Study objective: This study investigated the clinical features and disease course of sarcoidosis diagnosed in patients > 70 years of age.
Methods: A retrospective analysis was made of cases treated at the University Hospital in Nantes, France, between 1986 and 2000. The diagnosis of sarcoidosis was confirmed histopathologically. Cases involving progressive cancer and active tuberculosis were excluded.
Results: Thirty white patients with sarcoidosis diagnosed after age 70 years (mean, 74 years) were included. An alteration of general health (asthenia and/or anorexia and/or weight loss) was frequent (53%) and characteristic of the systemic form of the disease. Dyspnea was a fairly common sign (23%). The intrathoracic form of sarcoidosis was most frequent (43.3%). Diagnosis was difficult and lengthy, and symptomatology was atypical. Accessory salivary gland biopsy was an important contributing factor to diagnosis (70.6% were positive). Oral corticosteroid therapy was often required (60.7%). The disease course was satisfactory overall (81.8% of cases), but only for 50% of patients in intrathoracic stage IV.
Conclusions: The clinical presentation of sarcoidosis in elderly subjects is mainly characterized by an alteration of general health. Diagnosis is difficult and should include accessory salivary gland biopsy. Therapy frequently involves corticosteroids. Overall prognosis is similar to that for young subjects.(CHEST 2004; 126:1423-1430)
Key words: accessory salivary gland biopsy; elderly subjects; sarcoidosis
Abbreviation: ACE = angiotensin-converting enzyme
Sarcoidosis is a systemic granulomatous disease generally affecting the young and most often involving the lungs and mediastinum. Although sarcoidosis is infrequent in elderly persons, the clinical features and course of the disease can be determined as well as the possible benefit of diagnosis and treatment.
MATERIALS AND METHODS
This retrospective study concerned all patients > 70 years of age who received a diagnosis of sarcoidosis after admission to the University Hospital in Nantes, France.
Sarcoidosis can affect almost any organ or tissue, but the lungs and mediastinum are involved in most cases. All of the following criteria were required for patients included in this study: age [greater than or equal to] 70 years at diagnosis; absence of any known history of sarcoidosis; suspected intrathoracic or visceral involvement (according to clinical data and/or imaging), with one positive biopsy result, or with two positive biopsy results in different regions; absence of toxic or medicinal etiology; absence of concomitant progressive neoplasia; and diagnosis of sarcoidosis by the attending physician as a function of clinical involvement and disease course. Cases of isolated granulomatous hepatitis were not included because of their uncertain nosology. Granulomatous diseases of infectious etiology (notably active tuberculosis) or those associated with other dysimmune diseases responsible for granulomatous reactions (Crohn disease, rheumatoid arthritis, celiac disease) were also excluded.
The presence of noncaseating granulomas, with little or no necrosis, was required for diagnosis, but not specific for sarcoidosis.
Staging of Mediastinum-Lung Involvement
Chest radiography allowed intrathoracic involvement to be rated according to the customary four stages: normal radiography (stage 0), mediastinal adenopathy (stage I), parenchymal involvement associated with mediastinal adenopathy (stage II), infiltrating lung disease without mediastinal adenopathy (stage III), and pulmonary fibrosis (stage IV). (1,2)
Information on patients treated for sarcoidosis after 1995 was provided by the data processing department of the Nantes University Hospital from an institutional database (Programme de Medicalisation du Systeme d'Information). For previous years, the files of each department concerned were consulted. As certain departmental files did not indicate a diagnosis of sarcoidosis, some patients were identified on the basis of complementary data in files maintained by histopathology laboratories. To ensure satisfactory exhaustiveness, the year 1986 was chosen as the beginning of the investigation period.
Data were collected on cases diagnosed over a 14-year period (1986 to 2000).
General Population Characteristics
Thirty white patients (21 women and 9 men; mean age, 74 years; range, 70 to 81 years) satisfied the inclusion criteria (Table 1). The diagnosis of sarcoidosis was made after 75 years of age in 23.3% of cases (n = 7). Mean follow-up was 37.8 months. Eighty-three percent of patients were treated in internal medicine, geriatrics, pneumology, and mixed-care departments. Six cases of possible sarcoidosis were excluded because of associated cancer (n = 3), associated active tuberculosis (n = 1), lack of histopathologic studies (n = 1), and known history of sarcoidosis before age 70 years (n = 1).
