CLINICAL
AND
LABORATORY OBSERVATIONS
Autoimmune Neutropenia of Infancy With Recurrent Urinary Tract Infections: A Case Report Hiroaki Kanai, MD, Hiroki Sato, MD, and Yoshichika Takei, MD
Summary: Autoimmune neutropenia of infancy is characterized by minor intercurrent infections despite severe neutropenia; severe bacterial infections are uncommon. An infant developed recurrent urinary tract infections at 9 and 11 months of age. The identified uropathogens were Escherichia coli and Enterococcus faecalis, respectively. Empirical treatment with carbapenems, as broadspectrum antibiotics, promptly resolved the infection without sequelae. Febrile neutropenic children with cancer and autoimmune neutropenia can develop urinary tract infections; therefore, in such infants, urine culture should be obtained through catheterization. In febrile neutropenic infants with no apparent fever source, cephalosporin monotherapy should not be selected empirically because Enterococci can be the involved pathogens. Key Words: autoimmune neutropenia, infant-urinary tract infection, febrile neutropenia
(J Pediatr Hematol Oncol 2015;37:e131–e134)
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eutropenia is characterized by an absolute neutrophil count (ANC) 38.01C taken 2 hours apart and an ANC < 500/mL.6 In most FN cases, patients receive chemotherapy for cancer or hematological malignancies. Because development of FN is a strong indicator of SBIs, there are some clinical guidelines for the management of FN, even in children.6,7 However, the incidence of SBIs or efficacy of antibiotics in FN infants is unknown, because the population of oncologic infants is small. We report the case of an AIN infant who developed febrile urinary tract infections (UTIs) caused by Escherichia Received for publication January 10, 2014; accepted May 13, 2014. From the Department of Pediatrics, Suwa Central Hospital, Nagano, Japan. The authors declare no conflict of interest. Reprints: Hiroaki Kanai, MD, Department of Pediatrics, Suwa Central Hospital, Tamagawa 4300, Chino-city, Nagano 391-8503 Japan (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
coli and Enterococcus faecalis. The clinical course and treatment of this case are described; moreover, the role of clinicians is emphasized in this report.
CASE REPORT A 6-month-old girl was referred to our hospital for further examination of a right cervical mass. Her perinatal and family histories were unremarkable. There were no previous underlying diseases. On admission, the body temperature was 36.01C. Physical examination findings, other than a right cervical mass, were not remarkable. The only abnormal laboratory findings were a low ANC (1259/mL), high C-reactive protein (CRP) level (6.05 mg/dL), and an elevated white blood cell count (WBC) (13,680/mL). Enhanced computed tomography scanning indicated right purulent cervical lymphadenitis (22 29 mm). The patient was empirically treated with intravenous antibiotics (ceftriaxone 100 mg/kg/d, at 12 h intervals) after collecting blood and throat cultures. The lymphadenitis disappeared within a few days. The blood culture was negative, and the throat culture showed no significant pathogens. We decided that ceftriaxone was clinically effective, so the treatment was continued for 5 days during hospitalization. At discharge, although she was afebrile and the WBC had decreased to 11,910/mL, the ANC had decreased to 155/mL. The titers of cytomegalovirus and Epstein-Barr virus IgM and IgG antibodies were both negative serologically. Under periodical consultation, the ANC continued to be low (< 500/mL), although the hemoglobin and platelet levels were within the normal range. At 9 months, she was admitted to our hospital owing to fever for 2 days. The body temperature was 38.01C. Her physical examination was not remarkable. Once more, laboratory findings indicated a low ANC (894/mL) but a high CRP level (6.45 mg/dL). Hypogammaglobulinemia was not detected (IgG, 1232 mg/dL; IgA, 89 mg/dL; and IgM, 101 mg/dL). She was diagnosed with FN, and intravenous broad-spectrum antibiotics were immediately administered (meropenem 120 mg/kg/d combined with amikacin 15 mg/kg/d, at 8 h intervals). Before antibiotic administration, we collected a urine culture through catheterization in addition to blood culture, because we could not identify the infected organs from laboratory data and clinical symptoms. Urinary analysis did not indicate pyuria. The fever declined 1 day after admission; after 2 days, we received a positive urine culture result indicating infection with E. coli. The blood culture was negative. We diagnosed febrile UTI induced by E. coli, and deescalated the antibiotics to ceftriaxone (75 mg/kg/d, at 24 h intervals) (Table 1). Flow cytometry during hospitalization revealed positive results for antineutrophil autoantibodies. On the basis of the chronic neutropenia and presence of antineutrophil autoantibodies, she was diagnosed with AIN. Granulocyte immunofluorescence test results revealed anti-human neutrophil antigen (HNA)-1a and anti-HNA1b autoantibodies in the sera, suggesting autoantibodies targeting the pan-FcgRIIIb area on neutrophils. She was discharged 10 days after admission, and the antibiotic was changed to oral cefroxadine (30 mg/kg/d in 3 doses). The total antibiotic treatment duration was 14 days. Antibiotic prophylaxis treatment was started (trimethoprim-sulfamethoxazole; trimethoprim 1 mg/kg and sulfamethoxazole 5 mg/kg/d in 1 dose) because she was at high risk for SBIs, including UTIs.
