An Unusual Presentation of CNS Histoplasmosis Mimicking Metastatic Cancer
Prashanth Moku, Shady Piedra Abusharar, Fahad M Khalid, Rashmi Banjade and Hyma Polimera*
Penn State College of Medicine, USA
Submission: September 10, 2019; Published: September 18, 2019
*Corresponding author: Hyma Polimera Penn State College of Medicine, Penn State Health Milton S Hershey Medical center, 500 university drive, Hershey, PA 17033, USA
How to cite this article: Prashanth Moku, Shady Piedra Abusharar, Fahad M Khalid, Rashmi Banjade, Hyma Polimera. An Unusual Presentation of
CNS Histoplasmosis Mimicking Metastatic Cancer. JOJ Case Stud. 2019; 10(4): 555791. DOI: 10.19080/JOJCS.2018.09.555791.
Histoplasmosis capsulatum is a thermally dimorphic fungus that is known to cause histoplasmosis. Most histoplasma infections are mild or asymptomatic in immunocompetent individuals but affected individuals often present with manifestations of an inflammatory response to this infection. We report a case of disseminated histoplasmosis complicated by CNS and adrenal gland involvement.
Histoplasma Capsulatum is a thermally dimorphic fungus that is known to cause histoplasmosis. Inhalation of Histoplasma microconidia into alveolar spaces transforms them into yeasts. Most histoplasma infections are mild or asymptomatic in immunocompetent individuals. However, affected individuals often present with manifestations of an inflammatory response to this infection. Patients often present with bone marrow suppression (pancytopenia) and elevated liver enzymes . Clinical evaluation reveals a flu-like illness with findings of fever, headache, myalgia, dyspnea, chest pain and infection localized to the lungs . Additional manifestations can include involvement of adrenal glands, central nervous system, and skin . Herein, we present a case of disseminated histoplasmosis complicated by CNS and adrenal gland involvement.
A 62-year-old Caucasian man with history of coronary artery disease and bypass graft presented with progressive fatigue, anorexia, and a 75-lb weight loss over a 3-month period. Diagnostic workup by his primary care physician had included CT scans of chest and abdomen/pelvis with contrast that showed bilateral granular ground-glass opacities in lungs as well bilateral adrenal masses and hepatosplenomegaly. Subsequent brain MRI then revealed multiple enhancing lesions, which were concerning for metastasis (Figure 1). Abdominal MRI also revealed a 39.6mm x 33mm left adrenal mass that was concerning for metastasis given the patient’s associated
complaints of splenomegaly and pancytopenia (Figure 2).
He was then referred to an oncologist, who proceeded with
outpatient workup for presumed malignancy, but because of progressive fatigue, hypotension and hypoglycemia, he was admitted to an outside hospital. Later, he was transferred to our institution for further management. On admission, he was noted have pancytopenia and hypercalcemia (Ca=11.7).
Subsequent biopsy of adrenal gland showed nonencapsulated
small yeasts, suggestive of either Histoplasma or
Cryptococcus. He was started on IV amphotericin B for possible
histoplasmosis while waiting for further diagnostic work-up. His
serum and urine Histoplasma Ag returned positive with high
titers, adrenal tissue culture grew Histoplasma Capsulatum and
his blood cultures for fungus also grew Histoplasma Capsulatum
after several days. Lumbar puncture also revealed positive
CSF Histoplasma antigen, though the level was below level of
quantification. His immunological work-up was unremarkable
with non-reactive HIV test. Initial CD4 count was low at 166
(39%), but it quickly returned to normal after treatment with
IV Amphotericin B suggesting bone marrow suppression
from Histoplasmosis itself rather than an underlying immune
disorder. He was treated with eight weeks of IV amphotericin B
and transitioned to oral Itraconazole for a prolonged period of
time that he continues to remain on with good response.
Histoplasma Capsulatum is a thermally dimorphic fungus
which infects both immunocompetent and immunocompromised
hosts . It is endemic to the Ohio and Mississippi River
Valleys in the United States and parts of Latin America, Africa,
and Asia [5,6]. H. Capsulatum is commonly found in the soil
and contaminated material of bat or bird guano. Spread of
the disease occurs via inhalation of spores from disturbed
guano or soil . In immune-competent persons, spore
inhalation commonly results in an asymptomatic infection .
