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A Woman in Her 80s With Weakness, Hypoxia, and Bone Marrow Granulomas FREE TO VIEW

Atul K. Mehta, MD; Sudhir Krishnan, MD; Anil Kumar Changarath Vijayan, MD
Author and Funding Information

CORRESPONDENCE TO: Atul K. Mehta, MD, Department of Internal Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4):e119-e122. doi:10.1016/j.chest.2015.10.080
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A white woman in her 80s presented to the ED with nonproductive cough, fever, and 2 weeks of progressive generalized weakness. Previously ambulatory, she now was so weak she required assistance out of bed.

Figures in this Article

The patient's medical history was relevant for coronary artery disease and severe aortic stenosis after coronary artery bypass grafting with aortic valve replacement and recently detected pancytopenia.

A bone marrow biopsy performed 1 week before to explore the patient’s pancytopenia revealed normocellular marrow with trilineage hematopoiesis and nonnecrotizing granulomas with associated small lymphocyte aggregates (Fig 1). Flow cytometry and fluorescence in situ hybridization scans were negative for lymphoproliferative and myelodysplastic disorders although flow cytometry shows T-cell predominance to the lymphocyte population. Staining for tuberculosis and fungal infections were negative but were limited owing to poor cellularity and a lack of granulomas in the deeper sections of the samples.

Figure Jump LinkFigure 1 Nonnecrotizing granuloma with lymphoid aggregates (arrow) (hematoxylin and eosin stain, original magnification ×10).Grahic Jump Location

Vitals signs upon presentation were: BP, 138/48 mm Hg; heart rate 88 beats per min; respiratory rate, 26 breaths per min; oxygen saturation, 91% on room air; and temperature, 38°C. Soon after presentation, the patient’s oxygen saturation declined rapidly and required high-flow supplemental oxygen. Pulmonary examination revealed accessory muscle use and bilateral rales. Cardiovascular examination showed no jugular venous distension, regular rhythm, no S3 or S4, and 1 to 2+ pitting edema in both lower extremities. Neurologic examination demonstrated intact cranial nerves, no focal deficits, and intact strength.

WBC count was 2,680/μL, platelet count was 87,000/μL, hemoglobin level was 9.0 g/dL, C-reactive protein level was 3.3 mg/dL, erythrocyte sedimentation rate (ESR) was 22 mm/h, alkaline phosphatase level was 213 U/L, serum albumin level was 2.3 g/dL, and serum calcium level was 11 mg/dL. Urinalysis was normal.

Chest radiograph showed bilateral lung airspace disease, vascular congestion, and small pleural effusions (Fig 2). CT chest revealed nonsignificant lymphadenopathy in the aortopulmonary window, mild bilateral lung base opacities, and small bilateral pleural effusions. CT abdomen/pelvis showed mild splenomegaly. Echocardiography revealed an ejection fraction of 75% with grade 1 diastolic dysfunction.

Figure 2
Figure Jump LinkFigure 2 Anteroposterior chest radiograph image taken upon patient’s presentation. AP = anteroposterior.Grahic Jump Location

In addition, antinuclear antibody was negative and serum angiotensin-converting enzyme was <9 U/L. Ionized calcium level was 1.57 mmol/L, 1,25-dihydroxyvitamin D level was 69.1 pg/mL, parathyroid hormone level was 11 pg/mL, and parathyroid hormone-related protein level was 0.7 pmol/L. Protein electrophoresis and globulin levels were normal.

Blood cultures and histoplasmosis antigen were negative and interferon-gamma release assay for tuberculosis was indeterminate.

What conditions may explain the patient’s presentation?

Answer: Granulomatous lesions of unknown significance (GLUS) syndrome and sarcoidosis.

Finding a granuloma during an investigation of a patient’s condition is both a pivotal clue and a sobering challenge owing to the wide breadth of granulomatous disorders: malignancy, infection, environment, autoimmunity, vasculitis, and idiopathic or miscellaneous conditions.

GLUS syndrome (previous known as idiopathic granulomatosis fever) is a systemic disease consisting of prolonged fevers and granulomas observed on biopsy. The overall incidence is not clear, but in the more commonly biopsied sites (including the liver, spleen, lymph nodes, and/or bone marrow), it is estimated that 15% to 20% of all discovered granulomas result from GLUS syndrome. The true nature of the causes and pathophysiology of GLUS syndrome is unknown. It is theorized that an infectious cause could be the triggering event but no established link has been discovered. Because GLUS syndrome has similarities to autoimmune processes such as sarcoidosis, it is plausible that it is also driven by a hypersensitivity reaction.

