Case 3 -
Coccidioides Spp. Infection Associated with Eosinophilic Pneumonia
Frank Schneider, University of Pittsburgh, Pittsburgh, PA
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A 26-year-old man presented to an emergency room in Pittsburgh, PA, with a 10-day history of worsening shortness of breath, productive cough and fatigue. He was admitted and treated with azithromycin and ampicillin for presumed community-acquired pneumonia. Despite antibiotic therapy he continued to remain febrile with persistent leukocytosis (eosinophilia) and increasing supplemental oxygen requirements eventually requiring intubation. A chest CT showed extensive, bulky mediastinal lymphadenopathy and a dense airspace consolidation within the right upper lobe with small cavitation. In addition, there were innumerable widespread centrilobular nodules. A bronchoalveolar lavage showed atypical lymphoid cells with 20 percent eosinophils. At the same time the present transbronchial biopsy was obtained.
Case 3 - Slide 1
Case 3 - Figure 1
Airspaces filled with fibrin, macrophages, a single giant cell and scattered inflammatory cells (H&E x100).
Case 3 - Figure 2
Foamy histiocytes and fibrin in alveoli.Mononuclear inflammatory cells form a loose aggregate (H&E x200).
Case 3 - Figure 3
Macrophages and a multinucleated giant cell. Eosinophils are present within the airspace exudate and in alveolar septa (H&E x200).
Case 3 - Figure 4
Spherical structures within the vaguely granulomatous aggregate of airspace macrophages (center and edge of biopsy at 1 o'clock) (H&E x400).
Case 3 - Figure 5
A spherical fungal organism with refractile wall and poorly defined internal structure (H&E x400).
Case 3 - Figure 6
Two fungal organisms highlighted by a silver stain. The one in the lower left appears to contain some internal structures displacing the stain (Grocott methenamine silver x400).
Case 3 - Figure 7
The wall of the organisms is highlighted by a PAS stain (PAS x400).
Case 3 - Figure 8
A mucin stain fails to highlight a mucinous capsule around the organisms (Mucicarmine x400).
Case 3 - Figure 9
Chest CT showing right upper lobe airspace consolidation with cavitation and innumerable small centrilobular nodules.
A 26-year-old man presented to an emergency room in Pittsburgh with a 10-day history of
worsening shortness of breath, productive cough and fatigue. He was admitted and treated with
azithromycin and ampicillin for presumed community-acquired pneumonia. Despite antibiotic therapy he
continued to remain febrile with persistent leukocytosis (eosinophilia) and increasing supplemental
oxygen requirements eventually requiring intubation. A chest CT showed extensive, bulky mediastinal
lymphadenopathy and a dense airspace consolidation within the right upper lobe with small cavitation. In
addition, there were innumerable widespread centrilobular nodules. A bronchoalveolar lavage showed
atypical lymphoid cells with 20 percent eosinophils. At the same time the present transbronchial biopsy
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Routine sections show
an eosinophilic pneumonia characterized by fibrinous airspace exudates with macrophages and eosinophils.
The macrophages aggregate to form vaguely formed granulomas and rare giant cells. Within the alveolar
exudates, one can identify rare spherical structures approximately 10-15 micrometer in diameter. The
most prominent one has a thick, refractile wall. Some are surrounded by small neutrophilic
microabscesses. No budding is seen. There is no evidence of a lymphoproliferative process. Grocott
stains highlight the spherical structures. One seems to have a hardly discernible internal structure
(Figure 6, lower left). Mucicarmine and Alcian Blue stains fail to highlight mucin. A Fontana stain is
negative. Immunohistochemical stains for several lymphoid markers confirmed the absence of a
- Eosinophilic pneumonia and its various associations as outlined in the
- Fungal infection, especially Coccidioides, Blastomyces, Cryptococcus spp.
Coccidioides spp. infection associated with eosinophilic pneumonia.
This case offers the clinical consultant pathologist the opportunity to integrate morphologic,
radiographic and clinical findings. The case can be approached from three different angles: (1) the
clinical presentation as acute onset of respiratory symptoms in a young man with no significant other
medical history, (2) the radiographic findings of centrilobular nodules with cavitation associated with
airspace consolidation and mediastinal lymphadenopathy, and (3) the histologic finding of eosinophilic
pneumonia with structures resembling fungal yeast forms.
