT) scan of the chest revealed bilateral confluent ground-glass opacities and interlobular septal thickening predominant in the lower lobes (Fig 2). Pulmonary function tests at the time of presentation showed a restrictive defect with normal diffusing capacity of the lungs for carbon monoxide (Table 1). He underwent fiberoptic bronchoscopy with BAL and transbronchial lung biopsy. BAL fluid was clear with total cell count of 400/mL and predominant lymphocytes (> 90%) and scattered macrophages. Periodic acid-Schiff (PAS) staining of the BAL fluid demonstrated ovoid- or round-shaped PAS-positive structures. Transbronchial lung biopsy photomicrograph is shown in Figure 3. Interstitium showed moderate mononuclear inflammation and hemorrhage with numerous PAS-positive rounded structures (arrow in Fig 3) in the alveolar spaces.Figure 2A-D, High-resolution CT scan of the chest. A, B, Lung windows at different axial sections showing bilateral diffuse micronodular opacities, confluent ground-glass opacities, and septal thickening predominant in lower lobes. C, D, Mediastinal window at different axial sections show absence of calcification or pleural thickening.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Pulmonary Function Test Results of the PatientSpirometry variablesPredictedObserved% PredictedFVC, L4.863.4771FEV1, L4.143.1476FEV1/FVC82.7490.34109Peak expiratory flow rate, L/s9.578.7291Dlco, mL/mm Hg/min33.8032.0795Va, L6.584.5589KCO, Dlco/Va5.285.79110Total lung capacity, L6.585.0577RV'sb, Dlco/L1.450.8055Dlco = diffusing capacity of the lungs for carbon monoxide; KCO = Transfer Coefficient; RV'sb = Residual volume single breath; Va = Alveolar volume. Open table in a new tab Figure 3Photomicrograph of transbronchial lung biopsy specimen with hematoxylin-eosin stain sections showing calcospherites (arrow) at magnification ×100.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Dlco = diffusing capacity of the lungs for carbon monoxide; KCO = Transfer Coefficient; RV'sb = Residual volume single breath; Va = Alveolar volume. What is the diagnosis? Diagnosis: Pulmonary alveolar microlithiasis (PAM) PAM is a rare lung disease characterized by the accumulation of calcium phosphate deposits, also called as calcospherites or microliths, in the alveoli. It was first described in 1686 by Italian physician Marcello Malphigi. In 1918, Norwegian Harbitz described the radiologic signs and objective findings of the disease on autopsies and called it Harbitz syndrome. In 1933, Ludwig Puhr renamed the disease as PAM. The disease is categorized as an orphan disease with only about 1,100 cases reported worldwide so far. PAM typically presents between the second and fifth decade of life. There is no gender predilection. Both sporadic and familial cases occur. The familial cases are known to have autosomal recessive inheritance. The exact etiopathogenesis of PAM is incompletely understood. The most accepted theory involves a genetic change involving the SLC34A2 gene located on chromosome 4p15. The SLC34A2 gene encodes the sodium-dependent phosphate transporter protein, predominantly expressed in type II alveolar cells of the lungs. The protein normally functions to transport the phosphorus ion from the alveolar space into the type II alveolar cells. The decreased activity or loss of function of the protein leads to accumulation of phosphate within the alveolar lumen. This results in precipitation of phosphate with calcium and formation of intraalveolar calcium phosphate stones or microliths. PAM may have a heterogenous clinical presentation ranging from asymptomatic to pronounced symptoms. Symptoms (eg, cough, dyspnea on exertion) manifest as the disease progresses. Cough is usually dry, but rarely expectoration of microliths has been reported. The rate of progression is mostly slow; however, it will progress to respiratory failure and cor pulmonale as terminal manifestations over the next 10 to 20 years. The microliths have also rarely been reported in various extrapulmonary organs, such as gonads, prostate, pericardium, and kidney, which manifest as renal stones and testicular microliths. Blood investigations including serum calcium and phosphorous levels are usually normal. The identification of the SLC34A2 gene mutation suggests the diagnosis, but it is not widely available. The pulmonary function test in PAM usually shows a restrictive pattern with reduced total lung capacity and diffusing capacity of the lungs for carbon monoxide depending on the extent of lung involvement. The radiologic