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Background
From the inocuous Athlete's foot to the medical emergency of rhinocerebral Mucormycosis, fungi have the ability to mimic almost every known disease. The classification is confusing but from a practical standpoint, can be divided into superficial and deep fungi. Superficial fungi encompass the dermatophytes which infect hair, skin, and nails. Terms such as ringworm have been applied to these organisms. Deep fungal organisms, as the name suggests, invade the soft tissue and organs. They have a particularly virulent course in immunocompromised patients. Classic deep fungi include Candida, Aspergillus, Mucor, Coccidiodes, Histoplasma, and Blastomyces.
Actinomycosis
Aspergillosis
Blastomycosis
Candida (Deep, Thrush)
Chromomycosis (Chromoblastomycosis)
Coccidioidomycosis (Valley Fever)
Cryptococcosis
Dermatophyte (Ringworm, Jock Itch, Athlete's Foot)
Fusarium
Histoplasmosis
Lobomycosis
Mucormycosis
Mycetoma
Onychomycosis (Nail Fungal Infection)
Paracoccidioidomycosis (South American Blastomycosis)
Phaeohyphomycosis
Sporotrichosis
Tinea Nigra
Tinea VersicolorOUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION RENAL TRANSPLANT PATIENTS
Superficial fungal infections in 102 renal transplant recipients: a case-control study.Gulec AT, Demirbilek M, Seckin D, Can F, Saray Y, Sarifakioglu E, Haberal M.
Departments of Dermatology, Microbiology and General Surgery, Baskent university Faculty of Medicine, Ankara, Turkey.
J Am Acad Dermatol. 2003 Aug;49(2):187-92 Abstract quote BACKGROUND: Renal transplant recipients are predisposed to superficial fungal infections caused by graft-preserving immunosuppressive therapy. Reports have documented a wide range of prevalence rates for superficial fungal infections in this patient group.
OBJECTIVE: The aim of this study was to determine the prevalence and clinical and mycological features of superficial fungal infections in renal transplant recipients at our center.
METHODS: One hundred two consecutively registered renal transplant recipients (34 women, 68 men) and 88 healthy age- and sex-matched persons acting as controls (30 women, 58 men) underwent screening for the presence of superficial fungal infection. Skin scrapings and swabs were obtained from the dorsum of the tongue, upper part of the back, toe webs, and any suspicious lesions. Nail clippings were also collected. All samples were examined by direct microscopy and were stained with calcofluor white. The samples were cultured in Sabouraud dextrose agar, mycobiotic agar, and dermatophyte test medium. Candida species were identified on the basis of germ-tube production, spore formation in cornmeal agar, and results of biochemical testing. Dermatophytes were identified on the basis of colonial and microscopic morphologic features in conjunction with results of physiologic evaluation (in vitro hair perforation test, urease activity, temperature tolerance test, and nutritional test).
RESULTS: Sixty-five (63.7%) of the 102 renal transplant recipients had cutaneous-oral candidiasis, dermatophytosis, or pityriasis versicolor, whereas only 27 (30.7%) of controls had fungal infection. Pityriasis versicolor was the most common fungal infection in the patient group (36.3%), followed by cutaneous-oral candidiasis (25.5%), onychomycosis (12.7%), and fungal toe-web infection (11.8%). Pityriasis versicolor and oral candidiasis were significantly more common among the renal transplant recipients, whereas the frequency of dermatophytosis in patients and controls was similar. Candida albicans was the main agent responsible for oral candidiasis, and Trichophyton rubrum was the most common dermatophyte isolated. Analysis showed that age, sex, and duration of immunosuppression did not significantly affect the prevalence of superficial fungal infection. Cyclosporine treatment and azathioprine therapy were identified as independent risk factors for superficial fungal disease.
CONCLUSIONS: The prevalence of opportunistic infections with Pityrosporum ovale and C albicans is increased among renal transplant recipients, probably owing to the immunosuppressed state of this patient population. However, renal transplant recipients are not at increased risk of dermatophytosis.
LABORATORY CHARACTERIZATION IN SITU HYBRIDIZATION
- In situ hybridization in cutaneous deep fungal infections: a valuable diagnostic adjunct to fungal morphology and tissue cultures.
