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Case report |
Departments of 1Diagnostic Radiology 2Internal Medicine II 3Pathology 4Radiology 5Neuropathology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany
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Abstract |
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Introduction |
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Generally, the infection is rapidly progressive, usually with local spread but, occasionally haematogenous dissemination with multiorgan involvement can be seen. Furthermore, in the rhinocerebral form of mucormycosis, a perineural spread directly through the cribriform plate into the anterior fossa has also been recognized as a possible pathway of infection [6].
Early diagnoses of localized disease, as well as an association of aggressive antifungal therapy and surgery, are mandatory for patient's survival. In cases of disseminated infection, however, the prognosis remains unfavourable, despite aggressive patient management [7, 8].
This case series emphasises the role of the radiologist in the correct diagnosis of angiotropic fungal infections, by early assessment of haemorrhage and infarction, which are constant features of invasive mycosis, including the genre Mucorales.
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Case reports |
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). A decompression colonic tube was placed across the stenosis, which resulted in temporary amelioration of the patient's symptoms. However, 4 days later, the patient once again complained about severe abdominal cramp-like pains. Repeat CT revealed diffuse small and large intestine wall thickening, ascites and small extraluminal, left paracolical air bubbles indicating spontaneous bowel perforation. Areas of both normal and absent contrast enhancement were seen on CECT suggesting extensive necrosis (Figure 1b). Large and middle-sized arterial and venous mesenteric vessels proved patent, thus excluding thromboembolic occlusion. Subsequently, bowel wall perforation and extensive intestinal ischaemia due presumably to infection with angiotropic fungi was diagnosed and the patient underwent abdominal surgery. Perforations were found at multiple sites along the descendent colon at laparotomy, and necrotic large and small intestinal loops were resected. Furthermore, the greater omentum proved infiltrated by direct fungal invasion, as well as the peritoneum and parts of the abdominal wall. At inspection, areas of necrosis of the uterine body (Figure 1c) and parts of the wall of the urinary bladder were found, leading to hysterectomy and partial cystectomy. Histological examination showed extensive fungal invasion of the necrotic tissue and vascular spaces. Resected bowel segments (Figure 1d) correlated well with the infarcted intestinal segments seen on CECT. The patient died 12 days later, due to progressive fungal sepsis despite aggressive antifungal treatment. A diagnosis of gastrointestinal, uterine, cystic, omental and peritoneal infection by Rhizopus oryzae was confirmed by molecular pathological methods, extraction of fungal DNA and subsequent PCR-amplification, as well as by culture. Small vessel fungi invasion was diagnosed in all involved organs. Interestingly, the serum lactate concentration was within normal range at all times.
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), both highly suggestive of angiotropic mycosis. Following intravenous contrast material application, a large area of low-attenuation due to infarction was noticed around the core of this lesion (Figure 2b). At this point, the diagnosis of invasive pulmonary mycosis was set by the radiologist and intensified antifungal therapy was initiated. Shortly thereafter, the patient developed life-threatening pulmonary haemorrhage and underwent surgery (bilobectomy) with temporary amelioration of the respiratory symptoms. 3 weeks later, the patient presented with erythematous skin lesions displaying central necrosis that were widely distributed on both legs. An MR investigation of the lower extremities revealed non-specific, cutaneous patchy areas of hyperintense T2 signal, accompanied by subcutaneous reticulation. Neither abscess nor signs of extensive necrotizing fasciitis were found. The skin biopsy disclosed angioinvasive fungal organisms. At follow-up, the patient developed acute pain in the left hip, aggravated by flexion. On contrast-enhanced CT, a 10 cm x 4.5 cm x 4 cm large hypodense fluid collection in the left iliopsoas bursa with ring enhancement was found, suggesting abscess formation (Figure 2c). CT-guided puncture of this fluid collection was, however, non-diagnostic. Unfortunately, pulmonary infection relapsed and rapidly aggravated, and the patient died 3 weeks later due to multiorgan failure. Histological examination showed massive fungal invasion of pulmonary tissue and vascular spaces with main bronchial ulceration due to Rhizopus species. Bronchial walls of the right lung were thickened due to oedema and fungal infiltration surrounded by an area of lung infarction and peripherally by organizing pneumonia (Figure 2d).
