Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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On Sep 2018




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MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
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Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

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Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
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Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2011 | Month : November | Volume : 5 | Issue : 6 | Page : 1301 - 1306

Cladophialophora bantiana, the Neurotropic Fungus – A Mini Review

Ajantha GS, Raghavendra D. Kulkarni

Corresponding Author MBBS, MD (Microbiology), Associate Professor, Department of Microbiology, SDM College of Medical Sciences & Hospital, Sattur, Dharwad -580 009, India MBBS, MD (Microbiology), Professor and Head, Department of Microbiology, SDM College of Medical Sciences & Hospital, Sattur, Dharwad -580 009, India

Correspondence Address :
Ajantha GS,
Department of Microbiology,
SDM College of Medical Sciences & Hospital, Sattur,
Dharwad -580 009 (Karnataka State, India)
Email: ajju_dwd@rediffmail.com, ajanthaganavalli@gmail.com

Abstract

Cladophialophora bantiana is the most common and dangerous neurotropic fungus which causes brain abscess. The infection which is caused due to this fungus is risky, not only to the patient due to the poor prognosis, but also to the clinician because of the difficulty in its management as well as to the laboratory personnel who handle it. Only few clinicians are aware of this fungus. Complete awareness among the clinicians and other health care personnel is essential for the successful management of these infections. On this basis, we have reviewed the microbiological, clinical and the therapeutic aspects of the C. bantiana infections.

Keywords

Cladophialophora - Cladophialophora bantiana - Brain abscess - Neurotropic fungi – Dematiaceous fungi – Phaeoid fungi - Cerebral phaeohyphomycosis

INTRODUCTION
CNS infections which are caused by fungi except Cryptococcus neoformans are always a surprise, as the incidence is very less, especially in immunocompetent individuals (1). Apart from Cryptococcus neoformans, a few fungal species like Cladophialophora bantiana, Exophiala dermatitidis, Rhinocladiella mackenzie and Ochroconis gallopava are the recognized neurotropes. C. bantiana, a phaeoid fungus, is the commonest cause of cerebral phaeohyphomycosis (2),(3),(4). The purpose of this review was to provide adequate and clinico-microbiologically meaningful information to the health care personnel who were involved in the management of neurological infections. We searched the English language manuscripts which were published on ‘any date’, through PubMed, Google Scholar, ScienceDirect, MDConsult, Ovid and Medknow. The search terms which were used were ‘Brain abscess’, ‘Cerebral Phaeohyphomycosis’, ‘Phaeohyphomycosis’, ‘Cladophialophora’, ‘Cladophialophora bantiana’, ‘Cladophialophora bantianum’, ‘Xylohypha bantiana’, ‘Xylohypha emmonsii’, and ‘Cladosporium trichoides’.

Dematiaceous Fungi
Dematiaceous, melanized or phaeoid fungi are a heterogeneous collection of generally unrelated fungi which share the common phenotypic feature of being darkly coloured. Their dark pigmentation results from the presence of dihydroxynaphthalene melanin in the cell walls. There is an argument that the term, ‘dematiaceous’ is epistemologically incorrect. Therefore, the term ‘phaeoid’ (which is derived from the Greek word “phaeo,” meaning “dark”) came to be used as a replacement. Both the terms, ‘dematiaceous fungi’ or ‘phaeoid fungi’ have no real taxonomic significance (5), (6). Nowa- days, the term “melanized” is more frequently used. Though thedebate about using different terms to describe the same character continues, all these terms are in common use. Dematiaceous fungi, though they are mainly saprophytic, are important agents of human and animal diseases. At present, over 150 species and 70 genera of dematiaceous fungi are known to cause various diseases and the list of potential pathogens is expanding rapidly (7). This group includes hyphomycetes, coelomycetes and ascomycetes. The clinical conditions which are associated with dematiaceous fungi are broadly classified into chromoblastomycosis, eumycotic mycetoma, and phaeohyphomycosis (Table/Fig 1) (6), (8),(9),(10).

The second nomenclature committee of the International Society for Human and Animal Mycology (ISHAM) recommends that the term “phaeohyphomycosis” should be a generic term for any mycosis which involves a dematiaceous fungus (5). Clinical laboratories have to maintain high vigil and diligence in the task of identifying the dark moulds and in assessing their clinical significance.

Taxonomy of C. bantiana
C. bantiana is a melanized hyphomycetous (hyphomycetous - conidia not enclosed within any special structure) fungus which belongs to the order, Chaetothyriales (4). This fungus has been christened several times by taxonomists; hence, different names like Cladosporium bantianum, Cladosporium trichoides, Xylohypha bantiana and Xylohypha emmonsii have been found to be used for the same organism in the literature. (2),(3),(4),(5), (11).

