The Pediatric Infectious Disease Journal Volume 32, Number 12, December 2013

Cheng et al

described variable effectiveness. The most advocated alternative

for corticosteroid nonresponders is intravenous immune globulin
11.5g/kg/d for 12 doses.5,6
To prevent recurrence of DRESS, patients must avoid further use of the offending agent. Unfortunately, for patients on
multiple medications, no universally accepted procedure exists
to determine the drug responsible. DRESS is classified as a type
IV delayed hypersensitivity T-cellmediated reaction, and thus
patch testing has been beneficial in some patients.14 Patch tests
yielding positive results are highly indicative of patient sensitivity to the drug, but negative tests are inconclusive. Studies have
demonstrated positive patch tests in roughly 1 of 3 DRESS cases,
with positive predictive values around 5075% for aromatic antiepileptics.14 Alternatives to patch testing include drug rechallenge
(risking DRESS relapse) and lymphocyte transformation testing
(LTT). LTT is a laboratory-based in vitro technology that assesses
T-cell responses to multiple drugs.15 Although LTT is safe and not
influenced by corticosteroids, it is also cumbersome, not standardized for most medications, and typically negative in acute
DRESS.15 LTT is best performed 58 weeks after rash onset. Conversely, patch testing yields optimal results 16 months after clinical recovery, following a minimum of 1 month after cessation of
corticosteroids.14,15
REFERENCES
1. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma
and drug hypersensitivity syndrome (Drug Rash with Eosinophilia
and Systemic Symptoms: DRESS). Semin Cutan Med Surg.
1996;15:250257.
2. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the
clinical pattern of cutaneous side-effects of drugs with systemic
symptoms: does a DRESS syndrome really exist? Br J Dermatol.
2007;156:609611.
3. Kano Y, Shiohara T. The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug. Immunol Allergy Clin North Am.
2009;29:481501.
4. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature
review. Am J Med. 2011;124:588597.
5. Newell BD, Moinfar M, Mancini AJ, et al. Retrospective analysis of 32
pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS).
Pediatr Dermatol. 2009;26:536546.
6. Seth D, Kamat D, Montejo J. DRESS syndrome: a practical approach for
primary care practitioners. Clin Pediatr (Phila). 2008;47:947952.
7. Palmero D, Castagnino J, Musella RM, et al. Difficult clinical management
of anti-tuberculosis DRESS syndrome. Int J Tuberc Lung Dis. 2013;17:
7678.
8. Kim JH, Jang SH, Kim DH, et al. A case of DRESS syndrome induced
by the antituberculosis drugs, prothionamide, and para-aminosalycilic acid.
Ann Allergy Asthma Immunol. 2013;110:118119.
9. Rodrguez R, Jover V, Orozco I, et al. DRESS syndrome in a 19-year-old
patient following the administration of first-line antituberculosis drugs. J
Investig Allergol Clin Immunol. 2012;22:380381.
10. Lee JH, Park HK, Heo J, et al. Drug Rash with Eosinophilia and Systemic
Symptoms (DRESS) syndrome induced by celecoxib and anti-tuberculosis
drugs. J Korean Med Sci. 2008;23:521525.
11. Aquinas M, Allan WG, Horsfall PA, et al. Adverse reactions to daily and
intermittent rifampicin regimens for pulmonary tuberculosis in Hong Kong.
Br Med J. 1972;1:765771.
12. Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs.
Expert Opin Drug Saf. 2006;5:231249.
13. Gentile I, Talamo M, Borgia G. Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated
viral reactivation? Report of a case and literature review. BMC Infect Dis.
2010;10:49.
14. Elzagallaai AA, Knowles SR, Rieder MJ, et al. Patch testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review. Drug
Saf. 2009;32:391408.

1390 | www.pidj.com

15. Kano Y, Hirahara K, Mitsuyama Y, et al. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and
the type of drug eruption. Allergy. 2007;62:14391444.

