[
Chest Imaging and Pathology for Clinicians
]
A 66-Year-Old Woman With Fever, Cough, and a Tongue Lesion Viral Gandhi, MD; Amteshwar Singh, MD; Gail L. Woods, MD; and Oleg Epelbaum, MD, FCCP
A 66-year-old woman presented with acute onset of fever, chills, and productive cough associated with right-sided chest pain. During a recent hospitalization for dyspnea, she had been diagnosed with Coombs-positive autoimmune hemolytic anemia and had been taking a tapering dose of prednisone starting approximately 6 weeks prior to admission. In the interim, her dyspnea had resolved on treatment with steroids. At the time of presentation, her prednisone dose was 40 mg. Additional medical history included VTE, for which the patient was receiving anticoagulation therapy, and steroid-induced diabetes mellitus. Many years earlier, she had been treated for TB in her home country. The patient had immigrated to Queens, New York, from a Nepalese village 8 years prior. While still in Nepal, she had worked on a farm and had been in close proximity to cows. In Queens, she lived with her family in a house with a small garden but had no pets. Recent travel included a visit to Nepal 9 months ago and a trip to Syracuse, New York, one month prior to presentation. She was a never smoker and did not consume alcohol.
CHEST 2015; 147(4):e140-e147
On admission, she had normal hemodynamics, with a respiratory rate of 20 breaths/min and an oxygen saturation of 94% while breathing ambient air. Her temperature was 38.8°C. Physical examination revealed unlabored breathing with decreased breath sounds at the right base and crackles more cephalad. There was also a painless, 1-cm ulcer on the dorsum of the tongue (Fig 1). The remainder of the examination was unremarkable. CBC revealed a normal leukocyte and platelet count with a hemoglobin level of 11.2 g/dL. Serum sodium level was 132 mEq/L, and serum potassium level was 3.2 mEq/L. Serum creatinine concentration was 0.7 mg/dL. Liver function test results were normal. International normalized ratio was 3.7 with the
patient taking warfarin. Posteroanterior and lateral chest radiographs (Figs 2A, 2B) showed a dense opacity at the right lung base, obscuring the diaphragm. The previous posteroanterior and lateral chest radiographs taken about 6 weeks before were normal.
Manuscript received August 3, 2014; revision accepted December 10, 2014. AFFILIATIONS: From the Department of Internal Medicine (Dr Gandhi), and Division of Pulmonary and Critical Care Medicine (Dr Epelbaum), Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, Elmhurst, NY; Department of Internal Medicine (Dr Singh), Johns Hopkins University-Sinai Hospital, Baltimore, MD; and Division of Pediatric Pathology (Dr Woods), Arkansas Children’s Hospital, Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.
CORRESPONDENCE TO: Viral Gandhi, MD, Department of Internal Medicine, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, Elmhurst, NY 11373; e-mail: [email protected]. © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1858
e140 Chest Imaging and Pathology for Clinicians
The patient was started on cefepime and vancomycin for health-care-associated pneumonia. Prednisone was continued. Blood cultures and urine Legionella antigen testing were ultimately negative. Her subsequent hospital course was complicated by worsening anemia due to hemorrhoidal bleeding, which prompted cessation of anticoagulation and eventual hemorrhoidectomy. Two weeks into her hospital stay, she had recurrence of fever, this time with associated leukocytosis. Worsening right-sided opacification on chest radiography
[
147#4 CHEST APRIL 2015
]
prompted CT scan of the chest (Figs 2C, 2D), which revealed multilobar, dense consolidation with air bronchograms and foci of necrosis. There was no significant intrathoracic lymphadenopathy by CT scan criteria. Routine sputum cultures were positive only for Candida albicans. The tongue ulcer was scraped, and, at the same time, the patient underwent bronchoscopy with BAL and transbronchial biopsy. Ulcer scrapings, BAL fluid, and biopsy tissue were submitted for bacterial, fungal, and mycobacterial cultures. Biopsy tissue stained with hematoxylin and eosin (H&E) demonstrated granulomatous inflammation with numerous microorganisms (Figs 3A, 3B). Gomori methenamine silver and mucicarmine staining results are shown in Figures 3C and 3D.
Figure 1 – Necrotic ulcer, 1 cm in diameter, with heaped-up margins, found on the dorsum of the patient’s tongue.
Figure 2 – A, Posteroanterior chest radiograph showing dense opacification at the right lung base obscuring the diaphragm. B, Lateral chest radiograph. C, Axial CT scan of the chest showing multilobar, dense, masslike consolidation within which air bronchograms and a few scattered necrotic foci can be identified in the absence of proximal endobronchial obstruction or effusion. D, Coronal CT scan of the chest.
journal.publications.chestnet.org
e141
Figure 3 – A, Histology from a transbronchial biopsy specimen under low power showing granulomatous inflammation with a prominent cellular infiltrate (hematoxylin and eosin [H&E], original magnification 310). B, Higher magnification showing spherical organisms with refractile cell walls (red arrows) surrounding basophilic nuclei (white arrows) (H&E, original magnification 3100). C, Gomori methenamine silver stain with arrows pointing to several budding forms (original magnification 3100). D, The organisms demonstrated failure to stain with mucicarmine (original magnification 3100).
