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The new england journal of

medicine

1339

case records of the

massachusetts general hospital

Founded by

Richard C. CabotNancy Lee Harris, m.d.,

Editor

Jo-Anne O. Shepard, m.d.

,Associate Editor

Stacey M. Ellender,Assistant Editor

Sally H. Ebeling,Assistant Editor

Christine C. Peters,Assistant Editor

Case 10-2004: A 58-Year-Old Manwith Acute Myeloid Leukemia and Fever

after Chemotherapy

Jay A. Fishman, M.D., Bimalangshu R. Dey, M.D., and Robert P. Hasserjian, M.D.

From the Transplant Infectious Disease andCompromised Host Program, InfectiousDisease Division (J.A.F.), the Bone MarrowTransplant Unit, Hematology Oncology Di-vision (B.R.D.), and the Department of Pa-thology (R.P.H.), Massachusetts GeneralHospital; and the Departments of Medicine(J.A.F., B.R.D.), and Pathology (R.P.H.),Harvard Medical School.

N Engl J Med 2004;350:1339-47.

Copyright 2004 Massachusetts Medical Society.

Dr. Bimalangshu R. Dey

: A 58-year-old man with a large sacral ulcer was admitted to thehospital for chemotherapy to treat acute myeloid leukemia.

The patient had had recurrent infections of a pilonidal cyst for 20 years; the infectionshad required surgical dbridement on multiple occasions. Six weeks before admission

to this hospital, he was admitted to another hospital with a temperature as high as39.4C with chills and rigors. The pilonidal cyst had a malodorous, purulent dischargeand was surrounded by fluctuant, swollen tissue. Surgical incision and drainage were

performed. The white-cell count was 7500 per cubic millimeter, with 6 percent circu-lating blasts. The patient was treated with intravenous antibiotics, and the wound de-

veloped some granulation. A bone marrow biopsy and aspiration were performed, and

the aspirate was reported to show a hypercellular marrow with 15 percent myeloblastsand multilineage dysplasia features suggestive of a myelodysplastic syndrome withexcess blasts. The patients fever resolved, and he was discharged after two weeks.

Eighteen days before admission to this hospital, he was seen as an outpatient at this

hospitals Cancer Center for consultation regarding the diagnosis and treatment of hismyelodysplastic syndrome. He was asymptomatic and afebrile. Laboratory tests were

repeated (Tables 1 and 2), and a repeated bone marrow biopsy was scheduled. Fourdays later, chills, fever, and night sweats developed in association with a recurrent mal-

odorous discharge from the presacral wound, with mild local pain, and the patient wasadmitted the next day.

The temperature was 38.3C. There was an open wound, 10.0 by 7.5 cm, that was over

the sacrum; the wound was 4.0 cm deep, and there was granulation tissue at its baseand surrounding erythema. The results of laboratory tests are shown in Tables 1 and 2.

Vancomycin, levofloxacin, and metronidazole were administered intravenously. The pe-ripheral-blood smear contained 19 percent blasts and promonocytes (Table 1 and Fig.

1A). The bone marrow aspirate and biopsy specimen had features characteristic of acutemyeloid leukemia (Fig. 1B). A magnetic resonance imaging (MRI) study of the pelvisshowed no evidence of osteomyelitis or a rectosacral fistula. The fever resolved. Because

of the infected ulcer, the decision was made to defer induction chemotherapy for theacute leukemia, and he was discharged on the seventh hospital day, with instructions to

presentation of case

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Table 1. Hematologic Laboratory Data.

VariableOutpatient

VisitFirst

Admission

DaybeforeSecond

Admission Second Admission

Day 1 Day 8 Day 25 Day 26Hematocrit (%) 31.7 25.4 27.1 27.1 23.9 24.5 24.7

Platelets (per mm

3

) 109,000 81,000 76,000 53,000 18,000 40,000 35,000

White cells (per mm

3

) 26,200 43,700 88,000 52,400 1,800 3,100 4,600

Differential count (%)

Neutrophils 23 32 32 27 25 76 69

Lymphocytes 24 18 9 18 45 12 8

Monocytes 26 16 6 10 20 6 3

Blasts and promonocytes 23 19 46 34 10 0 0

Band forms and metamyelo-cytes

4 15 7 11 0 6 20

Absolute neutrophil count(per mm

3

)6,030 13,980 28,160 14,150 450 2,350 3,174

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to mi-cromoles per liter, multiply by 88.4. To convert the values for calcium to millimoles per liter, multiply by 0.25. To convertthe values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for uric acid to micromolesper liter, multiply by 59.48. To convert the values for bilirubin to micromoles per liter, multiply by 17.1.

