BRIEF REPORTS
old patient,10 a newborn with bone marrow failure complicated by
INFECTIONS IN PATIENTS WITH SHWACHMAN-
DIAMOND SYNDROME
Zachary M. Grinspan, MD,* and Cheryl A. Pikora, MD, PhD†
Abstract: Shwachman-Diamond syndrome (OMIM 260400) is a
multisystemic disorder characterized by pancreatic insufficiency,
bone marrow dysfunction, skeletal abnormalities and immune dys-
function. Prompted by the case of a 13-year-old girl with Shwachman-
Diamond syndrome who presented with pneumonia attributable to
Pseudomonas aeruginosa, we review infectious complications of this
disease. Pneumonia, recurrent otitis media and skin infections/abscesses
constitute the majority of infections among these children.
Key Words: Shwachman-Diamond syndrome, Pseudomonas,
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pneumonia, infections, neutrophil dysfunction
Accepted for publication September 13, 2004.
From the *General Pediatrics Division, Massachusetts General Hospital for
Children, and the †Division of Infectious Diseases, Children’s Hospital
Boston, Boston, MA
Address for reprints: Cheryl A. Pikora, MD, PhD, Division of Infectious
Diseases, Children’s Hospital, 300 Longwood Avenue, Boston, MA
02115. Fax 617-730-0254; E-mail cheryl.pikora@childrens.harvard.edu.
Copyright © 2005 by Lippincott Williams & Wilkins
DOI: 10.1097/01.inf.0000151042.90125.f6
S hwachman-Diamond syndrome (SDS) (OMIM 260400) is a rare,
autosomal recessive, multisystemic disorder attributed to muta-
tions in the Shwachman-Bodian-Diamond syndrome (SBDS) gene
on chromosome 7.1,2 The disease is characterized primarily by
exocrine pancreatic insufficiency, bone marrow dysfunction leading
to peripheral blood cytopenias, skeletal abnormalities and immune
dysfunction.2,3 Myelodysplastic syndrome develops in 10 – 44% of
patients diagnosed as having SDS, and 5–24% of cases progress to
leukemia.4 Comprehensive reviews of the hematologic and gastro-
intestinal manifestations of the disease, as well as treatment strate-
gies, were published recently,4 – 6 but the infectious complications of
SDS have not been extensively reviewed.
A 13-year-old girl with SDS, diagnosed at 1 month of age,
presented to our institution from an outside hospital after an episode
of hematemesis and a chest radiograph that revealed a right-side
cavitary lesion and pulmonary effusion. Bacterial cultures of pleural
fluid yielded Pseudomonas aeruginosa. Prompted by this experi-
ence, we examined the literature to tabulate the reported sites and
pathogens affecting these patients.
LITERATURE REVIEW
Several hundred cases of SDS have been reported in the
literature. We found 14 case series that described SDS-related
infections for at least 6 patients. Seven of these studies contained
sufficient detail on infectious complications for tabulation. Of the
153 individual patients described in these 7 studies, 50 (33%)
contracted pneumonia, 45 (29%) had recurrent otitis media and 23
(15%) acquired skin infections and/or abscesses. Other infectious
complications mentioned in ⱖ2 reports included 2 patients with
meningitis,2,7 3 with osteomyelitis8,9 and 4 with urinary tract infec-
tions.2,8,10 The incidence and severity of infections were greater
among patients with profound neutropenia.3,7
Bacterial causes included Staphylococcus aureus,7,8,10 Hae-
mophilus influenzae,8,10 Streptococcus pneumoniae,11 Klebsiel-
la,8,12 Escherichia coli,8,13 Proteus mirabilis,13 Shigella8 and
Pseudomonas species.8,10,13,14 Three viral infectious have been
described, ie, a presumed cytomegalovirus infection in a 7-month-
The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
congenitally acquired parvovirus B1915 and a 6-year-old girl with
measles complicated by bleeding gums and purpura without throm-
bocytopenia.7 A single parasitic infection (Giardia) was reported.7
DISCUSSION
SDS imparts a deficiency of neutrophil function as well as
number. The common pathogens and abscess sites seen in SDS are
similar to those classically seen in other disorders of neutrophils,
although with notable exceptions. For example, patients with disor-
ders of neutrophil motility (ie, Chediak-Higashi syndrome or hyper-
immunoglobulinemia E syndrome) or of leukocyte adhesion (leu-
kocyte adhesion deficiency) cannot localize neutrophils to sites of
infections and have little pus formation.16 In contrast, patients with
SDS develop frank abscesses,7–9,17 including pneumonia compli-
cated by empyema, as seen with our patient and others.7 As a second
example, neutropenia and disorders of intracellular killing (ie,
chronic granulomatous disease) predispose patients to fungal infec-
tions, such as Candida and Aspergillus species.16 However, none of
the reviewed case series described fungal infections among patients
with SDS, and we were not able to find any case reports.
The specific nature of the neutrophil defect in SDS is starting
to emerge. Genetically, the SBDS gene product functions in the
regulation of RNA metabolism through a pathway involving phos-
phoinositol phosphates.1 Defects in neutrophil motility and chemo-
taxis were reported for most10 or all17–22 patients with SDS tested in
several case series. Recent work suggests that the dysfunctional
SBDS gene product does not disturb baseline motility or chemotaxis
to temporal gradients of chemoattractants but does prevent neutro-
phil chemotaxis to spatial gradients.22 Therefore, SDS neutrophils
retain the ability to navigate toward areas of infection but once there
cannot effectively follow local signals to track down and kill
offending bacteria. Reports that effective chemotaxis can be restored
with lithium23 or thiamine24 therapy merit additional study.
In addition to neutrophil dysfunction, other aspects of the
immune system may be affected. Low serum concentrations of
assorted ␥-globulin subtypes were described for 28-64% of patients
in some case series,18,19 although other authors did not find immu-
noglobulin abnormalities.25 In addition, some patients have de-
creased T cell proliferative responses,18,19 defects in monocyte
motility,20 decreased numbers of natural killer cells19 and defective
complement activation.26 It is not known why bacterial infections
predominate over fungal infections.
Some patients with SDS do not manifest immunodeficiency.
Table 1 shows that at least 13 of 65 (20%) patients with SDS did not
have reported infectious complications.2,7,9 –11,17 This suggests that
the variety of SBDS mutations reported1,27 have different immuno-
logic phenotypes.
We conclude that the most likely bacterial pathogens in SDS are
S. aureus, H. influenzae and Gram-negative rods, including Pseudomo-
nas species. Antibiotic therapy for infections among these patients
should be targeted toward these microorganisms. Granulocyte colony-
stimulating factor, granulocyte/macrophage colony-stimulating factor
and (in some cases) bone marrow transplantation may be used to treat
the bone marrow dysfunction seen commonly in this disease.
REFERENCES
1. Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are
associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33:97–101.
2. Shwachman H, Diamond LK, Oski FA, Khaw KT. The syndrome of
pancreatic insufficiency and bone marrow dysfunction. J Pediatr. 1964;
65:645– 663.
3. Mack DR, Forstner GG, Wilschanski M, Freedman MH, Durie PR.
Shwachman syndrome: exocrine pancreatic dysfunction and variable
phenotypic expression. Gastroenterology. 1996;111:1593–1602.
