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symptoms and signs of UTI. However, we could not define a specific serotype that might have a predilection for the urinary tract because all the children summarized in Table 1 were infected by different serotypes. It is suggested that S. pneumoniae can cause UTI through multiple factors of the host immune system and bacterial virulence.
ACKNOWLEDGMENTS The Streptococcus pneumoniae isolates of cases 1 and 2 in this study were obtained from the Asian Bacterial Bank of the Asia Pacific Foundation for Infectious Diseases (ABB APFID, Seoul, South Korea). Serotyping, bile solubility and antimicrobial susceptibility testing using the broth microdilution method were performed at ABB of APFID. REFERENCES 1. Nguyen VQ, Penn RL. Pneumococcusuria in adults. J Clin Microbiol. 1988;26:1085–1087. 2. Miller MA, Kaplan BS, Sorger S, et al. Pneumococcosuria in children. J Clin Microbiol. 1989;27:99–101. 3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement M100-S23. Wayne, PA: Clinical and Laboratory Standards Institute; 2013. 4. Burckhardt I, Zimmermann S. Streptococcus pneumoniae in urinary tracts of children with chronic kidney disease. Emerg Infect Dis. 2011;17:120–122. 5. Krishna S, Sanjeevan KV, Sudheer A, et al. Pneumococcusuria: From bench to bedside. Indian J Med Microbiol. 2012;30:96–98. 6. Subcommittee on Urinary Tract Infection SCoQIaM. 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. 7. Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis. 2004;4:144–154. 8. Chromek M, Slamová Z, Bergman P, et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med. 2006;12:636–641. 9. Trnka P, Hiatt MJ, Tarantal AF, et al. Congenital urinary tract obstruction: defining markers of developmental kidney injury. Pediatr Res. 2012;72:446–454. 10. Lundstedt AC, McCarthy S, Gustafsson MC, et al. A genetic basis of susceptibility to acute pyelonephritis. PLoS One. 2007;2:e825. 11. Yuan FF, Marks K, Wong M, et al. Clinical relevance of TLR2, TLR4, CD14 and FcgammaRIIA gene polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol. 2008;86:268–270. 12. Weinberger DM, Harboe ZB, Sanders EA, et al. Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clin Infect Dis. 2010;51:692–699. 13. Ruiz V, Rodríguez-Cerrato V, Huelves L, et al. Adherence of Streptococcus pneumoniae to polystyrene plates and epithelial cells and the antiadhesive potential of albumin and xylitol. Pediatr Res. 2011;69:23–27.
DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS SYNDROME ASSOCIATED WITH ANTITUBERCULOSIS MEDICATIONS Julianna Cheng, MD, MSc, FRCPC,*† Surabhi Rawal, MD,‡ Ashley Roberts, MD, MEd, FRCPC,*§ and Orlee R. Guttman, MD, MEd, FRCPC*† Abstract: Drug reaction with eosinophilia and systemic symptoms is a potentially life-threatening syndrome of medication hypersensitivity associated with a wide variety of triggers. Diagnosis can be challenging, as clinical features suggest other conditions. We describe a 12-year-old boy with typical drug reaction with eosinophilia and systemic symptoms syndrome after antituberculosis therapy. Key Words: drug hypersensitivity, drug eruptions, antitubercular agents, drug reaction with eosinophilia and systemic symptoms syndrome
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Accepted for publication June 14, 2013. From the *University of British Columbia; †Division of Gastroenterology, Hepatology and Nutrition; ‡Department of Pediatrics; and §Division of Infectious Diseases, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Orlee R. Guttman, MD, MEd, FRCPC, British Columbia Children’s Hospital, 4480 Oak Street, Rm K4-201, Vancouver, British Columbia, Canada, V6H3V4. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0b013e3182a09f20
F