What is the diagnosis?
e142 Chest Imaging and Pathology for Clinicians
[
147#4 CHEST APRIL 2015
]
Diagnosis: Disseminated blastomycosis in a patient with impaired cell-mediated immunity Clinical Discussion
Blastomyces dermatitidis is unique among the endemic fungal infections in that it is virtually exclusive to North America. Historically, the highest incidence has been reported by the southern states, but the organism is also endemic to the Ohio and St. Lawrence River valleys as well as to the Great Lakes regions of the United States and Canada.1 The route of acquisition is inhalational following exposure to blastomycelial conidia, which tends to occur along waterways and via moist soil rich in decaying organic matter. Human contact with the organism is usually associated with recreational or occupational activities, and the classic predominance of male cases is thought to reflect societal roles rather than sex differences in susceptibility.2 Because the clinical manifestations of blastomycosis are so protean, this entity is a rare initial consideration, especially in the absence of a suggestive exposure history. Interestingly, failure to consider blastomycosis has even been reported by a medical center from an endemic region.3 Upon encountering yeast cells of Blastomyces in the alveoli, the host’s immune response is believed to neutralize the organism in the majority of exposed individuals, thus rendering the infection asymptomatic.4 When symptomatic infection does occur, the lung is the most commonly involved organ, where blastomycosis is one of the “great imitators.” The acute form of the disease is often mistaken for bacterial pneumonia, due to its presentation with rapid onset of fever, productive cough, dyspnea, and pleuritic pain. Miliary spread has been described, as have cases of ARDS.5,6 Chronic pulmonary blastomycosis, the more common form, evolves indolently and can mimic TB, reactivation of other endemic mycoses, and malignancy. In the majority of cases, the organism is able to evade lung immunity, resulting in extrapulmonary dissemination. Inclusion of blastomycosis on the list of so-called pulmonarycutaneous syndromes reflects the fact that skin is, by far, the most common distant site of involvement, observed in at least 20% of cases, followed by the osteoarticular and genitourinary systems.7,8 Verrucous lesions of cutaneous blastomycosis develop at sites of subcutaneous abscesses and can be mistaken for a variety of skin neoplasms.2 Ulcers of the skin and mucosal surfaces, including those of the tongue, are sequelae of external drainage of such abscesses.4 The various skin lesions of journal.publications.chestnet.org
blastomycosis, including tongue ulcers, are particularly attractive targets for sampling, due to their accessibility and the potential for an immediate clue to the diagnosis. It is likely that the diagnostic delay in the case we present could have been shortened by the prompt collection of an ulcer specimen. Table 1 lists various infectious, neoplastic, and inflammatory conditions that are capable of causing synchronous pulmonary and tongue lesions. Disease of the CNS takes the form of meningitis or mass lesions and likewise resembles other conditions. This patient’s history of corticosteroid use merits discussion of blastomycosis in the immunosuppressed individual. Cell-mediated immunity, more specifically the T-helper cell 1 response, is the primary line of defense against disease progression.9 Unlike that of histoplasmosis and coccidioidomycosis, however, dissemination of blastomycosis commonly occurs in the absence of immunosuppression. Nevertheless, the pattern and severity of disseminated infection in patients with AIDS and other forms of immunosuppression appear to differ from those of the normal host. CNS involvement, ordinarily a rare manifestation, has been reported with disproportionate frequency in the AIDS population.10 Thirty-four patients with non-HIV immunosuppressed blastomycosis were described in a series from the early 1990s and included almost as many cases of ARDS as had been published in the entire body of literature until that time.9 Miliary spread of blastomycosis has been reported after as brief a course of prednisone as 12 days of 30 mg daily.11 Of relevance to this patient, endogenous reactivation of blastomycosis in people born, but no longer residing, in endemic regions is known to occur in the setting of both AIDS and corticosteroid use.12,13 Mortality of untreated blastomycosis in the era prior to effective antifungal therapy was in the range of 60% to 80%. Thus, despite the possibility of spontaneous resolution, standard practice is to treat all cases. Amphotericin B (AmB) was the first agent that successfully cured blastomycosis. It was subsequently compared with a now-obsolete antifungal drug and proven to be superior in a prospective randomized trial—the only one of its kind in the realm of blastomycosis therapeutics.14 AmB remained the universal treatment of choice until the advent of the azole class of antifungal agents. Current guidelines recommend oral itraconazole for mild to moderate disease, with liposomal AmB reserved for severe cases and for immunocompromised hosts.15 It is customary to switch from AmB to itraconazole once clinical stability has been achieved and then treat for a e143
TABLE 1
] Conditions Capable of Causing Synchronous Lung and Tongue Lesions
Infectious
Neoplastic
Inflammatory
TB
Metastatic squamous cell carcinoma of the tongue
GPA
Disseminated blastomycosis
Metastatic leiomyosarcoma of the tongue
EGPA
Disseminated histoplasmosis
Lung malignancy metastatic to tongue
Amyloidosis
Chronic paracoccidioidomycosis
Extrapulmonary malignancy metastatic to tongue and lung
Sarcoidosis
Aspergillosis
Metastatic GCT of the oral cavity
Behçet disease
Zygomycosis
RRP
Caustic/thermal injury
Cystic echinococcosis
Paraneoplastic pemphigus
…
Actinomycosis
Lymphoma
…
EGPA 5 eosinophilic granulomatosis with polyangiitis; GCT 5 granular cell tumor; GPA 5 granulomatosis with polyangiitis; RRP 5 recurrent respiratory papillomatosis.
total of 6 to 12 months. Cure is the norm in treated blastomycosis; treatment failure, when it does occur, is usually due to overwhelming pulmonary involvement (eg, ARDS) early in the course of therapy. Advanced age, COPD, and African American ethnicity have been associated with increased mortality.8,16 Figure 4 depicts the various clinical syndromes associated with B dermatitidis infection and their salient characteristics. Radiologic Discussion
The radiographic manifestations of pulmonary blastomycosis are nonspecific, which contributes to the
frequent delays in diagnosis. On chest radiographs, the most commonly observed pattern of involvement in acute disease is airspace consolidation with air bronchograms and with or without cavitation.17-22 This often contributes to the initial misdiagnosis of acute blastomycosis as bacterial pneumonia. In immunocompromised hosts, a radiographic pattern such as the one seen in this case may also prompt consideration of rapidly progressive opportunistic pneumonia caused by such pathogens as mycobacteria, Nocardia species, Cryptococcus species, invasive molds, and other endemic fungi before the possibility of blastomycosis is entertained. Nodular and mass-like lesions are also
Figure 4 – Summary of the clinical syndromes associated with Blastomyces dermatitidis.
