Lesson 6, Volume 16—Pulmonary Sarcoidosis

By Anders Eklund, MD, FCCP

Objectives

1. Outline the epidemiology, etiology, pathology, and pathogenesis of pulmonary sarcoidosis.
2. Outline the clinical presentation and methods for investigation.
3. Highlight prognostic factors.
4. Discuss signs of disease activity and therapeutic alternatives.

Key words

alveolitis; bronchoalveolar lavage; granuloma; interstitial lung disease; sarcoidosis

Abbreviations

ACE = angiotensin-converting enzyme; EN = erythema nodosum; HLA = human leukocyte antigen; HRCT = high-resolution CT; TCR = T-cell receptor

Sarcoidosis is an inflammatory disorder that can affect any organ but has a predilection for the lungs, lymph nodes, eyes, liver, spleen, heart, skin, kidneys, and the nervous system. The hallmark of sarcoidosis is formation of noncaseating epithelioid cell granulomas but they do not per se prove the diagnosis. Clinical symptoms, chest radiograph findings, and pulmonary function tests should also be compatible with the disorder. The onset, clinical features, and prognosis are most variable with clear ethnic differences. An acute first appearance with erythema nodosum (EN) and/or ankle arthritis heralds a favorable outcome, while progressive pulmonary fibrosis may follow an insidious onset. No etiologic agent has been identified and no curative treatment is known.

Epidemiology

There are reports on significant differences between different ethnic groups in both incidence and prevalence. The age-adjusted annual incidence rate in blacks in the United States is about three-fold higher than that in Caucasians. There are also geographical differences in incidence and prevalence. This may reflect true differences but also mirror the intensity at which the diagnosis has been sought.^1-4 African Americans tend to run a more aggressive disease course than Caucasians do.⁴

Seasonal clustering has been reported with a peak incidence in the onset, particularly of acute sarcoidosis, in early spring. Additionally, there are reported clusters of cases,⁵ and it has been suggested that the disease is transmissible because close contact seems to increase the risk of contracting the disorder.⁶ Taken together, this supports the notion of an infectious cause.

Etiology

A large body of evidence favors the idea of a specific etiologic antigen in sarcoidosis, which triggers disease in genetically predisposed individuals. The supposed agent must have a low degree of transmission and a long latency period. A wide range of specific agents have been suggested to cause sarcoidosis (Table 1).

The finding of a skewed T-cell receptor (TCR) repertoire in BAL T cells of sarcoidosis patients strongly argue for the presence of a specific antigen. T lymphocytes expressing the ab TCR specifically recognize antigenic peptides presented by human leukocyte antigen (HLA) molecules expressed by antigen presenting cells. Moller et al⁷ first described a bias in the usage of a certain TCR V gene by lung T cells in sarcoidosis patients, indicating that a specific antigen had stimulated these cells.

Pathology

The granulomas in sarcoidosis are well-organized, noncaseating, and without signs of microorganisms (Fig 1). Cornerstones are the epithelioid cells, which often are multinucleated (Langhans' giant cells), and may contain various inclusion bodies. Interspersed between the cells are macrophages and some CD4-expressing T lymphocytes. In the periphery of the granulomas, CD8+ T cells, B cells, and monocytes can be seen. Fibroblasts and collagen fibers may surround the granulomas, constituting a prerequisite for development of fibrotic changes. In the lungs, the granulomas preferentially will have a peribronchial and perivascular distribution. They may resolve or eventually disrupt the alveolar structure, giving rise to cyst formation and bronchiectasis. Granulomas may also be seen in other conditions such as berylliosis and allergic alveolitis.

Figure 1. A nonnecrotizing epithelioid cell granuloma compatible with sarcoidosis.

Pathogenesis

In pulmonary sarcoidosis there generally is an alveolitis constituted of an accumulation of activated CD4+ T helper cells, creating an increased ratio between CD4+ and CD8+ BAL T cells. A CD4/CD8 ratio > 3.5 was shown to be highly specific for sarcoidosis.^8,9 The lung-accumulated T cells may have migrated from the peripheral blood or lymphoid tissue, or they may have proliferated locally. Reduced numbers of peripheral CD4+ T cells may explain the depressed cell-mediated immunity, a characteristic finding in patients with sarcoidosis.