findings in PAM are typical and are usually disproportionate to the clinical symptoms. A typical HRCT chest scan in symptomatic patients would show intraalveolar micronodular calcifications, ground-glass opacities, interlobular septal thickening, and crazy paving throughout the lungs. These radiologic changes evolve through four phases that are better identified on HRCT chest scan. In the first or precalcific phase, diffuse ground-glass opacity occurs with few poorly calcified microliths or even no evident calcifications, seen in predominant lower lobe and peribronchovascular distribution. The radiologic picture in the precalcific phase may be confused with miliary TB, silicosis, amyloidosis, sarcoidosis, and pulmonary alveolar proteinosis (PAP). In the second phase, a sandstorm appearance is seen with scattered calcified micronodules and preserved cardiac and diaphragmatic borders. The calcifications can be evident on the mediastinal windows. The third phase has progressive opacification of lung parenchyma with interstitial thickening and obscuration of cardiac and diaphragmatic borders referred to as vanishing heart phenomenon. The fourth phase is characterized by intense interstitial calcification with variable pleural calcification that appears as whiteout lung. The presence of subpleural cysts appears as the black pleural line on the HRCT chest scan. There is no clear cut distinction between the phases, and many patients have overlapping features. The definitive diagnosis of PAM requires demonstration of intraalveolar calcospherites seen as laminated concentric layers of calcium phosphate. The calcospherites can be detected in lung biopsy specimens, BAL, or rarely sputum. The transbronchial biopsy is acceptable for obtaining biopsy specimens because open lung biopsy is not always feasible. The calcospherites are also found to be PAS-positive; hence, PAS stain of the BAL fluid may give clue to the diagnosis. The PAS staining of BAL fluid is also positive in PAP, pulmonary amyloidosis, and some other interstitial lung diseases with high glycogen, glycoproteins. and proteoglycans. However, it is difficult to differentiate PAP from the precalcific phase of PAM due to similar radiologic picture and PAS-positive staining in BAL fluid. Thus, the only confirmatory evidence for PAM is the demonstration of the intraalveolar calcospherites. No definite treatment has yet been established for PAM. Various trials of disodium etidronate (a bisphosphonate known to inhibit microcrystal growth of hydroxyapatite), corticosteroids, therapeutic BAL, and gene therapy have been ineffective over the years. Risk reduction vaccinations (pneumococcal, influenza, and SARS-CoV-2) should be administered to all patients diagnosed with PAM. Supplemental oxygen therapy should be offered to patients with hypoxemia. Lung transplantation remains the only possible treatment for end-stage disease associated with right heart failure or respiratory failure. The diagnosis of PAM was made based on the radiologic findings and biopsy specimen showing calcospherites (arrow in Fig 3) that are diagnostic of PAM. The patient was probably in the precalcific phase of radiologic evolution; hence, the calcifications were not evident in the mediastinal window of HRCT scan. The patient was counseled regarding the disease and its prognosis. Because he had minimal symptoms, he was advised close clinical monitoring and follow-up. At 1-year follow-up, the patient was doing fine clinically without any progression. 1.PAM is a rare lung disease characterized by intraalveolar accumulation of microliths known as calcospherites.2.Sporadic and hereditary cases with autosomal recessive inheritance pattern have been reported. The pathogenesis of PAM involves defect in the SLC34A2 gene.3.The disproportionate radiologic involvement compared with the minor subjective complaints of the patient is the hallmark of PAM. The typical radiologic findings include diffuse innumerable fine micronodular calcifications that are more prominent in the bases.4.The definitive diagnosis of PAM requires demonstration of intraalveolar calcospherites in the biopsy specimen. The PAS positivity in BAL fluid of a patient with typical radiologic findings can also suggest the diagnosis. None declared. Author contributions: D. G., U. G., and M. P. were involved in planning, case noting, literature research, writing, review, editing, and final approval of the manuscript. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Gupta et al. (Fri,) studied this question.