Calcification and ossification of the lungs

INTRODUCTION — Metastatic and dystrophic calcification, defined as deposition of calcium salts in normal and abnormal tissues, respectively, can manifest in the lungs. Pulmonary ossification refers to bone tissue formation (calcification in a collagen matrix), with or without marrow elements, in the lung parenchyma.

While other organs can be affected by ectopic calcification and ossification, the lungs are particularly susceptible [1]. The pathogenesis of lung calcification and ossification is not well understood. Multiple factors contribute to the development of metastatic and dystrophic calcification, including increased serum levels of calcium and phosphate, alkaline phosphatase activity, and local tissue pH [1,2]. It is unlikely that any one physiologic derangement alone is responsible.

The etiologies, pathogenesis, clinical manifestations, disorders associated with pulmonary parenchymal calcification and ossification, and potential treatment modalities are reviewed here. An approach to interstitial lung disease is provided separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

DEFINITIONS AND CLASSIFICATION

Calcification without bone formation — Pathological soft tissue calcification without bone formation can be divided into two broad categories, metastatic and dystrophic calcifications, and the rare disorder pulmonary alveolar microlithiasis (table 1) [3]:

●Metastatic calcification is defined by calcium salt deposition in normal tissues [1,4]. Metastatic pulmonary calcification (MPC) may occur due to both benign and malignant causes, though the most common cause is end-stage kidney disease (ESKD) requiring hemodialysis [5-7]. (See 'Metastatic pulmonary calcification' below.)

●Dystrophic calcification is defined by calcification that occurs in areas of previously injured/abnormal tissue. Dystrophic calcification accounts for the majority of soft tissue calcifications. Prior tissue damage can be due to any number of causes, including infection (mycobacterial, fungal, or viral), noninfectious granulomatous diseases (eg, sarcoidosis), pneumoconioses, amyloidosis, and various fibrotic lung diseases. (See 'Dystrophic calcification' below.)

●Pulmonary alveolar microlithiasis (PAM) is a rare calcific disorder that is characterized by the intra-alveolar accumulation of round, calcified microliths [1,8]. PAM is caused by mutation of the SLC34A2 gene encoding the type IIb sodium phosphate cotransporter in alveolar type II cells [8]. (See 'Pulmonary alveolar microlithiasis' below.)

Pulmonary ossification — Pulmonary ossification, in contrast to calcification, refers to the formation of mature bone tissue often with marrow elements within the lungs (table 1). Ossification can be idiopathic or secondary to a primary pulmonary, cardiac, or extra-cardiopulmonary disorder. (See 'Pulmonary ossification' below.)

Pulmonary ossification can be subdivided into two histologic forms, both of which may be found in the same patient [9-11]:

●Nodular ossification – Nodular ossification is characterized by lobulated bone nodules within alveolar spaces, usually devoid of fat or marrow elements [12]. Nodular ossification usually develops in the setting of passive congestion and pulmonary edema, as from chronic heart failure or valvular abnormalities.

●Dendriform ossification – Dendriform ossification in the lungs is characterized by formation of branching bone tissue that often contains marrow elements. Dendriform ossification preferentially affects the alveolar interstitium and extends through alveolar septae [11]. Dendriform ossification is often associated with underlying fibrotic lung disease, chronic inflammation, or sequelae of acute respiratory distress syndrome but can also be idiopathic in nature [9,12].

METASTATIC PULMONARY CALCIFICATION — Metastatic pulmonary calcification (MPC) often presents with asymptomatic upper lung zone opacities on chest radiograph. It is important to keep this entity in mind when evaluating chest radiographs of patients with end-stage kidney disease (ESKD) or other predisposing factors to avoid unnecessary diagnostic testing.

Causes and pathogenesis — MPC occurs most commonly in ESKD patients on hemodialysis [4,5,13,14]. Most other causes are rare but include orthotopic liver transplantation, primary hyperparathyroidism, hypervitaminosis D, parathyroid carcinoma, and multiple myeloma, among others [1,15-17].

●Renal failure – In patients with ESKD, particularly those on hemodialysis, acidosis and secondary hyperparathyroidism increase calcium and phosphate release from bone, while intermittent alkalosis (absolute or relative) during hemodialysis provides a milieu that is conducive for calcium salt precipitation in soft tissues. Decreased glomerular filtration of phosphate also contributes to elevations in calcium-phosphate product [1,2,15,18,19].

