Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Invasive Fungal Sinusitis We will begin with a case presentation of a woman who presented with a rare and interesting form of chronic invasive fungal sinusitis. We will then discuss the spectrum of fungal sinus disease and some of the clinical features of invasive fungal sinusitis. We will then move on to some of the treatments we have seen in the past and some of the new treatment horizons that can be applied to this disease. Let us begin with the case presentation. M.P. is a 59-year-old Hispanic female admitted to Ben Taub with nausea, vomiting, right periorbital pain, and blurry vision. Work-up revealed hyponatremia and a diagnosis of syndrome of inappropriate antidiuretic hormone was established. She was admitted to the Medical Intensive Care Unit for fluid restriction and electrolyte management. A review of systems revealed no fevers, cough, nasal congestion, facial weakness, or headache. She did report worsening vision for the past five days. She has a past medical history of type 2 diabetes and has had a left above-knee amputation, as well as bilateral cataract surgery. Currently, her diabetes is well controlled with Glucovance, with sugars ranging from the 130s to 150s. On physical examination, she is an alert and pleasant. She was afebrile with stable vital signs. She had notable right eye proptosis as well as ptosis of the right upper lid, and she had mild periorbital edema. Her pupils were asymmetric, and the pupillary response could not be detected due to post surgical change. She had noted ophthalmoplegia with palsy of the right cranial nerves III, IV, and VI; and evaluation by Ophthalmology revealed only visual light perception with right optic nerve atrophy. Nasal endoscopy revealed middle turbinate edema. She had no discoloration of her mucosa or eschar, and she had purulence from the posterior nasal cavity and ethmoid region. She had no maxillary sinus tenderness. She had a white blood cell count of 4.8, with 68% neutrophils. She was slightly anemic and had a normal platelet count. Her CHEM 7 was notable for very low sodium at 111, her potassium was slightly low, and her glucose was 137. She had an HIV test at the time we evaluated her, which was negative, and she had a normal chest X-ray. A CT scan of the orbits and brain was obtained by the Medicine Service, and it revealed this soft tissue density in the right sphenoid sinus with inflammatory change extending into the right orbit. Even on these soft tissue windows here, you can see some possible bony involvement of the lateral wall of the sphenoid sinus. She also subsequently had an MRI. This is a T2-weighted gadolinium-enhanced MRI, and here on this coronal section, you can see the sphenoid sinus disease on the right, as well as some inflammation in the posterior right orbit. That is better appreciated on this axial slice. The Otolaryngology Service was consulted, the patient was taken to the Operating Room, and an endoscopic sphenoidotomy and debridement was performed. At the time of operation, she was found to have edematous mucosa with mild purulence in the right sphenoid ethmoid recess and thick, pasty, yellow-brown debris in the right sphenoid. Interestingly, on palpation, she had no apparent sphenoid wall dehiscence. Pathology specimens were sent, and they revealed submucosal fungal hyphae with necrosis. A calcofluor white stain was performed, and a diagnosis of invasive fungal sinusitis was established with the orbital apex syndrome, which is defined as visual loss and ophthalmoplegia. The primary determinant in invasive fungal disease is not really the pathogen as much as the state of the host, and, particularly, the host neutrophil. In the normal host neutrophil, the functions of chemotaxis, phagocytosis of the pathogens, and respiratory burst are the critical functions for defense against a fungus. When you look at fungal disease in general, it really is a disease of altered hosts. That can be in one of two ways: immunosuppression (due to a number of causes, such as diabetes or HIV, or bone marrow transplantation) or hypersensitivity and atypia in a patient. As fungal diseases are emerging, particularly with the onset of HIV over the past twenty years, fungal pathogens are beginning to form a more important part of this picture, as we are beginning to see some azole-resistant zygomycetes as well as the pigmented dematiaceous fungi. Fungal sinusitis as an entity was initially described in the late 1700s. By the mid-1800s to late 1800s, it was described in both noninvasive and invasive forms. It was in 1965 when Hora actually put the whole picture together and described fungal sinusitis as a spectrum disease ranging from noninvasive to invasive. If you look at the literature over the history of this disease, it has had some confusing nomenclature and, up until recent years, it has not really had a standard nomenclature. There have been various entities that relied on the infective agent. It was frequently