The genus, Cladophialophora represents the anamorph members of ascomycetes in the order, Chaetothyriales, in the family, Herpotrichiellaceae. (9) These members are encountered in human infections which range from mild cutaneous lesions to fatal CNS infections. (12) C. bantiana was earlier under the genus, Cladosporium and it was later transferred to the genus, Xylohypha. (13) C. carrioniiand C. devriesii also were included in the genus, Cladosporium. Large subunit rRNA sequencing studies and nutritional physiology tests have led to the taxonomic reclassification of many fungal pathogens into the genus, Cladophialophora. Other species which are included under the genus, Cladophialophora are C. emmonsii, C. modesta, C. arxii, C. saturnica, and C. boppii. (6), (14), (15).

The type species of the genus, C. carrionii, causes chromoblastomycosis. C. bantiana and C. modesta cause brain infections, C. devriesii and C. arxii cause disseminated disease and C. boppii, C. emmonsii and C. saturnica cause cutaneous infections. (12), (16), (17).

Microbiology of C.bantiana
Phaeoid fungi need intensive efforts for their identification upto the species level. Morphological, physiological and biochemical characters are used in their identification. Molecular studies now provide precision in the identification when the routine procedures are inconclusive. Among the vast array of these dematiaceous fungi, C. bantiana remains a comparatively easier species for identification,mainly because of its typical morphology and the source of the clinical specimen. It can grow on routine fungal culture media. The more commonly used media are potato dextrose agar, oatmeal agar and malt agar. Sabouraud’s dextrose agar is not generally preferred for black mould identification because the colonies may fail to develop their characteristic colour on this medium and the conidiation or sporulation may also be delayed or poor (6).

There are few important growth requirements and colony characteristics that may help towards the identification of this fungus. (6), (14), (18), (19) Its growth rate is moderate and it takes around 7-8 days of incubation to see visible growth. This fungus grows at both room temperature and at 370 C. The colonies mature within 15 days and they show a velvety texture and olivaceousgray to brown discolouration with a black reverse (Table/Fig 2). They do not produce any diffusible pigment.

C. bantiana has few important microscopic features which help in its identification. (6), (14), (18), (19) The fungus shows hyaline-to-brown, septate hyphae. Smooth walled, single-celled, pale olivaceous, ellipsoidal to spindle-shaped conidia of approximately 2.5-5 x 6-11 μm in size are seen. They are arranged in long, strongly coherent (non-fragile) chains and rarely show branching (Table/Fig 3) and (Table/Fig 4). The chains of the conidia arise directly from the hyphae. Chlamydoconidia are seen occasionally.

The Cladophialophora species are prone to identification problems because of the high degree of phenotypic similarity between its different species. Cladophialophora and Cladosporium can be differentiated, as the former do not display the dark scars of attachment. The type species of the genus Cladophialophora, Cladophialophora carrioni, shows densely-branched conidial chains. The chains arise from branched or unbranched denticles in C. carrioni.

There are some conventional biochemical tests and physiological tests which are commonly used in the identification of C. bantiana. (6), (20), (21) This fungus grows at 42-430 C, it can grow on media which contain cycloheximide, it is urease positive and the Fontana- Masson staining stains it black (Table/Fig 3). The Fontana- Masson stain is specific for melanin. This species is non-proteolytic on casein agar and it is unable to liquefy 12% gelatin. However, molecular methods like sequencing are the most dependable tools which can be used for its confirmation.

C. bantiana has rarely been isolated from nonhuman sources and only a few reports of its isolation from nature are on record. (20) The precise ecological niche of the fungus is unknown, but it is believed to be a soil fungus. (2), (12) The occupational association of the C. bantiana infection with farming is suggestive of the presence of this fungus in this environment.(22), (23).

Its primary pulmonary colonization may be important, following which it is transferred through the haematogenous route to the CNS. (2), (5), (16), (21), (24) This fungus has been shown to be present in the lungs of cerebral phaeohyphomycosis patients. (25) Animal experiments have shown that the organism is carried via blood to the CNS.(20) The presence of fungal elements in the arterial walls has been considered as the evidence of its spread to the CNS through the blood vessels. The multiple brain abscesses which are seen frequently also suggest its dissemination through the blood stream. (4) The rarely occurring cutaneous or subcutaneous infections result from its traumatic inoculation(26).

The laboratory personnel who handle this organism should not ignore the fact that pulmonary colonization is the initial eventand that the fungus is capable of infecting immunocompetent individuals. This species has been included in the list of fungi which should be kept under biosafety level-2 containment and therefore the use of a biosafety cabinet is imperative. (9), (18).

