Case ReportCladophialophora bantiana Cerebral PhaeohyphomycosisComplicated by Pulmonary Nocardiosis: A Tale of Two Infections

Muhammad Farhan Khaliq ,1 Rayan E. Ihle ,2 and Christopher P. Schirtzinger 3

1Department of Internal Medicine, Charleston Area Medical Center, Charleston, WV, USA2Department of Pulmonary Critical Care, West Virginia University, Charleston Division, Charleston, WV, USA3Department of Infectious Disease, Charleston Area Medical Center, Charleston, WV, USA

Correspondence should be addressed to Muhammad Farhan Khaliq; muhammadfarhankhaliq@gmail.com

Received 11 September 2018; Revised 2 March 2019; Accepted 26 March 2019; Published 17 April 2019

Academic Editor: Larry M. Bush

Copyright © 2019 Muhammad Farhan Khaliq et al. ,is is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work isproperly cited.

Cladophialophora bantiana, a melanized neurotropic fungus, is the most commonly reported agent of cerebral phaeohypho-mycosis. We present a case of cerebral phaeohyphomycosis due to C. bantiana with a concomitantNocardia infection in the lung.,e patient was a 64-year-old male who presented with one-week history of productive cough, confusion, and staggering gait.Brain MRI showed multiple enhancing masses, and chest CTdemonstrated multifocal consolidation. To confirm diagnosis, brainbiopsy was performed that showed Cladophialophora bantiana. Bronchoscopic lung biopsy confirmed infection with Nocardiaaraoensis. ,e patient was treated with trimethoprim-sulfamethoxazole, meropenem, voriconazole, and liposomal amphotericinin addition to partial resection of the brain mass. After several weeks in the hospital and deteriorating status with poor prognosis,medical care was withdrawn. Cladophialophora bantiana infection is rare and requires multidisciplinary approach for accuratediagnostic confirmation. Aggressive and long-term treatment with voriconazole along with early neurosurgical intervention mayoffer an improved chance of survival in these patients.

1. Introduction

Phaeohyphomycosis is the collective term for infectionscaused by dematiaceous or darkly pigmented fungi. ,eyderive their black color by generating melanin in their cellwalls. Cladophialophora bantiana (C. bantiana) is the mostcommonly encountered agent to cause cerebral phaeohy-phomycosis and is previously known as Cladosporium tri-choides, Xylohypha bantiana, and Xylohypha emmonsii[1, 2]. It belongs to the order Chaetothyriales (ascomycete).Other commonly encountered isolates of the class includeRhinocladiella mackenziei and Exophiala dermatitidis thathave reported to cause cerebral infection. Cases of C.bantiana are reported worldwide though a predominancefor warmer climates with high humidity is apparent. ,efungus can infect both immunocompetent and immuno-compromised hosts. A high index of suspicion is needed fordiagnosis with brain biopsy required for confirmation ofphaeohyphomycosis. Currently, lack of evidence and

management guidelines makes standardized treatmentchallenging. However, aggressive management with surgicalresection and long-term antifungal agents are associatedwith improved outcomes in some reports [3]. Despite thisapproach, mortality reaches up to 70% [2]. We report aseemingly immunocompetent patient who developed cere-bral phaeohyphomycosis but died due to secondarycomplications.

2. Case Presentation

A 64-year-old male, chronic smoker, construction worker,and avid hunter presented with a one-week history ofconfusion and staggering gait leading to a fall. He alsocomplained of cough productive with black sputum. Familyand travel histories were unremarkable; however, socialhistory was remarkable for a recent devastating flood in thetown where he lived that sustained a large amount of waterand mud damage. On presentation, his vital signs were

HindawiCase Reports in Infectious DiseasesVolume 2019, Article ID 4352040, 6 pageshttps://doi.org/10.1155/2019/4352040

normal. On examination, the patient was alert but notoriented. On chest auscultation, decreased breath soundswere noted in the left lower lobe. Neurological, cardiovas-cular, and abdominal examinations were otherwise withinnormal limits. His initial set of labs revealed mild leuko-cytosis, a negative procalcitonin, and hyponatremia. ChestX-ray (CXR) demonstrated left lower lobe pneumonia. Withthis information, he was therefore thought to havecommunity-acquired pneumonia and was initiated on azi-thromycin 500mg intravenous (IV) daily, ceftriaxone 1 g IVdaily, and IV hydration.

