Pulmonary Mucormycosis the Last 30 Years

REVIEW ARTICLE Pulmonary Mucormycosis The Last 30 Years

Francis Y. W. Lee, MD; Sherif B. Mossad, MD; Karim A. Adal, MD, MS

ulmonary mucormycosis is relatively uncommon but an important opportunistic fungal infection in immunocompromised persons. The literature on the subject is sparse. We describe a recent case and review the literature to delineate the clinical character- istics of this infection. We searched the MEDLINE database for articles published in the PEnglish-language literature since 1970 and carefully analyzed 87 cases. The main risk factors were diabetes mellitus, hematologic cancers, renal insufficiency, and organ transplantation. Several patients had no apparent immune compromise. There was a predilection for involvement of the upper lobes. Air crescent signs on chest x-ray films were predictors of pulmonary hemorrhage and death from hemoptysis. Fiberoptic bronchoscopy was a useful diagnostic method, and histopathologic examination was more sensitive than fungal cultures. The overall survival rate was 44%. Pa- tients treated with a combined medical-surgical approach had a better outcome than patients who did not undergo surgery. Thus, this relatively rare but often fatal disease should be suspected in immunocompromised patients who fail to respond to antibacterial therapy. Early recognition and aggressive management are warranted to maximize chances for cure. Optimal therapy requires systemic antifungal therapy, surgical resection, and, when possible, control of the patient’s underlying disease. Arch Intern Med. 1999;159:1301-1309

Pulmonary mucormycosis is a relatively agement, often involving surgical resec- uncommon infection that occurs mostly tion, can lead to a cure in selected patients, in immunocompromised persons. The first the goal of our review is to better charac- case of pulmonary mucormycosis was de- terize the population at risk, presenting scribed in 1876 by Furbringer.1 In a clas- symptoms, radiological appearance, diag- sic review in 1971, Baker2 thoroughly nostic methods, therapy, and outcome. describes all cases of mucormycosis previously reported. Since then, only ILLUSTRATIVE CASE scattered reports have been published, except for a review by Tedder et al,3 who The patient, a 39-year-old white man with describe 30 patients treated at their insti- a medical history of hypertension, myelo- tution and 225 additional patients de- dysplastic syndrome, and type 1 diabetes scribed in the literature. They include mellitus of 18 years’ duration compli- many patients with disseminated mucor- cated by retinopathy and renal failure, had mycosis in their analysis, thus weaken- received a cadaveric renal transplant in ing the applicability of their findings and 1991. He was seen in the outpatient clinic conclusions to isolated pulmonary dis- September 15, 1995, with a 2-week his- ease. In this article, we describe an immu- tory of sore throat, nonproductive cough, nocompromised patient with localized pul- dyspnea on exertion, fever, chills, gener- monary mucormycosis and review 86 alized malaise, and myalgias. Medica- other cases reported in the literature since tions at presentation included predni- 1970, when bronchoscopy became widely available. Because a high index of suspicion, earlier diagnosis, and aggressive man- This article is also available on our Web site: www.ama-assn.org/internal. From the Division of Internal Medicine (Dr Lee), Department of Infectious Disease (Drs Mossad and Adal), Cleveland Clinic Foundation, Cleveland, Ohio.

