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Fever of Unknown Origin Secondary to Pulmonary Histoplasmosis in Scleroderma-Related Interstitial Lung Disease

2022; Elsevier BV; Volume: 136; Issue: 4 Linguagem: Inglês

10.1016/j.amjmed.2022.11.018

1555-7162

Amanda Stanton, Sunita Mulpuru, Christopher Pease, Vincent Deslandes, Carolina Fischinger Moura de Souza, Smita Pakhalé,

Eosinophilic Disorders and Syndromes

A Caucasian male in his mid-50s presented to a community hospital in fall 2020 with a 1-month history of nonproductive cough, nausea, vomiting, chills, and nightly fevers greater than 40°C with associated diaphoresis. His past medical history included limited-cutaneous systemic sclerosis (Lc-SSc) diagnosed 5 years prior, SSc-related interstitial lung disease (SSc-ILD), dyslipidemia, osteoporosis, nephrolithiasis, and gastroesophageal reflux. His interstitial lung disease was diagnosed 2 years prior to presentation, and he was responding well to mycophenolate mofetil and oral low-dose prednisone daily. Most recent pulmonary function test showed a forced expiratory volume in 1 second to forced vital capacity ratio of 85%, forced expiratory volume in 1 second of 2.43 L or 74% predicted, total lung capacity 3.89 L or 60% predicted, and a diffusion capacity of 27% predicted. There was no history of recent travel, and the patient was a lifetime nonsmoker with no alcohol use. He was working as a cemetery caretaker with direct soil exposure, but there was no history of similar illness among his coworkers. He was prescribed azithromycin and moxifloxacin in the community for a presumed pneumonia. On admission to the community hospital, his vital signs were within normal range. He was started on piperacillin-tazobactam and received a few doses of trimethoprim-sulfamethoxazole for concern of Pneumocystis jirovecii infection. He defervesced and was afebrile for 4 days, but his cough and dyspnea remained. On day 8 of his admission, he developed a fever of 40.2°C, and he was transferred to a tertiary center for further workup and management. He was started again on piperacillin-tazobactam but continued to have nightly fevers. A bronchoscopy with broncho-alveolar lavage was performed and CT chest was repeated. Rheumatology and Infectious Diseases specialists were consulted. Given the extensive workup and negative culture results, cessation of antibiotic therapy was considered. However, this was restarted on day 17, as the patient gradually became more hypoxemic, eventually requiring high-flow nasal cannula. The patient's SSc-ILD was characterized initially on high-resolution CT by fine reticulation, traction bronchiectasis, and superimposed ground-glass opacities with lower lobe predominance in a pattern characteristic for mildly fibrotic nonspecific interstitial pneumonia (Figure 1). CT chest performed 8 days prior to admission showed increased diffuse reticular opacities with patchy areas of ground glass, concerning for mild progression of his nonspecific interstitial pneumonia with possible associated inflammation or superimposed atypical infection. There was no evidence of pulmonary embolism or other acute complication. On admission to the community hospital, white blood cell count was normal; however, his bloodwork was significant for elevated C-reactive protein at 121 mg/L, lactate dehydrogenase at 1412 IU/L, ferritin at 5157 mcg/L, and a moderate elevation in his transaminases. Blood bacterial, mycobacterial, and fungal cultures; urine bacterial cultures; COVID-19, influenza, and respiratory syncytial virus polymerase chain reaction testing; and Legionella urine antigen were negative. Hepatitis A, B, and C, cytomegalovirus, Epstein-Barr virus, and syphilis serologies also returned negative. At time of transfer, white blood count was 2.8 109/L, ferritin was 1921 mcg/L, and C-reactive protein was 82.5 mg/L. Multiple blood culture sets were negative. Repeat CT of the chest showed mild further progression of fibrosis with increased reticulation and traction bronchiectasis and new ground-glass opacities and fine nodularity involving the lungs away from the areas of fibrosis (Figure 2). There was no growth on preliminary routine bacterial, fungal, and mycobacterial cultures on his broncho-alveolar lavage. On day 18, cultures from his bronchoscopy were reported as growing Blastomyces dermatitidis after 6 days of incubation. This was based on the observation of the presence of yeast with a thick wall, as well as hyphae with microconidia, and the isolate was referred to the provincial public health reference microbiology laboratory for identification confirmation. Final microbiology results on day 27 indicated growth of Histoplasma capsulatum, and not B. dermatitidis. This was concluded after visualization of macroconidia on hyphae in the specimen after further incubation, characteristic for H. capsulatum and not Blastomyces. Both H. capsulatum and B. dermatitidis show growth within 1 to 4 weeks based on inoculum size and present as small white, cottony colonies.1Walsh TJ Hayden RT Larone DH. Larone's medically important fungi: a guide to identification.6th ed. ASM Press, Washington, DC2018Crossref Google Scholar,2Arauz AB Papineni P. Histoplasmosis.Infect Dis Clin N Am. 2021; 35: 471-491Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar A presumptive diagnosis of acute blastomycosis is often established based on the observation of large (12-15 mm) broad-based budding yeasts that have a characteristic thick, double-refractile wall.3Fang W Washington L Kumar N. Imaging manifestations of blastomycosis: a pulmonary infection with potential dissemination.Radiographics. 