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1.  Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism 
PLoS Medicine  2008;5(11):e219.
Resistance to triazoles was recently reported in Aspergillus fumigatus isolates cultured from patients with invasive aspergillosis. The prevalence of azole resistance in A. fumigatus is unknown. We investigated the prevalence and spread of azole resistance using our culture collection that contained A. fumigatus isolates collected between 1994 and 2007.
Methods and Findings
We investigated the prevalence of itraconazole (ITZ) resistance in 1,912 clinical A. fumigatus isolates collected from 1,219 patients in our University Medical Centre over a 14-y period. The spread of resistance was investigated by analyzing 147 A. fumigatus isolates from 101 patients, from 28 other medical centres in The Netherlands and 317 isolates from six other countries. The isolates were characterized using phenotypic and molecular methods. The electronic patient files were used to determine the underlying conditions of the patients and the presence of invasive aspergillosis. ITZ-resistant isolates were found in 32 of 1,219 patients. All cases were observed after 1999 with an annual prevalence of 1.7% to 6%. The ITZ-resistant isolates also showed elevated minimum inhibitory concentrations of voriconazole, ravuconazole, and posaconazole. A substitution of leucine 98 for histidine in the cyp51A gene, together with two copies of a 34-bp sequence in tandem in the gene promoter (TR/L98H), was found to be the dominant resistance mechanism. Microsatellite analysis indicated that the ITZ-resistant isolates were genetically distinct but clustered. The ITZ-sensitive isolates were not more likely to be responsible for invasive aspergillosis than the ITZ-resistant isolates. ITZ resistance was found in isolates from 13 patients (12.8%) from nine other medical centres in The Netherlands, of which 69% harboured the TR/L98H substitution, and in six isolates originating from four other countries.
Azole resistance has emerged in A. fumigatus and might be more prevalent than currently acknowledged. The presence of a dominant resistance mechanism in clinical isolates suggests that isolates with this mechanism are spreading in our environment.
Editors' Summary
Aspergillosis is a group of lung diseases caused by infection with Aspergillus, a mold (fungus) that grows on decaying plant matter. Because Aspergillus is widespread in the environment, people often breathe in its spores. For most people, this is not a problem—their immune system rapidly kills the fungal spores. However, people with asthma or cystic fibrosis sometimes develop allergic bronchopulmonary aspergillosis, a condition in which the spores trigger an allergic reaction in the lungs that causes coughing, wheezing. and breathlessness. Other people can develop an aspergilloma—a fungus ball that grows in cavities in the lung caused by other illnesses such as tuberculosis. However, the most serious form of aspergillosis is invasive aspergillosis. This pneumonia-like infection, which is fatal if left untreated, affects people who have a weakened immune system (for example, people with leukemia) and can spread from the lungs into the heart, brain, and other parts of the body. Aspergillosis is usually treated with triazole drugs, which inhibit an enzyme that the fungus needs to make its cell membranes; this enzyme is encoded by a gene called cyp51A. Voriconazole is the first-line therapy for aspergillosis but itraconazole and posaconazole are also sometimes used and ravuconazole is in clinical development.
Why Was This Study Done?
About half of patients with invasive aspergillosis recover if they are given triazoles. Worryingly, however, strains of Aspergillus fumigatus (the type of Aspergillus usually involved in invasive aspergillosis) with resistance to several triazoles have recently been isolated from some patients in The Netherlands. If multi-azole resistant strains of A. fumigatus become common, they could have a serious impact on the management of invasive aspergillosis. However, noone knows what proportion of A. fumigatus strains isolated from patients with aspergillosis are resistant to several azole drugs. That is, noone knows the “prevalence” of multi-azole resistance. In this study, the researchers investigate the prevalence and development of azole resistance in A. fumigatus.
What Did the Researchers Do and Find?
Since 1994, all fungal isolates from patients at the Radboud University Nijmegen Medical Center in the Netherlands have been stored. The researchers' search of this collection yielded 1,908 A. fumigatus isolates that had been collected from 1,219 patients over a 14-year period. Of these, the isolates from 32 patients grew in the presence of itraconazole. All the itraconazole-resistant isolates (which also had increased resistance to voriconazole, ravuconazole, and posaconazole) were collected after 1999; the annual prevalence of itraconazole-resistant isolates ranged from 1.7% to 6%. The researchers then sequenced the cyp51A gene in each resistant isolate. Thirty had a genetic alteration represented as TR/L98H. This “dominant resistance mechanism” consisted of a single amino acid change in the cyp51A gene and an alteration in the gene's promoter region (the region that controls how much protein is made from a gene). The researchers also analyzed A. fumigatus isolates from patients admitted to 28 other hospitals in the Netherlands. Itraconazole resistance was present in isolates from 13 patients (out of 101 patients) from nine hospitals; the TR/L98H genetic alteration was present in 69% of the itraconazole-resistant isolates. Finally, itraconazole resistance was present in six isolates from four other countries (out of 317 isolates from six countries); only one Norwegian isolate had the TR/L98H genetic alteration.
What Do These Findings Mean?
