Upload
vuongnguyet
View
216
Download
0
Embed Size (px)
Citation preview
Disseminated Balamuthia mandrillaris infection 1
Katherine R. Schafer1, Neil Shah2, MI Almira-Suarez3, Jennifer M. Reese4, George M. Hoke5, 2
James W. Mandell5, Sharon L. Roy6, Govinda Visvesvara6 3
1 Wake Forest University Health Sciences, 2 University of North Carolina at Chapel Hill, 3 4
George Washington University Hospital, 4 Mid-Atlantic Pathology Services, Inc., 5 University of 5
Virginia Health Sciences, 6 Centers for Disease Control and Prevention 6
Balamuthia mandrillaris is a rare cause of human infection but carries a high morbidity 7
and mortality when infections do occur. A case of disseminated Balamuthia infection is 8
presented. Early diagnosis and initiation of recommended therapy are essential for 9
increased chance of successful outcomes. 10
________________________________________________________ 11
Case Report. The patient was an 82-year-old white male with a history of necrobiosis lipoidica 12
versus granuloma annulare of the right hand who was admitted in April 2012 for acute onset of 13
fevers, chills, nausea, vomiting, lethargy, and altered mental status (AMS). He initially presented 14
to an outside hospital emergency department with a temperature of 38.5°C, heart rate of 97 15
beats per minute, and oxygen saturation of 88% on room air. His oxygen saturation improved 16
with nasal cannula oxygen. A chest x-ray was performed, which demonstrated findings 17
concerning for granulomatous disease. Due to his condition, he was transferred to our tertiary 18
care center for further evaluation and treatment. 19
Per his family, he had been healthy and without complaints prior to his current presentation. For 20
approximately 15 months, he had been treated by a dermatologist for skin lesions located on his 21
right thigh and hand as well as left upper extremity (LUE) and abdomen. He had multiple skin 22
biopsies from the right hand, LUE, and right thigh with negative bacterial, acid-fast bacillus 23
JCM Accepted Manuscript Posted Online 1 July 2015J. Clin. Microbiol. doi:10.1128/JCM.01549-15Copyright © 2015, American Society for Microbiology. All Rights Reserved.
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
(AFB), and fungal studies. During this period of time, he took itraconazole for three months 24
without clinical response and was thus started on prednisone. All lesions resolved except those 25
on his right hand. He was treated with a 14-day course of doxycycline and cephalexin for 26
possible cellulitis of the right hand prior to this admission. Previous work-up included a negative 27
syphilis screen and a normal ACE level (drawn for possible sarcoidosis). Chest X-ray (CXR) at 28
that time revealed nonspecific interstitial changes. 29
Review of systems was obtained from family members given the patient’s AMS. Per their report, 30
the patient endorsed a headache, but no neck pain or stiffness. He had no history of mouth 31
sores or genital ulcers and had a remote history of shingles. He had an episode of "bronchitis" 32
one month prior to admission (PTA) that was slow to improve but gradually resolved. 33
In terms of exposures, he had no international travel but did have sea water exposure on the 34
Gulf Coast of Alabama one month prior to admission. He had no pets but had been mowing 35
grass and spreading grass seed PTA. He had no known tick bites but spent time outdoors using 36
a metal detector for treasure hunting and digging in soil. Previously, he taught a bible study 37
group in a prison but had no known tuberculosis (TB) exposure and no previous TB testing. 38
On initial physical exam, he was febrile to 38.2°C and his oxygen saturation was 94% on two 39
liters nasal cannula. He was initially agitated and confused but progressed to somnolence over 40
a period of 12 hours. He had no cervical lymphadenopathy or nuchal rigidity. Cardiac, 41
pulmonary, and abdominal exams were unremarkable. On the right dorsal hand and proximal 42
fingers there was a collection of erythematous punched-out ulcers with overlying crusts that 43
extended onto the palm at the 5th metacarpal-phalangeal surface (Figure 1A). His initial 44
laboratory values were significant for a total white blood cell (WBC) count of 8.60 k/uL with 45
88.3% neutrophils and 4.8% lymphocytes. He also had a hemoglobin of 13.1 g/dL, hematocrit of 46
37.7%, sodium of 129 mmol/L, albumin of 2.9 g/dL, creatinine of 1.3 mg/dL, and glucose of 256 47
g/dL. 48
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
Computed Tomography (CT) of the head revealed age-indeterminate infarcts in the anterior limb 49
of the right internal capsule, left parafalcine frontal lobe and inferior left frontal lobe, favored to 50