History of Tuberculosis or Autoimmune Disease
Four of the included patients (13.3%) had a known history of tuberculosis: one primary infection in adolescence, and three pulmonary tuberculosis (two before diagnosis of sarcoidosis at age 40 years). Two patients with a recent contagion (< 10 years) were also included. Five patients had a history of autoimmune disease, and five others had an allergic disorder.
The clinical form (Table 1) was defined according to the main area of involvement observed. Intrathoracic forms were dominant (43.3%), followed by systemic forms (20%). The latter were characterized by an obvious alteration of general health (asthenia and/or anorexia and/or weight loss).
Clinical or Radiologic Signs Suggestive of Sarcoidosis
An alteration of general health was observed in 53% of cases (Table 2). Asthenia was frequent (43%), notably in intrathoracic and systemic forms. Anorexia was found in 23% of cases. Weight loss (n = 8) was characteristic of systemic forms, which mimicked (asthenia and fever) progressive tuberculosis or neoplasm. Dyspnea and cough were quite characteristic of the intrathoracic form, which was often revealed by recurrent bronchial episodes (38%). Dryness syndrome was noted initially in 16% of cases (n = 5), either as xerostomia (n = 4) or xerophthalmia (n = 1). In two cases, parotid uptake was observed in scintigraphy, and the parotid gland was enlarged in one case.
Ocular involvement was not searched for systematically. A single patent involvement of panuveitis type, with bilateral retinal lesions, was noted in the intrathoracic form. Systematic examinations detected signs of old iridocyclitis in one case and sequelae of bilateral retinal lesions in another.
Three patients had pericardial effusion, and three patients had a pacemaker implanted after severe conduction disorders. There were no asymptomatic cases. Alteration of general health (53%) and dyspnea (23%) were the main signs revealing the disease in these elderly subjects.
The fact that most of the cases required a long interval (mean, 31.2 months; range, 3 to 168 months) before essential evidence was established for a diagnosis of sarcoidosis is indicative of the difficulties encountered with elderly subjects. The evidence came from the clinical history, biological examinations, imaging studies, biopsies (quite decisive in this type of pathology), and disease course. In the diagnostic process, a positive biopsy result in conjunction with clinical involvement or suggestive imaging concerned 17 patients. Twelve other patients had positive biopsy results in two different regions. In one case, the diagnosis related to two doubtful biopsy results and failure of antituberculous therapy.
In addition to these sources of evidence, other elements were taken into account, ie, lymphocytic BAL, elevated angiotensin-converting enzyme (ACE) levels, suggestive gallium scintigraphy, failure of antituberculous therapy, search for negative Mycobacterium tuberculosis culture, and negative tuberculin skin test.
Lymphopenia, defined as a decrease in lymphocytes < 1,500/[micro]L, was noted in 84.6% of cases (Table 3). Mean lymphocytosis (n = 26) was 980/[micro]L (range, 350 to 1,750). In three cases, lymphopenia was < 500/[micro]L. C-reactive protein was high 12 times (60%, 9.4 to 197 mg/L). Hypergammaglobulinemia was found in 16% of patients (13.4 to 28.5 g/L). A rise in ACE levels (44.4% of assays) was not an efficient diagnostic tool in this group of elderly patients. Lymphocytic BAL was significant in 87% of studies. This examination was performed infrequently (n = 10), and two failures were noted. Among the seven patients with positive BAL findings, one patient had no intrathoracic involvement in radiology (no CT scan was performed). No alveolitis was found in one intrathoracic form.
Exclusion of Active Tuberculosis
The possibility of active tuberculosis was a major concern for the clinician. Only 9.1% of patients had no culture in specific medium. Stomach intubation was the most frequent examination (15 patients for 22 exploitable files), and the polymerase chain reaction technique was used once. Empiric antituberculous therapy was sometimes used as a diagnostic tool (n = 5, 22.7%), even though none of these patients had a positive tuberculin skin test result.
Tuberculin Skin Test
The tuberculin skin test result was very often negative (73%), but the number of positive cases was still substantial (27%). No reaction was phlyctenular (Tables 3, 4).
Sixty-three biopsies were performed (66.7% of results were positive). Ten patients (33.3%) underwent at least three biopsies (three to five biopsies) for sarcoidosis diagnosis, probably because of uncertainties and frequent negative results in histopathology (Table 3).