Alveolar macrophages, which have the capacity to process and present antigens to T cells, also accumulate in the lungs of sarcoidosis patients. The alveolar macrophages are activated and produce a number of proinflammatory cytokines and chemokines, resulting in further cell accumulation.^10,11 The inflammation in sarcoidosis is considered to be a characteristic T helper one immune response with granuloma formation. In the granulomas, epithelioid cells secrete angiotensin-converting enzyme (ACE), and measurements of ACE are considered to reflect the total granuloma burden.

In sarcoidosis, there is a polyclonal activation of B cells, creating elevated titers to a number of viral antigens as well as producing autoantibodies. The formation of immune complexes has been associated with EN, uveitis, and arthralgia.¹²

Most studies on the importance of the genetic background have focused on associations with HLA alleles, and several reports have associated sarcoidosis with the common autoimmune haplotype HLA-A1, -B8, -DR3, in some cases showing further correlations to acute disease and good prognosis.^13-16 Alternatively, through linkage disequilibrium, HLA associations may instead represent associations with other closely located genes.

Clinical Presentation

Mode of Presentation

Because of the great variation in the mode of presentation and the multiorgan involvement, almost any physician may come across a patient with sarcoidosis. The patient is often a nonsmoker between 20 and 40 years of age. In this age group, the disease is equally common in both sexes, but after the age of 50 there is another, but lower, incidence peak in women.²

Ethnicity plays an important role in the clinical manifestations. African Americans are reported to get more advanced constitutional and respiratory symptoms than Caucasians,³ and Japanese patients more often have eye involvement but less severe constitutional symptoms than Caucasians.¹⁷

Most cases will be detected after an insidious onset of symptoms such as fatigue, dry cough, and slightly elevated body temperature, whereas weight loss and dyspnea mostly signal more advanced disease. On the other hand, a substantial number of patients present with Löfgren's syndrome, which includes bilateral hilar lymphoma, high-grade fever, and EN, particularly on the lower limbs (women), and/or ankle joint arthritis (men).¹⁸ Löfgren's syndrome commonly presents during spring, usually predicts good prognosis with spontaneous resolution, and very rarely reappears once in remission.

Uveitis, causing blurred vision, red eyes, pain, and photophobia, is also a rather frequent sign of acute sarcoidosis. Uveitis has, however, a tendency to wax and wane over longer periods of time. It may be combined with parotid gland enlargement, xerostomia, fever, and one- or double-sided facial nerve palsy, and is then referred to as Heerfordt's syndrome.

There is a wide range of other presenting symptoms or signs, eg, renal stones, cardiac arrhythmia, and disconfiguration of scars.

Pulmonary Involvement

The lungs are probably the most frequently involved organs and have previously been reported to be engaged alone or together with the pleura and intrathoracic lymph nodes in > 90 % of the cases.¹⁹ Typical symptoms indicating pulmonary involvement are usually nonproductive cough and dyspnea with concomitant fatigue. Physical findings are mostly absent but wheezing may indicate bronchostenosis. Pulmonary changes can very well exist despite the patient being asymptomatic. In BAL fluid, there is generally a moderate increase in the total number of cells, and an increased percentage (~15 to 60%) of CD4+T lymphocytes (Fig 2). As a consequence, the CD4+/CD8+ ratio will be high. There are also reports on alveolitis in sarcoidosis dominated by CD8+ cells,²⁰ and neutrophils may accumulate in more advanced fibrosing cases.²¹ In the lung parenchyma, peribronchial- and perivascular-oriented granulomas can be found.

