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 Rhinosinusitis in Immunocompromised Children This will be the order of the topics discussed today. After a brief introduction, we will talk of the definition of invasive fungal rhinosinusitis, its pathophysiology, the main fungal pathogens, the clinical presentation, the diagnosis, the treatment, prevention, outcome and finally we will conclude. Invasive fungal rhinosinusitis is a rare life-threatening infection of the nose and paranasal sinuses characterized by mycotic infiltration of the submucosa and vasculature of the sinonasal cavity. It is well known to occur almost exclusively in immunocompromised patients. Its first mention in the literature was in 1885, where Paultauf described a case of rhinocerebral mucormycosis. McGill, in 1980, reported the first series of 4 patients with invasive fungal rhinosinusitis associated with hematological disease and neutropenia. Since then, more and more case series have been reported and the incidence of invasive fungal disease is expected to increase with the increasing number of immunocompromised patients. The new chemotherapeutic agents, the advances in hematological treatment including bone marrow transplantation, the improved control of bacterial infection and the growing number of AIDS patients all contribute to this situation. Drakos et al in 1993 reported that the incidence of invasive fungal disease was higher in patients with leukemia who were undergoing therapy. This is explained by more severe and prolonged neutropenia when compared to other causes of immunodeficiency. This situation is even worse in bone marrow transplantation, which explains highest incidence of invasive fungal disease in this group. In a study by Choi and al in 1995 on 80 pediatric patients undergoing bone marrow transplantation, an incidence of 2-4 % of invasive fungal rhinosinusitis was found. Hence, invasive fungal rhinosinusitis is especially important in the pediatric population. Dr Fisher already explained the differences between the 4 major groups of fungal infections. I would like to reemphasize the difference between the 2 invasive groups, based on the immune status. As already discussed, the acute form occurs almost exclusively in immunocompromised patients and will show prominent vascular invasion on histopathology. The usual duration in acute invasive fungal rhinosinusitis is less than 4 weeks, which explains the frequent misnomer of fulminant infection. On the other hand, the chronic form will show minimal or no vascular invasion in an immunocompetent patient. The course in this disease is more indolent, greater than 4 weeks’ duration. It is then the immune response of the host that will shape the fungal manifestation. And as a rule of thumb, the greater the immunodeficiency, the more fulminant the course. I would like to briefly discuss the pathophysiology as known at this time. It is suggested that it begins in the nasal cavity following inhalation of environmental spores. The middle turbinate is exposed to the greatest volume of nasal airflow, which allows for increase seeding at this site. Mucosal disruption by bacterial sinusitis, allergy or local trauma, as well as immunodeficiency, may allow fungi to initiate invasion. Proliferation of fungi with angiocentric invasion leads to tissue ischemia. Early on, this gives a typical white discoloration. Finally, black discoloration is a late finding signifying tissue necrosis. Extranasal extension of disease is thought to be primarily by retrograde thrombophlebitis and it is only later that direct extension through a bony erosion will occur. This explains why bony erosion on CT scan, which is considered the hallmark of invasive fungal infection, is present less than 50 % of the time. This drawing is taken from a paper published by Gillepsie et al. in 1998 that supports this theory of nasal seeding by spores. The drawing represents the percentage of biopsies positive for fungus at specific nasal and paranasal sites in 25 patients. As we can see, the middle turbinate demonstrated invasion almost 2 times as often as the next most common sites. Based on these findings, a biopsy of the middle turbinate is recommended when suspicion for fungal disease is high, even in the absence of gross disease. Hence, the term rhinosinusitis is especially appropriate. This understanding of the pathophysiology is also important to remember when we see a normal CT scan in a patient at risk. This could actually be a normal CT scan, but it could also be early invasive fungal rhinosinusitis, when still limited in the nasal cavity. A good visual exam of the nasal cavity will never be replaced by a CT scan. Let’s talk about fungal pathogens now. Fungal infection of the nose and paranasal sinuses is almost exclusively caused by moulds. Yeast infection as with Candiasis is only rarely reported in case series. These are the 3 main categories of fungal hyphae that can cause invasive fungal rhinosinusitis. The first category is the well known Zygomycosis or Mucormycosis. The Rhizopus specie account for 90% of all mucor infections, followed by the Mucor specie. The hyphae are typically larger, sparsely or non-septated. Branching