A 69-year-old man with relapsed acute lymphoid leukemia was treated with adriamycin, vincristine, and prednisolone. During
this chemotherapy, the patient developed sepsis and meningitis. Although many kinds of antimicrobial drugs, including
imipenem, meropenem, amphotericin-B, and γ-globulin were administered, the patient died of respiratory failure. A positive
result for Enterococcus faecalis was obtained in both blood and cerebrospinal fluid culture. Autopsy revealed multiple small
erosions in the lower esophagus. Histopathological examination showed multiple nuclear inclusion bodies of herpes simplex
virus in the squamous epithelial cells at the edge of the erosions. Moreover, proliferation of micrococci was observed at the
base of the erosions and in the lumina of the submucosal small vessels. These findings suggested that E faecalis entered the
blood circulation from this lesion. In many patients with febrile neutropenia, the pathogenesis of infection remains unclear.
Our case seems significant for clarifying the focus and pathogenesis of febrile neutropenia

Ikegaya, Satoshi

Iwasaki, Hiromichi

Naiki, Hironobu

Ueda, Takanori

Yoshida, Akira

University of Fukui Repository

Esophageal Erosion as a Possible Bacterial Entry Site 
   in an Acute Lymphoblastic Leukemia Patient 
               with Sepsis 
Satoshi  Ikegaya," Akira  Yoshida,b  Hiromichi  Iwasaki,' Hironobu  Naiki," 
                     Takanori  Ueda!'
 "Second  Department  of Pathology,  'First  Department  of Internal Medicine, and 
 Fukui Medical University,  Fukiti,  Japan
Division  of  Transiimion  Medicine,
Abstract 
  A  69-year-old man with relapsed acute lymphoid leukemia was treated with  adriamycin, vincristine, and prednisolone. Dur-
ing this chemotherapy, the patient developed sepsis and meningitis. Although many kinds of antimicrobial  drugs, including 
imipenem,  meropenern,  amphotericin-B, and  -y-globulin were administered, the patient died of respiratory failure. A positive 
result for  Enterococcus  .faecalis was obtained in both blood and  cerebrospinal fluid culture. Autopsy revealed multiple small 
erosions in the lower esophagus. Histopathological examination showed multiple nuclear inclusion bodies of herpes simplex 
virus in the squamous epithelial cells at the edge of the erosions. Moreover, proliferation of micrococci was observed at the 
base of the erosions and in the lumina of the submucosal small vessels. These findings suggested that E  faecalis entered the 
blood circulation from this lesion. In many patients with febrile  neutropenia, the pathogenesis of infection remains unclear. 
Our case seems significant for clarifying the focus and pathogenesis of febrile neutropenia.
Key  words: Entry  site; Sepsis; Esophageal  erosion.; Leukemia;  Enterococcus faccalis
 1,  Introduction
  It is widely known that  infectious diseases often are 
caused by various pathogens during neutropenia (neutrophil 
count  <500/A). In particular, when the neutrophil count is 
less than  1004.1.L, fatal infectious diseases may develop  111. 
During neutropenia, the pathogen cannot be identified in 
 many cases in spite of several blood culture tests  [2]. Antibi-
otics usually are administered empirically, without the 
results of culture tests, as soon as the patient  becomes 
febrile. 
  Because the pathogenesis of febrile neutropenia has 
not been clarified, evaluation of pathogenesis by autopsy 
may be significant. This report describes our use of 
autopsy to investigate the entry site of  Enterococcits  fae-
calis, which was the pathogen of sepsis and meningitis dur-
ing neutropenia in a patient with acute lymphoblastic 
leukemia.
  Correspondence and reprint requests: Satoshi  1kegaya. 
Second Department of  Pathology, Fukui Medical  University, 
 23-3 Shimoaizuki,  Matsuoka-cho, Yoshida-gun, Fukui  910-1193, 
Japan;  81-0776-61-3111 (ext 2237); fax:  81-0776-61-8123.
2. Case Report
  A  69-year-old Japanese man with pneumonia was 
referred to our hospital because his white blood cell (WBC) 
count increased to  12,400/p.L, including  80% blast cells.  on 
January 4, 1999. Respiratory sound was attenuated in the 
right lower lung, the liver and spleen were not palpable, and 
superficial lymph nodes were not swollen. 
  Small lymphoblasts showinga high nuclear cytoplasmic 
ratio and negative peroxidase staining were recognized, and 
the diagnosis made was acute lymphoblastic leukemia 
(ALL)  Li by French-American-British criteria. The surface 
markers of blasts showed positive  CD10.  CD19. KOR-
SA3544  [3], and HLA-DR.  Chromosomal nalysis revealed a
normal karyotype (46,XY). 
  Pneumonia wastreated with cefpirome 2  g/day and granu-
locyte colony-stimulating factor 150  µg  day intravenously. 
 Antileukemic hemotherapy was administered from January 
 28, 1999, according to the treatment protocol of the Japan 
Adult Leukemia Study Group ALL97. 
  Complete remission was achieved after induction chemo-
therapy, but the patient had a relapse after 3 courses of con-
solidation therapy. 
  The patient was treated with 4 courses of reinduction 
chemotherapy: however, remission was not achieved, and
 G-CSF  1  00  fa I I
 IPM/OS  2  a  I I
 int—,ni 
CFP 
 (rngica)
 00
40
 20
 0
 SW( 200 mg
 ITCZ  100  mg  r 1
 I/EPM  12  a 1 
asJAPH !SO JFISI I
 9/  2  0  9125
 