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 sone, 5 mg daily; cyclosporine, 125 mg twice a day; ofloxacin, 400 mg daily; ferrous polysaccharide; and in- sulin. On physical examination on admission to the hospital, he had a temperature of 38.4°C, and his lung fields were normal to auscultation. His chest radiograph revealed a new right upper lobe infiltrate that was not present on a radiograph taken 10 days before. His white blood cell count was 4.19ϫ109/L; hemoglo- bin level, 69 g/L; and platelet count, 52ϫ109/L; with serum levels of urea nitrogen, 9.3 mmol/L (26 mg/dL), and creatinine, 133 µmol/L (1.5 mg/dL). He had defervescence, with lessening of his symptoms, with the administration of intravenous van- comycin and ceftazidime. Blood and sputum cultures remained negative for pathogens. He was dis- charged from the hospital 4 days later with oral clarithromycin. The patient returned to the emergency department 4 days later Figure 1. A chest radiograph showing a right upper lobe infiltrate. with recrudescence of his previous symptoms and pleuritic chest pain. He was again febrile to 38.2°C, with bronchial breath sounds and a localized wheeze heard over the right upper lung. His blood pressure on admission was 132/64 mm Hg; res- pirations, 20/min; and oxygen satu- ration, 100% with the patient breath- ing room air. His chest radiograph revealed persistence of the right upper lobe infiltrate, which now ex- tended to the right hilum, with vol- ume loss and the development of a hilar mass (Figure 1). His white blood cell count was 5.8ϫ109/L with 0.74 neutrophils. The intravenous administration of a combination of ticarcillin and clavulanate, and eryth- romycin was started. Flexible fiber- Figure 2. A computed tomographic scan of the chest showing an infiltrative mass in the right upper lobe optic bronchoscopy performed on involving the right hilum. day 3 of his second hospital admission revealed narrowing of the an- brushings and histological exami- Histopathologic analysis of the terior and posterior segments of the nation of a biopsy specimen re- lung confirmed widespread angio- right upper lobe associated with mu- vealed broad nonseptate hyphae invasive infection with Mucorales cosal edema. Computed tomogra- with right-angle branching, consis- (Figure 3 and Figure 4). The or- phy of the sinuses revealed no ab- tent with mucormycosis. His ab- ganism grew and was found to be normalities. Computed tomography solute neutrophil cell count fell to Rhizopus arrhizus. His postopera- of the chest on the same day re- 1.02ϫ109/L. A course of intrave- tive course was complicated by a rise vealed right upper lobe consolida- nous amphotericin B (1 mg/kg of in the serum creatinine level to 212 tion and necrosis extending to the body weight) was initiated that µmol/L (2.4 mg/dL). His amphoteri- right hilum (Figure 2). The right evening. At thoracotomy on Sep- cin preparation was changed on upper lobe and right main bronchi tember 29, the right main pulmo- October 3 to a colloidal dispersion were both narrowed. A small right nary artery was found to be in- (Amphotec; 4 mg/kg) to minimize pleural effusion was also noted. Cy- vaded by a fungating mass, and a nephrotoxic effects. A nosocomial tologic analysis of endobronchial pneumonectomy was performed. left lower lobe pneumonia devel-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 by a culture positive for the causative organism. We searched the MEDLINE database for articles published in the English-language literature since 1970 using mucormycosis and pulmonary as keywords or text words. We used 1970 as a cutoff because of the year of publication of Baker’s article (1971) and because of the in- troduction of flexible fiberoptic bronchoscopy. Where applicable, we reviewed references cited in the above studies. Care was taken to en- sure that the same patient was not included twice in our analysis, as some patients were described more than once in the literature. Incom- plete case reports with limited clinical information were not included Figure 3. Irregularly shaped broad hyphae invading a blood vessel (hematoxylin-eosin stain, original in our analysis. The data were ana- magnification, ϫ180; inset: original magnification, ϫ210). lyzed with a database program (Re- flex 2.0; Borland [now Inprise Corp], Scotts Valley, Calif).

RESULTS

Eighty-six cases in the literature met our criteria for localized pulmonary mucormycosis without evidence of dissemination,4-80 leading to a total of 87 cases when our patient’s case is added.