●Orthotopic liver transplantation – MPC may also occur following orthotopic liver transplantation. The mechanism underlying this phenomenon is unclear, though concurrent renal failure, acid-base abnormalities, or administration of exogenous citrate from fresh frozen plasma used to treat coagulopathy may contribute. The resulting high plasma citrate levels result in alkalosis as citrate is metabolized to bicarbonate ion (HCO₃^-) and in chelation of ionized calcium, which stimulates release of parathyroid hormone and subsequent deposition of calcium in soft tissues [16,20]. Cases have also been reported following renal transplantation [21].

●Malignancy with hypercalcemia – MPC can accompany a variety of malignancies that are associated with hypercalcemia and/or elevated calcium-phosphate product. In these cases, hypercalcemia may be hormonally mediated or driven by bone lysis due to cancer metastases to the bones. Even in these cases of malignancy, the development of MPC is rare, which may be due, in part, to the generally poor prognosis associated with metastatic cancer [2,22].

Overall, the pathogenesis of MPC is mediated by excess serum calcium, an elevated calcium-phosphate product, and an alkaline environment.

●Excess calcium – While metastatic calcification can occur at normal serum calcium levels, the process is favored by an elevated calcium-phosphate product >70 mg²/dL² (normal is approximately 40 mg²/dL²) [2,13].

Factors in chronic hemodialysis patients, the most common at-risk group, that result in increased calcium-phosphate product include periodic acidosis that leaches calcium from bone, secondary/tertiary hyperparathyroidism, uremia, and hyperphosphatemia [2]. In cases of MPC with a normal calcium-phosphate product, a sensitizing or predisposing condition, such as elevated parathyroid hormone, exogenous vitamin D, or azotemia, may be required to prime the tissue for pulmonary calcification [1,2,23].

●Alkaline environment – Calcium salts precipitate under alkaline conditions. Notably, organs that are susceptible to metastatic calcification, such as the stomach, kidneys, and the lungs, secrete free hydrogen ions, creating a relatively alkaline tissue environment [2,24]. This mechanism may explain why the lung apices are more affected by MPC than the bases; ie, the higher ventilation-perfusion ratio in the apex results in lower end-capillary partial pressure of arterial carbon dioxide (PaCO₂), and therefore a higher pH as compared with the lung base [25].

Alkalosis alone may not be sufficient to develop ectopic calcification, but in synergy with other risk factors, it can promote deposition of calcium. For example, the relative alkalosis following hemodialysis, along with other aforementioned risk factors associated with ESKD, may contribute to this condition [5]. The milk-alkali syndrome, which is much less commonly seen now, can also cause metastatic calcification due to a combination of high blood calcium and metabolic alkalosis [26].

Among five patients with localized MPC, the calcification occurred distal to or adjacent to sites of pulmonary artery occlusion by thrombus or tumor [27]. While the lung tissues also had variable areas of infarction, pneumonia, and/or diffuse alveolar damage, MPC did not necessarily occur in these abnormal areas of the lungs and thus could not be classified solely to dystrophic calcifications. Possibly, local tissue alkalosis distal to the site of the pulmonary artery occlusion – from the combination of hyperventilation reducing the partial pressure of alveolar carbon dioxide (PaCO₂) and impaired blood flow decreasing delivery of PaCO₂ – enabled a more alkaline environment that favored calcium salt precipitation [27]. This is a reasonable hypothesis since the lungs receive oxygen supply from the bronchial artery branches and directly from the alveoli as well as blood from the pulmonary artery and thus are resistant to hypoxic-ischemia-induced anaerobic metabolism and lactic acidosis.

Additionally, alkaline phosphatase, an enzyme that catalyzes the production of free phosphate and thereby elevates the calcium-phosphate product, has maximal activity at an alkaline pH [28]. Alkaline phosphatase also enhances osteoblastic activity and thus may play a role in the process of pulmonary ossification as well [9,29].

Clinical presentation — Patients with MPC are often asymptomatic or may have symptoms related to their underlying disease. The clinical finding leading to a diagnosis of MPC tends to be a chest radiograph with upper lung zone opacities.

