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Intravenous Immunoglobulin Therapy for Cerebral Vasculitis Associated with Rocky Mountain Spotted Fever
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H. Christine Allen, Robert C. Welliver, Monica W. Fogarty, Morris Gessouroun, Emilie D. Henry
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H. Christine Allen, MD, Section of Pediatric Critical Care, Department of Pediatrics, College of Medicine, University of Oklahoma, 1200 Everett Drive Suite 8305, Oklahoma City, OK 73014, United States
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Case Report
1
Intravenous Immunoglobulin Therapy for Cerebral Vasculitis Associated with Rocky Mountain Spotted Fever H. Christine Allen1
Robert C. Welliver Sr.,2
Monica W. Fogarty3
1 Section of Pediatric Critical Care, Department of Pediatrics,
Q1
University of Oklahoma, Oklahoma City, Oklahoma, United States 2 Section of Infectious Diseases, Department of Pediatrics, University of Oklahoma, Oklahoma City, Oklahoma, United States 3 Department of Pediatrics Q1, University of Oklahoma, Oklahoma City, Oklahoma, United States
Morris Gessouroun1
Emilie D. Henry1
Address for correspondence Q2H. Christine Allen, MD, Section of Pediatric Critical Care, Department of Pediatrics, College of Medicine, University of Oklahoma, 1200 Everett Drive Suite 8305, Oklahoma City, OK 73014, United States (e-mail:
[email protected]).
J Pediatr Intensive Care 2016;00:1–3.
Abstract
Keywords
► cerebral vasculitis ► intravenous immunoglobulin ► Rocky Mountain spotted fever ► septic shock
Rocky Mountain spotted fever is a tick-borne illness that is prevalent in the south and the central United States, primarily during the summer months. Patients with the delayed diagnosis can experience increased mortality and morbidity, particularly poor neurological outcome. We present a case of a 7-year-old girl with Rocky Mountain spotted fever who was admitted with severe neurological changes and septic shock on day 8 of illness. She was initially diagnosed with Kawasaki disease and treated with intravenous immunoglobulin. Her treatment also included doxycycline, vancomycin, and ceftriaxone due to concerns regarding Rocky Mountain spotted fever and bacterial sepsis. During hospitalization, the patient required mechanical ventilation for respiratory distress, inotropic support, and fluid resuscitation for hypotension. Titers for Rocky Mountain spotted fever were ultimately positive, with magnetic resonance imaging of the brain demonstrating numerous punctate foci of restricted diffusion within the supratentorium, including the corpus callosum and basal ganglia. Although the patient presented late in the disease course, she ultimately had a good neurological outcome. We theorized that administration of intravenous immunoglobulin prevented ongoing neurological injuries from the cerebral vasculitis, which are associated with Rocky Mountain spotted fever.
Introduction Rocky Mountain spotted fever (RMSF) is a tick-borne illness caused by Rickettsia rickettsii, a gram-negative bacterium that was discovered in 1908 by Dr. Howard Ricketts.1 The infection produces a small- to medium-sized vessel vasculitis manifesting as a clinical triad of fever, headache, and rash.1 Prompt diagnosis and treatment result in an excellent prognosis. However, patients who experience a delay in diagnosis and treatment may have an increased morbidity
received November 4, 2015 accepted after revision July 3, 2016
and mortality. Approximately 30% of fatal cases of RMSF are secondary to a neurological cause and 35% are due to sepsis.2 More than half of children with RMSF will present with the classic triad, and less than half will have a history of tick attachment.1,3 In a retrospective chart review of 92 pediatric patients with RMSF, Buckingham et al found that coma, inotropic support, and the receipt of a fluid bolus were all independently associated with adverse outcomes.3 The presence of all three variables was 81% sensitive and 97% specific for an adverse outcome.3
Copyright © 2016 by Georg Thieme Verlag KG, Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0036-1587327. ISSN 2146-4618.
Q2
2
Rocky Mountain Spotted Fever and Intravenous Immunoglobulin Here, we present a case of a 7-year-old female patient who developed altered mental status and hypotension with delayed diagnosis of RMSF but who had a good neurological recovery. This recovery may have been due, in part, to the administration of intravenous immunoglobulin (IVIG).