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). Conventional diffusion-weighted single-shot EPI disclosed restricted diffusion in the cord lesion as well as in the cerebrum, corresponding to the infarctions diagnosed in both occipital lobes (see bright signal on Figure 3b). On the post-contrast T1 weighted spin echo (SE)-scans (after intravenous administration of gadolinium DTPA; Schering, Berlin, Germany), no enhancement was registered either in the spinal cord lesion or in either cerebral lesions. At the same time, the patient developed additional signs of respiratory infection with dyspnoea and productive cough. On the third day, the patient lapsed into coma and died following dissemination of Mucor infection.
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) heart and lung (Figure 3d). Microbiological diagnosis classified the fungus as belonging to the Rhizopus species. In the spinal cord and brain, the pathologist found multiple infarctions due to massive mycotic invasion of the blood vessel walls and perivascular spaces.
Case 4
A 43-year-old male patient with AML was admitted to our hospital in December 2002 for chemotherapy and developed signs of respiratory infection at severe neutropenia. He was treated with liposomal amphotericin B and the solitary nodular lesion in the right upper lung lobe began to regress (Figure 4a). The patient felt well until December 2002, when he was re-admitted for chemotherapy due to relapsing leukaemia. During the chemotherapy regimen, he developed simultaneous signs of paranasal sinus infection and upper respiratory tract infection (Figure 4b). At this time, the patient was receiving antifungal prophylaxis. Subsequently, a chest CT was carried out and disclosed renewed occurrence of halo signs around the known pulmonary nodule, suggesting reactivation of pulmonary infection. The antifungal therapy was intensified using high-dose liposomal amphotericin B. However, no improvement of rhinorrhoea, excessive lacrimation of the left eye and painful swelling of the left side of the face could be observed. Therefore, the patient underwent surgical debridement of the left maxillary sinus. 3 weeks later, MRI of the orbit and paranasal sinuses revealed progression of maxillary invasion by fungi with further involvement of the left frontal, sphenoid sinus and left orbit (Figure 4c). At this time, focal areas of absent contrast enhancement were documented as well as in the thickened sinus mucosa, as in the bone marrow of the involved ethmoidal and maxillary bones. At follow up, left-sided proptosis as well as ptosis and ecchymosis of the lids had occurred. As a consequence of the invasion of the left orbit by mucormycosis, an exenteratio bulbi was performed. 3 weeks later, a follow up MRI of the region showed progression of local fungal infection with contiguous bone infiltration and extension of the fungal process to the frontal dura (Figure 4d), also invading the brain, in spite of intensive antifungal therapy. The patient died 2 weeks later, presumably due to progressive invasion by Rhizopus of brain tissue. Relapsing AML was simultaneously diagnosed.
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Discussion |
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Thus, pulmonary infection most often consists of nodular or wedge-shaped areas of homogeneous airspace consolidation resembling typical thromboembolic infarction. Although the pathomechanisms of these two conditions are different, the final result is similar representing occlusion of a major pulmonary artery. Massive pulmonary haemorrhage can occur as a result of erosion of the pulmonary artery and could, therefore, be fatal.
In patients presenting with gastrointestinal involvement by mucormycosis, infiltration of the walls of blood vessels, especially arteries, initiate acute vasculitis and thrombosis followed by ischaemic infarction and diffuse or segmental bowel necrosis. Less commonly, infection of abdominal or pelvic organs by Mucorales may occur, resulting also in focal or diffuse organ necrosis due to vascular occlusion and secondary ischaemia.
In the more common involvement of the rhinocerebral region, arterial occlusion leads in time to infarction; this represents the key feature of infection to be assessed by imaging methods (MRI, CT). Primary involvement of the central nervous system may result in abscess formation, infarction or haemorrhage.
In most patients, the course of the disease is fulminant, often leading to patients' death before fungal infection can be diagnosed. In addition to this classical fulminant form, there have been reports regarding a more chronic form of mucormycosis [9, 10].
Among the localized infections, rhinocerebral mucormycosis is most common, being strongly associated with poorly controlled diabetes mellitus [11]. Secondary pulmonary infection may occur in these patients, due possibly to aspiration of infected nasal discharge. The second most frequently involved organ is represented by the lung [12]. Other recognized distinct clinical syndromes of mucormycosis are: cutaneous, gastrointestinal and widely disseminated forms of infection [13].