MPC generally does not compromise lung function, although severe cases have been described [1,2,18,30]. In patients with extensive MPC, restrictive physiology, decreased diffusion capacity, or hypoxemia may result. Rarely, progressive respiratory insufficiency and death may occur [2,7,31,32].

Evaluation — The evaluation of suspected MPC includes measurement of serum calcium and phosphate, assessment of pulmonary function, and review of imaging for characteristic features. Bone scintigraphy is occasionally needed to confirm the diagnosis.

Laboratory testing — For patients with ESKD, MPC is usually associated with elevated serum calcium and/or phosphate levels or calcium-phosphate product, as seen with tertiary hyperparathyroidism after long-standing stimulation of the parathyroid glands from secondary hyperparathyroidism. For patients with MPC associated with malignancy, serum parathyroid hormone may be elevated. In patients with clinical manifestations of primary hyperparathyroidism, an elevated parathyroid hormone in the setting of increased serum calcium level and reduced phosphate level is highly suggestive. (See "Parathyroid hormone assays and their clinical use", section on 'Clinical use of PTH assays'.)

Pulmonary function testing — When evaluating patients with suspected MPC, we typically obtain spirometry, plethysmographic lung volumes, diffusing capacity for carbon monoxide (DLCO), and six-minute walk testing with oximetry. The degree of physiologic impairment does not necessarily correlate with the degree of calcification seen on imaging studies; some patients with extensive calcification may be asymptomatic, while others with minimal visible calcification may have significant physiologic impairment, likely due to underlying or concomitant lung disorders [1,25].

Imaging — A chest radiograph is generally useful for detection of pleural, hilar, or mediastinal lymph node, or lung nodule calcification, but is relatively insensitive for identification of lung parenchymal calcification. The appearance of upper lung zone opacities can often be mistaken for other conditions such as bronchiectasis, fibrosis, or edema [25,31].

High-resolution computed tomography (HRCT) scans are more sensitive and specific than chest radiographs for the detection of pulmonary calcification [33-37]. Densitometry measurements of thin-slice (1 mm) HRCT confirm the high attenuation characteristic of calcified tissue even though calcification may not be apparent visually [33,38]. Thus, it is worth emphasizing that when the calcification is microscopic, CT images may not reveal areas of calcification, particularly if standard 7- or 10-mm-thick images are obtained [1].

Three HRCT patterns of metastatic pulmonary calcification can be seen, and these patterns may be present simultaneously in a given patient [33-35,39]:

●Multiple calcified nodules in a diffuse or localized distribution

●Diffuse or patchy areas of ground glass opacification

●Dense area(s) of consolidation that mimic a lobar pneumonia

Additional radiographic findings may include calcification of the tracheobronchial walls or chest wall blood vessels or a "ring" pattern of nodular calcification, particularly with MPC due to ESKD [39].

Bone scintigraphy — In equivocal cases, bone scintigraphy with the bone-avid radiotracer ^99mtechnetium-methylene diphosphate (^99mTc-MDP) may help distinguish pulmonary calcification from other conditions such as pneumonia or pulmonary edema [25,37,40-42]. Several cases have been reported of positive pulmonary bone scintigraphy without chest radiographic evidence of calcification [43,44].

Diagnosis — The diagnosis of MPC can often be made on the basis of HRCT scan [33-37]. When the HRCT findings are not diagnostic, ^99mTc-MDP scanning can confirm the diagnosis.

Treatment — In MPC, specific conditions that elevate the calcium-phosphate product should be corrected to prevent further calcification [1,45]. Renal transplantation for patients with ESKD often mitigates this process [46]. In some cases, however, MPC persists and progresses even with a functioning transplanted organ; some of these cases may be due to tertiary hyperparathyroidism [21,47]. In such severe cases, parathyroidectomy may be indicated [21,45].

Spontaneous resolution of MPC has also been described, though it is rare [45,48].

DYSTROPHIC CALCIFICATION — Dystrophic calcification in the lungs occurs in areas where the tissue has become altered, necrotic, or otherwise nonviable. Dystrophic calcification requires tissue injury and repair for calcification to occur [1,25].