A	Figure 2. BAL cytospins from a healthy nonsmoker (A), and a patient with sarcoidosis (B). Both show a predominance of large alveolar macrophages, but there is an increased percentage of lymphocytes in the cytospin from the sarcoidosis patient.
B

If the disease is relentlessly progressive the parenchyma shrinks, bronchial stenosis occurs,²² and bronchiectasis and cysts form. This causes the prerequisite for invasive Aspergillus infection, formation of aspergillomas. These may lead to even fatal hemorrhages.²³ End stages are chronic respiratory failure and cor pulmonale.

Pleural involvement with pneumothorax or effusion is a rather rare finding, occuring in just a few percent of patients.

Diagnosis

As there are no entirely specific histopathologic changes and as the cause of sarcoidosis remains unknown, the diagnosis is one of exclusion. It is therefore of utmost importance that a complete occupational (eg, exposure to beryllium and molds) and environmental history is taken, and that signs of infection are registered.

Radiography

Recently an international statement on sarcoidosis²⁴ recommended that, as previously, a conventional chest radiograph should constitute the basis for staging, and that a grading system from 0 to IV should be used (Table 2, Fig 3). CT is not for routine use but can be valuable when there are unusual manifestations or to confirm peribronchovascular nodules. In addition, high-resolution CT (HRCT) has a role in determining areas of activity. Ground-glass attenuation indicates active inflammation, and in selected cases repeated investigations with a limited number of HRCT sections can be a useful tool when determining the outcome of therapeutic interventions (Fig 4).

A	Figure 3. Conventional chest radiographs showing A, bilateral hilar lymphoma (BHL), stage I; B, BHL with parenchymal infiltrates, stage II; C, parenchymal infiltrates, stage III; and D, signs of fibrosis with shrinkage, stage IV.
B
C
D

A	Figure 4. A, CT showing bilateral nodular infiltrates along bronchovascular bundles and enlarged mediastinal lymph nodes. B, HRCT enhancing the nodular pattern.
B

Bronchoscopy

An onset with classical Löfgren's syndrome in a young adult could be sufficient to make the diagnosis, although a histologic confirmation should be the goal. This can be achieved by taking biopsy specimens from the mucosa or from the parenchyma by transbronchial technique using a fiber bronchoscope. The diagnostic yield will depend on the number and quality of biopsy specimens taken. Transbronchial needle aspiration of mediastinal nodes has been advocated by some. Bronchoscopy gives an opportunity to sample specimens for cultures of fungi and mycobacteria and to evaluate the extent of endobronchial changes such as plaque formation and stenosis, or to detect extrinsic compression causing atelectasis, for example. As BAL to retrieve cellular and noncellular components from the alveoli usually is easy to perform, it should be emphasized that a ratio of CD4+/CD8+ T cells in BAL fluid > 3.5 strongly indicates the diagnosis.^8,9 A high percentage of lymphocytes may support the diagnosis but is not diagnostic. BAL should not be regarded as a standard procedure, either to obtain the diagnosis or for follow-ups.

Additional Biopsy Techniques

Video-assisted thoracoscopy or thoracotomy to take biopsy specimens should be reserved for a very limited number of cases where other measurements to obtain a diagnosis have failed and where the treatment will depend on the diagnosis. In general, biopsy specimens should be taken in the least invasive way from an organ that appears involved and is readily accessible, eg, skin (except EN) and peripheral lymph nodes. A slightly more invasive method is to remove lymph nodes from the fossa supraclavicularis, usually on the right side (Daniels's biopsy).

In some cases the intrathoracic lymph node enlargement is unilateral and it may be difficult to rule out a malignant lymphoma. In such cases, mediastinoscopy should be considered.

Biopsy specimens for histologic examination can be taken from several other organs as well, eg, the salivary glands, conjunctiva, spleen, and liver. Intracutaneous injection of a suspension made up of sarcoid granulomatous tissue, ie, the Kveim-Siltzbach test, in order to look for a granulomatous reaction at the injection site has widely been abandoned for a number of reasons.

Physiology

A baseline pulmonary function test and serial follow-ups may prove most valuable to determine disease progression. Vital capacity is regarded to reflect the course of the disease fairly well, and if low, a stiff lung is probable.²⁵ A rather sensitive tool is the measurement of diffusion of carbon monoxide, which often is reduced at an early stage. If the disease resolves, it may normalize. Airflow limitation increases with more advanced radiographic stages. Bronchial hyperreactivity is not uncommon, whereas hypoxemia is.

