Sarcoidosis, a systemic granulomatous disease with an unknown cause, often poses diagnostic challenges due to its ability to mimic various other conditions. These conditions include infections, neoplasms, autoimmune, cardiovascular, and drug-induced diseases. This article highlights common sarcoidosis mimics that can lead to diagnostic pitfalls and delays in appropriate treatment. Moreover, it touches upon the health impacts of the Deepwater Horizon (DWH) oil spill, emphasizing the importance of considering environmental factors in differential diagnoses.
Sarcoidosis: A Diagnostic Mimic
Jonathon Hutchinson, an English physician, first described sarcoidosis in 1877. Over the past few decades, significant progress has been made in defining the clinical, radiological, immunological, and pathological features of sarcoidosis. The diagnosis relies on three major criteria: clinical presentation compatible with sarcoidosis, the presence of non-necrotizing granulomatous inflammation in tissue samples, and the exclusion of alternative causes of granulomatous disease.
Infectious Mimics
Nearly all infectious causes of granulomas can resemble sarcoidosis. Therefore, excluding an infectious etiology must be routine and relies more on laboratory studies than differentiating clinical features. Sarcoidosis is an often overlooked cause of fever of unknown origin (FUO).
In developing countries with high tuberculosis (TB) burdens, diagnosing sarcoidosis can be particularly challenging. TB is classically characterized by caseating granulomas, while sarcoidosis has non-caseating epithelioid cell granulomas. However, when caseous necrosis is not seen and acid-fast staining of biopsy specimens is negative, a patient with suspected TB infection can be mistakenly diagnosed with sarcoidosis. In an endemic area, clinical judgment is crucial.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to obtain TB-PCR samples makes ruling out TB more certain. In a study by Eom et al., 86 specimens were examined in 46 patients, and the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were analyzed. EBUS-TBNA TB PCR was found to be 56%, 100%, for sensitivity and specificity, respectively. Positive and negative predictive values were 100%, and 81%. Diagnostic accuracy was 85%.
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Characterization of sonographic features of lymph nodes by an EBUS can also aid in differentiating TB-associated lymphadenopathy (LAD) from sarcoidosis. Dhooria et al. analyzed 250 EBUS-guided TBNA procedures in patients with intrathoracic LAD and found that sonographic features of heterogeneous echotexture and coagulation necrosis are suggestive of TB rather than sarcoidosis. Heterogeneous echotexture (53.4 vs. 12.6%, P < 0.001) and coagulation necrosis (26.1 vs. 3.3%; P < 0.001) are suggestive of TB rather than sarcoidosis. A combination of a positive tuberculin skin test (TST) and either heterogeneous echotexture or coagulation necrosis sign had a specificity of 98% and positive predictive value of 91% for a diagnosis of tuberculosis. Use of an interferon-γ (IFN-γ) release assay has been reported to demonstrate a better predictive ability than tuberculin skin tests.
An accurate and timely diagnosis of sarcoidosis helps prevent unnecessary antituberculosis therapy (ATT) drug exposure. An accurate diagnosis of TB prevents exposure to immunosuppressive agents.
The presence of exudative pleural effusions may favor other diagnoses. Pleural effusions associated with sarcoidosis are uncommon (8.2%) and can be present at the time of diagnosis or at a later time, coinciding with an exacerbation. These effusions are typically right-sided, exudative, and lymphocytic predominant. Eosinophilic and neutrophilic effusions have been reported but are less common. The presence of an exudative effusion in the setting of sarcoidosis warrants infectious workup e.g., parapneumonic effusion, or empyema. Patients on immunosuppressive agents are particularly susceptible to opportunistic infections. The failure of pleural effusions to respond to corticosteroid treatment should raise suspicion for an underlying opportunistic infection or other complications such as pulmonary embolism.
Environmental and Occupational Mimics
Chronic beryllium disease (CBD) is clinically and pathologically indistinguishable from sarcoidosis. CBD risk is associated with fluorescent light manufacturing and in industries such as nuclear energy, ceramics, aerospace, automotive, electronics, and telecommunications. Symptoms of CBD include dry cough, progressive dyspnea on exertion, fatigue, and night sweats. The radiological features vary with common chest CT findings including small nodules, ground-glass opacification, mild hilar adenopathy, and septal lines.
