DIAGNOSTIC DILEMMA Aimee K. Zaas, MD Thomas J. Marrie, MD, Section Editors
Lost in the Woods: Granulomatosis with Polyangiitis Lindsay T. Fourman, MD, Amy G. Fogelman, MD Department of Medicine, Massachusetts General Hospital, Boston.
PRESENTATION The patient’s signs and symptoms initially suggested an infection, but after several evaluations it became clear that another process was at work. A 78-year-old woman was admitted to the hospital with a 5-month history of respiratory, ear, and nose complaints that were refractory to antibiotics and an unintentional weight loss of several pounds. She first presented to her primary care clinic after 5 days of rhinorrhea, cough, fevers, and night sweats. When questioned, she denied recent travel or sick contacts. A chest radiograph showed a patchy opacity in the right upper lobe and biapical pleural-parenchymal scarring. Given concern for reactivation tuberculosis, the patient was referred to the emergency department. Computed tomography (CT) of the chest showed bronchiectasis in the lingula and right lower lobe, tree-in-bud lingular nodules, mediastinal lymphadenopathy, and a patulous esophagus. She was discharged home with a 5-day regimen of azithromycin. Despite resolution of her symptoms, the patient soon experienced right-ear fullness and hearing loss, sinus congestion, and postnasal drainage. An otolaryngology evaluation identified a retracted and stiff right tympanic membrane with retrotympanic fluid. The Weber test lateralized to the right ear, whereas a Rinne test demonstrated that bone conduction was louder than air conduction on the right, indicating a right-sided conductive hearing loss. This was confirmed by audiology testing, which also showed a bilateral sensorineural hearing deficit (Figure 1). The patient underwent a 6-day methylprednisolone taper, and myringotomy of the right ear with suctioning of abundant serous fluid. One month before admission, the patient developed cough, fevers, and night sweats in the setting of continued Funding: None. Conflict of Interest: None. Authorship: All authors had a role in writing the manuscript. Requests for reprints should be addressed to Lindsay T. Fourman, MD, Massachusetts General Hospital, Department of Medicine, 55 Fruit Street, Boston, MA 02114. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.06.019
right ear fullness and impaired hearing. Surveillance chest CT demonstrated increased tree-in-bud opacities involving the lingula and bilateral lower lobes, enlarging mediastinal lymphadenopathy, and persistent bronchiectasis (Figure 2). Amoxicillin/clavulanate was prescribed empirically, but after 3 weeks of treatment she had no improvement in her symptoms. She then presented to our emergency department for further evaluation.
Figure 1 The audiogram plots the lowest-intensity sound the patient is able to detect at each frequency. Normal hearing is 10 to þ25 dB (shaded area), and speech frequencies typically range from 250 to 6000 Hz. Our patient had sloping to severe hearing loss in her right ear. Air conduction was worse than masked bone conduction, suggesting a significant conductive deficit. Bilateral moderate sensorineural hearing loss was also present, as was evidenced by the downward sloping of the masked bone conduction curves.
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2015
Figure 3 Indirect immunofluorescence demonstrated a perinuclear staining pattern that was confirmed by immunoassay for myeloperoxidase antibodies.
Figure 2 Computed tomography of the chest showed multifocal tree-in-bud opacities (T) and bronchiectasis (B).
ASSESSMENT On admission, the patient was febrile to 103 F (39.4 C) and tachycardic with a heart rate of 111 beats per minute. Her blood pressure and respirations were normal; oxygen saturation was 93% on room air. She was thin but did not appear toxic, and she had no petechiae, tenderness over the temporal arteries, palpable lymph nodes, heart murmurs, or abnormal lung sounds. Laboratory studies were notable for normal renal function (glomerular filtration rate, 79 mL/min) and mild anemia (hemoglobin, 9.7 g/dL). Inflammatory markers were elevated (erythrocyte sedimentation rate, 114 mm/h; C-reactive protein, 149.4 mg/L), with normal complement levels and negative antinuclear antibodies. Tests for human immunodeficiency virus antibodies, heterophile antibodies, cytomegalovirus IgM, Epstein-Barr virus IgM, and urine Legionella antigen were negative, as were the results of an interferon-g release assay and a viral respiratory panel. Blood, urine, and induced sputum cultures yielded no growth. A transthoracic echocardiogram showed no significant valvular disease or vegetations. Antineutrophil cytoplasmic antibodies (ANCAs) were positive with a perinuclear staining pattern (p-ANCA) (Figure 3). Enzyme-linked immunosorbent assay confirmed the presence of antibodies to myeloperoxidase, with an activity of 1332 U (positive, 2.8 U). Urinalysis showed 3þ blood, 2þ protein, and red blood cell casts on microscopy (Figure 4).