In severely immunocompromised patients, however, especially in individuals with lymphoproliferative or haematological disorders, rapidly progressive dissemination is frequent despite ongoing antifungal therapy. Furthermore, the spectrum of disease seems to differ from that seen in other risk groups. Thus, multiorgan involvement was encountered in all haematological patients presenting with mucormycosis infection in our series.
As management of mucormycosis is difficult, a high index of suspicion and early institution of empirical antifungal therapy is therefore critical, because once infection takes hold, treatment is often ineffective. Prompt treatment ideally consists of a combination of surgical removal of devitalized necrotic tissue together with long-term administration of intravenous antifungal therapy, with high-dose liposomal amphotericine B representing the current mainstay.
Depending on the initial localization of infection, imaging techniques may sometimes deliver an early presumptive diagnosis of angiotropic mycosis, e.g. in the lung (halo sign surrounding nodules or consolidations, crescent sign and central hypointensity), as already extensively researched in patients with invasive pulmonary aspergillosis. Irrespective of the various locations of infection, all patients in our series had haemorrhage and/or infarction (tissue necrosis) in common, which represent complications that are highly suggestive of angiotropic fungal infection in this clinical setting. Therefore, looking for these two complications at CT follow up in patients suspected of fungal infection seems to be the key to early diagnosis.
Accordingly, CT diagnosis of intestinal ischaemia in our first case was initially correct, showing non-enhancing segments of the small and large bowel wall. Retrospectively, hypoperfusion of parts of the uterine body was also visible at CT. Taking into consideration the young age and the fact that no past history of vascular or cardiac diseases were known in this patient, the presumption diagnosis of bowel ischaemia due to fungi in the setting of acute infection in an immunocompromised patient, as set by the radiologist, was correct.
Possible differential diagnoses include chemotherapy-induced necrotizing enteropathy and ischaemic colitis. At CT, chemotherapy-induced enteropathy appears as non-specific focal or diffuse bowel wall thickening with or without the target sign or regional mesenteric vascular engorgement and haziness. Such findings can be seen in either diseased or disease-free intestinal segments [14]. The ischaemic colitis was described in oncological patients with solid tumours who were treated with cisplatin and 5-FU, but this could easily be excluded in our patient [15]. Notably, multiorgan ischaemia preceded by clinical signs of infection, in this case of an immunocompromised patient, was primarily suggestive of fungal-induced vessel occlusion. Unfortunately, surgical management was delayed by severe neutropenia and thrombocytopenia and, despite ongoing antifungal prophylaxis, the patient died shortly after abdominal surgery.
In our second case, typical signs of pulmonary infarction with demarcation of a huge lung sequester, as well as fulminant pulmonary haemorrhage at follow up, enabled recognition of invasive pulmonary fungal infection; the former already prior to dissemination of infection. However, differentiation from other angioinvasive fungi (e.g. Aspergillus) is mandatory as some of the antifungal agents, for instance most azole derivates (fluconazole, itraconazole and voriconazole), are not active against Mucorales, as demonstrated in this case and, therefore, microbiological validation should be aimed for early in the course of the disease. The differential diagnosis of pulmonary infarction caused by Mucorales includes thromboembolic infarction due to disease or therapy related coagulopathy, which can usually be easily excluded by CT-angiography. Furthermore, infection due to other pathogens (bacterial, tuberculosis, actinomycosis) leading to abscess formation must be included in the differential diagnosis, even if the clinical setting in which they occur and the imaging findings differ somehow from those of angiotropic mycosis. The erythematous skin lesions on the legs of our patient that simultaneously developed necrosis were primarily suspicious of cutaneous fungal infection and, therefore, the diagnosis could be set early in the course of the disease by biopsy.