A diagnosis of CBD is favored over sarcoidosis when there is documented occupational exposure to beryllium. A diagnosis of CBD can be aided by the following three criteria: (1) symptomatic disease with a histopathological demonstration of non-caseating granuloma, pulmonary function impairment, and abnormal chest radiographs; (2) proof of beryllium sensitization by two independently positive beryllium lymphocyte proliferation assays (BeLPTs) in the absence of treatment with systemic corticosteroids for preceding 3 months, and (3) proof of beryllium exposure. Management of suspected CBD involves stopping all further exposure and continued clinical surveillance. Therapy with corticosteroids may be beneficial in selected patients, but the response is variable. Oral prednisone (doses ranging from 20 to 40 mg/day) for 3-6 months followed by a gradual taper to the lowest effective dose is deemed acceptable. Unfortunately, CBD is typically a progressive disease, and lifelong treatment may be required.
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Hypersensitivity pneumonitis (HP) has clinical, radiological, and histopathological features that overlap with sarcoidosis. HP pathogenesis results from a combination of immune complex-mediated (type III) and delayed-type (type IV) hypersensitivity reactions to antigen inhalation in a susceptible person. ACE may be elevated in 22% case. Features depend on subtype- non-fibrotic or fibrotic HP - GGO, mosaic attenuation, centrilobular nodules, fibrosis (irregular linear opacities; traction bronchiectasis and honeycombing) - Fibrosis is most severe in the mid or mid and lower lung zones or equally distributed in the three lung zones with relative basal sparing. The most common radiographic abnormalities include diffuse small round and reticular opacities. Small and poorly formed granulomas, comprising loose, poorly circumscribed clusters of epithelioid and multinucleated cells. Bronchiolocentric inflammation In Fibrotic HP-subpleural and centriacinar fibrosis, with or without bridging fibrosis. Removal from further exposure. HP can be categorized by disease duration into acute, subacute, and chronic subtypes. Raghu et al. The median age at diagnosis is 65 years, which is somewhat older than what is typical of sarcoidosis (20-39 years). Common presenting symptoms of HP include dyspnea, cough, wheezing, and, less frequently, constitutional symptoms such as weight loss. Physical examination may reveal the presence of rales.
The radiological features of HP depend upon the subtype. Typical radiologic features of non-fibrotic HP include high-resolution CT (HRCT) showing parenchymal infiltration with ground-glass opacities (GGO), and mosaic attenuation. HRCT may also demonstrate small airway disease, which can be described as ill-defined, small (<5 mm) centrilobular nodules on inspiratory images and air trapping on expiratory images, both in a diffuse distribution. Typical radiological features associated with fibrotic HP include an HRCT pattern of irregular linear opacities and or/coarse reticulation with lung distortion; traction bronchiectasis and honeycombing, all typical of lung fibrosis, and at least one abnormality that indicates small airway disease. The presence of three different lung densities, previously referred by radiologists as “head-cheese sign” and recently being referred to as the “three-density pattern,” is characteristically associated with HP.
Radiologically, granulomas associated with HP are interstitial and do not follow the lymphatics as in sarcoid. Also, sarcoidosis normally spares the lung bases. For both HP and advanced sarcoidosis, a prognosis-predicting factor is the extent of the fibrotic score calculated on HRCT scans. Further, HRCT can help differentiate active inflammation from fibrosis in patients with advanced-stage sarcoidosis. Honeycombing is uncommon in sarcoidosis but if present usually involves the middle and upper lung zones with relative sparing of the lung bases.
Bronchoalveolar lavage fluid (BALF) analysis of patients with HP reveals a predominance of lymphocytes, like sarcoidosis. A meta-analysis of 53 studies (3,112 patients) by Raghu et al. demonstrated that patients with HP had a higher proportion of BALF lymphocytes than patients with sarcoidosis (MD, 19%; 95% CI, 17-21%). This was found regardless of whether the study enrolled patients with non-fibrotic HP (17 studies; MD, 25%; 95% CI, 22-27%), fibrotic HP (16 studies; MD, 16%; 95% CI, 11-20%), or mixed populations with both non-fibrotic and fibrotic HP (21 studies; MD, 18%; 95% CI, 15-20%).