Due to his initial neurologic complaints, a brain com-puted tomography (CT) was completed (Figure 1), dem-onstrating a left frontal mass with surrounding cerebraledema and midline shift. Brain magnetic resonance imaging(MRI) (Figure 2) described the lesion as a conglomeration ofmultiple left frontal lobe enhancing masses causing midlineshift. ,is prompted the differentiation of metastatic ma-lignancy versus glioblastoma. Dexamethasone 4mg IV every6 hours and levetiracetam 1500mg IV twice daily werestarted after neurosurgical evaluation. CT of the chest(Figure 3) was performed for further characterization of thelung finding on CXR with the possibility of malignancy inquestion. It demonstrated a multifocal mass-like area ofconsolidation in the left lower lobe with necrosis and cav-itation interpreted as a low suspicion for malignancy withclose interval follow-up recommended (Figure 3). Pulmo-nology was consulted for evaluation with the considerationof bronchoscopy.

With the possibility of the brain lesion still being aglioblastoma, a stereotactic brain biopsy was performed firstinstead of a bronchoscopy. ,is biopsy revealed numerouslight brown, long sparsely branching septated hyphae withdilated spores positive on Gomori methenamine silver(GMS) stain and periodic acid-Schiff (PAS) light greenstains. Cultures were unfortunately not sent from this tissueat this time. Based on these pathology results, infectiousdisease consultation was sought, and empiric liposomalamphotericin 5mg/kg IV daily with concurrent vor-iconazole 300mg IV every 12 hours was initiated. At thistime with a possible disseminated fungal disease on thedifferential, bronchoscopy was pursued. ,ere were noendobronchial lesions present. Fungal culture of lung bi-opsies was completed at 35°C and revealed Nocardia. It wasfurther speciated with matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOFMS) and identified as Nocardia araoensis (Figure 4). ,epatient was therefore treated with trimethoprim-sulfamethoxazole 1600mg/280mg orally every 6 hoursand meropenem 2 grams IV every 8 hours. Blood culturesremained negative throughout his hospital course.

With the still unidentified fungal brain abscess and thesize of the lesion portending a poor prognosis if treated onlymedically, neurosurgery team performed a craniotomy withthe intention of complete resection. Unfortunately, only apartial resection was achievable due to the location and sizeof the mass. Fungal culture of the brain tissue was completedon BBL™ Sabouraud Dextrose Agar, BBL™ Inhibitory MoldAgar, and BBL™ Brain Heart Infusion Agar with 5% Sheep

Blood (BD Biosciences: Becton, Dickinson and Company,Sparks, MD) withmold isolated after 6 days after inoculationat 35°C. ,e isolates were described as velvety green-brown

Figure 1: CT brain axial view demonstrating left frontal lobe massconcerning for glioblastoma.

Figure 2: MRI brain axial view demonstrating multiple enhancingmasses coalescing into a larger mass with surrounding edemaresulting in midline shift involving anterior corpus callosum.

Figure 3: CTchest demonstrating multifocal pneumonia in the leftlung base with areas of suspected internal necrosis. No mediastinallymphadenopathy is visible.

2 Case Reports in Infectious Diseases

in color with very long chain length, minimal branching, andoval conida. Visual identification was made as Cladophia-lophora bantiana (Figures 5 and 6) after 20 days, referencingLarone’s “Medically Important Fungi” text [1]. ,e patientwas treated with concurrent liposomal amphotericin B andIV voriconazole for the first 5 days and then voriconazolealone due to its better bioavailability and central nervoussystem (CNS) penetration with lesser side effects.