Granulomatous diseases such as fungal infections, tuberculosis, or sarcoidosis can result in calcification in the setting of normal serum calcium levels. Excess production of 1,25 vitamin D by macrophages increases intestinal calcium and phosphate absorption, even in the absence of rising serum calcium concentration [49,50]. Serum levels of calcium and phosphate are normal [1,3]. (See "Hypercalcemia in granulomatous diseases".)

Imaging evidence of dystrophic calcification is frequently an incidental finding and may be completely asymptomatic [20].

The diagnosis is typically made based on the chest high-resolution computed tomography (HRCT) appearance [20,51].

Dystrophic calcification due to infection or other lung disease is treated by targeting the underlying disease process.

Pulmonary calcification due to infection — Many microbial infections can predispose to the development of pulmonary calcification. Infections that generate a granulomatous tissue response, such as those due to Histoplasma capsulatum, Coccidioides immitis, or Mycobacterium tuberculosis, can result in intrathoracic dystrophic calcifications [1]. Viral (eg, varicella) and parasitic (eg, Paragonimus westermani) infections can also result in pulmonary calcification [1]. As examples:

●Histoplasma infections can result in calcified mediastinal lymph nodes, broncholithiasis, mediastinal granuloma, and solitary or multiple calcified histoplasmomas [52-54]. Pneumocystis jirovecii infections in HIV-positive patients can lead to pulmonary or thoracic lymph node calcifications, and diffuse visceral calcification in disseminated disease [55-57].

●Tuberculosis can produce dystrophic calcifications in the form of parenchymal granulomas, mediastinal lymph node calcification, and/or calcified fibronodular areas of lung [54]. Diffuse nodular calcification of the lungs may follow miliary infections [58]. Patients with tuberculosis can also develop hypercalcemia due to excessive production of endogenous 1,25 vitamin D that predisposes to further calcification [59]. (See "Hypercalcemia in granulomatous diseases".)

●Varicella pneumonia can present with scattered reticular or nodular densities (image 1). These usually resolve with time but can result in asymptomatic miliary calcifications years after the acute event (image 2) [60,61]. Delayed development of pulmonary calcification after smallpox virus exposure has been reported [62,63]. Other DNA viruses, such as herpes simplex, have been described to cause pulmonary calcifications [64].

●Several parasitic infections can manifest with calcification in the lungs. Paragonimus westermani infections can cause pleural and lung parenchymal calcification, which is thought to be due to calcified mummification of the parasites and their eggs [65]. A calcified rim is sometimes seen with pulmonary and mediastinal echinococcal cysts [66-68].

Pulmonary calcification associated with other lung diseases — Pulmonary amyloidosis and sarcoidosis are examples of noninfectious diseases associated with pulmonary calcification. The clinical setting and radiographic appearance may be sufficient for diagnosis.

●Pulmonary amyloidosis – Primary amyloidosis occurs in the setting of aberrant production and deposition of mostly light-chain amyloid protein in tissues. Secondary calcification of amyloid fibrils may occur due to their affinity for calcium [69]. The airways and lung parenchyma are frequently affected sites of disease in patients with primary amyloidosis.

When calcification occurs, the typical radiographic appearance includes mixed interstitial and alveolar opacifications with varying degrees of calcification in the mid- and lower subpleural regions (image 3); ossification is rare [70,71].

●Sarcoidosis – Lung parenchymal sarcoidosis rarely results in micronodular calcifications that appear similar to pulmonary alveolar microlithiasis (PAM) on imaging studies [72] . Whereas the calcification in sarcoidosis is localized to epithelioid granulomas, distinct intra-alveolar microliths are seen in PAM on lung microscopy [1]. (See 'Pulmonary alveolar microlithiasis' below.)

PULMONARY ALVEOLAR MICROLITHIASIS — Pulmonary alveolar microlithiasis (PAM) is a rare, autosomal recessive disorder, characterized by widespread deposition of calcium phosphate microliths throughout the lungs (MIM: #265100) [8,73,74]. It occurs in the absence of disorders of calcium metabolism. PAM is found worldwide but has the highest prevalence in Turkey, Japan, and Italy [8]. Just over one-third of cases are familial, and there is a high rate of consanguinity among parents of affected patients, which suggests an underlying autosomal recessive disease with high penetrance [8].