DEMOGRAPHICS AND UNDERLYING CONDITIONS

Sixty-five patients were male and 22 were female, for a male-female ratio of 3:0. The mean age was 44 years (range, 2 months to 83 years). The ethnic group was not recorded con- Figure 4. Ribbon-shaped, nonsegmented hyphae with right-angle branching (hematoxylin-eosin stain, sistently in the literature, being re- original magnification, ϫ2000). ported for only 36 of 87 patients, with the following distribution: 16 oped that progressed despite broad- diastinum. Disease was defined as whites, 10 African Americans, 7 spectrum antibiotic therapy, neces- disseminated when 2 or more non- Asians, 2 Hispanics, and 1 Middle sitating mechanical ventilation. He contiguous organ systems were in- Eastern patient. died of sepsis on October 9. An au- volved or blood cultures grew the When we analyzed underly- topsy revealed pneumonitis of the causative organism. The presence of ing conditions in our study popula- left lower lobe, with silver staining sinus disease in addition to pulmo- tion, the largest group consisted of failing to show fungi. There was no nary disease was not considered dis- 49 patients (56%) with diabetes evidence of disseminated mucor. semination because it reflected fo- mellitus, of whom 10 (20%) pre- cal involvement of the respiratory sented with ketoacidosis. The next METHODS tract, and a case of rhinocerebral dis- largest group consisted of 28 pa- ease in the presence of pulmonary tients (32%) with hematologic can- Our retrospective review focuses on lesions was accepted only if it was cers, of whom 13 (46%) had neu- patients with localized pulmonary obvious that the cerebral lesion was tropenia. Of the 28 patients, 17 mucormycosis who did not have evi- due to direct extension from the si- (61%) had acute leukemia (8 with dence of dissemination. Pulmo- nuses. The diagnosis was accepted acute myeloid leukemia, 7 with acute nary mucormycosis was defined as only if it was established by histo- lymphocytic leukemia, and 2 with disease localized to the lungs or me- logical or cytologic examination or acute promyelocytic leukemia),

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 symptoms. Both groups had simi- Table 1. Presenting Symptoms and Physical Findings lar bacterial coinfection rates (34% in 87 Patients With Pulmonary Mucormycosis vs 29%) and survival rates (44% vs 41%). Patients, Patients, Presenting Symptoms No. (%) Physical Findings No. (%) MICROBIOLOGIC ASSESSMENT Fever 56 (64) Fever (temperature Ͼ38°C) 55 (63) Cough 53 (61) Tachypnea 20 (23) Chest pain 32 (37) Crackles 21 (24) A total of 59 specimens were sub- Dyspnea 25 (29) Decreased breath sounds 15 (17) mitted to the microbiology labora- Hemoptysis 23 (26) Wheezing 13 (15) tory for culture. Only 29 (49%) were Sputum production 18 (21) Dullness to percussion 8 (9) positive for the causative organ- Malaise 16 (18) Normal findings on examination 8 (9) ism. Of these, the most common iso- Weight loss 14 (16) Pleural rub 3 (3) lates belonged to the genus Rhizo- Superior vena cava obstruction 1 (1) Cervical adenopathy 1 (1) pus in 12 patients (41%). Our patient’s organism was identified as R arrhizus. Mucor was identified in 7 patients (24%), although it is un- Table 2. Radiographic Manifestations of Pulmonary Mucormycosis in 87 Patients clear whether these organisms truly belonged to the genus Mucor or if Patients, Patients, this was simply a generic designa- Distribution No. (%) Pulmonary Features No. (%) tion. Cunninghamella bertholletiae Upper part of the chest 39 (45) Infiltrate 34 (39) was identified in 6 patients (21%), Middle part of the chest 3 (3) Cavity 23 (26) Lower part of the chest 18 (21) Consolidation 18 (21) and in 1 patient, the pathogen was 45 Unilateral multilobular disease 5 (6) Air crescent sign 7 (8) Cunninghamella elegans, now Bilateral lung disease 14 (16) Pleural effusions 7 (8) reclassified as Apophysomyces Hilar or mediastinal disease 3 (3) Fistula 5 (6) elegans. Two patients grew organ- Normal 3 (3) Pneumothorax 3 (3) isms belonging to the genus Absidia Not done 2 (2) Pulmonary collapse 3 (3) and 1 to the genus Syncephalastrum. Coinfection was a feature in 28 patients (32%) only. Of these, 27 had whereas 