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Centers for Disease Control and Prevention, over 60% of people with HFMD were under 2 years of age; but a quarter were over the age of 18. In the adults with HFMD, 70% had exposure to a child care facility or school.2 The disease manifests as a painful maculopapular or vesicular rash on the distal extremities, commonly including the palms and soles. It has been noted on the buttocks and trunk as well. Desquamation of the skin can occur distally. It is associated with oral ulcers with or without the presence of fever.1,2 Painless nail changes have been noted 3–8 weeks later which have been perplexing to physicians and concerning to parents.3 Several studies have linked nail changes to cases of HFMD. It is thought to be due to an arrest of nail formation leading to onychomadesis or to Beau lines. Onychomadesis is the separation of the nail from the matrix below beginning proximally and spreading outward and can lead to nail loss. Beau lines, or transverse ridges, form with stoppage of nail growth.4 The interruption of nail formation is visible weeks after the insult and a resultant Beau line continue to grow out as the nail grows which is at a rate of approximately 1 mm/week.5
CASE PRESENTATION A 2 year old boy presented to clinic 3 weeks after the resolution of upper respiratory symptoms and a painful rash on the palms and soles, inhibiting walking. Blisters in the mouth interfered with eating. On presentation, his rash, blisters and congestion had resolved and he was afebrile, but was brought in due to concern for white lines across his fingernails with some of them lifting up. He still had remnants of hyperpigmented macules on the plantar surface of his feet but was otherwise well. His right thumb and first finger showed a horizontal line and indentation across the nail; the distal nail on the thumb was separated upward from the nail bed (Fig. 1). There was no history of trauma or recent medication use and no signs of fungal infection. He had started attending daycare a week prior to the development of symptoms.
DISCUSSION This child presented during the summer months following clinically diagnosed hand-foot-and-mouth disease and had nail dystrophies which were consistent with Beau lines as well as onychomadesis together. Presentation can be variable with rash consisting of macules, papules or vesicles isolated to the distal extremities or covering the buttocks and trunk. Oral lesions consistent with erosive
stomatitis may occur. The presence of fever is also variable.1,3 One study showed a significant correlation with the presence of desquamation and nail dystrophy; however, another could not show any association with disease severity and the development of nail abnormalities.1,6 More than 1 nail on either the digits of the hand or feet can be affected, with an average of 6–7 digits involved.1,6 The literature on this topic has been slowly increasing but there are not large cohorts studied in the United States. Onychomadesis is more frequently described than Beau lines. The frequency of nail changes in one study from Taiwan showed 20% (55/275) of patients with HFMD had nail abnormalities during a 2010 outbreak with 48/55 testing positive for coxsackievirus A6.1 Centers for Disease Control and Prevention, reported 4% nail shedding in a small US sample.2 Another study from Korea looked at 13 children with nail changes following HFMD and found that 8/13 had both onychomadesis and Beau lines, 2/13 had only onychomadesis and 3/13 had only Beau lines.6 Theories of the pathophysiology include inflammation of the nail matrix, a result of blisters on the fingers or possibly viral replication in the nail bed.1,6 Nail matrix arrest resulting in Beau lines and onychomadesis can also be seen in systemic illnesses such as Kawasaki disease and pemphigus vulgaris, as a result of local nail trauma, or following medication use. Inciting medications include anticonvulsants such as carbamazepine and valproic acid as well as some chemotherapeutic agents, retinoids and tetracycline.5,7,8 As in HFMD, these nail changes do not result in permanent disfigurement or discomfort. Changes resolve by the time the nail has grown out, in 1–2 months, or once the nail has shed and grows back. Previous clinical findings associated with HFMD should help put the family and pediatrician at ease when these nail abnormalities appear. REFERENCES 1. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackie A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346–351. 2. Centers for Disease Control and Prevention. Notes from the field: severe hand, foot, and mouth disease associated with Coxsackievirus A6— Alabama, Connecticut, California, and Nevada, November 2011–February 2012. MMWR. 2012;61:213–214. http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm6112a5.htm 3. Clementz GC, Mancini AJ. Nail matrix arrest following hand-foot-mouth disease: a report of five children. Pediatr Dermatol. 2000;17:7–11. 4. Haneke E. Onychomadesis and hand, foot and mouth disease—is there a connection? Euro Surveill. 2010;15:2. 5. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. A Textbook of Skin Disorders of Childhood and Adolescence. 2nd ed. Elsevier 1993: 507–508. 6. Shin JY, Cho BK, Park HJ. A Clinical Study of Nail Changes Occurring Secondary to Hand-Foot-Mouth Disease: Onychomadesis and Beau’s Lines. Ann Dermatol. 2014;26:280–283. 7. Piraccini BM, Iorizzo M, Starace M, et al. Drug-induced nail diseases. Dermatol Clin. 2006;24:387–391. 8. Ciastko AR. Onychomadesis and Kawasaki disease. CMAJ. 2002;166:1069.