PULMONARY NODULES IN AN
IMMUNOCOMPETENT CHILD WITH CAT SCRATCH
DISEASE
Anuja Bandyopadhyay, MD, Lindsay C. Burrage, MD,
and Blanca E. Gonzalez, MD
Abstract: We describe an immunocompetent child with cat scratch disease
and pulmonary nodules as part of her initial presentation. Although pulmonary manifestations have been reported with cat scratch disease, nodules are
rare in the normal host.
Key Words: cat scratch disease, Bartonella henselae, pulmonary nodules
Accepted for publication May 30, 2013.
From the Department of Pediatrics, Rainbow Babies and Childrens Hospital,
University Hospitals Case Medical Center, Cleveland, Ohio.
The authors have no conflicts of interest or funding to disclose.
Address for correspondence: Blanca E. Gonzalez, MD, Childrens Hospital,
Cleveland Clinic, 9500 Euclid Avenue/S25, Cleveland, OH 44195. E-mail:
Gonzalb3@CCF.org.
Copyright 2013 by Lippincott Williams & Wilkins
ISSN: 0891-3668/13/3212-1392
DOI: 10.1097/INF.0000000000000069

artonella henselae is the etiologic agent of cat scratch disease

(CSD). Most children with CSD present with lymphadenitis related to the site of inoculation. Disseminated infections can
occur with a wide spectrum of presentations, including osteomyelitis, meningitis, retinitis, hepatosplenic microabscesses, bacillary
angiomatosis and renal abscesses.1 Pulmonary manifestations are
rare but have been described in adults and children, especially in
immunocompromised hosts.117 The usual pulmonary manifestations are pleural effusions and pneumonia. Pulmonary nodules
are mostly seen in patients with bacillary angiomatosis.6,13 In this
article, we describe the second case of an immunocompetent child
with pulmonary nodules as a manifestation of CSD. The first case
was that of a 6-year-old immunocompetent boy reported in 2001 by
Marseglia et al.12

CASE REPORT
A 3-year-old African American girl was admitted to our
institution with an 8-day history of high fevers, night sweats, nonproductive cough and diarrhea. She had been seen in the emergency
room 3 days earlier for a chief complaint of diarrhea. She was well
appearing with no rashes or lymphadenopathy. Her lungs were clear
to auscultation, and there was no hepatosplenomegaly. The workup
included a negative rapid test for Streptococcus pyogenes, a negative urinalysis with urine culture and a normal chest radiograph.
She had an elevated white blood cell count of 16,000/mm3 with
20% lymphocytes and 11% band form neutrophils. The patient was
discharged with a diagnosis of likely viral gastroenteritis. Although
diarrhea resolved, the child was readmitted 3 days later with persistent fevers and cough.
Her medical history was unremarkable, and there were no
significant exposures or travel history. The initial C-reactive protein
was elevated (7.2mg/dL). Additional studies performed consisted
of purified protein derivative placement, HIV testing, rheumatoid
factor, antinuclear antibody panel and serologic IgM tests for Cryptococcus, Histoplasma, Mycoplasma, Coxiella, Brucella, Borrelia
2013 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal Volume 32, Number 12, December 2013

and Bartonella (reference range, negative, <1:16), which were all

negative. The initial Bartonella IgG was 1:64 (reference range,
negative, <1:64). Blood cultures remained sterile. During hospitalization, she continued to have daily fevers to 102F although her
cough resolved. A chest computed tomography (CT) with contrast
showed scattered 23mm nodular densities throughout the lungs,
but no significant axillary, mediastinal or hilar lymphadenopathy.
An abdominal CT showed multiple focal hypodensities throughout the liver and left kidney. A bone marrow biopsy showed no
evidence of malignancy. To rule out embolic lesions, a bone scan
and an echocardiogram were performed, which were both negative.
The CT scan was repeated on day 28 of illness because of
persistent fever. It revealed further progression of the pulmonary
and hepatic nodules. A liver wedge biopsy, performed on day 30,
revealed several large necrotizing granulomas. Special stains
(Giemsa stain, Steiner, Gram and acid fast Bacilli) were negative.
Bartonella DNA was detected by polymerase chain reaction (PCR).
A repeat serum Bartonella IgG test was performed and was positive at 1:256. Azithromycin and rifampin were started, and there was
quick defervescence. Upon further questioning, the mother recalled
that the children had been exposed to a feral kitten a few weeks
before the start of the illness. The patient was discharged home on
oral antibiotic therapy, remained afebrile and clinically improved.
Antibiotics were discontinued after a total course of 5 weeks. No
further imaging or immunological workup was performed as she
was asymptomatic, and her inflammatory markers had normalized.
The culture of the biopsied specimen had no growth aerobically or
anaerobically.