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TABLE 1. Antibiotic Sensitivity for Each Uropathogen
First UTI Escherichia Coli Benzylpenicillin Ampicillin Piperacillin Sulbactam/ampicillin Cefazolin Cefotiam Cefotaxime Ceftazidime Cefepime Imipenem/cilastatin Gentamicin Amikacin Levofloxacin Minocycline Vancomycin Linezolid Sulphamethoxazoletrimethoprim
R R I S S S S S S R S S S R
Second UTI Enterococcus Faecalis S S R R
R R S R S S R
I indicates intermediate; R, resistant; S, susceptible; UTI, urinary tract infection.
At 11 months, she developed a second febrile UTI. On admission, the body temperature was 38.61C. She did not show any symptoms, except fever. Laboratory findings showed a lower ANC (198/mL) and CRP level (1.14 mg/dL) than that of previous episodes. Similar to the latest admission, after collecting a urine culture through catheterization and blood culture, we administered the same intravenous antibiotics (meropenem and amikacin) empirically. The fever declined 1 day after admission. Although the urinary analysis also did not show pyuria at this time, the urine culture revealed E. faecalis. The blood culture was negative. After obtaining the urine culture, we deescalated to ampicillin (200 mg/ kg/d, at 6 h intervals) (Table 1). She was discharged 5 days after admission, and the antibiotic was changed to oral amoxicillin (60 mg/kg/d in 3 doses). She was treated for a total of 14 days. Because she developed febrile UTI under antibiotic prophylaxis, we performed renal ultrasonography and voiding cystourethrography, the results of which were normal. Then, we increased the antibiotic dose to 2 mg/kg of trimethoprim and 10 mg/kg of sulfamethoxazole per day in 2 doses. Currently, she is 15 months old, and although severe neutropenia (< 200/mL) persisted, she has not developed recurrence of UTI (Fig. 1). We plan to administer antibiotic prophylaxis until the neutropenia is resolved, because she had already experienced 2 episodes of febrile UTI. The patient’s guardian provided informed consent for all examinations and treatment of the patient.
DISCUSSION We described here a rare case of AIN in which recurrent febrile UTIs developed for a short time despite the absence of congenital anomalies of the kidney and urological tract. Some studies have reported that the majority of AIN patients had only benign infections despite severe neutropenia.1,4,5 However, few studies examined the epidemiology of infections in AIN patients. Bux et al4 reported that 12% of AIN patients suffered from SBIs, including sepsis, urogenital infections, and meningitis at the time of diagnosis, whereas 80% of the patients suffered from mild infections, particularity skin infections, otitis media, and infections of the upper respiratory tract. Another study examined intercurrent infections throughout the neutropenic period and showed that no patients
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FIGURE 1. The patient’s clinical course. The patient diagnosed with a right lymphadenitis at 6 months of age was treated with ceftriaxone; the infection resolved promptly while laboratory investigations revealed low absolute neutrophil counts. She developed febrile neutropenia at 9 months of age, and was treated empirically with carbapenems. Subsequently, UTI caused by Escherichia coli was diagnosed. At 11 months of age, she developed febrile UTI again despite antibiotic prophylaxis treatment with trimethoprim-sulfamethoxazole. Enterococcus faecalis was identified as the uropathogen. Because carbapenems were administered empirically, the infection resolved promptly. ANC indicates absolute neutrophil count; TMP/SMX: trimethoprimsulfamethoxazole; UTI: urinary tract infection.
