Santa Clara Valley Medical Center
Inpatient Pediatric Wards/PICU Rotation
Teaching Module
Fever without a Source
A 22-day-old term male infant presents to the ER with a chief complaint of
fussiness and a 1-day history of poor feeding. He has only had 2 wet diapers
today. He was born at 38 weeks to a 26 yo G1P1 woman by NSVD with a
positive GBS screen. Rupture of membranes occurred 12 hours prior to
birth, and mother was given 4 doses of ampicillin before delivery.
On exam, his vitals are T 38.4 C, HR 190, RR 52, wt 4 kg. He is asleep in his
mother's arms when you enter the room. You note some crusted dry mucus
below his nose. Findings on physical exam are otherwise normal and his
capillary refill time is less than 2 seconds centrally.
Question 1:
What is the approximate risk of a serious bacterial infection in this age
group?
A) 2%
B) 12%
C) 37%
D) 48%
Question 2:
Which bacteria cause the majority of serious bacterial infections in infants
under 29 days of age?
A) GBS
B) Strep. pneumoniae
C) E. coli
D) Listeria monocytogenes
E) A, B, and C
F) A, C, and D
Question 3: What is the next recommended step in management?
A) Thorough physical exam, then discharge home if well-appearing infant
B) Physical exam, CBC, UA, then discharge home if normal
C) Physical exam, CBC, UA, Blood culture, then discharge home after dose of
ceftriaxone
D) Admission for CBC, UA/Urine culture, and CSF panel/culture and
antibiotics
(Answers on following page)
Suzanne Swanson Mendez, MD
Answer to Question 1:
B) 12%
("Fever without a Source in Children 0 to 36 Months of Age," by Dr.
Ishimine. See full reference below). However, some studies have found the
prevalence of SBI in this age group to range from 5-14%.
Answer to Question 2:
F) GBS, E. coli, and L. monocytogenes
"Neonates are at a particularly high risk of SBI. The majority of febrile
neonates presenting to the ED are diagnosed ultimately with a nonspecific
viral illness, but approximately 12% of all febrile neonates presenting to a
pediatric emergency department have serious bacterial illness. When they
are infected, neonates are infected typically by more virulent bacteria (eg,
Streptococci group B, E. coli, and Listeria monocytogenes) and are more
likely to develop serious sequelae from viral infections (eg, HSV meningitis).
Group B Streptococcus, a common bacterial pathogen in the age group, is
associated with high rates of meningitis (39%), non-meningeal foci of
infection (10%), and sepsis (7%). This age group is the least likely to be
affected by the use of the pneumococcal vaccine because only a small
percentage of neonates are infected by this pathogen. Although infection is
uncommon, those neonates who are infected with Strep pneumoniae have a
mortality rate of 14%. The most common bacterial infections in this age
group are UTIs and occult bacteremia." (from "Fever without a Source in
Children 0 to 36 Months of Age," by Dr. Ishimine. See full reference below).
Answer to Question 3:
D) Admission for CBC with differential, UA/Urine culture, and CSF
panel/culture with antibiotics
This is currently the standard recommended management for a febrile infant
less than 29 days old and is the guideline that we tend to follow at Valley,
however you may see a different practice in other settings.
"Traditional risk-stratification strategies have used ancillary testing to
supplement the limited information available from the history and physical
exam. Unfortunately, it is difficult to predict accurately which neonates have
invasive disease, even when laboratory testing is used....Chest radiographs
are indicated only in the presence of respiratory symptoms, and stool
analyses are indicated only in the presence of diarrhea." (from reference by
Dr. Ishimine, as listed below).
The different risk-stratification strategies include using the Rochester,
Philadelphia, and Boston criteria. The peripheral wbc count has been used by
many practitioners to determine whether to perform a lumbar puncture but
does not have reliable predictability for meningitis in this age group. Serial
Suzanne Swanson Mendez, MD
CRP's can be helpful in ruling out sepsis in this age group but the initial CRP
at the time of presentation may be falsely negative. (see Dr. Benitz
reference).
