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Fatal Cunninghamella bertholletiae Infection in an Immunocompetent Patient
Fatal Cunninghamella bertholletiae
Infection in an Immunocompetent Patient*
Stuart Zeilender; M.D .; David Drenning, M.D .; Frederick L. Glauser, M.D. ; and Daniel Bechard, M.D ., EC.C .P.
The first fatal Cunninglwmella bertholletioe infection in 8 clinically immunocompetent host is reported. This case differs from previously reported cases by the lack of extensive vascular invasion and thrombosis. (Chest 1990; 97:1482-83)
Z
ygOmYCOsis represents an acute and almost uniformly fatal systemic fungal infection caused by species of the class Zygomycetes. These systemic infections are classified as rhinocerebral, pulmonary, gastrointestinal, cutaneous, and widely disseminated . Four species are pathogenic in humans: Rhizopus, Absidia, Mucor, and Cunninghamella in order of decreasing frequency. Case reports have described zygomycosis only in immunocompromised patients or those with a chronic illness. Classic predisposing disorders include diabetes mellitus, malignancy, steroid and antimetabolite therapy, cirrhosis, organ transplantation, and malnutrition. Pathologic features are similar regardless of species. Typically, there is tissue and vascular wall invasion, with subse quent vascular thrombosis and tissue bed infarction. Cunninghamella bertholletiae infection is extremely rare even though this fungus is ubiquitous in nature . Since the first report in a cancer patient in 1959, there have been 11 more cases confirmed in the literature.':" However, there are no documented zygomycetic infections in an immunocompetent host. We present the first reported case of C bertholletiae in a clinically immunocompetent patient. CASE REPORT
A 51-year-old white man with a history of alcoholic binges, none recently, was admitted for progressive dyspnea, productive cough , night sweat s, fevers with chills, and a 9.1 kg (20 lb) weight loss over the prior four months. He worked as a naval electrician with no asbestos, toxin, or chemical exposure and was treated for parotitis two and five months prior to admiss ion. His only medication was a nasal mist (Primatine Mist). Physical examination revealed an oral temperature of 38.3 Co, respiratory rate 30 breaths per minute, accessory muscle usage , normal parot id glands and right sided bibasilar rales, scatt ered rhonchi and wheezes. A three component friction rub was present. Hemoglobin value was 10 g/dl, WBC count, 18,000 cells/cu mm (55 percent neutrophils, 17 percent bands, 15 percent lymphocytes, 8 percent monocytes): and normal results from renal and liver funct ion stud ies. Serum albumin was 3.2 g/dl , Chest roentgenogram showed a right pleural based mass, a pleural effusion, pneumothorax, and bilateral interstitial markings . An exudative, bloody pleural effusion was drained by insertion of a chest tube (Fig 1). Purified protein derivative was negative and mumps and Candida skin test results were positi ve. Preliminary sputum cultures, although reported as growing a Rhizopus species, were interpreted as a laboratory contaminant. Pleural Huid, bronchial washings , and sputu m grew C bertholletiae. Amphotericin B, *From the Pulmonary Division, McGuire Veterans Administration Medical Center/Medical College of Virginia , Richmond . 1482
FIGURE 1. Persistent right pneumothorax, an upper lobe mass (cavity) and diffuse interstitial disease. 30 mg/day, was instituted , but the patient's oxygenation deteriorated, and on the 19th hospital day, he suffered a cardiorespiratory arrest and died. Post-mortem examination revealed a right upper lobe cavitary lesion, a right pleural effusion, right sided fibrinous pericarditis, and pleuritis. There was no evidence of a malignancy. Abscess wall and surrounding lung parenchyma sections (stained with Gomori methenamine silver) revealed hyphal fragment s with budding conidophores (Fig 2). Isolates were confirmed as C bertholletiae by the Centers for Disease Control in Atlanta. A zygomyco sis seru m ELISA antibody titer was 1:12,800 . The fungus was not recovered from the blood or from antemortem bone marrow cultures. Microscopy preparations from the cavitary lesion showed fungal elements characteristic of Cunninghamella species (Fig 3). In vitro susceptibility tests" revealed the minimum inhibitory concentration of amphotericin B was 25 jLglml; the minimum fungicidal concentration was greater than 100 jLglm\. Thus, this isolate was unusually resistant to amphotericin B. DISCUSSION