7 (25%) had chronic leu- with hemoptysis. The most promi- bacterial pneumonia, and 1 patient kemia (5 with chronic lymphocytic nent physical finding was fever in had Pneumocystis carinii pneumo- leukemia and 2 with chronic my- 55 patients (63%). The findings nia.60 All 28 patients had received eloid leukemia), and 1 each had otherwise were sparse, including 8 chemotherapy or steroids for their hairy cell leukemia, Hodgkin lym- patients with normal findings on underlying condition, and 23 pa- phoma, myelodysplastic syndrome, clinical examination. Unusual presen- tients (82%) presented with acute and agammaglobulinemia. Of the 11 tations included 1 patient with su- symptoms. patients (13%) with renal insuffi- perior vena cava obstruction who ciency, 6 were receiving dialysis. Ten was found at autopsy to have lung RADIOLOGICAL patients (11%) were organ trans- infarcts and invasion of the supe- PRESENTATION plant recipients. Of these, 6 received rior vena cava and pulmonary ar- renal transplants, 2 bone marrow tery by mucor37 and another patient Table 2 outlines the radiographic transplants, 1 a heart transplant, and with cervical lymphadenopathy who manifestations of pulmonary mucor- 1 a liver transplant. Of note, 8 pa- died of stridor due to granuloma- mycosis. Most patients (37 [43%]) tients (9%) had metabolic acidosis, in- tous and fibrous mediastinitis.48 One had involvement of the upper part cluding 1 patient with long-term sa- patient was seen because of left of the chest, with the right upper licylate ingestion, 1 with renal shoulder pain due to the Pancoast lobe (23 patients) more commonly insufficiency, 2 with diabetes melli- syndrome.67 Two patients were re- implicated than the left upper lobe tus without ketosis, and 2 diabetic pa- portedly asymptomatic at presenta- (16 patients), followed by the lower tients receiving dialysis. One patient tion.29,54 One had diabetes mellitus part of the chest (21%)—equally was taking deferoxamine and an- and the other did not have an un- divided between right and left other was taking iron supplements. derlying condition. Both had a right lungs (9 patients each)—and, Finally, 11 patients (13%) had no ap- upper lobe solitary pulmonary nod- rarely, the middle part of the chest parent underlying illness. ule and survived surgical resection (3 patients). The findings of a chest of the lesions. radiograph were rarely normal: 1 CLINICAL PRESENTATION We arbitrarily defined onset as patient had tracheal mucor present- acute if symptoms were present for ing with stridor,66 another had Table 1 summarizes presenting 30 days or less before presentation endobronchial disease with right symptoms and physical findings. and chronic if present for more than pulmonary artery involvement at These were mostly nonspecific. 30 days. Most patients (68 [78%]) autopsy,77 and a third died of mul- Cough was present in 53 patients had an acute onset, but a substan- tiple mucor-related pulmonary (61%) only, and 23 (26%) presented tial number (16 [18%]) had chronic infarcts.73

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Thirty-four patients (39%) were mucormycosis, with only 7 patients ing to the diagnosis in only 2 described as having an infiltrate or (8%) exhibiting this finding on patients. Direct laryngoscopy was consolidation, and 23 (26%) had a chest radiograph. One report used in a diabetic patient with tra- cavitary lesion. An air crescent sign described only bilateral effusions cheal mucormycosis who eventu- was described on chest radiograph on chest radiograph, but a com- ally required laryngotracheal resec- in 7 patients, all with upper lobe dis- puted tomographic scan of the tion and primary reanastomosis.66 ease. The presence of an air cres- thorax revealed a left lower lobe The diagnosis was made at autopsy cent sign seems to be significantly cavity, illustrating the value of in 23 patients. associated with an increased risk for computed tomographic imaging in The diagnosis was established massive hemoptysis. Chest pain, he- selected cases.58 by histological examination in 71 moptysis, or both were a feature in Fistulas were uncommon, oc- (93%) of 76 patients for whom it was 10 patients (43%) with a cavity