a

Serum SP-D (ng/ml)

60 **

40

20

0

Serum MCP-1 (pg/ml)

*

800

600

400

200

0

b

Pre treatment

Post treatment

Fig. 27.3  Biomarkers and dietary intervention in PAM. (a) Serum levels of SP-D and MCP-1 are elevated in PAM patients (open circle) compared to healthy volunteers (closed circle). (b) Low phosphate diet (LPD) prevents microlith accumulation in mice, when compared to mice on regular diet (RD). (From Saito, A., Nikolaidis, N.M., Amlal,

H., et al. Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment. Sci Transl Med 2015;7(313):313ra181; with permission)

Clinical Features

Approximately 50% of PAM patients are asymptomatic at time of diagnosis [46]. Dyspnea with exertion is the most frequent presenting symptom, occurring in about a quarter of patients at diagnosis. Nonproductive cough, chest pain, weakness, cyanosis, and hemoptysis have also been reported as presenting manifestations. Subjective complaints are commonly less severe than chest imaging suggests, a characteristic long associated with PAM and described as “clinicalradiological dissociation.” [47] Pneumothorax can occur, likely as a result of subpleural cyst rupture, but is uncommon. Smoking and pulmonary infection may ­accelerate disease progression, thought the available evidence is circumstantial and anecdotal [24].

While Npt2b is expressed in the mammary glands, intestines, kidneys, skin, prostate, and testes, extrapulmonary disease is not typically seen. Deposition of microliths in the male genitalia has been described in patients with PAM and can result in hematuria, testicular atrophy, obstructive azoospermia, and infertility [48–53]. This has led some to conclude that testicular microlithiasis is associated with PAM. It is important to note that testicular microlithiasis is quite common, affecting 0.6–9% of males in the general population, and that chance associations of a common disease with a rare disease are often dif cult to exclude. Corut et al. were not able to identify a clear link between testicular microlithiasis and mutations in SLC34A2 [24]. Until this issue is

better understood, due consideration of testicular microlithiasis is probably reasonable in males with PAM, since it is thought to predispose to testicular malignancies and male infertility [54–56].

Discoid lupus, rheumatoid arthritis, psoriasis, antiphospholipid syndrome, Sjogren’s syndrome, lymphocytic interstitial pneumonitis, non-Hodgkin lymphoma, pericardial cysts, osteopetrosis, hypertrophic osteoarthropathy, and pectus excavatum have all also been reported in patients with PAM. These were mostly limited to single patient reports, so it is unclear if there is any true association between these disorders and PAM. Some comorbid conditions, such as hypertrophic osteoarthropathy, were likely underreported in prior literature. Others, such as the autoimmune diseases listed above, seem more likely to be chance occurrences. Other heritable diseases have also reported in PAM, including diaphyseal aclasis (associated with multiple osteochondromas) and autosomal recessive Waardenburg-anophthalmia syndrome (associated with malformation of the eyes and the skeleton); but it is dif cult to distinguish between disease cotransmission in consanguineous marriages and a direct relationship between PAM and genetic disorders in these cases.

Pulmonary function tests can initially be normal. A restrictive ventilatory defect and reduced diffusing capacity (DLCO) typically develop over time. Echocardiography may reveal pulmonary hypertension and evidence of right heart failure [57], ndings which may prompt expedited evaluation for lung transplantation.

Serum phosphate and calcium are typically normal in patients with PAM, most likely because SLC34A2 is not abundantly expressed in the kidney and is not required for phosphate uptake in cases when dietary phosphate is abundant [58]. Takahashi et al. found elevated serum levels of surfactant protein-D (SP-D) in two consecutive patients, which may refect higher alveolar SP-D levels, compromised alveolar basement membrane integrity, altered polarity of alveolar type II cells, or a combination of the three [24]. Patients with PAM have also been shown to have elevated serum MCP-1 [42]. These reports suggest SP-D and MCP-1 as potential diagnostic biomarkers or indicators of disease activity or progression, though further investigation is needed.