Inhalation of airborne asexual sporangiophores is felt to
FIGURE 2. Histologic section of lung tissue showing invasion by Cunninghamella bertholletiae hyphal fragment with budding conidiophore. Methenamine silver stain original magnificat ion x 200. Fatal Cunninghamalla berthollatiae Infection (Zailendar af aI)
intact immune system which attenuated but could not eradicate the infection. Although our patient had an apparent clinically intact immune system, we cannot rule out local pulmonary immune deficiency or a diffuse subclinical deficiency. In summary, C bertholletiae represents a true pathogenic fungal species. We report the first case of pulmonary infection in a patient with an apparent competent immune system. C bertholletiae should be regarded as a true pathogen even in nonimmunocompromised patients if positive cultures are reported . Zygomycosis can occur without evidence of thrombosis. Effective therapy usually involves surgical debridement and the administration of systemic antifungal agents. ACKNOWLEDGMENT: We thank Philip Coudron and Nancy Warren for their expertise with the mycologic preparations and suggestions, and Smith Shadomy, Ph.D ., for performing ill vitro susceptibility testing of our isolate against amphotericin B. 3. A microscopic specimen from cavity shows a folded sporangiophore ending in a swollen vesicle (sporangium) which is covered with round sporangiola (calcaflor, original magnification, x 10(0). FIGURE
be the mechanism of fungal transmission, although rarely the organisms can proliferate in skin breaks or pass through intact mucous membranes. Alveolar macrophages, the first line of defense , inhibit fungal spore germination and hyphae growth and prevent tissue invasion. Inhibition of macrophage function (ie, cortisone therapy, iron overload) may allow fungal spore germination, proliferation, and subsequent tissue invasion." :" The previous cases of C bertholletiae have been reported in patients with underlying diseases associated with compromised host defenses.,." All patients except one" had classic tissue invasion, with subsequent blood vessel invasion and destruction of the perfused area. In contrast, our patient was clinically immunocompetent as evidenced by an elevated white blood cell count with a leftward shift, functioning cell-mediated immunity reflected by the positive response to control skin testing antigens, normal serum albumin and iron levels, a negative ELISA for human immunodeficiency virus, no prior history of repeated pulmonary infections, and no clinical evidence of malnutrition. However, specific leukocyte function studies (phagocytosis, chemotaxis, oxidative burst, Iysozymal enzyme function) were not tested. Our case has the following unusual features : (I) the significance of the recurrent parotid infections is unclear and this organ could have been the primary site of infection; (2) the original positive C bertholletiae cultures were discounted as laboratory contaminants, thus delaying early treatment. Only after the organism was isolated from multiple specimens was it realized that C bertholletiae was the pathologic agent in our patients' illness; and (3) our patient did not display the typical tissue and blood vessel invasion seen with zygomycosis. One other reported case describing limited tissue invasion was in a patient with thalassemia complicated by iron overload, neutropenia, and splenectomy.' We hypothesize that this lack of vascular involvement and dissemination was secondary to a relatively
REFERENCES Hutter RVP. Phycomycetous infection (mucormycosis) in cancer patients: a complication of therapy. Cancer 1959; 12:330-49 2 Kwon-Chung KJ, Young RC, Orlando M. Pulmonary mucormycosis caused by Cunninghamella elegans in a patient with chronic myelogenous leukemia. Am J Clin Pathol 1975; 64:54448