Case Report A 7-year-old white female patient was admitted to our center after 8 days of fever. She had a history of frequent episodes of acute otitis media and placement of tympanostomy tubes but was otherwise healthy. Immunizations were up to date. Before admission, on day 1 of illness, she had developed a sore throat and a fever reaching 39°C (103°F). Although a rapid test for group A streptococcal infection conducted at an urgent care clinic was negative, she was given amoxicillin due to recent exposure to children with strep throat. She was reevaluated by that clinic the next day for continued fever, and the amoxicillin dose was increased. However, after the development of a diffuse erythematous rash later that day, she was taken to an emergency department. Radiograph and urinalysis were normal, and she was discharged home with a diagnosis of viral illness. She returned to the urgent care clinic on day 3, where antibiotic coverage was changed to cefdinir after a positive rapid strep test, and on day 7, where she received intramuscular ceftriaxone for continued fever and rash, headache, and abdominal pain. The patient’s monospot test was negative. On day 8 of illness, she presented to our center with persistent rash and fever, as well as tachycardia. She received two 20 mL/kg bolus infusions of crystalloid and an additional dose of ceftriaxone (50 mg/kg). Laboratory tests revealed a platelet count of 35,000/mm3 (range: 150,000–400,000/ mm3), alanine aminotransferase level of 237 U/L (range: 17–64 U/L), aspartate aminotransferase level of 178 U/L (range: 12–48 U/L), erythrocyte sedimentation rate of 11 mm/h (range: 0–20 mm/h), procalcitonin level of 16.83 ng/ mL (> 2.00 ng/mL indicates high risk of progression to severe sepsis), C-reactive protein level of 282 mg/L (high > 3.0 mg/ L), sodium level of 138 mEq/L (range: 136–145 mEq/L), and antistreptolysin O titer of < 25 U/mL (< 166 U/mL is negative). The patient was admitted due to concerns for Kawasaki disease. A mildly erythematous conjunctiva, dry lips, strawberry tongue, and right cervical lymph node < 1 cm in diameter were noted. The examination also revealed a soft systolic murmur, diffuse abdominal tenderness, and hepatomegaly. Mild bilateral periungual desquamation was observed on the fourth toes, and diffuse petechiae were observed on the trunk, arms, legs, and palms. The patient had slight confusion, but was able to answer simple questions. She was started on aspirin and given 2 g/kg of IVIG, doxycycline, and vancomycin. Titers for antibodies to RMSF and Ehrlichia were drawn. On day 9 of illness, she was transferred to our pediatric intensive care unit due to tachypnea and a declining mental status. A noncontrast computed tomography of the head was normal. Her mental status continued to deteriorate to the Journal of Pediatric Intensive Care
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point of being lethargic and nonverbal. She developed hypotension, requiring fluid resuscitation and dopamine infusion. The patient was intubated, placed on mechanical ventilation, and sedated with fentanyl and midazolam infusions. On day 11 of illness, she was noted to have hypertonicity in all four extremities, myoclonus with stimulation, and bilateral ankle clonus. She withdrew all extremities in response to painful stimulation and had briskly reactive pupils. No purposeful movement was noted under light sedation. Other cranial nerves were not assessed, due to sedation. Brain magnetic resonance imaging (MRI) with contrast demonstrated numerous T2 hyperintense punctate foci with restricted diffusion, which were most prominent in the subcortical and periventricular white matter of the frontal and parietal lobes (►Fig. 1). This pattern has been previously described as “starry sky.”4,5 There was also restricted diffusion in the corpus callosum and bilateral basal ganglia. On day 13, we were able to wean the patient from sedation and dopamine. After extubation, the patient demonstrated generalized weakness but could move all extremities independently and was able to answer yes or no to simple questions. On day 15 of illness, her ankle clonus and myoclonus had completely resolved. Her initial RMSF titers on day 9 of illness were equivocal (IgM: 0.93, equivocal: 0.90–1.1). Repeat titers on day 14 were positive (IgM: 1.31, positive > 1.10). Due to generalized weakness, the patient was transferred to an inpatient pediatric rehabilitation facility. After 1 week, she was able to walk independently with a normal gait and no
Fig. 1 T2 axial view of magnetic resonance image revealing numerous hyperintense punctate foci with restricted diffusion in the subcortical and periventricular white matter of the frontal and parietal lobes. This is referred to as the “starry sky” appearance.
Rocky Mountain Spotted Fever and Intravenous Immunoglobulin tone asymmetries and was discharged. Cognitive testing revealed mild inattention and some impaired verbal memory, requiring follow-up with a speech therapist. Her intelligent quotient was otherwise normal.