Abbott JJ, Hamacher KL, Ahmed I.
Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
J Cutan Pathol. 2006 Jun;33(6):426-32. Abstract quote
Dimorphic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and cryptococcosis) can occur in immunocompromised and healthy individuals.
Cutaneous involvement is often secondary and may be the presenting sign of systemic disease. These ominous infections are frequently clinically indistinct, and patient prognosis is influenced by a timely diagnosis and treatment. Morphologic differentiation between these organisms is not definitive, and tissue cultures represent the diagnostic gold standard in current day practice. However, tissue cultures are rarely obtained and merely represent an afterthought in seemingly unsuspecting cases. Furthermore, when performed, they may take several days or weeks for completion.
In situ hybridization (ISH) utilizing oligonucleotide probes directed against fungal ribosomal RNA is a rapid and accurate assay for the identification of dimorphic fungi in paraffin-embedded tissue sections.
We present five patients in whom ISH both prospectively and retrospectively confirmed the presence of a cutaneous infection (histoplasmosis, blastomycosis, coccidioidomycosis, and cryptococcosis). In all of the skin sections analyzed, dimorphic fungi were morphologically apparent but not diagnostically discernible.
In summary, ISH is a valuable tool in the prompt diagnosis of cutaneous deep fungal infections.PCR
Diagnosis of invasive mold infection by real-time quantitative PCR.Pham AS, Tarrand JJ, May GS, Lee MS, Kontoyiannis DP, Han XY.
Laboratory Medicine, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Am J Clin Pathol 2003 Jan;119(1):38-44 Abstract quote We report the design and evaluation of a quantitative real-time polymerase chain reaction (PCR) assay to diagnose invasive mold infection (IMI) by detecting mold DNA in the serum.
This assay detected 200 fg to 20 ng (5-log range) mold DNA and permitted a cutoff of 110 fg (3 genomes). Human or candidal DNA was not amplified. Specificity also was demonstrated by negative results in all 35 patients (76 serum samples) with unlikely IMI at the cutoff. For patients with possible, probable, and documented IMI diagnosed by a combination of clinical, microbiologic, and histologic criteria, this real-time PCR showed positivity in 40% (12/30), 68% (19/28), and 85% (11/13) cases, respectively, in testing of multiple serum samples. The overall serum positivity rate for these patients was 15.1% (73/483).
Quantitative analysis of the positive serum samples estimated the bodily circulating mold burden to be 1.6 x 10(5) genomes (5.3 ng) by geometric mean with 4.2 x 10(7) genomes (1,400 ng) the highest.
These results suggest that for the diagnosis of IMI, this real-time PCR may be a promising alternative to other invasive methods. Further evaluation is underway.
QUALITY ASSURANCE Evaluation of the Status of Laboratory Practices and the Need for Continuing Education in Medical Mycology
Eunice R. Rosner, EdD
Errol Reiss, PhD
Nancy G. Warren, PhD
H. Jean Shadomy, PhD
Harvey B. Lipman, PhDAm J Clin Pathol 2002;118:278-286 Abstract quote
A survey to determine the need for training in medical mycology was sent to 605 US laboratories. Training needs were determined by comparing actual laboratory mycology practices with recommended practices, documenting the extent of mycology training reported by employees, and asking respondents to specify the fungi they considered most difficult to identify. The response rate was 56.7% (with only 316 laboratories providing sufficient information).Results showed a large degree of interlaboratory variation in practices and suggested that more judicious practices could lower costs and improve clinical relevance. Only 55.6% of laboratories reported that at least 1 employee attended a formal mycology continuing education program in the 4 years before the survey. Species of dermatophytes, dematiaceous fungi, and non-Candida yeasts were the most difficult to identify. Training may be needed in basic isolation procedures and in advanced topics such as identification of problematic molds and yeasts and antifungal susceptibility testing.
Educators should consider clinical relevance and cost-containment without sacrificing quality when designing courses. Support for additional mycology training may improve if hospital and laboratory administrators are alerted to potential dangers and costs involved in treating patients with invasive fungal infections.
CLINICAL VARIANTS CHARACTERIZATION ALTERNARIOSIS
- Cutaneous alternariosis in transplant recipients: clinicopathologic review of 9 cases.