Clinical features include fever, abdominal pain, anorexia, and weight loss with mild hepatomegaly or splenomegaly found on physical examination. Common but nondiagnostic markers include anemia, elevated alkaline phosphatase, elevated ESR, and hypergammaglobinemia. Biopsies suggestive of GLUS syndrome show epithelioid cell granulomas with or without necrosis often in association with B-cell lymphocytes. For the diagnosis of GLUS syndrome, the patient must have common clinical features in addition to granulomas on biopsy that are suggestive of GLUS. In addition, other common causes of granulomas must be excluded via histopathologic, microbiologic, serologic, and biochemical testing.

Although a treatment regimen has not been established, glucocorticoids were found to have the greatest clinical response as well as a very rapid one (especially the fevers), and are often used for initial treatment. After diagnosis, the usual course tends to have remissions and exacerbations. The syndrome classically is benign because it commonly lacks organ infiltration, but there is a case of confirmed GLUS syndrome in which chest radiograph images revealed bilateral hilar lymphadenopathy and pulmonary opacities.

Extrapulmonary sarcoidosis is close on the differential diagnosis to GLUS syndrome. Similarly, it can present with lymphadenopathy, splenomegaly, hepatomegaly, and abnormal blood counts. However, unlike GLUS syndrome, elevated serum calcium, 1,25-dihydroxyvitamin D, and angiotensin-converting enzyme are common findings in sarcoidosis although they are not specific or sensitive enough to clarify the diagnosis. In contrast to GLUS syndrome, thoracic imaging of sarcoidosis shows not just lymphadenopathy but also progressive parenchymal disease as sarcoidosis advances. Sarcoidosis is typically associated with histologic findings of noncaseating granulomas that are deficient in B cells and are associated with T-cell lymphocytes. Glucocorticoids, the standard of therapy for sarcoidosis, are often used to treat exacerbation with the duration sometimes prolonged; its actions on the disease can be variable in onset and degree in different patients.

Clinical Course

The patient was initially treated for pneumonia and acute decompensated heart failure concurrently owing to the presence of hypoxia, pulmonary infiltrates, and fever. Despite intervention, she continued to have fevers and escalating hypoxia prompting admission to the ICU. Echocardiography was not suggestive of decompensated heart failure, and infectious workup was negative. Considering the lack of clinical improvement with treatments, alternative diagnoses were explored to better explain the symptoms and investigative findings.

The case presented here has features that suggest GLUS syndrome, such as fever, anemia, and splenomegaly. The bone marrow biopsy revealed noncaseating granulomas with associated lymphocyte aggregates, but the lymphocytes could not be characterized further to allow differentiation between GLUS syndrome and sarcoidosis. It is unique that the patient presented with weakness but also hypoxia and elevated serum calcium and 1,25-dihydroxyvitamin D, all of which are more consistent with sarcoidosis than with GLUS syndrome. CT imaging of the chest revealed nonspecific lymphadenopathy and airspace disease, which is uncommon but has been reported for GLUS syndrome. Flow cytometry and FISH ruled out malignancies. Infectious workup, although not exhaustive, eliminated more likely causes of infectious granulomas in the patient. With so many overlapping features, it was difficult to distinguish GLUS syndrome and extrapulmonary sarcoidosis.

The patient declined a bronchoscopy. She empirically began receiving 1 mg/kg prednisone. Over the next 48 h, her respiratory status improved rapidly and the fevers dissipated, which is a characteristic response in GLUS syndrome. The patient was soon discharged on with the dosage of prednisone tapered off over 3 weeks.

Upon follow-up, the patient was found to have improvement of anemia and complete resolution of leukopenia and thrombocytopenia. Respiratory status had also returned to normal but fatigue and weakness still lingered.

  • 1.

    GLUS syndrome is characterized by prolonged fevers and epithelioid cell granulomas with or without necrosis; diagnosis is made after eliminating other common causes of granulomas.

  • 2.

    Laboratory findings suggestive of GLUS syndrome include anemia, elevated alkaline phosphatase, elevated ESR, and hypergammaglobinemia.

  • 3.

    Although a treatment plan is not yet established for GLUS syndrome, glucocorticoids appear to be the cornerstone of the regimen, with symptoms characteristically remitting quickly.

  • 4.

    Extrapulmonary sarcoidosis is close on the differential diagnosis to GLUS syndrome, with cellular analysis helping to distinguish between B-cell lymphocytes associated with granulomas of GLUS syndrome compared with T-cell lymphocytes associated with granulomas of sarcoidosis.

Financial/nonfinancial disclosures: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.


Figure Jump LinkFigure 1 Nonnecrotizing granuloma with lymphoid aggregates (arrow) (hematoxylin and eosin stain, original magnification ×10).Grahic Jump Location
Figure Jump LinkFigure 2 Anteroposterior chest radiograph image taken upon patient’s presentation. AP = anteroposterior.Grahic Jump Location



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