You initiate a sepsis evaluation that includes a CBC with differential, Blood
culture, C-reactive protein, urinalysis/urine culture by urethral
catheterization, and a lumbar puncture, and you arrange for admission for
suspected sepsis.
Question 4:
Which antibiotics are recommended for treatment of suspected serious
bacterial infection in this age group?
A) Ampicillin and gentamicin
B) Vancomycin and gentamicin
C) Ampicillin and ceftriaxone
D) Azithromycin
(Answer on next page)
Suzanne Swanson Mendez, MD
Answer to Question 4:
A) Ampicillin and gentamicin
According to Dr. Ishimine’s article, "Because of the high rates of serious
bacterial infections, all febrile neonates should receive antibiotics. Typically,
these patients are treated with a third-generation cephalosporin or
gentamicin. Ceftriaxone is not recommended for neonates who have
jaundice because of the concern for inducing unconjugated
hyperbilirubinemia. Other third-generation cephalosporins, such as
cefotaxime, or gentamicin are used in this age group. Additionally, although
the incidence of L monocytogenes is quite low, ampicillin is still
recommended in the empiric treatment of these patients.
Neonatal herpes simplex virus infections occur in approximately 1 per 3200
deliveries in the U.S. Neonates with HSV infections usually present within
the first 2 weeks of life, and only a minority of infected children have fever.
Rates of morbidity and mortality are high with neonatal HSV, but treatment
with high-dose acyclovir improves outcomes in patients. Acyclovir is not
recommended routinely for empiric treatment in addition to standard
antibiotics in febrile infants but should be considered in febrile infants with
risk factors for neonatal HSV. Risk factors include primary maternal
infection, especially those infants delivered vaginally, prolonged rupture of
membranes at delivery, the use of fetal scalp electrodes, skin, eye, or mouth
lesions, seizures, and CSF pleocytosis.”
“Febrile neonates should be hospitalized, regardless of the results of
laboratory studies. Outpatient management of these patients has been
suggested and occurs frequently when patients present to pediatricians'
offices. However, given the lack of prospective studies addressing this
approach as well as the limitations inherent in the screening evaluation in the
emergency department and frequent difficulties in arranging follow-up
evaluation, hospitalization is strongly recommended." (from "Fever without a
Source in Children 0 to 36 Months of Age," by Dr. Ishimine. See full
reference below).
However, a recent meta-analysis suggests that some febrile infants, even
those in the first month of life, might be able to be classified as “low-risk”
and avoid antibiotic therapy:
http://pediatrics.aappublications.org/cgi/content/abstract/125/2/228
Also, the question arises what to do when CSF cannot be obtained. For these
cases, provided the infant is well-appearing and clinically stable, observation
in the hospital without antibiotics can be a judicial management strategy.
Suzanne Swanson Mendez, MD
Question 5:
The mother returns from picking up her other child from school and mentions
that her 2-year-old also has a fever, runny nose, and cough at home. You
send NP swabs for RSV, Influenza A and B PCR. The NP swab returns
positive for RSV. How does this possibly change your management?
A) A positive RSV test increases your suspicion for a urinary tract infection
B) A positive RSV test increases your suspicion for meningitis
C) A positive RSV test decreases your suspicion for bacteremia
D) None of the above
(Answer on next page)
Suzanne Swanson Mendez, MD
Answer to Question 5:
D) None of the above
In a prospective, cross-sectional study of over 1,200 infants aged 60 days or
less, those testing positive for RSV had a rate of serious bacterial infections
of 7.0% (SBI, as defined by either meningitis, bacteremia, UTI, or bacterial
enteritis). This is in contrast to the RSV-negative group, which had a SBI rate
of 12.5%. You can find the article
here: http://pediatrics.aappublications.org/cgi/content/abstract/113/6/1728
The most common SBI in both groups of infants was a urinary tract infection,
with 5.4% of the RSV-positive infants versus 10.1% of the RSV-negative
infants being given the diagnosis of a UTI. The infants with a positive RSV
test had a statistically significant decreased rate of UTIs, and also had lower
rates of bacteremia and meningitis but these rates did not reach statistical
significance. A study in 2009 of infants 60 days and younger with influenza
also yielded similar results.
http://pediatrics.aappublications.org/cgi/content/abstract/124/1/30
However, the question is how does this change our clinical management?