METHODS
A PubMed search was performed using words Bartonella
and lung or Bartonella and pulmonary. We included articles that contained age, gender, immune status and description of
pulmonary findings and diagnostic methodology. Children were
defined as patients who were 18 years of age and younger.

RESULTS
Fifteen articles describing 23 cases of Bartonella infections
with pulmonary manifestations were found in the literature.29,1117
The first case was reported in 1957 and the most recent in 2010.15,16
Demographics of the patients are shown in Table1. Most patients
were adult males with immunocompromising conditions. All
patients had contact with a kitten, cat or dog before development of
the disease, with 7 patients showing papules or scratch scars at the
sites of the inoculation. All patients were febrile. Nine patients had
overt pulmonary symptoms such as cough or chest pain on presentation and 3 patients had hemoptysis. Most patients presented with

Scratch Diesease

peripheral lymphadenopathy, of which the axilla was the most common location.
Pleural effusion2,3,8,16,17 and pneumonia3,8,16 were the most common presentations in children, whereas pulmonary nodules5,6,13 were
mainly seen in adult patients. The latter were found predominantly in
patients with T-cell defects, namely HIV and renal transplant recipients. There was 1 reported case of diffuse air space disease/acute respiratory distress syndrome in a child2 and in an adult each.4 There
were 2 reported cases of pleurisy in adults,11 but none in children.
Pleural fluid characteristics were described in 4 patients. The
fluid had elevated white blood cells (mean white blood cells 2346/
mm: range 1643900) and a predominance of neutrophils. The lactate dehydrogenase was measured in 3 patients, and it was above
1500 IU/L in 2 patients. The diagnosis of pulmonary manifestations was made either by chest radiograph or by CT scan. Pulmonary nodules in children and in adults were identified by CT scan.
We found only 1 pediatric patient in the literature search with pulmonary nodules12; a 6-year-old patient without pulmonary symptoms in the setting of hepatosplenic CSD.
Hepatosplenic manifestations were present in 13 patients.
These included microabscesses in the liver and spleen, hepatomegaly and hepatitis. Neurologic manifestations were seizures
and change in mental status in 6 patients and papillitis/retinitis in
2 patients.
To establish the diagnosis, multiple methods were used
depending on the date of the report. Before 1994, intradermal reaction to CSD antigen (skin test) was used to diagnose 4 cases. Thereafter, the diagnoses were established by tissue stains (WarthinStarry stain), antibody titers or PCR of the tissue or pleural fluid.
Macrolides, tetracycline or trimethoprim-sulfamethoxazole
was used as therapy in 20 of the 23 patients, but exact duration of
therapy was not reported and 3 patients improved with inappropriate or no treatment at all. Symptoms resolved on average by 45 days
of illness (range, 5180 days). Two patients, who had HIV, died.

DISCUSSION
Pulmonary manifestations of B. henselae are uncommon and
seem to occur more frequently in patients with immunodeficiencies,
mainly T-cell dysfunction.117 To our knowledge, only 7 pediatric
patients have been reported in the medical literature and, in contrast
to adult patients, all have been immunocompetent children.2,3,8,9,12,16,17
As other authors have hypothesized, it is possible that this is the
result of the dissemination of the organism into the pleural space
or lung parenchyma as suggested by the detection of B. henselae in
lung parenchyma or pleural fluid by PCR in many patients reported
in the literature.5,6,8 Pulmonary nodules nevertheless are rare, and
this brief report being the second known pediatric case.

TABLE 1. Demographics and Clinical Characteristics of Patients With Pulmonary Manifestations of CSD

Mean age; years (range)

Male gender
Immunocompetent
Immunocompromised
Animal exposure
Fever
Pulmonary symptoms (cough/hemoptysis/pleuritic chest pain/chest retractions)
Central nervous system symptoms (seizures, headache and blurry vision)
Gastrointestinal symptoms (abdominal pain, emesis, diarrhea)
Peripheral lymphadenopathy (epitrochlear, axillary, submandibular, preauricular and
inguinal)
Hepatosplenic involvement (hepatitis, hepatic or splenic lesions)

Adults (N = 16)4,5,6,7,10,13,14,15

Children* (N = 8)2,3,8,9,12,16,17

28.37 (1950)
14
3
13
16
16
9
3
3
11

6.56 (311)
6
8
0
8
8
4
3
4
7

*Includes the current case.