DIAGNOSIS Fevers, night sweats, and weight loss in an elderly woman almost invariably portend a poor prognosis if the etiology is not rapidly identified and treated. This patient’s
evolving respiratory and otorhinologic symptoms, along with her worsening tree-in-bud opacities on chest CT, helped to guide our differential diagnosis. However, given the insidious development of her illness and the involvement of multiple organ systems, it was not immediately clear whether all aspects of her case reflected a unifying diagnosis. Progression of tree-in-bud opacities on a background of scattered bronchiectasis correlated clinically with recrudescence of nonproductive cough and constitutional symptoms a month before hospitalization. The bronchiectasis seen on imaging may have represented an old injury from an antecedent infection or subacute damage due to ongoing immune activation. Alternatively, the branching, nodular pattern referred to as tree-in-bud opacities likely reflected an acute process, namely bronchiolar mucous impaction and
Figure 4 Urine microscopy was performed. The urine sediment contained red blood cell casts and dysmorphic red blood cells, suggestive of glomerulonephritis.
Fourman and Fogelman
Tree-in-Bud Opacities
peribronchiolar inflammation. In a retrospective study, treein-bud opacities were associated most often with pulmonary infections (72%) and aspiration (25%).1 Nontuberculous mycobacterial pulmonary disease was a major consideration in this patient’s case because it frequently presents with chronic cough and constitutional symptoms.2 A range of chest imaging findings have been reported, including cavitary lesions, nodules, air-space disease, and bronchiectasis, which is noted typically in the right middle lobe and lingula.3 Patients with nodular/bronchiectatic nontuberculous mycobacterial disease tend to be postmenopausal women with a thin body habitus, much like our patient.4 Her pattern of lung disease on chest CT, namely clusters of bronchiectasis and tree-in-bud opacities separated by regions of normal lung parenchyma, confers a specificity of 94% for nontuberculous mycobacterial infection.1 Although this entity accounts for many aspects of this patient’s presentation, 3 negative induced sputum cultures directed us to search for alternative etiologies. In addition to our patient’s respiratory complaints, we had to account for the hearing loss and sinus congestion that were prominent aspects of this case. Although it was possible that multiple disease processes were underway, her seemingly disparate symptoms and their staggered onset over many months prompted us to consider vasculitis as a unifying diagnosis. In particular, involvement of her upper airways made granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis, the most likely illness in the differential diagnosis. Granulomatosis with polyangiitis is a necrotizing, smallvessel vasculitis that most commonly affects the respiratory tract and kidney.5 In 1 prospective cohort of 158 patients with the disease, 90% first sought care for upper and/or lower airway symptoms. These problems were often attributed to allergy or infection, leading to a delay in diagnosis of more than 1 year in one-third of cases. Sinusitis, rhinorrhea, otitis media, and hearing loss were common presenting complaints.6 Renal involvement, a hallmark of disseminated disease, tended to occur later in the course of granulomatosis with polyangiitis.7 Serologic, radiologic, and histologic testing are useful adjuncts in the diagnosis of granulomatosis with polyangiitis. Detection of ANCAs using immunofluorescence and enzyme-linked immunosorbent assay yields a 96% sensitivity and 98.5% specificity for ANCA-associated vasculitis.5 Although cytoplasmic ANCAs (c-ANCAs) are a typical finding in patients with granulomatosis with polyangiitis, perinuclear ANCAs (p-ANCAs) occur in approximately 10% of those with the disorder.7 Pulmonary disease has protean manifestations on chest CT, including nodules, cavities, ground-glass opacities, and consolidation. Tree-in-bud opacities have been reported but are rare.8 Biopsies of affected tissues show a spectrum of pathology, including vasculitis, granulomas, and necrosis.7 Our patient’s progressive respiratory and otorhinologic symptoms led us to suspect granulomatosis with polyangiitis
3 early in her hospital course. Her constitutional complaints, elevated inflammatory markers, and normocytic anemia added nonspecific support for this diagnosis.6 More convincingly, p-ANCAs were detected on immunofluorescent staining of neutrophils and confirmed by high myeloperoxidase antibody titers. Chest CT showed tree-in-bud opacities that did not regress despite antibiotic therapy, and urine microscopy revealed red blood cell casts consistent with glomerulonephritis. When these findings were taken together, a diagnosis of disseminated granulomatosis with polyangiitis with ear, nose, lung, and renal involvement was made.