Discussion Patients with RMSF who are diagnosed and treated early with doxycycline have an excellent prognosis. Delayed diagnosis, occurring after day 5 of symptoms, can result in significant morbidity and mortality.2,6,7 Alvarez-Hernandez and coworkers observed a twofold increase in the risk of death in those who received doxycycline after 5 days,6 with others reporting that the risk of death may be up to five times greater with delayed treatment.7 In fatal cases of RMSF, cause of death has been frequently secondary to a neurological cause (30%) or to sepsis and hypotension (35%).2 In the retrospective study by Buckingham et al, of 92 children hospitalized with RMSF, three died. Of those surviving, 13 patients (15%) had neurological deficits at the time of discharge. All of the patients who died or had neurological deficits had altered mental status and required treatment in an intensive care unit, with almost half of these patients (48%) having adverse outcomes. The study found that altered mental status, hypotension requiring inotropic support, and a fluid bolus were all independently associated with either death or functionally significant neurological deficits.3 In a recently published case, describing a patient similar to ours, a 7-year-old patient presented on day 8 of illness with altered mental status and hypotension.5 She was treated with doxycycline and aggressive supportive care. The patient’s MRI results were also similar to our patient, which showed bilateral subcortical, periventricular, and deep white matter; corpus callosum hyperintense lesions with sparing of the basal ganglia and thalami; and the starry sky appearance. Unfortunately, at 2-month follow-up, the patient continued to have a severe neurological impairment, whereas our patient had essentially a normal neurological examination after discharge from the rehabilitation hospital. In another related case report, a 4-year-old patient with RMSF was treated with doxycycline on day 4 of illness, resulting in clinical improvement. On day 9, however, the patient became irritable and developed erythematous lips and swollen hands and feet. She was subsequently diagnosed with Kawasaki disease. Treatment with 2 g/kg of IVIG resulted in resolution of symptoms within 72 hours.8 The authors speculated that (1) this could be a coincidental finding, (2) the patient had Kawasaki disease with a nonspecific serologic response to RMSF, (3) this was RMSF vasculitis mimicking Kawasaki disease, or (4) RMSF was acting as a superantigen, resulting in a host immune response leading to vasculitis, as seen in Kawasaki disease.8 The mechanism of the central nervous system injury in RMSF is unknown. The small- to medium-sized vessel vasculitis caused by R. rickettsii occurs by the bacterium invading the nucleus of the endothelial cell, causing lysis and injury as
Allen et al.
it continues to propagate. If untreated, this can result in disseminated vasculitis with areas of microhemorrhage, increased vascular permeability, and edema.1 IVIG is a wellknown treatment for Kawasaki disease, another systemic small- to medium-sized vessel vasculitis with a specific predilection for the coronary arteries. In Kawasaki disease, treatment with IVIG within the first 10 days significantly reduces the risk of coronary artery aneurysms (20–25 vs. 2– 4%).9 Our case is unique in that our patient is the only known reported with RMSF treated on day 8 of illness with IVIG in addition to appropriate antibiotic therapy. Our patient was diagnosed late during the disease course and had hypotension and neurological changes, both of which are significant predictors of a poor outcome.3 Although treatment with IVIG was due to a misdiagnosis, we speculate that IVIG treatment may have contributed to her survival and complete neurological recovery from RMSF, raising the possibility that IVIG ameliorates ongoing cerebral and systemic vasculitis in patients with delayed diagnosis, septic shock, or severe neurological involvement, all independently associated with an adverse outcome.3,7 To this end, IVIG therapy may be warranted in patients who have a late diagnosis or show neurological changes. However, the most efficacious timing is presently unknown. Perhaps, as with Kawasaki disease, early treatment would show the most benefit. The potential use of IVIG as a treatment for RMSF and the timing of therapy warrant further study.
References 1 Chen LF, Sexton DJ. What’s new in Rocky Mountain spotted fever?
Infect Dis Clin North Am 2008;22(3):415–432, vii–viii 2 Dahlgren FS, Holman RC, Paddock CD, Callinan LS, McQuiston JH.
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Fatal Rocky Mountain spotted fever in the United States, 1999– 2007. Am J Trop Med Hyg 2012;86(4):713–719 Buckingham SC, Marshall GS, Schutze GE, et al; Tick-borne Infections in Children Study Group. Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children. J Pediatr 2007;150(2):180–184, 184.e1 Crapp S, Harrar D, Strother M, Wushensky C, Pruthi S. Rocky Mountain spotted fever: ‘starry sky’ appearance with diffusionweighted imaging in a child. Pediatr Radiol 2012;42(4): 499–502 Sun LR, Huisman TA, Yeshokumar AK, Johnston MV. Ongoing cerebral vasculitis during treatment of Rocky Mountain spotted fever. Pediatr Neurol 2015;53(5):434–438 Alvarez-Hernandez G, Murillo-Benitez C, Candia-Plata MdelC, Moro M. Clinical profile and predictors of fatal Rocky Mountain spotted fever in children from Sonora, Mexico. Pediatr Infect Dis J 2015;34(2):125–130 Kirkland KB, Wilkinson WE, Sexton DJ. Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis 1995;20(5):1118–1121 Bal AK, Kairys SW. Kawasaki disease following Rocky Mountain spotted fever: a case report. J Med Case Reports 2009;3:7320 Yim D, Curtis N, Cheung M, Burgner D. An update on Kawasaki disease II: clinical features, diagnosis, treatment and outcomes. J Paediatr Child Health 2013;49(8):614–623
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