only curring in 5 patients (6%) only, but done and by cytologic examination on chest radiograph, as opposed to they were fatal in 3 of the patients. in 18 (62%) of 29 patients for whom 5 patients (71%) with an air cres- The types of fistulas described in- it was done, whereas cultures were cent sign, suggesting that the latter clude bronchocutaneous,61 bron- positive for fungi in only 29 (49%) may herald the onset of pulmonary chopleural,51,55,74 and bronchoarte- of 59 specimens submitted. In one infarction and the erosion of pul- rial with pseudoaneurysm.16 report,43 “dicing” or homogenizing monary vessels.34 More specifi- of the specimen was noted to result cally, only 1 patient (5%) with a cav- DIAGNOSIS in a negative culture result because ity, but 3 patients (43%) with an air of the aseptate nature of the fun- crescent sign, died of massive he- The most common method used to gus. This may explain, at least in moptysis. make the diagnosis of pulmonary part, why fungal cultures provided Pleural effusions seem to be mucormycosis in our review was the lowest yield among the 3 mo- relatively uncommon in pulmonary flexible fiberoptic bronchoscopy, dalities. which was used in 35 (40%) of 87 patients, and 34 of these had vis- THERAPY AND OUTCOME Table 3. Endobronchial Appearance ible endobronchial disease. Our re- in 34 Patients With Pulmonary view also confirms the hypothesis of Of the 87 patients, 38 (44%) sur- Mucormycosis Diagnosed Donahue et al20 that diabetic pa- vived. Twenty-two patients (25%) by Fiberoptic Bronchoscopy tients have a predilection for endo- died of the infection, and 15 (17%) bronchial disease because the most died of massive hemoptysis. The re- Patients, common predisposing factor was maining 12 patients (14%) died of Findings No. (%) diabetes mellitus in 29 (85%) of unrelated causes. If we exclude Stenosis 8 (24) these 34 patients. Table 3 out- deaths unrelated to the fungal in- Erythematous mucosa 6 (18) lines the variety of features seen with fection or hemoptysis, the overall Obstruction of airway 4 (12) Gelatinous or mucoid secretions 4 (12) bronchoscopy in these 34 patients. survival rate was 51% (38 of 75 pa- Fungating or polypoid mass 4 (12) Stenosis and obstruction were seen tients). We also looked at the ef- Granulation tissue 3 (9) in 12 patients (35%). fects of predisposing factors on the Mucosal ulceration 2 (6) Seventeen patients (20%) re- outcome (Table 4). Patients with White and creamy, or purulent 2 (6) quired open lung biopsy or surgi- renal insufficiency or metabolic aci- exudate cal resection for diagnosis. Trans- dosis did the worst, with no survi- Toothpastelike exudate 2 (6) Tracheitis 2 (6) thoracic needle aspiration and vors. Patients with hematologic con- Fibrinoid necrotic slough 1 (3) thoracentesis were successfully used ditions had a survival rate of only Plaques 1 (3) for diagnosis in 6 and 3 patients, re- 25% (7 of 28 patients). Within this Vocal cord paralysis 1 (3) spectively. Sputum culture was a re- group, only 1 (8%) of 13 patients markably insensitive method, lead- with neutropenia survived, com- pared with 6 (40%) of 15 patients without neutropenia. Diabetic pa- Table 4. Underlying Condition and Outcome in 87 Patients With Pulmonary Mucormycosis* tients, organ transplant recipients, and patients with no predisposing Underlying Death From Death From factors had similar survival rates— Condition Progression of Massive Unrelated between 45% and 60%. (No. of Patients) Mucormycosis Hemoptysis Death Alive Table 5 summarizes the thera- Diabetes mellitus (49), No. (%) 5 (10) 12 (24) 4 (8) 28 (57) peutic choices for all patients in our Hematologic condition (28), No. (%) 9 (32) 4 (14) 8 (29) 7 (25) series and outlines the overall mor- Renal insufficiency (11), No.† 3 6 2 0 tality in each group. A total of 55 pa- Organ transplant (10), No.† 1 0 3 6 tients received antifungal therapy, Metabolic acidosis (8), No.† 4 3 1 0 but medical therapy was the only Deferoxamine or iron supplements (2), No.† 1 0 1 0 No underlying condition (11), No.† 4 0 2 5 form of treatment in 31 patients. Amphotericin B was used in almost *Some patients had more than 1 underlying condition. all patients. Seven patients also re- †Percentages are not given because of the small number of patients in this category (Ͻ15). ceived an azole. Of the 31 patients