called sinus aspergillosis or rhinocerebral mucormycosis. Then, there have been names based on morphology, such as mycetoma, which actually is a little inaccurate as well. In 1997, DeShazo reviewed the literature on fungal sinusitis and proposed a standard classification by which to look at these cases. He, as before, broke it down into noninvasive and invasive forms. Then he characterized five major types. The first of the noninvasive forms was allergic fungal sinusitis as well as the sinus fungus ball. Of the invasive forms, the most common is what he described as acute or fulminant invasive sinusitis. He attempted to combine the syndromes that had been seen with Mucor and diabetics in the past, as well as a syndrome that had been termed fulminant sinusitis that had been seen with aspergillosis. Then he reported on two cases and reviewed about six more of a distinct entity that he termed chronic invasive fungal sinusitis, and that is the disease entity that our patient presented with. Finally, he described granulomatous invasive, which is again a bit confusing, because, in the previous literature, this type of fungal sinusitis had been called chronic invasive by some authors. So, first, let us take a brief look at the noninvasive forms of fungal sinusitis, and first look at allergic fungal sinusitis (AFS). This is actually a disease that is in immunocompetent individuals who are actually hypersensitive. It is a type I Gell and Coombs hypersensitivity reaction, and it typically occurs to the pigmented or dematiaceous fungi as well as the highland molds. In the past, it was thought that this most commonly resulted from exposure to Aspergillus. Now it is pretty well recognized that dematiaceous fungi, particularly Bipolaris, are the most common cause of allergic fungal sinusitis. Just in terms of morphology, you will note the pigmentation of the Bipolaris species and the classic 45-degree branching hyphae of the Aspergillus species. Patients who have allergic fungal sinusitis produce a very characteristic allergic mucin. On gross pathology, you see a sort of thick, greenish-brown, classically described as peanut buttery mucin, which is composed of degrading eosinophils, Charcot-Leyden crystals, and inflammatory infiltrate. In this H&E section, you see the allergic mucin coat, as well as inflammatory infiltrate of eosinophils and plasma cells. AFS is thought to occur in about five to ten percent of patients with chronic sinusitis, and it frequently presents with nasal polyposis, which often can be unilateral. Occurrence is sort of the rule with allergic fungal sinusitis. Often, patients, before they receive a diagnosis, will have undergone multiple sinus surgeries. The important thing for this lecture is to note that allergic fungal sinusitis does not progress to invasive disease. There are some classic CT findings with allergic fungal sinusitis. You see soft tissue densities, particularly on the soft tissue windows, with these interspersed hyperdensities and you can see bony sclerosis or scalloping, as well as expansion of bone due to pressure effect. But, classically, you do not see infiltration of the bone. The second type of noninvasive fungal sinusitis that DeShazo proposed was the fungus ball. Classically, in the literature, this has been described as aspergilloma or sinus mycetoma, which are both sort of misnomers. Aspergilloma was the assumption that all fungus balls were caused by Aspergillus, which we now know can be caused by other species, particular Mucor. The term "sinus mycetoma" is more commonly than not used to describe the fungus ball in the literature; but, technically a mycetoma is a distinct fungal disease in itself, composed of small subcutaneous nodules, particularly in the hands and feet, caused by Actinomyces. So, although mycetoma of the sinus is somewhat of a misnomer, it is important to realize that the terminology exists. These are extra mucosal masses of fungal hyphae that actually may progress to invasion, so if they become a part of immunocompromise on the host, can actually progress to a form of fungal invasion. It is thought that perhaps this is the precursor to the chronic invasive disease that we saw in our patient. Usually, surgical removal of these is adequate therapy. This slide illustrates a classic CT appearance, and you can also see some interspersed calcifications on sinus fungus balls. The largest series actually comes out of France. For some reason, it is more prevalent in France than in other nations. In a series by Karci, nearly 20% of these patients had this discovered on imaging for other causes. Frequently sinus fungus balls can be asymptomatic; so, perhaps, that is why they progress to the invasive forms in patients who go on to develop immunocompromise. Most occur only in a single sinus, and the majority of cultures taken from a fungus ball are negative; so it is important to get staining and see the fungal hyphae. Histology reveals a characteristic mass of fungal hyphae in the extra