From a clinical perspective, acute onset respiratory distress in a younger individual can have several
etiologies . Entities to be considered include pneumonia, diffuse alveolar hemorrhage, acute
eosinophilic pneumonia, acute hypersensitivity pneumonia, cryptogenic (or idiopathic) organizing
pneumonia, a rapidly infiltrative neoplastic process such as leukemia or other cancers, pulmonary edema,
and acute interstitial pneumonia (AIP). Adult respiratory distress syndrome (ARDS), whose morphologic
correlate (diffuse alveolar damage) is often indistinguishable from AIP, is a diagnosis of exclusion. If
a biopsy has been obtained, a diagnosis of ARDS is appropriate only if the pathologist cannot identify
any of the processes above.
The radiographic findings in this patient highlight different anatomic compartments. Centrilobular
nodules indicate an involvement of the bronchovascular bundles and can be seen in respiratory, cellular
or follicular bronchiolitis, hypersensitivity pneumonia, sarcoidosis or Langerhans cell histiocytosis
. Airspace consolidation usually occurs when alveolar gas is replaced by something else
"something else" could be edema fluid, pus, blood, surfactant, macrophages, or other cells. Cavities in
lung tissue can be the result of necrosis or cystic dilation of an anatomic lung structure. Their
presence raise the possibility of infection, malignancy, rheumatologic disease (e.g. Sjögren syndrome),
Langerhans cell histiocytosis, pulmonary embolism or infarction .
Histologically, eosinophilic lung disease can either be the primary manifestation of disease (simple
pulmonary eosinophilia (Löffler Syndrome), idiopathic acute or chronic eosinophilic pneumonia, allergic
reactions to cigarette smoke or drugs) or a secondary feature of an underlying condition
entities associated with pulmonary eosinophilia can usually be excluded based on the clinical history.
For example, the absence of muscle, joint or bowel symptoms helps to exclude eosinophilic lung disease
secondary to rheumatoid arthritis, eosinophilic gastroenteritis, or inflammatory bowel disease. Absence
of asthma makes Churg-Strauss syndrome an unlikely diagnosis. Peripheral blood eosinophilia, present in
this patient, is regularly found in simple pulmonary eosinophilia (Löffler Syndrome), hypereosinophilic
syndrome, infectious processes (including fungal and parasitic infections such as filariasis) and chronic
eosinophilic pneumonia. Both Löffler Syndrome and chronic eosinophilic pneumonia do not fit the clinical
presentation with severe symptoms and rapid onset of disease. One is left with a differential diagnosis
including idiopathic acute eosinophilic pneumonia, infection, allergic reactions (e.g. to drugs or
cigarette smoke) and eosinophilic airways disease (allergic bronchopulmonary aspergillosis,
bronchocentric granulomatosis). If there were no identifiable organisms in the present biopsy material,
it may be most appropriate to offer this differential diagnosis in the pathology report.
Taking into account the differential diagnoses from all three of the approaches outlined above, an
infectious etiology appears to be the most likely cause for the patient's presentation. The presence of
fungal organisms indeed allowed for placing the case into the infectious disease category.
Identification of fungal organisms in tissue rests mostly on size and shape. Common (and not so common)
fungal species affecting the lung, their morphologic characteristics and differential diagnoses (DD) are
The size of the organisms in this case (10-15 micrometer) places them into the range of Blastomyces
dermatitidis or small Coccidioides spp. Although a refractile capsule (Fig. 5) is characteristic for
Blastomyces, a diagnosis of Blastomyces should only be made on morphologic grounds if the typical
broad-based budding is seen. In addition, the barely visible internal structures in one of the spherules
support the presence of endospores and a diagnosis of Coccidioidomycosis. While peripheral blood
eosinophilia is not uncommon in Coccidioides infection, infiltrative eosinophilic lung disease, as seen
in this patient, is rare . Negative mucin and Alcian Blue stains confirm the absence of a mucinous
capsule. This and the negative Fontana stain argue against a diagnosis of Cryptococcus spp. Although
foreign material (e.g. seeds of beans or peas) can rarely resemble spherules of Coccidioides spp., a
diagnosis of aspiration did not fit well with the imaging findings.
- Aspergillus spp.