be chronic infarcts. CXR showed diffuse, bilateral opacities. CT scan of the chest revealed 51
diffuse centrilobular nodules with intralobular septal thickening. Given his presentation and 52
imaging findings, he was empirically started on intravenous (IV) ceftriaxone and azithromycin for 53
coverage of community-acquired pneumonia. 54
On hospital day (HD) 1, infectious diseases was consulted and the patient was empirically 55
started on treatment for meningoencephalitis including IV vancomycin, ceftriaxone, acyclovir 56
and trimethoprim-sulfamethoxazole (an unknown penicillin allergy precluded the use of 57
ampicillin for coverage of Listeria) in addition to the antibiotics for pneumonia. Repeat 58
examination at that time did reveal nuchal rigidity. Cerebrospinal fluid (CSF) analysis via lumbar 59
puncture revealed an opening pressure of 21cm H2O, protein of 54mg/dL and glucose of 60
86mg/dL. Cell count was remarkable for 14 WBCs (57% lymphocytes, 3% neutrophils and 40% 61
monocytes). No organisms were identified on gram stain. Dermatology was also consulted for 62
skin biopsies and cultures of the patient’s right hand. 63
On HD 2, preliminary report of the patient’s skin biopsy revealed a dense mixed acute and 64
chronic dermal inflammatory infiltrate. Scattered organisms, morphologically compatible with 65
ameba, were noted within lacunar spaces (Figure 1B, original magnification x 400). The 66
organisms showed granular to vacuolated cytoplasm with irregular contours, and contained 67
enlarged nuclei with large central karyosomes (Figure 1C, original magnification x 1000). The 68
patient was therefore empirically started on liposomal amphotericin and voriconazole for 69
coverage of disseminated amebiasis and amebic encephalitis (AE). All other antibiotics except 70
for azithromycin were discontinued. Despite treatment with broad spectrum antibiotics, the 71
patient continued to become increasingly obtunded, eventually requiring transfer to the intensive 72
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
care unit (ICU) on HD 3 for closer monitoring and worsening hypoxia, intermittently requiring 73
increased oxygen supplementation. 74
75
On HD 4, the Centers for Disease Control and Prevention (CDC) was contacted for further 76
therapeutic options. CDC recommended combination therapy shown to have efficacy in 77
previous cases, including pentamidine, sulfadiazine, flucytosine, fluconazole (or itraconazole), 78
and azithromycin (or clarithromycin) as well as miltefosine, which at the time required approval 79
by the Food and Drug Administration (FDA) and overseas delivery before it could be used (1-4). 80
As there was not yet definitive identification of the ameba species, sulfadiazine 1.5g every 6 81
hours, pyrimethamine 200 mg once then 75 mg daily, and leucovorin 25 mg daily were added, 82
based on case reports of successful treatment of Acanthamoeba encephalitis (5). His 83
azithromycin dose was increased to 1800 mg daily as well. At this time, miltefosine was 84
ordered. 85
Given the persistent AMS and concern for AE, magnetic resonance imaging (MRI) of the brain 86
was obtained, which revealed multiple parenchymal supra- and infratentorial rounded lesions 87
with surrounding white matter edema and faint enhancement. The largest lesions were in the 88
left posterior temporal lobe. Other lesions were seen in the left dorsal pons and left frontal lobe. 89
Radiology favored these lesions to be infectious in nature. Neurosurgery was consulted on HD 4 90
for urgent biopsy of the patient’s largest brain mass. At this time, the patient’s sodium level 91
continued to decrease to a nadir of 121 mmol/L. Because of his worsening hyponatremia and 92
the small size of the lesions, they deferred brain biopsy and recommended repeat MRI for 93
evaluation of progression of his lesions. Also, because of the patient’s worsening respiratory 94
symptoms, he underwent evaluation with bronchoscopy. Fluid analysis of the broncho-alveolar 95
lavage (BAL) was negative for Legionella pneumophila, Pneumocystis jiroveci, acid fast bacilli, 96
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
viruses, and fungal etiologies. Gram negative rods were visible from the BAL Gram’s stain so 97
cefepime was added to his antibiotic regimen. 98
On HD 5, the patient’s condition remained unchanged with no signs of improvement. Following 99
CDC recommendations, flucytosine 1750mg IV q 12 hours was added to his treatment regimen. 100
Miltefosine was being held in customs at this time, pending FDA release. 101
On HD 6, a repeat MRI demonstrated increase in the number and size of prior lesions. These 102
