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A 45-Year-Old Woman With 3 Weeks of Cough and Night Sweats FREE TO VIEW

Than Htaik Kyaw, MD; Lacey Sullivan, MD; Ross C. Klingsberg, MD
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CORRESPONDENCE TO: Than Htaik Kyaw, MD, Department of Pulmonary and Critical Care, Tulane University School of Medicine, 1430 Tulane Ave, SL 9, New Orleans, LA 70112


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


Chest. 2016;149(3):e87-e90. doi:10.1016/j.chest.2015.08.014
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A 45-year-old woman who received a renal transplant 7 years prior presented with a 3-week history of low-grade fever, night sweats, and a dry cough with scant sputum production. Additionally, she reported generalized weakness and increased fatigability. She denied hemoptysis or weight loss, and there had been no change in medication or foreign travel. She had no history of latent tuberculosis or sick contacts. She had recently relocated to Baton Rouge, Louisiana. She was sexually active with her boyfriend who worked as a prison guard. She also reported that she was briefly incarcerated 7 years ago shortly after her renal transplantation. Her immunosuppression consisted of tacrolimus, mycophenolate, and prednisone.

Figures in this Article

Vital signs on admission were within normal range except for a temperature of 38.3°C. She appeared as a middle-aged woman in no apparent distress. There was no neck stiffness, jugular venous distension, or cervical lymphadenopathy. Heart and lung examination were unremarkable. Abdomen was without tenderness or organomegaly. Extremities were without edema, clubbing, or cyanosis. There were no rashes or cutaneous lesions. She was awake and alert with no focal neurological findings.

CBC was notable only for a hemoglobin concentration of 7.6 g/dL and a complete metabolic profile was notable only for a sodium concentration of 131 mmol/L. Autoimmune serologies were also negative and erythrocyte sedimentation rate was normal. Routine bacterial cultures of blood, urine, and sputum were negative. Sputum for acid-fast bacilli was also negative. Also negative were Epstein-Barr virus polymerase chain reaction, BK virus polyoma quantitative polymerase chain reaction, HIV-1 antibody, human T-cell lymphotropic virus I/II antibody, and parvovirus B18 DNA.

Because of the miliary appearance of nodules on chest radiograph and CT scan (Figs 1, 2), the patient’s immunosuppressed state, and the presence of TB risk factors, she was placed in respiratory isolation and a four-drug anti-TB regimen was begun. QuantiFERON Gold TB test and purified protein derivative were obtained and were reported as negative.

Figure 1
Figure Jump LinkFigure 1 Chest radiograph on admission demonstrating diffuse, bilateral tiny nodular lesions of the lungs in a miliary pattern of distribution.Grahic Jump Location
Figure 2
Figure Jump LinkFigure 2 CT scan lung window demonstrating diffuse micronodules in a miliary pattern of distribution.Grahic Jump Location

Two days later, her clinical condition worsened and her supplemental oxygen requirement increased from ambient air to 3 L/min. A bronchoscopic right middle lobe transbronchial needle aspiration and BAL were performed (Figs 3,4,5).

Figure 3
Figure Jump LinkFigure 3 Hematoxylin and eosin stain ×20 from the transbronchial biopsy.Grahic Jump Location
Figure 4
Figure Jump LinkFigure 4 Periodic acid–Schiff stain ×40.Grahic Jump Location
Figure 5
Figure Jump LinkFigure 5 Grocott methenamine silver stain ×40.Grahic Jump Location

What is the diagnosis?

Diagnosis: Pulmonary blastomycosis with miliary pattern

Blastomyces dermatitidis is a dimorphic fungus that is endemic to certain parts of North America, with very rare reports from other parts of the world. The endemic regions for Blastomyces dermatitidis have included areas along the Mississippi, Ohio, and St Lawrence rivers as well as areas bordering the Great Lakes in Canada and New York. Cell-mediated immunity and production of type I cytokines are the main defenses against pathogenic fungi. Although there does not appear to be an increased rate of blastomycosis in patients who are immunosuppressed, these patients are more likely to develop severe or disseminated disease.

Blastomycosis has a wide variety of clinical presentations, which makes it more difficult for health providers to consider when generating a differential diagnosis. Some patients may present with acute symptoms such as fever, cough, and purulent sputum that mimics bacterial pneumonia. Others may present with a more indolent picture, with additional symptoms of weight loss, night sweats, and hemoptysis. The latter presentation mimics that of pulmonary TB or histoplasmosis.

Radiographically, pulmonary blastomycosis may present as alveolar infiltrates or as a lung mass resembling malignancy. The alveolar infiltrates may have uni- or multilobar involvement. Pulmonary blastomycosis can also present as a cavitary lesion. In rare cases, it can present in a miliary or diffuse alveolar pattern associated with ARDS. Of 35 case reports reviewed, 11% had a miliary pattern. These cases were typically found in patients who are elderly with disseminated disease.