The fungi which are commonly encountered in non‑traumatic brain infections are C. bantiana, C. modesta, Exophiala dermatitidis, Fonsecaea monophora, Ochroconis gallopava and Rhinocladiella mackenzie. Amongst them, C. bantiana is the most frequentlyisolated fungus from cerebral phaeohyphomycosis. (2) This fungus has the ability to cause CNS infections in immunocompetent young individuals with no underlying risk factors for the fungal invasion. (2), (4) The infection with C. bantiana is commonly reported in transplant recipients, intravenous drug abusers or in patients on steroids. The condition may be mistaken for tubercular abscess. (27) Though extracranial infection is extremely rare, the fungus has also been reported to cause cutaneous and subcutaneous phaeohyphomycosis. (16), (24), (29), (26).

The virulence attributes of C. bantiana have not been adequately understood. Melanin production and thermotolerance (above 400C) have been considered to be the important virulence factors which are responsible for its pathogenicity. (12) Animal pathogenicity studies have confirmed its affinity to the glial tissue. (20) The evolutionary advantage, if any, of its growth in the living brain tissue remains unclear. (16) Neurotropism is related to the introns in the 18S rDNA subunit of the fungi. (30) Melanin may play a role in the CNS localization, probably, as it scavenges the free radicals which are produced by the phagocytic cells.(4) Melanin, as a virulence factor, has also been suggested in the CNS metastasis of malignant melanoma. Although the tumour spreads to many parts of the body, it has a predilection for the brain.(4), (31) However, melanin may not be the only factor for the CNS infection, as many other melanized fungi are not the frequent invaders of the CNS.

The infection provokes a granulomatous reaction which contains large numbers of giant cells. The fungal elements inside the phagocytes retain their viability. The suppression of innate cellular immunity by using cortisone is demonstrated to promote the C. bantiana infection. The first line of defense probably includes the complement system and PMNs, but T cell-mediated immunity also plays a role. (16), (22).

CerebralPhaeohyphomycosis
C. bantiana infections are increasing in recent years.(2) The organism has a general preference for warmer climates with high humidity. Cases from arid climatic zones are rare.(16) Most infections occur in the 2nd or 3rd decades of life. However, it is noteworthy that the youngest patient who was reported was a six day old neonate(32).

The brain infection may present as a solitary, well-defined abscess, multiple abscesses or poorly demarcated cerebritis with extensive necrotic lesions.(2), (5), (7), (23), (25) Brain abscess is the commonest manifestation.(2) The abscesses are usually hemispheric and they affect the white matter and show a predilection for the frontal lobes. However, choroid plexus, thalamic, diencephalic, and cerebellar involvement can also occur.(16), (23) The extent and delineation of the lesions may vary according to the immune status and to immune response of the subject.(6) Rare presentations such as meningitis and meningoencephalitis have also been reported. (2), (32) Whether the character of the lesion is an important determinant of the clinical outcome or not, is not clear. (2), (23) Diffuse lesions or multiple lesions may complicate the surgical management(33).

CNS infections which are caused by C. bantiana have been reported worldwide. (16), (21), (22), (24), (25), (28), (33) The first cultureproven case was reported in 1952. 34 The first culture-proven Indian case was reported from Mumbai in 1966. (35) Many reports from various parts of India are available since then(23), (27), (36),(37),(38),(39),(40),(41).

Recently, we isolated this fungus from a case of brain abscess. During the literature search, we could not come across any report of the isolation of this pathogen from north Karnataka. Therefore,to the best of our knowledge, this is the first culture-proven case of cerebral phaeohyphomycosis which was caused by C. bantiana, from north Karnataka. The patient was treated by a near-total excision of the lesion and amphotericin B for two weeks, followed by fluconazole for six months. He was advised 5‑flucytocin in addition to amphotericin-B; however, he could not afford any antifungal other than fluconazole. The patient was doing well at follow up after three months. The case was discussed, where the radiological aspects were highlighted(42).

Management
Cerebral phaeohyphomycosis is one of the most difficult conditions to treat. The mortality rate could reach up to as high as 70%, even in the treated cases. (2) When left untreated, the CNS infections which are caused by C. bantiana can be fatal within one to six months. (18) Complete excision of the brain abscess is better than simple aspiration or partial excision, and this is recommended. (2), (4), (5) Total excision of the well-defined abscess helps in reducing the pressure effects, reduction of the fungal load and in enhancing the response to the antifungal therapy. However, recurrence is a noted problem(23).