irst described in 1996, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome typically manifests as a triad of fever, rash and lymphadenopathy, with additional visceral involvement.1 Aromatic anticonvulsants are the most common etiologic agents, and thus the term has been used interchangeably with anticonvulsant hypersensitivity syndrome as well as with drug-induced hypersensitivity syndrome.2 The incidence in individuals taking anticonvulsant medications is reported at 1/1000–1/10,0003; the incidence with other agents is less clear. Symptoms of DRESS syndrome generally arise 2–6 weeks after drug initiation and can pose a considerable diagnostic challenge. Presenting features of DRESS overlap with those of other disorders, including dermatological (Stevens–Johnson syndrome, toxic epidermal necrolysis), rheumatologic (Kawasaki disease, systemic onset juvenile idiopathic arthritis, systemic lupus erythematosus), hematologic (macrophage activation syndrome, hematologic malignancies) and infectious (Epstein-Barr virus, cytomegalovirus, HIV, parvovirus, mycoplasma, chlamydia and staphylococcus scalded skin syndrome). Timely recognition and management of DRESS is vital as mortality rates as high as 10% have been reported.3
CASE REPORT A previously well 12-year-old boy, recently immigrated from Korea, was diagnosed with tuberculosis based on positive Mantoux and radiologic evidence of a pleural effusion. Immigration screening had revealed active, isoniazid-resistant tuberculosis in his father. The patient started ethambutol 800 mg daily, rifampin 600 mg daily and pyrazinamide 1g daily. Four weeks later the patient presented with a pruritic rash, diarrhea and fever. He was diagnosed with a viral illness, and supportive measures were recommended. Three days later he returned to hospital with vomiting and worsening abdominal pain and distension. On admission, the patient was febrile at 39.9°C with otherwise normal vital signs. An extensive blanchable, erythematous maculopapular rash was seen on the torso and proximal extremities, with purpura on the distal extremities. His abdomen was exquisitely tender with a liver edge palpable at 11 cm below the costal margin and bulging flanks, but no splenomegaly. His extremities and scrotum were edematous. He had cervical and submandibular lymphadenopathy. Investigations revealed eosinophilia (1.26 × 109/L), lymphopenia (0.25 × 109/L), atypical lymphocytosis (1.60 × 109/L) and thrombocytopenia (85 × 109/L). Albumin was low at 23 g/L and transaminases elevated: alanine aminotransferase 588 U/L, aspartate aminotransferase 461 U/L and gamma-glutamyltransferase 121 U/L. International normalized ratio was 1.42. Bilirubin, creatinine and urea were normal. The patient’s tuberculosis medications were discontinued. A loading dose of intravenous methylprednisolone 0.8 mg/kg was © 2013 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 32, Number 12, December 2013
administered, followed by 0.5 mg/kg twice daily. Despite this, liver function deteriorated (peak international normalized ratio 1.8), and he developed acute renal failure (peak creatinine 273 μmol/L). He received albumin infusions and oral vitamin K. Infectious studies found negative serology for cytomegalovirus, Epstein-Barr virus, human herpes virus 6 (HHV6), hepatitis A, B, C and E, HIV 1 and 2, parvovirus B19, leptospirosis and measles. Polymerase chain reaction (PCR) for cytomegalovirus, Epstein-Barr virus and HHV6 was also negative. Antinucleic acid, anti-DNA and antineutrophil cytoplasmic antibody were negative. Liver biopsy performed on day 3 revealed only lymphocytic infiltration of the portal tracts with focal interface hepatitis. Gradually the patient improved clinically, and liver and renal function normalized. He was discharged on oral prednisone 10 days after admission. Two weeks later, however, he returned to hospital with 48 hours of fever and myalgias. On admission, he was febrile at 38.3°C with an otherwise entirely normal physical examination. Liver enzymes were again elevated: alanine aminotransferase 133 U/L, aspartate aminotransferase 237 U/L, gamma-glutamyltransferase 59 U/L. Serum creatine phosphokinase was elevated at 3164 U/L, and myoglobinuria was present. Urea and creatinine were elevated at 13 mmol/L and 93 μmol/L, respectively. At admission, his prednisone dose was increased to 50 mg twice daily. He quickly defervesced, and his muscle pain resolved. Skin patch testing for ethambutol, rifampin and pyrazinamide was negative (while on steroids). On repeat testing, IgG for HHV6 was now positive, although HHV6 PCR remained negative. The patient began a new antituberculosis regimen of amikacin, levofloxacin, cycloserine and para-aminosalicylic acid. He was weaned off prednisone over the next 9 weeks with no further clinical or biochemical recurrence of DRESS and remains well 1 year later.