These findings indicate that azole resistance is emerging in A. fumigatus and may already be more prevalent than generally thought. Given the dominance of the TR/L98H genetic alteration in the azole-resistant clinical isolates, the researchers suggest that A. fumigatus isolates harboring this alteration might be present and spreading in the environment rather than being selected for during azole treatment of patients. Why azole resistance should develop in A. fumigatus in the environment is unclear but might be caused by the use of azole-containing fungicides. Further studies are now urgently needed to find out if this is the case, to measure the international prevalence and spread of A. fumigatus isolates harboring the TR/L98H genetic alteration, and, most importantly, to develop alternative treatments for patients with azole-resistant aspergillosis.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus Medical Encyclopedia has a page on aspergillosis (in English and Spanish)
The UK National Health Service Direct health encyclopedia has detailed information about all aspects of aspergillosis
The US Centers for Disease Control and Prevention also has information about aspergillosis
Paul Verweij and colleagues show that azole resistance has emerged inAspergillus fumigatus in The Netherlands and that a dominant resistance mechanism is present in clinical isolates.
PMCID: PMC2581623  PMID: 18998768
2.  Cerebral Aspergillosis with Multiple Enhancing Nodules in the Right Cerebral Hemisphere in the Immune-Competent Patient 
Aspergillosis in the central nervous system (CNS) is a very rare disease in immune-competent patients. There was a case of a healthy man without a history of immune-compromised disease who had invasive aspergillosis with unusual radiologic findings. A 48-year-old healthy man with diabetes mellitus, presented with complaints of blurred vision that persisted for one month. Brain magnetic resonance imaging (MRI) showed multiple nodular enhancing lesions on the right cerebral hemisphere. The diffusion image appeared in a high-signal intensity in these areas. Cerebrospinal fluid examination did not show any infection signs. An open biopsy was done and intraoperative findings showed grayish inflammatory and necrotic tissue without a definitive mass lesion. The pathologic result was a brain abscess caused by fungal infection, morphologically aspergillus. Antifungal agents (Amphotericin B, Ambisome and Voriconazole) were used for treatment for 3 months. The visual symptoms improved. There was no recurrence or abscess pocket, but the remaining focal enhanced lesions were visible in the right temporal and occipital area at a one year follow-up MRI. This immune-competent patient showed multiple enhancing CNS aspergillosis in the cerebral hemisphere, which had a good outcome with antifungal agents.
PMCID: PMC3730037  PMID: 23908709
Aspergillosis; Cerebral; Enhancement; Immune-competent; Multiple
3.  Cranial aspergilloma masquerading as meningioma 
BMJ Case Reports  2013;2013:bcr2012008118.
Cranial aspergillosis may present as meningitis, cerebral abscess, cerebral infarcts/haemorrhages or extra-axial mass. Extra-axial cranial aspergilloma may mimic meningioma owing to mass-like characteristics and intense contrast enhancement on MRI there by delaying the diagnosis and further worsening the already bad prognosis in these patients. We present a 45-year-old gentleman who presented with signs of raised intracranial hypertension, secondary optic atrophy and a contrast-enhancing mass arising from the planum sphenoidale. Postoperatively, mass was diagnosed as aspergilloma on histopathology and culture. Despite antifungal treatment, patient could not be saved due to large artery infarcts in the immediate postoperative period. We discuss the clinical and MRI features that could help to have sufficient and early suspicion of fungal aetiology in these patients.
PMCID: PMC3604443  PMID: 23307467
4.  A Case of Acute Cerebral Aspergillosis Complicating Influenza A/H1N1pdm 2009 
Infection & Chemotherapy  2013;45(2):225-229.
Invasive aspergillosis is a rare complication in patients with influenza infection. Several cases of invasive pulmonary aspergillosis accompanying influenza infections were reported during the influenza A/H1N1pdm 2009. We encountered a case of acute cerebral aspergillosis in a patient with influenza A/H1N1pdm 2009 infection. A 24-year-old man with uncontrolled diabetes was diagnosed with influenza A/H1N1pdm 2009 infection. Initial evaluation indicated methicillin-sensitive Staphylococcus aureus pneumonia and diabetic ketoacidosis along with influenza. During his hospital course, multiple new rim-enhancing mass lesions not evident in the initial evaluation developed in the fronto-parietal cortical and subcortical white matter and right cerebellum. Pathology and culture results confirmed the presence of Aspergillus fumigatus. Surgical drainage combined with a total of 18 weeks of antifungal therapy resulted in complete resolution of the infection. This case demonstrates that cerebral aspergillosis can present alongside influenza in patients with diabetes or those under intensive care. Clinical suspicion of invasive aspergillosis is required for a definite diagnosis and better prognosis in such cases.
PMCID: PMC3780949  PMID: 24265971
Central nervous system; Invasive aspergillosis; Influenza; Brain abscess; Diabetes mellitus
5.  Invasive maxillary sinus aspergillosis: A case report successfully treated with voriconazole and surgical debridement 
Introduction: Invasive aspergillosis of the paranasal sinuses is a rare disease and often misdiagnosed; however, its incidence has seen substancial growth over the past 2 decades. Definitive diagnosis of these lesions is based on histological examination and fungal culture. Case Report: An 81-year-old woman with a history of pain in the left maxillary region is presented. The diagnosis was invasive maxillary aspergillosis in immunocompetent patient, which was successfully treated with voriconazole and surgical debridement. Possible clinical manifestations, diagnostic imaging techniques and treatment used are discussed. Since the introduction of voriconazole, there have been several reports of patients with invasive aspergillosis who responded to treatment with this new antifungal agent. Conclusions: We report the importance of early diagnosis and selection of an appropriate antifungal agent to achieve a successful treatment.
Key words:Invasive aspergillosis, voriconazole, fungal sinusitis, antifungal agent, open sinus surgery.