e144 Chest Imaging and Pathology for Clinicians
[
147#4 CHEST APRIL 2015
]
described and can be cavitary.19,20,22 Miliary involvement is seen less often, occurring in 5% to 28% of patients.5 The rare ARDS presentations will be accompanied by the diffuse bilateral infiltrates required for the diagnosis of that syndrome.6 Hilar lymphadenopathy and pleural effusions are unusual and are generally found alongside parenchymal involvement.23 If the presence of an associated pleural effusion is, in fact, suggested by plain radiography, advanced imaging such as CT scan or ultrasound should be performed immediately to exclude significant pleural involvement that might, on the one hand, require urgent drainage and, on the other, provide early and minimally invasive diagnostic material.24,25 Mass-like lesions and fibrocavitary disease are the characteristic findings of the chronic form of blastomycosis, which frequently first raise suspicion for neoplasia or more common indolent granulomatous diseases such as TB and histoplasmosis.17,21 Airspace and interstitial opacification can also occur; in fact, in one large series there was no statistically significant difference between acute and chronic presentations vis-à-vis these two radiographic patterns.22 The considerable radiographic overlap between the acute and chronic forms may be attributable, at least in part, to variable definitions of these terms across the case series. Studies examining the chest CT scan patterns of blastomycosis have not separated acute from chronic presentations, but have increased the reported frequency of masses, nodules, and intrathoracic lymphadenopathy.26,27 Aside from the superior imaging offered by CT scanning, greater detection of these lesions may reflect an inherent bias inasmuch as patients with plain radiographs concerning for neoplasia are more likely to be referred for
CT imaging than those with radiographs suggestive of bacterial pneumonia. Pathologic Discussion
B dermatitidis is a thermally dimorphic fungus, meaning that it exists as a mold at room temperature and as a yeast at body temperature. Conversion from the mold to the yeast form upon reaching the human alveoli is believed to be essential to its pathogenesis.1 The initial host response to B dermatitidis is neutrophilic, with eventual transition to pyogranulomatous inflammation (Fig 3A).4 In tissue stained with H&E, yeast cells of B dermatitidis are round, with basophilic nuclei; thick, double-contoured refractile cell walls; and characteristic broad-based buds (Figs 3B, 3C).28 These cells typically measure 10 to 12 mm in diameter, but, infrequently, micro forms 2 to 4 mm in diameter or larger cells 25 to 40 mm in diameter are encountered and, when present, may cause diagnostic confusion. The micro forms may resemble yeast cells of Histoplasma capsulatum, but the latter produce narrow-based buds and do not possess thick cell walls (Fig 5A). The larger, nonbudding cells of B dermatitidis may be difficult to distinguish from immature spherules of Coccidioides immitis. For definitive identification, several tissue sections should be examined, searching for the characteristic mature spherules of C immitis, which can measure up to 200 mm in diameter (Fig 5B), and for yeast cells with features typical of B dermatitidis, as described. In addition, cells of B dermatitidis are often weakly acid fast, whereas C immitis exhibits negative staining. Yeast cells of Cryptococcus neoformans are usually 8 to 12 mm in diameter, similar in
Figure 5 – A, Biopsy specimen from lung showing budding yeast cells of Histoplasma capsulatum (arrows) (Gomori methenamine silver, original magnification 3 100). B, Fine-needle aspirate of a lung nodule showing a spherule of Coccidiodes immitis (arrow) in a background of acute inflammatory cells (Papanicolaou, original magnification 3 100). C, Section of brain parenchyma showing the presence of Cryptococcus neoformans (arrows) (H&E, original magnification 3100). Inset: The capsule of the yeast cells stains strongly with mucicarmine (original magnification 3 100). See Figure 3 legend for expansion of abbreviation.
journal.publications.chestnet.org
e145
size to those of B dermatitidis; however, the former are distinguished by their thin cell walls, narrow-based buds, and a thick polysaccharide capsule that appears as a clear halo in H&E-stained tissue (Fig 5C). Additional tissue stains that are diagnostically helpful include mucicarmine, which stains the capsule of C neoformans red (Fig 5C, inset), and a melanin stain such as Fontana-Mason, which stains the cell wall of capsule-deficient strains brown. Both stains are negative with B dermatitidis.
whether the acute blastomycosis of this immunosuppressed individual represented endogenous reactivation of the organism brought to Queens from rural Nepal or new infection acquired during her recent trip to Syracuse, New York. The patient remained on azole therapy—having never received AmB—for approximately 12 months and was asymptomatic at treatment end. Her chest radiograph upon completion of therapy was significant only for residual pleural thickening.
Historically, efforts to use serologic testing for the diagnosis of blastomycosis have been hampered by poor sensitivity and specificity. More recently, advanced enzyme-linked immunosorbent assay techniques have enabled the rapid detection of B dermatiditis antigen in serum and urine samples. While specificity remains a problem due to cross-reactivity with H capsulatum, sensitivity has been reported to exceed 90%, as compared with the 77% seen with antibody detection by enzyme-linked immunosorbent assay.2
Acknowledgments
Culture yield in blastomycosis can exceed 90% but with the attendant disadvantage of delays in diagnosis, which can already be substantial in this disease.29 Fortunately, from a diagnostic perspective, organism burden, especially in immunocompromised patients, is frequently great enough to permit rapid identification of B dermatiditis by direct examination.4 Although a potassium hydroxide wet preparation of a respiratory specimen ought to be the shortest route to diagnosis, such a smear is not always performed and is positive in only 53% to 64% of cases.22,29,30 In fact, cytologic analysis has been shown to be not only more sensitive than microbiologic wet smears but also more expeditious.30 When biopsy tissue is available, as in this case, the characteristic morphologic features of B dermatiditis we have described may prove to be the first available clue to the diagnosis. It is worth noting that direct examinations of any type are not sensitive enough to reliably exclude blastomycosis when negative, while all such positive results remain presumptive until confirmed by culture.
