Case
A 3-year old boy was referred to the pediatric infectious disease clinic because of persistent
fevers for 8 days. He was born at term via spontaneous vaginal delivery. The delivery was
complicated by maternal chorioamnionitis and meconium, resulting in a 3-day stay in the
neonatal intensive care unit. His past medical history was also notable for a protracted left
cervical lymphadenitis at 2.5 years of age. He was treated with 10 days of cephalexin and 3 days
of amoxicillin/clavulanate prior to undergoing incision and drainage, followed by a 10-day
course of clindamycin. Tuberculin skin test was negative, and bacterial and acid-fast bacilli
cultures did not reveal any pathogens. Clinical resolution required approximately 4-6 weeks.
The patient was up to date on his immunizations. He lived at home with his parents and 2-month
old sister and attended a local daycare. Family history was unremarkable. The family denied
animal contact or insect bites. Four days prior to presentation, the patient had returned from a 14-
day trip to Thailand with his family. While in Thailand, he had developed fevers and was treated
with a 4-day course of amoxicillin/clavulanate for presumed streptococcal pharyngitis. The
following day, he developed non-bloody diarrhea and 2-3 episodes of non-bilious, non-bloody
emesis. Upon his return to the United States, he continued to have fevers and a few episodes of
watery diarrhea. He was subsequently seen by his pediatrician and was referred to the pediatric
infectious disease clinic.
At the clinic, the patient was well appearing. His weight was 15.1 kg (32nd percentile), and height
was 102.3 cm (56th percentile). Vital signs revealed a temperature of 37.2oC, heart rate of 123
beats/minute, blood pressure of 99/47 mmHg, and respiratory rate of 20 breaths per minute.
Physical examination was normal. Laboratory studies revealed a white blood count (WBC) of
10.9 x103
/mm3 with differential of 65% neutrophils, 5% bands, 17% lymphocytes, 4% reactive
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3
lymphocytes, 4% monocytes, and 4% metamyelocytes; hemoglobin of 9.5 gm/dL; hematocrit of
29%; and platelet count of 315 x103
/mm3
. C-reactive protein was elevated at 13.8 mg/dL (normal
<1.0). Monospot test was negative, and EBV panel revealed past disease. Thick and thin smears
for malaria were negative, dengue IgG was positive at 1.72 (<1.64) and IgM was negative. Blood
and stool cultures had growth of Gram-negative bacilli, identified as nontyphoidal Salmonella
(NTS), Group E serotype Weltevreden, susceptible to ampicillin, ceftriaxone, and
sulfamethoxazole/trimethoprim (SMX/TMP). He was admitted to the hospital and was treated
with IV ceftriaxone. He defervesced within 48 hours and continued to remain well appearing
without hemodynamic instability throughout his admission. Repeat blood cultures after the start
of treatment were negative. He received 5 days of IV ceftriaxone and was transitioned to oral
SMX/TMP 10 mg/kg/day divided twice a day to complete a 14-day treatment course. After
completion of antibiotic therapy, two stool cultures obtained on separate occasions were negative
for NTS.
Eight days after completion of antibiotic therapy, fever recurred with a peak temperature of
39.4oC. The patient again presented to the pediatric infectious disease clinic for evaluation. He
remained well appearing with normal physical examination. Blood culture again had growth of
Gram-negative bacilli, identified as the same pan-susceptible NTS as his previous episode of
bacteremia. Given this recurrence, evaluation for a metastatic focus was initiated. Trans-thoracic
echocardiogram, full-body diffusion-weighted MRI, and abdominal ultrasound were all negative.
He was treated with IV ceftriaxone for 6 days, and three subsequent blood cultures were
negative. He was subsequently transitioned to oral high dose amoxicillin (80 mg/kg/day) every 8
hours for a total duration of 4 weeks.
Further evaluation revealed the patient’s underlying diagnosis.
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4
The recurrence of NTS bacteremia without a metastatic focus and the previous history of cervical
adenitis refractory to medical and surgical therapy prompted evaluation of the patient’s immune
system. Fourth-generation HIV test, pneumococcal and tetanus antibody titers, CH50, and T- &
B-cell enumeration were all normal. However, dihydrorhodamine test (DHR) showed essentially
absent superoxide production with a pattern suggestive of autosomal recessive chronic
granulomatous disease (CGD). Further testing indicated absent expression of gp91phox and
p22phox protein by Western blot, with essentially absent superoxide production. He was
determined to have a missense mutation in the CYBB gene which codes for the third
transmembrane domain of gp91, consistent with X-linked CGD. Interestingly, his mother was
negative for this CYBB mutation, and therefore the patient was suspected of having a de novo
mutation.