PMCID: PMC4282918  PMID: 25593673
6.  An unexpected cause of orbital apex syndrome in an immune-competent elderly male 
Oxford Medical Case Reports  2014;2014(6):115-117.
Invasive aspergillosis causing orbital apex syndrome (OAS) in an immune-competent individual is a very rare phenomenon, scarcely reported in medical literature. A 68-year-old male presented with progressive loss of vision in the right eye, starting after a cataract surgery. Neurological examination suggested OAS. Imaging was suggestive of mass lesion causing destruction of ethmoid bone. Biopsy of the lesion could not be done initially in view of its proximity to the major neuro-vascular bundle in the orbital apex and cavernous sinus and the major risk involved in the procedure relative to its yield. There was no response to empirical therapy with antibacterials, steroids or Amphotericin-B. Gradually the mass increased in size and was amenable to biopsy. Endoscopy guided biopsy revealed invasive aspergillosis. Switching over to voriconazole lead to successful management. This case highlights the importance of early diagnosis and selection of an appropriate antifungal therapy in the management of invasive aspergillosis.
PMCID: PMC4369989  PMID: 25988050
7.  Repeated Aspergillus isolation in respiratory samples from non-immunocompromised patients not selected based on clinical diagnoses: colonisation or infection? 
BMC Infectious Diseases  2012;12:295.
Isolation of Aspergillus from lower respiratory samples is associated with colonisation in high percentage of cases, making it of unclear significance. This study explored factors associated with diagnosis (infection vs. colonisation), treatment (administration or not of antifungals) and prognosis (mortality) in non-transplant/non-neutropenic patients showing repeated isolation of Aspergillus from lower respiratory samples.
Records of adult patients (29 Spanish hospitals) presenting ≥2 respiratory cultures yielding Aspergillus were retrospectively reviewed and categorised as proven (histopathological confirmation) or probable aspergillosis (new respiratory signs/symptoms with suggestive chest imaging) or colonisation (symptoms not attributable to Aspergillus without dyspnoea exacerbation, bronchospasm or new infiltrates). Logistic regression models (step–wise) were performed using Aspergillosis (probable + proven), antifungal treatment and mortality as dependent variables. Significant (p < 0.001) models showing the highest R2 were considered.
A total of 245 patients were identified, 139 (56.7%) with Aspergillosis. Aspergillosis was associated (R2 = 0.291) with ICU admission (OR = 2.82), congestive heart failure (OR = 2.39) and steroids pre-admission (OR = 2.19) as well as with cavitations in X-ray/CT scan (OR = 10.68), radiological worsening (OR = 5.22) and COPD exacerbations/need for O2 interaction (OR = 3.52). Antifungals were administered to 79.1% patients with Aspergillosis (100% proven, 76.8% probable) and 29.2% colonised, with 69.5% patients receiving voriconazole alone or in combination. In colonised patients, administration of antifungals was associated with ICU admission at hospitalisation (OR = 12.38). In Aspergillosis patients its administration was positively associated (R2 = 0.312) with bronchospasm (OR = 9.21) and days in ICU (OR = 1.82) and negatively with Gold III + IV (OR = 0.26), stroke (OR = 0.024) and quinolone treatment (OR = 0.29). Mortality was 78.6% in proven, 41.6% in probable and 12.3% in colonised patients, and was positively associated in Aspergillosis patients (R2 = 0.290) with radiological worsening (OR = 3.04), APACHE-II (OR = 1.09) and number of antibiotics for treatment (OR = 1.51) and negatively with species other than A. fumigatus (OR = 0.14) and aspergillar tracheobronchitis (OR = 0.27).
Administration of antifungals was not always closely linked to the diagnostic categorisation (colonisation vs. Aspergillosis), being negatively associated with severe COPD (GOLD III + IV) and concomitant treatment with quinolones in patients with Aspergillosis, probably due to the similarity of signs/symptoms between this entity and pulmonary bacterial infections.
PMCID: PMC3519644  PMID: 23145899
Aspergillus; COPD; Clinical management; Aspergillosis
8.  Invasive Aspergillosis in a Renal Transplant Recipient Successfully Treated with Interferon-Gamma 
Invasive aspergillosis is a serious complication of solid organ transplantation. An early diagnosis is hampered by the lack of reliable serum markers and, even if appropriately diagnosed and treated with current antifungal agents, has a high mortality rate. We report a case of invasive pulmonary and cerebral aspergillosis in a renal transplant patient treated with IFN-γ in conjunction with combination anti-fungal therapy for six weeks in whom complete resolution of the fungal infection was achieved. Renal function remained intact throughout the treatment period. Surveillance CT scans of the chest and head showed resolution of prior disease but revealed a new left upper lobe mass four months after completion of treatment with IFN-γ. Biopsy of the lesion was positive for primary lung adenocarcinoma, for which she underwent left upper lobe resection. The pathology report confirmed clear surgical margins and lymph nodes and no evidence of fungal hyphae. IFN-γ should be considered early in the management of invasive aspergillosis in renal transplant patients. To date, allograft rejection has not been encountered.
PMCID: PMC3504275  PMID: 23259133
9.  PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue 
Journal of Clinical Pathology  2005;58(11):1180-1184.
Background: Invasive fungal infections are often diagnosed by histopathology without identification of the causative fungi, which show significantly different antifungal susceptibilities.
Aims: To establish and evaluate a system of two seminested polymerase chain reaction (PCR) assays to identify and discriminate between agents of aspergillosis and mucormycosis in paraffin wax embedded tissue samples.