3 Kiehn TE, Edwards F, Armstrong D, Tosen Pp, Weitzman I. Pneumonia caused by Cunninghamella bertholletiae complicating chronic lymphatic leukemia. J Clin Microbiol1979; 10:37479 4 BoyceJM, Lawson LA, Lockwood WR, Hughes JL. Cunn inghamella bertholletiae wound infection of probable nosocomial origin. South Med J 1981; 74:1132-35 5 McGinnisMR, WalkerDH, DominyIE, Kaplan \v. Zygomyeosis caused by Cunninghamella bertholletiae: clinicaland pathologic aspects. Arch Pathol Lab Med 1982; 106:282-86 6 Brennan RO, Crain BJ, Proctor AM , Dura ck DT. Cunninghamella: Anewly recognized cause of rhinocerebral mucormycosis. Am J Clin Patholl983; 80:98-102 7 Kolbeck PC, Makhoul RG, Bollinger RR, Sanfilippo F. Widely disseminated Cunninghamella mucormycosis in adult renal transplant patients: case report and review of the literature . Am J Clin Patholl985: 83:747-53 8 Sands JM, Macher AM, Ley TJ, Nienhuis AW. Disseminated infection caused by Cunninghamella bertholletiae in a patient with beta-thallassemia: case report and review of the literature . Ann Intern Med 1985; 102:59-63 9 Ventura GJ, Kantarjia HM, Anaissie E, Hopfer RJ, Fainstein V. Pneumonia with Cunninghamella species in patients with hematologic malignancies: a case report and review of the literature . Cancer 1986; 58:1534-36 10 Nimmo GR, Whiting RF, Strong Rw. Disseminated mueormycosis due to Cunninghamella bertholletiae in a liver transplant recipient. Postgrad Med J 1988;64:82-84 11 Rex JH, Ginsberg AM, Fries LF, Pass HI, Kwon-Chung KJ. Cunninghamella bertholletiae infection associated with deferoxamine therapy. Rev Inf Dis 1988; 1187-94 12 Shadomy S, Espinel-Ingrolf A, Cartwright RY. Laboratory studies with antifungal agents. In: Lennette EH , Balows A, Hausler Jr WJ, ShadomyS, eds. Manual ofclinical microbiology, Washington, DC: American Society for Microbiology, 1985:99199 13 WaldorfAR, Levitz SM, Diamond RD. In vivo bronchoalveolar macrophage defense against Rhizopus ory::ae and Aspergillu.v fumigatus. J Infect Dis 1984; 150:752-60 CHEST I 97 I 6 I JUNE , 1990
1483
Infection in an Immunocompetent Patient*
Stuart Zeilender; M.D .; David Drenning, M.D .; Frederick L. Glauser, M.D. ; and Daniel Bechard, M.D ., EC.C .P.
The first fatal Cunninglwmella bertholletioe infection in 8 clinically immunocompetent host is reported. This case differs from previously reported cases by the lack of extensive vascular invasion and thrombosis. (Chest 1990; 97:1482-83)
Z
ygOmYCOsis represents an acute and almost uniformly fatal systemic fungal infection caused by species of the class Zygomycetes. These systemic infections are classified as rhinocerebral, pulmonary, gastrointestinal, cutaneous, and widely disseminated . Four species are pathogenic in humans: Rhizopus, Absidia, Mucor, and Cunninghamella in order of decreasing frequency. Case reports have described zygomycosis only in immunocompromised patients or those with a chronic illness. Classic predisposing disorders include diabetes mellitus, malignancy, steroid and antimetabolite therapy, cirrhosis, organ transplantation, and malnutrition. Pathologic features are similar regardless of species. Typically, there is tissue and vascular wall invasion, with subse quent vascular thrombosis and tissue bed infarction. Cunninghamella bertholletiae infection is extremely rare even though this fungus is ubiquitous in nature . Since the first report in a cancer patient in 1959, there have been 11 more cases confirmed in the literature.':" However, there are no documented zygomycetic infections in an immunocompetent host. We present the first reported case of C bertholletiae in a clinically immunocompetent patient. CASE REPORT
