Pulmonary Pitfalls

Sarcoidosis: Protean Presentations and Pitfalls in Diagnosis

Nicholas I. Klimberg, MD1 • Samuel Louie, MD2 • Richart W. Harper, MD2-4

1Internal Medicine Residency Program, UC Davis Medical Center, Sacramento, California
2Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, UC Davis Medical Center, Sacramento, California
3Interstitial Lung Disease Specialty Clinic, UC Davis Health, Sacramento, California
4Sacramento VA Medical Center, VA Northern California Health Care System, Mather, California

Klimberg NI, Louie S, Harper RW. Sarcoidosis: protean presentations and pitfalls in diagnosis. Consultant. 2020;60(7):e11. doi:10.25270/con.2020.07.00003

The authors report no relevant financial relationships.

Samuel Louie, MD, UC Davis Medical Group Sacramento, 2825 J St, Ste 400, Sacramento, CA 95816 (sylouie@ucdavis.edu)


Sarcoidosis will remain a diagnostic challenge in the 21st century by virtue of its protean manifestations and presentations. Science has revealed that sarcoidosis is distinguished by acute and chronic Th1-mediated granulomatous inflammation, resulting in noncaseating epithelioid cell granulomas in multiple body organs. The difficulties in ascertaining a correct diagnosis have posed a clinical conundrum for clinicians since the ailment was called “Mortimer’s malady” by Dr. Jonathan Hutchinson in 19th-century England.1

A common pitfall is to overlook sarcoidosis as a diagnosis of exclusion.2 Experienced primary care providers may mistake a case of sarcoidosis for allergic conjunctivitis, lymphoma, lung cancer, or HIV after reviewing a chest radiograph,3 whereas an allergist may diagnose severe asthma after spirometry in the setting of dyspnea, wheezing, and cough. A dermatologist may first consider acne or psoriasis, whereas a cardiologist will presume congestive heart failure or atrioventricular block from coronary artery disease in the presence of chest pains. Chronic dyspnea and chronic dry cough are clearly not specific to sarcoidosis, which most often affects the lungs and/or the mediastinal lymph nodes.2,3 The ability to confidently diagnose sarcoidosis is complicated by a lack of definitive laboratory blood tests. The histologic presence of noncaseating granulomas from tissue biopsies (eg, transbronchial lung biopsies) has been the gold standard but also is nonspecific. The broad differential diagnosis of granulomatous lung disease mandates a reasonable clinical investigation before settling on sarcoidosis (Table 1).

Table 1

We present a case that highlights our diagnostic approach to sarcoidosis at UC Davis and the limitations of current assessment tools, including the Sarcoidosis Diagnostic Score (SDS) with a critical review on the utility of bronchoalveolar lavage fluid (BALF) evaluation, specifically the BALF CD4+ to CD8+ T-lymphocyte ratio (CD4/CD8 ratio).


Among the pitfalls to avoid in diagnosing sarcoidosis are the following:

  • Forgetting sarcoidosis in the differential diagnosis of chronic dyspnea in addition to other interstitial lung diseases, asthma, chronic obstructive pulmonary disease, and cardiomyopathy.
  • Overlooking extrapulmonary manifestations of sarcoidosis that can provide clues to a multiorgan disease or disorder.
  • Omitting the SDS for every suspected patient to promote diagnostic certainty.
  • Foregoing expert histopathologic examination of biopsy samples from affected tissues.
  • Overlooking the diagnostic yield of fiberoptic bronchoscopy with transbronchial lung biopsies, bronchoalveolar lavage (BAL), and endobronchial ultrasonography (EBUS) whenever intrathoracic lymphadenopathy is present.
  • Overestimating the value of the CD4/CD8 ratio in BALF in the quest to diagnose sarcoidosis.


At UC Davis, we integrate clinical and radiographic findings with histologic demonstration of noncaseating granulomas from tissue biopsies with the exclusion of other causes of granulomatous diseases to diagnose sarcoidosis. However, an underappreciated pitfall is that tissue biopsies can fail to confirm sarcoidosis even when clinical suspicion is high. Similarly, the presence of granulomas may be wrongly attributed to sarcoidosis when they are due to a different etiology that may not manifest until late in the patient’s clinical course. The inherent danger to patient safety under these circumstances is caused by a delay in achieving the correct diagnosis (eg, cancer, lymphoma), resulting in significant morbidity from improper treatment or adverse reactions from systemic corticosteroids meant for sarcoidosis.