179
Grinspan and Pikora The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005

TABLE 1. Infectious Complications of SDS

Recurrent Skin
No. of
Study Location Sites of Infections Organisms Pneumonia Otitis Infections/
Patients
Media Abscesses

Infectious complications
detailed
Shwachman et al,2 Boston, 6 2 without infectious complications, 1 Escherichia coli 1 3 1
1964 MA paronychia, 1 pneumonia, 3 recurrent
otitis media, 1 Escherichia coli UTI,
1 meningitis
Launiala et al,11 1967 Helsinki, 6 2 without infectious complications, Pneumococcus sp. 4
Finland 4 respiratory infections, pneumonia,
carditis or pneumococcal septicemia
(numbers unclear)
Burke et al,7 1967 Melbourne, 11 All with recurrent infections, 6 pneumonia Staphylococcus sp., 6 4 5
Australia (1 with empyema), 4 recurrent otitis Giardia
media, 5 skin infections and/or abscesses,
2 ulcerative stomatitis, 2 tonsillitis,
1 each liver abscess, Staphylococcus
enteritis, meningitis, nonsuppurative
arthritis of knee, mastoiditis, Giardia,
measles, wound infection
Aggett et al,9 1980 London, 21 4 without infectious complications, 12 8 3
U.K. 14 pneumonia/respiratory tract infections,
8 recurrent otitis media, 3 abscesses,
2 osteomyelitis, 2 septicemia
Ruutu et al,17 1984 Helsinki, 8 All with recurrent infections, 7 repeated 3 7 1
Finland otitis media, 1 gluteal abscess,
3 pneumonia (including the 1 patient
without otitis media), 1 purulent
conjunctivitis and otitis media pyoderma
Ginzberg et al,8 1999 Toronto, 88 Unclear how many total infectious Staphylococcus 21 18 14
Canada complications, 18 with recurrent sinusitis, aureus,
otitis media or both, 21 with lower Haemophilus
respiratory tract infection, 1 with UTI, influenza, E.
14 “deep tissue infections” including 6 coli, Klebsiella,
septicemia, 3 oral cellulitis/dental abscess, Pseudomonas
1 osteomyelitis, 3 abscesses, 1 aeruginosa,
Staphylococcus skin infection, 7 fever of Shigella
unknown origin, 1 shigellosis
Cipolli et al,10 1999 Verona, 13 5 without infectious complications, 5 with S. aureus, H. 3 5
Italy recurrent otitis media, 3 with bacterial influenza, P.
pneumonia, 1 presumed CMV aeruginosa (all
pneumonitis, 2 recurrent UTIs in patients with
pneumonia)
Total 153 50 (33)* 45 (29) 24 (16)
Infectious complications
mentioned but
insufficient data
for tabulation
Saunders et al,25 Toronto, 10 Multiple infections, including pneumonia,
1979 Canada otitis media, sinusitis, osteomyelitis,
UTIs, lymphadenitis, skin infections and
infections of surgical incisions
Aggett et al,18 1979 London, 14 11 with “recurrent and severe infections
U.K. requiring hospital care”
21
Smith et al, 1996 London, 21 All with “severe bacterial infections”
U.K.
3
Mack et al, 1996 Toronto, 25 19 with recurrent minor infections (otitis
Canada media, tonsillitis or pharyngitis), 14 (of
these 19) with “deep tissue infections,”
including pneumonia, abscesses, sepsis,
osteomyelitis and/or septic arthritis; 2 (of
the 19) died of sepsis
Dror et al,19 2001 Toronto, 14 6 with recurrent URIs, gastroenteritis and
Canada short episodes of unexplained fever,
7 with recurrent bacterial infections,
including otitis media and pneumonia
Cunningham et al.,28 Dundee, 9 6 with no infectious complications, 2 with
2002 U.K. recurrent infections, 2 with respiratory
infections
Stepanovic et al,22 Iowa City, 14 14 with recurrent infections, 11 with severe
2004 IA infections (including cellulitis, pneumonia
and bacteremia, requiring intravenous
antibiotic therapy)
*Numbers in parentheses, percent.
UTI indicates urinary tract infection; CMV, cytomegalovirus; URI, upper respiratory tract infection.

180 © 2005 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
4. Dror Y, Freedman MH. Shwachman-Diamond syndrome. Br J Haema-
tol. 2002;118:701–713.
5. Smith OP. Shwachman-Diamond syndrome. Semin Hematol. 2002;39:
95–102.
6. Rothbaum R, Perrault J, Vlachos A, et al. Shwachman-Diamond syndrome:
report from an international conference. J Pediatr. 2002;141:266 –270.
7. Burke V, Colebatch JH, Anderson CM, Simons MJ. Association of
pancreatic insufficiency and chronic neutropenia in childhood. Arch Dis
Child. 1967;42:147–157.
8. Ginzberg H, Shin J, Ellis L, et al. Shwachman syndrome: phenotypic
manifestations of sibling sets and isolated cases in a large patient cohort
are similar. J Pediatr. 1999;135:81– 88.
9. Aggett PJ, Cavanagh NP, Matthew DJ, Pincott JR, Sutcliffe J, Harries
JT. Shwachman’s syndrome: a review of 21 cases. Arch Dis Child.
1980;55:331–347.
10. Cipolli M, D’Orazio C, Delmarco A, Marchesini C, Miano A, Mastella
G. Shwachman’s syndrome: pathomorphosis and long-term outcome.
J Pediatr Gastroenterol Nutr. 1999;29:265–272.
11. Launiala K, Furuhjelm U, Hjelt L, Visakorpi JK. A syndrome with
pancreatic achylia and granulocytopenia. Acta Paediatr Scand. 1967;
177(suppl):28 –29.
12. Strevens MJ, Lilleyman JS, Williams RB. Shwachman’s syndrome and
acute lymphoblastic leukaemia. Br Med J. 1978;2:18.
13. Danks DM, Haslam R, Mayne V, Kaufmann HJ, Holtzapple PG.
Metaphyseal chondrodysplasia, neutropenia, and pancreatic insuffi-
ciency presenting with respiratory distress in the neonatal period. Arch
Dis Child. 1976;51:697–702.
14. Dokal I, Rule S, Chen F, Potter M, Goldman J. Adult onset of acute
myeloid leukaemia (M6) in patients with Shwachman-Diamond syn-
drome. Br J Haematol. 1997;99:171–173.
15. Miniero R, Dalponte S, Linari A, Saracco P, Testa A, Musiani M. Severe
Shwachman-Diamond syndrome and invasive parvovirus B19 infection.
Pediatr Hematol Oncol. 1996;13:555–561.
16. Ballow M, O’Neal KM. Approach to the patient with recurrent infec-
tions. In: Middleton E, ed. Allergy: Principles and Practice. 5th ed. St.
Louis, MO: Mosby; 1998:1249 –1329.
17. Ruutu P, Savilahti E, Repo H, Kosunen TU. Constant defect in neutro-
phil locomotion but with age decreasing susceptibility to infection in
Shwachman syndrome. Clin Exp Immunol. 1984;57:249 –255.
18. Aggett PJ, Harries JT, Harvey BA, Soothill JF. An inherited defect of
neutrophil mobility in Shwachman syndrome. J Pediatr. 1979;94:391–394.
19. Dror Y, Ginzberg H, Dalal I, et al. Immune function in patients with
Shwachman-Diamond syndrome. Br J Haematol. 2001;114:712–717.
20. Repo H, Savilahti E, Leirisalo-Repo M. Aberrant phagocyte function in
Shwachman syndrome. Clin Exp Immunol. 1987;69:204 –212.
21. Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological
abnormalities in Shwachman-Diamond syndrome. Br J Haematol. 1996;
94:279 –284.
22. Stepanovic V, Wessels D, Goldman FD, Geiger J, Soll DR. The
chemotaxis defect of Shwachman-Diamond syndrome leukocytes. Cell
Motil Cytoskeleton. 2004;57:158 –174.
23. Azzará A, Carulli G, Ceccarelli M, Pucci C, Raggio R, Ambrogi F. In
vivo effectiveness of lithium on impaired neutrophil chemotaxis in
Shwachman-Diamond syndrome. Acta Haematol. 1991;85:100 –102.
24. Szüts P, Katona Z, Ilyes M, Szabo I, Csato M. Correction of defective
chemotaxis with thiamine in Shwachman-Diamond syndrome. Lancet.
1984;1:1072–1073.
25. Saunders EF, Gall G, Freedman MH. Granulopoiesis in Shwachman’s
syndrome (pancreatic insufficiency and bone marrow dysfunction). Pe-
diatrics. 1979;64:515–519.
26. Sacchi F, Maggiore G, Marseglia G, Marconi M, Nespoli L, Siccardi
AG. Association of neutrophil and complement defects in two twins with
Shwachman syndrome. Helv Paediatr Acta. 1982;37:177–181.
27. Nakashima E, Mabuchi A, Makita Y, et al. Novel SBDS mutations
caused by gene conversion in Japanese patients with Shwachman-
Diamond syndrome. Hum Genet. 2004;114:345–348.