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 roids, but 10 of these had an under- ease,82,83 but it is unclear why more Table 5. Treatment and Outcome lying hematologic condition. Nine cases of mucormycosis have not in 87 Patients With patients (23%) had diabetes melli- been reported. Whether this re- Pulmonary Mucormycosis tus, 6 (15%) had sarcoma or carci- flects that such patients are not at in- Patients, Deaths, noma, and 4 (10%) had uremia. creased risk for this particular in- Treatment No. (%) No. (%) Only 4 (12%) of 32 patients for fection or simply that mucormycosis whom an outcome is reported were is less common than aspergillosis re- Medical therapy only* 31 (36) 17 (55) 3 Surgery 30 (34) 8 (27) cured. The review by Tedder et al mains to be determined. Pneumonectomy 6 2 in 1994 combines 30 patients treated The association of mucormy- Lobectomy 22 5 at their institution with 225 cases cosis with deferoxamine therapy Debridement and 11 from the literature. Again, they do and iron overload states is well rec- cavernostomy not restrict their review to pulmo- ognized, and several such cases Laryngotracheal 10 84-90 resection nary cases and include patients with have been reported. Iron avail- Drainage procedure 3 (3) 2 (67) disseminated disease. ability is critical for the growth of Chest tube 2 2 We limited our review to pa- mucor, and when transferrin is Removal of mass with 10 tients with localized pulmonary mu- saturated with iron and more free bronchoscope cormycosis because we thought that iron becomes available to the fun- No therapy 23 (26) 22 (96) it represents a different disease in gus, the fungistatic capacity of outcome and therapeutic options. serum is decreased.91 To explain *See the subsection “Therapy and Outcome” in the “Results” section for details. This strengthens the conclusions why deferoxamine, an iron chela- that can be deduced from such a se- tor, paradoxically increases suscep- ries, with the recognition, of course, tibility to mucormycosis, it has receiving medical therapy alone, 17 that the retrospective nature of the been hypothesized that the fungi patients (55%) died: 6 with mas- study has unavoidable inherent limi- use deferoxamine as a siderophore. sive hemoptysis, 7 of overwhelm- tations, including incomplete data The iron chelate of deferoxamine ing fungal sepsis, and the remain- and selection bias in the literature abolishes the fungistatic effect of ing 4 of unrelated causes. Thirty to report successes more than fail- serum on Rhizopus species and patients were treated surgically with ures. To minimize the former, we increases the in vitro growth of the or without antifungal therapy, and limited our series to patients with fungus, much more than iron alone 3 underwent an adjunctive drain- sufficient data reported. and more than the effect on Asper- age procedure. Patients who under- In all 3 reviews, the mean age gillus species.92 Part of the reason went surgery had a mortality of 27%, is in the 40s, and the male-female ra- that acidosis increases the suscepti- with 5 of the 8 deaths due to unre- tio is between 2.4:1 and 3:1. This bility of the host to mucormycosis lated causes. Twenty-three pa- preponderance of male patients is may be by temporarily disrupting tients, most of whose diagnosis was difficult to explain, and none of the the capacity of transferrin to bind made at autopsy, received no spe- risk factors explain it. These re- iron.93 cific antifungal therapy or surgery. main the same over the years, ex- Not surprisingly, the clinical All but 1 died: 12 of the infection, 8 cept for the emergence of organ presentation of pulmonary mucor- of massive hemoptysis, and 2 of un- transplantation as a significant un- mycosis is not specific. The pres- related causes. derlying predisposing disease. Dia- ence of hemoptysis should bring mu- betes mellitus and hematologic can- cormycosis to mind because it is one COMMENT cers continue to lead the list. The of the angioinvasive fungi. The chro- finding of 12 patients with no ap- nicity of the symptoms (Ͼ30 days) The