is classically at 90º, but sometimes some 45º branching are seen. Rhinocerebral infection is the mst common presentation of mucormycosis. The second class is the Hyalohyphomycosis group. Aspergillus is the best known example. Fusarium is another frequently incriminated specie. The hyphae are thinner, regularly septated, with characteristic 45º branching. Hyphae of this group cause mainly lung infections, but sinusitis is also well described, accounting for 2-5% of all aspergillus infections. Aspergillus flavus and Aspergillus fumigatus are the two most frequent etiologies of invasive fungal sinusitis. The last group is the Phaeohyphomycosis or dematiaceous hyphae group.Though it can give invasive fungal disease, it is most commonly an etiology of noninvasive fungal sinusitis. The most frequent species are Alternaria and Bipolaris. The hyphae are typically brown with the Fontana Masson stain, which is very useful to differentiate them from the other species. They are typically enlarged or globose in shape. A patient with invasive fungal rhinosinusitis will typically present with persisting fever of more than 48 hours despite broad-spectrum antibiotics. This symptom is reported to be present almost 100% of the time. The other symptoms are present in 20-60% of the time depending on the paper. The facial numbness is a classic symptom of early mucormycosis, so it is important to look for it in order to do a early diagnosis. Neurologic and ophthalmologic symptoms like change in mental status or proptosis are usually late findings and are associated with a bad prognosis. We have to remember that this patient group has a decreased inflammatory response, so the initial symptoms can be subtle. Nevertheless, if we maintain a high index of suspicion, 2 or more symptoms are usually found. So, the association of persisting fever with one or more symptoms in an at-risk patient should prompt a thorough physical exam. A thorough nasal endoscopy should be performed on every immunocompromised patient who continues to have fever of unknown origin after 48 hours of appropiate broad-spectrum antibiotics, or who has localizing sinonasal symptoms like we just listed. The most consistent physical finding is an alteration in the appearance of the nasal mucosa. So, this can be discoloration, from white to frank black. This can also be granulation or ulceration. Like we said before, the disease is thought to begin in the nasal cavity in most cases before extending into the paranasal sinuses, so a careful look at the middle and inferior turbinate, the septum and the floor of the nose is warranted. Decrease mucosal bleeding or sensation also should be noted because these may be signs of fungal invasion. Rarely, a normal appearing mucosa can be present despite fungal infection. Finally, a complete head and neck exam is important to look for facial swelling or erythema or for a palate lesion signifying advanced disease. A full cranial nerve evaluation and neurologic exam, as well as appropriate ophthalmologic assessment is mandatory. So, now. How do we make the diagnosis? It is important to be alert to signs and symptoms of this disease because early diagnosis will improve survival. This is well accepted in the literature. We do know that a high index of suspicion is necessary because the symptoms are often subtle. So, in order to do an efficient diagnosis, the initial critical step is to properly identify an at-risk patient. So what are the risk factors of this disease? Well, first, like we already said, invasive fungal rhinosinusitis occurs almost only in immunocompromised patients and therefore, any condition giving impaired neutrophilic response constitutes the primary and major risk factor. Hence, an absolute neutrophil count below 500 cells/ml for more than 7 days is strongly correlated with the development of invasive fungal disease. Also, immunosuppressant drugs, AIDS, metabolic abnormalities like ketoacidosis or hemochromatosis and poorly controlled type 1 diabetes mellitus are all associated. Of course, bone marrow transplantation and all hematologic diseases and malignancy are very important etiologies of immunosuppression in the pediatric population. There are also some significant secondary risk factors that have been identified. The 2 most important ones are prolonged course of steroids and at least 2 weeks of broad-spectrum intravenous antibiotics. Also, indwelling catheters, nasal intubations, prolonged hospitalization and presence of sinus disease before immunosuppression are all factors to be looked for when assessing the history. The presence of sinus disease prior immunosuppression as a risk factor is especially interesting because it is potentially modifiable. We will come back to this later. So when a patient at risk is identified and that the history and physical exam as previously described are found to be compatible with an invasive fungal rhinosinusitis, a CT scan of the sinuses is warranted. It will document the presence of sinusitis, it will define the sinus anatomy, which will be useful if the patient is brought to the operating room, and finally it may confirms the diagnosis if bony erosion or extranasal extension is