,e presence of two rare infections in an otherwiseimmunocompetent individual prompted an immunologicalevaluation including immunological levels of Immuno-globulin (Ig) A, E, G, and M, Herpes Simplex virus PCR,CD4 counts, T4/T8 ratio, B cell count, and Natural killer cellcount and however did not reveal a cause of low IgG. He wastherefore treated with human IV immunoglobulin (IVIG)Octagam® 5% 500mg/kg IV. His 6week hospital course wascomplicated by cachexia, physical deconditioning, poorneurological status, and aspiration pneumonia with re-current episodes of sepsis. Considering his poor overall stateof health and grim prognosis with incomplete resection,palliative services were consulted and family decided towithdraw further medical care and transfer to hospice forcomfort care.

3. Discussion

Fungal infections account for less than 2% of brain abscesses[4]. Cerebral phaeohyphomycosis refers to infection of thebrain caused by “dematiaceous” or melanin-producingfungi. Melanin deposited in their cell wall serves as a vir-ulence factor and aids in evasion from the host’s immu-nological response [5, 6]. ,ese organisms are neurotropicand have a propensity to cause cerebral abscesses. Clado-phialophora bantiana is the most common isolate reportedglobally [7]. It belongs to the order Chaetothyriales (asco-mycete). Other commonly encountered isolates of theclass include Rhinocladiella mackenziei and Exophiala der-matitidis that have reported to cause cerebral infection.Cases of C. bantiana are reported worldwide though apredominance for warmer climates with high humidity isapparent. Interestingly, this mold affects slightly more

immunocompetent than immunocompromised hosts[3, 8, 9]. Males are more often affected with a mean age of40 years [6, 8].

Several environmental factors and nature of occupationappear to have some role, and the pathogen commonlyinoculates through the skin after laceration. Inhalation ofspores, direct extension from paranasal sinuses, and pene-trating trauma to the brain are among the other suggestedmodes of infection [9].,ere has been no ethnic predilectionreported; however, areas of warm humid climate have higherincidence [10]. Indeed, our patient’s frequent outdoor ex-posure and the town’s recent flood damage with exposure tohumid, muddy conditions with the decaying plant materialwere likely his risks of exposure as there were no woundsfound on our patient. He was also infected with Nocardia, aubiquitous pathogen foundmostly in soil, which strengthensthe role of environmental exposures in this case. Our patienthad no signs of soft tissue injury or infection, and respiratorycultures obtained via bronchoscopy were negative for theorganism as were blood cultures. Hematogenous spread is areasonable assumption in this gentleman after inhalation of

Figure 5: Cladophialophora bantiana showing septate hyphae withbranching at 40x magnification from brain biopsy.

Figure 6: Cladophialophora bantiana growing on Sabouraud Agarfrom brain biopsy demonstrating velvety-textured olive-coloredcolonies.

Figure 4: Nocardia araoensis growing on cultures obtained fromlung biopsy at 100x magnification stained with Kinyoun acid-faststain.

Case Reports in Infectious Diseases 3

the organism, given the presence of multiple masses differingfrom the presentation expected in traumatic or direct ex-tension in which a solitary brain abscess would be found.

In fact, the most common manifestation of CNSphaeohyphomycosis is a solitary brain abscess which occursin approximately two-thirds of cases, but multiple easilyidentifiable abscesses can also be seen on CTscan orMRI [8].,e lesions demonstrated on our patient’s MRI are con-sistent with findings reported in other studies [3, 11].Common symptomatic manifestations include headache,seizures, behavior changes, fever, and neurological andbehavioral deficits. Moreover, patients may present withinsidious headaches and slowly evolving neurological signs.,ese reported findings are consistent with our patient’spresentation of slowly evolving confusion, staggering gait,and ultimately altered consciousness. In a review of theliterature, the mean duration of diagnosis after developmentof symptoms were reported to be 115 days [8]. Indeed, in thiscase, definitive diagnosis of Cladophialophora was madeafter 41 days with fungal abscess determined well before.