Table 2. Blood Chemical Values.*

VariableOutpatient

VisitFirst

Admission Second AdmissionReference

Range

Day 1 Day 8 Day 26

Sodium (mmol/liter) 138 137 137 131 142 135145

Potassium (mmol/liter) 3.6 3.8 3.9 3.4 3.4 3.44.8

Chloride (mmol/liter) 104 104 103 93 94 100108

Carbon dioxide (mmol/liter) 26 28.6 29.3 26.0 31.8 2430

Urea nitrogen (mg/dl) 15 16 13 27 70 825

Creatinine (mg/dl) 1.4 1.3 1.3 2.5 3.1 0.61.5

Calcium (mg/dl) 8.7 8.9 7.9 7.9 8.9 8.510.5

Phosphorus (mg/dl) 2.7 3.2 3.3 2.8 2.64.5

Uric acid (mg/dl) 6.9 7.8 4.9 6.4 3.68.5

Albumin (g/dl) 3.0 2.7 2.4 2 1.6 3.14.3

Globulin(g/dl) 5.8 5.6 5.0 4.5 4.4 2.64.1

Bilirubin (mg/dl)

Total 0.2 0.2 0.3 1.5 7.2 01.0

Direct 0.1 0.1 0.7 4.4 00.4

Alkaline phosphatase (U/liter) 68 58 53 41 212 45115

Aspartate aminotransferase (U/liter) 30 23 17 40 18 1040Alanine aminotransferase (U/liter) 17 16 8 10 7 1055

Lactate dehydrogenase (U/liter) 317 282 294 365 218 110210



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take oral antibiotics and sitz baths and to use topi-

cal papain ointment.Six days after he was discharged, the patients

white-cell count had risen to 88,000 per cubic mil-

limeter, with 46 percent blasts. The next day he wasreadmitted for chemotherapy to treat his rapidly

evolving acute leukemia.The patient was married and worked as a manag-

er. His wife and children were well, and he had hadno infectious exposures. There was no family histo-ry of leukemia. He had smoked one pack of ciga-

rettes daily until one month before admission, andhe drank alcohol occasionally. He had no other

medical problems, and he stated that he had not re-cently had headache, nausea, vomiting, chest pain,

shortness of breath, altered bowel habits, loss of ap-

petite, or weight loss.On physical examination, the patient was afe-

brile. The blood pressure was 126/70 mm Hg, the

pulse 84 beats per minute, and the respiratory rate16 breaths per minute. Examination of the skin,

chest, abdomen, arms, and legs disclosed no abnor-malities. There was an ulcerated area, 6.0 by 4.0 cm,

over the sacrum; it was 3.0 cm deep, with granula-tion tissue at the base. The edges were clean and ten-

der, with slight erythema and induration in the sur-rounding area; there was no fluctuance or purulentdischarge. The results of laboratory tests performed

on the day of the patients readmission to this hos-pital are shown in Tables 1 and 2.

Dr. Robert P. Hasserjian:

The peripheral-blood smear

obtained at the time of the first admission to thishospital contained immature monocytoid cells anda few blasts with Auer rods (Fig. 1A). The specimen

obtained from the bone marrow biopsy was mark-edly hypercellular and contained predominantly

large cells with folded nuclei and moderate amountsof pale cytoplasm, features characteristic of mono-blasts (Fig. 1B). Blasts constituted 45 percent of the

cells in the bone marrow aspirate. Dysplasia waspresent in all three cell lines, as shown by hypogran-

ular neutrophils, small megakaryocytes with hy-polobulated nuclei, and nuclear irregularity in the

few erythroid elements identified. Immunopheno-

typing of a bone marrow aspirate by flow cytometryrevealed CD45+, dimly CD34+, HLA-DR+ blasts ex-

pressing the myeloid markers CD33, myeloperoxi-dase, and CD117 and the monocytic markers CD64

and CD14. Cytogenetic analysis revealed a normalkaryotype (46,XY). These findings confirmed the

diagnosis of acute myeloid leukemia.According to the current World Health Organiza-

tion classification of myeloid neoplasms, this case

is classified as acute myeloid leukemia with multi-lineage dysplasia because of dysplastic features in

more than one cell line.

