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Cases Journal
Open Access
Case Report
Disseminated cryptococcosis with meningitis, peritonitis, and
cryptococcemia in a HIV-negative patient with cirrhosis: a case
report
Baligh Ramzi Yehia*, Michael Eberlein, Stephen D Sisson and David N Hager
Address: Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 9020, Baltimore, Maryland,
USA
Email: Baligh Ramzi Yehia* - byehia@jhmi.edu; Michael Eberlein - meberle3@jhmi.edu; Stephen D Sisson - ssisson@jhmi.edu;
David N Hager - dhager1@jhmi.edu
* Corresponding author
Abstract
Introduction: Cryptococcus neoformans is an encapsulated yeast that causes serious infections in
immunocompromised populations. The majority of cases occur in HIV-infected individuals.
Disseminated disease is uncommon, and very rarely includes peritonitis.
Case presentation: We report a case of a 41-year-old, HIV-negative, Caucasian man with
alcoholic liver cirrhosis who presented with fever and seizure. Disseminated cryptococcosis with
meningitis, peritonitis, and cryptococcemia was diagnosed, and despite adequate treatment the
patient developed multi-system organ failure and eventually expired.
Conclusion: Disseminated cryptococcosis, particularly with peritonitis, is an uncommon
manifestation of Cryptococcus neoformans infection. Liver cirrhosis serves as a risk factor for
disseminated disease in HIV-negative patients. A high clinical suspicion and early initiation of
therapy is needed to recognize and treat patients effectively.
Introduction
Cryptococcus neoformans is a ubiquitous encapsulated yeast
that predominately causes significant infections in immu-
nocompromised individuals, with eighty to ninety per-
cent of all cases occurring in those with HIV infection
[1,2]. The most common sites of infection are the central
nervous system (CNS) and lungs [1-4]. Disseminated dis-
ease is uncommon and when present almost always
occurs in HIV-infected patients [2]. Cryptococcal peritoni-
tis occurs even less frequently then disseminated disease
and is considered a rare manifestation of cryptococcosis
[1]. Here, we present a case of disseminated cryptococco-
sis with meningitis, peritonitis, and cryptococcemia
occurring in a HIV-negative patient with alcoholic liver
cirrhosis.
Case presentation
A 41-year-old Caucasian man presented to the emergency
department with a 1-month history of jaundice, halluci-
nations, and ataxia. He was initially treated for acute alco-
holic hepatitis with pentoxifylline and steroids, hepatic
encephalopathy with lactulose, and started on empiric
therapy for spontaneous bacterial peritonitis (SBP) with
ceftriaxone. His mental status returned to baseline, but he
Published: 28 October 2009
Cases Journal 2009, 2:170 doi:10.1186/1757-1626-2-170
Received: 19 October 2009
Accepted: 28 October 2009
This article is available from: http://www.casesjournal.com/content/2/1/170
© 2009 Yehia et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cases Journal 2009, 2:170 http://www.casesjournal.com/content/2/1/170
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continued to have worsening liver and renal failure. Hepa-
torenal syndrome was diagnosed and he was started on
octreotide, midrodine and albumin.
His medical history was notable for an ischemic stroke
with mild residual deficit, gastric bypass surgery, uncom-
plicated lumbar spinal fusion surgery, and alcohol
induced cirrhosis of the liver. Social history suggested that
he consumed approximately one pint of vodka per day.
Family history was noncontributory. He was not taking
any medications at home.
On hospital day 22, he sustained a tonic-clonic seizure,
which lasted 4 minutes. Given his prolonged post-ictal
state and low blood pressure he was transferred to the
intensive care unit (ICU). Evaluation at that time revealed
a severely obtunded and jaundiced man. Vital signs
showed a temperature of 38.4°C, heart rate of 92 beats/
min, blood pressure of 109/62, and respiratory rate of 19
breaths/min. Oxygen saturation by pulse oximetry was
95% on room air. Head and neck examination revealed
scleral icterus and a supple neck. Diffuse coarse crackles
were noted on auscultation of the chest. The cardiac
rhythm was regular with a normal rate. No murmurs were
appreciated. His abdomen was markedly distended, con-
sistent with ascites. Guarding, rebound tenderness, and
organomegaly were not appreciated. Neurologic examina-
tion revealed sluggish pupils, a weak gag reflex, and move-
ment of the extremities only in response to painful
stimuli. No asymmetry was appreciated.