Radiographically, C. bantiana abscess cannot be dif-ferentiated with certitude from bacterial abscesses, meta-static tumors, or primary tumors such as high-grade gliomasand can result in a delay of diagnosis [12]. ,is case pre-sented inWest Virginia has the second highest prevalence oflung cancer nationwide [13]. Often, these lung cancer casespresent in later stages with metastasis to the brain. ,eresemblance of this patient’s dual lung and brain lesions tolung cancer with cerebral metastasis, along with the patient’srisk factor of prolonged tobacco use, contributed to a delayin diagnosis. Because of this diagnostic bias, initial biopsysamples were only sent for pathology. ,is missed oppor-tunity of collecting culture data also further delayed de-finitive diagnosis until more tissue was obtained.

Despite the opportunistic nature of fungal infections,more than half of patients affected with primary cerebralphaeohyphomycosis are immunocompetent individuals[3, 8, 9]. ,ese patients often only have involvement of thebrain as in our patient, whereas patients with underlying riskfactors, such as transplantation, corticosteroid therapy, di-abetes mellitus, or neutropenia, have disseminated infectionwith widespread involvement. ,e presence of two rareinfections in our case does suggest that a weakened cell-mediated immune response and subsequent immunocom-promised state were a mediating factor for our patient. Uponevaluation, he was later found to have low immunoglobulinlevels confirming this risk. It is particularly difficult to es-tablish the diagnosis of cerebral phaeohyphomycosis in animmunocompromised host where opportunistic infectionsand malignancies like lymphoma become more likely eti-ologies. Cerebral biopsy with histological studies and ex-haustive microbiological cultures for bacteria, mycobacteria,and fungi are considered the diagnostic standard and shouldalways be performed even when an infectious etiology is nothigh on the differential, as illustrated above.

Cladophialophora species are prone to identificationdifficulties due to high degree of phenotypic similarities[10, 14]. C. bantiana does have several characteristics onculture that can lend to identification [1, 14, 15]. However,

it is crucial to identify specific species as significant dif-ferences in pathogenicity, and virulence has been reportedwithin the closely related species. Newer methods such asrolling circle amplification (RCA) that target species-specific padlock probes for the internal transcribedspacer regions of rDNA and matrix-assisted laserdesorption-ionization time-of-flight mass spectrometry(MALDI-TOF MS), based on the detection of mass-to-charge (m/z) ratios of protonated ions from ribosomalproteins, have proven to be a timely, accurate, and re-producible method for the identification of differentspecies [16]. In the current case, C. bantiana was identifiedbased on morphologic characteristics described in Lar-one’s Medically Important Fungi text [1]. Molecular andproteomic testing were not performed to confirm specificspeciation and should be performed when possible.Nonetheless, antifungal therapy for treatment in allphaeohyphomycoses is largely the same and based onclinical experience with antifungal agents and surgicalintervention.

Mortality rate of cerebral phaeohyphomycosis is 70% ormore despite aggressive measures including neurosurgicalintervention and long-term systemic antifungal therapy[3, 8, 9]. ,ere has not been a significant difference insurvival noted with the use of any specific antifungal agent;however, one study did show significantly improved out-comes with the combination of amphotericin, flucytosine,and itraconazole used concurrently [3, 8]. One studyevaluating the in vitro activity of antifungals found thatitraconazole, posaconazole, and isavuconazole had thelowest minimum inhibitory concentrations (MICs) andwere generally more active than amphotericin [10].Amphotericin is also less preferred due to its poor pene-tration into the CNS, electrolyte disturbances, and renaltoxicity [17, 18]. Another study also demonstrated lowMICs against all azoles except fluconazole with mixedresults for amphotericin [8]. Flucytosine susceptibility wasnot tested in either of those studies. Echinocandins, despitea low-side effect profile and lesser drug-drug interaction,demonstrate no susceptibility against these organisms withconsistently highMICs [2, 8].,e duration of the treatmentvaries for an individual patient, and there is no consensusabout how long the course of treatment should be.

Although invasive treatment of bacterial brain abscesseshas evolved in an era of minimally invasive neurosurgicalmanagement, surgical resection is still recommended asadjunctive therapy in brain abscesses particularly in fungalinfections [17, 19, 20]. As antifungal penetration may beparticularly low in areas of necrosis, removal of microbialburden of potentially viable fungi may aid in recovery [18].Some studies suggest that full surgical resection may beassociated with improved survival rates as compared topartial resection or aspiration alone [3, 5, 8, 21]. Lastly, it isessential to note that residue requires proper handling andadherence to care of surgical instruments as C. bantiana ison the Biosafety Level 2 containment list [5]. Preventinginfection of new individuals is of utmost importance, giventhe very high mortality and difficulties in diagnosis andtreatment as discussed above.