28. Cunningham J, Sales M, Pearce A, et al. Does isochromosome 7q
mandate bone marrow transplant in children with Shwachman-Diamond
syndrome? Br J Haematol. 2002;119:1062–1069.
© 2005 Lippincott Williams & Wilkins
S. maltophilia Necrotizing Gingivitis
ACUTE NECROTIZING ULCERATIVE GINGIVITIS
AND BACTEREMIA CAUSED BY
STENOTROPHOMONAS MALTOPHILIA IN AN
IMMUNOCOMPROMISED HOST
Isao Miyairi, MD,*§ Jeremy A. Franklin, MD,*§
Martin Andreansky, MD, PhD,‡§ Katherine M. Knapp, MD,*§
and Randall T. Hayden, MD†
Abstract: An 8-year-old girl with leukemia developed acute necro-
tizing ulcerative gingivitis with Stenotrophomonas maltophilia and
herpes simplex virus. Progression to bacteremia with pathologic
evidence of osteomyelitis occurred despite appropriate antimicrobial
therapy. This case highlights the importance of prompt recognition,
debridement and appropriate therapy in immunocompromised pa-
tients with acute necrotizing ulcerative gingivitis.
Key Words: acute necrotizing ulcerative gingivitis,
Stenotrophomonas maltophilia, osteomyelitis, herpes simplex
virus, immunocompromised
Accepted for publication September 2, 2004.
From the Departments of *Infectious Diseases, †Pathology and ‡Hematol-
ogy-Oncology, St. Jude Children’s Research Hospital, and the §Depart-
ment of Pediatrics, University of Tennessee Health Science Center,
Memphis, TN
Supported by National Cancer Institute Cancer Center Support CORE grant
P30 CA 21765 and the American Lebanese Syrian Associated Charities.
Address for reprints: Isao Miyairi, MD, Department of Infectious Diseases,
St Jude Children’s Research Hospital, 332 North Lauderdale, Memphis,
TN 38105-2794. Fax 901-495-3099; E-mail Isao.Miyairi@stjude.org.
DOI: 10.1097/01.inf.0000151038.82538.de
A cute necrotizing ulcerative gingivitis (ANUG) is an inflamma-
tory process of the oral cavity characterized by ulceration of the
oral papillae, pain, bleeding and pseudomembranous necrotic exu-
date formation along the margins of the gingiva. It is an important
cause of morbidity in immunocompromised1 and malnourished
patients.2 It is also a significant predisposing condition to noma, an
infectious disease that destroys the orofacial and neighboring tissues
and is associated with mortality as high as 70 –90%.2 A multifacto-
rial pathogenesis has been proposed for ANUG. Alteration of
systemic immunity by nutritional deficiency or chemotherapy cou-
pled with alterations in local immunity by viral infection or disrup-
tion of the oral mucosa by cytotoxic chemotherapy may allow
selective growth of a range of pathogenic bacteria.2 Fusobacterium3
and spirochete4 infection have been implicated in healthy hosts,
whereas the microbiology of immunocompromised hosts is less
well-understood.
We present a patient with acute lymphocytic leukemia (ALL)
who developed ANUG associated with herpes simplex virus (HSV),
together with histopathologic and microbiologic evidence of
Stenotrophomonas maltophilia infection. The patient subsequently
developed invasive disease with bacteremia and osteomyelitis
caused by S. maltophilia. The latter is increasingly being recognized
as an important nosocomial pathogen in debilitated patients.5 To our
knowledge, this is the first reported case of ANUG associated with
S. maltophilia. This study was approved by the internal review
board.
CASE REPORT
The patient is an 8-year-old girl with precursor B cell ALL
diagnosed 4 years before admission. The patient achieved prompt
remission and completed standard risk chemotherapy (FRALLE
181
Miyairi et al The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
protocol6); however, she experienced a relapse of ALL 1 year before
admission. The patient responded to reinduction and remained in
remission throughout intensification therapy. Two months before the
present admission, a second relapse was confirmed and the patient
was treated with fludarabine, Ara-C and granulocyte colony-stimu-
lating factor.
Three weeks before admission, the patient developed a right
subclavian subcutaneous port infection with a waxing and waning
course treated with teicoplanin until she was transferred to our
facility for possible bone marrow transplantation. On admission, the
patient was febrile and neutropenic with swelling and tenderness
over the port site; the antibiotic regimen was changed to vancomycin
and meropenem. The port was removed on hospital day 3, and
culture of the port grew Pseudomonas aeruginosa. Based on culture
results, tobramycin was added to the regimen. The patient remained
febrile and 2 days later developed left jaw pain with mild gingival
erythema and a 2- to 3-mm gingival ulcer. Her leukocyte count was
600/mm3 with an absolute neutrophil count of 0. On hospital day 7,
direct fluorescent antibody assay of the oral ulcer and culture of
nares revealed herpes simplex virus; acyclovir was started. Plaque
reduction testing of the isolate demonstrated a dose inhibitory to
50% growth for acyclovir of ⬍0.25 ␮g/mL. Concomitant cultures
from the ulcer grew S. maltophilia, as did consecutive blood cultures
drawn on hospital days 8 and 9. Intravenous trimethoprim-sulfame-
thoxazole treatment was started on hospital day 10. The patient
remained febrile, and cultures drawn on hospital days 10, 11 and 12
remained positive for S. maltophilia. Agar dilution-based suscepti-
bility S. maltophilia isolate from a peripheral blood culture showed
susceptibility to only amikacin, ticarcillin/clavulanic acid, ceftazi-
dime and cefepime and intermediate susceptibility to levofloxacin.
On hospital day 12, antibiotic coverage was changed to
amikacin and ticarcillin/clavulanic acid based on susceptibility test-
ing results. Blood cultures subsequently became negative; however,
the patient continued to have high fevers (ⱖ39.5°C) and increasing
jaw pain; the ulcer grew to 4 mm in width and ⬃3 cm in length,
lining the inner margin of the gingiva and extending from the region
of the left canine to the left second molar. It was covered with a
brown-black pseudomembrane which occasionally dislodged and
caused bleeding. By hospital day 20, the surrounding soft tissue of
the palate was markedly indurated. Computerized tomography of the
neck and sinus revealed left maxillary sinus opacification, soft tissue
swelling of the hard palate, bony involvement of the hard palate and
cervical lymphadenopathy. The patient’s primary canine and first
and second molars were extracted, and the surrounding necrotic
tissue was debrided under general anesthesia.
Histopathologic examination of the debrided specimen
showed fibrous tissue, bone and necrotic material. Tissue Gram stain
revealed abundant Gram-negative rod-like organisms, scattered and
in broad sheets. Immunohistochemical stains for herpes simplex
virus were negative. Cultures taken from the surgical specimen grew
S. maltophilia and rare Enterococcus faecalis. Viral cultures from
this material were negative. Antimicrobial therapy and local care
were continued with improvement of the oral lesion and jaw pain.
The leukemia progressed despite chemotherapy, and the patient died
2 months later.
DISCUSSION
This is the first reported case of ANUG associated with S.
maltophilia, offering insights into both disease pathogenesis and
appropriate treatment.
Multiple reports have shown the presence of viruses (primar-
ily herpesviridae) in patients with ANUG.3,7 Polymerase chain
reaction has been used to document the presence of cytomegalovi-
182
rus, Epstein-Barr virus, HSV, human herpesvirus-6 in patients with
ANUG.8 The presence of HSV in this case supports the thesis that
infection by HSV predisposes to superinfection or adherence by
bacteria.2 HSV was not seen in tissue obtained at the time of the
debridement after 3 weeks of effective antiviral therapy with acy-
clovir.
Histopathologic evidence of bacterial overgrowth by Fuso-
bacterium sp.3 and identification of Treponema pallidum4 in ANUG
plaques have been shown as evidence of bacterial pathogenesis in
ANUG in healthy patients. Much less is known about the pathoge-
netic role of bacteria in immunocompromised patients with ANUG.
A review of ANUG cases in the pediatric cancer patient population
identified chemotherapeutic induction, primary disease relapse and
neutropenia as risk factors for the development of ANUG. Reports
have documented the presence of P. aeruginosa in oral lesions
associated with ANUG.7,9 However, a direct role of bacteria in
disease pathogenesis remains to be proved in immunocompromised
patients. Our case provides histopathologic evidence of S. malto-
philia infection and suggests that such opportunistic bacteria can
play a significant role in the pathogenesis of ANUG in immuno-
compromised patients.