The calci ed microliths of pulmonary alveolar microlithiasis produce highly characteristic radiographic ndings, de ned by a ne diffuse basilar-predominant micronodular pattern that produces the classic “sandstorm” appearance described in the literature. (Fig. 27.4) These in ltrates can obscure the heart borders, diaphragm, and great vessels (the “vanishing heart” phenomenon) [59]. Air broncho-

grams can often be seen coursing through areas of consolidation as well.

High-resolution computed tomography of the chest shows widespread microcalci cations throughout both lungs. (Fig. 27.3) Although these densities are typically diffusely distributed, they can also predominate in the posterior segments of the lower lobes. An increase in microliths in the upper lobes has been described in smokers. Ground-glass opacities and airspace consolidations can occupy large proportions of the lung elds, particularly in patients with progressive disease [53, 60]. Linear radiolucencies at the pleural boundaries abutting the heart, diaphragm and chest wall can produce the “black pleura” sign, another characteristic radiological feature of PAM that is likely secondary to the subpleural cystic changes that are often seen on cross sectional imaging and pathological evaluations [61, 62]. These cystic changes appear to be the result of alveolar duct dilation [53]. In a small series of cases in Brazil, ground-glass opacities and small parenchymal nodules were the primary CT ndings. In addition, small subpleural nodules and subpleural cysts were seen frequently (in 92% and 85% of cases, respec-

Fig. 27.4  Radiographic appearance of pulmonary alveolar microlithiasis. (a) Chest radiograph and high-resolution computed tomography of the chest, (b) lung windows, and (c) mediastinal windows of an elderly male with PAM. Note the diffuse basilar-predominant micronodular “sandstorm” appearance on chest radiograph and small subpleural, s-

sural, and septal microcalci cations along with diffuse ground-glass opacities seen on HRCT. (d) Chest radiograph and (e) HRCT lung windows showing ground-glass in ltrates from a 2-year-old infant with PAM who underwent transplant (see Figs. 27.1 and 27.2). (https://doi. org/10.1016/j.ehpc.2018.04.004)

tively). Other common ndings in decreasing order of prevalence included subpleural linear calci cations, crazy paving, nodular ssures, interlobular septal calci cations, and dense consolidations [63]. In general, these radiographic ndings tend to correlate well with pathologic ndings [58].

PAM is most often confused with miliary tuberculosis, in part because the regions where consanguineous marriage is common frequently overlap with areas with high tuberculosis prevalence. Sometimes this overlap manifests in the same patient; there have been at least ve cases of superimposed tuberculosis infection in patients with PAM [4]. Once felt to be pathognomonic for pulmonary alveolar proteinosis, crazy paving on high resolution CT has also

been described in PAM and can lead to misdiagnosis; however, the bone-level density of pulmonary parenchymal opacities noted on the mediastinal windows distinguish PAM from PAP [4, 64]. Another consideration in the differential is metastatic pulmonary opaci cation which can occur in the setting of end-stage renal disease or in hyperparathyroidism, milk-alkali syndrome, talcosis, amiodarone toxicity, iodinated oil embolism, and aspirated or extravasated contrast media [65]. Additional mimics include healed varicella or variola pneumonia; pneumoconioses like silicosis; pulmonary hemosiderosis; and granulomatous diseases like sarcoidosis, histoplasmosis, and amyloidosis. (Fig. 27.5)

Fig. 27.5  Differential diagnosis of pulmonary alveolar microlithiasis. (a) Miliary tuberculosis. [Note centrilobular (arrow) and subpleural (arrowhead) nodules] (b) Dendriform ossi cation. (c) Metastatic pulmonary calci cations. (d) Healed Varicella pneumonia. [(a) Reprinted with permission of Radiological Society of North America. Copyright © 2020. Nachiappan A C, Rahbar K, Shi X, et al. Pulmonary tuberculosis: Role of radiology in diagnosis and management. RadioGraphics

2017;37:52–72. (d) Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. George, R., Weill, H., et al. 1967. “Roentgenographic Appearance of Viral and Mycoplasmal Pneumonias.” Am Rev. Resp Dis*. Vol 96; pp. 1144–1150. *Journal now titled: the American Journal of Respiratory and Critical Care Medicine]