A diagnosis of HP can be made with high confidence in patients with an identified provocative exposure and who have a typical HP radiological pattern on HRCT and with BALF revealing predominant lymphocytosis. Treatment involves prompt and complete avoidance of further exposure to the inducer. Systemic corticosteroids are used in treatment however, their use has no effect on long-term outcomes and is often reserved for patients with more severe symptoms. Fibrotic HP is associated with worse prognosis particularly with persistent exposure to the inciting agent, cigarette smoking, lower baseline vital capacity, and lack of BALF lymphocytosis.
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Cardiovascular Mimics
When presented with a patient with sarcoidosis and worsening shortness of breath, an assessment for pulmonary embolism (PE) and pulmonary hypertension (PH) is warranted. Sarcoidosis, as with other chronic inflammatory conditions, has been associated with an increased risk of venous thromboembolism (VTE). Swigris et al. reported a greater than 2-fold higher risk of pulmonary embolism in patients with sarcoidosis when compared to the general population. In addition to PE, thrombosis secondary to localized inflammation has also been reported in the literature. Mural thrombosis in myocardial sarcoidosis, cerebral vein thrombosis in neurosarcoidosis and thoracic vein thrombosis in mediastinal sarcoidosis have all been reported.
While the precise mechanism is not yet defined, chronic inflammation associated with sarcoidosis likely predisposes to endothelial cell injury with the inflammatory cytokines activating the coagulation cascade. Extrinsic vascular compression at a mediastinal or hilar level may lead to venous stasis thus progressing to localized thrombosis. Up to 38% of sarcoidosis patients demonstrate the presence of antiphospholipid antibodies.
Fischer et al. reported elevated pulmonary-artery pressure in 6-23% of patients at rest and in as many as 43% with exertion. SAPH has been reported in up to 74% of patients with advanced sarcoidosis. In one case-series, Schorr et al. reported a 7-fold increased risk for death over a 3-year follow-up in patients with SAPH. Pulmonary fibrosis leading to obliteration of the pulmonary vessels is considered the most common mechanism for developing PH. SAPH is classified as World Health Organization (WHO) group 5 due to its complex and multifactorial mechanisms.
The optimal management for pulmonary hypertension in sarcoidosis is not well-defined. Along with treatment directed at active sarcoid inflammation (corticosteroid and steroid-sparing agents), therapy should focus on correcting hypoxia when present and managing comorbidities such as sleep apnea and cardiac dysfunction. Reduced diffusing capacity of the lung for carbon monoxide (DLCO) correlates with the severity of SAPH. Currently, the use of pulmonary hypertension specific therapy for the management of SAPH is controversial, and thus far pulmonary arterial hypertension specific therapies have not been approved. Lung transplantation may also be considered in this high risk group. A reduced DLCO (<35% predicted) and a 6MWD of <300 m are associated with worse transplant-free survival.
Neurological Mimics
Any part of the nervous system may be involved in sarcoidosis. Neurological involvement occurs in 5-15% of patients and often precedes the diagnosis of sarcoidosis in up to 74%. Neurosarcoidosis can mimic other neurologic diseases including neoplasm (lymphoma, metastasis), infectious etiologies (meningoencephalitis) and other inflammatory diseases (angiitis/vasculitis, demyelinating disorders). Neurosarcoidosis can present as multiple supratentorial and/or infratentorial masses (35%) or solitary masses (15%). The differential diagnosis includes gliomas, primary B cell lymphoma, metastatic disease, infarct, and demyelinating disease. Motor dysfunction is present in up to 50% of cases.
Cerebrospinal Fluid (CSF) findings in neurosarcoidosis may reveal elevated protein (50-70% of patients), elevated CSF pressure with a lymphocytic pleocytosis (57-72% of patients), and a reduced glucose level (up to 18% patients). None of these abnormalities are specific for neurosarcoidosis. Several studies evaluated the role of elevated CSF angiotensin-converting enzyme (ACE) level for diagnosing neurosarcoidosis. The sensitivity of CSF ACE varies depending on the location of the central nervous system (CNS) involvement. For example, higher levels are rarely seen with spinal cord involvement. The ACE assay is not a specific test as it can be elevated in bacterial and viral encephalitis, neurosyphilis, malignant CNS tumors, Huntington's disease, multiple sclerosis and neuroleptic-treated schizophrenic patients.