4 Case Reports in Infectious Diseases

4. Conclusions

Several distinctive aspects exist to our case. ,e presence ofboth lung and brain masses in a high-risk patient in an areaof high lung cancer incidence and with radiographiccharacteristics of glioblastoma with possible pneumoniaprompted only consideration of malignancy on the differ-ential of the brain abscess. ,is diagnosis was delayed by notsending culture data from the initial brain biopsy. ,epresence of a completely separate lung infection also con-tributed to delay. Based on the limited existing evidence andexperience from our case, it is easy to conclude that out-comes depend on early and accurate diagnosis. We suggestmultidisciplinary approach involving neurology, neurosur-gery, infectious disease, microbiology, and pathology foraccurate diagnostic confirmation and minimizing delay.Confirmatory molecular testing of molds is now recom-mended for accurate identification and susceptibility testing.Multimodal therapy with two to three antifungals along withsurgical resection may improve outcomes. However, there isa paucity of data and guidelines to determine a standardizedapproach to infections from these rare black molds. Casesshould be handled with care not only for proper diagnosisbut also for prevention of infecting individuals involved inthe patient’s case.

Abbreviations

CNS: Central nervous systemCT: Computed tomographyCXR: Chest X-rayGMS: Gomori’s methenamine silverIV: IntravenousIVIG: Intravenous immunoglobulinMALDI-TOF MS: Matrix-assisted laser desorption-

ionization time-of-flight massspectrometry

MIC: Minimum inhibitory concentrationsMRI: Brain magnetic resonancePAS: Periodic acid-SchiffPCR: Polymerase chain reactionRCA: Rolling circle amplification.

Disclosure

,e case was presented as a poster in American ,oracicSociety Conference 2018. Abstract can be found at https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A5474.

Conflicts of Interest

,e authors declare that they have no conflicts of interest.

Authors’ Contributions

MFK collected medical information and drafted the man-uscript. REI and CPS participated in the care, reviewed theavailable literature, and contributed to critical review of the

literature. All authors read and approved the finalmanuscript.

References

[1] D. H. Larone, Medically Important Fungi: A Guide toIdentification, American Society for Microbiology (ASM),Washington, DC, USA, 5th edition, 2011.

[2] C. Garzoni, L. Markham, P. Bijlenga, and J. Garbino, “Cla-dophialophora bantiana: a rare cause of fungal brain abscess.Clinical aspects and new therapeutic options,” Medical My-cology, vol. 46, no. 5, pp. 481–486, 2008.

[3] S. G. Revankar, D. A. Sutton, and M. G. Rinaldi, “Primarycentral nervous system phaeohyphomycosis: a review of 101cases,” Clinical Infectious Diseases, vol. 38, no. 2, pp. 206–216,2004.

[4] M. C. Brouwer and D. van de Beek, “Epidemiology, diagnosis,and treatment of brain abscesses,” Current Opinion in In-fectious Disease, vol. 30, no. 1, pp. 129–134, 2017.

[5] M. Ahmad, D. Jacobs, H. Wu et al., “Cladophialophorabantiana: a rare intracerebral fungal abscess-case series andreview of literature,” Surgery Journal, vol. 3, no. 2, pp. e62–e68, 2017.

[6] P. Gandham, “Cladophialophora bantiana,” InternationalJournal of Research inMedical Sciences, vol. 2, no. 1, pp. 38–41,2014.

[7] A. Atul and R. Vichal, “A case of cerebral abscess due toCladophialophora bantiana,” Journal of Microbiology andInfectious Disease, vol. 2, no. 4, pp. 171–173, 2015.

[8] A. Chakrabarti, H. Kaur, S. M. Rudramurthy et al., “Brainabscess due to Cladophialophora bantiana: a review of 124cases,” Medical Mycology, vol. 54, no. 2, pp. 111–119, 2016.