MANAGEMENT Prompt diagnosis and management of granulomatosis with polyangiitis is crucial. Whereas the average lifespan of an untreated individual is 1-2 years, immunosuppressive regimens can improve long-term morbidity and mortality substantially.6,9 In consultation with the nephrology service, we prescribed rituximab and a 6-month prednisone taper for our patient, and her symptoms quickly improved. We present the case of an elderly woman with disseminated granulomatosis with polyangiitis. By the time she was admitted to the hospital she had experienced 5 months of symptoms that had been evaluated by primary care, emergency medicine, pulmonary, and otolaryngology physicians. Each of her complaints was managed individually and ascribed to routine causes. Given that cough, sinusitis, and otitis media are often benign, this case served to remind us of the blind spot to which clinicians are prone when managing garden-variety complaints. Moreover, the fragmented nature of her course over time and organ systems tempted us to view it piecemeal rather than as a single process. Although it would be easy to get “lost in the woods,” this patient’s diagnosis relied on our ability to see the forest for the trees.
References 1. Miller WT Jr, Panosian JS. Causes and imaging patterns of tree-in-bud opacities. Chest. 2013;144:1883-1892. 2. Jarzembowski JA, Young MB. Nontuberculous mycobacterial infections. Arch Pathol Lab Med. 2008;132:1333-1341. 3. Moore EH. Atypical mycobacterial infection in the lung: CT appearance. Radiology. 1993;187:777-782. 4. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. 5. Lutalo PM, D’Cruz DP. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener’s granulomatosis). J Autoimmun. 2014;48-49:94-98. 6. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-498. 7. Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117:39-50. 8. Ananthakrishnan L, Sharma N, Kanne JP. Wegener’s granulomatosis in the chest: high-resolution CT findings. AJR Am J Roentgenol. 2009;192: 676-682. 9. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). Br Med J. 1958;2:265-270.
Lost in the Woods: Granulomatosis with Polyangiitis Lindsay T. Fourman, MD, Amy G. Fogelman, MD Department of Medicine, Massachusetts General Hospital, Boston.
PRESENTATION The patient’s signs and symptoms initially suggested an infection, but after several evaluations it became clear that another process was at work. A 78-year-old woman was admitted to the hospital with a 5-month history of respiratory, ear, and nose complaints that were refractory to antibiotics and an unintentional weight loss of several pounds. She first presented to her primary care clinic after 5 days of rhinorrhea, cough, fevers, and night sweats. When questioned, she denied recent travel or sick contacts. A chest radiograph showed a patchy opacity in the right upper lobe and biapical pleural-parenchymal scarring. Given concern for reactivation tuberculosis, the patient was referred to the emergency department. Computed tomography (CT) of the chest showed bronchiectasis in the lingula and right lower lobe, tree-in-bud lingular nodules, mediastinal lymphadenopathy, and a patulous esophagus. She was discharged home with a 5-day regimen of azithromycin. Despite resolution of her symptoms, the patient soon experienced right-ear fullness and hearing loss, sinus congestion, and postnasal drainage. An otolaryngology evaluation identified a retracted and stiff right tympanic membrane with retrotympanic fluid. The Weber test lateralized to the right ear, whereas a Rinne test demonstrated that bone conduction was louder than air conduction on the right, indicating a right-sided conductive hearing loss. This was confirmed by audiology testing, which also showed a bilateral sensorineural hearing deficit (Figure 1). The patient underwent a 6-day methylprednisolone taper, and myringotomy of the right ear with suctioning of abundant serous fluid. One month before admission, the patient developed cough, fevers, and night sweats in the setting of continued Funding: None. Conflict of Interest: None. Authorship: All authors had a role in writing the manuscript. Requests for reprints should be addressed to Lindsay T. Fourman, MD, Massachusetts General Hospital, Department of Medicine, 55 Fruit Street, Boston, MA 02114. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.06.019
right ear fullness and impaired hearing. Surveillance chest CT demonstrated increased tree-in-bud opacities involving the lingula and bilateral lower lobes, enlarging mediastinal lymphadenopathy, and persistent bronchiectasis (Figure 2). Amoxicillin/clavulanate was prescribed empirically, but after 3 weeks of treatment she had no improvement in her symptoms. She then presented to our emergency department for further evaluation.