Few studies have examined the prevalence of human coloni-
zation with S. maltophilia; however, alteration of the oral microflora
resulting both from changes in the mucosal epithelium and to
antimicrobial selective pressure may predispose immunocompro-
mised patients to colonization. Bacteremia associated with central
venous catheters is a common manifestation of infection with this
organism, but a wide variety of infections have been seen.5 Muco-
cutaneous lesions manifesting as ecthyma gangrenosum and stoma-
titis have also been linked to S. maltophilia.10 Although this is the
first report of ANUG associated with S. maltophilia, culture of oral
mucosal tissues is not routinely performed; the presence of this
organism may therefore be underappreciated. S. maltophilia bone
and joint infections are uncommon and, when reported, have been
related to orthopedic surgery or trauma. The invasive nature of
disease in our case mimics the progression of ANUG to noma
observed in the presence of pathogenic bacteria (eg, Fusobacterium
necrophorum).2 Although S. maltophilia is usually considered to be
an organism of low pathogenicity, the present case should heighten
the recognition of this organism as a potential orodental pathogen in
immunocompromised patients. Further studies are needed to dem-
onstrate the significance of oral colonization by S. maltophilia in the
development of invasive disease.
Therapy for ANUG consists of antibiotic therapy and local
wound care. Prompt response is generally the rule in healthy hosts.
Delayed or incomplete response is common in the immunocompro-
mised host because of poor tissue healing and effects of cytotoxic
medication. However, this case suggests that altered oral flora,
particularly multidrug-resistant bacterial species, can play a role in
this population. Such consideration is critical in the choice of
antibiotic coverage and underscores the importance of obtaining
adequate culture material. Although ANUG is a disease limited to
the gingiva, this case of ANUG caused by a trimethoprim-sulfame-
thoxazole-resistant S. maltophilia isolate highlights the possibility
for dissemination of invasive disease. Surgical removal of infected
and necrotic tissue may have altered the course of disease. Prompt
recognition of the condition and aggressive therapy including dental
extraction and debridement should be considered in immunocom-
promised hosts.
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FAILURE OF SERIAL HUMAN IMMUNODEFICIENCY
VIRUS TYPE 1 DNA POLYMERASE CHAIN
REACTIONS TO IDENTIFY HUMAN
IMMUNODEFICIENCY VIRUS TYPE 1 CLADE A/G
Stephen K. Obaro, MD, Phyllis Losikoff, MD, MPH,
Joseph Harwell, MD, and David Pugatch, MD
Abstract: The most commonly used test to screen for human
immunodeficiency virus type 1 (HIV-1) infection in HIV-exposed
infants in the United States is HIV-1 qualitative DNA polymerase
chain reaction (PCR). However, the commercially available HIV-1
DNA PCR lack optimal sensitivity to detect non-subtype B subtypes
of HIV-1. We report here HIV-1 infection in a West African infant
that went undetected by serial HIV-1 DNA PCR tests.
Accepted for publication September 8, 2004.
From the Division of Pediatric Infectious Diseases, Brown Medical School,
Rhode Island Hospital, Providence, RI
Reprints not available.
DOI: 10.1097/01.inf.0000151040.57772.40
CASE
T he patient is a male infant born to a 16-year-old Liberian
primiparous woman who emigrated to the United States from a
refugee camp in Ghana, 1.5 years before this pregnancy. The mother
was diagnosed with human immunodeficiency virus (HIV) infection
by routine screening during the second trimester of pregnancy. The
mother had no prior hospitalizations or known illness. She denied
intravenous drug use or known HIV-positive contacts and reported
2 lifetime sexual partners. The father of this child is West African.
At 26 weeks gestation, the mother had an HIV-1 RNA plasma
viral load of 5149 copies/ml (HIV-1 RNA; bDNA Bayer version
3.0) and an absolute CD4 count of 0.351 K/␮L (24%). At that time,
she was hepatitis B surface and core antibody-positive, rapid plasma
reagin-unreactive and rubella-immune; and urine was negative for
Chlamydia and gonorrhea by ligase chain reaction. She was pre-
scribed twice daily Trizivir (abacavir sulfate, lamivudine and
© 2005 Lippincott Williams & Wilkins
HIV-1 PCRs
zidovudine). At 37 weeks gestation, 5 weeks after starting antiret-
roviral therapy, a repeat HIV-1 RNA viral load was 5438 copies/mL,
and absolute CD4 count was 0.248 K/␮L (16.5%). These results
raised the concern of possible drug resistance or nonadherence, and
her medication was empirically changed to stavudine, nelfinavir and
lamivudine. An HIV-1 resistance genotype test subsequently dem-
onstrated that the virus contained no identifiable mutations confer-
ring resistance to any antiretroviral medications.
The infant was delivered by elective caesarian section at 39
weeks gestation. The mother received a loading dose of intravenous
zidovudine followed by maintenance during the procedure. There
was no premature rupture of membranes and the operative delivery
was uneventful.
At delivery, the infant weighed 3250 g and appeared well.
Treatment with zidovudine and lamivudine therapy was begun
within 8 hours of delivery, and his initial HIV-1 qualitative DNA
polymerase chain reaction (PCR; Amplicor; Roche) was negative.
Lamivudine was discontinued after 48 hours once the results of the
mother’s resistance genotype were known. The mother was advised
not to breast-feed and was counseled regarding the administration of
zidovudine. She did not attend a follow-up visit scheduled at 4
weeks.
The infant was seen at 7 weeks of age, and there were no
acute clinical concerns. At that time, a second HIV-1 DNA PCR was
requested, and, as is standard practice, the zidovudine was stopped,
and the infant was prescribed trimethoprim-sulfamethoxazole at 150
mg/m2 body surface area 3 consecutive days weekly.
By age 4 months, the infant had 3 negative HIV-1 qualitative
DNA PCR tests. He was clinically well, trimethoprim-sulfamethox-
azole was discontinued and he was scheduled to return for HIV-1
antibody testing at 18 months. The infant was seen at 20 month of
age with a normal physical examination, except for shotty cervical
and axillary lymph nodes. The mother denied breast-feeding the
infant. His HIV-1 enzyme-linked immunosorbent assay and Western
blot test was still reactive. A repeat HIV-1 qualitative DNA PCR
was still negative; however, quantitative viral load by HIV-1 RNA
PCR was 750,000 copies/mL (Amplicor HIV-1 MONITOR version
1.0; Roche), CD4⫹ T lymphocyte count was 19.5% and absolute
count was 0.663 K/␮L. The infant was prescribed antiretroviral
therapy, zidovudine, abacavir, lamivudine and lopinavir/ritonavir.
Subtype analysis, genotypic and phenotypic drug resistance tests
identified the infant’s virus as HIV-1 subtype A/G with no identi-
fiable genetic mutations conferring resistance to antiretroviral med-
ications. Compliance with treatment in this infant has not been
optimal and at 30 months of age, although he is clinically stable, he
has a viral load of 202,358 HIV-1 RNA copies/mL and absolute
CD4 count of 0.719 K/␮L (21.8%).
DISCUSSION
Diagnosis of HIV infection in early infancy generally relies
on detection of HIV proviral DNA by PCR.1 Our patient was
diagnosed with HIV-1 acquired by vertical transmission after per-
sistently negative HIV-1 DNA PCR results. The infant, of West
African descent, had HIV-1 clade A/G virus, which was not detected
by serial HIV-1 qualitative DNA PCR.