To aid in diagnosing sarcoidosis, Bickett and colleagues developed the SDS that may help identify sarcoidosis vs other granulomatous diseases.4 Using a previously published sarcoidosis organ assessment instrument,5 patients were assigned points based on the presence of findings deemed “highly probable” or “at least probable” for the diagnosis of sarcoidosis. In the presence of a biopsy showing granulomatous inflammation, a biopsy SDS of greater than 6 points had a sensitivity of 99.3% and a specificity of 100%. In the absence of a biopsy, a clinical SDS greater than 4 had a lower sensitivity (76.9%) but a very high specificity (98.6%). Included in this organ assessment instrument is the use of BALF assessment of lymphocytic alveolitis and an elevated CD4/CD8 ratio.4


The diagnostic utility of BAL and T-cell subset analysis of aspirated BALF is underappreciated. The 1999 American Thoracic Society (ATS)/European Respiratory Society (ERS)/World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) combined statement on sarcoidosis6 and the 2012 ATS practice guidelines on BAL cellular analysis7 both concluded that BAL with a cell count of at least 15% and an increased CD4/CD8 T-lymphocyte ratio greater than 3.5, combined with appropriate clinical and radiological patterns, strongly support the diagnosis of sarcoidosis. A recent meta-analysis evaluated further the diagnostic utility of the CD4/CD8 ratio in sarcoidosis and reported a pooled sensitivity of 70% and a specificity of 83%.8

We present the case of a woman with clinical and radiological features of suggestive of sarcoidosis to serve as a practical example of the clinical conundrum and pitfalls that face clinicians today.


A 65-year-old woman was referred for a chronic cough and wheezing. She had no history of respiratory disease or cardiovascular disease. She denied smoking, alcohol use, and drug use. Her exposure history was notable for frequent naphthalene-containing mothball use. Despite removal of the mothballs from her home, she continued to experience frequent exacerbations marked by dyspnea.

She was diagnosed clinically with bronchial asthma and was trialed on various combinations of inhalers indicated for asthma treatment. Her symptoms improved notably with prednisone, but not with antibiotics or inhaler use, prompting further diagnostic workup. Infectious, autoimmune, and hypersensitivity evaluations were nondiagnostic. A contrast-enhanced high-resolution computed tomography (CT) scan of the chest demonstrated scattered fibrotic changes, interlobular septal thickening mostly in the upper lobes bilaterally and the right lower lobe, and mediastinal lymphadenopathy (Figure).


Fiberoptic bronchoscopy was performed with BAL of the lingula and transbronchial biopsies of the right lower lobe. BALF analysis was significant for a white blood cell count of 369/mL and a differential cell count of 3% neutrophils, 41% lymphocytes and 2% eosinophils. Flow cytometry of the lavage fluid demonstrated a CD4/CD8 ratio of 19. Biopsies did not demonstrate granulomas or inflammation; however, the tissue specimens were noted by the pathologist to be scant.

Based on her CT chest findings and BALF CD4/CD8 ratio, her biopsy SDS of 5, making sarcoidosis a reasonable diagnosis despite the nondiagnostic lung biopsy results.

She was started on maintenance oral corticosteroids, which led to improved control of her symptoms. However, a 6-month follow-up high-resolution CT of the chest demonstrated interval worsening with traction bronchiectasis. A right-sided video-assisted thoracoscopic surgical biopsy was performed, with tissue findings suggestive of emphysema and superimposed nonspecific interstitial pneumonia without granulomatous inflammation. Based on this, we concluded that her lung disease was related to continued naphthalene use or other environmental exposure and not pulmonary sarcoidosis.


This patient’s case highlights the pitfalls that invoke reluctance from pulmonologists to utilize BAL flow cytometry in patients with undiagnosed interstitial lung diseases; the patient was diagnosed with sarcoidosis based on a consistent clinical presentation and an elevated BALF CD4/CD8 ratio. Although expert society guidelines support the utility of the CD4/CD8 ratio in diagnosing sarcoidosis, this practice is not universally accepted. We believe that a more complete understanding of the patient factors that influence BALF analysis will improve the diagnostic utility of this test (Table 2).

Table 2

This patient had several features that may have falsely elevated the BAL CD4/CD8 ratio.