EVIDENCE OF STAPHYLOCOCCAL TOXIC SHOCK SYNDROME CAUSED BY MRSA IN A MOTHER–NEWBORN PAIR Christina A. Rostad, MD, Rebecca Pass Philipsborn, MD, MPA, and Frank E. Berkowitz, MBBCh, MPH FIGURE 1. Transverse ridge along the thumbnail with distal separation of the nail from the bed.
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Abstract: A neonate and his mother presented with fever and erythroderma. The mother met full diagnostic criteria for staphylococcal toxic shock syndrome, whereas the neonate lacked hypotension and multiorgan dysfunction. A wound culture from the neonate’s circumcision site grew
© 2014 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 4, April 2015
methicillin-resistant Staphylococcus aureus containing the tst gene. This provides evidence of the first reported case of toxic shock syndrome caused by methicillin-resistant Staphylococcus aureus in a mother–newborn pair. Key Words: methicillin-resistant Staphylococcus aureus, toxic shock syndrome, neonatal toxic-shock syndrome-like exanthematous disease Accepted for publication September 23, 2014. From the Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA. The authors have no conflicts of interest or funding to disclose. Address for correspondence: Christina A. Rostad, MD, Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, 2015 Upper Gate Drive, Atlanta, GA. E-mail: [email protected]. Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000580
A
3-day-old male presented with fever, erythroderma and swelling at his circumcision site. He had been born at a gestational age of 39 weeks and 1 day via spontaneous vaginal delivery. There were no complications with the pregnancy or delivery, and maternal prenatal laboratory test results were normal. The neonate was circumcised and discharged home after 24 hours of life. On the day of presentation, he developed fever (temperature 100.7°F), irritability and rash. His physical examination was notable for jaundice, diffuse erythroderma and swelling with exudate around the circumcision site. His laboratory values demonstrated a white blood cell count (WBC) of 7870 per μL (70% neutrophils, 16% lymphocytes, 8% atypical lymphocytes, 4% eosinophils and 2% monocytes), a hematocrit of 69.2%, a platelet count of 49,000 per μL and a slightly elevated C-reactive protein (1.4 mg/dL). The cerebrospinal fluid (CSF) was bloody with 0 WBC/μL, 3525 red blood cells/μL, and protein and glucose concentrations of 71 mg/dL and 51 mg/dL, respectively. The urinalysis was normal. Serum chemistry tests revealed an aspartate aminotransferase of 83 U/L (normal = 47–150 U/L), alanine aminotransferase of 29 U/L (normal = 13–45 U/L) and total bilirubin concentration of 14.8 mg/dL, with a direct component of 0 mg/dL. Serum electrolytes and creatinine were unremarkable. The prothrombin time and partial thromboplastin time were not prolonged, but the D-dimer concentration was elevated (3433 ng/ mL, normal = 0–220 ng/mL) and the fibrinogen concentration was decreased (180 mg/dL, normal = 200–400 mg/dL). The patient was admitted to the hospital and treated presumptively for neonatal sepsis with ampicillin and cefotaxime. Acyclovir was added for empiric herpes simplex virus (HSV) coverage due to the infant’s age. Vancomycin was also added due to concern for staphylococcal wound infection. The following day, the patient’s mother was admitted to the medical intensive care unit at an affiliated institution with fever, myalgias, erythroderma and hypotensive shock. Her physical examination was notable for erythroderma and vaginal hyperemia. She was diagnosed clinically with endometritis, and she treated empirically with vancomycin, piperacillin-tazobactam and clindamycin. Pelvic ultrasonography and computed tomography were negative for retained products of conception and no vaginal foreign bodies were identified. Her laboratory values demonstrated a WBC of 29,300 per μL with 61% segmented neutrophils, 33% band forms, 2% metamyelocytes, 1% myelocytes, 1% monocytes and 2% eosinophils. Her platelet count reached a nadir of 142,000 per μL and her serum creatinine peaked at 1.1 mg/dL. She had an elevated aspartate aminotransferase 69 U/L (normal = 10–36 U/L), alanine aminotransferase 53 U/L (normal = 7–35 U/L) and serum bilirubin (total bilirubin 7 mg/dL, with a direct component of 3.5 mg/ dL), in addition to coagulopathy (prothtrombin time of 17 seconds, © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Mother–Newborn Toxic Shock Syndrome
partial thromboplastin of 46.4 seconds, D-dimers of 8800 ng/ mL and fibrinogen concentration of 633 mg/dL). Her urinalysis demonstrated sterile pyuria with a strongly positive leukocyte esterase on dipstick and a WBC of 58 per high-power field. Results for blood, urine and throat cultures were negative, and a vaginal culture was not performed. A wound culture of purulent exudate from the neonate’s circumcision site had a heavy growth of methicillin-resistant Staphylococcus aureus (MRSA) and a light growth of Escherichia coli. Blood, urine and CSF cultures were all negative, as were HSV surface cultures and CSF HSV DNA polymerase chain reaction. He was therefore treated with vancomycin for MRSA and cefazolin to cover E. coli for a total 10-day course. His symptoms resolved and he completely recovered. His mother also completely recovered and was discharged home with oral levofloxacin and clindamycin to complete a 10-day course. Both the infant and his mother developed desquamation on the hands within 2 weeks of their admissions. Thus, the mother met full diagnostic criteria for confirmed toxic shock syndrome (TSS). Although the neonate did not meet full TSS diagnostic criteria, he demonstrated multiple clinical features consistent with toxic shock syndrome toxin-1 (TSST-1) mediated disease. Subsequent testing of the neonate’s MRSA isolate for the TSST-1 gene via polymerase chain reaction was positive. The isolate was further characterized as protein A (spa) type t002 with type IV SCCmec element and clindamycin resistance.