(Also, the question also arises about how to define a UTI, but that's enough
for a whole separate learning topic!)
For the under 29 day old infant, the guidelines would suggest proceeding
with a full septic workup and antibiotics. However, for the 29-60 day old
infant, many practioners would only check a UA/urine culture and possibly a
blood culture but forego the lumbar puncture, given the lower risk of
bacteremia and meningitis, but this is an evolving topic. Please see the
recent article in Pediatrics: "Performance of Low-Risk Criteria in the
Evaluation of Young Infants with Fever: Review of the Literature" for more.
http://pediatrics.aappublications.org/cgi/content/abstract/125/2/228
At Valley, if an infant is RSV-positive but otherwise well-appearing, we may
choose to send the child home prior to 48 hours of culture growth, but the
cultures need to be followed daily by our medical team until at least 48-72
hours of growth and the family must be reliable for follow-up.
Of note, at Valley, blood cultures are continuously monitored by a machine
and an alert sounds if bacterial growth is detected. For CSF and urine
cultures, these are checked daily in the microbiology lab during the hours of
8am to 5pm. So if a CSF culture or urine culture is sent at 2am, you will not
know if it's been negative for 24 hours until at least 8am (and often 10am)
the day after admission. Sometimes this does alter our management, and it
does bring up the question of the timing of growth on cultures.
One recent article regarding central venous catheter infections noted that
nearly all were positive by 36 hours, though this depended on bacterial type
(Gram negatives vs. positives in particular):
http://pediatrics.aappublications.org/cgi/content/abstract/121/1/135.
Suzanne Swanson Mendez, MD
Another article from the pre-Prevnar era with pediatric outpatients noted
95% of positive blood cultures were positive by 48 hours:
http://pediatrics.aappublications.org/cgi/content/abstract/106/2/251.
However, the amount of blood drawn from a younger infant is usually less
than that drawn from older children or children with central venous
catheters, which can result in falsely negative cultures. So, it does make
sense to maintain caution when interpreting a negative blood culture result
prior to 36-48 hours in this age group.
Also, in the late spring and summer seasons, or if there is a history of
enteroviral-like symptoms in the family (vomiting, headache, diarrhea),
consider sending the CSF for an Enteroviral PCR. If this returns positive, it is
unlikely that the infant has an SBI.
References/Recommended Reading:
Benitz WE et al, "Serial Serum C-Reactive Protein Levels in the Diagnosis of
Neonatal Infection," Pediatrics 1998; 102; e41.
(http://www.pediatrics.org/cgi/content/full/102/4/e41)
Caviness AC et al, "The Prevalence of Neonatal Herpes Simplex Virus
Infection Compared wtih Serious Bacterial Illness in Hospitalized Neonates,"
Journal of Pediatrics, vol. 153, no. 2, pp. 164-9.
Ishimine P, "Fever Without Source in Children Ages 0 to 36 Months,"
Pediatric Clinics of North America, 53: 167-194, 2006.
http://hsc.unm.edu/emermed/PED/physicians/residents/articles/Fever%20Wi
thout%20a%20Source%20in%20Children%200%20to%2036%20Months%2
0of%20Age.pdf
Huppler AR et al, "Performance of Low-Risk Criteria in the Evaluation of
Young Infants with Fever: Review of the Literature," PEDIATRICS Vol. 125
No. 2 February 2010, pp. 228-233.
http://pediatrics.aappublications.org/cgi/content/abstract/125/2/228
Suzanne Swanson Mendez, MD