Pediatric Infectious Disease Newsletter

January 2010  

New therapies for Clostridium difficile Infection
Clostridium difficile has emerged as a significant infection in the last several years. New approaches are being sought to increase the therapeutic armamentarium. In a recent article, Lowy et al compared in a randomized study, 200 patients that received routine antibiotic therapy only vs monoclonal antibody against C. difficile toxins A (CDA1) and B (CDB1) and routine antibiotic therapy. The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.

The rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P<0.001). The recurrence rates among patients with more than one previous episode of C. difficile infection was also lower in the monoclonal group  [7% vs 38%,(P=0.006)]. The mean duration of the initial hospitalization for inpatients did not differ significantly.  This new therapeutic approach may prove useful, in particular in patients with recurrences or at risk for severe disease and complications such as immunocompromised patients.

Lowy, I et al. Treatment with Monoclonal Antibodies against Clostridium difficile Toxins. New England Journal of Medicine. 362(3):197-205, January 21, 2010.
Ataxia and Ptosis... Where is the tick?
A 2 1/2 year-old female presents to the hospital with a 2 day history of mild ptosis, difficulty walking and episodes of falling while walking.  She had no history of fever, symptoms of respiratory illness, vomiting, diarrhea, changes in hearing or vision, seizures, weakness, headache or rash.  There was no history of recent immunizations. No other family members were ill and there was no exposure to tuberculosis.  The family pets are 2 fish.  The family recently spent 3 weeks in rural West Virginia. The child played in the woods.  She had contact with various animals at the West Virginia State Fair where she acquired multiple mosquito bites, handled trout and went for an elephant ride.  The family returned to Florida 2 days before onset of illness. 
Her physical examination was significant only for several mosquito bites on the extremities, mild ptosis, and ataxia with no weakness in the upper or lower extremities.  All laboratory studies and a brain MRI were unremarkable.
On the second day of hospital admission, the patient's mother noted a lesion on the child's scalp. The lesion was examined by the pediatric staff and found to be a tick. The tick was carefully removed with a tweezer and identified as a fully engorged American dog tick, Dermacentor variabilis.  Within 6 hours after removal of the tick, the patient's coordination was improving. She was discharged one day later with minimal ataxia.  She was diagnosed with Tick paralysis.
Tick paralysis is a neurologic syndrome that is frequently confused with other acute neurologic disorders. It usually presents as an ascending paralysis but may also present with ataxia, especially in children. Paralysis is caused by a potent neurotoxin produced by an attached, engorged female tick with the onset of tick paralysis occurring five to seven days after a female tick attaches itself to the skin. If the tick is not found and removed, respiratory weakness can lead to progressive hypoventilation, lethargy, coma, and death. It is ironic that prompt removal of the tick leads to prompt recovery.
Tick paralysis has been related to the bite of 43 different species of tick and has a world-wide distribution. In North America the Dermacentor species of tick have been implicated most often, most commonly D. andersoni but also D. variabilis. Other species in North America have been Amblyomma americanum, A. maculatum, and Ixodes scapularis.
It is not uncommon to miss the diagnosis of tick paralysis especially in girls because the tick is often on the scalp and hidden by long hair.  When faced with a child with ataxia or ascending paralysis, detection is possible with nothing more than a thorough skin examination and a fine-toothed comb applied to the hair to look for hidden ticks.

Tick paralysis. Edlow JA, McGillicuddy DC. Infect Dis Clin North Am. 2008 Sep;22(3):397-413
Cluster of tick paralysis cases-Colorado, 2006Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2006 Sep 1;55(34):933-5
Pediatric tick paralysis: discussion of two cases and literature review. Li Z, Turner RP. Pediatr Neurol. 2004 Oct;31(4):304-7. Review.
Not Your Everyday Cause of Arthritis!!!!
We recently evaluated a young child that presented with a mono-articular arthritis. Blood cultures identified Brucella spp.

Important clinical pearls regarding Brucellosis for the general pediatrician

Brucella is one of the most common bacterial zoonosis in the world that causes significant morbidity. However, <100 cases occur in the US each year and most cases are usually imported or in lab personnel. It is a gram negative coccobacilli frequently misidentified by the lab initially.

Risk factors include ingestion unpasteurized goat cheese, other contaminated dairy products, contact with infected animals and travel to endemic areas (Mediterranean basin, South and Central America, Eastern Europe, Asia, Africa, and the Middle East) CDC Yellowbook 2010

Humans are infected by ingestion, skin abrasions, conjunctiva, and inhalation

Symptoms may be very non-specific (>50% have fever at presentation) resembling other illnesses with a wide clinical spectrum. You should suspect brucella infection in any child presenting with FUO and/or arthritis (most common site knee and/or hip) that has risk factors listed above.