1

This type of acute leukemiamay arise as a primary disorder or may evolve from

a preexisting myelodysplastic syndrome. Althoughthe bone marrow specimen from the other hospitalwas not reviewed here, the fact that it showed mul-

tilineage dysplasia with fewer than 20 percent mye-loblasts supports the interpretation that this is an

acute leukemia evolving from a myelodysplastic syn-drome.

pathological discussion

Figure 1. Specimens of Peripheral Blood and Bone Mar-

row Obtained on the First Day of the First Admission.

A smear of peripheral blood (Panel A) shows an imma-

ture monocytoid cell with a folded nucleus, multiple

prominent nucleoli, and moderately abundant pale cyto-plasm (left) and a blast containing an Auer rod (right)

(Wrights stain, 1200). The bone marrowbiopsy speci-

men contains large blast cells with folded nuclei (Panel

B; hematoxylin and eosin, 500). Megakaryocytic dyspla-

sia, identified by the small cell size and simplified nucleiwith separated nuclear lobes, is evident (arrows).

A

B



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Acute myeloid leukemia with multilineage dysplasiaafter a myelodysplastic syndrome.

Dr. Dey:

Remission-induction chemotherapy for

acute myeloid leukemia was begun on the secondhospital day with idarubicin at a dose of 18 mg per

square meter of body-surface area given intrave-nously daily for three days and cytarabine at a dose

of 200 mg per square meter by continuous infusiondaily for seven days. Oral levofloxacin, acyclovir, andfluconazole were given as prophylaxis. On the fifth

hospital day, four days after the initiation of chemo-therapy, fever to 38.3C developed, and oral mucosal

lesions were noted. The levofloxacin was discontin-

ued, and vancomycin and ceftazidime were admin-istered, but on the sixth day, the patients tempera-ture rose to 40.0C. The results of stool cultures andassays were negative for Clostridium difficile

. On the

eighth hospital day, the temperature again rose to40.0C, and diarrhea developed. A renal ultrasound

image showed no obstruction. On the ninth day, thepatient became hypotensive, with a systolic blood

pressure of 70 mm Hg and a decline in urine output.Methylprednisolone and dopamine were adminis-

tered.He was transferred to the medical intensive care

unit. Voriconazole was substituted for the flucona-

zole. The next day the trachea was intubated becauseof hypoxemia and progressive acidosis; the arterial

pH was 7.23, the arterial carbon dioxide tension was51 mm Hg, and the arterial oxygen tension was 67

mm Hg. The presacral wound appeared unchanged.Multiple blood, urine, and stool cultures were ster-ile, and examination of urine and stool specimens

showed no abnormalities. Computed tomographic(CT) scanning of the chest without the use of con-

trast material showed bilateral perihilar air-spacedisease, with scattered peripheral nodular opacities

in both lungs, particularly in the upper lobes find-ings most consistent with an infectious process. CTscanning of the abdomen and pelvis revealed no ab-

scesses. Granulocyte colony-stimulating factor andmetronidazole were administered.

Over the next three days, the patient was febrileand hypotensive, his creatinine level continued to

rise, and his urine output continued to decrease.Mechanical ventilation was continued, and norepi-

nephrine was administered. Bronchoscopy with

bronchoalveolar lavage showed no evidence of in-fection; Grams stains, fungal smears, and cultures

of bronchoalveolar lavage specimens revealed noabnormalities.

On the 14th day, the temperature rose to 38.8C.