The accessory salivary gland was sampled most often (27% of all biopsies for 56.7% of patients), and the results were quite satisfactory (70.6% were positive). This biopsy was performed early in only 17% of cases. Positive results concerned all clinical forms, and were a major factor in the diagnosis for 12 patients. The biopsy result was positive five of eight times in thoracic forms, and thus was more efficient than unguided procedures (Table 3).
Results for bronchial biopsies were less satisfactory (38% were positive), as were those for transbronchial biopsies. However, biopsies directed at morphologic or clinical abnormalities (skin, adenopathy, mediastinal tissues, etc.) were quite useful.
Mediastinum-lung involvement (56.7%) can suggest sarcoidosis or confirm other evidence of the disease (Table 3). A chest CT scan (n = 18) was performed for 85% of intrathoracic forms, and nearly always when intrathoracic involvement was suspected on the basis of clinical or radiologic evidence. CT scan performed after chest radiograph guided diagnostic strategy and could confirm a process of pulmonary fibrosis.
Gallium scintigraphy was useful in six cases, showing at least suggestive intrathoracic uptake. Two of these cases corresponded to intrathoracic stage 0.
Description of Clinical Forms According to Dominant Clinical Involvement
Intrathoracic Form (n = 13): The intrathoracic form was often revealed by dyspnea or recurrent bronchial episodes (n = 4). Pleural effusion (n = 2) was exudative and massive and associated in one case with florid parenchymal involvement (stage II) [Table 4]. In another case, sarcoidosis (stage II, salivary gland biopsy positive) was revealed by obstructing bronchial aspergillosis treated by inhaled corticosteroids and oral itraconazol. The intrathoracic form of sarcoidosis was often severe (four stage IV, and two deaths directly imputable to the course of pulmonary fibrosis). Stages III and IV represented 54% of intrathoracic forms (26.6% of all cases).
Systemic Form (n = 6): The systemic form of sarcoidosis associated an alteration of general health (often febrile) with a complex clinical picture. Weight loss (n = 5) was marked (> 10 kg in three cases). Fever was noted in three cases (> 38.5[degrees]C in two patients). Deep or superficial extrathoracic adenopathy and/or hepatomegaly were frequent (n = 4). Mediastinal and lung involvement was found in three cases. A pseudomyalgia rheumatica syndrome with peripheral arthritis was the cause in one case. Acute articular involvement was noted in two cases. In another case, the clinical picture was associated with neuropathy of the lower limbs, facial nerve palsy, and intercostal pain. Gallium scintigraphy showed mediastinal uptake, and neuromuscular and salivary gland biopsies revealed granulomatous inflammation. Granulomatous hepatitis was noted in another case. Diarrhea was observed in two cases, but no specific lesions were detected in colonoscopy (aspecific subacute colitis in one case). Exudative pleural effusion and medullary granulomas were found in one of these cases.
Articular Form (n = 3): Articular sarcoidosis was characterized by subacute or chronic inflammatory polyarthralgia affecting essentially large (n = 3) and small (n = 2) joints. One case was revealed by a granulomatous subpalpebral swelling and another by superficial adenopathy and an enlarged parotid gland. Diffuse muscular involvement occurred in the third case, causing severe musculotendinous sequelae. Granulomas were found in muscle and synovial biopsies.
Node Form (n = 3): The node form was characterized by cervical adenopathy (n = 3), together with supraclavicular adenopathy in two cases. Involvement of different node groups may have been successive. Xerostomia was noted in two cases (parotid involvement documented by scintigraphy in one case).
Forms Revealed by Cutaneous Manifestations (n = 3): In one case, aspecific erythema nodosum had developed over a 4-year period (positive salivary gland biopsy), and two other cases showed specific erythematous and squamous as well as papular granulomatous lesions.
Renal Form (n = 1): Renal sarcoidosis, characterized by rapidly progressive renal failure, showed granulomatous interstitial nephropathy in histopathologic studies. The blood calcium level was normal. The response to corticosteroid therapy was transient, and terminal renal failure developed.
Lacrimal Form (n = 1): Granulomatous swelling of the lacrimal gland was associated with lymphocytic BAL in the absence of radiologic signs of intrathoracic involvement. A salivary gland biopsy result was positive.
Course of Clinical Patients
Sixty-one percent of patients received general corticosteroid therapy (usually starting at 1 mg/kg/d of prednisone equivalent) [Table 4]. This treatment was administered to 67% of patients with the intrathoracic form of sarcoidosis and 56% of those with other forms. Another immunosuppressant (azathioprine) was used in two cases of intrathoracic sarcoidosis. One patient was treated with inhaled corticosteroids. Other patients received hydroxychloroquine (n = 3), thalidomide (n = 1), and potassium iodide (n = 1) for skin or joint involvement.