Conclusions The patient was started on oral itraconazole for the presumptive diagnosis of blastomycosis, based on the findings from the bronchoscopic biopsy specimen. Her BAL cytology specimen likewise revealed yeast forms morphologically consistent with B dermatiditis. Subsequently, fungal cultures obtained from the tongue ulcer, BAL fluid, and bronchoscopic biopsy tissue all grew B dermatiditis, as well. It was unclear
e146 Chest Imaging and Pathology for Clinicians
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Bariola JR, Vyas KS. Pulmonary blastomycosis. Semin Respir Crit Care Med. 2011;32(6):745-753. 2. McKinnell JA, Pappas PG. Blastomycosis: new insights into diagnosis, prevention, and treatment. Clin Chest Med. 2009;30(2):227-239. 3. Lemos LB, Baliga M, Guo M. Blastomycosis: the great pretender can also be an opportunist. Initial clinical diagnosis and underlying diseases in 123 patients. Ann Diagn Pathol. 2002;6(3):194-203. 4. Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23(2):367-381. 5. Stelling CB, Woodring JH, Rehm SR, Hopper DW, Noble RC. Miliary pulmonary blastomycosis. Radiology. 1984;150(1):7-13. 6. Meyer KC, McManus EJ, Maki DG. Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med. 1993;329(17):1231-1236. 7. Lemos LB, Guo M, Baliga M. Blastomycosis: organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi. Ann Diagn Pathol. 2000;4(6):391-406. 8. Chapman SW, Lin AC, Hendricks KA, et al. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect. 1997;12(3):219-228. 9. Pappas PG, Threlkeld MG, Bedsole GD, Cleveland KO, Gelfand MS, Dismukes WE. Blastomycosis in immunocompromised patients. Medicine (Baltimore). 1993;72(5):311-325. 10. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1992;116(10):847-853. 11. Berger R, Kraman S. Acute miliary blastomycosis after ‘short-course’ corticosteroid treatment. Arch Intern Med. 1981;141(9):1223-1225. 12. Laskey W, Sarosi GA. Endogenous activation in blastomycosis. Ann Intern Med. 1978;88(1):50-52. 13. Ehni W. Endogenous reactivation in blastomycosis. Am J Med. 1989;86(6 pt 2):831-832. 14. Busey JF. Blastomycosis. 3. A comparative study of 2-hydroxystilbamidine and amphotericin B therapy. Am Rev Respir Dis. 1972;105(5):812-818. 15. Chapman SW, Dismukes WE, Proia LA, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(12):1801-1812. 16. Dworkin MS, Duckro AN, Proia L, Semel JD, Huhn G. The epidemiology of blastomycosis in Illinois and factors associated with death. Clin Infect Dis. 2005;41(12):e107-e111. 17. Cush R, Light RW, George RB. Clinical and roentgenographic manifestations of acute and chronic blastomycosis. Chest. 1976; 69(3):345-349.
[
147#4 CHEST APRIL 2015
]
18. Rabinowitz JG, Busch J, Buttram WR. Pulmonary manifestations of blastomycosis. Radiological support of a new concept. Radiology. 1976;120(1):25-32. 19. Halvorsen RA, Duncan JD, Merten DF, Gallis HA, Putman CE. Pulmonary blastomycosis: radiologic manifestations. Radiology. 1984;150(1):1-5. 20. Sheflin JR, Campbell JA, Thompson GP. Pulmonary blastomycosis: findings on chest radiographs in 63 patients. AJR Am J Roentgenol. 1990;154(6):1177-1180. 21. Brown LR, Swensen SJ, Van Scoy RE, Prakash UB, Coles DT, Colby TV. Roentgenologic features of pulmonary blastomycosis. Mayo Clin Proc. 1991;66(1):29-38. 22. Patel RG, Patel B, Petrini MF, Carter RR III, Griffith J. Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases. South Med J. 1999;92(3):289-295. 23. Failla PJ, Cerise FP, Karam GH, Summer WR. Blastomycosis: pulmonary and pleural manifestations. South Med J. 1995;88(4):405-410.
journal.publications.chestnet.org
24. Hargis JL, Bone RC, Miller FC, Wilson FJ. Pulmonary blastomycosis diagnosed by thoracocentesis. Chest. 1980;77(3):455. 25. Alvarez GG, Burns BF, Desjardins M, Salahudeen SR, AlRashidi F, Cameron DW. Blastomycosis in a young African man presenting with a pleural effusion. Can Respir J. 2006;13(8):441-444. 26. Winer-Muram HT, Beals DH, Cole FH Jr. Blastomycosis of the lung: CT features. Radiology. 1992;182(3):829-832. 27. Ronald S, Strzelczyk J, Moore S, et al. Computed tomographic scan evaluation of pulmonary blastomycosis. Can J Infect Dis Med Microbiol. 2009;20(4):112-116. 28. Graybill JR, Anstead GM, Queiroz-Telles F. The diagnosis of endemic mycoses. In: Maertens JA, Marr KA, eds. Diagnosis of Fungal Infections. New York, NY: Informa Healthcare USA, Inc; 2007:291-354. 29. Martynowicz MA, Prakash UBS. Pulmonary blastomycosis: an appraisal of diagnostic techniques. Chest. 2002;121(3):768-773. 30. Trumbull ML, Chesney TM. The cytological diagnosis of pulmonary blastomycosis. JAMA. 1981;245(8):836-838.