Typical laboratory tests may not be helpful. In blood culture bottles, the organism will typically grow within 48-96 hours. However, if there is a high index of suspicion, cultures should be held for > 5 days.  Serology can be used under certain circumstances.

Duration of antimicrobial therapy is at least 6 weeks with combination antimicrobial therapy. For children >8 years of age, doxycycline may be used. Younger children are typically treated with combination therapy using trimethoprim-sulfamethoxazole and rifampin. Some experts will recommend the addition of an IV aminoglycoside for the first 7-14 days for more severe disease.

Lancet Infect Dis 2007;7:775-86

More information is available on the following websites:
Characteristics of Influenza Infection in Young Infants
Influenza vaccination is not recommended for infants younger than six months of age. Therefore, it is very vital that household contacts are vaccinated to reduce potential transmission of influenza within the household.

Young children, particularly those less than 2 years of age are at the highest risk of complications secondary to influenza infection.

Investigators at the University of Utah set out to describe the outcomes of serious bacterial infections in influenza-infected infants under three months of age. This was a retrospective cohort study. Investigators identified all lab confirmed influenza cases during the respiratory viral season in children less than 24 months of age.  Data was obtained over a four-year period. They reviewed the medical records of all identified infants.  

There were 833 children identified less than 24 months age during the influenza season. Thirty-seven percent were hospitalized.  There were a total of 218 infants identified under 3 months of age.  Forty-nine percent of these infants were hospitalized.  Older children were more likely to have a high-risk medical condition compared to infants <3 months age. There were only 8 infants with comorbid conditions including h/o prematurity, congenital heart disease, and spinal muscular atrophy.  There was not a statistical difference in length of hospital stay of >48 hours when compared to older children 12-<24 months of age.  Seventy percent of infants < 3 months of age had hospital stays of <48 hours. There were only 5 (2.3%) case of serious bacterial infection (SBI) in infants <3 months of age (organisms were 4 E. coli UTIs and one infant with salmonella bacteremia). All infants with SBI were >=28 days old.  Infants <3 months of age with influenza infection generally had a good outcome with short hospitalizations.  The risk of meningitis and bacteremia in this cohort with influenza infection is low.

Ped Infect Dis Journal. 2010;29 (1):6-9
Multistate Outbreak of Human Salmonella Typhimurium Infections Associated with Aquatic Frogs --- United States, 2009
Salmonella illness remains a major public health problem in the United States, with an estimated 1.4 million human Salmonella infections, 15,000 hospitalizations, and 400 deaths annually. Although most Salmonella infections are food-borne, animal contact is an important source of human salmonellosis. Studies conducted during 1996--1997 determined that approximately 74,000 Salmonella infections each year in the United States resulted from reptile and amphibian exposure.

During April--July 2009, the Utah Department of Health identified five cases of Salmonella Typhimurium infection with indistinguishable pulsed-field gel electrophoresis (PFGE) patterns, predominantly among children.  In August, CDC began a multi-state outbreak investigation to determine the source of the infections.  As of December 30, 2009, the CDC had identified 85 S. Typhimurium human isolates with the outbreak strain from 31 states. In a multi-state case-control study, exposure to frogs was found to be significantly associated with illness (63% of cases versus 3% of controls; matched odds ratio [mOR] = 24.4).  

Among 14 case-patients who knew the type of frog, all had exposure to an exclusively aquatic frog species, the African dwarf frog.  Environmental samples from aquariums containing aquatic frogs in four homes of case-patients yielded S. Typhimurium isolates matching the outbreak strain. Preliminary trace-back information has indicated these frogs likely came from the same breeder in California. Reptiles (e.g., turtles) and amphibians (e.g., frogs) have long been recognized as Salmonella carriers and three multi-state outbreaks of human Salmonella infections associated with turtle contact have occurred since 2006. However, this is the first reported multi-state outbreak of Salmonella infections associated with amphibians.

The most likely source of transmission in this outbreak was contact with water from the frogs' aquariums.  Because African dwarf frogs are small and tend to rest at the bottom of aquariums where children have difficulty reaching them, direct handling, as the source of transmission is less likely. Amphibians are known carriers of Salmonella.  African dwarf frogs are purely aquatic animals, typically <2 inches long from nose to tail stub, and sold as ornamental aquarium pets.  In one study, 21% of aquarium frogs tested from 16 retailers were positive for Salmonella.  Furthermore, Salmonella bacteria shed from frogs are readily recoverable from aquarium water where frogs are housed.  Salmonella can survive for an extended period in the environment, and indirect transmission through environmental contamination might occur.  

In this reported investigation, in 30% of patient households, aquariums were cleaned in the kitchen sink, posing a risk for cross-contamination with food preparation areas. CDC has published guidelines for consumers on how to reduce the risk for Salmonella infection from amphibians and reptiles (available on the CDC website). Preventive measures include washing hands thoroughly with soap and water after touching animals or cleaning aquariums.  No regulations prohibit the sale of small frogs, but education measures might help reduce the risk for Salmonella transmission.

