|Year : 2019 | Volume
| Issue : 2 | Page : 703-711
Assessment of prognostic factors in patients diagnosed with acute invasive fungal rhinosinusitis in Egypt
Abd Ellatif I El-Rashidy, Omar A El-Banhawy, Ibrahim A Abd El-Shafy, Ahmed M Basha
Otorhinolaryngology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
|Date of Submission||18-Nov-2017|
|Date of Acceptance||29-Jan-2018|
|Date of Web Publication||25-Jun-2019|
Ahmed M Basha
Otorhinolaryngology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom
Source of Support: None, Conflict of Interest: None
To evaluate the prognostic factors in patients with invasive fungal rhinosinusitis and their effects on disease outcome.
Invasive fungal sinusitis is a fatal disease and its relative rarity has made precise identification of treatment protocols and prognostic factors difficult.
Patients and methods
Twenty patients diagnosed with invasive fungal sinusitis were recruited for a descriptive study. All patients were treated with antifungal drugs with proper control of their underlying diseases. Surgical debridement of necrotic and gangrenous tissue was performed in 15 patients. We divided the patients into two groups (surviving and nonsurviving). Both the groups were compared regarding the suggested prognostic factors such as the timing of presentation, the extent of gangrene at the time of presentation, state of the underlying disease, surgical treatment, and the involvement of other nearby structures.
The overall survival rate was 45%. There was a significant difference between both groups regarding the control of original disease (P = 0.0001). There was a significant difference between both groups regarding neurological deficit (P = 0.0001) as the intracranial involvement lowered survival outcome. There was a significant difference between both groups regarding the timing of presentation (P = 0.010) with early presentation improving the survival outcome. There was a significant difference between both groups regarding the extent of gangrene (P = 0.028) with extensive gangrene at the time of presentation lowering the survival outcome.
Patients with early presentation and good control of underlying diseases had better survival outcomes. Extensive surgical debridement offered better results, but the improvement was not to the level of statistical significance. However, patients with extensive gangrene and intracranial involvement generally had worse survival outcomes; therefore, these conditions were considered negative prognostic factors.
Keywords: amphotericin B, invasive fungal sinusitis, mucormycosis, prognostic factors, survival outcome
|How to cite this article:|
El-Rashidy AI, El-Banhawy OA, Abd El-Shafy IA, Basha AM. Assessment of prognostic factors in patients diagnosed with acute invasive fungal rhinosinusitis in Egypt. Menoufia Med J 2019;32:703-11
|How to cite this URL:|
El-Rashidy AI, El-Banhawy OA, Abd El-Shafy IA, Basha AM. Assessment of prognostic factors in patients diagnosed with acute invasive fungal rhinosinusitis in Egypt. Menoufia Med J [serial online] 2019 [cited 2019 Sep 20];32:703-11. Available from: http://www.mmj.eg.net/text.asp?2019/32/2/703/260926
| Introduction|| |
Invasive fungal sinusitis (IFS) is an aggressive and often fatal angioinvasive infection of the nose, paranasal sinuses and the neighbouring structures, which causes significant morbidity and mortality in the immunocompromised patient population. The causative fungal organisms, which typically function as saprophytes in the environment, can become pathogenic in humans under certain circumstances. The typical species responsible for invasive sinonasal infections are Aspergillus, Rhizopus, Rhizomucor and Mucor,.
Although IFS has been considered a rare disease, improvement of nasal endoscopy has made it increasingly identified in immunocompromised patients like those with haematological malignancies, immune-deficiency disorders and uncontrolled diabetes mellitus. Nasal endoscopy typically shows areas of mucosal ischaemia or tissue necrosis, and radiological investigations usually show nonspecific findings of sinus opacification; however, the diagnostic standard is histopathological evaluation and culture of nasal biopsies. Histopathological confirmation of the diagnosis requires the presence of invasive fungal elements within the submucosal tissues.
Medical and surgical treatments for IFS have improved with improved outcomes, but mortality remains high. Survival rates in the general population have varied from 20 to 80%. Previously identified negative prognostic factors included the presence of a haematologic malignancy, advanced age, and intracranial, or orbital involvement. Survival is favoured by early diagnosis and prompt initiation of culture-directed antifungal therapy and surgical debridement. The aim of this study was to determine the important prognostic factors affecting outcomes in patients diagnosed with IFS.
| Patients and Methods|| |
This study was a descriptive case series study conducted on 20 patients diagnosed with acute invasive fungal sinusitis (AIFS) recruited from the Department of Otorhinolaryngology, Head and Neck Surgery, Menofiya University, spanning the period from October 2014 to December 2016. The study was conducted after obtaining approval from the ethics committee of the hospital, and a written consent was obtained from every patient before surgical intervention. The diagnosis of AIFS was based on clinical, radiological and histopathological data.