mucosal fashion that is characteristic of the fungus ball. Invasive fungal sinusitis is a different clinical entity that actually presents in several different ways. DeShazo proposed the following sub-groups: 1) acute, or fulminant, invasive; 2) chronic invasive; and, 3) granulomatous invasive. It is relatively rare, but studies might include various categories from DeShazo's classification. Overall, invasive fungal sinusitis has a 50%-80% mortality; so, it has quite a high mortality. If we look again at the classification proposed by DeShazo, this has been described as an acute or fulminant form. Again, this group includes disease seen in diabetics classically with Mucor; as well as fulminant infections with Aspergillus; the chronic invasive form, which is a discrete syndrome seen particularly in type 2 diabetics; and finally, the granulomatous form. This can occur in immunocompetent individuals but, by and large, it is highly associated with immunocompromise. You look at these various risk factors for invasive fungal sinusitis. When you see sinus disease in a patient with these risk factors, it really requires that you keep this in the back of your mind. The crucial factor in the treatment of this disease is getting the earliest possible diagnosis, and often it really requires a high index of suspicion. The acute, fulminant invasive fungal sinusitis is by and large the most common form presenting to otolaryngologists in the United States. The chronic invasive syndrome is quite rare, and the granulomatous syndrome rarely, if ever, occurs in the United States. The acute invasive form is rapidly progressive. It can progress to death within hours to days, and it is typically caused by the class known as the zygomycetes or the Mucor and Rhizopus. Rhizopus is the most common and virulent pathogen of this disease, which can also be caused by Aspergillus. Gillespie and O'Malley reviewed 25 patients with invasive fungal sinusitis, and looked at their presentation. Nearly two-thirds presented with either fever or facial periorbital pain, and up to half presented with nasal congestion and headache. In this study, 88% presented with two or more of these findings, and just over a quarter had visual complaints or ophthalmoplegia. Physical examination can provide significant diagnostic information in the patient that has known risk factors for invasive fungal sinusitis. The earliest physical findings present on endoscopy, including the classic early pallor of the mucosa. Also, one can see any discoloration or granulation of the mucosa, which is due to ischemia due to angioinvasion. As the disease progresses, a black eschar develops with necrosis, and it can actually extend all the way to the palate, particularly in invasive Mucor disease. Diagnosis of this disease really requires a biopsy. DeShazo gave two criteria for the diagnosis: radiologic sinusitis and demonstration of hyphal invasion in the bone, submucosa, or vessels. It is important to note, histologically, a special fungal prep, such as potassium hydroxide or calcofluor white. Taking cultures can be valuable in terms of tailoring your medical therapy, but frequently will return negative or will take up to a week to obtain, which is too late for successful therapy. Histologic findings include submucosal hyphae, perivascular and angioinvasion, and microvessel thrombosis that has occurred as a result of the fungal invasion. Gillespie and O'Malley also examined the role of biopsy. In their series of 25 patients who had a known diagnosis of invasive sinus disease, the percentages of biopsy-positive specimens were examined. This revealed that the most common site of positive pathology is at the middle turbinate. This led them to investigate the role of middle turbinate biopsy in diagnosing invasive fungal sinusitis in the immunocompromised host. They looked at 25 patients who underwent middle turbinate biopsy, and eight were positive for invasive fungal sinusitis. This correlated with 75% sensitivity and a 100% specificity and positive predicted value for middle turbinate biopsy for the diagnosis of invasive fungal sinusitis. Though the numbers in this study were small, it suggests that selective biopsy of the middle turbinate, when there is suspicion, can aid in the diagnosis. Imaging is not diagnostic, but it also can give important helpful information. CT imaging with contrast can show which sinuses are involved, which can direct where biopsies should be performed and give anatomic information at the time of surgery. In patients who do have invasive fungal sinusitis, up to 50% can show evidence of invasion on the scan. Also, scans can show bony invasion or invasion into the soft tissues. It is important to know that up to 12% of patients with invasive fungal sinus disease will have a normal scan; so, you cannot really rely on CT abnormalities to make a quick diagnosis. An MRI can be useful, as well, for several reasons. It better shows orbital involvement from extension of the sinus