In suspected neurosarcoidosis associated aseptic meningitis, CSF should be sent for routine microbiological studies, fungal, and mycobacterium cultures, mycobacterium TB polymerase chain reaction (PCR). Cytology and flow cytometry should also be considered. Once the infection …
The Deepwater Horizon Oil Spill: A Case Study in Environmental Health Impacts
The Deepwater Horizon (DWH) oil spill, the largest in United States history, significantly impacted the health of people and communities in the Gulf of Mexico region. These impacts amplified adverse effects of prior disasters and may compound those of future traumas. Studies have shown some negative mental and physical health outcomes associated with DWH in some spill workers, as well as some coastal residents in all Gulf States. The spill was also associated with negative effects in the living resources, tourism, and recreation sectors, at least in the short term. Compared with others, people dependent on these sectors reported more health and financial concerns.
Consumer concerns about the safety and marketability of seafood persisted well after data demonstrated very low risk. Parents were concerned about possible exposures of children as they played on beaches, but this risk was found to be minor. Spill-related stress was an overarching factor associated with adverse health outcomes, and some residents reported greater stress from navigating the legal and claims processes following the spill than from the spill itself. Research revealed a serious lack of baseline health, environmental, and socioeconomic data against which to compare spill effects.
Large oil spills can adversely impact the health of responders, cleanup workers, and residents, and the public welfare of affected communities. The DWH spill also resulted in deaths of 11 oil industry workers. Physical and mental health effects have been reported and are closely related in disaster contexts, in part because environmental contamination results in significant stress. How people adapt to repeated exposure to stress depends on an array of psychological, sociodemographic, economic, social, physical, and other variables. Inhabitants of the Gulf region are particularly susceptible to oil spill health impacts due to widespread, preexisting health disparities, continuing exposure to contaminants, and location in a disaster-prone region.
Relatively few spills have been shown to directly and adversely affect human mental and/or physical health, although many may have socioeconomic, ecological, or other effects of concern. Whether any direct human effects occur from future spills will depend upon incident-specific conditions such as spilled oil type and volume, location, time of year, response actions, and safety and health protocols. Human susceptibilities to oil spill effects may be increased by pre-existing conditions, incident-specific and general life stressors, traumas, and previous disaster experience.
DWH impacts on individuals, families, groups, businesses, and communities were extensive, and they compounded negative effects of previous disasters such as Hurricane Katrina in the Gulf. In turn, these effects are likely to exacerbate traumas of subsequent disasters as well as ongoing threats from chemical pollution, oil seeps, and harmful algal blooms.
Oil spill response and cleanup workers (hereafter referred to as workers) can be exposed to a variety of hazards, including the oil and its components, burning oil, dispersants, and cleaning agents, plus mixtures of oil, dispersants, and other chemicals. Response to the Exxon Valdez oil spill led to many changes in oil spill preparedness, training, response, and worker safety and health, including use of personal protective equipment (PPE) in the United States and globally. Most studies of human health effects occurred in non-US countries where many workers from the community as well as volunteers engaged in oil spill cleanup with little protective gear. Studies that included pre-disaster health data were generally small, had shorter follow-up periods, and primarily investigated acute health symptoms. Acute health impacts were studied for up to one year after oil spill exposure in workers and affected community members to assess anxiety and post-traumatic stress, eye and skin irritation, and respiratory tract consequences.
Human health studies following the DWH spill, the largest of their kind in history, are ongoing. Two epidemiological studies examine effects on the health of workers: the NIEHS Gulf Long Term Follow-Up Study (GuLF STUDY) and the US Coast Guard (USCG) Deepwater Horizon Oil Spill Cohort study. The GuLF STUDY is assessing a range of human health effects, including worker access to mental health services. It uses extensive data on actual and estimated exposures and health outcomes derived from surveys, home visits, and clinical records. Such limitations as self-reporting errors, confounding factors, and potential biases are documented in all papers and are frequently investigated with sensitivity analyses. The full cohort includes 32,608 people. Approximately 25,000 of these were actual workers, and the remainder were non-workers for comparison (i.e., people who were trained but not hired). The period of oil spill work activities was from April 20, 2010, through June 2011. Workers performed a variety of tasks with different exposure profiles under the primary categories of response, support operations, cleanup on water, decontamination, cleanup on land, and administration.