Methods: DNA of 52 blinded samples from five different centres was extracted and used as a template in two PCR assays targeting the mitochondrial aspergillosis DNA and the 18S ribosomal DNA of zygomycetes.
Results: Specific fungal DNA was identified in 27 of 44 samples in accordance with a histopathological diagnosis of zygomycosis or aspergillosis, respectively. Aspergillus fumigatus DNA was amplified from one specimen of zygomycosis (diagnosed by histopathology). In four of 16 PCR negative samples no human DNA was amplified, possibly as a result of the destruction of DNA before paraffin wax embedding. In addition, eight samples from clinically suspected fungal infections (without histopathological proof) were examined. The two PCR assays detected a concomitant infection with Absidia corymbifera and A fumigatus in one, and infections with Rhizopus arrhizus and A fumigatus in another two cases.
Conclusions: The two seminested PCR assays described here can support a histopathological diagnosis of mucormycosis or aspergillosis, and can identify the infective agent, thereby optimising antifungal treatment.
PMCID: PMC1770765  PMID: 16254108
mucormycosis; aspergillosis; zygomycetes; polymerase chain reaction
10.  Refractory invasive aspergillosis controlled with posaconazole and pulmonary surgery in a patient with chronic granulomatous disease: case report 
Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Among primary immunodefiencies, chronic granulomatous disease (CGD) has the highest prevalence of invasive fungal diseases. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients. In patients whose aspergillosis is refractory to voriconazole, therapeutic options include changing class of antifungal, for example using an amphotericin B formulation, an echinocandin, combination therapy, or further use of azoles. Posaconazole is a triazole derivative which is effective in Aspergillosis prophylaxis and treatment. Rarely, surgical therapy may be needed in some patients. Lesions those are contiguous with the great vessels or the pericardium, single cavitary lesion that cause hemoptysis, lesions invading the chest wall, aspergillosis that involves the skin and the bone are the indications for surgical therapy.
Chronic granulomatous disease (CGD) is an inherited immundeficiency caused by defects in the phagocyte nicotinamide adenine dinucleotidephosphate (NADPH) oxidase complex which is mainstay of killing microorganisms. CGD is characterized by recurrent life-threatening bacterial and fungal infections and by abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enteritis, genitourinary obstruction, and wound dehiscence. The diagnosis is made by neutrophil function testing and the genotyping.
Herein, we present a case with CGD who had invasive pulmonary aspergillosis refractory to voriconazole and liposomal amphotericine B combination therapy that was controlled with posaconazole treatment and pulmonary surgery.
PMCID: PMC3914384  PMID: 24401677
Chronic granulomatous disease; Invasive pulmonary aspergillosis; Posaconazole
11.  A comparative clinicopathologic study of endogenous mycotic endophthalmitis: variations in clinical and histopathologic changes in candidiasis compared to aspergillosis. 
PURPOSE: Endophthalmitis caused by endogenous Candida and Aspergillus species has emerged as a visually threatening complication in patients with immune deficiency of various causes. Twenty-five patients who underwent enucleation, 13 with endogenous Aspergillus endophthalmitis and 12 with endogenous Candida intraocular infections, were evaluated. Both clinical features and intraocular spread of the fungi were studied to determine which clinical and/or histopathologic features could help distinguish aspergillosis from Candida infections. METHODS: Clinical information was sought from each case to determine whether there was any underlying systemic condition and to delineate the characteristic clinical features seen at initial presentation. The results of vitreous and other tissue cultures for bacteria and fungi were evaluated. Patients with AIDS were excluded. The enucleated globes were processed for histopathologic analysis to detect location of the fungal elements, inflammatory response, and vascular invasion by the fungi. RESULTS: With respect to the various predisposing systemic conditions, Candida species endophthalmitis was noted in patients with a history of gastrointestinal surgery, hyperalimentation, or diabetes mellitus, whereas aspergillosis was present in patients who had undergone organ transplantation or cardiac surgery. The vitreous was the primary focus of infection for Candida, whereas subretinal or sub-retinal pigment epithelium infection was noted in eyes with aspergillosis. Retinal and choroidal vessel wall invasion by fungal elements was noted in cases of aspergillosis but not in cases with candidiasis. The high rate of cerebral and cardiac infection in patients with Aspergillus endophthalmitis was not seen in those with Candida infection. CONCLUSIONS: The present study indicates that unlike Candida endophthalmitis, aspergillosis is seen in organ transplant or cardiac surgery patients, and its initial clinical presentation includes extensive areas of deep retinitis/choroiditis. Contrary to the findings in Candida endophthalmitis, vitreous biopsy may not yield positive results in aspergillosis. Aspergillus endophthalmitis is usually associated with a high rate of mortality caused by cerebral and cardiac complications.
PMCID: PMC1298225  PMID: 11190022
12.  Nasopharyngeal carcinoma presenting with rapidly progressive severe visual disturbance: a case report 
Nasopharyngeal carcinoma is one of the most difficult tumors to diagnose correctly at the initial phase because of the occasional lack of nasal symptoms. The perineural spread of the trigeminal nerve is one of the most common and important routes in the intracranial paracavernous extension of nasopharyngeal carcinoma, but visual loss is very rare.