A medical history regarding age, sex, occupation, residence, presence of debilitating diseases, whether the patient was on treatment or not, the timing and mode of presentation, previous nasal surgeries and nasal symptoms such as nasal obstruction, anosmia or hyposmia, crust formation, epistaxis, discharge, facial pain, headache, facial fullness or oedema was obtained from every patient. We also obtained a history of ocular manifestations such as decreased visual acuity, diplopia, eye swelling or proptosis. Neurological symptoms included facial hypoesthesia or anaesthesia, cranial nerve defects and disturbed consciousness level, and palatal symptoms including regurgitation of food or fluid from the nose, palatal hypoesthesia or anaesthesia and nasal tone of voice.
The clinical examination for study patients included diagnostic nasal endoscopy to assess the colour of mucosa including whether there were whitish areas on the turbinate or septum or gangrenous areas and their distributions. We examined patients for the presence of crusts or discharge, either anterior or posterior and for the presence of polyps or masses or any abnormality in the anatomy of the nose. Endoscopic-guided biopsy was routinely obtained from the anterior end of the middle turbinate for histopathological examination because this area is the most common site for harbouring the fungus as described by Gillespie et al.. The patients were tested for hypoesthesia or anaesthesia by assessing the sensory function of the maxillary nerve which is known to be the main sensory supply of the nose. This was done by comparing healthy and diseased sides for the perception of touch sensation applied by a cotton-tipped probe to areas of sensory supply of the maxillary nerve, which include the upper lip, lateral and posterior portions of the nose, the upper cheek, anterior temple, mucosa of the nose, upper jaw, upper teeth and the roof of the mouth,.
An oral examination was performed for every patient to assess gangrenous areas in the palate or areas with changed colour, palatal necrosis or ulcers, hypoesthesia or anaesthesia, gingivitis and dental caries, especially in patients with diabetes. We conducted ocular examinations for patients to assess visual acuity, retinal haemorrhage, papilloedema, central retinal artery occlusion, proptosis if present along with its degree and ptosis or ophthalmoplegia with its type, whether internal or external.
The radiological assessment of patients included computed tomography to identify suspicious criteria for AIFS such as mucosal thickening, hypoattenuating opacification of the sinus, soft tissue attenuation, bone destruction which may be extensive or very subtle or even inapparent (extension through intact bone via vascular invasion), fat stranding outside the sinus perimeter such as intraorbital fat, masticator space and pterygopalatine fossa.
MRI is the modality of choice to assess soft tissue extension. The findings within the sinus itself are variable, and range from mucosal thickening, to complete opacification of the sinus. In T1: intermediate low signal, T2: fungal mass is of intermediate to low signal, often associated with fluid or blood elsewhere in the paranasal sinuses. T1-weighted images with contrast: absent sinus mucosal enhancement suggests necrosis; invasion outside the sinus appears as increased enhancement. Particular attention should be paid to assessment of invasion beyond the sinuses. Early invasion should be sought, and findings that are particularly important include stranding of the periantral fat, intraorbital fat, masticator space, pterygopalatine fossa, subtle enhancement (T1 C+ fat-sat), leptomeningeal enhancement and intracranial granulomas: low signal on both T1 and T2.
Histopathological assessment was performed for endoscopic nasal biopsies in the pathology department to confirm the diagnosis of AIFS using silver staining. Also, nasal swabs for culture and sensitivity were taken.
Treatment of AIFS generally requires a multidisciplinary approach. In our study, treatment of the underlying immune-debilitating disease began immediately along with the following protocol:
All patients who were hospitalized underwent the following treatment steps:
Systemic antifungal drugs, namely amphotericin B (X GEN Pharmaceuticals Inc., Horseheads, NY, USA) intravenous infusion at a dose of 1–1.5 mg/kg body weight with a usual total dose of 2.5–3 g/day should be immediately started. Amphotericin B can have acute side effects, including chills, fever, headache, thrombocytopenia, nausea and vomiting. Long-term reactions include nephrotoxicity, ototoxicity, hypokalemia and bone marrow depression.
Nasal lavage with saline or antiseptic preparation, for example, povidone iodine was performed daily along with the daily removal of crusts and assessment of the nasal mucosa for colour changes and sensation deficits.
Antibiotics and antioedematous measures were indicated with cases complicated by facial cellulitis. ICU admission was undertaken if the patients developed intracranial complications or complications of underlying diseases, such as hepatic coma or renal encephalopathy.