seen. Like we already said, most of the time, the findings will be non specific, with only mucosal thickening and sometimes air-fluid levels. Also, we have to remember that a normal CT scan is possible in early disease, when limited in the nasal cavity. MRI is very accurate in confirming intracranial or orbital extension, so this study is recommended when the clinical picture is suggestive of its presence. Intracranial or orbital involvement by invasive fungal disease has an extremely worse prognosis despite aggressive surgery. So by obtaining an MRI confirming the presence of extranasal extension, we may prevent unnecessary procedures in patients who are unlikely to benefit from surgery. Some papers suggest to do an MRI first instead of a CT scan, because it may represent better the true extent of the disease. This is not widely accepted. So obtaining the CT scan first is still the standard of care. Histopathologic evaluation of biopsies is required to confirm the diagnosis of invasive fungal rhinosinusitis. Biopsies of the middle turbinate or any gross anomaly of the mucosa must be done, in the clinic for adults patients or in the operating room for children or uncooperative patients. In high risk patients, a biopsy of the middle turbinate should always be done even if the mucosa appears normal. Like we already saw, the middle turbinate is the most common location of early disease and macroscopic changes may not be present at that time. Specimens should be sent for frozen and permanent sections. The Gomori silver stain is the most useful stain to identify the fungus. They will be easily identified as black filaments. Just a reminder to always check the platelets before undergoing any biopsy! The fungal disease will be invasive if it meets the following criteria on histopathology. First, the hyphal forms will be seen within the submucosa with or without angiocentric invasion. Second, there will be tissue necrosis with minimal host inflammatory cell infiltration. The pathology will confirm presence of invasive fungal disease, but it can rarely be more precise than identifying the class of pathogens. Here is a picture of a classic mucor invasion on Gomori silver stain where we can see the little black filaments within the submucosa. Other useful diagnostic tools include culture from material biopsied. It is not as precise as histopathology, being known for both false-positive, and false-negative results. But nevertheless, when truly positive, it will confirm the exact pathogen invading and this will complete the information gained with pathology. Also, serolgy and skin testing are being developed and are sometimes useful, but mostly in noninvasive fungal sinusitis. Now, let’s talk about treatment. It is now a known fact in the literature that the mainstay of treatment is intensive antifungal antibiotics and aggressive surgical débridement. This is the only chance of survival. Here is a picture of our patient post medial maxillectomy and septectomy. An aggressive surgical débridement and antifungal medication permitted recovery. The importance of surgery is emphasized in a retrospective study of 17 patients done by Iwen and al in 1997, that showed that all patients who did not have surgery died. Surgery accomplishes different goals. It slows the progression of the disease, allowing time for bone marrow to recover. It reduces the fungal load, so that gives a chance to the few neutrophils present. And finally, it provides a specimen for culture. Unfortunately, even though surgery is essential, this is not what will cure the patient. Recovery of neutrophil counts is mandatory to completely get over the disease. Surgery will only buy time. The standard of care is aggressive débridement either endoscopically or externally to clear bleeding margins. Here is another picture of our little patient. A second look procedure is recommended in 48-72 hours if there is suspicion of residual disease. After surgical control of the disease, a weekly rigid endoscopy is recommended until reversal of neutropenia and once a month for 6 months thereafter. A reminder again to make sure to have the platelets above 60. The other pillar of treatment is high dose amphotericin B, which is the most efficient antifungal antibiotic for most invasive pathogens. It should be given at the higher dose tolerated until a total of 2 grams or greater is obtain. It will not be sufficient to cure infection if used alone. More recently, use of a lipid complex formulation of amphotericin B, called liposomal amphotericin, has been extremely promising in treating invasive fungal infections. Its special formulation allows increased systemic concentrations, with fewer secondary effects. However, its high cost limits its widespread use. Currently, it is reserved for proven renal toxicity and progression of disease under optimal treatment with regular amphothericin B. More recent treatment options include GM CSF (granulocyte macrophage colony stimulating factor), a medication given to stimulate bone marrow’s cell production. WBC transfusions, as done with our patient, are also described. Both of these treatments have unclear proven efficacy, and are then still controversial. Since