DISCUSSION We present evidence of the first case of staphylococcal TSS in a mother–newborn pair caused by MRSA containing the TSST-1 producing gene. Previously reported cases of staphylococcal TSS in mother–newborn pairs were either culture negative or were caused by methicillin-susceptible S. aureus which produced toxins other than TSST-1.1,2 Staphylococcal TSS is a toxin-mediated clinical syndrome characterized by fever, erythroderma, shock and multiorgan dysfunction. It is caused by strains of S. aureus which produce superantigen exotoxins, the most common of which is TSST-1. TSST-1 induces polyclonal Vβ2+ T cell activation and proliferation by bypassing the usual major histocompatibility complex-restricted interaction between antigen presenting cells and T cells.3 The subsequent cytokine storm is responsible for the systemic inflammatory response characteristic of TSS. Despite the prevalence of MRSA, reports of staphylococcal TSS caused by methicillin-resistant strains are rare; this report may reflect an evolving epidemiology of TSS in the United States. Clinicians caring for neonates should maintain a high index of suspicion for staphylococcal TSS because S. aureus is generally resistant to the usual antimicrobials used to treat neonatal sepsis. Additionally, neonates may be misdiagnosed because they typically do not meet full diagnostic criteria for TSS; indeed, our patient lacked hypotension and had only 2 components of multiorgan dysfunction. The reason for the incomplete clinical presentation of neonates has not been fully elucidated. Epidemiologic data suggests that TSST-1 causes a spectrum of clinical disease in adults.4 This spectrum of disease is modulated by components of both the cellular and humoral immune systems.5–7 It therefore appears likely that components of the immature neonatal immune system drive the spectrum of disease in this population. There is evidence that a recently described clinical syndrome termed neonatal toxic shock syndrome-like exanthematous disease (NTED) also lies on the spectrum of TSST-1-mediated disease in neonates. This syndrome, first reported in Japan in the 1990s, has www.pidj.com | 451
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Qamar et al
been attributed to TSST-1 based on its association with high colonization rates with TSST-1-producing S. aureus8,9 and based on the findings of massive polyclonal Vβ2+ T cell expansion in affected neonates.7 The pathogenesis of NTED is thought to be the same as that of TSS; however, affected neonates demonstrate a rapid decline of Vβ2+ T cells7 and ultimately fail to meet TSS diagnostic criteria. NTED is characterized by fever, exanthema and thrombocytopenia. In contrast to TSS, shock and multiorgan dysfunction are rare, and symptoms usually spontaneously regress within a few days. Despite the milder clinical course, a wide spectrum of disease is also seen with NTED. Although our patient shared some features of NTED, his presentation differed in several ways. First, in addition to fever, erythroderma and thrombocytopenia, he also had coagulopathy, hyperbilirubinemia and palmar desquamation. Secondly, his wound infection and clinical symptoms were severe enough to warrant antimicrobial therapy, whereas symptoms of NTED spontaneously resolve without intervention. Thirdly, the infant’s mother had a clinical diagnosis of TSS, which has not been previously reported with NTED. Lastly, the patient’s microbiologic isolate, MRSA spa type 002 with type IV SCCmec, is distinct from those previously reported to cause NTED.9 Despite these differences, it seems likely that TSST-1 produces a spectrum of disease that is modulated by components of the neonatal immune response. The expression of this response likely includes, but is not limited to, the clinical features of NTED. Clinicians should maintain a high index of suspicion for TSST-1 mediated disease in the neonatal population, as the clinical presentation is heterogeneous and often incomplete, and the causative pathogen may be resistant to standardly utilized antimicrobials.
ACKNOWLEDGMENTS The authors thank Joseph A. Snitzer as the attending physician who provided care to the patient. The authors also thank Valerie Albrecht, Mitch Granade, Linda McDougal and David Lonsway from the Centers for Disease Control and Prevention for performing TSST-1 PCR testing and S. aureus strain typing.