The presentation of blastomycosis in this case, a miliary pattern in a patient who is immunocompromised, is extremely rare, with only a few cases reported in patients with HIV infection.

Serology testing for blastomycosis is an unreliable indicator of active disease in patients with a miliary or nodular pattern of blastomycosis. Rather, the diagnosis requires identification of the organism from body fluids or tissue biopsy. The most rapid technique for diagnosis of blastomycosis is examination of clinical specimens after pretreatment of the specimen with potassium hydroxide (KOH). However, nonvisualization of the organism on KOH examination does not reliably rule out blastomycosis. In the setting of pulmonary blastomycosis, respiratory material for KOH examination can be obtained via production of sputum or bronchoscopy. Direct examination of such respiratory specimen was reported to reveal Blastomyces in 37% to 46% of patients with blastomycosis.

Culture remains the gold standard for diagnosis. The organism will grow as a white mold that turns brown within a few days. Full identification may take several weeks.

Acute pulmonary blastomycosis may be self-limited in some patients who are immunocompetent. However, in patients who are immunocompromised, any manifestations of pulmonary blastomycosis should prompt initiation of antifungal therapy to prevent the development of extrapulmonary disease because spontaneous resolution is unlikely to occur. Moreover, pulmonary blastomycosis in the patient who is immunocompromised can progress to ARDS.

Itraconazole is the initial treatment of choice for children and nonpregnant women with pulmonary or disseminated blastomycosis of mild to moderate severity. Adults should be given 200 mg once or twice daily, whereas children are treated with 10 mg/kg/d (maximum dose, 400 mg daily). It is given for 6 to 12 months’ duration. Serum levels of itraconazole should be determined after at least 2 weeks to ensure adequate drug levels.

For moderate to severe pulmonary or extrapulmonary blastomycosis or in patients who are immunocompromised, treatment with amphotericin B deoxycholate at 0.7 to 1 mg/kg/d or a lipid formulation of amphotericin B at 3 to 5 mg/kg/d is recommended for 1 to 2 weeks until clinical improvement, at which time therapy can be switched to an oral azole, preferably itraconazole.

Blastomycosis at any site in patients who are immunocompromised such as those with AIDS, on chronic corticosteroids or anti-tumor necrosis factor agents, and/or with organ transplants require at least 1 year of treatment and may require lifelong suppressive therapy if immunosuppression cannot be reversed.

Amphotericin B therapy is recommended for severe cases of blastomycosis during pregnancy, when azoles should be avoided because of their risk of teratogenicity.

Patients with severe pulmonary blastomycosis, especially those who are immunocompromised, may develop ARDS, which is associated with an extremely high mortality rate of 50% to 89%. In such cases, combination therapies with amphotericin B and itraconazole or addition of methylprednisolone have been used, but there are no clear guidelines for the management of severe cases of blastomycosis.

Clinical Course

BAL Gram stain and KOH microscopy did not reveal any significant abnormality. However, the biopsy demonstrated fungal elements morphologically consistent with Blastomycoses dermatitis, demonstrating thick retractile double wall capsules with internal basophilic granular contents in periodic acid–Schiff and Grocott methenamine-silver stains. Urinary antigens for Blastomycoses were also positive.

The patient was transferred to the medical intensive care unit after bronchoscopy because continued worsening of respiratory status. Liposomal amphotericin B was initiated within 8 h after bronchoscopy and the fever subsided within 24 h. Nevertheless, she progressed to severe ARDS despite further decreases in immunosuppression. Her condition continued to deteriorate and she developed severe sepsis with shock and multiorgan failure. She died on medical intensive care unit day 11.

  • 1.

    Pulmonary blastomycosis should be considered in patients presenting with a miliary pattern of disease in endemic areas.

  • 2.

    Serological testing is an unreliable means of establishing the diagnosis. Examination and culture of respiratory secretions and/or tissue biopsy is often necessary.

  • 3.

    Treatment with an antifungal agent is recommended for pulmonary blastomycosis in patient who is immunocompromised: itraconazole for mild cases and amphotericin B for the moderate to severe cases.

  • 4.

    Severe cases may progress to ARDS with an associated mortality rate in the range of 50% to 90% despite antifungal therapy.

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.


Figures

Figure Jump LinkFigure 1 Chest radiograph on admission demonstrating diffuse, bilateral tiny nodular lesions of the lungs in a miliary pattern of distribution.Grahic Jump Location
Figure Jump LinkFigure 2 CT scan lung window demonstrating diffuse micronodules in a miliary pattern of distribution.Grahic Jump Location
Figure Jump LinkFigure 3 Hematoxylin and eosin stain ×20 from the transbronchial biopsy.Grahic Jump Location
Figure Jump LinkFigure 4 Periodic acid–Schiff stain ×40.Grahic Jump Location
Figure Jump LinkFigure 5 Grocott methenamine silver stain ×40.Grahic Jump Location

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