review by Baker2 in 1971 thor- parent underlying illness was unex- in no way helped rule out mucor- oughly describes all cases of mucor- pected because mucormycosis has mycosis, and the duration of symp- mycosis previously reported. He been traditionally considered a dis- toms at the time of presentation reports on 49 cases of primary ease of immunocompromised pa- should not be used to exclude pul- pulmonary mucormycosis, al- tients and suggests that a height- monary mucormycosis from the dif- though, from our criteria, some of ened level of suspicion may be ferential diagnosis in any patient. these could be classified as dissemi- warranted in immunocompetent pa- Similarly, none of the radiological nated mucormycosis. This leaves 39 tients as well. None of the patients findings were characteristic, al- patients with mucormycosis lim- in our series or that of Tedder et al3 though we found a predilection for ited to the lungs, with a mean age had the acquired immunodefi- the upper lobes, a finding not pre- of 44 years (range, 11⁄2-72 years). In ciency syndrome. We found only viously described on plain radiog- his series, 24 patients were male and 1 case report81 in the German-lan- raphy. The presence of an air cres- 10 female (5 were not specified), for guage literature of a patient who had cent sign is noteworthy and should a male-female ratio of 2.4:1. Hema- diffuse infiltrates and whose condi- increase the urgency of the workup tologic conditions were the most fre- tion was diagnosed at autopsy. Pa- because massive hemoptysis and quent underlying disease, occur- tients infected with the human im- death were more common in these ring in 18 (46%) of the 39 patients, munodeficiency virus are at risk for patients. This sign appears to be a and 17 of these had leukemia. Eleven infections with Aspergillus species, useful diagnostic clue for fungal in- patients (28%) were taking ste- another angioinvasive fungal dis- fection, and aspergillosis and cryp-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 tococcosis need to be considered as involvement survived in the first should heighten concerns about the well.94,95 Computed tomography ap- 100 years since the disease was possibility of a fungal infection. pears to have some benefit in the di- originally described. In our series, The diagnosis is rarely obtained by agnosis of angioinvasive fungal in- 44% of all patients (n = 38) sur- cultures because of processing in fections, especially mucor and vived, and if we exclude patients microbiology laboratories, and Aspergillus species. Jamadar et al96 re- who died of unrelated causes, this more aggressive bronchoscopic or viewed the computed tomographic percentage increases to 51% (38 of surgical approaches should be pur- appearance of 8 patients with pul- 75 patients). A premortem diagno- sued to obtain histopathologic monary mucormycosis and found a sis was made in 62 (71%) of 87 specimens. The presence of an air predilection for the upper lobes in patients. Of these, 38 patients crescent sign on radiological imag- 16 (84%) of 19 patients, in agree- (61%) survived, and, if we exclude ing often portends a poor prognosis ment with our findings. They also deaths unrelated to mucormycosis, if surgical therapy is delayed. We cite cavitation, air crescent sign, halo we come up with a survival rate of agree with recommendations that sign, and rim enhancement as ra- 72%. These figures compare favor- adequate treatment of pulmonary diological evidence of necrosis in ably with the data by Tedder et al,3 mucormycosis requires an aggres- these patients. where there was only a 35% sur- sive approach, with a combination Noninvasive diagnosis with vival in patients with disease of both medical and surgical mea- sputum cultures is difficult to confined to the lungs. In both sures to effect a cure.98 Optimal achieve, and, in fact, even when series, renal failure portended a therapy begins with an early diag- culturing surgical specimens, false- poor outcome, and neutropenia nosis and, in addition to systemic negative culture results can be was clearly a predictor of death in antifungal therapy and surgical obtained. This may be due in part our series. As noted by