IMAGES IN ID——WHAT’S THE DIAGNOSIS?

Necrotizing Pneumonia in an Immunocompromised Host

Dennis Zambrano, MD,* Michael Croix, MD,* Jessica Bohrhunter, PhD,†
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William Bonnez, MD,* and Ted Louie, MD*

CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/14/2023

Key Words: necrotizing pneumonia, immunocompromised host, Later that evening, preliminary results from BAL cultures grew
blastomycosis mold and one colony of yeast, later identified as Candida
albicans. Voriconazole was added to her antimicrobial regimen.
CASE SUMMARY On hospital day 3, respiratory status continued to deteriorate,
and she remained febrile. Serum β-D-glucan drawn on admis-
A 38-year-old female native of Rochester, NY, with medical
sion returned positive, and she was transitioned to intravenous
history significant for Crohn disease, treated with infliximab, aza-
isavuconazonium. Her respiratory status continued to worsen
thioprine, and prednisone (20 mg daily) was admitted on
overnight requiring mechanical ventilation. She was diagnosed
September 4, 2020 for a flare of her illness. Computed tomogra- with acute respiratory distress syndrome and transferred to the in-
phy (CT) angiography of the chest obtained to evaluate right upper
tensive care unit. Her antifungal therapy was changed to liposo-
chest pain showed patchy infiltrate surrounding an irregular focal
mal amphotericin B with the addition of methylprednisolone.
consolidation in the right upper lung. Upon discharge, the chest
She was successfully extubated 4 days later.
pain disappeared, and the patient was advised to repeat imaging Although BAL fungal cultures had identified a mold, it was
in 3 months. Her prednisone dose was doubled for her Crohn dis-
very slow growing, thus not exhibiting the specific morphologic
ease. On October 1, her chest pain returned, worsened by inspira-
features that allow identification. On admission, the fungal micro-
tion. She was seen in the emergency department where repeat CT
biologic evaluation included 2 lysis-centrifugation (Isolator) fun-
angiography revealed enlargement of the previous right upper
gal blood cultures, a BAL calcofluor white fungal smear, serum
lung consolidation. She was given a 7-day empiric course of
galactomannan (Bio-Rad) and β-D-glucan (Fungitell) assays,
amoxicillin-clavulanate pending a follow-up pulmonology ap-
and a urine histoplasma antigen assay (MiraVista). Two days after
pointment. In the interval, her chest pain worsened, and she devel- ICU admission, the urine histoplasma antigen assay was reported
oped a nonproductive cough and night sweats. On October 21, she
positive (≥4 ng/mL) at 15.59 ng/mL, and the presumptive diagno-
underwent outpatient bronchoscopy. Bronchial washings and right
sis became pulmonary histoplasmosis. The galactomannan was
upper lung bronchoalveolar lavage (BAL) Gram stains showed
reported as negative. There were no physical examination findings
greater than 25 neutrophils and less than 10 squamous cells. suggesting ocular, cutaneous, bone, or neurologic involvement,
Gram-positive cocci were present in the Gram stain of the
and no additional imaging was obtained.
cytospin smear. No acid-fast bacilli grew in culture. The fungal
What is your diagnosis?
smear of fluid from the BAL was negative during hospitalization.
The aerobic culture of the BAL grew less than 10,000 colony-
forming units of contaminating flora from the upper respiratory DISCUSSION
tract. None of the samples grew Legionella species.
Laboratory review of the lactophenol cotton blue preparation
The patient was admitted on October 25 with worsening from growth on solid media revealed conidia and conidiophores
chest pain, production of brown sputum, onset of chills, and poor
(Fig. 2) and fluorescent double-walled budding yeast on
oral intake. Her temperature was 39.9°C, with a heart rate of 126
calcofluor white smear of BAL consistent with Blastomyces
beats per minute, blood pressure of 116/64 mm Hg, respiratory
(Fig. 3). Six days after discharge, Blastomyces dermatitidis was
rate of 28 breaths per minute, and oxygen saturation of 98% on identified from the BAL fungal culture confirmed by DNA probe
room air. Physical examination was significant for diminished
(Mayo Clinic Diagnostics Laboratories). The fungal smear from
breath sounds in the right upper lung field without signs of consol-
the original BAL fluid was reviewed by the microbiology labora-
idation. The complete blood cell count was 25.4 cells/μL, with
tory after diagnosis, and the original report was later corrected
88.1% granulocytes, 1% lymphocytes, 4% monocytes, and 0.2% stating double-walled budding yeast were present.
eosinophils. She had a hemoglobin level of 11.6 g/dL and platelet
The patient was treated with 10 days of IV liposomal ampho-
count of 648,000 elements/μL. Her lactate level was 3.4 mmol/L;
tericin B 5 mg/kg daily and 7 days of IV methylprednisolone
sedimentation rate, 130 mm/h; and C-reactive protein level,
1 mg/kg daily. Amphotericin B was discontinued due to hypoka-
487 mg/mL. She was treated empirically for sepsis from presumed
lemia, and she was started on itraconazole. Other immunosuppres-
pulmonary source with intravenous piperacillin-tazobactam, van-
sive medications were discontinued. Serial CT scans during
comycin, and azithromycin. Repeat CT angiography of the chest
follow-up showed interval improvement in the size of the cavitary
revealed interval increase in size of the right upper lobe consolida- lesion from 6.5  7.9 cm to 2.7  1.6 cm after 8 months of ther-
tion, with new central cavitation, and extensive patchy ground
apy, and it remains on itraconazole. The patient has continued to
glass and consolidative opacities throughout both lungs (Fig. 1).
experience moderate dyspnea on exertion without further hemop-
tysis, weight loss, or fever.
From the *Division of Infectious Diseases, and †Department of Pathology and
Laboratory Medicine, University of Rochester School of Medicine and Den-
Blastomyces dermatitidis is a dimorphic fungus that exists as
tistry, Rochester, NY. a mold in the environment and as a yeast at physiologic tempera-
Correspondence to: Michael Croix, MD, Division of Infectious Diseases, tures. It is commonly distinguished from other fungi by its charac-
University of Rochester Medical Center, Box 689, 601 Elmwood Ave, teristic broad-based budding in the yeast form. Blastomyces is
Rochester, NY 14642. E‐mail: Michael_Croix@urmc.rochester.edu.
The authors have no funding or conflicts of interest to disclose.
usually associated with soil rich in organic debris and decaying
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. vegetation although isolation from the environment is difficult.1,2
ISSN: 1056-9103 Until recently, B. dermatitidis was considered the only causative