experienced SBIs such as bacteremia/sepsis, meningitis, or UTIs, whereas 36% had mild infections.8 Recently, it was reported that the incidence of at least 1 infectious episode in 38 AIN patients was 32%, and a total of 25 episodes were observed.9 Only 5 episodes were SBIs, including pneumonia and bacteremia; UTIs were not reported. Because these reports did not show a detailed description of bacterial infections, the exact incidence, sites, and pathogens of the bacterial infection and the prognosis are still not known. The course of our patient provides 2 important clinical suggestions. First, clinicians should collect urine cultures through catheterization when infants develop FN. FN is a common problem in pediatric oncology and is strongly correlated with SBIs. As approximately 60% of FN episodes are caused by SBIs with or without bacteremia, and patients are predisposed to overwhelming sepsis, physicians must perform prompt examinations and administer empirical antibiotics throughout the neutropenic period.10 However, most FN patients do not show specific symptoms other than fever at the time of their first evaluation, and SBIs are difficult to identify. Therefore, some guidelines for the management of oncologic FN patients recommend broad-spectrum intravenous antibiotics before the culture results are available.6,7 Although blood cultures should be obtained in most patients, cultures from other sites such as the nasal cavity, sputum, and stool are not recommended routinely when patients do not show specific symptoms. The guideline states that cultures of urine are indicated if symptoms of UTI exist, a urinary catheter is in place, or the urinalysis findings are abnormal.6 The guideline for pediatric FN patients with cancer recommends that urine cultures be obtained when a clean-catch or midstream urine sample can be collected, while routine urinalysis and culture is controversial.7 However, obtaining clean-catch or midstream urine samples from infants or young children is difficult and time consuming; moreover, the samples are not
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often collected under sterile conditions. Therefore, urine cultures must be collected through catheterization for precise diagnosis.11 UTI is one of the most common bacterial infections in children; so far, it is the leading cause of SBIs in infants and young children and can cause significant morbidity, including urosepsis and renal scaring. Therefore, prompt diagnosis and early (usually empirical) antibiotic treatment of children with suspected UTI are needed before urine culture results are available. A recent clinical guideline indicates that, if a clinician cannot detect an apparent fever source in febrile children, they should ensure that a urine specimen is obtained.11 The overall prevalence of UTIs in febrile infants was reported to be approximately 5%,12 and 75% of UTI children have their first infection before 2 years of age.13 It is noteworthy that the age of onset of AIN is similar to the peak age of onset of pediatric UTIs. The exact incidence of UTIs in pediatric FN patients is unknown. Santolaya et al14 examined 263 episodes of FN in 170 oncologic children and found that 4.6% (12 episodes) were UTIs. Hakim et al15 examined the etiology of 337 pediatric FN episodes, and found only 2 UTIs; however, the data or uropathogens were not shown. One study examined the incidence of UTIs in 45 pediatric oncology patients and reported it to be 8.6% (5 of 58 FN episodes, 4 patients).16 No patients had bacteremia. An important point in this study was that the patients were not infants; 1 patient was 2 years old, and the other patients were children or adolescents. According to these reports, the incidence of UTIs in oncologic FN children varies, and the incidence could be profoundly affected by the patient’s age. Furthermore, the diagnostic method of UTIs was not described, and urine specimens of all FN patients were not obtained in these studies. Moreover, it was reported that urinary leukocytes are not often increased in neutropenic UTI patients.17 Some cases may have been underdiagnosed, and the exact incidence was not obvious. Naturally, there are no systematic studies on the incidence of UTIs in AIN patients. As even healthy infants have a risk of developing UTIs, and most AIN patients are mainly infants and young children, AIN patients are at high risk of developing UTIs. Therefore, in febrile AIN patients with no apparent fever source, clinicians should not rely on urinary leukocytes, and appropriate urine cultures should be collected through catheterization. Furthermore, clinicians should consider UTIs even in oncologic FN infants with no apparent fever source. Second, clinicians should not select cephalosporin monotherapy to treat FN infants empirically, at least until the results of urine and blood cultures become evident. In oncologic FN patients, antibiotics should provide coverage against the most prevalent and life-threatening pathogens.6 Therefore, fourth-generation cephalosporins, ceftazidime or cefepime, and piperacillin/tazobactam or carbapenems are recommended as empirical therapies.6,7 UTIs are generally mediated by gram-negative rods among which E. coli is the principal pathogen followed in frequency by Klebsiella spp., Proteus spp., Pseudomona aeruginosa, and Enterococci. An increasing resistance of E. coli isolates to b-lactam antibiotics has been reported, and non-E. coli isolates have been reported to be significantly more resistant than E. coli isolates to most antimicrobial agents.18 A recent study found that uropathogens, including E. coli became resistant to ceftazidime and cefepime.19 It was also reported that approximately 15% of Enterococci are resistant to amoxicillin.20 In addition, note that Enterococci Copyright
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Autoimmune Neutropenia of Infancy With UTI