lesions also showed peri-lesional edema and faint enhancement. At that time, neurosurgery 103
planned to perform a biopsy with radiologic guidance on HD 10 as his serum sodium 104
normalized. 105
On HD 7, the bacterial culture from BAL grew “few” Pseudomonas aeruginosa which were 106
sensitive to cefepime. The patient’s inability to handle secretions became more pronounced and 107
his clinical status continued to deteriorate, requiring increasing oxygen and low-dose 108
vasopressor support. A family meeting was held to discuss goals of care; the family decided to 109
continue antibiotics but change code status to “Do Not Resuscitate or Intubate.” 110
On HD 8, CDC reported preliminary identification of ameba forms on skin biopsy which favored 111
Balamuthia. Pyrimethamine and leucovorin were discontinued and the patient was started on 112
pentamidine 300mg IV daily. 113
On HD 9, the patient began to have periods of apnea and expired with family at the bedside. 114
The family agreed to proceed with a limited autopsy of brain only. Post mortem gross 115
examination revealed numerous red to brown soft lesions involving bilateral parietal, frontal and 116
temporal lobes, left pons and basal ganglia, and cerebellum, predominantly in subcortical white 117
matter, with many lesions extending to the gray-white junction. Histopathologic examination 118
revealed the granulomatous nature of the lesions, with predominantly cyst forms and occasional 119
trophozoites, consistent with an amebic infection (Figure 2). Additionally, purulent and 120
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
granulomatous inflammation was noted in many subpial and perivascular spaces. Real-time 121
PCR assays performed on fresh-frozen autopsy brain material determined the amebic species 122
as Balamuthia mandrillaris. The CDC performed immunofluorescent staining of the skin biopsy, 123
which was positive for Balamuthia mandrillaris (Figures 1D and 1E). The final diagnosis was 124
disseminated Balamuthia mandrillaris infection. 125
_________________________________________________________________________ 126
Microbiology. Balamuthia mandrillaris is a free-living ameba that lives in soil, dust, and water 127
(6). The species name derives from the first site from which it was isolated in 1986—the brain 128
of a mandrill. The first human case of Balamuthia-associated granulomatous encephalitis was 129
described in 1990. In the lab, Balamuthia feeds on small ameba but not bacteria, which makes 130
its growth in lab challenging. Cultivation of this organism in the lab requires axenic culture or 131
growth in mammalian cell cultures (7). The exact pathogenesis of Balamuthia is incompletely 132
defined at this time, although cell-to-cell contact appears necessary for this process and the 133
organism may have an affinity for binding to the extracellular matrix (2, 7-9). However, human 134
infection appears to begin with either inhalation or percutaneous inoculation of Balamuthia cysts 135
or trophozoites. The organisms are then believed to either migrate through tissue or via 136
hematogenous spread to the location or locations where disease becomes manifest, which can 137
include the brain and skin most commonly but other organs as well. A mouse model of 138
Balamuthia encephalitis proposes the following as one possible mode of infection: the organism 139
is inhaled through the nasal passages, adheres to the nasal epithelium, and then travels along 140
the olfactory nerve into the central nervous system (10). 141
Epidemiology. Balamuthia has been identified in infections in both immunocompromised and 142
immunocompetent patients. There is no clear predilection based on age or sex but cases have 143
been reported from individuals at the extremes of age and the earliest reported cases were in 144
patients with AIDS or substance abuse disorders (2, 11). While there is an over-representation 145
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
of Hispanic ethnicity among reported cases, the cause of this association is not understood and 146
may be related to surveillance, exposure, biology, or other factors or combinations of factors (9, 147
12). Transmission through organ transplantation has also occurred (13, 14). 148
Clinical Presentation. Balamuthia mandrillaris has two primary clinical presentations: cutaneous 149
and granulomatous amebic encephalitis (GAE), both of which may have a prodrome of weeks to 150
months. There are also case reports of sinus infections and pulmonary involvement, typically 151
abscesses (7). Patients may present with isolated cutaneous findings or typical 152
encephalopathy/encephalitis symptoms. The latter presentation may also include meningeal 153