Pathophysiology — In 2006, the gene responsible for PAM, SLC34A2 at 4p15.2, was identified independently by groups in Japan and Turkey. The gene variants in nearly all patients who have been studied lead to abnormal or abolished gene function [8,75-78]. To date, over 30 SLC34A2 variants have been identified [79,80].

The SLC34A2 gene encodes a type IIb sodium-dependent phosphate transporter that has essential roles in the homeostasis of inorganic phosphate. It is the only phosphate transporter that is highly expressed in the lung and is found in type II alveolar cells (ATII), which make and degrade surfactant, a major component of which is phospholipid. The protein functions to transport phosphate ion from degraded phospholipids in alveoli into ATII cells. When the sodium-dependent phosphate transport protein 2B is dysfunctional, ATII cells are unable to clear phosphate ion from the alveolar space, resulting in the formation of microliths [81,82]. Studies suggest that the severity of disease may be associated with specific variants in the SLC34A2 gene [83].

While SLC34A2 is also expressed in other organs, microliths usually do not form due to the presence of redundant ion transporters, accounting for the low incidence of extrapulmonary manifestations of PAM [8].

Clinical manifestations — Most patients with PAM (88 percent) are under the age of 50 years, with approximately 35 percent under the age of 20 at time of diagnosis [84]. Despite dramatic imaging findings, most patients are asymptomatic at the time of diagnosis, and PAM is often found incidentally during imaging studies performed for another reason, or screening of family members of affected patients [85]. When symptoms develop, they usually occur in the third or fourth decade, although presentation over age 60 has been reported [86]. However, children who present at age five years or younger are more likely to be symptomatic and present with cough and severe acute respiratory failure [87].

In a large series identified by literature review, a family history of PAM was identified in one-third [85]. Symptoms included dyspnea (24 percent), nonproductive cough (14 percent), chest pain (6 percent), and asthenia (3 percent).

Evaluation — Imaging studies are key to the diagnosis; laboratory tests are usually normal.

●Laboratory testing – Serum calcium and phosphorus levels are usually normal [88]. While a next generation sequencing test for SLC34A2 is commercially available (https://www.fulgentgenetics.com/Pulmonary-Alveolar-Microlithiasis), imaging studies are so characteristic that genetic testing is generally not required to make the diagnosis.

●Pulmonary function tests – Pulmonary function tests (PFTs) are obtained at intervals to identify and monitor respiratory impairment. PFTs may be normal initially and later show a restrictive pattern with reduced diffusion capacity [1,82].

●Imaging – The chest radiograph shows a "sandstorm" appearance of diffuse scattered micronodules with a predilection for the lung bases, often obscuring the contours of the heart and diaphragm [85,89,90]. In children, ground glass opacities are frequent while calcifications are fewer, smaller, and mainly restricted to the lower lobes [87].

HRCT reveals micronodular calcifications primarily located along bronchovascular bundles, and subpleural and perilobular regions [85,89,91-93]. Diffuse ground glass opacities are often present [94]. Calcific thickening of the interlobular septa may be seen, as well as subpleural cystic changes [48,78,82].

Tc-99m methylene diphosphonate (MDP) whole-body bone scintigraphy may also be employed in the case of unclear standard imaging. Scans will show widespread involvement in the lungs [95].

●Flexible bronchoscopy – While bronchoscopy is usually not needed for diagnosis, bronchoalveolar lavage (BAL) and transbronchial biopsy can be useful if the diagnosis is uncertain. Lamellar microliths have been identified in lavage fluid and on transbronchial biopsy [85].

Diagnosis and differential diagnosis — The diagnosis of PAM can usually be determined by the imaging findings showing a classic “sandstorm” with obscuration of the cardiac borders and micronodular calcifications bronchovascular bundles, subpleural and perilobular regions [85,89]. BAL and/or transbronchial biopsy can confirm intra-alveolar lamellar microliths [82,96]. Lung biopsy is rarely needed, particularly in a family with a known affected member.

The differential diagnosis includes the following processes:

●PAM can be differentiated from diffuse pulmonary ossification based on the larger size of the nodules in pulmonary ossification and the typical underlying disease processes (eg, chronic pulmonary venous congestion, idiopathic pulmonary fibrosis). (See 'Pulmonary ossification' below.)

●Metastatic pulmonary calcification has a strong upper lung zone predilection and usually develops in patients with end-stage kidney disease (ESKD), thus making it easy to differentiate from PAM. (See 'Metastatic pulmonary calcification' above.)