In 1997, Barlow et al2 published a review of 22 cases of false
negative HIV-1 DNA PCR in infants of infected mothers, which
consisted of subtypes A, B, C, D and G. Subsequently there have
been more reports of non-clade B infection that were not detected by
HIV-1 qualitative DNA-PCR.3,4 This case with a clade A/G recom-
binant virus emphasizes the changing epidemiology of HIV in the
United States and the need for practitioners to be cautious with
interpretation of HIV-1 DNA PCR-negative results in persons from
183
Sawardekar The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
regions where non-subtype B HIVs are prevalent. Such recombinant
viral forms may have implications for disease diagnosis and man-
agement.5 Recent data suggest that non-B subtypes may be less
susceptible to all classes of antiretroviral therapy and may develop
drug resistance more rapidly once exposed to highly active antiret-
roviral therapy.6 At the time of this infant’s diagnosis, the prevailing
guidelines on management of HIV-exposed infants did not address
the problem with false negative HIV-1 DNA PCR in non-B subtype
HIV infections.7 However, the current guidelines in the United
States recommend8 repeat testing with one of the newer HIV-1 RNA
amplification assays, when non-B subtype infection is likely. Al-
though the newer HIV-1 RNA PCR assays have improved sensitiv-
ity for detecting non-B subtype virus 关eg, Nuclisens HIV-1 qb or
quantiplex HIV-RNA 3.0 (bDNA) or Ampliclor HIV-1 MONITOR
version 1.5兴,9,10 these assays may not detect some non-B subtypes,
particularly group O HIV strains.11 The impact of false negative
HIV tests may likely increase with increasing numbers of immi-
grants from regions where non-subtype B HIV infection is prevalent.
Increasing recombinant forms of the virus may warrant continuous
revision of the primers used for PCR assays or adoption of the more
practical approach of parallel testing of infant and mother plasma for
HIV virus amplification by PCR, as is currently recommended in the
United Kingdom.12
REFERENCES
1. Dunn DT, Brandt CD, Kirvine A, et al. Sensitivity of HIV-1 DNA
polymerase chain reaction in the neonatal period and the relative con-
tributions of intra-uterine and intra-partum transmission. AIDS. 1995;9:
F7–F11.
2. Barlow KL, Tosswill JHC, Parry JV, Clewley JP. Performance of the
Amplicor human immunodeficiency virus type 1 PCR and analysis of
specimens with type 1 PCR with false-negative results. J Clin Microbiol.
1997;35:2846 –2853.
3. Haas J, Geiss M, Bohler T. False-negative polymerase chain reaction-
based diagnosis of human immunodeficiency virus type 1 in children
infected with HIV strains of African origin. J Infect Dis. 1996;174:244 –
245.
4. Kline NE, Schwarwald H, Kline MW. False negative DNA polymerase
chain reaction in an infant with subtype C HIV-1 infection. Pediatr
Infect Dis J. 2002;21:885– 886.
5. Zaman MM, Recco RA, Haag R. Infection with non-B subtype HIV type
1 complicates management of established infection in adult patients and
diagnosis of infection in newborn infants. Clin Infect Dis. 2002;34:417–
418.
6. Spira S. Impact of clade diversity on HIV-1 virulence, antiretroviral drug
sensitivity, and drug resistance. J Antimicrob Chemother. 2003;51:229 –
240.
7. Guidelines for the use of antiretroviral agents in pediatric HIV infection.
Available at: http://AIDSinfo.nih.gov. Accessed Dec 14, 2001.
8. Guidelines for the use of antiretroviral agents in pediatric HIV infection.
Available at: http://AIDSinfo.nih.gov. Accessed Jan 20, 2004.
9. Antunes R, Figueiredo S, Bartolo I, et al. Evaluation of the clinical
sensitivities of three viral load assays with plasma samples from a
pediatric population predominantly infected with human immunodefi-
ciency virus type 1 subtype G and BG recombinant forms. J Clin
Microbiol. 2003;41:3361–3367.
10. Plantier JC, Gueudin M, Damond F, Braun J, Mauclere P, Simon F.
Plasma RNA quantification and HIV-1 divergent strains. J Acquir
Immune Defic Syndr. 2003;33:1–7.
11. Geelen S, Lange J, Borleffs J, Wolfs T, Weersink A, Schuurman R.
Failure to detect a non-B HIV-1 subtype by the HIV-1 Amplicor
Monitor test, version 1.5: a case of unexpected vertical transmission.
AIDS. 2003;17:781–782.
12. Lyall EGH, Blott M, de Ruiter A, et al. Guidelines for the management
of HIV infection in pregnant women and the prevention of mother-to-
child transmission. HIV Med. 2001;2:314 –334.
184
SHIGELLOSIS CAUSED BY SHIGELLA BOYDII IN A
PRETERM NEONATE, MASQUERADING AS
NECROTIZING ENTEROCOLITIS
Kiran P. Sawardekar, MD, MRCPCH
Abstract: A rare case of neonatal shigellosis caused by Shigella
boydii in a preterm neonate, severe enough to necessitate intensive
care support, is presented. The roles of breast-feeding, hand-washing
and surveillance for enteric infections in the prevention of shigello-
sis in low risk settings such as a special care baby unit are
highlighted.
Key Words: shigellosis, necrotizing enterocolitis, neonate,
Shigella boydii
Accepted for publication September 14, 2004.
From the Special Care Baby Unit, Department of Pediatrics, Nizwa Hospital,
Sultanate of Oman
Reprints not available.
DOI: 10.1097/01.inf.0000151043.77959.b6
S higellosis among neonates is an uncommon condition.1,2 In the
developed world, one-half of the described cases of neonatal
shigellosis occur as a result of periparturient transmission among
term neonates during the early neonatal period.3 In contrast, the
condition is often reported from developing countries with poor
sanitary standards and overcrowding, occurring among bottle-fed
neonates receiving formula feedings during the late neonatal peri-
od.4 However, shigellosis among preterm neonates in a special care
baby unit (SCBU) with stringent infection control practices is
extremely rare.
The severity and complication rates of shigellosis among
neonates, especially preterm infants, could be devastating. Neonatal
shigellosis may mimic necrotizing enterocolitis or sepsis. Cases of
severe neonatal shigellosis are caused most often by Shigella sonnei
or less commonly by Shigella flexneri,5 with Shigella boydii being
the least common strain. The impact of a community outbreak of
Shigella infection on breach of infection control barriers in a SCBU
has not been reported previously. I report a case of shigellosis
caused by S. boydii in a preterm neonate in an SCBU and analyze its
implications for infection control.
CASE REPORT
The SCBU of Nizwa Hospital is a regional neonatal referral
unit for the Al-Dakhliya region of Oman (population, 265,000). A
male, preterm, growth-restricted neonate with an estimated gesta-
tional age of 35 weeks and a birth weight of 1575 g was admitted to
the SCBU in October 2002. The mother was a 20-year-old primi-
gravida from the Bedouin tribe who had experienced antepartum
hemorrhage. The neonate had respiratory distress, systemic hypo-
tension and apnea of prematurity, which resolved by the third
postnatal day. An isolated, 4-mm, ostium secundum, atrial septal
defect was an incidental finding on an echocardiogram performed to
evaluate a murmur. Toxoplasma, rubella and cytomegalovirus
screening and chromosomal analysis results were normal. The infant
was fed expressed breast milk through gavage because of an imma-
ture suck, but he progressed to full feeding by the 12th postnatal day
and was thriving well.
On the 20th postnatal day, the infant suddenly developed
abdominal distension, feeding intolerance, temperature instability
and frequent prolonged apneic episodes, with subsequent develop-
ment of clonic seizures. An arterial blood gas analysis revealed
mixed respiratory and metabolic acidosis. A preliminary diagnosis
© 2005 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
of late onset sepsis or necrotizing enterocolitis was made, and
appropriate cultures and investigations were undertaken. Antimicro-
bial therapy with broad spectrum antibiotics was started, with
anticonvulsant administration and respiratory support. The complete
blood cell count, blood chemistry assay, coagulation profile and
chest radiograph results were normal. A stool examination revealed
occult blood, and an abdominal roentgenogram showed bowel wall
edema with colonic dilatation, without intramural gas. The follow-
ing day, the neonate passed several slimy stools with blood. A stool
culture yielded S. boydii. Blood and urine cultures did not reveal
growth. Cerebrospinal fluid analysis and culture results were nor-
mal. Computed tomographic scans of the brain did not reveal any
abnormality.
