Pulmonary Mucormycosis with Massive Fatal Hemoptysis* Henry W. Mu"ay, M.D.

Abrupt, massive, and fatal hemoptysis occurred in two patients with pulmonary muconnycosis. One patient had uDControlled diabetes mellitus and the other acute leu-

M uconnycosis,

an invasive fungal infection caused by members of the family Mucoraceae (genera Rhizopus, Absidia, Mucor), occurs predominantly in debilitated or immunosuppressed hosts. An increase in the frequency of mucormycosis at autopsy has recently been noted in patients with leukemia and lymphoma.' Despite increased recognition only six patients with mucormycosis confined to the lungs have survived. 2-7 This report describes the two patients with pulmonary mucormycosis seen over one year at this institution, both of whom died following massive hemoptysis with abrupt exsanguination and asphyxiation. Fatal pulmonary hemorrhage has been reported only twice before with mucormycosis. 8,,9 CASE REPoRTS CASE

1

A 64-year-old white man was admitted to the New York Hospital on October 2, 1972, in diabetic coma. He was a poorly-controlled insulin-requiring diabetic, and in 1966 had been treated elsewhere for active pulmonary tuberculosis. Physical examination revealed an obtunded afebrile man with rapid Kussmaul breathing, blood pressure SO/50 mm Hg, and pulse 120/minute. Pertinent findings included retinal microaneurysms, bibasilar rales, 13 em liver span, and a right gaze preference. Initial laboratory data included: white blood cell count ( WBC) 17,000/mm 3 (87 percent polymorphonuclear leukocytes, 13 percent lymphocytes), hematocrit 41 percent, platelet count 220,OOO/mm3 ; sodium lOB mEq/L, potassium 7.5 mEq/L, chloride 80 mEq/L, carbon dioxide ( C~ ) content 5 mM/L, blood urea nitrogen 73 mg percent, creatinine 3.5 mg percent, amylase 100 units, blood sugar 1074 mg percent, prothrombin time 12.1 seconds (control 11.0 seeonds), urinalysis: 4 plus sugar, moderate acetone. Senun acetone was positive in a 1: 4 dilution. Electrocardiogram °From the Department of Medicine, The New York HospitalCornell Medical Center, New York City. Manuscript received October 21; revision accepted November 27.

Reprint requests: Dr. Mu"ay, Department of Medicine, Johns Hopkins Hospital, Baltimore 21205

CHEST, fa: 1, JULY, 1975

kemia in remission. PU1monary artery erosion by mucormycotic hyphae caused the hemorrhage in botb cases. Mucormycosis is an unusual cause of massive hemoptysis.

revealed changes of hyperkalemia, skull films were normal, and chest film showed left apical scarring. Arterial blood gases on nasal oxygen revealed: pH 6.87, C~ content 3 mM/L, PC02 17, P02 163. Lumbar puncture (LP) was normal except for an opening pressure of 250 nun water and sugar 507 mg percent. The patient was critically ill during the first two weeks. Major complications included poorly-controlled hyperglycemia, renal failure requiring peritoneal dialysis, and fever unresponsive to antimicrobial agents (cephalothin, chloramphenicol, gentamicin) including isoniazid and rifampin. Sputum cultures grew normal flora. Cultures of blood and urine for bacteria and fungi and sputum smears for acid-fast bacilli were all negative. On the lwenty-second hospital day the patient was afebrile, alert, and no longer receiving antimicrobial therapy. A right hilar infiltrate was noted at this time (Fig 1, left) and P aeruginosa and Serratia isolated from the sputum were presumed to represent colonization of the upper respiratory tract. Fungus was not recovered. One week later the patient became febrile, hypotensive, and unresponsive. LP was unremarkable and cephalothin and gentamicin were reinstituted. On the thirty-first day abrupt, massive, and uncontrollable hemorrhage developed from the patient's endotracheal tube, and he died several minutes later. Postmortem examination revealed diabetic glomerolosclerosis, an extensive right cerebral infarct, and evidence of left apical 6brocaseous tuberculosis with negative smears and cultures for acid-fast bacilli. The bronchus to the right upper lobe near the hilum was lined by necrotic tissue containing irregular, branching non-septate muoonnycotic hyphae (Fig 2). The hyphae had invaded and eroded 'the wall of the adjacent branch of the right pulmonary artery which was thrombosed (Fig 3). There was recent massive intra-alveolar hemorrhage and hemorrhagic infarction. Fungal cultures were negative, and no evidence of disseminated mucormycosis was found. CASE