are intrinsically resistant to cephalosporins. Because treatment failure must be avoided in FN patients, clinicians should select antibiotics that are effective against gramnegative rods and gram-positive cocci, including Enterococcci, as empirical therapy. If available, antibiotics should be selected based on local antibiotic sensitivity patterns to prevent not only treatment failure but also the frequent use of broad-spectrum antibiotics, because resistance patterns can vary between countries, or even between different regions in the same country. In this study, there is 1 concern that febrile AIN children and oncologic FN children must be managed in the same manner. We definitely are not suggesting that FN in AIN is comparable with that in oncologic patients. As we mentioned above, most AIN children do not experience SBIs, including UTIs.1,4,5,8,9 However, it is widely considered that precise diagnosis and early (generally empirical) antibiotic treatment in pediatric UTI cases are mandatory. Delayed antibiotics or treatment failure in children with febrile UTI can lead to urosepsis and renal scarring, even in previously healthy children. There is no evidence that UTIs do not become severe in AIN infants. In addition, the incidence of UTIs in AIN children is predicted to be comparable with that of previously healthy children because the peak age of onset of UTIs and AIN is similar.5,10 Furthermore, because few studies have examined SBIs in AIN, mortality rates are unclear, and we could not deny that SBIs were caused by coagulase-negative staphylococci or Pseudomonas. Thus, we administered broad-spectrum antibiotics empirically at each onset of fever in the present case. However, currently, the emergence of antibiotic resistance is a major public health problem, and it is crucial to avoid inappropriate prescription of antibiotics, including overprescribing or using broadspectrum antibiotics. Because the patient in the present case was an infant, and we could not refer ANC and urinary WBC as a method suggestive of UTI when she developed fever with no apparent source of infection, we considered febrile UTI and/or bacteremia. In addition, our policy on antibiotic use is that, even when broad-spectrum antibiotics are empirically administered, clinicians must obtain appropriate cultures before antibiotic therapy, and the choice of antibiotic should be reevaluated according to the sensitivity testing results of the isolated pathogens. However, reviewing the clinical course retrospectively, it seemed sufficient to administer single and more narrow-spectrum antibiotics as empirical treatment. Therefore, when our patient developed fever with no apparent source but was not sick, we considered the empirical administration of oral or more narrow-spectrum parental antibiotics as needed, after obtaining appropriate cultures. In conclusion, the present case raises concerns about the potential risk of UTIs in FN infants, and alerts clinicians to the possibility of treatment failure with cephalosporin monotherapy. We indicate that urine culture through catheterization is indispensable in febrile AIN infants with no apparent fever source, as which is also required in previously healthy febrile infants. Furthermore, our anecdotal case suggests that UTIs may be underdiagnosed or misdiagnosed in FN children, regardless of the cause of neutropenia, because urine cultures are not routinely collected, and broad-spectrum antibiotics are empirically administered in many FN episodes. Further studies are necessary to determine the epidemiology of sites and pathogens of UTIs in FN infants with both AIN and malignancy.
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ACKNOWLEDGMENT The authors thank Dr Kazuhiro Nakamura (Associate Professor, Department of Pediatrics, Hiroshima University School of Medicine, Hiroshima, Japan) for performing the granulocyte immunofluorescence test, and all the technicians from the laboratory of Suwa Central Hospital for providing blood and microbiology data. REFERENCES 1. Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther. 2005;7:208–214. 2. James RM, Kinsey SE. The investigation and management of chronic neutropenia in children. Arch Dis Child. 2006;91:852–858. 3. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013;50: 198–206. 4. Bux J, Behrens G, Jaeger G, et al. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood. 1998;91:181–186. 5. Lalezari P, Khorshidi M, Petrosova M. Autoimmune neutropenia of infancy. J Pediatr. 1986;109:764–769. 6. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011;52:e56–e93. 7. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30:4427–4438. 8. Sella R, Flomenblit L, Goldstein I, et al. Detection of antineutrophil antibodies in autoimmune neutropenia of infancy: a multicenter study. Isr Med Assoc J. 2010;12:91–96. 9. Fioredda F, Calvillo M, Burlando O, et al. Infectious complications in children with severe congenital, autoimmune or idiopathic neutropenia: a retrospective study from the Italian Neutropenia Registry. Pediatr Infect Dis J. 2013;32:410–412.
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10. Santolaya ME, Alvarez AM, Becker A, et al. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol. 2001;19:3415–3421. 11. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128: 595–610. 12. Hoberman A, Chao HP, Keller DM, et al. Prevalence of urinary tract infection in febrile infants. J Pediatr. 1993;123: 17–23. 13. Ismaili K, Wissing KM, Lolin K, et al. Characteristics of first urinary tract infection with fever in children: a prospective clinical and imaging study. Pediatr Infect Dis J. 2011;30: 371–374. 14. Santolaya ME, Alvarez AM, Avile´s CL, et al. Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia. Clin Infect Dis. 2002;35:678–683. 15. Hakim H, Flynn PM, Knapp KM, et al. Etiology and clinical course of febrile neutropenia in children with cancer. J Pediatr Hematol Oncol. 2009;31:623–629. 16. Sandoval C, Sinaki B, Weiss R, et al. Urinary tract infections in pediatric oncology patients with fever and neutropenia. Pediatr Hematol Oncol. 2012;29:68–72. 17. Klaassen IL, de Haas V, van Wijk JA, et al. Pyuria is absent during urinary tract infections in neutropenic patients. Pediatr Blood Cancer. 2011;56:868–870. 18. Ladhani S, Gransden W. Increasing antibiotic resistance among urinary tract isolates. Arch Dis Child. 2003;88:444–445. 19. Senel S, Karacan C, Erkek N, et al. A single-center experience of antimicrobial resistance patterns in pediatric urinary tract infection. Med Princ Pract. 2010;19:359–363. 20. Haller M, Brandis M, Berner R. Antibiotic resistance of urinary tract pathogens and rationale for empirical intravenous therapy. Pediatr Nephrol. 2004;19:982–986.