DISCUSSION We describe a 12-year-old boy with fever, rash, lymphadenopathy, hepatic dysfunction and eosinophilia presenting 4 weeks after initiation of 3 antituberculosis medications. The presentation was suggestive of DRESS, for which the diagnostic criteria are: (1) rash ≥3 weeks after drug commencement, (2) prolonged clinical symptoms ≥2 weeks after drug discontinuation, (3) fever >38°C, (4) liver or renal dysfunction, (5) hematologic abnormalities (leukocytosis >11 × 109, atypical lymphocytes >5% and/or eosinophilia >1.5 × 109), (6) lymphadenopathy and (7) viral reactivation (HHV6).3 The presence of all 7 criteria constitutes a typical diagnosis, whereas 5 criteria suggest a probable or atypical diagnosis. Clinical criteria have also been used in a scoring system by RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions)2 and subsequently validated.4 Additions in this classification include ruling out other etiologies (negative antinucleic acid blood culture, serology for hepatitis viruses, chlamydia and mycoplasma) and involvement of at least 1 internal organ (not limited to liver or kidney). Although hepatic involvement is the most common (up to 90% of cases), several organs may be affected including the kidneys, gastrointestinal tract, lungs and muscles, with rare endocrine, cardiovascular or central nervous system involvement.1,3,5 Using the RegiSCAR score, 5 indicates a definite case.2 The patient in our report scored 7 points, yielding a definite diagnosis of DRESS. The presence of significant constitutional symptoms, rash and hematologic findings suggests DRESS rather than simple drugrelated hepatotoxicity, which presents as isolated hepatocellular injury or cholestasis. Although DRESS typically occurs 3–4 weeks after drug initiation, onset has been reported as early as 5 days to as late as © 2013 Lippincott Williams & Wilkins
DRESS Syndrome
16 weeks.4–6 Furthermore, thyroid manifestations can occur up to 2–3 months after resolution.5 Additional support for the diagnosis in atypical cases may include liver and/or skin biopsy.1,5,6 Liver biopsy specimens typically show an eosinophilic infiltrate with or without granulomata, accompanied by necrosis and/or cholestasis.1 In liver failure, disseminated hepatic necrosis may be seen. Common pharmacologic triggers for DRESS include aromatic anticonvulsants (phenobarbital, phenytoin, carbamazepine), antibiotics (trimethoprim/sulfamethoxazole, minocycline), dapsone, allopurinol and nevirapine.4 The list of etiologic agents is rapidly expanding, and cases have been reported with >50 drugs, including other anticonvulsants, antibiotics, nonsteroidal anti-inflammatory drugs and cardiovascular medications.3–5 Only a handful of previous reports have described DRESS in patients taking antituberculosis agents.7–10 The syndrome has been associated with combination therapy using first-line (isonizaid, rifampin, pyrazinamide, ethambutol) or second-line agents (prothionamide, para-aminosalycilic acid), but in most patients the triggering medication(s) could not be isolated. In patients taking first-line antituberculosis drugs, DRESS syndrome may be mistaken for more common drug reactions, particularly to rifampin. Indeed, early series describing reactions to rifampin include patients who might now be recognized to have DRESS.11 Cutaneous reactions such as flushing or rash are the most common adverse effects of rifampin, and usually occur early in the treatment course.12 Fever may occur as part of a flu-like syndrome that typically presents after the third month of therapy.12 The lymphadenopathy, leukocyte disturbances and HHV6 reactivation of DRESS syndrome are not generally seen in patients taking rifampin. There has been debate in the literature over HHV6 as trigger versus consequence of DRESS. Recent reports support the latter (viral reactivation), which is consistent temporally as HHV6 DNA is typically detected 3–4 weeks after onset of rash.6 Moreover, significantly decreased levels of serum immunoglobulins and CD19+ B cells have been shown in patients with DRESS, together with elevated CD8+ T cells, interferon-γ and interleukin-5.13 This milieu favors reactivation of HHV6 and other herpes viral genomes harbored in T cells, similar to the order of reactivation in patients with graft-versus-host disease.13 In our patient, the presence of HHV6 IgG with negative HHV6 PCR likely represents previous infection, although primary HHV6 infection could be responsible. HHV6 reactivation is less likely, given the negative PCR. However, it is not possible to confirm this without a previous negative HHV6 IgG measurement. The most important management step for DRESS is cessation of offending medication(s). Supportive therapy is often initiated with analgesia, antipyretics, fluid replacement and topical preparations (antihistamines, corticosteroids).6 No randomized studies have evaluated the role of any specific therapy for DRESS, and no consensus guidelines exist for its management. The majority of therapeutic strategies are therefore gleaned from case reports or series. The mainstay of pharmacologic treatment is systemic corticosteroids at 1–2 mg/kg/d for an average of 6 weeks.5,6 Steroids have been shown to inhibit interleukin-5 and accumulation of eosinophils.6 The average time to clinical resolution is typically 4–6 weeks, but patients may paradoxically have a period of worsening upon withdrawal of the offending drug and interludes of resolution/exacerbation over weeks to months.6 N-acetylcystine has been suggested as complementary therapy for DRESS given its potential to prevent free radical– related hepatotoxicity and modulate inflammatory cytokine production.13 However, literature surrounding its use in DRESS has www.pidj.com | 1389