2

A 72-year-old white man was admitted to the New York Hospital on September 23, 1973, with fever and a perirectal abscess of several weeks' duration. Physical examination was remarkable for a temperature of 39°C, marked pallor, and a draining perirectal abscess. Initial studies revealed: WBC I,OOO/mm3 (30 percent lym-

PULMONARY MUCORMYCOSIS 65

FIGURE 1. (Left) Chest film (Case 1) one week before death showing right hilar infiltrate. ( Right) Chest film (Case 2) showing bilateral infiltrates at the time amphotericin B therapy was instituted. phocytes, 18 percent monocytes, 13 percent polymorphonuclear leukocytes, 6 percent bands, 4 percent myelocytes, 28 percent promyeloeytes, 1 percent blasts), hematocrit 16.5 percent, and platelet count 3O,OOO/mm3 • Results of blood chemistries, prothrombin time, urinalysis, electrocardiogram and chest film were all normal. Bone marrow aspirate and biopsy were compatible with acute promyelocytic leukemia, and the patient received three doses of daunombicin (60 mg/M2) intravenously. The patient's course was complicated by pancytopenia with marked leukopenia (as low as 50 to 100 cells/mms ) and persistent fever despite treatment with clindamycin, gentamicin and carbenicillin. All bacterial and fungal cultures of blood, urine, and sputum were negative. Culture of the perirectal abscess grew E coli sensitive to gentamicin. SabinFeldman dye test, cytomegalovirus titer, and Candida and Aspergillus serology were all negative. Blood sugar never exceeded 120 mg percent. On the 15th day, bilateral patchy pulmonary infiltrates appeared (Fig 1, right) and Klebsiella, Candida albicans, and Aspergillus were isolated from the sputum. Amphotericin B was added to the antibiotic regimen, and clindamycin and

~ o"

FIGURE 2. Mucormycotic hyphae in right mainstem bronchus. Gomori methanamine silver stain, magnification x 1000.

66 HENRY W. MURRAY

carbenicillin were discontinued. Concomitant with bone marrow recovery and continued antimicrobial therapy, the patient became afebrile and improved clinically over the next ten days . The infiltrates began to resolve. Bone marrow examination on the 23rd day was compatible with remission, and blood counts and differential had returned to normal levels (WBC 6OOO/mm 3 , hematocrit 39 percent, platelet count 266,000/mm 3 ) . Prothrombin and partial thromboplastin times were normal. On the 29th hospital day, the patient abruptly coughed up approximately 1000 ml of blood, suffered a prompt cardiopulmonary arrest, and died. Total amphotericin B received was 350 mg. At autopsy, multiple areas of hemorrhagic infarction and bronchopneumonia were found, many of which contained small cavities filled with necrotic debris. All bronchi were filled with blood and there was.erosion of the bronchus and the segmental artery to the right upper lobe . Diffuse vascular disruption was present and mucormycotic hyphae were found adjacent to the pulmonary vessels. Postmortem fungal cultures were negative.

FIGURE 3. Mucormycotic hyphae in right upper lobe pulmonary artery. Hematoxylin and eosin stain, magnification x 100.