Copyright
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AND
LABORATORY OBSERVATIONS
Autoimmune Neutropenia of Infancy With Recurrent Urinary Tract Infections: A Case Report Hiroaki Kanai, MD, Hiroki Sato, MD, and Yoshichika Takei, MD
Summary: Autoimmune neutropenia of infancy is characterized by minor intercurrent infections despite severe neutropenia; severe bacterial infections are uncommon. An infant developed recurrent urinary tract infections at 9 and 11 months of age. The identified uropathogens were Escherichia coli and Enterococcus faecalis, respectively. Empirical treatment with carbapenems, as broadspectrum antibiotics, promptly resolved the infection without sequelae. Febrile neutropenic children with cancer and autoimmune neutropenia can develop urinary tract infections; therefore, in such infants, urine culture should be obtained through catheterization. In febrile neutropenic infants with no apparent fever source, cephalosporin monotherapy should not be selected empirically because Enterococci can be the involved pathogens. Key Words: autoimmune neutropenia, infant-urinary tract infection, febrile neutropenia
(J Pediatr Hematol Oncol 2015;37:e131–e134)
N
eutropenia is characterized by an absolute neutrophil count (ANC) 38.01C taken 2 hours apart and an ANC < 500/mL.6 In most FN cases, patients receive chemotherapy for cancer or hematological malignancies. Because development of FN is a strong indicator of SBIs, there are some clinical guidelines for the management of FN, even in children.6,7 However, the incidence of SBIs or efficacy of antibiotics in FN infants is unknown, because the population of oncologic infants is small. We report the case of an AIN infant who developed febrile urinary tract infections (UTIs) caused by Escherichia Received for publication January 10, 2014; accepted May 13, 2014. From the Department of Pediatrics, Suwa Central Hospital, Nagano, Japan. The authors declare no conflict of interest. Reprints: Hiroaki Kanai, MD, Department of Pediatrics, Suwa Central Hospital, Tamagawa 4300, Chino-city, Nagano 391-8503 Japan (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
coli and Enterococcus faecalis. The clinical course and treatment of this case are described; moreover, the role of clinicians is emphasized in this report.
CASE REPORT A 6-month-old girl was referred to our hospital for further examination of a right cervical mass. Her perinatal and family histories were unremarkable. There were no previous underlying diseases. On admission, the body temperature was 36.01C. Physical examination findings, other than a right cervical mass, were not remarkable. The only abnormal laboratory findings were a low ANC (1259/mL), high C-reactive protein (CRP) level (6.05 mg/dL), and an elevated white blood cell count (WBC) (13,680/mL). Enhanced computed tomography scanning indicated right purulent cervical lymphadenitis (22 29 mm). The patient was empirically treated with intravenous antibiotics (ceftriaxone 100 mg/kg/d, at 12 h intervals) after collecting blood and throat cultures. The lymphadenitis disappeared within a few days. The blood culture was negative, and the throat culture showed no significant pathogens. We decided that ceftriaxone was clinically effective, so the treatment was continued for 5 days during hospitalization. At discharge, although she was afebrile and the WBC had decreased to 11,910/mL, the ANC had decreased to 155/mL. The titers of cytomegalovirus and Epstein-Barr virus IgM and IgG antibodies were both negative serologically. Under periodical consultation, the ANC continued to be low (< 500/mL), although the hemoglobin and platelet levels were within the normal range. At 9 months, she was admitted to our hospital owing to fever for 2 days. The body temperature was 38.01C. Her physical examination was not remarkable. Once more, laboratory findings indicated a low ANC (894/mL) but a high CRP level (6.45 mg/dL). Hypogammaglobulinemia was not detected (IgG, 1232 mg/dL; IgA, 89 mg/dL; and IgM, 101 mg/dL). She was diagnosed with FN, and intravenous broad-spectrum antibiotics were immediately administered (meropenem 120 mg/kg/d combined with amikacin 15 mg/kg/d, at 8 h intervals). Before antibiotic administration, we collected a urine culture through catheterization in addition to blood culture, because we could not identify the infected organs from laboratory data and clinical symptoms. Urinary analysis did not indicate pyuria. The fever declined 1 day after admission; after 2 days, we received a positive urine culture result indicating infection with E. coli. The blood culture was negative. We diagnosed febrile UTI induced by E. coli, and deescalated the antibiotics to ceftriaxone (75 mg/kg/d, at 24 h intervals) (Table 1). Flow cytometry during hospitalization revealed positive results for antineutrophil autoantibodies. On the basis of the chronic neutropenia and presence of antineutrophil autoantibodies, she was diagnosed with AIN. Granulocyte immunofluorescence test results revealed anti-human neutrophil antigen (HNA)-1a and anti-HNA1b autoantibodies in the sera, suggesting autoantibodies targeting the pan-FcgRIIIb area on neutrophils. She was discharged 10 days after admission, and the antibiotic was changed to oral cefroxadine (30 mg/kg/d in 3 doses). The total antibiotic treatment duration was 14 days. Antibiotic prophylaxis treatment was started (trimethoprim-sulfamethoxazole; trimethoprim 1 mg/kg and sulfamethoxazole 5 mg/kg/d in 1 dose) because she was at high risk for SBIs, including UTIs.