The neonate made an uneventful recovery. Respiratory sup-
port was discontinued after 48 hours and antimicrobial agents after
7 days of treatment. At the time of discharge from the SCBU on the
30th postnatal day, the neonate weighed 2072 g and was being
exclusively breast-fed. On inquiry, the mother reported that she had
experienced a diarrheal episode 1 week after delivery and 2 other
family members had experienced diarrhea 1 month before the illness
involving the neonate. The mother’s stool culture, obtained after
illness was suspected in the neonate, yielded negative results. No
medical or nursing staff members in the SCBU reported symptoms
consistent with Shigella infection during this period. Subsequent
follow-up monitoring of the infant for 1 year revealed that he was
thriving, with no neurodevelopmental sequelae.
With additional investigation, a study of stool isolates in the
Al-Dakhliya region revealed that there had been an increase of
Shigella infection in the latter half of the year 2002. A surge of
Shigella infection had also occurred in the latter half of the year
2000, and 2 cases of shigellosis, caused by S. sonnei and S. flexneri,
were observed among term neonates in the rooming-in wards during
the same period. Subsequently, our intensified surveillance for
neonatal shigellosis has resulted in no cases being reported in the
past 2 years from the SCBU or rooming-in wards.
DISCUSSION
Shigellosis among newborns presents as a diarrheic or dys-
enteric syndrome or may be evidenced only as a septic or toxic
neonate.1 Extraintestinal symptoms are an important feature of
shigellosis, especially during the initial period, and sometimes
precede the development of diarrhea.5
Of the 4 species of Shigella, bacteremia is rarely observed with
infections caused by S. boydii.6 In this context, shigellosis caused by S.
boydii in an exclusively breast-fed neonate is extremely rare, and this is
possibly the first such report for a preterm neonate in a SCBU.
I assume that the mother was the source of the baby’s infection
on the basis of clinical symptoms, because her stool culture did not
yield Shigella; this might have occurred because the stool specimen was
collected almost 10 days after the disappearance of the mother’s
symptoms. Inadequate hand-washing by the mother could have resulted
in contamination of the expressed breast milk fed to the neonate through
gavage. The local custom, in some tribes, of family members having
meals together on a large common platter could result in transmission
of Shigella among close contacts. Shigellosis is associated with a high
rate of secondary household transmission.5
The level of protection from shigellosis with breast-feeding is
a matter of scientific interest. Breast milk in disease-endemic areas
contains antibodies to both virulence plasmid-coded antigens and
lipopolysaccharides,7 which may partially explain the age-related
risk of acquiring the disease.5 The protection from infection pro-
vided by breast milk is provided by immunologic factors and,
through nonimmunologic mechanisms, by many components in
© 2005 Lippincott Williams & Wilkins
Relapsing Bacteremia
breast milk. Lactoferrin, a glycosylated protein in breast milk,
causes disruption of outer membrane virulence proteins required for
invasion (i.e. IpaB) and for intracellular and extracellular spread (i.e.
IcsA) of S. flexneri.7 Immunologic protection in disease-nonendemic
areas may be incomplete and species-specific.
Neonates with shigellosis can be a source of infection to other
neonates in the SCBU and to the unit staff. Awareness of the
infection, aggressive approach to diagnosis, early initiation of treat-
ment, emphasis on proper hand-washing and the use of gloves
continue to be the critical components of infection control mea-
sures.2 However, enteric isolation techniques may fail to check the
spread of shigellosis once it is established.8
ACKNOWLEDGMENTS
I thank the Medical Superintendent, Nizwa Hospital, for
permission to publish the case report; Professor Olufemi Jaiyesimi,
Head of the Department of Pediatrics, Nizwa Hospital, for critical
review of the manuscript; and Dr. Vibha Sachdeva, Specialist
Microbiology, Nizwa Hospital, for the data on regional stool iso-
lates.
REFERENCES
1. Haltalin KC. Neonatal shigellosis: report of 16 cases and review of the
literature. Am J Dis Child. 1967;114:603– 611.
2. Viner Y, Miron D, Gottfried E, Segal D, Luder A. Neonatal shigellosis.
Isr Med Assoc J. 2001;3:964 –966.
3. Neter E. Shigella sonnei infection at term and its transfer to the newborn.
Obstet Gynecol. 1961;17:517–519.
4. Bennish ML, Harris JR, Wojtyniak BJ, Struelens M. Death in shigellosis:
incidence and risk factors in hospitalized patients. J Infect Dis. 1990;161:
500 –506.
5. Gomez HF, Cleary TG. Shigella. In: Feigin RD, Cherry JD, eds. Textbook
of Pediatric Infectious Diseases. 4th ed. Philadelphia, PA: Saunders;
1998:1307–1317.
6. Martin T, Habbick BF, Nyssen J. Shigellosis with bacteremia: a report of
two cases and a review of the literature. Pediatr Infect Dis J. 1983;2:21–
26.
7. Cleary TG. Human milk feeding provides redundant protection from
bacillary dysentery. Pediatr Res. 1999;45:742.
8. Beers LM, Burke TL, Martin DB. Shigellosis occurring in newborn
nursery staff. Infect Control Hosp Epidemiol. 1989;10:147–149.
STAPHYLOCOCCUS AUREUS RELAPSING BACTEREMIA
ORIGINATING FROM ENDOVASCULAR THROMBI
Piet Leroy, MD,* Antonio Gavilanes, MD, PhD,†
Cees Vink, PhD,‡ and Jan Jacobs, MD, PhD‡
Abstract: Two infants presented with a recurrent methicillin-sus-
ceptible Staphylococcus aureus bacteremia occurring ⬎2 months
after the initial bacteremia. In both patients, clonal identity of the
successive Staphylococcus aureus isolates, confirmed by pulsed
field gel electrophoresis, pointed to relapsing bacteremia. Ultrasono-
graphically proved persistence of an endovascular thrombus was
considered as the focus of persistent infection in each case.
Key Words: Staphylococcus aureus, relapsing bacteremia,
thrombus
Accepted for publication September 14, 2004.
From the Divisions of *Pediatric Intensive Care, †Neonatal Intensive Care
and ‡Medical Microbiology, University Hospital Maastricht, Maastricht,
the Netherlands
Reprints not available.
DOI: 10.1097/01.inf.0000153175.77914.01
185
Leroy et al The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
S taphylococcus aureus is one of the most frequently recovered
organisms in bacteremia. Bacteremia with S. aureus is some-
times difficult to eradicate, and recurrent bacteremia is not uncom-
mon.1 In recurrent bacteremia, new infections must be distinguished
from relapsing infections that originate from a persistent infectious
focus. Unremoved foreign body, indwelling catheters 关eg, central
venous catheter (CVC), ventriculoperitoneal shunts兴, persistent deep
tissue infection 关eg, endocarditis, abscess, mediastinitis, osteomy-
elitis and meningitis兴, vancomycin therapy and hemodialysis are
well-defined risk factors for relapsing S. aureus bacteremia in
adults.2– 4
We observed 2 infants recently who developed consecutive
episodes of S. aureus bacteremia occurring ⬎2 months apart.
PATIENTS
Patient 1 was a premature girl (gestational age, 30 weeks;
birth weight, 700 g) who underwent at day 12 after birth a hemico-
lectomy with colostomy because of necrotizing enterocolitis. A first
episode of S. aureus bacteremia occurred at days 24, 25 and 26 after
birth. A CVC was identified as the portal of entry (growth of ⬎15
colonies of S. aureus from catheter tip culture). A CVC-related
thrombus in the inferior vena cava and right atrium was ultrasono-
graphically diagnosed. The CVC was removed, and the patient was
treated intravenously with flucloxacillin and rifampin for 3 weeks.
She did not receive anticoagulant treatment. Clinical recovery was
complete, and she had no infectious problem for the next 79 days. At
day 105 after birth, 1 week after surgical reconstruction of the colon,
a second episode of S. aureus bacteremia occurred. Clinically and
radiologically, there were again no signs of wound infection, skin
infection, arthritis, osteomyelitis, endocarditis, meningitis or ab-
scess. Surveillance cultures from the nose, throat, skin and perineum
showed no growth of S. aureus. Ultrasonography showed persis-
tence of the right atrial thrombus, which we considered to be the
likely focus of relapsing bacteremia. The patient was treated suc-
cessfully with flucloxacillin and rifampin for 6 weeks, administered
intravenously for the first 3 weeks.