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described variable effectiveness. The most advocated alternative for corticosteroid nonresponders is intravenous immune globulin 1–1.5 g/kg/d for 1–2 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-cell–mediated 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 50–75% 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 5–8 weeks after rash onset. Conversely, patch testing yields optimal results 1–6 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;15:250–257. 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;156:609–611. 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;29:481–501. 4. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588–597. 5. Newell BD, Moinfar M, Mancini AJ, et al. Retrospective analysis of 32 pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS). Pediatr Dermatol. 2009;26:536–546. 6. Seth D, Kamat D, Montejo J. DRESS syndrome: a practical approach for primary care practitioners. Clin Pediatr (Phila). 2008;47:947–952. 7. Palmero D, Castagnino J, Musella RM, et al. Difficult clinical management of anti-tuberculosis DRESS syndrome. Int J Tuberc Lung Dis. 2013;17: 76–78. 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;110:118–119. 9. Rodríguez 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;22:380–381. 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;23:521–525. 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;1:765–771. 12. Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf. 2006;5:231–249. 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;32:391–408.
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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;62:1439–1444.
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 Children’s 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, Children’s Hospital, Cleveland Clinic, 9500 Euclid Avenue/S25, Cleveland, OH 44195. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/13/3212-1392 DOI: 10.1097/INF.0000000000000069
B
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.1–17 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 (7.2 mg/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
Cheng et al
symptoms and signs of UTI. However, we could not define a specific serotype that might have a predilection for the urinary tract because all the children summarized in Table 1 were infected by different serotypes. It is suggested that S. pneumoniae can cause UTI through multiple factors of the host immune system and bacterial virulence.
ACKNOWLEDGMENTS The Streptococcus pneumoniae isolates of cases 1 and 2 in this study were obtained from the Asian Bacterial Bank of the Asia Pacific Foundation for Infectious Diseases (ABB APFID, Seoul, South Korea). Serotyping, bile solubility and antimicrobial susceptibility testing using the broth microdilution method were performed at ABB of APFID. REFERENCES 1. Nguyen VQ, Penn RL. Pneumococcusuria in adults. J Clin Microbiol. 1988;26:1085–1087. 2. Miller MA, Kaplan BS, Sorger S, et al. Pneumococcosuria in children. J Clin Microbiol. 1989;27:99–101. 3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement M100-S23. Wayne, PA: Clinical and Laboratory Standards Institute; 2013. 4. Burckhardt I, Zimmermann S. Streptococcus pneumoniae in urinary tracts of children with chronic kidney disease. Emerg Infect Dis. 2011;17:120–122. 5. Krishna S, Sanjeevan KV, Sudheer A, et al. Pneumococcusuria: From bench to bedside. Indian J Med Microbiol. 2012;30:96–98. 6. Subcommittee on Urinary Tract Infection SCoQIaM. 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. 7. Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis. 2004;4:144–154. 8. Chromek M, Slamová Z, Bergman P, et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med. 2006;12:636–641. 9. Trnka P, Hiatt MJ, Tarantal AF, et al. Congenital urinary tract obstruction: defining markers of developmental kidney injury. Pediatr Res. 2012;72:446–454. 10. Lundstedt AC, McCarthy S, Gustafsson MC, et al. A genetic basis of susceptibility to acute pyelonephritis. PLoS One. 2007;2:e825. 11. Yuan FF, Marks K, Wong M, et al. Clinical relevance of TLR2, TLR4, CD14 and FcgammaRIIA gene polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol. 2008;86:268–270. 12. Weinberger DM, Harboe ZB, Sanders EA, et al. Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clin Infect Dis. 2010;51:692–699. 13. Ruiz V, Rodríguez-Cerrato V, Huelves L, et al. Adherence of Streptococcus pneumoniae to polystyrene plates and epithelial cells and the antiadhesive potential of albumin and xylitol. Pediatr Res. 2011;69:23–27.
DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS SYNDROME ASSOCIATED WITH ANTITUBERCULOSIS MEDICATIONS Julianna Cheng, MD, MSc, FRCPC,*† Surabhi Rawal, MD,‡ Ashley Roberts, MD, MEd, FRCPC,*§ and Orlee R. Guttman, MD, MEd, FRCPC*† Abstract: Drug reaction with eosinophilia and systemic symptoms is a potentially life-threatening syndrome of medication hypersensitivity associated with a wide variety of triggers. Diagnosis can be challenging, as clinical features suggest other conditions. We describe a 12-year-old boy with typical drug reaction with eosinophilia and systemic symptoms syndrome after antituberculosis therapy. Key Words: drug hypersensitivity, drug eruptions, antitubercular agents, drug reaction with eosinophilia and systemic symptoms syndrome
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Accepted for publication June 14, 2013. From the *University of British Columbia; †Division of Gastroenterology, Hepatology and Nutrition; ‡Department of Pediatrics; and §Division of Infectious Diseases, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Orlee R. Guttman, MD, MEd, FRCPC, British Columbia Children’s Hospital, 4480 Oak Street, Rm K4-201, Vancouver, British Columbia, Canada, V6H3V4. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0b013e3182a09f20
F
irst described in 1996, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome typically manifests as a triad of fever, rash and lymphadenopathy, with additional visceral involvement.1 Aromatic anticonvulsants are the most common etiologic agents, and thus the term has been used interchangeably with anticonvulsant hypersensitivity syndrome as well as with drug-induced hypersensitivity syndrome.2 The incidence in individuals taking anticonvulsant medications is reported at 1/1000–1/10,0003; the incidence with other agents is less clear. Symptoms of DRESS syndrome generally arise 2–6 weeks after drug initiation and can pose a considerable diagnostic challenge. Presenting features of DRESS overlap with those of other disorders, including dermatological (Stevens–Johnson syndrome, toxic epidermal necrolysis), rheumatologic (Kawasaki disease, systemic onset juvenile idiopathic arthritis, systemic lupus erythematosus), hematologic (macrophage activation syndrome, hematologic malignancies) and infectious (Epstein-Barr virus, cytomegalovirus, HIV, parvovirus, mycoplasma, chlamydia and staphylococcus scalded skin syndrome). Timely recognition and management of DRESS is vital as mortality rates as high as 10% have been reported.3
CASE REPORT A previously well 12-year-old boy, recently immigrated from Korea, was diagnosed with tuberculosis based on positive Mantoux and radiologic evidence of a pleural effusion. Immigration screening had revealed active, isoniazid-resistant tuberculosis in his father. The patient started ethambutol 800 mg daily, rifampin 600 mg daily and pyrazinamide 1g daily. Four weeks later the patient presented with a pruritic rash, diarrhea and fever. He was diagnosed with a viral illness, and supportive measures were recommended. Three days later he returned to hospital with vomiting and worsening abdominal pain and distension. On admission, the patient was febrile at 39.9°C with otherwise normal vital signs. An extensive blanchable, erythematous maculopapular rash was seen on the torso and proximal extremities, with purpura on the distal extremities. His abdomen was exquisitely tender with a liver edge palpable at 11 cm below the costal margin and bulging flanks, but no splenomegaly. His extremities and scrotum were edematous. He had cervical and submandibular lymphadenopathy. Investigations revealed eosinophilia (1.26 × 109/L), lymphopenia (0.25 × 109/L), atypical lymphocytosis (1.60 × 109/L) and thrombocytopenia (85 × 109/L). Albumin was low at 23 g/L and transaminases elevated: alanine aminotransferase 588 U/L, aspartate aminotransferase 461 U/L and gamma-glutamyltransferase 121 U/L. International normalized ratio was 1.42. Bilirubin, creatinine and urea were normal. The patient’s tuberculosis medications were discontinued. A loading dose of intravenous methylprednisolone 0.8 mg/kg was © 2013 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 32, Number 12, December 2013