e147
Chest Imaging and Pathology for Clinicians
]
A 66-Year-Old Woman With Fever, Cough, and a Tongue Lesion Viral Gandhi, MD; Amteshwar Singh, MD; Gail L. Woods, MD; and Oleg Epelbaum, MD, FCCP
A 66-year-old woman presented with acute onset of fever, chills, and productive cough associated with right-sided chest pain. During a recent hospitalization for dyspnea, she had been diagnosed with Coombs-positive autoimmune hemolytic anemia and had been taking a tapering dose of prednisone starting approximately 6 weeks prior to admission. In the interim, her dyspnea had resolved on treatment with steroids. At the time of presentation, her prednisone dose was 40 mg. Additional medical history included VTE, for which the patient was receiving anticoagulation therapy, and steroid-induced diabetes mellitus. Many years earlier, she had been treated for TB in her home country. The patient had immigrated to Queens, New York, from a Nepalese village 8 years prior. While still in Nepal, she had worked on a farm and had been in close proximity to cows. In Queens, she lived with her family in a house with a small garden but had no pets. Recent travel included a visit to Nepal 9 months ago and a trip to Syracuse, New York, one month prior to presentation. She was a never smoker and did not consume alcohol.
CHEST 2015; 147(4):e140-e147
On admission, she had normal hemodynamics, with a respiratory rate of 20 breaths/min and an oxygen saturation of 94% while breathing ambient air. Her temperature was 38.8°C. Physical examination revealed unlabored breathing with decreased breath sounds at the right base and crackles more cephalad. There was also a painless, 1-cm ulcer on the dorsum of the tongue (Fig 1). The remainder of the examination was unremarkable. CBC revealed a normal leukocyte and platelet count with a hemoglobin level of 11.2 g/dL. Serum sodium level was 132 mEq/L, and serum potassium level was 3.2 mEq/L. Serum creatinine concentration was 0.7 mg/dL. Liver function test results were normal. International normalized ratio was 3.7 with the
patient taking warfarin. Posteroanterior and lateral chest radiographs (Figs 2A, 2B) showed a dense opacity at the right lung base, obscuring the diaphragm. The previous posteroanterior and lateral chest radiographs taken about 6 weeks before were normal.
Manuscript received August 3, 2014; revision accepted December 10, 2014. AFFILIATIONS: From the Department of Internal Medicine (Dr Gandhi), and Division of Pulmonary and Critical Care Medicine (Dr Epelbaum), Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, Elmhurst, NY; Department of Internal Medicine (Dr Singh), Johns Hopkins University-Sinai Hospital, Baltimore, MD; and Division of Pediatric Pathology (Dr Woods), Arkansas Children’s Hospital, Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.
CORRESPONDENCE TO: Viral Gandhi, MD, Department of Internal Medicine, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, Elmhurst, NY 11373; e-mail: [email protected]. © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1858
e140 Chest Imaging and Pathology for Clinicians
The patient was started on cefepime and vancomycin for health-care-associated pneumonia. Prednisone was continued. Blood cultures and urine Legionella antigen testing were ultimately negative. Her subsequent hospital course was complicated by worsening anemia due to hemorrhoidal bleeding, which prompted cessation of anticoagulation and eventual hemorrhoidectomy. Two weeks into her hospital stay, she had recurrence of fever, this time with associated leukocytosis. Worsening right-sided opacification on chest radiography
[
147#4 CHEST APRIL 2015
]
prompted CT scan of the chest (Figs 2C, 2D), which revealed multilobar, dense consolidation with air bronchograms and foci of necrosis. There was no significant intrathoracic lymphadenopathy by CT scan criteria. Routine sputum cultures were positive only for Candida albicans. The tongue ulcer was scraped, and, at the same time, the patient underwent bronchoscopy with BAL and transbronchial biopsy. Ulcer scrapings, BAL fluid, and biopsy tissue were submitted for bacterial, fungal, and mycobacterial cultures. Biopsy tissue stained with hematoxylin and eosin (H&E) demonstrated granulomatous inflammation with numerous microorganisms (Figs 3A, 3B). Gomori methenamine silver and mucicarmine staining results are shown in Figures 3C and 3D.
Figure 1 – Necrotic ulcer, 1 cm in diameter, with heaped-up margins, found on the dorsum of the patient’s tongue.
Figure 2 – A, Posteroanterior chest radiograph showing dense opacification at the right lung base obscuring the diaphragm. B, Lateral chest radiograph. C, Axial CT scan of the chest showing multilobar, dense, masslike consolidation within which air bronchograms and a few scattered necrotic foci can be identified in the absence of proximal endobronchial obstruction or effusion. D, Coronal CT scan of the chest.
journal.publications.chestnet.org
e141
Figure 3 – A, Histology from a transbronchial biopsy specimen under low power showing granulomatous inflammation with a prominent cellular infiltrate (hematoxylin and eosin [H&E], original magnification 310). B, Higher magnification showing spherical organisms with refractile cell walls (red arrows) surrounding basophilic nuclei (white arrows) (H&E, original magnification 3100). C, Gomori methenamine silver stain with arrows pointing to several budding forms (original magnification 3100). D, The organisms demonstrated failure to stain with mucicarmine (original magnification 3100).