Antifungal therapy is essential in spite of surgical excision. The probability of residual fungal elements cannot be ruled out even after a thorough excision. (37) In addition, there are no standard guidelines for antifungal therapy which are available so far. The recommendations are based on anecdotal personal experiences. The rarity of this infection does not permit in gathering evidence which is based on authentic clinical trials. Monotherapy is not preferred as it often results in treatment failure. (4) Although amphotericin B has an antifungal activity against C. bantiana, the fungus may have innate or acquired resistance to it. (5) In an Indian case series, mixed results were noted with the drug. (23) Flucytosine has an antifungal activity against C. bantiana, and it also has excellent penetration into the CSF. (2) Because of the increasing risk of resistance, it has to be used in combination with other antifungal agents. (43) Ketoconazole, miconazole and fluconazole are not recommended. (18) In spite of having negligible activity, fluconazole has been used in some of the cases because of its low cost. (10) Identical problems were encountered in our case and because of the financial inability of the patient, we had to put him on fluconazole, hoping for at least a little support to the immune apparatus, to combat the residual fungal elements after thorough excision. Voriconazole has a fungicidal effect on C. bantiana. (44) It has good penetration into the CNS, but its MIC for C. bantiana is high. The clinical significance of the high MIC is not clear. Both success and failure have been reported. (10), (28), (33), (45), (46) Hence, it might not be the first choice of treatment in such infections(14).

Caspofungin has poor antifungal activity against this fungus. Posaconazole and itraconazole have the best in vitro activity against C. bantiana, followed by isavuconazole. (14) Concerns over the adverse effects and the lack of intravenous formulations are the problems with itraconazole. (7) Isavuconazole needs further evaluation. Experimental studies in murine models have shown best responses with posaconazole, where it prolonged the survival and reduced the level of the brain’s fungal burden significantly as compared to itraconazole. (47) At present, posaconazole appears to be the promising drug against C. bantiana as it also has good penetration into the CNS. (14) However, it must be noted that the action of posaconazole against C. bantiana is static and not cidal(47).

The number of isolates which have been tested against various antifungal drugs to date is low and therefore, the susceptibility profiles have a limited predictive value. The clinical correlation data are limited. (10) Complete surgical excision in combination with multi-antifungal therapy, seems to be the best treatment option at present. Initial combination therapy with liposomal amphotericin B and high dose azole (itraconazole, voriconazole or posaconazole), with or without 5-FC has been suggested in the literature. (2), (4), (14), (23), (27) Again, there is no standard guideline on the duration of the therapy. It can be as short as 3 months, which can be extendable up to or more than a year. The therapy should be continued until a complete radiographical resolution occurs. (4) The importance of a continuous long term follow up cannot be over emphasized.

Difficulties in the Developing World
Most of the antifungals which are available for human therapy have two important drawbacks; the first being toxicity and the second, the cost. In the developing world, the cost becomes the primary issue. In addition to affordability, the uncertainty of the outcome is another deterrent which influences the decision making to initiate the therapy, as ultimately it is the patient who is going to select one of the different therapeutic options which are offered to him/her. The investigations and hospitalization charges add to the expenses. The approximate cost of only 6-8 weeks of the most economical therapy exceeds at least three hundred thousand Indian National Rupees. Because of this limitation, many cases in India are being treated with non-lipid based amphotericin B, with or without combination, which is within the reach of the Indian population. In many cases, even fluconazole has been used in spite of its proved inefficacy.

The development of a more effective as well as economical antifungal therapy, along with an accurate non-invasive diagnostic technique only will end this uncertainty about the outcome of the treatment and will ensure a better prognosis for this fatal fungal infection. Also, the pace of the research on this topic has to be stepped up further. It should be emphasized on the clinical fraternity that advanced imaging techniques including MR spectroscopy are far from being perfect in the establishment of the aetiological diagnosis. The culture and identification of the causative fungal agent is indispensible for its management. The identification of the fungus upto the species level is crucial in selecting the antifungal agent, as the choice of the antifungal agent varies with the species. When the fungus is isolated from clinical samples, a compatible histopathology is also a must.

Conclusion

Brain abscesses are diagnosed early and more frequently because of the advancements in radiology. C. bantiana is one of the most important fungal agents which cause nontraumatic brain abscess. Culturing and histopathological studies together give the confirmatory evidence of the aetiological diagnosis. The laboratory physicians need to exercise a meticulous approach while handling the specimens. Awareness, as well as a high index of suspension among the clinicians is the key in diagnosing this potentially fatal neurotropic fungal infection. Though the therapy is difficult, newer azoles like posaconazole have shown some promising results.

Conflict of Interest:None declared.

Key Message

C. bantiana is the commonest cause of non-traumatic CNS infections.

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