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TABLE 1. Antibiotic Sensitivity for Each Uropathogen
First UTI Escherichia Coli Benzylpenicillin Ampicillin Piperacillin Sulbactam/ampicillin Cefazolin Cefotiam Cefotaxime Ceftazidime Cefepime Imipenem/cilastatin Gentamicin Amikacin Levofloxacin Minocycline Vancomycin Linezolid Sulphamethoxazoletrimethoprim
R R I S S S S S S R S S S R
Second UTI Enterococcus Faecalis S S R R
R R S R S S R
I indicates intermediate; R, resistant; S, susceptible; UTI, urinary tract infection.
At 11 months, she developed a second febrile UTI. On admission, the body temperature was 38.61C. She did not show any symptoms, except fever. Laboratory findings showed a lower ANC (198/mL) and CRP level (1.14 mg/dL) than that of previous episodes. Similar to the latest admission, after collecting a urine culture through catheterization and blood culture, we administered the same intravenous antibiotics (meropenem and amikacin) empirically. The fever declined 1 day after admission. Although the urinary analysis also did not show pyuria at this time, the urine culture revealed E. faecalis. The blood culture was negative. After obtaining the urine culture, we deescalated to ampicillin (200 mg/ kg/d, at 6 h intervals) (Table 1). She was discharged 5 days after admission, and the antibiotic was changed to oral amoxicillin (60 mg/kg/d in 3 doses). She was treated for a total of 14 days. Because she developed febrile UTI under antibiotic prophylaxis, we performed renal ultrasonography and voiding cystourethrography, the results of which were normal. Then, we increased the antibiotic dose to 2 mg/kg of trimethoprim and 10 mg/kg of sulfamethoxazole per day in 2 doses. Currently, she is 15 months old, and although severe neutropenia (< 200/mL) persisted, she has not developed recurrence of UTI (Fig. 1). We plan to administer antibiotic prophylaxis until the neutropenia is resolved, because she had already experienced 2 episodes of febrile UTI. The patient’s guardian provided informed consent for all examinations and treatment of the patient.
DISCUSSION We described here a rare case of AIN in which recurrent febrile UTIs developed for a short time despite the absence of congenital anomalies of the kidney and urological tract. Some studies have reported that the majority of AIN patients had only benign infections despite severe neutropenia.1,4,5 However, few studies examined the epidemiology of infections in AIN patients. Bux et al4 reported that 12% of AIN patients suffered from SBIs, including sepsis, urogenital infections, and meningitis at the time of diagnosis, whereas 80% of the patients suffered from mild infections, particularity skin infections, otitis media, and infections of the upper respiratory tract. Another study examined intercurrent infections throughout the neutropenic period and showed that no patients
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FIGURE 1. The patient’s clinical course. The patient diagnosed with a right lymphadenitis at 6 months of age was treated with ceftriaxone; the infection resolved promptly while laboratory investigations revealed low absolute neutrophil counts. She developed febrile neutropenia at 9 months of age, and was treated empirically with carbapenems. Subsequently, UTI caused by Escherichia coli was diagnosed. At 11 months of age, she developed febrile UTI again despite antibiotic prophylaxis treatment with trimethoprim-sulfamethoxazole. Enterococcus faecalis was identified as the uropathogen. Because carbapenems were administered empirically, the infection resolved promptly. ANC indicates absolute neutrophil count; TMP/SMX: trimethoprimsulfamethoxazole; UTI: urinary tract infection.
