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Infectious Diseases in Clinical Practice:
doi: 10.1097/01.idc.0000194286.39578.27
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Pneumonia in a Neutropenic Patient With Leukemia

Fredricks, David N. MD*†; Myerson, David MD, PhD†‡

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*Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, †Department of Medicine, Division of Allergy and Infectious Diseases, ‡Program in Pathology, Fred Hutchinson Cancer Research Center, and §Department of Pathology, University of Washington, Seattle, WA.

Address correspondence and reprint requests to David N. Fredricks, MD, Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, North, D3-100, Box 19024 Seattle, WA 98109-1024. E-mail: dfredric@fhcrc.org.

A56-year-old man with chronic myelogenous leukemia in lymphoblastic crisis received chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone. He developed fever with neutropenia while on levofloxacin prophylaxis and so was switched to piperacillin-tazobactam in the hospital, then ampicillin-clavulanate for outpatient treatment of presumed sinusitis. After a day of outpatient management, he was readmitted complaining of shortness of breath, cough, and crushing chest tightness. He reported no recent travel and no exposure to animals, but did report a recent aspiration episode with hamburger. He had a fever of 38.4°C, a respiratory rate of 44 breaths per minute, and hypotension. On examination, he had shallow breaths with wheezes and rales noted in both lower lungs. A chest x-ray showed bibasilar consolidation. He had an absolute neutrophil count of 10 cells/μL. Progressive hypoxemia ensued, prompting intubation and mechanical ventilation. Electrocardiograms, cardiac enzymes, and an echocardiogram were normal. Blood and urine cultures were sterile. An endotracheal tube aspirate showed 2+ gram-positive cocci and 2+ gram-variable rods on direct examination and, on culture, grew viridans streptococci, enterococci, and a motile hemolytic Bacillus species. The endotracheal tube aspirate was toxic to cell monolayers used for viral culture. Bronchoscopy performed on hospital day 2 revealed diffuse airway edema with sloughed mucosa, but cultures of bronchoalveolar lavage (BAL) fluid yielded no growth. A second BAL sample was obtained on hospital day 10 and was also sterile. The patient remained febrile despite treatment with vancomycin, imipenem, levofloxacin, and liposomal amphotericin B. He developed progressive respiratory failure and died. Histological evaluation of cyto-spin preparations of both BAL fluids demonstrated intracellular microorganisms in alveolar macrophages (Fig. 1).

Figure 1
Figure 1
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Diagnosis: Bacillus cereus pneumonia.

BAL fluid was subjected to broad-range fungal 18S rDNA polymerase chain reaction, and no fungal rDNA was detected. High levels of bacterial DNA were detected with broad-range 16S rDNA polymerase chain reaction of BAL fluid, and sequence analysis of the DNA showed 99.8% similarity over 1476 base pairs with 16S rDNA from B. cereus, type strain ATCC 14579. A sham tissue digest and no-template polymerase chain reaction controls had no evidence of bacterial DNA, demonstrating that Bacillus DNA did not arise from reagent contamination.

Several lines of evidence support the diagnosis of B. cereus pneumonia in this patient. A motile hemolytic Bacillus species was recovered from the initial endotracheal tube aspirate, which is consistent with B. cereus and not Bacillus anthracis. Bacillus thuringiensis is another member of the B. cereus group that is usually motile and hemolytic and can be distinguished from B. cereus by biochemical tests such as arginine dihydrolase activity. B. cereus is known to produce numerous toxins, including 4 hemolysins, several enterotoxins (diarrheal and emetic toxins), and enzymes such as phospholipases, collagenase, and protease.1 These toxins play a role in the more common clinical scenario of food poisoning related to B. cereus. The toxicity of the sputum aspirate for cell culture monolayers suggests that such toxins were present in respiratory fluid and may have produced the airway edema and sloughed mucosa noted at the first bronchoscopy. B. cereus has been reported to cause pneumonia with damage to airways, such as pseudomembranous tracheobronchitis.2 The morphology of microorganisms within alveolar macrophages in the BAL samples likely reflects the effect of cell wall-active antibiotics that have impaired bacterial cell wall synthesis and cell division, producing curved tubular structures.3,4 The rectangular morphology displayed in Figure 1B is more characteristic of Bacillus species. Gram stains of this organism can be difficult to interpret. B. cereus grown in the laboratory tends to be gram-positive, whereas B. cereus obtained from clinical material may be gram-positive, gram-negative, or gram-variable. It is not widely appreciated that B. cereus can be visualized with methenamine silver stain5 (Fig. 2). This case highlights the importance of looking for intracellular organisms in BAL samples.

Figure 2
Figure 2
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At autopsy, the patient had diffuse edema of the lungs with evidence of hemorrhage and alveolar collections of neutrophils (despite having neutropenia). No organisms were visible with tissue Gram stain or methenamine silver stain, and cultures yielded no growth. Imipenem, vancomycin, and levofloxacin have been reported to inhibit the growth of B. cereus.6-8 However, toxins that persist after B. cereus has been eradicated may mediate much of the tissue damage in this infection. Clindamycin has excellent activity against B. cereus and may reduce toxin production by inhibiting protein synthesis.9 B. cereus can produce β-lactamases and is resistant to several β-lactam antibiotics.1 Our patient developed infection while being treated with β-lactam/β-lactamase inhibitor drug combinations.

B. cereus is common in the environment and can be a laboratory contaminant. Thus, cultures from nonsterile sites may be dismissed as not clinically significant. However, B. cereus is a pathogen in immunocompromised persons,10 and pneumonia caused by this organism is usually fatal, even with use of appropriate antibiotics.7,11,12 B. cereus also causes endophthalmitis, bacteremia, meningitis, and endocarditis.

B. cereus, B. thuringiensis, and B. anthracis are close evolutionary kin, with nearly identical 16S rRNA gene sequences. Some investigators have proposed grouping these 3 bacteria to make one B. cereus species with separate subspecies designations.13,14 However, whole-genome analysis shows that there are significant genetic differences between these bacteria.15 B. anthracis has virulence plasmids pX01 coding for genes that include protective antigen, lethal factor, and edema factor and pX02 coding for a polyglutamic acid capsule. B. cereus lacks these plasmids but has a pleiotropic regulator of virulence gene that controls more than 100 virulence-associated genes. A recent report describes detection of a plasmid 99.6% similar to pX01 in a B. cereus isolate recovered from a patient with an anthraxlike respiratory illness.16 Although the B. anthracis plasmid pX02 coding for capsule was not detected in that isolate, a polysaccharide capsule cluster was detected on a second previously unidentified plasmid. That report suggests that transfer of toxin coding plasmids between Bacillus species may be more promiscuous than previously appreciated.

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ACKNOWLEDGMENT

The authors thank Caitlin Smith for her technical contributions. This work was supported by grants from the NIH, CA-15704, CA-18029, and HL-36444.

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