administered, followed by 0.5 mg/kg twice daily. Despite this, liver function deteriorated (peak international normalized ratio 1.8), and he developed acute renal failure (peak creatinine 273 μmol/L). He received albumin infusions and oral vitamin K. Infectious studies found negative serology for cytomegalovirus, Epstein-Barr virus, human herpes virus 6 (HHV6), hepatitis A, B, C and E, HIV 1 and 2, parvovirus B19, leptospirosis and measles. Polymerase chain reaction (PCR) for cytomegalovirus, Epstein-Barr virus and HHV6 was also negative. Antinucleic acid, anti-DNA and antineutrophil cytoplasmic antibody were negative. Liver biopsy performed on day 3 revealed only lymphocytic infiltration of the portal tracts with focal interface hepatitis. Gradually the patient improved clinically, and liver and renal function normalized. He was discharged on oral prednisone 10 days after admission. Two weeks later, however, he returned to hospital with 48 hours of fever and myalgias. On admission, he was febrile at 38.3°C with an otherwise entirely normal physical examination. Liver enzymes were again elevated: alanine aminotransferase 133 U/L, aspartate aminotransferase 237 U/L, gamma-glutamyltransferase 59 U/L. Serum creatine phosphokinase was elevated at 3164 U/L, and myoglobinuria was present. Urea and creatinine were elevated at 13 mmol/L and 93 μmol/L, respectively. At admission, his prednisone dose was increased to 50 mg twice daily. He quickly defervesced, and his muscle pain resolved. Skin patch testing for ethambutol, rifampin and pyrazinamide was negative (while on steroids). On repeat testing, IgG for HHV6 was now positive, although HHV6 PCR remained negative. The patient began a new antituberculosis regimen of amikacin, levofloxacin, cycloserine and para-aminosalicylic acid. He was weaned off prednisone over the next 9 weeks with no further clinical or biochemical recurrence of DRESS and remains well 1 year later.
DISCUSSION We describe a 12-year-old boy with fever, rash, lymphadenopathy, hepatic dysfunction and eosinophilia presenting 4 weeks after initiation of 3 antituberculosis medications. The presentation was suggestive of DRESS, for which the diagnostic criteria are: (1) rash ≥3 weeks after drug commencement, (2) prolonged clinical symptoms ≥2 weeks after drug discontinuation, (3) fever >38°C, (4) liver or renal dysfunction, (5) hematologic abnormalities (leukocytosis >11 × 109, atypical lymphocytes >5% and/or eosinophilia >1.5 × 109), (6) lymphadenopathy and (7) viral reactivation (HHV6).3 The presence of all 7 criteria constitutes a typical diagnosis, whereas 5 criteria suggest a probable or atypical diagnosis. Clinical criteria have also been used in a scoring system by RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions)2 and subsequently validated.4 Additions in this classification include ruling out other etiologies (negative antinucleic acid blood culture, serology for hepatitis viruses, chlamydia and mycoplasma) and involvement of at least 1 internal organ (not limited to liver or kidney). Although hepatic involvement is the most common (up to 90% of cases), several organs may be affected including the kidneys, gastrointestinal tract, lungs and muscles, with rare endocrine, cardiovascular or central nervous system involvement.1,3,5 Using the RegiSCAR score, 5 indicates a definite case.2 The patient in our report scored 7 points, yielding a definite diagnosis of DRESS. The presence of significant constitutional symptoms, rash and hematologic findings suggests DRESS rather than simple drugrelated hepatotoxicity, which presents as isolated hepatocellular injury or cholestasis. Although DRESS typically occurs 3–4 weeks after drug initiation, onset has been reported as early as 5 days to as late as © 2013 Lippincott Williams & Wilkins
DRESS Syndrome
16 weeks.4–6 Furthermore, thyroid manifestations can occur up to 2–3 months after resolution.5 Additional support for the diagnosis in atypical cases may include liver and/or skin biopsy.1,5,6 Liver biopsy specimens typically show an eosinophilic infiltrate with or without granulomata, accompanied by necrosis and/or cholestasis.1 In liver failure, disseminated hepatic necrosis may be seen. Common pharmacologic triggers for DRESS include aromatic anticonvulsants (phenobarbital, phenytoin, carbamazepine), antibiotics (trimethoprim/sulfamethoxazole, minocycline), dapsone, allopurinol and nevirapine.4 The list of etiologic agents is rapidly expanding, and cases have been reported with >50 drugs, including other anticonvulsants, antibiotics, nonsteroidal anti-inflammatory drugs and cardiovascular medications.3–5 Only a handful of previous reports have described DRESS in patients taking antituberculosis agents.7–10 The syndrome has been associated with combination therapy using first-line (isonizaid, rifampin, pyrazinamide, ethambutol) or second-line agents (prothionamide, para-aminosalycilic acid), but in most patients the triggering medication(s) could not be isolated. In patients taking first-line antituberculosis drugs, DRESS syndrome may be mistaken for more common drug reactions, particularly to rifampin. Indeed, early series describing reactions to rifampin include patients who might