Case presentation
We report the case of a 54-year-old Japanese man with nasopharyngeal carcinoma, who presented with rapid and severe disturbance of left monocular visual acuity and eye movement with a 10-month history of ipsilateral otitis media and facial pain. Magnetic resonance imaging revealed a lesion in the left fossa of Rosenmüller, pterygopalatine fossa, sphenoid and ethmoid sinus, and the left cavernous sinus extending to the orbital apex through the superior orbital fissure. The histopathological diagnosis was nonkeratinizing undifferentiated nasopharyngeal carcinoma. Epstein–Barr virus was detected by in situ hybridization. Although focal radiotherapy induced remarkable tumor shrinkage and relieved ocular motor disturbance and facial pain, his visual acuity did not improve.
The awareness of cranial nerves in addition to intracranial and orbital apex involvement, as in this case, is important for appropriate diagnosis and treatment planning of nasopharyngeal carcinoma.
PMCID: PMC4227451  PMID: 25373786
Cranial nerves; Epstein–Barr virus; Nasopharyngeal carcinoma; Orbital apex; Visual disturbance
13.  Cerebral aspergillosis in a patient with leprosy and diabetes: a case report 
BMC Research Notes  2014;7:689.
Opportunistic fungi are dispersed as airborne, ground and decaying matter. The second most frequent extra-pulmonary disease by Aspergillus is in the central nervous system.
Case presentation
The case subject was 55 years old, male, mulatto, and an assistant surveyor residing in Teresina, Piauí. He presented with headache, seizures, confusion, fever and left hemiparesis upon hospitalization in 2006 at Hospital São Marcos. Five years previously, he was diagnosed with diabetes mellitus, and 17 months previously he had acne margined by hyperpigmented areas and was diagnosed with leprosy. Laboratory tests indicated leukocytosis and magnetic resonance imaging showed an infarction in the right cerebral hemisphere. Cerebrospinal fluid examination showed 120 cells/mm3 and was alcohol-resistant bacilli negative. Trans-sphenoidal surgery with biopsy showed inflammation was caused by infection with Aspergillus fumigatus. We initiated use of parenteral amphotericin B, but his condition worsened. He underwent another surgery to implant a reservoir of Ommaya–Hickmann, a subcutaneous catheter. We started liposomal amphotericin B 5 mg/kg in the reservoir on alternate days. He was discharged with a prescription of tegretol and fluconazole.
This report has scientific interest because of the occurrence of angioinvasive cerebral aspergillosis in a diabetic patient, which is rarely reported. In conclusion, we suggest a definitive diagnosis of cerebral aspergillosis should not postpone quick effective treatment.
PMCID: PMC4203891  PMID: 25280605
Cerebral aspergillosis; Leprosy; Diabetes; Mycotic arteritis; Aspergillus fumigatus
14.  Treatment of bronchopulmonary aspergillosis with observations on the use of natamycin 
Thorax  1968;23(5):519-523.
The problems of treatment in bronchopulmonary aspergillosis are discussed and illustrated by 11 case reports—four with aspergilloma, six with allergic aspergillosis, and two with probable allergic aspergillosis. A simple and effective treatment of aspergilloma, by local surgical evacuation of the cavity followed by irrigation with natamycin (Pimaricin), is described in three cases. Prior treatment of these cases with inhalations or intrabronchial instillations of natamycin was of doubtful benefit. The therapy of allergic aspergillosis is reviewed and an active approach is urged, based on the probable pathogenesis of the disease. This includes consideration of physical methods of removing bronchial plugs, mucolytic agents, steroids, and antifungal drugs given by aerosol in the absence of any that are suitable for systemic use. Steroids improved ventilatory function and were effective in resolving and preventing further episodes of pulmonary eosinophilia, but not usually in clearing the fungus from the bronchial tree, probably because permanent damage had already been sustained; they also carry the theoretical risk of allowing fungal invasion. Natamycin inhalations alone are considered of little value in the active disease, although their place in prophylaxis and when used with steroids remains to be evaluated. Mucolytic agents may help to clear the bronchial secretions, especially when these have become chronically impacted.
PMCID: PMC471841  PMID: 5303008
15.  Localized primary renal aspergillosis in a diabetic patient following lithotripsy – a case report 
Primary renal aspergillosis is rare in diabetic patients. Diagnosis of localized primary renal Aspergillus infection in diabetic patients requires careful investigations due to its benign presentation and lack of associated systemic clinical features. There is also paucity of information on the role of conservative treatment of such localized infection with antifungal agents only. Here, we describe a case of localized renal aspergillosis in a type 2 diabetic patient with a brief review of literature.
Case presentation
We describe a case of unilateral renal aspergillosis following intracorporeal pneumatic lithotripsy (ICPL) in a type 2 diabetic man. The patient presented with mild pain in the left lumbar region and periodic expulsion of whitish soft masses per urethra, which yielded growth of Aspergillus fumigatus. He was treated initially with amphotericin B; however, it was stopped after 2 weeks, as he could not tolerate the drug. Subsequently, he was successfully treated with oral itraconazole.
Localized renal aspergillosis may be suspected in diabetic patients having history of urinary tract instrumentation, mild lumbar pain, passage of suspicious masses in urine and persistent pyuria. Examination of the suspicious substances expelled per urethra is essential for diagnosis as routine multiple urine analysis may yield negative results. Conservative treatment with oral itraconazole alone is effective in cases with incomplete obstruction.
PMCID: PMC1906785  PMID: 17567923
16.  Proven invasive pulmonary mucormycosis successfully treated with amphotericin B and surgery in patient with acute myeloblastic leukemia: a case report 
Invasive mucormycosis (zygomycosis) is the third most frequent fungal infection in patients with hematologic malignancies. It often results in a fatal outcome mainly due to the difficulty of early diagnosis and its resistance to antimycotics.