MMWR. January 8, 2010 / 58(51&52);1433-1436
Public Health Threat of New, Reemerging, and Neglected Zoonoses in the Industrialized World
Microbiologic infections acquired from animals, known as zoonoses, pose a risk to public health. An estimated 60% of emerging human pathogens are zoonotic. Of these pathogens, >71% have wildlife origins. These pathogens can switch hosts by acquiring new genetic combinations that have altered pathogenic potential or by changes in behavior or socioeconomic, environmental, or ecologic characteristics of the hosts.

We are witnessing increasing globalization, with persons, animals, and their products moving around the world.  This movement enables unprecedented spread of infections at speeds that challenge the most stringent control mechanisms.  Furthermore, continual encroachment of humans into natural habitats by population expansion or tourism brings humans into new ecologic environments and provides opportunity for novel zoonotic exposure.  Climatic changes have facilitated the expansion of compatible conditions for some disease vectors, remodeling dynamics for potentially new, emerging, and reemerging zoonoses.
Some of the zoonoses that may affect children are reviewed below.

Recreational Zoonoses
Sporting activities can expose humans to zoonotic infections. Hunting wildlife has been associated with infections such as brucellosis and tularemia.  Less obvious routes arise from activities such as water sports.  Leptospira spp.-infected animals excrete viable organisms in their urine, which can persist in aquatic environments for prolonged periods.  After a triathlon event in 1998, a total of 52 of 474 athletes tested were diagnosed with leptospirosis.  Suspicion of water sport-related infections with hepatitis A and Leptospira spp. led to closure of an area of Bristol, United Kindom, where docks were used for recreational water activities.

Role of Companion Animals
Companion animals have many forms of contact and opportunities to transmit multiple zoonoses.  The sexual stage of the life cycle of Toxplasma spp. occurs in cats, thus exposing humans to infection in situations in which hygienic measures have not been observed. Cats also serve as reservoir for Bartonella henselae, the etiologic agent of cat-scratch fever.  Cowpox virus can also be transmitted to humans by contact with cats.  Animal bites can result in zoonotic infections, typified by infection with Pasteurella multocida. Even in the absence of a bite, contact with animals (e.g., licking of wounds) can result in infection. More recently, attention has focused on transmission of Rickettsia felis into the human environment by cat fleas.

Dogs are the most likely source when humans become infected with rabies virus and are potential sources of Toxocara spp.  This emerging threat is becoming apparent with importation of rescued dogs and global movement of dogs with their owners, which has resulted in several cases of leishmaniasis in the absence of sand fly vectors. Dogs can be a source of methicillin-resistant Staphylococcus aureus and could play a role in zoonotic spread of genetic elements responsible for antimicrobial drug resistance.  Contact with dogs in Mediterranean regions has been implicated as a likely source of infection in recent cases of Mediterranean spotted fever reported in traveling humans.

Cats and dogs can introduce plague or rabies into human environments and have been associated with Q fever in humans and dermatophytosis (ringworm). Scavenger habits of these animals bring them into contact with many zoonotic agents, and close living relationships with humans such as sharing meal plates or beds offer many opportunities for disease transmission.

Pet rats have recently been incriminated as the source of Leptospira icterrohemoragiae infection in their owners. Psittacine birds are an established risk factor for acquisition of Chlamydophila psittaci.  During recent years, the market for exotic pets has greatly increased.  This increase has resulted in transmission of several unusual organisms, such as exotic Salmonella spp., which are often associated with pet reptiles. Media attention was captured after an outbreak of monkeypox in America that affected >70 persons in 2003.  After infected African rodents had been imported for the pet trade, the infection spread into native North American black-tailed prairie dogs and was subsequently disseminated among humans.

Tourism has exponentially increased in recent years. This finding has resulted in increasing numbers of imported zoonoses, such as a variety of rickettsial spotted fevers, brucellosis, melioidosis, genotype I hepatitis E, tick-borne encephalitis, and schistosomiasis.  A rapid increase in cases of African tick bite fever has been associated with travelers to sub-Saharan Africa and the eastern Caribbean. This disease, which is caused by R. africae, is transmitted by a particularly aggressive Amblyomma sp. tick; >350 imported cases have been observed in recent years.  Infection sequalae, such as subacute neuropathy, may be found long after travel when tick bite fever eschars have disappeared.  An estimated >1 million international journeys are made each day, and a staggering 700 million tourists travel on an annual basis. Detailed travel histories of patients who show clinical signs and symptoms of disease are needed.