now be recognized to have DRESS.11 Cutaneous reactions such as flushing or rash are the most common adverse effects of rifampin, and usually occur early in the treatment course.12 Fever may occur as part of a flu-like syndrome that typically presents after the third month of therapy.12 The lymphadenopathy, leukocyte disturbances and HHV6 reactivation of DRESS syndrome are not generally seen in patients taking rifampin. There has been debate in the literature over HHV6 as trigger versus consequence of DRESS. Recent reports support the latter (viral reactivation), which is consistent temporally as HHV6 DNA is typically detected 3–4 weeks after onset of rash.6 Moreover, significantly decreased levels of serum immunoglobulins and CD19+ B cells have been shown in patients with DRESS, together with elevated CD8+ T cells, interferon-γ and interleukin-5.13 This milieu favors reactivation of HHV6 and other herpes viral genomes harbored in T cells, similar to the order of reactivation in patients with graft-versus-host disease.13 In our patient, the presence of HHV6 IgG with negative HHV6 PCR likely represents previous infection, although primary HHV6 infection could be responsible. HHV6 reactivation is less likely, given the negative PCR. However, it is not possible to confirm this without a previous negative HHV6 IgG measurement. The most important management step for DRESS is cessation of offending medication(s). Supportive therapy is often initiated with analgesia, antipyretics, fluid replacement and topical preparations (antihistamines, corticosteroids).6 No randomized studies have evaluated the role of any specific therapy for DRESS, and no consensus guidelines exist for its management. The majority of therapeutic strategies are therefore gleaned from case reports or series. The mainstay of pharmacologic treatment is systemic corticosteroids at 1–2 mg/kg/d for an average of 6 weeks.5,6 Steroids have been shown to inhibit interleukin-5 and accumulation of eosinophils.6 The average time to clinical resolution is typically 4–6 weeks, but patients may paradoxically have a period of worsening upon withdrawal of the offending drug and interludes of resolution/exacerbation over weeks to months.6 N-acetylcystine has been suggested as complementary therapy for DRESS given its potential to prevent free radical– related hepatotoxicity and modulate inflammatory cytokine production.13 However, literature surrounding its use in DRESS has www.pidj.com | 1389
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described variable effectiveness. The most advocated alternative for corticosteroid nonresponders is intravenous immune globulin 1–1.5 g/kg/d for 1–2 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-cell–mediated 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 50–75% 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 5–8 weeks after rash onset. Conversely, patch testing yields optimal results 1–6 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;15:250–257. 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;156:609–611. 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;29:481–501. 4. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588–597. 5. Newell BD, Moinfar M, Mancini AJ, et al. Retrospective analysis of 32 pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS). Pediatr Dermatol. 2009;26:536–546. 6. Seth D, Kamat D, Montejo J. DRESS syndrome: a practical approach for primary care practitioners. Clin Pediatr (Phila). 2008;47:947–952. 7. Palmero D, Castagnino J, Musella RM, et al. Difficult clinical management of anti-tuberculosis DRESS syndrome. Int J Tuberc Lung Dis. 2013;17: 76–78. 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;110:118–119. 9. Rodríguez 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;22:380–381. 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;23:521–525. 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;1:765–771. 12. Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf. 2006;5:231–249. 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;32:391–408.
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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;62:1439–1444.
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 Children’s 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, Children’s Hospital, Cleveland Clinic, 9500 Euclid Avenue/S25, Cleveland, OH 44195. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/13/3212-1392 DOI: 10.1097/INF.0000000000000069
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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.1–17 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 (7.2 mg/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