Scintigraphy

⁶⁷Ga and ²⁰¹Tl have been used to visualize granulomatous changes.²⁶ Recently, a radiolabelled (¹¹¹In-DTPA-D-Phe) somatostatin analogue (OctreoScan; Mallinckrodt Medical; Petten, Netherlands) was introduced,²⁷ as it has some advantageous physical properties, and as somatostatin receptors are expressed on granulomatous cells (Fig 5). However, the radiation dose is not negligible. It should therefore only be used in selected cases when extrathoracic biopsy sites are sought.

Figure 5. Octreotide scintigraphy showing a pronounced accumulation of the isotope in the submandibular region.

Laboratory Findings

There is no specific biochemical marker for activity in sarcoidosis, but a number of parameters that could be measured in blood, urine, and BAL fluid may help. In acute sarcoidosis with signs of EN and arthritis, C-reactive protein and the erythrocyte sedimentation rate are often elevated. Anemia is sometimes present, as are thrombocytopenia and pancytopenia, but they are rarely severe. Peripheral lymphopenia could be a consequence of the recruitment of lymphocytes to sites of inflammation, eg, the alveoli. The CD4+/CD8+ ratio in peripheral blood may become very low. Hematologic changes can reflect not only redistribution between various compartments and spleen enlargement, but also bone marrow involvement.

Measurement of serum angiotensin-converting enzyme (ACE) activity²⁸ is frequently used to monitor sarcoidosis activity. The value of serum ACE in reflecting the disease activity is limited, however, and it should be used as a complement to the overall judgment of the disease activity based on clinical, radiographic, and lung function findings. Treatment with ACE inhibitors will give "false" low serum ACE values. During the first weeks following the appearance of Löfgren's syndrome, serum ACE may be normal, and it will also be reduced shortly after treatment with corticosteroids has begun.

It has been known that < 10 % of patients with sarcoidosis have increased concentrations of serum calcium. Calcitriol (1,25-dihydroxyvitamin D₃) is formed in excess by macrophages in the alveoli and in granulomata, and this results in an enhanced capability to absorb calcium from the gut.^29,30 Hypercalciuria exists much more frequently than hypercalcemia.

The humoral immunologic response in sarcoidosis is activated by an activation of B cells. Serum IgG is more frequently elevated than IgA and IgM. Slight but unspecific elevations of titers of different autoantibodies are common.

Liver enzymes, alkaline phosphatases as well as transaminases, may be abnormal in a fluctuating manner. To differentiate from primary biliary cirrhosis, antimitochondrial antibodies should be tested.

A number of other biochemical markers have been reported to be of some value in determining activity, eg, serum neopterin, b₂ microglobulin, and more recently interferon-g and the soluble interleukin-2 receptor. Elevated levels of interferon-g were seen in patients with sarcoidosis and, at least in some patients, high values seem to improve the prognosis for clearing of the radiographic picture.³¹

Several attempts to use BAL fluid analyses to monitor the activity in sarcoidosis have been made. So far, no single reliable marker has been detected (eg, hyaluronan, procollagen III N terminal peptide, vitronectin, albumin, and fibronectin).

Prognosis

Acute onset with Löfgren's syndrome predicts a favorable prognosis in the majority of cases, whereas a more protracted disease course is common after an insidious debut. Spontaneous resolution has been estimated to occur in at least 50% and possibly up to 90% of patients with stage I disease. This figure decreases with more advanced radiographic stages: 40 to 70% of patients in stage II and just about 30% in stage III have spontaneous resolution. In stage IV, total remission is no longer possible. Unfavorable prognosis is predicted if the patient is of African American origin, > 40 years of age, if symptoms have been present for > 6 months at diagnosis, and when multiple organs are involved. Also, lupus pernio and radiographic stages III and IV are regarded as ominous signs.