Gilaberte M, Bartralot R, Torres JM, Reus FS, Rodriguez V, Alomar A, Pujol RM.
Department of Dermatology, Hospital del Mar, Barcelona, Spain.
J Am Acad Dermatol. 2005 Apr;52(4):653-9. Abstract quote
OBJECTIVES: We sought to evaluate and review the clinical and histopathologic features of cutaneous infections caused by the environmental opportunistic fungus Alternaria observed in transplant recipients.
METHODS: We conducted a retrospective study of cases of cutaneous alternariosis in transplant recipients given a diagnosis in 3 hospitals in Catalonia, Spain, between 1991 and 2001. The clinical and evolution features were reviewed. A panel of histopathologic features was evaluated by two independent observers in all cutaneous biopsy specimens.
RESULTS: In all, 9 transplant recipients (8 men and 1 woman) presenting opportunistic cutaneous alternariosis were studied. The patients were 4 renal, 2 cardiac, 1 liver, and 2 lung transplant recipients. All patients were treated with different immunosuppressive therapeutic regimes. The lesions were solitary (3 patients) or multiple grouped (6 patients): papules (4 patients), plaques (5 patients), inflammatory nodules (2 patients), and recurrent cellulitis with secondary ulceration (1 patient), mainly located on the lower extremities. No extracutaneous involvement was detected. A previous traumatic event was recorded in two patients. A total of 12 cutaneous biopsy specimens were reviewed. Biopsy specimens from early lesions (<3 months evolution) were often characterized by the presence of epidermal changes (3/6 pseudoepitheliomatous hyperplasia; 50%), a diffuse dermal mixed inflammatory infiltrate of lymphocytes, plasma cells, histiocytes, neutrophils, and giant cells, and rare and focal granuloma formation. Dermal abscess or necrotizing folliculitis was occasionally noted. In biopsy specimens from more advanced lesions (>3 months evolution), the presence of a granulomatous inflammatory infiltrate was a constant feature. Suppurative granulomas (2/6; 33%) and sarcoidlike granulomas (2/6; 33%) were noted. In all biopsy specimens, fungal structures with a typical round-to-oval, thick refractile wall were identified.
CONCLUSION: Different clinical and histopathologic patterns can be noted in cutaneous alternariosis. Clinically the lesions manifest as solitary or grouped papules, plaques, or nodules mainly involving the lower extremities. Histologically, a relationship between the evolution of the cutaneous lesions and granuloma formation is detected. An increased awareness regarding the clinical and histopathologic features of cutaneous alternariosis in transplant recipients is important to achieve early detection and treatment.FUNGAL SINUSITIS
- Paranasal Fungal Sinusitis: Contributions of Histopathology to Diagnosis: A Report of 60 Cases and Literature Review.
Taxy JB.
*Department of Pathology, Advocate Lutheran General Hospital, Park Ridge daggerThe University of Chicago, Chicago, IL.
Am J Surg Pathol. 2006 Jun;30(6):713-720. Abstract quote
Sixty cases of fungal sinusitis are presented from 2 institutions, accumulated from 1971 to 2005. Fifty cases were from a large suburban general hospital and 10 from a major university referral center. Two of the 50 and 3 of the 10, respectively, were immunocompromised patients and had acute fulminant disease.
This suggests that encountering the various forms of this disease may, in part, be dependent on the referral nature of the institution. The remainder were immune competent and had chronic symptoms of nasal discharge, stuffiness, and facial pain. Imaging studies frequently showed sinus expansion, opacification, and bone erosion, although no clinical or radiographic features were predictive of extrasinus extension.
Chronic fungal sinusitis is principally represented by fungus ball/mycetoma and allergic fungal sinusitis. The recent literature suggests a predominance of or a predominant interest in allergic fungal sinusitis. Hyphal colonies and the presence of allergic mucin with scattered organisms are histologic observations and are the respective keys to these diagnoses. However, the etiologic role of the fungus in chronic cases is not settled. Patients with chronic sinusitis who yield positive sinus cultures only, but have no organisms visualized histologically, are not universally regarded as having fungal sinusitis. The interest in fungal sinusitis has generated a prominent role for the pathologist.