Overall, the course was considered satisfactory in 82% of cases (improvement in 64% and stabilization in 18%). When a patient was treated by general corticosteroid therapy, improvement or stabilization was observed in 81% of cases overall, 71% for all intrathoracic forms, and 50% for stage IV intrathoracic sarcoidosis. The form was considered severe for 26.6% of all patients because of marked intrathoracic or other involvement (renal, peripheral nervous system, or ocular). The intrathoracic form of sarcoidosis had a more severe prognosis: four deaths vs one death for the other forms. Two deaths were directly attributable to chronic respiratory failure secondary to fibrosis (stage IV). Among stage IV cases, only one patient improved under treatment (after 12 months of follow-up); another was considered stable (but died of an unstated cause); and two others had a worsening of their respiratory problems. Corticosteroid therapy for fibrosis appeared to be inefficient, despite association of azathioprine in two cases. The patient with bronchial aspergillosis improved with inhaled corticosteroids followed by itraconazole. As the course of the renal form of sarcoidosis was unfavorable, peritoneal dialysis was considered. The complications related to treatment are difficult to evaluate retrospectively, but seem to have been essentially infectious: lung disease caused by cytomegalovirus, tuberculous abscess (in a patient with stage IV sarcoidosis who died from pulmonary fibrosis), and Alternaria infection.
Sarcoidosis generally affects young subjects and is relatively rare in older persons. (3-5) A retrospective series (from 1951 to 1986) reported by Stadnyk et al (3) found 17 elderly patients (7.8%) among 219 reviewed cases of biopsy-proven sarcoidosis. This is the only published series concerned specifically with the clinical characteristics and course of sarcoidosis in patients > 65 years of age (mean age, 70.9 years; vs 74 years in our series). Women were preponderant, as in our series, although it would appear that the onset of sarcoidosis is earlier in men. (6)
There were no asymptomatic cases in our series, whereas fortuitous discovery is common in the young, (6-8) probably because of a greater frequency of systematic radiologic examinations. General signs are the primary indicators in older people. However, alteration of general health, a major sign in our series (53% of patients), was less frequent in other nongeriatric series (6.3% for Judson et al, (9) 16% for Chapelon et al, (6) and 13.7% for Garret et al (8)) and often led to empiric antituberculous therapy. (8) Sarcoidosis is also a possible etiology for unexplained prolonged lever in elderly subjects. (10) Pulmonary functional signs (46.3%) were prominent "organ symptoms," as clearly documented in other studies, (3,4,9) and patients showed dyspnea, cough, chest pain, hemoptysis, and recurrent infection. Mediastinum-lung involvement (57% of cases) was less frequent than in other series (90% for Garret et al, (8) 83% for Chapelon et al, (6) and 82% for Stadnyk et al (3)), which tends to confirm the symptomatic a typia and diagnostic difficulty encountered in older persons. Articular involvement consisted especially of chronic, subacute, or acute inflammatory polyarthralgias or polyarthritis affecting particularly the large joints, as classically described. (11,12) However, acute articular manifestations were less frequent in our series, and chronic manifestations more frequent. (6,11) Renal, neurologic, or muscular localizations are uncommon, often difficult to diagnose, and not always susceptible to corticosteroid therapy. (6,13-19) Lacrimal involvement has been documented in older subjects. (20) Dryness syndrome often exists, and its importance is probably underrated. This symptom is more often related to parotid than lacrimal involvement. Although ocular involvement was only reported three times in our series, sarcoidosis is a frequent etiologic diagnosis for uveitis in older persons. (21,22) Retinal periphlebitis (one case) is also an acknowledged complication. (23) Pericarditis is not the most frequently reported form of cardiac involvement. (24) Cardiac sarcoidosis is especially characterized by conduction and rhythm disorders." (25) Three cases of pericarditis occurred in our series, but three other patients underwent pacemaker implantation for conduction disorders that may have been sarcoidosis related.
Little is known about the relations between sarcoidosis and tuberculous or other mycobacteria. Their mutual involvement seems likely, (26,27) and an association between sarcoidosis and tuberculosis has been reported. (6,8) A history of tuberculosis was fairly frequent in our patients (13%), and retrospective collection of data probably underestimated this aspect. One patient acquired tuberculosis while receiving corticosteroid therapy (negative tuberculin skin test result).