Laboratory studies were obtained and revealed a white
blood cell (WBC) count of 62 × 103 cells/mm3, with 89%
polymorphonucleated cells (PMNs), and a platelet count
of 112 × 103 per mm3. His INR was 1.5. An extended met-
abolic and liver panel demonstrated: sodium 127 mEq/L,
BUN 63 mg/dL, creatinine 6.8 mg/dL, total bilirubin 39.8
mg/dL, AST 201 U/L, ALT 109 U/L, and alkaline phos-
phatase 349 U/L. Ammonia was 38 μmol/L. Arterial
blood gas showed a pH of 7.33, PCO2 of 35 mm Hg, PO2
of 184 mm Hg, and HCO3 concentration of 15 mEq/L on
40% oxygen. HIV antibody was found to be negative and
HIV-1 RNA undetectable.
Given his seizure, fever, and leukemoid reaction, he was
started on empiric therapy with cefepime, vancomycin,
ampicillin, and acyclovir. Levetiracetam (Keppra) was ini-
tiated for seizure control. An MRI of the brain was nega-
tive for any evidence of intracranial bleeding or other
space occupying lesions. An EEG was unremarkable. Lum-
bar puncture was attempted, but unsuccessful due to the
patient's prior spine surgery. Paracentesis revealed ascitic
fluid with a WBC of 797 per mm3 with 81% PMNs,
despite therapy with ceftriaxone. Ascites gram stain, bacte-
rial and fungal cultures were negative. Because of his pro-
gressive clinical deterioration amphotericin was added to
his regimen on hospital day 23.
Lumbar puncture under fluoroscopy was performed on
hospital day 24 and cerebrospinal fluid (CSF) analysis
revealed 104 WBCs per mm3 with 98% PMNS, glucose 47
mg/dL, and protein 84 mg/dL. CSF gram stain demon-
strated yeast and culture grew Cryptococcus neoforman (Fig-
ure 1). CSF cryptococcal antigen was also positive.
Though initially negative, blood cultures also grew C. neo-
formans. Flucytosine was added to his medical regimen for
better CSF coverage.
The patient was diagnosed with disseminated cryptococ-
cosis with meningitis, peritonitis, and cryptococcemia.
Meningitis and cryptococcemia, as demonstrated by posi-
tive Cryptococcus neoformans cultures, and peritonitis,
based on peritoneal fluid leukocytosis in the setting of
low suspicion for SBP. The leukemoid reaction was attrib-
uted to alcoholic hepatitis, as cryptococcemia is not a
known cause and no other infections were identified.
Unfortunately, the patient continued to deteriorate with
refractory hypotension and multi-system organ failure.
Given his overall clinical picture and poor prognosis, the
patient's family ultimately elected to withdraw life sup-
porting measures. The patient expired soon thereafter.
Discussion
Cryptococcus neoformans is an encapsulated yeast that pre-
dominately affects immunocomprimised individuals. In
addition to HIV infection, immunosuppressive medica-
tions, solid-organ transplantation, chronic organ failure
(renal and liver), hematologic malignancy, chronic lung
disease, and rheumatologic disorders can also predispose
individuals to this infection [3].
Meningoenecephalitis and pulmonary infiltrates are the
two most common manifestations of cryptococcal disease
[1,2,5]. Disseminated cryptococcosis is defined by 1) a
positive culture from at least two different sites, or 2) a
positive blood culture [5]. In a series of 33 HIV-negative
patients with disseminated disease, cirrhosis was the most
frequent predisposing condition and was associated with
a grave prognosis [5,6]. Leukocyte impairment, comple-
ment dysfunction, and decreased opsonin activity are
believed to predispose cirrhotic patients to cryptococcosis
[1].
Cryptococcal peritonitis is an unusual manifestation of C.
neoformans [1]. Infection of ascitic fluid accounts for less
than 5% of all cryptococcosis cases in HIV-negative
patients [1,4-6]. When liver cirrhosis is jointly considered,
the prevalence of cryptococcal peritonitis is exceedingly
rare [1,4-6]. Our literature review only identified 19 cases
Cases Journal 2009, 2:170 http://www.casesjournal.com/content/2/1/170
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of cryptococcal peritonitis in HIV-negative patients with
liver cirrhosis [1,4-6].
The clinical presentation of disseminated cryptococcosis
is variable and depends on the organ systems involved. C.
neoformans has been identified in cultures from blood,
CSF, sputum, ascites, urine, bone marrow, and skin [2,5].