Exposure in immune-incompetent patients, due to its mode
of transmission via spore inhalation, histoplasmosis most
commonly manifests in the lungs, ranging from pneumonitis to
severe acute respiratory distress syndrome (ARDS). The yeast
form is disseminated via macrophages as they travel throughout
the body . CNS involvement in histoplasmosis is either a
manifestation of disseminated infection or an isolated focal
infection. CNS involvement has been reported in 5-10% of cases
of disseminated histoplasmosis, but isolated CNS histoplasmosis
is rare, and the exact pathophysiologic mechanism is not known.
Although CNS histoplasmosis is increased in individuals with
impaired cellular immunity, about 20-30% of patients with this
condition are immunocompetent .
The clinical features, appropriate diagnostic testing, and
treatment regimens recommended for the evaluation, and
management of CNS histoplasmosis are based on case reports,
and small case series of patients . The most common
manifestations of CNS histoplasmosis consist of chronic
meningitis and hydrocephalus. Less common presentations
include acute meningitis, encephalitis, small ring enhancing
lesions throughout the brain and spinal cord, brain abscesses and
stroke due to infected emboli. In rare cases, patients with CNS
histoplasmosis may present with cachexia and hypercalcemia .
Symptoms range from headache, mental status changes, cranial
nerve palsies, behavioral changes and ataxia . Morbidity, and
mortality appear to be high in patients with CNS histoplasmosis
with high rates of relapse .
The diagnosis of CNS histoplasmosis can be challenging.
Multiple tests for diagnosis of H. capsulatum in the CNS are
necessary due to the variability in symptoms and the number
of false-negative tests. Culturing of the CSF or CNS parenchymal
tissue is the gold standard for diagnosis of CNS histoplasmosis.
Antigen detection in CSF culture has a sensitivity of 38%
and a specificity of 98%. Additional tests for H. capsulatum
polysaccharide antigen (HPA) in CSF, urine, or serum can be
performed to aid in the diagnosis and monitor response to
therapy. The sensitivity of HPA in the CSF is 38% in all patients
and 67% in patients with AIDS. However, the sensitivity of
Histoplasma antigen in Urine and Serum is 71%, and 38%
respectively [6,8]. Antibody testing in CSF and serum has 80
to 89% and 92% sensitivity, respectively, although these tests are susceptible to cross-reactivity leading to false positives.
Serologic testing is especially difficult with AIDS patients and
often provides false negatives even with an active infection. In
addition, positive CSF culture results are similar to results seen
in other fungal and tuberculous meningitis. Therefore, other
tests must be performed. MRI often shows single or multiple
ring-enhancing lesions in CNS histoplasmosis. However, ringenhancing
lesions can also be indicative of an abscess, a necrotic
tumor, subdural and epidural empyema or toxoplasmosis.
Histoplasmosis should be considered if symptoms correlate
to that of the infection or if the patient has had exposure to an
endemic area .
Optimal treatment for CNS histoplasmosis is unclear. No
prospective studies with an evidence-based approach are
available. Antifungal therapy is recommended for up to 12
months in immunocompetent patients. Despite appropriate
therapy there is risk of failure and relapse which warrants
long term suppressive therapy. Based upon expert opinion and
the limited available data, IDSA (Infectious Diseases Society
of America) guidelines recommend liposomal amphotericin B
at a dose of 5mg/ kg daily for a total of 175mg/kg given over
4-6weeks followed by itraconazole 200mg 2-3 times daily
for at least one year and until resolution of CSF abnormalities
including HPA [4,9].
In conclusion, clinicians should have a low threshold for
considering CNS histoplasmosis as a cause for brain lesions.
CNS histoplasmosis is a rare condition but requires prompt
diagnosis in order to initiate appropriate treatment regimen.
Our case depicts a patient who initially presented with concerns
for metastatic disease in setting of hypercalcemia, pancytopenia,
significant weight loss and generalized weakness. Diagnostic
testing further revealed multiple enhancing lesions in brain
and bilateral adrenal masses, which was strongly suspicious
of malignancy. A subsequent adrenal gland biopsy was crucial
in demonstrating multiple yeasts and thus, aiding in diagnosis.
In the context of the aforementioned biopsy results and the
typical findings of granulomatous involvement of histoplasmosis
presenting with hypercalcemia, there was strong evidence
to support a diagnosis of disseminated histoplasmosis. Our
patient did not have any significant risk factors, he was a normal
host with no underlying immunodeficiency disorder, and he
did not have significant exposure history like spelunking or
exposure to bats or bird droppings. Overall, we present a case of
disseminated histoplasmosis with CNS and adrenal involvement
in an immunocompetent host with a unique presentation as
disseminated histoplasmosis with enhancing CNS lesions.