experienced SBIs such as bacteremia/sepsis, meningitis, or UTIs, whereas 36% had mild infections.8 Recently, it was reported that the incidence of at least 1 infectious episode in 38 AIN patients was 32%, and a total of 25 episodes were observed.9 Only 5 episodes were SBIs, including pneumonia and bacteremia; UTIs were not reported. Because these reports did not show a detailed description of bacterial infections, the exact incidence, sites, and pathogens of the bacterial infection and the prognosis are still not known. The course of our patient provides 2 important clinical suggestions. First, clinicians should collect urine cultures through catheterization when infants develop FN. FN is a common problem in pediatric oncology and is strongly correlated with SBIs. As approximately 60% of FN episodes are caused by SBIs with or without bacteremia, and patients are predisposed to overwhelming sepsis, physicians must perform prompt examinations and administer empirical antibiotics throughout the neutropenic period.10 However, most FN patients do not show specific symptoms other than fever at the time of their first evaluation, and SBIs are difficult to identify. Therefore, some guidelines for the management of oncologic FN patients recommend broad-spectrum intravenous antibiotics before the culture results are available.6,7 Although blood cultures should be obtained in most patients, cultures from other sites such as the nasal cavity, sputum, and stool are not recommended routinely when patients do not show specific symptoms. The guideline states that cultures of urine are indicated if symptoms of UTI exist, a urinary catheter is in place, or the urinalysis findings are abnormal.6 The guideline for pediatric FN patients with cancer recommends that urine cultures be obtained when a clean-catch or midstream urine sample can be collected, while routine urinalysis and culture is controversial.7 However, obtaining clean-catch or midstream urine samples from infants or young children is difficult and time consuming; moreover, the samples are not
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often collected under sterile conditions. Therefore, urine cultures must be collected through catheterization for precise diagnosis.11 UTI is one of the most common bacterial infections in children; so far, it is the leading cause of SBIs in infants and young children and can cause significant morbidity, including urosepsis and renal scaring. Therefore, prompt diagnosis and early (usually empirical) antibiotic treatment of children with suspected UTI are needed before urine culture results are available. A recent clinical guideline indicates that, if a clinician cannot detect an apparent fever source in febrile children, they should ensure that a urine specimen is obtained.11 The overall prevalence of UTIs in febrile infants was reported to be approximately 5%,12 and 75% of UTI children have their first infection before 2 years of age.13 It is noteworthy that the age of onset of AIN is similar to the peak age of onset of pediatric UTIs. The exact incidence of UTIs in pediatric FN patients is unknown. Santolaya et al14 examined 263 episodes of FN in 170 oncologic children and found that 4.6% (12 episodes) were UTIs. Hakim et al15 examined the etiology of 337 pediatric FN episodes, and found only 2 UTIs; however, the data or uropathogens were not shown. One study examined the incidence of UTIs in 45 pediatric oncology patients and reported it to be 8.6% (5 of 58 FN episodes, 4 patients).16 No patients had bacteremia. An important point in this study was that the patients were not infants; 1 patient was 2 years old, and the other patients were children or adolescents. According to these reports, the incidence of UTIs in oncologic FN children varies, and the incidence could be profoundly affected by the patient’s age. Furthermore, the diagnostic method of UTIs was not described, and urine specimens of all FN patients were not obtained in these studies. Moreover, it was reported that urinary leukocytes are not often increased in neutropenic UTI patients.17 Some cases may have been underdiagnosed, and the exact incidence was not obvious. Naturally, there are no systematic studies on the incidence of UTIs in AIN patients. As even healthy infants have a risk of developing UTIs, and most AIN patients are mainly infants and young children, AIN patients are at high risk of developing UTIs. Therefore, in febrile AIN patients with no apparent fever source, clinicians should not rely on urinary leukocytes, and appropriate urine cultures should be collected through catheterization. Furthermore, clinicians should consider UTIs even in oncologic FN infants with no apparent fever source. Second, clinicians should not select cephalosporin monotherapy to treat FN infants empirically, at least until the results of urine and blood cultures become evident. In oncologic FN patients, antibiotics should provide coverage against the most prevalent and life-threatening pathogens.6 Therefore, fourth-generation cephalosporins, ceftazidime or cefepime, and piperacillin/tazobactam or carbapenems are recommended as empirical therapies.6,7 UTIs are generally mediated by gram-negative rods among which E. coli is the principal pathogen followed in frequency by Klebsiella spp., Proteus spp., Pseudomona aeruginosa, and Enterococci. An increasing resistance of E. coli isolates to b-lactam antibiotics has been reported, and non-E. coli isolates have been reported to be significantly more resistant than E. coli isolates to most antimicrobial agents.18 A recent study found that uropathogens, including E. coli became resistant to ceftazidime and cefepime.19 It was also reported that approximately 15% of Enterococci are resistant to amoxicillin.20 In addition, note that Enterococci Copyright
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Autoimmune Neutropenia of Infancy With UTI