A 51-year-old white man with a history of alcoholic binges, none recently, was admitted for progressive dyspnea, productive cough , night sweat s, fevers with chills, and a 9.1 kg (20 lb) weight loss over the prior four months. He worked as a naval electrician with no asbestos, toxin, or chemical exposure and was treated for parotitis two and five months prior to admiss ion. His only medication was a nasal mist (Primatine Mist). Physical examination revealed an oral temperature of 38.3 Co, respiratory rate 30 breaths per minute, accessory muscle usage , normal parot id glands and right sided bibasilar rales, scatt ered rhonchi and wheezes. A three component friction rub was present. Hemoglobin value was 10 g/dl, WBC count, 18,000 cells/cu mm (55 percent neutrophils, 17 percent bands, 15 percent lymphocytes, 8 percent monocytes): and normal results from renal and liver funct ion stud ies. Serum albumin was 3.2 g/dl , Chest roentgenogram showed a right pleural based mass, a pleural effusion, pneumothorax, and bilateral interstitial markings . An exudative, bloody pleural effusion was drained by insertion of a chest tube (Fig 1). Purified protein derivative was negative and mumps and Candida skin test results were positi ve. Preliminary sputum cultures, although reported as growing a Rhizopus species, were interpreted as a laboratory contaminant. Pleural Huid, bronchial washings , and sputu m grew C bertholletiae. Amphotericin B, *From the Pulmonary Division, McGuire Veterans Administration Medical Center/Medical College of Virginia , Richmond . 1482
FIGURE 1. Persistent right pneumothorax, an upper lobe mass (cavity) and diffuse interstitial disease. 30 mg/day, was instituted , but the patient's oxygenation deteriorated, and on the 19th hospital day, he suffered a cardiorespiratory arrest and died. Post-mortem examination revealed a right upper lobe cavitary lesion, a right pleural effusion, right sided fibrinous pericarditis, and pleuritis. There was no evidence of a malignancy. Abscess wall and surrounding lung parenchyma sections (stained with Gomori methenamine silver) revealed hyphal fragment s with budding conidophores (Fig 2). Isolates were confirmed as C bertholletiae by the Centers for Disease Control in Atlanta. A zygomyco sis seru m ELISA antibody titer was 1:12,800 . The fungus was not recovered from the blood or from antemortem bone marrow cultures. Microscopy preparations from the cavitary lesion showed fungal elements characteristic of Cunninghamella species (Fig 3). In vitro susceptibility tests" revealed the minimum inhibitory concentration of amphotericin B was 25 jLglml; the minimum fungicidal concentration was greater than 100 jLglm\. Thus, this isolate was unusually resistant to amphotericin B. DISCUSSION
Inhalation of airborne asexual sporangiophores is felt to
FIGURE 2. Histologic section of lung tissue showing invasion by Cunninghamella bertholletiae hyphal fragment with budding conidiophore. Methenamine silver stain original magnificat ion x 200. Fatal Cunninghamalla berthollatiae Infection (Zailendar af aI)
intact immune system which attenuated but could not eradicate the infection. Although our patient had an apparent clinically intact immune system, we cannot rule out local pulmonary immune deficiency or a diffuse subclinical deficiency. In summary, C bertholletiae represents a true pathogenic fungal species. We report the first case of pulmonary infection in a patient with an apparent competent immune system. C bertholletiae should be regarded as a true pathogen even in nonimmunocompromised patients if positive cultures are reported . Zygomycosis can occur without evidence of thrombosis. Effective therapy usually involves surgical debridement and the administration of systemic antifungal agents. ACKNOWLEDGMENT: We thank Philip Coudron and Nancy Warren for their expertise with the mycologic preparations and suggestions, and Smith Shadomy, Ph.D ., for performing ill vitro susceptibility testing of our isolate against amphotericin B. 3. A microscopic specimen from cavity shows a folded sporangiophore ending in a swollen vesicle (sporangium) which is covered with round sporangiola (calcaflor, original magnification, x 10(0). FIGURE