Case presentation
A 52-year-old Caucasian man was diagnosed with acute myeloblastic leukemia. Following the induction chemotherapy he developed febrile neutropenia. Meropenem (3×1000mg/day) was introduced empirically. A chest computed tomography showed soft-tissue consolidation change in his right upper lobe. A bronchoscopy was performed and the histology indicated invasive pulmonary aspergillosis based on fungal hypha detection. Also, high risk patients are routinely screened for invasive fungal infections using commercially available serological enzyme-linked immunosorbent assay tests: galactomannan and mannan (Bio-Rad, France), as well as anti-Aspergillus immunoglobulin G and/or immunoglobulin M and anti-Candida immunoglobulin G and/or immunoglobulin M antibodies (Virion-Serion, Germany). Galactomannan showed low positivity and voriconazole therapy (2×400mg/first day; 2×300mg/following days) was implemented. The patient became afebrile and a partial remission of disease was established. After 2 months, the patient developed a fever and a chest multi-slice computed tomography showed soft-tissue mass compressing his upper right bronchus. Voriconazole (2×400mg/first day; 2×300mg/following days) was reintroduced and bronchoscopy was repeated. Histologic examination of the new specimen was done, as well as a revision of the earlier samples in the reference laboratory and the diagnosis was switched to invasive pulmonary mucormycosis. The treatment was changed to amphotericin B colloidal dispersion (1×400mg/day). The complete remission of acute myeloblastic leukemia was verified after 2 months. During his immunerestitution, a high positivity of the anti-Aspergillus immunoglobulin M antibodies was found in a single serum sample and pulmonary radiography was unchanged. A lobectomy of his right upper pulmonary lobe was done and the mycology culture of the lung tissue sample revealed Rhizopus oryzae. He remained in complete remission for more than 1 year.
Invasive mucormycosis was successfully treated with amphotericin B, surgery and secondary itraconazole prophylaxis. As a rare disease invasive mucormycosis is not well understood by the medical community and therefore an improvement of education about prevention, diagnosis and treatment of invasive mucormycosis is necessary.
PMCID: PMC3879024  PMID: 24299522
Acute myeloblastic leukemia; Early laboratory diagnosis; Invasive pulmonary mucormycosis
17.  Combining standard clinical methods with PCR showed improved diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies and prolonged neutropenia 
BMC Infectious Diseases  2015;15:251.
We assessed the diagnostic value of standard clinical methods and combined biomarker testing (galactomannan assay and polymerase chain reaction screening) in a prospective case–control study to detect invasive pulmonary aspergillosis in patients with hematological malignancies and prolonged neutropenia.
In this observational study 162 biomarker analyses were performed on samples from 27 febrile neutropenic episodes. Sera were successively screened for galactomannan antigen and for Aspergillus fumigatus specific nucleic acid targets. Furthermore thoracic computed tomography scanning was performed along with bronchoscopy with lavage when clinically indicated. Patients were retrospectively stratified to define a case-group with “proven” or “probable” invasive pulmonary aspergillosis (25.93 %) and a control-group of patients with no evidence for of invasive pulmonary aspergillosis (74.07 %). In 44.44 % of episodes fever ceased in response to antibiotic treatment (group II). Empirical antifungal therapy was administered for episodes with persistent or relapsing fever (group I). 48.15 % of patients died during the study period. Postmortem histology was pursued in 53.85 % of fatalities.
Concordant negative galactomannan and computed tomography supported by a polymerase chain reaction assay were shown to have the highest discriminatory power to exclude invasive pulmonary aspergillosis. Bronchoalveolar lavage was performed in 6 cases of invasive pulmonary aspergillosis and in 15 controls. Although bronchoalveolar lavage proved negative in 93 % of controls it did not detect IPA in 86 % of the cases. Remarkably post mortem histology convincingly supported the presence of Aspergillus hyphae in lung tissue from a single case which had consecutive positive polymerase chain reaction assay results but was misdiagnosed by both computed tomography and consistently negative galactomannan assay results. For the galactomannan enzyme-immunoassay the diagnostic odds ratio was 15.33 and for the polymerase chain reaction assay it was 28.67. According to Cohen’s kappa our in-house polymerase chain reaction method showed a fair agreement with the galactomannan immunoassay. Combined analysis of the results from the Aspergillus galactomannan enzyme immunoassay together with those generated by our polymerase chain reaction assay led to no misdiagnoses in the control group.
The data from this pilot-study demonstrate that the consideration of standard clinical methods combined with biomarker testing improves the capacity to make early and more accurate diagnostic decisions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0995-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4487853  PMID: 26126706
Invasive pulmonary aspergillosis; Biomarkers; Combination testing; Acute leukemia; Neutropenic fever
18.  A Case of Invasive Pulmonary Aspergillosis with Direct Invasion of the Mediastinum and the Left Atrium in an Immunocompetent Patient 
We report a case of invasive pulmonary aspergillosis invading the mediastinum and the left atrium. A 70-year-old woman was hospitalized for dyspnea. She had been well controlled for her diabetes mellitus and hypertension. The chest X-ray disclosed mediastinal widening, and the computed tomography scan of the chest showed that there was a large mediastinal mass and this lesion extended into the left atrium and right bronchus. The cardiac echocardiography showed that a huge mediastinal cystic mass compressed in the right atrium and a hyperechoic polypoid lesion in the left. The pathology from the bronchoscopic biopsy observed abundant fungal hyphae which was stained with periodic acid-Schiff and Gomori's methenamine silver. Despite the treatment with antifungal agents, she died from cardiac tamponade after three months. Invasive pulmonary aspergillosis, which involves the mediastinum and the heart, is very rare in immunocompetent patients.