Surgical treatment was indicated for cases presenting with gangrenous areas in the nose, radiological evidence of soft tissue shadow obliterating sinuses, hard palate ulcers or gangrene, or proptosis and gradual loss of vision.
Aggressive surgical debridement was performed for all patients unless contraindicated because the general condition of the patient did not allow it like in patients with a high bleeding tendency. Debridement was performed in all gangrenous areas, areas of discharge, crusts, necrotized bone or cartilage, abnormally coloured mucosa or any unhealthy tissues until healthy edges were reached with intact vasculature, sensation and appearance.
Surgical options included open maxillectomy either total or partial, in extensive fungal invasion eroding the bone of the hard palate with extensive gangrene. Additionally, endoscopic debridement was indicated for limited disease processes affecting the nasal septum, lateral nasal wall, and floor of the nose or limited sinus affection. Sinus affection was more than expected from the radiological investigations.
The patients were examined every day for the first 2 weeks, then twice weekly till improvement to assess the presence of gangrenous areas and the colour and sensation of the surrounding nasal and sinus mucosa, along with the removal of discharge and crusts. Facial swelling was assessed along with visual acuity. The degree of consciousness was an essential part of the follow-up. The state of the original disease was assessed, for example, with random blood sugar, kidney and liver function tests, along with the follow-up of side effects of the antifungal medication such as hypokalaemia and kidney function.
Patients will be divided into two groups according to survival: group 1 including surviving patients and group 2 including nonsurviving patients. Both groups were compared regarding the timing of presentation, underlying immune-compromising diseases, the extent of gangrene, invasion of nearby structures (orbit, palate, brain), and surgical treatment to assess the assumed prognostic factors.
Data were collected and analyzed using the statistical package for the social sciences (SPSS) program for statistical analysis, (version 20; SPSS Inc., Chicago. Illinois, USA). Quantitative data are shown as the mean, SD and range. Qualitative data are expressed as frequencies and percentages. The χ2-test was used to measure associations between qualitative variables. Fisher's exact test was used for 2 × 2 qualitative variables when more than 25% of the cells had an expected count of less than 5. Kaplan–Meier survival analysis was plotted when appropriate. P values were considered statistically significant when less than 0.05.
| Results|| |
In our study, the surviving group included patients with mean age at 48 years and distributed as four men and five women, while the nonsurviving group included patients with mean age at 58 years and distributed as seven men and four women [Table 1]. There was no significant difference between the two groups regarding age and sex. The survival rate was 45% (9/20). In 11 patients, the results of histopathological analysis of the biopsies and the cultures of the swabs taken showed mucormycosis (right angled branching nonseptated hyphae); unfortunately, biopsies were not taken in the rest of the patients as they died so soon that we could not make any interventional procedure. Moreover, some patients had bleeding tendencies (hepatic and blood malignancy patients) that made the physicians following their underlying diseases advising against any invasive intervention.
|Table 1: Comparison between dead and survived patients as regards sociodemographic data|
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Our study showed a significant difference between surviving and nonsurviving patients regarding neurological deficits (P = 0.0001). However, there was no significant difference between the two groups regarding orbital involvement or palatal involvement at the time of presentation (P = 1 and 0.617, respectively) [Table 2].
|Table 2: Comparison between died and survived patients as regard complication|
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Also, the study had shown a significant difference between surviving and nonsurviving patients regarding the control of original disease (P = 0.0001) [Table 3]. Additionally, our study showed that combination therapy (surgery and medical treatment) was better than medical treatment alone, but the difference did not reach statistical significance (P = 0.319). However, among the types of surgery, total maxillectomy operations appeared to have the best survival outcomes compared with other procedures (P = 0.0021) [Table 4] and [Figure 1].
|Table 3: Comparison between dead and survived patients as regards original disease|
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|Table 4: Comparison between dead and survived patients as regards surgical treatment|
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|Figure 1: A picture of a female patient diagnosed with acute invasive fungal sinusitis of the surviving group presented with facial oedema, then the patient after three months from total maxillectomy operation.|
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Our study also tells that there is a significant difference between surviving and nonsurviving patients regarding the timing of presentation with early presentation (during the first week) resulting in better survival outcomes (P = 0.010) [Table 5]. It also showed no difference in survival outcome regarding the mode of presentation whether patients presented at outpatient clinics or with patients were admitted to inpatient wards or ICU departments.
|Table 5: Comparison between dead and survived patients as regards timing and mode of presentation|
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Our study showed a significant difference between surviving and nonsurviving patients, regarding the extent of gangrene at the time of presentation as defined by diagnostic nasal endoscopy and surgical records (P = 0.028) [Figure 2] and [Table 6]. There was no significant difference between the two groups regarding computed tomography and MRI findings (P = 0.37 and 0.9, respectively) ([Table 7] and [Figure 3],[Figure 4],[Figure 5],[Figure 6].