A diffuse maculo-papular rash may be an important diag-
nostic clue indicating disseminated disease [7]. Central
nervous system (CNS) involvement is the most common
manifestation of disseminated cryptococcosis [5]. Patients
often present in a subacute manner with headache and
fever. Other symptoms can include seizures, confusion,
dementia, and bizarre behavior. Cerebral edema leading
to elevated intracranial pressure can cause blurred vision,
diplopia, confusion, hearing loss, and severe headaches
[8]. In patients with cryptococcal peritonitis, diagnosis
can often be delayed due to lack of specific signs and
symptoms and low clinical suspicion among healthcare
providers [1]. Abdominal pain, increased abdominal
girth, fever, and dyspnea are typical complaints of patients
with cryptococcal peritonitis [1,4].
In patients with CNS disease, imaging of the brain is usu-
ally unremarkable and lumbar puncture is often necessary
to establish the diagnosis. CSF analysis typically reveals a
lymphocytic pleocytosis with elevated protein and
decreased glucose. Opening pressure during lumbar punc-
ture is often elevated to values greater than 20 cm H2O [8].
India ink staining will identify C. neoformans in the CSF of
patients with HIV greater than 90% of the time and in
more than 50% of infected patients without HIV [9]. The
CSF cryptococcal antigen is almost universally positive in
established CNS infection, but may be negative very early
in a patient's clinical course [8,9]. Similar to CNS infec-
tion, diagnosis of peritoneal disease relies on analysis of
ascites fluid and not imaging studies. Diagnosis can be
difficult, requiring multiple ascites fluid samples and pro-
longed culture time [10]. Ascitic fluid usually demon-
strates a low protein level and moderately elevated WBC
Lactophenol Cotton Blue stain of CSF culture noted encapsulated yeast consistent with Cryptococcus neoformans (× 100, × 400)Figure 1
Lactophenol Cotton Blue stain of CSF culture noted encapsulated yeast consistent with Cryptococcus neoform-
ans (× 100, × 400).
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Cases Journal 2009, 2:170 http://www.casesjournal.com/content/2/1/170
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count [1]. Cryptococcal antigen testing can be performed
on ascites fluid, although limited studies exist on its use
and utility [1]. The diagnostic gold standard for C. neofor-
mans infection is growth of the organism in culture from
an otherwise sterile site [8,9].
Treatment regimens are determined by anatomic site of
infection and host immune status. Though no specific
guidelines exist for the treatment of cryptococcal peritoni-
tis, recommendations for the treatment of CNS disease are
well established [11]. Immunocompetent patients with
cryptococcal meningitis should be treated with amphoter-
icin B and flucytosine for 6-10 weeks, or amphotericin B
and flucytosine for 2 weeks followed by fluconazole (400
mg/d) for a minimum of 10 weeks [11]. For immunosup-
pressed patients without HIV infection, it is recom-
mended that cryptococcal meningitis be treated with
amphotericin B +/- flucytosine for 2 weeks followed by 8-
10 weeks of fluconazole (400-800 mg/d), and then fluco-
nazole (200 mg/d) for an additional 6-12 months [11].
Patients with isolated cryptococcal meningitis typically
improve with appropriate therapy. Depressed levels of
consciousness, high CSF cryptococcal antigen titer, and
cryptococcemia are associated with a poor prognosis [9].
An opening pressure greater than 25 cm H2O is the most
important prognostic factor and is associated with
increased morbidity, including diminished mental capac-
ity, vision loss, cranial nerve palsies, and hydrocephalus
[8]. Prognosis for HIV-negative patients with dissemi-
nated cryptococcosis and liver cirrhosis is poor, with 30
day mortality documented at 100% in one study [5]. In
patients with cryptococcemia, liver cirrhosis was the
strongest independent predictor of 30-day morality (haz-
ard ratio 16.3, 95% CI 2.6-101.7, p = 0.003), even when
compared to HIV infection [6].
Conclusion
In summary, disseminated cryptococcosis, particularly
with peritonitis, is an uncommon manifestation of C. neo-
formans infection. Liver cirrhosis serves as a risk factor for
disseminated disease in HIV-negative patients and is asso-
ciated with a grave prognosis. A high clinical suspicion
and early initiation of therapy is needed to recognize and
treat patients effectively.
Consent
Unfortunately, the patient expired and despite multiple
attempts to contact the family, the next of kin was not
available. The patient case is presented anonymously, and
there is no reason to think that the patient or their family
would object to publication.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
BY, ME, and DH were involved in the direct care of the
patient, and contributed to the literature search, data col-
lection, data analysis, and manuscript preparation. SS was
involved in the literature search, data analysis, and manu-
script preparation. All authors have read and approve of
the submitted manuscript.
Acknowledgements
The authors would like to thank Norman J Barker, M.S. and the Pathology
Photography Laboratory at Johns Hopkins University for their assistance.
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