Treatment

The activity of the disease should be evaluated by taking clinical symptoms, radiographic findings, lung function tests, and, to some degree, laboratory findings into account.³² Sarcoidosis patients with extrathoracic manifestations should, if the manifestations are extensive or difficult to evaluate, be examined by specialists within the respective fields. Patients who are at risk of developing severe or long-standing pulmonary sarcoidosis should be monitored and, if necessary, treated by a pulmonologist, whereas young patients with Löfgren's syndrome may be followed up by a general practitioner once the diagnosis is secured.

In patients with an acute onset, as in Löfgren's syndrome, there may be pain and swelling of joints calling for treatment with nonsteroidal anti-inflammatory drugs for some weeks or months, but oral steroids are uncommonly required and should not be routinely used. Local injections of steroids in affected joints will reduce symptoms. When the acute symptoms have subsided, two or three follow-ups during the first year will usually be sufficient. If the radiograph then has cleared, a final check up a year later should be sufficient.

In stable disease, evaluations with chest radiography, some laboratory tests (eg, hematologic, electrolytes, creatinine, and possibly serum ACE) once or twice yearly is often enough. In cases where there may be progressive disease, the lung function should be monitored as well. In patients with stage II or III sarcoidosis, if there are signs of deterioration (as judged by symptoms, lung function, and chest radiographs) before and after a 3- to 6-month period, treatment with oral steroids may be indicated. Even patients with stage IV disease should be given a trial of steroids under close supervision for a few months to see if there are any reversible changes. If signs of aggressive disease are present, earlier treatment may be warranted. It seems that regular treatment is better than treatment on demand.³³ Most recommend a dose corresponding to 20 to 40 mg daily of prednisolone or its equivalent. In steroid responders, the dose is slowly tapered, but treatment should continue for at least 1 year. In the short run, corticosteroids may prove effective; however, the long-term efficacy is much less obvious, as relapses often occur during tapering or after discontinuation of therapy. Multiple relapses during tapering indicate that a low maintenance dose of steroids for years may be warranted.

As always, when steroids are administered over a longer period of time, there should be an increased awareness of signs of osteoporosis, which may be assessed by bone density evaluation. Some advocate inhaled steroids in the treatment of sarcoidosis, while others still regard the effect as unproven.^34,35 In patients with bronchial hyperreactivity, inhaled steroids may give symptomatic relief. Possibly, administration of a combination of inhaled and oral steroids will reduce unwanted steroid-induced side effects.

Another way of avoiding adverse effects of treatment with steroids may be the concomitant use of other immunosuppressive drugs so that the dose of steroids can be reduced (Table 3). There are several options, eg, methotrexate 10 to 20 mg given once a week,³⁶ or azathioprine, 50 to 200 mg daily.^37,38 A broad spectrum of possible adverse effects (eg, hematologic and on liver function) must be monitored and long-term therapy should be given only to those showing a clearly favorable response. Azathioprine could be advantageous in these cases. Adequate birth control is essential as these agents are teratogenic.

As effects of cytotoxic drugs such as chlorambucil and cyclophosphamide are anecdotal, and the use of cyclosporine A in pulmonary sarcoidosis is very limited, these agents are not recommended.

Recently, other drugs have been tested, eg, pentoxifylline, which exerts tumor necrosis factor–inhibitory activity and inhibits interleukin-2 receptor expression in lymphocytes.^39,40

Specific Treatment of Lung Involvement

The pulmonary involvement may give rise to formation of cysts, and fungi can grow in the cysts. In particular, Aspergillus fumigatus may grow invasively, and preferentially after immunosuppressive treatment has been given. Long-term specific antifungal therapy with itraconazole, for example, may be warranted, but the effect is controversial. Topical instillation of amphotericin B has been used by some. A single aspergilloma can possibly be removed surgically, provided that lung function permits surgical removal.²³ In relentlessly progressive, severe cases, lung or heart-lung transplantation should be considered.⁴¹ However, recurrence of the disease in the allograft is not uncommon, although it will not necessarily give rise to clinical symptoms.

References

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