CHEST, 68: 1, JULY, 1975

DISCUSSION

The association of mucormycosis and the debilitated or immunologically compromised host has been well documented.v'P''" Over three-fourths of the reported cases of pulmonary mucormycosis without dissemination have occurred in patients with leukemia or lymphoma.l':'" Pulmonary infection with the fungus has also been associated with diabetes mellitus, agammaglobulinemia, renal failure, solid tumors, and with patients receiving corticosteroids for non-neoplastic diseases. 10,I 9-24 The classic form of mucormycosis in patients with diabetes mellitus is rhinocerebral.Pr'" Pulmonary mucormycosis in a patient with diabetes mellitusand no malignancy as in our first case, is uncommon and has been reported previously in 13 instances. 11,19 Antemortem diagnosis of mucormycosis is exceedingly difficult primarily because the fungus, as in our two cases, is rarely cultured despite adequate preand postmortem specimens. 1,11,15.25 Although early biopsy of involved tissues for histopathologic confirmation of infection is strongly recommended,I,11,25 systemic antifungal therapy is most often reluctantly initiated on the basis of clinical suspicion alone. Thus, it is not surprising that only six patients with pulmonary mucormycosis have survived.r" Massive hemoptysis, defined as pulmonary bleeding of more than 600 ml within 24 to 48 hours, is most frequently associated with tuberculosis, bronchiectasis, lung abscess, and bronchogenic carcinoma. 26,27 Massive hemorrhage has also been uncommonly reported in other pulmonary infections including actinomycosis," histoplasmosis," aspergillosis,29 and hepatopulmonary amebiasis." The diagnostic approaches and conservative management of massive hemoptysis have been well-outlined in previous reports. 26.31-33 The recent literature supports the useful role of surgery for the control of bleeding and in the prevention of asphyxiation, the major cause of death. 26,27,31,32 Minor hemoptysis in pulmonary mucormycosis is uncommon,1.12,19 and massive hemorrhage has been reported only twice. Winston 8 in 1965 described a 29-year-old man who presented with nonspecific symptoms and was found to have diabetic ketoacidosis and a right hilar infiltrate which persisted for several weeks. Biopsy obtained at bronchoscopy showed only inflammatory tissue. Nine days after discharge the patient died suddenly. Autopsy revealed pulmonary hemorrhage, invasion and obstruction of the right mainstem bronchus and erosion of the adjacent pulmonary artery by mucorCHEST, 68: 1, JULY, 1975

mycotic hyphae. Reich and Renzetti" in 1970 reported a 33-year-old man with juvenile-onset diabetes who had blood-streaked sputum and a right upper lobe abscess cavity unresponsive to antimicrobial therapy. Fungal cultures of material obtained at bronchoscopy, abscess debridement, and cavernostomy were overgrown by bacteria. Pulmonary arteriogram demonstrated occlusion of the anterior segmental artery to the right upper lobe. The patient died following massive hemoptysis. Major findings at autopsy were thrombosis and erosion of the right pulmonary artery, and muconnycotic hyphae in the necrotic lung debris and pulmonary artery segment. In both cases, postmortem review of biopsies obtained at bronchoscopy revealed characteristic hyphae which had not been recognized antemortem. Reich and Renzetti" suggested that angiographic demonstration of a thrombosed vessel in an acute pulmonary process in the appropriate clinical setting should raise the possibility of mucormycosis because invasion of blood vessels, thrombosis, and infarction are well-documented .complications.1.10.12,13 It should be noted that similar histopathology may also be associated with invasive aspergillosis." Mucormycotic hyphae have been observed to grow along the internal elastic lamina of the large arteries and to dissect the lamina away from the vessel media, 10 thus predisposing to rupture. Why hyphae were found adjacent to but not in the disrupted pulmonary vessel walls in Case 2 is not clear, but may have been related to the antifungal therapy given before death. Fatal pulmonary hemorrhage should now be added to the enlarging list of complications of invasive fungal diseases in the compromised host. The reason for the predilection for vascular invasion in mucormycosis is obscure." Of interest is that in the four cases which have terminated in massive hemoptysis, the site of vessel erosion has been the right main pulmonary artery or its proximal branch to the right upper lobe. In contrast to the majority of patients with massive hemoptysis who suffer one or more minor episodes of previous hemoptysis," the first pulmonary bleeding in three of these four patients with mucormycosis was fatal. In retrospect, even if the diagnosis of mucormycosis has been made antemortem, the abrupt and massive nature of the hemoptysis precluded any effective hemostatic or surgical measures. That our leukemic patient suffered this catastrophe despite amphotericin B therapy and hematologic remission further emphasizes the need for continued vigorous early diagnostic and therapeutic efforts in pulmonary mucormycosis. PULMONARY MUCORMYCOSIS 67

ACKNOWLEDGMENTS: The author is indebted to Mrs. Gwendolyn Williams for her secretarial assistance, Drs. Diana Lewin, Nicholas Hardin, and Allan Gibofsky for the pathologic material, Dr. Alphonso Timpanelli for permission to report one of the cases, and to Drs. Richard B. Roberts and Alexander G. Bearn for review of the manuscript and their helpful criticism. REFERENCES

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Pulmonary mucormycosis with massive fatal hemoptysis.

Abrupt, massive, and fatal hemoptysis occurred in two patients with pulmonary mucormycosis. One patient had uucontrolled diabetes mellitus and the oth...
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