Tedder et al, resection, control of the patient’s to sampling error when highly although not as strikingly as in underlying disease. necrotic tissue is submitted for cul- ours, the survival of patients treated ture and no viable fungus is pres- only medically was much worse Accepted for publication October 1, ent or that the microbiology labo- than for patients who underwent a 1998. ratory usually processes specimens surgical procedure. These observa- Reprints: Karim A. Adal, MD, for fungal culture after initially ho- tions have a great potential for bias MS, Department of Infectious Dis- mogenizing the specimen. This because patients more fit for sur- ease, Desk S32, Cleveland Clinic dicing decreases the sensitivity of gery and with a better possible out- Foundation, 9500 Euclid Ave, the sputum culture because this come may well be the ones under- Cleveland, OH 44195 (e-mail: microorganism is aseptate and is going surgery. Despite this, the [email protected]). killed by this process. This is an contrast between the group treated important concept and reinforces medically alone and the group REFERENCES the high level of suspicion that one treated surgically is impressive. must have to notify the laboratory Surgical resection is important in the treatment of pulmonary mucor 1. Furbringer P. Beobachtungen uber lungenmy- when submitting a specimen for cose beim menschen. Arch Pathol Anat Physiol appropriate processing. For that because of the angiocentric nature Klin Med. 1876;66:330-365. purpose, we summarize the vari- of the fungus, with its propensity 2. Baker RD. Mucormycosis. In: The Pathologic ous appearances of mucormycosis toward invading the pulmonary Anatomy of Mycoses: Human Infection With Fungi, at bronchoscopy, in the hope of vasculature, often resulting in mas- Actinomyces, and Algae. New York: Springer- Verlag NY Inc; 1971:832-918. educating our pulmonary and sur- sive hemoptysis. 3. Tedder M, Spratt JA, Anstadt MP, Hedge SS, Ted- gical colleagues in that regard. der SD, Lowe JE. Pulmonary mucormycosis: re- Endobronchial features seen with CONCLUSIONS sults of medical and surgical therapy. Ann Tho- mucormycosis may provide impor- rac Surg. 1994;57:1044-1050. 4. Agger WA, Maki DG. Mucormycosis: a complica- tant clues for selecting the appro- Pulmonary mucormycosis is a rela- tion of critical care. Arch Intern Med. 1978;138: priate methods for specimen col- tively rare disease, but with a grow- 925-927. lection, preparation, and staining. ing number of immunosuppressed 5. Al-Majed S, Al-Kassimi F, Ashour M, Mekki OM, Finally, the high incidence of patients, it may become more com- Sadiq S. Removal of endobronchial mucormyco- obstruction may help explain the mon. Maintaining a high level of sis lesion through a rigid bronchoscope. Thorax. 1992;47:203-204. frequent occurrence of bacterial suspicion is important in any 6. Bartrum RJ Jr, Watnick M, Herman PG. Roent- coinfection, likely due to postob- patient in the right clinical setting genographic findings in pulmonary mucormyco- structive pneumonia. with a pneumonic process that fails sis. Am J Roentgenol Radium Ther Nucl Med. Survival seems to have in- to respond to antibacterial agents, 1973;117:810-815. 7. Benbow EW, Bonshek RE, Stoddart RW. Endo- creased. Substantially more patients either clinically or radiologically. In bronchial zygomycosis. Thorax. 1987;42:553- are now being diagnosed premor- some patients, an apparent initial 554. tem, which may help explain the improvement is followed by recru- 8. Berns JS, Lederman MM, Greene BM. Nonsurgi- better outcome. In Baker’s article,2 descence of symptoms shortly after, cal cure of pulmonary mucormycosis. Am J Med 12% (4/32) of the patients survived. maybe due to a transient response Sci. 1984;287:42-44. 97 9. Bhatt ON, Miller R, Le Riche J, King EG. Aspira- In 1977, Murray noted in an edi- of a postobstructive bacterial pneu- tion biopsy in pulmonary opportunistic infec- torial that only 6 (9%) of 70 monitis secondary to endobron- tions. Acta Cytol. 1977;21:206-209. patients with localized pulmonary chial disease. These scenarios 10. Bigby TD, Serota ML, Tierney LM, Matthay MA.

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