process, and it better shows intracranial extension and large vascular involvement. This is important because when a patient has intracranial extension or large vascular involvement, the mortality of invasive fungal sinusitis approaches 100%. MRI has been advocated for avoiding large, deforming, and morbid operations on patients who have a very poor prognosis; and it has actually been shown that, in certain cases, with severely neutropenic patients or patients with intracranial extension, surgery might actually increase mortality. In this respect, MRI imaging can be very useful. The treatment options are really multi-modal, with both surgical and medical approaches, but ultimately treatment must be aimed at the reversal of the underlying condition. The absolute best predictor for success in these patients is reversal of neutropenia or, in patients with severe diabetes, reversal of ketoacidosis. In the ketoacidotic state in diabetics, there is altered iron transfer and binding capacity, and the excess iron is quite toxic to neutrophil function. Surgically, since the advent of endoscopic sinus surgery, surgery for invasive fungal sinus disease has become much more local. There are many fewer radical craniofacial or orbital exenteration procedures. The primary goal of surgery is to delay the progression of the disease and reduce fungal load until bone marrow/neutrophil function recovers, as well as to provide a specimen to culture in order to tailor medical therapy. In terms of medical therapy, traditionally the workhorse has been high-dose amphotericin- B given to a total dose of 2-4 grams. The mechanism of amphotericin-B is that it combines ergosterol, which is an important steroid in the fungal cell membrane, and causes porosity of the membrane. Traditionally, amphotericin-B has been highly limited by its renal toxicity, and this can be improved by liposomal delivery of amphotericin-B. You can deliver up to five times the dosage of ampho-B when it is conjugated with a liposome. The problem is, one day of liposomal ampho-B therapy is $220, as compared to $6 for standard amphotericin-B. So, liposomal therapy is reserved for patients who bump their creatinine to above 2.5 on standard ampho therapy or have worsening disease despite standard amphotericin. A second major medical category is the azoles, which block the synthesis of ergosterol. A recent study published in The New England Journal of Medicine shows its efficacy, particularly in invasive Aspergillus infections. It compared voriconazole versus standard amphotericin-B therapy, and it showed that in patients who have invasive Aspergillus infections, there is much better overall success and survival with voriconazole, as well as fewer adverse effects. It is important to note that if fungus cultures return with Aspergillus, then an azole should really be part of the medical management. Finally, this is a brand new class of antifungal, the echinocandins. The prototype is caspofungin. It inhibits (1,3)-beta-D-glucan synthesis, which is another important component of the cell membrane of the fungus. This just came out this September in The New England Journal of Medicine, in a randomized study of nearly 1100 patients who had neutropenic fever, the majority of unknown cause. They compared this with the liposomal form of amphotericin-B. The overall efficacy was determined by preventing fungal infection and treating the fungal infections that were known. Mortality and overall side effects or resolution of fever was about the same between the two groups. But in the subset of patients that actually had a known fungal infection at the time they instituted treatment, there was much better success with the caspofungin therapy. In the subset of patients with a known fungal infection, there were five patients with invasive fungal sinusitis in this study. Two out of the three treated with caspofungin went on to have a recovery, whereas none of the two treated with amphotericin-B went on to have a recovery. So, this provides some suggestive evidence that caspofungin may be an important part of the treatment of fungal disease in the future. In terms of reversal of the underlying condition in neutropenic patients, G-CSF, or granulocyte colony-stimulating factor, can be very useful. In one of the few case reports of chronic invasive fungal sinusitis with recovery, G-CSF was part of the armamentarium. It is interesting, because in this study the patient was not neutropenic. But it has actually been shown that in normal healthy volunteers who have neutrophils isolated and are then treated with G-CSF and then subsequently have neutrophils isolated again, the G-CSF, even in normal individuals, increases neutrophil counts but also improves chemotaxis, phagocytosis, and the respiratory burst of neutrophils. It is important to keep this in mind: even in patients who may not be neutropenic, G-CSF can be valuable. In addition to acute, fulminant invasive fungal sinusitis, there are two other major types of invasive