Figure 1 The audiogram plots the lowest-intensity sound the patient is able to detect at each frequency. Normal hearing is 10 to þ25 dB (shaded area), and speech frequencies typically range from 250 to 6000 Hz. Our patient had sloping to severe hearing loss in her right ear. Air conduction was worse than masked bone conduction, suggesting a significant conductive deficit. Bilateral moderate sensorineural hearing loss was also present, as was evidenced by the downward sloping of the masked bone conduction curves.
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The American Journal of Medicine, Vol -, No -,
-
2015
Figure 3 Indirect immunofluorescence demonstrated a perinuclear staining pattern that was confirmed by immunoassay for myeloperoxidase antibodies.
Figure 2 Computed tomography of the chest showed multifocal tree-in-bud opacities (T) and bronchiectasis (B).
ASSESSMENT On admission, the patient was febrile to 103 F (39.4 C) and tachycardic with a heart rate of 111 beats per minute. Her blood pressure and respirations were normal; oxygen saturation was 93% on room air. She was thin but did not appear toxic, and she had no petechiae, tenderness over the temporal arteries, palpable lymph nodes, heart murmurs, or abnormal lung sounds. Laboratory studies were notable for normal renal function (glomerular filtration rate, 79 mL/min) and mild anemia (hemoglobin, 9.7 g/dL). Inflammatory markers were elevated (erythrocyte sedimentation rate, 114 mm/h; C-reactive protein, 149.4 mg/L), with normal complement levels and negative antinuclear antibodies. Tests for human immunodeficiency virus antibodies, heterophile antibodies, cytomegalovirus IgM, Epstein-Barr virus IgM, and urine Legionella antigen were negative, as were the results of an interferon-g release assay and a viral respiratory panel. Blood, urine, and induced sputum cultures yielded no growth. A transthoracic echocardiogram showed no significant valvular disease or vegetations. Antineutrophil cytoplasmic antibodies (ANCAs) were positive with a perinuclear staining pattern (p-ANCA) (Figure 3). Enzyme-linked immunosorbent assay confirmed the presence of antibodies to myeloperoxidase, with an activity of 1332 U (positive, 2.8 U). Urinalysis showed 3þ blood, 2þ protein, and red blood cell casts on microscopy (Figure 4).
DIAGNOSIS Fevers, night sweats, and weight loss in an elderly woman almost invariably portend a poor prognosis if the etiology is not rapidly identified and treated. This patient’s
evolving respiratory and otorhinologic symptoms, along with her worsening tree-in-bud opacities on chest CT, helped to guide our differential diagnosis. However, given the insidious development of her illness and the involvement of multiple organ systems, it was not immediately clear whether all aspects of her case reflected a unifying diagnosis. Progression of tree-in-bud opacities on a background of scattered bronchiectasis correlated clinically with recrudescence of nonproductive cough and constitutional symptoms a month before hospitalization. The bronchiectasis seen on imaging may have represented an old injury from an antecedent infection or subacute damage due to ongoing immune activation. Alternatively, the branching, nodular pattern referred to as tree-in-bud opacities likely reflected an acute process, namely bronchiolar mucous impaction and
Figure 4 Urine microscopy was performed. The urine sediment contained red blood cell casts and dysmorphic red blood cells, suggestive of glomerulonephritis.