signs (9). The cutaneous manifestations can vary from ecthyma-like lesions to erythematous 154
plaques. 155
The pulmonary findings in our case represent a different presentation from other cases 156
described in the literature. Although we do not have definitive tissue diagnosis for his 157
pulmonary process, it likely represents disseminated amebic infection given the presence of the 158
organism in two other anatomic locations (skin and brain). 159
Diagnosis. The diagnostic difficulty derives from the non-specific presentation, which may not 160
suggest amebic infection early in the disease course. A thorough exposure history, skin exam, 161
and neurologic assessment may suggest inclusion of this entity on the differential diagnosis. If 162
neurologic symptoms are present, brain MRI may be helpful and may show space-occupying, 163
ring-enhancing lesions. If cutaneous involvement is present, skin biopsy can be diagnostic if 164
trophozoite forms are seen. Balamuthia, although difficult to distinguish from Acanthamoeba 165
species on H &E staining, may have 2–3 nucleoli visible. Immunofluorescent staining, PCR, 166
and an experimental serologic test can be performed at CDC to distinguish between Balamuthia 167
and Acanthamoeba species. Cerebrospinal fluid examination may reveal a lymphocytic 168
pleocytosis, elevated protein, normal or low glucose, and normal or mildly elevated opening 169
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
pressure. Brain biopsies may show both trophozoite and cyst forms of Balamuthia that show 170
positive immunofluorescent staining. 171
Consideration of Balamuthia infection early in the disease course is the most important element 172
of diagnostic workup. Once the diagnosis is included in the differential, further diagnostic 173
workup, treatment guidance, and prompt access to miltefosine can be obtained by contacting 174
the CDC Emergency Operations Center at 770-488-7100. Additionally, further information 175
about the clinical features of Balamuthia and its basic workup is available on the CDC website 176
at http://www.cdc.gov/parasites/balamuthia/health_professionals/index.html. 177
Treatment/Prognosis. Prognosis is poor, in part because the diagnosis is often not considered 178
until late in the disease course. There is no clear standard therapy for infections with B. 179
mandrillaris. Pentamidine, flucytosine, fluconazole and sulfadiazine plus either azithromycin or 180
clarithromycin (combined with surgical resection if CNS lesions are present) has been used 181
successfully in a few cases (2). Additionally, miltefosine, an agent used to treat leishmaniasis, 182
has demonstrated some in vitro effect on Balamuthia infections and has been used successfully 183
in combination therapy of Balamuthia GAE and skin infections (4, 15). Miltefosine is not readily 184
available in the United States but can now be obtained directly from CDC under an FDA-185
approved investigational new drug protocol for treatment of free-living ameba infections (16). 186
Amphotericin B, TMP/SMX, and polymixin B have shown little to no in vitro effects on 187
Balamuthia (7). Other work suggests that cyst formation in brain tissue may be hindered by 188
ketoconazole, cytochalasin D, and cycloheximide (17). 189
In summary, Balamuthia mandrillaris infection is a rare, but important, cause of encephalitis and 190
cutaneous infection. It is difficult to diagnose and early tissue biopsy is extremely important. 191
This disease carries a very high mortality. Treatment is poorly defined but early diagnosis, 192
prompt ameba-specific treatment, and increased availability of miltefosine through CDC may 193
have a positive effect on improving outcomes in the future. 194
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
195
Disclaimer: The findings and conclusions in this report are those of the authors and do not 196
necessarily represent the official position of the Centers for Disease Control and Prevention. 197
1. Cary LC, Maul E, Potter C, Wong P, Nelson PT, Given C, Robertson W. 2010. Balamuthia 198
mandrillaris meningoencephalitis: survival of a pediatric patient. Pediatrics 125:e699-703. 199
2. Deetz TR, Sawyer MH, Billman G, Schuster FL, Visvesvara GS. 2003. Successful treatment of 200
Balamuthia amoebic encephalitis: presentation of 2 cases. Clinical infectious diseases : an official 201
publication of the Infectious Diseases Society of America 37:1304-1312. 202
3. Jung S, Schelper RL, Visvesvara GS, Chang HT. 2004. Balamuthia mandrillaris 203
meningoencephalitis in an immunocompetent patient: an unusual clinical course and a 204
favorable outcome. Archives of Pathology & Laboratory Medicine 128:466-468. 205
4. Martínez DY, Seas C, Bravo F, Legua P, Ramos C, Cabello AM, Gotuzzo E. 2010. Successful 206