REFERENCES 1. Green SL, LaPeter KS. Evidence for postpartum toxic-shock syndrome in a mother–infant pair. Am J Med. 1982;72:169–172. 2. Lacoste A, Torregrosa A, Dubois S, et al. [Maternal-fetal staphylococcal toxic shock syndrome with chorioamniotitis]. Arch Pediatr. 2006;13:1132–1134. 3. Choi Y, Lafferty JA, Clements JR, et al. Selective expansion of T cells expressing V beta 2 in toxic shock syndrome. J Exp Med. 1990;172:981–984. 4. DeVries AS, Lesher L, Schlievert PM, et al. Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features, and molecular characteristics. PLoS One 2011;6:e22997. 5. Dateki S, Kumamoto T, Takayanagi T, et al. Differential T-cell response in a young child and neonates with toxic shock syndrome. Pediatr Int. 2009;51:155–156. 6. Kamel NS, Banks MC, Dosik A, et al. Lack of muco-cutaneous signs of toxic shock syndrome when T cells are absent: S. aureus shock in immunodeficient adults with multiple myeloma. Clin Exp Immunol. 2002;128:131–139. 7. Takahashi N, Kato H, Imanishi K, et al. Immunopathophysiological aspects of an emerging neonatal infectious disease induced by a bacterial superantigen. J Clin Invest. 2000;106:1409–1415. 8. Takahashi N, Nishida H, Kato H, et al. Exanthematous disease induced by toxic shock syndrome toxin 1 in the early neonatal period. Lancet. 1998;351:1614–1619. 9. Kikuchi K, Takahashi N, Piao C, et al. Molecular epidemiology of methicillin-resistant Staphylococcus aureus strains causing neonatal toxic shock syndrome-like exanthematous disease in neonatal and perinatal wards. J Clin Microbiol. 2003;41:3001–3006.
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Prevalence and Clinical Burden of NDM-1 Positive Infections in Pediatric and Neonatal Patients in Pakistan Muhammad Usman Qamar, MPhil,* Fouzia Nahid, MPhil,* Timothy R. Walsh, PhD,† Rubina Kamran, MPhil,‡ and Rabaab Zahra, PhD* Abstract: In a neonatal/pediatric Gram-negative infection study from Islamabad, 71/82 strains were carbapenem resistant with 12/82 positive for New Delhi Metallo-β-lactamase and many being extensively antibiotic resistant. Burden and outcome analysis on 9 patients showed that 4/9 died after inadequate therapy regardless of organism type. Key Words: NDM-1, carbapenem resistance, neonates, Pakistan Accepted for publication September 23, 2014. From the *Department of Microbiology, Quaid-i-Azam University, Islamabad, 45320 Pakistan; †School of Medicine, Department of Infection, Immunity and Biochemistry, Cardiff University, Heath Park, Cardiff, United Kingdom; and ‡Department of Microbiology and Pathology, Pakistan Institute of Medical Sciences Hospital, Islamabad, Pakistan. The authors have no conflicts of interest to disclose. Address for correspondence: Rabaab Zahra, PhD, Department of Microbiology, Quaid-i-Azam University, Islamabad, 45320 Pakistan. E-mail: rzahra@qau. edu.pk. 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 journal’s website (www.pidj.com). Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000582
T
reatment of infections in children particularly neonates is becoming increasingly difficult because of the occurrence of extensively drug-resistant organisms. Globally, the most common causes of neonatal/pediatric deaths are infectious diseases (68%) that include pneumonia (18%), diarrhea (15%) and malaria (8%).1 As the prevalence of ESBL-producing organisms is very high,2 the treatment for severe infections often uses carbapenems; however, resistance to carbapenems is emerging of which the most potent mechanism of resistance is carbapenamases such as New Delhi Metallo-β-lactamase (NDM-1). Carbapenem resistance in infections in children results in treatment failure and severely limits future treatment regimes. The carriage of NDM-1 in Gramnegative organisms in Pakistan has been assessed in a few pilot studies2,3 but its prevalence in pathogens causing infections in neonates/pediatrics and their subsequent clinical outcome has not been evaluated. Accordingly, this study examined the prevalence of blaNDM-1 in clinical isolates in children ≤5 years of age in Pakistan. In addition, we also determined the risk factors for infection such as age, sex, underlying disease, length of hospital stay and assessed the burden of resistance in children with NDM-1 positive pathogens.