2013 Lippincott Williams & Wilkins

www.pidj.com|1391

The Pediatric Infectious Disease Journal Volume 32, Number 12, December 2013

Bandyopadhyay et al

Establishing the diagnosis of CSD requires a high level of

suspicion. Margileth revised the criteria established by Carithers
to diagnose CSD requiring 3 of the 4 following criteria to establish
the diagnosis: (1) history of cat or flea exposure; (2) exclusion by
serology of other causes of adenopathy, sterile lymph node purulent
discharge, positive PCR assay or liver/spleen lesions on CT scan;
(3) positive serologies by enzyme immunoassay or immunofluorescent antibody assay with a titer greater or equal to 1:64 and (4)
biopsy showing granulomatous inflammation consistent with CSD
or a positive Warthin-Starry silver stain.1,1820 Our patient did not
present with lymphadenopathy but fulfilled other criteria, such as
a positive serology and lesions on CT; later, we were able to verify
the history of cat exposure. Ultimately, the diagnosis was confirmed
with a positive PCR from the liver tissue as well as an elevation of
the titers later in the disease. The varying sensitivities of the serologies for B. henselae, especially early in the disease process, make
the diagnosis of this disease complicated at times, especially when
the disease presents in an unusual manner.

ACKNOWLEDGMENTS
The authors thank Drs Lydia Furman, Johanna Goldfarb
and Charles Foster for their review of the manuscript.
REFERENCES
1. Florin TA, Zaoutis TE, Zaoutis LB. Beyond cat scratch disease: widening spectrum of Bartonella henselae infection. Pediatrics. 2008;121:e1413e1425.
2. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 221992. A 6 1/2-year-old girl with status epilepticus, cervical lymphadenopathy, pleural effusions, and respiratory distress. N
Engl J Med. 1992;326:14801489.
3. Abbasi S, Chesney PJ. Pulmonary manifestations of cat-scratch disease; a case
report and review of the literature. Pediatr Infect Dis J. 1995;14:547548.
4. Black JR, Herrington DA, Hadfield TL, et al. Life-threatening cat-scratch
disease in an immunocompromised host. Arch Intern Med. 1986;146:
394396.
5. Caniza MA, Granger DL, Wilson KH, et al. Bartonella henselae: etiology
of pulmonary nodules in a patient with depressed cell-mediated immunity.
Clin Infect Dis. 1995;20:15051511.
6. Dutta A, Schwarzwald HL, Edwards MS. Disseminated bartonellosis presenting as neuroretinitis in a young adult with human immunodeficiency
virus infection. Pediatr Infect Dis J. 2010;29:675677.
7. Katner HP, Treen B, Pankey GA, et al. Pleural effusion and anicteric hepatitis associated with cat-scratch disease. Documentation by cat-scratch bacillus. Chest. 1986;89:302303.
8. Koranyi K. Fever, back pain and pleural effusion in a four-year-old boy.
Pediatr Infect Dis J. 1994;13:657, 672.
9. Margileth AM. Cat scratch disease: nonbacterial regional lymphadenitis. The
study of 145 patients and a review of the literature. Pediatrics. 1968;42:803818.
10. Margileth AM, Baehren DF. Chest-wall abscess due to cat-scratch disease
(CSD) in an adult with antibodies to Bartonella clarridgeiae: case report
and review of the thoracopulmonary manifestations of CSD. Clin Infect Dis.
1998;27:353357.
11. Margileth AM, Wear DJ, English CK. Systemic cat scratch disease: report
of 23 patients with prolonged or recurrent severe bacterial infection. J Infect
Dis. 1987;155:390402.
12. Marseglia GL, Monafo V, Marone P, et al. Asymptomatic persistent pulmonary infiltrates in an immunocompetent boy with cat-scratch disease. Eur J
Pediatr. 2001;160:260261.
13. Moore EH, Russell LA, Klein JS, et al. Bacillary angiomatosis in patients
with AIDS: multiorgan imaging findings. Radiology. 1995;197:6772.
14. Schlossberg D, Morad Y, Krouse TB, et al. Culture-proved disseminated catscratch disease in acquired immunodeficiency syndrome. Arch Intern Med.
1989;149:14371439.
15. Sheldon GC, Smellie H. Cat-Scratch disease with pneumonia. Br Med J.
1957;2:446447.
16. Takeda N, Ishiwada N, Fukasawa C, et al. Pediatric pneumonia,