In the third case, the location of all lesions, their fulminant course, as well as the missing contrast material enhancement and the lowered apparent diffusion coefficients were suggestive for ischaemic brain and spinal cord [16–18]. Acute or subacute infarction of the spinal cord can present variable patterns of intramedullary oedema, the central grey matter being usually most severely affected with a typical butterfly-like central signal abnormality. Infarction of the spinal cord is more frequent near the thoracolumbar junction, with frequent involvement of the conus medullaris, because collateral supply to the anterior spinal artery is relatively sparse in this region. On the contrary, infarction of the cervical segment of the spinal cord is infrequent due to redundancy of radicular supply to the anterior spinal artery at this level. However, in the setting of cerebral vasculitis (e.g. related to toxicity of chemotherapeutic regimens or paraneoplastic), atypical locations of ischaemia may occur. Therefore, vasculitis was favoured as the most probable cause for paraplegia in this patient. Other causes for vasculitis (e.g. syphilis, collagen vascular disease) could be excluded by anamnesis and laboratory analysis. Further differential diagnoses include systemic embolisation, trauma, as well as inflammatory or degenerative neuronal disorders. However, all these conditions could be excluded by the patient's past history and laboratory data. Another possible differential diagnosis of cerebral or spinal cord mucormycosis also includes cerebritis and myelitis caused by other pathogens. However, as already mentioned, the lack of contrast enhancement of all lesions was not typical for infectious foci.
Despite improvement of diagnostic accuracy by means of advanced imaging techniques such as diffusion tensor imaging (DTI), perfusion imaging and proton magnetic resonance (MRS), there are still poor data in the specialist literature on this issue. Siegal et al reported on the possible differentiation of cerebral mucormycosis from bacterial abscesses by use of (MRS) [19]. Accordingly, MRS was showing markedly elevated lactate, depleted N-acetyl aspartate and metabolite resonance attributable to succinate and acetate in that case, which was essentially similar to that of bacterial abscess, but without the commonly seen resonances of the amino acids valine, leucine and isoleucine.
In conclusion, spinal cord and cerebral lesions as well as the pulmonary masses in this patient were expression of vessel occlusion by fungus resulting in ischaemia and tissue necrosis, as confirmed by the pathologist. There was also perifocal haemorrhage around the pulmonary lesions as they occurred.
In the fourth case, paranasal tissue necrosis could be diagnosed correctly at MR-follow up due to progressing non-enhancing parts of the involved mucosa of the maxillary sinus on MRI that were indicative for ischaemia. MRI is also playing a major role in assessing disease progress either through the cribriform plate into the frontal lobe of brain or into the retro-orbital region and then through the apex of the orbit into the brain. Possible differential diagnoses include infection due to other pathogens as well as rhino-maxillary involvement by lymphoma, other forms of vasculitis (e.g. Wegener's disease, Churg-Strauss) or carcinoma. All these conditions show, however, other growth kinetics and can be easily excluded by biopsy. It is noteworthy that the initial lung nodule accompanied by typical halo sign was suggestive for invasive pulmonary fungal infection, where nodules represent haemorrhagic lung parenchymal necrosis.
This case series also demonstrates the temporal sequence of mucormycosis dissemination and the poor control of infection by combined surgical and antimicrobial therapy in haematological immunocompromised patients, regardless of the sites of infection.
A dramatic improvement in prognosis of mucormycosis infection, attributed mainly to correct pre-mortem diagnosis leading to aggressive surgery and liposomal amphotericin B administration, has been reported by some authors since 1970 [20, 21]. However, most of their patients had localized infection and suffered from diabetes mellitus.
Early presumptive radiological diagnosis of angioinvasive fungal infection at the time when they are still localized is, therefore, paramount for correct patient management and improved prognosis. Nevertheless, differentiation between the more common Aspergillus infection and Mucor remains unreliable; therefore broad-spectrum antifungal agents are indispensable. Unfortunately, once dissemination becomes manifest, in the course of the disease, neither surgery (performed in three of four patients) nor intensified antifungal therapy with liposomal amphotericin B can positively influence outcome.
In summary, identification of haemorrhage or infarction in immunocompromised patient should be regarded as an indicator of possible infection by angiotropic fungi, including the genre Mucorales. Thus, early diagnosis of localized mucormycosis may facilitate management and improve prognosis by early institution of intensified antifungal therapy and surgery, before they spread systemically.
Received for publication April 4, 2005. Revision received September 6, 2005. Accepted for publication October 11, 2005.
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