The norepinephrine was discontinued. The next daythe patient was unresponsive, despite the discontin-

uation of treatment with sedative agents for 12hours. On the 16th day, anuria with increasing flu-

id retention developed, and hemodialysis was initi-ated. The temperature rose to 38.3C. He continuedto be unresponsive. CT scanning of the head showed

no abnormalities. Examination of a bone marrowspecimen on the 14th day after chemotherapy was

begun showed hypocellularity, without evidence ofresidual leukemia. On the 18th hospital day, the pa-

tient was more alert, but the temperature rose to39.4C. A CT scan of the chest disclosed improve-

ment in the air-space disease in both lungs, exceptthat a focus in the left upper lobe had become moreconsolidated. Quinupristindalfopristin was added

to the patients medications on the 19th day becausevancomycin-resistantEnterococcus faecalis

was detect-

ed in cultures of the sacral ulcer and on a rectalswab. A sputum culture grew vancomycin-sensitiveenterococcus. Cultures of the blood and urine were

sterile. On the 20th day, continuous venovenous he-modialysis was begun. Between the 20th and 26th

days, despite a gradual rise in absolute neutrophilcount to normal by the 25th day (Table 1), a fever

with temperatures ranging from 38.3 to 39.4C per-

sisted, and the patients trachea remained intubated;dialysis and treatment with vasoactive drugs were

necessary to maintain an adequate systemic arteri-al pressure.

Dr. Dey:

As the hematologist treating this patient,I thought it likely that the patients clinical deterio-

ration after the fifth hospital day was due to multiplefactors. The diarrhea was probably due to the anti-

microbial therapy and the treatment with cytara-bine. The high fevers and hypotension could have

indicated infection, tumor lysis with cytokine re-lease, or both, although drug-induced fever causedby the cytarabine and mucositis with bacterial su-

perinfection could not be ruled out. The inability toobtain diagnostic microbiologic cultures could have

been due to the use of broad-spectrum antimicrobialagents, or it could have indicated that the fever had

pathological diagnosis

presentation of case

(continued)

differential diagnosis



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a noninfectious cause. The acute renal failure could

have been the result of the tumor lysis syndrome orsevere hypotension and subsequent acute tubularnecrosis. The patients stuporous mental state was

probably mainly metabolic in origin and may haveincluded components of uremic encephalopathy,

hepatic encephalopathy, and both sedation and fe-ver. Hypotension, infection, hyperalimentation, or

drugs may have caused hepatocellular injury, whichresulted in elevated values on liver-function testing.

Because of the persistence of fever despite the he-matologic recovery during the fourth week of hos-pitalization, I was concerned that an undiagnosed

infection was present and requested a consultationwith the Infectious Disease Division.

Dr. Jay A. Fishman

: Infection in immunocompro-

mised persons is often rapidly progressive and lifethreatening. Thus, the appropriate design of initialempirical antimicrobial regimens for such patients

is critically important. Although progress has beenmade in the prevention and treatment of many

infections common to such hosts, the case underdiscussion poses two common problems for the cli-nician. First, if fever in a patient receiving broad-

spectrum antimicrobial agents is due to infection,which organisms are likely to be involved? Second,

which antimicrobial agents should be used? If thespectrum of coverage is too narrow, the patient may

die of sepsis, but at the same time the negative con-

sequences of excess antimicrobials (e.g., resistance,toxic effects, drug interactions, and allergic reac-

tions) are not trivial.

guidelines for treating infections

in immunocompromised patients

Progress in the care of patients with neutropenia isreflected in a series of excellent guidelines devel-oped for categories of infection that are common to

this group, particularly patients with fever and neu-tropenia.

2-9 These guidelines provide information

about the pathogens most often associated with in-fections in each patient group, as well as approaches

to the selection of antimicrobial agents. Such guide-lines are very useful as a starting point for therapy.

Unfortunately, the application of general guide-

lines to specific patients is often difficult. A patientmay have allergies or other conditions, such as im-

pairment of renal or hepatic function, that limit theuse of certain antimicrobial agents. The epidemio-

logic features of infections vary according to insti-

tution and practice for prescribing antimicrobialagents. Guidelines become outdated as new diag-nostic tools and therapies become available. In ad-

dition, opinion is not uniform with regard to theoptimal use of antimicrobial agents in febrile, im-

munocompromised patients. The evaluation andcomparison of data from clinical trials are often

complicated by variations in study design and end-point analysis. The best use of vancomycin, amino-

glycosides, antifungal therapies, immune globulins,and other agents remains uncertain, as does theirtiming.