An awareness of the various forms of the disease and thorough histopathologic study, including submission of all tissues removed at surgery and recognition of allergic mucin, are essential. Acute fulminant/invasive fungal sinusitis may require frozen section for adequate management.
Fungal sinusitis: histologic spectrum and correlation with culture.
Granville L, Chirala M, Cernoch P, Ostrowski M, Truong LD.
Department of Pathology, The Methodist Hospital and Baylor College of Medicine, Houston, TX, USA.
Hum Pathol. 2004 Apr;35(4):474-81. Abstract quote
Fungi are important etiologic agents of sinusitis. However, features of fungal sinusitis including the histologic spectrum, diagnostic mishaps, incidence, and fungal types have not been systematically studied.
From 1996 through 2001, a total of 788 surgical pathology sinus specimens from 384 cases was retrieved. Fungal sinusitis was diagnosed in 58 specimens (7%) from 47 cases (12%).
Four histologic categories of fungal sinusitis were identified: (1) allergic fungal sinusitis in 34 cases (copious mucin, abundant eosinophils, Charcot-Leyden crystals (so-called allergic mucin), with rare noninvasive fungal hyphae); (2) mycetoma/fungus ball in 11 cases (tightly packed fungal hyphae without allergic mucin or tissue invasion); (3) chronic invasive fungal sinusitis in 1 case (tissue granulomas with fungal hyphae); and (4) acute fulminant fungal sinusitis in 1 case (fungal vascular invasion). The diagnosis was initially missed in 16/34 (47%) cases of allergic fungal sinusitis despite typical features; incorrect classification was noted in 47% of cases. Sixty-seven percent of cases had positive fungal cultures, dematiaceous fungi being the most common.
Allergic fungal sinusitis accounted for the majority of fungal sinusitis. Although misdiagnosis or incorrect classification is rather frequent for fungal sinusitis, awareness of the distinctive morphologic features of this entity may prevent these errors.PENICILLIUM
Lymphadenopathy due to penicillium marneffei infection: diagnosis by fine needle aspiration cytology.Chaiwun B, Khunamornpong S, Sirivanichai C, Rangdaeng S, Supparatpinyo K, Settakorn J, Ya-In C, Thorner P.
Departments of Pathology (BCSK, SR, JS, CY), Radiology (CS), and Internal Medicine (KS), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Mod Pathol 2002 Sep;15(9):939-43 Abstract quote Penicillium marneffei is an opportunistic fungal infection that usually causes disseminated disease, mainly in immunocompromised individuals, especially those with HIV infection. Untreated cases are usually fatal. Diagnosis is traditionally made by biopsy and/or culture; successful diagnosis by fine needle aspiration (FNA) has only been reported once.
We present eight cases of HIV-infected patients with lymphadenopathy caused by P. marneffei infection, in which the diagnosis was made by FNA. In all cases, intracellular and extracellular yeast forms were visualized, and the characteristic cross-septation of P. marneffei was highlighted by GMS staining. All diagnoses were confirmed by culture. Anti-fungal treatment for P. marneffei was initiated, resulting in marked clinical improvement. We conclude that a diagnosis of lymphadenopathy caused by P. marneffei can reliably be made by FNA. The diagnosis is more rapid than biopsy or culture, allowing rapid institution of therapy, particularly important in immunocompromised patients.
In all our cases, not only were lymphoma and other causes of lymphadenopathy ruled out, but also the necessity for an open surgical biopsy was obviated. This can be especially beneficial to patients (e.g., three in our study) in which lymphadenopathy is confined to deep intra-abdominal nodes.
SKIN
- Tropical dermatology: fungal tropical diseases.
Lupi O, Tyring SK, McGinnis MR.
Department of Medical Clinics (Dermatology), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
J Am Acad Dermatol. 2005 Dec;53(6):931-51, quiz 952-4. Abstract quote
Fungal infections are common in tropical countries and can have an important impact on public health. Lobomycosis is a common fungal infection in the tropical rain forest of South America, and paracoccidioidomycosis (South American blastomycosis) is a widespread and sometimes severe illness. Penicilliosis marneffei is an opportunistic infection of AIDS patients in southeast Asia. Chromoblastomycosis and mycetomas are causes of morbidity around the world. Sporotrichosis is a worldwide subcutaneous mycosis with a high incidence in tropical countries and is an important illness in immunocompromised patients. Rhinosporidiosis was classed as a fungal infection but is now considered a protistan parasite that belongs to the class Mesomycetozoea. It is included in this review because of its historical classification.