this disease is highly aggressive, interest is naturally given to anything who could potentially decrease its incidence. Prevention of invasive fungal rhinosinusitis is possible when working on 4 different levels. The first level is to decrease exposure to pathogenic fungi. Has we already discussed, infection is thought to begin in the nasal cavity after inhalation of fungi normally present in the soil. By decreasing exposure to environmental spores, we should prevent sinusitis. HEPA filtration (high efficiency particulate air filtration) is recognized as an effctive way to decrease infections in neutropenic patients and is now a standard of care. Laminar air flow rooms are also described as useful, but their high cost and doubtful efficacy do not make them widely used. In TCH, rooms in the BMT unit are equipped with HEPA filtration only. Other recommendations are to avoid potted plants, flowers and ground pepper in special units, to always use a mask when outside of the room and to regularly clean the vents and ducts of the hospital. Special attention must be given to isolate patients when constructions are done near the special unit since this is associated with clusters of disease. The second level that we can work on, is to do prophylactic treatment of a patient that we know will be neutropenic. The major target group would be the leukemia and BMT patients, these patients being at higher risk. The major pathogen to cover would be Aspergillus, since it is by far the most common in invasive fungal disease. Unfortunately, low dose amphotericin B or nasal spray of ampho B as a prophylaxis have not been proven effective and therefore are not recommended as standard of care for the moment. On the other hand, secondary prophylaxis in patients who already had an invasive fungal disease is recommend. If these patients undergo an induction chemotherapy or a BMT, the risk of recurrence of the infection is higher than 50%. Regular doses of amphothericin B for the length of the neutropenia is proven to decrease recurrences of about 50%. Finally, the last level of prevention is management of rhinosinusitis prior to immunosuppression. Like we said previously, prior sinus disease is a known risk factor of invasive fungal disease. Signs and symptoms of rhinosinusitis should be sought for when assessing a patient before an immunosuppressant treatment. If Hx is positive, a CT scan of the sinuses and an ENT consultation should be obtained. Early management of the sinusal problems if feasible will decrease local inflammation and then decrease mucosal weakness. For better control, in those patients identified at risk, a weekly nasal endoscopy should be performed for surveillance. Prophylaxis with low dose amphotericin B may be effective in this group. Choi and al in 1995 did and interesting review of 80 pediatric patients undergoing BMT. All the patients had a CT scan or an Xray of the sinuses done before transplantation. In all patients who had negative radiologic findings, no invasive fungal rhinosinusitis occurred. On the other hand, 11 % of the patients with positive findings developed disease. We should then be particularly efficient when a patient is referred for this indication. The prognosis is mainly dependent on the immunologic status of the host, which will determinate the manifestation of the fungal infestation. As we said earlier, the greater the immunodeficiency, the more fulminant the course. Clearly, resolution of neutropenia is the most important factor in the outcome of invasive fungal rhinosinusitis. Unfortunately, neutrophil recovery is not predictive of survival, since death occur in this patient group also. The overall mortality remains around 50-80 %, with 100 % mortality if intracranial or orbital involvement is present. Surgery in this group must then be appropriately counseled According to Gillepsie et al, based on a review of 25 patients, improved survival can be predicted in instances when complete surgical excision can be achieved to clear bleeding margins, disease is limited or primarily involving the nasal cavity and the patient respond to GM CSF treatment with increase in WBC count. This again emphasizes the importance of early detection of disease, when the disease is more easily amenable to complete surgery. So, in conclusion, wWe are presently reviewing all the otolaryngologic fungal infections occurring in the last 10 year in TCH. We have so far identified 12 patients including this case presented today. The results will be available soon. Case presentation: PS is a previously healthy 5-year-old female who was diagnosed with severe aplastic anemia at the McAllen Medical Center in July 2001. After chemotherapy treatment in August 2001, she developed a fever of unknown origin, unsuccessfully treated with broad-spectrum antibiotics. She was transferred to TCH on September 5 th. She had right frontal headaches and rhinorrhea for 3 weeks and had developed right periorbital swelling 2 days before. On physical exam, she had inflamed nasal mucosa without necrosis and right preseptal edema without orbital involvement, as confirmed by the Ophthalmologist. A maxillofacial CT scan showed pansinusitis without bony