Finally, many fevers in immunocompromisedpatients are noninfectious in origin; processes that

include pulmonary emboli, graft-versus-host dis-ease, drug toxicity, or engraftment syndromes may

cause fever. Even in patients with clinical evidenceof infection, a specific pathogen is not identified in

more than half the cases. Infections due to uncom-mon viruses (e.g., human herpesvirus 6, parvovirusB19, and metapneumovirus) or to organisms that

are difficult to isolate in microbiologic culture (i.e.,slow-growing organisms, those requiring special

mediums, or cell-wall-deficient bacteria) may go un-recognized. Patients often have multiple, simulta-neous conditions, such as infections, adverse drug

reactions, and coexisting medical conditions thatinfluence both the susceptibility to infection and the

ability of physicians to establish a diagnosis.There are few guidelines for the treatment of pa-

tients, such as this one, who have fever that devel-

ops or persists after recovery from neutropenia.

3,10

Some localized infectious processes, such as pneu-

monia, perineal abscess, and fungal infections, maybecome clinically apparent only after leukocytes re-

turn to mount an inflammatory response. The de-gree of residual impairment of immunity in such pa-

tients is unknown, although they are generally lessprone to rapidly progressive sepsis than they arewhen neutropenia is present. Unfortunately, it is of-

ten impossible to obtain a microbiologic diagnosison the basis of cultures obtained from patients re-

ceiving broad-spectrum antimicrobial agents.

general principles

Four principles may be used to guide the selectionof antimicrobial agents. First, the treatment of any

documented infection must be completed and res-olution of the infection documented. Second, after

the resolution of neutropenia, physical examinationand radiologic studies often reveal sites of infection

discussion of management



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that were previously unrecognized. Samples should

be taken from these sites for histologic or microbi-ologic evaluation. Third, additional antimicrobialagents should be selected on the basis of the pa-

tients medical history, exposure history, and aspectsspecific to his or her clinical condition. Fourth, the

physician needs to remember that the fever may notbe of infectious origin; other causes of fever, such

as drugs, may need to be considered. The strategymust be flexible enough to be modified as new data

emerge and clinical conditions evolve.In immunocompromised patients, there is a lim-

ited window of opportunity during which antimi-

crobial therapy can effectively prevent death frominfection. This observation has two implications:

most patients will receive empirical therapy (at leastuntil microbiologic data are available), and proce-

dures that define the nature and extent of infectionare essential. These procedures include radiograph-

ic examinations (particularly MRI and CT scans),biopsies to obtain specimens for histologic exami-nation and culture, and other microbiologic assays

(based on detection of antigens or specific nucleicacids).

11

The use of aggressive diagnostic approach-

es is especially important because of the relative ab-sence of physical signs or symptoms of infectionin many immunocompromised patients. Infection

is often advanced or disseminated by the time of di-agnosis. Thus, the suspicion that infection is present

is critical. Minor abnormalities may be signs of im-pending sepsis or of tissue-invasive infection (Ta-

ble 3).

risk of infection

For each patient, I ask, How great is this personsrisk of infection? And for which infections are the

risks greatest? For any patient, this risk is deter-mined by the relationship between his or her epide-

miologic exposures and a measure of his or hersusceptibility to infection, which is termed the netstate of immune suppression. The net state of im-

mune suppression is a function of all the factorscontributing to the persons risk of infection. Most

patients have several types of immune defects.Pathogens that may be present (so-called epide-

miologic exposures) may be intrinsic or extrinsic,and they may have been acquired in the hospital orcommunity; moreover, exposures may be recent or

distant in time. The potential pathogens vary ac-cording to the nature of the patients immune defi-

cits. An organism is likely to become invasive or toset up shop if the host lacks functional compo-

nents of the immune system that are needed to con-

trol or kill that pathogen. Thus, extracellular bacte-ria are common pathogens in the absence of

neutrophils or other phagocytes, and the majorityof infections in patients with neutropenia are de-rived from endogenous flora.

12

In contrast, viruses

have greater importance as a cause of opportunis-tic infection in the absence of cell-mediated cytotox-

ic (T-cell) responses.The risk of infection is also determined by the

burden of organisms (i.e., the intensity of exposure),

the native virulence of the organism, and the natureof the exposure (e.g., whether it is gastrointestinal,

is pulmonary, originates at a catheter, or arises fromold granulomas). In a person who is not immuno-

compromised (Table 4), the number of organisms

at various sites varies greatly. Thus, in patients withneutropenia, the frequency of infection originating

in the gastrointestinal tract may reflect the burdenof organisms in the gastrointestinal tract as well as

the frequency of injury to the gastrointestinal mu-cosa. Shifts in patterns of colonization are common-

ly associated with hospitalization and with the useof antimicrobial agents. Each episode of neutrope-nia, chemotherapy, infection, catheter insertion,

skin breakdown, mucositis, or colitis increases thelikelihood that infection or colonization of tissues

will persist and that colonizing organisms will beresistant to various antimicrobial agents. Access to

information about the patients prior infections andexposures to antimicrobial agents is essential.