●Sarcoidosis rarely presents with diffuse micronodular calcifications. On histopathology, the calcification in sarcoidosis is localized to epithelioid granulomas, while distinct intra-alveolar microliths are seen in PAM. (See "Clinical manifestations and diagnosis of sarcoidosis".)

●Other diseases associated with parenchymal calcification, such as tuberculosis, idiopathic pulmonary hemosiderosis, pneumoconiosis (eg, silicosis), and nodular amyloidosis can be considered in the diagnosis. (See "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Radiologic findings' and "Idiopathic pulmonary hemosiderosis" and "Silicosis" and 'Pulmonary calcification associated with other lung diseases' above.)

Treatment and prognosis — There is no established therapy for PAM. Systemic glucocorticoids, chelating agents, and whole lung bronchoalveolar lavage have not demonstrated benefit [8,77,97]. The few cases that responded to glucocorticoid treatment were most likely related to effects on accompanying interstitial lung disease. Lung transplantation has been successful, and recurrence of PAM in the transplanted lungs has not been reported with follow up out to 15 years [98-100]. (See "Lung transplantation: Disease-based choice of procedure".)

●Investigational therapy – Given the underlying abnormalities in phosphate transportation, bisphosphonates, which have an inhibitory effect on the precipitation of hydroxyapatite microcrystals, have been tried in small pediatric studies, resulting in improved long-term outcomes in some patients [8,101,102]. In contrast, two case reports described a lack of radiologic improvement after 6 to 18 months of etidronate [103,104]. Of note etidronate has largely been superseded by other bisphosphonates for the treatment of osteoporosis. In a single case report, sodium thiosulfate, a calcium-chelating and -solubilizing agent, failed to improve PAM [105]. Given the indolent nature of PAM in many patients, additional studies of bisphosphonate therapy would be needed prior to more widespread use.

●Prognosis – Progression of PAM is generally slow, and it often takes decades before patients develop symptoms or reduced pulmonary function. However, long-term prognosis is poor with most patients eventually progressing to respiratory failure [8,106]. A few case reports describe full or near term pregnancy in patients with PAM [107,108].

PULMONARY OSSIFICATION — Pulmonary ossification can be localized or diffuse and may be idiopathic or caused by underlying cardiac, pulmonary, or systemic disorders. Some conditions associated with pulmonary ossification are also associated with metastatic or dystrophic calcification and may represent a continuum [1].

Nodular versus dendriform ossification — Two histologic types of pulmonary ossification have been described, nodular and dendriform [9-11,109]:

●Nodular – Nodular ossification is characterized by lamellar deposits of osteoid material within alveolar spaces visible on histopathology. Marrow elements are often absent. Nodular ossification is typically associated with underlying cardiac disorders such as mitral stenosis, chronic left ventricular failure, or idiopathic hypertrophic subaortic stenosis that result in chronic pulmonary venous congestion [1].

●Dendriform – Dendriform pulmonary ossification (DPO) is characterized by branching spicules of bone and marrow elements in the interstitium that may extend into the alveolar spaces (picture 1). It is the more common form of idiopathic pulmonary ossification and is also seen in patients with underlying lung fibrosis of the usual interstitial pneumonia pattern [9,110].

Pathogenesis — Pulmonary ossification usually occurs in the setting of preexisting tissue injury, though it may be idiopathic in nature. The process of ossification is complex and likely involves other physiologic alterations beyond dysregulation of serum calcium and phosphate, including angiogenesis, chronic venous congestion, and/or lung fibrosis [1,25].

Chronic injury or insult, such as chronic inflammation or increased shear stress as occurs in pulmonary fibrosis, may induce metaplastic transformation of fibroblasts to osteoblasts and has been suggested as a key element in the pathogenesis of ectopic ossification [1,111,112]. Tissue hypoxia or anoxia from this injury results in an environment that may stimulate the process [113]. Furthermore, elevated levels of intracellular calcium at sites of tissue and cellular injury can activate phospholipases and multiple other enzymes that promote cellular death and necrosis [9]. Phospholipids that enter cells after injury degrade into fatty acids, and subsequent binding of calcium to these fatty acids promotes calcification at the sites of injury [9,29]. Once a nidus of calcification forms, further calcium and phosphate crystallization can propagate [1]. Shifts in pH from acidic to alkaline as injury progresses enhance the process of calcification [114].