Cutler SJ, Fooks AR, van der Poel WHM. Public health threat of new, reemerging, and neglected zoonoses in the industrialized world. Emerg Infect Dis 2010 Jan

Available from CDC website
EBV infection and Hyperuricemia
Uric acid is the end product of purine metabolism in humans. Increased cell turnover may result in hyperuricemia (function of increased purine turnover).  In pediatrics, we commonly think of malignancy as part of the differential diagnosis in patients with hyperuricemia. However, we rarely think about this condition occurring with infection.

A group of investigators studied patients with infectious mononucleosis (clinical characteristics, evidence of heterophil antibody (positive monospot), and >50% lymphocytes on the differential WBC count). Serologic blood tests were done on admission and repeated 4 to 5 weeks later (convalescent sample). Urinary excretion of uric acid was measured as well.  There were 11 patients with EBV diagnosis and 12 controls (admitted patients with acute febrile illness to the URI ward).  

Fifty-five percent (6/11) of the patients with the diagnosis of mononucleosis had serum uric acid levels >8mg/dl at presentation with only one patient in the control group with level >8mg/dl. The cases also had greater urinary excretion of uric acid compared to the control group.  There were no complications (uric acid nephropathy) related to the hyperuricemia. The authors commented that patients with infectious mononucleosis maintain adequate hydration and alkalinization of the urine to reduce the potential risk of developing uric acid nephropathy.

J Clin Endorinol Metab 1974; 38:652-654
Etiologic Diagnosis of Infectious Encephalitis
Despite having many diagnostic tools, on many occasions, we are unable to identify the etiologic agent causing encephalitis in children.  French investigators conducted a prospective study to describe patients with encephalitis. This was a multi-center study conducted in France from January 1 to December 31, 2007. A patient was defined as having encephalitis if they were >=28 days of age, hospitalized in mainland France, acute onset of illness, one CSF lab abnormality, T>=38, and having neurologic changes (altered mental status, seizure, focal signs).

Data was evaluated from 253 eligible patients. Age range was 1 month to 89 years (median age 55 years; mean 50 years). 10% (26/253) were <16 years of age. 30% of patients had comorbid conditions.

An infectious agent was identified in 131/253 (52%) of the patients. Of the 131 patients, 69% had viral encephalitis and 30% bacterial encephalitis (one patient with fungal encephalitis). HSV (42%), VZV (15%), Tuberculosis (15%), and Listeria (10%). For the remaining patients, there was no identifiable etiology or other various agents were identified (CMV, EBV, Enterovirus, Tick-borne encephalitis, Toscana virus, Lyme disease, Mycoplasma, Rickettsia conorii, Francisella, Legionella, Influenza A, Cryptococcus, and West Nile virus). There was no tuberculosis or listeria identified in any of the pediatric patients(<17 years of age).

CSF WBC indices:
HSV encephalitis (median wbc 76 (range 0-710))
VZV encephalitis (median wbc 150 (range 0-1240))
Listeria encephalitis (median wbc 310 (range 49-1700))
M. tuberculosis encephalitis (median wbc 140 (range 4-640))

At the time of admission, 240 (95%) of the patients presented with altered mental status.  Additionally, 37% had focal neurologic signs, 30% with seizures, 5% coma, and 25% with decreased level of consciousness. By day 5 of admission, 65% of the patients still had altered mental status. Twenty-six (10%) patients had a fatal outcome (all adults). The highest case-fatality rates occurred in patients with tuberculosis and listeria. Of those that survived encephalitis, 62% continued to have neurologic signs at discharge and 10% had behavioral disorders.

This study identified an etiologic agent for encephalitis in 52% of the patients. This is higher than previously published reports.  The most frequent causes in this report were HSV and VZV as reported in other studies.  However, this study found a larger proportion of patients with tuberculosis and listeria as compared to previous studies. Although, no coinfections were identified, it is possible that coinfections may have been missed since once an etiology was identified, no further investigation was carried out.  There was "no single clinical or CSF feature sufficient to evoke the etiologic cause of encephalitis." The pediatric data was limited in this study.

Clinical Infectious Disease 2009;49:1838-1847
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In This Issue
New therapies for Clostridium difficile Infection
Ataxia and Ptosis... Where is the tick?
Not Your Everyday Cause of Arthritis!!!
Characteristics of Influenza Infection in Young Infants
Multistate Outbreak of Human Salmonella Typhimurium Infections Associated with Aquatic Frogs
Public Health Threat of New, Reemerging, and Neglected Zoonoses in the Industrialized World
EBV infection and Hyperuricemia
Etiologic Diagnosis of Infectious Encephalitis
Infectious Disease Newsletter Feedback
David M. Berman, D.O.
Juan Dumois III, M.D.
Shirley Jankelevich, M.D.
Allison Messina, M.D.
Dale Bergamo, M.D.
Patricia Emmanuel, M.D.
Jorge Lujan-Zilbermann, M.D.
Carina A. Rodriguez, M.D.
Katie Namtu, Pharm.D.

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