First, age is an important consideration specific to BALF analyses. Several studies have demonstrated that the normal aging lung is associated with an elevated CD4/CD8 ratio.22,25 The effect of age appears to be sex-dependent, with women having an increasing CD4/CD8 ratio with aging compared with men.23

The patient’s use of oral corticosteroids is an important confounder. Two small studies have demonstrated a decreased CD4/CD8 ratio after 6 months of oral corticosteroid treatment13 or have demonstrated a decrease in the CD4/CD8 ratio independent of the lymphocyte percentage after oral corticosteroid administration.26

One study demonstrated a significantly elevated BALF CD4/CD8 ratio in patients previously treated with oral corticosteroids compared to asymptomatic, untreated patients.12 Inhaled corticosteroid use appears to consistently lower CD4/CD8 ratios. Several studies have demonstrated a decrease in both BALF lymphocytosis and CD4/CD8 ratios after treatment with inhaled budesonide.15,27 We can conclude from these contradictory studies that the use of corticosteroids alters the lung immune response in unpredictable ways, making any interpretation of BALF differential cell counts unreliable if not unwarranted in the presence of confounding factors.

Patients with structural lung disease, and specifically bronchiectasis, have increased BALF CD4/CD8 ratios.24 These cellular changes were associated with increased expression of cytokines interleukin 8 (IL-8), IL-1β, IL-6, tumor necrosis factor α (TNF-α), and IL-12. Both IL-1β and TNF-α are important for lymphocyte recruitment. However, the reason for this persistently altered immune response in this patient population is unknown.

The frequent use of both oral and inhaled corticosteroids in our patient, her age, and the presence of traction bronchiectasis likely contributed to the significantly elevated CD4/CD8 ratio leading to the erroneous diagnosis of sarcoidosis with the SDS.

Other clinical features that are important to consider when interpreting the BALF CD4/CD8 ratio include smoking history, sarcoidosis activity, and stage of disease at the time of diagnostic testing. Multiple studies have demonstrated that tobacco smoke exposure lowers BALF CD4/CD8 ratios.9,10 Another study has demonstrated a significant difference in CD4/CD8 ratio between smokers and nonsmokers, specifically in stage 2 sarcoidosis.23 Studies have also demonstrated a decrease in lymphocytes on BALF cell differential in smokers compared with both nonsmokers and ex-smokers.28,29

Patients with symptomatic sarcoidosis have significantly higher CD4/CD8 ratios compared with asymptomatic patients.17-20 Staging is also important, with decreasing CD4/CD8 ratios correlating with increasing radiographic stage of disease.17 Therefore, in an undiagnosed, symptomatic patient with significant alveolitis on imaging, the CD4/CD8 ratio provides a higher level of diagnostic certainty if elevated or may prompt further testing if normal or reduced.

The SDS is a novel tool that may substantially improve our confidence in diagnosing sarcoidosis. Apprehension is a constant companion when making a diagnosis of sarcoidosis, and the SDS provides great hope that clinicians can have some level of assuredness before embarking on immunosuppressive drug therapies. Retrospective application of the SDS for the patient presented here (SDS of 5) suggests a likelihood ratio greater than 60 for the diagnosis of sarcoidosis.4 However, there are several caveats to the use of the SDS in this patient. First, the SDS does not appear to address negative lung biopsy results. Although the SDS was highly predictive in patients who did not have a biopsy, it likely does not apply in patients who had biopsies that were nondiagnostic. Next, the chest CT results had additional findings of peripheral reticulations and traction bronchiectasis. Although these features can be seen in sarcoidosis, the presence of atypical features may trump the scoring of highly probable features on chest CT. Finally, the SDS may have more power when the scoring is not isolated to one organ system. We presume that the presence of one “highly probable” feature and one “at least probable” feature both from the lung will have lower specificity than the same score derived from two different organ systems.


Sarcoidosis is protean in its presentations and requires a multimodal approach to diagnosis after excluding more common etiologies such as asthma. Transbronchial lung biopsy and lymph node biopsy remain the most common invasive procedure to discover noncaseating granulomas that can confirm the clinical diagnosis of sarcoidosis. BAL, while frequently performed during fiberoptic bronchoscopy, remains controversial in the diagnostic algorithm for sarcoidosis. Given potential confounding patient factors, the clinician and pulmonologist should exercise caution when interpreting BALF results in suspected cases of sarcoidosis. In the absence of confounders, BALF can be a valuable adjunct in the quest to diagnose sarcoidosis.


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