be the mechanism of fungal transmission, although rarely the organisms can proliferate in skin breaks or pass through intact mucous membranes. Alveolar macrophages, the first line of defense , inhibit fungal spore germination and hyphae growth and prevent tissue invasion. Inhibition of macrophage function (ie, cortisone therapy, iron overload) may allow fungal spore germination, proliferation, and subsequent tissue invasion." :" The previous cases of C bertholletiae have been reported in patients with underlying diseases associated with compromised host defenses.,." All patients except one" had classic tissue invasion, with subsequent blood vessel invasion and destruction of the perfused area. In contrast, our patient was clinically immunocompetent as evidenced by an elevated white blood cell count with a leftward shift, functioning cell-mediated immunity reflected by the positive response to control skin testing antigens, normal serum albumin and iron levels, a negative ELISA for human immunodeficiency virus, no prior history of repeated pulmonary infections, and no clinical evidence of malnutrition. However, specific leukocyte function studies (phagocytosis, chemotaxis, oxidative burst, Iysozymal enzyme function) were not tested. Our case has the following unusual features : (I) the significance of the recurrent parotid infections is unclear and this organ could have been the primary site of infection; (2) the original positive C bertholletiae cultures were discounted as laboratory contaminants, thus delaying early treatment. Only after the organism was isolated from multiple specimens was it realized that C bertholletiae was the pathologic agent in our patients' illness; and (3) our patient did not display the typical tissue and blood vessel invasion seen with zygomycosis. One other reported case describing limited tissue invasion was in a patient with thalassemia complicated by iron overload, neutropenia, and splenectomy.' We hypothesize that this lack of vascular involvement and dissemination was secondary to a relatively
REFERENCES Hutter RVP. Phycomycetous infection (mucormycosis) in cancer patients: a complication of therapy. Cancer 1959; 12:330-49 2 Kwon-Chung KJ, Young RC, Orlando M. Pulmonary mucormycosis caused by Cunninghamella elegans in a patient with chronic myelogenous leukemia. Am J Clin Pathol 1975; 64:54448
3 Kiehn TE, Edwards F, Armstrong D, Tosen Pp, Weitzman I. Pneumonia caused by Cunninghamella bertholletiae complicating chronic lymphatic leukemia. J Clin Microbiol1979; 10:37479 4 BoyceJM, Lawson LA, Lockwood WR, Hughes JL. Cunn inghamella bertholletiae wound infection of probable nosocomial origin. South Med J 1981; 74:1132-35 5 McGinnisMR, WalkerDH, DominyIE, Kaplan \v. Zygomyeosis caused by Cunninghamella bertholletiae: clinicaland pathologic aspects. Arch Pathol Lab Med 1982; 106:282-86 6 Brennan RO, Crain BJ, Proctor AM , Dura ck DT. Cunninghamella: Anewly recognized cause of rhinocerebral mucormycosis. Am J Clin Patholl983; 80:98-102 7 Kolbeck PC, Makhoul RG, Bollinger RR, Sanfilippo F. Widely disseminated Cunninghamella mucormycosis in adult renal transplant patients: case report and review of the literature . Am J Clin Patholl985: 83:747-53 8 Sands JM, Macher AM, Ley TJ, Nienhuis AW. Disseminated infection caused by Cunninghamella bertholletiae in a patient with beta-thallassemia: case report and review of the literature . Ann Intern Med 1985; 102:59-63 9 Ventura GJ, Kantarjia HM, Anaissie E, Hopfer RJ, Fainstein V. Pneumonia with Cunninghamella species in patients with hematologic malignancies: a case report and review of the literature . Cancer 1986; 58:1534-36 10 Nimmo GR, Whiting RF, Strong Rw. Disseminated mueormycosis due to Cunninghamella bertholletiae in a liver transplant recipient. Postgrad Med J 1988;64:82-84 11 Rex JH, Ginsberg AM, Fries LF, Pass HI, Kwon-Chung KJ. Cunninghamella bertholletiae infection associated with deferoxamine therapy. Rev Inf Dis 1988; 1187-94 12 Shadomy S, Espinel-Ingrolf A, Cartwright RY. Laboratory studies with antifungal agents. In: Lennette EH , Balows A, Hausler Jr WJ, ShadomyS, eds. Manual ofclinical microbiology, Washington, DC: American Society for Microbiology, 1985:99199 13 WaldorfAR, Levitz SM, Diamond RD. In vivo bronchoalveolar macrophage defense against Rhizopus ory::ae and Aspergillu.v fumigatus. J Infect Dis 1984; 150:752-60 CHEST I 97 I 6 I JUNE , 1990
1483