What is the diagnosis?
e142 Chest Imaging and Pathology for Clinicians
[
147#4 CHEST APRIL 2015
]
Diagnosis: Disseminated blastomycosis in a patient with impaired cell-mediated immunity Clinical Discussion
Blastomyces dermatitidis is unique among the endemic fungal infections in that it is virtually exclusive to North America. Historically, the highest incidence has been reported by the southern states, but the organism is also endemic to the Ohio and St. Lawrence River valleys as well as to the Great Lakes regions of the United States and Canada.1 The route of acquisition is inhalational following exposure to blastomycelial conidia, which tends to occur along waterways and via moist soil rich in decaying organic matter. Human contact with the organism is usually associated with recreational or occupational activities, and the classic predominance of male cases is thought to reflect societal roles rather than sex differences in susceptibility.2 Because the clinical manifestations of blastomycosis are so protean, this entity is a rare initial consideration, especially in the absence of a suggestive exposure history. Interestingly, failure to consider blastomycosis has even been reported by a medical center from an endemic region.3 Upon encountering yeast cells of Blastomyces in the alveoli, the host’s immune response is believed to neutralize the organism in the majority of exposed individuals, thus rendering the infection asymptomatic.4 When symptomatic infection does occur, the lung is the most commonly involved organ, where blastomycosis is one of the “great imitators.” The acute form of the disease is often mistaken for bacterial pneumonia, due to its presentation with rapid onset of fever, productive cough, dyspnea, and pleuritic pain. Miliary spread has been described, as have cases of ARDS.5,6 Chronic pulmonary blastomycosis, the more common form, evolves indolently and can mimic TB, reactivation of other endemic mycoses, and malignancy. In the majority of cases, the organism is able to evade lung immunity, resulting in extrapulmonary dissemination. Inclusion of blastomycosis on the list of so-called pulmonarycutaneous syndromes reflects the fact that skin is, by far, the most common distant site of involvement, observed in at least 20% of cases, followed by the osteoarticular and genitourinary systems.7,8 Verrucous lesions of cutaneous blastomycosis develop at sites of subcutaneous abscesses and can be mistaken for a variety of skin neoplasms.2 Ulcers of the skin and mucosal surfaces, including those of the tongue, are sequelae of external drainage of such abscesses.4 The various skin lesions of journal.publications.chestnet.org
blastomycosis, including tongue ulcers, are particularly attractive targets for sampling, due to their accessibility and the potential for an immediate clue to the diagnosis. It is likely that the diagnostic delay in the case we present could have been shortened by the prompt collection of an ulcer specimen. Table 1 lists various infectious, neoplastic, and inflammatory conditions that are capable of causing synchronous pulmonary and tongue lesions. Disease of the CNS takes the form of meningitis or mass lesions and likewise resembles other conditions. This patient’s history of corticosteroid use merits discussion of blastomycosis in the immunosuppressed individual. Cell-mediated immunity, more specifically the T-helper cell 1 response, is the primary line of defense against disease progression.9 Unlike that of histoplasmosis and coccidioidomycosis, however, dissemination of blastomycosis commonly occurs in the absence of immunosuppression. Nevertheless, the pattern and severity of disseminated infection in patients with AIDS and other forms of immunosuppression appear to differ from those of the normal host. CNS involvement, ordinarily a rare manifestation, has been reported with disproportionate frequency in the AIDS population.10 Thirty-four patients with non-HIV immunosuppressed blastomycosis were described in a series from the early 1990s and included almost as many cases of ARDS as had been published in the entire body of literature until that time.9 Miliary spread of blastomycosis has been reported after as brief a course of prednisone as 12 days of 30 mg daily.11 Of relevance to this patient, endogenous reactivation of blastomycosis in people born, but no longer residing, in endemic regions is known to occur in the setting of both AIDS and corticosteroid use.12,13 Mortality of untreated blastomycosis in the era prior to effective antifungal therapy was in the range of 60% to 80%. Thus, despite the possibility of spontaneous resolution, standard practice is to treat all cases. Amphotericin B (AmB) was the first agent that successfully cured blastomycosis. It was subsequently compared with a now-obsolete antifungal drug and proven to be superior in a prospective randomized trial—the only one of its kind in the realm of blastomycosis therapeutics.14 AmB remained the universal treatment of choice until the advent of the azole class of antifungal agents. Current guidelines recommend oral itraconazole for mild to moderate disease, with liposomal AmB reserved for severe cases and for immunocompromised hosts.15 It is customary to switch from AmB to itraconazole once clinical stability has been achieved and then treat for a e143
TABLE 1
] Conditions Capable of Causing Synchronous Lung and Tongue Lesions
Infectious
Neoplastic
Inflammatory
TB
Metastatic squamous cell carcinoma of the tongue
GPA
Disseminated blastomycosis
Metastatic leiomyosarcoma of the tongue
EGPA
Disseminated histoplasmosis
Lung malignancy metastatic to tongue
Amyloidosis
Chronic paracoccidioidomycosis
Extrapulmonary malignancy metastatic to tongue and lung
Sarcoidosis
Aspergillosis
Metastatic GCT of the oral cavity
Behçet disease
Zygomycosis
RRP
Caustic/thermal injury
Cystic echinococcosis
Paraneoplastic pemphigus
…
Actinomycosis
Lymphoma
…
EGPA 5 eosinophilic granulomatosis with polyangiitis; GCT 5 granular cell tumor; GPA 5 granulomatosis with polyangiitis; RRP 5 recurrent respiratory papillomatosis.
total of 6 to 12 months. Cure is the norm in treated blastomycosis; treatment failure, when it does occur, is usually due to overwhelming pulmonary involvement (eg, ARDS) early in the course of therapy. Advanced age, COPD, and African American ethnicity have been associated with increased mortality.8,16 Figure 4 depicts the various clinical syndromes associated with B dermatitidis infection and their salient characteristics. Radiologic Discussion
The radiographic manifestations of pulmonary blastomycosis are nonspecific, which contributes to the
frequent delays in diagnosis. On chest radiographs, the most commonly observed pattern of involvement in acute disease is airspace consolidation with air bronchograms and with or without cavitation.17-22 This often contributes to the initial misdiagnosis of acute blastomycosis as bacterial pneumonia. In immunocompromised hosts, a radiographic pattern such as the one seen in this case may also prompt consideration of rapidly progressive opportunistic pneumonia caused by such pathogens as mycobacteria, Nocardia species, Cryptococcus species, invasive molds, and other endemic fungi before the possibility of blastomycosis is entertained. Nodular and mass-like lesions are also
Figure 4 – Summary of the clinical syndromes associated with Blastomyces dermatitidis.