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 Zambrano et al
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FIGURE 1. Computed tomography of chest with contrast shows
right upper lobe consolidation, with central cavitation, and extensive
patchy ground glass and consolidative opacities worse on right.
organism of blastomycosis. Phylogenetic analysis suggested 2
species were present, B. dermatitidis and Blastomyces gilchristii.3
In the United States, blastomycosis usually occurs in the south-
eastern and south-central states that border the Mississippi and
Ohio Rivers, the Midwestern states, and states that border the
great lakes.1,4 Blastomyces is not reportable in New York State,
but a recent retrospective analysis suggests increasing incidence
of Blastomyces in the capital district.5
When blastomycosis infections occur, the greatest challenge
in making the diagnosis is considering Blastomyces species as the
offending organism. A retrospective review of cases in Minnesota
revealed that the mean time to diagnosis was 31 days.6 The reason
for this is that the symptoms of acute pulmonary blastomycosis
may be indistinguishable from a viral or bacterial pneumonia.
Most commonly, patient presents with days to weeks of fever,
FIGURE 2. Lactophenol cotton blue stain, 400 magnification,
showing rounded to pear-shaped conidia and conidiophores.
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Infectious Diseases in Clinical Practice • Volume 30, Number 3, May 2022
FIGURE 3. Calcofluor stain 400 magnification, showing
characteristic round yeast with broad-based budding.
chills, night sweats, nonproductive cough, and unilateral pleuritic
chest pain.6,7 Chest x-rays may reveal alveolar infiltrates, lobar
consolidations with or without cavitation, and or mass lesions.7
The incidence of Blastomyces cavitary disease, as seen with our
patient, varies widely with incidence of 0% to 37% reported, but
should be considered in the differential of cavitary lung disease
particularly when mold is present.8 Chronic pulmonary histoplas-
mosis may also present with cavitary disease; however, it is more
commonly seen in older White males with underlying chronic ob-
structive pulmonary disease.
Further complicating the picture is the lack of clearly identi-
fiable risk factors. The Minnesota cohort identified that only 35%
of patients with symptomatic infection met criteria for immuno-
compromised status from illness or medication including tumor
necrosis factor α (TNF-α) antagonists, chemotherapy, or antire-
jection agents.6 Other patients at risk of severe infection include
those with common medical co-comorbidities including diabetes,
chronic obstructive pulmonary disease, cirrhosis, and kidney dis-
ease.6 Surprisingly, TNF-α antagonists have not been shown to be
a major risk factor for blastomycosis infections.9 Between 2004
and 2012, only a total of 9 cases were reported postmarketing to
the Food and Drug Administration in patients on anti-TNF agents
with confirmed Blastomyces infections.10 Patients on TNF antago-
nists, especially in severe cases of inflammatory bowel disease with
multiple other immunosuppressive medications, most commonly
experience fungal infections such as histoplasmosis, candidiasis,
and aspergillosis.10 Unlike Histoplasma, a prolonged latency period
between initial exposure and development of infection has not been
well described with Blastomyces. A case series of 15 patients with
acquired immunodeficiency syndrome reported on 4 patients who
developed blastomycosis several years after not leaving an endemic
area, but epidemiologic data were limited.11
Definitive diagnosis of B. dermatitidis is growth in culture.
The organism is easily isolated from respiratory secretions, and
both sputum cultures and bronchial washings are positive 86%
and 100% of the time, respectively.12 Cytology with direct visual-
ization of the organism is also commonly used. Serological and