Diagnosis

The diagnosis of PAM is often readily established with characteristic imaging, especially in the setting of positive family history. In those cases where doubt still exists, further diagnostic studies may be helpful. Expectorated sputum has produced microliths in some cases [66, 67]. Bronchoalveolar lavage can aid in diagnosis: Although the sensitivity and spec- i city for such ndings is unknown, BAL can produce microliths with the typical morphological appearance or lamellar structure and periodic-acid Schiff-positive staining on histological sections. Scanning electron microscopy can reveal the porous surface reminiscent of bone that is typical for microliths. In addition, a lavage is useful for exclusion of other possible differential diagnoses, such as infectious diseases. Transbronchial lung biopsy appears to have reasonable yield and safety pro le but is not required when the presentation and imaging are characteristic [68]. Despite the multiple avenues available for making a non-invasive diagnosis, use of lung biopsy is still quite common. In their review of 1022 worldwide cases, Castellana et al. found that since 1980, 56.6% of patients underwent invasive procedures for diagnosis (BAL and/or transbronchial biopsy, open lung biopsy, or autopsy) as compared to 36.7% in the previous era [69]. The rate of open lung biopsies remained steady (23.1% vs. 25.4%), however. These ndings suggest that the disease remains unfamiliar to many physicians, which is not surprising given its rarity. In general, lung biopsy should be reserved for cases where uncertainty persists despite more conservative diagnostic methods.

Screening family members of the index case for disease should be considered in those who wish to proceed after appropriate genetic counseling. Genotyping for SLC34A2 mutations is now commercially available. Documenting the mutation is not currently helpful for disease management given the absence of any reports of clinically relevant genotype-phenotype associations.

Management

The long-term prognosis of PAM is incompletely understood. The wide range of ages of patients reported in the world literature suggest a variable course that may be modi-ed by environmental factors including smoking. Few case series have reported longitudinal outcomes of patients with PAM. The largest of these was a 2009 study of 53 Japanese

subjects which included 28 patients who were rst diagnosed in childhood. Of those who had 20to 49-year follow-up periods, 42.9% had died of respiratory failure related to PAM, with a mean age of death of 46.2 years. These results suggest a poor overall long-term prognosis, even in ­asymptomatic patients diagnosed in childhood [58]. MCP-1 and SP-D, as noted above, are potential biomarkers for diagnosis and disease activity, but they require further testing to validate their role in management.

Of the empiric therapies that have been reported, the bisphosphonate, etidronate, is perhaps the most frequently employed but is controversial. Etidronate is FDA-approved for treatment of Paget’s disease and heterotopic ossi cation, though a subsequent Cochrane review on the ef cacy of the approach for the latter was withdrawn. Etidronate not only inhibits bone resorption by osteoclasts, which would not necessarily be desirable if these or other myeloid derived cells play a role in controlling stone accumulation, but also prevents hydroxyapatite crystal formation and bone mineralization [70, 71]. This property is unique to etidronate, and gives it a theoretical advantage over other bisphosphonates. Since 1992, several case series have highlighted use of etidronate for PAM, especially in pediatric patients [29, 72–77]. The data are limited, and results are mixed. Several showed improvements in lung function and reduction of radiographic opaci cation of the lungs. In another three cases, etidronate did not provide any bene ts in these clinical parameters [76]. To our knowledge, use of etidronate has not been reported in adults with PAM and further studies are needed before the drug can be routinely recommended in any patient population.

Other treatments that have been attempted have not been effective. Corticosteroids and chelating agents like systemic sodium thiosulfate have not been shown to modify disease course [78]. Serial whole-lung lavage was considered a possible treatment modality in the past since microliths are con-ned to the alveolar lumen but unfortunately there is no evidence for the merit of this approach [79–81].

At this point, treatment is primarily supportive. All patients who are hypoxemic at rest, during sleep, or with exertion should be started on supplemental oxygen. As with all patients with chronic lung diseases, PAM patients should receive pneumococcal and infuenza immunizations. Referral to pulmonary rehabilitation is likely helpful as well. Screening for the development of secondary pulmonary hypertension and right heart failure with serial transthoracic echocardiography is reasonable, as many patients eventually develop cor pulmonale.