e144 Chest Imaging and Pathology for Clinicians
[
147#4 CHEST APRIL 2015
]
described and can be cavitary.19,20,22 Miliary involvement is seen less often, occurring in 5% to 28% of patients.5 The rare ARDS presentations will be accompanied by the diffuse bilateral infiltrates required for the diagnosis of that syndrome.6 Hilar lymphadenopathy and pleural effusions are unusual and are generally found alongside parenchymal involvement.23 If the presence of an associated pleural effusion is, in fact, suggested by plain radiography, advanced imaging such as CT scan or ultrasound should be performed immediately to exclude significant pleural involvement that might, on the one hand, require urgent drainage and, on the other, provide early and minimally invasive diagnostic material.24,25 Mass-like lesions and fibrocavitary disease are the characteristic findings of the chronic form of blastomycosis, which frequently first raise suspicion for neoplasia or more common indolent granulomatous diseases such as TB and histoplasmosis.17,21 Airspace and interstitial opacification can also occur; in fact, in one large series there was no statistically significant difference between acute and chronic presentations vis-à-vis these two radiographic patterns.22 The considerable radiographic overlap between the acute and chronic forms may be attributable, at least in part, to variable definitions of these terms across the case series. Studies examining the chest CT scan patterns of blastomycosis have not separated acute from chronic presentations, but have increased the reported frequency of masses, nodules, and intrathoracic lymphadenopathy.26,27 Aside from the superior imaging offered by CT scanning, greater detection of these lesions may reflect an inherent bias inasmuch as patients with plain radiographs concerning for neoplasia are more likely to be referred for
CT imaging than those with radiographs suggestive of bacterial pneumonia. Pathologic Discussion
B dermatitidis is a thermally dimorphic fungus, meaning that it exists as a mold at room temperature and as a yeast at body temperature. Conversion from the mold to the yeast form upon reaching the human alveoli is believed to be essential to its pathogenesis.1 The initial host response to B dermatitidis is neutrophilic, with eventual transition to pyogranulomatous inflammation (Fig 3A).4 In tissue stained with H&E, yeast cells of B dermatitidis are round, with basophilic nuclei; thick, double-contoured refractile cell walls; and characteristic broad-based buds (Figs 3B, 3C).28 These cells typically measure 10 to 12 mm in diameter, but, infrequently, micro forms 2 to 4 mm in diameter or larger cells 25 to 40 mm in diameter are encountered and, when present, may cause diagnostic confusion. The micro forms may resemble yeast cells of Histoplasma capsulatum, but the latter produce narrow-based buds and do not possess thick cell walls (Fig 5A). The larger, nonbudding cells of B dermatitidis may be difficult to distinguish from immature spherules of Coccidioides immitis. For definitive identification, several tissue sections should be examined, searching for the characteristic mature spherules of C immitis, which can measure up to 200 mm in diameter (Fig 5B), and for yeast cells with features typical of B dermatitidis, as described. In addition, cells of B dermatitidis are often weakly acid fast, whereas C immitis exhibits negative staining. Yeast cells of Cryptococcus neoformans are usually 8 to 12 mm in diameter, similar in
Figure 5 – A, Biopsy specimen from lung showing budding yeast cells of Histoplasma capsulatum (arrows) (Gomori methenamine silver, original magnification 3 100). B, Fine-needle aspirate of a lung nodule showing a spherule of Coccidiodes immitis (arrow) in a background of acute inflammatory cells (Papanicolaou, original magnification 3 100). C, Section of brain parenchyma showing the presence of Cryptococcus neoformans (arrows) (H&E, original magnification 3100). Inset: The capsule of the yeast cells stains strongly with mucicarmine (original magnification 3 100). See Figure 3 legend for expansion of abbreviation.
journal.publications.chestnet.org
e145
size to those of B dermatitidis; however, the former are distinguished by their thin cell walls, narrow-based buds, and a thick polysaccharide capsule that appears as a clear halo in H&E-stained tissue (Fig 5C). Additional tissue stains that are diagnostically helpful include mucicarmine, which stains the capsule of C neoformans red (Fig 5C, inset), and a melanin stain such as Fontana-Mason, which stains the cell wall of capsule-deficient strains brown. Both stains are negative with B dermatitidis.
whether the acute blastomycosis of this immunosuppressed individual represented endogenous reactivation of the organism brought to Queens from rural Nepal or new infection acquired during her recent trip to Syracuse, New York. The patient remained on azole therapy—having never received AmB—for approximately 12 months and was asymptomatic at treatment end. Her chest radiograph upon completion of therapy was significant only for residual pleural thickening.
Historically, efforts to use serologic testing for the diagnosis of blastomycosis have been hampered by poor sensitivity and specificity. More recently, advanced enzyme-linked immunosorbent assay techniques have enabled the rapid detection of B dermatiditis antigen in serum and urine samples. While specificity remains a problem due to cross-reactivity with H capsulatum, sensitivity has been reported to exceed 90%, as compared with the 77% seen with antibody detection by enzyme-linked immunosorbent assay.2
Acknowledgments
Culture yield in blastomycosis can exceed 90% but with the attendant disadvantage of delays in diagnosis, which can already be substantial in this disease.29 Fortunately, from a diagnostic perspective, organism burden, especially in immunocompromised patients, is frequently great enough to permit rapid identification of B dermatiditis by direct examination.4 Although a potassium hydroxide wet preparation of a respiratory specimen ought to be the shortest route to diagnosis, such a smear is not always performed and is positive in only 53% to 64% of cases.22,29,30 In fact, cytologic analysis has been shown to be not only more sensitive than microbiologic wet smears but also more expeditious.30 When biopsy tissue is available, as in this case, the characteristic morphologic features of B dermatiditis we have described may prove to be the first available clue to the diagnosis. It is worth noting that direct examinations of any type are not sensitive enough to reliably exclude blastomycosis when negative, while all such positive results remain presumptive until confirmed by culture.