fungal sinus disease. The chronic invasive form was described as a syndrome by deShazo, and he described two patients whose presentations were exactly the same as our patient. The subsequent six that he pulled from the literature presented exactly the same as well. They were type 2 diabetics who were relatively well-controlled. They were not in a state of ketoacidosis, and they basically presented with the orbital apex syndrome. This form is very slowly progressing, but it still portends a very poor prognosis and the majority of these patients succumb to this disease within about five or six months. The final form in his classification is termed granulomatous sinusitis, which has been described as paranasal sinus granuloma. This is a syndrome seen almost exclusively in the Sudan. It is seen in immunocompetent individuals, and it is almost exclusively caused by Aspergillusflavus. Usually, surgical excision is adequate therapy for the granulomatous sinusitis, but it is known to have fairly frequent recurrence. Looking back to our patient, after surgical therapy the patient's sodium improved and she was given amphotericin-B with a subsequent increase in her creatinine. She subsequently was put on the liposomal amphotericin. Her cultures were a bit evasive and were finally sent to the CDC. They returned as likely Aspergillus species. So, she had itraconazole added to her regimen. On follow-up examination, she had regained some of her extraocular function, but her vision remained unchanged. On endoscopy, her sphenoid sinus was well aerated. In summary, fungal sinusitis represents several distinct diseases. It is really the host factors that determine the pathogenesis of the disease. Invasive fungal sinus disease has a very high morbidity and mortality. For optimal outcome, really rapid diagnosis and then reversal of the underlying condition is critical to success. Case Presentation M.P. is a 59-year-old Hispanic female who presented to BTGH with several days of nausea, vomiting, blurry vision, and increasing peri-orbital pain. She denied cough, fevers, chills, sweats or recent weight loss. She also denied headache, nasal congestion or rhinorrhea. Her vision had been worsening for the previous five days. Past medical history is notable for type II diabetes mellitus, a left above-knee amputation, and bilateral cataract surgery. She currently controls her diabetes with glucovance. She has no history of alcohol, tobacco, or recreational drug use. Physical examination revealed a pleasant female with notable right eye proptosis and peri-orbital edema. She was afebrile with stable vital signs. Cranial nerve examination revealed significant deficits of CN III, IV and VI on the right. Pupillary response was not detected secondary to post-surgical change. There was no maxillary sinus tenderness. Nasal endoscopy revealed right middle turbinate edema without discoloration or eschar. There was mild purulence from the posterior nasal cavity/ethmoid region. Admission laboratory data revealed sodium of 111, potassium of 3.3, and BUN/ creatinine of 13/0.6. Her glucose was 137. WBC was 4.8 with 69% neutrophils. Hemoglobin/hematocrit was 9.7/27.8, and platelet count was 308,000. An HIV test was negative. A diagnosis of SIADH was established, and the patient was admitted to the medical intensive care unit for fluid and electrolyte management. Ophthalmologic evaluation revealed visual acuity of only light discrimination. CT and MRI of the brain revealed a soft tissue mass density in the right sphenoid sinus with possible erosion of the inferolateral sinus wall as well as inflammatory change in the right orbit. The patient was taken to the operating room for right sphenoid sinusotomy with debridement of the sphenoid sinus. There was edematous mucosa and minimal purulence in the right spheno-ethmoid recess and thick, yellow-brown debris in the right sphenoid with no palpable dehiscence of the sphenoid wall. Biopsy specimens revealed fungal hyphae in the submucosa, confirming a diagnosis of invasive fungal sinusitis with subsequent orbital apex syndrome. Culture was inconclusive but revealed likely aspergillus species. Post-operatively the patient was started on high-dose IV liposomal amphotericin-B and voriconazole. Her sodium improved, and follow-up examination revealed a well-aerated sphenoid sinus with slightly improved ocular motility, but no significant change in vision. Bibliography: Abzug MJ, Walsh TJ. Interferon-gamma and colony-stimulating factors as adjuvant therapy for refractory fungal infections in children. Pediatr Infect Dis J 2004;23:769-773. Chakrabarti A, Sharma SC, Chander J. Epidemiology and pathogenesis of paranasal sinus mycoses. Otolaryngol Head Neck Surg 1992;107:745-750. 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Chronic fungal sinusitis in apparently normal hosts. Medicine 1988;67:231-247. Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2006 Baylor College of Medicine
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