In the past, most of these mycoses were restricted to specific geographic areas and natural reservoirs. There are, however, situations in which people from other regions come in contact with the pathogen. A common situation involves an accidental contamination of a traveler or worker who has contact with a tropical mycosis. Even minor trauma to the skin surface or inhalation of the fungal conidia can infect the patient. Thus recognition of the clinical symptoms and the dermatologic findings of the diseases, as well as the geographic distribution of the pathogens, can be critical in diagnosis of the tropical mycoses. This review discusses some of the more common tropical subcutaneous and systemic mycoses, as well as their signs, symptoms, methods of diagnosis, and therapies.
LEARNING OBJECTIVE: At the completion of this learning activity, participants should be able to recognize the clinical and histologic presentations of tropical fungal diseases with cutaneous manifestations and be familiar with the appropriate therapies.
HISTOPATHOLOGY CHARACTERIZATION GENERAL Diagnosis of Invasive Septate Mold Infections
A Correlation of Microbiological Culture and Histologic or Cytologic Examination
Jeffrey J. Tarrand, MD
Mathias Lichterfeld, MD
Irfan Warraich, MD
Mario Luna, MD
Xiang Y. Han, MD
Gregory S. May, PhD and Dimitrios P. Kontoyiannis, MDAm J Clin Pathol 2003;119:854-858 Abstract quote
We correlated results of microbiologic culture and histopathologic examination for 2,891 consecutive samples from autopsy tissue, surgical or biopsy tissue, and bronchoalveolar lavage (BAL) or bronchial washing (BW) specimens.
For 23 autopsy cases with suspected invasive septate mold infections by histopathologic examination, culture yielded a mold in 12 cases (52%). For 1,683 surgical or biopsy samples, histopathologic evidence of invasive septate mold infection was present in 30 samples, 9 of which also grew mold by culture (30%); 20 additional samples grew mold in culture alone, possibly representing culture contamination. Of 1,185 BAL and BW samples, mold was evident in 28 by cytologic examination and culture, 20 by cytologic examination alone, and 68 by culture alone. These results suggest a positive concordance for culture and histologic-cytologic examination of 23%, although both methods were negative in 96% of surgical and biopsy tissue and BAL and BW samples.
The septate molds cultured from these samples were Aspergillus fumigatus (19), Aspergillus flavus (15), Aspergillus terreus (13), Aspergillus niger (7), Fusarium species (3), and Scedosporium apiospermum (2). A flavus was isolated significantly more frequently from tissue than from BAL and BW samples.
SPECIAL STAINS/
IMMUNO-
HISTOCHEMISTRY
CHARACTERIZATION
Department of Pathology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
The Congo red staining properties of Candida organisms in clinical tissue specimens have not, to the best of our knowledge, previously been reported.
The objective of this study was to determine if the Congo red staining characteristics of Candida vs. Histoplasma, Pityrosporum and Blastomyces could provide useful diagnostic information. Archival tissue specimens that contained Histoplasma, Pityrosporum, Candida and Blastomyces were stained with Congo red. The results of the Congo red staining were compared with the diagnoses which were originally rendered on the tissue.
Nine out of nine cases (100%) of Blastomyces were Gomori methenamine silver (GMS) positive and Congo red positive, seven out of seven cases (100%) of Histoplasma were GMS positive and Congo red negative, and eight out of eight cases (100%) that had Pityrosporum were GMS positive and Congo red positive; these results corroborate with previously described staining patterns for each respective organism. Nine out of nine cases (100%) that had Candida were GMS positive and Congo red negative.
Differential Congo red staining of Candida organisms can provide a rapid and accurate method of diagnosis in tissue specimens vs. Blastomyces and Pityrosporum, but not vs. Histoplasma.Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
PAS stain-A common stain used to identify fungus in tissue sections. It stands for Periodic Acid Schiff.
GMS stain-A common stain used to identify fungus in tissue sections. It is a silver based stain that stains the organisms black in routine tissue sections.
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