The presence of collagen also enhances calcification and may explain why pulmonary ossification is often seen in patients with fibrotic lung disease. Several growth factors and cytokines implicated in pulmonary disease states may also contribute to the process of ossification. Of note, many of the growth factors listed above also participate in the process of pulmonary fibrosis and may therefore form a link between underlying pulmonary disorders, such as idiopathic pulmonary fibrosis (IPF), and subsequent pulmonary ossification [115]. Cytokines involved in extracellular matrix formation and inflammation, such as transforming growth factor-beta (TGF-beta) are key in the pathogenesis of lung fibrosis. These same cytokines also promote differentiation of alveolar macrophages or fibroblasts into osteoclasts and osteoblasts in the presence of conducive microenvironmental conditions [1,9]. In addition, bone morphogenetic protein-2, interleukin-4, and interleukin-1 may promote ectopic bone formation, bone remodeling, and osteoclast transformation [1,9,10,116-118]. Alveolar hemorrhage may also predispose to ossification as hemosiderin deposits attract calcium salts [9,119].

Angiogenesis is required for normal bone formation and likely also plays a role in pathogenic calcification in the lungs. Osteogenic protein-1 (OP-1) is a bone growth factor that upregulates alkaline phosphatase activity and also enhances production of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor [120]. VEGF expression is similarly increased by parathyroid hormone, which is elevated in some cases of metastatic calcification. Prostaglandins E1 (PGE1) and PGE2 also stimulate both bone formation and VEGF production [1,121,122].

Predisposing factors — Pulmonary ossification has been described in various settings, including idiopathic pulmonary hemosiderosis [123], lung mucoepidermoid cancer [124], osteogenesis imperfecta [125], and rapid appearance and disappearance with diffuse alveolar hemorrhage [126]. Familial cases have also been reported [127-129].

●Fibrosing interstitial lung disease – Among 892 patients with fibrosing interstitial lung disease (ILD), there was a high prevalence (10 to 20 percent) of pulmonary ossification overall [110]. A significantly higher prevalence of pulmonary ossification was noted among patients with IPF than with other ILDs, and a diagnosis of IPF was shown to be an independent risk factor for pulmonary ossification. The presence of DPO may be a useful marker for differentiating IPF from other ILDs, but more studies are needed [130].

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – Extensive DPO has been reported following SARS-CoV-2 pneumonia, most often in patients who have underlying ILD [131]. Cicatricial organizing pneumonia that develops as a sequelae COVID-19 pneumonia or ARDS may also predispose to the development of DPO [132]. In one case, residual SARS-CoV-2 viral load was detected in explanted lung tissue, suggesting a link between incomplete viral clearance and chronic pulmonary disease [133]. While it remains unclear why fibroproliferation (as in the case of fibrosing interstitial lung disease or severe ARDS) predisposes to DPO, it is interesting to note that the signaling pathways of bone morphogenic protein (BMP) and TGF-beta are highly interconnected, and crosstalk between these pathways in the setting of inflammation may promote bone formation [134].

●Chronic acid aspiration – In a retrospective study of 52 patients with radiographic evidence of DPO, defined as micronodules in the peripheral interstitium, contiguous clusters, and nodules in a branching pattern but without usual interstitial pneumonitis or focal lung disease, 75 percent of the patients had gastroesophageal reflux, obstructive sleep apnea, or a chronic neurologic disorder, raising the possibility that DPO without lung fibrosis may be due to chronic aspiration [135,136].

Clinical presentation — Pulmonary ossification is rare (estimated United States prevalence of 0.5 percent, and incidence of 0.28 cases per year) and typically presents in older men, though pulmonary ossification has been reported in women and younger adults [11,137,138]. Many cases are found incidentally during imaging performed for another reason; some cases are diagnosed at autopsy [10]. Most patients are asymptomatic or have symptoms related to the underlying lung disease.

Diagnostic evaluation — The diagnosis of DPO is based on the appearance of the lungs on high resolution computed tomography (HRCT) and the clinical setting [9]. Radiographic recognition of pulmonary ossification is important as it may avoid the risks associated with lung biopsy.