Among immunocompromised patients, over

time exposure of organisms to selection pressurefrom antimicrobial agents has shifted the distribu-

tion of common bacterial flora from predominantlygram-positive bacteria (e.g., staphylococci) to gram-

Table 3. Common Signs of Unrecognized Infection

in Immunocompromised Patients.

Confusion

Skin with faint erythema or lymphangitic streaking

Pleurisy, dyspnea, or cough but a clear chest radiograph

Pain without physical findings (e.g., at site of insertionof a Hickman catheter, perirectal area, or abdomen)

Minimal erythema or serous drainage at site of insertionof a catheter, surgical site, abscess, or drain

Faint rashes or streaking

Minimally elevated values on liver-function tests and forlactate dehydrogenase and creatine kinase

Unexplained rise or fall in platelet or leukocyte counts



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negative organisms (e.g., Escherichia coli

) to resistant

gram-negative organisms (e.g., pseudomonas spe-cies) and back to resistant gram-positive organisms

(e.g., vancomycin-resistant enterococci, fluoroquin-olone-resistant streptococci). With prolonged neu-tropenia, along with improved treatment of bacterial

infections and the selection pressure of prophy-laxis, resistance to azole antifungal agents has

emerged. Resistance of cytomegalovirus to ganci-clovir has been observed. As a result, sicker patients

tend to become progressively more difficult to treat

(Table 5).

care of this patient

Discussions about this patient between myself and

Dr. Dey began by telephone on the 26th hospitalday, as follows: I have a patient with acute myeloid

leukemia who has received chemotherapy with pro-longed neutropenia, which is resolving. He nowhas fever, is critically ill, and has some unique risks

for infection. These features of the case, includingthe large skin wound in the sacral area and the lack

of a clinical response to multiple antimicrobialagents, became the essential clues to management

for this person (Table 6). The goal of consultationwas not to stop the use of various antimicrobialagents (although a laudatory goal), nor was it to treat

persistent fever, but rather, the goal was to deter-mine whether infection was present and to select the

optimal therapy on the basis of pathogens knownto be or likely to be present.

On physical examination, the patient appeared

to be critically ill; his trachea was intubated, he wassedated, and he was receiving continuous veno-

venous hemodialysis in the intensive care unit. Histemperature was 38.3C, his blood pressure 80/60mm Hg while he was receiving pressor agents, his

heart rate 82 beats per minute, and his respiratoryrate 14 breaths per minute with mechanical ventila-

tion. There was a deep sacral ulcer, 5 by 8 cm. Therewas granulation tissue and no exudate, and no bone

was exposed. The remainder of the findings on ex-

amination were normal. Radiographic tests (CT andMRI) revealed no deep infection in the abdomen,

chest, or perirectal area. His white-cell count hadclimbed to 4600 per cubic millimeter, with an ab-

solute neutrophil count of 3174 per cubic millimeterwhile he was receiving granulocyte colony-stimu-

lating factor.Potential pathogens in this patient fell into two

groups: documented infectious organisms and like-

ly pathogens. Multiple blood cultures had been ster-ile; a single isolate of coagulase-negative staphylo-

coccus from blood drawn from a Hickman catheterwas considered a contaminant. A sputum culture

had grown a few yeast (

Candida albicans

) and mod-erate numbers of vancomycin-susceptible

E. faecalis

.A Grams-stained sputum specimen contained few

neutrophils and no organisms. Cultures of both arectal swab and the pilonidal-cyst ulcer grewE. faeca-

lis

(resistant to vancomycin, doxycycline, erythro-mycin, and tetracycline and sensitive to ampicillin,

Table 4. Approximate Concentration of Bacteria

in Tissues from the Normal Human Host.