METHODS Clinical Isolates During July 2011 to March 2012, 82 meropenem-resistant Gram-negative isolates from children ≤5years age were collected from 3 children hospitals in Pakistan: The Children’s hospital, the Pakistan Institute of Medical Sciences (PIMS), Islamabad (n = 52), The Children’s Hospital Multan (n = 20) and Nishtar Hospital, Multan (n = 10). Clinical detailed data was collected from PIMS on 9 patients examining comorbidities, length of hospital stay and outcome and are listed in Table, Supplemental Digital Content 1, http://links.lww.com/INF/C34. © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Rostad et al
Centers for Disease Control and Prevention, over 60% of people with HFMD were under 2 years of age; but a quarter were over the age of 18. In the adults with HFMD, 70% had exposure to a child care facility or school.2 The disease manifests as a painful maculopapular or vesicular rash on the distal extremities, commonly including the palms and soles. It has been noted on the buttocks and trunk as well. Desquamation of the skin can occur distally. It is associated with oral ulcers with or without the presence of fever.1,2 Painless nail changes have been noted 3–8 weeks later which have been perplexing to physicians and concerning to parents.3 Several studies have linked nail changes to cases of HFMD. It is thought to be due to an arrest of nail formation leading to onychomadesis or to Beau lines. Onychomadesis is the separation of the nail from the matrix below beginning proximally and spreading outward and can lead to nail loss. Beau lines, or transverse ridges, form with stoppage of nail growth.4 The interruption of nail formation is visible weeks after the insult and a resultant Beau line continue to grow out as the nail grows which is at a rate of approximately 1 mm/week.5
CASE PRESENTATION A 2 year old boy presented to clinic 3 weeks after the resolution of upper respiratory symptoms and a painful rash on the palms and soles, inhibiting walking. Blisters in the mouth interfered with eating. On presentation, his rash, blisters and congestion had resolved and he was afebrile, but was brought in due to concern for white lines across his fingernails with some of them lifting up. He still had remnants of hyperpigmented macules on the plantar surface of his feet but was otherwise well. His right thumb and first finger showed a horizontal line and indentation across the nail; the distal nail on the thumb was separated upward from the nail bed (Fig. 1). There was no history of trauma or recent medication use and no signs of fungal infection. He had started attending daycare a week prior to the development of symptoms.
DISCUSSION This child presented during the summer months following clinically diagnosed hand-foot-and-mouth disease and had nail dystrophies which were consistent with Beau lines as well as onychomadesis together. Presentation can be variable with rash consisting of macules, papules or vesicles isolated to the distal extremities or covering the buttocks and trunk. Oral lesions consistent with erosive
stomatitis may occur. The presence of fever is also variable.1,3 One study showed a significant correlation with the presence of desquamation and nail dystrophy; however, another could not show any association with disease severity and the development of nail abnormalities.1,6 More than 1 nail on either the digits of the hand or feet can be affected, with an average of 6–7 digits involved.1,6 The literature on this topic has been slowly increasing but there are not large cohorts studied in the United States. Onychomadesis is more frequently described than Beau lines. The frequency of nail changes in one study from Taiwan showed 20% (55/275) of patients with HFMD had nail abnormalities during a 2010 outbreak with 48/55 testing positive for coxsackievirus A6.1 Centers for Disease Control and Prevention, reported 4% nail shedding in a small US sample.2 Another study from Korea looked at 13 children with nail changes following HFMD and found that 8/13 had both onychomadesis and Beau lines, 2/13 had only onychomadesis and 3/13 had only Beau lines.6 Theories of the pathophysiology include inflammation of the nail matrix, a result of blisters on the fingers or possibly viral replication in the nail bed.1,6 Nail matrix arrest resulting in Beau lines and onychomadesis can also be seen in systemic illnesses such as Kawasaki disease and pemphigus vulgaris, as a result of local nail trauma, or following medication use. Inciting medications include anticonvulsants such as carbamazepine and valproic acid as well as some chemotherapeutic agents, retinoids and tetracycline.5,7,8 As in HFMD, these nail changes do not result in permanent disfigurement or discomfort. Changes resolve by the time the nail has grown out, in 1–2 months, or once the nail has shed and grows back. Previous clinical findings associated with HFMD should help put the family and pediatrician at ease when these nail abnormalities appear. REFERENCES 1. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackie A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346–351. 2. Centers for Disease Control and Prevention. Notes from the field: severe hand, foot, and mouth disease associated with Coxsackievirus A6— Alabama, Connecticut, California, and Nevada, November 2011–February 2012. MMWR. 2012;61:213–214. http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm6112a5.htm 3. Clementz GC, Mancini AJ. Nail matrix arrest following hand-foot-mouth disease: a report of five children. Pediatr Dermatol. 2000;17:7–11. 4. Haneke E. Onychomadesis and hand, foot and mouth disease—is there a connection? Euro Surveill. 2010;15:2. 5. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. A Textbook of Skin Disorders of Childhood and Adolescence. 2nd ed. Elsevier 1993: 507–508. 6. Shin JY, Cho BK, Park HJ. A Clinical Study of Nail Changes Occurring Secondary to Hand-Foot-Mouth Disease: Onychomadesis and Beau’s Lines. Ann Dermatol. 2014;26:280–283. 7. Piraccini BM, Iorizzo M, Starace M, et al. Drug-induced nail diseases. Dermatol Clin. 2006;24:387–391. 8. Ciastko AR. Onychomadesis and Kawasaki disease. CMAJ. 2002;166:1069.