[9] A. S. Kantarcioglu and G. S. Hoog, “Infections of the centralnervous system by melanized fungi: a review of cases pre-sented between 1999 and 2004,” Mycoses, vol. 47, no. 1-2,pp. 4–13, 2004.

[10] H. Badali, G. S. de Hoog, I. Curfs-Breuker, C. H. W. Klaassen,and J. F. Meis, “Use of amplified fragment length poly-morphism to identify 42 cladophialophora strains related tocerebral phaeohyphomycosis with in vitro antifungal sus-ceptibility,” Journal of Clinical Microbiology, vol. 48, no. 7,pp. 2350–2356, 2010.

[11] D. K. Harrison, S. Moser, and C. A. Palmer, “Central nervoussystem infections in transplant recipients by Cladophialo-phora bantiana,” Southern Medical Journal, vol. 101, no. 3,pp. 292–296, 2008.

[12] B. Hakyemez, C. Erdogan, N. Yildirim, and M. Parlak,“Glioblastoma multiforme with atypical diffusion-weightedMR findings,” 3e British Journal of Radiology, vol. 78,no. 935, pp. 989–992, 2005.

[13] R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics2018,” CA: A Cancer Journal for Clinicians, vol. 68, no. 1,pp. 7–30, 2018.

[14] G. S. Ajantha and R. D. Kulkarni, “Cladophialophora banti-ana, the neurotropic fungus–a mini review,” Journal ofClinical Diagnosis and Research, vol. 5, pp. 1301–1306, 2011.

[15] T. Matsumoto and L. Ajello, “Agents of phaeohyphomycosis,”in Medical Mycology, L. Ajello and R. F. Hay, Eds., pp. 503–524, Arnold, London, UK, 9th edition, 1998.

[16] C. F. Cañete-Gibas and N. P. Wiederhold, “,e black yeasts:an update on species identification and diagnosis,” CurrentFungal Infection Reports, vol. 12, no. 2, pp. 59–65, 2018.

[17] Z. Aljuboori, R. Hruska, A. Yaseen, F. Arnold, B. Wojda, andH. Nauta, “Fungal brain abscess caused by “Black Mold”

Case Reports in Infectious Diseases 5

(Cladophialophora bantiana)—a case report of successfultreatment with an emphasis on how fungal brain abscess maybe different from bacterial brain abscess,” Surgical NeurologyInternational, vol. 8, no. 1, p. 46, 2017.

[18] S. Schwartz, D. P. Kontoyiannis, T. Harrison, and M. Ruhnke,“Advances in the diagnosis and treatment of fungal infectionsof the CNS,”3e Lancet Neurology, vol. 17, no. 4, pp. 362–372,2018.

[19] M. C. Brouwer, A. R. Tunkel, G. M. McKhann, andD. van de Beek, “Brain abscess,” New England Journal ofMedicine, vol. 371, no. 5, pp. 447–456, 2014.

[20] https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A5474.

[21] M. Roche and E. Smyth, “A case of septic arthritis due toinfection with Gemella morbillorum,” Journal of Infection,vol. 51, no. 3, pp. e187–e189, 2005.

6 Case Reports in Infectious Diseases

Stem Cells International

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Disease Markers

Hindawiwww.hindawi.com Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwww.hindawi.com Volume 2013

Hindawiwww.hindawi.com Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwww.hindawi.com Volume 2018

PPAR Research

Hindawi Publishing Corporation http://www.hindawi.com Volume 2013Hindawiwww.hindawi.com

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwww.hindawi.com Volume 2018

Journal of

ObesityJournal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwww.hindawi.com Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwww.hindawi.com Volume 2018

Diabetes ResearchJournal of

Hindawiwww.hindawi.com Volume 2018

Hindawiwww.hindawi.com Volume 2018

Research and TreatmentAIDS

Hindawiwww.hindawi.com Volume 2018

Gastroenterology Research and Practice

Hindawiwww.hindawi.com Volume 2018

Parkinson’s Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwww.hindawi.com

Submit your manuscripts atwww.hindawi.com