Invasive Fungal Sinusitis, a Potentially Fatal Condition

For millions of Americans, chronic sinusitis and related sinus disorders can be annoying, periodically painful, and in worst cases, debilitating. But few would think that a sinus condition can be fatal.

In most cases, it is not. But the consequences can be deadly for the unfortunate patients diagnosed with invasive fungal sinusitis (IFS). The condition can be divided into several entities including acute fulminant IFS, granulomatous IFS and chronic IFS. Of these entities, acute fulminant IFS is the most common type, although it is still seen infrequently.

Fungal infections of the paranasal sinuses are uncommon and usually occur in individuals who are immunocompromised. Invasive infections cause tissue invasion and destruction of adjacent structures (e.g., orbit, central nervous system).

The vast majority of patients with IFS have deficient immune systems at the time of disease onset. Patients with hematologic malignancy, systemic chemotherapy, bone marrow transplantation, immuno-suppressive agents following solid organ transplant, and Acquired Immunodeficiency Syndrome (AIDS) are immunocompromised as a result of functional leukopenia, most importantly neutropenia (the presence of a small number of neutrophils in the circulating blood). A diagnosis of diabetes mellitus, with poor glucose control (especially those in diabetic ketoacidosis) presents a risk factor in the development for this condition as well as those on chronic systemic steroids. These latter two conditions predispose patients to IFS as a result of compromised neutrophil function. Though rare, there are documented cases in the literature of IFS in otherwise healthy individuals.

The reported mortality for IFS is between 50 and 80 percent. Organisms from Aspergillus and Mucoracaea (Mucor) fungi cause IFS and mortality results from intracranial invasion by these organisms. Early diagnosis and treatment are the keys to successful treatment outcomes for this condition, and this requires a high degree of suspicion in at-risk patient populations. Aggressive surgical removal of tissue, anti-fungal pharmacotherapy and granulocyte replenishment are the current treatments for this disease. When treatment fails, it is important for the clinician to differentiate mortality related directly to IFS as opposed to as a result of the patient's underlying medical condition, especially in the patients with poor health resulting from hematologic malignancy.

The growing number of patients with immunodeficiency secondary to aggressive chemotherapeutic regimens, bone marrow transplantation, solid organ transplantation, and AIDS necessitates a better understanding of the pathogenesis of this disease. Accordingly, a research team from Atlanta conducted a retrospective study of 45 individual cases of 43 patients with IFS treated over the past 15 years at a tertiary care academic hospital. The authors of "Invasive Fungal Sinusitis: A 15-Year Review from a Single Institution," are John M. DelGaudio, MD, Shatul L. Parikh, and Giridhar Venkatraman, MD, , from the Department of Otolaryngology -- Head and Neck Surgery, Emory University School of Medicine, Atlanta, Georgia. Their findings will be presented at the annual meeting of The American Rhinologic Society http:// www.american-rhinologic.org/ being held May 2-3, 2003, at the Gaylord Opryland Hotel, Nashville, TN.

Methodology: A retrospective chart review was performed at Emory University Hospital from the period of June 1988 through March 2003. Inclusion criteria were a histopathologic diagnosis of IFS from surgical specimen or biopsy; or evidence of nasal mucosal ischemia or necrosis by endoscopy, or sinus destruction by radiographic studies along with a positive nasal or sinus fungal culture. Forty-five cases met these inclusion criteria.

Information regarding underlying medical diagnosis, cause of immunosuppression, absolute neutrophil count, antifungal pharmacotherapy, method of surgical intervention, infecting fungus, morbidity and mortality was collected. Finally, patients were grouped according to their underlying diagnosis and according to their infecting organism to determine similarities and differences between etiology, treatment, and outcome of IFS patients based on their underlying disease.

Results: Forty-five IFS cases were treated at Emory University Hospital between June 1988 and March 2003. Forty-three individual patients were found to have IFS during the study period, with two patients relapsing, resulting in 45 total cases. IFS was confirmed by pathology in 41 of 45 cases while four of 45 patients had confirmed IFS by radiography, endoscopy and positive fungal cultures. All 43 patients in this study were immunocompromised with hematologic malignancy (28) and diabetes (10) the leading causes for this condition. Overall mortality was 18 of 45 cases (40 percent), but mortality directly as a result of IFS was 8 of 45 (18 percent). The IFS specific mortality rate for patients with hematologic conditions was 11 percent compared to 40 percent for diabetic patients. Forty-two of 45 cases had one or more operative procedures and all patients were started on antifungal pharmacotherapy.

Intracranial involvement was present in all three patients with hematologic malignancy who died as a result of IFS, with two also having orbital involvement and one case undergoing orbital exenteration. None of the patients who survived the IFS or died of other causes had intracranial involvement. Of patients with hematologic malignancy, six of 28 cases (21 percent) had Mucor as the causative fungus of IFS, while the other 22 (79 percent) had Aspergillus. Antifungal pharmacotherapy was used in all cases. Granulocyte replenishment either by direct granulocyte transfusion or by granulocyte colony-stimulating factor was used in most cases. All patients that survived their hematologic malignancy and their IFS had recovery of their absolute neutrophil count (ANC), whereas all who died of IFS or died of their hematologic malignancy with persistent failed to recover from neutropenia.. Patients with diabetes mellitus accounted for 10 cases of IFS. Six males and four females ranged in age from 18 to 81 years (mean 52). The absolute neutrophil count (ANC) was normal or elevated at IFS symptom onset and during treatment in all patients. Mortality resulting from IFS was 40 percent, and neurologic or visual morbidity was 66% in survivors. Mortality resulting from IFS was 29 percent for Mucor and 11 percent for Aspergillus.

Conclusions: The clinical challenge of diagnosing and treating IFS is evident by the high mortality rates for this disease. Early diagnosis with aggressive medical and surgical intervention is critical for survival. The study revealed an overall lower mortality rate when compared to other studies. Intracranial spread of disease is the highest predictive indicator for mortality.

Acute fulminant IFS should not be considered a single disease, but two entities that should be approached and treated differently. Neutropenic patients more commonly have invasive Aspergillosis. For neutropenic patients, recovering the ANC is the most critical factor for survival. Surgical debridement and antifungal pharmacotherapy are important to decrease fungal load in affected tissue until the ANC recovers. Patients in this study who recovered their ANC recovered from their IFS.

Recurrence of neutropenia in patients who have recovered from IFS can result in recurrence of the IFS in the same location, likely indicating suppression but not eradication of the fungus with recovery of the ANC.

Diabetic patients have a higher morbidity and mortality because of lack of a high index of suspicion for IFS coupled with a predisposition for the more virulent pathogen Mucor, as a cause of their IFS. This results in more advanced stages of disease at diagnosis. Aggressive surgical debridement is the mainstay of treatment, along with correcting the underlying metabolic abnormality. Higher rates of neurologic and visual sequelae are found in this group when compared to other subgroups with IFS.