1  011 1  0/5
Fever
     Respiratory failure mil^ 
Disturbance of consciousness 
                 Convulsion ^I•
Figure 1. Clinical course. G-CSF indicates granulocyte colony-stimulating factor;  IPMICS.  imipenem/cilastatin;  SPFX.  sparfloxacin: MEPM. 
 meropenem;  ITCZ, itraconazole; AMPH.  amphotericin B;  SBTICPZ,  sulhactam/cdoperazone;  ey-glb. ISP.  isepamicin;  CRP, C-reactive  pro-
tein:  VCR,  vintristine; DXR.  adriarnycin: PSL.  prednisolone.
the peripheral blood  lymphoblast cell count increased from 
September 20, 1999,  Peripheral blood counts were as fol-
lows:  WBC,  4400/4 (lymphocytes.  I  I  To: myelocytes,  1 %; 
and  lymphoblasts,  88%); hemoglobin. 7 3  g/cIL; and platelets. 
 17,000/1.LL. Theresults of biochemical nd coagulation tests 
revealed no abnormal findings except elevation of lactate 
dehydrogenase up to 1543  IU/L (normal  range, 220 to 
460  lU/L). Combination chemotherapy, including  adriamycin, 
 vincristine, and  prednisolone was administered beginning on 
September  28,  1999. The clinical course is shown in Figure 1. 
 Sparfloxacin 200 mg/day and itraconazole 100  mg/clay 
were administered as prophylaxis for infection from  Sep-
tember 20, 1999, because the mature granulocyte count was 
 MIL. Leukemic ell numbers were significantly decreased by 
 antileukemic chemotherapy, but the patient became febrile 
(39.0°C) on September 29. Immediately,  sulbactam/cefopera-
zone 4  glday and isepamicin 400 mg/day were administered 
empirically. However, these antibiotics were not effective. 
C-reactive protein level increased to18.4  mg/dL on October  1, 
and respiratory insufficiency was observed from October 2, 
neither pathogen or focus of infection having been identi-
fied by various clinical tests. Convulsions and disturbance of 
consciousness occurred on October 3. Lumbar puncture 
was performed on suspicion of meningitis. Cerebrospinal 
fluid (CSF) pressure was 18 cm H2O, and the cell count was 
 1  03/mL.  All leukocytes in the CSF were mononuclear. 
Although many kinds of antimicrobial drugs were adminis-
tered, the patient died of respiratory failure on October 5. 
  E  litecalis was detected in cultures of blood and CSF 
obtained on October 2 and October 4, respectively. Both 
 E  faecalis  pecimens showed the same drug sensitivities. Spu-
tum obtained from the right second carina during autopsy 
was cultured. In this microbial examination  Enterococcus
 *churl, not E  faecalis, was detected (Table 1). Surveillance 
culture results were positive  for  Eme^ococcuss species in the 
stool and a-Streptococcus in the pharynx. 
  Autopsy revealed multiple small erosions in the lower 
esophagus.  Histopathological examination showed multiple 
nuclear inclusion bodies of herpes simplex virus (HSV) in 
the  squamous epithelial cells  at the edge of the erosions. 
Moreover, proliferation of  micro-cocci was observed at the 
base of the erosions and in the  lumina of  subrnucc.isal mall 
vessels. Diffuse dispersing microabscesses were recognized in
the cortex of the kidney and cardiac muscles. ft was con-
cluded that E  faecalis entered the blood circulation from this 
lesion to the systemic body (Figure 2). No infectious 
pathogen was recognized in the lungs, but diffuse alveolar
Table 1. 
Drug Sensitivity of Bacteria from  Positive Culture  Tests*
Materials: Blood Cerebrospinal Fluid Sputum
Date: 10/2/1999  10/4/1999  10/9/1999
Bacterium: E faecalis  E  faecalis  E  faeciurn
Minimum Inhibitory Concentration
Sensitivity 
 Penicillin G 
 Ampicillin 
 Piperacillin 
 Erythromycin 
 Minocycline 
 Imiperiem 
 Vancomycin 
 Levofloxacin
 58 
 52 
 5  <  '16 
 R  >  4 
 S4 
 52 
 5  <  2 
 R  >  4
58 
 52 
 S<16 
 R  >  4 
 54 
 52 
 5  <  2 
 R>4
R 8 
 R  > 8 
 R  > 64 
 R  > 4 
 52 
 R  >  8 
 5  <  2 
 R  >  4
 WE indicates Enterococcus; 5, susceptibility; R, resistance.
A Jill'
• ^
:1 1
I
                                                            ,
,-- -      4 . .—   - . . . i.. _--, '^ 11711 
.0111 :2 ill rligK. 
  , . • 4               • 1 
    N I ...- 1 : li — : ... ..41.•••• . 
          Af.:•7-1.'.. ...NI 1                                                 a 1.1.ri 1,,• ,,, "... ,_ 
 , . ... ..,• • •••/. ' 1 rillt.4.-  
' ' ' r• , , .. 
                                                                                          4. 
        . .
                                                                