●Laboratory testing – As with dystrophic calcification, serum levels of calcium and phosphate are generally normal.

●Pulmonary function tests – When the disease is severe, restrictive lung disease and reduced diffusion capacity are seen on lung function tests. However, when pulmonary ossification is secondary to another underlying lung disease, such as IPF, the respiratory symptoms and dysfunction are often due to the primary disorder [1,9,139].

●Imaging – Chest radiographs demonstrate coarse reticular opacities in the lower lung zones [1]. HRCT demonstrates linear 1 to 5 mm calcific densities, typically in the lung periphery (picture 2); punctate, miliary, or nodular calcifications are also seen [1,9,38,119,135,138]. Confirmation is provided by measurements showing the density of lesions is consistent with bone.

Treatment and complications — Treatment options for pulmonary ossification are relatively limited. Oral glucocorticoids, calcium-binding drugs, and low-calcium diets have no demonstrated benefit, though systematic studies have not been conducted [1,9]. Similarly, bisphosphonates appear unlikely to be of benefit but have not been fully studied. As with most forms of pulmonary calcification, treatment in symptomatic patients should be aimed at any underlying pulmonary processes that are amenable to intervention.

Several cases of (spontaneous) pneumothorax have been reported in patients with DPO; one plausible pathogenic mechanism is that subpleural calcified (spicules) impaled the pleural space, leading to the air leak [10,127,128,140-143].

SUMMARY AND RECOMMENDATIONS

●Definitions and classification – Pulmonary calcification and ossification are relatively rare diseases (table 1). Metastatic and dystrophic calcification are defined as deposition of calcium salts in normal and abnormal tissues, respectively. Pulmonary ossification refers to bone tissue formation (calcification in a collagen matrix) in the lungs, with or without marrow elements. (See 'Definitions and classification' above.)

●Metastatic pulmonary calcification – Metastatic pulmonary calcification (MPC) is defined by calcium salt deposition in normal tissues. MPC can result from benign or malignant processes, though the most common cause is end-stage kidney disease (ESKD) being treated with chronic hemodialysis. (See 'Metastatic pulmonary calcification' above.)

•On high-resolution computed tomography (HRCT), MPC can present with any of three patterns alone or in combination: multiple calcified nodules in a diffuse or localized distribution, diffuse or patchy areas of ground glass opacification, and/or dense area(s) of consolidation mimicking a lobar pneumonia. Scanning with ^99mtechnetium-methylene diphosphate (^99mTc-MDP) can be helpful when the HRCT findings are not sufficiently diagnostic. (See 'Imaging' above.)

•For patients with MPC, conditions that elevate the calcium-phosphate product should be corrected to prevent further calcification. (See 'Treatment' above.)

●Dystrophic calcification – Dystrophic calcification refers to deposition of calcium salts in abnormal tissue, such as occurs in infection (mycobacterial, fungal, or viral), noninfectious granulomatous diseases, pneumoconioses, amyloidosis (image 3), and various fibrotic lung diseases. (See 'Dystrophic calcification' above.)

●Pulmonary alveolar microlithiasis – Pulmonary alveolar microlithiasis (PAM) is a unique form of pulmonary calcification due to a genetic defect in a lung-specific sodium phosphate cotransporter (SLC34A2). (See 'Pulmonary alveolar microlithiasis' above.)

•In PAM, the chest radiograph shows a "sandstorm" appearance with diffuse scattered calcific micronodules and the HRCT shows micronodular calcifications primarily along bronchovascular bundles, subpleural and perilobular regions. The diagnosis of PAM can usually be made based on the HRCT appearance, and lung biopsy is rarely needed, particularly in a family with a known affected member. (See 'Evaluation' above.)

●Pulmonary ossification – Pulmonary ossification refers to the formation of mature bone tissue within the lungs. Ossification can be idiopathic or secondary to a primary pulmonary, cardiac, or metabolic disorder. HRCT demonstrates linear 1 to 5 mm calcific densities, typically in the lung periphery. (See 'Pulmonary ossification' above.)

•While pulmonary ossification is often asymptomatic, it may be a marker of disease severity, as in the case of pulmonary fibrosis. Treatment for symptomatic patients is usually aimed at treating the underlying pulmonary disease. (See 'Treatment and complications' above.)