Fourman and Fogelman
Tree-in-Bud Opacities
peribronchiolar inflammation. In a retrospective study, treein-bud opacities were associated most often with pulmonary infections (72%) and aspiration (25%).1 Nontuberculous mycobacterial pulmonary disease was a major consideration in this patient’s case because it frequently presents with chronic cough and constitutional symptoms.2 A range of chest imaging findings have been reported, including cavitary lesions, nodules, air-space disease, and bronchiectasis, which is noted typically in the right middle lobe and lingula.3 Patients with nodular/bronchiectatic nontuberculous mycobacterial disease tend to be postmenopausal women with a thin body habitus, much like our patient.4 Her pattern of lung disease on chest CT, namely clusters of bronchiectasis and tree-in-bud opacities separated by regions of normal lung parenchyma, confers a specificity of 94% for nontuberculous mycobacterial infection.1 Although this entity accounts for many aspects of this patient’s presentation, 3 negative induced sputum cultures directed us to search for alternative etiologies. In addition to our patient’s respiratory complaints, we had to account for the hearing loss and sinus congestion that were prominent aspects of this case. Although it was possible that multiple disease processes were underway, her seemingly disparate symptoms and their staggered onset over many months prompted us to consider vasculitis as a unifying diagnosis. In particular, involvement of her upper airways made granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis, the most likely illness in the differential diagnosis. Granulomatosis with polyangiitis is a necrotizing, smallvessel vasculitis that most commonly affects the respiratory tract and kidney.5 In 1 prospective cohort of 158 patients with the disease, 90% first sought care for upper and/or lower airway symptoms. These problems were often attributed to allergy or infection, leading to a delay in diagnosis of more than 1 year in one-third of cases. Sinusitis, rhinorrhea, otitis media, and hearing loss were common presenting complaints.6 Renal involvement, a hallmark of disseminated disease, tended to occur later in the course of granulomatosis with polyangiitis.7 Serologic, radiologic, and histologic testing are useful adjuncts in the diagnosis of granulomatosis with polyangiitis. Detection of ANCAs using immunofluorescence and enzyme-linked immunosorbent assay yields a 96% sensitivity and 98.5% specificity for ANCA-associated vasculitis.5 Although cytoplasmic ANCAs (c-ANCAs) are a typical finding in patients with granulomatosis with polyangiitis, perinuclear ANCAs (p-ANCAs) occur in approximately 10% of those with the disorder.7 Pulmonary disease has protean manifestations on chest CT, including nodules, cavities, ground-glass opacities, and consolidation. Tree-in-bud opacities have been reported but are rare.8 Biopsies of affected tissues show a spectrum of pathology, including vasculitis, granulomas, and necrosis.7 Our patient’s progressive respiratory and otorhinologic symptoms led us to suspect granulomatosis with polyangiitis
3 early in her hospital course. Her constitutional complaints, elevated inflammatory markers, and normocytic anemia added nonspecific support for this diagnosis.6 More convincingly, p-ANCAs were detected on immunofluorescent staining of neutrophils and confirmed by high myeloperoxidase antibody titers. Chest CT showed tree-in-bud opacities that did not regress despite antibiotic therapy, and urine microscopy revealed red blood cell casts consistent with glomerulonephritis. When these findings were taken together, a diagnosis of disseminated granulomatosis with polyangiitis with ear, nose, lung, and renal involvement was made.
MANAGEMENT Prompt diagnosis and management of granulomatosis with polyangiitis is crucial. Whereas the average lifespan of an untreated individual is 1-2 years, immunosuppressive regimens can improve long-term morbidity and mortality substantially.6,9 In consultation with the nephrology service, we prescribed rituximab and a 6-month prednisone taper for our patient, and her symptoms quickly improved. We present the case of an elderly woman with disseminated granulomatosis with polyangiitis. By the time she was admitted to the hospital she had experienced 5 months of symptoms that had been evaluated by primary care, emergency medicine, pulmonary, and otolaryngology physicians. Each of her complaints was managed individually and ascribed to routine causes. Given that cough, sinusitis, and otitis media are often benign, this case served to remind us of the blind spot to which clinicians are prone when managing garden-variety complaints. Moreover, the fragmented nature of her course over time and organ systems tempted us to view it piecemeal rather than as a single process. Although it would be easy to get “lost in the woods,” this patient’s diagnosis relied on our ability to see the forest for the trees.
References 1. Miller WT Jr, Panosian JS. Causes and imaging patterns of tree-in-bud opacities. Chest. 2013;144:1883-1892. 2. Jarzembowski JA, Young MB. Nontuberculous mycobacterial infections. Arch Pathol Lab Med. 2008;132:1333-1341. 3. Moore EH. Atypical mycobacterial infection in the lung: CT appearance. Radiology. 1993;187:777-782. 4. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367-416. 5. Lutalo PM, D’Cruz DP. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener’s granulomatosis). J Autoimmun. 2014;48-49:94-98. 6. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-498. 7. Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117:39-50. 8. Ananthakrishnan L, Sharma N, Kanne JP. Wegener’s granulomatosis in the chest: high-resolution CT findings. AJR Am J Roentgenol. 2009;192: 676-682. 9. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). Br Med J. 1958;2:265-270.