Patient 2 was a newborn full term girl with esophageal atresia
for which surgical correction was performed at day 2 after birth. A
first episode of S. aureus bacteremia occurred at days 19 and 20 after
birth. There were clinically and radiologically no signs of wound
infection, skin infection, arthritis, osteomyelitis, endocarditis, men-
ingitis or abscess. A CVC-related intravascular thrombus occluding
the inferior vena cava was ultrasonographically diagnosed. The
CVC was removed. The patient was treated intravenously with
flucloxacillin and gentamicin for 5 days, followed by flucloxacillin
monotherapy for 8 days and subsequently vancomycin monotherapy
for 12 days. Flucloxacillin was replaced by vancomycin because of
bacteremia at day 25 with Staphylococcus epidermidis that was
flucloxacillin-resistant. Anticoagulant treatment consisted of heparin
intravenously followed by low molecular weight heparin subcuta-
nously. Clinical, hematologic and biochemical signs of infection
disappeared completely.
Because of severe tracheomalacia, she needed continuous
ventilatory support and tracheostomy. At day 95 after birth, after a
CVC-free interval of 75 days without infection, a second episode of
S. aureus bacteremia occurred. Clinically and radiologically, there
were no signs of any deep tissue infection. A culture recovered from
an endotracheal aspirate (tracheal cannula) was positive for S.
aureus. Surveillance cultures from the skin, nose and perineum
showed no growth of S. aureus. A persistent occluding thrombus of
the inferior vena cava was ultrasonographically demonstrated and
was considered to be the likely focus of relapsing bacteremia. The
patient was treated successfully with flucloxacillin and rifampin for
186
6 weeks. Between days 95 and 222, several blood cultures remained
sterile. Patient died at day 222 of respiratory failure. An autopsy was
not performed.
METHODS
Blood cultures were performed using BacTec PedsPlus/F bot-
tles that were incubated and continuously monitored in the BacTec
9240 system (Becton Dickinson Diagnostic Instrument Systems,
Maylan, France). Samples from positive flagged bottles were Gram-
stained and plated on standard microbiologic medium. Isolates were
identified by their Gram stain reaction, colony morphology and
positive reactions in the catalase and tube coagulase tests.
In both patients, the genetic relatedness of the successively
cultured S. aureus strains was assessed by pulsed field gel electro-
phoresis (PFGE) of genomic macrorestriction fragments. Chromo-
somal DNA of the S. aureus isolates was subjected to SmaI restric-
tion enzymes. The resulting fragments were separated by PFGE (ie,
electrophoresis during which the direction of the electric field in the
agarose gel is periodically changed). After staining with ethidium
bromide, PFGE patterns were compared and interpreted by estab-
lished guidelines.5,6
RESULTS
In both patients, the successive S. aureus isolates from the
first and second bacteremic episodes showed identical PFGE pat-
terns (Fig. 1), indicating the relapsing nature of the 2 recurrent
bacteremias.7 A different S. aureus strain recovered at day 97 from
a tracheal aspirate in patient 2 showed a distinct PFGE pattern. All
isolates were susceptible to methicillin, flucloxacillin, cefazolin,
erythromycin and gentamicin.
DISCUSSION
We describe 2 infants with recurrent episodes of S. aureus
bacteremia occurring, respectively, 79 and 75 days apart. In both
intervals, there were no clinical or bacteriologic signs of S. aureus
infection or colonization.
Recurrent bacteremia is defined as a bacteremia occurring
after appropriate therapy for a previous bacteremic episode and after
all signs and symptoms have resolved. Recurrent bacteremia can be
categorized as (1) relapsing (caused by the same strain) or (2)
reinfection (caused by a new strain or species).7 In our patients, the
results of PFGE patterns were consistent with relapse of an identical
S. aureus bacteremia.2,4
S. aureus bacteremia is rarely diagnosed in the absence of a
focus of infection.8 Because most S. aureus bacteremias are endog-
enous in origin and persistent S. aureus carriership for extended
periods is well-described, we cannot exclude for certain the theo-
retical possibility of same clone reinfection.9,10 Nevertheless in the
absence of any other potential focus, such as deep tissue infection or
foreign body, and given the absence of S. aureus colonization as
evidenced by surveillance cultures, clinical and microbiologic evi-
dence point to the persisting endovascular thrombus as the residual
focus of relapsing S. aureus bacteremia in each patient.
For these reasons, we presume that the endovascular throm-
bus was the focus of relapsing bacteremia in both patients. Patients
with suspected S. aureus-infected thrombi (ie, S. aureus bacteremia
in the presence of endovascular thrombi) may need prolonged
antibiotic treatment to prevent relapsing bacteremia. Unlike current
guidelines for catheter-related S. aureus bacteremia,11 but analo-
gously to the antibiotic treatment of infective endocarditis caused by
S. aureus,8 duration of an appropriate antibiotic treatment should be,
in our opinion, at least 6 weeks. Whether this advice can be extended
© 2005 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
FIGURE 1. A, PFGE patterns of blood cultures isolates (S.
aureus) in patient 1 on day 24 (lane 1), day 25 (lane 3), day 26
(lane 4) and day 105 (lane 5). Lane 2 is a control strain. B, PFGE
patterns of blood cultures isolates (S. aureus) in patient 2 on
day 19 (lane 1), day 20 (lane 2) and day 95 (lane 4). The S.
aureus strain recovered from a tracheal aspirate on day 97
(lane 3) shows a different banding pattern.
to all infected thrombi, irrespective of the causative microorganism,
remains uncertain.
The importance of additional anticoagulant therapy in the
prevention of thrombus-associated relapsing bacteremia is unclear.
One of the 2 patients had a relapsing bacteremia despite anticoag-
ulant therapy. Current guidelines for management of catheter-related
thrombosis in infants and children fail to provide well-supported
evidence for the potential additive effect of anticoagulant therapy in
treatment or prevention of thrombus associated bacteremia.12,13
REFERENCES
1. Esperson F, Fremodt-Miller N, Thamdrup Rosendal V, et al.
Staphylococcus aureus bacteremia in children below the age of one year:
a review of 407 cases. Acta Pediatr Scand. 1989;78:56 – 61.
© 2005 Lippincott Williams & Wilkins
Lymphopenia and HIV
2. Fowler V, Kong L, Corey GR, et al. Recurrent Staphylococcus aureus
bacteremia: pulsed-field gel electrophoresis findings in 29 patients.
J Infect Dis. 1999;179:1157–1161.
3. Jensen A, Wachmann C, Espersen F, et al. Treatment and outcome of
Staphylococcus aureus bacteremia: a prospective study of 278 cases.
Arch Intern Med. 2002;162:25–32.
4. Chang FY, Peacock JE, Musher DM, et al. Staphylococcus aureus
bacteremia: recurrence and impact of antibiotic treatment in a prospec-
tive multicenter study. Medicine (Baltimore). 2003;333–339.
5. Tenover C, Arbeit RD, Goering RV, et al. Interpreting chromosomal
DNA restriction produced by pulsed-field gel electrophoresis: criteria for
bacterial strain typing. J Clin Microbiol. 1995;33:2233–2239.
6. Bannerman T, Hancock G, Tenover C, et al. Pulsed-field gel electro-
phoresis as a replacement for bacteriophage typing of Staphylococcus
aureus. J Clin Microbiol. 1995;33:551–555.
7. Wendt C, Messer SA, Hollis J, et al. Recurrent Gram-negative bactere-
mia: incidence and clinical patterns. Clin Infect Dis. 1999;28:611– 617.
8. Sattler C, Correa A. Coagulase-positive staphylococcal infections
(Staphylococcus aureus). In: Feigin RD, Cherry JD, Demmler GJ,
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12. Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in
children. Chest. 2001;119:S344 –S370.