Biopsies are essential to the diagnosis of sarcoidosis. The accessory salivary gland biopsy is simple to perform and relatively uninvasive, but is not used systematically. (6,28) Results were positive in 70.6% of cases in our series, and were more informative than bronchial biopsies. Sensitivity was slightly better than in most published series concerning younger subjects. (6,29-31) The diagnosis of sarcoidosis can be reached by mediastinoscopy, which is highly informative when imaging shows accessible adenopathy. In such cases, transbronchial biopsies can prove inadequate. Recourse to mediastinoscopy is not exceptional in the older subject, (3) but accessory salivary gland biopsy should be performed first." (28) Guided biopsies are also quite informative and can facilitate earlier diagnosis. (6,9,28)
Cutaneous reaction to tuberculin was often negative (73% of cases). These results are in agreement with those of published studies. (6) A rise in ACE was observed in only 44.4% of cases in our series, 58% in that of Chapelon et al, (6) and 32% in that of Garret et al. (8) As the frequency of renal failure and diabetes is high in elderly subjects (thereby increasing ACE levels, especially in those with diabetic retinopathy (32)), the ACE assay is of little value in the diagnostic process. BAL and gallium citrate scintigraphy were rarely used in our series, but are of interest for the diagnosis of sarcoidosis. (6,8,33) BAL fluid was lymphocytic in intrathoracic sarcoidosis, even when the chest radiograph was normal (n = 1). (34) Hypergammaglobulinemia has been reported in sarcoidosis, (35) and lymphopenia is common, (36) as in our series. However, lymphopenia is not an efficient diagnostic tool because of numerous possible etiologies (tuberculosis, denutrition, etc.).
The disease was not always easy to control, but the results were generally satisfactory. Only two patients had clearly progressive disease (stage 4), and both died of a mediastinum-lung form, the major pathogenesis for sarcoidosis deaths. (3,37-39) The follow-up period was not yet sufficiently long for some stage III or IV patients. The disease course was considered satisfactory (improvement or stabilization) in 82% of eases in our series vs 82% (for 554 cases, all ages combined) in that of Chapelon et al. (6) Sixty-one percent of our patients received general corticosteroid therapy, which is comparable to data reported in studies concerning young patients. (6,8) The course of sarcoidosis in elderly subjects is probably no more critical than in the young, but treatment is required especially for severe cases of mediastinum-lung or extrapulmonary involvement. (40)
This retrospective series reviewed 30 cases of sarcoidosis in older persons treated over a 14-year period at the University Hospital in Nantes, France. Intrathoracic and systemic forms of sarcoidosis accounted for 63% of all clinical forms.
Sarcoidosis has a different presentation in elderly than young subjects. An alteration of general health is the major sign, except for intrathoracic forms in which pulmonary functional signs reveal the disease.
If sarcoidosis is suspected, an accessory salivary gland biopsy should be included in initial examinations, regardless of clinical form. This simple biopsy can clarify the diagnosis and avoid any need for more onerous investigations. Guided biopsies are also useful in the case of a clinical or morphologic abnormality. BAL, gallium scintigraphy, and antituberculous therapy can also be helpful in difficult cases.
Although the prognosis for sarcoidosis is life threatening in 27% of cases, organ involvement does not seem to be more severe in the older subject. The disease course is generally similar to that of young subjects, and stage IV intrathoracic forms and some types of organ involvement remain difficult to treat.
Thus, sarcoidosis is not a disease exclusively of the young. In older patients, suitable treatment leads to improvement or stabilization of the disease in > 80% of cases. Once the very particular clinical signs of the disease are recognized, the older patient can benefit from treatment and improved quality of life.
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* From the Federation of Geriatric Medecine, Department of Geriatric Medecine (Drs. Chevalet and Brisseau), Hopital Leon Bellier; and Departments of Geriatric Medecine (Drs. Clement and Rodat), Pathology (Dr. Moreau), and Pulmonary Diseases (Dr. Clarke), Nantes University Hospital, Nantes, France. Manuscript received April 22, 2003; revision accepted May 5, 2004.
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Correspondence to: Pascal Chevalet, MD, Department of Geriatric Medecine, Hopital Leon Bellier, 41 rue Curie, BP 84607, 44046 Nantes Cedex 1, France; e-mail: firstname.lastname@example.org
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