• • 
                                                                               .1. •
^ 
• 40. 
              : •                                                                      • 11,
,,2: 
                                                                                                                               •
      ••••••• 7.•=414.                                                                 • . • . 
              ...4.C.1111111111. .•  
1-airANIAALF--e — 
                            -----
        4: ' . . _iiik.exit, 
   .  
 ,4.`•:41-~:e       ',10• •tity 
                                         Y1rv- — -                                                   i.....1; . - - - _:... k .14 . . ---' pi ,frpt,„ 4:9 ... -.•   •••• -L" :- • ..,,oi ..44? ,,..,c, '-'.v 1) i• , -.,    .. - , dr . . .r i • . ‘.r t ... . 4,-. 1,- / , ,, , . -   • 4: ".. - .-6.-„:.....-....,4,-.. - , . I, . :-:,'  , 
in
, .., ,.. - • --.. • .....: ._ _ it ..„. ,....,4,-.....„,,......_. i.._  
4 -.r.d. ' -4 • . V --t-                    Al'_.&... p • '.• -_` - . r
, lir . , . • .C. . - - . - , , ' .N. rE4 
144 .., •,.. ( A , . -.''''`vrel      = i                                                                                                        --,......, . 
                                                                                                                                                                 .. ... 
 tii ..-.-* 4/.4;4,1,, "..4.- ,, .4' -• -1.. r  ... . . . 
•.
_ , ... , , • ... , . • • - -1,... - • 1:' . -.5 `. , e'sg 4.4 . • -• ,,, . . - oi.... '
. '..4.4. ' ".. • .. . • ,, : •-• f i • r • • . • . . ....•                                      - . 0 
       i 
   4..s.           ..3'j-i-,•,-  ti .A;:--•••,,,.               -'‘ ..;'..,. 4...e••ri.•4/." 
•
       '
.'-.4:...'k'^.1'•r•.1.. ,..,...'
.•                                   -'1....• .,-4 .4         ,"r. .
,rje%-"'2s..._7.17-           ..''-.•t.-rk..'-4,4?1'1. .....-1:C'‘'7.- 
..,.,,..- . 
                                                                    4, ,_.•                   
. • 1k. , ' - • .... "''' -4. 4- .1. AC: 04                            ....• 1'4 ilipih .,. _--r- 0 , .,4il...z.i- v., _ ....4K _awl kir                 , '1                0 .r. a .4--
.1:47.1..  '11..'l_.                                                  II                                                               •
Figure 2. Esophageal  erosion detected  by autopsy (original magnification.A,  XL;  B,  X5:  C,  X25;  I),  X100).  Airows indicate multiple  erosions in the 
lower esophagus (A),  proliferation of  micrococci at the base of  .crosions  (4.multipic.nuclear bodies of herpes simplex virus  (C), and  micrococci in 
the lumina of  submucosal vessels  0•
 damage with hyalinization was observed,  and it is  assumed 
that acute respiratory distress syndrome occurred. No infec-
tious focus was recognized in the stomach or gut.
3. Discussion
  Intensive antileukemic chemotherapy has resulted in high 
remission-induction rates for patients with acute leukemia, 
whereas myelosuppression, themain toxic effect of intensive 
therapy, directly causes infectious disease [4]. 
  Fever in neutropenic patients (neutrophil count,  <50014 
or  <1000/p1 with a predicted decline to  -500/1.s.L) was 
defined as febrile neutropenia by the Infectious Diseases 
Society of America (IDSA) in 1997 [5]. In general, the entry 
site of bacteria often is uncertain even after the pathogen has 
been  identified by  blood culture. In our case, both sepsis and 
meningitis were caused by the same  E  faecalis. We observed 
multiple nuclear inclusion bodies of HSV at the edge of the 
erosions and proliferation of  micrococci at the base of the 
erosions and in the lumina of submucosal small vessels in the 
lower esophagus. No entry site of bacteria was recognized in
the stomach, gut, bronchus mucosa,  lungs„  urinary tract,  skin,
or oral membrane. Therefore it is reasonable toconsider that 
E faecalis may have entered via esophageal erosions caused 
by HSV infection. 
  To our knowledge there has been no report identifying 
esophageal erosion as a bacterial entry site in a patient with 