PMCID: PMC4127410  PMID: 25114701
Invasive Pulmonary Aspergillosis; Immunocompetence; Mediastinal Neoplasms; Heart Neoplasms
19.  A Congruous Superior Quadrantanopsia Following a Junctional Scotoma Induced by Asperogillosis 
A 69-year old man presented to us with decreased vision in his right eye and a relative afferent pupillary defect. Under the presumption that he was suffering from retrobulbar optic neuritis or ischemic optic neuropathy, visual field tests were performed, revealing the presence of a junctional scotoma. Imaging studies revealed tumorous lesions extending from the sphenoid sinus at the right superior orbital fissure, with erosion of the right medial orbital wall and optic canal. Right optic nerve decompression was performed via an endoscopic sphenoidectomy, and histopathologic examination confirmed the presence of aspergillosis. The patient did not receive any postoperative antifungal treatment; however, his vision improved to 20 / 40, and his visual field developed a left congruous superior quadrantanopsia 18 months postoperatively. A junctional scotoma can be caused by aspergillosis, demonstrating the importance of examining the asymptomatic eye when a patient is experiencing a loss of vision in one eye. Furthermore, damage to the distal optic nerve adjacent to the proximal optic chiasm can induce unusual congruous superior quadrantanopsia.
PMCID: PMC3149145  PMID: 21860581
Aspergillus; Hemianopsia; Optic nerve; Scotoma
20.  Invasive aspergillosis in an immunocompetent patient with fever and a cardiac mass 
Infectious Disease Reports  2011;3(2):e12.
Invasive aspergillosis is an often fatal disease that usually occurs in immunocompromised patients. We report a case of invasive aspergillosis presenting as a febrile respiratory infection with a cardiac mass in an immunocompetent patient. Invasive asper-gillosis should be considered in the differential diagnosis of an otherwise undiagnosed invasive febrile respiratory illness, even in immunocompetent patients. Echocardiography should be performed to evaluate for endocarditis in such cases. Prompt initiation of appropriate antifungal therapy is warranted, even before the diagnosis of invasive aspergillosis is confirmed.
PMCID: PMC3892591  PMID: 24470909
invasive aspergillosis; endocarditis; immunocompetent.
21.  Localised invasive sino-orbital aspergillosis: characteristic features 
Background/aim: To describe the characteristic constellation of historical, clinical, radiographic, and histopathological findings of localised invasive sino-orbital aspergillosis based on the authors’ recent experience of four consecutive cases presenting over a 6 month period. Treatment and outcome are reviewed.
Methods: A case series of four patients with review of the English language literature.
Results: There have been 17 reported cases of invasive sino-orbital aspergillosis in healthy individuals over the past 33 years. The authors report four patients who presented during a 6 month period with persistent and significant pain followed by progressive ophthalmic signs—clinical histories reflecting the literature. Similar imaging findings were also noted: focal hypodense areas within apical infiltrates on contrasted computed tomography correspond to abscesses seen at surgery, and sinus obliteration or involvement of the adjacent sinus lining was noted on magnetic resonance imaging. Bone erosion (often focal) was also seen. There is frequently a delay in making the correct diagnosis, and often disease progression occurs despite treatment.
Conclusions: The authors encountered four cases of invasive sino-orbital aspergillosis, three of which occurred in otherwise healthy individuals. The clinician must be aware of the characteristic presentation so that earlier diagnosis, management, and improved outcomes can be achieved.
PMCID: PMC1772124  PMID: 15090423
orbital aspergillosis; orbital infection
22.  Mucormycosis of the hard palate masquerading as carcinoma 
Clinics and Practice  2012;2(1):e28.
A growing number of medically compromised patients are encountered by dentists in their practices. Opportunistic fungal infections such as mucormycosis usually occur in immunocompromised patients but can infect healthy individuals as well. Mucormycosis is an acute opportunistic, uncommon, frequently fatal fungal infection, caused by a saprophytic fungus that belongs to the class of phycomycetes. Among the clinical differential diagnosis we can consider squamous cell carcinoma. Such cases present as chronic ulcers with raised margins causing exposure of underlying bone. There is a close histopathological resemblance between mucormycosis and aspergillosis. Microscopically, aspergillosis has septate branching hyphae, which can be distinguished from mucormycotic hyphae by a smaller width and prominent acute angulations of branching hyphae. A definitive diagnosis of mucormycosis can be made by tissue biopsy that identifies the characteristic hyphae, by positive culture or both. The culture of diseased tissue may be negative and histopathologic examination is essential for early diagnosis. Mucormycosis was long regarded as a fatal infection with poor prognosis. However with early medical and surgical management survival rates are now thought to exceed 80%. In the present case, the fungus was identified by hematoxylin and eosin stain and confirmed by Grocott's silver methenamine special staining technique. Removal of the necrotic bone, which acted as a nidus of infection, was done. Post-operatively patient was advised an obturator to prevent oronasal regurgitation. Since mucormycosis occurs infrequently, it may pose a diagnostic and therapeutic dilemma for those who are not familiar with its clinical presentation.