EVIDENCE OF STAPHYLOCOCCAL TOXIC SHOCK SYNDROME CAUSED BY MRSA IN A MOTHER–NEWBORN PAIR Christina A. Rostad, MD, Rebecca Pass Philipsborn, MD, MPA, and Frank E. Berkowitz, MBBCh, MPH FIGURE 1. Transverse ridge along the thumbnail with distal separation of the nail from the bed.
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Abstract: A neonate and his mother presented with fever and erythroderma. The mother met full diagnostic criteria for staphylococcal toxic shock syndrome, whereas the neonate lacked hypotension and multiorgan dysfunction. A wound culture from the neonate’s circumcision site grew
© 2014 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 4, April 2015
methicillin-resistant Staphylococcus aureus containing the tst gene. This provides evidence of the first reported case of toxic shock syndrome caused by methicillin-resistant Staphylococcus aureus in a mother–newborn pair. Key Words: methicillin-resistant Staphylococcus aureus, toxic shock syndrome, neonatal toxic-shock syndrome-like exanthematous disease Accepted for publication September 23, 2014. From the Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA. The authors have no conflicts of interest or funding to disclose. Address for correspondence: Christina A. Rostad, MD, Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, 2015 Upper Gate Drive, Atlanta, GA. E-mail: [email protected]. Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000580
A
3-day-old male presented with fever, erythroderma and swelling at his circumcision site. He had been born at a gestational age of 39 weeks and 1 day via spontaneous vaginal delivery. There were no complications with the pregnancy or delivery, and maternal prenatal laboratory test results were normal. The neonate was circumcised and discharged home after 24 hours of life. On the day of presentation, he developed fever (temperature 100.7°F), irritability and rash. His physical examination was notable for jaundice, diffuse erythroderma and swelling with exudate around the circumcision site. His laboratory values demonstrated a white blood cell count (WBC) of 7870 per μL (70% neutrophils, 16% lymphocytes, 8% atypical lymphocytes, 4% eosinophils and 2% monocytes), a hematocrit of 69.2%, a platelet count of 49,000 per μL and a slightly elevated C-reactive protein (1.4 mg/dL). The cerebrospinal fluid (CSF) was bloody with 0 WBC/μL, 3525 red blood cells/μL, and protein and glucose concentrations of 71 mg/dL and 51 mg/dL, respectively. The urinalysis was normal. Serum chemistry tests revealed an aspartate aminotransferase of 83 U/L (normal = 47–150 U/L), alanine aminotransferase of 29 U/L (normal = 13–45 U/L) and total bilirubin concentration of 14.8 mg/dL, with a direct component of 0 mg/dL. Serum electrolytes and creatinine were unremarkable. The prothrombin time and partial thromboplastin time were not prolonged, but the D-dimer concentration was elevated (3433 ng/ mL, normal = 0–220 ng/mL) and the fibrinogen concentration was decreased (180 mg/dL, normal = 200–400 mg/dL). The patient was admitted to the hospital and treated presumptively for neonatal sepsis with ampicillin and cefotaxime. Acyclovir was added for empiric herpes simplex virus (HSV) coverage due to the infant’s age. Vancomycin was also added due to concern for staphylococcal wound infection. The following day, the patient’s mother was admitted to the medical intensive care unit at an affiliated institution with fever, myalgias, erythroderma and hypotensive shock. Her physical examination was notable for erythroderma and vaginal hyperemia. She was diagnosed clinically with endometritis, and she treated empirically with vancomycin, piperacillin-tazobactam and clindamycin. Pelvic ultrasonography and computed tomography were negative for retained products of conception and no vaginal foreign bodies were identified. Her laboratory values demonstrated a WBC of 29,300 per μL with 61% segmented neutrophils, 33% band forms, 2% metamyelocytes, 1% myelocytes, 1% monocytes and 2% eosinophils. Her platelet count reached a nadir of 142,000 per μL and her serum creatinine peaked at 1.1 mg/dL. She had an elevated aspartate aminotransferase 69 U/L (normal = 10–36 U/L), alanine aminotransferase 53 U/L (normal = 7–35 U/L) and serum bilirubin (total bilirubin 7 mg/dL, with a direct component of 3.5 mg/ dL), in addition to coagulopathy (prothtrombin time of 17 seconds, © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Mother–Newborn Toxic Shock Syndrome
partial thromboplastin of 46.4 seconds, D-dimers of 8800 ng/ mL and fibrinogen concentration of 633 mg/dL). Her urinalysis demonstrated sterile pyuria with a strongly positive leukocyte esterase on dipstick and a WBC of 58 per high-power field. Results for blood, urine and throat cultures were negative, and a vaginal culture was not performed. A wound culture of purulent exudate from the neonate’s circumcision site had a heavy growth of methicillin-resistant Staphylococcus aureus (MRSA) and a light growth of Escherichia coli. Blood, urine and CSF cultures were all negative, as were HSV surface cultures and CSF HSV DNA polymerase chain reaction. He was therefore treated with vancomycin for MRSA and cefazolin to cover E. coli for a total 10-day course. His symptoms resolved and he completely recovered. His mother also completely recovered and was discharged home with oral levofloxacin and clindamycin to complete a 10-day course. Both the infant and his mother developed desquamation on the hands within 2 weeks of their admissions. Thus, the mother met full diagnostic criteria for confirmed toxic shock syndrome (TSS). Although the neonate did not meet full TSS diagnostic criteria, he demonstrated multiple clinical features consistent with toxic shock syndrome toxin-1 (TSST-1) mediated disease. Subsequent testing of the neonate’s MRSA isolate for the TSST-1 gene via polymerase chain reaction was positive. The isolate was further characterized as protein A (spa) type t002 with type IV SCCmec element and clindamycin resistance.