Conclusions The patient was started on oral itraconazole for the presumptive diagnosis of blastomycosis, based on the findings from the bronchoscopic biopsy specimen. Her BAL cytology specimen likewise revealed yeast forms morphologically consistent with B dermatiditis. Subsequently, fungal cultures obtained from the tongue ulcer, BAL fluid, and bronchoscopic biopsy tissue all grew B dermatiditis, as well. It was unclear
e146 Chest Imaging and Pathology for Clinicians
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Bariola JR, Vyas KS. Pulmonary blastomycosis. Semin Respir Crit Care Med. 2011;32(6):745-753. 2. McKinnell JA, Pappas PG. Blastomycosis: new insights into diagnosis, prevention, and treatment. Clin Chest Med. 2009;30(2):227-239. 3. Lemos LB, Baliga M, Guo M. Blastomycosis: the great pretender can also be an opportunist. Initial clinical diagnosis and underlying diseases in 123 patients. Ann Diagn Pathol. 2002;6(3):194-203. 4. Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23(2):367-381. 5. Stelling CB, Woodring JH, Rehm SR, Hopper DW, Noble RC. Miliary pulmonary blastomycosis. Radiology. 1984;150(1):7-13. 6. Meyer KC, McManus EJ, Maki DG. Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med. 1993;329(17):1231-1236. 7. Lemos LB, Guo M, Baliga M. Blastomycosis: organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi. Ann Diagn Pathol. 2000;4(6):391-406. 8. Chapman SW, Lin AC, Hendricks KA, et al. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect. 1997;12(3):219-228. 9. Pappas PG, Threlkeld MG, Bedsole GD, Cleveland KO, Gelfand MS, Dismukes WE. Blastomycosis in immunocompromised patients. Medicine (Baltimore). 1993;72(5):311-325. 10. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1992;116(10):847-853. 11. Berger R, Kraman S. Acute miliary blastomycosis after ‘short-course’ corticosteroid treatment. Arch Intern Med. 1981;141(9):1223-1225. 12. Laskey W, Sarosi GA. Endogenous activation in blastomycosis. Ann Intern Med. 1978;88(1):50-52. 13. Ehni W. Endogenous reactivation in blastomycosis. Am J Med. 1989;86(6 pt 2):831-832. 14. Busey JF. Blastomycosis. 3. A comparative study of 2-hydroxystilbamidine and amphotericin B therapy. Am Rev Respir Dis. 1972;105(5):812-818. 15. Chapman SW, Dismukes WE, Proia LA, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(12):1801-1812. 16. Dworkin MS, Duckro AN, Proia L, Semel JD, Huhn G. The epidemiology of blastomycosis in Illinois and factors associated with death. Clin Infect Dis. 2005;41(12):e107-e111. 17. Cush R, Light RW, George RB. Clinical and roentgenographic manifestations of acute and chronic blastomycosis. Chest. 1976; 69(3):345-349.
[
147#4 CHEST APRIL 2015
]
18. Rabinowitz JG, Busch J, Buttram WR. Pulmonary manifestations of blastomycosis. Radiological support of a new concept. Radiology. 1976;120(1):25-32. 19. Halvorsen RA, Duncan JD, Merten DF, Gallis HA, Putman CE. Pulmonary blastomycosis: radiologic manifestations. Radiology. 1984;150(1):1-5. 20. Sheflin JR, Campbell JA, Thompson GP. Pulmonary blastomycosis: findings on chest radiographs in 63 patients. AJR Am J Roentgenol. 1990;154(6):1177-1180. 21. Brown LR, Swensen SJ, Van Scoy RE, Prakash UB, Coles DT, Colby TV. Roentgenologic features of pulmonary blastomycosis. Mayo Clin Proc. 1991;66(1):29-38. 22. Patel RG, Patel B, Petrini MF, Carter RR III, Griffith J. Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases. South Med J. 1999;92(3):289-295. 23. Failla PJ, Cerise FP, Karam GH, Summer WR. Blastomycosis: pulmonary and pleural manifestations. South Med J. 1995;88(4):405-410.
journal.publications.chestnet.org
24. Hargis JL, Bone RC, Miller FC, Wilson FJ. Pulmonary blastomycosis diagnosed by thoracocentesis. Chest. 1980;77(3):455. 25. Alvarez GG, Burns BF, Desjardins M, Salahudeen SR, AlRashidi F, Cameron DW. Blastomycosis in a young African man presenting with a pleural effusion. Can Respir J. 2006;13(8):441-444. 26. Winer-Muram HT, Beals DH, Cole FH Jr. Blastomycosis of the lung: CT features. Radiology. 1992;182(3):829-832. 27. Ronald S, Strzelczyk J, Moore S, et al. Computed tomographic scan evaluation of pulmonary blastomycosis. Can J Infect Dis Med Microbiol. 2009;20(4):112-116. 28. Graybill JR, Anstead GM, Queiroz-Telles F. The diagnosis of endemic mycoses. In: Maertens JA, Marr KA, eds. Diagnosis of Fungal Infections. New York, NY: Informa Healthcare USA, Inc; 2007:291-354. 29. Martynowicz MA, Prakash UBS. Pulmonary blastomycosis: an appraisal of diagnostic techniques. Chest. 2002;121(3):768-773. 30. Trumbull ML, Chesney TM. The cytological diagnosis of pulmonary blastomycosis. JAMA. 1981;245(8):836-838.
e147