PMCID: PMC3981330  PMID: 24765427
fungal infection; mucormycosis; necrotic bone; phycomycetes; squamous cell carcinoma.
23.  Invasive pulmonary aspergillosis accompanied by soft tissue lesions during treatment of a patient with hyperthyroidism: a case report 
Invasive pulmonary aspergillosis (IPA) is difficult to diagnose because it requires histopathology and tissue culture, as well as due to its rapid progression. Invasive pulmonary aspergillosis is the primary cause of pulmonary mycosis in China, which can occur in patients with neutrophil deficiency, leukaemia or lymphoma, malignant tumours, or chronic obstructive pulmonary disease with long-term corticosteroid use or bacterial exacerbations. Such fungal infections can lead to disseminated disease and death within weeks, and the mortality rate for untreated invasive aspergillosis is high. Therefore, increased awareness of invasive aspergillosis in non-traditional hosts is warranted due to the high mortality rate experienced by patients with this disease. Invasive pulmonary aspergillosis has become a principal cause of life-threatening infections in immunocompromised patients. Invasive aspergillosis frequently involves the lung parenchyma and is infrequently accompanied by soft tissue lesions. We present an unusual case of a patient with agranulocytosis that was caused by methimazole that was given to control his hyperthyroidism, and IPA that was accompanied by unusual maxillofacial soft tissue swelling that required treatment with voriconazole. Upon follow-up 11 months later, a chest computed tomography scan (CT) revealed that most lesions had been completely absorbed. Moreover, his maxillofacial ulcers had become encrusted, and the soft tissue swelling had subsided.
PMCID: PMC4472550  PMID: 26155194
invasive pulmonary aspergillosis; Aspergillus; voriconazole; hyperthyroidism; agranulocytosis; methimazole
24.  CD4+ T Cells Mediate the Protective Effect of the Recombinant Asp f3-Based Anti-Aspergillosis Vaccine ▿  
Infection and Immunity  2011;79(6):2257-2266.
The mortality and morbidity caused by invasive aspergillosis present a major obstacle to the successful treatment of blood cancers with hematopoietic cell transplants. Patients who receive hematopoietic cell transplants are usually immunosuppressed for extended periods, and infection with the ubiquitous mold Aspergillus fumigatus is responsible for most cases of aspergillosis. Previously, we demonstrated that vaccination with recombinant forms of the A. fumigatus protein Asp f3 protected cortisone acetate-immunosuppressed mice from experimentally induced pulmonary aspergillosis. Here, we investigated the vaccine's protective mechanism and evaluated in particular the roles of antibodies and T cells. After vaccination, Asp f3-specific preinfection IgG titers did not significantly differ between surviving and nonsurviving mice, and passive transfer of anti-Asp f3 antibodies did not protect immunosuppressed recipients from aspergillosis. We experimentally confirmed Asp f3's predicted peroxisomal localization in A. fumigatus hyphae. We found that fungal Asp f3 is inaccessible to antibodies, unless both cell walls and membranes have been permeabilized. Antibody-induced depletion of CD4+ T cells reduced the survival of recombinant Asp f3 (rAsp f3)-vaccinated mice to nonimmune levels, and transplantation of purified CD4+ T cells from rAsp f3-vaccinated mice into nonimmunized recipients transferred antifungal protection. In addition, residues 60 to 79 and 75 to 94 of Asp f3 contain epitopes that induce proliferation of T cells from vaccinated survivors. Vaccine-primed CD4+ T cells are not expected to clear the fungal pathogen directly; however, they may locally activate immunosuppressed phagocytes that elicit the antifungal effect.
PMCID: PMC3125823  PMID: 21422177
25.  Dural arteriovenous fistula discovered in patient presenting with recent head trauma 
Male, 32
Final Diagnosis: Dural arterio-venous fistula
Symptoms: Eye redness • post-trauma headache • tinnitus
Medication: —
Clinical Procedure: Fistula embolization
Specialty: Neurology
Mistake in diagnosis
A dural arteriovenous fistula (DAVF), is an abnormal direct connection (fistula) between a meningeal artery and a meningeal vein or dural venous sinus. The pathogenesis of DAVF still remains unclear. Sinus thrombosis, head trauma, chronic central nervous system, hypercoagulable state, surgery, and hormonal influence are the pre-disposing factors that initiate this disease. The symptoms experienced by the patient will depend on the location of the fistula.
Case Report:
Thirty-two year old Hispanic male who presented one day after a rear ended motor vehicle collision (MVC) with a severe throbbing headache in the left parietal region, left eye redness but no retro-orbital pain and tinnitus in the left ear. He was initially misdiagnosed to have a carotid-cavernous fistula but upon cerebral angiogram was actually diagnosed with a dural arterio-venous fistula in the posterior fossa venous system followed by successful embolization of the fistula.
A cerebral angiography is the gold standard for detection and characterization of a DAVF and will distinguish it from a CCF. Endovascular surgery involves a catheter-based technique for embolization of the lumen of arteries feeding the DAVF, or directly into the vein draining the DAVF. It is very important to recognize the typical findings of patients presenting with a DAVF then quickly proceeding with a cerebral angiogram to determine the exact location of the fistula and the appropriate treatment plan. By diagnosing and treating a DAVF as early as possible, the associated fatal complications can be averted.
PMCID: PMC3816749  PMID: 24194975
dural arteriovenous fistula; cerebral angiography; endovascular embolization; trauma

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