|Figure 2: A picture of a male patient diagnosed with acute invasive fungal sinusitis of the non surviving group with gangrene of the hard palate with periorbital oedema with extensive gangrene of the nasal septum.|
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|Table 6: Comparison between dead and survived patients as regards the extent of gangrene|
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|Table 7: Comparison between patients who died and patients who survived as regards radiological findings|
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|Figure 3: A picture of CT nose and PNS of a patient of the non surviving group, coronal section showing soft tissue density filling the right ethmoidal sinuses with mucosal thickening of the right maxillary sinus. A case diagnosed with acute invasive fungal rhinosinusitis.|
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|Figure 4: A picture of MRI T1 weighted images with contrast of the nose and PNS axial cut of a female paatient diagnosed with acute invasive fungal sinusitis of the non surviving group, showinfg hypointense lesion of the left maxillary sinus with proptosis of the left eye.|
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|Figure 5: A picture of CT nose and PNS coronal section soft tissue window with no contrast showing soft tisssue density filling right maxillary sinus and ethmoidal sinuses with hetrogenecity. A case diagnosed with acute invasive fungal rhinosinusitis of the surviving group.|
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|Figure 6: A picture of MRI T2 weighted image with contrast of a patient diagnosed with acute invasive fungal sinusitis of the surviving group 3 months from medial maxillectomy operation.|
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| Discussion|| |
The incidence of IFS has increased in the past few years to such an extent that it should be considered in all patients with chronic rhinosinusitis. Early and accurate diagnosis is essential because the prognosis is often governed by rapid initiation of antifungal therapy and/or surgical debridement. Despite improvements in both medical and surgical therapies for IFS, mortality remains high because the advancement and standardization of IFS treatment protocols have been limited by the rarity of the disease and a resulting lack of published, randomized studies.
The precise prognostic factors that contribute to favourable versus poor survival rates remain largely unclear. The commonly regarded positive prognostic factors have generally been extracted from a small case series. Examples included early diagnosis, aggressive surgical debridement and the use of amphotericin B. Dozens of potential negative prognostic factors have also been identified, including the presence of haematologic malignancy, advanced age, intracranial extension or orbital involvement. We anticipate that the conclusions of this report will help identify at-risk patients and perhaps allow for the tailoring of patient-specific treatment protocols.
In our study, we found that the sole presentation of diabetes carried better prognosis than other immune-debilitating diseases. This finding agreed with the opinion of Turner et al., who explained the potential reversibility of the underlying predisposing medical disorder. An enhanced survival rate in diabetics was observed in our study reaching 62% compared with 23% in hepatic patients, 40% in renal patients and 36% in patients with blood malignancies. This is despite the aggressive nature of the zygomycetes (Mucor, Rhizopus, Rhizomucor) which are generally more common in diabetics.
The poor survival rate in hepatic patients can be explained by practical problems in the management of IFS in patients with cirrhosis, especially decompensated cases. Defective coagulation and thrombocytopenia in such patients make surgical management of the involved tissues difficult. The reluctance of patients and their relatives or even surgeons and anesthesiologists about surgical interventions is an important factor. Additionally, amphotericin B is the cornerstone of pharmacological therapy with its significant side effects of renal toxicity and electrolyte imbalance, rendering it difficult to administer in patients with cirrhosis.
Leukaemic patients often present with pancytopenia including severe thrombocytopenia due to the underlying disease or chemotherapy with the consequent bleeding tendency. Hence, proper tissue sampling may not be feasible; or it can only be performed after a significant delay. Additionally, aggressive surgical debridement is more difficult in these patients. In patients with chronic kidney disease, decreased cell-mediated immunity and impaired neutrophil function, including chemotaxis and phagocytosis have been documented. In addition, the accompanying acidosis has been suspected to increase the susceptibility to mucormycosis since the iron required for hyphal growth is released from transferring as the blood pH decreases.
In our study, patients with early presentation had better survival outcomes (88.9%) than those who presented later (11.1%); hence the timing of presentation was identified as a positive prognostic factor for survival outcome. This result was in agreement with Dhiwakar et al. and other published studies which reported that early presentation with the immediate start of amphotericin B and surgical debridement before extensive invasion offered a better prognosis.
Additionally, we found that patients with less gangrenous areas or no gangrene at the time of presentation had better survival outcomes (85%) than those with extensive gangrene (12.5%). This result is in agreement with previously published studies including one by Gillespie et al., and can be explained by lesser areas of gangrene carrying a lower fungal load with easier surgical debridement and better prognosis.