treatment of Balamuthia mandrillaris amoebic infection with extensive neurological and 207
cutaneous involvement. Clin Infect Dis 51:e7-11. 208
5. Seijo Martinez M, Gonzalez-Mediero G, Santiago P, Rodriguez De Lope A, Diz J, Conde C, 209
Visvesvara GS. 2000. Granulomatous amebic encephalitis in a patient with AIDS: isolation of 210
acanthamoeba sp. Group II from brain tissue and successful treatment with sulfadiazine and 211
fluconazole. J Clin Microbiol 38:3892-3895. 212
6. John D, Howard M. 1995. Seasonal distribution of pathogenic free-living amebae in Oklahoma 213
waters. Parasitology Research 81:193-201. 214
7. Visvesvara GS, Moura H, Schuster FL. 2007. Pathogenic and opportunistic free-living amoebae: 215
Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS 216
immunology and medical microbiology 50:1-26. 217
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
8. Kiderlen AF, Tata PS, Ozel M, Laube U, Radam E, Schafer H. 2006. Cytopathogenicity of 218
Balamuthia mandrillaris, an opportunistic causative agent of granulomatous amebic 219
encephalitis. The Journal of eukaryotic microbiology 53:456-463. 220
9. Mandell GL, Bennett JE, Dolin R. 2009. Mandell, Douglas, and Bennett's Principles and Practice 221
of Infectious Diseases, vol 7. Churchill Livingstone. 222
10. Kiderlen AF, Laube U. 2004. Balamuthia mandrillaris, an opportunistic agent of granulomatous 223
amebic encephalitis, infects the brain via the olfactory nerve pathway. Parasitology research 224
94:49-52. 225
11. Visvesvara GS. 2010. Amebic meningoencephalitides and keratitis: challenges in diagnosis and 226
treatment. Current opinion in infectious diseases 23:590-594. 227
12. Botterill E, Yip G. 2011. A rare survivor of Balamuthia granulomatous encephalitis. Clinical 228
neurology and neurosurgery 113:499-502. 229
13. Centers for Disease Control and P. 2010. Balamuthia mandrillaris transmitted through organ 230
transplantation --- Mississippi, 2009. MMWRMorbidity and mortality weekly report 59:1165-231
1170. 232
14. Gupte AA, Hocevar SN, Lea AS, Kulkarni RD, Schain DC, Casey MJ, Zendejas-Ruiz IR, Chung WK, 233
Mbaeyi C, Roy SL, Visvesvara GS, da Silva AJ, Tallaj J, Eckhoff D, Baddley JW. 2014. 234
Transmission of Balamuthia mandrillaris through solid organ transplantation: utility of organ 235
recipient serology to guide clinical management. Am J Transplant 14:1417-1424. 236
15. Bravo FG, Alvarez PJ, Gotuzzo E. 2011. Balamuthia mandrillaris infection of the skin and central 237
nervous system: an emerging disease of concern to many specialties in medicine. Current 238
opinion in infectious diseases 24:112-117. 239
16. Anonymous. 2013. Investigational drug available directly from CDC for the treatment of 240
infections with free-living amebae. MMWR Morb Mortal Wkly Rep 62:666. 241
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
17. Siddiqui R, Matin A, Warhurst D, Stins M, Khan NA. 2007. Effect of antimicrobial compounds on 242
Balamuthia mandrillaris encystment and human brain microvascular endothelial cell 243
cytopathogenicity. Antimicrobial Agents and Chemotherapy 51:4471-4473. 244
245
246
Figure 1 Dermatologic presentation and pathology. Figure 1A: Erythematous punched out 247
ulcers with overlying crusts on the right dorsal hand. Figure 1B: Histopathology from the right 248
hand showing a dense mixed acute and chronic dermal inflammatory infiltrate and scattered 249
amebic trophozoites within lacunar spaces (arrows). (Original magnification x 400). Figure 1C: 250
High-power view of an amebic organism demonstrating granular to vacuolated cytoplasm with 251
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
irregular contours (pseudopods) containing a nucleus with a large central karyosome (arrow). 252
(Original magnification x 1000). Figure 1D: Low power view of immunofluorescence from skin 253
biopsy. (Original magnification x 100). Figure 1E: High power view of immunofluorescence from 254
skin biopsy with visible amoebic organisms. (Original magnification x 1000). 255
256
Figure 2 Central nervous system lesions. Figure 2A: MRI axial FLAIR image demonstrating 257
multiple focal, rounded hyperintense lesions in the pons, cerebellum, and occipital lobes. Figure 258
2B: Gross section of the pons and cerebellum; softened granular lesion in the pons (see arrow). 259
Figure 2C.: Microscopic examination of the pontine lesion; prominent granulomatous 260
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from
inflammation (yellow asterisk) in abundant necrotic background. A single amebic cyst is seen 261
(black arrow) in the mid-lower field of the picture. 262
on March 29, 2018 by guest
http://jcm.asm
.org/D
ownloaded from