DISCUSSION We present evidence of the first case of staphylococcal TSS in a mother–newborn pair caused by MRSA containing the TSST-1 producing gene. Previously reported cases of staphylococcal TSS in mother–newborn pairs were either culture negative or were caused by methicillin-susceptible S. aureus which produced toxins other than TSST-1.1,2 Staphylococcal TSS is a toxin-mediated clinical syndrome characterized by fever, erythroderma, shock and multiorgan dysfunction. It is caused by strains of S. aureus which produce superantigen exotoxins, the most common of which is TSST-1. TSST-1 induces polyclonal Vβ2+ T cell activation and proliferation by bypassing the usual major histocompatibility complex-restricted interaction between antigen presenting cells and T cells.3 The subsequent cytokine storm is responsible for the systemic inflammatory response characteristic of TSS. Despite the prevalence of MRSA, reports of staphylococcal TSS caused by methicillin-resistant strains are rare; this report may reflect an evolving epidemiology of TSS in the United States. Clinicians caring for neonates should maintain a high index of suspicion for staphylococcal TSS because S. aureus is generally resistant to the usual antimicrobials used to treat neonatal sepsis. Additionally, neonates may be misdiagnosed because they typically do not meet full diagnostic criteria for TSS; indeed, our patient lacked hypotension and had only 2 components of multiorgan dysfunction. The reason for the incomplete clinical presentation of neonates has not been fully elucidated. Epidemiologic data suggests that TSST-1 causes a spectrum of clinical disease in adults.4 This spectrum of disease is modulated by components of both the cellular and humoral immune systems.5–7 It therefore appears likely that components of the immature neonatal immune system drive the spectrum of disease in this population. There is evidence that a recently described clinical syndrome termed neonatal toxic shock syndrome-like exanthematous disease (NTED) also lies on the spectrum of TSST-1-mediated disease in neonates. This syndrome, first reported in Japan in the 1990s, has www.pidj.com | 451
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been attributed to TSST-1 based on its association with high colonization rates with TSST-1-producing S. aureus8,9 and based on the findings of massive polyclonal Vβ2+ T cell expansion in affected neonates.7 The pathogenesis of NTED is thought to be the same as that of TSS; however, affected neonates demonstrate a rapid decline of Vβ2+ T cells7 and ultimately fail to meet TSS diagnostic criteria. NTED is characterized by fever, exanthema and thrombocytopenia. In contrast to TSS, shock and multiorgan dysfunction are rare, and symptoms usually spontaneously regress within a few days. Despite the milder clinical course, a wide spectrum of disease is also seen with NTED. Although our patient shared some features of NTED, his presentation differed in several ways. First, in addition to fever, erythroderma and thrombocytopenia, he also had coagulopathy, hyperbilirubinemia and palmar desquamation. Secondly, his wound infection and clinical symptoms were severe enough to warrant antimicrobial therapy, whereas symptoms of NTED spontaneously resolve without intervention. Thirdly, the infant’s mother had a clinical diagnosis of TSS, which has not been previously reported with NTED. Lastly, the patient’s microbiologic isolate, MRSA spa type 002 with type IV SCCmec, is distinct from those previously reported to cause NTED.9 Despite these differences, it seems likely that TSST-1 produces a spectrum of disease that is modulated by components of the neonatal immune response. The expression of this response likely includes, but is not limited to, the clinical features of NTED. Clinicians should maintain a high index of suspicion for TSST-1 mediated disease in the neonatal population, as the clinical presentation is heterogeneous and often incomplete, and the causative pathogen may be resistant to standardly utilized antimicrobials.
ACKNOWLEDGMENTS The authors thank Joseph A. Snitzer as the attending physician who provided care to the patient. The authors also thank Valerie Albrecht, Mitch Granade, Linda McDougal and David Lonsway from the Centers for Disease Control and Prevention for performing TSST-1 PCR testing and S. aureus strain typing.