The USCG cohort study consisted of 53,519 USCG personnel, 8,696 of whom responded to the spill and 44,823 who were not responders. The USCG study used health data from military medical encounters and cross-sectional survey data. Importantly, the USCG study can access a substantial amount of baseline health data for its participants, because medical data are available for all active-duty Coast Guard members from 2007 forward. For the study, exposure levels and symptoms were based on self-reported and clinical data from the total cohort. While many health studies use self-reported information, including for toxic exposures, such data can be subject to recall and other biases. To determine effects, physical health assessments evaluate elements of exposure pathways.
THC and BTEX are generally considered to be the more toxic components of oil. Primary exposure pathways to the oil, burning oil (particulates), and oil spill chemicals are inhalation and direct contact (skin and eye). Due to the way offshore and onshore air quality measurements and exposure estimates were made, reported or observed symptoms cannot be linked to a specific crude oil chemical. From available data, it appears that total hydrocarbon exposure levels for workers likely were low compared to occupational standards. However, an onshore study conducted from May 1 to September 30, 2010, assessed coastal ambient air quality for benzene and particulate concentrations (PM2.5) using air monitoring data from the US Environmental Protection Agency (EPA) and BP. The EPA’s Air Quality Index was compared prior to and during the spill. Onshore concentrations were generally higher following the spill, with benzene 2 to 19 times higher and PM2.5 10 to 45 times higher.
GuLF STUDY findings to date have included nonfatal and fatal heart disease and reduced lung function in some workers. Reduced lung function has been documented in workers exposed to oily plants and wildlife compared to unexposed workers. While Kwok et al. linked reduced lung function with adverse mental health outcomes, Gam et al. found no association of depression and post-traumatic stress with lung function. When Strelitz et al. compared individual workers involved in DWH cleanup work with non-workers, they found a positive association between several oil spill related exposures and an increased risk of nonfatal heart attacks one to three years post spill. Factors associated with oil spill work, such as heat, strenuous conditions, physical exertion, and the health limitations of the individual worker, make it difficult to ascertain whether the risk of heart disease can be related directly to exposure to oil spill pollutants. However, risk of heart disease has been associated with oil pollutants, cleanup activities, burned oil particulates, and volatile organic compounds. The emotional stress related to the spill was also a possible cause of increased physical health risks such as heart attacks. Other analyses suggest that physical health symptoms contribute to cleanup workers’ risk for mental health issues.
Dispersants warrant separate mention given the widespread public concern about their unprecedented use during DWH. Although studied for decades by oil spill scientists, dispersants remain a controversial response option. Because the measurements and support documentation related to the dispersants were insufficient to allow reliable estimation of exposure levels across the Gulf, the GuLF STUDY used responses to survey questions to assess dispersant exposure and estimated that about 10% of its cohort could have been exposed to dispersants. Although only 5% of the Coast Guard personnel who responded to the Deepwater Horizon Oil Spill Cohort study health questionnaire reported contact with both oil and dispersants, for example, through assignments to conduct Special Monitoring of Applied Oil Spill Technologies, self-reported adverse neurological health effects were worse for those workers than for those exposed only to oil, and heat exposure also exacerbated symptoms.
Human impacts of oil spills are much less studied than environmental impacts, physical health effects are better researched among spill workers than in other populations, and mental health distress is better researched among community residents. Oil and associated chemical components have a wide range of known or putative toxic outcomes, including endocrine disrupting, carcinogenic, cytotoxic, immunotoxic, mutagenic, and genotoxic effects. Physical health problems or indicators identified with oil exposure include assorted respiratory issues; irritation of skin, eyes, nose, throat; chest pain; cardiovascular disease; gastrointestinal complaints; headaches, dizziness, fatigue, memory issues; and abnormal blood cell counts and liver and kidney function tests. Laboratory experiments suggest that dispersant and dispersant-oil mixtures produce effects indicative of lung diseases such as asthma and chronic obstructive pulmonary disease and mixtures may affect the gut microbiome. Evidence for mental health distress associated with the DWH oil spill is mixed. Two large, population-based surveys in the Gulf Coast region suggest only modest or minimal changes in mental or behavioral health-at the aggregate level-before versus after the DWH spill. However, results across a range of other, more targeted studies indicate increased reports…