Site or SpecimenApproximate Concentration

of Organisms

no./g of specimen

Skin 10

3

Groin or axilla 10

6

Bile or liver Sterile

Stomach 10

3

Small intestine 10

4

Large intestine 10

11

Lungs Sterile

Nasal secretions 10

5

Saliva 10

8

Urine 3 days), with a stay in the intensivecare unit

Renal or hepatic dysfunction (e.g., ascites or a condition

requiring dialysis)

Catheterization: urinary, venous, or dialysis

Mucosal injury or Clostridium difficile

colitis

Constipation

Endoscopy

Use of broad-spectrum antibiotics

Deep-vein thrombosis, atelectasis, or inactivity

Metabolic conditions: malnutrition, uremia,or hyperglycemia

Viral coinfection

Prolonged hospitalization



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quinupristindalfopristin, chloramphenicol, line-

zolid, and rifampin).There was no clinical response to the addition

of multiple antimicrobial agents; in fact, the pa-

tients fever was higher. No focus of infection hadbecome manifest with the return of neutrophils.

We suspected that if he had sepsis, it was derivedfrom his deep skin ulcer, although this area did notappear to be grossly infected. It also seemed possi-

ble that some of the antimicrobial agents mighthave been contributing to his fever and hypoten-

sion. The period of greatest risk (three weeks of ab-solute neutropenia) had passed. He had completed

courses of guideline-specified antimicrobial thera-

py during the weeks he had neutropenia and hadreceived, in addition, a variety of broad-spectrum

antimicrobial agents. Therefore, I thought that hisantibiotic coverage could be safely narrowed. I sug-

gested that we treat the obvious skin ulcer with in-travenous ampicillin (for susceptible enterococcus

from the wound and rectum) and metronidazole(for presumed anaerobic organisms from the sameareas) and that we eliminate the other drugs.

Dr. Dey:

The granulocyte colony-stimulating fac-tor was discontinued on the 27th day. The quinu-

pristindalfopristin, ceftazidime, and acyclovir werediscontinued on the 28th day. Within 48 hours, the

patient became afebrile, became fully awake, and nolonger required pressor agents or ventilatory sup-port. Abnormalities in the results of liver-function

tests improved markedly after discontinuation ofthe quinupristindalfopristin. Cultures remained

sterile.A repeated bone marrow biopsy was performed

the day before discharge and showed hypercellu-

larity with trilineage hematopoiesis, without evi-dence of leukemia. The patient gradually recoveredand was discharged after 44 days of hospitalization.

He is currently undergoing consolidation chemo-therapy as an outpatient.

Dr. Philip Amrein (Hematology and Oncology):Is it possible that some patients who are receiving

the appropriate antibiotics and remain febrileeven while their cultures remain sterile do indeed

have sepsis? Is it possible that the cultures do notgrow pathogens because of the presence of the an-tibiotics?

Dr. Fishman:

In some cases, microbiologic cul-tures are sterilized by antimicrobial agents. This is

particularly true of patients with low-grade bactere-mic infections and those with loculated infections,

such as biliary obstruction, small-bowel perfora-tions, or other small abscesses, as was suspected in

this patient.

Dr. Nancy Lee Harris

(Pathology): In this patient,do you think the fever was caused by drugs or by in-

fection?

Dr. Fishman:

I think that drugs clearly had a role

in causing his fever. When we stopped the quinu-pristindalfopristin and voriconazole, the patientscondition improved rapidly without the addition of

new antimicrobial agents. The chemotherapeuticagents may also have contributed to the fever. How-

ever, it is equally likely that he had intermittent bac-teremia from his deep pilonidal cyst. So I suspect

that he had a combination of infections and adverse

drug reactions.

Dr. Howard Weinstein (Pediatric Hematology and

Oncology): Is there any role for granulocyte trans-fusions in patients with neutropenia? And what is

the role of prophylactic oral antibiotics in patientswho have neutropenia but no fever? Most of the al-

gorithms for empirical antibiotic therapy in pediat-ric oncology are for patients with neutropenia andfever; we do not give antibiotics to afebrile patients.

Dr. Fishman:

Granulocyte transfusions remaincontroversial, with advocates and detractors in equal

numbers. Transfusion reactions are common, andin many patients the granulocyte counts increase

only slightly after transfusion. There is a substan-tial risk of transmission of cytomegalovirus andother viruses. However, some controlled clinical tri-

als have shown a benefit in patients with document-ed infections. Many of us would try granulocyte

transfusions if other approaches failed. Clinical tri-als are needed in this area.