are intrinsically resistant to cephalosporins. Because treatment failure must be avoided in FN patients, clinicians should select antibiotics that are effective against gramnegative rods and gram-positive cocci, including Enterococcci, as empirical therapy. If available, antibiotics should be selected based on local antibiotic sensitivity patterns to prevent not only treatment failure but also the frequent use of broad-spectrum antibiotics, because resistance patterns can vary between countries, or even between different regions in the same country. In this study, there is 1 concern that febrile AIN children and oncologic FN children must be managed in the same manner. We definitely are not suggesting that FN in AIN is comparable with that in oncologic patients. As we mentioned above, most AIN children do not experience SBIs, including UTIs.1,4,5,8,9 However, it is widely considered that precise diagnosis and early (generally empirical) antibiotic treatment in pediatric UTI cases are mandatory. Delayed antibiotics or treatment failure in children with febrile UTI can lead to urosepsis and renal scarring, even in previously healthy children. There is no evidence that UTIs do not become severe in AIN infants. In addition, the incidence of UTIs in AIN children is predicted to be comparable with that of previously healthy children because the peak age of onset of UTIs and AIN is similar.5,10 Furthermore, because few studies have examined SBIs in AIN, mortality rates are unclear, and we could not deny that SBIs were caused by coagulase-negative staphylococci or Pseudomonas. Thus, we administered broad-spectrum antibiotics empirically at each onset of fever in the present case. However, currently, the emergence of antibiotic resistance is a major public health problem, and it is crucial to avoid inappropriate prescription of antibiotics, including overprescribing or using broadspectrum antibiotics. Because the patient in the present case was an infant, and we could not refer ANC and urinary WBC as a method suggestive of UTI when she developed fever with no apparent source of infection, we considered febrile UTI and/or bacteremia. In addition, our policy on antibiotic use is that, even when broad-spectrum antibiotics are empirically administered, clinicians must obtain appropriate cultures before antibiotic therapy, and the choice of antibiotic should be reevaluated according to the sensitivity testing results of the isolated pathogens. However, reviewing the clinical course retrospectively, it seemed sufficient to administer single and more narrow-spectrum antibiotics as empirical treatment. Therefore, when our patient developed fever with no apparent source but was not sick, we considered the empirical administration of oral or more narrow-spectrum parental antibiotics as needed, after obtaining appropriate cultures. In conclusion, the present case raises concerns about the potential risk of UTIs in FN infants, and alerts clinicians to the possibility of treatment failure with cephalosporin monotherapy. We indicate that urine culture through catheterization is indispensable in febrile AIN infants with no apparent fever source, as which is also required in previously healthy febrile infants. Furthermore, our anecdotal case suggests that UTIs may be underdiagnosed or misdiagnosed in FN children, regardless of the cause of neutropenia, because urine cultures are not routinely collected, and broad-spectrum antibiotics are empirically administered in many FN episodes. Further studies are necessary to determine the epidemiology of sites and pathogens of UTIs in FN infants with both AIN and malignancy.
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ACKNOWLEDGMENT The authors thank Dr Kazuhiro Nakamura (Associate Professor, Department of Pediatrics, Hiroshima University School of Medicine, Hiroshima, Japan) for performing the granulocyte immunofluorescence test, and all the technicians from the laboratory of Suwa Central Hospital for providing blood and microbiology data. REFERENCES 1. Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther. 2005;7:208–214. 2. James RM, Kinsey SE. The investigation and management of chronic neutropenia in children. Arch Dis Child. 2006;91:852–858. 3. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013;50: 198–206. 4. Bux J, Behrens G, Jaeger G, et al. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood. 1998;91:181–186. 5. Lalezari P, Khorshidi M, Petrosova M. Autoimmune neutropenia of infancy. J Pediatr. 1986;109:764–769. 6. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011;52:e56–e93. 7. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30:4427–4438. 8. Sella R, Flomenblit L, Goldstein I, et al. Detection of antineutrophil antibodies in autoimmune neutropenia of infancy: a multicenter study. Isr Med Assoc J. 2010;12:91–96. 9. Fioredda F, Calvillo M, Burlando O, et al. Infectious complications in children with severe congenital, autoimmune or idiopathic neutropenia: a retrospective study from the Italian Neutropenia Registry. Pediatr Infect Dis J. 2013;32:410–412.
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10. Santolaya ME, Alvarez AM, Becker A, et al. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol. 2001;19:3415–3421. 11. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128: 595–610. 12. Hoberman A, Chao HP, Keller DM, et al. Prevalence of urinary tract infection in febrile infants. J Pediatr. 1993;123: 17–23. 13. Ismaili K, Wissing KM, Lolin K, et al. Characteristics of first urinary tract infection with fever in children: a prospective clinical and imaging study. Pediatr Infect Dis J. 2011;30: 371–374. 14. Santolaya ME, Alvarez AM, Avile´s CL, et al. Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia. Clin Infect Dis. 2002;35:678–683. 15. Hakim H, Flynn PM, Knapp KM, et al. Etiology and clinical course of febrile neutropenia in children with cancer. J Pediatr Hematol Oncol. 2009;31:623–629. 16. Sandoval C, Sinaki B, Weiss R, et al. Urinary tract infections in pediatric oncology patients with fever and neutropenia. Pediatr Hematol Oncol. 2012;29:68–72. 17. Klaassen IL, de Haas V, van Wijk JA, et al. Pyuria is absent during urinary tract infections in neutropenic patients. Pediatr Blood Cancer. 2011;56:868–870. 18. Ladhani S, Gransden W. Increasing antibiotic resistance among urinary tract isolates. Arch Dis Child. 2003;88:444–445. 19. Senel S, Karacan C, Erkek N, et al. A single-center experience of antimicrobial resistance patterns in pediatric urinary tract infection. Med Princ Pract. 2010;19:359–363. 20. Haller M, Brandis M, Berner R. Antibiotic resistance of urinary tract pathogens and rationale for empirical intravenous therapy. Pediatr Nephrol. 2004;19:982–986.
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