13. Journeycake JM, Buchanan GR. Thrombotic complications of central
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A NOVEL MUTATION IN THE INTERLEUKIN-2
RECEPTOR ␥ GENE AS THE CAUSE OF
LYMPHOPENIA IN A NEONATE VERTICALLY
EXPOSED TO HUMAN IMMUNODEFICIENCY VIRUS
Jennifer Neubert, MD,* Alfons Meindl, PhD,‡
Albert Theisen, MD,§ Ortwin Adams, MD,† Ansgar Schulz, MD,储
Oliver Feyen, PhD,* and Tim Niehues, MD*
Abstract: Perinatal transmission prophylaxis has led to a significant
reduction of vertical human immunodeficiency virus (HIV) infec-
tion. Antiretroviral drugs are being widely used before and during
pregnancy, although these drugs can have possible adverse effects
on the fetus and newborn. In this context, we report a unique case of
X-linked severe combined immunodeficiency in a neonate vertically
exposed to HIV.
Key Words: gene mutation, human immunodeficiency virus
infection, lymphopenia
Accepted for publication August 27, 2004.
From the *Division of Pediatrics and Rheumatology at the Childrens Hos-
pital and the †Department of Virology, Heinrich Heine University,
Duesseldorf, Germany; the ‡Institute for Human Genetics, Ludwig Maxi-
millians-University, Munich, Germany; §private practice of internal
medicine, Cologne, Germany; and 㛳Paediatric Immunology at the Chil-
drens Hospital University Ulm, Ulm, Germany
Reprints not available.
DOI: 10.1097/01.inf.0000148934.36915.5d
187
Neubert et al The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005

A ntiretroviral treatment as part of perinatal prophylaxis is now a

standard treatment of human immunodeficiency virus (HIV)-
infected pregnant women. Because of possible side effects, close
monitoring of children who are exposed to HIV and antiretroviral
treatment in utero is essential.1
CASE REPORT
In 1996, HIV was diagnosed in a 26-year-old woman origi-
nating from the Congo. At the time of diagnosis, her viral load was
⬍500 bDNA copies/mL (Quantiplex version 2.0; Chiron Corp.), and
the CD4 count was 26% (410 CD4 cells/␮L). Antiretroviral therapy
was initiated after diagnosis with zidovudine and lamivudine, and 1
year later nelfinavir was added to her treatment. With this therapy,
viral load was between ⬍50 bDNA copies/mL and 330 bDNA
copies/mL, and the CD4 count was stable. In 2001, antiretroviral
therapy was interrupted, and she became pregnant shortly thereafter.
During the entire pregnancy and at the time of birth, maternal viral
load was below detection limit (⬍50 bDNA copies/mL) (Quantiplex
version 3.0; Chiron Corp.).
At 31 weeks of gestation, antiretroviral therapy was started
intravenously. The neonate was treated with zidovudine orally for 6
weeks. The child was not breast-fed.
While on a routine visit at the age of 8 weeks, lymphocyte
subsets were analyzed by flow cytometry as a routine analysis in an
HIV-exposed child. Interestingly flow cytometry revealed T cell and
natural killer (NK) cell lymphopenia with absent CD3⫹CD4⫹,
CD3⫹CD8⫹ and CD3⫺CD56⫹ cells. B cells (CD20⫹) were present
(Fig. 1). IgG was 189 mg/dL, IgA ⬍5 mg/dL and IgM ⬍7 mg/dL;
lymphocytes failed to respond to phytohemagglutinin and OKT3
stimulation in a standard mitogen assay.
We first interpreted these findings as a result of vertical HIV
transmission despite prophylactic effort. However, there were no
signs of poor adherence, and HIV-DNA polymerase chain reaction
(PCR) for peripheral blood of the infant was repeatedly negative in
different laboratories. Because of muscle hypotonia and slight opis-
thotonus, lumbar puncture and cranial magnetic resonance imaging
were performed but did not reveal any abnormality. In addition,
HIV-DNA PCR of the cerebrospinal fluid was negative.
Moreover the immunologic phenotype of absent CD4⫹,
CD8 and CD56⫹ cells and hypogammaglobulinemia was consid-
⫹

with zidovudine and lamivudine to prevent mother-to-child HIV ered to be unusual for vertical HIV infection. Therefore we evalu-
transmission. Cesarean section was performed at 32 weeks of ated the child for a severe combined immunodeficiency (SCID) as
gestation because of eclampsia with hypertonia and edema. Before the cause of lymphopenia. Although the family history of this patient
and during the cesarean section, the mother received zidovudine was uneventful, molecular genetic examination in a blood sample of

FIGURE 1. Flow cytometry revealing

T cell and NK cell lymphopenia.
A–D, Flow cytometry plots of a pe-
ripheral blood sample gated on lym-
phocytes. In the right upper quad-
rant of A, there is an absence of
CD3⫹CD4⫹ cells. In the right upper
quadrant of B, there is an absence of
CD3⫹CD8⫹ cells. In the right upper
quadrant of C, there is a clear pop-
ulation of CD20⫹HLA-DR⫹ cells.
There are ⬍1% of CD3⫺CD56⫹ cells
in the left upper quadrant of D.
PERCP indicates peridinin chloro-
phyll protein; FITC, fluorescein iso-
thiocyanate; PE, phycoerythrin.

188 © 2005 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal • Volume 24, Number 2, February 2005
the child was performed and revealed X-linked SCID with a muta-
tion in the gene of the ␥ chain of the interleukin 2 receptor (IL2R␥).
A nucleotide substitution was found in exon 4 at position 594
(G3 A) leading to a stop codon at amino acid position 197. This
mutation has not been described for X-linked SCID before. Inter-
estingly the mutation could not be found heterozygously in his
mother.
The patient received T cell-depleted blood stem cell trans-
plantation (SCT) without conditioning at the age of 5 months. Apart
from gastroenteritis caused by rotavirus, the child did not have any
serious infections before SCT. Because the mother was HIV-posi-
tive, a sister of the mother served as the HLA-haploidentical donor.
The patient died of pneumonia of unknown cause 36 days
after SCT. No significant reconstitution of the T cell compartment
was observed until death. No postmortem studies or thymic tissue
analysis were done.
COMMENT
To our knowledge, this is the first report of X-linked SCID in
a child vertically exposed to HIV. X-linked SCID in the boy was
clearly demonstrated both by genetic analysis and by confirming the
typical B⫹T⫺NK⫺ immunophenotype. We wondered whether
the child had both primary immunodeficiency and HIV infection.
In the absence of CD4⫹ T cells, we tested other potential targets.
Neither neurons nor dendritic cells were infected, and PCR analysis
of cerebrospinal fluid and liver tissue were also negative for HIV. A
liver biopsy had been performed because of elevated transaminase
values. Thus it is very unlikely that the child was HIV-positive.
Because genetic analysis did not reveal the mutation in IL2R␥
gene of the mother, the mutation in this gene occurred either
© 2005 Lippincott Williams & Wilkins
Lymphopenia and HIV
spontaneously in the child or alternatively as the consequence of a
germline mosaic in his mother.
Antiretroviral treatment has been reported to be mutagenic in
monkeys exposed to such drugs in utero.2 There are also reports on
toxicity in human beings exposed to antiretroviral treatment in
utero.3
In the patient described in this study, toxicity during preg-
nancy as the cause for the mutation in the X-linked SCID gene
seems unlikely, because antiretroviral treatment was applied only
between 31 and 32 weeks of gestation, and at this stage lymphopoi-
esis has advanced considerably.
More likely, the occurrence of X-linked SCID and exposure
to HIV was merely coincidence; however, it cannot be entirely ruled
out that the HIV infection of the mother and the antiretroviral
treatment before pregnancy could have increased the risk for the
occurrence of a mutation in the ␥ chain of the IL2R.
REFERENCES
1. Public Health Service Task Force. Recommendations for use of antiret-
roviral drugs in pregnant HIV-1 infected women for maternal health and
interventions to reduce perinatal HIV-1 transmission in the United States.
February 4, 2002.
2. Olivero OA, Fernandez JJ, Antiochos BB, Wagner JL, Claire ME, Poirier
MC. Transplacental genotoxicity of combined antiretroviral nucleoside
analogue therapy in erythrocebus monkeys. J Acquir Immune Defic Syndr.
2002;29:323–329.
3. Sussmann HE, Olivero OA, Meng Q, et al. Genotoxicity of 3⬘-azido-3⬘-
deoxythymidine in the human lymphoblastoid cell line, TK&: relation-
ships between DNA incorporation, mutant frequency, and spectrum of
deletion mutations in HPRT. Mutat Res. 1999;429:249 –252.
189