Table 6. Clinical Features of This Patient.

Acute myeloid leukemia with induction chemotherapy (on-going)

Severe neutropenia (prolonged, with mucositis)

Intubation in the intensive care unit

Hypotension with use of pressor agentsAcute renal dysfunction (and hemodialysis)

Placement and replacement of Hickman catheter

Peripheral venous catheter and Foley urinary catheter

Prior treatment with levofloxacin, acyclovir, and flucona-zole as prophylaxis

Pilonidal cyst with multiple operations and one episodeof sepsis (large, open sacral wound)

Microbiologic cultures unrevealing



9/9

n engl j med 350;13



1347

The routine use of antibiotics in neutropenia in

the absence of fever should be limited to specifichigh-risk patients: those likely to have prolongedand severe neutropenia, those who have had prior

episodes of fever or infection during neutropenia,and those who have a likely source of infection,

such as this patient who had an open ulcer. In pa-tients with a history of herpes simplex virus or var-

icellazoster infections or of thrush, prophylaxis isalso worthwhile. Those receiving high-dose corti-

costeroids may benefit from trimethoprimsulfa-

methoxazole prophylaxis against pneumocystis in-fection. As much as possible, I prefer to individualizeprophylaxis for each patient, with risk stratification

for specific infections.

Dr. Fishman reports serving as a consultant to Gilead, Roche, andImerge BT; receiving research support from Fujisawa Healthcare;

receiving educational program support from Fujisawa Healthcareand Roche; and serving on the speakers bureaus of Pfizer, Roche,Fujisawa Healthcare, and Aventis.

references

1.

Brunning R, Matutes E, Harris NL, Flan-drin G. Acute myeloid leukemia with multi-lineage dysplasia. In: Jaffe ES, Harris NL,Stein H, Vardiman J, eds. Pathology andgenetics of tumours of haematopoietic andlymphoid tissues. Vol. 3 of World HealthOrganization classification of tumours.Lyons, France: IARC Press, 2001:88-9.

2.

Hughes WT, Armstrong D, Bodey GP, et

al. 2002 Guidelines for the use of antimicro-bial agents in neutropenic patients with can-cer. Clin Infect Dis 2002;34:730-51.

3.

Pizzo PA, Robichaud KJ, Gill FA, Witeb-sky FG. Empiric antibiotic and antifungaltherapy for cancer patients with prolongedfever and granulocytopenia. Am J Med 1982;72:101-11.

4.

Schimpff SC. Empiric antibiotic therapyfor granulocytopenic cancer patients. Am JMed 1986;80:13-20.

5.

Klastersky J, Zinner SH, Calandra T, et

al. Empiric antimicrobial therapy for febrilegranulocytopenic cancer patients: lessonsfrom four EORTC trials. Eur J Cancer ClinOncol 1988;24:Suppl 1:S35-S45.

6.

Viscoli C. The evolution of the empiricalmanagement of fever and neutropenia incancer patients. J Antimicrob Chemother1998;41:Suppl D:65-80.

7.

Rolston KV, Mullen CA, Wade JC.

NCCN: fever and neutropenia. SupportiveCare Cancer 2002;10:58-64.

8.

European Organization for Researchand Treatment of Cancer (EORTC) Interna-tional Antimicrobial Therapy CooperativeGroup, National Cancer Institute of CanadaClinical Trials Group. Vancomycin added toempirical combination antibiotic therapy forfever in granulocytopenic cancer patients.

J Infect Dis 1991;163:951-8. [Erratum,J Infect Dis 1991;164:832.]

9.

National Comprehensive Cancer Net-

work home page. (Accessed February 5,2004, at http://www.nccn.org.)

10.

Barton TD, Schuster MG. The cause offever following resolution of neutropenia inpatients with acute leukemia. Clin Infect Dis1996;22:1064-8.

11.

Donowitz GR, Harman C, Pope T, Stew-art FM. The role of the chest roentgenogramin febrile neutropenic patients. Arch Intern

Med 1991;151:701-4.

12.

Bodey GP, Buckley M, Sathe YS, Frei-reich EJ. Quantitative relationships betweencirculating leukocytes and infection inpatients with acute leukemia. Ann InternMed 1966;64:328-40.

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