sepsis, but esophageal erosion by a virus was recognized in 
13% of all autopsy cases in our hospital from  1998 to 2000 
(unpublished observation). Moreover, the frequency 
increases to 25% when limited to hematological diseases. 
Becker et al reported that the frequency  of esophagitis 
caused by  HSV is 0.5% to  6% in unselected patients [6]. 
However, to our knowledge there have been no reports that 
HSV infection may be a cause of E  faecalis epticemia. 
  Guidelines from the US Centers for Disease Control and 
Prevention recommend preventive administration of acy-
clovir to HSV antibody-positive patients receiving hemato-
poietic stem cell transplants, but there is no consensus  proto-
col in the case of conventional  ntileukemic  chemotherapy. 
The intensity of antileukemic chemotherapy has increased in 
recent years.  Prophylaxis for viral infection should now be 
considered, especially for patients with lymphoid malignancy 
treated with intensive chemotherapy.
  In a previous  tudy, gram-negative rod infection was fre-
quently observed uring neutropenia.  Pseuelurnonas  aertigi-
nosa, in particular, has a high mortality rate as a pathogen [7]. 
Monotherapy with a cephem or carbapenem, and combina-
tion therapy with an antipseudomonal cephem and  aminogly-
coside are recommended in the febrile neutropenia guideline 
of the IDSA [5]. In this case antibiotics were selected accord-
ing to these guidelines. However, ithas been reported that the 
frequency of gram-positive bacterial infection has increased 
in recent years [8,9]. Several  f3-lactam antibiotics were admin-
istered to our patient. However, there was no improvement. 
Therefore it is also necessary to consider administration  of
vancomycin the case of gram-positive bacterial infections. 
  Until  now„ in many cases of febrile  neutropenia, the exact 
pathogenesis of infection has remained  unclear. it is  impor-
tant to investigate by autopsy the entry site of bacterial infec-
tion. Thus our case seems ignificant for clarifying the focus 
and pathogenesis of febrile neutropenia.
References
1.  Balducci  Haldrook  JC,  Morrison FS, et  al_ Acute leukemia and 
  infections: perspectives from a general hospital. Am J  Hemarol. 
 1983;15:57-63. 
2.  Pennington  JE. Fever  neutropenia and malignancy: a clinical syn-
  drome in evolution.  Cancer.  1977:39:1.3454349.
3.  Mori T. Sugita K. Suzuki  T, et  al. A novel  monoclonal antibody. 
 KOR-SA3544, which reacts to Philadelphia chromosome-positive 
 acute  lymphoblastic leukemia cells with high sensitivity. Leukemia. 
 1995:9:1233-1239. 
4. Iwasaki H, Misaki H,  Nakamura  T. Ueda  T. Surveillance of the 
  serum Candida antigen titer for initiation of antifungal therapy 
  after post-remission chemotherapy in patients with acute 
 Leukemia.  Inn  Henuttot  2000:71:266-272. 
5. Hughes WT. Armstrong  D. Bodey  GP, et al. 1997 guidelines for  the 
  use of  antimicrobial agents in neutropenic patients with unex-
  plained fever. Infectious Diseases Society of America.  Clin Infect 
  Dis. 1997:25:551-573. 
6. Becker  K, Lubke Borchard F. Haussinger D. Inflammatory 
  esophageal diseases caused by herpes simplex virus infections: 
  overview and report of 15 personal cases.  2:  Gastroenterol.  1996:34! 
  286-295. 
7. Yokota T.  Teshinia H.  Okajima Y, et al. Septicemia associated 
  with  hematopoietic disorders and its features according to 
  respective primary disorders. Kansenshogaku Zasshi.  1996:70: 
  108-115. 
8.  De Pauw BE. Donnelly JP. Infection in the  immunocornpromised 
  host: general principles. In: Mandell GL. Bennett  .1E. Dolin  R, eds. 
  Principles  and Practice of Infectious  Disease. 5th  ed. Philadelphia: 
  Churchill Livingstone:  2000:3079-3090. 
9. Horiuchi A, Hasegawa H. Masaoka  T. et al. Actual conditions of 
  bacterial infection associated with hematopoietic disorders: 
  changes in 10 years.  Hanshin Study Group of  Flematopoietic Dis-
  orders and Infections.  Kansenshogaku  Zasshi.  .1990;64:299-309.


Esophageal erosion as a possible bacterial entry site in an acute lymphoblastic leukemia patient with sepsis

Abstract

Similar works

Full text

Available Versions

University of Fukui Repository