pleural effusion, and pericarditis following cat scratch disease and

1392 | www.pidj.com

serological cross-reactions among Bartonella henselae and Rickettsia

japonica determined by indirect fluorescence antibodies. Kansenshogaku
Zasshi. 2007;81:206209.
17. Whitman BW, Krafte-Jacobs B. Cat-scratch disease associated with pleural
effusions and encephalopathy in a child. Respiration. 1995;62:171173.
18. Opavsky MA. Cat scratch disease: the story continues. Can J Infect Dis.
1997;8:4349.
19. Margileth AM. Cat scratch disease. Adv Pediatr Infect Dis. 1993;8:121.
20. Carithers HA. Cat-scratch disease; notes on its history. Am J Dis Child.
1970;119:200203.

HOARSENESS AS A PRESENTING SIGN IN

CHILDREN WITH KAWASAKI DISEASE
Shelby C. Leuin, MD,* Swetha Shanbhag, BS,
Denise Lago, PA-C,* Yuichiro Sato, MS, Xiaoying Sun, MS,
Sonia Jain, PhD, Jane C. Burns, MD, and
Adriana H. Tremoulet, MD, MAS
Abstract: We noted that many patients with Kawasaki disease (KD) were
hoarse at presentation and thus evaluated the frequency of hoarseness in
children with acute KD. New onset hoarseness was noted in 86 of 287
(30%) prospectively assessed KD patients. Laryngoscopic examination of 3
hoarse patients with acute KD revealed edema and erythema of the larynx.
Key Words: Kawasaki disease, hoarseness, coronary artery dilatation, vasculitis
Accepted for publication June 14, 2013.
From the *Division of Otolaryngology; Department of Pediatrics, Rady Childrens Hospital San Diego; and Department of Family and Preventive Medicine, University of California San Diego, San Diego, CA.
These data were presented in part at the Society for Ear, Nose, and Throat
Advances in Children Annual Meeting in Kansas City, MO, on December
2, 2011, and the 10th International Kawasaki Disease Symposium in Kyoto,
Japan, on February 710, 2012.
This work was supported in part by grants from The Robert Wood Johnson Foundation and The Hartwell Foundation (A.H.T.) and from the NIH, National
Heart, Lung, Blood Institute, HL69413 (J.C.B.) and T35HL007491 (S.S.).
The authors have no other funding or conflicts of interest to disclose.
Address for correspondence: Adriana H. Tremoulet, MD, MAS, University of
California San Diego, 9500 Gilman Drive, MC 0831, La Jolla, CA 920930831. E-mail: atremoulet@ucsd.edu.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journals website (www.pidj.com).
Copyright 2013 by Lippincott Williams & Wilkins
ISSN: 0891-3668/13/3212-1394
DOI: 10.1097/INF.0b013e3182a0960b

everal lines of evidence suggest a respiratory portal of entry

for the agent that triggers Kawasaki disease (KD) in genetically
susceptible children. These include presentation with enlarged anterior cervical lymph nodes that drain the posterior pharynx in 30%
of patients, retropharyngeal edema imaged by computed tomography and occasional reports of pulmonary nodules during the acute
phase of the illness.14 We noted that many of our patients were
hoarse at the time of presentation, although this finding had not
been previously reported in the literature. We therefore added the
presence or absence of hoarseness to our standardized admission
case report forms for KD patients beginning in 2004. The objective
of this study was to determine the frequency of hoarseness in acute
KD and to compare the patient characteristics between those with
and without hoarseness. Indirect laryngoscopy was performed in a
subset of hoarse KD patients.
2013 Lippincott Williams & Wilkins