erosion. A right ESS performed at that time showed no organism on both biopsy and culture. Due to persistent symptoms, a second ESS was performed a week later. Biopsy of the right middle turbinate and the septum was now positive for an invasive fungal infection. The culture grew Aspergillus flavus. A right medial maxillectomy and septectomy was immediately performed. High dose Amphotericin B Lipid Complex, Caspofungin and GM CSF were begun. Control endoscopic debridement one week later showed persistent fungal infection. Daily white blood cell transfusions were then begun. The fever and all periorbital swelling finally resolved with the recovery of the neutrophil count the following week. Three control ESS with biopsy done over the next 5 weeks were negative for fungus. The patient underwent an allogenic bone marrow transplantation on November 15 th. She developed a fever a week later. Another control ESS with biopsy still showed no fungal infection. Last week, the patient developed a severe GVH disease. She was placed on steroids and immunosuppressive drugs. Caspofungin and ABLC treatment are still administered to this date. Bibliography: Berlinger NT . Sinusitis in immunodeficient and immunosuppressed patients. Laryngoscope 1985;95:29-33. Decker CF. Sinusitis in the immunocompromised host. Curr Infect Dis Rep 1999;1:27-32. deShazo RD, O’Brien M, Chapin K, Soto-Aguilar M, Gardner L, Swain R. A new classification and diagnostic criteria for invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 1997;123:1181-1188. Dhong HJ, Lee, JC, Ryu JS, Cho DY. Rhinosinusitis in transplant patients. Clin Otolaryngol 2001;26:329-333. Drakos PE , Nagler A, Or R, Naparstek E, Kapelushnik J, Engelhard D. Invasive fungal sinusitis in patients undergoing bone marrow transplantation. Bone Marrow Transplant 1993;12:203-208. Ferguson , BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am 2000;33:227-235. Gillespie MB, Huchton DM, O’Malley BW. Role of middle turbinate biopsy in the diagnosis of fulminant invasive funga rhinosinusitis. Laryngoscope 2000;110:1832-1836. Gillespie MB , O’Malley BW Jr, Francis HW. An approach to fulminant invasive fungal rhinosinusitis in the immunocompromised host. Arch Otolaryngol Head Neck Surg 1998;124:520-526. Hospenthal DR, Byrd JC, Weiss RB. Successful treatment of invasive aspergillosis complicating prolonged treatment-related neutropenia in acute myelogenous leukemia with amphotericin B lipid complex. Med Pediatr Oncol 1995;25:119-122. Howells RC, Ramadan HH. Usefulness of computed tomography and magnetic resonance in fulminant invasive fungal rhinosinusitis. Am J Rhinol 2001;15:255-261. Ikeda K, Tanno N, Suzuki H, Oshima T, Kano S, Takasaka T. Unilateral sinonasal disease without bone destruction. Differential diagnosis using diagnostic imaging and endonasal endoscopic biopsy. Arch Otolaryngol Head Neck Surg 1997;123:198-200. Iwen PC, Rupp ME, Hinrichs SH. Invasive mold sinusitis. 17 cases in immunocompromised patients and review of the literature. Clin Infect Dis 1997;24:1178-1184. Kaczmarski R, Pagliuea A, Pullon H, Philpott-Howard J, Salisbury J, Mufu G. Fulminant fungal sinusitis following intensive chemotherapy. Q J Med 1990;75:365-370. Kavanagh KT, Hughes WT, Parham DM, Chanin LR. Fungal sinusitis in immunocompromised children with neoplasms. Ann Otol Rhinol Laryngol 1991;100:331-336. Kennedy CA , Adams GL, Neglia JP, Giebink GS. Impact of surgical treatment on paranasal fungal infections in bone marrow transplant patients. Otolaryngol Head Neck Surg 1997;116:610-616. Lansford BK, Bower CM, Seibert RW. Invasive fungal sinusitis in the immunocompromised pediatric patient. Ear Nose Throat J 1995;74:566-573. Lueg EA, Ballagh RH, Forte V. Analysis of the recent cluster of invasive fungal sinusitis at the Toronto Hospital for Sick Children. J Otolaryngol 1996;25:366-370. Malani PN, Kauffman CA. Prevention and prophylaxis of invasive fungal sinusitis in the immunocompromised patient. Otolaryngol Clin North Am 2000;33:301-312. Mirza N, Lanza DC. Diagnosis and management of rhinosinusitis before scheduled immunosuppression: A schematic approach to the prevention of acute fungal rhinosinusitis. Otolaryngol Clin North Am 2000;33:313-321. Rizk SS, Kraus DH, Gerresheim G, Mudan S. Aggressive combination treatment for invasive fungal sinusitis in immunocompromised patients. Ear Nose Throat J 2000;79:278-280. Schell WA . Histopathology of fungal rhinosinusitis. Otolaryngol Clin North Am 2000;33:251-276. Sterman BM. Sinus surgery in bone marrow transplantation patients. Am J Rhinol 1999;13:315-317. Viollier AF, Peterson DE, deJongh CA, Newman KA, Gray WC, Sutherland JC, Moody MA, Schimpff SC. Aspergillus sinusitis in cancer patients. Cancer 1986;15:58:366-371. Walsh TJ, Groll AH. Emerging fungal pathogens: evolving challenges to immunocompromised patients for the twenty-first century. Transpl Infec Dis 1999;1:247-261. Wiatrak BJ, Willging P, Myer CM 3 rd, Cotton RT. Functional endoscopic sinus surgery in the immunocompromised child. Otolaryngol Head Neck Surg 1991;105:818-825. Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2005 Baylor College of Medicine
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