urine antigen testing for blastomycosis is available; however, se-
rum studies lack both sensitivity and specificity, and the urine an-
tigen may have cross-reactivity with other fungi.7 Further compli-
cating the picture, antibody tests designed for other fungal infec-
tion may show cross-reactivity with Blastomyces antigens. For
instance, the MiraVista Diagnostics histoplasma antibody tests
have shown cross-reactivity in urine and serum antigens with
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 Infectious Diseases in Clinical Practice • Volume 30, Number 3, May 2022
other endemic mycoses, including Blastomyces as was the case for
our patient.13 Serum Aspergillus galactomannan testing may cross
react with B. dermatitidis in the mold form.14 Serum β-D-glucan is
often negative in active Blastomyces infections due to low-level
production of β-D-glucan.15 It is unusual that serum β-D-glucan
was positive in our patient perhaps due to the severity of her dis-
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ease. In vivo, the organism is present in the yeast form and may
be identified by direct visualization of the characteristic broad-
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/14/2023
based budding yeast under calcofluor-white stain performed on
a smear of the sample. In culture, the organism grows in the mold
form and identification of characteristic conidia and conidio-
phores with lactophenol cotton blue tease mount is necessary to
identify Blastomyces. Alternatively, diagnosis may be made by
use of mass spectrometry, which may be performed with accurate
identification before phenotypic features are present.16
The Infectious Diseases Society of America has published
clinical practice guidelines for the management of blastomycosis.17
Treatment revolves around amphotericin B and either itraconazole
or fluconazole. For moderate to severe pulmonary disease, current
guidelines recommend treatment with intravenous liposomal am-
photericin B at a dosage of 3 to 5 mg/kg per day or amphotericin
B deoxycholate at a dosage of 0.7 to 1 mg/kg per day. Treatment
is recommended for 1 to 2 weeks or until clinical improvement,
followed by itraconazole for 6 to 12 months or until resolution of
radiological abnormalities. Immunocompetent patients without se-
vere disease may be started on oral itraconazole, 200 mg orally 3
times daily for 3 days, followed by 200 mg twice daily for 6 to
12 months. Our patient was initially started on voriconazole, then
isavuconazonium before starting guideline therapy. Although these
agents are not optimal treatment for blastomycosis, limited data
show effectiveness when guideline therapy is not tolerated. Unlike
histoplasmosis, the Infectious Diseases Society of America guide-
lines for blastomycosis do not recommend for or against using cor-
ticosteroids in pulmonary disease as insufficient data were available
at the time of publication. A retrospective case series of 43 pa-
tients found no mortality benefit in patients with acute respiratory
distress syndrome and pulmonary blastomycosis who received
corticosteroids, despite suggestion of benefit from prior case reports.18
CONCLUSIONS
Clinicians should be aware of the possibility of fungal infec-
tions including blastomycosis in patients on TNF-α antagonists.
Clinicians should also be aware that Blastomyces can cross react
with histoplasma in urine and serum antigen studies. Lastly, the
geographic distribution of infectious diseases including blastomy-
cosis can change over time.
ACKNOWLEDGMENTS
The authors thank Matthew William Hale, MD, from the Depart-
ment of Internal Medicine, University of Rochester Medical Center,
and Patrick Donahoe, MD, and Christina Dony, MD, from the Division
of Pulmonary Medicine, University of Rochester Medical Center.
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Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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