- Hyphae, 3-6 micrometer wide
- Branching at 45 angles
- Alveolar hemorrhage and fibrin with necrotic alveolar septa
- Mucoraceae (Mucor, Rhizopus, Absidia spp.):
- Hyphae, 10-15 micrometer wide
- Branching at 90 angles
- Hemorrhagic infarction with sparse or absent inflammatory infiltrate
- DD: broader hyphae and wider angle branching than Aspergillus spp.
- Pseudoallescheria boydii
- Hyphae, 2-5 micrometer with rounded ends
- Necrosis and acute inflammation
- DD: Aspergillus spp., usually needs culture confirmation
- Torulopsis glabrata
- Yeasts, 2-4 micrometer
- Necrosis and acute inflammation
- DD: resembles Candida spp., but does not form pseudohyphae
- Candida spp.
- Yeasts, pseudohyphae, both 3-5 micrometer
- Small necrotic areas with varying acute inflammation
- Pneumocystis jirovecii
- Cysts, 4-5 micrometer
- Alveolar foamy casts with macrophages, reactive pneumocytes and interstitial lymphoplasmacytic infiltrate
- Cryptococcus neoformans
- Yeasts, 2-15 micrometer
- Mucinous capsule
- Granulomas with or without necrosis in immunocompetent patients, conspicuous lack of response in immunocompromised patients
- DD: unencapsulated organisms can be mistaken for Histoplasma capsulatum
- Histoplasma capsulatum
- Yeasts, 2-4 micrometer
- Narrow-based budding
- Necrotizing granulomas with fibrotic wall, scattered giant cells and mixed chronic inflammation
- Endemic areas: Mississippi and Ohio River valleys
- Blastomyces dermatitides
- Yeasts, 8-15 micrometer
- Thick, refractile wall
- Broad-based budding
- Microabscesses with necrotic neutrophils and organisms surrounded by palisading histiocytes
- Endemic area: Southern, south central and Great Lakes region of the United States, but cases outside these areas not unusual
- Coccidioides immitis and posadasii
- Yeasts (spherules), up to 40-60 micrometer, containing endospores up to 5 micrometer
- Fibroinflammatory exudates with neutrophils and macrophages, necrotizing granulomas
- Endemic areas: Arizona, New Mexico, Utah (all C. posadasii), Southern California (C. immitis)
- DD: small immature spherules can mimic Pneumocystis, Histoplasma or Candida spp.; medium-sized spherules can mimic Blastomyces or Cryptococcus spp.
- Paracoccidioides brasiliensis
- Yeast, 4-40 micrometer
- Multiple narrow-based buds (Mariner's wheel morphology)
- Endemic area: South America
Cultures confirmed the presence of Coccidioides spp. 10 days after the biopsy was obtained. A
morphological iagnosis of fungal infection was made the day following the biopsy, allowing the patient to
start antifungal treatment. He recovered fully and was discharged home 19 days after he presented to the
Review of the Literature/Treatment Options:
Coccidioidomycosis is contracted by inhalation of arthroconidia usually contained in dusty soil
The disease is subclinical in most patients. In the majority of the remainder it presents either as
subacute "Valley fever" that lingers for weeks or months and then regresses, often without therapy, or as
community-acquired pneumonia between 1 and 3 weeks after exposure . Serologies are useful in
establishing the diagnosis, and repeated serologic testing is useful even if earlier attempts were
negative . A PCR-based test has been shown to have high sensitivity, but less so in
paraffin-embedded tissue . Culturing the organisms can take several days to weeks and carries the
risk of exposure to laboratory personnel to airborne infectious arthroconidia. Uncomplicated cases of
coccidioidomycosis are expected to resolve without antifungal therapy. If treatment is desired, the
drugs of choice are azole antifungals. Amphotericin B will usually only be considered in most severe
cases. Duration of treatment is several months because of the risk of relapse .
- Acute pulmonary coccidioidomycosis can rarely
present as eosinophilic pneumonia. An infectious etiology should be ruled out carefully when seeing this
pattern of lung disease.
- Immature Coccidioides spherules can be small and
lack visible endospores, causing confusion with Blastomyces or Cryptococcus spp.
- Morphologic diagnosis of the organisms can be very
valuable to the clinical team as it usually precedes availability of culture results by several days if
- Considering the clinical presentation and
radiographic features of patients for whom only limited biopsy material is available may help the
pathologist to narrow down the differential diagnosis.
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