REFERENCES 1. Green SL, LaPeter KS. Evidence for postpartum toxic-shock syndrome in a mother–infant pair. Am J Med. 1982;72:169–172. 2. Lacoste A, Torregrosa A, Dubois S, et al. [Maternal-fetal staphylococcal toxic shock syndrome with chorioamniotitis]. Arch Pediatr. 2006;13:1132–1134. 3. Choi Y, Lafferty JA, Clements JR, et al. Selective expansion of T cells expressing V beta 2 in toxic shock syndrome. J Exp Med. 1990;172:981–984. 4. DeVries AS, Lesher L, Schlievert PM, et al. Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features, and molecular characteristics. PLoS One 2011;6:e22997. 5. Dateki S, Kumamoto T, Takayanagi T, et al. Differential T-cell response in a young child and neonates with toxic shock syndrome. Pediatr Int. 2009;51:155–156. 6. Kamel NS, Banks MC, Dosik A, et al. Lack of muco-cutaneous signs of toxic shock syndrome when T cells are absent: S. aureus shock in immunodeficient adults with multiple myeloma. Clin Exp Immunol. 2002;128:131–139. 7. Takahashi N, Kato H, Imanishi K, et al. Immunopathophysiological aspects of an emerging neonatal infectious disease induced by a bacterial superantigen. J Clin Invest. 2000;106:1409–1415. 8. Takahashi N, Nishida H, Kato H, et al. Exanthematous disease induced by toxic shock syndrome toxin 1 in the early neonatal period. Lancet. 1998;351:1614–1619. 9. Kikuchi K, Takahashi N, Piao C, et al. Molecular epidemiology of methicillin-resistant Staphylococcus aureus strains causing neonatal toxic shock syndrome-like exanthematous disease in neonatal and perinatal wards. J Clin Microbiol. 2003;41:3001–3006.
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Prevalence and Clinical Burden of NDM-1 Positive Infections in Pediatric and Neonatal Patients in Pakistan Muhammad Usman Qamar, MPhil,* Fouzia Nahid, MPhil,* Timothy R. Walsh, PhD,† Rubina Kamran, MPhil,‡ and Rabaab Zahra, PhD* Abstract: In a neonatal/pediatric Gram-negative infection study from Islamabad, 71/82 strains were carbapenem resistant with 12/82 positive for New Delhi Metallo-β-lactamase and many being extensively antibiotic resistant. Burden and outcome analysis on 9 patients showed that 4/9 died after inadequate therapy regardless of organism type. Key Words: NDM-1, carbapenem resistance, neonates, Pakistan Accepted for publication September 23, 2014. From the *Department of Microbiology, Quaid-i-Azam University, Islamabad, 45320 Pakistan; †School of Medicine, Department of Infection, Immunity and Biochemistry, Cardiff University, Heath Park, Cardiff, United Kingdom; and ‡Department of Microbiology and Pathology, Pakistan Institute of Medical Sciences Hospital, Islamabad, Pakistan. The authors have no conflicts of interest to disclose. Address for correspondence: Rabaab Zahra, PhD, Department of Microbiology, Quaid-i-Azam University, Islamabad, 45320 Pakistan. E-mail: rzahra@qau. edu.pk. 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 journal’s website (www.pidj.com). Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000582
T
reatment of infections in children particularly neonates is becoming increasingly difficult because of the occurrence of extensively drug-resistant organisms. Globally, the most common causes of neonatal/pediatric deaths are infectious diseases (68%) that include pneumonia (18%), diarrhea (15%) and malaria (8%).1 As the prevalence of ESBL-producing organisms is very high,2 the treatment for severe infections often uses carbapenems; however, resistance to carbapenems is emerging of which the most potent mechanism of resistance is carbapenamases such as New Delhi Metallo-β-lactamase (NDM-1). Carbapenem resistance in infections in children results in treatment failure and severely limits future treatment regimes. The carriage of NDM-1 in Gramnegative organisms in Pakistan has been assessed in a few pilot studies2,3 but its prevalence in pathogens causing infections in neonates/pediatrics and their subsequent clinical outcome has not been evaluated. Accordingly, this study examined the prevalence of blaNDM-1 in clinical isolates in children ≤5 years of age in Pakistan. In addition, we also determined the risk factors for infection such as age, sex, underlying disease, length of hospital stay and assessed the burden of resistance in children with NDM-1 positive pathogens.
METHODS Clinical Isolates During July 2011 to March 2012, 82 meropenem-resistant Gram-negative isolates from children ≤5years age were collected from 3 children hospitals in Pakistan: The Children’s hospital, the Pakistan Institute of Medical Sciences (PIMS), Islamabad (n = 52), The Children’s Hospital Multan (n = 20) and Nishtar Hospital, Multan (n = 10). Clinical detailed data was collected from PIMS on 9 patients examining comorbidities, length of hospital stay and outcome and are listed in Table, Supplemental Digital Content 1, http://links.lww.com/INF/C34. © 2014 Wolters Kluwer Health, Inc. All rights reserved.