Not surprisingly, our study also showed that intracranial invasion carried worse prognosis and was considered an independent negative predictive factor with a survival rate of 15.3%. This finding was in agreement with Turner et al. who found that such patients were almost twice as likely to die as patients without intracranial involvement.
Interestingly, orbital complications of IFS, including ophthalmoplegia, vision loss, and proptosis, were not identified as negative prognostic factors in the current study. This finding is in contrast to the findings of a previous and relatively large case series published by Bhansali et al., who reported decreased survival outcomes associated with vision loss and ophthalmoplegia. However, all surviving cases in our study showed loss of vision and ophthalmoplegia of the affected eye. In contrast, Choi et al. reported that permanent loss of light perception in the affected eye occurred in 80% of their case series patients, who had no visual loss prior to infection and showed worsening vision after infection.
Additionally, palatal invasion at the time of presentation was not shown to have a direct impact on survival outcomes in our study, in agreement with Foshee et al. and in contrast to Gode et al., who found that palatal involvement was associated with higher mortality.
This difference between our study and the above-mentioned studies can be explained by differences in the treatment protocol applied in each study affecting the management of local extension and its further effects on recovery. In our study, open maxillectomy offered a great option for managing extensive local extension with either palatal or orbital involvement with a further improvement in treatment outcome.
The survival rate with antifungal medication alone was 20%, which was much lower than the survival rate of cases receiving combination therapy, which was 53.3%. Although the cure rate with combination therapy was higher, the difference in mortality rate with these two therapeutic approaches (i.e., antifungal therapy alone vs. combination therapy), was not significant (P = 0.319). However, Turner et al. found that surgery, regardless of approach, was an independent predictor of improved survival in patients with AIFS, with highly significant results (P < 0.0001). We attributed this disagreement to the difference in sample size with a smaller number of cases in our study due to a relative rarity of cases. The better outcome of combination therapy could be explained by improved antimicrobial penetration and a reduced burden of fungal organisms with a decreasing risk of regional and systemic spread of disease. In our study, the time interval between the onset of diagnosis and death in patients who died was longer in patients who underwent surgical manoeuvres including two patients whose deaths were attributed to their original diseases rather than fungal invasion.
These findings raise the issue of the reasons for not performing surgical debridement for all patients in our study. There were many reasons for such decisions including the conscious choice of some patients or their relatives in nonoriented patients to decline surgical intervention, fearing possible disfigurement or orbital exenteration. In other instances of intracranial or multisystem involvement, coagulation defects in hepatic, renal and blood diseases can render the surgical option unfeasible or cause it to be declined by the treatment team whether surgeons or anaesthesiologists.
Amphotericin B administered either intravenously or by local irrigation was used as the main antifungal therapy in all 20 patients. However, Turner et al. have shown that liposomal amphotericin B was more efficient and had less nephrotoxicity than deoxycholate-amphotericin B. The high cost of liposomal amphotericin B and its difficult availability in our market made it difficult to use it in the current study.
Immediately start with amphotericin B intravenously as an empirical treatment administered upon clinical suspicion or radiological suspicion of IFS in immunocompromised patients lowered the aggressiveness, bone destruction and hence mortality in our study. Due to its known adverse effects, such as renal toxicity and electrolyte imbalance, it has its limitations in end-stage renal and hepatic patients and we used it for local nasal irrigation in some cases as a primary or adjunctive antifungal therapy, as described by Cohen-Ludmann et al..
When choosing an open versus endoscopic approach for the treatment of IFS, patient-specific factors should always be considered such as the extent of gangrene and subsites affected in the disease process. All the patients in the current study who received open surgical approaches had more significant fungal burdens and/or necrosis with extensive local spread and gangrene. Among the different types of surgeries discussed in our study, total maxillectomy offered a perfect survival rate of 100%, suggesting that aggressive debridement is fundamental to decrease the fungal load and lowers the aggressiveness of the disease and hence mortality.
At the end of this study, the overall survival rate was 45% which was relatively poor reflecting the need for the development of standardized treatment protocols and clear identification of factors that contribute to patient survival. Against this finding was the fact that IFS remains an uncommon disease, with only a handful of cases presenting every year.
| Conclusion|| |
IFS continues to have a high mortality rate. Patients with early presentation and good control of underlying diseases had better survival outcomes with diabetics and recovered better than nondiabetics. Extensive surgical debridement offered better results but not reaching the level of statistical significance. However, patients with extensive gangrene and intracranial involvement generally have worse survival outcomes and considered as negative prognostic factors.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]