CGD is a defect in innate immunity caused by a defect in the phagocyte NADPH oxidase
enzyme, which leads to failure of neutrophils and monocytes to produce superoxide (O2-) when
stimulated by variety of bacterial and fungal pathogens. CGD affects approximately 1 in 200,000
people 1
. The NADPH oxidase consists of gp91phox and p22 phox on the plasma membrane and
cytosolic proteins: p40phox
, p47phox
, and p67phox
. Mutations in any of the genes encoding these
five structural proteins are known to cause CGD. Mutations in the gene encoding gp91 phox are
inherited in an X-linked pattern and account for approximately 70% of cases while those
affecting p22phox
, p47phox
, or p67phox are inherited in an autosomal recessive manner and account
for the other 30% of cases2
. Diagnosis of CGD is confirmed by the dihydrorhodamine (DHR)
assay, which uses flow cytometry to measure production of hydrogen peroxide in the presence of
perioxidase.
ACC
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The clinical manifestations of CGD include infections of the skin/soft tissue, lymph nodes, lungs,
and bones. Among 368 CGD patients included in a United States registry, the most commonly
identified pathogens were Aspergillus species, Staphylococcus species, Burkholderia cepacia
complex, Nocardia species and Serratia marcescens3
. However, in a European cohort of 438
CGD patients, the third most commonly isolated pathogen, after Staphylococcus aureus (30%)
and Aspergillus species (26%), was Salmonella species (16%)
4
.
Salmonella species are facultative anaerobic Gram-negative bacilli that replicate within
macrophages. Since patients with CGD lack an oxidative burst and thus are unable to kill
microorganisms engulfed by phagocytes, this contributes to their susceptibility to this particular
pathogen and can lead to prolonged carriage6
. Recurrent NTS disease including bacteremia has
been reported in patients with CGD. Safe et. al5
described a 20-year old who had Salmonella
enteritidis phage type 8 isolated from his blood cultures on three separate occasions over a 7-
year period. During the first episode, the patient was treated with a 10-day course of intravenous
ampicillin. Seven years later, the patient had a second episode of S. enteritidis phage type 8
bacteremia and was treated with a 3-month course of sulfamethoxazole/trimethoprim
(SMX/TMP). However, three months after stopping therapy, the bacteremia recurred, and this
time, he received a 6-month course of SMX/TMP, which was ultimately effective in eradicating
the infection. Burniat et. al6
described three children with CGD who had acute and recurrent
Salmonella infections. The first case was a 9-year old with S. typhimurium bacteremia who failed
initial treatment with ampicillin but improved after a 10-day course of oral chloramphenicol. He
became ill again 1 month later, and S. typhimurium was isolated from his stool. He was then
treated with a 15-day course of chloramphenicol followed by chronic therapy with amoxicillin
and had no recurrences over the ensuing 28 months. The second case was a 1-year old with S. .
6
dublin bacteremia who was treated with ampicillin, gentamicin, and chloramphenicol for six
weeks and had no recurrence of disease. The third case was a 4-year old with high fevers and S.
thompson isolated from stool culture. She was initially treated with a regimen of oral
chloramphenicol for 15 days. However, 2 months later, S. thompson infection recurred and was
treated with another 15-day course of oral chloramphenicol followed by amoxicillin for 1 week.
The patient had a second recurrence 1 month later, was again treated with oral chloramphenicol,
but this time followed by daily prophylactic amoxicillin, and had no further episodes over 21
months.
For uncomplicated Salmonella bacteremia, empiric therapy with ceftriaxone is recommended
until susceptibility testing is available.8
The recommended duration of therapy is 7 to 14 days,
8
and relapse is rare. In an observational study of 199 patients with NTS bacteremia, no
recurrences were observed over a 12-month period 9
. Episodes of recurrence and relapses have
been described in immunocompromised populations such as HIV, adults with diabetes,
autoimmune disease, liver disease, renal transplantation and those taking immunosuppressive
medications 10. Patients with impaired immune system such as those with HIV have been known
to have high risk of mortality and frequent recrudescence from NTS bacteremia12. Due to high
risk of relapse some experts have suggested a longer duration of therapy of 4 to 6 weeks13
.
Our patient completed a second course of antimicrobial therapy with amoxicillin for NTS
bacteremia. Since DHR testing was abnormal indicating CGD, he was treated with an extended
course of four weeks in order to minimize risk of recurrence. Following completion of therapy
for bacteremia, he was started on SMX/TMP and itraconazole for antibacterial and antifungal
prophylaxis, respectively. As highlighted in this case, primary immune deficiencies can have
wide array of clinical presentations. Recurrence of NTS bacteremia should prompt evaluation of
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