2007; 27: 641-655https://doi.org/10.1148/rg.273065122Crossref PubMed Scopus (65) Google Scholar In the appropriate clinical context, morphological identification alone has a high specificity, but confirmation of the identification with the use of DNA probes is required for both organisms, and this is usually done in a reference mycology laboratory. When a lactophenol-blue stained tape preparation of the isolate was initially viewed under microscopy, the presence of septate hyaline hyphae with smooth microconidia borne on short branches (so-called “lollipops”) was observed, a feature, which is common to both organisms (Figure 3). This stage predates the apparition of the classic large, thick-walled, tuberculate macroconidia of H. capsulatum, which becomes visible only after further incubation (Figure 4).4Wheat LJ Freifeld AG Kleiman MB et al.Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.Clin Inf Dis. 2007; 45: 807-825https://doi.org/10.1086/521259Crossref PubMed Scopus (991) Google Scholar Also present were larger cells with a thick cell wall, which may have been forming macroconidia and may have been confused for yeast forms. Visualization of yeast forms of Blastomyces is not expected at 25°C incubation, which is the temperature normally used for incubation in the clinical mycology laboratory.Figure 4Microscopic image of Histoplasma capsulatum showing a mature culture with an abundance of tuberculate macroconidia. The black arrow indicates a “lollipop-like” structure, present in the early stages of Histoplasma growth and appearing prior to the macroconidia.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Diffuse ground-glass opacities in isolation are an uncommon manifestation of fungal infection on CT and are most frequently seen in Pneumocystis jirovecii infection, which did not fit this patient's presentation. According to the literature, CT findings of pulmonary blastomycosis most commonly include focal or patchy consolidation, often with mass-like opacities that mimic malignancy. Diffuse small nodules (miliary nodules) may be seen in hematogenous spread of infection but are uncommon. Cavitation and lymph node enlargement may occur.3Fang W Washington L Kumar N. Imaging manifestations of blastomycosis: a pulmonary infection with potential dissemination.Radiographics. 2007; 27: 641-655https://doi.org/10.1148/rg.273065122Crossref PubMed Scopus (65) Google Scholar Our patient had no progressive lymphadenopathy or calcified lymph nodes on CT, and the findings of ground-glass opacities could also have been explained by progression of his SSc-ILD, which was a major confounder. Miliary nodules are a common manifestation of disseminated (hematogenous) histoplasmosis and present on CT with diffuse, randomly distributed, very small nodules. At times, these nodules may be difficult to visualize, particularly in thick-slice CT studies and in the presence of motion artifacts and may appear as diffuse ground-glass opacities. Upon careful evaluation of CT images in this patient, including maximum intensity projection reconstructions that facilitated the detection of pulmonary nodules, very small punctate nodules were present, best seen in the areas of lung with no chronic ILD involvement (Figure 2), thus supporting a diagnosis of histoplasmosis. The patient met criteria for the initiation of parenteral antifungals due to his severe clinical presentation with hypoxemia. Antibiotics were stopped, and he was started on amphotericin B. His fevers stopped a couple days later, and his hypoxemia resolved gradually. Amphotericin B was continued for 13 days and then transitioned to oral itraconazole. He was discharged on itraconazole a couple of days later, saturating 94% on room air at rest, with the plan to complete a 12-week course of antifungal therapy, instead of 6 months to 1 year for blastomycosis.5Chapman SW Dismukes WE Proia LA et al.Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Inf Dis. 2008; 46: 1801-1812https://doi.org/10.1086/588300Crossref PubMed Scopus (493) Google Scholar He had outpatient follow up with Infectious Diseases and successfully completed this regimen. Repeat pulmonary function tests and CT imaging showed stability when compared to those performed several months prior to his infection.